Melanoma and ionizing radiation: is there a causal relationship?

This review was initiated in response to concerns that ionizing radiation could be a cause of melanoma. Studies presenting the relative risks for melanoma after external ionizing radiation exposure were in seven categories: (1) The Canadian Radiation Dose Registry, (2) nuclear industry workers, (3) subjects near nuclear test blasts, (4) survivors of the atomic bombings of Japan, (5) airline pilots and cabin attendants, (6) recipients of medical radiation, and (7) radiological technicians. Relative risks for leukemia in each of the studies were used to confirm the likelihood of exposure to ionizing radiation. When studies within a category were compatible, meta-analytic methods were used to obtain combined estimates of the relative risk, and a meta-regression analysis of melanoma relative risk compared to leukemia relative risk was used to examine consistency across exposure categories. Generally, exposure categories with elevated relative risks of leukemia had proportionately elevated relative risks of melanoma. This suggests that people exposed to ionizing radiation may be at increased risk of developing melanoma, although alternative explanations are possible. Future epidemiological studies of ionizing radiation effects should include melanoma as an outcome of interest.     

Cytogenetic monitoring by use of the micronucleus assay among hospital workers exposed to low doses of ionizing radiation

The aim of this study was to assess occupationally induced chromosomal damage in a large population of hospital workers exposed to low doses of ionizing radiation. We used the cytokinesis-block micronucleus (CBMN) assay in the peripheral lymphocytes of 132 exposed workers compared with 69 controls matched for gender, age and smoking habits. The CBMN assay was combined with fluorescence in situ hybridization with a human pan-centromeric DNA probe in 32 exposed subjects and 30 controls randomly chosen from the initial populations. Occupational dosimetry records were collected over the last 10-year period and revealed very low exposure levels. The average binucleated micronucleated cell rate (BMCR) was significantly higher in the exposed subjects than in the controls (14.9 per thousand+/-8.1 versus 11.8 per thousand+/-6.5; P=0.011). About one-third of the micronuclei were centromere-negative in the exposed and control groups. BMCR significantly positively correlated with donor age in the exposed population; this correlation was at the border of significance in the control group. In the two groups, BMCR was significantly greater in females than in males, and the significant correlation between age and BMCR was observed in the female population, but not in the male one. No effect of smoking habits emerged. Univariate analysis revealed a possible influence of familial cancer history and diagnostic medical radiation dose (estimated from examinations reported in the questionnaire) on BMCR. Multiple regression analysis, taking into account all the previous confounding factors, showed that only occupational exposure status, gender and age had a significant effect on BMCR. In conclusion, the present study shows that chromosomal damage leading to micronucleated lymphocytes is more frequent in hospital workers exposed to ionizing radiation than in controls, despite the very low levels of exposure.     

Childhood exposure to ionizing radiation to the head and risk of schizophrenia

While the association between exposure to ionizing radiation and cancer is well established, its association with schizophrenia is unclear. The aim of our study was to assess risk of schizophrenia after childhood exposure to ionizing radiation to the head (mean dose: 1.5 Gy). The study population included an exposed group of 10,834 individuals irradiated during childhood for treatment of tinea capitis in the 1950s and two unexposed comparison groups of 5392 siblings and 10,834 subjects derived from the National Population Registry individually matched to the exposed group by age, sex (when possible), country of birth, and year of immigration to Israel. These groups were followed for a median 46 years for diagnosis of schizophrenia updated to December 2002. The Cox proportional hazards model stratified by matched sets was used to compare the risk of schizophrenia between the groups. Based on 1,217,531 person-years of follow-up, 451 cases were identified. No statistically significant association was found between radiation exposure and schizophrenia for the total group (hazard ratio per 1 Gy to the brain: 1.05, 95% confidence interval: 0.93-1.18) or within subgroups of sex, dose categories or latent period. When comparing a subgroup of subjects irradiated under 5 years of age with the matched unexposed group, the estimated hazard ratio reached 1.18 (95% confidence interval: 0.96-1.44; P = 0.1). The results of our analysis do not support an association between exposure to ionizing radiation and risk of schizophrenia. More research on possible effects of early exposure to ionizing radiation on schizophrenia specifically and brain tissue in general is needed.     

