Leveraging Advances in Modern Science to Revitalize Low-Dose Radiation Research in the United States (2022) / Chapter Skim
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5 Prioritized Research Agenda
5 Prioritized Research Agenda
Pages 127-188
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From page 127... ...
. These challenges arise because the effects of low-dose and low-dose-rate radiation exposures are assumed to be subtle and difficult to distinguish from those caused by other stressors or "spontaneous" changes that adversely affect the normal functions of cells, tissues, and organs.
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• Establishment of cause-effect relationships, although an important goal of low-dose radiation epidemiological studies, is often challenged by study design conditions which could result in a number of possible explanations for the observed associations or lack thereof. In the absence of an inte grated mechanistic understanding, epidemiological studies are unable to make strong judgments as to whether an observed association represents a cause-effect relationship between low-dose radiation exposure and the adverse health outcome.
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have the potential to provide more reliable radiation risk estimates by acknowledging the shared and unshared uncertainties in radiation doses. • Limited biomarkers associated with low-dose and lose-dose-rate radiation induced adverse health effects (tissues, cell types, individuals)
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The proposed research agenda aims to fill these gaps by integrating information from epidemiological analyses of the adverse health effects of low-dose radiation with information on cell and molecular responses of humans and laboratory models to exposures to low-dose and low-dose-rate radiation revealed by new-generation analytical tools. Approaches for integrating information from radiation biology and epidemiology to enhance low-dose health risk assessment are described in detail elsewhere (NCRP, 2020a)
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In the committee's judgment, the 11 research priorities will enable more accurate estimation of adverse health effects that result from exposure to lowdose and low-dose-rate radiation and will dramatically improve knowledge of the complex cellular and molecular processes that are engaged during transduction of low-dose and low-dose-rate radiation damage into adverse health outcomes. The committee also noted that some of the research priorities can have additional benefits including capacity building, training of the next generation of radiation researchers, and development of tools that could be transferrable to other lines of research.
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populations. E2 Improve estimation of risks for cancer More precisely define health outcomes to enable exclusion of diseases B1–B4; I1–I3 and non-cancer health outcomes from caused by other effects, identifying easily measured signatures low-dose and low-dose-rate external and that can serve as disease surrogates by improving dosimetry and internal radiation exposures.
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I2 Harmonized databases to support Develop accessible databases that document exposure levels, rates, E1–E3; B1–B4 biological and epidemiological studies. types, and durations as well as cell, molecular, and health outcomes for human populations and experimental models.
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Scientific and Decision-Making Value Powerful analytical tools are now available or are being developed that allow more accurate measurement of radiation exposures and exposure rates and more precise definition of the adverse health effects that may arise due to radiation exposures. Application of these tools in epidemiological studies of human populations will improve investigations of adverse health effects that may be caused by low-dose and low-dose-rate exposures.
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. Current Status and Promising Research Directions Epidemiological studies aiming to directly quantify the adverse health effects that result from low-dose and low-dose-rate radiation exposures, either internal or external, will require careful selection and detailed characterization of study populations that allow examination of lifetime risks of radiation exposures.
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for disease occurrence needed for low-dose and low-dose-rate epidemiological studies requires significant effort and resources. However, assembly of informative, new cohorts may become feasible in the future by employing more efficient sampling methods and by taking advan tage of more precise information about radiation exposures and disease phenotypes that inform on etiology that is expected to be captured in future, computationally accessible electronic medical records (EMRs)
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Inadequately accounting for confounding can lead to bias in an estimate of the association between radiation exposure and adverse health outcome.2 Strategies to increase the accuracy of radiation exposure estimates may include accessing records of medical exposure types and levels; using individual and in-home radiation monitors that report continuously on occupational and environmental exposures; generating accessible geospatial databases of environmental radiation and other contaminants; and utilizing computational algorithms that accurately estimate organ- and cell-specific dose and dose rates from external and/or internal sources and that account for source radiation type, internal versus external exposure, and body size and composition, anatomic location, and sex. These algorithms may be further improved by incorporating information from biological studies using new-generation nanoscale analysis tools that reveal how individual photons or ions alter DNA, individual proteins, and organelles in individual cells and how these alterations are subsequently processed biologically.
