Target medium oxygen consumption for different radiation qualities: chemical track structure simulations, experimental measurements, and relevance for ultra-high dose rate FLASH irradiationsONLINE ONLY

The radiosensitivity of biological systems is strongly affected by the system oxygenation as quantified by its oxygen enhancement ratio (OER). On the molecular level, this effect is considered to be strongly related to the indirect damage of radiation (damage mediated by the radiation induced chemical species). The latest extension of the GSI Monte Carlo particle track structure code TRAX can simulate the chemical track evolution for ion or electron radiation in water targets including the presence of dissolved molecular oxygen. Furthermore, we can investigate the impact of oxygenation on intra-irradiation pulse oxygen depletion and the related production of superoxide and perhydroxyl radicals in water targets.

In order to cross-check our benchmarked simulations and to complement them with results on target media other than water, we have recently started a series of experiments on radiation-induced oxygen depletion. Radiolytic oxygen removal in sealed containers is also closely linked to the production yields of peroxyl radicals (in the case of water, O2•− and HO2•) and can therefore provide important information for modelling and eventually also an estimation of radiation damage. We developed a set-up based on an optical sensor for oxygen detection and here we will present the data thus obtained in biologically relevant fully oxygenated samples and for different radiation qualities. Oxygen consumption yields for water samples are compared to the theoretical predictions and the influence of the target composition is investigated for the more chemically complex solutions.

Last, based on a mechanistic model for radiolytic yields at 1 µs, we examine the difference between FLASH and conventional irradiation with electrons, protons, and C ions. For low LET radiation, a significant oxygen consumption in the target at realistic doses is observed only for very hypoxic starting conditions. When accounting for a proportional contribution by carbon-centered radicals to mimic a more realistic chemical environment, the effect is still not compatible with in vivo experimental evidence. According to our model, the oxygen depleted after a pre-clinical experimental dose of 30 Gy in physioxic conditions leads to a 1.7% decreased ROS production but shows no effect on OER-weighted dose. In hypoxia representative of radioresistant tumors (<1% pO2), >20% less ROS production and >6% less DOER are predicted, contrarily to the supposed normal tissue sparing.

For high LET radiation expected in target, radical yield and oxygen depletion are considerably reduced due to early intra-track recombination of the chemical species, so that analogous effects appear at even higher doses.

Taken together, our results rule out pure oxygen depletion as the main responsible of better normal tissue radioresistence (“FLASH effect”) observed in ultra-high dose rate radiotherapy. Instead, the formation and reactions of organic radicals are expected to play a major role in biological tissues and could also differentiate conventional and “FLASH” irradiation regimes.