Relative biological effectiveness of simulated solar particle event proton radiation to induce acute hematological change in the porcine model

摘要

Yucatan minipigs aged 8–14 weeks were purchased from Sinclair Bio Resources, LLC (Auxvasse, MO) and acclimated for 7 d in the Loma Linda University Medical Center (LLUMC) animal facility prior to beginning the experiments. The animals were housed individually with ad lib access to water and fed twice daily with standard minipiglet chow. The animal care and treatment procedures were approved by the Institutional Animal Care and Use Committee of the LLUMC and the University of Pennsylvania. In the pSPE radiation experiment, the animals were exposed to beams comprised of protons with energy distribution up to 155 MeV and a custom depth dose profile designed to closely resemble the September 1989 SPE radiation, as with the eSPE. The source, modulation and characterization of the proton beams as well as the proton dose calibration, delivery and monitoring have previously described in detail [14], and these details are not repeated here. Briefly, the characterization of the proton beam was completed using radiographic film, radiochromic film and ionization chambers. The Geant4-based Monte Carlo dose-modeling software tool was utilized to estimate dose to specific organs. A detailed description of the radiation transport simulation and dose distribution analysis will appear in a future publication and has been omitted here because it is beyond the scope of this work. Briefly, a model of the electron beam used in these studies was developed and validated against measurements of lateral and depth dose profiles of the electron beam used at PENN. The proton beam was modeled as a broad parallel beam with energies chosen to closely match the depth dose profile of the proton beam provided at LLUMC. The software incorporates computed tomography (CT) images of appropriately sized Yucatan minipigs to construct the computational geometry which was used for the calculation of 3-D dose distributions during the radiation transport simulation. The experiments reported here were simulated using the electron and proton beam models with beam angles varied to correspond to the average animal orientation during irradiations at PENN and LLUMC. Organ doses were computed for each irradiation scenario by accumulating the 3-D dose distribution within organ volumes, which were delineated on the same CT sets used in these simulations. For both the electron and proton irradiation exposures, animals were not anesthetized but restrained in custom-made, aerated plexiglass chambers ～ 31 (w) × 69 (l) × 36 cm (h). Animal exposures were ～ 3 h long, with a dose rate of 0.83 Gy/min for the pSPE exposures and an average dose rate of 1.1 Gy/min for the eSPE exposures. To ensure uniform whole-body irradiation, irradiation chambers were rotated at regular dose intervals. At 4 h, at 1, 4 (protons only), 7 (electrons only), 14 and 30 d after the proton or electron radiation exposure, a whole-blood sample was collected from each animal (cranial vena cava), and placed into a collection tube containing EDTA. The blood samples (refrigerated) were sent to Antech Diagnostics (Irvine, CA, with numerous laboratories in the USA) and analyzed using a Bayer Advia 120 Hematology Analyzer within 24 h of the blood sample collection. The mean counts of WBCs, lymphocytes, neutrophils, monocytes, eosinophils, red blood cells (RBCs) and platelets of all animals before irradiation were calculated for each experiment and used as the baseline control values for the respective blood cell types in the same experiment. For each animal at each time-point after irradiation, the count of each blood cell type was divided by the respective baseline control value, and the result was expressed as a fraction of the control for further analyses.