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Adaptive Response to Low Dose Radiation

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									  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
                                   with just
                 aberrations than is seen. a large dose!
     50                                                      Observed
     40                                                      Expected
              0          0.5         150      0.5 + 150
                               Dose cGy
                                                Shadley and Wolff 1987
Adaptive Response

  What about
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
 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

                                          died of leukemia died before 600
                         0.8                            days.
                         0.4                        Adaptive
About half of a population of mice
are expected to die by the time they
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.
                            10 cGy
                        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.
            0 cGy
Number of Tumors

           1 cGy
          10 cGy
                       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
Relative Risk

                4    All solid tumors

                1    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.

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