The biological effects of diagnostic cardiac imaging on chronically exposed physicians: the importance of being non-ionizing

Ultrasounds and ionizing radiation are extensively used for diagnostic applications in the cardiology clinical practice. This paper reviewed the available information on occupational risk of the cardiologists who perform, every day, cardiac imaging procedures. At the moment, there are no consistent evidence that exposure to medical ultrasound is capable of inducing genetic effects, and representing a serious health hazard for clinical staff. In contrast, exposure to ionizing radiation may result in adverse health effect on clinical cardiologists. Although the current risk estimates are clouded by approximations and extrapolations, most data from cytogenetic studies have reported a detrimental effect on somatic DNA of professionally exposed personnel to chronic low doses of ionizing radiation. Since interventional cardiologists and electro-physiologists have the highest radiation exposure among health professionals, a major awareness is crucial for improving occupational protection. Furthermore, the use of a biological dosimeter could be a reliable tool for the risk quantification on an individual basis.     

Micronuclei in humans induced by exposure to low level of ionizing radiation: influence of polymorphisms in DNA repair genes

Understanding the risks deriving from protracted exposure to low doses of ionizing radiation has remarkable societal importance in view of the large number of work settings in which sources of IR are encountered. To address this question, we studied the frequency of micronuclei (MN), which is an indicator of DNA damage, in a population exposed to low levels of ionizing radiation and in matched controls. In both exposed population and controls, the possible influence of single nucleotide polymorphisms in XRCC1, XRCC3 and XPD genes on the frequency of micronuclei was also evaluated. We also considered the effects of confounding factors, like smoking status, age and gender. The results indicated that MN frequency was significantly higher in the exposed workers than in the controls [8.62+/-2.80 versus 6.86+/-2.65; P=0.019]. Radiological workers with variant alleles for XRCC1 or XRCC3 polymorphisms or wild-type alleles for XPD exon 23 or 10 polymorphisms showed a significantly higher MN frequency than controls with the same genotypes. Smoking status did not affect micronuclei frequency either in exposed workers or controls, while age was associated with increased MN frequency in the exposed only. In the combined population, gender but not age exerted an influence on the yield of MN, being higher in females than in males. Even though there is a limitation in this study due to the small number of subjects, these results suggest that even exposures to low level of ionizing radiation could have genotoxic effects and that XRCC3, XRCC1 and XPD polymorphisms might contribute to the increased genetic damage in susceptible individuals occupationally exposed to chronic low levels of ionizing radiation. For a clear conclusion on the induction of DNA damage caused by protracted exposure to low doses of ionizing radiation and the possible influence of genetic polymorphism in DNA repair genes larger studies are needed.     

The effects of 884 MHz GSM wireless communication signals on headache and other symptoms: an experimental provocation study

Findings from prior studies of possible health and physiological effects from mobile phone use have been inconsistent. Exposure periods in provocation studies have been rather short and personal characteristics of the participants poorly defined. We studied the effect of radiofrequency field (RF) on self-reported symptoms and detection of fields after a prolonged exposure time and with a well defined study group including subjects reporting symptoms attributed to mobile phone use. The design was a double blind, cross-over provocation study testing a 3-h long GSM handset exposure versus sham. The study group was 71 subjects age 18-45, including 38 subjects reporting headache or vertigo in relation to mobile phone use (symptom group) and 33 non-symptomatic subjects. Symptoms were scored on a 7-point Likert scale before, after 1(1/2) and 2(3/4) h of exposure. Subjects reported their belief of actual exposure status. The results showed that headache was more commonly reported after RF exposure than sham, mainly due to an increase in the non-symptom group. Neither group could detect RF exposure better than by chance. A belief that the RF exposure had been active was associated with skin symptoms. The higher prevalence of headache in the non-symptom group towards the end of RF exposure justifies further investigation of possible physiological correlates. The current study indicates a need to better characterize study participants in mobile phone exposure studies and differences between symptom and non-symptom groups.     

