Mobile telecommunications have developed considerably in recent years. With the proliferation of wireless technologies, there is much public anxiety about the potential health impact associated with exposure to radiofrequency (RF) radiation from these novel products. Contradictory scientific evidence, often reported in the popular media, has further fueled public concern. Some epidemiological studies have reported that ipsilateral use of a mobile phone is associated with an increased risk for brain tumors, while other studies have reported an association between brain tumor risk and mobile phone use for longer than 10 years. However, other large epidemiological studies have failed to find similar associations. Despite the existence of national and international RF-radiation exposure guidelines, there are increasing public demands for precaution with respect to human exposure to RF radiation. Since current epidemiological evidence is insufficient to make a definitive judgment on the health risks of low-level RF radiation exposure, laboratory evidence assessing biological plausibility and theoretical mechanisms of interaction are important. A number of studies have reported that RF radiation may induce alterations in gene/protein expression in a variety of cells/tissues that may be associated with potentially harmful health outcomes, while other studies have shown no clear effects related to RF radiation. This review focuses on the current scientific evidence related to changes in protein and gene expression induced by low-level RF radiation.

Double-strand breaks (DSBs) are the most critical radiation-induced lesions, because they result in the fragmentation of the DNA molecule and because a single unrepaired DSB may lead to cell death. We present the results of radiation-induced fragmentation of plasmid DNA analyzed by atomic force microscopy (AFM) to allow the visualization of individual DNA molecules. Linear ΦX174 plasmid DNA was exposed to a wide range of doses of low-LET X rays and high-LET carbon, nickel and uranium ions. The induced DNA fragments were detected and measured based on the recorded AFM images and fragment length distributions were derived for each radiation type and dose. The results show a dose- and radiation type-dependent DNA fragmentation with a significantly larger fraction of short fragments produced by high-LET radiation compared to X rays. This can be considered as experimental evidence of DSB clustering due to inhomogeneous energy deposition at the level of the plasmid DNA molecule. Additionally, the experimentally derived fragment profiles were compared and found to be in agreement with the prediction of a model simulating the fragmentation of DNA molecules induced by radiation.

To characterize the DNA damage induced by K-shell ionization of phosphorus atom in DNA backbone on the level of hydration, the yields of DNA strand breaks and base lesions arising from the interaction of ultrasoft X rays with energies around the phosphorus K edge were determined using dry and fully hydrated pUC18 plasmid DNA samples. Base lesions and bistranded clustered DNA damage sites were revealed by postirradiation treatment with the base excision repair proteins endonuclease III (Nth) and formamidopyrimidine-DNA glycosylase (Fpg). The yield of prompt single-strand breaks (SSBs) with dry DNA irradiated at the phosphorus K resonance energy (2153 eV) is about one-third that below the phosphorus K edge (2147 eV). The yields of prompt double-strand breaks (DSBs) were found to be less dependent on the X-ray energy, with the yields being about two times lower when irradiated at 2153 eV. Heat-labile sites were not produced in detectable amounts. The yields of base lesions were dependent on the energy of the X rays, especially when the DNA was fully hydrated. Bistranded clustered DNA damage sites, revealed enzymatically as additional DSBs, were produced in dry as well as in hydrated DNA with all three energies of X rays. The yields of these enzyme-sensitive sites were also lower when irradiated at the phosphorus K resonance energy. On the other hand, the yields of prompt SSBs and enzyme-sensitive sites for the two off-resonance energies were, larger than those determined previously for γ radiation. The results indicate that the photoelectric effect caused by X rays and dense ionization and excitation events along the tracks of low-energy secondary electrons are more effective at inducing SSBs and enzyme-sensitive sites. The complex types of damage, prompt and enzymatically induced DSBs, are preferentially induced by phosphorus K resonance at 2153 eV rather than simple SSBs and isolated base lesions, particularly in hydrated conditions. It is concluded that not only the phosphorus K resonance and resulting emission of low-energy LMM-Auger electrons (∼120 eV) but also the level of hydration plays an important role in the induction of complex damage in plasmid DNA.

