Revisiting the Historic Strontium-90 Ingestion Beagle Study Conducted at the University of California-Davis: Opportunity in Archival Materials.

Strontium-90 is a radionuclide found in high concentrations in nuclear reactor waste and nuclear fallout from reactor accidents and atomic bomb explosions. In the 1950s, little was known regarding the health consequences of strontium-90 internalization. To assess the health effects of strontium-90 ingestion in infancy through adolescence, the Atomic Energy Commission and Department of Energy funded large-scale beagle studies at the University of California-Davis. Conducted from 1956 to 1989, the strontium-90 ingestion study followed roughly 460 beagles throughout their lifespans after they were exposed to strontium-90 in utero (through feeding of the mother) and fed strontium-90 feed at varying doses from weaning to age 540 days. The extensive medical data and formalin-fixed paraffin-embedded tissues were transferred from UC Davis to the National Radiobiology Archive in 1992 and subsequently to the Northwestern University Radiobiology Archive in 2010. Here, we summarize the design of the strontium-90 ingestion study and give an overview of its most frequent recorded findings. As shown before, radiation-associated neoplasias (osteosarcoma, myeloproliferative syndrome and select squamous cell carcinomas) were almost exclusively observed in the highest dose groups, while the incidence of neoplasias most frequent in controls decreased as dose increased. The occurrence of congestive heart failure in each dose group, not previously assessed by UC Davis researchers, showed a non-significant increase between the controls and lower dose groups that may have been significant had sample sizes been larger. Detailed secondary analyses of these data and samples may uncover health endpoints that were not evaluated by the team that conducted the study.

Gene Expression and Early Radiation Response of Two Distinct Neuroblastoma Cell Lines.

INTRODUCTION: Neuroblastoma is one of the most common childhood cancers with one of the lowest survival rates, accounting for 15% of childhood cancer mortality. Approximately half of children treated for high-risk neuroblastoma will relapse following remission, while another 15% of patients do not respond to initial treatment. External beam radiation is infrequently used for treatment of pediatric cancer such as neuroblastoma, typically reserved for palliative care in patients with aggressive metastatic disease who fail to respond to alternative treatments. Understanding effects of radiation on neuroblastoma cells could improve efficacy of this final means of therapy to decrease tumor burden and stabilize the disease. METHODS: In this study, we found that two microRNAs with opposite functions were expressed in two neuroblastoma cell lines with marked differences in radiosensitivity. Clonogenic assays were used to evaluate the radiation responses for these 2 cell lines, designated SK-N-AS and SK-N-DZ; cells were then irradiated at doses that cause 90% cell killing based on clonogenic assay and their RNA isolated and subjected to microarray analysis. In addition, cells were transfected with pre-miRNA constructs that led to overexpression of microRNAs miR-34a and miR-1228 to determine possible microRNA regulation of radiation response. RESULTS: Statistically significant differences were detected for expression of several thousand genes when the 2 cell lines were compared with each other. In comparison, radiation exposure resulted in only minor gene expression differences of less than 2-fold at the 1 h postirradiation timepoint in both cell lines. Overexpression of miR-34a and miR-1228 in either cell line did not alter this outcome. DISCUSSION: While these two neuroblastoma cell lines are phenotypically diverse and gene expression differences between them are extensive, we observed that the regulation of gene expression in both cell lines is in a stable equilibrium at early timepoints after exposure to ionizing radiation.

Lessons learned in the practice of community-based participatory research with community partner collaboration in study design and implementation: the community scientist model.

Engagement of community participation is an innovative driver of modern research. However, to benefit the communities being studied, it is imperative to continuously evaluate ethical considerations, the relationship dynamic between researchers and community members, and the responsiveness of research teams to the needs and preferences of communities. Northwestern University's Center for Health Equity Transformation founded a community scientist program in 2018 that implemented a study using the Community-Based Participatory Research (CBPR) model. This project is an ongoing study of heavy metal exposure by geographic location in Chicago. Community scientists from various backgrounds, communities, and organizations formed an advisory panel, partnering with the cancer research team. This commentary describes lessons learned in structuring meaningful community involvement and benefit in CBPR, with a focus on three lessons learned that relate to ethics, relationships, and responsiveness. Our findings lay new groundwork for iteratively shaping best practices in CBPR.

Findings from international archived data: Fractionation reduces mortality risk of ionizing radiation for total doses below 4 Gray in rodents.