Cell cycle delay in murine pre-osteoblasts is more pronounced after exposure to high-LET compared to low-LET radiation

Space radiation contains a complex mixture of particles comprised primarily of protons and high-energy heavy ions. Radiation risk is considered one of the major health risks for astronauts who embark on both orbital and interplanetary space missions. Ionizing radiation dose-dependently kills cells, damages genetic material, and disturbs cell differentiation and function. The immediate response to ionizing radiation-induced DNA damage is stimulation of DNA repair machinery and activation of cell cycle regulatory checkpoints. To date, little is known about cell cycle regulation after exposure to space-relevant radiation, especially regarding bone-forming osteoblasts. Here, we assessed cell cycle regulation in the osteoblastic cell line OCT-1 after exposure to various types of space-relevant radiation. The relative biological effectiveness (RBE) of ionizing radiation was investigated regarding the biological endpoint of cellular survival ability. Cell cycle progression was examined following radiation exposure resulting in different RBE values calculated for a cellular survival level of 1 %. Our findings indicate that radiation with a linear energy transfer (LET) of 150 keV/μm was most effective in inducing reproductive cell killing by causing cell cycle arrest. Expression analyses indicated that cells exposed to ionizing radiation exhibited significantly up-regulated p21(CDKN1A) gene expression. In conclusion, our findings suggest that cell cycle regulation is more sensitive to high-LET radiation than cell survival, which is not solely regulated through elevated CDKN1A expression.     

RADIATION: MEDICAL DIAGNOSTIC USES

Use of radiologic procedures in diagnosis now contributes a significant dose of ionizing radiation to our population. Whether this presents a real risk to the health of the present and future population cannot be determined with certainty from evidence available at this time. Hence, it appears proper to keep the dose to every patient as low as practical consistent with good medical practice. The average dose can be significantly reduced by having more physicians apply the known techniques for minimizing the exposure to the patient.The medical profession has a direct professional concern for the actual or potential risk of damage resulting from the radiation that patients are exposed to during diagnostic x-ray procedures, since these procedures constitute the largest single man-made source of genetically significant radiation our population is now exposed to.It is important to distinguish two distinctly different types of radiation effects—somatic effect, in which the damage affects the health of the person irradiated, and genetic effect that is capable of producing constitutional defects in future progeny over many generations.     

Radiation responses in plasma membrane. Review of the present state and future trends.

Over the last several decades, the membrane system of the cell has been shown to be a fairly sensitive target for ionizing radiation. As the complex features of membrane functions and structure are revealed more and more, the interest of radiation biology grows. The present review of the biological aspects of ionizing radiation exposure suggests the importance of cell-to-cell contacts through junctions, and the signaling mechanism through receptors.     

Computed tomographies and cancer risk in children: a literature overview of CT practices,risk estimations and an epidemiologic cohort study proposal

Radiation protection is a topic of great public concern and of many scientific investigations, because ionizing radiation is an established risk factor for leukaemia and many solid tumours. Exposure of the public to ionizing radiation includes exposure to background radiation, as well as medical and occupational exposures. A large fraction of the exposure from diagnostic procedures comes from medical imaging. Computed tomography (CT) is the major single contributor of diagnostic radiation exposure. An increase in the use of CTs has been reported over the last decades in many countries. Children have smaller bodies and lower shielding capacities, factors that affect the individual organ doses due to medical imaging. Several risk models have been applied to estimate the cancer burden caused by ionizing radiation from CT. All models predict higher risks for cancer among children exposed to CT as compared to adults. However, the cancer risk associated with CT has not been assessed directly in epidemiological studies. Here, plans are described to conduct an historical cohort study to investigate the cancer incidence in paediatric patients exposed to CT before the age of 15 in Germany. Patients will be recruited from radiology departments of several hospitals. Their individual exposure will be recorded, and time-dependent cumulative organ doses will be calculated. Follow-up for cancer incidence via the German Childhood Cancer Registry will allow computation of standardized incidence ratios using population-based incidence rates for childhood cancer. Dose–response modelling and analyses for subgroups of children based on the indication for and the result of the CT will be performed.     

