Overview of EPA’s Research Program for Endocrine Disruptors

1. Overview of EPA’s Research Program for Endocrine Disruptors Elaine Z. Francis, Ph.D. National Program Director for ORD’s Endocrine Disruptors Research Program Endocrine Disruptors Methods Validation Subcommittee October 30, 2001

2. Outline • Background • EPA’s Office of Research and Development • Why ORD is studying EDCs • Research • Better understanding of science • Determining the extent of the problem • Supporting EPA’s screening & testing program • Coordination of Activities • EPA’s leadership role on endocrine disruptors • Summary

3. Background

4. Office of Research and Development… …is the research arm of the Agency • Provide the scientific foundation to support EPA’s mission by: • Conducting research and development to identify, understand, and solve current and future environmental problems • Providing independently peer reviewed research results and assessments that foster the sound use of science and technology in Agency decisions. • Providing responsive technical support to EPA’s Programs and Regions • Collaborating with our scientific partners in academia and other agencies, state and tribal governments, private sector organizations, and nations • Exercising leadership in addressing emerging environmental issues and advancing the science and technology of risk assessment and risk management

5. ORD Locations 3 National Laboratories 2 National Centers 2 Offices 13 Locations

6. High Priority Research Areas • Particulate Matter • Drinking Water • Clean Water • Global Change • Ecological Risks • Human Health Risks (including Children’s Health Risks) • Endocrine Disruptors • Pollution Preventionand New Technologies

7. Why is EPA studying EDCs? • Evidence suggests that environmental exposure to man-made chemicals that mimic hormones (endocrine disruptors) may cause adverse health effects in human and wildlife populations • Chemicals of concern (i.e., pesticides, industrial) are EPA’s responsibility (e.g., TSCA, FIFRA, FQPA) • Many uncertainties in our knowledge of endocrine disruptors • nature of effects (e.g., developmental/reproductive, cancer, neurobehavioral) • extent of the problem (e.g., declining wildlife populations) • dose-response relationships (e.g., which chemicals, what levels of exposure, shape of dose-response curve)

8. Blueprint for Research

9. ORD’s Research Plan • One of ORD’s highest risk-based priorities • Identified EDCs as emerging public health and environmental issue (1994) • Organized and hosted two international research needs workshops (1995) • Published interim guidance document (1997) • Published peer-reviewed research plan (1998) (www.epa.gov/ORD/WebPubs/final) • Developed Multi-Year Plan (2001)

10. Multi-Year Plan: Long-Term Goals • Provide a better understanding of the science underlying the effects, exposure, assessment, and management of endocrine disruptors • Determine the extent of the impact of endocrine disruptors on humans, wildlife, and the environment • Support EPA’s screening and testing program

11. Better understanding of science What are the dose-response relationships? Needed extrapolation tools? Effects of multiple EDCs? Management of unreasonable risks? Risk assessment approaches? Determining the extent of the problem What effects are occurring in human & wildlife populations? Exposure determinations? What chemical classes are responsible? Major sources and fates? Supporting EPA’s screening & testing program Adequacy of testing guidelines? Key Research Questions Aligned under Long Term Goals

12. Linkage and Timeline for APGs to Meet Long Term Goal 1 FY01 FY02 FY03 FY04 FY05 FY06 FY07 Evaluate exposure methods, measurement protocols, and models for the assessment of risk management efficacy on EDCs Develop new risk management tools Determine critical biological factors during development resulting in toxicities later in life Evaluate existing risk management tools to reduce exposure to EDCs Identify risk management EDCs research Characterize the effects of exposure to multiple EDCs, in various combination such as those with similar and different mechanisms of action Determine degree to which effects of EDCs with defined mechanisms/modes of action can be extrapolated across classes of vertebrates Determine the shape of the dose-response curve in a variety of species exposed to ambient levels of EDCs Identify key risk assessment issues and develop guidance for assessing endocrine disruptors Shading denotes APG appears in multiple LTGs Provide a Better Understanding of Science Underlying the Effects, Exposure, Assessment, and Management of Endocrine Disruptors

