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Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment? HEALTH EFFECTS OF EXPOSURE TO LOW LEVELS OF IONIZING RADIATIONS: Time for Reassessment? EXECUTIVE SUMMARY The US Environmotection Agency Office of Radiation and Indoor Air asked the National Research Council to evaluate whether sufficient new data exist to warrant a reassessment of health risks reported in Health Effects of Exposure to Low Levels of Ionizing Radiations (BEIR V) in 1990. To respond to this request, the National Research Council assembled the Committee on Health Risks of Exposure to Low Levels of Ionizing Radiations. The work of the committee was conducted in what was called the BEIR VII phase-1 study. To assist the committee during its deliberations, various scientists were consulted for advice, and a workshop on the impact of biology on risk assessment was held in collaboration with the Department of Energy Office of Health and Environmental Research. The intent of the workshop was to address the implications of new understanding of the biologic basis of radiation injury and carcinogenesis for risk assessment. The following is a synopsis of the conclusions of the BEIR VII phase-1 study: Information that has become available since the 1990 publication of Health Effects of Exposure to Low Levels of Ionizing Radiations (BEIR V) makes this an opportune time to proceed with BEIR VII phase-2, a comprehensive reanalysis of health risks associated with low levels of ionizing radiations. Such a study should begin as soon as possible and is expected to take about 36 months to complete.
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Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment? The committee based that judgment on the following considerations: Substantial new epidemiologic evidence has accumulated since the 1990 BEIR V report was published. The present committee's phase-1 report cites 39 new epidemiologic studies that fall into this category (see Table 1). Additional studies that have a direct bearing on the subject should become available in the next 3 years, the estimated period required to complete the phase-2 study. Some of the new epidemiologic data are on subjects on which information previously had been sparse, such as cancer mortality in those exposed to whole-body irradiation in childhood. Studies of carcinogenesis completed since publication of the last BEIR report have focused on mechanisms and the cellular and molecular events that are involved in the neoplastic process. The understanding of molecular events involved in carcinogenesis has increased significantly. Mechanisms that might be involved in radiation carcinogenesis have been identified. Further knowledge of these mechanisms that should become available in the next 3 years might affect estimation of the radiation-response curve at low doses. Over the next few years, investigators will be applying two closely linked approaches using animal models of carcinogenesis. These will likely contribute to a better understanding of mechanisms of radiation-induced cancer. In the first of these two approaches, genetically engineered mice with alterations in specific genes will be used to determine the influence of these genes on the susceptibility of the mice to radiation-induced cancer. In the second approach, studies will be conducted of the inherent differences in susceptibility to radiation-reduced cancer among different mouse strain, the objective being to identify the genes involved in controlling susceptibility. Researchers responsible for this new generation of animal studies are taking advantage of the current rapid developments in molecular genetics. Progress on both approaches should be substantial over the next few years. Significant results of relevance to risk estimation are expected to be available for the proposed BEIR VII phase-2 study. Evidence regarding specific biologic events that can affect the shape of the dose-response curve at low doses is accumulating. Information on such phenomena as DNA repair, signal transduction, chromosomal instability, ''bystander" effects, and adaptation, although preliminary, might eventually affect risk analyses of low-dose and low-dose-rate exposures. The Committee Recommends That the Individuals Responsible for the Proposed Phase-2 Study Include a comprehensive review of all relevant epidemiologic data related to low-LET (low linear energy transfer), i.e. sparsely ionizing, radiation.
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Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment? Define and establish principles on which quantitative analyses can be based, including requirements for epidemiologic data and cohort characteristics. In this respect, the committee should consider biologic factors (such as the dose and dose-rate effectiveness factor, relative biologic effectiveness, genomic instability, and adaptive responses) and appropriate methods to develop etiologic models (favoring simple as opposed to complex models), estimate population detriment, and attribute causation in specific cases. Assess the current status and relevance to risk models of biologic data and models of carcinogenesis. This should include a critical assessment of all data that might affect the shape of the dose-response curve at low doses, in particular, evidence of thresholds or the lack thereof in dose-response relationships and the influence of adaptive responses and radiation hormesis. Consider potential target cells and problems that might exist in determining dose to the target cell. Consider any recent evidence regarding genetic effects not related to cancer. Any such data, even if obtained from high radiation exposures or at high dose rates, should be considered. With Respect to Modeling, the Committee Recommends That the Individuals Responsible for the Proposed Phase-2 Rtudy Develop appropriate risk models for major cancer types and other outcomes, including benign disease and genetic effects. Specifically, the responsible committee should develop models appropriate for use in future development of probability-of-causation tables and should consider the fitting of purely empirical models to original data from studies or combined studies, the fitting of purely empirical models with recta-analytic techniques, and the fitting of semiempirical biology-based models to epidemiologic data. Provide examples of specific risk calculations based on the risk models and explain the appropriate use of the models. Describe and define the limitations and uncertainties of the risk models and their results. The committee conducting the proposed phase-2 study should be directed to develop best-estimate models for purposes of risk assessments as opposed to developing conservative models for purposes of radiation protection. Discuss the role and effect of modifying factors, including host (such as individual susceptibility and variability, age, and sex), environment (high background radiation exposure), and lifestyle (such as alcohol and cigarette consumption).
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Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment? Identify critical gaps in knowledge that should be filled by future research. To accomplish the charge suggested here, the membership of the committee responsible for the proposed BEIR VII phase-2 study will require expertise in epidemiology, biostatistics, radiation physics and dosimetry, molecular biology, risk assessment and communication, cancer modeling, animal and cellular radiation biology, somatic cell genetics, cell-cycle regulation and apoptosis, and the causation and repair of DNA damage induced by ionizing radiation. The committee recommends that the experts chosen have adequate resources and access to data for the computing, statistical analyses, and modeling required to complete the study. A major goal of the BEIR VII phase-2 study will be to better quantify and characterize the uncertainties associated with risk estimates and to produce the most realistic estimates of uncertainties.
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