DOI: 10.1148/radiol.2421060171
(Radiology 2007;242:244-251.)
© RSNA, 2007
Leukocyte DNA Damage after Multi–Detector Row CT: A Quantitative Biomarker of Low-Level Radiation Exposure1
Kai Rothkamm, Dipl Phys, Dr rer nat,
Sheena Balroop, MSc,
Jane Shekhdar, MSc,
Patricia Fernie, DCR(R) and
Vicky Goh, MRCP, FRCR
1 From the Department of Radiation Oncology & Biology, University of Oxford (K.R.), Gray Cancer Institute (K.R., S.B.); Department of Medical Physics (J.S.); and Paul Strickland Scanner Centre (P.F., V.G.), Mount Vernon Hospital, Rickmansworth Road, Northwood, Middlesex HA6 2JR, England. Received January 29, 2006; revision requested March 7; revision received April 5; final version accepted June 1. Funded by the Royal College of Radiologists/Society and College of Radiographers and the Gray Laboratory Cancer Research Trust.
Address correspondence to K.R. (e-mail: rothkamm{at}gci.ac.uk).
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ABSTRACT
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Purpose: To prospectively determine if 
H2AX (phosphorylated form of H2AX histone variant)-based visualization and quantification of DNA damage induced in peripheral blood mononuclear cells (PBMCs) can be used to estimate the radiation dose received by adult patients who undergo multidetector computed tomography (CT).
Materials and Methods: After institutional review board approval and written informed patient consent were obtained, eight women and five men (mean age, 63.8 years) who would be undergoing chest-abdominal-pelvic CT or chest CT only were recruited. Venous blood samples obtained before scanning were exposed to different radiation doses in vitro and incubated for 5–30 minutes to obtain reference values of H2AX focus yield. Additional blood samples were taken 5–30 minutes after CT. Leukocytes were isolated, fixed, and stained for H2AX expression. The H2AX focus yields were determined with fluorescence microscopy, and the radiation doses delivered during CT were estimated by comparing post-CT focus yields with in vitro pre-CT focus yields. These CT radiation doses were compared with doses calculated by using phantom dosimetry and Monte Carlo data sets. Data were analyzed by using linear regression, the dispersion index test, and the contaminated Poisson method.
Results: Compared with the H2AX focus yields in blood samples taken before CT (0.06 focus per cell ± 0.01 [mean ± standard error of mean]), the yields in blood samples taken 5 minutes after chest-abdominal-pelvic CT (0.52 focus per cell ± 0.02) were 8–10-fold higher and corresponded to a mean radiation dose of 16.4 mGy (95% confidence interval: 15.1, 17.7). The mean yield of 0.24 focus per cell ± 0.04 in one patient after chest CT corresponded to a mean radiation dose of 6.3 mGy ± 1.4. In comparison, phantom dosimetry–calculated total blood doses were 13.85 mGy with whole-body CT and 5.16 mGy with chest CT.
Conclusion: H2AX focus yield in blood cells may be a useful quantitative biomarker of human low-level radiation exposure.
© RSNA, 2007
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INTRODUCTION
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Diagnostic x-rays contribute 14% of the total (man-made plus natural) annual amount of radiation delivered to the general population, and computed tomography (CT) is the largest single source of these x-rays (1–3). The risk of cancer from diagnostic x-ray exposure has been debated widely. However, investigators in a recent study estimated that diagnostic x-ray use in the United Kingdom causes 0.6% of the cumulative risk of cancer to individuals until they reach age 75 years—the equivalent of 700 cases per year, in which bladder cancer, colon cancer, and leukemia are the most common malignancies (1). To date, low-level radiation exposure from diagnostic x-rays has been monitored by using physical or chemical dosimeters. These sensitive devices can detect doses in the range of 0.1–50.0 mGy. However, they determine only the exposure at a reference position outside the body and are unable to assess the actual dose deposited in the body.
In vivo assessment of the biologic response to low-level radiation exposure would represent an original approach to dosimetry. Ionizing radiation induces a broad spectrum of damage in genes. Among these damage forms, DNA double-strand breaks (DSBs) are considered the most powerful lesions for cell killing, chromosome aberration formation, and cancer induction (4). One of the earliest stages in the cellular response to DSBs is the phosphorylation of the histone variant H2AX. By using a fluorescent antibody specific for the phosphorylated form of H2AX (H2AX) and immunofluorescence microscopy, one can visualize discrete nuclear foci at sites of DSBs (5). The formation and loss of H2AX foci after x-ray irradiation has been measured in primary human fibroblast cultures exposed to radiation doses as low as 1 mGy, and focus yields have been shown to increase linearly with dose (6). This H2AX yield–based method may be useful as a biologic dosimeter for diagnostic radiation exposure. Our purpose in this study was to prospectively determine if the H2AX yield–based visualization and quantification of DNA damage induced in peripheral blood mononuclear cells (PBMCs) can be used to estimate the radiation dose received by adult patients who undergo multi–detector row CT.
