[Citation in PubMed] [Related Articles]

Introduction--Workshop on Characterizing the Effects of Endocrine Disruptors on Human Health at Environmental Exposure Levels

Ronald L. Melnick

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina USA

The National Institute of Environmental Health Sciences (NIEHS), with co-sponsorship from the U.S. Environmental Protection Agency (U.S. EPA), U.S. Food and Drug Administration/National Center for Toxicological Research (FDA/NCTR), 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, on 11­13 May 1998. This workshop provided a forum for discussion of methods and data needed to improve risk assessments of endocrine disruptors, with special emphasis on perturbations occurring during critical stages of development and on characterizing potential health effects at environmental exposure levels. Workshop participants were asked to suggest ways to make better use of our current knowledge on endocrine signaling pathways for quantitative evaluations of potential linkages between exposure to chemicals that perturb endocrine function and adverse health effects.

Reports in the scientific literature and in the media have raised concerns that certain persistent environmental chemicals may be producing adverse effects in wildlife and in humans by interfering with the endocrine system. Some of the effects include reproductive and developmental abnormalities, increases in certain hormone-related cancers (breast, prostate, testis), and declines in wildlife populations. The term endocrine disruptors is used to describe exogenous agents that act by mimicking or antagonizing natural hormones in the body that are responsible for maintaining homeostasis and controlling normal development. Because hormone receptor systems are similar in humans and animals, effects observed in wildlife species raise concern of potential human health effects. Evaluating potential low-dose effects of environmental estrogens was identified as a major research priority at the 1997 NIEHS conference "Estrogens in the Environment."

The format of the present workshop, as well as the specific issues that needed to be addressed, was conceived by an organizing committee composed of K. Korach, C. Portier, M. Shelby, and R. Melnick (chair; NIEHS); R. Kavlock (U.S. EPA); P. Foster (Chemical Industry Institute of Toxicology); D. Sheehan and B. Delclos (FDA/NCTR); F. vom Saal (University of Missouri); and R. Miller (Dow Chemical Co.). To address the workshop objectives, the organizing committee identified six breakout group topics:

• Homeostasis and endocrine function in adults

• Endocrine function during development

• Species variability, interindividual variability, and tissue specificity

• Dose­response and mechanistic modeling

• Case study: estimating risk from exposure to diethylstilbestrol (DES)

• Case study: estimating risk from environmental exposure to polychlorinated biphenyls (PCBs)

Scientists with expertise in toxicology, endocrinology, cell and molecular biology, mathematical modeling of biologic processes, exposure assessment, and other related fields were invited to participate in these breakout groups (8 per group). In addition each breakout group included 8­10 observers who participated in the group discussions. A series of questions was posed to each breakout group as a means of providing direction on how to address the main theme of this workshop. Each breakout group was charged with preparing a report that would provide guidance and recommendations on the use of mechanistic information on endocrine disruptors that would lead to biologically based and scientifically credible evaluations of potential low-dose effects of endocrine disruptors on human health. The term low-dose was used at this workshop to indicate doses that are likely to be encountered in the environment.

The first two breakout groups (chaired by G. Stancel and J. Gorski, respectively) were asked to focus on information needed to create baseline models describing quantitative relationships among processes maintaining homeostasis or controlling normal development and the adequacy of animal models and in vitro assays for quantifying perturbations induced by exogenous agents. The third group (chaired by C. Walker) addressed issues related to the physiologic and biochemical bases for species and interindividual differences in response to an endocrine-disrupting chemical and how this information could be used to assess risk in sensitive subpopulations. The fourth group (chaired by M. Andersen) focused on the development, value, and use of mechanistically based mathematical models that link perturbations in normal hormone levels and tissue response with external exposure to an endocrine-active agent and its target tissue dosimetry. The fifth and sixth groups (chaired by J. Cunha and B. Brouwer, respectively) focused on the extensive exposure and toxicity data on DES and PCBs and how that information could be used to estimate human risk resulting from exposure to environmental estrogens or other environmental agents that act by altering endocrine functions.

Several overarching issues discussed in the breakout groups include the following:

Adequacy of animal and in vitro models. Are the currently used animal models and in vitro models adequate for evaluating potential effects of endocrine-active agents in humans with respect to effects on homeostasis and endocrine function in adults, endocrine function during development, and variability in human sensitivity? How well do effects in animals or in in vitro models represent potential qualitative and quantitative changes in humans? Do we need new and more sensitive models? What are the research needs that might provide a better mechanistic understanding of the range of potential effects in humans?

Utility of biologically based mechanistic models. What information is needed to create biologically based mathematical models that realistically represent the physiologic processes affected by endocrine-active agents? What must be included in these models to quantify relationships among processes maintaining homeostasis and controlling normal development, to account for human variability, to evaluate effects of endocrine disruptors, and to estimate how exposure to such agents may alter risks from normal levels of endogenous hormones? Can an integrated biologically based mathematical model that describes relationships among exposure to an endocrine active agent, tissue dosimetry, tissue interactions, mechanism of action, and biologic response lead to more scientifically credible low-dose extrapolations? If not, what research is needed to provide answers that reduce uncertainties and improve the risk assessment process?

Utility of biomarkers. Are there biomarkers identified in some studies of endocrine-active agents that may be useful as indicators of exposure to related compounds or that may reflect changes associated with increased risk of an adverse effect?

Adequacy of current testing methods for detecting low-dose effects. Do current testing methods examine the most sensitive end points--from biologic and methodologic perspectives? Are additional tests or models needed to detect and characterize low-dose effects?

Thresholds and low-dose response. Do currently available data support or deny the existence of threshold responses for endocrine-disrupting chemicals? How do endocrine-active agents affect responses and alter risks from normal levels of endogenous hormones?

The following six articles in this issue of Environmental Health Perspectives Supplements contain peer-reviewed reports from the workshop breakout groups.

Last Updated: July 20, 1999