In addition to cell cycle arrest, DNA repair or/and apoptosis, ionizing radiation can also induce premature senescence, which could lead to very different biological consequences depending on the cell type. We show in this report that low-dose radiation-induced senescent stromal fibroblasts stimulate proliferation of cocultured breast carcinoma cells. Such effects of senescent fibroblasts appear to result from their ability to induce the expression in carcinoma cells of mitotic genes and subsequent mitotic division. The elevated proliferation of breast carcinoma cells correlates with resistance to radiation as well as to adriamycin. Of interest is the observation that exposure to lower doses (<20 cGy) augments the ability of senescent fibroblasts to promote the survival of cocultured breast carcinoma cells. The resistance appears to be mediated partially by the Akt pathway, because expression of a dominant negative Akt mutant in breast carcinoma cells results in a partial reversal of the radioresistance. The ability of fibroblasts to modulate the radiosensitivity of nearby carcinoma cells implicates the importance of targeting the stroma during therapy.

These studies examined the effects of X radiation and interleukin 3 (IL-3), which is an effective cytokine for the generation of megakaryocytopoiesis from X-irradiated hematopoietic stem/progenitor cells, on the terminal process of human megakaryocytopoiesis and thrombopoiesis. Mature megakaryocytes were induced by culturing CD34 cells from normal human peripheral blood in a serum-free liquid culture stimulated with thrombopoietin. The experiments contained the following groups: control cultures with nonirradiated cells incubated for 15 days; cultures treated with IL-3 on day 7 or day 11, cultures irradiated with 2 Gy on day 7 or day 11, and cultures treated with IL-3 immediately after X irradiation. The nonirradiated control cultures produced megakaryocytes from day 7, and both the megakaryocyte and platelet generation reached a peak on day 12–13. When X irradiation was performed on day 7, both the megakaryocyte and platelet numbers decreased remarkably, while no significant effect was observed on those numbers when cultures were X-irradiated on day 11. IL-3 showed neither protective nor promoting effects on the terminal stages of megakaryocytic maturation and platelet production. The results demonstrated that mature megakaryocytes are radiosensitive but that the radiosensitivity decreased with the terminal stages of megakaryocytic maturation, especially for the megakaryocytes entering into proplatelet formation.

Inducible nitric oxide synthase (iNOS) expression and NO production increase after radiation exposure. We showed previously that inhibiting iNOS expression prevents hemorrhage injury; we therefore investigated whether inhibiting iNOS expression also limits radiation injury. Human Jurkat T cells were exposed to γ radiation (2, 4, 6 or 8 Gy), and cell lysates were collected for analysis at selected times afterward. Radiation exposure increased iNOS expression within 4 h postirradiation by increasing the levels of the iNOS transcription factors NF-κB and KLF6. By 24 h postirradiation cell viability was reduced. In these cells, NO production, lipid peroxidation, protein nitration, apoptosomes (formed by cytochrome c, caspase 9 and Apaf-1), and caspase 3 activity were significantly elevated, suggesting that the iNOS pathway had been activated. Treatment with the iNOS inhibitors 17-DMAG or L-NIL-6 24 h prior to irradiation limited these changes, as did treatment with iNOS siRNA to silence the iNOS gene. These results suggest radiation injury involves the iNOS pathway, and iNOS-mediated NO produced endogenously in the T cell alters overall T-cell function and results in apoptosis and cell lethality. Control of iNOS expression may represent a useful approach for protecting T cells from radiation injury.

