A general classification of U-shaped dose-response relationships in toxicology and their mechanistic foundations

The development of a comprehensive database of chemical hormetic responses (i.e., U-or inverted U-shaped dose-response relationships) using objective a priori study design, statistical and study replication criteria has recently been reported. 1 An assessment of this database reveals the existence of a wide range of hormetic dose-reponse relationships including those demonstrating a direct stimulation or an overcompensation response to a disruption of homeostasis. These two broad types of hormetic responses are affected by temporal factors and display unique patterns of dose-range stimulation, magnitude of stimulatory response and relationship of the maximum stimulatory response to the NOAEL. A general classification of U-shaped dose-response relationships is proposed to provide a more organized framework to evaluate the highly distinctive and diverse hormetic responses within the context of establishing underlying biological mechanisms and exploring risk assessment implications.