Partial-body Radiation Exposure Research Articles

Cytogenetic Effects in Patients after Computed Tomography Examination.

Millions of people around the world are exposed to low doses of ionizing radiation from diagnostic computed tomography (CT) scans. Currently available data on the potential cancer risk after CT scans are contradictory and therefore demand further investigations. The aim of the current study was to obtain estimations of genome damage after CT scans in 42 non-cancer patients and to conduct a comparison of the results with 22 control subjects. The frequency of dicentric ring chromosomes and chromosome breaks was significantly increased in irradiated patients compared to the controls. The distribution of dicentrics among the cells demonstrated non-Poisson distribution that reflected non-uniform and partial-body radiation exposure. A fraction of patients followed Poisson distribution, which is typical for uniform whole-body exposures. Some patients demonstrated a level of dicentrics similar to the control subjects. The individual variations in the frequency and dicentric distribution suggested complex mechanisms of chromosome aberration induction and elimination that could be associated with individual radiosensitivity, as well as previous diagnostics that used ionizing radiation or the redistribution of small fractions of irradiated lymphocytes within the circulatory pull. In conclusion, CT scans may cause genome damage and possible increases in cancer risk. The introduction of a specific follow-up of such patients, especially in the case of repeated CT scans, is suggested.

Chromosome aberration dynamics in breast cancer patients treated with radiotherapy: Implications for radiation biodosimetry

Although radiological accidents often result in partial-body radiation exposure, most biodosimetry studies focus on estimating whole-body exposure doses. We have evaluated time-dependent changes in chromosomal aberrations before, during, and after localized fractionated radiotherapy. Twelve patients with carcinoma in situ of the breast who underwent identical adjuvant radiation therapy (50 Gy in 25 fractions) were included in the study. Lymphocytes were collected from patients before, during, and after radiotherapy, to measure chromosome aberrations, such as dicentric chromosomes and translocations. Chromosome aberrations were then used to calculate whole- and partial-body biological absorbed doses of radiation. Dicentric chromosome frequencies in all study participants increased during radiotherapy (p < 0.05 in Kruskal-Wallis test). Increases of translocation frequencies during radiotherapy were observed in seven of the twelve patients. The increased levels of dicentric chromosomes and translocations persisted throughout our 1-year follow-up, and evidence of partial-body exposure (such as Papworth’s U-value > 1.96) was observed more than 1 year after radiotherapy. We found that cytogenetic biomarkers reflected partial-body fractionated radiation exposure more than 1 year post-exposure. Our findings suggest that chromosome aberrations can be used to estimate biological absorbed radiation doses and can inform medical intervention for individuals suspected of fractionated or partial-body radiation exposure.

Interventional radiologists have a higher rate of chromosomal damage due to occupational radiation exposure: a dicentric chromosome assay.

There are growing concerns regarding radiation exposure in medical workers who perform interventional fluoroscopy procedures. Owing to the nature of certain interventional procedures, workers may be subjected to partial-body radiation exposure that is high enough to cause local damage. We aimed to investigate the level of radiation exposure in interventional radiologists in South Korea by performing cytogenetic biodosimetry, particularly focusing on partial-body exposure. Interventional radiologists (n = 52) completed a questionnaire, providing information about their work history and practices. Blood samples were collected and processed for a dicentric chromosome assay. We determined Papworth's U-value to assess the conformity of dicentrics with the Poisson distribution to estimate the partial-body exposures of the radiologists. Radiologists had a higher number of dicentrics than the normal population and industrial radiographers. Indeed, subjects with a U-value of > 1.96, an indicator of heterogeneous exposure, were observed more frequently; 4.67 ± 0.81% of their body was irradiated at an average dose of 4.64 ± 0.67 Gy. Logistic regression analysis revealed that the total duration of all interventional procedures per week was associated with partial-body exposure levels. Our findings suggest that interventional radiologists had greater chromosomal damages than those in other occupational groups, and their partial-body exposure levels might be high enough to cause local damage. Use of special dosimeters to monitor partial-body exposure, as well as restricting the time and frequency of interventional procedures, could help reduce occupational radiation exposure. • Interventional radiologists had a higher number of dicentrics than the normal population and industrial radiographers. • The level of partial-body exposure of interventional radiologists might be high enough to cause occupational local damage such as a skin cancer in fingers. • Restricting the duration and frequency of interventional procedures might be helpful in reducing occupational radiation exposure.

Comparative metabolic profiles of total and partial body radiation exposure in mice using an untargeted metabolomics approach.

