MODELLING RADIOBIOLOGY EFFECTS OF X-RAYS IN SMALL LABORATORY ANIMALS TO DEVELOP GUIDELINES FOR PRECLINICAL COMPUTED TOMORGRAPHY IMAGING

通过x射线获得的图像为医生提供解剖学信息，并协助诊断或发展健康问题。以类似的方式，这种成像技术用于临床和临床前研究。当医生或临床研究中使用时，一个人接受的x射线（电离辐射）剂量是有规定的。这在临床前研究中是不正确的，因为x射线剂量是未知的，不受管制的，也没有指导方针。过度暴露可能会给动物造成不必要的痛苦，并可能影响研究结果，特别是在纵向研究中。本项目的目标是通过改进CT成像实验方法，制定x射线（CT）剂量指南，以尽量减少或消除任何动物的痛苦，减少使用的动物数量。多年来，人们已经知道电离辐射会导致细胞/DNA损伤。例如，电离辐射被用作癌症治疗来杀死细胞。世界癌症研究中心和英国癌症研究中心提倡继续进行临床前癌症研究，但寻求改进的、更可靠的结果。临床前癌症研究的一个主要部分是药物开发、测试、肿瘤治疗和放射治疗。这类研究通常包括CT、PET/CT或SPECT/CT。回顾最近10项使用啮齿动物进行的临床前癌症研究（536,000年），平均每项研究n=60只啮齿动物。这相当于3200万只啮齿动物。在1年多的时间里，局部使用了250只啮齿动物进行PET/CT研究。改进CT方法可能会将使用的啮齿动物数量减少20%至200只。使用20%的度量标准和类似的研究趋势，在癌症研究中有可能挽救1,60,000,000只啮齿动物。此外，药物研究已经超越了癌症治疗，在过去的5年里完成了超过28.6万项临床前研究。在相同的指标和n=50的情况下，药物研究中的啮齿动物数量可以减少到< 1200万。随着研究需求的增加，需要了解x射线的影响。可以通过在临床研究和癌症治疗计划中常规使用的成熟的辐射模拟软件来获得理解。模拟工具具有20年有效、可靠和一致的预测，剂量计算算法精度优于1%，提供器官、细胞和DNA电离辐射损伤的详细信息。该项目旨在使用这些模拟技术来评估临床前电离辐射的影响，并通过x射线束测量进行验证。辐射模拟完全取代了动物，确定了辐射阈值，并设定了基础的临床前CT剂量规则。了解临床前x射线剂量的生物学效应提供了答案，改进了CT实验方法，提高了结果的稳健性和可靠性；减少动物数量。此外，去年，在与癌症或药物研究无关的研究中，有10万只啮齿动物接受了CT、PET/CT或SPECT/CT检查。这显示了CT的广泛应用，可能有10万只啮齿动物遭受了不必要的痛苦，可能有2万只啮齿动物是不必要的。临床前研究界认识到需要并正在追求成像方法和电离标准的改进。最近，开辟了若干传播这方面研究的途径。欧洲分子成像学会（ESMI）和核医学和分子成像学会设立了专门的委员会和会议论坛。该资助机构通过博客和F1000网关开放访问提供出版支持和结果传播。传播、政策制定和实施的关键机会是在EMSI标准委员会，该申请人是该委员会的主要成员。该项目的结果将对英国、欧洲和美国的临床前成像产生重大影响。（检索：ISI Web of Science 8/2019）。

Images acquired by X-rays provide doctors with anatomical information and assist in diagnoses or progression of health problems. In a similar manner, this imaging technique is used for clinical and preclinical research. When used by doctors or in clinical research the amount of X-ray (ionizing radiation) dose a person receives is regulated. This is not true in preclinical research where overexposure to ionizing radiation occurs since X-ray doses are unknown, unregulated and there are no guidelines. Overexposure potentially causes unnecessary suffering to animals and may impact research results, especially in longitudinal studies. The goal of this project is to set X-ray (CT) dose guidelines in order to minimize or eliminate any animal suffering and reduce the number of animals used by refining CT imaging experimental methods. It has been known for years that ionizing radiation causes cell/DNA damage. For instance, ionizing radiation is used as a cancer treatment to kill cells. Worldwide Cancer Research and Cancer Research UK are advocating for continued preclinical cancer research but seek improved, more reliable results. A major part of preclinical cancer research is drug development, testing, tumour treatment and radiotherapy. This type of research generally includes CT, PET/CT or SPECT/CT. Reviewing 10 of the most recent preclinical cancer studies using rodents (>536,000, 5yrs) the average per study was n=60 rodents. This equates to >32,000,000 rodents. Locally, 250 rodents were used in PET/CT research studies over 1 year. Refining the CT method potentially would reduce the number of rodents used by 20% to 200 rodents. Using the 20% metric and similar research trend, the potential to save >6,000,000 rodents exits in cancer studies. Furthermore, drug research extends beyond cancer treatment with over 286,000 preclinical studies done in the last 5 years. With the same metrics and n=50, >14,000,000 rodents could be reduced to <12,000,000 in drug research. Along with the demand for increased research the demand for understanding the impact of X-rays is needed. Understanding can be gained with well-established radiation simulation software used routinely in clinical research and cancer treatment planning. Simulation tools have 20 years of valid, reliable and consistent predictions with dose calculation algorithms accuracies better than 1%, providing details on organ, cell and DNA ionizing radiation damage. This project is designed to use these simulation techniques to evaluate the impact of preclinical ionizing radiation along with X-ray beam measurements for validation. Radiation simulations completely replace animals, determine radiation thresholds and set foundational preclinical CT dose regulations. Knowing the biological effects of preclinical X-ray doses provides answers, refines CT experimental methods, improves robustness and reliability of outcomes; reducing number of animals. Additionally, last year >100,000 rodents received a CT, PET/CT or SPECT/CT in studies unrelated to cancer or drug research. This demonstrates CT is widely used, potentially 100,000 rodents may have suffered unnecessarily and possibly 20,000 rodents weren't needed. The preclinical research community recognizes the need for and is pursuing improvements in imaging methods and ionizing standards. Recently, several avenues for dissemination of research in this regard opened up. The European Society for Molecular Imaging (ESMI) and the Society of Nuclear Medicine and Molecular Imaging set up specific committees and conference forums. This funding body offers publication support and dissemination of results through blogs and the F1000 gateway open access. A key opportunity for dissemination, policy making and implementation is in the EMSI STANDARD committee, which this applicant is a lead member. Results from this project will have a substantial future impact on preclinical imaging in the UK, Europe and USA. (Searches:ISI Web of Science 8/2019).