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AbstractPurposeConclusionRadiation exposures do not seem to increase the proportion of mice dying from tumors, but rather cause a shift in the appearance of spontaneous cancers, allowing them to appear earlier, and hence produce a life shortening effect. Then, it was possible to estimate the effect of the dose rate on the carcinogenic effects of radiation using life shortening effects as a measure.The dose response for the induction of life shortening was linear under acute exposure conditions, which indicates that the response under chronic exposure conditions is also likely to be linear, and hence the dose rate factor (DRF) would be constant throughout the dose. Furthermore, the life shortening effect decreased sharply with an increase in age at exposure. To separate the dose rate effect from the effects of age under long-term exposure conditions, a thought experiment was designed which consisted of 8 repeated exposures to an acute 1 Gy dose at intervals of 50 days with an assumption that the effect is additive, and the results were compared with those observed in a chronic continuous exposure experiment (20 mGy per day for 400 days, for a total of 8 Gy: Tanaka et al. 2003). The results showed 211 days of life shortening in the former and 120 days in the latter, which provided a DRF of 1.8 (211/120). If one assumes that a tissue reaction is the primary cause of radiation carcinogenesis, the contrasting two concepts, radiation hormesis and linear-non-threshold model at low doses, would become compatible. [ABSTRACT FROM AUTHOR]

It has long been thought that the carcinogenic effect of radiation resulted from the induction of oncogenic mutations which then led to an increase in the proportion of cancer-bearing individuals. However, even as early as the 1960s, there were indications that the carcinogenic effect of radiation might result from the induction of an earlier onset of cancer. Recently, the former notion was challenged by its inability to explain time-dependent decline of the relative risk following an exposure to radiation, and a parallel shift of mouse survival curves toward younger ages following an exposure to radiation. The two observations are clearly understood if it is assumed only that a radiation exposure causes an earlier onset of spontaneously occurring cancers. In the present study, a critical review was conducted which examined papers that showed dose responses which apparently supported the mutation induction theory of radiation carcinogenesis. It was found that there were two types of misleading experimental designs: one consisted of studies in which observations were prematurely terminated, and which consequently hid a complete story of radiation carcinogenesis. The other set of papers used age adjustments which were derived from the idea that the life shortening effect of radiation needs to be compensated for since tumor mortality becomes higher among older subjects. This type of adjustment appeared reasonable but was found actually to be a different form of description on an earlier onset of cancer following radiation exposures. In mouse experiments, radiation exposures did not lead to the induction of a large increase in the proportion of tumor deaths when life-long observations were made. Human epidemiologic data are also in line with the earlier onset hypothesis of radiation action. It should be cautioned, however, that the earlier onset model applies only to malignancies whose mortality increases rapidly with the increase of age and does not apply to diseases of short latency such as childhood leukemia and thyroid cancers. [ABSTRACT FROM AUTHOR]

The article discusses the effects of ionizing radiation exposure on offspring and future generations. It highlights the concerns surrounding the potential harmful effects of radiation on prenatal development and reproductive health. The article references numerous studies and reports that have investigated the risks and consequences of radiation exposure, particularly during critical periods of pregnancy. It emphasizes the need for more research and data to better understand the complexities involved and calls for long-term epidemiological studies and advancements in genetic and molecular techniques. [Extracted from the article]

Radiotherapy-induced glioblastomas (RIGB) are a well-known late and rare complication of brain irradiation. Yet the clinical, radiological and molecular characteristics of these tumors are not well characterized. This was a retrospective multicentre study that analysed adult patients with newly diagnosed glioblastoma over a 10-year period. Patients with RIGB were identified according to Cahan's criteria for radiation-induced tumors. A case-control analysis was performed to compare known prognostic factors for overall survival (OS) with an independent cohort of IDH-1 wildtype de novo glioblastomas treated with standard temozolomide chemoradiotherapy. Survival analysis was performed by Cox proportional hazards regression. A total of 590 adult patients were diagnosed with glioblastoma. 19 patients (3%) had RIGB. The mean age of patients upon diagnosis was 48 years ± 15. The mean latency duration from radiotherapy to RIGB was 14 years ± 8. The mean total dose was 58Gy ± 10. One-third of patients (37%, 7/19) had nasopharyngeal cancer and a fifth (21%, 4/19) had primary intracranial germinoma. Compared to a cohort of 146 de novo glioblastoma patients, RIGB patients had a shorter median OS of 4.8 months versus 19.2 months (p-value: <.001). Over a third of RIGBs involved the cerebellum (37%, 7/19) and was higher than the control group (4%, 6/146; p-value: <.001). A fifth of RIGBs (21%, 3/19) were pMGMT methylated which was significantly fewer than the control group (49%, 71/146; p-value:.01). For RIGB patients (32%, 6/19) treated with re-irradiation, the one-year survival rate was 67% and only 8% for those without such treatment (p-value:.007). The propensity for RIGBs to develop in the cerebellum and to be pMGMT unmethylated may contribute to their poorer prognosis. When possible re-irradiation may offer a survival benefit. Nasopharyngeal cancer and germinomas accounted for the majority of original malignancies reflecting their prevalence among Southern Chinese. [ABSTRACT FROM AUTHOR]

Assessment of absorbed doses on organs and tissues of miners during radon exposure in the Schneeberg mines in the sixteenth century and calculation of the probability of occurrence of radiation-induced lung cancer and lung fibrosis, considering the life expectancy characteristic and the absence of smoking. The expected radon concentration at the Schneeberg mines has been estimated using published data. Modeling of the accumulation of radon in the working tunnels of mine workings was carried out using the RESRAD-Build 4.0, based on the radium concentration in soil and geometric parameters of the mining tunnel from the engravings in Agricola's book. The dynamics of radionuclides in the human body were performed using the WinAct software in accordance with data from ICRP Publications 130 and 137. The values of absorbed doses on the tissues of the respiratory tract were obtained using the IDAC 2.1 program. Several models based on the epidemiology of uranium miners have been used to calculate radiation risks from radon exposure. The probability of male survival at birth and the age-specific frequency of spontaneous lung cancer not associated with radiation for miners of the sixteenth century (nonsmoking men aged 20–40 years) were estimated to properly calculate the radiation risks. The expected radon concentration in the Schneeberg mines was assessed in the range of 75–100 kBq m−3. The average value of the equilibrium factor was estimated as 0.49 ± 0.03. The annual exposure of miners to radon decay products was assessed as 125–165 WLM year−1. The annual values of absorbed doses to different sections of the respiratory tract were calculated, the maximum absorbed doses of α-radiation are formed on the bronchial and bronchiolar regions of the lungs (2.23 Gy year−1). The deterministic effects as radiation fibrosis of the lungs with 10 years of experience in the mines of Schneeberg have a probability of occurrence from 60 to 100%. All the models used for radiation risk assessments showed that the lifetime risk of developing lung cancer for nonsmoking Schneeberg miners is many times lower than the risk of developing deterministic radiation effects. In contrast, for the smoking cohort of miners in the nineteenth century lung cancer become the dominant cause of death. The deterministic radiation effects of Schneeberg miners in sixteenth century, exposed to extremely high levels of radon, such as radiation pneumosclerosis or pulmonary fibrosis, are more likely than the development of radiation-induced lung cancer. [ABSTRACT FROM AUTHOR]

Increasing epidemiological and biological evidence suggests that radiation exposure enhances cancer risk in a dose-dependent manner. This can be attributed to the 'dose-rate effect,' where the biological effect of low dose-rate radiation is lower than that of the same dose at a high dose-rate. This effect has been reported in epidemiological studies and experimental biology, although the underlying biological mechanisms are not completely understood. In this review, we aim to propose a suitable model for radiation carcinogenesis based on the dose-rate effect in tissue stem cells. We surveyed and summarized the latest studies on the mechanisms of carcinogenesis. Next, we summarized the radiosensitivity of intestinal stem cells and the role of dose-rate in the modulation of stem-cell dynamics after irradiation. Consistently, driver mutations can be detected in most cancers from past to present, supporting the hypothesis that cancer progression is initiated by the accumulation of driver mutations. Recent reports demonstrated that driver mutations can be observed even in normal tissues, which suggests that the accumulation of mutations is a necessary condition for cancer progression. In addition, driver mutations in tissue stem cells can cause tumors, whereas they are not sufficient when they occur in non-stem cells. For non-stem cells, tissue remodeling induced by marked inflammation after the loss of tissue cells is important in addition to the accumulation of mutations. Therefore, the mechanism of carcinogenesis differs according to the cell type and magnitude of stress. In addition, our results indicated that non-irradiated stem cells tend to be eliminated from three-dimensional cultures of intestinal stem cells (organoids) composed of irradiated and non-irradiated stem cells, supporting the stem-cell competition. We propose a unique scheme in which the dose-rate dependent response of intestinal stem cells incorporates the concept of the threshold of stem-cell competition and context-dependent target shift from stem cells to whole tissue. The concept highlights four key issues that should be considered in radiation carcinogenesis: i.e. accumulation of mutations; tissue reconstitution; stem-cell competition; and environmental factors like epigenetic modifications. [ABSTRACT FROM AUTHOR]