A large scale population exposure to ionizing radiation during intentional or unintentional nuclear accidents undoubtedly generates a complex scenario with partial-body as well as total-body irradiated victims. A high throughput technique based rapid assessment method is an urgent necessity for stratification of exposed subjects independent of whether exposure is uniform total-body or non-homogenous partial-body. Here, we used Nuclear Magnetic Resonance (NMR) based metabolomics approach to compare and identify candidate metabolites differentially expressed in total and partially irradiated mice model. C57BL/6 male mice (8-10weeks) were irradiated total-body or locally to thoracic, hind limbor abdominal regions with 10Gy of gamma radiation. Urine samples collected at 24h post irradiation were examined using high resolution NMR spectroscopy and the datasets were analysed using multivariate analysis. Multivariate and metabolic pathway analysis in urine samples collected at 24h post-radiation exhibited segregation of all irradiated groups from controls. Metabolites associated with energy metabolism, gut flora metabolism and taurine were common to partial and total-body irradiation, thus making them potential candidates for radiation exposure. Nevertheless, a distinct metabolic pattern was observed in partial-body exposed groups with maximum changes observed in the hind limb region indicating differential tissue associated radiation sensitivity. The organ-specific changes may provide an early warning regarding the physiological system at risk after radiation injury. The study affirms potentiality of metabolite markers and comparative analysis could be an important piece of information for an integrated solution to a complex research question in terms of radiation biomarkers.

MiRNA Expression Patterns Differ by Total- or Partial-Body Radiation Exposure in Baboons.

In a radiation exposure event, a likely scenario may include either total-body irradiation (TBI) or different partial-body irradiation (PBI) patterns. Knowledge of the exposure pattern is expected to improve prediction of clinical outcome. We examined miRNA species in 17 irradiated baboons receiving an upper-body, left hemibody or total-body irradiation of 2.5 or 5 Gy. Blood samples were taken before irradiation and at 1, 2, 7, 28 and 75-106 days after irradiation. Using a qRT-PCR platform for simultaneous detection of 667 miRNAs, we identified 55 miRNAs over all time points. Candidate miRNAs, such as miR-17, miR-128 or miR-15b, significantly discriminated TBI from different PBI exposure patterns, and 5-to-10-fold changes in gene expression were observed among the groups. A total of 22 miRNAs (including miR-17) revealed significant linear associations of gene expression changes with the percentage of the exposed body area (P < 0.0001). All these changes were primarily observed at day 7 postirradiation and almost no miRNAs were detected either before or after 7 days. A significant association in the reduction of lymphocyte counts in TBI compared to PBI animals corresponded with the number of miRNA candidates. This finding suggests that our target miRNAs predominantly originated from irradiated lymphocytes. In summary, gene expression changes in the peripheral blood provided indications of the exposure pattern and a suggestion of the percentage of the exposed body area.

Clinically Relevant Doses of Enalapril Mitigate Multiple Organ Radiation Injury.

Angiotensin-converting enzyme inhibitors (ACEi) are effective mitigators of radiation nephropathy. To date, their experimental use has been in fixed-dose regimens. In clinical use, doses of ACEi and other medication may be escalated to achieve greater benefit. We therefore used a rodent model to test the ACEi enalapril as a mitigator of radiation injury in an escalating-dose regimen. Single-fraction partial-body irradiation (PBI) with one hind limb out of the radiation field was used to model accidental or belligerent radiation exposures. PBI doses of 12.5, 12.75 and 13 Gy were used to establish multi-organ injury. One third of the rats underwent PBI alone, and two thirds of the rats had enalapril started five days after PBI at a dose of 30 mg/l in the drinking water. When there was established azotemic renal injury enalapril was escalated to a 60 mg/l dose in half of the animals and then later to a 120 mg/l dose. Irradiated rats on enalapril had significant mitigation of combined pulmonary and renal morbidity and had significantly less azotemia. Dose escalation of enalapril did not significantly improve outcomes compared to fixed-dose enalapril. The current data support use of the ACEi enalapril at a fixed and clinically usable dose to mitigate radiation injury after partial-body radiation exposure.

DIM (3,3′-diindolylmethane) confers protection against ionizing radiation by a unique mechanism

DIM (3,3'-diindolylmethane), a small molecule compound, is a proposed cancer preventive agent that can be safely administered to humans in repeated doses. We report that administration of DIM in a multidose schedule protected rodents against lethal doses of total body irradiation up to 13 Gy, whether DIM dosing was initiated before or up to 24 h after radiation. Physiologic submicromolar concentrations of DIM protected cultured cells against radiation by a unique mechanism: DIM caused rapid activation of ataxia-telangiectasia mutated (ATM), a nuclear kinase that regulates responses to DNA damage (DDR) and oxidative stress. Subsequently, multiple ATM substrates were phosphorylated, suggesting that DIM induces an ATM-dependent DDR-like response, and DIM enhanced radiation-induced ATM signaling and NF-κB activation. DIM also caused activation of ATM in rodent tissues. Activation of ATM by DIM may be due, in part, to inhibition of protein phosphatase 2A, an upstream regulator of ATM. In contrast, DIM did not protect human breast cancer xenograft tumors against radiation under the conditions tested. In tumors, ATM was constitutively phosphorylated and was not further stimulated by radiation and/or DIM. Our findings suggest that DIM is a potent radioprotector and mitigator that functions by stimulating an ATM-driven DDR-like response and NF-κB survival signaling.

