Overview of USEPA’s Endocrine Disruptors Research Program Elaine Z. Francis, Ph.D. National Program Director Pesticides and Toxics Research Program Environmental Technology Council January 26, 2006

Outline What are Endocrine Disruptors? Examples of EPA’s research Collaborations Future directions and where ETC can provide support

What Are Endocrine Disruptors?

Endocrine 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? 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

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 Courtesy of Lou Guillette, UF Exposed Buckeye Plant, Fenhalloway River, FL Mosquitofish

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?

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 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 ( ): 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

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 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 1 Anway et al Science 308:1466-9

Examining the ability to extrapolate across species Wilson et al., Environ Sci Technol 38(23): Examples 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 2

Examples 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) 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 Ti me Tra cer resp onse 0 Ti me Trac er resp onse 0 Inf lue nt Ef flu en t \

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

Determining the magnitude of adverse impacts of EDCs on human health  Supporting 12 epidemiology studies across federal agencies Swan et al 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 2

Coordinating Research Across US Federal Agencies and Collaborating Internationally Endocrine Disruptors Interagency Working Group – ; 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? 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 News

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

Summary 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