ORD Multi-Year Plan for Endocrine Disruptors 

MULTI-YEAR PLAN (FY2000-2012) FOR

ENDOCRINE DISRUPTORS 1 

OFFICE OF RESEARCH AND DEVELOPMENT

US ENVIRONMENTAL PROTECTION AGENCY

December 2003 

1

ORD Multi-Year Planning Committee Members: James Avery, OSP; Elaine Francis, NCER; 

Ross Highsmith, NERL; Robert Kavlock , NHEERL; Michael Loughran, ORMA; Gregory

Sayles, NRMRL; Michel Stevens, NCEA; Hugh Tilson, NHEERL; Greg Toth, NERL

Past Committee Members: Andy Avel, NRMRL; Sue McMaster, NHEERL; David Reese

(NCER), Chuck Steen, NERL

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The Office of Research and Development’s (ORD) multi-year plans (MYPs) present ORD’s 

proposed research (assuming constant funding) in a variety of areas over the next 5-8 years. The 

MYPs serve three principal purposes: to describe where our research programs are going, to 

present the significant outputs of the research, and to communicate our research plans within 

ORD and with others. Multi-year planning permits ORD to consider the strategic directions of 

the Agency and how research can evolve to best contribute to the Agency’s mission of protecting 

human health and the environment. 

MYPs are considered to be “living documents.” ORD intends to update the MYPs on a regular 

basis to reflect the current state of the science, resource availability, and Agency priorities. ORD 

will update or modify future performance information contained within this planning document 

as needed. These documents will also be submitted for external peer review. 
ORD Multi-Year Plan for Endocrine Disruptors 

TABLE OF CONTENTS

I. INTRODUCTION 3

II. BACKGROUND 5

III. PROGRESS TO DATE/CHANGES FROM PREVIOUS VERSION 8

IV. LONG-TERM GOALS 12

V. DESCRIPTION OF THE FLOW DIAGRAMS 15

VI. GUIDANCE FOR IMPLEMENTATION OF MULTI-YEAR PLAN 32

VII. REFERENCES 33

VIII. ACRONYMS 34

APPENDIX POTENTIAL ADDITIONAL RESEARCH 36

TABLE 1. LONG TERM GOAL 1 42

TABLE 2. LONG TERM GOAL 2 54

TABLE 3. LONG TERM GOAL 3 65

ACCOMPANYING ATTACHMENTS: 

FIGURE 1. LINKAGE AND TIMELINE FOR APGS TO MEETING 

LONG TERM GOAL 1

FIGURE 2. LINKAGE AND TIMELINE FOR APGS TO MEETING 

LONG TERM GOAL 2

FIGURE 3. LINKAGE AND TIMELINE FOR APGS TO MEETING 

LONG TERM GOAL 3

FIGURE 4. ENDOCRINE DISRUPTORS RESEARCH PROGRAM DESIGN LOGIC 

MODEL 

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ORD Multi-Year Plan for Endocrine Disruptors 

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ORD Multi-Year Plan for Endocrine Disruptors 

I. INTRODUCTION 

It has been suggested that humans and domestic and wildlife species have suffered adverse health 

consequences resulting from exposure to chemicals in the environment that interact with the endocrine 

system. However, considerable uncertainty exists regarding the relationship(s) between adverse health 

outcomes and exposure to environmental contaminants. Collectively, chemicals with the potential to 

interfere withthe function of endocrine systems are called endocrine disrupting chemicals (EDCs). EDCs 

have been defined as exogenous agents that interfere with the production, release, transport, metabolism, 

binding, action, or elimination of the natural hormones in the body responsible for the maintenance of 

homeostasis and the regulation of developmental processes. 

To date, these problems have primarily been identified in wildlife species with relatively high 

exposures to specific compounds, including organochlorines such as DDT and its metabolites, PCBs and 

dioxins, or indomestic animals foraging onplantswithhighlevels ofphytoestrogens (Kavlock et al., 1996). 

Effects noted in wildlife that have a documented or presumed relationship to altered endocrine function 

include imposexinmolluscs exposed to the alkyltins, vitellogenin inductioninfishlivingnearsewage outfalls 

(recently linked to concentrations of ethynyl estradiol), changesinsexsteroidsinfishnear kraft-mill outfalls, 

abnormal reproductive development in alligators in Lake Apopka following a pesticide spill, nearly 

complete mortality of Lake Ontario lake trout in the sac-fry stage presumably resulting from exposure to 

dioxin-like compounds, eggshell thinning in birds from exposure to DDT and its metabolites, and birth 

defects in Lake Michigan cormorants exposed to PCBs and other Ah-receptor ligands. Also, a variety 

of adverse effects onreproductive development have beenobserved inlaboratoryrodents exposed to very 

low levels of dioxin. 

In humans, the consequences of prenatal exposure to DES on the reproductive tract of both 

females and males are well known and developmental neurological problems have been identified in 

children exposed to PCBs and/or PCDFs. In addition, reports of declines in the quality and quantity of 

sperm production in humans over the last four decades, and increases in certain cancers that may have 

an endocrine-related basis (breast, prostate, testicular) have led to speculation about environmental 

etiologies. 

While there is a large wealth of data available onsome endocrine disruptors, muchmore research 

is needed in order for the Agency to carry out its large number of mandates. For example, despite the 

above mentioned effects, we know little about their causes and the concentrations of EDCs that would 

induce effects at the population level . Nevertheless, it is known that the normal functions of all organ 

systems are regulated by endocrine factors. Small disturbances in endocrine function, especially during 

certain stages of the life cycle such as development, pregnancy and lactation, can lead to profound and 

lasting effects. 

Given EPA’s overall mandate to protect both public-health and the environment, it is in a unique 

positionto provide leadership in this area. Individualscientists across EPA’slaboratories and centers had 

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ORD Multi-Year Plan for Endocrine Disruptors 

been doing researchrelated to endocrine disruptorsformany years. Then, inresponse to increasing public 

health concerns in the early to mid-nineties, the Office ofResearchand Development decided to integrate 

and expand its ongoing efforts into a consolidated endocrine disruptors research program. To initiate the 

program, two workshopswereheld in1995 where the opinions ofinternationalexperts were sought tohelp 

formulate a national research plan for endocrine disrupting chemicals (Kavlock et al., 1996; Ankleyet al., 

1997). 

Researchonendocrine disruptors wasidentified as one of the six high-priority topics in the ORD 

Strategic Plan (USEPA, 1996; USEPA, 1997, USEPA, 2000). This was based upon recognition of: 1) 

the potential scope of the problem, 2) the possibilityof serious effects on the health of populations, 

3) the persistence of some endocrine-disrupting agents in the environment, and 4) the widespread 

global concern about the fate and transport over national borders. 

ORD’s Research Plan for Endocrine Disruptors 

(www.epa.gov/ORD/WebPubs/final/revendocrine.pdf), published in 1998, was developed from the 

recommendations provided by the USEPA-sponsored workshops, the scientific judgement of the ORD 

Research Planning Committee, and reviews and input from the chairpersons for the risk assessment 

breakout groups of the Raleigh workshop, internal peer reviewers from across the Agency, the ORD 

Science Council, and an external peer review panel convened by the Agency’s Risk Assessment Forum. 

The framework for ORD’s EDCs research program is designed around the risk assessment/risk 

management paradigm. The objectives ofthe EDCsresearchprogramare to improve our knowledge and 

understanding of endocrine disruptors in the environment so that we can improve our methods of 

assessment and risk management. This, inturn, willassist the Agencyinidentifying the chemicals that pose 

an unreasonable risk, developing ways to prevent or reduce their release into the environment, and 

developing means to remediate in-place EDCsthat pose anunreasonable risk. Further, the research plan 

specifically addresses scientific questions that have arisen as a result of legislation enacted in 1996. The 

Safe DrinkingWater Act Amendments(SDWAA) and the Food QualityProtectionAct(FQPA) mandate 

the development of a screening and testing programto evaluate the potentialof chemicals found in drinking 

watersources and food,respectively, tohave estrogenic or other hormonalactivity. Thus, EPA’s research 

program strikes a balance between “problem-driven” and “core” research. It includes areas that are 

uniquely of importance to EPA in helping the Agency meet its legislative mandates and includes research 

areas that serve to improve the basic understanding of EDCs, in general. 

The research described in this MYP assumes annual resources of approximately $11-12 million. 

It should be noted that throughout the document ORD describes research that it is conducting either on 

EDCs, in general, or on specific chemicals or classes of chemicals. It should not be construed that just 

because ORD is studying specific chemicals or classes of chemicals that this means that the Agency has 

determined that these chemicals or classes are officially designated as “endocrine disruptors.” Those 

determinations will be made by the Agency through the implementation of the Endocrine Disruptors 

Screening Program. 

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ORD’s research on endocrine disruptors falls under EPA’s Goal 4 Objective 4 Subobjective 4.1: Goal 4,Healthy 

Communities and Ecosystems, commits the Agency to protect, sustain, or restore the health of people, communities, 

and ecosystems using integrated and comprehensive approaches and partnerships. Objective 4: Through 2010, 

provide and apply a sound scientific foundation to EPA’s goal of healthy people, communities, and ecosystems by 

conducting leading-edge research and developing a better understanding and characterization of environmental 

outcomes under Goal 4. Subobjective 4.1. Through 2012, conduct research that contributes to the overall health of 

humans, their communities, and ecosystems. Research will provide a foundation for protecting, sustaining, or restoring 

human and ecological health. Research will focus on pesticides and toxics, global climate change, cross-cutting research 

on the health of humans, their communities, and ecosystems. 

II. BACKGROUND 

Agency’s priorities and regulatory programs 

The authorities and responsibilities ofEPAare mandated primarily bythirteenmajor environmental 

statutes (CRS Report to Congress, 1995). These statutes direct EPA to perform a wide variety of 

activities with the goal of protecting human health and the environment. Chemicals that are known or 

suspected of being endocrine disruptors are included in these mandated activities. In order to meet the 

needs of its mandates, EPA needs the tools to be able to: 1) identify EDCs, 2) evaluate their potential 

effects on human health and the environment, 3) discernwhenadditionaldata are needed, 4) develop the 

appropriate protocols, should additional data be required, 5)set allowable levels of exposure or releases 

to the environment that are protective of human health and the environment, 6) develop technological 

controls to prevent/reduce releases, in the first place, and 7) remediate the risks associated with in-place 

EDCs. The Research Plan and this MYP set forth the research that is needed by program and regional 

offices to carry out their legislative requirements. 

Science questions from research strategy 

The Research Plan identified a number of key areas of uncertainty, in the formof questions, that 

needed to be addressed. The Multi-Year Planning Committee considered the nine questions from the 

Research Plan as still valid and criticaland augmented the listwithan additional question to address risk 

assessment methodologies. Addressing these key science issues is critical to give the Agency program and 

regionalofficesthe tools theyneed to meetmandates asrelated to EDCs. The key questions are not in any 

order of priority, but rather follow the order identified in the Research Plan. 

• What effects are occurring in exposed human and wildlife populations? 

• What are the chemical classes of interest and their potencies? 

• What are the dose-response characteristics in the low-dose region? 

• Do our testing guidelines adequately evaluate potential endocrine-mediated effects? 

• What extrapolation tools are needed? 

• What are the effects of exposure to multiple EDCs and will a TEF approach be applicable? 

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• 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? 

Non-EPA research 

The broad nature of the EDCs issue necessitates a coordinated effort on both the national and 

internationallevel. In November 1995, the Committee on Environment and NaturalResources(CENR), 

under the President’s National Science and Technology Council (NSTC), identified endocrine disruptors 

as an initiative. The CENR established a working group on endocrine disruptors that is chaired by 

ORD/EPA with vice chairs from the Department of the Interior (DOI) and the National Institute of 

Environmental Health Sciences (NIEHS). In addition to the three aforementioned agencies, participants 

include:the NationalOceanic andAtmospheric Administration(NOAA), the NationalScience Foundation 

(NSF), the Food andDrugAdministration(FDA),theCentersfor DiseaseControland Prevention(CDC), 

the Agency for Toxic Substances and Disease Registry (ATSDR), the National Cancer Institute (NCI), 

the SmithsonianInstitution, the Department ofEnergy (DOE), the Department ofAgriculture (USDA), the 

Department of Defense (DOD), and the Office of Science and Technology Policy (OSTP). 

The CENR working group: 1) Developed a framework for federal research related to the human 

health and ecological effects of EDCs. The document reviews the state of the science and major 

uncertainties related to endocrine disrupting chemicals and established a framework for research areas that 

need attention. This framework categorizes major research needs into three groups; methods development, 

model development, and laboratory and field data acquisition. 2) Developed an internet-accessible 

searchable data base of on-going federally funded research on EDCs (htpp://www.epa/gov/endocrine). 

3) Overlaid the framework with the inventory to identify highpriorityresearchgapsinthe federal portfolio 

(Reiter et al., 1998). The inventory and the analysis point out what research is ongoing across the federal 

government that relates to the various LTGs and APGs identified in this Multi-Year Plan. These activities, 

along with the recognition that the key uncertainties regarding endocrine disruptors are complex, that 

interests across the agencies are overlapping, and that federal resources are limited, have helped ensure 

that there is close cooperation and collaboration on endocrine disruptors research across the federal 

government. 

Additionally, many of the endocrine disrupting chemicals are persistent inthe environment so there 

is widespread global concern about their fate and transport over national and international boundaries. 

While evidence for a global concern is growing, the breadth of the current scientific uncertainties related 

to what effects are actually attributable to environmental exposures, what chemicals are responsible for the 

effects, and what risk management steps need to be taken to protect public health and the environment 

necessitate international cooperation and communication. To begin to address this issue from a global 

perspective,severalkeycollaborative efforts have beenundertaken. The US federal inventory of research 

was updated and expanded in 1998 to include research projects from Europe, Canada, and Japan and, 

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thus, establish a Global Endocrine Disruptors Research Inventory (GEDRI) that includes almost 800 

projects. The inventory provides us with a searchable database as to what research is ongoing across 

continents that relates to the various LTGs and APGs identified in this Multi-Year Plan. In addition, the 

US chaired a steering committee under the auspices of the International Programme on Chemical 

Safety/World Health Organization/Organization for Economic Cooperation and Development that 

developed a “Global State-of-the-Science Review,” (WHO, 2002). Both the inventory and the 

internationalassessment are a result of recommendations made at the 1997 G-8EnvironmentalMinisters’ 

Meeting. 

Inadditionto ongoing researchacross the US federalgovernment and those ofother countries, the 

chemical industry is also engaged in research in this area. The American Chemistry Council (ACC) is a 

trade association of more than 190 member companies that represents the majority of the manufacturers 

ofindustrial chemicals inthe US. ACC coordinates the chemical industry’s research and testing programs. 

Under the auspices of an Endocrine Issues Science Forum, ACC supports an annual compilation of 

industry-sponsored endocrine research projects (www.endocrinescience.com/background.cfm). A number 

of these research efforts have been incorporated into GEDRI. They have ongoing research activities in 

many areas that complement EPA’s intra- and extramural programs, e.g., studies on testing and testing 

methodology, mechanisms of action, epidemiology, animal toxicology, wildlife studies, aquatic toxicology, 

environmental exposure, and environmental chemistry. 

Focus of EPA’s contribution 

InORD’s Research Plan, those areas where EPAshould be playing atleast a moderate role were 

selected first,takinginto considerationthe researchactivities ofother agencies and organizations. Priorities 

for both the Research Plan and the Multi-Year Plan were assigned based upon an assessment of the 

importance of the research to the EPA programand regionaloffices, onthe magnitude ofthe uncertainties 

inthe knowledge base, the sequence of research needed to obtain the final answer, the possibility that the 

research would result in a significant product for hazard identification, risk characterization or risk 

management and, finally, the technical feasibility of conducting a successful project. 

EPA’s program strikes a balance between “problem-driven” and “core” research. It includes 

areas that are uniquely of importance to EPA in helping the Agency meet its legislative mandates and 

includes research areas that serve to improve the basic understanding of EDCs, in general, that is 

complementary to research programs conducted at other federal agencies, in other countries, or by 

industry. ORD has significant expertise in the areas oftoxicology, endocrine effects, behavioralsciences, 

and environmental exposures, relating to both humans and ecological systems and in providing solutions 

to solving environmentalproblems. ORD scientists are respected members of the scientific community and 

leaders in the field. Therefore, ORD can make a significant contribution in the areas of improving our 

understanding of endocrine disruptors, their impact on human health and the environment and the 

management of the risks they pose. 

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III. PROGRESS TO DATE/CHANGES FROM PREVIOUS VERSIONS 

Progress to Date - Research Highlights 2000-2002 (Note: Highlights are aligned by Long Term Goal 

(LTG), which are defined inSectionIV. Some highlights may fit under more than one LTG but are aligned 

here under the single most appropriate one.) 

LTG1: PROVIDEABETTER UNDERSTANDING OF SCIENCE UNDERLYING THE 

EFFECTS, EXPOSURE, ASSESSMENT, AND MANAGEMENT OF 

ENDOCRINE DISRUPTORS 

• Determined that the nature of estrogen and dioxin interaction in birds (chickens) is quite different 

than that observed in mammals. (NCER) 

• Determined that neonatal exposure of male rats to low and high concentrations of nonylphenol or 

bisphenolA failed to show any effect onprostate growth- i.e., could notreproduce the U-shaped 

growth response curve observed to occur when animals are exposed in utero. (NCER) 

• Determined that TCDD and related compounds delay ovulation in rats by one or two days in a 

dose and time dependent manner and that mechanismis occurring at two levels: hypothalamus and 

ovary. (NCER) 

• Discoveredanew(third)estrogenreceptor invertebrates(Atlantic croaker) and demonstratedthat 

estrogens and xenoestrogens can act on cells at the membrane level. (NCER) 

• Determined thatsome mixtures ofEDCs(e.g,. PCBs and methoxychlor) may be oflessertoxicity 

than either agent by itself. (NCER) 

• Reported initial development of first fathead minnow Cy3/Cy5 glass-based microarray platform 

using exposure-specific cDNAtargets including those discovered bysubtractioncloning following 

exposuretoethinylestradiol. Development was enabled by collaboration in microarray production 

and bioinformatic analyses with the University of Cincinnati Department of Environmental Health 

Sciences (Dr. Craig Tomlinson), and Children's HospitalMedicalCenter Department ofPediatric 

Bioinformatics (Dr. Bruce Aronow). Presentation of genomics approach (including EDCs) was 

made at the first International Workshop and Consortium on Technology and Application of 

Ecotoxicogenomics, Pensacola Florida (Sept. 2002)(To be published inEcotoxicology in 2003). 

(NERL) 

• Published two articlesinEnvironmental Toxicology and Chemistryfocused onthe development of 

molecular diagnostic indicators of exposure ofaquatic speciestoestrogens(2001,2002). (NERL) 

• “Vitellogeningene transcription; A relative quantitative exposureindicatorofenvironmental 

estrogens”Lattier, D.L.,Gordon, D.A.,Burks,D.J., andToth, G.P. 2001. Environmental 

Toxicology And Chemistry. 20:1979-1985. 