13. Linkage and Timeline for APGs to Meet Long Term Goal 1 FY01 FY02 FY03 FY04 FY05 FY06 FY07 Evaluate exposure methods, measurement protocols, and models for the assessment of risk management efficacy on EDCs Develop new risk management tools Determine critical biological factors during development resulting in toxicities later in life 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: Effects of early developmental exposure to endocrine disrupting pesticides on reproductive function in adults 2002 NCER APM: Lab and field analysis of mechanisms by which tributyltin, alone and in combination with 3 methylcholanthrene, causes pseudohermaphroditism in marine gastropods 2003 NCER APM: Examination of the effects of mixtures of endocrine disruptors on health endpoints 2003 NHEERL Evaluate existing risk management tools to reduce exposure to EDCs Identify risk management EDCs research Characterize the effects of exposure to multiple EDCs, in various combination such as those with similar and different mechanisms of action Determine degree to which effects of EDCs with defined mechanisms/modes of action can be extrapolated across classes of vertebrates Determine the shape of the dose-response curve in a variety of species exposed to ambient levels of EDCs Identify key risk assessment issues and develop guidance for assessing endocrine disruptors Shading denotes APG appears in multiple LTGs Provide a Better Understanding of Science Underlying the Effects, Exposure, Assessment, and Management of Endocrine Disruptors

14. Linkage and Timeline for APGs to Meet Long Term Goal 2 FY01 FY02 FY03 FY04 FY05 FY06 FY07 Develop field methods to assess environmental exposures in tissues and environmental compartments Determine sources of exposure and environmental fates of EDCs Develop multimedia exposure models Determine efficacy of wildlife species as sentinels Determine critical biological factors during development resulting in toxicities later in life Determine extent to which exposure to EDCs contribute to onset or increase in severity of diseases Evaluate several classes of chemicals suspected of being EDCs in field studies & ascertain degree to which they adversely affect wildlife at the population level Determine whether adverse developmental/re-productive effects are occurring in human populations Evaluate several classes of chemicals suspected of being EDCs & determine potencies in laboratory studies Shading denotes APG appears in multiple LTGs Determine the Extent of the Impact of Endocrine Disruptors on Humans, Wildlife, and the Environment

15. Linkage and Timeline for APGs to Meet Long Term Goal 3 FY01 FY02 FY03 FY04 FY05 FY06 FY07 Develop standardized protocols for testing chemicals for their potential endocrine-mediated effects to meet FQPA requirements Evaluate existing testing guidelines for their adequacy to evaluate endocrine-mediated effects Develop standardized protocols for screening chemicals for their potential endocrine-mediated effects to meet FQPA requirements Identify key risk assessment issues and develop guidance for assessing endocrine disruptors Support EPA’s Screening and Testing Program Shading denotes APG appears in multiple LTGs

16. Intramural Research:

17. Effects Research: LTGs 1, 2, & 3 • Evaluates adequacy of current testing guidelines • Develops new/improved protocols for screening and testing program • Determines classes of chemicals that act as EDCs and their potencies • Determines the dose-response curves for EDCs at environmentally relevant concentrations • Investigates mode of action of certain EDCs • Conducts comparative endocrinology studies • Examines population level effects

18. Research to Support EDSP • Receptor binding/transcriptional activation assays (in vitro screens) • Tissue slice assay (in vitro screen) • Hershberger assay (in vivo screen) • Female pubertal assay in rats (in vivo screen) • Male pubertal assay in rats (in vivo screen) • Developmental toxicity screen in rats (in vivo alternative screen) • Frog metamorphosis assay (in vivo screen) • Fish 21-day reproduction screen in the fathead minnow (in vivo screen) • Two generation mammalian reproduction study (in vivo test) • Invertebrate reproduction assay (in vivo test)

19. Exposure Research: LTGs 1 & 2 • Identifies and improves understanding of major exposure routes and processes • Develops predictive models estimating the extent and magnitude of exposures • Humans and ecosystems

20. Risk Assessment Research: LTGs 1, 2 & 3 • Developing position paper on how results from EDSP could be incorporated into hazard characterization assessments • Developing case study for methods on integrating human health and ecological EDC data into risk assessments

21. Risk Management Research: LTGs 1 & 2 • Identifying major sources of EDCs entering the environment, with focus on: • contaminated sediments • wastewater treatment plants • confined animal feeding operations • sources of combustion • drinking water treatment plants • Developing tools for risk management of EDCs, such as biodegradation processes or pollution prevention strategies

22. Extramural Research-Science to Achieve Results (STAR): LTGs 1, 2 & 3

23. History of Extramural Program • Supported through STAR Program since ‘96 • EPA-only RFAs in 1996 and 1997 • Multi-Agency participation in 1998/99 and 2000 • Exploring broader partnerships • e.g., EU, American Chemistry Council • Current portfolio includes 32 grants and 1 fellowship (www.epa.gov/ncerqa) • Broad array of topics, species, chemicals • Support approximately $17.5 M total • Additional $10 M in awards pending decisions • Grants awarded by other research programs - 18 ($4.6 M) • 2002 RFA on Exposure Issues

