1. Adaptive Response to Low Dose Radiation

2. Adaptive Response
When large radiation exposure is preceded by a small “tickle” dose, the effect of the large dose is sometimes diminished

3. The first time you go to the beach in the
summer, you don’t usually spend 8 hours in
the sun. You begin by being out an hour or
two and add additional time as their skin
adapts to the sunny condition and develops
protective mechanisms….

4. Adaptive Response
In some cases, cells also show an “adaptive response” to radiation, although researchers are still trying to understand how the protective mechanisms work. Small doses of radiation appear to stimulate protective responses, triggering DNA repair mechanisms and the elimination of severely damaged cells.

5. Adaptive response has been demonstrated on various levels
Molecular
Cellular
Tissue
Whole animal
Human (cellular)

6. …and for a variety of biological changes.
Chromosome damage (Olivieri 1984)
DNA damage (Le et al 1998)
Mutation (Sanderson et al. 1986)
Cell transformation (Redpath and Antoniono 1998)
Cell killing (Ishi and Watanabe 1996)
Gene Induction (Yin 2003)

7. Adaptive response is specific
There seems to be a genetic basis for
adaptive response, since it is
demonstrated only in specific cell
lines, tissues, animal lines and individuals.
It is demonstrated only for
specific biological changes.

8. Adaptive Response Aberrations Dose cGy
When a small dose of radiation is given before a larger one, it would be expected there would be more chromosome aberrations than when just the large dose was given. But that is not what happens. With a small “tickle” dose before the larger dose, there were only about half as many aberrations than with just a large dose!
With a very small dose of radiation, little if any difference from normal is expected in chromosome aberrations, and no difference is seen.
A larger number of chromosome aberrations is expected to be seen when the dose of the radiation is high, and is.
A very small number of chromosome aberrations are expected without any radiation, and a very small number occur. 90 80 70 60
Aberrations 50
Observed 40
Expected 30
The next important area of study is to determine the influence of low doses of radiation on the response of cells and tissues to subsequent larger radiation doses. The slide demonstrates that a small dose of radiation results in an adaptive response that makes it more resistant to the subsequent large radiation exposure. It is essential to determine the genes that are involved in production of this adaptive response and ultimately to determine if and how this adaptive response can alter the risk from low doses of radiation. It has been suggested that the low doses of radiation produce a protective response that would reduce the risk from radiation relative to that predicted from the linear-no-threshold model. 20 10
0.5
150
Dose cGy
Shadley and Wolff 1987

9. Adaptive Response
What about CANCER?

10. Cells transforming to cancerous cells
Dose (cGy)
Transformation Frequency 10 20 30 40 50 60 70 80 90
100
Redpath et al. 2001
At very low doses, the transformation frequency is below that predicted by linear extrapolation
Linear Prediction of Transformation
Actual Transformation
Sometimes a low radiation exposure of cGy, close to the yearly background level, appears to act as the “tickle” dose, and reduces cancer rates.

11. Adaptive Responses for Leukemia
Mice that were exposed to a small “tickle” dose of radiation before the large dose of radiation, developed cancer later and lived longer than the mice that received only a large dose of radiation.
In this experiment, mice that were exposed to high doses of radiation died of leukemia died before 600 days.
1.0
Exposed
Control
Adaptive
0.8
0.6
Survival Probability
0.4
0.2
About half of a population of mice are expected to die by the time they are 700 days old, and usually all die before 1000 days.
0.0
Time (days)
Mitchel et al 1999

12. Lymphomas in Trp53+/- Mice
Lymph Tumors in Mice
Although the survival rate was not effected by 1 or 10 cGy radiation exposures, the control group, which did not receive any radiation, developed more tumors than either of the radiated groups. 50 40 30 20 10
0 cGy
1 cGy
10 cGy
Number of Tumors
% Death
Lymphomas in Trp53+/- Mice
Mitchel et al. 2003

13. Osteosarcomas in Trp53+/- Mice
Bone Tumors in Mice
There were also fewer bone tumors when the mice were given 1 cGy of radiation than when they had no radiation. However, this time, mice receiving 10 cGy developed more tumors than the controls before they died. 25 20 15 10 5
0 cGy
1 cGy
10 cGy
Number of Tumors
% Death
Osteosarcomas in Trp53+/- Mice
Mitchel et al. 2003

14. Relative risk for different types of radiation-induced human cancer
Cells transforming to cancer 5 4 3 2 1
Breast cancer
Leukemia
Relative Risk
All solid tumors
Normal risk without radiation
Dose (cSv)
Redpath et al.2001

15. Impact of Adaptive Response
Adaptive response may be useful in radiation therapy to protect normal tissue.
Induction of repair genes may decrease the response to low-dose radiation.
If adaptive response is demonstrated at low doses and dose-rates, it may have an impact on radiation protection standards.