• "17a-Ethynylestradiolinduced vitellogenin gene transcriptionquantified infathead minnow 

(pimephales promelas) adult male livers, embryo larvae and gills." Lattier, D.L., Reddy, 

T.V., Gordon, D.A., Lazorchak, J.M., Smith, M.E., Williams, D.E., Wiechman, B., 

Miracle, A.L., Flick, R.W., and Toth, G.P. 2002. Environmental Toxicology And 

Chemistry. 21(11):2385-2393. 

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ORD Multi-Year Plan for Endocrine Disruptors 

• Facilitated technology transfer of estrogenic molecular diagnostic indicators to EPA Regional 

scientistsandwater resource managers. Classroom and laboratory training occurred during August 

of 2002 (Region 9, San Francisco). Followup with Region 9 Tribal Scientists and State of 

California scientists occurred in February, 2003. Scientists from Regions 1, 2 and 3 were trained 

in Spring 2003. (NERL) 

• Collaborated with NHEERL-MED and RTD on exposure and effects of androgenic compounds 

associated withConfined AnimalFeeding Operations (CAFOs)- joint posters presented at 2002 

SETAC describing chemical and biological evidence of androgenic substances found in several 

CAFO effluents. (NERL) 

• Collaborated on a cosponsored Region 3/5 RARE Research Project to develop and validate 

analytical methods for alkylphenols and corresponding ethoxylates. (NERL) 

• Conducted research to characterize the transformation, bioavailability and occurrence of selected 

enantiomers of chiral pesticides in environmental matrices and food products. (NERL) 

• Published report on the use of internet resources for the study of ecological effects of 

anthropogenic chemicals released into the environment, including endocrine disrupting chemicals. 

(NHEERL) 

• Reported that the anabolic steroid trenbolone acetate, a growthpromotor used incattle and found 

in waste sites, had significant androgenic activity in vivo and in vitro. (NHEERL) 

• Reported on models to extrapolate risks of endocrine disrupting chemicals from individuals to 

wildlife populations. (NHEERL) 

• Reported on development of cancer associated with developmental exposure to endocrine 

disruptors. (NHEERL) 

• Reported on consensus toxic equivalency factors to predict reproductive effects of endocrine 

disruptors in mixtures. (NHEERL) 

• Published review on the health effects of dioxin and dioxin-related compounds. (NHEERL) 

• Found that environmental agents that inhibit aromatase can act as endocrine disruptors . 

(NHEERL) 

• Reported that some organophosphate insecticides have direct effects on the androgen receptor. 

(NHEERL) 

• Reported on effects of diphenylether compounds on nervous system function and thyroid gland 

function following developmental exposure in animal models. (NHEERL) 

• Reportedonpersistentsensoryand cognitive effects ofdevelopmentalexposure to polychlorinated 

biphenyl compounds in animals. (NHEERL) 

• Completed internal peer review of the document, Risk Management Evaluation of EDCs, and 

preparing for external peer review. (NRMRL) 

• Used the Risk Management Evaluation of EDCs to identify and prioritize initialrisk management 

research projects. (NRMRL) 

• Conducted a workshop in January 2002 to complement the Risk Management Evaluation of 

EDCs. The workshop established the current state of risk management research on EDCs. The 

proceedings of the workshop was published as a multimedia CD-ROM (EPA/625/C-02/015). 

(NRMRL) 

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ORD Multi-Year Plan for Endocrine Disruptors 

• Initiated risk management research on remediation of environmentalreservoirs contaminated with 

suspected EDCs including aquatic sediments and drinking water. 

• Began to adapt analytical chemistry and bioassays methods to evaluate the performance of risk 

management processes. (NRMRL) 

• Formed a NRMRL/NERL collaboration on wastewater treatment research. (NRMRL) 

LTG 2: DETERMINE THE EXTENT OF THE IMPACT OF ENDOCRINE 

DISRUPTORS ON HUMANS, WILDLIFE, AND THE ENVIRONMENT 

• Determined levels ofphytoestrogens inhumanamniotic fluid and effects of exposure to those levels 

in rats on markers of sexual development. (NCER) 

• Identified androgenic compounds (male hormone mimics) in paper mill effluent using a screening 

assay developed using mosquitofish. (NCER) 

• Found no evidence for immunosuppression in developing and hatchling American alligators 

exposed to a range of concentrations and combinations of EDCs (DDE, dieldrin, endosulfan, 

methoxychlor, toxaphene, chlordane). (NCER) 

• Determined exposure to high levels of polybrominated biphenyls (PBBs) prenatally and via breast 

milk may impact puberty in girls. (NCER) 

• WithNRMRL, completed sampling of50 waster water treatment plants (WWTP) for a surveyof 

estrogenic activities to compare the relative effectiveness of treatment processes (Summer, Fall 

2002). (NERL) 

• Collaborated with the State of New Mexico Department of the Environment to determine the 

exposure potentialof27EDCsonthe GallinasRiver, above and belowthe CityofLas Vegas, NM 

watersupply. The State ofNew Mexico splitsamples withORD-EERD and analyzed 27 potential 

Endocrine Disrupting compounds while ORD-EERD assessed the estrogenic potentialof the same 

samples using the fathead minnow Vitellogenin gene expression assay. (NERL) 

• Completed large scale exposure study assessing 260 young children’s aggregate exposures to 

pesticides, EDCs, and other persistent organic pollutants(Children’s TotalExposure to Pesticides 

and other Persistent Organic Pollutants. Study conducted in NC and OH. Samples analyzed. 

Final analyses planned for FY03/04. (NERL) 

• Completed joint HUD/CPSP/EPA assessment of children’s exposures in >160 daycare centers 

randomly selected across the US. Samples being analyzed. Final analyses planned for FY03/04. 

(NERL) 

• Developed and had externally peer reviewed study design and protocol for assessing very young 

children’s exposuresto pesticides and EDCs(studytostart inFY03/04, pending OMB approval). 

Pilot study conducted in Jacksonville, FL in collaboration with CDC, NHEERL, and Duval 

County. (NERL) 

• Completed exposure assessment of >120 farm applicators and their families in NC and IA to 

produce data to evaluate the NCI exposure algorithms in support of the Interagency AHS. Final 

analyses planned for FY03/04. (NERL) 

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• Reported that although androstenedione was present at detectable quantitiesincontaminated river 

water, the compound was not associated with androgenic activity of water from the site. 

(NHEERL) 

• Report of masculinized female juvenile alligators from Lake Apopka, suggesting juveniles ofboth 

genders exhibit altered endocrine and reproductive dysfunction. (NHEERL) 

• Launched risk management researchoncharacterizing suspected EDC sourcesto the environment 

including investigations ofwastewater treatment plants,concentratedanimalfeedingoperations and 

combustion processes. (NRMRL) 

LTG 3: SUPPORT EPA’S SCREENING AND TESTING PROGRAM 

• Developed an estrogen-responsive transgenic zebrafish whose expression can be monitored by 

fluorescence capture of reporter gene activity. (NCER) 

• Developed, characterized, and optimized/standardized an in vitro spermatogenesis model for 

detecting spermatotoxicants, including EDCs, using dogfish shark testis. (NCER) 

• Developed/refined an in vivo model using medaka to identify EDCs. (NCER) 

• Developed integrated array of computational tools undergoing validation by OPPTS for setting 

priorities for screening and testing (S&T) program. (NCER) 

• Reported on a Short-term Test Method for Assessing the Reproductive Toxicity of EndocrineDisrupting Chemicals Using the Fathead Minnow (EPA Document). (NHEERL) 

• Reported on a modelusing a 3-D structuralapproachto predict chemicals for their ability to bind 

to the estrogen receptor. (NHEERL) 

• Provided anoverview onthe use ofstructure-activityrelationshipsforranking and prioritizing large 

chemical inventories, including endocrine disruptors. (NHEERL) 

• Reported that the estrogen-responsive reporter gene assayintrout wasresponsive toestrogenover 

a wide range of environmentally relevant temperatures. (NHEERL) 

• Reported ona novelcell ine that can be used to detect hormone receptor agonists and antagonists 

for screening purposes. (NHEERL) 

Changes from Previous Versions 

Asthe result of anFY2002 appropriations redirect offundsforresearchinthe development of alternatives 

to animal testing, ORD has given rise to an innovative program, entitled Computational Toxicology (CT). 

The intent of this program is integrate modern computing and information technology with the technology 

of molecular biology and chemistry to improve EPA’s prioritization of data requirements and risk 

assessmentsfortoxic chemicals. As “proof-of-concept,” ORD will first develop methods for the immediate 

priority-settingissuesfacingOPPTS inevaluating endocrine disruptors as mandated byCongressinFQPA. 

This versionofthe MYP includes anAPGand related APMs that are associated withthe CTresearchthat 

is implementing this “proof-of-concept” program. 

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In addition, in the Appendix Potential Additional Research, we have taken the methods, tools and 

approaches we described in the previous version and describe howwe propose to apply themto a casestudythat would be conducted in an integrated fashion using the expertise fromallofORD’s Laboratories 

and Centers. 

IV. LONG-TERM GOALS 

The Research Plan is the road map that identifies the research that is needed to improve our 

understanding of endocrine disruptors. It should be referred to in order to understand the overall research 

program that is envisioned. This Multi-Year Plan identifies the elements of the Research Plan that ORD 

will beworking oninanintegrated fashion, across branches, divisions, Laboratories, and Centers, over the 

next five to ten years. the Water Quality, Safe Communities, and Ecosystem Protection MYPs, 5) 

developing integrated risk assessments willbe ofvalue to Goals 3, 4,8.1and 8.2 researchunder Safe Food, 

Safe Communities,EcosystemProtection, and Human Health Risk Assessment MYPs, and 6) developing 

risk management approaches, including pollution prevention methods, will be valuable to research under 

the Pollution Prevention MYP. 

As noted previously, the Research Plan identified nine key areas of uncertainty and the MYP 

Committee added a tenth area. The Committee used these areas as a basis to derive three Long-Term 

Goals (LTGs). The three LTGs with the key areas of uncertainty they address are as follows: 

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

management of endocrine disruptors 

• Determine what are the dose-response characteristic in the low-dose region 

• Determine what extrapolation tools are needed 

• Determine what are the effects of exposure to multiple EDCs and will a TEF approach be 

applicable 

• Determine how can unreasonable risks be managed 

• Determine what approaches are needed to assess risks to humans and wildlife 

2) Determine the extent ofthe impact of endocrine disruptors onhumans, wildlife, and the environment 

• Determine how and to what degree are human and wildlife populations exposed to EDCs 

• Determine what effects are occurring in exposed human and wildlife populations 

• Determine what are the chemical classes of interest and their potencies 

• Determine what are the major sources and environmental fates of EDCs 

3) Support EPA’s screening and testing program 

• Determine whetherour testing guidelines adequately evaluate potentialendocrine-mediated 

effects 

It should be noted that the LTGs identified by the Multi-Year Planning Committee are consistent 

with not only the key areas of uncertainty identified by EPA’s Research Plan, but also assessments 

conducted bythe following organizations:1) the researchneedsframework and prioritydata gapsidentified 

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by the Endocrine Disruptors Working Group (Reiter et al., 1998) of the Committee on Environment and 

Natural Resources (CENR) under the President’s National Science and Technology Council (NSTC), 2) 

research needs identified by the National Research Council in its 1999 report “Hormonally Active Agents 

Environmental Agents,” (NRC, 1999), 3) research needs developed at a joint US-European Union 

workshop held under the auspices of US-EU Science and Technology Agreement (JRC, NIEHS, EPA, 

1999), and 4) the internationally developed document Global Assessment of the State-of-the-Science of 

Endocrine Disruptors (WHO, 2002). Therefore, it is well-recognized and accepted that resolution of these 

goals are key to being able to:1) improve our understanding ofthe science regarding endocrine disruptorsspecifically in the areas of effects, exposure, risk assessment, and risk management, 2) determine the 

extent of the problem endocrine disruptors are causing to humans and the environment, and 3) develop 

scientifically valid methodsto screenand testforagentsinthe environment that maybe endocrine disruptors. 

ORD is committed to addressing particular aspects of each of these LTGs. These aspects are 

reflected in the Annual Performance Goals (APGs) and their respective Annual Performance Measures 

(APMs) described ingreater detail inSectionV and inattached supporting Tables 1-3. The attached flow 

diagrams for each of the LTGs (Figures 1-3) depict the time line for completion of the APGs and their 

interrelatedness and should help put the information in Section V into simpler context. 

The degree of emphasis for each LTG is based on criteria similar to those used when assigning 

priorities in the Research Plan: 1) an assessment of the importance of the research to the EPA 

program/regional offices, 2) the magnitude of the uncertainties in the knowledge base, 3) the sequence of 

research needed to obtain the final answer, 4) the possibility that the research would result in a significant 

product for hazard identification, 5) risk characterizationor risk management , 6) the technical feasibility of 

conducting a successful project, and 7) legislatively mandated time frames. The following table summarizes 

the relative emphasis of each LTG over the period of FY2000 through 2012. 

LTG Emphasis from 2000 through 2012 

1 Level through 2008 and then increasing 

2 Level through 2008 and then increasing 

3 Level through 2008 and then decreasing 

Successfully addressing these LTGs will require a highly coordinated effort. It is anticipated that 

each Laboratory and Center within ORD will develop an implementation plan for EDCs that will further 

facilitate the coordination and sequencing ofthe researchelementsto occur. The Implementation Plans will 

be consistent with the Research Plan and the Multi-Year Plan. These documents should be considered 

collectively when trying to understand the overall endocrine disruptors research program, what specific 

research the Laboratories and Centers will be carrying out, and when. Recognizing the dynamic nature of 

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ORD Multi-Year Plan for Endocrine Disruptors 

research, theMulti-YearPlanningCommitteerecommendsthatthe priorities and sequencing inthe Research 

Plan, in the Multi-Year Plan, and inthe individualImplementationPlans be revisited periodically so that the 

overall research program can be modified as the knowledge base increases. 

The following section on Description of the Flow Diagrams will lay out which specific aspects of 

the LTGs ORD plans to address. However, given the breadth of the goals and the complexity of the issue, 

it will require coordinated efforts across the federal government, academia, industry, non-governmental 

organizations, and with our international counterparts to fully address these goals. The mechanisms for 

collaboration are highlighted in Section II. 

The endocrine disruptors research program is one of a few ORD research programs that includes 

a diverse multi-disciplinary set of research areas for both human health and wildlife. This set includes: 1) 

evaluation of effects in human health and wildlife, 2) determining exposures in human and ecosystems, 3) 

development of integrated risk assessment approaches for human and wildlife populations and 4) 

development of risk management approaches to mitigate exposures in human and wildlife populations. 

Meeting these high level goals will enable us to achieve the Goal 4.4.1 GPRA sub-objective, as it relates 

to endocrine disruptors, to “conduct research that contributes to the overall health of humans, their 

communities, and ecosystems” by combining human health and ecological considerations. 

The EDCsMYP does notrely directly onresearchconducted under other MYPs and other MYPs 

do not rely directly on research conducted under the EDCs MYP. However, it should be noted that the 

research conducted under this MYP will provide results that are indirectly valuable across a number of 

MYPs and Agency Goals. A few of the examples where endocrine disruptors researchwillbe ofvalue to 

other Agency Goals and MYPs are provided in the following table. 

Examples of EDCs Research - Goal Goals and MYPs that benefit indirectly 

Exposures to multiple endocrine disruptors Goals 4 aggregate exposure and cumulative risk 

issues - Safe Food, Ecosystem Protection, and 

Human Health Risk Assessment MYPs 

4.4.1 

Development of protocols for screening and 

testing 

Goal 4 test methods development program - Safe 

Communities MYP 

Understanding critical biological factors during 

development 

Goals 2, and 4 sensitive subpopulation issues -

Drinking Water, Safe Food, and Human Health 

Risk Assessment MYPs 

Understanding impacts of endocrine disruptors 

on wildlife 

Goals 2, and 4 ecological methods, models, and 

measures research - Water Quality, Safe 

Communities, and Ecosystem Protection MYPs 

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ORD Multi-Year Plan for Endocrine Disruptors 

Developing integrated risk assessment methods Goals 4, risk assessment methods development 

programs - Safe Food, Safe Communities, 

Ecosystem Protection, and Human Health Risk 

Assessment MYPs 

Developing risk management approaches, 

including pollution prevention methods 

Goal 5 pollution prevention methods - Pollution 

Prevention MYP 

V. DESCRIPTION OF THE FLOW DIAGRAMS 

The flowdiagrams, as noted previously, depict the APGsthat willsupport the LTGs, the time frame 

for their completion, and how they are interrelated. In the development of the Multi-Year Plan, the 

Committee took the following into consideration when determining the AnnualPerformance Goals (APGs): 

1) the key questions identified in the Research Plan, 2) the original33 subissuesidentified in the Research 

Plan, 3) the research themes that were being identified within several laboratory implementation plans 

(specifically NHEERL’s Multi-Year Implementation Plan and NRMRL’s Risk Management Evaluation), 

and 4) an assessment ofongoing and anticipated ORD research efforts. As a result, 20 discrete research 

areas (APGs) were identified in which ORD can make a significant impact, between the intramural and 

extramuralSTARgrants programs, inadvancing the state of the science on endocrine disruptors within the 

next 7 years. Schedules for these research areas were estimated based upon knowledge of: 1) existing 

resources, 2) intramural capacity and capability, 3) projected timelines for awarded grants, 4) the 

complexity of the area, and 5) in several cases, Congressionally-driven deadlines. 

Annual Performance Measures (APMs) representing discrete segments of research to be completed 

within the defined schedule were developed for eachAPG. The APMs (Tables 1-3) will help to determine 

progress made towards completing the APG. The APMs in the Tables represent the expected product 

from a given research area. Therefore, the Tables, for the most part, do not necessarily show continual 

progress of a research area from start to finish, but rather just the major “milestones.” Each APM is 

attributed to one of ORD’s Laboratories or Centers. It should be noted that, for the most part, those that 

are attributed to NCER are products of STAR grants. Some APMs (those in italics) appear in multiple 

MYPs. It is important to note that the Tables capture the APGs and APMs currently anticipated. The 

Committee recognizes the need to update the matrix periodically, as new Milestones are anticipated and as 

emphases shift. However, the Committee agrees that the current APGs will drive the development of the 

Laboratory- and Center-specific ImplementationPlans and the projects/topics onwhichtheir efforts will be 

focused for the next five to seven years. 

Please note that guidance for the development of the MYP called for the use of the term “Annual 

Performance Measure”toacknowledge those activitiesthat collectivelywould address anAPG. However, 

the APMs described in this MYP should not be confused with or ever designated as ORD or Agency 

APMs used in cross-Agency planning and accountability activities. It is anticipated, that APMs from the 

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ORD Multi-Year Plan for Endocrine Disruptors 

MYP will be aggregated and integrated to derive “Annual Performance Measures” for Agency 

accountability activities when required. 

The 21 APGs for the Multi-Year Plan are described below. For each APG, the objective, the 

significance/impact, and the schedule of the research are described. It is assumed that the various APMs, 

when aggregated, will lead to the achievement of the APG. In order to facilitate understanding how the 

achievement of the APGs will lead to achieving LTGs, the descriptions for the APGs are aligned 

chronologically underthe LTG(s)theysupport. Please note that in a couple of cases an APG may support 

more than one LTG. Similarly, in Tables 1-3, an APM may support more than one APG. Since the MultiYear Plan identifies which areas of the Research Plan our efforts will focus on for the next 7 years, the 

descriptions below include the cross-reference to the relevant subissues in the Research Plan. For more 

detail and context, the reader should refer to the Research Plan itself. 