24. ‘00 Multi-Agency RFA (EPA, NIEHS, NIOSH, NCI) • Investigate the relationship between exposure to endocrine disruptors and reproductive/developmental effects in humans • Working population or general population • Study design should clearly differentiate exposure categories • Quantitative relationships between chemical exposure and adverse reproductive effects in humans • Effects of interest: • Reduced fertility or other altered reproductive function • Pregnancy outcomes • Latent effects on reproduction among offspring exposed in utero • Hormonally mediated cancers of reproductive tract among offspring exposed in utero

25. Extramural Program: Chemicals Under Study Total: 83

26. Zebra fish Medaka Dogfish shark Mosquitofish Bonnet head shark Atlantic Croaker Non-specified Waterflea Mudsnail Grass shrimp Amphipod Copepod Rat Nude mouse ER knockout mouse Mouse, non-specified Rabbit Rhesus monkey Japanese quail Zebra finch Chicken Gull Non-specified Xenopus Rana Non-specified Morelet’s crocodile Alligator Human

27. Coordination of Activities

28. Across Federal Agencies • CENR Endocrine Disruptors Working Group - convened since 1995 (www.epa.gov/endocrine) • EPA, Chair; NIEHS/DOI, Vice Chairs • Representation: 14 federal agencies • Research needs document • Inventory of federal research • Established national priorities • Co-sponsored two multi-agency requests for applications (RFAs) for extramural grants

29. Internationally • G-8 Environmental Ministers Meeting • IPCS/WHO/OECD Steering Committee (ORD chairs) • Developed Global Endocrine Disruptors Research Inventory • Developing a “Global State of the Science” report (2002) • US-EU Joint Collaborations • Meetings in Ispra, Italy (1999) and Sweden (2001)- identified research recommendations & forge collaborations • Discussions on linking solicitations for research proposals • Collaborations with Japan • Research • Workshops • OECD

30. Highlights and Summary

31. Highlights of Research Results and Their Impacts • Results of studies on atrazine, a commonly used herbicide, and vinclozolin, a fungicide, were critical to improving the Agency’s risk assessments and setting tolerances • Pioneering research on anti-androgenic effects of some environmental chemicals (e.g., DDE) • Exposure to high levels of PBBs prenatally and via breast milk may impact puberty in girls

32. Highlights of Research Results and Their Impacts(cont’d) • Products from research supporting Agency’s needs for S&T methods - e.g., improved QSAR approaches, support documents for male and female pubertal assays, method to assess effects in invertebrates, and evaluation of suitability of frog metamorphosis assay • Discovery of a new (third) estrogen receptor in vertebrates and demonstration that estrogens and xenoestrogens can act on cells at the membrane level which helps improve the understanding of how EDCs elicit responses

33. Highlights of Research Results and Their Impacts(cont’d) • Identification of androgenic compounds in paper mill effluent, using a screening assay in fish • Developed methods for collecting samples - soil, sediment, wastewater, water, terrestrial and aquatic biota • Developed analytic methods for some EDCs

34. Future Research, Outcomes, and Impacts • Development of new assays for the Agency’s S&T program • Determining the magnitude of adverse impacts of EDCs on human health • Estimation of the impacts at the population level from exposures to EDCs in representative wildlife species

35. Future Research, Outcomes, and Impacts(cont’d) • Characterization of the effects of exposure to EDCs during adolescence in non-human primates • Development of approaches for reducing exposures to EDCs from contaminated sediment, wastewater treatment outfalls, confined animal feeding operations, and combustion sources

36. Future Research, Outcomes, and Impacts(cont’d) • Development of improved methods and models for exposure assessments • Development of improved approaches for integrated risk assessments • Incorporating mechanisms of action • Understanding shape of the dose-response curve • Integrating human health and ecological data • Taking into consideration risks to susceptible populations, especially children • Aggregate exposure and cumulative risk determinations

37. Future Directions • Nature of EDCs issue is so broad and complex it necessitates continued coordinated efforts through intramural and extramural programs and nationally and internationally • e.g., joint or coordinated solicitations for grants • Determine best way to communicate research results • e.g., State of the Science Reports, integrated website • External peer review of the Multi-Year Plan • Grantees Workshop in 2002

38. Summary • There is global concern regarding exposures to some environmental agents that interfere with endocrine systems • EPA continues to lead national and international efforts to coordinate EDCs research programs • EPA’s research is providing immediate results for implementing the screening and testing program mandated by FQPA and SDWAA • EPA’s long-term research program on EDCs focuses on the most critical uncertainties in determining whether humans and wildlife populations are being impacted by levels of EDCs in the environment, in identifying the sources of those exposures, and approaches to reduce/prevent them