Murine partial-body radiation exposure model for biodosimetry studies — Preliminary report

Abstract The objective of the present study was to establish a murine partial-body radiation exposure model for studies supporting the identification and validation of novel biological dosimetry diagnostic assays. A lead shielding – Plexiglas ® irradiation apparatus with cutouts to permit irradiation of single-mouse-holder constrained CD2F1 male mice to total-body (3/3), mid- and lower-body (2/3), mid-body only (1/3), and 100% lead shielding sham-treated (0 Gy) controls (0/3) with a 250-kVp X-ray source (dose: 6 Gy, dose rate: 0.50 Gy min −1 ) was used. Doses and dose uniformity were measured using alanine – electron paramagnetic resonance (EPR) and ionization chambers. Dosimetry mapping results showed ∼2 and ∼12% non-uniformity in the radiation fields for the two smaller (1/3, 2/3) and one larger (3/3) fields, respectively. Hematology results showed no marked differences in neutrophil and platelet counts 1 and 2 days (d) after irradiation. The lymphocyte counts, as expected, demonstrate a progressive decline below baseline levels 1 and 2 d after irradiation with increasing fraction of the body exposed, while the neutrophil to lymphocyte ratios show the inverse effect, with a progressive increase with the fraction of body exposed. The bone marrow biomarker, Flt3 ligand, demonstrated a progressive increase in values with increasing fraction of the body exposed; the 2 d response was enhanced compared to 1 d. The radioresponse 1 d after irradiation for the acute phase reactant protein biomarker, serum amyloid A (SAA) that is synthesized by the liver, was significantly influenced depending on whether the mouse head was in the radiation field. Use of multiple biomarkers based on hematology and proteomic targets provide an enhancement in early-phase partial-body radiation exposure assessment.

Qγ−H2AX, an analysis method for partial-body radiation exposure using γ-H2AX in non-human primate lymphocytes

We previously used the γ-H2AX assay as a biodosimeter for total-body-irradiation (TBI) exposure (γ-rays) in a rhesus macaque (Macaca mulatta) model. Utilizing peripheral blood lymphocytes and plucked hairs, we obtained statistically significant γ-H2AX responses days after total-body exposure to 1-8.5 Gy ((60)Co γ-rays at 55 cGy min(-1)). Here, we introduce a partial-body exposure analysis method, Q(γ-H2AX), which is based on the number of γ-H2AX foci per damaged cells as evident by having one or more γ-H2AX foci per cell. Results from the rhesus monkey - TBI study were used to establish Q(γ-H2AX) dose-response calibration curves to assess acute partial-body exposures. γ-H2AX foci were detected in plucked hairs for several days after in vivo irradiation demonstrating this assay's utility for dose assessment in various body regions. The quantitation of γ-H2AX may provide a robust biodosimeter for analyzing partial body exposures to ionizing radiation in humans.

Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles.

In the event of a terrorist-mediated attack in the United States using radiological or improvised nuclear weapons, it is expected that hundreds of thousands of people could be exposed to life-threatening levels of ionizing radiation. We have recently shown that genome-wide expression analysis of the peripheral blood (PB) can generate gene expression profiles that can predict radiation exposure and distinguish the dose level of exposure following total body irradiation (TBI). However, in the event a radiation-mass casualty scenario, many victims will have heterogeneous exposure due to partial shielding and it is unknown whether PB gene expression profiles would be useful in predicting the status of partially irradiated individuals. Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice. These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79–100%) compared to non-irradiated mice. Interestingly, PB signatures of partial body irradiation were poorly predictive of radiation status by site of injury (range 16–43%), suggesting that the PB molecular response to partial body irradiation was anatomic site specific. Importantly, PB gene signatures generated from TBI-treated mice failed completely to predict the radiation status of partially irradiated animals or non-irradiated controls. These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.

