Author
Melnick, Ronald L.

Title
Introduction-Workshop on characterizing the effects of endocrine disruptors on human health at environmental exposure levels

Journal
Environmental Health Perspectives 107 Suppl 4:603-604. 1999.

Summary
The National Institute of Environmental Health Sciences, U.S. Environmental Protection Agency (EPA), U.S Food and Drug Administration/National Center for Toxicological Research and the Chemical Manufacturers Association held a workshop "Characterizing the effects of endocrine disruptors on human health at environmental exposure levels" in Raleigh, North Carolina in May 1998. For many years anecdotal evidence has indicated that environmental chemicals produce adverse effects in wildlife and humans by disrupting normal endocrine signals. These adverse effects include decreased fecundity, birth defects, abnormal sexual differentiation and hormonal cancers. Endocrine disruption in humans has been well studied following the tragic use of diethylstilbestrol (DES), a synthetic estrogen used to prevent miscarriages, and following accidental chemical exposures such as dioxin contamination in the residents of Seveso, Italy or consumption of PCB-contaminated rice oil by Yusho/Yu-Cheng residents. These unfortunate incidents demonstrate that exposure to chemical contaminants produces both acute effects and long-term effects, including reproductive cancers, infertility and potentially devastating effects on future offspring. However, the mechanism(s) underlying these adverse toxic effects have yet to be determined.

Scientists with expertise in toxicology, endocrinology, cell and molecular biology, mathematical modelling, exposure assessments and other specialities participated in group sessions examining six topics:

Homeostasis and endocrine function in adults
Endocrine function during development
Species variability, interindividual variability, and tissue specificity
Dose-response and mechanistic modeling
Case-study:estimating risk from exposure to diethylstilbestrol (DES)
Case-study:estimating risk from environmental exposure to polychlorinated biphenyls (PCBs)

Within each session, key themes were addressed including the use of animal studies and mechanistic models, the importance of low-dose models, dose-response relationships and common pathophysiological endpoints and biomarkers of endocrine disruption in both animals and humans.

The conclusions drawn from the working groups on these topics can be summarized into a few key points.

1. Adverse health effects must be clearly defined based on their biological significance and not merely statistical significance. One working group defined an adverse effect resulting from endocrine disruption as any change in a homeostatic parameter that falls outside the normal range for a species.
   
   
2. Individuals may be more sensitive to the adverse effects of endocrine disruptors during particular periods of development. This is particularly true during embryo/fetal development, wherein exposure to certain chemicals has been shown to produce long-term developmental and reproductive abnormalities. Studies designed to examine chemical exposure in adult animals/humans will not necessarily yield relevant information regarding in utero exposure to the same agent.
   
   
3. Designing studies to examine the adverse effects of low-dose chemical exposure was a key theme throughout the workshop. To properly assign an endocrine mechanism(s) of action to a particular chemical requires that the chemical produces its effects via receptor binding and post receptor signalling, or enhanced hormone production or increased turnover at target tissues. Dose-response relationships should be determined for test compounds, incorporating data from different developmental periods. The term 'low-dose' is fairly controversial. The working groups discuss the importance of low-dose assessments but fail to discuss the range of dosages that would fit their definition. Furthermore, low-dose chemical exposure is certain to be much greater than currently prescribed oral contraceptives. Given that the potency of environmental chemicals is much less than oral contraceptives, and exposure levels would also be expected to be much lower, the term 'low-dose' may not be entirely meaningful.
   
   
4. The development of mechanistic models to assess the effects of compounds on a model system is of great interest. Selection of the appropriate test compounds and clearly defined biological end-points are paramount to the success of the model, however, the ability to extrapolate data to different species, dose-response-relationships would be truly valuable. Determination of the role of species, interindividual and tissue specificities related to adverse health effects may be aided by the use of a model. It is important to point out that while the use of a model can be instrumental in study design, selection of animal models and for comparison of test compounds, mechanistic computer modelling cannot replace traditional scientific investigations.
   
   
5. Acute and long-term health effects following accidental chemical exposures (Seveso, Yusho/Yucheng), misuse of prescription medications (DES) must be examined thoroughly to both prevent the recurrence of the incident as well as to enable a greater understanding of the actions of these chemicals. Continued investigation into the mechanisms of action of these chemicals, their relative potencies and the sensitivity of each stage of development to estrogenic exposure is essential.
   
   
6. Accurate risk assessments of PCB exposure requires standardized doses, PCB congener mixtures, exposure periods (i.e., adult vs. neonate) and measurement of PCB contamination. These recommendations can be generalized to most test compounds, for which exposure assessment, dose, mixture and other parameters are not standardized, making comparisons between studies extremely difficult.

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