Basics of Biological Effects of Ionizing Radiation

1. Basics of Biological Effects of Ionizing Radiation Lecture Module 1

2. 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

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

4. 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

5. Photoelectric effect.: incident photon is totally absorbed and ejects electron from atom. This effect dominates with low-energy photons interacting with heavier elements InCompton 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

6. 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

7. 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

8. ChargedParticles • 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

9. Units of radioactivity 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 × 1010 Bq

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

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

12. 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)

13. However, each type deposits its energy in different way 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 High-LET Low-LET • X and -rays are sparsely ionizing radiations • Energy is distributed homogeneously • -,-particles and neutrons and densely ionizing radiations. • The energy is distributedinhomogeneously

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

15. Relationship between RBE and LET

16. Equivalent Dose • 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

17. Equivalent Dose • 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: • HT,R = Q x DT,R • where DT,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

18. Radiation quality or weighting factors ICRP-60 (1991), ICRP-92 (2004)

19. Chromosomalstructure 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

20. 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

21. 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

22. Direct action of radiation is dominant process for high–LET,such as neutrons or α-particles • For low-LETradiation, direct action represents about 20%, andindirect 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) H2O H2O•+ + e- (1) H2O H2O* (2)

23. 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 H2O •+ + H2O H3O+ + •OH (3) H2O •+ •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 e- + H2O e- aq (5) H2O* (6) •OH + H• • Globally, and after further reactions, radiolysis of water in presence of oxygen produces: •OH, e- aq, H• , O2 •-, H2O2, H2.

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

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

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

27. Cellcycle and checkpoints

28. DSB are critical DNA lesions. Their mis-repair or non-repair leads to formation of aberrations likedicentrics. 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 G0 phase and during cell cycle in G1 but can also occur in later phases. HR can occur only when DNA is replicated, in S and G2 phase.

29. Non-homologous end joining