LTG1: PROVIDEA BETTER UNDERSTANDINGOFSCIENCEUNDERLYINGTHE 

EFFECTS, EXPOSURE, ASSESSMENT, AND MANAGEMENT OF 

ENDOCRINE DISRUPTORS 

The products of the research conducted under this LTG will: 1) improve our understanding regarding 

environmentalexposures and effects ofEDCsand 2)result inthe development ofimprovedmethodsforrisk 

assessment and risk management. In other words, this LTGwillresult inthe development of tools that can 

be applied inthe conduct ofresearchunder LTG2 intrying to determine the extent of the impact of EDCs. 

The LTG 1 research can be thought of, therefore, as basic or “core” research. Therefore, the results will 

be of value to most of EPA’s program and regional offices, other federal agencies, agencies in other 

countries, and the scientific community at large. 

APG: Characterize the effects of exposure to multiple EDCs, in various combinations such 

as those with similar and different mechanisms of action (FY03) 

Objective: To understand the impacts on humans and wildlife of exposures to mixtures of EDCs 

at environmentally relevant levels. 

Significance/Impact: Understandingwhethereffectsfollowing exposuresto mixtures ofEDCswill 

be additive,synergistic, canceleachother out (estrogens and anti-estrogens), or otherwise, willlead 

to improved human health and ecological risk assessments. 

Schedule: The question ofthe interactions ofmixtures ofEDCsis a criticalone for bothhumanand 

ecological risk assessments. There are efforts ongoing intramurally with PCBs, PHAHs, dioxins, 

phthalates, and triazines, and through STAR looking at tributyltin in combination with other 

contaminants. We anticipate being able to complete the ongoing researchto addressthis APG by 

FY03. However, based upon the results of these data it may be necessary to conduct additional 

studies in later years. 

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ORD Multi-Year Plan for Endocrine Disruptors 

Research Plan Subissue: EFF.6.1 

APG: Determine the shape of the dose-response curve in a variety ofspecies exposedto 

ambient levels of endocrine disruptors (FY05) 

Objective: To develop a more complete understanding of specific chemicalmechanisms of action 

particularly for mechanisms that operate in the low end of the dose-response curve. 

Significance/Impact: Understanding of how EDCs elicit toxicity through receptor-based 

interactions, membrane receptors, enzyme alterations, and other non-nuclear receptor-based 

pathways, will lead to improved methods to interpret data (particularly from the screening and 

testing program) and, thus, improved risk assessments. Most of what we know about endocrine 

disruptors is a result of laboratory studies or as a result of environmental spills/accidents where 

exposures in both types of studies were relatively high. Understanding how EDCs operate at the 

low end of the dose-response curve is particularly relevant to evaluating effects at ambient 

environmental levels of exposure. Gathering this information in a variety of species will lead to 

improved methods for extrapolating data across species. 

Schedule: Because data from this research are critical to help interpret the results from the 

screening and testing program, this research is ongoing now in both our intramural and STAR 

programs. Because of the complexities associated with elucidating mechanisms of action, the 

ongoing research that is addressing this APG will not be completed until FY05. However, it 

appears warranted to issue a STARsolicitationfor additionalresearchinthis area, based uponthe 

recommendations that came out of the “Low-Dose Peer Review Panel on Endocrine Disruptors” 

sponsored byEPAand NIEHS. Therefore, once awards are made for those grants, in all likelihood 

it will be necessary to push back the date for completion of this APG. 

Research Plan Subissue: EFF.3.1 

APG: Identify key risk assessment issues and develop guidance for assessing endocrine 

disruptors (FY06) 

Objective: To work collaboratively across ORD laboratories and centers to: 1) identify, 

characterize, prioritize, and assess the potential exposures and effects to selected suspect EDCs, 

and 2) develop a framework to integrate experimentaland observationaldata forbothhumanhealth 

and ecological effects in order to conduct holistic risk assessments for EDC modes of action 

(MOAs) 

Significance/Impact: The development of tools that factor in how best to incorporate MOAs, 

multiple chemicalexposure, criticallifestages,criteria foradversity, dose-response relationships and 

inter-species comparisons are criticalforthe development ofimproved humanhealthand ecological 

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ORD Multi-Year Plan for Endocrine Disruptors 

risk assessments for EDCs. The methods that will be developed also will have broader impact on 

Agency risk assessments beyond EDCs. 

Schedule: These tools willbe needed asthe knowledge base onEDCs increases, particularly with 

the screening and testing program. Limited efforts are ongoing. While we have designated its 

completion in FY06, program/regional offices are asking that the work be completed even earlier, 

if possible, because of its importance to the screening and testing program. Further, the research 

should be evaluated periodically to ensure it is addressing keydata gapsthatremain/develop as the 

knowledge base increases and risk assessments are performed routinely. 

Research Plan Subissue: LNK.1.1 

APG: Determine the critical biological factors during development resulting in toxicities 

occurring later in life (FY06) 

Objective: To determine the criticalfactorsthataccountforexposuresduringdevelopmentresulting 

in toxicities occurring later in life (e.g. windows of vulnerability, developmental tissue dosimetry, 

modes of action) to inform appropriate human health and ecological risk assessments for these 

effects and the chemicals involved. 

Significance/Impact: To address a critical issue in the controversies over potential endocrine 

disruptionlinked to environmentalchemicalexposure,thatis,the impactofdevelopmentalexposures 

on function later in life. Development is a period when hormone-mediated changes in gene 

expression can have permanent consequences that may not be apparent until later in life because 

functionalchanges do not occur until puberty or adulthood and duringwhichextraordinarychanges 

occur. Thus, the developing organismmaybe more vulnerable to toxic effects at lower doses than 

would produce adverse effects in adults. It also has been suggested that there are processes for 

whichthere maybe no apparent threshold due to limitations in the kinds of regulatory, surveillance, 

and repair processes that create biological thresholds in adults. Research in this area will provide 

the critical information needed for assessing the potential consequences of in utero and childhood 

exposures, bothrepresenting periods ofsensitivityofhumanand wildlife populations. Since, EDCS 

research focuses on the mode of action of a compound, the impact of these effects on 

developmental processes is critical to risk assessment. The determination of developmental 

anomalies caused by a compound, the identification of the dose required to produce such effects 

and an understanding the mode and mechanism of action involved provides information that can 

allow for informed decisions on the potential risk to the developing human and wildlife species. 

Furthermore, mode of action analyses of the low-dose issue could have a major influence on the 

Agency’s approach to risk assessment of endocrine disruptors. 

Schedule: Because ofthe importance of addressing thisuncertainty, the breadthofthe researchthat 

will be needed, and the complexity of the issues, although there is ongoing research in this area, it 

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ORD Multi-Year Plan for Endocrine Disruptors 

will take 5-6 years before we can make a significant impact in this area. However, our in-house 

expertise is highly capable of addressing this issue as it relates to both human health and wildlife. 

In addition, there are several ongoing grants that are contributing to our being able to meet this 

challenge. 

Research Plan Subissue : LNK.2.3 

APG: Determine the degree to whichthe effects of EDCs withdefinedmechanisms/modes 

of action can be extrapolated across classes of vertebrates (FY07) 

Objective: To determine the degree to whichthe effects ofEDCswithdefinedmechanisms/modes 

of action (MOAs) can be extrapolated across classes of vertebrates. 

Significance/Impact: 1) To reduce the uncertainty associated with extrapolating effects of 

chemicals across species. 2) To understand the degree to which quantitative extrapolation is 

defensible/possible, comparative toxicologicalstudies using chemicals withwell-defined MOAs are 

necessary. The EDC program, because of its focus on systems controlled by endocrine function 

which appear to be highly conserved and, in some cases, reasonably well-characterized across 

species, offers a logical opportunity around which to formulate and test hypotheses related to 

across-species extrapolation of chemical toxicity. Research will have a direct and, potentially, 

relatively immediate impact on the regulation of EDCs in terms of defining the degree to which 

screening and testing based on an assumption of similar MOAs across species is technically and 

scientifically defensible. Of broader significance, the development of approaches to evaluate and 

conduct inter-species extrapolation research should ultimately help reduce uncertainties in both 

human health and ecological risk assessments. 

Schedule: Currently there are limited intramural efforts ongoing in this area. However, since this 

was one of the focus areas identified in NHEERL’s implementation plan it is anticipated that more 

efforts will commence. Because data from this research is critical to help interpret the results from 

the screening and testing program, the conduct of this research should be from now and should be 

evaluated periodically as data become available fromthe S&T to ensure that itfocuses on questions 

that require addressing. Because of the complexity of the issues being addressed, the need for 

developing physiologically-based toxicokinetic (PBTK models), and the fact that there are limited 

efforts currently ongoing, indicate that this APG will not be addressed until FY07. 

Research Plan Subissue: EFF.4.2; EFF3.1 

APG: Evaluate exposure methods, measurement protocols, and models for the 

assessment of risk management efficacy on EDCs (FY08) 

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ORD Multi-Year Plan for Endocrine Disruptors 

Objective: Develop exposure methods, measures, and multimedia, multi-pathway models to assist 

in the measurement of risk management success. 

Significance/Impact: As risk management approaches are identified and/or developed there will 

be a need to identify and adapt and/or develop bioassay screening tools and other analytical 

methods to assess their efficacy. Measurements research will be performed to define the extent of 

the exposure issue (e.g., bioavailability/uptake) and assist in defining risk management needs. In 

additionto serving as tools onriskmanagement approaches, exposure measures(e.g., chemicaland 

biological indicators) will be valuable to screen and characterize exposures, improve exposure 

estimates in future epidemiological studies, and assist indeveloping and verifying exposure models. 

This effort will entail cross laboratory participation from NRMRL, NERL, and NHEERL. 

Schedule: Researchhas begun onthis effort and is being coordinated withprojectsofsimilarscope 

in the other ORD laboratories and centers. Molecular biological indicators are being developed 

through FY07 to measure exposure of aquatic species to single and multiple EDCs. These are 

DNA microarray-based indicators and offer the potential to measure exposure to specific 

endocrine-disrupting components of chemicalmixtures. . Innovative analytical methods are being 

developed and field validated for some pesticides, alkylphenols, phthalates, and other classes of 

suspected EDCs. Multimedia, multi-pathway models are being developed to characterize EDC 

exposures, identify critical gaps, and define further research. The exposure, effects, and risk 

management research programs will develop in an iterative approach with future tools defined 

through the analysis of past and current research results. 

Research Plan Subissue: EXP.2.3 

APG: Computational Toxicology Program: Provide at least one computational model for 

assessing endocrine disruptor compounds (FY08) 

Objective: The scientific approach consists of first describing in detail the endocrine systems 

in representative species and identifying primarypathways bywhicha chemicalcould disrupt these 

systems. Employing this diagnostic approach, an expanded series of in silico, in vitro and ex vivo 

models and assays will be employed to discriminate specific pathways and develop models for 

specific classes of chemicals that exert toxic effects through each of the pathways. 

Significance/Impact: If successful, these models could facilitate priority-setting among large 

numbers of chemicals byranking eachchemical sequentially for its similarity to the chemicalclasses 

that disrupt each pathway. In the near-term, the program will provide high quality databases that 

can be used to develop, in the mid-term, additional predictive, computer-based structure activity 

models. In the longer-term, the research efforts will refine existing in vivo assays to increase the 

amount of diagnostic information gained for the invested resources by eliminating redundancies 

among these assays and reducing the number of animals needed. 

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ORD Multi-Year Plan for Endocrine Disruptors 

Schedule: ORD anticipates developing over the next three to five years additional computer 

models, and associated in vitro assays that will predict, from chemical structure, the potential for 

a compound to elicit the initial chemical-biological interactions that trigger molecular, biochemical, 

and physiological events that can ultimately lead to adverse reproductive or developmental 

outcomes. The computer models will be developed, and iteratively evaluated and improved, by 

employing data sets derived from in vitro assays that are responsive to, and diagnostic of, specific 

toxicological pathways. The employment of genomics will comprise the next generation of 

techniques to identify chemical-biological interactions that initiate endocrine disruption to further 

define the subsequent biological events diagnostic of specific pathways. These techniques will 

efficiently expand knowledge basesto supportnewcomputermodels that predict‘keystone’ events 

from chemical structure. 

Inthe nextthreeto five years, additional in vitro assays willbe developed and evaluated to broaden 

the means ofidentifyingpathways of endocrine disruption. Over the long term(five to tenyears) new 

in vivo approaches will be developed and evaluated for their ability to capture increased 

information, with a reduction in the number of separate tests that are conducted and a decrease in 

animalusage. Again, the use of genomics tools will be essential tomeeting this objective. While we 

indicate that this APG will be completed in FY08, we recognize the need to re-evaluate this date 

as the research program unfolds. 

Research Plan Subissue: EFF.1.1, EFF.3.1, EXP.2.3, LNK.4.1, LNK.4.2 

APG: Identify risk management EDC research (FY08) 

Objective: To evaluate the state of science of EDCs and identify risk management research 

opportunities to reduce EDC exposure to human populations and ecosystems. 

Significance/Impact: A risk management evaluation(RME)willallowORDtoidentifymajor EDC 

sources and to develop a comprehensive risk management researchprogramthat isfocused on the 

major sources of EDCs, employs research results from other ORD laboratories and center, and is 

coordinated across ORD. This RME will identify opportunities of greatest need and greatest 

potential for making significant impacts to the reduction of EDC releases and exposures. 

Schedule: Researchthat addressesthis APGwillbe continuous. Although the matrix lists this APG 

to be addressed in FY08, as more information becomes available on sources of EDCs, the need 

for additional risk management research will be evaluated to ensure it is focused on the most 

appropriate sources. 

Research Plan Subissue: LNK.4.1; LNK.4.2 

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ORD Multi-Year Plan for Endocrine Disruptors 

APG: Develop at least two new risk management tools to reduce exposure to EDCs 

(FY09) 

Objective: To develop new risk management tools for addressing EDCs. 

Significance/Impact: If existing methods are deemed inadequate to address the risks posed by 

EDCs, new tools will be developed. Development of new tools will lead to cost-effective 

approaches to mitigating exposuresto EDCs; pollutionpreventionapproaches to minimize the use, 

release, or production of EDCs; and site remediation methods. 

Schedule: Once majorsources ofEDCshave beenidentified and an evaluation of existing tools is 

underway, research on developing tools to manage unreasonable risks will begin. Therefore, this 

research effort is scheduled to begin a few years into the 2000-2012 time frame. As more 

information becomes available on sources of EDCs and data become available as to the feasibility 

of using existing tools, research for this APG will be evaluated to ensure it is focused on the most 

appropriate sources. It is anticipated that initial research to address this APG will be completed in 

FY09 and that its impact on the reduction of EDC releases to the environment and the need for 

additional new RM tools will be re-evaluated. 

Research Plan Subisssue: LNK.4.2 

APG: Evaluate at least three existing risk management tools to reduce exposure to EDCs 

(FY09) 

Objective: To determine whether existing risk management tools can be applied to major sources 

of EDCs to mitigate exposures 

Significance/Impact: There are a number of existing riskmanagement tools that possibly could be 

applied to reduce exposures to EDCs. This research will determine which existing technologies can 

be applied or modified to reduce exposure. If technologies exist that can be applied to major 

sources of exposure, the impact could potentially be a major reduction of EDC release to the 

environment (e.g., revision to the waste water treatment process that would remove EDCs from 

effluent and/or sludge). 

Schedule: Once majorsources ofEDCshave beenevaluated,researchonthe potentialapplication 

of existing tools to manage unreasonable risk will begin. Current thinking has early efforts focusing 

onthe following sources:sewage treatment plants,sources of combustion, drinkingwater treatment 

plants, sediments, and CAFOs. As more information becomes available on sources of EDCs, 

research for this APG will be evaluated to ensure it is focused on the most appropriate sources. 

Given the current sources of concern, it is anticipated that research to address this APG will be 

completed in FY09. 

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ORD Multi-Year Plan for Endocrine Disruptors 

Research Plan Subissue: LNK.4.2 

APG: Develop systems models to test and predict vulnerability of the neuroendocrine system to 

contaminant-induced effects 

Objectives: Disruptionofneuroendocrine systems ininvertebrates, aquatic, and amphibianspecies 

is a potential target for environmental chemicals. However, such effects may be mediated via 

different biologicalpathways withinand acrossspecies. In addition, it is possible that environmental 

chemicals withdifferent modes of actioncould interact inanonadditivemannerbyaffectingdifferent, 

but converging, neuroendocrine pathways. The scientific approach consists of developing a basic 

understanding of the neuroendocrine systems in non-mammalian species and using emerging 

toxicogenomic and proteomic techniques to identify potential common pathways of action. This 

research will focus on potential reproductive or developmental effects across various nonmammalian species because they are crucial to understanding chemical effects in non-mammalian 

species at the population level. 

Significance/Impact: This research will result in the identification of key biological events across 

multiple non-mammalian species that are sensitive to neuroendocrine disruption. This information 

is important for reducing uncertainties associated with extrapolation across non-mammalian species 

and forpredictingpotentialnon-additive interactions amongchemicals that affect the neuroendocrine 

system by different pathways. Ultimately, this research could lead to models that would facilitate 

priority-setting among large numbers of environmental contaminants having effects on the 

neuroendocrine system in non-mammalian species. 

Schedule: ORD willfirst conductresearchto understand howthe neuroendocrine systemintarget 

non-mammalian species is associated with normal reproductive and developmental outcomes. 

Research will then focus on using emerging toxicogenomic and proteomic techniques as a means of 

identifying common molecular endpoints that could be perturbed by environmental contaminants. 

Once common molecular endpoints of neuroendocrine function are identified across different 

species, effects of contaminants willbe studied. These results will be used to develop computational 

or other predictive models to test for effects of contaminants and to provide the basis for 

extrapolationacrossnon-mammalianspecies. Eventually, this research will lead to the development 

of a model to predict contaminant-induced effects in non-mammalian species associated with 

multiple and potentially interacting neuroendocrine modes of action. 

Research Plan Subissue: LNK.2.3; EFF.4.2; EFF.3.1; EFF.3.4; EFF.5.3 

LTG 2: DETERMINE THE EXTENT OF THE IMPACT OF ENDOCRINE 

DISRUPTORS ON HUMANS, WILDLIFE, AND THE ENVIRONMENT 

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ORD Multi-Year Plan for Endocrine Disruptors 

The products ofthe researchconducted underthis LTGwill improve our understanding regarding the extent 

to which current environmental exposures to EDCs impact human and wildlife populations and the 

environment. As noted above, the methods, approaches, and tools developed through LTG 1 and 

elsewhere will be applied under LTG 2 in trying to determine the extent of the impact of EDCs. The LTG 

2 researchcan be thought of, therefore, as more “applied” research. The results of this researchwillbe of 

value to most of EPA’s program and regional offices, other federal agencies, agencies in other countries, 

and the scientific community at large. 

APG: Develop field methods to assess environmental exposures in tissues and 

environmental compartments (FY02) 

Objective: To develop improved field and analyticalmethodsto collect,separate, characterize and 

identify EDCs in environmental media and tissues. 

