A GENERAL CLASSIFICATION OF U-SHAPED DOSE-RESPONSE RELATIONSHIPS IN TOXICOLOGY AND THEIR MECHANISTIC FOUNDATIONS

The development of a comprehensive database of chemical hermetic respo nses (i.e., U- or inverted U-shaped dose-response relationships) using objective a priori study design, statistical and study replication cr iteria has recently been reported.(1) An assessment of this database r eveals the existence of a wide range of hermetic dose-reponse relation ships including those demonstrating a direct stimulation or an overcom pensation response to a disruption of homeostasis. These two broad typ es of hermetic responses are affected by temporal factors and display unique patterns of dose-range stimulation, magnitude of stimulatory re sponse and relationship of the maximum stimulatory response to the NOA EL. A general classification of U-shaped dose-response relationships i s proposed to provide a more organized framework to evaluate the highl y distinctive and diverse hermetic responses within the context of est ablishing underlying biological mechanisms and exploring risk assessme nt implications.