Ionizing radiation is omnipresent and unavoidable on Earth; nevertheless, the range of doses and modes of radiation delivery that represent health risks remain controversial. Radiation protection policy for civilians in US is set at 1 mSv per year. Average persons from contemporary populations are exposed to several hundred milliSieverts (mSv) over their lifetimes from both natural and human made sources such as radon, cosmic rays, CT-scans (20-50 mSv partial body exposure per scan), etc. Health risks associated with these and larger exposures are focus of many epidemiological studies, but uncertainties of these estimates coupled with individual and environmental variation make it is prudent to attempt to use animal models and tightly controlled experimental conditions to supplement our evaluation of radiation risk question. Data on 11,528 of rodents of both genders exposed to x-ray or gamma-ray radiation in facilities in US and Europe were used for this analysis; animal mortality data argue that fractionated radiation exposures have about 2 fold less risk per Gray than acute radiation exposures in the range of doses between 0.25 and 4 Gy.

Development of Fe3O4 core-TiO2 shell nanocomposites and nanoconjugates as a foundation for neuroblastoma radiosensitization.

BACKGROUND: Neuroblastoma is the most common extracranial solid malignancy in childhood which, despite the current progress in radiotherapy and chemotherapy protocols, still has a high mortality rate in high risk tumors. Nanomedicine offers exciting and unexploited opportunities to overcome the shortcomings of conventional medicine. The photocatalytic properties of Fe3O4 core-TiO2 shell nanocomposites and their potential for cell specific targeting suggest that nanoconstructs produced using Fe3O4 core-TiO2 shell nanocomposites could be used to enhance radiation effects in neuroblastoma. In this study, we evaluated bare, metaiodobenzylguanidine (MIBG) and 3,4-Dihydroxyphenylacetic acid (DOPAC) coated Fe3O4@TiO2 as potential radiosensitizers for neuroblastoma in vitro. RESULTS: The uptake of bare and MIBG coated nanocomposites modestly sensitized neuroblastoma cells to ionizing radiation. Conversely, cells exposed to DOPAC coated nanocomposites exhibited a five-fold enhanced sensitivity to radiation, increased numbers of radiation induced DNA double-strand breaks, and apoptotic cell death. The addition of a peptide mimic of the epidermal growth factor (EGF) to nanoconjugates coated with MIBG altered their intracellular distribution. Cryo X-ray fluorescence microscopy tomography of frozen hydrated cells treated with these nanoconjugates revealed cytoplasmic as well as nuclear distribution of the nanoconstructs. CONCLUSIONS: The intracellular distribution pattern of different nanoconjugates used in this study was different for different nanoconjugate surface molecules. Cells exposed to DOPAC covered nanoconjugates showed the smallest nanoconjugate uptake, with the most prominent pattern of large intracellular aggregates. Interestingly, cells treated with this nanoconjugate also showed the most pronounced radiosensitization effect in combination with the external beam x-ray irradiation. Further studies are necessary to evaluate mechanistic basis for this increased radiosensitization effect. Preliminary studies with the nanoparticles carrying an EGF mimicking peptide showed that this approach to targeting could perhaps be combined with a different approach to radiosensitization - use of nanoconjugates in combination with the radioactive iodine. Much additional work will be necessary in order to evaluate possible benefits of targeted nanoconjugates carrying radionuclides. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12645-021-00081-z.

Use of X-Ray Fluorescence Microscopy for Studies on Research Models of Hepatocellular Carcinoma.

Introduction: TheraSphere® microspheres containing yttrium 90Y are among many radioembolization agents used clinically to reduce liver tumor burden, and their effects on cancer volume reduction are well-established. At the same time, concerns about off target tissue injury often limit their use. Deeper investigation into tissue distribution and long-term impact of these microspheres could inform us about additional ways to use them in practice. Methods: Healthy rat liver and rabbit liver tumor samples from animals treated with TheraSpheres were sectioned and their elemental maps were generated by X-ray fluorescence microscopy (XFM) at the Advanced Photon Source (APS) synchrotron at Argonne National Laboratory (ANL). Results: Elemental imaging allowed us to identify the presence and distribution of TheraSpheres in animal tissues without the need for additional sample manipulation or staining. Ionizing radiation produced by 90Y radioactive contaminants present in these microspheres makes processing TheraSphere treated samples complex. Accumulation of microspheres in macrophages was observed. Conclusions: This is the first study that used XFM to evaluate the location of microspheres and radionuclides in animal liver and tumor samples introduced through radioembolization. XFM has shown promise in expanding our understanding of radioembolization and could be used for investigation of human patient samples in the future.