While some evidence of an effect of radiation exposure on respiratory disease at low dose levels has now emerged, there is heterogeneity in the risks between different studies and countries. In this paper, we aim to show the effect of radiation on three different sub-types of respiratory disease mortality through the analysis of the NRRW cohort in UK. The NRRW cohort consisted of 174,541 radiation workers. Doses to the surface of the body were monitored using individual film badges. Most of the doses are associated with X-rays and gamma rays and to a less extent of beta and neutron particles. The overall mean 10-year lagged lifetime external dose was 23.2 mSv. Some workers were potentially exposed to alpha particles. However, doses from internal emitters were not available for the NRRW cohort. 25% of male workers and 17% of female workers were identified as being monitored for internal exposure. The Poisson regression methods for grouped survival data with a stratified baseline hazard function were used to describe the dependence of the risk on cumulative external radiation dose. The disease was analyzed by the following subgroups: Pneumonia (1066 cases including 17 cases of influenza), COPD and allied disease (1517 cases) and other remaining respiratory diseases (479 cases). There was very little radiation effect on pneumonia mortality, but evidence of a reduction in mortality risk for COPD and allied disease (ERR/Sv= −0.56, 95%CI: −0.94, −0.06; p =.02) and an increase in risk for other respiratory disease mortality (ERR/Sv = 2.30, 95%CI: 0.67, 4.62; p =.01) with increasing cumulative external dose were observed. The effects of radiation were more prominent amongst workers monitored for internal exposure. The reduction in mortality risk of COPD and allied disease per cumulative external dose was statistically significant for the radiation workers monitored for internal exposure (ERR/Sv= −0.59, 95%CI: −0.99, −0.05; p =.017) but not significant among the workers who were not monitored (ERR/Sv= −0.43, 95%CI: −1.20, 0.74; p =.42). A statistically significant increased risk was observed for other respiratory diseases among monitored radiation workers (ERR/Sv = 2.46, 95%CI: 0.69, 5.08; p =.019), but not among unmonitored workers (ERR/Sv = 1.70, 95%CI: −0.82, 5.65; p =.25). The effects of radiation exposure can be different depending on the type of respiratory disease. No effect was seen in pneumonia; a reduction in mortality risk of COPD, and increased mortality risk of other respiratory diseases were observed with cumulative external radiation dose. More studies are needed to verify these findings. [ABSTRACT FROM AUTHOR]

It has long been thought that the carcinogenic effect of radiation is due to the induction of oncogenic mutations, which means that a fraction of the irradiated individuals will be affected in a dose-dependent manner. This dogma was recently challenged because it was found that the model does not properly explain the life shortening effect of radiation which is seen as a parallel shift of mouse survival curves toward younger ages following an exposure to radiation. Specifically, according to the mutation induction theory, an irradiated mouse or human population evolves into two subpopulations with different mean lifespans, which would lead to a wider distribution of individual lifespans, and hence to a shallower slope in the survival curve, which is not what is observed. Instead, the parallel shift indicates that a large fraction of the irradiated mice are affected (but there are exceptions). Thus, it was thought important to pursue how the excess risk for cancer develops following an exposure to radiation. In the present study, cancer mortality data from mice and atomic-bomb survivors is presented to understand the increasing patterns of cancer risks. In both species, it was found that cancer mortality starts to increase earlier in the exposed group. The results are consistent with the notion that in many irradiated organs (but not all) radiation-induced tissue damage can lead to the development of an altered microenvironment (most probably inflammation), which is favorable to the growth of spontaneously arising tumor cells and can lead to an earlier onset of the diseases or to an apparently increased risk of cancer. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the studies described in this mini review article was to identify nontoxic compounds that could prevent or suppress the radiation induced malignant transformation of cells and be useful as human cancer preventive agents. Conclusions: (1) Many different types of potential anticarcinogenic substances were evaluated initially for their abilities to prevent or suppress radiation induced malignant transformation in vitro, and certain anticarcinogenic protease inhibitors (APIs) were observed to be the most powerful anticarcinogenic agents at suppressing this surrogate endpoint biomarker of radiation carcinogenesis. (2) Within the category of APIs, those that inhibited the activity of chymotrypsin were effective at far lower molar concentrations than other APIs. The soybean-derived protease inhibitor known as the Bowman-Birk inhibitor (BBI) is a particularly powerful chymotrypsin inhibitor that is able to prevent radiation induced transformation in vitro (at concentrations down to nanomolar levels) as well as radiation induced carcinogenesis in vivo without toxicity. (3) There were many other unusual characteristics of APIs that led to the selection of one of these APIs, BBI, as the most appropriate compound for us to develop as a human cancer preventive agent. As one example, the APIs have an irreversible effect on carcinogenesis, while the effects are reversible for most anticarcinogenic agents when they are removed from carcinogenesis assay systems. (4) Numerous studies were performed in attempts to determine the potential mechanisms by which the APIs could prevent or suppress radiation induced carcinogenesis in in vitro and in vivo systems, and the results of these studies are described in this review article. The APIs and the proteases which interact with them appear to play important roles in radiation carcinogenesis. (5) Preparations for human trials using BBI began decades ago. The cost of preparing purified BBI was far too high to consider performing human trials with this agent, so BBI Concentrate (BBIC), a soybean extract enriched in BBI, was developed for the specific purpose of performing human trials with BBI. BBIC achieved Investigational New Drug (IND) Status with the Food and Drug Administration in April, 1992, and human BBIC trials began at that time. (6) Several human trials were performed using BBIC and they indicated many potentially beneficial health effects produced by BBIC administration to people in various forms (e.g. tablets). 7) It is hypothesized that BBI takes the place of a-1-antichymotrypsin, an important regulatory compound in the human body, and helps to maintain homeostasis. [ABSTRACT FROM AUTHOR]

The aim of the Million Person Study of Low-Dose Health Effects (MPS) is to examine the level of radiation risk for chronic exposures received gradually over time and not acutely as was the case for the Japanese atomic bomb survivors. Nuclear power plant (NPP) workers comprise nearly 15 percent of the MPS. Leukemia, selected cancers, Parkinson's disease, ischemic heart disease (IHD) and other causes of death are evaluated. The U.S. Nuclear Regulatory Commission's Radiation Exposure Information and Reporting System (REIRS) and the Landauer, Inc. dosimetry databases identified 135,193 NPP workers first monitored 1957–1984. Annual personal dose equivalents [Hp(10)] were available for each worker. Radiation records from all places of employment were sought. Vital status was determined through 2011. Mean absorbed doses to red bone marrow (RBM), esophagus, lung, colon, brain and heart were estimated by adjusting the recorded Hp(10) for each worker by scaling factors, accounting for exposure geometry and energy of the incident gamma radiation. Standardized mortality ratios (SMR) were calculated. Radiation risks were estimated using Cox proportional hazards models. Nearly 50% of workers were employed for more than 20 years. The mean duration of follow-up was 30.2 y. Overall, 29,124 total deaths occurred, 296 from leukemia other than chronic lymphocytic leukemia (CLL), 3382 from lung cancer, 140 from Parkinson's disease and 5410 from IHD. The mean dose to RBM was 37.9 mGy (maximum 1.0 Gy; percent >100 mGy was 9.2%), 43.2 mGy to lung, 43.7 mGy to colon, 33.2 mGy to brain, and 43.9 mGy to heart. The SMRs (95% CI) were 1.06 (0.94; 1.19) for leukemia other than CLL, 1.10 (1.07; 1.14) for lung cancer, 0.90 (0.76; 1.06) for Parkinson's disease, and 0.80 (0.78; 0.82) for IHD. The excess relative risk (ERR) per 100 mGy for leukemia other than CLL was 0.15 (90% CI −0.001; 0.31). For all solid cancers the ERR per 100 mGy (95% CI) was 0.01 (–0.03; 0.05), for lung cancer −0.04 (–0.11; 0.02), for Parkinson's disease 0.24 (–0.02; 0.50), and for IHD −0.01 (–0.06; 0.04). Prolonged exposure to radiation increased the risk of leukemia other than CLL among NPP workers. There was little evidence for a radiation association for all solid cancers, lung cancer or ischemic heart disease. Increased precision will be forthcoming as the different cohorts within the MPS are combined, such as industrial radiographers and medical radiation workers who were assembled and evaluated in like manner. [ABSTRACT FROM AUTHOR]