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MATERIALS AND METHODS
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Patients and CT Scanning Parameters
After institutional review board approval and written informed patient consent were obtained, 13 patients (five men, eight women; mean age, 63.8 years; range 57–74 years) with proved cancer were recruited prospectively (V.G.). Four patients had colorectal cancer; two, ovarian cancer; one, renal cancer; one, breast cancer; two, lung cancer; two, lymphoma; and one, melanoma. All patients underwent clinically indicated CT. Twelve patients underwent whole-body CT from the C4 spinal level to the symphysis pubis; one patient underwent chest CT only. Any patient who had been treated with radiation therapy or chemotherapy within 12 weeks before the CT examination had been excluded. All patients were scanned with a 16–detector row scanner (Sensation 16; Siemens Medical Solutions, Forchheim, Germany) after the intravenous administration of 100 mL of iobitridol (Xenetix; Guerbet, Paris, France) (300 mg of iodine per milliliter at 4 mL/sec). The following imaging parameters were used: 120 kV, effective amperages of 100 mAs for the chest and 160 mAs for the abdomen and pelvis, rotation time of 0.5 second, table feed of 24 mm, detector width of 1.5 mm, reconstruction width of 2.0 mm, small field of view of 500 mm, and matrix of 512 mm. Scanning lengths were 23–30 cm for the chest and 40–52 cm for the abdomen and pelvis.
In Vitro x-Ray Irradiation, Blood Sample Processing, and Cell Incubation
Blood samples (2 mL) were taken from the antecubital vein (P.F., V.G.) of all patients before they underwent CT. Additional samples were taken after the CT examination: initially from patients 1 and 3 at 20 minutes and from patient 2 at 20 and 30 minutes. After confirming a marked increase in H2AX foci in these pilot samples, we intended to collect samples from the 10 remaining patients at 5, 15, and 30 minutes after CT to also determine the kinetic features of H2AX loss over time in individual patients. For patient 12, however, staining of the post-CT samples for H2AX expression failed at all time points, probably because of technical error. In addition, no blood samples could be taken from patients 4, 5, 9, and 11 at 30 minutes because of collapsed veins. Thus, H2AX analysis was successfully performed with nine patients at 5 and 15 minutes, with three patients at 20 minutes, and with six patients at 30 minutes. The baseline blood samples (in tubes) from each patient were exposed to different radiation doses (S.B., K.R.) by using a Pantak x-ray generator (Pantak, East Haven, Conn) with 4.3-mm aluminum filtration: at 150 kV, 0.083 Gy/min at 7 mA for doses up to 0.1 Gy and 0.160 Gy/min at 13 mA for higher doses; and at 240 kV, 0.19 Gy/min at 7 mA for doses up to 0.1 Gy and 0.40 Gy/min at 13 mA for higher doses. The samples were then incubated for 5, 15, 20, and 30 minutes at 37°C for comparison with in vivo samples or for 1, 2, 4, and 20 hours at 37°C for comparison of repair kinetics with primary human fibroblasts. All samples were taken within 2 minutes of the intended time point. For incubation times longer than 30 minutes, blood samples were diluted 1:1 in Roswell Park Memorial Institute medium (RPMI; Sigma-Aldrich, St Louis, Mo) to maintain cell viability.
PBMCs were isolated by using Ficoll density-gradient centrifugation with Histopaque 1077 (Sigma-Aldrich) (7), spotted onto slides, and left to dry for 2 minutes (S.B.). Normal human fibroblasts (MRC-5; European Collection of Cell Cultures, Porton Down, Salisbury, United Kingdom) were grown (S.B., K.R.) in Eagle minimum essential medium (Cambrex, Nottingham, England) supplemented with 10% fetal calf serum (PAA Laboratories, Somerset, United Kingdom) and antibiotics. The cells were irradiated in stationary monolayers on coverslips at room temperature and then incubated for various times at 37°C. The normal fibroblasts served as a control against which leukocyte focus formation could be validated.
Immunocytochemical Staining and Fluorescence Microscopy
The PBMCs were fixed for 10 minutes in 3.7% paraformaldehyde at room temperature, for 10 minutes in 100% methanol at –20°C, and for 1 minute in 100% acetone at –20°C (S.B.). The samples were blocked in phosphate-buffered saline with 2% bovine serum albumin twice for 2 minutes each at room temperature. The samples were incubated with mouse anti-H2AX antibody (clone JBW301; Upstate, Charlottesville, Va) and rabbit anti-53BP1 antibody (Novus Biologicals, Littleton, Colo) at 4°C overnight, washed in phosphate-buffered saline and 1% bovine serum albumin twice for 2 minutes each, and incubated with Alexa Fluor 488–conjugated goat antimouse and Alexa Fluor 532–conjugated goat antirabbit secondary antibodies (Invitrogen, Paisley, United Kingdom) for 1 hour at room temperature. The cells were then washed in phosphate-buffered saline twice for 2 minutes each and mounted by using Vectashield mounting medium with 4,6-diamidino-2-phenylindole (Vector Laboratories, Burlingame, Calif) (S.B.). Fluorescence images were obtained by using a Nikon TE300 inverted fluorescence microscope (Nikon UK, Kingston upon Thames, Surrey, United Kingdom) equipped with a cooled charge-coupled device camera and acquisition software (K.R.). For quantitative analysis, the foci were counted by eye during imaging by using an objective magnification of x100 (K.R.). Analysis of foci in PBMCs was performed in only those cells with lymphocyte-like morphology. The slides were coded, and scoring of focus numbers per cell was performed with the observer blinded to the sample type (ie, type of treatment of the sample [control or irradiated, in vivo or in vitro, CT or radiography, time after irradiation]).
Estimation of Radiation Dose in Blood with Phantom Dosimetry
CT dose index measurements obtained with an ionization chamber and other exposure factors were entered on the ImPACT CT Patient Dosimetry Calculator spreadsheet (ImPACT, London, England) (J.S.). The spreadsheet calculated organ-specific radiation doses by using NRPB-SR250 Monte Carlo data sets matched to the CT system. Calculated doses were based on average scanning lengths of 28 cm for chest CT and 44 cm for chest-abdominal-pelvic CT, with an overlap of 2 cm. Organ-specific blood volumes were adopted from previously reported reference data (8). Sex-specific blood volumes and radiation dose calculations were averaged. To obtain the total blood dose, organ-specific doses were weighted according to the blood content in each organ and then summed.
Estimation of Radiation Dose in Blood at H2AX Analysis
Reference values for yield of H2AX foci induced per unit radiation dose in each cell were calculated for the in vitro irradiated blood samples at 5, 15, 20, and 30 minutes after exposure by averaging the yields across all patients for each time point (K.R.). The focus yield in the blood sample taken after CT was divided by the reference value for the corresponding time point to determine the radiation dose delivered during CT.
Data and Statistical Analyses
For each data point, at least 40 cells and at least 40 foci were scored (K.R.). The mean number of cells scored and the standard error of the mean were calculated, and linear regression analyses were performed. To compare the time course of H2AX focus loss between different in vitro and in vivo exposure conditions, mean focus yields were normalized to the 5-minute level. The dispersion index test (9) was used (K.R.) to determine whether distributions of foci per cell deviated from Poisson statistics. The proportion of irradiated blood was calculated by using the contaminated Poisson method (10,11). With this method, one assumes that the measured distribution consists of a combination of the Poisson distribution, which represents the irradiated fraction, and the nonirradiated fraction.
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RESULTS
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Validation of H2AX Foci in Irradiated Human PBMCs and Fibroblasts
The yield of H2AX foci, measured 5 minutes after in vitro exposure of the blood samples to x-rays, increased linearly with radiation dose in PBMCs (Fig 1). Mean H2AX focus yields of 29.3 foci per cell per gray ± 0.8 (standard error of the mean) and 28.2 foci per cell per gray ± 0.9 were determined by using linear regression analysis of samples exposed to x-rays at 240 and 150 kV, respectively (r2 = 0.999 for all conditions). A similar mean yield (31.3 foci per cell per gray ± 1.3) in the normal human fibroblasts exposed to x-rays at 240 kV (P = .22) was determined. Mean background yields of H2AX in untreated samples were 0.06 focus per cell ± 0.02 in PBMCs and 0.04 focus per cell ± 0.01 in fibroblasts. Kinetic analysis revealed a similar time course for the loss of H2AX foci after exposure of the PBMCs and fibroblasts to 0.5-Gy x-rays (Fig 2), consistent with published kinetics of DSB repair in human fibroblasts (6,12,13).
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Figure 1: Graph shows linear induction and similar yields of H2AX foci in PBMCs and primary human fibroblasts (MRC-5) after in vitro x-ray irradiation. Mean numbers of foci per cell are shown. Error bars represent standard errors of the mean at analysis of 40–150 cells. The line is a linear fit to the data points for PBMCs exposed to x-rays at 150 kV.
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Figure 2: Graph shows similar time courses for loss of H2AX foci in PBMCs and primary human fibroblasts (MRC-5) after 0.5-Gy x-ray irradiation in vitro. Foci were counted at different times after in vitro exposure to x-rays at 240 kV. Mean numbers of foci per cell are shown. Error bars represent standard errors of the mean at analysis of 40–100 cells. The line is a guide for the eye.
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H2AX Focus Yield after Multidetector CT
Analysis of post-CT blood samples was not successful in one patient (patient 12) who underwent whole-body CT. However, data were obtained from the remaining 12 patients. Radiation-induced H2AX foci were detected in samples taken 5 minutes after scanning (Fig 3). All H2AX foci were colocalized with foci of another DNA damage response protein, 53BP1 (Fig 3). Focus yields per cell were 8–10-fold higher in blood samples taken 5 minutes after whole-body CT (0.52 focus per cell ± 0.02) compared with pre-CT yields (0.06 focus per cell ± 0.01) (Fig 4).
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Figure 4: Graph shows radiation-induced formation and loss of H2AX foci in leukocytes in blood samples taken before CT scanning and irradiated in vitro with 0-, 20-, and 100-mGy x-rays and in leukocytes in blood samples taken after chest-abdominal-pelvic CT (CAP-CT) and chest CT only (C-CT). For each data point, 40–400 cells were scored. Error bars represent standard errors of the mean at analysis of the numbers of cells.
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Numbers of foci decreased 5–30 minutes after irradiation both in vivo and in vitro, indicating ongoing DSB repair. Mean focus yields, normalized to the 5-minute level in in vitro and in vivo exposed blood, decreased with similar dose-independent kinetics (Fig 5). For all conditions, about half of the induced foci were resolved within 30 minutes after radiation exposure.
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Figure 5: Graph shows similar mean values of loss of radiation-induced H2AX foci in PBMCs after chest-abdominal-pelvic CT (CAP-CT) and chest CT only (C-CT) and after in vitro exposure to 20, 100, and 500 mGy of x-ray radiation. For each treatment group, the mean numbers of foci per cell were normalized to the yield measured 5 minutes after exposure. Error bars represent standard errors of the mean at analysis of 40–360 cells in one patient who underwent chest CT only and in one patient whose blood sample was irradiated at 500 mGy and at analysis of the data for two to eight patients who underwent chest-abdominal-pelvic CT and whose blood samples were irradiated at 20 and 100 mGy.
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No large interindividual variation in background yields, initial yields, or loss of H2AX foci was observed in the blood samples of eight patients 5 and 15 minutes after exposure or in the samples of three and six patients 20 and 30 minutes, respectively, after whole-body CT (Fig 4). However, H2AX yields in the PBMCs of the patient who underwent chest CT only (mean, 0.24 focus per cell ± 0.04) (Fig 4) were significantly lower than those in the patients who underwent whole-body CT (P < .001) and significantly higher than the preexposure levels (P < .001), indicating that H2AX focus yields may reflect levels of radiation exposure.
CT Dose Calculations at Phantom Dosimetry and H2AX Analysis
The expected radiation dose in blood calculated at phantom dosimetry was 13.85 mGy for whole-body CT and 5.16 mGy for chest CT (Table 1). Reference focus yields after in vitro x-ray irradiation were 27.95 foci per cell per gray ± 0.02 for blood samples incubated for 5 minutes, 19.9 foci per cell per gray ± 0.14 for samples incubated for 15 minutes, 18.8 foci per cell per gray ± 0.37 for samples incubated for 20 minutes, and 14.7 foci per cell per gray ± 0.27 for samples incubated for 30 minutes. On the basis of these yields, the mean focus yield in 11 patients who underwent whole-body CT corresponded to a mean radiation dose of 16.4 mGy ± 0.8 (95% confidence interval: 15.1, 17.7). The focus yields detected in one patient (patient 13) after chest CT corresponded to a mean radiation dose of 6.3 mGy ± 1.4 (Fig 6).
