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

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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.