Overview of USEPA’s Endocrine Disruptors
Research Program
Overview of USEPA’s Endocrine Disruptors
Research Program
Elaine Z. Francis, Ph.D.
National Program DirectorPesticides and Toxics Research Program
Environmental Technology CouncilJanuary 26, 2006
Elaine Z. Francis, Ph.D.
National Program DirectorPesticides and Toxics Research Program
Environmental Technology CouncilJanuary 26, 2006
OutlineOutline
• What are Endocrine Disruptors?
• Examples of EPA’s research
• Collaborations
• Future directions and where ETC can provide support
What Are Endocrine Disruptors?What Are Endocrine Disruptors?
Endocrine SystemEndocrine System
• Plays a key role in the development, growth, reproduction and behavior of humans and wildlife Glands - organs that secrete hormones Hormones - chemical messengers
released into the bloodstream Receptors - cellular components that
interact with hormones
• Plays a key role in the development, growth, reproduction and behavior of humans and wildlife Glands - organs that secrete hormones Hormones - chemical messengers
released into the bloodstream Receptors - cellular components that
interact with hormones
What is an Endocrine Disruptor?
What is an Endocrine Disruptor?
• An endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations.
(IPCS/WHO, 2002)
Effluents
Flame Retardants
Fungicides
Herbicides
Insecticides
Metals
Pharmaceuticals
Phenols
Plasticizers
PAHs
Soy Products
Surfactants
WWTP, pulp and paper mills, CAFOs
PBDEs
Vinclozolin
Atrazine
Methoxychlor
Tributyltin
Ethinyl Estradiol
Bisphenol A
Phthalates
PCBs, dioxin
Genistein
Alkylphenol
Ethoxylates
Some Classes of Known or Suspected EDCs
Some Classes of Known or Suspected EDCs
Purported Adverse Effects: Wildlife
Purported Adverse Effects: Wildlife
• Eggshell thinning in bird populations due to DDT• Abnormal reproductive development in alligators in Lake
Apopka, Florida following pesticide spill• Nearly complete mortality of young Lake Ontario trout from
exposure to dioxin-like compounds• Simultaneous presence of both male and female reproductive
organs (imposex) in mollusks exposed to alkyltins• Synthesis in male fish living near sewage outfalls of a
hormonally regulated protein (vitellogenin) normally found only in female fish
• Birth defects in Lake Michigan birds exposed to PCBs and other chemicals
• Eggshell thinning in bird populations due to DDT• Abnormal reproductive development in alligators in Lake
Apopka, Florida following pesticide spill• Nearly complete mortality of young Lake Ontario trout from
exposure to dioxin-like compounds• Simultaneous presence of both male and female reproductive
organs (imposex) in mollusks exposed to alkyltins• Synthesis in male fish living near sewage outfalls of a
hormonally regulated protein (vitellogenin) normally found only in female fish
• Birth defects in Lake Michigan birds exposed to PCBs and other chemicals
Androgens in the Environment: Effects of Pulp Mill Effluent on Fish
Androgens in the Environment: Effects of Pulp Mill Effluent on Fish
Courtesy of Lou Guillette, UF
ExposedBuckeye Plant, Fenhalloway River, FL
Mosquitofish
Purported Adverse Effects: Humans
Purported Adverse Effects: Humans
• Reproductive tract cancers and abnormalities in offspring of women who used DES during pregnancy
• Neurodevelopmental problems in children exposed prenatally to PCBs
• Exposure to high levels of PBBs prenatally and via breast milk may lead to early onset of puberty in girls
• Speculation regarding the declines in male reproductive health
• Speculation regarding increases in certain cancers (breast, prostate, testicular) that may have endocrine-related basis
• Evidence suggests that environmental exposure to man-made chemicals that mimic hormones may cause adverse health effects in human and wildlife populations
• Chemicals of concern (i.e., pesticides, industrial, contaminants of drinking water) are EPA’s responsibility (e.g., TSCA, FIFRA, FQPA, SDWAA)
• FQPA and SDWAA requirements to develop and implement a screening and testing program
• In spite of how much we know, there are still many scientific 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)
Why is the USEPA concerned about EDCs?
Why is the USEPA concerned about EDCs?
Examples of EPA’s Research on Endocrine Disruptors
Examples of EPA’s Research on Endocrine Disruptors
Updated NHEERL
Implementation Plan
Program Review
by BOSC
Diverse Nature of Research Program - Unique Among Research Organizations
Diverse Nature of Research Program - Unique Among Research Organizations
• Multi-disciplinary set of research areas for both human health and wildlife – cuts across the risk assessment/risk management paradigm
• Research partners – bring diverse talents to address a science question• Across divisions within a lab • Across National Labs • With scientists from academia, other federal agencies, industry
• Research approaches• Computational, field, lab• Molecular to whole organisms• Invertebrates to humans• Biological, analytical, engineering
Multi-Year Plan (2000-2012):
Long-Term Goals
Multi-Year Plan (2000-2012):
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
• 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 and wildlife populations?
– Exposure determinations?
– What chemical classes are responsible?
– Major sources and fates?
• Supporting EPA’s screening and testing program
– Adequacy of testing guidelines?