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Figure 6: Graph shows H2AX yield–based calculations of radiation doses delivered during chest-abdominal-pelvic CT in patients 1–11 and during chest CT only in patient 13 that are consistent with phantom dosimetry measurements. A = mean value for patients 1–11. Error bars represent standard errors of the mean at analysis of 50–360 cells; error bar for A represents standard error of the mean of values for patients 1–11.
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Overdispersion of H2AX Focus Distribution Reveals Partial Body Exposure to Radiation
Clear deviations of the focus distributions from the Poisson distributions were apparent at chest and whole-body CT and resulted in dispersion indexes higher than 2 (Table 2). U values higher than 1.960 for whole-body CT and higher than 3.891 for chest CT confirmed a significant nonrandom distribution of foci at the 5% and 0.01% significance levels, respectively. In contrast, focus distributions in the in vitro irradiated samples showed good correlation with Poisson distributions. Calculated fractions of irradiated blood were significantly smaller than 100% with both CT protocols but not with in vitro irradiation (Table 2).
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DISCUSSION
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To date, most biodosimetric measurements of ionizing radiation exposure have involved the analysis of radiation-induced chromosomal alterations in peripheral blood lymphocytes taken from exposed persons. Since the yield of aberrant chromosomes depends on the radiation dose, it can be used as an indirect quantitative measure of radiation exposure. Dicentric chromosomes and rings are scored with conventional chromosome dosimetry approaches. However, the low yields of these elements after low-dose exposure limit the applicability of this technique to doses greater than 100 mGy for sparsely ionizing radiation (11,14). Chromosome-specific fluorescent hybridization probes have been used to analyze translocations for retrospective biologic dosimetry, but, again, the detection limit has been in the range of several hundred milligrays (15).
In our study, we assessed H2AX phosphorylation in the blood cells of patients who underwent CT to determine whether H2AX yield analysis can be used as a sensitive biologic dosimeter of human exposure to low-level radiation. In contrast to most diagnostic x-ray examinations, CT is ideal for this type of testing because the exposure levels are planned, well defined in space and time, and quick (less than 20 seconds for whole-body scanning) and the doses are sufficiently high so as to be easily registered at H2AX analysis. Furthermore, detailed dosimetric information and, importantly, sufficient numbers of exposed individuals are available.
In in vitro experiments, the yield of H2AX foci increased linearly with radiation dose in PBMCs. The initial yields of foci formed in PBMCs after x-ray irradiation and the kinetics of foci loss were similar to those reported for stationary fibroblast cultures, for which a one-to-one correlation between radiation-induced H2AX foci and DSBs has been demonstrated (6,12). These in vitro results indicate that H2AX foci in PBMCs represent DSBs and can be used to determine DNA damage responses and estimate radiation doses at diagnostic exposure levels. Similar yields of H2AX foci were observed after exposures to x-rays at 150 and 240 kV, suggesting that focus yields are independent of radiation quality in this energy range. Therefore, similar focus yields can be expected after exposures to the more effectively filtered (with titanium filter vs aluminum filter used in radiographic units) x-rays at 120 kV used in CT scanners. This similarity enables the calculation of radiation doses on the basis of in vitro yields.
Our study results, in agreement with previous in vitro data (16,17), demonstrate that diagnostic CT scanning activates the component of the DNA damage response in human blood cells that involves the phosphorylation of H2AX at DSB sites and the recruitment of 53BP1 to these sites. All of these responses occurred within minutes of radiation exposure, with kinetics that were similar for in vitro and in vivo samples. The observed time course of H2AX focus loss in the PBMCs in our study was similar for all patients and doses and for both in vitro and in vivo irradiated cells. However, the restriction of the analysis to short times covering mainly the fast component of the biphasic repair kinetics may have precluded the detection of differences in the slow component and yield of residual foci. It remains to be seen whether residual focus yields can be used as a measure of a patient's DSB repair capacity, as has been suggested recently (18).
Chest CT scanning—and to a lesser extent whole-body CT scanning—represents partial body exposure to radiation and should therefore result in a nonuniform deposition of radiation damage to blood cells, which in turn should be reflected by a nonrandom distribution of H2AX foci in the analyzed cells. In the present study, this overdispersion was experimentally confirmed in blood samples taken after CT scanning. In the in vitro irradiated samples, random distributions of H2AX foci were observed, indicating the stochastic nature of radiation-induced focus formation after homogeneous radiation exposure.