Ionizing radiation is a well-known carcinogen, and epidemiologic efforts have been made to evaluate cancer risks following a radiation exposure. The basic approach has been to estimate increased levels of cancer mortality resulting from exposures to radiation, which is consistent with the somatic mutation theory of cancer. However, the possibility that an irradiation might cause an earlier onset of cancer has also been raised since the earliest days of animal studies. Recently, the mutation induction model has been challenged because it is unable to explain the observed dose-related parallel shift of entire mouse survival curves toward younger ages following an irradiation. This is because if it is assumed that only a fraction of the irradiated individuals are affected, the irradiated population would consist of two subpopulations with different mean lifespans, which makes the overall distribution of individual lifespans broader, and hence the slope of the survival curves shallower. To explain this parallel shift, it is necessary to assume that all individuals of a population are affected. As a result of these observations, possible mechanisms which could account for the parallel shift of mouse survival curves were sought by examining the radiation induction of various types of tissue damage which could facilitate an earlier onset of spontaneously arising cancers. A proposed mechanism postulates that a radiation exposure leads to tissue inflammation which subsequently stimulates spontaneously arising cancers and allows them to appear earlier than usual. This notion is not unprecedented, and because the background incidence of cancer increases exponentially with an increase in age, a slight shift of the onset age toward younger ages may make it appear as if the risk is increased. In this scenario, a radiation exposure induces DNA damage, cell death, chromosome aberrations etc., which leads to the multi-pathway responses including activation of stromal fibroblasts, macrophages and various inflammatory factors. Such an inflamed microenvironment favors the growth of spontaneously arising tumor cells although currently, the sequential order or relative importance of the individual factors remains to be known. [ABSTRACT FROM AUTHOR]

The overall aim of this contribution to the 'Second Bill Morgan Memorial Special Issue' is to provide a high-level review of a recent report developed by a Committee for the National Council on Radiation Protection and Measurements (NCRP) titled 'Approaches for Integrating Information from Radiation Biology and Epidemiology to Enhance Low-Dose Health Risk Assessment'. It derives from previous NCRP Reports and Commentaries that provide the case for integrating data from radiation biology studies (available and proposed) with epidemiological studies (also available and proposed) to develop Biologically-Based Dose-Response (BBDR) models. In this review, it is proposed for such models to leverage the adverse outcome pathways (AOP) and key events (KE) approach for better characterizing radiation-induced cancers and circulatory disease (as the example for a noncancer outcome). The review discusses the current state of knowledge of mechanisms of carcinogenesis, with an emphasis on radiation-induced cancers, and a similar discussion for circulatory disease. The types of the various informative BBDR models are presented along with a proposed generalized BBDR model for cancer and a more speculative one for circulatory disease. The way forward is presented in a comprehensive discussion of the research needs to address the goal of enhancing health risk assessment of exposures to low doses of radiation. The use of an AOP/KE approach for developing a mechanistic framework for BBDR models of radiation- induced cancer and circulatory disease is considered to be a viable one based upon current knowledge of the mechanisms of formation of these adverse health outcomes and the available technical capabilities and computational advances. The way forward for enhancing low-dose radiation risk estimates will require there to be a tight integration of epidemiology data and radiation biology information to meet the goals of relevance and sensitivity of the adverse health outcomes required for overall health risk assessment at low doses and dose rates. [ABSTRACT FROM AUTHOR]

The space radiation environment is a complex combination of fast-moving ions derived from all atomic species found in the periodic table. The energy spectrum of each ion species varies widely but is prominently in the range of 400–600 MeV/n. The large dynamic range in ion energy is difficult to simulate in ground-based radiobiology experiments. Most ground-based irradiations with mono-energetic beams of a single one ion species are delivered at comparatively high dose rates. In some cases, sequences of such beams are delivered with various ion species and energies to crudely approximate the complex space radiation environment. This approximation may cause profound experimental bias in processes such as biologic repair of radiation damage, which are known to have strong temporal dependencies. It is possible that this experimental bias leads to an over-prediction of risks of radiation effects that have not been observed in the astronaut cohort. None of the primary health risks presumably attributed to space radiation exposure, such as radiation carcinogenesis, cardiovascular disease, cognitive deficits, etc., have been observed in astronaut or cosmonaut crews. This fundamentally and profoundly limits our understanding of the effects of GCR on humans and limits the development of effective radiation countermeasures. [ABSTRACT FROM AUTHOR]

MacCune–Albright syndrome (MAS) is a rare autosomal dominant osteo-hormonal disorder. MAS is characterized by a severe form of polyostotic fibrous dysplasia, 'café-au-lait' pigmentation of the skin and multiple endocrinopathies. MAS was shown to be caused by mosaic missense somatic mutations in the GNAS gene coding for the alpha-subunit of the stimulatory G-protein. MAS is also associated with radiation-induced malignant tumors, like osteosarcoma, fibrosarcoma and chondrosarcoma but their origin remains misunderstood. In parallel, bisphosphonates treatment was shown to improve the MAS patients' outcome, notably by increasing bone density but, again, the molecular mechanisms supporting these observations remain misunderstood. Here, by using fibroblast and osteoblast cell lines derived from 2 MAS patients, the major radiobiological features of MAS were investigated. Notably, the clonogenic cell survival, the micronuclei and the γH2AX, pATM and MRE11 immunofluorescence assays were applied to MAS cells. It appears that cells from the 2 MAS patients are associated with a moderate but significant radiosensitivity, a delayed radiation-induced nucleoshuttling of the ATM kinase likely caused by its sequestration in cytoplasm, suggesting impaired DNA double-strand breaks (DSB) repair and signaling in both fibroblasts and osteoblasts. Such delay may be partially corrected by using bisphosphonates combined with statins, which renders cells more radioresistant. Our findings represent the first radiobiological characterization of fibroblasts and osteoblasts providing from MAS patients. Although the number of studied cases is reduced, our findings suggest that the MAS cells tested belong to the group of syndromes associated with moderate but significant radiosensitivity. Further investigations are however required to secure the clinical transfer of the combination of bisphosphonates and statins, to reduce the disease progression and to better evaluate the potential risks linked to radiation exposure. [ABSTRACT FROM AUTHOR]

Recently, low dose radiotherapy delivered to the whole lung has been proposed as treatment for the pneumonia due to COVID-19. Although there is biological plausibility for its use, the evidence supporting its effectiveness is scarce, and the risks associated with it may be significant. Thus, based on a virtual case simulation, we estimated the risks of radiation-induced cancer (RIC) and cardiac disease. Lifetime attributable risks (LAR) of RIC were calculated for the lung, liver, esophagus, and breast of female patients. The cardiovascular risk of exposure-induced death (REID) due to ischemic heart disease was also calculated. The doses received by the organs involved in the treatment were obtained from a simulation of conformal radiotherapy (RT) treatment, delivering a dose of 0.5 Gy–1.5 Gy to the lungs. We considered a LAR and REID <1% as acceptable, 1–2% cautionary, and >2% unacceptable. The lung was at the highest risk for RIC (absolute LAR below 5200 cases/100,000 and 2250 cases/100,000 for women and men, respectively). For women, the breast had the second-highest LAR, especially for young women. The liver and esophagus had LARs below 700/100,000 for both sexes, with a higher incidence of esophageal cancer in women and liver cancer in men. Regarding the LAR cutoff, we observed an unacceptable or cautionary LAR for lung cancer in all women and men <60 years with an RT dose >1 Gy. LAR for lung cancer with an RT dose of 1 Gy was cautionary for women >60 years of age and men <40 years of age. No LAR estimation was unacceptable for the RT dose ≤0.7 Gy in all groups irrespective of sex or age at exposure. Only 0.5 Gy had an acceptable REID. A RT dose ≤0.5 Gy provides an acceptable LAR estimate (≤1%) for RIC and REID, irrespective of sex and age. The current ongoing trials should initially use doses ≤0.5 Gy to maintain the risks at an acceptable level and include only patients who fail or do not have any other treatment option. [ABSTRACT FROM AUTHOR]

Keywords: Biologically based models of cancer risk; radiation epidemiology; molecular biology; integrative modeling; adverse outcome pathways EN Biologically based models of cancer risk radiation epidemiology molecular biology integrative modeling adverse outcome pathways 2 11 10 01/18/21 20210101 NES 210101 Introduction Increasing grasp of disease processes leading to cancer and concomitantly the establishment of observational data sets for the general population prompted the development of biologically based models of cancer risk (BBCR models) (Armitage and Doll [4]; Moolgavkar et al. [64]; Moolgavkar and Knudson [65]). In radiation epidemiology the first deployment of BBCR models occurred with the Life Span Study (LSS) of Japanese a-bomb survivors decades after their application to observational cancer data (Little et al. [55]; Little [54]; Heidenreich et al. [37]; Kai et al. [42]). Early pioneering studies of radiation risk in the LSS were based on descriptive models which linked excess rates of cancer incidence and mortality to radiation exposure by statistical association (Wakabayashi et al. [85]; Thompson et al. [82]). Persistent radiation effects and radiation-associated inflammation Radiation can modulate cancer initiation, progression, and transformation in multiple ways thereby leading to multiple cancer types. [Extracted from the article]

