Low-dose Ionizing Radiation Exposure Research Articles

Evaluation of the genotoxic effects of chronic low-dose ionizing radiation exposure on nuclear medicine workers

Nuclear medicine workers are occupationally exposed to chronic ionizing radiation. It is known that ionizing radiation may have damaging effects on chromosomes. In the present study, we investigated the genotoxic effects of ionizing radiation on nuclear medicine workers. We used two different indicators of genotoxicity methods: sister chromatid exchange (SCE) and micronucleus (MN). The present research was carried out using 21 nuclear medicine workers (11 females and 10 males) during two periods: during normal working conditions and after a 1-month vacation. The radiation dose varied from 1.20 to 48.56 mSv, which accumulated during the occupational exposure time between two vacations. Peripheral blood samples were taken from each subject for two distinct lymphocyte cultures (SCE and MN) in each period. In nearly all subjects, SCE values increased significantly during radiation exposure compared to the postvacation period (P<.05). Similarly, MN frequencies in most of the subjects increased significantly during radiation exposure compared to the postvacation period (P<.05). This study revealed that both SCE and MN frequencies in most of the subjects were significantly higher during exposure to ionizing radiation than after a 1-month vacation period. However, this genotoxic effect was reversible in most of the subjects.

Proteomic analysis of low dose arsenic and ionizing radiation exposure on keratinocytes

Human exposure to arsenic and ionizing radiation (IR) occur environmentally at low levels. While the human health effects of arsenic and IR have been examined separately, there is little information regarding their combined effects at doses approaching environmental levels. Arsenic toxicity may be affected by concurrent IR especially given their known individual carcinogenic actions at higher doses. We found that keratinocytes responded to either low dose arsenic and/or low dose IR exposure, resulting in differential proteomic expression based on 2-DE, immunoblotting and statistical analysis. Seven proteins were identified that passed a rigorous statistical screen for differential expression in 2-DE and also passed a strict statistical screen for follow-up immunoblotting. These included: alpha-enolase, epidermal-fatty acid binding protein, heat shock protein 27, histidine triad nucleotide-binding protein 1, lactate dehydrogenase A, protein disulfide isomerase precursor, and S100A9. Four proteins had combined effects that were different than would be expected based on the response to either individual toxicant. These data demonstrate a possible reaction to the combined insult that is substantially different from that of either separate treatment. Several proteins had different responses than what has been seen from high dose exposures, adding to the growing literature suggesting that the cellular responses to low dose exposures are distinct.

Low dose ionizing radiation exposure and cardiovascular disease mortality: cohort study based on Canadian national dose registry of radiation workers

The purpose of our study was to assess the risk of cardiovascular disease (CVD) mortality in a Canadian cohort of 337 397 individuals (169 256 men and 168 141 women) occupationally exposed to ionizing radiation and included in the National Dose Registry (NDR) of Canada. Exposure to high doses of ionizing radiation, such as those received during radiotherapy, leads to increased risk of cardiovascular diseases. The emerging evidence of excess risk of CVDs after exposure to doses well below those previously considered as safe warrants epidemiological studies of populations exposed to low levels of ionizing radiation. In the present study, the cohort consisted of employees at nuclear power stations (nuclear workers) as well as medical, dental and industrial workers. The mean whole body radiation dose was 8.6 mSv for men and 1.2 mSv for women. During the study period (1951-1995), as many as 3 533 deaths from cardiovascular diseases have been identified (3 018 among men and 515 among women). In the cohort, CVD mortality was significantly lower than in the general population of Canada. The cohort showed a significant dose response both among men and women. Risk estimates of CVD mortality in the NDR cohort, when expressed as excess relative risk per unit dose, were higher than those in most other occupational cohorts and higher than in the studies of Japanese atomic bomb survivors. The study has demonstrated a strong positive association between radiation dose and the risk of CVD mortality. Caution needs to be exercised when interpreting these results, due to the potential bias introduced by dosimetry uncertainties, the possible record linkage errors, and especially by the lack of adjustment for non-radiation risk factors.