Reactive oxygen species (ROS) are believed to be involved in radiation-induced xerostomia, and the application of antioxidants may be a promising method for treating patients suffering from salivary gland dysfunction. In this study, we examined the ability of the antioxidant superoxide dismutase (SOD) to restore radiation-induced salivary gland dysfunction using a mouse model of radiation-induced salivary gland hypofunction and ultraviolet B (UVB)-irradiated human salivary gland cells. We administered lecithinized SOD (PC-SOD) prior to and after irradiation and measured the amount of saliva secreted. To confirm ROS generation, flow cytometry was performed using an oxidant-sensitive fluorescent dye, dihydroethidium, and CM-H₂DCFDA. While no significant decrease in saliva secretion was observed after irradiation in the mice that were treated with PC-SOD, a significant reduction in saliva secretion was noted in the irradiated mice that were not treated with PC-SOD. Furthermore, flow cytometry clearly revealed that PC-SOD eliminated superoxide (O₂⁻) induced by UVB radiation. These results suggested that PC-SOD may protect against exocrine gland dysfunction induced by radiation, presumably by rapidly converting O₂⁻ to hydrogen peroxide. We believe that our results may advance the potential application of antioxidants for the prevention of ROS-induced xerostomia.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been suggested to be a valuable method for characterizing the physiological microenvironment of tumors and thus a promising method for individualizing cancer treatment. The aim of this study was to test the hypothesis that valid parametric images of the tumor microenvironment can be obtained by pharmacokinetic analysis of DCE-MRI series. Cells of four human melanoma xenograft lines (A-07, D-12, R-18 and T-22) were used as preclinical models of human cancer. DCE-MRI was performed at 1.5 T at a spatial resolution of 0.23 × 0.47 × 2.0 mm³ and a time resolution of 14 s. Gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA) was used as contrast agent. The DCE-MRI data were analyzed on a voxel-by-voxel basis by using a pharmacokinetic model recommended for analysis of clinical DCE-MRI series. Parametric DCE-MR images were compared with tumor blood perfusion measured by the ⁸⁶Rb uptake method, and fractional volume of the extravascular extracellular space assessed by analysis of histological preparations. Parametric images reflecting tumor blood perfusion and fractional volume of the extravascular extracellular space were obtained. The numerical values of the DCE-MRI-derived parameters were not significantly different from the absolute values of tumor blood perfusion or fractional volume of the extravascular extracellular space in any of the tumor lines. This study shows that DCE-MRI can provide valid quantitative parametric images of the tumor microenvironment in preclinical cancer models and thus supports the suggestion that DCE-MRI may be developed to be a clinically useful method for individualization of microenvironment-based cancer treatment, a possibility that merits increased clinical interest.

For the past 5 years, a radio-chemotherapy approach based on the photoactivation of platinum atoms (PAT-Plat) consisting of treating tumors with platinated compounds and irradiating them above the platinum K edge (78.4 keV) has been developed at the European Synchrotron Radiation Facility (Grenoble, France). Compared to other preclinical modalities, PAT-Plat provides the highest survivals of rats bearing the rodent F98 glioma. However, further investigations are required to optimize its efficiency and to allow its clinical application. Here we examined in vitro and in vivo whether monochromatic X rays are more efficient than high-energy photons in producing the PAT-Plat effect by measuring DNA double-strand breaks (DSBs) and survival of glioma-bearing rats and whether an increase in the platinum concentration in the tumor results in increased rat survival. DSBs were assessed by pulsed-field gel electrophoresis with different DNA fragment migration programs and with γ-H2AX immunofluorescence. In vivo, F98 glioma cells were injected intracerebrally, treated with a single intracranial injection of cisplatin or carboplatin 13 days after tumor implantation, and irradiated the day after with 78.8 keV X rays or 6 MV photons. Our results indicate that 78.8 keV X rays are more efficient than high-energy photons at producing the PAT-Plat effect. At low concentrations, cisplatin is more efficient than carboplatin; this is likely due to more efficient DNA binding and DSB repair inhibition. High concentrations of carboplatin inside tumors do not necessarily lead to protracted survival of rats. The therapeutic benefit of anti-glioma synchrotron strategies appears to be correlated with the percentage of unrepaired DSBs but not with the number of DSBs induced.

