1. IAEA International Atomic Energy Agency Basics of Biological Effects of Ionizing Radiation Lecture Module 1

2. IAEA Biological effects of radiation Ionizing radiations have many beneficial applications, but they also may have detrimental consequences for human health and for environment Since X-rays were discovered in 1895, it was quickly realized that they may be harmful To protect people and the environment it is essential to understand how radiation-induced effects occur 2

3. IAEA Absorbing ionizing radiation What is ionizing radiation? electromagnetic (X and γ- rays) corpuscular (α- and β-particles and neutrons ) A radiation can be considered as ionizing if deposited energy is high enough to ionize the traversed material Types Each type interacts in its own way with material 3

4. IAEA Interactions of ionizing radiation with matter Photons For energies lower than 50 MeV there are three main processes by which photons interact with matter: Photoelectric effect Compton scattering Pair production 4

5. IAEA Photoelectric effect.: incident photon is totally absorbed and ejects electron from atom. This effect dominates with low- energy photons interacting with heavier elements In Compton scattering electron is also ejected, but incident photon survives and is scattered by losing some of its energy. In water or biological tissues, this effect dominates at energies above 50 keV 5

6. IAEA Pair production is process in which its energy is converted into electron-positron pair. This interaction starts occurring at energies higher than 1 MeV. Unlike electron, positron will eventually disappear annihilating one electron of surrounding material. Positron-electron pair is converted into two photons with energy of about 0.5 MeV 6

7. IAEA Neutrons Neutrons interact with nuclei (elastic and inelastic diffusion, nuclear reactions, captures), and produce emission of secondary charged particles (like protons, alpha particles or nuclear fragments heavier than carbon, oxygen, nitrogen or hydrogen) which are responsible for tissue ionization and for biological effect + elastic diffusion with production of proton and another neutron + + - collision with nucleus with the production of various charged particles: protons, nuclear fragments, electrons 7

8. IAEA Charged Particles These interact with nuclei (nuclear interactions) and to greater extent with electrons (electronic interactions) As they slow down energy deposited per depth unit (or LET) increases until particle comes to halt, and there is sudden peak of energy (Bragg peak) Relative ionization with depth 8

9. IAEA Radioactive decay is process by which atomic nucleus of unstable atom loses energy by emitting ionizing particles (ionizing radiation) Radioactive decay is stochastic process at level of single atoms and chance that given atom will decay is constant over time, so that given large number of identical atoms (nuclides), the decay rate for collection is predictable to extent allowed by law of large numbers Important measure is the ACTIVITY SI unit of activity is becquerel (Bq). 1 Bq is defined as one transformation (or decay) per second. Former unit of radioactivity was curie (Ci): 1 Ci is equal to 3.7 × 10 10 Bq Units of radioactivity 9

10. IAEA Images from: http://www.flickr.com/photos/mitopencourseware Cobalt-60 decay emitting a b - particle Examples of radioactive decay Radium-26 decay emitting an a - particle 10

11. IAEA Number of radioactive atoms decreases by exponential decay Image from: http://www.flickr.com/photos/mitopencourseware 11

12. IAEA Quantities used in radiation studies Amount of radiation producing effect is specified as energy deposited per unit mass in irradiated material. This is absorbed dose (D) Where  is energy absorbed in mass  m. This is measured as J/kg and SI unit is gray (Gy) 12

13. IAEA However, each type deposits its energy in different way Low-LET High-LET  -,  -particles and neutrons and densely ionizing radiations. The energy is distributed inhomogeneously X and  -rays are sparsely ionizing radiations Energy is distributed homogeneously Linear energy transfer (LET) is measure of energy transferred by ionizing particle to traversed material. This measure is typically used to quantify effects of ionizing radiation on biological specimens and is usually expressed in units of keV/µm 13

14. IAEA High LET radiation types are more efficient in producing damage To normalize the Relative Biological Effectiveness is used 14

15. IAEA Relationship between RBE and LET 15

16. IAEA Equivalent absorbed radiation dose (equivalent dose) - computed average measure of radiation absorbed by fixed mass of biological tissue accounts for different biological damage potential of different types of ionizing radiation on different organs, considering differences in their RBE Equivalent dose is a judged quantity for assessing health risk of radiation exposure Equivalent Dose 16

