1. Biological Effects of Ionizing Radiation Effects of Radiation at the Molecular and Cellular Level Phases of Damage in Irradiated Organism Lecture IAEA Post Graduate Educational Course Radiation Protection and Safe Use of Radiation Sources IAEA Post Graduate Educational Course in Radiation Protection and Safety of Radiation Sources

2. Module III.1 - Effects of Radiation at the Molecular and Cellular Level2 Introduction  This lecture presents phases of damage in irradiated organism and the mechanism of damage at every phase  It covers description of mechanism of direct and indirect effects of radiation, radiation damage at cellular level, cell sensitivity and factors which are modifying the damage of the cells

3. Module III.1 - Effects of Radiation at the Molecular and Cellular Level3 Content  Phases of of damage in irradiated organisms  Direct and indirect effects  Target theory  Cellular level of damage  Radiosensitivity  Factors modifying cell damage

4. Module III.1 - Effects of Radiation at the Molecular and Cellular Level4 Overview Descendents

5. Module III.1 - Effects of Radiation at the Molecular and Cellular Level5 Phases of damage in irradiated organisms  Physical  Physico-chemical  Chemical  Biochemical  Cellular level  Systemic level

6. Module III.1 - Effects of Radiation at the Molecular and Cellular Level6 Physical phase  Timing -  10 –15 s  Interaction between radiation and target atoms results in ionization or excitation  Chemical changes: formation of H 2 O +, H 2 O*, and subexcitation electrons, e -, in local track regions (  0.1  m)

7. Module III.1 - Effects of Radiation at the Molecular and Cellular Level7 Chemical phase  Prechemical stage n Timing ~  10 –15 s to 10 –12 s  Chemical stage n Timing ~  10 –12 s to 10 –6 s

8. Module III.1 - Effects of Radiation at the Molecular and Cellular Level8 Radiolysis of water molecule  Ionisation Radiation + H-O-H H 2 O + + e - H + + OH - H + + OH -  Free radicals Radiation + H-O-H H o + OH o RH + OH o R o H 2 O RH + OH o R o H 2 O

9. Module III.1 - Effects of Radiation at the Molecular and Cellular Level9 Radiolysis of water molecule (Cont’d)  Hydrogen peroxide OH o + OH o H 2 O 2 OH o + OH o H 2 O 2or O 2 + e - O 2 - O 2 + e - O 2 - O 2 - + H + HO 2 O 2 - + H + HO 2 HO 2 + H o H 2 O 2 HO 2 + H o H 2 O 2

10. Module III.1 - Effects of Radiation at the Molecular and Cellular Level10 Types of subcellular effects

11. Module III.1 - Effects of Radiation at the Molecular and Cellular Level11 Indirect actions  H 2 O + + e –  H + + OH o + e –  e - + H 2 O  H 2 O --  OH - + H o  e - + H +  H o  e - + H 2 O  e aq - (solvated electron)

12. Module III.1 - Effects of Radiation at the Molecular and Cellular Level12 Biochemical reactions  Possible targets: n Enzymes n Membranes n Chromosomes sDNA as a primary target for cell damage from ionizing radiation sThe lethal and mutagenic effects of moderate doses of radiation result primarily from damage to cellular DNA

13. Module III.1 - Effects of Radiation at the Molecular and Cellular Level13 Consequences of unrepaired radiation damage to chromosome  Cell survives n With impaired metabolism  Cell death

14. Module III.1 - Effects of Radiation at the Molecular and Cellular Level14 Target theory

15. Module III.1 - Effects of Radiation at the Molecular and Cellular Level15 Cellular level of damage  Radio-induced cell death n Cell necrosis n Apoptosis n Mitotic delay