Salford et al. reported in 2003 that a single 2-h exposure to GSM-900 mobile telephony signals induced brain damage (increased permeability of the blood-brain barrier and presence of dark neurons) 50 days after exposure. In our study, 16 Fischer 344 rats (14 weeks old) were exposed head-only to the GSM-900 signal for 2 h at various brain-averaged SARs (0, 0.14 and 2.0 W/kg) or were used as cage or positive controls. Albumin leakage and neuron degeneration were evaluated 14 and 50 days after exposure. No apoptotic neurons were found 14 days after the last exposure using the TUNEL method. No statistically significant albumin leakage was observed. Neuronal degeneration, assessed using cresyl violet or the more specific marker Fluoro-Jade B, was not significantly different among the tested groups. No apoptotic neurons were detected. The findings of our study did not confirm the previous results of Salford et al.

This paper provides the first comprehensive report on mortality by type of leukemia among the Japanese atomic bomb survivors in the Life Span Study (LSS). Analyses include 310 deaths due to leukemia during the period 1950–2000 among 86,611 people in the LSS. Poisson regression methods were used to evaluate associations between estimated bone marrow dose and leukemia mortality. Attention was given to variation in the radiation dose–leukemia mortality association by time since exposure, age at exposure, city and sex. The excess relative rate per gray of acute myeloid leukemia was best described by a quadratic dose–response function that peaked approximately 10 years after exposure. Acute lymphatic leukemia and chronic myeloid leukemia mortality were best described by a linear dose–response function that did not vary with time since exposure. Adult T-cell leukemia was not associated with estimated bone marrow dose. Overall, 103 of the 310 observed leukemia deaths were estimated to be excess deaths due to radiation exposure. In the most recent decade of observation (1991–2000), the estimated attributable fraction of leukemia deaths among those survivors exposed to >0.005 Gy was 0.34, suggesting that the effect of the atomic bombings on leukemia mortality has persisted in this cohort for more than five decades.

The multistage paradigm is widely used in quantitative analyses of radiation-influenced carcinogenesis. Steps such as initiation, promotion and transformation have been investigated in detail. However, progression, a later step during which malignant cells produced in the earlier steps can develop into clinical cancer, has received less attention in computational radiobiology; it has often been approximated deterministically as a fixed, comparatively short, lag time. This approach overlooks important mechanisms in progression, including stochastic extinction, possible radiation effects on tumor growth, immune suppression and angiogenic bottlenecks. Here we analyze tumor progression in background and in radiation-induced lung cancers, emphasizing tumor latent times and the stochastic extinction of malignant lesions. A Monte Carlo cell population dynamics formalism is developed by supplementing the standard two-stage clonal expansion (TSCE) model with a stochastic birth-death model for proliferation of malignant cells. Simulation results for small cell lung cancers and lung adenocarcinomas show that the effects of stochastic malignant cell extinction broaden progression time distributions drastically. We suggest that fully stochastic cancer progression models incorporating malignant cell kinetics, dormancy (a phase in which tumors remain asymptomatic), escape from dormancy, and invasiveness, with radiation able to act directly on each phase, need to be considered for a better assessment of radiation-induced lung cancer risks.

The Local Effect Model (LEM) is a track-structure model that was developed to predict the biological response of a cell to irradiation with any ion. Because it needs to be studied both experimentally and theoretically, a mathematical formalization of the LEM based on three main postulates and three secondary approximations is proposed for a more detailed analysis. The general relationship that links cell survival to the mean number of lethal events is deduced. A Monte Carlo simulation is also proposed to calculate the local dose. It is shown that the local dose is highly heterogeneous even for uniform X irradiations. This observation raises questions about the estimation of the density of ion-induced lethal events from the expression of cell survival after exposure to X rays. Finally, it is shown that a strict theory of local effects based solely on local dose cannot reproduce nonlinear structures in cell survival curves, such as the shoulders observed after low-LET irradiation.