Health outcomes of low-dose ionizing radiation exposure among medical workers: a cohort study of the Canadian national dose registry of radiation workers

Medical workers can be exposed to low-dose ionizing radiation from various sources. The potential cancer risks associated with ionizing radiation exposure have been derived from cohort studies of Japanese atomic bomb survivors who had experienced acute, high-level exposure. Since such extrapolations are subject to uncertainty, direct information is needed on the risk associated with chronic low-dose occupational exposure to ionizing radiation. To determine the occupational doses of ionizing radiation and examine possible associations with mortality rates and cancer incidence in a cohort of medical workers deriving from the National Dose Registry of Canada (NDR) over the period of 1951-1987. Standardized mortality and incidence ratios (SMR and SIR, respectively) were ascertained by linking NDR data for a cohort of 67 562 medical workers (23 580 males and 43 982 females) with the data maintained by the Canadian Mortality, and Cancer Incidence databases. Dosimetry information was obtained from the National Dosimetry Services. During the follow-up period, 1309 incident cases of cancer (509 in males, 800 in females) and 1325 deaths (823 in males, 502 in females) were observed. Mortality from cancer and non-cancer causes was generally below expected as compared to the general Canadian population. Thyroid cancer incidence was significantly elevated both among males and females, with a combined SIR of 1.74 and 90% CI: 1.40-2.10. The findings confirm previous reports on an increased risk of the thyroid cancer among medical workers occupationally exposed to ionizing radiation. Over the last 50 years, radiation protection measures have been effective in reducing radiation exposures of medical workers to the current very low levels.

Response from authors of “Extracellular matrix alterations in conventional renal cell carcinomas by tissue microarray profiling influenced by the persistent, long-term, low-dose ionizing radiation exposure in humans”

Response from authors of “Extracellular matrix alterations in conventional renal cell carcinomas by tissue microarray profiling influenced by the persistent, long-term, low-dose ionizing radiation exposure in humans”

Innovative Computational Methods for Transcriptomic Data Analysis: A Case Study in the Use of FPT for Practical Algorithm Design and Implementation

Tools of molecular biology and the evolving tools of genomics can now be exploited to study the genetic regulatory mechanisms that control cellular responses to a wide variety of stimuli. These responses are highly complex, and involve many genes and gene products. The main objectives of this paper are to describe a novel research program centered on understanding these responses by i.developing powerful graph algorithms that exploit the innovative principles of fixed parameter tractability in order to generate distilled gene sets; ii.producing scalable, high performance parallel and distributed implementations of these algorithms utilizing cutting-edge computing platforms and auxiliary resources; iii.employing these implementations to identify gene sets suggestive of co-regulation; and iv.performing sequence analysis and genomic data mining to examine, winnow and highlight the most promising gene sets for more detailed investigation. As a case study, we describe our work aimed at elucidating genetic regulatory mechanisms that control cellular responses to low-dose ionizing radiation (IR). A low-dose exposure, as defined here, is an exposure of at most 10 cGy (rads). While the consequences of high doses of radiation are well known, the net outcome of low-dose exposures continues to be debated, with support in the literature for both detrimental and beneficialmore » effects. We use genome-scale gene expression data collected in response to low-dose IR exposure in vivo to identify the pathways that are activated or repressed as a tissue responds to the radiation insult. The driving motivation is that knowledge of these pathways will help clarify and interpret physiological responses to IR, which will advance our understanding of the health consequences of low-dose radiation exposures.« less

Secretory clusterin (sCLU) is a hallmark sensor of DNA damage, cell stress, and cellular senescence: Evidence for similar regulation of sCLU expression after cellular stress and replicative senescence

As the molecular processes in signal transduction during cell stress and senescence (aging), and cancer progression are elucidated, it is clear that certain elements are common amongst these cellular events. Our working hypothesis is that specific cell stress processes activated during the stress of cellular replicative senescence become permanently expressed during early carcinogenic initiation events. Many of these responses to stress are pro-survival and are important to understand. Our data strongly suggest that the signal transduction processes involved in induction of secretory clusterin (sCLU) expression after ionizing radiation (IR) exposure and during cellular replicative senescence are identical. This pathway involves the formation of DNA double-strand breaks and activation of ataxia telengiectasia mutated (ATM). ATM, in turn, stimulates production of insulin-like growth factor (IGF)-1 ligand synthesis by an unknown mechanism. Increased IGF-1 then activates the IGF-1R/c-Src/MAPK/Egr-1 pathway and promotes Egr-1 binding to the CLU promoter to induce expression. The induction of sCLU is complicated by the presence of an inhibitory process involving p53. By elucidating the molecular events and signal transduction in the induction of sCLU, during cell stress (e.g., low-dose IR exposure), replicative senescence, and tumorigenesis, we theorize that we have found a common stress response pathway.

Mutation Induction in Cultured Human Cells after Low-dose and Low-dose-rate γ-ray Irradiation: Detection by LOH Analysis

To study the genetic effects of low-doses and low-dose-rate ionizing radiation (IR), human lymphoblastoid TK6 cells were exposed to 30 mGy of gamma-rays at a dose-rate of 1.2 mGy/hr. The frequency of early mutations (EMs) in the thymidine kinase (TK) gene locus was determined to be 1.7 x 10(-6), or 1.9-fold higher than the level seen in unirradated controls. These mutations were analyzed with a loss of heterozygosity (LOH) detection system, a methodology which has been shown to be sensitive to the effects of radiation. Among the 15 EMs observed after IR exposure, 8 were small interstitial-deletion events restricted to the TK gene locus. However, this specific type of event was not found in unirradiated controls. Although these results were observed under the limited conditions, they strongly suggest that the LOH detection system can be used for estimating the genetic effects of a low-dose IR exposure delivered at a low-dose-rate.

Biologically Based Analysis of Lung Cancer Incidence in a Large Canadian Occupational Cohort with Low-Dose Ionizing Radiation Exposure, and Comparison with Japanese Atomic Bomb Survivors

Lung cancer incidence is analyzed in a large Canadian National Dose Registry (CNDR) cohort with individual annual dosimetry for low-dose occupational exposure to gamma and tritium radiation using the two-stage clonal expansion model (TSCE) and extensions of the model with up to 10 initiation steps. Models with clonal expansion turned off provide very poor fits and are rejected. Characteristic and distinct temporal patterns of excess relative risk (ERR) are found for dose response affecting early, middle, or late stages of carcinogenesis, that is, initiation with one or more stages, clonal expansion, or malignant conversion. Both fixed lag and lag distributions are used to model time from first malignant cell to incidence. Background rates are adjusted for gender and birth cohort. Lacking individual smoking data, surrogate annual smoking doses based on U.S. annual per capita cigarette consumption appear to account for much of the birth cohort effect, leaving radiation dose response relatively unchanged. The mean cumulative exposure for males receiving nonzero cumulative doses of gamma and tritium radiation was 18.2 mSv. The males have a significant dose response with 33 out of a total of 322 lung cancer cases attributable to radiation. There were 78 incident lung cancer among females, (with mean cumulative exposure of 3.8 mSv among females with nonzero exposure). The dose response for females appears smaller than for males but does not differ significantly from zero or from the male dose response. Findings for males include significant dose-response relationships for promotion and malignant conversion, but not initiation, and a protraction effect (sometimes called an inverse-dose-rate effect, where risk increases with protraction of a given dose). The dose response predicted by our analysis appears consistent with the risk for lung cancer incidence in the Japanese atomic bomb survivors cohort, provided that proper adjustments are made for duration of exposure and differences in background rate parameters. We acknowledge support from the Department of Energy (DOE) under grant DE-FG02-03ER63675, and from the Center for Disease Control (CDC) under grant R01 0H07864. This report makes use of data obtained from the Radiation Effects Research Foundation (RERF) in Hiroshima, Japan. RERF is a private foundation funded equally by the Japanese Ministry of Health and Welfare and the U.S. Department of Energy through the U.S. National Academy of Sciences. The conclusions in this report are those of the authors and do not necessarily reflect the scientific judgment of RERF or its funding agencies.

Extracellular matrix alterations in conventional renal cell carcinomas by tissue microarray profiling influenced by the persistent, long-term, low-dose ionizing radiation exposure in humans

The present study was carried out in order to examine molecular alterations of extracellular matrix (ECM), associated with cell-cell communication in conventional (clear-cell) renal cell carcinomas (cRCCs) influenced by persistent long-term, low-dose ionizing radiation (IR) exposure to patients living more than 19 years after the Chernobyl accident in Cesium 137 (137Cs)-contaminated areas of Ukraine. The ECM major components such as fibronectin, laminin, E-cadherin/beta-catenin complexes and p53 tumor suppressor gene protein, and transforming growth factor beta 1 (TGF-beta1) were immunohistochemically (IHC) evaluated in cRCCs from 59 Ukrainian patients, which represented 18 patients living in non-contaminated areas and 41 patients from 137Cs-contaminated areas. In contrast, a control group of 19 Spanish patients with analogue tumors were also investigated. For IHC evaluation, a tissue microarray technique was used. Decrease or loss and abnormal distribution of fibronectin, laminin, E-cadherin/beta-catenin complexes accompanied by elevated levels of p53 and TGF-beta1 were detected in the Ukrainian cRCCs from 137Cs-contaminated areas with statistically significant differences. Thus, our study suggests that chronic long-term, low-dose IR exposure might result in global remodeling of ECM components of the cRCCs with disruption in peri-epithelial stroma and epithelial basement membranes.

Cellular Mechanisms for Low-Dose Ionizing Radiation–Induced Perturbation of the Breast Tissue Microenvironment

Radiation exposure is an important form of environmental carcinogen and has been associated with increased risk of breast cancer. Epigenetic events, especially those involving alterations in the breast stromal microenvironment, may play an important role in radiation-induced carcinogenesis but remain not well understood. We here show that human mammary stromal fibroblasts respond to protracted low-dose ionizing radiation exposures by displaying a senescence-like phenotype. Using a three-dimensional coculture system to model the interactions of different mammary cell types with their neighbors and with their environment, we provide a direct experimental proof that ionizing radiation-induced senescence-like fibroblasts significantly perturb the mammary stromal microenvironment, which is highlighted by impaired formation of pseudopodia networks due to marked cytoskeletal alterations in senescence-like fibroblasts and increased extracellular matrix degradation because of the up-regulation of multiple secreted matrix metalloproteinases. Within such a perturbed environment, mammary ductal morphogenesis is completely disrupted and epithelial cells instead grow into enlarged cystic structures, which further develop and become disorganized cell masses on inactivation of cellular death pathways. Breast carcinoma cells growing in such an environment are enabled to fully express their malignant potential as evidenced by the alpha6beta4 integrin/phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway-dependent invasive growth. Our results suggest that ionizing radiation, in addition to causing gene mutations in epithelial cells, can contribute to breast carcinogenesis by perturbing the tissue microenvironment that leads to dysregulated cell-cell and cell-matrix interactions.

