Occupancy-driven attenuation in radiation-sensitive chromatin domains as a statistical-mechanical model of the overkill effect and RBE maximum

The reduction in biological effectiveness at high linear energy transfer (LET), commonly referred to as the overkill effect, remains an active area of investigation in high-LET radiobiology. Here, we present a statistical-mechanical framework in which attenuation emerges from the progressive occupancy of a finite population of radiation-sensitive chromatin domains. An effective free-energy formalism is used to describe the equilibrium occupancy state, yielding an LET-dependent occupancy fraction and an attenuation function representing the fraction of chromatin domains remaining available for the formation of additional biologically independent lethal events. The model predicts a continuous occupancy transition accompanied by a fluctuation maximum, identifying a characteristic LET range in which occupancy effects become most pronounced. When combined with a previously published LET-dependent damage-production model for carbon-ion irradiation of V79 cells, the framework predicts a maximum in lethal-lesion yield followed by a decline despite continued increases in damage production. The qualitative comparison of the RBE data in published works reveals the typical pattern of growth, peak value, and decline of the biological effectiveness, although the predicted values of the RBE continue to be lower than the experimental ones. These results suggest that finite chromatin-domain occupancy may provide a possible physical interpretation of attenuation, the overkill effect, and the emergence of an RBE maximum.