Endocrine Disruptors Signal the Need for Receptor Models and Mechanisms to Inform Policy

for simplifying this diversity into a few unifying concepts that are directly applicable to the development of risk assessment criteria. Convergent discussions at the close of the Receptor Biology Roundtable addressed the linkages of receptor theory to the development of objective public policy for risk assessment and minimization. School of Medicine Receptor occupancy by endogenous stimuli is ac-La Jolla, California 92093-0636 companied by conformational changes that result in receptor activation, due to changes either in the functional properties of the receptors themselves or in the interaction of the receptor molecule with transducer and ef-Worldwide concerns have emerged about a group of fector systems. As shown in Figure 1A, one can imagine environmental agents (collectively termed endocrine a receptor as existing in one of two states: active (Ra) disruptors) that may be producing adverse health effects and inactive (R i). This two-state system can be repre-in human beings and wildlife by mimicking or interfering sented by three constants: the equilibrium dissociation with the actions of endogenous hormones. (National constants, KDa and KDi, for the Ra and Ri states of the Science and Technology Council Report " The Health receptor, respectively, and an isomerization constant, and Ecological Effects of Endocrine Disrupting Chemicals "). In response to a U. S. Congress mandate through two 1996 laws, the Safe Drinking Water Act and the Food Quality Protection Act, the Environmental Protection Agency (EPA) is developing screening and testing guidelines to evaluate nearly 87,000 chemicals and mixtures for their possible effects on the endocrine system This effort is part of an EPA-wide initiative to develop science-intensive approaches for assessing health risks of environmental agents. A Receptor Biology Roundtable involving leading academic , industrial, and regulatory agency scientists and organized Health). The group gathered for the Roundtable reviewed the essential elements of receptor theory and the rapidly expanding molecular insights concerning receptor mechanisms and signaling pathways in an effort to define the knowledge base that should be incorporated in developing risk assessment approaches for en-docrine disruptors. As expressed at the turn of the century by Ehrlich, cor-(A) The simplest two-state system can be described as a receptor pora non agunt nisi fixata, agents cannot act unless they interconverting between two states, Ra (active) and Ri (inactive), that bind. The cellular binding entity has been termed the are in equilibrium Ra → ← R i. KDi and KDa are the equilibrium dissociation receptor, a molecule that has …