17. IAEA Equivalent dose cannot be measured directly. Dose for each tissue T and each type of radiation R (often denoted by HT,R) is calculated by: H T,R = Q x D T,R where D T,R is total energy of radiation absorbed in unit mass of tissue T, and Q is radiation quality factor that depends on type and energy of that radiation. Quality factor is related to relative biological effectiveness of radiation SI unit for equivalent dose is severt (Sv) - dose of absorbed radiation, in Gy, that has same biological effect as dose of one joule of gamma rays absorbed in one kilogram of tissue Sv has replaced the previous unit rem (roentgen equivalent man): 100 rem = 1 Sv Equivalent Dose 17

18. IAEA Radiation quality or weighting factors Radiation Type EnergyW (ICRP-60)W (ICRP-92) Photonsall11 Electrons, muons all11 Neutrons<10 keV5function Neutrons10-100 keV10function Neutrons>100 keV- 2Mev20function Neutrons>2 -20 MeV10function Neutrons>20Mev5function Protons<2 MeV52 α-particles, fission fragments all20 ICRP-60 (1991), ICRP-92 (2004) 18

19. IAEA Chromosomal structure Association of DNA and histones in nucleosome structure has been demonstrated in considerable detail. DNA is external to the histone core of nucleosome. Some studies support existence of axial core structure formed by non-histone proteins or non-histone protein scaffold in metaphase chromosome 19

20. IAEA Human karyotype Human karyotype - characteristic complement for humans, and consists of 23 pairs of large linear chromosomes of different sizes, giving total of 46 chromosomes in every diploid cell. Human chromosomes are normally combined into seven groups from A to G plus pair of sex chromosomes X and Y. Chromosomal groups are: A:1-3, B: 4 and 5, C: 6 -12, D: 13-15, E: 16-18, F: 19 and 20 and G: 21 and 22. Male Female 20

21. IAEA Energy deposited in and near DNA Ionizing radiation produces discrete energy deposition events in time and space DNA is damaged directly and indirectly by generation of reactive species mainly produced by radiolysis of water 21

22. IAEA Direct action of radiation is dominant process for high–LET, such as neutrons or α-particles For low-LET radiation, direct action represents about 20%, and indirect action is about 80%. Radiolysis of water produces free radicals (atoms or molecules with unpaired electrons that are highly reactive). Free radicals are usually denoted by a dot ( ) Radiolysis of water generates water radical and electron (1). Electron may still have enough energy to cause further ionizations in neighbourhood. Ionizing radiation can also cause excitation events (2) H2OH2OH 2 O + + e - (1) H2OH2OH2O*H2O* (2) 22

23. IAEA Water radical cation is very strong acid that loses proton to neighbouring water molecule and forms OH radical which is oxidizing agent (3, 4), that is probably the most damaging radical H 2 O + H 3 O + + OH(3)+ H 2 O H 2 O + OH + H + (4) Electron becomes hydrated by water (5) and electronically excited water can decompose into OH and H (6). So, three kinds of free radicals are initially formed OH, H, and e - aq + H 2 Oe-e- (5)e - aq H2O*H2O* (6) OH + H Globally, and after further reactions, radiolysis of water in presence of oxygen produces: OH, e - aq, H, O 2 -, H 2 O 2, H 2. 23

24. IAEA Low-LET radiation can produce localized cluster of ionizations within single electron track High-LET radiation produces somewhat larger number of ionizations that are closer together Damage in DNA 24

25. IAEA Estimation of numbers of radiation - induced different types of DNA lesions after 1 Gy irradiation with low-LET radiation Types of DNA lesions 25

26. IAEA Cell has complex signal transduction, cell-cycle checkpoint and repair pathways to respond to DNA damage 26

27. IAEA Cell cycle and checkpoints 27

28. IAEA DSB are critical DNA lesions. Their mis-repair or non-repair leads to formation of aberrations like dicentrics. There are two main mechanisms to repair DSB: Homologous recombination (HR) and non-homologous end-joining (NHEJ) Two mechanisms operate in different phases of cell cycle. NHEJ occurs mainly in the quiescent G 0 phase and during cell cycle in G 1 but can also occur in later phases. HR can occur only when DNA is replicated, in S and G 2 phase. 28

29. IAEA Non-homologous end joining 29

30. IAEA 30