Monte Carlo-Modelled Dose Calibration Curves for use in Modernized Biodosimetry

生物剂量测定（BD）是一种用于评估电离辐射（IR）剂量的工具。为了了解这种暴露的生物效应，需要进行准确的物理剂量测定。剂量-响应校准曲线（CC）是通过用已知剂量辐照血液样品并测量每个剂量的生物损伤来生成的。这一方法取决于有良好校准的物理剂量测定法和评估生物损害的方法。现有的测量暴露于IR的DNA损伤的实验方法是完善的，但是缓慢且昂贵。目前，最灵敏的检测方法的检测下限约为100 mSv。这些方法需要现代化，以特定于IR，具有出色的灵敏度，以准确测量和较低的剂量，并快速获得更高的样品通量。 蒙特卡罗（MC）建模是一种工具，可用于模拟各种辐射轨迹结构及其对DNA损伤的影响，包括由此产生的染色体几何形状和畸变。TOPAS-nBio等软件为研究亚细胞尺度的辐射生物学提供了强大的工具包，并极大地推进了这一研究领域。准确和知情的BD要求CC代表感兴趣的特定照射场景，包括相关剂量范围、剂量率以及辐射类型和质量。这项研究计划的长期目标是：（1）使用新技术实现BD方法的现代化;（2）建立经过验证的基于MC的方法来模拟CC，该方法可以根据暴露场景进行转换。这些模拟的CC将具有成本效益，并将允许更复杂的照射情景，如长期剂量率和混合束照射。今后五年的短期目标是：（1）建立血细胞中DNA损伤的经验证的MC模型，（2）验证通过FISH从X射线照射测量的易位的经建模的CC，（3）基于空间等效剂量估计宇航员BD的概念验证剂量，以及（4）在低剂量区（小于100 mSv）模拟生物损伤以外推CC。这项工作将在加拿大卫生部的一个政府研究实验室进行。至于建议项目的可行性，所需的许褚是随时可供使用的。此外，我们通过合作建立了良好的联系，可以根据需要访问其他资源和专业知识中心。HC制定了政策，优先考虑健康的工作环境，并在我们工作的各个方面促进多样性和包容性。所要求的资金将支持这一研究方案，重点是征聘和培训高素质的人员。这些结果将有助于理解空间环境和低剂量研究计划在生物相关剂量下不同辐射质量对DNA损伤的机制。

Biodosimetry (BD) is a tool for assessing the dose of ionizing radiation (IR) to which someone has been exposed. In order to understand the biological effects of this exposure, accurate physical dosimetry is required. Dose-response calibration curves (CC) are generated by irradiating blood samples with known doses and measuring the biological damage from each dose. This approach hinges on having well-calibrated physical dosimetry and methods to assess biological damage. Existing experimental methods measuring DNA damage from exposure to IR are well-established, but are slow and expensive. Currently the most sensitive of the assays has a lower limit of detection around 100 mSv. These methods need to be modernized to be specific to IR, to have excellent sensitivity to measure accurately and at lower doses and to be rapid for higher sample throughput. Monte Carlo (MC) modelling is a tool that can be used to simulate various radiation track structures and their implications for DNA damage including the resulting chromosomal geometry and aberrations. Software such as TOPAS-nBio provides a powerful toolkit to investigate radiation biology at sub-cellular scales and has greatly advanced this field of research. Accurate and informed BD requires CC that are representative of specific exposure scenarios of interest, including the relevant dose range, dose rate, and radiation type and quality. The long-term goals of this proposed research program are to (1) modernize BD methods using novel technologies and (2) establish validated, MC-based methods to model CC that could be transformed according to the exposure scenario. These modelled CC would be cost-effective, and would allow for more complex exposure scenarios such as protracted dose-rates and mixed beam exposures. Over the next five years, the short-term goals are to: (1) establish a validated MC model for DNA damage in blood cells, (2) validate a modelled CC for translocations as measured by FISH from X-ray exposures, (3) estimate a proof-of-concept dose for astronaut BD based on a space equivalent dose, and (4) model biological damage in the low dose regions (less than 100 mSv) to extrapolate CC. This work would take place in a government research laboratory at Health Canada (HC). Regarding feasibility of the proposed project, the necessary equipment is readily available and accessible for use. Furthermore, we are well-connected through collaborations to access other resources and centers of expertise as needed. HC has policies in place prioritizing healthy working environments, and promoting diversity and inclusivity in all aspects of our work. The funds requested would support this research program by focusing on the recruitment and training of highly qualified personnel. These results would help to understand the DNA damage mechanism from different radiation qualities at biologically relevant doses for both the space environment and the low-dose research programs.