Interactive hormonal activity of chemical mixtures.

" There clearly is a need to expand our thinking about ... how best to a&dresspossible human health risk associated with exposure to chemical mixtures withpotentialfor hormone mimetic chemical interactions." Interactive Hormonal Activity of Chemical Mixtures Public and legislative concern that chemicals in our environment may be affecting human health by mimicking natural hormones and disrupting normal endocrine function remains focused on estrogenic activity. This has fueled the development of a number of in vitro assays to screen chemicals for estrogenic activity including the activity of chemical mixtures. There is controversy over the potential of such chemicals in combination to have synergistic properties (1,2). Many/most of these assays reflect the importance of high-affinity receptor proteins located within target cells in mediating the biological action (3). Endocrine system disruption implies interference with a complex multicomponent process. Existing studies may be overly focused on estrogenic activity and reproductive and developmental endpoints, in addition to having other limitations. In the first place, proper selection of the chemicals to study is likely to be crucial for demonstrating any type of interactive effects. This is based on the fact that natural hormones and their agonists contain multiple molecular recognition domains (such as the A and D-ring domains in estradiol), which are distinct in the overall expression of activity (4). Hormone mimics (full agonists) must put into play a total interaction energy comparable to that of the natural hormone. The multifunctionality of hormones in molecular recognition processes may be important in dimerization or domain clustering processes involving either of two fundamental mechanisms by which information is relayed from one macromolecule to another in the cell; one involves allostery and the other proximity (5). These molecular properties are not limited to halogenated hydrocarbons, even though there has been preoccupation with this broad class of chemicals in endocrine disruptor projects funded by federal agencies (6). At a minimum, the chemicals selected for mixture study should represent structures containing each of the important recognition domains as well as combinations thereof. In addition, the potentially more important issue of antagonism (7) of natural endogenous hormones has been largely neglected. Antagonism implies a lower degree of molecular recognition and specificity because an antagonist only needs to block access to a receptor (4). The environmental significance of such probe mixtures in a real world contamination sense is another issue. However, identifying the important molecular recognition domains involved is important in delineating the …