Significance/Impact: Improved methodologies willoptimize monitoringand analyticalthroughput. 

Results ofthis researchwillprovide improved sample extractionmethods,extract preconcentration, 

chromatographic separation, and analyte detection. 

Schedule: Efforts have been ongoing forseveralyearsintramurally to develop improved methods 

to detect EDCs in water, sediment, soil, and animal tissue. These efforts are expected to be 

completed in FY02. 

Research Plan Subissue: EXP.2.2 

APG: Determine the efficacy of various wildlife species as sentinels (FY04) 

Objective: To select appropriate sentinel species for context-specific studies. 

Significance/Impact: To address the need to identify appropriate animal models for different 

scenarios that require testing - e.g., 1) representation ofdifferent life history strategies; 2) species 

vagility with respect to exposure distribution; 3) representation of multiple taxonomic and trophic 

levels; 4) manipulability of species in laboratory tests; 5) availabilityofbaseline information; and 6) 

the degree of distribution of a species. 

Schedule: A number of research activities are underway as a result of previously announced 

solicitationsthrough the STARextramuralgrants programand some intramuralefforts. The research 

cuts across a varietyofspeciesincluding fish, birds,reptiles, and invertebrates. Another request for 

proposals may be announced in the future, pending the outcome of these studies. Reports from 

current studies are expected to be completed in the FY03-FY04 timeframe. 

Research Plan Subissue : EFF.5.3 

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ORD Multi-Year Plan for Endocrine Disruptors 

APG: Evaluate several classes of chemicals suspected of being endocrine disruptors in 

field studies and ascertain the degree towhichthey are, orhave the potential to, adversely 

affect wildlife at the population level (FY04) 

Objective: 1) To develop and interpret measurement endpoints collected at lower levels of 

biological organization that could be extrapolated into understanding impacts at population or 

community levels and 2) to use specific chemical classes to ascertain the degree to which EDCs 

are, or have the potential to adversely affect wildlife at the population level. 

Significance/Impact: One of the biggest unanswered questions in assessments of ecological risk, 

in general, is the “So what?” one. That is, what does it mean, in terms of a population or 

community, to observe an adverse effect in an individual or groups of individual fish and wildlife. 

This research will improve the ability to quantify the significance of effects observed at individual 

levels, to impacts at a larger scale. Results of this research will not only be of value specifically to 

the issue of EDCS, but also across ecologicalrisk assessment, ingeneral. The field research in this 

APG will complement results of the laboratory-based studies being conducted for the previous 

APG. Collectively, data from these two APGs will provide us with much needed information for 

between-chemical and between-species extrapolations. 

Schedule: Research in this area will have broader impact on ecological risk assessments than just 

for EDCs. There are ongoing efforts within the intramural program to address this APG such as 

studying the effects of retinoids in amphibians and effects of EDCS in South Florida wildlife 

populations. This research is complemented by studies funded through the STAR program, as a 

result ofa solicitationspecifically focused onpopulation-leveleffects. The extramural research cuts 

across a varietyofspecies, such as fish, alligators, amphibians, crustaceans, birds, and a varietyof 

chemicals including PCBs, PAHs, tributyltin, and pesticides. The intramural and extramural efforts 

are scheduled for completion by FY04. 

Research Plan Subissue: EFF.5.2; also to some extent EFF.4.1 and EFF.4.2 

APG: Evaluate several classes of chemicals (e.g., triazines, phthalates, organochlorines) 

suspectedofbeing endocrine disruptors anddetermine theirpotenciesinlaboratory studies 

(FY04) 

Objective: To conduct laboratorystudies on several agreed upon classes of chemicals suspected 

of being endocrine disruptors. 

Significance/Impact: To be able to definitely understand the mechanisms of action, potencies, 

dose-response relationships of several agreed upon classes of suspected EDCs. The research 

addressing this APGisthe laboratorycomponent ofthe complementaryfield studiesinthe following 

APG and will help elucidate understanding potential impacts on human health. Collectively, data 

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ORD Multi-Year Plan for Endocrine Disruptors 

from these two APGs will provide us with much needed information for between-chemical and 

between-species extrapolations. 

Schedule: Efforts are underway through our intramural and STAR programs to conduct studies 

inlaboratoryanimals ona number of environmental agents suspected of endocrine disruption, e.g., 

phytoestrogens, certain PHAHs, triazines,methoxychlor, dioxins, PCBs. This APGis expected to 

be addressed in FY04. 

Research Plan Subissue : Related to EFF.3.1, EFF.3.4, EFF.3.5 

APG: Determine the critical biological factors during development resulting in toxicities 

occurring later in life (FY06) 

See description under LTG 1. 

APG: Determine the extent to which exposure to EDCs contribute to the onset or increase 

in the severity of diseases (FY07) 

Objective: 1) To determine the extent to which exposure to EDCs contribute to the onset or 

increase in the severity ofdiseases and 2) to develop adequate, validated animalmodels that would 

enhance the ability to assess the potential of EDCs to produce disease in human populations. 

Significance/Impact: 1) The extent to which EDCs induce or influence the emergence of 

endocrine-related disorderssuchas endometriosis, prostate and testicular cancers, functionalmale 

and female reproductive disorders, and other diseases such as those of the cardiovascular, 

immunological, or neurological systems yet to be determined. 2) Once developed, the animal 

models will be valuable to test hypotheses that low, environmentally relevant doses of EDCs can 

induce similar conditions inhumans. Many of the issues surrounding EDCs center on the possibility 

that these chemicals can lead to or predispose the organism to various disease states. Diseases 

associated withthe endocrine systemimpactmillions of Americans and their impact on the economy 

is in the billions of dollars annually. By appropriately examining specific hypotheses raised in this 

researcharea and developing better models, informationconcerning the extent to whichEDCs can 

induce or modify disease conditions will be provided. 

Schedule: One ofthe biggest unanswered questions related to EDCsis whethertheyare impacting 

human health. The development of animal models to test hypotheses could help us address that 

question. There are a few limited ongoing efforts in this area within our intramural program. Since 

this area has been identified by NHEERL as a key focus area it is anticipated that more research 

will be conducted in the future. Given the current limited efforts and the complexity of the issue, 

significant impacts in this area are not anticipated until FY07. 

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ORD Multi-Year Plan for Endocrine Disruptors 

Research Plan Subissue: EFF.3.3 

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ORD Multi-Year Plan for Endocrine Disruptors 

APG: Determine whether adverse developmental/reproductive effects are occurring in 

human populations following exposures to EDCs (FY08) 

Objective: To determine the extent to whichhumandevelopment/reproductionis being adversely 

affected by exposure to EDCs 

Significance/Impact: To address one of the biggest unanswered questions related to EDCs, that 

is, whether humans are being adversely impacted by exposure to EDCs. Given that development 

and reproduction appear to be highly sensitive endpoints in laboratory animal and wildlife studies 

and that there are reported alterations in particular endpoints (e.g., hypospadias, cryptorchidism, 

sperm quality), if any adverse effects are to be found, then evaluating these endpoints in humans 

appears to be logical. 

Schedule: One ofthe biggest unanswered questions related to EDCsis whethertheyare impacting 

human health. Work under this area is, by nature, exclusively through the STAR program. 

Currently there are six studies that are aligned with this APG , five of which are the result of an 

FY00 joint solicitation with NIOSH/CDC, NIEHS, and NCI The epidemiology studies are 

examining the effects of exposures of a variety of environmental contaminants on a variety of 

endpoints. Specifically they are evaluating the effects of: 1) PBBs on puberty in girls, 2) heptachlor 

onreproductionand immune function, 3) phthalates on breast and genitalia development, 4) dioxin 

onmale reproductive development, 5) organochlorines and PCBs onendometriosis,and 6) PBDEs 

on thyroid function. The other federal partners are funding an additional total of seven studies as 

a result ofthe joint RFA. This group of 12 grants from the same solicitation will be followed closely. 

Givenlengthoftime to conduct studies in human populations,significant impactsinthis area are not 

anticipated until at least FY08. 

Research Plan Subissue: LNK.2.3; LNK.2.4 

APG: Determine sources of exposure and environmental fates of EDCs (FY08) 

Objective: To determine the extent ofenvironmentaland humanexposuresto EDCs, characterize 

the sources and factors influencing these exposures, and develop and evaluate risk management 

strategies to reduce exposures. 

Significance/Impact: It is important to understand the extent of EDC exposures and the factors 

influencing the source-to-exposure-to-dose relationships in order to develop effective risk 

management strategies. Gaining improved understanding regarding the fate and transport processes, 

the interactions of EDCs fromthe source to the receptor, and collecting high quality exposure data 

for the development of multimedia, multi-pathway models are critical for ecological and human 

health risk assessments. Application of newly-developed biological indicators of exposure to the 

study of components of mixtures offers the potential to validate and refine these models. 

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ORD Multi-Year Plan for Endocrine Disruptors 

Schedule: Efforts are already underway through our intramural program to identify key sources 

of EDCs and characterize the extent of EDC exposures. Emphasis is being placed initially on: 1) 

contaminated sediments, 2) sources of combustion, 3) consolidated animal feeding operations 

(CAFOs), 4) waste water treatment plants, 5) drinking water treatment plants, and 6) pesticide 

applications. Biologicaland chemicalindicators of exposure, developed under Long Term Goal 1, 

are being applied to field studiesto characterize the spatialand temporalvatioationassociated with 

these issue-related exposure scenarios. Characterization of children’s exposures to EDCs is also 

being emphasized. Intramural research on studying transport, transformation, and fate of EDCs in 

environmental media is also underway. A series of multimedia, multi-pathway models are being 

developed, evaluated and refined to investigate the physical, chemical and metabolic processes 

associated with environmental exposures (e.g., sorption/desorption processes) and human 

exposures (e.g., source-to-exposure-to-effects modules). Risk management strategies will be 

developed and evaluated for specific sources of EDC exposures. The results of the exposure, 

effects, and risk management researchwillbe fullyintegrated. Research related to this APG will be 

completed in FY08. It may be necessary to periodically review data as the knowledge base 

increases to ensure that all state of the art information on the major sources are considered in the 

risk management research program. 

Research Plan Subissue: LNK.4.1; EXP.2.1 

LTG 3: SUPPORT EPA’S SCREENING AND TESTING PROGRAM 

The products of the research conducted under this LTG will result in the evaluation of current testing 

protocols and the development of new ones to evaluate the potential endocrine effects of environmental 

agents. This research is criticalto OPPTS and OW in their meeting the Congressional mandates in FQPA 

and SDWAA for development of a screening and testing program. Development of protocols will also be 

of value to other federal agencies, agencies in other countries, and international organizations, such as the 

OECD under which protocol development forindustrialcountries are harmonized. Furthermore, research 

under this LTG will result in the development of improved methods for risk assessment that will also be of 

particular value to OPPTS and OW, as well as to other EPA program and regional offices, other federal 

agencies, agencies in other countries and the scientific community at large. 

APG: Evaluate existing testing guidelines for their adequacy to evaluate endocrine 

mediated effects (FY01) 

Objective: To determine whether testing guidelines already in place are adequate to evaluate 

chemicals for their potential to induce endocrine effects. 

Significance/Impact: To support the legislative mandates of the Food Quality Protection Act 

(FQPA) and the Safe Drinking Water Act Amendments (SDWA) of 1996 that require EPA to 

develop and implement a screening and testing program for endocrine disruptors. Before 

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ORD Multi-Year Plan for Endocrine Disruptors 

developing new methods for evaluating the potential of chemicals to disrupt the endocrine system 

it is important to evaluate the existing methods for their adequacy. Based on this assessment, either 

additional parameters maybe added to the existing protocols to better assess the potential activity 

of chemicals or, as noted in APGs below, new methods will need to be developed. 

Schedule: Many ofthe existing protocols, (e.g., for developmentaltoxicity, reproductive toxicity, 

developmental neurotoxicity, neurotoxicity), have recently undergone a harmonization effort within 

the Agencyand withthe OrganizationforEconomicCooperationandDevelopment(OECD). Since 

the enactment of FQPA, ORD’s scientists have been evaluating the existing protocols for human 

health and wildlife and determiningwhat, ifany additionalparameters, could improve their ability to 

detect potential endocrine disruptors. Since this effort has been ongoing for several years, it is 

anticipated that this APG will be addressed in FY01. 

Research Plan Subissue: EFF.2.1; EFF.5.1 

APG: Develop standardized protocols for screening chemicals for their potential endocrine 

mediated effects to meet FQPA requirements (FY06) 

Objectives: To develop short-term methods to screen for EDCs with specific modes of action 

(MOAs) and to develop quantitative structure activity relationship (QSARs) models to serve as 

screening/priority setting tools. 

Significance/Impact: To support the legislative mandates of the Food Quality Protection Act 

(FQPA) and the Safe Drinking Water Act Amendments (SDWA) of 1996 that require EPA to 

develop and implement a screening and testing programfor endocrine disruptors. This research is 

addressingthe recommendations made byanadvisorypanel(EDSTAC, 1998) convenedfollowing 

the enactment of the legislation regarding the need for several short-term in vivo and in vitro 

mammalianand several in vivo non-mammalianassays as part ofa Tier 1 or screening battery. The 

researchleading to the development of protocols is critical to the success of the Agencyinfulfilling 

its Congressional mandates to develop and implement a screening and testing program. After the 

development, standardization and validation, these screening and testing protocols willbe used not 

only by the USEPA to require the testing of chemicals, but also internationally through the OECD’s 

test guidelines program and possibly by other regulatory agencies. The process to develop and 

implement screening and testing program has a high profile and the products will be closely 

scrutinized by the US Congress, stakeholders, and the scientific community within the US and 

internationally. 

Schedule: Because of the timetables of the Congressional mandates, the research for this APG has 

been (since 1997) and will continue to be of highest priority until achieved in FY03. There is a 

significant amount ofresearchongoing intramurally to addressthis APG - studies aimed atfinalizing 

the development of in vitro methods, in vivo studies, and QSAR approaches. Furthermore, 

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NHEERL’s implementation plan identified this as a focus area, and, therefore, even greater effort 

is anticipated shortly. In addition, there are a number of projects through STAR (from early 

solicitations) that are resulting in the development of potential screens for EDCs. 

Research Plan Subissue: EFF.1.1; EFF2.1; EFF.5.1 

APG: Identify key risk assessment issues and develop guidance for assessing endocrine 

disruptors (FY06) 

See description under LTG 1. 

APG: Develop standardized protocols for testing chemicals for their potential endocrine 

mediated effects to meet FQPA requirements (FY08) 

Objectives:To develop Tier 2 levelmethodsto test chemicals fortheir potentialto elicit endocrinemediated effects. 

Significance/Impact: To support the legislative mandates of the Food Quality Protection Act 

(FQPA) and the Safe Drinking Water Act Amendments (SDWA) of 1996 that require EPA to 

develop and implement a screening and testing program for endocrine disruptors. This research is 

addressing the recommendations made by EDSTAC (1998) regarding the need for Tier 2 tests in 

a variety of species, i.e., mammalian, avian, fish, amphibian, and invertebrates. (See APG 

immediately above for additional information on Significance/Impact.) 

Schedule: Because of the timetables of the Congressional mandates, the research for this APG has 

been (since 1997) and will continue to be of highest priority until achieved in FY05. Research is 

ongoing intramurally to develop improved Tier 2 assays in fish, amphibians, and mammals. 

Furthermore, NHEERL’s implementation plan identified this as a focus area, and, therefore, even 

greater effort is anticipated shortly. 

Research Plan Subissue: EFF2.1; EFF.5.1 

APG: Computational Toxicology Program: Provide at least one computational model for 

assessing endocrine disruptor compounds. 

See description under LTG 1. 

What the MYP says about the EDCs research program at a glance 

There are a total of 21 unique APGs identified in the EDCs MYP. The APGsforthe programare 

arrayed across a twelve year period starting with FY01 and ending with FY12. The first three years have 

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ORD Multi-Year Plan for Endocrine Disruptors 

only a single APG each. There are three APGsscheduled for completioninFY04, FY06, and FY07 each. 

At present there are 5 APGs slated for completion in FY08, 2 APGs in FY09, and one in FY12. The 

APMs are aligned by year and by Laboratory/Center starting in FY00 and ending inFY12. Those APMs 

listed in FY00-02 are ones that have been successfully completed. The majorityofthe APMs are aligned 

through FY06 withjust a few scattered ones in later years. It is envisioned, as this process progresses and 

the MYP is updated, that the later years willdepict increasing numbers of APMs as has occurred witheach 

of the annualrevisions that hastakenplace since FY00. The majority of the current and projected EDCs 

research program is concentrated in two areas: effects and risk management. 

The effects related research is being conducted for both human health and wildlife and is ongoing 

intramurally within NHEERL and extramurally through the STAR program. The emphasis on the intramural 

effects program is more related to human health and for the STAR program there is a balance between 

human health and wildlife grants. Both the intramural and STAR programs effects-related research are 

addressing all three Long-Term Goals and their associated APGs. The complementary research in these 

programs will go a long way to helping us make a significant impact in the critical areas under which these 

programs are aligned. These programs have been ongoing for a number ofyears, and, therefore, achieved 

a number of Milestones in FY00 that merited inclusion when the MYP was first developed. Because the 

effects issues are many and are so complex, research to address a number ofthe LTGs willbe ongoing for 

quite a few years, at least through FY12. 

The risk management research program is an intramural program with NRMRL which has been 

phasing in for the last few years. One APM was achieved in FY00 and FY01 and two in FY02. After 

that, on an annual basis, there are increasing numbers of APMs that will be achieved across a number of 

APGsthat address LTGs 1 and 2 and specifically areas associated withsources of exposure and managing 

unreasonable risks. Several sources of EDCs have been identified on which to focus the near term research: 

contaminated sediments,sources of combustion, CAFOs, waste water treatment plants, and drinkingwater 

plants. As research progresses toward identifying and perhaps developing methods to mitigate exposures 

from these sources, new sources will be identified and, thus, the program will be continually maintained 

through at least FY09. Among the federal agencies participating in the CENR working group, EPA stands 

virtually alone in the area of risk management research. 

EPA must demonstrate a strong leadership role in designing and conducting relevant exposure 

research for the foreseeable future. EDC exposure research appears as a high priority data gap on every 

notable organization’s list. High quality, real world exposure data and corresponding exposure factors are 

deemed critical for the Agency’s risk assessments. Prior to FY03, NERL’s EDC exposure research 

program focused on: 1) developing field exposure methods, 2) the collection of exposure data and critical 

exposure factors associated with children’s exposures to EDCs, and 3) the development of multimedia, 

multi-pathwaymodels to assess ecologicaland human exposures. Some APMs associated withthis earlier 

exposure researchwere completed in FY00-02, withmore being completed inFY03 and beyond. NERL, 

working collaboratively withthe other ORD laboratories and centers, hasredefined its current programand 

designed an integrated EDC exposure research program to efficiently and effectively employ the limited 

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ORD Multi-Year Plan for Endocrine Disruptors 

EDC resources to address the highest priority science issues. The NERL program leverages on other 

ORD laboratory/center EDC researchprograms, planned FederalAgency-sponsoredprograms containing 

EDC research components (e.g., National Children’s Study, NHANES), and on relevant exposure 

research activities outlined in MYPs for Safe Food, Safe Communities, Human Health Risk Assessment, 

and Ecosystem Protection. A strong NERL and NCER relationship will be established to successfully 

employthe extramural STAR grant program to address critical exposure-related data gaps that cannot be 

addressed solely with the intramural resources. 

