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 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 A verydose was given. Butradiation, little ifhappens. expected A larger number dose of that is not aberrationsdifference a be large very number of chromosome what any are With small theWith a small smallof chromosome aberrations is expected tofrom normal is before radiation, dose, radiation isnumber occur. dose expected indose and a very were high, and is. seen any the chromosome aberrations, about difference “tickle” withoutwhenthe larger of the there small onlyand no half as many 90 with just aberrations than is seen. a large dose! 80 70 60 50 Observed 40 Expected 30 20 10 0 0 0.5 150 0.5 + 150 Dose cGy Shadley and Wolff 1987 Adaptive Response What about CANCER? Cells transforming to cancerous cells At very low doses, the transformation frequency is below that predicted by linear extrapolation Linear Prediction of Transformation Actual Transformation Transformation Frequency 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. 0 10 20 30 40 50 60 70 80 90 100 Dose (cGy) Redpath et al. 2001 Adaptive Responses for Mice that were exposed to a small “tickle” dose of Leukemia 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 1.0 exposed to high doses of radiation Survival Probability Control died of leukemia died before 600 0.8 days. 0.6 0.4 Adaptive Exposed 0.2 About half of a population of mice are expected to die by the time they 0.0 and are 700 days old,200 usually all die600 0 400 800 1000 before 1000 days. Time (days) Mitchel et al 1999 Lymph Tumors in Mice Although the survival rate was not effected by 1 or 10 cGy radiation exposures, the control 50 group, which did not receive 0 cGy Number of Tumors any radiation, developed more 40 tumors than either of the 1 cGy radiated groups. 30 10 cGy 20 10 0 0 20 40 60 80 100 % Death Lymphomas in Trp53+/- Mice Mitchel et al. 2003 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 0 cGy Number of Tumors 20 1 cGy 15 10 cGy 10 5 0 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 Breast cancer Leukemia Relative Risk 4 All solid tumors 3 2 1 Normal risk without radiation 0 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.