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They may quantify individual characteristics (e.g., genetic, epigenetic, and im mune status) that may influence risk of developing adverse health outcomes from low-dose and low-dose-rate radiation exposures.
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Even less is known about the levels of risk for health outcomes other than cancer, including cardiovascular disease, neurological disorders, immune dysfunction, cataracts, and heritable genetic effects. However, if such risks exist at low doses and dose rates, they could lead to substantial changes in risk-benefit analyses for activities that involve low-dose radiation exposures.
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. Current Status and Promising Research Directions Cancer is the most well-established adverse health outcome resulting from radiation exposure (Berrington de González et al., 2017; Hauptmann et al., 2020; Kitahara et al., 2015; Little et al., 2022a; UNSCEAR, 2006a)
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, ideally with respect to factors relevant to etiology and that are not influenced by treatment strategies that may change over time or with economic status. Quantitative health outcomes and molecular surrogates thereof that are suggested by epidemiological studies at higher doses or that have been shown in laboratory model studies to be related to low-dose and low-dose-rate radiation exposure might be given special attention.
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These tools are summarized in Section 5.4.1 for Priority I1. 5.2.3 Determine Factors That Alter the Low-Dose and Low-Dose-Rate Radiation-Related Adverse Health Effects (Priority E3)
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. Knowledge of the effects of these other factors on low-dose and low-dose-rate radiation-induced health outcomes may allow for more individualized risk assessments and risk management.
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It is currently also unclear if the immunological changes following low-dose radiation exposures actually link to the same long-term and late clinical disease outcomes as high-dose radiation exposures or if other outcomes are more relevant (Boerma et al., 2022)
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. Whether these findings are consistent for tobacco and radiation exposures on other outcomes also associated with tobacco exposure (e.g., bladder cancer and cardiovascular disease)
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Laboratory model-based studies tend to be better controlled, adequately statistically powered, and less prone to confounding, therefore substantially strengthening the evidence for disease causation and the underlying dose-response relationships, provided they accurately model the disease pathogenesis following irradiation. The following sections suggest several aspects of mechanism-based biological research that may increase understanding of how low-dose and low-dose-rate radiation exposures lead to adverse health effects, including development of improved laboratory models (see Section 5.3.1)
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Extrapolation from experimental data to possible effects in humans is considered more reliable when similar molecular responses and/or outcomes are observed in a variety of model systems. Integration of the information gained from laboratory models and from epidemiological studies will improve understanding of the mechanisms underlying low-dose and low-dose-rate radiation-induced adverse health outcomes, improve risk estimates for the low-dose and low-dose-rate exposures experienced by the U.S.
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Processes that appear important can then be promoted for assessment in animal models and eventually for association with radiation exposure in epidemiological studies. Mice are the animal species most commonly used for studies of physiology and disease formation, and several strains have been exceedingly well characterized biologically and genetically.
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as well as the proximal and distal environments in which these cells exist. Animal models also are being developed for the study of adverse health outcomes other than cancer that might be caused by low-dose and low-doserate radiation exposures.
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The fact that these signals can come from cells that are in close proximity to the irradiated cell or from distal organs such as the brain only adds further complexity and underscores the need to study radiation responses in vivo as much as possible. Proximal interactions are often referred to as "bystander responses" and are well recognized by radiation biologists (Tomita and Maeda, 2015; UNSCEAR, 2021)
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Diagnostic biomarkers may identify adverse outcomes that are preferentially induced by low-dose and low-dose-rate radiation such that these can be assessed in epidemiological studies or that are associated with other etiologies so that cases with these biomarkers can be excluded. Biomarkers of response may identify cellular and molecular features or biological processes that change in response to low-dose and low-dose-rate radiation exposures.
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Indeed, it remains to be determined whether activation of each response biomarker is associated with an increase or decrease in adverse health effects. In addition, it is already known that circulating small molecules such as miRNA can act as radiation-damage signaling molecules and that they tie in with health outcomes (Chakraborty et al., 2020; Soares et al., 2021)
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These studies on individual cells could lead to development of an "atlas" of mechanistic changes that may enable more precise definition of disease subtypes that are more strongly associated with low-dose radiation exposure. Such approaches will also aid the identification of biomarkers that could be applied in population studies and for the development of AOPs.
