Introduction to Radiobiology Lesson 1

Transcription

1 Introduction to Radiobiology Lesson 1 Master of Advanced Studies in Medical Physics A.Y Edoardo Milotti Physics Dept. University of Trieste

2 Radiation damages all kinds of human tissues both healthy and diseased as well as other materials An area of ulceration on the hand, caused by exposure to radiation therapy Edoardo Milotti - Radiobiology 2

3 Aim of radiotherapy: destroy cancer cells, limit damage to healthy tissues The purpose of these lessons is twofold: 1. gain a basic knowledge of the phenomenology of radiation damage to tissues 2. understand the optimization of therapy, based on the concept of maximum damage to cancer cells, minimum damage to healthy tissues Edoardo Milotti - Radiobiology 3

4 Tissues are difficult, material science is easy, so let s start with materials. Consider graphite in nuclear reactors The Windscale (Sellafield) nuclear power plant, where the worst nuclear accident in the UK took place in The accident was due to uncontrolled energy release from the graphite in the reactor. Edoardo Milotti - Radiobiology 4

5 Nuclear reactors and the Wigner Effect The Windscale accident was due to uncontrolled energy release from graphite in the nuclear reactor. Wigner energy occurs in graphite under neutron irradiation because atoms are displaced from their normal lattice positions into configurations of higher potential energy (on average this corresponds to ~ 25 ev per displaced atom). Graphite unit cell Edoardo Milotti - Radiobiology 5

6 a A single b Di-interstitial (C 2 ) a (C 2 ) 2 interstitials b Equilibrium positions of di-interstitials The hexagonal structure of graphite Figure 2.2 The structure of graphite and the formation of interstitials (from Simmons 1965 and Kelly 1981) Edoardo Milotti - Radiobiology 6

7 Fast neutrons undergo a series of collisions and produce displacement cascades Primary knock-on atom Fast neutron Vacant Lattice sites X Displaced atoms Figure 2.1 Distribution of displaced atoms and vacant lattice sites (from Simmons 1965) A 1 MeV neutron produces on average about 900 displacements Not all displacements produce defects, as a displaced C can fill a vacancy The interstial atom-vacancy pairs are called Frenkel defects Edoardo Milotti - Radiobiology 7

8 The quantity of accumulated stored energy is a function of fast neutron flux, irradiation time, and temperature. The higher the irradiation temperature, the lower is the amount of stored energy. In all cases, a saturation point may be achieved in terms of the total amount of stored energy for long periods of irradiation. The maximum amount of stored energy ever found in a graphite sample is ~2,700 J/g, which if all released at once could theoretically lead to a temperature rise of approximately 1500 C assuming adiabatic conditions. The Wigner effect has been known for a long time, and in reactors that use graphite as a moderator there are established procedures to periodically release the stored energy with annealing cycles. Edoardo Milotti - Radiobiology 8

9 Energy released by irradiated graphite as temperature increases Energy release with temperature Irradiatio n tem peratu re 200 C Annealing tem perature ( C) Figure 2.4 Schematic annealing spectra for graphite (from Simmons 1965) Edoardo Milotti - Radiobiology 9

10 Radiation damage in materials Radiation damage in CR-39 plastic Fig. 3. Typical pictures of etched track pits caused by two di erent particles. (a) 5.4-MeV particles (b) 0.9-MeV protons. CR-39 dosimeter Edoardo Milotti - Radiobiology 10

11 Radiation damage to plastic scintillators Edoardo Milotti - Radiobiology 11

12 Radiation damage to human tissues is different from damage in inert material 1. Damage mechanisms are different 2. Cells and tissues have (limited) self-repair capabilities In these lessons we are going to learn about both topics Edoardo Milotti - Radiobiology 12

13 Ionizing radiation Table I: Comparison of Ionizing Radiation Characteristic Alpha (α) Proton (p) Radiation (E K = 1 MeV) Beta (β) or Electron (e) Photon (γ or X ray) Neutron (n) Symbol α or He p or H 0 1e or β 0 0 γ 0 1 n Charge neutral neutral Ionization Direct Direct Direct Indirect Indirect Mass (amu) Velocity (cm/sec) c= Speed of Light 2.3% 4.6% 94.1% 100% 4.6% Range in Air 0.56 cm 1.81 cm 319 cm 82,000 cm* 39,250 cm* * range based on a 99.9% reduction Edoardo Milotti - Radiobiology 13

14 Alpha particle (He nucleus) easily stopped, small penetration, very damaging Beta particle (electron) longer penetration, less damaging Gamma ray and X-ray localized ionization, less damaging Edoardo Milotti - Radiobiology 14

15 Energy loss by ionization/excitation de/dx Edoardo Milotti - Radiobiology 15

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20 The Bragg peak de dx x(e) = Z E0 E dx de de Bragg curve of 5.49 MeV alpha particles in air. This radiation is produced from the initial decay of radon ( 222 Rn). Stopping power (which is essentially identical to LET) is plotted here versus particle range. (Adapted from the Wikipedia article Edoardo Milotti - Radiobiology 20

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22 (adapted from and ) Edoardo Milotti - Radiobiology 22

23 Stopping power or LET (Linear Energy Transfer)? Same definition BUT... de dx Stopping power includes only the ionization losses of individual charged particles. LET is the energy released in tissues per unit track length per particle by a beam of particles, and includes secondary particles as well. In contrast to the stopping power, which has a typical unit of MeV/cm, the unit reserved for the LET is kev/µm. Edoardo Milotti - Radiobiology 23

24 Alpha particle (He nucleus) easily stopped, small penetration, very damaging Beta particle (electron) longer penetration, less damaging Gamma ray and X-ray localized ionization, less damaging Edoardo Milotti - Radiobiology 24

25 Stopping power vs. LET An ionizing particle produces ion/electron pairs along the track and loses energy, and the Bethe formula gives the mean energy loss per unit length. Stopping power also includes interactions with nuclei that are neglected in the definition of LET LET is defined so as to include neutral particles as well. Photons, and other neutral particles, produce ion/electron pairs only when they are absorbed; in this case the mean energy loss per unit length is the average due to secondary charged particles kicked off by the absorbed neutral particles. The secondary particles interact in turn and produce tubes of excited and ionized molecules. - + Edoardo Milotti - Radiobiology

26 Typical LET values (in tissue or tissue-like material) Edoardo Milotti - Radiobiology 26

27 Track structure (example, low-energy electrons) Edoardo Milotti - Radiobiology 27

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29 electrons in water Ionizations excitations Edoardo Milotti - Radiobiology 29

30 α particles Ionizations excitations Edoardo Milotti - Radiobiology 30

31 Carbon ions Ionizations excitations Edoardo Milotti - Radiobiology 31

32 Water radiolysis and production of ROS (Reactive Oxygen Species) For indirect action of x rays the chain of events from the absorption of the incident photon to the final biological damage is as follows: Typical time scale involved in these 5 steps: Incident x-ray photon Fast electron or positron Ion radical Free radical Breakage of bonds Biological effect (1) The physics of the process takes of the order of s. (2) The ion radicals have a lifetime of the order of s. (3) The free radicals have a lifetime of the order of 10-5 s. (4) The step between the breakage of bonds and the biological effect may take hours, days or years. Edoardo Milotti - Radiobiology 32

33 Molecular oxygen and the superoxide anion Oxygen molecule: double bond hides the electrons Superoxide anion: added electron forces the other atom to display an unpaired electron. Edoardo Milotti - Radiobiology 33

34 ygen in the air ( I ), and e of this important elethis, and onk of the best 2and 10 parts MnOn (by volved in a gas j& by ). s very reactive. