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: .
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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)