Hyperbolic function of the neuroelectrical effects in the cerebral form of radiation lesions

A theoretical synthesis of electrical parameters of interaction between gamma radiation and excited membranes of nervous and muscular tissues suggests a correlation between power (dose-rate, R) and duration of exposure (T), of the liminal stimulation of a neuron by gamma radiation: R = 6 + 8/T. In studying early transient neurologic disorders (ETND) the threshold charges of ionizing radiation have been defined for various probabilities of occurrence of one of the ETND symptoms.     

Mammary gland and radiation: Knowns and unknowns

Effective breast cancer management and decreasing breast cancer fatalities is contingent upon reliable diagnostic procedures and treatment modalities, including those based on ionizing radiation. On the one hand, ionizing radiation is widely used for cancer diagnostics and therapy, on the other hand it is genotoxic cancer-causing agent. Here we discuss recent studies on the effects of low (diagnostic) and high (treatment) doses of ionizing radiation on healthy breast cells, breast cancer cells, and cancer cells resistant to common drug therapies.     

Involvement of the pathway phosphatidylinositol-3-kinase/AKT-1 in the establishment of the survival response to ionizing radiation

Ionizing radiation is one of the agents inducing activation of DNA repair, cell cycle arrest, apoptosis and cell death. Here we report evidence for an enhanced activity of DNA polymerase beta, one of the repair enzymes, concomitant to the activation of the pathway phosphatidylinositol-3-kinase/AKT-1 (PI-3-kinase/AKT-1), which delivers a survival signal in Friend erythroleukemia cells exposed to 15 Gy. Significantly, the preincubation of the cellls with PI-3-kinase inhibitors wortmannin and LY 294002, disactivating this pathway, sensitizes the cells to ionizing radiation by further reducing the rate of proliferation without substantial variations of the number of dead cells. Thus, we suggest a role for these enzymes in maintaining survival programs upon exposure to ionizing radiation and in giving to these cells a chance to recover from this stress.     

Use of chemical dosimetry for comparison of ultrasound and ionizing radiation effects on cavitation

A comparison of the effects of ultrasound produced by low- and high-frequency ultrasonic apparatuses upon biological systems is one of the basic problems when studying ultrasound cavitation effects. One possibility for how to compare these effects is the indirect method which uses well-known physical quantities characterizing the interaction of ionizing radiation with matter and which also converts these quantities to one common physical quantity. The comparison was performed with two methods applied to the chemical dosimetry of ionizing radiation. The first method employed a two-component dosimeter which is composed of 50 % chloroform and 50 % re-distilled water (i.e. Taplin dosimeter). The other method used a modified iodide dosimeter prepared from a 0.5 M potassium iodide solution. After irradiation or ultrasound exposure, measurable chemical changes occurred in both dosimeters. The longer the exposure, the greater the chemical changes. These effects are described by the relationship of these changes versus the exposure times in both dosimeters. The UZD 21 ultrasonic disintegrator (with a frequency of 20 kHz, 50 % power output) was used as a low-frequency ultrasound source, and the BTL-07 therapeutic instrument (with a frequency of 1 MHz and intensity of 2 W/cm2) was used as a high-frequency cavitation ultrasound source. For comparison, a 60 Co gamma source was applied (60 Co, gamma energies of 1.17 and 1.33 MeV, activity of 14 PBq). Results of this study have demonstrated that the sonochemical products are generated during exposure in the exposed samples of both dosimeters for all apparatuses used. The amount of these products depends linearly upon the exposure time. The resulting cavitation effects were recalculated to a gray-equivalent dose (the proposed unit is cavitation gray [cavitGy]) based on the sonochemical effects compared to the effects of ionizing radiation from the 60 Co source.     