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population. Current Status and Promising Research Directions Radiation exposures around 10 mGy lead to molecular, cellular, and health outcomes that are not as well defined as those at higher doses, in particular cytotoxic doses.
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will provide information about the mechanisms that operate following low-dose and low-dose-rate radiation exposures. Importantly, the damage caused by 15 Damage produced by high-LET radiation including from alpha particles from ingested radionuclides typically does cause double strand breaks (Stap et al., 2008)
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The role of DNA damage and repair in the context of non-cancer health outcomes and the radiation doses at which this damage occurs is little understood. In cataract formation, for example, genes such as ATM, RAD9, and PTCH1 are known to modify the induction of lens opacities following radiation exposures, but these genes are generally not considered to be significant contributors to atherosclerotic disease.
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Scientific and Decision-Making Value Estimates of the risks of adverse health outcomes from low-dose and low-dose-rate radiation exposures may be modulated by events unique to an individual or confounded by exposure to factors other than low-dose and low-dose-rate radiation that produce the same adverse health outcomes. Modifiers that are identified in studies of laboratory model systems can be tested in epidemiological studies for their impact on risk estimation in human populations.
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Traditionally, this relationship has been thought to be dose dependent with low doses being considered anti-inflammatory in certain disease states but not others. This concept needs to be reexamined under well-defined conditions and over a wide range of doses using modern technologies.
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These can be identified by treating laboratory models with agents known from the literature or public-domain genetic or chemical perturbation databases to produce adverse health outcomes or biomarker responses similar to those produced by low-dose and low-dose-rate radiation. If a biomarker is not unique to radiation, then agents that induce the same diagnostic biomarkers as low-dose and low-dose-rate radiation are potential confounders of the radiation-biomarker association in observational epidemiological studies (see Section 5.2.2 for Priority E2)
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Current Status and Promising Research Directions -Omics analysis tools enable assessment of the molecular components that comprise cells and tissues. Work in this area was initiated by the development of robust, fast, and low-cost nucleic acid sequencing tools to support the Human Genome Program co-led by DOE and NIH.
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PRIORITIZED RESEARCH AGENDA 161 can quickly generate sequences for entire genomes and transcriptomes for less than $1,000.17 Work in this area continues today, driven by NIH and DOE programs and substantial U.S. industry investments.
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. These techniques, when applied to tissues exposed to low-dose radiation or to diseased tissues from individuals in exposed populations, will provide fine phenotyping of cell populations (e.g., immune system)
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Their increasing availability in medical centers throughout the United States, increasing safety, and decreasing cost make it reasonable to consider deploying them in future radiation health effects studies. These technologies are being applied to improve disease detection and treatment so that overall mortality resulting from radiation exposures may be decreased.
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. The information these tools provide on the cellular compositions of normal and diseased tissues, on functional states, and on the functional consequences of interactions between cells may be used to define more precise disease phenotypes in epidemiological studies and to elucidate the cellular and molecular mechanisms that are influenced by low-dose and low-dose-rate radiation.
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Deployment of IoMT devices for low-dose and low-dose-rate radiation studies offers the possibility of accurate assessments of individual exposures to radiation and physiological changes that may be associated with such exposures. Wearable dosimeters may continuously report exposures of radiation from environmental or medical procedures.
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Deployment of IoMT devices already exists in some occupational settings (where personal electronic dosimeters are used) and can be considered for future-generation epidemiological studies aimed at improving estimates for risk of exposure to low-dose and low-dose-rate radiation.
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These machine learning tools applied to measurements of cells and tissues following exposure to low-dose and low-dose-rate radiation will allow identification of the features and regulatory mechanisms that are influenced by radiation as well as precise health effects that result from exposures. Tools that link features and mechanisms to health effect phenotypes will suggest potentially causal relationships that can be tested in experimental systems.
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5.4.2 Harmonized Databases to Support Biological and Epidemiological Studies (Priority I2) Scientific or Decision-Making Value Funding agencies and publishers of scientific articles increasingly require plans for data management and data sharing for research they support or publish.
