The traditional testing paradigm in toxicology is based on the 16th century concept that “the dose makes the poison” or as dose increases toxicity always increases; thus, all dose-response curves are assumed to be monotonic. However, the discovery that many chemicals used in plastic, pesticides and other products have the capacity to disrupt the normal functioning of the endocrine system has forced a paradigm shift in toxicology, since a common feature of endocrine-active compounds is non-monotonicity. The basis for non-monotonic dose-response relationships for hormonally active chemicals is that many interact with cellular receptors that are “tuned” to respond to very low concentrations. At very low concentrations of a hormone, stimulation of an increase in receptors for the hormone in tissues often occurs, leading to an increase in sensitivity to the hormone. However, much higher doses of the hormone inhibit these receptors, leading to a decrease in sensitivity to the hormone and the absence of the responses that occur at low-doses. Thus, at very high doses hormones stimulate entirely different suites of responses relative to low doses. Nonetheless, despite decades of research and thousands of published studies demonstrating the non-monotonic dose-response relationship for endocrine active compounds, traditional very high-dose testing procedures are still used by regulatory bodies throughout the world to assess the risks posed by all manmade chemicals. These testing procedures will produce false estimates of safety for any endocrine disrupting chemical.