Environmental Factor, August 2007, National Institute of Environmental Health Sciences
Conference Looks to Future of Research on Endocrine Disruption
By Eddy Ball
NIEHS and the U. S. Environmental Protection Agency (EPA) sponsored a meeting in Durham on August 27-29 for scientists with regulatory, public health and research interests in the area of endocrine disrupting compounds (EDCs). Held at the Durham Marriott at the Civic Center and attracting nearly 250 participants, the meeting focused on the topic "Future Research on Endocrine Disruption: Translation of Basic and Animal Research to Understand Human Disease." The conference was organized by staff in the NIEHS Division of Extramural Research and Training Cellular, Organ and Systems Pathobiology Branch (COSPB) (http://www.niehs.nih.gov/research/supported/dert/cospb/index.cfm) and their colleagues.
The impact of EDCs on human health remains a controversial topic among the research and regulatory communities. According to conference organizers, more than two decades of research has shown clear and adverse health effects in animal tests, but it has been difficult to develop a consensus among scientists regarding the effects in humans - a concern that inspired the meeting's innovative agenda to expand the scope and raise the visibility of research in this area.
The meeting included morning lectures, afternoon disease-focused breakout group sessions and a poster session. In addition, a special early-bird session addressed specific student needs, such as career choice and special grant programs for trainees and junior investigators.
The meeting opened with meeting chair COSPB Health Scientist Administrator Jerry Heindel, Ph.D., expressing his pleasure with the large turnout. "When we set up this meeting, we were hoping to get 150 people," he said. "We actually had to shut off registration early. For us, that's really exciting because it says that the research community is as interested in endocrine disruption research as we are at NIEHS."
The conference was divided into four sessions:
- Translation of Animal and Human Data, with talks on DES (Diethylstilbestrol), Testicular Dysgenesis Syndrome, Dioxin and Endometriosis, PCBs (Polychlorinated biphenyls), Thyroid Function and Behavior, and Arsenic and Diabetes.
- Mixture Studies and Biomarker Development in Human and Animal Studies, with discussions of Concepts, Experimental Approaches and Implications for Risk Assessment, Biomonitoring Data, Genomic and Proteomic Biomarkers of Bisphenol A in the Mammary Gland, and Phthalate Exposure and Male Reproductive Tract Abnormalities.
- Role of Genetics and Epigenetics in Response to EDCs in Animal and Human Studies, with talks focusing on Genetic/Molecular Epidemiology and Epigenetics for the Toxicologist and Epidemiologist (see article in Science Notebook)
- Designing Animal Studies for Maximal Impact on Policy, with discussions of EDC Research and Risk Assessment from an EPA perspective and an overview of EDC Research Lessons Learned.
The meeting concluded with disease-focused reports by groups assessing the strength of evidence linking EDCs to specific conditions:
- Thyroid Dysfunction
- Testicular Dysgenesis
- Obesity/Diabetes (Developmental Basis of Obesity)
- Male Reproduction (Fertility/Prostate Cancer)
- Puberty/Polycystic Ovary Syndrome/Endometriosis/Fibroids/Premature Menopause
- Female Reproduction (Fertility)
- Breast Cancer
The groups assessed future research directions and resource needs as they endeavored to answer the conference challenge: "What should be done to develop the specific data (and what are those data) that would provide... 'strong compelling data' of EDC effects on a specific disease/dysfunction in humans?" (see Setting the Stage)
Heindel plans to publish specific recommendations by the groups. The groups called for expanding testing using "omics" platforms to uncover distinctive signatures of EDCs and their effects, as well as to discover more sensitive biomarkers. "Omics" applications, such as proteomics and genomics, are distinguished by their unbiased and global analyses performed using high-throughput technology.
Discussants saw access to human tissue as an important step toward understanding the parallels between animal and human exposures and making the translation from animal results to health effects in humans. Because of the ethical concerns about conducting research on pregnant woman and fetuses, it will be critical, the groups agreed, to identify markers in such surrogate tissue as urine through validating biomarkers in available human reproductive media, such as amniotic fluid.
The groups also expressed a need to understand more completely the effects of cumulative exposure and the timing of exposure windows, deficits that have made it harder to demonstrate the effects of EDC exposure in humans. Work is needed as well in understanding the effects of mixtures on exposures and in developing dose response patterns.
"Setting the Stage" - Opening Remarks from Jerry Heindel
As the first session of the conference began, Heindel presented the audience with the hypothesis behind NIEHS funding of EDC research. "This is the hypothesis we're working under: that hormonally active compounds in the environment, called endocrine disruptors, are having a significant impact on human health, and that impact is the increase of disease and dysfunction," he said. "In order to protect and improve health... we have to focus more on integration and translation of research."
The missing ingredient, Heindel continued, is human data. Even after more than 20 years of research, the data have not been forthcoming, and without that body of evidence, convincing skeptics of the health threats of EDC exposure will continue to be difficult. Heindel pointed to major challenges for researchers:
- The changes resulting from EDC exposure are small and functional - and more sensitive endpoints than are usual or, in many cases, possible in human studies are needed
- The role of polymorphisms compounds the problems of research - highlighting the need for a comprehensive genomic approach
- Environmentally relevant exposures appear to be low - mandating the development of very sensitive personal exposure assessments
- The dose responses are likely "non-monotonic" in many cases - pointing to the need for calculating extended dose responses
- The effects are expected to be due to multiple chemicals with varying sensitivities and half-lives - indicating the need for a sophisticated mixtures approach
- The effects are probably due to multiple exposures - underscoring the need for a life-span approach to exposure
- Exposures at various developmental stages - from conception to adulthood - appear to interact to produce adverse health effects in adulthood
- Some of the effects may be trans-generational, requiring researchers to look beyond the initial exposures to understand the full range of effects
- Current assessment approaches are inadequate - researchers must be willing to take advantage of new technologies to improve exposure assessment and biomarkers of exposure and toxicity
"Many of us will have to shift our focus to disease and dysfunction, instead of just toxicity," Heindel argued. Effective translational research will depend on integration of all aspects of research. Heindel pointed to work needed in the areas of technology development and bioinformatics, understanding mechanisms, clinical assessment, and applications and interventions.
While epidemiology is challenging, Heindel observed, "A good epidemiological study can be worth a hundred animal studies. And there are nice examples of that with DES and [1,2]-dibromo--chloropropane, where one good human study was enough to get rid of that chemical."