Thyroid cancer of papillary histology (PTC) is the dominant type in radio-epidemiological cohorts established after nuclear accidents or warfare. Studies on post-Chernobyl PTC and on thyroid cancer in the life span study (LSS) of Japanese a-bomb survivors consistently revealed high radiation risk after exposure during childhood and adolescence. For post-Chernobyl risk assessment overexpression of the CLIP2 gene was proposed as molecular biomarker to separate radiogenic from sporadic PTC. Based on such binary marker a biologically-based risk model of PTC carcinogenesis has been developed for observational Chernobyl data. The model featured two independent molecular pathways of disease development, of which one was associated with radiation exposure. To gain credibility the concept for a mechanistic risk model must be based on general biological features which transcend findings in a single cohort. The purpose of the present study is therefore to demonstrate portability of the model concept by application to PTC incidence data in the LSS. By exploiting the molecular two-path concept we improve the determination of the probability of radiation causing cancer (POC). The current analysis uses thyroid cancer incidence data of the LSS with thyroid cancer diagnoses and papillary histology (n = 292) from the follow-up period between 1958 and 2005. Risk analysis was performed with both descriptive and biologically-based models. Judged by goodness-of-fit all applied models described the data almost equally well. They yielded similar risk estimates in cohorts post-Chernobyl and LSS. The preferred mechanistic model was selected by biological plausibility. It reflected important features of an imperfect radiation marker which are not easily addressed by descriptive models. Precise model predictions of marker prevalence in strata of epidemiological covariables can be tested by molecular measurements. Application of the radiation-related molecular pathway from our preferred model in retrospective risk assessment decreases the threshold dose for 50% POC from 0.33 (95% confidence interval (CI) 0.18; 0.64) Gy to 0.04 (95% CI 0.01; 0.19) Gy for females and from 0.43 (95% CI 0.17; 1.84) Gy to 0.19 (95% CI 0.05; 1.00) Gy for males. These improvements are still not sufficient to separate radiation-induced from sporadic PTC cases at very low doses <0.015 Gy typical for the Fukushima accident. Successful application of our preferred mechanistic model to LSS incidence data confirms and improves the biological two-path concept of radiation-induced PTC. Model predictions suggest further molecular validation studies to consolidate the basis of biologically-based risk estimation. [ABSTRACT FROM AUTHOR]

Purpose: Humans are increasingly exposed to ionizing radiation (IR). Both low (<100 mGy) and high doses can cause stochastic effects, including cancer; whereas doses above 100 mGy are needed to promote tissue or cell damage. 10–15% of radiotherapy (RT) patients suffer adverse reactions, described as displaying radiosensitivity (RS). Sensitivity to IR's stochastic effects is termed radiosusceptibility (RSu). To optimize radiation protection we need to understand the range of individual variability and underlying mechanisms. We review the potential mechanisms contributing to RS/RSu focusing on RS following RT, the most tractable RS group. Conclusions: The IR-induced DNA damage response (DDR) has been well characterized. Patients with mutations in the DDR have been identified and display marked RS but they represent only a small percentage of the RT patients with adverse reactions. We review the impacting mechanisms and additional factors influencing RS/RSu. We discuss whether RS/RSu might be genetically determined. As a recommendation, we propose that a prospective study be established to assess RS following RT. The study should detail tumor site and encompass a well-defined grading system. Predictive assays should be independently validated. Detailed analysis of the inflammatory, stress and immune responses, mitochondrial function and life style factors should be included. Existing cohorts should also be optimally exploited. [ABSTRACT FROM AUTHOR]

The release of radioactivity into the atmosphere from the Fukushima Daiichi accident has been estimated by Japan’s government as about one-tenth of that from the Chernobyl accident. The area in Japan contaminated with cesium-137—at the same levels that caused evacuation around Chernobyl—is also about one-tenth as large. The estimated number of resulting cancer deaths in the Fukushima area from contamination due to more than 1 curie per square kilometer is likely to scale correspondingly—on the order of 1,000. On March 16, 2011, the Nuclear Regulatory Commission advised Americans in the region to evacuate out to 50 miles (NRC 2011a). If the Japanese government had made the same recommendation to its citizens, it would have resulted in the early evacuation of about two million people instead of 130,000. Because contaminated milk was interdicted in Japan, the number of (mostly non-fatal) thyroid cancer cases will probably be less than 1 percent of similar cases in Chernobyl. Unless properly dealt with, however, fear of ionizing radiation could have long-term psychological effects on a large portion of the population in the contaminated areas. [ABSTRACT FROM PUBLISHER]

Inhibitor of apoptosis protein (IAP) antagonists have shown activity in preclinical models of head and neck squamous cell carcinoma (HNSCC), and work across several cancer types has demonstrated diverse immune stimulatory effects including enhancement of T cell, NK cell, and dendritic cell function. However, tumor-cell-intrinsic mechanisms for this immune upregulation have been largely unexplored. In this study, we show that ASTX660, an antagonist of cIAP1/2 and XIAP, induces expression of immunogenic cell death (ICD) markers in sensitive HNSCC cell lines in vitro. Experiments in syngeneic mouse models of HNSCC showed that ASTX660 can also enhance radiation-induced ICD in vivo. On a functional level, ASTX660 also enhanced killing of multiple murine cell lines by cytotoxic tumor-infiltrating lymphocytes, and when combined with XRT, stimulated clonal expansion of antigen-specific T lymphocytes and expression of MHC class I on the surface of tumor cells. Flow cytometry experiments in several human HNSCC cell lines showed that MHC class I (HLA-A,B,C) was reliably upregulated in response to ASTX660 + TNFα, while increases in other antigen processing machinery (APM) components were variable among different cell lines. These findings suggest that ASTX660 may enhance anti-tumor immunity both by promoting ICD and by enhancing antigen processing and presentation. [ABSTRACT FROM AUTHOR]

Introduction: There are numerous shared risk factors in the etiopathogenesis of coronary artery disease (CAD) and cancer both at epidemiologic and molecular level. Additionally, different modalities of treatment of cancer such as radiation, chemotherapy, immunotherapy, and hormonal therapies further increase the risk of CAD and acute coronary syndrome. Most large database analysis and single-center experiences have shown that cancer patients undergoing PCI are at an increased risk of in-hospital mortality, bleeding, repeat revascularization.Areas covered: In this review article the authors discuss the associations between CAD and cancer, challenges for PCI in cancer patients and outcome data.Expert opinion: Interventionists performing PCI on cancer patients should be cognizant of the heightened risk of bleeding, thrombosis, possible need for interruption of dual-antiplatelet therapy, and the increased risk of target lesion revascularization in this cohort. These risks may be partially mitigated by utilization of best practices such as the use of radial artery access, intravascular imaging for lesion assessment and stent optimization and avoidance of complex stenting strategies. Finally, it is of paramount importance to have a multidisciplinary approach consisting of the treating cardiologist, medical and/or surgical oncologist, and palliative medicine, and involve the patient and their family in making informed decisions. [ABSTRACT FROM AUTHOR]

Radiotherapy is routinely used in the treatment of lung cancer patients. However, it often causes malignant effects, such as promoting cancer cell migration and invasion. Previous studies demonstrated that ionizing radiation (IR) promotes cancer cell invasion by stimulating the β-catenin, IL-6, STAT3, and Bcl-XL signaling pathway or the PI3K, Akt, and NF-κB signaling pathway. Both Bcl-XL and NF-κB stimulate the secretion of matrix metalloproteases (MMPs), including MMP-2 and MMP-9. In the present study, linarin isolated from Chrysanthemum morifolium flowers significantly decreased the IR-induced cell migration and invasion at a concentration of 5 μM in A549 cells. This effect was mediated via MMP-9 downregulation and the suppression of NF-κB activation by inhibiting NF-κB and IκB-α phosphorylation. However, linarin did not affect the STAT3/Bcl-XL pathway or the stabilization of β-catenin. Overall, these results suggest that linarin repressed the MMP-9-dependent invasion pathway by regulating NF-κB activity, thereby inhibiting IR-induced cancer metastasis. [ABSTRACT FROM AUTHOR]