Our analysis of H2AX focus induction and loss in blood samples taken from patients after CT enabled clinical validation of this assay as a biologic dosimeter for human radiation exposures. Estimated radiation doses of 13.6–20.0 mGy for 11 patients who underwent chest, abdominal, and pelvic CT and of 6.3 mGy for one patient who underwent chest CT are evidence of the consistency of this technique. The technique also has high sensitivity compared with standard biodosimetric methods: Doses as low as 6 mGy can be detected. Furthermore, the observed overdispersion of the distribution of H2AX foci with both scanning protocols, which reflects the spatially controlled dose delivery during these examinations, potentially could be used to improve dose determinations in cases of partial body exposures.
The H2AX yield–based radiation doses for chest and whole-body CT were 22% and 18% higher, respectively, than the calculated doses derived by the ImPACT dosimetry software. This discrepancy may be explained by the finding that multisection helical CT is associated with a higher radiation dose burden to patients (19,20) that has not yet been accounted for in dose calculation programs. The multisection scanner used in our study (Sensation 16) has been reported to deliver, on average, an 18% higher radiation dose compared with the dose calculated by the ImPACT software (21); this datum is consistent with our results. Furthermore, the software dose calculation does not take into account the automatic tube current modulation (22) or the additional x-ray tube rotations required to reconstruct a given volume at helical scanning (23).
Although the H2AX assay used in our study encompasses some of the features that one would expect from an ideal biodosimetric assay—specifically, sensitivity to doses of a few milligrays, linear dose response across a broad dose range, minimally invasive sample collection, and ability to reveal partial body exposures—it has limitations that prevent its general applicability to all types of biodosimetric tasks. In particular, the fast signal loss (50% during the first half hour followed by a slower loss of the remaining foci over several hours) makes it difficult to use this approach for dose determinations after unplanned accidental acute exposures and protracted low-dose exposures. Also, to our knowledge, no reliable automated scoring system for data collection is yet available; results are instead obtained by using tedious manual scoring. Furthermore, although baseline yields of foci were low and indicated little patient-to-patient variation in our study, higher yields and greater variation may occur, especially in patients with a recent history of radiation therapy or chemotherapy for cancer.
Our study results suggest that H2AX yield in blood cells can be used as a sensitive biomarker of DNA damage and repair following medical, occupational, environmental, and accidental exposure to ionizing radiation as long as information about the timing of the exposure is available. This analysis may be especially useful as a biologic dosimeter for certain cases of medical exposure where physical dosimetry fails to reveal well-defined exposure levels. These cases include therapeutic applications such as intensity-modulated radiation therapy, where scatter radiation results in an ill-defined "dose bath" of normal tissues outside of the targeted area, and complex interventional radiologic procedures. Furthermore, analysis of H2AX focus loss in blood samples taken from patients with cancer may reveal information about the capability for systemic DNA DSB repair in these patients, which may be a useful indicator of their response to radiation therapeutic treatments. In conclusion, our study results suggest that H2AX analysis is a biologic dosimetry method in which the H2AX focus yield may be a useful biomarker of medical, occupational, environmental, and accidental exposure to ionizing radiation.
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ADVANCES IN KNOWLEDGE
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- Whole-body CT increases DNA damage in leukocytes, as measured according to the yield of the phosphorylated form of the H2AX histone variant, by a factor of eight to 10 above baseline.
- The yield of the phosphorylated form of the H2AX histone variant at sites of DNA damage in leukocytes can be used to assess the radiation dose delivered during multidetector CT and can act as a quantitative biomarker of human low-level radiation exposure.
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ACKNOWLEDGMENTS
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We thank the radiographers of the Paul Strickland Scanner Centre for their support and Dr Alan Edwards (Health Protection Agency, Chilton, Didcot, United Kingdom) for help with the dispersion analysis.
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FOOTNOTES
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Abbreviations: DSB = double-strand break • PBMC = peripheral blood mononuclear cell • H2AX = phosphorylated form of H2AX histone variant
Author contributions: Guarantor of integrity of entire study, K.R.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, K.R., V.G.; clinical studies, P.F., V.G.; experimental studies, K.R., S.B.; statistical analysis, K.R.; and manuscript editing, K.R., V.G.
Authors stated no financial relationship to disclose.
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ABSTRACT
INTRODUCTION
