Risk of Leukemia after Protracted Exposures to Low Doses of Ionizing Radiation

描述(申请人提供)：背景：大量美国人口通过职业暴露或背景辐射接触到小剂量辐射。额外的辐射暴露来自最近X光和计算机断层扫描等诊断放射学检查的使用增加。公众对暴露在辐射中的短期和长期健康影响的担忧，特别是白血病，这是最容易被辐射诱发的癌症之一，而建造新的核电站和辐射废物处理场的提议进一步加剧了公众的担忧。虽然高剂量和中剂量的电离辐射对白血病的影响已在许多研究中得到证实，但低剂量的影响尚不清楚。为了在这一领域进行研究并发展我的科学事业，我需要在四个目标领域进行额外的培训和指导，包括流行病学研究的设计和实施、遗传和分子流行病学的研究方法、分析与辐射相关的风险和基因-环境相互作用的高级统计培训，以及关于科学研究、手稿写作和拨款准备的道德行为的一般培训。目的：我们建议从一个新的多学科角度研究低剂量电离辐射暴露与白血病风险之间的关系，并评估环境和遗传因素在癌症发生中的作用。总体科学目标是扩大与辐射有关的白血病风险的现有研究机构，公共卫生目标是量化这种风险，将其解释为确定辐射安全限度，告知辐射者以及普通公众，并制定预防战略。我的个人目标是利用加州大学旧金山分校流行病学和生物统计学系、人类遗传学研究所和海伦·迪勒家庭综合癌症中心的资源，以及我的杰出导师团队，成为辐射癌症流行病学的独立研究员。我的长期目标是整合流行病学方法、统计模型和分子流行病学的知识，寻找辐射暴露的易感因素。研究和培训计划：在三项拟议研究中的第一项(辐射生物标记物研究)中，我们建议使用各种细胞遗传学测试来分析以前从Chornobyl清洁工人那里收集的口腔细胞，以了解辐射暴露的持久影响。此外，我们将收集新的唾液样本，并将辐射损害与通过RADRUE方法从问卷中估计的剂量关联起来。在第二项研究(基因多态研究)中，通过对两个已知与电离辐射暴露和白血病风险增加相关的癌基因(AML1和MLL)进行基因测试，将获得关于辐射后白血病发生的生物学机制的新信息。在风险分析研究中，来自Chornobyl清理工人的白血病研究的数据将与加拿大荧光队列研究的数据相结合，以估计白血病的辐射依赖风险，并将它们与高剂量研究预测的风险进行比较。我们还提出了一项围绕感知需求建立的全面培训计划，包括由三名导师和几名顾问和贡献者提供的一对一培训、正式课程、实际实验室轮换、研讨会和会议。加州大学旧金山分校的医学中心以其合作研究精神和许多旨在促进研究和年轻研究人员个人成长的培训计划和奖学金而闻名。加州大学旧金山分校是获得NIH研究资金金额最多的两所学校之一，并以坚定地致力于指导年轻研究人员而闻名。癌症相关性：这个项目将提高我们对低剂量电离辐射对白血病发生的影响的理解，并解决与辐射相关的致癌知识中的一些剩余空白。这些数据还将提供一个难得的机会，来探索低剂量辐射暴露是否存在致癌效应，以及比较辐射暴露的各种生物标志物的质量和耐用性。研究结果将有助于评估诊断辐射程序造成的低剂量辐射照射的风险，并解决目前公共和职业辐射安全限值的适当性问题，这些限值主要基于对暴露于高剂量电离辐射的受试者的研究。

DESCRIPTION (provided by applicant): Background: Large groups of the U.S. population come in contact with small doses of radiation through occupational exposures or from background radiation. Additional radiation exposures come from the recent rise in utilization of diagnostic radiology examinations such as x-rays and computed tomography scans. Public's concern about the short and long-term health effects of exposure to radiation, especially leukemia, one of the cancers most susceptible to induction by radiation, is further fueled by proposals to build new nuclear power plants and radiation waste disposal sites. While the effects of high and moderate doses of ionizing radiation on leukemia have been shown in many studies, the effects of lower doses are not clear. To conduct research in this area and to develop my scientific career, I need additional training and mentoring in four target areas, including design and conduct of epidemiological studies, research methods in genetic and molecular epidemiology, advanced statistical training to analyze radiation-related risks and gene-environment interactions, and general training in the ethical conduct of scientific research, manuscript writing and grant preparation. Objective: We propose to examine the association between exposures to low doses of ionizing radiation and risk of leukemia and to assess the role of environmental and genetic factors in carcinogenesis from a new multidisciplinary perspective. The overall scientific objective is to expand the existing body of research on radiation-related risks of leukemia and the public health objective is to quantify such risks, interpret them for the setting of radiation safety limits, inform those exposed to radiation, as well as the general public, and develop preventive strategies. My personal goal is to use the resources of the Department of Epidemiology and Biostatistics, the Institute for Human Genetics and the Helen Diller Family Comprehensive Cancer Center at UCSF and my team of outstanding mentors to become an independent researcher in radiation cancer epidemiology. My long-term goal is to integrate knowledge of epidemiological methods, statistical modeling, and molecular epidemiology in the search for susceptibility factors of radiation exposures. Research and Training Plan: In the first of the three proposed studies (Radiation Biomarkers study), we propose to use various cytogenetic tests to analyze buccal cells previously collected from Chornobyl clean-up workers for lasting effects of radiation exposure. In addition, we will collect new samples of saliva and correlate radiation damage with doses estimated from questionnaires by the RADRUE method. In the second study (Gene Polymorphism study), new information on the biological mechanism of leukemogenesis after radiation exposure would be obtained by conducting genetic tests of two oncogenes (AML1 and MLL) known to be associated both with ionizing radiation exposure and with increased risk of leukemia. In the Risk Analysis study, data from the Leukemia study of Chornobyl clean-up workers will be combined with the data from the Canadian Fluoroscopy Cohort study to estimate radiation-dependent risks of leukemia and to compare them to the risks predicted from high-dose studies. We also propose a comprehensive training plan built around perceived needs, including one-on-one training with three mentors and several consultants and contributors, formal courses, practical laboratory rotations, seminars and meetings. The medical center at UCSF is known for its collaborative research spirit and its many training programs and fellowships geared toward promoting research and the individual growth of young investigators. UCSF is one of the top two schools in the amount of NIH research funding received and is known for its strong commitment to mentoring of young researchers. Cancer relevance: This project will improve our understanding of the effects of low doses of ionizing radiation on development of leukemia and address a number of remaining gaps in knowledge with respect to radiation- related carcinogenesis. The data will also allow a rare opportunity to explore the existence of carcinogenic effects of radiation exposure at low doses as well as to compare the quality and durability of various biological markers of radiation exposure. Study findings will help evaluate the risks of low-dose radiation exposure from diagnostic radiation procedures and address appropriateness of current public and occupational radiation safety limits which are primarily based on the studies of subjects exposed to high doses of ionizing radiation.