Leveraging Advances in Modern Science to Revitalize Low-Dose Radiation Research in the United States (2022) / Chapter Skim
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From page 149... ...
. In addition, most investigations so far have focused on the early stages of carcinogenesis, initiation in particular, and relatively little is known about the effects of radiation exposures on later stages of carcinogenesis.
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In other words, indirect effects of radiation on cells surrounding the cells of origin for radiation-associated cancers and non-cancerous pathologies could be as important as the direct radiation effects noted above in determining the outcomes of exposures and therefore need to be modeled accordingly. This is clearly demonstrated by pioneering studies that have shown that the incidence of cancers and by extension other diseases can be strongly influenced by the microenvironment(s)
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Biomarkers for risk, diagnosis, and response will be particularly important for low-dose and low-dose-rate radiation research. Biomarkers of risk may identify individuals who are susceptible to radiation-induced adverse outcomes.
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. The multidisciplinary low-dose and low-dose-rate radiation research program envisioned by this committee might directly engage with these programs.
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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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Biomarkers are also being developed for other health endpoints that may be important in low-dose and low-dose-rate radiation research including cardiovascular diseases (Dhingra and Vasan, 2017) , neurodegenerative diseases (Hansson, 2021)
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The impact of low-dose radiation exposures, and exposures to differing radiation qualities, on mutational loads in individuals is unknown but can now be assessed by modern highthroughput sequencing methods in human and animal model studies.16 Also relevant to low-dose radiation exposures is the role of transmissible genomic instability (i.e., the phenomenon of persistent elevation of mutation frequency in the descendants of irradiated cells)
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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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. Moreover, these tools can be integrated with similar data on normal and diseased tissues that are available in public databases emerging from NIH and international programs such as TCGA, the International Cancer Genome Consortium, HuBMAP, and NCI's HTAN to facilitate identification of precise disease signatures that can be tested for association with low-dose radiation exposure.
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These tools can be readily applied to reveal the responses to perturbations including those induced by low-dose and low-dose-rate radiation. These revolutionary tools, in aggregate, allow quantification of subtle cellular and molecular processes important in radiation research that have previously not been possible, including changes in single cells as a result of the interactions of those cells with radiation.
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These tools have been enhanced by the development of experimental and computational workflows that allow analysis of DNA and RNA in archived tissues and by the development of easily accessible reference databases, against which test sequences can be compared in efforts to identify differences between normal and diseased cell populations and between individuals and to identify contaminating microbial species and/or changes that result from external perturbations including exposure to ionizing radiation. Nucleic acid sequencing tools have been further enhanced by the development of experimental and computational workflows that enable assessment of aspects of the spatial organization of chromatin within cells and/or epigenomic DNA modifications that influence gene expression and cellular function.
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. Many aspects of mass spectrometry–based analysis are being accelerated by NIH's Clinical Proteomic Tumor Analysis Consortium (Ellis et al., 2013)
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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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. These tools, when applied in radiation biology, will allow direct study of the structures and organizations of the proteins, protein complexes, and organelles that are directly and indirectly affected by ionizing radiation.
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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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The number of agents and complexity of rules can be as large as computational capability allows. ABMs are already used to describe the responses of complex biological systems to ionizing radiation.24 Partial differential equation (PDE)
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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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These tools can be aggregated, as in done in Galaxy, to support accessible, reproducible, and transparent computational research.33 These and similar reference databases will be valuable in low-dose radiation research -- for example, by serving as references against which radiation-perturbed normal 25 See https://www.ncbi.nlm.nih.gov/genbank. 26 See https://gdc.cancer.gov.
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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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5.4.4 Facilities for Low-Dose and Low-Dose-Rate Exposures (Priority I4) Scientific and Decision-Making Value The potential gains from a new low-dose radiation research program are highly dependent on available facilities that are tailored to the specific needs of this line of research.
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NIST did not respond to the committee's request and a UNC representative told the committee that facilities that house nanobeams for irradiation of cells and animals at UNC are still in the research stage. An assessment of multiple large radiation facilities that have capabilities to carry out low-dose research revealed that diminished support for radiation research in the United States has left the radiation research community with inadequate exposure facilities to support low-dose and lowdose-rate radiation research and address high-priority issues: • There are no facilities available to facilitate inhalation studies to understand the effects of internal emitters on the lungs; in the past, the United States had a facility at the Inhalation Toxicology Research Institute in New Mexico, but this facility was terminated.
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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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178 REVITALIZE LOW-DOSE RADIATION RESEARCH IN THE UNITED STATES TABLE 5.2 Continued Radiation Type or Description of Start; End Dose Range Facility Facility Location Year Main Purpose (max; min) CSU Low-dose-rate Main CSU -- ; No Mice and Information γ ray (137Cs)
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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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populations will be needed to support a revitalized low-dose radiation research program in the United States. 5.5 ESTIMATED TIMELINE AND COSTS The development of a robust research program that can provide information about the risks to humans that may result from exposures to lowdose and low-dose-rate radiation and about the involved mechanisms will require significant investments in biological research, dosimetry, epidemiology, facilities, data curation and coordination, education and outreach, and communication.
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FIGURE 5.2 Illustration of the interacting hubs of the low-dose radiation multidisciplinary program.
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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 (see Appendix A) , that is, at the level of $30 million and $40 million annually, respectively, but needs to rise to the level of $100 million annually thereafter and remain at that level through about 2037.
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program and with non-U.S. low-dose radiation research programs.
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This will require the $100 million annual program scale recommended by the committee. Appropriations at the level of $5 million per year are not adequate to even initiate a meaningful low-dose radiation research program -- as seen in 2021 when funds for the program were at that level and the program was not initiated.
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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 also notes that appropriations at the level of $5 million per year are not adequate to even initiate a meaningful low-dose radiation research program -- as seen in 2021 when funds for the program were at that level and the program was not initiated. The committee cautions that inadequate funding for the program will lead to continued scientific and policy debates about risks of low doses of radiation and the possible inadequate protection of patients, workers, and members of the public from the adverse effects of radiation.
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A revitalized low-dose radiation research program can likewise leverage and further develop these capabilities to enable scientific innovation and breakthroughs in radiation biology and epidemiology. Recommendation A: Agencies responsible for the management of the multidisciplinary low-dose radiation program should fund low-dose and low-dose-rate radiation research in the 11 high-priority research topics identified by the committee and can address the scopes outlined in Finding 1.
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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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Recognizing that the research agenda proposed by this committee extends beyond the resources of a single federal agency and will require coordination across several agencies, these elements apply to any agency that is involved or will be involved in low-dose and low-dose-rate radiation research. The committee also summarizes its views on a possible model for leadership of the coordination of low-dose radiation research in the United States (see Section 6.8)
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Intellectual input from those with broader expertise not directly associated with radiation research is also needed; for example, improved knowledge about the impact of low-dose and low-dose-rate exposures on epigenetic effects may come from those who have not previously studied radiation effects as long as there is access to the required radiation exposure equipment or data. Additionally, immunologists, modelers, social scientists, and specialty clinicians such as cardiologists, neurologists, and ophthalmologists are also expected to contribute to multidisciplinary lowdose radiation research; therefore, the program needs to identify ways to attract them to radiation research and offer appropriate training.
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