Overview of EPA

1
Overview of EPAs Research Program for Endocrine
Disruptors

• Elaine Z. Francis, Ph.D.
• National Program Director for ORDs Endocrine
  Disruptors Research Program
• Endocrine Disruptors Methods Validation
  Subcommittee
• October 30, 2001

2
Outline

• Background
• EPAs Office of Research and Development
• Why ORD is studying EDCs
• Research
• Better understanding of science
• Determining the extent of the problem
• Supporting EPAs screening testing program
• Coordination of Activities
• EPAs 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
  EPAs 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 EPAs
  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 Childrens Health
  Risks)
• Endocrine Disruptors
• Pollution Prevention and 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 EPAs responsibility (e.g., TSCA,
  FIFRA, FQPA)
• Many uncertainties in our knowledge of endocrine
  disruptors
• nature of effects (e.g., developmental/reproductiv
  e, 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)

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Blueprint for Research
9
ORDs Research Plan

• One of ORDs 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)

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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 EPAs screening and testing program

11
Key Research Questions Aligned under Long Term
Goals

• 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 EPAs screening testing program
• Adequacy of testing guidelines?

• Better understanding of science
• What are the dose-response relationships?
• Needed extrapolation tools?
• Effects of multiple EDCs?
• Management of unreasonable risks?
• Risk assessment approaches?

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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-product
ive 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 EPAs Screening and Testing Program
Shading denotes APG appears in multiple LTGs
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Intramural Research
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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

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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)

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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

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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

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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

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Extramural Research-Science to Achieve Results
(STAR) LTGs 1, 2 3
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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

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00 Multi-Agency RFA (EPA, NIEHS, NIOSH, NCI)

• Investigate the relationship between exposure to
  endocrine disruptors and reproductive/developmenta
  l 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

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Extramural Program Chemicals Under Study
Total 83
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Rat Nude mouse ER knockout mouse Mouse,
non-specified Rabbit Rhesus monkey
Japanese quail Zebra finch Chicken Gull Non-specif
ied
Xenopus Rana Non-specified
Morelets crocodile Alligator
Human
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Coordination of Activities
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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

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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

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Highlights and Summary
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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 Agencys 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
(contd)

• Products from research supporting Agencys needs
  for ST 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
(contd)

• 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 Agencys ST
  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 (contd)

• 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 (contd)

• 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

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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
• EPAs research is providing immediate results for
  implementing the screening and testing program
  mandated by FQPA and SDWAA
• EPAs 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