Purpose: Projects evaluating the effects of radiation, within the National Institutes of Quantum and Radiological Science and Technology (QST), National Institute of Radiological Sciences (NIRS), have focused on risk analyses for life shortening and cancer prevalence using laboratory animals. Genetic and epigenetic alterations in radiation-induced tumors have been also analyzed with the aim of better understanding mechanisms of radiation carcinogenesis. As well as the economic and practical limitations of repeating such large-scale experiments, ethical considerations make it vital that we store and share the pathological data and samples of the animal experiments for future use. We are now constructing such an archive called the Japan-Storehouse of Animal Radiobiology Experiments (J-SHARE). Methods: J-SHARE records include information such as detailed experimental protocols, necropsy records and photographs of organs at necropsy. For each animal organs and tumor tissues are dissected, and parts are stored as frozen samples at −80 °C. Samples fixed with formalin are also embedded in paraffin blocks for histopathological analyses. Digital copies of stained tissues are being systematically saved using a virtual slide system linked to original records by barcodes. Embedded and frozen tissues are available for molecular analysis. Conclusion: Similar archive systems for radiation biology have also been under construction in the USA and Europe, the Northwestern University Radiation Archive (NURA), and STORE at the BfS, respectively. The J-SHARE will be linked with the sister-archives and made available for collaborative research to institutions and universities all over the world. [ABSTRACT FROM AUTHOR]

Purpose: Recently, new studies have brought to light the potential risks of low dose radiation (LDR) in cancer. In this review, we discuss in detail the detrimental effects of LDR in some model organisms and animal models, as well as potential risks to human beings from some routine medical screening procedures. Furthermore, cellular mechanisms by which LDR exerts its negative effects like endoplasmic reticulum stress, epigenetic changes and microRNAs are also reviewed. A few studies are discussed that have reported some benefits of LDR through changes in energy metabolism. Lastly, we focus on breast cancer, one of the predominant forms of cancer potentially affected by LDR and some of the benefits of n-3 polyunsaturated fatty acids (PUFA) as dietary compounds that offer protection against radiation effects on cancer cells and cancer progression. Conclusions: Overall, LDR exerts mainly damaging effects through diverse cell and molecular mechanisms, with a few beneficial effects reported. In some cancers, surrounding adipose tissue of the breast may contribute to obesity-related cancer. Further, preclinical data suggest that anti-inflammatory dietary compounds such as PUFA and other dietary interventions may protect against radiation effects on cancer cells and cancer progression. [ABSTRACT FROM AUTHOR]

Basal-like breast cancers have the highest rates of locoregional recurrence after radiation. By correlating gene expression with early locoregional recurrence, we nominate TTK protein kinase as a mediator of radioresistance. TTK inhibition radiosensitizes in vitro and in vivo through a novel mechanism of impaired homologous recombination and represents a promising translational strategy. [ABSTRACT FROM AUTHOR]

Purpose: This paper provides an update and summary on the organization of European research in the field of low dose risk and radiation protection. To address declining resources and competence in radiation protection and related research across European countries, a High Level and Expert Group (HLEG) was established in 2007. The HLEG identified key policy and scientific questions to be addressed through a strategic research agenda for low dose radiation risk. This initiated the establishment of a European Research Platform, called MELODI (Multidisciplinary European Low Dose Research Initiative). Dr Bill Morgan closely followed the European low dose programme and chaired the international Advisory Boards of DoReMi Network of Excellence and the MELODI platform. Conclusion: The MELODI research platform is dedicated to low dose ionizing radiation risk. In 2010, MELODI was founded as a registered association with 15 members. As of September 2016, the associations membership increased to 46. A major activity of MELODI is the establishment and updating of a long-term Strategic Research Agenda (SRA) for research on low dose risk in Europe. The SRA is intended to guide the priorities for national and European research programmes and the preparation of competitive calls at the European level. A key priority for radiation protection research is to improve health risk estimates for exposures corresponding to the dose limits for occupational exposures and to reference levels for the exposure of the population in emergency situations. [ABSTRACT FROM AUTHOR]

Purpose:To examine the ability of the meadowsweet preparation to inhibit carcinogenesis induced by ionizing radiation in female rats. Materials and methods:The chemical composition of meadowsweet (Filipendula ulmaria) raw material (ethanol and aqueous extracts of meadowsweet flowers) has been studied for the presence of flavonoids, tannins and catechins. Adult female LIO strain rats were subjected to a single whole body γ-irradiation at a dose of 4 Gy in animal experiments. One group of irradiated rats served as control while the other group, starting from the 10th day after irradiation and until the end of the experiment, was given meadowsweet as a decoction of the flowers instead of drinking water. The average daily intake of meadowsweet (dry raw material) was 1 g/kg body weight. Rats were observed for 16 months. Results:The analyzed meadowsweet extracts showed a sufficiently high content of flavonoids and tannins. In irradiated rats after 16 months the overall incidence of tumors was 79.6% (in 82 of 103 rats), the incidence of malignant tumors was 43.7% and the overall tumor multiplicity was 1.48. Most tumors were localized in the mammary gland – 57.3%. In rats that received meadowsweet, the incidence of all malignant tumors and overall multiplicity of tumors were significantly decreased by 1.5 and 1.3 times, respectively. The greatest reduction of many parameters has been identified for breast tumors: the overall incidence was decreased by 1.5 (p = 0.0174) and the overall multiplicity and multiplicity of malignant tumors – by 1.6 (p = 0.0002) and 2.2 (p = 0.0383) times, respectively. Conclusions:Meadowsweet preparation showed inhibiting activity on radiation carcinogenesis. [ABSTRACT FROM AUTHOR]

Purpose:This review evaluates the role of dose rate on cell and molecular responses. It focuses on the influence of dose rate on key events in critical pathways in the development of cancer. This approach is similar to that used by the U.S. EPA and others to evaluate risk from chemicals. It provides a mechanistic method to account for the influence of the dose rate from low-LET radiation, especially in the low-dose region on cancer risk assessment. Molecular, cellular, and tissues changes are observed in many key events and change as a function of dose rate. The magnitude and direction of change can be used to help establish an appropriate dose rate effectiveness factor (DREF). Conclusions:Extensive data on key events suggest that exposure to low dose-rates are less effective in producing changes than high dose rates. Most of these data at the molecular and cellular level support a large (2–30) DREF. In addition, some evidence suggests that doses delivered at a low dose rate decrease damage to levels below that observed in the controls. However, there are some data human and mechanistic data that support a dose-rate effectiveness factor of 1. In summary, a review of the available molecular, cellular and tissue data indicates that not only is dose rate an important variable in understanding radiation risk but it also supports the selection of a DREF greater than one as currently recommended by ICRP (2007) and BEIR VII (NRC/NAS 2006). [ABSTRACT FROM AUTHOR]

PurposeSecond cancers are among the most serious sequelae for cancer survivors who receive radiotherapy. This article aims to review current knowledge regarding how the risk of radiotherapy-associated second cancer can be minimized by biological measures and to discuss relevant research needs. ResultsThe risk of second cancer can be reduced not only by physical measures to decrease the radiation dose to normal tissues but also by biological means that interfere with the critical determinants of radiation-induced carcinogenesis. Requirements for such biological means include the targeting of tumor types relevant to radiotherapy-associated risk, concrete safety and efficacy evidence and feasibility and minimal invasiveness. Mechanistic insights into the process of radiation carcinogenesis provide rational approaches to minimize the risk. Five mechanism-based strategies are proposed herein based on the current state of knowledge. Epidemiological studies on the joint effects of radiation and lifestyle or other factors can provide evidence for factors that modify radiation-associated risks if deliberately controlled. ConclusionsMechanistic and epidemiological evidence indicates that it is possible to develop interventional measures to minimize the second cancer risk associated with radiotherapy. Research is needed regarding the critical determinants of radiation-induced carcinogenesis available for intervention and joint effects of radiation and controllable factors. [ABSTRACT FROM PUBLISHER]

Purpose: To carry out a comparative study of inhibition of radiation carcinogenesis using alpha-difluoromethylornithine (DFMO), tinctures of ginseng, eleutherococcus and leuzea in female rats. Materials and methods: Locally bred female LIO-strain rats were subjected to a single whole body γ-irradiation dose of 4 Gy at 12 weeks of age. Modifying drugs were given with drinking water from the 10th day after irradiation until the end of the experiment (for 16 months). Results: Irradiated rats developed tumors 70.0-79.6% (malignant tumors: 43.7-45.0%) with a multiplicity of 1.48-1.75 (malignant: 0.5-0.58), while in unirradiated animals the incidence of all/malignant tumors was 21.9%/7.7% with multiplicity of 0.22/0.08. In exposed rats tumors most often developed in the mammary gland - 57.3%, reproductive and endocrine organs - 27.2%, and other localizations - 29.1%. All drugs, except leuzea, significantly reduced incidence and multiplicity of tumors, overall or at some localizations in irradiated rats. Highest, and practically equal inhibition, was shown by ginseng and DFMO, while eleutherococcus was clearly inferior. Ginseng reduced overall tumor incidence and multiplicity by 1.5 and 2.4 times, malignant tumor incidence and multiplicity - by 2.5 and 2.9 times, respectively. Conclusions: The ginseng extract is the most promising radiation carcinogenesis inhibitor tested. [ABSTRACT FROM AUTHOR]

Purpose: Inhalation of radon progeny can cause high lung and respiratory tract radiation doses. The aim of this paper was to examine the relationship between radon progeny and cancers of the extra-thoracic airways in the German uranium miner cohort for an extended follow-up through 2008. Methods: The cohort included 58,690 workers employed between 1946 and 1989 at the Wismut company. Exposure to radon progeny in Working Level Months (WLM) was determined from a comprehensive job-exposure matrix. The mean (max) cumulative exposure to radon among exposed cohort members (86%) was 280 WLM (3,224 WLM). Internal Poisson regression models were applied to estimate the linear Excess Relative Risk (ERR) per unit of cumulative exposure to radon. Results: A small increase in the mortality from all cancers of the extra-thoracic airways combined with increasing cumulative exposure to radon was found (ERR/100 WLM = 0.036, p = 0.12), based on 234 deaths. The estimated ERR per 100 WLM for relevant cancer sub-groups were: 0.017 (p > 0.5) larynx (n = 94); 0.077 (p = 0.20) pharynx (n = 74); and 0.030 (p > 0.5) tongue and mouth (n = 55). Conclusion: Results indicated a small but not statistically significant increase in mortality from cancers of the extra-thoracic airways in relation to radon. Low statistical power and uncontrolled confounding were limitations of this study. [ABSTRACT FROM AUTHOR]

Purpose: To review the literature on radiation-induced normal tissue injury in the context of treatment of primary and metastatic brain tumors with a focus on Michael Robbins' work on mechanisms of injury and approaches to mitigation, and also to identify other potential opportunities to improve treatment outcome and quality of life (QOL). Background: Brain tumors remain a significant challenge for patients, their families, the physicians treating them, and researchers seeking more effective treatments. Current treatment of brain tumors involves combinations of radiotherapy with surgery, chemotherapy, and molecularly targeted agents. As patient survival improves with advances in treatment there is an increasing concern for the cognitive deficits that may become apparent months or years after treatment some of which are related to radiation-induced brain damage. One area of Michael Robbins' research was unraveling the mechanisms of radiation-induced cognitive deficits, which formed the basis for the development of some mitigators of radiation injury. Extrapolating from this, new opportunities to identify and develop putative predictive biomarkers of radiation-induced brain damage can be explored. Conclusions: Predictive biomarkers of radiation-induced brain injury may enable stratifying patients for customization of treatment and thus aid in improving the QOL and possibly prolonging survival. Here we discuss the challenges involved in leveraging recent advances in radiation-specific biomarker research and translating them to radiotherapy, which for the foreseeable future is likely to remain a cornerstone of the treatment of brain tumors. [ABSTRACT FROM AUTHOR]

Purpose: Development of radioprotective agents has focused primarily on cytoprotection from relatively high doses of therapeutic radiation and nuclear disasters. Epidemiological studies and radiobiological models report the potential for stochastic effects from relatively low-dose radiation exposure. Diagnostic studies like computed tomography (CT) expose the patient to a small but significant amount of radiation, which has been reported to increase the risk for carcinogenesis. Young patients expected to undergo multiple CT studies may benefit from a protective agent given prior to CT. This review includes published data of agents that have been shown to protect against radiation-induced carcinogenesis. A discussion follows regarding the data that describes the extent of radiation exposure during CT, as well as technical modifications, which also reduce radiation exposure. Results/Conclusions: Most experiments have used in vivo animal models or in vitro cell lines. Ethical barriers prevent large-scale human studies, although, there are two prospective human studies from the Chernobyl nuclear accident. Collectively, all of these studies provide evidence of statistically significant reductions in radiation-induced carcinogenesis. Protection is achieved by several mechanisms, which include free radical scavenging, caloric restriction, non-steroidal anti-inflammatory agents, humoral factors, and an oxidative agent. Enhanced efficacy is achieved when targeting multiple mechanisms. The data presented provides the scientific foundation for future development of a radioprotectant that may reduce the risk of carcinogenesis from low-dose exposure when certain at-risk populations undergo diagnostic studies like CT. [ABSTRACT FROM AUTHOR]

The bioactive flavonoid baicalein has been shown to have radioprotective activity, although the molecular mechanism is poorly understood in vivo. C57BL/6 mice were irradiated with X-rays (15 Gy) with and without baicalein treatment (5 mg/kg/day). Irradiation groups showed an increase of NF-κκB-mediated inflammatory factors with oxidative damage and showed inactivation of FOXO and its target genes, catalase and SOD. However, baicalein suppressed radiation-induced inflammatory response by negatively regulating NF-κκB and up-regulating FOXO activation and catalase and SOD activities. Furthermore, baicalein inhibited radiation-induced phosphorylation of MAPKs and Akt, which are the upstream kinases of NF-κκB and FOXOs. Based on these findings, it is concluded that baicalein has a radioprotective effect against NF-κκB-mediated inflammatory response through MAPKs and the Akt pathway, which is accompanied by the protective effects on FOXO and its target genes, catalase and SOD. Thus, these findings provide new insights into the molecular mechanism underlying the radioprotective role of baicalein in mice. [ABSTRACT FROM AUTHOR]

Ultraviolet and visible spectroscopic measurements were used to investigate prepared undoped and Mn-doped sodium phosphate glasses before and after successive gamma irradiation. The effects of both glass composition and MnO2 content on the generation of radiation-induced defects were investigated. Undoped sodium phosphate glass shows strong UV absorption, which is attributed to the presence of trace iron impurities present in the raw materials. Mn-doped glasses reveal an additional visible broad band centered at about 500 nm due to Mn3+, which has recently been related to the 5Eg →5T2g transition. The radiation-induced bands are correlated with the generation of liberated electron-hole pairs during the process of gamma irradiation and the possibility of photochemical reactions especially with trace iron impurities and manganese ions. The intensity and the position of the induced bands are observed to depend on the type and composition of glass, concentration of the dopant and also on the irradiation dose. Manganese ions when present in relatively higher content have been found to show a shielding behavior towards the effects of progressive gamma irradiation causing a retardation of the growth of the induced defects. Infrared and Raman spectra of the undoped and Mn-doped glasses were measured to investigate the structural phosphate groups present and the effect of MnO2 on the network structure. An ESR investigation was carried out to confirm the state of manganese ions in the prepared sodium phosphate glasses. [ABSTRACT FROM AUTHOR]

Purpose: To assess the cell cycle-dependent influence of gemcitabine on ionizing radiation-induced DNA double-strand breakage (DSB) and rejoining measured by pulsed-field gel electrophoresis (PFGE). Materials and methods: WIDR cells (human colon carcinoma) were synchronized by serum starvation/stimulation providing populations with 7% (G1) or 50% S-phase cells, respectively. Following drug treatment (0.5 μg/ml for 2 hours) cells were irradiated (up to 90 Gy) or incubated for repair (up to 6 h after 40 Gy). Cell cycle changes were monitored by flow cytometry, DNA fragmentation was assessed by PFGE as fraction of electrophoretically mobile DNA. Results: Without drug treatment, irradiated S-phase cells exhibited lower PFGE signals than the G1 cells due to the well known electrophoretic immobility of replicative DNA fragments, but DSB rejoining was not different. Gemcitabine pretreatment increased the apparent initial radiation-induced DNA fragmention specifically for S-phase cells. This effect was rapidly reversed (1 h) during incubation for repair. Conclusions: The data indicate that gemcitabine causes the formation of additional radiation-induced DSB in S-phase cells or destabilizes the replicative structures that otherwise prevent DNA fragment migration during PFGE. The latter would be rapidly restituted superimposing DSB rejoining. This is discussed in relation to the recently proposed role of mismatch repair in gemcitabine radiosensitization. [ABSTRACT FROM AUTHOR]

A few data sets have been used for assessing the risk of radiation-associated bladder cancer. The most important are the Japanese atomic bomb survivors and patients exposed to ionizing radiation for medical purposes. According to a report from the United Nations Commission on the Effect of Ionizing Radiation, there is convincing evidence of a relationship between exposure to ionizing radiation and bladder cancer. In contrast to many other malignancies it is not clear how age at exposure and gender affect the risk of bladder cancer. Furthermore, the potential interaction between smoking and radiation exposure needs to be studied in greater detail. [ABSTRACT FROM AUTHOR]