There is an extremely limited effort underway in the area of risk assessment guidance, guidelines, 

and methods development. Greater emphasis needs to be placed in this area in order to have the tools 

necessary to be able to integrate effects and exposure data related to human health and the environment. 

As our intramuraland extramuralprograms are generating results and data startcomingintothe Agencyfrom 

the screening and testing program, we need to be able to have methods available to integrate the findings. 

Further, the efforts needed inthe areaofEDCsare onesthat willhave farreaching effects beyond just EDCs 

in terms of how the Agency conducts risk assessments for human health and wildlife. EPA has shown 

leadership for almost 20 years in the development of risk assessment guidance and here they have the 

capability to push the science even further. 

VI. GUIDANCE FOR IMPLEMENTATION OF MULTI-YEAR PLAN 

Because of the breadth of uncertainties associated withthe endocrine-disruption hypothesis, effective 

implementation of this multi-year plan requires extensive coordination and communication among the 

research managers in ORD, and continued involvement of an ORD Multi-Year Planning Committee, to 

ensure that the most relevant and defensible research projects are selected for funding. Several key 

components will help ensure the success of an integrated research program for endocrine disruptors that 

implements the multi-year plan: 

Intramural Coordination: 

• The individual National Laboratories and Centers, if they have not done so already, should develop 

Implementation Plans for addressing the research activities identified in the Research Plan and the 

multi-year plan. These Implementation Plans should be reviewed by the ORD Multi-Year Planning 

Committee fortheir abilityto provide a useful and integrated research output to the Program/Regional 

Offices. 

• For the intramural research, it is presumed that investigator-initiated responses to internal (either ona 

laboratory or center basis or across ORD) requests for applications (RFAs) that are derived from the 

Research Plan, the Multi-Year Plan, and individual laboratory/center Implementation Plans, will 

provide the basis forthe coordinated ORD researcheffort inendocrine disruption. The process should 

be similar and parallel to that already being used for the last 7 years in the STAR program. 

• Coordination within the intramural program is especially important for research that transcends 

branches, divisions, laboratories, or centers. For example, combined field and lab and effect and 

exposure projects should require close collaboration among nearly every component of ORD. 

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ORD Multi-Year Plan for Endocrine Disruptors 

• Annualreports ofprogress and updating ofthe multi-year planby each Laboratoryand Center, under 

the auspices of the multi-year planning committee, will facilitate the exchange of information within 

ORD, assist in the directionofwork to the highest priorityareas, help fine-tune the research directions 

as new information from the program emerges, and importantly, communicate with EPA’s 

Program/RegionalOffices onprogressinunderstanding the nature and extent ofthe EDC problemand 

solutions to address them. 

Intramural and Extramural Coordination 

• Recognizing that integration ofthe intramuralresearchprogramwith the extramural grants is crucial to 

effective resource utilization, intramural and extramural RFAs should be targeted to achieve both the 

breadth and depth ofbalance needed to addressthe problems. The multi-year plan and the Research 

Plan have identified those areas which are most amenable to being conducted either within our own 

laboratories/center or through the STAR program. 

• From the submissions in response to intramuraland extramuralRFAs, projectsshould be selected for 

funding on the basis of both scientific excellence and programmatic relevancy using criteria identified 

in the Research Plan. 

• Results from both the intramural and extramural program should be integrated and assimilated into a 

state of ORD science assessment (SOOSA), that is updated routinely. 

• Interactions between the recipients of the STAR grants and the intramural investigators involved in 

endocrine disruptor research through such mechanisms as annual or bi-annual workshops should be 

encouraged, as this would help exchange information and expand collaborations. 

VII. REFERENCES 

Ankley, GT, RD Johnson, GToth, LC Folmar, NE Detenbeck and SP Bradbury. 1997. Development of 

a Research Strategy for Assessing the Ecological Risk of Endocrine Disruptors. Reviews in Toxicology 

1:71-106. 

Chemical Manufacturers Association. 1999. Endocrine Issues Research Summary. 

CRS Report for Congress. Summaries of Environmental Laws Administered by the Environmental 

Protection Agency. M.R. Lee, Coordinator. Congressional Research Service. The Library of Congress. 

January 3, 1995. 

EDSTAC. 1998. Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) Final 

Report. 

Joint Research Centre European Commission, National Institute of Environmental Health Science, 

EnvironmentalProtectionAgency. 1999. Expert Panel Meeting on Opportunities for Collaborative EU/US 

Research Programmes on Endocrine Disrupting Chemicals. 

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ORD Multi-Year Plan for Endocrine Disruptors 

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

C Maczka, R Miller, J Moore, R Rolland, G Scott, DM Sheehan, T Sinks, and HA Tilson. 1996. 

Research Needs for the Risk Assessment of Health and EnvironmentalEffects ofEndocrine Disruptors: A 

Report of the U.S. EPA Sponsored Workshop. Environmental Health Perspectives 104 (Supplement 

4):715-740. 

National Research Council. 1999. Hormonally Active Agents in the Environment. National Academy 

Press: Washington, DC. 

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

1998. The U.S. Federal Framework for Research on Endocrine Disruptors and an Analysis of Research 

Programs Supported during Fiscal Year 1996. Environmental Health Perspectives 106(3):105-113. 

USEPA. 1996. Strategic Plan for the Office of Research and Development. Washington, DC, EPA/600R96-059. 

USEPA. 1997. 1997 Update to ORD’s Strategic Plan. Washington, DC, EPA/600/R-97/015. 

USEPA. 1998. Research Plan for Endocrine Disruptors. Office of Research and Development. 

Washington, DC. EPA/600/R-98/087. 

WHO. 2002. Global Assessment of the State-of-the-Science of Endocrine Disruptors. Damstra, T, 

Barlow, S, Bergman, A, Kavlock, R, Van Der Kraak, G (eds.). 

VIII. ACRONYMS 

ACC American Chemistry Council

APG Annual Performance Goal

APM Annual Performance Measure

ATSDR Agency for Toxic Substances and Disease Registry

CAFO Confined Animal Feeding Operation

CDC Centers for Disease Control and Prevention

CENR Committee on Environment and Natural Resources

CT Computational Toxicology

DDT Dichlorodiphenyltrichloroethane

DES Diethylstilbestrol

DOD Department of Defense

DOE Department of Energy

DOI Department of Interior

EDCs Endocrine Disrupting Chemicals

EDSTAC Endocrine Disruptors Screening and Testing Advisory Committee

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ORD Multi-Year Plan for Endocrine Disruptors 

EPA Environmental Protection Agency

EU European Union

FDA Food and Drug Administration

FQPA Food Quality Protection Act

G-8 Governments of the 8 leading nations

GEDRIGlobal Endocrine Disruptors Research Inventory

GPRA Government Performance and Results Act

IPCS International Programme on Chemical Substances

JRC Joint Research Centre

LTG Long-Term Goal

MOA Mechanism/mode of Action

MYP Multi-Year Plan

NCEA National Center for Environmental Assessment

NCER National Center for Environmental Research

NCI National Cancer Institute

NERL National Exposure Research Laboratory

NHEERL National Health and Environmental Effects Research Laboratory

NIEHS National Institute of Environmental Health Sciences

NIOSH National Institute for Occupational Safety and Health

NOAA National Oceanographic and Atmospheric Agency

NRC National Research Council

NRMRL National Risk Management Research Laboratory

NSF National Science Foundation

NSTC National Science and Technology Council

OECD Organization for Economic Cooperation and Development

ORD Office of Research and Development

OSTP Office of Science and Technology Policy

PAH Polyaromatic Hydrocarbon

PBTK Physiologically Based Toxicokinetic

PCBs Polychlorinated Biphenyls

PCDFs Polychlorinated Dibenzofurans

PHAH Polyhalogenated Aromatic Hydrocarbon

QSAR Quantitative Structure Activity Relationship

RFA Request for Applications

RM Risk Management

RME Risk Management Evaluation

SDWAA Safe Drinking Water Act Amendments 

SOOSA State of ORD Science Assessment

STAR Science to Achieve Results

S&T Screening and Testing

TEF Toxicity Equivalent Factor

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ORD Multi-Year Plan for Endocrine Disruptors 

USDA US Department of Agriculture 

WHO World Health Organization 

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ORD Multi-Year Plan for Endocrine Disruptors 

APPENDIX

POTENTIAL ADDITIONAL RESEARCH

In the event that additional resources become available, the EDC research program would be 

expanded to pursue additional lines of research or accelerate the conduct of research already captured in 

the 2000-2012 timeframe. This new or accelerated research addresses the 10 critical questions identified 

in the Research Strategy and falls within existing APGs aligned within LTGs 1 and 2. 

In the background section different methods, tools, and approaches are identified that would move the 

EDCsprograma lotmore forward should additionalresources become available. These are not prioritized 

here but can be, based upon the amount of additional funds that may become available and the progress 

made in the current program. The new or accelerated areas are aligned under the APG(s) that would most 

benefit from this research. In the application section that follows, a specific case study is identified where 

we propose application of the methods, tools, and approaches to work in an integrated crossLaboratory/Center manner to work on a real-world situation. 

BACKGROUND 

APGs - Provide at least one computational model for assessing endocrine disruptor compounds; 

Determine degree to which effects of EDCs with defined mechanisms/modes of action can be 

extrapolated across classes of vertebrates 

Progress in the ability to sequence the human genome has led to a rapid development of laboratory 

methodsto profile the expression ofmRNAs and proteins. cDNAmicroarrayand proteomicstechnologies 

that assess gene expression on a genome-wide basis may provide a “global” perspective about how an 

organism responds to specific stressors, such as exposure to endocrine disruptors. This information can 

define cellular networks or response genes, identify target molecules or toxicity, provide future biomarkers 

and alternative test procedures, and identifyindividualswithincreased susceptibilityto endocrine disruptors. 

Measuring specific changesingene expression in humans and other species that are exposed to endocrine 

disruptors could leadto a “signature”for a givenpathwayoftoxicity. Comparisonof effectsfromanimaland 

human assays will permit a direct assessment of interspecies extrapolation. This is important because there 

is significant uncertainty about how to extrapolate data from many current in vitro assays and rodent 

bioassays to humans. 

The overall approach of this research program will be to develop microarray technologies to assess 

changes in expression ofgenesfor highprioritytargetsitessuchas the estrogenor androgenreceptors. This 

effort represents and is consistent with a part of the new Computational Toxicology research program as 

it relates to endocrine disruptors. Specific changes in gene expression in humans and other species exposed 

to endocrine disruptor and other environmental chemicals will be evaluated to identify patterns of changes 

for a given pathway associated with endocrine disruption. Once these patterns of change have been 

identified, more focused arrays will be developed to assess the potential toxicity of chemicals in a rapid, 

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prospective manner. This research could result in better interspecies extrapolation, greater confidence in 

animalmodels, a reductioninthe number of animals needed fortesting, and insightsinto pathways oftoxicity 

and mechanisms of endocrine disruption. Results fromthese studies could also lead to the development of 

new tools for human exposure assessment. Using patterns of changes from genomic or proteomic studies 

could help identify the agent and dose to which individuals or populations have been exposed. Surveillance 

programs could result for humans and animals where exposure to and/or contamination by endocrine 

disruptors are suspected. 

Collaboration between intramural and extramural research scientists will be given a high priority. 

Workshops involving ORD and extramural scientists will be needed to develop principles for the selection 

of appropriate endpoints to be included in microarrays. Basic research on microarray technology and 

approaches to the statistical analysis of patterns of changes observed ingenomic and proteomic studies will 

be supported intramurally, as well as by grants through the STAR program. Workshops involving ORD 

scientists and regionaland programofficescientists willalso be needed to explore approaches and principles 

for the use of genomic and proteomic data in a risk assessment context. 

APGs - Characterize sources of exposure and environmental fates of EDCs; Evaluate exposure 

methods,measurement protocols,and models for the assessment of riskmanagement efficacy on 

EDCs 

There are limited quality data describing real world ecological or human EDC exposures and/or the 

key factors associated with these EDCs. All the research that has been done up to this point has been on 

the chemistryof selected EDCs. Biologicalactivityhas never beenadequately tracked except insome very 

focused source-biased studies. The relationships among chemicals and mixtures and their bioavailability is 

a complete unknown. As a result of these shortfalls, risk assessors resort to using default assumptions 

and/or mathematical outputs from exposure models that have not beenevaluated withreal world exposure 

data todevelopriskassessments and implement risk management strategies. Equally important, the majority 

ofthe contemporaryEDC exposure researchhas beenfocused onaddressing eitherthe ecologicalorhuman 

exposure methodologies and science issues, with few studies looking at the integrated ecologicalto human 

EDC exposure issue. However, the real world fate and transport of EDCs through the environment 

ultimately impacts human exposures to EDCs. Similarly, many human activities result in increased EDC 

exposures to the environment. 

With additional resources, NERL plans initially to conduct a workshop to identify the key EDC 

exposure issues (including major routes, exposure factors, exposure to dose relationships, etc.) and then 

develop anintegrated ecologicaland human exposure research study design to addressthe most important 

issues. Nationally and internationally recognized EDC exposure experts will be invited to attend this 

workshop. ORD will take the workshop input and develop a draft integrated eco/human exposure study 

design and conduct a small scale exposure study to characterize the extent of EDC key factors influencing 

ecological and human exposures to EDCs. The initial tests of the study design will attempt to address the 

highest priority issues and hypotheses, based on available resources and opportunities to collaborate with 

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ORD Multi-Year Plan for Endocrine Disruptors 

other EPA and federal agency programs. The results of this study will be used to upgrade the integrated 

exposure study design in preparation for pilot testing. 

The results ofthis additionalresearchwillprovide the scientific community key data characterizing the 

extent ofEDC exposures and the relationship betweenecologicalexposuresand humanexposurestoEDCs. 

APG - Identify key risk assessment issues and develop guidance for assessing endocrine 

disruptors 

The MYP for EDCs must, in its final measurement, be able to provide for proper evaluation of EDC 

risks. Developing guidance for EDC risk assessment is identified as high priority by program and regional 

offices to support their risk management decisions. The goal of this project area for FY06 is development 

of a framework to improve integration of human and ecological information on EDCs into Agency risk 

assessments. Thissupportsthe ORD MYP whichcalls for case studies that integrate health and ecological 

exposures and effects, followed by a framework for risk assessment, and finally a guidance document. 

Assessment research must consider the major scientific uncertainties in the potential health and 

environmental effects of EDC through understanding of results from multiple in vitro and in vivo assay 

systems, and new scientific approaches (e.g., genomics), on multiple hormone systems in multiple species. 

Information and results from effects, exposure, and risk management intramural and extramural programs 

will feed into this research area. 

Current ongoing researchisfocused onidentificationofissues criticalto EDC risk assessment, and on 

developing case studies which consider integration of human health and ecological data in hazard and risk 

assessment. The case study projects (FY01, 02) focus on key EDCs as examples to explore incorporation 

of EDC-related testing data into hazard and risk assessment. This provides background for development 

of anassessment framework to improve integration of human health and ecological assessment. However, 

current funding and staffing is inadequate to provide a concentrated focus to address the increased data and 

research on EDCs. This has limited activity to two case studies and basic evaluation of risk assessment 

decisionpointsimportant to EDCs. A proposal for evaluation of biomarkers common to environmental and 

human species was delayed to FY04 to utilize information from grants (NCER), since there was too little 

funding to initiate work internally. While much of the development work for the framework will be done 

withinORD due to potentialpolicyimplications,fundingforintra- and extramuralscientific consultations and 

collaboration, including workshops and peer reviews, will be necessary to assure proper development and 

acceptance of Agency assessment approaches. Additional resources will allow development work on the 

framework to start earlier and improve our ability to meet APG/APM deadlines in this project area. 

Successful completion of the Agency’s activities under this GPRA objective will provide the Agency 

with a consistent approach which supports domestic and international EDC risk assessment activities and 

supportseffective prioritizationofenvironmentalexposuredeterminations and risk management researchand 

solutions. 

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ORD Multi-Year Plan for Endocrine Disruptors 

APGs - Evaluate at least three existing risk management tools to reduce exposure to EDCs; 

Develop at least two newrisk management tools to reduce exposure to EDCs; Evaluate exposure 

methods,measurement protocols,and models for the assessment or riskmanagement efficacy on 

EDCs 

New risk management research will provide a greater understanding of sources of EDCs and our 

ability to remove EDCs from various environmental media. Specifically, new researchwillallow a greater 

understanding ofwastewater treatment ofEDCs, the fate ofEDCsinsediments, the efficacyof conventional 

and innovative drinking water treatment processes to remove EDCs, and the development of tools for 

pollution prevention. 

First, ongoing researchonunderstanding the fate ofEDCsin conventional municipal sewage treatment 

plants willbe expanded to investigate other commonsewage treatment plant designs. Specifically, the ability 

of septic systems and constructed wetlands to treat EDCs (e.g., alkylphenolic compounds and steroid 

hormones) will be studied. Approximately 30% of U.S. households use some form of on-site sewage 

treatment such as septic systems. Also, as urban sprawl continues, suburban communities are increasingly 

employing decentralized (small-community) wastewater treatment systems such as constructed wetlands. 

The ability of septic systems and constructed wetland to treat EDCs is virtually unknown. This work will 

gatherinformationonthe treatabilityof EDCs by these common waste treatment systems and develop new 

tools to enhance these treatment as needed. 

Second, work will commence to evaluate the ability of conventional and innovative drinking water 

treatment processestoremoveEDCsfromsource water. Certain EDCs such as alkylphenolic compounds, 

steroid hormones, and bisphenolA have been observed in surface water. In addition, there are preliminary 

observations of these compounds in finished drinking water. The ability of treatment systems to remove 

these compounds is virtually unknown. This work will evaluate the ability of conventional treatment 

processessuchasfiltration, coagulation and sedimentation, to remove EDCs. Conventional treatment can 

be amendedwithvarious innovative processes suchasgranularactivatedcarbonandmembrane separations. 

This newwork willalso determine the efficacy of removing EDCs with these innovative treatment systems. 

Third, new work will determine if natural processes in EDC-contaminated sediments can control 

exposure of aquatic wildlife to EDCs. Hydrophobic EDCs that exit sewage treatment plants such as 

alkylphenolic compounds will partition to aquatic sediments. This new work will evaluate the natural ability 

ofbiologicaland chemicalprocesses in sediments to transform EDCs into innocuous products. Sediments 

that cannot remove EDCs will accumulate these chemicals causing long-term exposure to aquatic wildlife. 

This work will generate a portion of the information needed to manage the risk of EDCs associated with 

sewage treatment systems bydeveloping anunderstanding ofthe abilityofnaturalprocessestomangeEDCs 

released into the environment. 

Fourth, pollution prevention (P2) approaches will be developed in this new work. Many known or 

likely EDCscontinue to be produced and used inindustrialproducts. For example, alkylphenol ethoxylates 

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ORD Multi-Year Plan for Endocrine Disruptors 

continue to be used as domestic and industrialdetergent, phthalate esters continue to beused as plasticizers, 

and bisphenol A continues to be a building block in certain plastics. This new work will involve two 

components: (1) the adaptation of existing P2 software that will identify substitutes for EDCs that possess 

the desired chemical properties, and (2) development of an advanced quantitative structural activity 

relationship (QSARs)that willevaluate the endocrine activityofthe proposed chemicalsubstitute. The new 

work will be applied initially to searching for substitutes for phthalates that are not estrogenic. 