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program, which provides disease treatments tailored to an individual's unique genes and environment.32 Recently, work during the COVID-19 pandemic demonstrated the feasibility of making EMRs computationally accessible to identify higher-risk populations and for other purposes, while maintaining the required confidentiality. In addition, a growing number of geospatial databases are becoming available that inform on aspects of the environment, health care, economic status, social status, transportation, and other factors, which may reveal confounding events when included in next-generation epidemiological studies.
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Recent developments in several aspects of radiation dosimetry suggest that future low-dose and low-dose-rate radiation studies can benefit from improved personal dosimeters, computational phantoms, biokinetic and source-term models, and tools for environmental radiation exposure. In parallel with these developments for radiation dosimetry, modern statistical and computational methods for dose reconstruction are needed to fully integrate detailed dosimetry data into modern analyses of epidemiological studies.
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. The mesh phantoms have the added functionality of being deformable, permitting 35 Developed by the Medical Internal Radiation Dose (MIRD)
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These include development of 3D models of tissue microstructure (e.g., definition of kidney model at the nephron level) to model internal radionuclide deposition and archived samples to determine 3D spatial distribution of deposition.36 At the whole-organ level, models of both intraorgan and interorgan blood vasculature used to differentiate radionuclide decays in organ parenchyma from radionuclide decays in organ blood content can further inform the dose distribution in the human body using phantom models to estimate radiation dose, bridging organ-level with organ microstructure dosimetry for low-dose radiation exposures and uptakes.
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. Despite advances in dosimetric modeling, errors in estimated radiation doses can arise from uncertainty in dosimetry parameters, as well as from measurement error in the underlying radiation exposure data (see Section 5.2.1)
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and outcomes (e.g., errors to outcome misclassification; Bennett et al., 2017; Keogh et al., 2020; Shaw et al., 2020, 2021; Wu et al., 2019) .38 Failure to further develop and apply these methods in epidemiological studies, particularly the large studies that will be required to detect radiation health effects at low doses with sufficient statistical power, will continue to limit the statistical analysis and interpretation of large and complex dose reconstructions for quantifying radiation risk.
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• Facilities similar to the deep underground facilities in Europe and Canada designed to eliminate the effects of background radiation are of restricted access or of limited capabilities. The committee is aware of the underground radiation biology laboratory at the radioactive waste disposal site Waste Isolation Pilot Plant in New Mexico (Castillo et al., 2021; Van Voorhies et al., 2020)
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176 REVITALIZE LOW-DOSE RADIATION RESEARCH IN THE UNITED STATES TABLE 5.2 Available Facilities for Low-Dose and Low-Dose-Rate Research in the United States Radiation Type or Description of Start; End Dose Range Facility Facility Location Year Main Purpose (max; min) AFRRI Triga reactor AFRRI 1969; no Materials, Information (mixed field complex plan cells, animals; not provided gamma/neutron)
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PRIORITIZED RESEARCH AGENDA 177 Available to Outside Users; References Dose Rate Inhalation Available Adjacent Demonstrating (standard setup) Experiments Infrastructure Capabilities From less than 10 No Yes; Yes Bene et al., 2021 R/h to more than 100 kR/h From less than 1 No Yes; Yes Bene et al., 2021 R/h to more than 100 kR/h From less than 1 No Yes; Yes Bene et al., 2021 R/h to more than 100 kR/h From 0.05 to 6 No Yes; Yes Bene et al., 2021 Gy/min Low dose rate No Yes but not for Information not not standard but radiobiology; Not provided possible available Currently 9.3 No Yes; Yes Kato et al., 2006 mGy/h but can increase to 500 mGy/h or decrease to background 1 mGy/h to 100 No Yes; Yes Amdur and Bedford, mGy/h 1994; Bedford, 2001; Huang et al., 2011; Kato et al., 2006, 2007; Ochola et al., 2019; Peng et al., 2012; Ulsh et al., 2001; Wilson et al., 2008 3.6 mGy/h to a No Intended; Yes Information not factor of 20 lower provided continued
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Laboratory (cells, 0.2 mGy tissues, or animals) and electronics testing NSRL Ions (electron- Brookhaven ~2003; Radiobiology >>1 Gy; as beam ion source, National >2030 research low as 0.1 to tandem Van de Laboratory (cells, 0.2 mGy Graaf)