Low dose radiation induced immunomodulation: Effect on macrophages and CD8+ T cells

Purpose: The aim of the present investigation was to study the effect of fractionated whole body low dose ionizing radiation (LDR) on the functional responses of T lymphocytes, their subpopulations and macrophages.Materials and methods: C57BL/6 mice were exposed to 4 cGy from a 60Co source, at 0.31 cGy/min, at 24 h intervals for 5 days (total dose 20 cGy). Phagocytic activity was measured by flow cytometry using Bioparticles® and nitric oxide generation was estimated by spectrophotometry. Proliferation of lymphocytes in response to concanavalin A (con A) and alloantigens was measured by 3H thymidine incorporation. Expression of cell surface markers was assessed by flow cytometric analysis of antibody labeled cells. Target cell killing by cytotoxic T cells (CTL) generated against allogenic cells was assessed by flow cytometry using PKH26 labeled target cells. Cytokines were estimated by enzyme linked immunosorbent assay.Results: Exposure to LDR enhanced nitric oxide secretion and phagocytosis. The expression of early activation antigen, CD69, was enhanced in CD8+ T lymphocytes concomitant with enhanced proliferation in response to con A. In addition, mixed lymphocyte reaction (MLR) and CTL response were augmented and secretion of interferon gamma (IFN-γ) was suppressed following LDR exposure.Conclusions: LDR exposure enhanced the function of macrophages and responses of CD8+ T cells in C57BL/6 mice.

Transcription factors activated in mammalian cells after clinically relevant doses of ionizing radiation.

Over the past 15 years, a wealth of information has been published on transcripts and proteins 'induced' (requiring new protein synthesis) in mammalian cells after ionizing radiation (IR) exposure. Many of these studies have also attempted to elucidate the transcription factors that are 'activated' (i.e., not requiring de novo synthesis) in specific cells by IR. Unfortunately, all too often this information has been obtained using supralethal doses of IR, with investigators assuming that induction of these proteins, or activation of corresponding transcription factors, can be 'extrapolated' to low-dose IR exposures. This review focuses on what is known at the molecular level about transcription factors induced at clinically relevant (< or =2 Gy) doses of IR. A review of the literature demonstrates that extrapolation from high doses of IR to low doses of IR is inaccurate for most transcription factors and most IR-inducible transcripts/proteins, and that induction of transactivating proteins at low doses must be empirically derived. The signal transduction pathways stimulated after high versus low doses of IR, which act to transactivate certain transcription factors in the cell, will be discussed. To date, only three transcription factors appear to be responsive (i.e. activated) after physiological doses (doses wherein cells survive or recover) of IR. These are p53, nuclear factor kappa B(NF-kappaB), and the SP1-related retinoblastoma control proteins (RCPs). Clearly, more information on transcription factors and proteins induced in mammalian cells at clinically or environmentally relevant doses of IR is needed to understand the role of these stress responses in cancer susceptibility/resistance and radio-sensitivity/resistance mechanisms.

Mutation induction in human cells after low dose X ray exposure.

Mutations induced after low dose ionising radiation exposure have been intensively analysed not only for radiation risk estimation but also for basic understanding of cellular responses. Human lymphoblastoid TK6-20C cells were irradiated with 100 mGy of X rays and mutation at the heterozygous thymidine kinase (TK) locus was selected by trifluorothymidine (TFT) resistance. Although the mutation frequency at the TK locus increased from 5.6 x 10(-6) to 7.4 x 10(-6), this increase was not statistically significant. However, molecular analysis of TK mutants exhibiting loss of heterozygocity (LOH) demonstrated a clear effect of such low dose IR exposure. Exposure to 100 mGy X ray increased the fraction of hemizygous-LOH from 10% to 42%. In previous experiments, a similar tendency in the increase of hemizygous-LOH was also observed in TK6 cells after exposure to a 2 Gy dose of X rays. This type of LOH can be considered as a result of end-joining repair of DNA double strand breaks.

Dynamics of changes in micronucleus frequencies in subjects post cessation of chronic low-dose radiation exposure.

