[ RadSafe ] Berkeley Lab News Release: New Take on Impacts of Low Dose Radiation

ROY HERREN royherren2005 at yahoo.com
Wed Dec 21 01:32:56 CST 2011

For the full article please see 

 Roy Herren 

From: "Perle, Sandy" <sperle at mirion.com>
To: The International Radiation Protection (Health Physics) Mailing List 
<radsafe at health.phys.iit.edu>
Sent: Tue, December 20, 2011 1:58:15 PM
Subject: [ RadSafe ] Berkeley Lab News Release: New Take on Impacts of Low Dose 

Very interesting study conducted at Lawrence Berkley National Laboratory

Researchers with the U.S. Department of Energy (DOE)'s Lawrence Berkeley 
National Laboratory (Berkeley Lab), through a combination of time-lapse live 
imaging and mathematical modeling of a special line of human breast cells, have 
found evidence to suggest that for low dose levels of ionizing radiation, cancer 
risks may not be directly proportional to dose. This contradicts the standard 
model for predicting biological damage from ionizing radiation - the 
linear-no-threshold hypothesis or LNT - which holds that risk is directly 
proportional to dose at all levels of irradiation.

"Our data show that at lower doses of ionizing radiation, DNA repair mechanisms 
work much better than at higher doses," says Mina Bissell, a world-renowned 
breast cancer researcher with Berkeley Lab's Life Sciences Division. "This 
non-linear DNA damage response casts doubt on the general assumption that any 
amount of ionizing radiation is harmful and additive."

Bissell was part of a study led by Sylvain Costes, a biophysicist also with 
Berkeley Lab's Life Sciences Division, in which DNA damage response to low dose 
radiation was characterized simultaneously across both time and dose levels. 
This was done by measuring the number of RIF, for "radiation induced foci," 
which are aggregations of proteins that repair double strand breaks, meaning the 
DNA double helix is completely severed.

"We hypothesize that contrary to what has long been thought, double strand 
breaks are not static entities but will rapidly cluster into preferred regions 
of the nucleus we call DNA repair centers as radiation exposure increases," says 
Costes. "As a result of this clustering, a single RIF may reflect a center where 
multiple double strand breaks are rejoined. Such multiple repair activity 
increases the risks of broken DNA strands being incorrectly rejoined and that 
can lead to cancer."

Costes and Bissell have published the results of their study in the Proceedings 
of the National Academy of Sciences in a paper titled "Evidence for formation of 
DNA repair centers and dose-response nonlinearity in human cells." Also 
co-authoring the paper were Teresa Neumaier, Joel Swenson, Christopher Pham, 
Aris Polyzos, Alvin Lo, PoAn Yang, Jane Dyball, Aroumougame Asaithamby, David 
Chen and Stefan Thalhammer.

The authors believe their study to be the first to report the clustering of DNA 
double strand breaks and the formation of DNA repair centers in human cells. The 
movement of the double strand breaks across relatively large distances of up to 
two microns led to more intensely active but fewer RIF. For example, 15 RIF per 
gray (Gy) were observed after exposure to two Gy of radiation, compared to 
approximately 64 RIF/Gy after exposure to 0.1Gy. One Gy equals one joule of 
ionizing radiation energy absorbed per kilogram of human tissue. A typical 
mammogram exposes a patient to about 0.01Gy.

Corresponding author Costes says the DNA repair centers may be a logical product 
of evolution.

"Humans evolved in an environment with very low levels of ionizing radiation, 
which makes it unlikely that a cell would suffer more than one double strand 
break at any given time," he says. "A DNA repair center would seem to be an 
optimal way to deal with such sparse damage. It is like taking a broken car to a 
garage where all the equipment for repairs is available rather than to a random 
location with limited resources."

However, when cells are exposed to ionizing radiation doses large enough to 
cause multiple double strand breaks at once, DNA repair centers become 
overwhelmed and the number of incorrect rejoinings of double strand breaks 

"It is the same as when dozens of broken cars are brought to the same garage at 
once, the quality of repair is likely to suffer," Costes says.

The link between exposure to ionizing radiation and DNA damage that can give 
rise to cancerous cells is well-established. However, the standards for cancer 
risks have been based on data collected from survivors of the atomic bomb blasts 
in Japan during World War II. The LNT model was developed to extrapolate low 
dose cancer risk from high dose exposure because changes in cancer incidence 
following low dose irradiation are too small to be measurable. Extrapolation was 
done on a linear scale in accordance with certain assumptions and the laws of 

"Assuming that the human genome is a target of constant size, physics predicts 
DNA damage response will be proportional to dose leading to a linear scale," 
Costes explains. "Epidemiological data from the survivors of the atomic bombs 
was found to be in agreement with this hypothesis and showed that cancer 
incidence increases with an increase in ionizing radiation dose above 0.1 Gy. 
Below such dose, the picture is not clear."

Previous studies failed to detect the clustering of double break strands and the 
formation of DNA repair centers because they were based on single-time or 
single-dose measurements of RIF at a discrete time after the initial exposure to 
ionizing radiation. This yields a net number of RIF that does not account for 
RIF that have not yet appeared or RIF that have already made repairs and 
disappeared. The time-lapse imaging used by Costes, Bissell and their co-authors 
showed that RIF formation continues to occur well beyond the initial radiation 
exposure and after earlier repair issues have been resolved. Time-lapse imaging 
also indicates that double strand break clustering takes place before any RIF 
are formed.

"We hypothesize that double strand break clustering occurs rapidly after 
exposure to ionizing radiation and that RIF formation reflects the repair 
machinery put in place around a single cluster of double strand breaks," Costes 
says. "Our results provide a more accurate model of RIF dose response, and 
underscore fundamental concerns about static image data analysis in the dynamic 
environment of the living cell."

Previous studies also mostly involved fibroblast cells whereas Costes, Bissell 
and their colleagues examined epithelial cells, specifically an immortalized 
human breast cell line known as MCF10A, which has a much higher background of 
RIF than fibroblasts, even without ionizing irradiation. To compensate for this 
higher background, Costes developed a mathematical method that enables 
background to be corrected for on a per- nucleus basis in unirradiated cells. 
Still the use of a special line of immortalized breast cells is an issue that 
Costes and his colleagues plan to address.

"We are now looking at primary breast epithelial cells that have been removed 
from healthy donors to determine if our results are repeated beyond just a 
single cell line and under more realistic physiological conditions," Costes 
says. "We'd also like to know if our findings hold true for fibroblasts as well 
as epithelial cells. Also, we'd like to know if double strand break clustering 
is the result of a random coalescence or if there is an active transport 
mechanism that moves these double strand breaks towards pre-existing DNA repair 

Working in collaboration with Rafael Gomez-Sjoberg of Berkeley Lab's Engineering 
Division, Costes and his group are also developing a special microfluidics 
lab-on-a-chip device that is integrated into an X-ray microbeam. The goal is to 
provide a means by which cells can be kept in a controlled microenvironment 
while being irradiated with multiple doses. This microfluidic array will be used 
to characterize DNA damage response in breast and blood cells collected from 
human donors.

"By characterizing DNA damage response in cells from many different human 
donors," Costes says, "we should be able to determine the variation across 
humans and gain a better understanding of how sensitivity to DNA damage from 
ionizing radiation might vary from individual to individual."

This research was supported by the DOE Office of Science.

Sander C. Perle
Mirion Technologies
Dosimetry Services Division
2652 McGaw Avenue
Irvine, CA 92614

+1 (949) 296-2306 (Office)
+1 (949) 296-1130 (Fax)

Mirion Technologies: http://www.mirion.com/ 
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