The completion of this new work will deliver important risk management information to key 

environmental stakeholders. The Office of Water, state and local environmental agencies, and the public 

will use the results of this work to develop risk management strategies for EDCs associated with sewage 

treatment and drinking water sources The P2 work willprovide the Agency and interested industries tools 

to propose or develop substitute chemicals for EDCs that are currently produced. 

As noted previously, in the section that follows, a specific case study is identified where we propose 

application of the methods, tools, and approaches identified in the Background section to work in an 

integrated cross-Laboratory/Center manner on a real-world situation. Depending on the amount of 

additional resources that may become available, a decision will be made to either propose one or more of 

the areas identified above or the following integrated case study, where every ORD laboratory/center has 

a role on a single environmental problem. 

APPLICATION: CASE STUDYIntegrated Concentrated Animal Feeding Operations (CAFOs) Project: Associated Impacts on 

Human and Wildlife Populations and Risk Management Options 

The Office of Water is attempting to control nutrient, sediment, and chemical run-off from concentrated 

animal feeding operations (CAFOs) through NPDES permits and Effluent LimitationGuidelines. CAFOs 

and the production of large volumes of animal waste are major environmental concerns facing every EPA 

Region. Stressors of increasing concern include veterinary synthetic estrogens and androgenic steroids 

associated withanimalproductionas well as naturalhormones. Natural estrogenic and androgenic steroids 

and their excretionproducts are found inanimalurine. Studies in Europe have shown that natural estrogenic 

substances, such as estradiol, when released to waterways may cause adverse effects on aquatic species. 

Also synthetic steroids, such as the synthetic androgen trenbolone, are widely used in animal feed 

operations inthe US. Based on studies published by European researchers, this synthetic steroid, and its 

metabolites, are persistent in the environment. NHEERL studies established that trenbolone is a potent in 

vivo reproductive toxicant in fathead minnows, and in vitro mammalian and fish cell line studies have also 

confirmed it acts as an androgen receptor agonist. Preliminary, unpublished field studies conducted bythe 

USFWS in the mid-west suggest an association between cattle feedlots that employ trenbolone and 

alterations in the condition of naturally occurring fathead minnow populations 

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ORD Multi-Year Plan for Endocrine Disruptors 

The impact ofthese stressors on surface waters, groundwater, sediment, aquatic ecosystems, wildlife, and 

humans is largely unknown. In addition, there is limited information available on the reduction in risk that 

will result from the changes in animal waste management described in the revisions to CAFO regulations. 

While other Federal Agencies are also working on this issue, the fact that this is a high profile regulatory 

issue for EPAdictatesthat EPAshould be providing leadership in this area. Other Agencies withwhomwe 

are already cooperating with or planning to cooperate with on CAFOs include USDA, USGS, FDA, and 

CDC. The convergence of a high profile regulatory program with a multi-disciplinary scientific challenge 

establishes an excellent case study to demonstrate ORD’s ability to integrate its capabilities across the 

Laboratories/Centers and engage scientistsfromthe programand regionaloffices, other FederalAgencies, 

and academia to work collaboratively to solve a significant Agency concern. 

This proposed research program responds to a critical, emerging regulatory challenge, by: 1) establishing 

techniques to quantify and characterize the magnitude and extent of human and wildlife population effects 

and causes of impairment by multiple chemical stressors caused by CAFOs, 2) developing improved 

methods for integrated human and ecological risk assessments, 3) determining the efficacy of proposed 

CAFO waste management schemes, and 4) developing new risk management options for stressors from 

CAFOs. The integrated research would include: 

• Combining analytical chemistry and molecular science capabilities to develop biologically-based 

diagnostic techniques to establish toxicity identification, evaluation protocols, isolation of natural and 

synthetic hormones, veterinary pharmaceutical agents, and pathogens in feedlot effluent. (NHEERL, 

NERL, NRMRL, NCER) 

• Developing a draft integrated eco/human exposure study design and conducting exposure studies to 

characterize the extent of key factors influencing ecological and human exposures to nutrients, endocrine 

disrupting chemicals (EDCs), other environmental chemicals including veterinary pharmaceuticals, and 

pathogens at the localized level. Evaluating the potential for regional scale impacts with remote sensing. 

(NERL, NCER) 

• Quantifyingdose responserelationshipsfor adverse reproductive, and othertoxic effectsto refine health 

and ecological risk assessments. (NHEERL, NCEA, NCER) 

• Using these data as a practical case study supporting the development of Agency risk assessment 

guidelines EDCs which integrate human and ecological information. (NCEA) 

• Evaluating the abilityof conventional and innovative wastewater treatment processesto remove CAFO 

stressors to groundwater and surface water in order to reduce impacts to source water and offer 

management options for effluent control and pollution prevention. (NRMRL) 

• Sponsoring a solicitation for competitive grants with universities that would link the intramural and 

extramural scientists and, thus, significantly expand the scope of scientific investigations and promote 

partnerships with state and localagencies(e.g., through land grant universities and extension programs) 

charged to manage feeding operations. (NCER) 

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ORD Multi-Year Plan for Endocrine Disruptors 

TABLE 1.

LONG TERM GOAL 1. Provide a better understanding of the science underlying the 

effects, exposure, assessment and management of endocrine disruptors 

ANNUAL PERFORMANCE GOALS AND MEASURES YEAR LAB/ 

CENTER 

APG - Characterize the effects of exposure to multiple EDCs, in 

various combinations such as those with similar and different 

mechanisms of action 

2003 ORD 

APM Determination of the mechanism(s) by which developmental 

exposure to PCBs disrupts thyroid hormones to produce 

ototoxicity, characterization of the effects of exposure to 

mixtures of PHAHs and determination of whether non-AH 

receptor mechanisms underlie the neurotoxicity of some 

PHAHs 

2001 NHEERL 

APM Report on effects of early developmental exposure to 

endocrine disrupting pesticides on reproductive function in 

adults 

2002 NCER 

APM Report on lab and field analysis of mechanisms by which 

tributyltin, alone and in combination with 3 

methylcholanthrene, causes pseudohermaphroditism in marine 

gastropods 

2003 NCER 

APM 

220 

Report on the effects of mixtures of dioxin-like chemicals on 

development in the rat 

2003 NHEERL 

APG - Determine the shape of the dose-response curve in a 

variety of species exposed to ambient levels of EDCs 

2005 ORD 

APM Conduct in vitro studies to determine the dose and time 

response relationships between exposure to chlorotriazines, 

alterations in the CNS and changes in pituitary hormone 

secretion 

2000 NHEERL 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on effects of pre- and peri-natal exposures to PCBs 

on the metabolism of estrogens and androgens and on the 

ability of methoxychlor to cause reproductive toxicity at 

environmentally relevant levels of exposure 

2001 NCER 

APM Conduct in vivo studies to determine the dose and time 

response relationships between exposure to chlorotriazines, 

alterations in the CNS and changes in pituitary hormone 

secretion 

2001 NHEERL 

APM Evaluation of toxicant-induced alterations in mammalian 

reproductive development to compare dose response 

relationships, critical periods of exposure, in vivo tissue levels 

of the active toxicant and in vivo and in vitro mechanisms of 

action 

2001 NHEERL 

APM Evaluation of the effect of chlorotriazines on the ovulatory LH 

surge and their potential disruption of pregnancy 

2001 NHEERL 

APM Determine dose-responses for glucocorticoid and thyroid 

hormone disruption during chemically induced cancer in 

rodents 

2002 NHEERL 

APM Evaluate dose metrics for developmental toxicants for use in 

low dose extrapolations 

2002 NHEERL 

APM Report on analysis of effects of low, environmentally relevant 

exposure to EDCs during fetal development on prostatic 

growth at different stages of the life cycle 

2003 NCER 

APM 

220 

Report on the effects of mixtures of dioxin-like chemicals on 

development in the rat 

2003 NHEERL 

APM 

26 

Report on dose-response effects of EDCs that affect thyroid 

homeostasis as a target 

2004 NHEERL 

APM 

27 

Report on dose-response effects of EDCs acting by 

androgenic or anti-androgenic activity 

2004 NHEERL 

APM Announce RFA soliciting research to characterize exposures 

to EDCs and determine the effects of low, ambient level 

exposures to EDCs 

2004 NCER 

APM Report on the effects of chloroatrazines and metabolites on 

pubertal development in rats 

2005 NHEERL 

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ORD Multi-Year Plan for Endocrine Disruptors 

APG - Identify key risk assessment issues and develop 

guidance for assessing endocrine disruptors 

2006 ORD 

APM Complete one case study resulting in integrated human health 

and ecological assessments for selected classes of EDCs 

2001 NCEA 

APM Produce a workshop report for the EDSTAC screening 

process for EDCs and determine application of EDSTAC 

testing program for chemical hazard and risk assessment 

2001 NCEA 

APM Framework for conducting human health and ecological doseresponse assessments for classes of EDCs at environmentally 

relevant concentrations 

2004 NCEA 

APM Develop an integrated health and ecological risk assessment 

guideline for EDCs 

2006 NCEA 

APG 118 - Determine critical biological factors during 

development resulting in toxicities later in life 

2006 ORD 

APM Report on effects of pre- and peri-natal exposures to PCBs 

on the metabolism of estrogens and androgens and on the 

ability of methoxychlor to cause reproductive toxicity at 

environmentally relevant levels of exposure 

2001 NCER 

APM Report on analysis of the most sensitive developmental stages 

in birds to EDCs 

2001 NCER 

APM Determination of the mechanism(s) by which developmental 

exposure to PCBs disrupts thyroid hormones to produce 

ototoxicity, characterization of the effects of exposure to 

mixtures of PHAHs and determination of whether non-AH 

receptor mechanisms underlie the neurotoxicity of some 

PHAHs 

2001 NHEERL 

APM Evaluation of toxicant-induced alterations in mammalian 

reproductive development to compare dose response 

relationships, critical periods of exposure, in vivo tissue levels 

of the active toxicant and in vivo and in vitro mechanisms of 

action 

2001 NHEERL 

APM Determine whether GABA-A receptor activation plays a role 

in endocrine mediated developmental neurotoxicity 

2001 NHEERL 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM Evaluation of 

in rats prior to puberty on lateral prostate inflammation at 120 

days of age 

2001 NHEERL 

APM Report on analysis of the ability of phytoestrogens (at human 

intake levels) to alter the normal sexually dimorphic 

development of the brain, behavior, and neuroendocrine 

control of reproduction in rats 

2002 NCER 

the effects of increasing serum prolactin levels 

APM Report on identification of the most critical stage in the life 

cycle of quail to the effects of endocrine disruptors 

2002 NCER 

APM Report on effects of exposure to EDCs during early critical 

stages of embryonic development and the appearance of 

prostatic abnormalities in later life 

2002 NCER 

APM Report on effects of early developmental exposure to 

endocrine disrupting pesticides on reproductive function in 

adults 

2002 NCER 

APM Development of a method to assess potential health risks 

associated with exposure to EDCs which are developmental 

toxicants 

2002 NHEERL 

APM Evaluation of dose metrics for developmental toxicants for use 

in low dose extrapolation 

2002 NHEERL 

APM Evaluation of the effects of atrazine on the female 

reproductive system following lactational exposure 

2002 NHEERL 

APM Examination of the effects of developmental exposure to both 

synthetic thyroid inhibitors and environmental pollutants with 

potentially similar thyroid activity on the ontogeny of learning 

and memory in rodent models 

2002 NHEERL 

APM Report on analysis of effects of low, environmentally relevant 

exposure to EDCs during fetal development on prostatic 

growth at different stages of the life cycle 

2003 NCER 

APM Report on analysis of effects of adolescent exposure to 

methoxychlor in rhesus monkeys on subsequent reproductive, 

immunological, brain, and skeletal function during puberty 

2003 NCER 

APM Report on analysis of effects of EDCs on growth factors and 

receptors that control growth and development of the testis 

2003 NCER 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM 

118 

Report on methods to assess endocrine disruptors in pubertal 

male and female rats 

2003 NHEERL 

APM 

220 

Report on the effects of mixtures of dioxin-like chemicals on 

development in the rat 

2003 NHEERL 

APM (Further) Examination of the effects of developmental 

exposure to both synthetic thyroid inhibitors and 

environmental pollutants with potentially similar thyroid activity 

on the ontogeny of learning and memory in rodent models 

2003 NHEERL 

APM 

221 

Report on altered growth patterns in reproductive tissue in 

animals prenatally exposed to dioxin 

2003 NHEERL 

APM 

28 

Report on dose-response effects of perinatal exposure to 

EDC-active pesticides and immunocompetence 

2004 NHEERL 

APM 

29 

Evaluation of the effects of atrazine on the female 

reproductive system following prepubertal exposure 

2004 NHEERL 

APG 119 - Determine degree to which effects of EDCs with 

defined mechanisms/modes of action can be extrapolated across 

classes of vertebrates 

2007 ORD 

APM Report on the molecular mechanisms underlying estrogen 

receptor functions in ER knockout mice 

2000 NCER 

APM Report on comparative analysis in mice, fish, birds, and frogs 

of the endocrine disrupting activities of PCBs and PAHs at 

the molecular level (estrogen receptor) and at the tissue and 

organ levels 

2002 NCER 

APM Determine relevance of rodent thyroid hormone assay for 

other species, including amphibians, birds, and fish 

2002 NHEERL 

APM 

222 

Report on comparative developmental toxicology studies with 

native and non-native amphibian species exposed to EDCs 

with established mechanisms of action 

2003 NHEERL 

APM 

30 

Report on effects of EDCs on aromatase activity in multiple 

species 

2004 NHEERL 

APM 

31 

Report on molecular methods to identify androgenic and antiandrogenic effects of EDCs in multiple species 2004 NHEERL 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM 

32 

Report on structure activity relationships, in vitro, and in 

vivo models to assess reproductive effects of EDCs in small 

fish models 

2004 NHEERL 

APM Report on aquatic models to define toxicity pathways as a 

basis for extrapolation across species and biological levels of 

organization 

2006 NHEERL 

APM Report on molecular methods to characterize endocrine 

disrupting effects of environmental chemicals 

2006 NHEERL 

APG - Evaluate exposure methods, measurement protocols, and 

models for the assessment of risk management efficacy on 

EDCs 

2008 ORD 

APM 

83 

Develop a protocol for conducting an exposure analysis 

for children that includes all relevant pathways (also in 

Safe Food and Human Health MYPs) 

2004 NERL 

APM 

216 

Develop a second generation aggregate exposure model 

(SHEDS) for pesticides that characterizes uncertainty and 

variability in model inputs and outputs (also in Safe Food 

and Human Health MYPs) 

2004 NERL 

APM 

127 

Characterize the ratios of different forms of 

organophosphates and other widely used (and growing 

market share), non-persistent (i.e., more generally toxic) 

pesticides in environmental and food samples (also in 

Ecosystem Protection MYP) 

2004 NERL 

APM 

30 

Develop a prototype source-to-exposure-to-dose modeling 

framework that enables the complex computation for 

human exposure modeling (also in Safe Food and Human 

Health MYPs) 

2004 NERL 

APM 

33 

Analysis and report on factors for children’s exposure to 

pesticides that may lead to high-level, short-term 

exposure to pesticides (also in Safe Food and Human 

Health MYPs) 

2004 NERL 

APM 

37 

Initiate Follow-on children’s xxposure study to 

characterize aggregate exposures for selected pesticides, 

EDCs, and persistent pollutants (also in Safe Food and 

Human Health MYPs) 

2004 NERL 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM 

34 

Peer-reviewed design for field study to evaluate protocols 

for obtaining reliable data on children’s exposure to 

pesticides, EDCs, and other persistent pollutants (also in 

Safe Food and Human Health MYPs) 

2004 NERL 

APM 

201 

Report on application of EDC detection methods to risk 

management strategies for aquatic ecosystems 

(also in Ecosystem Protection MYP) 

2004 NERL 

APM 

271 

Report on presence of estrogenic and androgenic 

substances in effluents from concentrated animal feeding 

operations (also in Ecosystem Protection MYP) 

2004 NERL 

APM 

272 

Use of minnow vitellogenin gene expression methods for 

monitoring and detection of estrogenicity from PCB 

contamination in Lake Hartwell 

2004 NERL 

APM SOP for a bioassay of estrogenic activity adapted to risk 

management applications 

2004 NRMRL 

APM Report on analytic method to monitor natural and synthetic 

hormones associated with risk management of CAFOs 

2004 NRMRL 

APM Report on analytic method to monitor natural and synthetic 

hormones for the characterization of wastewater treatment 

plants 

2004 NRMRL 

APM Technical report - bioavailability of two or three selected 

chiral pesticides with EDC properties 

2005 NERL 

APM Development and evaluation through targeted pilot studies of 

analytical methods for alkylphenol ethoxylates with EDC 

properties 

2005 NERL 

APM Development and evaluation of DNA microarray methods for 

diagnostic characterization of select EDCs and other model 

environmental stressors 

2005 NERL 

APM Provide OPPTS, Regions and States with evaluated method 

for characterizing exposure to two or more suspect EDC 

metals 

2005 NERL 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on integrated EDC field study of EDCs from 

concentrated animal feeding operations - NERL molecular 

diagnostics and analytical chemistry - NHEERL toxicity and 

effects measurements - NRMRL risk management technology 

evaluation 

2005 NERL 

NRMRL 

NHEERL 

APM Innovative, low burden exposure research tools 

supporting the design and implementation of the National 

Children’s Study (also in Human Health MYP) 

2005 NERL 

APM Provide an updated toolbox of improved data, methods, 

algorithms, exposure factors, etc. for modeling young 

children’s aggregate exposures to pesticides and other 

key environmental contaminants (also in Air Toxics, Safe 

Food, Safe Communities, and Human Health MYPs) 

2005 NERL 

APM Report on genomic analyses of exposure of fathead 

minnows to binary and ternary chemical mixtures (also in 

Ecosystem Protection MYP) 

2005 NERL 

APM Provide NHEERL, OPPTS and the scientific community with 

an evaluated method for characterizing chlorotriazine 

exposure in tissues 

2006 NERL 

APM Development and evaluation of innovative analytical and 

sampling method for assessing exposures to one or two EDC 

suspected phthalates 

2006 NERL 

APM Report on development and evaluation of biological indicators 

of exposure of several teleosts and invertebrate organisms to 

model EDCs 

2006 NERL 

APM SOP for a bioassay of androgenic activity adapted to risk 

management applications 

2006 NRMRL 

APM Provide the Regions and States with evaluated exposure tools 

and documentation for their use in assessing the efficacy of 

remediation technologies for EDCs 

2007 NERL 

APM Evaluated and upgraded EDC compartmental model 2007 NERL 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM Demonstrate the use of NERL’s human exposure 

modeling tools and databases to characterize and assess 

young children’s exposures to pesticides and other 

environmental contaminants (also in Human Health 

MYP). 

