Abstract
BACKGROUND: Micronuclei (MN), which are chromosome fragments, are formed after exposure to ionizing radiation. Radiation-induced MN is currently used as a quantitative indicator of the chromosomal aberrations detectable at a relatively early phase (e.g., within one cell-cycle progression). Meanwhile, the MN formation assay is also used to evaluate radiosensitivity (e.g., cell-killing). As such, the technique to assay the MN formation has been followed with increasing interest. However, the meaning of MN and the corresponding cellular responses remains uncertain. PURPOSE: This study presents a biophysical model for estimating MN frequency and theoretically explores the cellular responses associated with MN formation, such as the relationship between MN formation and cell survival. METHODS: We used an integrated microdosimetric-kinetic (IMK) model that allows the prediction of cell survival after radiation exposure, and we extended the IMK model by introducing a probability of MN formation from lethal lesions by misrepair. To validate the developed model, we estimated the dose, linear energy transfer (LET), and dose-rate dependencies of MN frequency as well as its relative biological effectiveness (RBE(MN)) and compared them to the corresponding experimental data reported in the literature and measured in this study. The estimation approach of MN frequency from cell survival data and vice versa was also tested. RESULTS: Our developed IMK model enables the prediction of the MN formation frequency and the RBE(MN) depending on LET and dose rate for both cancer and normal cells. Comparing the experimental data within this work and the literature, the modeling study clearly shows that radiation-induced MN is intrinsically related to cell killing after radiation exposure. Our model analyses confirmed that the RBE values for cell survival and MN frequency are equivalent under the same irradiation conditions. CONCLUSIONS: The present model indicates that the analysis of MN is useful in both radiation therapy and radiation protection to quantitatively evaluate curative effects and histological damage at early stages after exposure.