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Science to Practice
Science to Practice: Can Antioxidant
Supplements Protect against the
Possible Harmful Effects of Ionizing
Radiation from Medical Imaging?
James A. Brink, MD
Summary: A novel mixture of antioxidants was shown to reduce for-
Department of Diagnostic Radiology
mation of double-strand DNA breaks (DSBs), as indicated
Yale University School of Medicine by phosphorylated histone variant g-H2AX foci, in human
333 Cedar St lymphocytes following in vitro radiation with a radiation
New Haven, CT 06520 dose equivalent to 10 mGy (1). While provocative, it is too
e-mail: james.brink@yale.edu soon to conclude that antioxidant supplements should be
used to protect against any future harmful effects of ioniz-
John D. Boice, Jr, ScD
ing radiation potentially associated with medical imaging
National Council on Radiation Protection
(2). It is unclear whether g-H2AX foci are associated with
and Measurements increased cancer rates, no experimental study has found
Bethesda, Md any protective agent to reduce future cancer rates, and ex-
Department of Medicine posures typical of diagnostic imaging examinations are in
Vanderbilt University School of Medicine the range that epidemiologic investigation is unable to de-
and Vanderbilt-Ingram Cancer Center tect an increase in cancer rates (even if one exists). None-
Nashville, Tenn theless, such research is encouraged as medical radiation
is the number one source of population exposure in the
See page 59 United States. Patients who undergo frequent medical im-
aging examinations can accumulate doses that are in the
range at which excess cancers have been demonstrated,
and any protection afforded by a nontoxic antioxidant com-
pound would be an exciting accomplishment.

The Setting idative stress is thought to play a role in

The medical community has long relied the development of many diseases in-
on time, distance, and shielding as the cluding cancer, inflammatory disease,
primary extrinsic means of protecting and cardiovascular disease. Laboratory
against the potentially harmful effects experiments have shown that antioxi-
of ionizing radiation. However, soon af- dant molecules can counteract the in-
ter the 1945 atomic bombings in Japan duction and associated damage of oxi-
that ended World War II, investigators dative stress (4).
began seeking intrinsic radiation pro- After World War II, many antiox­
tection with biologic agents (3). idants were found to protect against
The likely mechanism by which ion- the harmful effects of ionizing radiation
izing radiation may initiate carcinogen- when administered prior to exposure.
esis is through DSBs. Fortunately, DSBs
are usually repaired efficiently. However,
carcinogenesis may occur when DSBs
overwhelm existing cellular repair mech-
anisms and are misrepaired. Ionizing
radiation causes DSBs primarily through
oxidation, the development of “free rad-
icals,” which are highly reactive unsta-
ble molecules that can damage DNA
and lead to cell death (4). Many exter-
Potential conflicts of interest are listed at the end of this nal agents cause “oxidative stress,” such
article.
as tobacco smoke, radiation, and cer-
Q
RSNA, 2012 tain chemicals in the environment. Ox-

