Dose and dose rate dependence of the tissue sparing effect at ultra-high dose rate studied for proton and electron beams using the zebrafish embryo model.

Purpose: A better knowledge of the dependence of the tissue sparing effect at ultra-high dose rate (UHDR) on physical beam parameters (dose, dose rate, radiation quality) would be helpful towards a mechanistic understanding of the FLASH effect and for its broader clinical translation.
To address this, a comprehensive study on the normal tissue sparing at UHDR using the zebrafish embryo (ZFE) model irradiated with protons and electrons was conducted.

Methods: 1 day old ZFE were irradiated over a wide dose range (15-95 Gy) in three different beams (proton entrance channel, proton spread out Bragg peak and 30 MeV electrons) at UHDR and reference dose rate. After irradiation the ZFE were incubated for 4 days and then analyzed
for their development and morphological characteristics.

Results: Dose-effect curves for four different biological endpoints of ZFE (pericardial edema, curved spine, embryo length and eye diameter) were obtained and a sparing effect was observed for all three beams. It was demonstrated that proton relative biological effectiveness and UHDR sparing are both relevant to consider in order to predict the resulting dose response. Dose dependent FLASH modifying factors (FMF) for ZFE, calculated based on the obtained dose-effect curves, were found to be compatible with rodent data from the literature. It was found that the UHDR sparing effect saturates at doses above ~50 Gy with an FMF of ~0.7-0.8. Only a moderate dependence of the tissue sparing effect in ZFE on the biological endpoint, but a strong dose rate
dependence were observed.

Conclusion: The ZFE model was shown to be a suitable high-throughput pre-clinical model for radiobiological studies on FLASH radiotherapy, providing results comparable to rodent models. The obtained results emphasize to further clarify the nature of the observed dose rate dependence.