Scope of EPA’s EDCs Research Program: Key Questions Aligned
Under Long Term Goals
Scope of EPA’s EDCs Research Program: Key Questions Aligned
Under Long Term Goals
• Determining classes of chemicals that act as EDCs and their potencies (Anti)androgens, (anti)estrogens, antithyroids
• Investigating mode of action of certain EDCs Results of studies on atrazine and vinclozolin were critical to improving
the Agency’s risk assessments and setting tolerances Pioneering research on androgens/anti-androgens Thyroid hormone homeostasis as a target for environmental chemicals
• Studying approaches to cumulative risk to EDCs
• Determining the dose-response curves for EDCs at environmentally relevant concentrations
Examples of Research - LTG 1Examples of Research - LTG 1
• Studying the impact of developmental exposures in the short term and later in life Characterizing cellular and
molecular mechanisms of abnormal reproductive development
• Effects of methoxychlor and vinclozolin during testis development and subsequent impact on male fertility – transgenerational epigenetic effects
Examples of Research – LTG 1Examples of Research – LTG 1
Anway et al. 2005. Science 308:1466-9
• Examining the ability to extrapolate across species
Wilson et al., 2004. Environ Sci Technol 38(23):6314-21
Examples of Research – LTG 1Examples of Research – LTG 1
Examples of Research – LTG 1Examples of Research – LTG 1
• Identifying major sources of EDCs entering the environment, focusing on: wastewater treatment plants drinking water treatment plants concentrated animal feeding
operations contaminated sediments sources of combustion
• Developing tools to minimize exposures to EDCs
• Paper Mill Effluents Identified androgenic compounds and
masculinization of female fish
• Drinking Water Determining performance Analytical methods development – steroids and alkylphenols
• CAFOs High levels of estrogens found in swine lagoons Androgenic activity found in run-off from cattle farms Characterized impact of exposures on current aquatic organisms and
estimated future population-level effects Developing analytical methods
Examples of Research – LTG 2Examples of Research – LTG 2
Examples of Research – LTG 2 Wastewater TreatmentExamples of Research – LTG 2 Wastewater Treatment
• Source Characterization National Effluent Study (NERL/NRMRL) OW Influent/Effluent Survey (OW/NRMRL/NERL) Effluent and Receiving Waters studies (ORSANCO/NERL/NRMRL -
Ohio R., Wheeling and ALCOSAN) Fate of APs in land-applied biosolids
• Determining Performance Fate in pilot scale municipal treatment Biodegradation of alkylphenols and hormones under WWTP and
sediment redox conditions Full-scale wastewater treatment On-site treatment (septic, constructed wetlands)
Wastewater Treatment (cont’d)Wastewater Treatment (cont’d)
• Methods to determine performance GC/MS for steroid hormones, APs - effluent, raw,
biosolids HPLC for long-chain APs Adaptation of fish estrogenicity assay LC/MS/MS for (de)conjugated hormones
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• Determining the magnitude of adverse impacts on wildlife Evidence that EDCs are affecting wildlife at individual level Evidence that EDC effects in individuals are causing
population-level effects What tools are needed to provide linkage between
population level effects and diagnostic evidence of EDC impacts
Examples of Research – LTG 2 Examples of Research – LTG 2
• Determining the magnitude of adverse impacts of EDCs on human health Supporting 12 epidemiology studies
across federal agencies• Swan et al. 2005 reported decrease in
AGD in male infants with prenatal phthalate exposure
• Exposure to high levels of PBBs prenatally and via breast milk may impact puberty in girls
• Conducted large scale exposure studies to assess exposures of children to environmental chemicals, including some suspected EDCs
Examples of Research – LTG 2Examples of Research – LTG 2
Assays Under Development Under LTG 3: Supporting Agency’s Screening and Testing Program
Assays Under Development Under LTG 3: Supporting Agency’s Screening and Testing Program
In utero/lactation -tier ? aa
Fish lifecycle
Mysid Lifecycle
Amphibian dev, repro
Avian 2-gen
Mammalian 2-gen
T2 - In vivo
Fish screen
Frog metamorphosis
Pubertal (male)
Pubertal (female)
Uterotrophic
Hershberger
T1 - In vivo
- H295R aa
Steroidogenesis
- rat sliced testes
- recombinant aa
Aromatase - placenta
hrAR binding aa
AR (rat cytosol)
hrER binding aa
ER (rat cytosol)
T1 - In vitro
aa alternate
Coordinating Research Across US Federal Agencies and Collaborating InternationallyCoordinating Research Across US Federal Agencies and Collaborating Internationally
• Endocrine Disruptors Interagency Working Group –1995-2000; 2003-
• Provided support for Administrator for G-8 Environmental Ministers Meetings
• Chaired IPCS/WHO/OECD Steering Committee Developed Global Endocrine Disruptors Research Inventory Developed a “Global State of the Science” report (WHO, 2002)
• Collaborate with EU, Japan, World Health Organization, Global Water Research Coalition
• Participate on OECD work groups
• Exploring establishing Global Endocrine Disruptors Working Group
What’s in the Future?What’s in the Future?
• Taking into consideration recommendations by external scientific panel at Program Review
• Continuing to develop new methods/tools and applying them to environmentally relevant issues
• Interest in expanding our partnerships and collaborations
PPCPs in the NewsPPCPs in the News
How ETC Can Support EDCs Research
How ETC Can Support EDCs Research
• Evaluate innovative treatment technologies for managing CAFO wastes, domestic wastes managed on-site, tertiary treatment technologies for managing domestic and industrial wastes commonly disposed of through wastewater treatment systems ETC could facilitate collaborations between industry and
EPA to develop new and innovative risk management strategies for CAFOs, on-site WWT, water reuse
ETC could bring technology-based systems to the low tech CAFO and WWT management strategies
ETC could help identify economic and incentive based strategies to influence more active development of innovative treatment technologies
SummarySummary
• There is global concern regarding exposures to some environmental agents that interfere with endocrine systems
• USEPA is collaborating with other US federal agencies and other countries on screening and testing and research programs
• USEPA’s research is providing immediate results in developing assays for implementation in the screening and testing program
• USEPA’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
• ETC can help identify and broker technology solutions
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