Development of Multi-Scale X-ray Fluorescence Tomography for Examination of Nanocomposite-Treated Biological Samples.

Research in cancer nanotechnology is entering its third decade, and the need to study interactions between nanomaterials and cells remains urgent. Heterogeneity of nanoparticle uptake by different cells and subcellular compartments represent the greatest obstacles to a full understanding of the entire spectrum of nanomaterials' effects. In this work, we used flow cytometry to evaluate changes in cell cycle associated with non-targeted nanocomposite uptake by individual cells and cell populations. Analogous single cell and cell population changes in nanocomposite uptake were explored by X-ray fluorescence microscopy (XFM). Very few nanoparticles are visible by optical imaging without labeling, but labeling increases nanoparticle complexity and the risk of modified cellular uptake. XFM can be used to evaluate heterogeneity of nanocomposite uptake by directly imaging the metal atoms present in the metal-oxide nanocomposites under investigation. While XFM mapping has been performed iteratively in 2D with the same sample at different resolutions, this study is the first example of serial tomographic imaging at two different resolutions. A cluster of cells exposed to non-targeted nanocomposites was imaged with a micron-sized beam in 3D. Next, the sample was sectioned for immunohistochemistry as well as a high resolution "zoomed in" X-ray fluorescence (XRF) tomography with 80 nm beam spot size. Multiscale XRF tomography will revolutionize our ability to explore cell-to-cell differences in nanomaterial uptake.

Paramagnetic Mn8Fe4-co-Polystyrene Nanobeads as a Potential T1-T2 Multimodal Magnetic Resonance Imaging Contrast Agent with In Vivo Studies.

In developing a cluster-nanocarrier design, as a magnetic resonance imaging contrast agent, we have investigated the enhanced relaxivity of a manganese and iron-oxo cluster grafted within a porous polystyrene nanobead with increased relaxivity due to a higher surface area. The synthesis of the cluster-nanocarrier for the cluster Mn8Fe4O12(O2CC6H4CH═CH2)16(H2O)4, cross-linked with polystyrene (the nanocarrier), under miniemulsion conditions is described. By including a branched hydrophobe, iso-octane, the resulting nanobeads are porous and ∼70 nm in diameter. The increased surface area of the nanobeads compared to nonporous nanobeads leads to an enhancement in relaxivity; r1 increases from 3.8 to 5.2 ± 0.1 mM-1 s-1, and r2 increases from 11.9 to 50.1 ± 4.8 mM-1 s-1, at 9.4 teslas, strengthening the potential for T1 and T2 imaging. Several metrics were used to assess stability, and the porosity produced no reduction in metal stability. Synchrotron X-ray fluorescence microscopy was used to demonstrate that the nanobeads remain intact in vivo. In depth, physicochemical characteristics were determined, including extensive pharmacokinetics, in vivo imaging, and systemic biodistribution analysis.

A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma.

Glioblastoma (GBM) is one of the most difficult cancers to effectively treat, in part because of the lack of precision therapies and limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain and blood-tumor barriers. We have developed a precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference-based spherical nucleic acids (SNAs), which consist of gold nanoparticle cores covalently conjugated with radially oriented and densely packed small interfering RNA (siRNA) oligonucleotides. On the basis of previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in nonhuman primates and a single-arm, open-label phase 0 first-in-human trial (NCT03020017) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs (drug moniker: NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event level, followed by tumor resection. Safety assessment revealed no grade 4 or 5 treatment-related toxicities. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy, and silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient tumors, with gold enrichment observed in the tumor-associated endothelium, macrophages, and tumor cells. NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison of matched primary tumor and NU-0129-treated recurrent tumor. Our results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of GBM.

Analyses of cancer incidence and other morbidities in neutron irradiated B6CF1 mice.