Purpose: In biophysical modeling for several instances of radiation-induced radioprotection, i.e., adaptive response (AR), hyper-radiosensitivity and induced radioresistance (HRS/IRR), and the inverse dose-rate effect (IDRE), empirical fits are premised for the thresholds and transitions of the radioprotection. We provide realistic model formulations for the observed behaviors, which we apply to both HRS/IRR and IDRE. Materials and methods: We use homeostatic balance equations, including cell biophysical endogenic adjustments (originating from within the cell), providing a radiation-induced 'trigger' or continuous thresholds and transitions. Results: A 'trigger' threshold requires an instantaneous, step function. Current HRS/IRR transition model does not provide 'triggered' threshold but continuous progression from high sensitivity to reduced radiosensitivity, although the investigators premise 'trigger' behavior. IDRE data suggest 'triggered' thresholds at discrete dose rates. It appears that HRS/IRR and IDRE at low dose and dose rate intentionally provide protection against potentially carcinogenic mutations. Conclusions: The homeostatic formulation shows, when applied to the IRR using a dose and dose rate dependent Linear-Quadratic model (LQ2), that the IRR protection is 'triggered' at a discrete low dose and induced by a transitory increase in the damage repair rate constant in the LQ2 model of the single event, linear response, radiation damage. Since both IDRE and IRR have 'triggered' thresholds and as a result of increased endogenic damage recognition, increased mobilization of repair resources, activation of cell cycle arrest and/or increased repair rate, we premise that both may be from the same endogenic radioprotection biochemical mechanisms. [ABSTRACT FROM AUTHOR]

The range of diagnostic and therapeutic applications of ultraviolet A (UVA) radiation has been continuously expanding. UVA radiation is a well-known mutagenic factor capable of damaging both cells and tissues. At the same time there is a very limited information on long-term consequences of irradiating the skin with different doses of UVA and long-wavelength ultraviolet B (UVB) radiation used in therapies of skin disorders. It was demonstrated that for UVA doses of 0.1 to 1000 mJ/cm 2 the sensitivity of the porcine skin to the UVA-induced breaking of nuclear DNA is similar to that of the human skin. Results indicate that porcine skin may serve as a model system for population studies of the deleterious effects of UVA irradiation of the skin cells. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether chronic exposure to DMBA or MNNG in combination with or without UVB exposure would induce skin carcinomas in swine. Methods: Eight gilts were exposed to 100 mJ of UVB in their left side, allowed to recuperate, and divided into two groups. Each gilt received identical high doses (DMBA 50 µM; MNNG 250 mM), low doses (DMBA 500 nM; MNNG 2.5 mM), carrier (DMSO), or nothing added treatments in the UVB and non-UVB sides. Animals were exposed weekly for 30 weeks and skin samples collected at 10, 20, and 30 weeks from initiation of exposure. An additional sample was collected 16 weeks following cessation of exposure. All samples were scored for dermal morphology, including intracellular epidermal edema, intercellular epidermal edema, papillary dermal edema, perivascular infiltrates, pyknotic stratum basale cells, collagen necrosis, and epidermal-dermal separation, and the data were analyzed by ANOVA. MNNG and UVB light had a significant effect on epidermal thickness and the number of cell layers. The greatest increase in epidermal thickness occurred from 20 weeks to 30 weeks in the UVB plus MNNG treatment. Treatment with MNNG resulted in intracellular and intercellular epidermal edema, dermal edema, and dermal inflammation at both the low and high doses of MNNG. In contrast, all the morphological evaluations of the DMBA treatments were less severe than the MNNG. Conclusion: Our findings show that although chronic exposure to MNNG and DMBA, with or without UVB exposure, caused severe to mild dermatopathological changes, neither resulted in the development of skin carcinomas. These results indicate that at least with respect to responses to DMBA and MNNG, the swine model mimics more closely the responses seen in human skin. [ABSTRACT FROM AUTHOR]

There have been reports in the media and claims in the courts that radiofrequency (RF) emissions from mobile phones are a cause of cancer, and there have been numerous public objections to the siting of mobile phone base antennas because of a fear of cancer. This review summarizes the current state of evidence concerning whether the RF energy used for wireless communication might be carcinogenic. Relevant studies were identified by searching MedLine with a combination of exposure and endpoint terms. This was supplemented by a review of the over 1700 citations assembled by the Institute of Electrical and Electronics Engineers (IEEE) International Committee on Electromagnetic Safety as part of their updating of the IEEE C95.1 RF energy safety guidelines. Where there were multiple studies, preference was given to recent reports, to positive reports of effects and to attempts to confirm such positive reports. Biophysical considerations indicate that there is little theoretical basis for anticipating that RF energy would have significant biological effects at the power levels used by modern mobile phones and their base station antennas. The epidemiological evidence for a causal association between cancer and RF energy is weak and limited. Animal studies have provided no consistent evidence that exposure to RF energy at non-thermal intensities causes or promotes cancer. Extensive in vitro studies have found no consistent evidence of genotoxic potential, but in vitro studies assessing the epigenetic potential of RF energy are limited. Overall, a weight-of-evidence evaluation shows that the current evidence for a causal association between cancer and exposure to RF energy is weak and unconvincing. However, the existing epidemiology is limited and the possibility of epigenetic effects has not been thoroughly evaluated, so that additional research in those areas will be required for a more thorough assessment of the possibility of a causal connection between cancer and the RF energy from mobile telecommunications. [ABSTRACT FROM AUTHOR]

Exposure to ionizing radiation can result in delayed effects that can be detected in the progeny of an irradiated cell multiple generations after the initial exposure. These effects are described under the rubric of radiation-induced genomic instability and encompass multiple genotoxic endpoints. We have developed a green fluorescence protein (GFP)-based assay and demonstrated that ionizing radiation induces genomic instability in human RKO-derived cells and in human hamster hybrid GM10115 cells, manifested as increased homologous recombination (HR). Up to 10% of cells cultured after irradiation produce mixed GFP+/- colonies indicative of delayed HR or, in the case of RKO-derived cells, mutation and deletion. Consistent with prior studies, delayed chromosomal instability correlated with delayed reproductive cell death. In contrast, cells displaying delayed HR showed no evidence of delayed reproductive cell death, and there was no correlation between delayed chromosomal instability and delayed HR, indicating that these forms of genome instability arise by distinct mechanisms. Because delayed hyperrecombination can be induced at doses of ionizing radiation that are not associated with significantly reduced cell viability, these data may have important implications for assessment of radiation risk and understanding the mechanisms of radiation carcinogenesis. [ABSTRACT FROM AUTHOR]

Estimates of radiation-induced malignancies come principally from the atomic (A)-bomb survivors and show an excess incidence of carcinomas that is linearly related to dose from about 5 cGy to 2.5 Gy. Above and below this dose range there is considerable uncertainty about the shape of the dose-response relationship. Both the International Commission of Radiation Protected (ICRP) and the National Council of Radiation Protection (NCRP) suggest that cancer risks at doses lower than those at which direct epidemiological observations are possible should be obtained by a linear extrapolation from higher doses. The demonstrated bystander effect for irradiation exaggerates the consequences of small doses of radiation and implies that a linear extrapolation from high doses would underestimate low dose risks. It is possible to make estimates of the cancer risk of diagnostic radiological procedures. Helical computed tomography in children is of particular interest since it is rapidly increasing in use and the doses involved are close to the lower limit of significance in the A-bomb survivors. For example, an abdominal computed tomographic scan in a 1-year-old child can be estimated to result in a lifetime cancer risk of about 1:1000. In the context of radiotherapy, some normal tissues receive 70 Gy, while a larger volume receives a lower dose, but still far higher than the range for which data are available from the A-bomb survivors. Data are available for the risk of radiation-induced malignancies for patients who received radiotherapy, e.g. for prostate or cervical cancer. New technologies such as intensity modulated radiation therapy could result in a doubling of radiation-induced second cancers since the technique involves a larger total-body dose due to leakage radiation and the dose distribution obtained involves a larger volume of normal tissue exposed to lower radiation doses. [ABSTRACT FROM AUTHOR]

