Integrating Adaptive Responses Into Hormesis: δ Plot Analysis of the Yonezawa Effect in the Micronucleus Test

Objectives: Cells and organisms respond dynamically to environmental stimuli such as radiation and chemicals. Depending on the assay system, these responses have been described as hormesis, adaptive responses, J-shaped responses, and biphasic responses. In micronucleus assays using cultured cells, however, the intrinsically low baseline frequency of micronuclei makes it difficult to obtain a clear J-shaped dose-response curve characteristic of hormesis. To address this limitation, we conducted challenge and cross-challenge experiments. Methods: In challenge tests, cells were first exposed to low priming doses and then to a high challenging dose. In cross-challenge tests, cells were pretreated with low doses of one chemical (e.g., mitomycin C) and subsequently exposed to a high dose of another (e.g., AF-2). Results: In both approaches, pre-exposure suppressed micronucleus formation induced by the high dose. δ-Plot analysis was applied to quantify the Yonezawa effect, a well-established radiation-induced adaptive response. The data fit the δ-plot model well, indicating that the observed effects are consistent with hormesis as preconditioning. Conclusion: Because "adaptive response" is overly broad and terms such as "J-shaped response" or "biphasic response" are overly narrow, we propose integrating these phenomena under the concept of hormesis, providing a unified framework for interpreting low-dose biological effects.