The Department of Energy conduced ten large-scale neutron irradiation experiments at Argonne National Laboratory between 1972 and 1989. Using a new approach to utilize experimental controls to determine whether a cross comparison between experiments was appropriate, we amalgamated data on neutron exposures to discover that fractionation significantly improved overall survival. A more detailed investigation showed that fractionation only had a significant impact on the death hazard for animals that died from solid tumors, but did not significantly impact any other causes of death. Additionally, we compared the effects of sex, age first irradiated, and radiation fractionation on neutron irradiated mice versus cobalt 60 gamma irradiated mice and found that solid tumors were the most common cause of death in neutron irradiated mice, while lymphomas were the dominant cause of death in gamma irradiated mice. Most animals in this study were irradiated before 150 days of age but a subset of mice was first exposed to gamma or neutron irradiation over 500 days of age. Advanced age played a significant role in decreasing the death hazard for neutron irradiated mice, but not for gamma irradiated mice. Mice that were 500 days old before their first exposures to neutrons began dying later than both sham irradiated or gamma irradiated mice.

Effects of low dose and low dose rate low linear energy transfer radiation on animals - review of recent studies relevant for carcinogenesis.

Purpose: Carcinogenic effects of radiation are often assumed to be universally understood, more often than, for example, carcinogenic effects of many different chemicals. This in turn leads to an assumption that any dose of radiation, delivered at any dose rate, poses a serious health challenge. This remains an issue of dispute and low dose radiation research is focused on understanding whether these exposures contribute to cancer incidence. This review is focused on the low linear energy transfer (low LET) radiation exposures for which the data is the most abundant in recent years. Materials and methods: Review of the literature between 2008 and today, highlighting some of the most diverse studies in low dose research. Results: Low dose and low dose rate, low LET ionizing radiation animal studies suggest that the effects of exposure very much depend on animal genotype and health status.Conclusions: Only the integration of all of the data from different models and studies will lead to a fuller understanding of low dose radiation effects. Therefore, we hope to see an increase in international archival efforts and exchange of raw data information opening the possibilities for new types of meta analyses.

Analyses of cancer incidence and other morbidities in gamma irradiated B6CF1 mice.

With increasing medical radiation exposures, it is important to understand how different modes of delivery of ionizing radiation as well as total doses of exposure impact health outcomes. Our lab studied the risks associated with ionizing radiation by analyzing the Northwestern University Radiation Archive for animals (NURA). NURA contains detailed data from a series of 10 individual neutron and gamma irradiation experiments conducted on over 50,000 mice. Rigorous statistical testing on control mice from all Janus experiments enabled us to select studies that could be compared to one another and uncover unexpected differences among the controls as well as experimental animals. For controls, mice sham irradiated with 300 fractions died significantly earlier than those with fewer sham fractions and were excluded from the pooled dataset. Using the integrated dataset of gamma irradiated and control mice, we found that fractionation significantly decreased the death hazard for animals dying of lymphomas, tumors, non-tumors, and unknown causes. Gender differences in frequencies of causes of death were identified irrespective of irradiation and dose fractionation, with female mice being at a greater risk for all causes of death, except for lung tumors. Irradiated and control male mice were at a significantly greater risk for lung tumors, the opposite from observations noted in humans. Additionally, we discovered that lymphoma deaths can occur quickly after exposures to high doses of gamma rays. This study systematically cross-compared outcomes of different modes of fractionation evaluated across different Janus experiments and across a wide span of total doses. It demonstrates that protraction modulated survival and disease status differently based on the total dose, cause of death, and sex of an animal. This novel method for analyzing the Janus datasets will lead to insightful new mechanistic hypotheses and research in the fields of radiation biology and protection.

Activation of DNA damage repair factors in HPV positive oropharyngeal cancers.

The mechanisms regulating viral pathogenesis of human papillomavirus (HPV) associated oropharyngeal squamous cell cancers (OPSCC) are not well understood. In the cervix, activation of DNA damage repair pathways is critical for viral replication but little is known about their role in OPSCC. APOBEC factors have been shown to be increased in OPSCC but the significance of this is unclear. We therefore examined activation of DNA damage and APOBEC factors in HPV-induced OPSCC. Our studies show significantly increased levels of pCHK1, FANCD2, BRCA1, RAD51, pSMC1 and γH2AX foci in HPV-positive samples as compared to HPV-negative while the ATM effector kinase, pCHK2, was not increased. Similar differences were observed when the levels of proteins were examined in OPSCC cell lines. In contrast, the levels of APOBEC3B and 3A were found to be similar in both HPV-positive and -negative OPSCC. Our studies suggest members of ATR pathway and FANCD2 may be important in HPV-induced OPSCC.

