Adaptive Response to Low Dose Radiation

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

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….

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.

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

…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)

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.

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 0.5 + 150 Dose cGy Shadley and Wolff 1987

Adaptive Response What about CANCER?

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 1- 10 cGy, close to the yearly background level, appears to act as the “tickle” dose, and reduces cancer rates.

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 0 200 400 600 800 1000 Time (days) Mitchel et al 1999

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 0 20 40 60 80 100 % Death Lymphomas in Trp53+/- Mice Mitchel et al. 2003

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 0 20 40 60 80 100 % Death Osteosarcomas in Trp53+/- Mice Mitchel et al. 2003

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 0.1 1 10 100 Dose (cSv) Redpath et al.2001

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.