Adaptive response and human benefit: Part I. A microdosimetry dose-dependent model.

PURPOSE: It is important to evaluate how adaptive response may be of human benefit from the risks of ionizing radiation. The purpose of this work is to develop and apply a microdosimetric dose response model capable of explicitly determining, for broad beam exposures, the threshold and progressive activation of natural spontaneous and radiation damage protective mechanisms associated with adaptive response and other cellular negative response behavior.
MATERIALS AND METHODS: A biophysical model was developed quantifying the accumulation of Poisson distributed microdose specific energy hits to cell critical nucleus volumes. The model was applied to the adaptive response data of Wiencke et al., Redpath et al., Azzam et al. and Pohl-Ruling et al. The model was also applied to non-adaptive response data showing dose response reductions below the zero dose natural spontaneous level and to data exhibiting mid-range non-monotonic dose response plateaus.
RESULTS: We find good fits of the model to all data. For adaptive response, a significant result is, that only one or two specific energy hits of low linear energy transfer (LET) radiation in the cell nucleus activates the protective mechanisms for both the natural spontaneous and radiation damage. Several data support a dose plateau for radon progeny alpha production of chromosome aberrations in human lymphocytes. Using the model, a bystander factor of about 30 is obtained with the model for high dose rate, in vitro alpha particle data. For low dose rate in vivo, the bystander effect is minimal suggesting for alphas that the bystander effect may be dose rate dependent. There is no evidence of bystander effects in the low LET adaptive response data analysis.
CONCLUSIONS: The microdosimetry model allows concise determinations of specific energy hits within the cell critical nucleus volume to activate both protective and damage mechanisms. One or two low LET hits can result in reduction of both zero dose natural spontaneous and radiation-induced, carcinogenic causing damage. The model should be useful in comparing in vitro and in vivo broad beam to single track microbeam exposure data. The model is capable of determining, to an accuracy of +/- one specific energy hit, the minimum threshold for induction of radioprotective mechanisms--crucial to assessing the potential human benefit of adaptive response and other negative dose response behavior.