Purpose : Because of the crucial practical importance of acute radiation exposure associated with combined injuries, the study was undertaken to investigate the effect of various doses of ascorbic acid on the survival and healing of wounds in mice exposed to whole-body γ -radiation. Materials and methods : Animals were given double-distilled water or different doses of ascorbic acid by intraperitoneal injection before exposure to 0 or 10 Gy whole-body γ -radiation to evaluate the effect of ascorbic acid on radiation-induced mortality. The animals were monitored daily for the symptoms of radiation sickness and mortality. In a separate experiment, animals were administered with either double-distilled water or different doses of ascorbic acid before exposure to 0 or 6 Gy whole-body γ -radiation to investigate the effect of ascorbic acid on the irradiated wound. A full-thickness skin wound was created on the dorsum of the irradiated mice and the progression of wound contraction was monitored by capturing video images of the wound at various post-irradiation periods. Result : Treatment of mice with various doses of ascorbic acid elevated survival of mice and a highest number of survivors (67 and 33% for 10 and 30 days post-irradiation) was observed for 250 mg kg -1 ( p <0.002 and<0.02 for 10- and 30-day survival, respectively). Ascorbic acid treatment caused a dose-dependent elevation in the wound contraction and highest contraction was observed for 250 mg kg -1 . The wound contraction was significantly greater at 3 ( p <0.005), 6 (<0.05) and 9 (<0.05) days post-irradiation with 250 mg kg -1 ascorbic acid. The complete healing of the wound was effected by day 22.8 post-irradiation in the ascorbic acid-treated irradiation group. Conclusion : Administration of ascorbic acid protected mice against radiation-induced sickness, mortality and improved healing of wounds after exposure to whole-body γ -radiation. Additional studies will be directed toward analysing the role of successive administration of ascorbic acid to protect non-target tissues during radiotherapy and in initiating and supporting the cascade of tissue repair processes in radiotherapy delayed wounds. [ABSTRACT FROM AUTHOR]

Responds to Mark Plumb's article commenting on a number of issues in related to the article by Nakanishi et al. in volume 7, 1991 issue of 'The International Journal of Radiation Biology.' Dose-dependent expression of microsatellite instability in acute myeloid leukemia in atomic bomb survivors; Need to be cautious in drawing parallels with the Japanese atomic bomb survivor data.

Declares that the striking similarities in the leukemias in both atomic bomb survivors and in therapy patients indicate that a significant portion of the atomic bomb survivor leukemias described by M. Nakanishi et al. were indeed induced. Microsatellite and genetic instability in acute myeloid leukemias; Need for mathematical models and statistical analyses to test experimental data.

Purpose : Human gliomas are known to be radioresistant and the aim was to determine if this resistance in part could be due to an adaptive response. Materials and methods : Human U-87MG glioma cells were used. Three different radiation regimens that could be related to clinical treatments were tested for their ability to cause an adaptive response. Cell survival and DNA double-strand breakage were the measured endpoints. Results : All three regimens caused an adaptive response in terms of cell survival when given priming doses of radiation. The DNA double-strand break endpoint also showed fewer breaks when the adaptive response occurred. Conclusions : Using irradiation regimens that closely resembled clinical applications, in vitro data are presented that show an adaptive response in human glioma cells. This effect in part could be responsible for the radioresistance of human gliomas. [ABSTRACT FROM AUTHOR]

Purpose : To review the estimates of the risk of childhood cancer per unit dose of radiation received in utero derived from the largest case-control study of obstetric X-ray examinations and to compare them with the childhood cancer risk coefficients obtained from the cohorts of Japanese atomic bomb survivors irradiated either in utero or as young children. Materials and methods : Data from the Oxford Survey of Childhood Cancers (OSCC) case-control study of foetal exposure to diagnostic X-rays and from the cohort studies of the Japanese survivors of the atomic bombings of Hiroshima and Nagasaki were used, together with associated dose estimates. Excess relative risk and excess absolute risk coefficients were compared, fully taking into consideration the various sources of uncertainty. Results : The excess relative risk coefficient for childhood (<15 years of age) cancer obtained from the OSCC was around 50 Gy -1 , leading to an excess absolute risk coefficient for incident cases of about 8% Gy -1 . However, the statistical, dosimetry, modelling and other uncertainties associated with these risk estimates are appreciable, and there is reason to believe that these coefficients could be systematic overestimates. When these uncertainties and those associated with the equivalent risk coefficients derived from the Japanese cohort exposed in utero are taken into account, the risk estimates for childhood cancer obtained from these two sources are compatible. These coefficients are consistent with the high relative risk of childhood leukaemia among the Japanese survivors exposed as children. The absence of cases of childhood solid tumours among the Japanese children irradiated after birth in contrast to the significant excesses found in both intrauterine exposure studies might be explained by the cells from which these cancers originate being predominantly sensitive only to exposure in utero . Conclusions : The consistency of the childhood cancer risk coefficients derived from the Oxford Survey and from the Japanese cohort irradiated in utero supports a causal explanation of the association between childhood cancer and an antenatal X-ray examination found in case-control studies. This implies that doses to the foetus in utero of the order of 10 mSv discernibly increase the risk of childhood cancer. However, uncertainties in risk estimates are such that it is difficult to conclude reliably from these epidemiological data what the level of risk at these low doses might be, beyond the inference that the risk is not zero or has been grossly underestimated. [ABSTRACT FROM AUTHOR]

Purpose: To compare quantitative estimates of lifetime cancer risk in humans for exposures to internally deposited radionuclides and external radiation. To assess the possibility that risks from radionuclide exposures may be underestimated. Materials and methods: Risk estimates following internal exposures can be made for a small number of alpha-particle-emitting nuclides. (1) Lung cancer in underground miners exposed by inhalation to radon-222 gas and its short-lived progeny. Studies of residential [sup 222]Rn exposure are generally consistent with predictions from the miner studies. (2) Liver cancer and leukaemia in patients given intravascular injections of Thorotrast, a thorium-232 oxide preparation that concentrates in liver, spleen and bone marrow. (3) Bone cancer in patients given injections of radium-224, and in workers exposed occupationally to [sup 226]Ra and [sup 228]Ra, mainly by ingestion. (4) Lung cancer in Mayak workers exposed to plutonium-239, mainly by inhalation. Liver and bone cancers were also seen, but the dosimetry is not yet sufficiently good enough to provide quantitative estimates of risks. Comparisons can be made between risk estimates for radiation-induced cancer derived for radionuclide exposure and those derived for the A-bomb survivors, exposed mainly to lowLET (linear energy transfer) external radiation. Data from animal studies, using dogs and rodents, allow comparisons of cancer induction by a range of alpha- and beta-/gamma-emitting radionuclides. They provide information on relative biological effectiveness (RBE), dose response relationships, dose-rate effects and the location of target cells for different malignancies. Results: For lung and liver cancer, the estimated values of risk per Sv for internal exposure, assuming an RBE for alphaparticles of 20, are reasonably consistent with estimates for external exposure to low-LET radiation. This also applies to bone cancer when risk is calculated on the basis of average bone... [ABSTRACT FROM AUTHOR]

β-Carotene is a strong singlet oxygen quencher and, under most conditions, exhibits strong antioxidant properties. Based on these properties, and a number of epidemiological studies, it was suggested that an above average intake of the carotenoid might reduce cancer risks. Earlier studies had found that β-carotene, when added to commercial closed-formula rodent diets, provided significant photoprotection to ultraviolet light (UV) carcinogenesis. However, clinical trials found that β-carotene supplementation evoked no change in incidence of nonmelanoma skin cancer and that smokers suffered a significant increase in lung cancer incidence. Further, recent studies, employing β-carotene-supplemented semidefined diets, not only failed to find a photoprotective effect, but significant exacerbation of UV carcinogenic expression resulted. Based on the relative electron transfer rate constants for interactions between β-carotene, a-tocopherol (vitamin E), and vitamin C, a mechanism was proposed for the repair of β-carotene radical cation, a strongly oxidizing radical resulting from β-carotene interactions with many oxidizing species. It was theorized that vitamin C repaired the carotenoid radical cation. As mice have no nutritional requirement for vitamin C and smokers are known to exhibit low levels of the vitamin, it was suggested that differences in the relative levels of vitamin C in closed-formula rations (no vitamin C) in which photoprotection occurred, and semidefined diets (containing vitamin C) in which exacerbation resulted, might account for the differences in response. Hairless mice were fed β-carotene-supplemented semidefined diets containing varying levels of vitamins E and C (either increasing their concentrations or reducing them to reflect levels found in closed-formula rations) and subjected to a UV carcinogenesis protocol. Increasing levels of vitamins E and C did not ameliorate β-carotene exacerbation of UV carcinogenesis. Nor did elimination of vitamin C from the diet. Reduced levels of dietary vitamin E augmented β-carotene exacerbation of UV carcinogenic expression, suggesting vitamin E and β-carotene interaction. It is concluded that the photoprotective effect of β-carotene reported earlier by others, or the noninjurious effect of β-carotene found in our studies with closed-formula rations, might depend on interaction with other dietary factors that are either absent, or present in ineffectual concentrations, in the semidefined diet in which exacerbation of UV carcinogenesis occurs. Those factors could be other carotenoids, their isomers, or some yet unidentified phytochemical(s). [ABSTRACT FROM AUTHOR]