Much confusion surrounds the concept of hormesis and what its biological meaning represents. This paper provides a definition of hormesis that addresses its historical foundations, quantitative features, and under-lying evolutionary and toxicologically based mechanistic strategies. Hormesis should be considered an adaptive response characterized by biphasic dose responses of generally similar quantitative features with respect to amplitude and range of the stimulatory response that are either directly induced or the result of compensatory biological processes following an initial disruption in homeostasis. Given the limited magnitude of the stimulatory response (i.e., usually 30–60% greater than controls at maximum), heightened study design and replication requirements are often necessary to ensure reliable judgments on causality. Even though hormesis is considered an adaptive response, the issue of beneficial/harmful effects should not be part of the definition of hormesis, but reserved to a subsequent evaluation of the biological and ecological context of the response.

Hormesis, a dose-response relationship phenomenon characterized by low-dose stimulation and high-dose inhibition, has been frequently observed in properly designed studies and is broadly generalizable as being independent of chemical/physical agent, biological model, and endpoint measured. This under-recognized and -appreciated concept has the potential to profoundly change toxicology and its related disciplines with respect to study design, animal model selection, endpoint selection, risk assessment methods, and numerous other aspects, including chemotherapeutics. This article indicates that as a result of hormesis, fundamental changes in the concept and conduct of toxicology and risk assessment should be made, including (a) the definition of toxicology, (b) the process of hazard (e.g., including study design, selection of biological model, dose number and distribution, endpoint measured, and temporal sequence) and risk assessment [e.g., concept of NOAEL (no observed adverse effect level), low dose modeling, recognition of beneficial as well as harmful responses] for all agents, and (c) the harmonization of cancer and noncancer risk assessment.

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The occurrence of U-shaped dose-response relationships (often termed hormesis) has been documented in numerous biological, toxicological, and pharmacological investigations. Many of the endpoints studied are of considerable significance to public health (e.g. body weight, cholesterol levels, ethanol consumption, longevity, cancer incidence, etc). Despite the fact that U-shaped dose-responses are widely and independently observed, little attempt has been made to assess this phenomenon in an integrative manner. This review provides an overview of the historical foundations of hormesis and a discussion of its definition within a mechanistic framework. The occurrence, generalizability, and biological significance of U-shaped dose-response relationships along with the concept of biological optimality are addressed.