Insights into platinum-induced peripheral neuropathy-current perspective.

Cancer is a global health problem that is often successfully addressed by therapy, with cancer survivors increasing in numbers and living longer world around. Although new cancer treatment options are continuously explored, platinum based chemotherapy agents remain in use due to their efficiency and availability. Unfortunately, all cancer therapies affect normal tissues as well as cancer, and more than 40 specific side effects of platinum based drugs documented so far decrease the quality of life of cancer survivors. Chemotherapy-induced peripheral neuropathy is a frequent side effects of platinum-based chemotherapy agents. This cluster of complications is often so debilitating that patients occasionally have to discontinue the therapy. Sensory neurons of dorsal root ganglia are at the core of chemotherapy-induced peripheral neuropathy symptoms. In these postmitotic cells, DNA damage caused by platinum chemotherapy interferes with normal functioning. Accumulation of DNA-platinum adducts correlates with neurotoxic severity and development of sensation of pain. While biochemistry of DNA-platinum adducts is the same in all cell types, molecular mechanisms affected by DNA-platinum adducts are different in cancer cells and non-dividing cells. This review aims to raise awareness about platinum associated chemotherapy-induced peripheral neuropathy as a medical problem that has remained unexplained for decades. We emphasize the complexity of this condition both from clinical and mechanistical point of view and focus on recent findings about chemotherapy-induced peripheral neuropathy in in vitro and in vivo model systems. Finally, we summarize current perspectives about clinical approaches for chemotherapy-induced peripheral neuropathy treatment.

Elemental Zn and its Binding Protein Zinc-α2-Glycoprotein are Elevated in HPV-Positive Oropharyngeal Squamous Cell Carcinoma.

Human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is biologically distinct from HPV-negative HNSCC. Outside of HPV-status, few tumor-intrinsic variables have been identified that correlate to improved survival. As part of exploratory analysis into the trace elemental composition of oropharyngeal squamous cell carcinoma (OPSCC), we performed elemental quanitification by X-ray fluorescence microscopy (XFM) on a small cohort (n = 32) of patients with HPV-positive and -negative OPSCC and identified in HPV-positive cases increased zinc (Zn) concentrations in tumor tissue relative to normal tissue. Subsequent immunohistochemistry of six Zn-binding proteins-zinc-α2-glycoprotein (AZGP1), Lipocalin-1, Albumin, S100A7, S100A8 and S100A9-revealed that only AZGP1 expression significantly correlated to HPV-status (p < 0.001) and was also increased in tumor relative to normal tissue from HPV-positive OPSCC tumor samples. AZGP1 protein expression in our cohort significantly correlated to a prolonged recurrence-free survival (p = 0.029), similar to HNSCC cases from the TCGA (n = 499), where highest AZGP1 mRNA levels correlated to improved overall survival (p = 0.023). By showing for the first time that HPV-positive OPSCC patients have increased intratumoral Zn levels and AZGP1 expression, we identify possible positive prognostic biomarkers in HNSCC as well as possible mechanisms of increased sensitivity to chemoradiation in HPV-positive OPSCC.

The Transition from Metal-Based to Metal-Free Contrast Agents for T1 Magnetic Resonance Imaging Enhancement.

Magnetic resonance imaging (MRI) has received significant attention as the noninvasive diagnostic technique for complex diseases. Image-guided therapeutic strategy for diseases such as cancer has also been at the front line of biomedical research, thanks to the innovative MRI, enhanced by the prior delivery of contrast agents (CAs) into patients' bodies through injection. These CAs have contributed a great deal to the clinical utility of MRI but have been based on metal-containing compounds such as gadolinium, manganese, and iron oxide. Some of these CAs have led to cytotoxicities such as the incurable Nephrogenic Systemic Fibrosis (NSF), resulting in their removal from the market. On the other hand, CAs based on organic nitroxide radicals, by virtue of their structural composition, are metal free and without the aforementioned drawbacks. They also have improved biocompatibility, ease of functionalization, and long blood circulation times, and have been proven to offer tissue contrast enhancement with longitudinal relaxivities comparable with those for the metal-containing CAs. Thus, this Review highlights the recent progress in metal-based CAs and their shortcomings. In addition, the remarkable goals achieved by the organic nitroxide radical CAs in the enhancement of MR images have also been discussed extensively. The focal point of this Review is to emphasize or demonstrate the crucial need for transition into the use of organic nitroxide radicals-metal-free CAs-as against the metal-containing CAs, with the aim of achieving safer application of MRI for early disease diagnosis and image-guided therapy.