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PRIORITIZED RESEARCH AGENDA 179 Available to Outside References Dose Rate Inhalation Users; Available Demonstrating (standard setup) Experiments Adjacent Infrastructure Capabilities 10 cGy/day to No Yes; Yes Ochola et al., 2019; 0.41 cGy/min Shakhov et al., 2012 1 mGy/day No Yes; Yes Acharya et al., 2019; Borak et al., 2021; Perez et al., 2020 Standard setup No Yes but limited; Yes Unternaehrer-Hamm et is 100–200 cGy/ al., 2020 min but can range from 1 to 300 cGy/min Standard setup No Yes but limited to Information not is 100–200 cGy/ outside clinical care provided min but can hours; Yes range from 1 to 300 cGy/min 5–600 cGy/min No Yes but limited; Yes Information not provided Between 0.01 No Yes; Yes La Tessa et al., 2016; and 1 Gy/min Simonsen et al., 2020 Between 0.01 No Yes; Yes La Tessa et al., 2016; and 1 Gy/min Simonsen et al., 2020 Up to 3 Gy/h No Yes; Yes Marino, 2017; Xu et al., 2015 continued
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at selected dose rate NOTE: AFRRI = Armed Forces Radiobiology Research Institute; ATLAS = Argonne Tandem Linac Accelerator System; CSU = Colorado State University; CUIMC = Columbia University Irving Medical Center; HBL = horizontal beam lateral; LET = linear energy transfer; LLUMC = Loma Linda University Medical Center; NSRL = NASA Space Radiation Laboratory; RARAF = Radiological Research Accelerator Facility. Overall, a substantial investment in facilities specifically designed for internal and external exposures to low-dose and low-dose-rate radiation of types relevant to exposed or potentially exposed U.S.
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FIGURE 5.2 Illustration of the interacting hubs of the low-dose radiation multidisciplinary program.
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Periodic reassessments are required as large epidemiological studies and necessary research infrastructures are established. Although the committee recognizes that the exact form of the program will be determined by the funding agency after consultation with stakeholders, the following prototypical program is intended to justify the $100 million annual funding level.
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. • An epidemiology hub comprising three epidemiology centers, an epidemiology data coordinating center, and a dosimetry center (cost ~$30 million annually)
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These include improving cancer risk assessments for different radiation types and modes of exposure, understanding risks of health outcomes other than cancer, and improving dosimetry. Similar to this committee's research agenda, ICRP and MELODI prioritize the need for a more individualized risk assessment.
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3. It proposes the establishment of new epidemiological studies that can address questions about risks at low doses and dose rates and proposes that the appropriate populations are selected with input from the research community and other stakeholders, including the impacted communities.
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The committee estimates that funding needed to set up the program is on par with the congressionally authorized funds for 2023 and 2024, that is, at the level of $30 million and $40 million annually, respectively, but need to rise to the level of $100 million annually thereafter and remain at that level through about 2037. Although the committee recognizes that the exact form of the program will be determined by the funding agency after consultation with stakeholders, it provided a prototypical program comprising interacting hubs focusing on basic and translational biology, analytical and computational technologies, and epidemiology, intended to justify the $100 million annual funding level.
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popula tion including the full range of potential adverse health effects, risks associated with doses around 10 milligray, and the potential impacts of genetic, lifestyle, environmental, and other factors that may also affect radiation-related risk estimates. Epidemiological studies designed to overcome these limitations can better elucidate adverse health effects of radiation exposure at low doses and low dose rates relevant to the U.S.
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188 REVITALIZE LOW-DOSE RADIATION RESEARCH IN THE UNITED STATES Finding 7: Significant investments over a sustained period spanning several decades are necessary to develop a multidisciplinary low-dose radiation research program in the United States that leverages exist ing and developing research infrastructure that will achieve the goals outlined in Finding 1. The committee's best estimate is that the invest ments required during the first 10–15 years of the program are at the level of $100 million annually and periodic reassessments are required as large epidemiological studies and necessary research infrastructures are established.
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