FY05 LDRD Final Report Molecular Radiation Biodosimetry LDRD Project Tracking Code: 04-ERD-076

Jones, I M ; A.Coleman, M ; Lehmann, J ; Manohar, C F ; Marchetti, F ; Mariella, R ; Miles, R ; Nelson, D O ; Wyrobek, A J

Lawrence Livermore National Laboratory

关键词: 61 Radiation Protection And Docimetry;    63 Radiation, Thermal, And Other Environmental Pollutant Effects On Living Organisms And Biological Materials;    Biological Materials;    Chromosomal Aberrations;    Detection;   

DOI  :  10.2172/902308
RP-ID  :  UCRL-TR-218890
RP-ID  :  W-7405-ENG-48
RP-ID  :  902308

美国|英语

来源: UNT Digital Library

【 摘 要 】

In the event of a nuclear or radiological accident or terrorist event, it is important to identify individuals that can benefit from prompt medical care and to reassure those that do not need it. Achieving these goals will maximize the ability to manage the medical consequences of radiation exposure that unfold over a period of hours, days, weeks, years, depending on dose. Medical interventions that reduce near term morbidity and mortality from high but non-lethal exposures require advanced medical support and must be focused on those in need as soon as possible. There are two traditional approaches to radiation dosimetry, physical and biological. Each as currently practiced has strengths and limitations. Physical dosimetry for radiation exposure is routine for selected sites and for individual nuclear workers in certain industries, medical centers and research institutions. No monitoring of individuals in the general population is currently performed. When physical dosimetry is available at the time of an accident/event or soon thereafter, it can provide valuable information in support of accident/event triage. Lack of data for most individuals is a major limitation, as differences in exposure can be significant due to shielding, atmospherics, etc. A smaller issue in terms of number of people affected is that the same dose may have more or less biological effect on subsets of the population. Biological dosimetry is the estimation of exposure based on physiological or cellular alterations induced in an individual by radiation. The best established and precise biodosimetric methods are measurement of the decline of blood cells over time and measurement of the frequency of chromosome aberrations. In accidents or events affecting small numbers of people, it is practical to allocate the resources and time (days of clinical follow-up or specialists laboratory time) to conduct these studies. However, if large numbers of people have been exposed, or fear they may have been, these methods are not suitable. The best current option for triage radiation biodosimetry is self-report of time to onset of emesis after the event, a biomarker that is subject to many false positives. The premise of this project is that greatly improved radiation dosimetry can be achieved by research and development directed toward detection of molecular changes induced by radiation in cells or other biological materials. Basic research on the responses of cells to radiation at the molecular level, particularly of message RNA and proteins, has identified biomolecules whose levels increase (or decrease) as part of cellular responses to radiation. Concerted efforts to identify markers useful for triage and clinical applications have not been reported as yet. Such studies would scan responses over a broad range of doses, below, at and above the threshold of clinical significance in the first weeks after exposure, and would collect global proteome and/or transcriptome information on all tissue samples accessible to either first responders or clinicians. For triage, the goal is to identify those needing medical treatment. Treatment will be guided by refined dosimetry. Achieving this goal entails determining whether radiation exposure was below or above the threshold of concern, using one sample collected within days of an event, with simple devices that first responders either use or distribute for self-testing. For the clinic, better resolution of dose and tissue damage is needed to determine the nature and time sensitivity of therapy, but multiple sampling times may be acceptable and clinical staff and equipment can be utilized. Two complementary areas of research and development are needed once candidate biomarkers are identified, validation of the biomarker responses and validation of devices/instrumentation for detection of responses. Validation of biomarkers per se is confirmation that the dose, time, and tissue specific responses meet the reporting requirements in a high proportion of the population, and that variation among nonexposed people due to age, life-style factors, common medical conditions, variables that are not radiation related, do not lead to unacceptable frequencies of false negatives or false positives. Validation of detection requires testing of devices/instruments for accuracy and reproducibility of results with the intended reagents, sampling protocols, and users. Different technologies, each with intrinsic virtues and liabilities, will be appropriate for RNA and protein biomarkers. Fortunately, device and instrumentation development for other clinical applications is a major industry. Hence the major challenges for radiation biodosimetry are identification of potential radiation exposure biomarkers and development of model systems that enable validation of responses of biomarkers and detection systems.