To assess DNA damage remaining in peripheral lymphocytes, 48 individuals were evaluated twice for lymphocyte micronucleus frequencies by the cytokinesis-blocking cytochalasin B (CBMN) analysis post relocation from radio-contaminated apartments after various periods of time. The frequencies of CBMN at the first evaluation were significantly higher than those at the second examination (Chang et al., 1999c). These individuals were categorized into three groups: those with cumulative exposure of >300 mSv (defined as high exposure, HDose), those with 100-300 mSv (MDose) and those with <100 mSv (LDose). Using the Poisson mixed-effect model (Little et al., 1996), the estimated mean CBMN frequencies ( per thousand) for individuals in HDose, MDose and LDose exposure categories when they had only recently relocated were 21.8, 17.6 and 15.4, respectively. The estimated mean duration post relocation for the CBMN frequencies of these individuals to reduce to 10.2, the second CBMN frequency, on average, was 47.5, 37.2 and 28.3 months in the three exposure groups, respectively. The rates of change in CBMN frequencies were shown to be significantly higher in the HDose group than in the MDose and LDose groups. The results suggested a characteristic dose-dependent decline in the CBMN frequencies in the exposed population post cessation of chronic low-dose ionizing radiation exposure.

Evaluation of the effectiveness of a teratogen information service: a survey of patient and professional satisfaction.

We have evaluated the effectiveness of the Wisconsin Teratogen Project (WTP), a teratogen information service, using two retrospective surveys. We surveyed medical professionals who utilized the WTP and patients who had received teratogen counseling in a clinic setting. The results from the medical professional survey indicated that medical professionals rely on the WTP for accurate and convenient teratogen information. A tendency to rely on the Physician's Desk Reference as an alternative resource was noted, reinforcing the need to encourage professionals to use teratogen information service projects. Major findings and conclusions from the patient survey included: patients found counseling to be most helpful if, whenever possible, numeric risks were provided; recommendations made in the absence of known risk were not considered by patients to be helpful for providing reassurance; overall compliance with recommendations was high but behavioral recommendations seemed to reduce reassurance and increase dissatisfaction with the service for some patients; and pregnant women exposed to low-dose ionizing radiation were more likely to have considered termination of pregnancy prior to referral but were not more likely to terminate following counseling. Our findings suggest that although the WTP is considered an effective service overall, teratogen counselors should give special consideration to patient and counseling characteristics as these can significantly influence the perception of the risk counseling provided. Particular attention should be given to patients with low-dose ionizing radiation exposure, since misperception of its teratogenic risk is extremely common.

Fetal murine hemopoiesis following in utero low-dose irradiation

ABSTRACT The influence of in utero low-dose ionizing radiation exposure on murine hemopoietic embryogenesis was investigated. In vitro assays such as micro plasma-clot cultures and double-layer soft agar cultures served as sensitive biodosimeters to determine erythropoietic and granulopoietic injuries. Day-10·5, HA/1CR, pregnant mice were irradiated with 0, 50, 100, 150,200, or 300 rads, and day-14·5 fetal livers were studied for colony-forming unit-erythroid (CFU-E), buist-forming unit-erythroid (BFU-E), granulocyte-macrophage colony-forming cell (GM-CFC), and macrophage-colony-forming cell (M-CFC) activity. Fetuses subjected to doses of 200 rads or higher on day 10-5 of gestation responded with a decrease in day-14·5 liver cellularity, reflecting injury to the developing organ and its inability to recover to the nonirradiated values. Difference in response between erythropoietin(EPO)-dependent and EPO-independent CFU-E strongly suggests existence of two populations of erythroid progenitor cells with different radiosensitivities. A dose of 200 rads markedly reduced CFU-E recovery, and a dose of 100 rads was sufficient to reduce BFU-E recovery to almost 10% of 0-rad values. Nonirradiated day-14·5 fetal liver had more GM-CFC compared to any of the irradiated fetuses, and a dramatically reduced M-CFC recovery occurred with each increase in dose following 150 rads. Our results showed that (1) fetal liver granulopoiesis is more sensitive to radiation injury compared to erythropoiesis, and (2) fetal liver has a greater potential for erythropoiesis recovery.