2008 NERL 

APM SOP for a bioassay of thyroid-endocrine activity adapted to 

risk management applications 

2008 NRMRL 

APG - Provide at least one computational model for assessing 

endocrine disruptor compounds 

2008 ORD 

APM Announce RFA for the development of HTPS for prioritizing 

chemicals for testing for potential endocrine disruption 

2003 NCER 

APM Announce RFA for incorporation of computational methods, 

through the use of systems biology approaches, in hazard 

identification and risk assessment 

2003 NCER 

APM Report on the linkage of genomics-driven exposure indicators 

to effects in fish exposed to androgenic compounds 

2005 NERL 

APM Report on roles of pharmacokinetic and pharmacodynamic 

factors in dose-response and relative potency for compounds 

with endocrine activity using computational methodologies 

2005 NHEERL 

APM Evaluate one in vitro technique for assessment of 

steroidogenesis 

2005 NHEERL 

APM Publish database on binding affinities of chemicals for the 

estrogen receptor 

2005 NHEERL 

APM Report on the use of genomic data to validate the output of 

PB/PK/PD models in fish 

2006 NERL 

APM Report on the use of computational techniques to evaluate 

endocrine disruptor effects on GnRH 

2006 NHEERL 

APM Establish database for non-pesticide chemicals from industrial 

sources to develop and refine a model for interspecies 

extrapolation 

2006 NHEERL 

APM Report on a high throughput zebrafish embryo gene 

expression system for screening EDCs 

2007 NCER 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on a mechanistic approach to screening chemicals and 

mixtures for endocrine activity using an invertebrate model 

2007 NCER 

APM Report on development and application of a bioluminescent 

yeast-reporter system for screening chemicals for estrogenic 

and androgenic effects 

2007 NCER 

APM Report on developing high throughput screening approaches 

for prioritizing chemicals for the EDSP 

2007 NCER 

APM Establish database for inorganic chemicals from industrial 

sources to develop and refine a model for interspecies 

extrapolation 

2007 NHEERL 

APM Report on molecular endpoints to be used in extrapolation 

models of effects of industrial chemicals in fish 

2008 NHEERL 

APG - Identify risk management EDCs research 2008 ORD 

APM Identify RM research needs from draft Risk Management 

Evaluation (RME) 

2000 NRMRL 

APM Complete revision of RME for first round of EDCs of 

concern 

2001 NRMRL 

APM Revision of RME for second round of EDCs of concern 2005 NRMRL 

APM Revision of RME for third round of EDCs of concern 2008 NRMRL 

APG - Evaluate at least three existing risk management tools to 

reduce exposure to EDCs 

2009 ORD 

APM Report describing the efficacy of conventional treatment of 

steroid hormones and alkylphenol ethoxylates in sewage to 

support ORD efforts to further characterize and manage EDC 

risks 

2003 NRMRL 

APM Report on emissions of suspected EDC compounds from 

combustion sources to support ORD efforts to further 

characterize and manage EDC risks 

2003 NRMRL 

APM Interim progress report on the treatability of selected 

endocrine disrupting chemicals as requested by the Office 

of Water (also in Drinking Water MYP) 

2003 NRMRL 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on the reduction in suspected EDCs achievable 

using existing manure management practices at CAFOs 

(also in Water Quality MYP). 

2004 NRMRL 

APM Report on performance of sludge digestion on reducing 

suspected EDCs in biosolids 

2005 NRMRL 

APM Report on the drinking water treatability of selected 

reproductive hormones 

2005 NRMRL 

APM Report on the ability of natural processes to manage 

estrogenic alkylphenols in aquatic sediments 

2005 NRMRL 

APM Report on the reduction of EDCs achieved by current 

biosolids management practices for Class A and Class B 

materials (also in Water Quality MYP) 

2006 NRMRL 

APM Report on the fate of other EDCs in wastewater treatment 

plants 

2007 NRMRL 

APM Report on fate of EDCs in septic systems 2007 NRMRL 

APM Report on the ability of natural processes to manage steroid 

hormones in aquatic sediments 

2007 NRMRL 

APM Report on drinking water treatability of selected EDCs 

(surfactant degradation products) (also in Drinking 

Water MYP) 

2007 NRMRL 

APM Determine treatability of selected additional EDCs (also 

in Drinking Water MYP) 

2009 NRMRL 

APG - Develop at least two new risk management tools to 

reduce exposure to EDCs 

2009 ORD 

APM Report on optimizing wastewater treatment plant operation 

for removing steroid hormones and alkylphenolic EDCs 

2005 NRMRL 

APM Report on a methodology to predict potential endocrine 

activity using shape signatures for use in pollution prevention 

tools 

2005 NRMRL 

APM Report on the potential of biodegradation to remove 

hormones from groundwater associated with CAFOs 

2006 NRMRL 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM Publish a pollution prevention computational tool that suggests 

substitutes for EDCs 

2006 NRMRL 

APM Report on how to reduce environmental risk from 

synthetic and natural hormones emanating from CAFO 

manure management systems (also in Water Quality 

MYP) 

2007 NRMRL 

APM Report on optimizing septic systems to remove EDCs 2009 NRMRL 

APG - Develop systems models to test and predict 

vulnerabilities of the neuroendocrine system to contaminantinduced effects 

2012 ORD 

APM 

26 

Report on dose-response effects of EDCs that affect thyroid 

homeostasis as a target 

2004 NHEERL 

APM Report on at least 1 procedure for measuring 

transgenerational effects in invertebrates to xenobiotics 

2005 NHEERL 

APM Provide report from workshop on current knowledge of 

testing for neuroendocrine toxicity pathways and systems 

biology in aquatic species 

2005 NHEERL 

APM Develop at least one approach for diagnosing mode-of-action 

for endocrine-disrupting chemicals in an amphibian model 

using toxicogenomic/proteomic techniques 

2006 NHEERL 

APM Develop at least 1 technique based on toxicogenomic/ 

proteomic approaches as the basis for extrapolating across 

small fish species 

2007 NHEERL 

APM Report on generalized amphibian model for testing adverse 

developmental effects associated with multiple endocrine 

pathways 

2008 NHEERL 

APM Report on the use of genomic approaches and computational 

models to test for effects of contaminants on reproductive and 

developmental processes in aquatic species 

2009 NHEERL 

APM Report on at least 1 model to define toxicity pathways as a 

basis for extrapolation across vertebrate aquatic species 

2010 NHEERL 

Page 57
ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on linked systems models for predicting contaminantinduced effects in aquatic species arising from multiple, 

interacting endocrine pathways 

2011 NHEERL 

Shading denotes APG and associated APMs appear in multiple LTGs 

Italics denotes APM appears in multiple MYPs 

Page 58
ORD Multi-Year Plan for Endocrine Disruptors 

TABLE 2.

LONG TERM GOAL 2. Determine the extent of the impact of endocrine disruptors on 

humans, wildlife, and the environment 

ANNUAL PERFORMANCE GOALS AND MEASURES YEAR LAB/ 

CENTER 

APG - Develop field methods to assess environmental 

exposures in tissues and environmental compartments 

2002 ORD 

APM Interim reports on the development of user-friendly biological 

measures of estrogenicity of pesticides and suspected EDCs 

as a tool for evaluating their presence in water 

2000 NERL 

APM Journal article on describing entry of agriculture based 

pharmaceuticals into ecosystems 

2000 NERL 

APM Interim report documenting performance of confirmatory 

methods for toxic metals in the fresh water and sediment 

analysis 

2000 NERL 

APM Standard operating procedure of laboratory confirmation of 

trace elements in water, soil, and sediments 

2000 NERL 

APM Pilot study to test power of analytical methods for measuring 

suspected EDCs 

2001 NERL 

APM Journal article on speciation and detection of organotins from 

environmental media 

2001 NERL 

APM Interim report on alkylphenol methodology 2001 NERL 

APM Report to Regions 3 and 5 on alkylphenol methodology 2002 NERL 

APM Report on preliminary results from EDC investigation of 

selected Neuse River sites 

2002 NERL 

APG 121 - Determine efficacy of wildlife species as sentinels 2004 ORD 

APM Report on common markers for EDC effects in wildlife and 

human systems 

2004 NCEA 

Page 59 
ORD Multi-Year Plan for Endocrine Disruptors 

APM 

34 

Report on comparative growth and reproductive responses of 

invertebrate population to xenobiotics 

2004 NHEERL 

APM 

47 

Report on the sensitivity and reproducibility of an estrogenresponsive sheepshead minnow cDNA macroarray: field 

application and assessment 

2004 NHEERL 

APM Report on efficacy of wildlife species (e.g., fish, reptile, avian, 

invertebrate species) as sensitive indicators of endocrine 

disrupting effects of chemicals in the environment 

2004 NCER 

APG 122 - Evaluate several classes of chemicals suspected of 

being EDCs & determine potencies in laboratory studies 

2004 ORD 

APM Report on whether exposure to dietary phytoestrogens will 

cause delayed neuro- and reproductive toxicity 

2000 NCER 

APM Report on analysis of adverse reproductive system effects in 

human daughters from mother's exposure to halogenated 

hydrocarbons (PBBs) 

2001 NCER 

APM Report on analysis of effects of methoxychlor and 

environmental estrogen receptor in ER knockout mice 

2001 NCER 

APM Determination of the mechanism(s) by which developmental 

exposure to PCBs disrupts thyroid hormones to produce 

ototoxicity, characterization of the effects of exposure to 

mixtures of PHAHs and determination of whether non-AH 

receptor mechanisms underlie the neurotoxicity of some 

PHAHs 

2001 NHEERL 

APM Identify the etiology of metabolic quinones in mammary 

cancer induced by EDCs 

2001 NHEERL 

APM Determine the influence of classes of EDCs on proliferation 

and apoptosis in human mammary cells 

2001 NHEERL 

APM Conduct in vivo studies to determine the dose and time 

response relationships between exposure to chlorotriazines, 

alterations in the CNS and changes in pituitary hormone 

secretion 

2001 NHEERL 

APM Evaluation of the effect of chlorotriazines on the ovulatory LH 

surge and their potential disruption of pregnancy 

2001 NHEERL 

Page 60
ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on analysis of the ability of phytoestrogens (at human 

intake levels) to alter the normal sexually dimorphic 

development of the brain, behavior, and neuroendocrine 

control of reproduction in rats 

2002 NCER 

APM Report on mechanisms of halogenated aromatic hydrocarbon 

toxicity in birds 

2002 NCER 

APM Report on analysis of the antagonisms between the protective 

effects of endogenous steroid, progesterone, and the 

endocrine disrupting effect of TCDD in the development of 

endometriosis 

2002 NCER 

APM Report on effects of dioxins on ovarian function 2002 NCER 

APM Evaluation of the effects of atrazine on the female 

reproductive system following lactational exposure 

2002 NHEERL 

APM Report on the effects of developmental exposure to both 

synthetic thyroid inhibitors and environmental pollutants with 

potentially similar thyroid activity on the ontogeny of learning 

and memory in rodent models 

2002 NHEERL 

APM Report on analysis of effects of PCBs on thyroid function in 

birds in the lab and field 

2003 NCER 

APM 

220 

Report on the effects of mixtures of dioxin-like chemicals on 

development in the rat 

2003 NHEERL 

APM 

221 

Report on altered growth patterns in reproductive tissue in 

animals prenatally exposed to dioxin 

2003 NHEERL 

APM 

118 

Report on methods to assess endocrine disruptors in 

prepubertal female rats 

2003 NHEERL 

APM 

48 

Report on the effects of atrazine on the female reproductive 

system following prepubertal exposure 

2004 NHEERL 

APG 123 - Evaluate several classes of chemicals suspected of 

being EDCs in field studies & ascertain degree to which they 

adversely affect wildlife at the population level 

2004 ORD 

APM Report on the effects of EDCs on one or more wildlife 

populations in South Florida 

2001 NHEERL 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM Determine acute and chronic effects of retinoids on amphibian 

development 

2001 NHEERL 

APM Report on analysis of the role of EDCs as a cause of shark 

infertility on Florida's Gulf Coast 

2002 NCER 

APM Report on analysis of the linkage between EDC exposure in 

alligators at the level of the individual and population 

2002 NCER 

APM Report on analysis of the effects of EDC exposure in the field 

and laboratory on immune system and host resistance in 

alligators 

2002 NCER 

APM Report on analysis of the nature, extent, mechanisms by which 

EDCs interfere with normal sexual development in fish 

2002 NCER 

APM Report on comparative analysis in mice, fish, birds, and frogs 

of the endocrine disrupting activities of PCBs and PAHs at 

the molecular level (estrogen receptor) and at the tissue and 

organ levels 

2002 NCER 

APM Report on whether environmental exposure to EDCs has 

caused developmental abnormalities in frogs and the 

mechanisms for such effects 

2003 NCER 

APM Report on analysis of the effects of endosulfan and PAH 

photoactivation products at the molecular, cellular, organism, 

and population levels in 2 crustacean species 

2003 NCER 

APM Report on lab and field analysis of mechanisms by which 

tributyltin, alone and in combination with 3 

methylcholanthrene, causes pseudohermaphroditism in marine 

gastropods 

2003 NCER 

APM Report on analysis of effects of PCBs on thyroid function in 

birds in the lab and field 

2003 NCER 

APM Report on analysis of biomarkers of reproductive and larval 

functions in fish to predict effects of EDCs on croaker 

population dynamics 

2003 NCER 

APM Report on lab and field analysis of the effect of retinoids as 

inducers of abnormal limb development in frogs 

2003 NCER 

Page 62
ORD Multi-Year Plan for Endocrine Disruptors 

APM 

49 

Report on the sensitivity and reproducibility of an estrogenresponsive sheepshead minnow cDNA macroarray: field 

application and assessment 

2004 NHEERL 

APG 118 - Determine critical biological factors during 

development resulting in toxicities later in life 

2006 ORD 

APM Report on effects of pre- and peri-natal exposures to PCBs 

on the metabolism of estrogens and androgens and on the 

ability of methoxychlor to cause reproductive toxicity at 

environmentally relevant levels of exposure 

2001 NCER 

APM Report on analysis of the most sensitive developmental stages 

in birds to EDCs 

2001 NCER 

APM Determination of the mechanism(s) by which developmental 

exposure to PCBs disrupts thyroid hormones to produce 

ototoxicity, characterization of the effects of exposure to 

mixtures of PHAHs and determination of whether non-AH 

receptor mechanisms underlie the neurotoxicity of some 

PHAHs 

2001 NHEERL 

APM Evaluation of toxicant-induced alterations in mammalian 

reproductive development to compare dose response 

relationships, critical periods of exposure, in vivo tissue levels 

of the active toxicant and in vivo and in vitro mechanisms of 

action 

2001 NHEERL 

APM Determine whether GABA-A receptor activation plays a role 

in endocrine mediated developmental neurotoxicity 

2001 NHEERL 

APM Evaluation of the effects of increasing serum prolactin levels 

in rats prior to puberty on lateral prostate inflammation at 120 

days of age 

2001 NHEERL 

APM Report on analysis of the ability of phytoestrogens (at human 

intake levels) to alter the normal sexually dimorphic 

development of the brain, behavior, and neuroendocrine 

control of reproduction in rats 

2002 NCER 

APM Report on identification of the most critical stage in the life 

cycle of quail to the effects of endocrine disruptors 

2002 NCER 

Page 63
ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on effects of exposure to EDCs during early critical 

stages of embryonic development and the appearance of 

prostatic abnormalities in later life 

2002 NCER 

APM Report on effects of early developmental exposure to 

endocrine disrupting pesticides on reproductive function in 

adults 

2002 NCER 

APM Development of a method to assess potential health risks 

associated with exposure to EDCs which are developmental 

toxicants 

2002 NHEERL 

APM Evaluate dose metrics for developmental toxicants for use in 

low dose extrapolations 

2002 NHEERL 

APM Evaluation of the effects of atrazine on the female 

reproductive system following lactational exposure 

2002 NHEERL 

APM Examination of the effects of developmental exposure to both 

synthetic thyroid inhibitors and environmental pollutants with 

potentially similar thyroid activity on the ontogeny of learning 

and memory in rodent models 

2002 NHEERL 

APM Report on whether environmental exposure to EDCs has 

caused developmental abnormalities in frogs and the 

mechanisms for such effects 

2003 NCER 

APM Report on identification of effects of EDCs on prostate gland, 

testis development, and spermatogenesis 

2003 NCER 

APM Report on analysis of effects of low, environmentally relevant 

exposure to EDCs during fetal development on prostatic 

growth at different stages of the life cycle 

2003 NCER 

APM Report on analysis of effects of adolescent exposure to 

methoxychlor in rhesus monkeys on subsequent reproductive, 

immunological, brain, and skeletal function during puberty 

2003 NCER 

APM Report on analysis of effects of EDCs on growth factors and 

receptors that control grown and development of the testis 

2003 NCER 

APM 

220 

Report on the effects of mixtures of dioxin-like chemicals on 

development in the rat 

2003 NHEERL 

Page 64
ORD Multi-Year Plan for Endocrine Disruptors 

APM (Further) Examination of the effects of developmental 

exposure to both synthetic thyroid inhibitors and 

environmental pollutants with potentially similar thyroid activity 

on the ontogeny of learning and memory in rodent models 

2003 NHEERL 

APM 

221 

Report on altered growth patterns in reproductive tissue in 

animals prenatally exposed to dioxin 

2003 NHEERL 

APM 

225 

Report on the effects of atrazine on the male and female 

reproductive system following developmental exposure 

2003 NHEERL 

APM 

50 

Report on critical windows of exposure for alterations in 

mammary gland development and lactational function 

2004 NHEERL 

APM 

51 

Report on the effects of atrazine on the female reproductive 

system following prepubertal exposure. 

2004 NHEERL 

APM Report on the effects of atrazine to modify mammary gland 

morphology when delivered during critical periods of 

development 

2006 NHEERL 

APG 124- Determine extent to which exposure to EDCs 

contribute to onset or increase in severity of diseases 

2007 ORD 

APM Characterization of environmental agents as risk factors in 

human prostate 

2001 NCEA 

APM Determination of the mechanism(s) by which developmental 

exposure to PCBs disrupts thyroid hormones to produce 

ototoxicity, characterization of the effects of exposure to 

mixtures of PHAHs and determination of whether non-AH 

receptor mechanisms underlie the neurotoxicity of some 

PHAHs 

2001 NHEERL 

APM Evaluation of the effects of increasing serum prolactin levels 

in rats prior to puberty on lateral prostate inflammation at 120 

days of age 

2001 NHEERL 

APM Report on mechanisms of EDCs in thyroid carcinogenesis 2002 NCER 

APM Report on analysis of the antagonisms between the protective 

effects of endogenous steroid, progesterone, and the 

endocrine disrupting effect of TCDD in the development of 

endometriosis 

2002 NCER 

Page 65
ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on effects of dioxins on ovarian function 2002 NCER 

APM Evaluation of the effects of atrazine on the female 

reproductive system following lactational exposure 

2002 NHEERL 

APM Examination of the effects of developmental exposure to both 

synthetic thyroid inhibitors and environmental pollutants with 

potentially similar thyroid activity on the ontogeny of learning 

and memory in rodent models 

2002 NHEERL 

APM Report on the magnitude and nature of thyroid alterations in 

relation to exposure to EDCs 

2003 NCER 

APM Report on effects of DES, genistein, bisphenol A on sperm 

counts and quality of the relationship between these endpoints 

and changes in gene expression 

2003 NCER 

APM Report on effects of low, environmentally relevant exposure 

to EDCs during fetal development on prostatic growth at 

different stages of the life cycle 

2003 NCER 

APM Report on the effects of developmental exposure to both 

synthetic thyroid inhibitors and environmental pollutants with 

potentially similar thyroid activity on the ontogeny of learning 

and memory in rodent models 

2003 NHEERL 

APM 

221 

Report on altered growth patterns in reproductive tissue in 

animals prenatally exposed to dioxin 

2003 NHEERL 

APM 

52 

Report on the effects of atrazine on the female reproductive 

system following prepubertal exposure. 

