Endocrine disruption: historical perspectives and its impact on the future of toxicology testing.

The endocrine system is one of the body’s major homeostatic control systems whose aim is to maintain normal functions and development in the face of a constantly changing environment. Working in tandem with the nervous system, which mainly is responsible for rapid and immediate responses, the approximately 30 different glands comprising the endocrine system tend to act in a slower and more sustained manner to regulate processes as diverse as the female reproductive cycle, bone growth, cell proliferation, and psychosocial behavior. Multiple endocrine glands also work in concert with one another to form complex feedback loops, which tightly regulate critical physiological processes. Like all homeostatic control systems, the capacity to maintain physiological parameters within normal bounds is finite, and when this capacity is exceeded by chemical exposures, drugs, or environmental stressors, adverse consequences can ensue. In the mid-1990’s, concerns about the potential for environmental chemicals, drugs, and other stressors to alter endocrine physiology rapidly mounted and received a great deal of attention within the toxicology community as well as in the public media. These circumstances spurred a flurry of research on mechanisms of toxicity, new questions about how to deal with cumulative exposures to endocrine-active compounds (EACs) from man-made, dietary, and endogenous sources, and the creation of major chemical screening and testing programs focused on endocrine-mediated modes of toxic action. In this review, we will trace the path of knowledge regarding the effects of exogenous agents on the endocrine system, the events which gave rise to the explosion of interest in this topic in the mid-1990’s, and how it led to a fundamentally different paradigm in toxicity testing as well as a great deal of basic research on mechanisms of endocrine-mediated toxicity. We first cover the history of testing for endocrine-mediated toxicity, followed by coverage of key historical events in basic science, and then bring the two together to discuss implications of the science on testing both now and for the future.