Neuroprotective Role of Selected Antioxidant Agents in Preventing Cisplatin-Induced Damage of Human Neurons In Vitro.

Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect of platinum-based chemotherapy and decreases the quality of life of cancer patients. We compared neuroprotective properties of several agents using an in vitro model of terminally differentiated human cells NT2-N derived from cell line NT2/D1. Sodium azide and an active metabolite of amifostine (WR1065) increase cell viability in simultaneous treatment with cisplatin. In addition, WR1065 protects the non-dividing neurons by decreasing cisplatin caused oxidative stress and apoptosis. Accumulation of Pt in cisplatin-treated cells was heterogeneous, but the frequency and concentration of Pt in cells were lowered in the presence of WR1065 as shown by X-ray fluorescence microscopy (XFM). Transition metals accumulation accompanied Pt increase in cells; this effect was equally diminished in the presence of WR1065. To analyze possible chemical modulation of Pt-DNA bonds, we examined the platinum LIII near edge spectrum by X-ray absorption spectroscopy. The spectrum found in cisplatin-DNA samples is altered differently by the addition of either WR1065 or sodium azide. Importantly, a similar change in Pt edge spectra was noted in cells treated with cisplatin and WR1065. Therefore, amifostine should be reconsidered as a candidate for treatments that reduce or prevent CIPN.

Radiation databases and archives - examples and comparisons.

Studies of ionizing radiation effects through the archiving of data began with standardizing medical treatments in the early 1900s shortly after the discovery of X-rays. Once the breadth of the delayed effects of ionizing radiation was recognized, the need for long-term follow up became apparent. There are now many human archives of data from nuclear disasters and accidents, occupational exposures, and medical procedures. Planned animal irradiation experiments began around the time of the Cold War and included a variety of doses, fractions, dose rates, and types of ionizing radiation. The goal of most of these studies was to supplement information coming from human data through carefully planned experimental conditions and immediate and uninterrupted data collection. This review aims to highlight major archives and databases that have shaped the field of radiation biology and provide a broad range of the types of datasets currently available. By preserving all of these data and tissue sets, radiation biologists can combine databases and conduct large-scale analyses of detailed existing data and perform new assays with cutting edge scientific approaches.

Funding for radiation research: past, present and future.

For more than a century, ionizing radiation has been indispensable mainly in medicine and industry. Radiation research is a multidisciplinary field that investigates radiation effects. Radiation research was very active in the mid- to late 20th century, but has then faced challenges, during which time funding has fluctuated widely. Here we review historical changes in funding situations in the field of radiation research, particularly in Canada, European Union countries, Japan, South Korea, and the US. We also provide a brief overview of the current situations in education and training in this field. A better understanding of the biological consequences of radiation exposure is becoming more important with increasing public concerns on radiation risks and other radiation literacy. Continued funding for radiation research is needed, and education and training in this field are also important.

Reflections on Basic Science Studies Involving Low Doses of Ionizing Radiation.

Investigation of health effects of low doses of radiation as a field of study has been riddled with difficulties since its inception. In this document we will use 100 mGy as the cutoff upper limit for low-dose radiation, borrowing this definition from the U.S. Department of Energy, although other agencies and researchers sometimes include up to five-fold higher doses under the same title. Difficulties in this area of research are most often ascribed to the fact that effects of low doses of radiation are subtle and difficult to distinguish from the plethora of other low-grade stresses. Thus, for example, most epidemiological studies include hundreds of thousands of samples and generate risk estimates that are statistically meaningful only when they are considered on a scale of hundreds or thousands of people. A logical approach to remedy the situation for low-dose research was to conduct well-controlled animal studies with hundreds of animals; nevertheless, even after many such studies were completed, our understanding of the biological basis for risk from low-dose radiation exposure is still not conclusive. In this paper we argue that the problem lies in the fact that our approach to animal studies is not comprehensive but conceptually binary. While some researchers apply epidemiological models to animal data, others look into molecular and cellular biology only. Very few studies are conducted to bridge this gap and consider how a realistic model of DNA damage could be integrated into a realistic model of radiation carcinogenesis.