Radiology: Volume 264: Number 1—July 2012 n radiology.rsna.org 1

SCIENCE TO PRACTICE: Antioxidant Supplements and Ionizing Radiation
These agents protected animals against
radiation injury, but most were toxic to
humans (3). Subsequently, glutathione-
elevating agents such as N-acetylcysteine
and alpha-lipoic acid, which are non-
toxic to humans, were found to protect
normal tissues against radiation dam-
age. In addition, several dietary supple-
ments such as vitamins E, C, and beta
carotene were shown to have a radio-
protective value.
The Science
Investigators have long desired a means
to measure and quantify the chromo-
somal damage that follows radiation ex-
posure. Recently, an immunofluorescent
method for identifying surrogate mea­
sures of DSBs in peripheral blood lym-
phocytes was developed (1). This assay
has allowed investigators to estimate the
number and location of DSBs after irra-
diation with doses typically associated
with medical imaging.
After induction of DSBs, the his-
tone variant H2AX is phosphorylated.
With use of a primary antibody targeted
against these g-H2AX foci and a fluores-
cent secondary antibody, DSBs may be
identified with fluorescent microscopy.
Each fluorescent focus represents one
DSB, and the number of DSBs corre-
lates with the radiation dose.
Kuefner et al (1) used this tech-
nique to investigate the effect of a
mixture of antioxidants and glutathi-
one-elevating compounds in reducing
the number of g-H2AX foci. Blood lym-
phocytes from 25 healthy volunteers
were incubated with this antioxidant
mixture prior to irradiation at a dose
commensurate with many clinical com-
puted tomography examinations (10
mGy). Preincubation of the blood lym-
phocytes with antioxidants for 15 mi-
nutes led to a 23% reduction in the
number of g-H2AX foci. The experi-
ment was extended in 17 healthy vol-
unteers who ingested orally the antioxi-
dant mixture prior to donating a blood
sample for in vitro irradiation. Simi-
larly, oral pretreatment with the antiox-
idant mixture 60 minutes prior to irra-
diation in vitro led to a 58% reduction
of g-H2AX foci. As the number of fluo-
2 radiology.rsna.org
rescent foci corresponds to the number
of DSBs, one can presume that the mag-
nitude of genetic damage caused by a
10-mGy exposure is reduced significantly
with use of the antioxidant mixture, both
in vitro and in vivo.
The Practice
The scientific evidence linking the use
of a mixture of antioxidants and gluta-
thione-elevating compounds with a re-
duction in the number of DSBs in pe-
ripheral blood lymphocytes is an
exciting step toward a biologic protec-
tive agent against the potential damag-
ing effects of ionizing radiation at low
doses. However, the actual risk associ-
ated with low-dose exposures to medi-
cal imaging remains elusive—10 mGy is
a very low dose, and from an epidemio-
logic perspective, it has not been possi-
ble to measure a statistically significant
excess of cancer below approximately
100–150 mGy (5). The actual risk at 10
mGy is thus uncertain and is estimated
by extrapolation from effects observed
at higher doses. And the method of ex-
trapolation is debatable. While most
rely on the linear no-threshold model to
guide extrapolation, recent data using
the same immunofluorescent method
for measuring DSBs following radiation
in a special line of human breast cells
have suggested that cancer induction
may not be linearly proportional to
dose; DNA repair mechanisms appear
to work much better at lower doses
than at higher doses (6,7). By using
time-lapsed live imaging and mathemat-
ical modeling of g-H2AX foci kinetics, it
was shown that while the induction of
g-H2AX foci increases with increasing
radiation dose, the rate at which g-
H2AX foci disappear decreases. The
authors concluded that when cells are
exposed to ionizing radiation with dos-
es sufficiently large to cause multiple
DSBs at once, DNA repair centers may
become overwhelmed, and the number
of failed DSB repairs increases.
While the results of the biologic study
reported by Kuefner and colleagues are
encouraging, it is one of many encourag-
ing laboratory studies on the biochemis-
try of antioxidants, in spite of several clin-
Brink and Boice
ical trials that have generally found no
benefit to antioxidants (4). Thus, al-
though the biologic evidence for a possi-
ble beneficial effect from antioxidants has
been improved with use of the immuno-
fluorescent technique described by Kuef-
ner et al, additional research is needed to
connect the biologic benefit observed in
the laboratory to a true benefit in patient
outcome. An overriding issue recognized
by the authors is whether g-H2AX foci
induced by x-rays in blood lymphocytes
are related to the induction of cancer in
other cells, such as breast epithelial cells.
Further, even if such a link were con-
firmed at high doses, the value of reduc-
ing DSBs fol­lowing lower doses is unclear
given that any associated increase in the
lifetime risk of cancer could not be mea-
sured in human studies.
Disclosures of Potential Conflicts of Interest:
J.A.B. No potential conflicts of interest to disclose.
J.D.B. No potential conflicts of interest to disclose.
References
1. Kuefner MA, Brand M, Ehrlich J, Braga L,
Uder M, Semelka RC. Effect of antioxidants
on x-ray–induced g-H2AX foci in human
blood lymphocytes: preliminary observations.
Radiology 2012;264(1):59–67.
2. Mettler FA Jr, Brenner D, Coleman CN,
Kaminski JM, Kennedy AR, Wagner LK. Can
radiation risks to patients be reduced with-
out reducing radiation exposure? The sta­
tus of chemical radioprotectants. AJR Am J
Roentgenol 2011;196(3):616–618.
3. Prasad KN. Rationale for using multiple anti-
oxidants in protecting humans against low
doses of ionizing radiation. Br J Radiol 2005;
78(930):485–492.
4. Antioxidant supplements for health: an intro-
duction. National Center for Complementary
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Published May 2010. Accessed March 5, 2012.
5. Ozasa K, Shimizu Y, Suyama A, et al. Studies
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and noncancer diseases. Radiat Res 2012;
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6. Neumaier T, Swenson J, Pham C, et al. Evi-
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7. New take on impacts of low dose radiation.
HealthCanal.com. http://www.healthcanal
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Impacts-Low-Dose-Radiation.html. Published
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n Radiology: Volume 264: Number 1—July 2012