2004 NHEERL 

APM Report on the effects of atrazine to modify mammary gland 

morphology when delivered during critical periods of 

development 

2006 NHEERL 

APG - Determine whether adverse developmental/ reproductive 

effects are occurring in human populations 

2008 ORD 

APM Announce RFA soliciting research on multi-disciplinary human 

studies demonstrating quantitative relationships between 

chemical exposures and manifestations of adverse effects on 

reproductive development mediated via alterations in the 

endocrine system 

2000 NCER 

Page 66
ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on analyses of adverse reproductive system effects in 

human daughters from mother's exposure to halogenated 

hydrocarbons (PBBs) 

2001 NCER 

APM Report on epidemiology study on effects of organochlorines 

and PCBs exposures on endometriosis 

2007 NCER 

APM Report on epidemiology study on effects of early exposures 

to phthalates on breast and genitalia development in males 

and females 

2007 NCER 

APM Report on epidemiology study on effects of dioxins on in 

utero and childhood exposures on male reproductive 

development 

2008 NCER 

APM Report on epidemiology study on effects of gestational and/or 

lactational exposure to heptachlor on reproductive and 

immune function 

2008 NCER 

APM Report on epidemiology study on effects of PBDEs on thyroid 2008 NCER 

APG - Characterize sources of exposure and environmental 

fates of EDCs 

2008 ORD 

APM 

37 

Initiate follow-on children’s exposure study to 

characterize aggregate exposures for selected pesticides, 

EDCs, and persistent pollutants (also in Safe Food and 

Human Health MYPs) 

2002 NERL 

APM 

34 

Peer-reviewed design for field study to evaluate protocols 

for obtaining reliable data on children’s exposure to 

pesticides, EDCs, and other persistent pollutants (also in 

Safe Food and Human Health MYPs) 

2002 NERL 

APM Determine the extent to which combustion sources contribute 

to EDCs in the environment 

2002 NRMRL 

APM Determine the extent to which CAFOs contribute to EDCs in 

the environment 

2002 NRMRL 

APM 

30 

By 2003, complete field monitoring study (CTEPP) to 

evaluate aggregate exposures of 260 young children in their 

homes and daycare centers to persistent organic pollutants 

2003 NERL 

Page 67
ORD Multi-Year Plan for Endocrine Disruptors 

APM 

23 

Interim report on applicator exposures to pesticides in the 

Agricultural Health Study (also in Safe Communities) 

2003 NERL 

APM Submit a paper on emissions of EDC compounds from 

combustion sources to support ORD efforts to further 

characterize and manage EDC risks 

2003 NRMRL 

APM Announce RFA soliciting research to characterize exposures 

to EDCs and determine the effects of low, ambient level 

exposures to EDCs 

2004 NCER 

APM Determine the extent of exposure to key ecosystems to 

selected antibiotics derived from CAFOs in the Neuse River 

Basin 

2004 NERL 

APM 

273 

Vitellogenin gene expression in minnows and Pearl Dace from 

control and dosed lakes in Canadian Experimental Lake area 

2004 NERL 

APM 

272 

Use of minnow vitellogenin gene expression methods for 

monitoring and detection of estrogenicity from PCB 

contamination in Lake Hartwell 

2004 NERL 

APM 

280 

Homeostasis disruption: unforeseen effects of PPCPs in 

the environment (also in Drinking Water MYP) 

2004 NERL 

APM 

218 

Analysis of aggregate exposures to young children in their 

homes and daycare centers to persistent organic 

pollutants (includes pesticides, EDCs, and other persistent 

organic compounds) (also in Safe Food and Human 

Health MYPs) 

2004 NERL 

APM 

229 

Analysis of children studies’ results to identify key 

uncertainties and critical data gaps (also in Safe Food 

and Human Health MYPs) 

2004 NERL 

APM 

217 

Analysis of the farm applicator and family exposure 

results from the Agricultural Health Study (also in Safe 

Communities MYP) 

2004 NERL 

APM Report on the androgenic characteristics of products from 

biomass combustion 

2004 NRMRL 

APM Report on potential of swine CAFOs to contribute EDCs 

to groundwater (also in Water Quality MYP) 

2004 NRMRL 

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ORD Multi-Year Plan for Endocrine Disruptors 

APM Transfer of molecular diagnostic indicator technology to 5 

EPA Regional laboratories 

2005 NERL 

APM Report on regional scale studies of molecular diagnostic 

indicators in fish from watersheds in the Midwestern 

United States (also in Ecosystem Protection MYP) 

2005 NERL 

APM Complete field measurements of aggregate exposures of 

infants and toddlers to pesticides, EDCs, and other 

environmental contaminants 

2006 NERL 

APM Implementation of integrated ecological/human exposure field 

measurements study 

2006 NERL 

APM Report on emission factors for androgenic EDCs from 

biomass sources 

2006 NRMRL 

APM Provide ORD and OPPTS with summary workshop 

recommendations for the key objectives and design criteria 

for an integrated ecological and human exposure field study 

2007 NERL 

APM Analysis of aggregate exposures of infants and toddlers in 

homes to pesticides and other environmental 

contaminants. (also in Safe Food MYP) 

2007 NERL 

APM Assessment of key factors influencing aggregate 

exposures of young children in one or two cohorts along 

the US/Mexico border (also in Human Health MYP) 

2008 NERL 

APM Report from NCER/NERL EDC exposure study 2008 NERL 

APM Report on analysis of National Children’s Study exposure 

data and relationships to health and stressor data (also in 

Safe Food and Human Health MYPs) 

2008 NERL 

NCEA 

NHEERL 

APM Report on estimation of overall contribution of androgenic 

activity to the environment by combustion sources 

2008 NRMRL 

Shading denotes APG and associated APMs appear in multiple LTGs 

Italics denotes APM appears in multiple MYPs 

Page 69
ORD Multi-Year Plan for Endocrine Disruptors 

TABLE 3.

LONG TERM GOAL 3. Support EPA’s Screening and Testing Program 

ANNUAL PERFORMANCE GOALS AND MEASURES YEAR LAB/ 

CENTER 

APG - Evaluate existing testing guidelines for their adequacy to 

evaluate endocrine-mediate effects 

2001 ORD 

APM Evaluate multi-generation reproductive test guideline for use in 

Tier 1 testing of potential EDCs 

2001 NHEERL 

APG - Develop standardized protocols for screening chemicals 

for their potential endocrine-mediated effects to meet FQPA 

requirements 

2006 ORD 

APM Report on the development of an in vitro test system and 

markers of action for xenoestrogens during spermatogenesis 

2000 NCER 

APM Determine the molecular basis for the anti-androgenic effects 

of some endocrine active environmental chemicals by 

examining their ability to bind AR, induce nuclear AR import 

and inhibit AR-mediated transactivation and subsequent ARDNA binding 

2000 NHEERL 

APM Comparison of the results of several in vitro estrogen 

agonist/antagonist assays to results obtained in vivo in an 

assay that assesses the ability of a compound to induce 

estrogen responses in uterus, vagina and brain. 

2000 NHEERL 

APM Report on development of a biological model (fish) for 

viewing tissue and organ specific changes in gene expression 

caused by EDCs 

2001 NCER 

APM Report on validation of animal model (fish) for detecting 

EDCs 

2001 NCER 

APM Report on development of in vitro test system (shark testis) 

for effects of EDCs on spermatogenesis 

2001 NCER 

APM Determine whether GABA-A receptor activation plays a role 

in endocrine mediated developmental neurotoxicity 

2001 NHEERL 

Page 70
ORD Multi-Year Plan for Endocrine Disruptors 

APM Develop three of the short term mammalian in vivo tests 

recommended by the EDSTAC; the Hershberger and the 

male and female pubertal assays . 

2001 NHEERL 

APM Report on development of an animal model (fish) for 

screening suspected EDCs 

2002 NCER 

APM Report on development of QSAR based models for 

predicting in vivo and in vitro endocrine disrupting effects of 

synthetic chemicals 

2002 NCER 

APM Develop an understanding of the relationship between 

molecular structure and effects on the estrogen receptor 

2002 NHEERL 

APM Develop a short-term reproductive assay with the fathead 

minnow to address a recommendation of the EDSTAC 

2002 NHEERL 

APM Develop a tail resorption assay with Xenopus to address a 

recommendation of the EDSTAC 

2002 NHEERL 

APM Development of a biomarker that incorporates utilization of a 

complex developmental process (metamorphosis) critical to 

the completion of the life cycle of previously identified 

xenobiotic sensitive populations in the marine environment 

(crustaceans) 

2002 NHEERL 

APM 

115 

Report on the use of short-term screens for thyroid hormone 

disruptors 

2003 NHEERL 

APM 

121 

Report on the binding of chemicals from selected classes of 

environmental agents to proteins in the thyroid hormone 

system 

2003 NHEERL 

APM 

224 

Report on the validation of the Hershberger Assay for use by 

OECD 

2003 NHEERL 

APM 

109 

Report on integrated in vitro methods and QSAR models 

using 3-D molecular descriptors for chemical prioritization 

and ranking for EDCs 

2003 NHEERL 

APM 

223 

Report on stable cell lines expressing androgen and estrogen 

receptors, together with respective complex promoter 

luciferase reporters 

2003 NHEERL 

Page 71
ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on comparison of in vitro and ex vivo systems for 

identifying the effect of environmental chemicals on 

steroidogenesis 

2005 NHEERL 

APM Report on standardization of short-term mammalian in vivo 

test recommended by EDSTAC 

2005 NHEERL 

APM Report on standardization of an in vitro test to examine the 

effect of environmental chemicals on the androgen receptor 

using transfected cell lines 

2006 NHEERL 

APG - Identify key risk assessment issues and develop 

guidance for assessing endocrine disruptors 

2006 ORD 

APM Complete one case study resulting in integrated human health 

and ecological assessments for selected classes of EDCs 

2001 NCEA 

APM Produce a workshop report for the EDSTAC screening 

process for EDCs and determine application of EDSTAC 

testing program for chemical hazard and risk assessment 

2001 NCEA 

APM Framework for conducting human health and ecological doseresponse assessments for classes of EDCs at environmentally 

relevant concentrations 

2004 NCEA 

APM Develop an integrated health and ecological risk assessment 

guideline for EDCs 

2006 NCEA 

APG - Develop standardized protocols for testing chemicals for 

their potential endocrine-mediated effects to meet FQPA 

requirements 

2008 ORD 

APM Report on method to assess potential health risks associated 

with exposure to EDCs which are developmental toxicants 

2002 NHEERL 

APM Develop a short-term reproductive assay with the fathead 

minnow to address a recommendation of the EDSTAC 

2002 NHEERL 

APM Report on tail resorption assay with Xenopus to address a 

recommendation of the EDSTAC 

2002 NHEERL 

Page 72
ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on field validation of laboratory-based diagnostic 

measurements indicative of exposure to estrogenic 

compounds; plasma levels of vitellogenin, brain aromatase 

level and activity and liver induction of vitellogenin mRNA. 

2002 NHEERL 

APM 

115 

Report on the use of short-term screen for thyroid hormone 

disruptors 

2003 NHEERL 

APM Provide a review of the one-generation study comparing two 

anti-androgens 

2005 NHEERL 

APM Produce one standardize protocol for in utero/lactational 

assay and evaluate its utility using one prototypic endocrinedisrupting chemical 

2007 NHEERL 

APM Report on the cumulative risk of reproductive toxicants 

following in utero exposure using in vivo testing protocols 

2008 NHEERL 

APG - Provide at least one computational model for assessing 

endocrine disruptor compounds 

2008 ORD 

APM Announce RFA for the development of HTPS for prioritizing 

chemicals for testing for potential endocrine disruption 

2003 NCER 

APM Announce RFA for incorporation of computational methods, 

through the use of systems biology approaches, in hazard 

identification and risk assessment 

2003 NCER 

APM Report on the linkage of genomics-driven exposure indicators 

to effects in fish exposed to androgenic compounds 

2005 NERL 

APM Report on roles of pharmacokinetic and pharmacodynamic 

factors in dose-response and relative potency for compounds 

with endocrine activity using computational methodologies 

2005 NHEERL 

APM Evaluate one in vitro technique for assessment of 

steroidogenesis 

2005 NHEERL 

APM Publish database on binding affinities of chemicals for the 

estrogen receptor 

2005 NHEERL 

APM Report on the use of genomic data to validate the output of 

PB/PK/PD models in fish 

2006 NERL 

Page 73
ORD Multi-Year Plan for Endocrine Disruptors 

APM Report on the use of computational techniques to evaluate 

endocrine disruptor effects on GnRH 

2006 NHEERL 

APM Establish database for non-pesticide chemicals from industrial 

sources to develop and refine a model for interspecies 

extrapolation 

2006 NHEERL 

APM Report on a high throughput zebrafish embryo gene 

expression system for screening EDCs 

2007 NCER 

APM Report on a mechanistic approach to screening chemicals and 

mixtures for endocrine activity using an invertebrate model 

2007 NCER 

APM Report on development and application of a bioluminescent 

yeast-reporter system for screening chemicals for estrogenic 

and androgenic effects 

2007 NCER 

APM Report on developing high throughput screening approaches 

for prioritizing chemicals for the EDSP 

2007 NCER 

APM Establish database for inorganic chemicals from industrial 

sources to develop and refine a model for interspecies 

extrapolation 

2007 NHEERL 

APM Report on molecular endpoints to be used in extrapolation 

models of effects of industrial chemicals in fish 

2008 NHEERL 

Shading denotes APG and associated APMs appear in multiple LTGs 

Page 74
pears in 

FIGURE 1 

Linkage and Timeline for APGs to Meet Long Term Goal 1 

FY04 FY05 FY06 FY07 FY08 FY09 FY10 

ading denotes APG 

multiple LTGs 

Determine the 

shape of the doseresponse curve in 

a variety of 

species exposed to 

ambient levels of 

EDCs 

Determine 

critical 

biological 

factors during 

development 

resulting in 

toxicities later 

in life 

Identify key risk 

assessment issues and 

develop guidance for 

assessing endocrine 

disruptors 

Determine 

degree to 

which effects 

of EDCs with 

defined 

mechanisms/m 

odes of action 

can be 

extrapolated 

across classes 

of vertebrates 

Evaluate at least 3 

existing risk 

management tools 

to reduce 

exposure to EDCs 

Develop at least 2 

new risk 

management tools 

Identify risk 

management 

EDCs research 

Evaluate 

exposure 

methods, 

measurement 

protocols, and 

models for the 

assessment of 

risk 

management 

efficacy on 

EDCs 

Provide at least 1 

computational 

model for assessing 

endocrine disruptor 

compounds 

** 

** 

*Receive

APGs in 

** Recei

* 

vide a Better Understanding of Science Underlying the Effects, Exposure, Assessment, and 

Endocrine Disruptors 
FIGURE 2 

Linkage and Timeline for APGs to Meet Long Term Goal 2 

FY03 FY04 FY05 FY06 FY07 FY08 FY09 FY10 

Characterize 

sources of 

exposure and 

environmental 

fates of EDCs 

Determine 

efficacy of 

wildlife species 

as sentinels 

Evaluate several 

classes of chemicals 

suspected of being 

EDCs in field studies 

& ascertain degree to 

which they adversely 

affect wildlife at the 

population level 

Evaluate several 

classes of chemicals 

suspected of being 

EDCs & determine 

potencies in 

laboratory studies 

Determine 

critical 

biological 

factors during 

development 

resulting in 

toxicities later 

in life 

Determine whether 

adverse 

developmental/reproductive effects 

are occurring in 

human populations 

Determine extent to 

which exposure to 

EDCs contribute to 

onset or increase in 

severity of diseases 

** 

* 

* 

* Feed int

risk mana

** Feeds i

rmine the Extent of the Impact of Endocrine Disruptors on Humans, Wildlife, and the Envi
FY02 

FIGURE 3 

Linkage and Timeline for APGs to Meet Long Term Goal 3 

FY03 FY04 FY05 FY06 FY07 FY08 FY09 FY10

Develop 

standardized 

protocols for 

screening 

chemicals for 

their potential 

endocrinemediated 

effects to 

meet FQPA 

requirements 

Shading denotes APG 

appears in multiple LTGs 

Identify key 

risk 

assessment 

issues and 

develop 

guidance for 

assessing 

endocrine 

disruptors 

Develop 

standardized 

protocols for 

testing 

chemicals for 

their potential 

endocrinemediated 

effects to 

meet FQPA 

requirements 

Provide at least 1 

computational model 

for assessing 

endocrine disruptor 

compounds 

Support EPA’s Screening and Testing Program
Design Logic Model

Research 

Activities 

Outputs Short-Term 

Outcomes Customers 

Reached 

Intermediate 

Outcomes 

Long-Term 

Outcomes 

•Evaluate effects of 

EDCs in humans 

and wildlife 

•Determine 

exposures in 

humans and 

ecosystems 

•Develop integrated 

risk assessment 

approaches for 

human and wildlife 

populations 

•Develop risk 

management 

approaches to 

mitigate exposures 

in human and wildlife 

populations 

•Improved protocols 

for screening and 

testing EDCs 

•Characterization of 

EDC effects on 

humans and wildlife 

•Exposure methods, 

measures, and 

models, Guidance for 

assessing EDCs 

•Risk management 

tools and approaches 

•Development of 

standardized screening 

and testing protocols 

•Determination of dose 

response relationship, 

particularly at ambient 

levels of EDCs 

•Determination of extent 

to which EDCs 

contribute to onset or 

increased severity of 

diseases 

•Determination of 

sources of exposure 

and environmental fates 

of EDCs 

•Determination of 

efficacy of risk 

management 

approaches 

•EPA Program 

Offices (e.g, 

OPPTS, OW) and 

Regions 

•States 

•Scientific 

Community 

•Regulated 

Community 

•Other Federal and 

international 

organizations 

•Provide sound science 

in support of FQPA 

and SDWAA screening 

and testing program 

•Improve knowledge 

and understanding of 

EDCs in the 

environment 

•Identify and remediate 

in place the chemicals 

tha tpose an 

unreasonable risk 

•Prevent or reduce the 

release of EDCs into 

the environment that 

pose an unreasonable 

risk 

•Reduce or 

prevent risk to 

humans and 

wildlife from 

exposure to EDCs 

•Outcomes 

assessed will be 

determined by the 

wildlife and huma

health effects 

defined and 

quantified through 

research activities 

Environmental Indicators 

Outreach and Effective Transfer 

CENR Working Group, scientific conferences 

and workshops, scientific publications 

Performance Measurement 

Externalities 

Congressional appropriation and Administration budget decisions, changes in EPA science priorities, changes 

in EPA regulatory requirements, availability of investment capital