Endocrine disruptors and reproductive development: a weight-of-evidence overview.
It is clear that the endocrine system presents a number of target sites for the induction of adverse effects by environmental agents (Fig. 1). There are numerous examples demonstrating that reproductive and developmental processes may be exquisitely sensitive to exposure and there are clear effects induced by presumed endocrine-disrupting chemicals in a variety of species. The concerns raised by studies of wildlife and humans place added significance on a better understanding of the myriad of effects attributed to endocrine disruptors. But there remains a large void between the study of relatively high exposure levels used in laboratory settings versus the relatively low levels found in the general environment. It is also equally clear that the term "endocrine disruption' has been applied to situations where the biological basis is far from conclusive. This may be a moot point in situations where populations are experiencing adverse effects on reproduction, but as scientists we must be vigilant of the appropriate use of descriptive terminology, particularly in cases where public awareness and concern are as great as this. Not only is there a need for better test procedures (both in vivo and in vitro) to characterize the potential of environmental agents to disrupt endocrine function in laboratory species, but there is also a need for a more comprehensive understanding of the normal physiological processes associated with reproduction and development in those wildlife species studied. At the same time, obtaining better information on the transport, fate and bioavailability of chemicals released into the environment remains an important but imposing task. The goals of risk characterization are to carefully delineate cause-and-effect relationships, define the dose-response relationships, and determine whether environmental exposures exceed acceptable levels. A concerted research effort is needed to fill the voids in our knowledge and reduce the large uncertainties that exist today. Only then can regulatory actions take place within the confines of legislative mandates, remediation strategies and considerations of international use and transport. Towards this end, the US Environmental Protection Agency (EPA) sponsored two workshops in 1995 (Ankley et al. 1996, Kavlock et al. 1996) at which groups of international scientists began the process of identifying research needs. Similar efforts also took place in several European countries at about the same time (Danish Environmental Protection Agency 1995, Medical Research Council 1995, Umweltbundesamt 1995). More recently, a Working Group on Endocrine Disruptors has been established within the Committee on the Environment and Natural Resources of the US Government's National Science and Technology Council. The objectives of this Working Group are to (1) formulate a framework for identifying research needs related to the health and ecological effects of endocrine-disrupting chemicals; (2) conduct an inventory of on-going federal research programs; and (3) identify research gaps and facilitate a co-ordinated research plan to address them. These efforts were largely completed in the Fall of 1996 and the information will be made available via the Internet (http;@www.cpa.gov/endocrine). The group also plans to work more broadly with other governments and private industry and public interest groups conducting research on this tissue to co-ordinate research and disseminate scientific information. Persons wishing to know more about this effort should contact the authors. The issue of endocrine disruption has raised the consciousness of many researchers, both within and outside the toxicology community, and has attracted considerable public and political interest. We now have the beginnings of international co-operation to identify the most important scientific uncertainties and to dedicate resources to address the critical gaps. (ABSTRACT TRUNCATED)