Time factors in combined exposures of mouse embryos to radiation and mercury

Summary There are situations in which the exposure to more than one agent results in an enhanced risk for the exposed organism, that is in which the observed effect exceeds the effect expected from the addition of the individual effects. Our knowledge of such hazards is rather limited, in particular for those agents that occur in the environment of man. When early mouse embryos in vitro were exposed to ionizing radiation and mercuric chloride, the observed risk was higher than expected from the individual effects. This increase in risk was due to an interaction between mechanisms induced by ionizing radiation and mercury. To gain some more insight into the mode of interaction, the time requirements of mercury exposure were studied. The amount of interaction did not depend on mercury exposure before or during irradiation. However, to achieve an enhanced risk, exposure had to start as soon as possible after irradiation and had to last as long as possible. This time dependence suggests that if inhibition of DNA-repair is involved in the mechanism of interaction at all, then there must be an additional late process that is also impaired by mercury.Dedicated to Prof. W. Jacobi on the occasion of his 60th birthday     

The effect of alpha-phenyl-N-t-butylnitrone on ionizing radiation-induced apoptosis in U937 cells

Ionizing radiation induces the production of reactive oxygen species (ROS), which play an important causative role in apoptotic cell death. alpha-Phenyl-N-t-butylnitrone (PBN) is one of the most widely used spin-trapping compounds for investigating the existence of free radicals in biological systems. We investigated the effects of PBN on ionizing radiation-induced apoptosis in U937 cells. Upon exposure to 2 Gy of gamma-irradiation, there was a distinct difference between the control cells and the cells pre-treated with 2 mM PBN for 2 h in regard to apoptotic parameters, cellular redox status, mitochondria function and oxidative damage to cells. PBN effectively suppressed morphological evidence of apoptosis and DNA fragmentation in U937 cells exposed to ionizing radiation. The [GSSG]/[GSH+GSSG] ratio and the generation of intracellular ROS were higher and the [NADPH]/[NADP+ +NADPH] ratio was lower in control cells compared to PBN-treated cells. The ionizing radiation-induced mitochondrial damage reflected by the altered mitochondrial permeability transition, the increase in the accumulation of ROS, and the reduction of ATP production were significantly higher in control cells compared to PBN-treated cells. PBN pre-treated cells showed significant inhibition of apoptotic features such as activation of caspase-3, up-regulation of Bax and p53, and down-regulation of Bcl-2 compared to control cells upon exposure to ionizing radiation. This study indicates that PBN may play an important role in regulating the apoptosis induced by ionizing radiation presumably through scavenging of ROS.     

Gene expression as a biomarker for human radiation exposure

Accidental exposure to ionizing radiation can be unforeseen, rapid, and devastating. The detonation of a radiological device leading to such an exposure can be detrimental to the exposed population. The radiation-induced damage may manifest as acute effects that can be detected clinically or may be more subtle effects that can lead to long-term radiation-induced abnormalities. Accurate identification of the individuals exposed to radiation is challenging. The availability of a rapid and effective screening test that could be used as a biomarker of radiation exposure detection is mandatory. We tested the suitability of alterations in gene expression to serve as a biomarker of human radiation exposure. To develop a useful gene expression biomonitor, however, gene expression changes occurring in response to irradiation in vivo must be measured directly. Patients undergoing radiation therapy provide a suitable test population for this purpose. We examined the expression of CC3, MADH7, and SEC PRO in blood samples of these patients before and after radiotherapy to measure the in vivo response. The gene expression after ionizing radiation treatment varied among different patients, suggesting the complexity of the response. The expression of the SEC PRO gene was repressed in most of the patients. The MADH7 gene was found to be upregulated in most of the subjects and could serve as a molecular marker of radiation exposure.     

