Radiation-induced DNA damage and the relative biological effectiveness of 18F-FDG in wild-type mice

Mutagenesis Radiation-induced DNA damage and the relative biological effectiveness of18F-FDG in wild-type mice Kristina Taylor 0 Jennifer A. Lemon 0 Douglas R. Boreham 0 0 Department of Medical Physics and Applied Radiation Sciences, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4K1 , Canada © The Author 2014. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: . - *To whom correspondence should be addressed. Tel: +1 905-525-9140 ext. 27538; Fax: +1 905-522-5982; Email: Received on February 20, 2014; revised on March 28, 2014; accepted on April 1, 2014 Clinically, the most commonly used positron emission tomography (PET) radiotracer is the glucose analog 2-[18F] fluoro-2-deoxy-d-glucose (18F-FDG), however little research has been conducted on the biological effects of 18F-FDG injections. The induction and repair of DNA damage and the relative biological effectiveness (RBE) of radiation from 18F-FDG relative to 662 keV γ-rays were investigated. The study also assessed whether low-dose radiation exposure from 18F-FDG was capable of inducing an adaptive response. DNA damage to the bone marrow erythroblast population was measured using micronucleus formation and lymphocyte γH2A.X levels. To test the RBE of 18F-FDG, mice were injected with a range of activities of 18F-FDG (0–14.80 MBq) or irradiated with Cs-137 γ-rays (0–100 mGy). The adaptive response was investigated 24h after the 18F-FDG injection by 1 Gy in vivo challenge doses for micronucleated reticulocyte (MN-RET) formation or 1, 2 and 4 Gy in vitro challenges doses for γH2A.X formation. A significant increase in MN-RET formation above controls occurred following injection activities of 3.70, 7.40 or 14.80 MBq (P < 0.001) which correspond to bone marrow doses of ~35, 75 and 150 mGy, respectively. Per unit dose, the Cs-137 radiation exposure induced significantly more damage than the 18F-FDG injections (RBE  =  0.79 ± 0.04). A  20% reduction in γH2A.X fluorescence was observed in mice injected with a prior adapting low dose of 14.80 MBq 18F-FDG relative to controls (P < 0.019). A 0.74 MBq 18F-FDG injection, which gives mice a dose approximately equal to a typical human PET scan, did not cause a significant increase in DNA damage nor did it generate an adaptive response. Typical 18F-FDG injection activities used in small animal imaging (14.80 MBq) resulted in a decrease in DNA damage, as measured by γH2A.X formation, below spontaneous levels observed in control mice. The 18F-FDG RBE was <1.0, indicating that the mixed radiation quality and/or low dose rate from PET scans is less damaging than equivalent doses of gamma radiation. Introduction The use of diagnostic imaging in health care has seen a dramatic increase over the last two decades. In the USA, nuclear medicine procedures have increased >7% per annum, with positron emission tomography (PET) showing the greatest increases at 57% per year with expected increases due to its unprecedented sensitivity for the detection of biological processes (1, 2). Clinically, the most commonly used PET radiotracer is the glucose analog 2-[18F] fluoro-2-deoxy-d-glucose (18F-FDG). PET scans with 18F-FDG are used to image disease states characterised by alterations in metabolism: epilepsy (3), Alzheimer’s disease (4), infection (5), heart disease (6, 7) but most often, malignancy (8, 9). 18F-FDG is transported into the cytoplasm of metabolically active cells by glucose transport membrane proteins (GLUT) and undergoes phosphorylation to form 18F-FDG-6-phosphate by hexokinase (10). At this point, 18F-FDG becomes trapped in the cell because of the substitution at the hydroxyl group (11). The absorbed radiation dose in tissue depends on the glucose requirements of that tissue. The radiation exposure is a result of positrons (β+, Emax = 634 keV) emitted by 18F-FDG and subsequent annihilation photons (γ-rays, 511 keV). During a typical clinical protocol involving the administration of 350–750 MBq 18F-FDG (12), most tissues will be irradiated throughout the patient’s body (4–9 mGy). However, in organs with high energy requirements, doses can be much higher, i.e. the brain (10–36 mGy) and heart (16–51 mGy) or organs within the excretory system including kidneys (7–23 mGy) and bladder (13–233 mGy) through which the radiopharmaceutical is voided (13–17). Dose is delivered at a low decaying dose rate reflective of the physical (109.7min) and biological half-life of 18F-FDG. The biological half-life depends on the residence times of the radiopharmaceutical within different tissues. The MIRD dose estimate report for 18F-FDG provides a whole body residence time of 2.38± 0.12 h (15). It is important to note that regardless of the site being imaged, an injection of the radiopharmaceutical 18F-FDG will result in systemic uptake and radiation exposure (18). It has been reported that, compared to all other nuclear medic (...truncated)