Study of Endocrine-Disrupting Compounds: Past Approaches and New Directions1, The

SYNOPSIS.

Over the last decade, evidence has mounted demonstrating that human-made compounds released into the environment are disrupting endocrine systems of animals. Research has centered largely on direct steroidogenic or antisteroidogenic effects of these compounds with a recent focus on development of rapid in vitro assays employing estrogen receptors. A literature search and analysis confirms attention placed on estrogen and anti-estrogen-like aspects of endocrine disruption at the receptor level. Non-steroidal components of the hypothalamic-pituitary-end gland axes have received much less attention in the published endocrine disruption literature. Furthermore, aspects of endocrine physiology, such as the ability of animals to cope with stress or communicate chemically, have also received relatively less literature attention when compared to disruption of development and reproduction. As researchers continue to investigate complex mixes of human-synthesized compounds in the environment, it is critical to broaden the spectrum of hormonal disruption investigated beyond estrogenic and androgenic actions and to determine how exposure to mixes affects physiological function beyond reproduction. Last, in the field of endocrine disruption, it also important to begin to use data on individuals for development of hypotheses regarding fitness risks, changes in population dynamics, and the potential for ecosystem level disruption.

In their environments, organisms are exposed to a wide variety of naturally occurring chemicals. In the last 100 years, humans have introduced hundreds of new, synthetic compounds into the environment. Many of these compounds are known, and even were specifically developed to influence microbial, plant, and animal physiological function. Some have had unintended physiological consequences on non-target species. How these compounds ultimately influence physiology and fitness of individual organisms, dynamics of populations, and ultimately functioning of ecosystems, is not well understood.

Many human-introduced compounds influence the endocrine system of animals (Colborn et al., 1993; Oberdorster and Cheek, 2001) and have been termed "endocrine disrupting compounds" (EDCs). By interfering at multiple levels of the endocrine pathways, these compounds disrupt physiological processes including development, reproduction, general metabolism and behavior. Given that there are thousands of humanintroduced compounds now mixing in our environment, and the complexity of even a single organism's physiology, the possible mechanisms for disruption and range of physiological outcomes are enormous. Yet, only a small fragment of this potential physiological disrupting capacity has been investigated. I will provide definitions of endocrine disruption and then review the distribution of literature involving the 1) hormone investigated as being targets for disruption, 2) biochemical mechanisms of endocrine disruption, and 3) physiological systems that are effected by EDCs. This search will test the hypotheses that the disruptor literature focuses on first, estrogens and androgens as the targets of disruption, second, on receptor binding as the mechanism of disruption and third on reproduction and development as a physiological focus in the literature. I will discuss how bias in the literature may drive our research into mixes of compounds known to exist in our environment.

ENDOCRINE DISRUPTORS: DEFINITIONS

In part, because of the complex political and regulatory climate, defining what an "endocrine disruptor" is has been difficult. The United States Environmental Protection Agency (USEPA), as of February 2004, has accepted with qualifications Kavlock et al.'s 1996 (p. 715) definition of an endocrine disruptor as "an exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body which are responsible for the maintenance of homeostasis, reproduction, development and or behavior." The current agency position goes on to state it "... does not consider endocrine disruption to be an adverse effect per se, but rather to be a mode or mechanism of action potentially leading to other outcomes, for example carcinogenic, reproductive, or developmental effects, routinely considered in reaching regulatory decisions. Evidence of endocrine disruption alone can influence priority setting for further testing and the assessment of the results of this testing could lead to regulatory action if adverse effect are shown to occur" (http://www.epa.gov/scipoly/ oscpendo/edsparchive/2-3attac.htm). Therefore, the USEPA's working statement regarding endocrine disruption does not make any statement regarding whether such disruption has negative impacts on an individual's ability to function, but leaves open the possibility of introducing regulatory statutes based on results of specific testing regimes. The USEPA's Endocrine Disruptor Screening Program now outlines these tests (http://www.epa.gov/scipoly/oscpendo/ edspoverview/index.htm). Alternatively, a European Commission Report, less mechanistic in its definition, makes clear potential negative outcomes of exposure to EDCs. This report states "an endocrine disruptor is an exogenous substance that causes adverse health effects in an intact organism, or its progeny, secondary to changes in endocrine function. A potential endocrine disruptor is a substance that possesses properties that might be expected to lead to endocrine disruption in an intact organism" (European Commission, 1997). The e.hormone website follows more along the European Commission report; it defines endocrine disruption as "the process by which an exogenous substance causes adverse health effects consequent to changes in endocrine function" (http://e.hormone.tulane.edu/ learning/learning.html). Note that all definitions include the focus that an endocrine disruptor is a compound that interferes with endogenous endocrine function.