A systematic review on the effect of low-dose radiation on hearing

Numerous studies have documented the adverse effects of high-dose radiation on hearing in patients. On the other hand, radiographers are exposed to a low dose of ionizing radiation, and the effect of a low dose of radiation on hearing is quite abstruse. Therefore, the present systematic review aimed to elucidate the effect of low-dose ionizing radiation on hearing. Two authors independently carried out a comprehensive data search in three electronic databases, including PUBMED/MEDLINE, CINAHL, and SCOPUS. Eligible articles were independently assessed for quality by two authors. Cochrane Risk of Bias tool was used assess quality of the included studies. Two articles met the low-dose radiation exposure criteria given by Atomic Energy Regulatory Board (AERB) and National Council on Radiation Protection (NCRP) guidelines. Both studies observed the behavioral symptoms, pure-tone hearing sensitivity at the standard, extended high frequencies, and the middle ear functioning in low-dose radiation-exposed individuals and compared with age and gender-matched controls. One study assessed the cochlear function using transient-evoked otoacoustic emissions (TEOAE). Both studies reported that behavioral symptoms of auditory dysfunction and hearing thresholds at extended high frequencies were higher in radiation-exposed individuals than in the controls. The current systematic review concludes that the low-dose ionizing radiation may affect the hearing adversely. Nevertheless, further studies with robust research design are required to explicate the cause and effect relationship between the occupational low-dose ionizing radiation exposure and hearing.

     

Semen Abnormalities,Sperm DNA Damage and Global Hypermethylation in Health Workers Occupationally Exposed to Ionizing Radiation

Background

Cytogenetic studies have demonstrated that low levels of chronic radiation exposure can potentially increase the frequency of chromosomal aberrations and aneuploidy in somatic cells. Epidemiological studies have shown that health workers occupationally exposed to ionizing radiation bear an increased risk of hematological malignancies.

Objectives

To find the influence of occupational radiation exposure on semen characteristics, including genetic and epigenetic integrity of spermatozoa in a chronically exposed population.

Methods

This cross sectional study included 134 male volunteers of which 83 were occupationally exposed to ionizing radiation and 51 were non-exposed control subjects. Semen characteristics, sperm DNA fragmentation, aneuploidy and incidence of global hypermethylation in the spermatozoa were determined and compared between the non-exposed and the exposed group.

Results

Direct comparison of the semen characteristics between the non-exposed and the exposed population revealed significant differences in motility characteristics, viability, and morphological abnormalities (P<0.05–0.0001). Although, the level of sperm DNA fragmentation was significantly higher in the exposed group as compared to the non-exposed group (P<0.05–0.0001), the incidence of sperm aneuploidy was not statistically different between the two groups. However, a significant number of hypermethylated spermatozoa were observed in the exposed group in comparison to non-exposed group (P<0.05).

Conclusions

We provide the first evidence on the detrimental effects of occupational radiation exposure on functional, genetic and epigenetic integrity of sperm in health workers. However, further studies are required to confirm the potential detrimental effects of ionizing radiation in these subjects.     

The effect of α-phenyl-N-t-butylnitrone on ionizing radiation-induced apoptosis in U937 cells

Ionizing radiation induces the production of reactive oxygen species (ROS), which play an important causative role in apoptotic cell death. α-Phenyl-N-t-butylnitrone (PBN) is one of the most widely used spin-trapping compounds for investigating the existence of free radicals in biological systems. We investigated the effects of PBN on ionizing radiation-induced apoptosis in U937 cells. Upon exposure to 2 Gy of γ-irradiation, there was a distinct difference between the control cells and the cells pre-treated with 2 mM PBN for 2 h in regard to apoptotic parameters, cellular redox status, mitochondria function and oxidative damage to cells. PBN effectively suppressed morphological evidence of apoptosis and DNA fragmentation in U937 cells exposed to ionizing radiation. The [GSSG]/[GSH+GSSG] ratio and the generation of intracellular ROS were higher and the [NADPH]/[NADP⁺+NADPH] ratio was lower in control cells compared to PBN-treated cells. The ionizing radiation-induced mitochondrial damage reflected by the altered mitochondrial permeability transition, the increase in the accumulation of ROS, and the reduction of ATP production were significantly higher in control cells compared to PBN-treated cells. PBN pre-treated cells showed significant inhibition of apoptotic features such as activation of caspase-3, up-regulation of Bax and p53, and down-regulation of Bcl-2 compared to control cells upon exposure to ionizing radiation. This study indicates that PBN may play an important role in regulating the apoptosis induced by ionizing radiation presumably through scavenging of ROS.