Alternative Approaches to Dose–Response Modeling of Toxicological Endpoints for Risk Assessment: Nonmonotonic Dose Responses for Endocrine Disruptors

Characterization of the dose response is an important step in the risk assessment process. For years, risk assessment agencies have relied on the toxicological principle that “the dose makes the poison” and that effects scale linearly with dose. Yet, there are numerous examples from vitamins, essential nutrients, hormones, and environmental chemicals that defy this simplistic expectation. Nonmonotonic dose responses have been reported in hundreds of studies of endocrine-disrupting chemicals, and further evaluations have revealed a number of mechanisms responsible for these curves. This article reviews evidence supporting the existence of nonmonotonic dose responses and discusses why these have continued to generate controversy. It concludes with an explanation of how deviations from linear dose responses can make the determination of ”safe” levels of exposure difficult using traditional risk assessment procedures.