Hormesis: U-shaped dose responses and their centrality in toxicology.

The fundamental nature of the dose response is neither linear or threshold, but rather U-shaped. When studies are properly designed to evaluate biological activity below the traditional toxicological threshold, low-dose stimulatory responses are observed with high frequency and display specific quantitative features. With a few exceptions, the low-dose stimulatory response is usually not more than twofold greater than the control response, with a stimulatory zone that is more variable, ranging from less than tenfold to more than several orders of magnitude of the dose. Considerable mechanistic evidence indicates that hormetic effects represent overcompensation in response to disruptions in homeostasis that are mediated by agonist concentration gradients with different affinities for stimulatory and inhibitory regulatory pathways.