16. Module III.1 - Effects of Radiation at the Molecular and Cellular Level16 Cell necrosis

17. Module III.1 - Effects of Radiation at the Molecular and Cellular Level17 Apoptosis

18. Module III.1 - Effects of Radiation at the Molecular and Cellular Level18 Cell survival curves  Exponential survival n S(D)/S(0) = exp(-aD) n Bacteria, viruses, mammalian cells: hematopoietic stem cells.  Survival curves with shoulders  Logarithmic dose-effect relation n S(D)/S(0) = exp-(aD + bD 2 ) n Linear and quadratic coefficients

19. Module III.1 - Effects of Radiation at the Molecular and Cellular Level19 Bergonié-Tribondeau Law  Cells are radiosensitive if they: n have a high mitotic rate n have long mitotic future n are less differentiated

20. Module III.1 - Effects of Radiation at the Molecular and Cellular Level20 Radiosensitivity  Importance of understanding: n Predicting the extent of damage to individual tissues and organs n Explanation of immediate effects

21. Module III.1 - Effects of Radiation at the Molecular and Cellular Level21 Mammalian cell sensitivity groups  1. Mature lymphocytes, erythroblasts, & spermatogonia.  2. Granulosa, myelocytes, intestinal crypt cells & germinal. Cells of epidermal layer of skin.  3. Gastric glands, endothelial (lining) cells of small blood vessels.  4. Osteoblasts, chondroblasts, spermatocytes & spermatids.  5. Granulocytes, osteocytes, & sperms.  6. Parenchymal, duct cells of glands, fibroblasts.  7. The relatively radioresistant cells. Connective tissue cells, fibrocytes, reticular cells (fixed hematopoietic stem cells), chondrocytes (cartilage) & phagocytes.  8. Muscle and nerve cells.

22. Module III.1 - Effects of Radiation at the Molecular and Cellular Level22 Modifying factors for radiation damage  Relative biological effectiveness  Oxygen tension  Dose rate  Chemical protective agents  Temperature  Sex  Species

23. Module III.1 - Effects of Radiation at the Molecular and Cellular Level23 Relative Biologic Effectiveness (RBE)  Why it should be characterized?  RBE - given biological criterion for a well-defined effect: n cell survival, chromosomal aberrations, and gene mutations

24. Module III.1 - Effects of Radiation at the Molecular and Cellular Level24 Oxygen effect  Possible explanation: n Oxygen increases in the production of hydrogen peroxide n Oxygen slows down the recombination of certain other radiolytic products and then increase the capacity for damage by extending their effective lifespan  Practical application

25. Module III.1 - Effects of Radiation at the Molecular and Cellular Level25 Dose rate

26. Module III.1 - Effects of Radiation at the Molecular and Cellular Level26 Chemical protective agents  Results of experiments with animals  Agents can reduce the effective dose of radiation by a factor of 1.5 to 2.0 when administered before exposure  More effective to be applied intravenously prior to the exposure  Examples: cysteine, cystamine, and glutathione  Common for them: presence of a sulphydryl group

27. Module III.1 - Effects of Radiation at the Molecular and Cellular Level27 Other modifying factors  Temperature n Increase in radioresistance by lowering an animal’s body temperature  Sex n Females tend to be slightly more resistant than males in many species  Species n The more primitive the species - the more radioresistant the organism

28. Module III.1 - Effects of Radiation at the Molecular and Cellular Level28 Summary  This lecture presented materials about phases of damage in irradiated organism and the mechanism of damage at every phase  The materials of the lecture should be learned at the introductory stage of radiobiology learning  Comments are welcomed

29. Module III.1 - Effects of Radiation at the Molecular and Cellular Level29 Where to Get More Information  Physical and chemical mechanisms in molecular radiation biology. Glass W.A., Varma M.N. Eds, Plenum Press, New York 1991.  Kiefer J. Biological Radiation effects. Springer Verlag, Berlin, Heidelberg 1990; 444.  IAEA Regional Basic Professional Training Course on Radiation Protection, India, 1998. Training Materials.  IAEA Regional Basic Professional Training Course on Radiation Protection, Germany, 1997. Training Materials.