Time-course of translocation and dicentric frequencies in a radiation accident case

Purpose : To assess the persistence of exchange aberrations measured by FISH chromosome painting after accidental radiation exposure. Materials and methods : Chromosome analyses were carried out in peripheral lymphocytes of a 13-year-old boy exposed to protracted low dose-rate whole-body and short-time partial-body irradiation from a radiation accident in Estonia in 1994. Up to November 1998, the frequencies of translocations and dicentrics were periodically measured using FISH chromosome painting of the target chromosomes 1, 4 and 12, with a simultaneous pancentromeric probe. Results : For the yields of dicentrics, an expected rapid temporal decline was found with a half-time of 14.2 ±1.9 months. The yields of reciprocal translocations also revealed a gradual but significant reduction with a half-time of 51.7 ±12.7 months. Conclusion : An unchanged temporal persistence of so-called stable translocations cannot be assumed. Any significant reduction of this aberration type with time obviously limits the application of FISH-based translocation measurements for reliable long-term biodosimetry after combined protracted whole-body and partial-body radiation exposure.

Chromosome Aberrations in Peripheral Lymphocytes and Radiation Dose to Active Bone Marrow in Patients Treated for Cancer of the Cervix

An international study of cervical cancer patients reported a doubling of the risk for leukemia following radiotherapy. To evaluate the extent of residual chromosome damage in circulating T-cell lymphocytes in this population, approximately 200 metaphases were examined from each of 96 irradiated and 26 nonirradiated cervical cancer patients treated more than 17 years ago (average 23 years). Radiation dose averaged over the total red bone marrow was estimated to be 8.1 Gy. The type and frequency of stable and unstable chromosome aberrations were quantified in 24,117 metaphases. Unstable aberrations did not differ significantly between irradiated and nonirradiated patients (P greater than 0.5). Stable aberrations (i.e., translocations, inversions, or chromosomes with deleted segments), however, were significantly higher among irradiated (2.8 per 100 cells) compared to nonirradiated (0.7 per 100 cells) women (P less than 10(4). The frequency of these stable aberrations was found to increase significantly with increasing dose to the bone marrow. These data indicate that a direct relationship between radiation dose and extent of damage to somatic cells persists in populations and can be detected many years after partial-body radiation exposure. The stable aberration rate in irradiated cervical cancer patients was 50 to 75% lower than those observed 25 years or more after radiation exposure in atomic bomb survivors and in ankylosing spondylitis patients treated with radiotherapy. The average marrow dose was only 1 Gy in the examined atomic bomb survivors and 3.5 Gy in the ankylosing spondylitis patients. It appears, then, that a very high dose delivered to the pelvic cavity in fractionated doses resulted in far fewer persistent stable aberrations than lower doses delivered either in acute whole-body exposure or in fractionated doses to the spinal column and sacroiliac joints. The higher radiation dose and the concentration of that dose in a smaller area of the body appear to be responsible for the lower rate of persistent aberrations observed in cervical cancer patients.

The biological and clinical effects of acute whole or partial body irradiation

The author reviews briefly the clinical effects of whole or partial body radiation exposure in terms of damage to normal tissue structure and function. The current biological understanding of the cellular organisation and radiosensitivity of three tissues critical to survival i.e. the bone marrow the gastrointestinal epithelium and the central nervous system, is presented together with an assessment of how damage to each interrelates with the complex dose and time dependent clinical signs and symptoms commonly associated with whole body radiation exposure.

Human Health Effects of Low Doses of Ionizing Radiation: The BEIR III Controversy

Controversy in the BEIR III Subcommittee on Somatic Effects concerning human health effects of low doses of low-LET radiation has centered on (a) the appropriate dose-response relationship by which extrapolation to low doses of data obtained at relatively high doses should be governed, and (b) the appropriate human evidence which should be the basis of estimation of lifetime cancer risk from radiation exposure. It is shown that the use of the linear no-threshold dose-response relationship for extrapolation purposes is an excellent approximation that is in agreement with widely accepted fundamental radiobiological principles. The appropriate human data for derivation of cancer risks are the composite age-specific risks derived from all epidemiologic studies of human cancer resulting from partial-body and whole-body radiation exposure; this composite is in good agreement with the currently available cancer incidence dose-response data obtained from the Nagasaki Tumor Registry. The current version of BEIR III significantly underestimates the radiationinduced cancer risk because it ignores the effect of high-dose-rate, low-LET radiation on cell survival in relation to cancer induction probability, and because it emphasizes cancer mortality rather than cancer incidence. Use of the appropriate basis of risk estimates gives a lifetime cancer risk per rad per million persons exposed of 260 to 880 excess incident cases for males, and 550 to 1620 excess cases for females. This result is about five times higher than the values given in the current version. Rossi's contention that the appropriate relationship is that the carcinogenic effect of radiation is proportional only to dose squared is contrary to the majority of current theoretical, experimental, and epidemiological evidence. The controversy and the way in which it was resolved raises important questions about how the public and its representatives can in the future obtain objective scientific evaluations of issues that may have significant economic, social, and political implications.