Linking microdosimetric measurements to biological effectiveness: a review of theoretical aspects of MKM and other models

Different qualities of radiation are known to cause different biological effects at the same absorbed dose. Enhancements of the biological effectiveness are a direct consequence of the energy deposition clustering at the scales of DNA molecule and cell nucleus whilst absorbed dose is a macroscopic averaged quantity which does not take into account heterogeneities at the nanometer and micrometer scales. Microdosimetry aims to measure radiation quality at cellular or sub-cellular levels trying to increase the understanding of radiation damage mechanisms and effects. A review of the major models based on experimental microdosimetry, with an emphasis on the Microdosimetric Kinetic Model (MKM) will be presented in this work, enlightening the advantages of each one in terms of accuracy, initial assumptions and agreement with experimental data. The MKM has been used to predict different kinds of radiobiological quantities such as the Relative Biological Effects for cell inactivation or the Oxygen Enhancement Ratio (OER). Recent developments of the MKM will be also presented, including new non-Poissonian correction approaches for high linear energy transfer (LET) radiation, the inclusion of partial repair effects for fractionation studies and the extension of the model to account for non-targeted effects. We will also explore developments for improving the models by including track structure and the spatial damage correlation information by using the full fluence spectrum and, briefly, nanodosimetric quantities to better account for the energy-deposition fluctuations at the intra- and inter-cellular level.