Hormesis, adaptation, and the sandpile model.

Hormesis, characterized by stimulation (or inhibition) along some portion of the dose-response curve followed by its opposing action along some other portion of that curve, speaks to all those dose-response relationships characterized by a change in sign and reversal in direction of the curve as it progresses along the x axis (a nonmonotonic dose-response curve). Although this is better known in toxicology than in pharmacology, it behooves all clinicians to appreciate that if a particular dose of a medication is not efficacious, it does not necessarily follow that a higher dose will be more efficacious. The point of maximum stimulation (variable from individual to individual and variable within an individual over time) might be such that a lower dose of the medication would prove more therapeutic. Calabrese's hypothesis is that hormesis is a manifestation of the body's adaptive response to stress. This commentary emphasizes the importance of recognizing that such adaptations are always accomplished at some cost to the system in terms of its adaptation (nutrient and energetic) reserves. There is no gain without pain. Finally, the sandpile, a complex adaptive system whose evolution is characterized by iterative cycles of collapse and recovery, disruption and repair, challenge and adaptive reconstitution, may be a useful model for the cumulative impact over time of stress on the body, highlighting the complex nature of the body's responsiveness to varying degrees of stress.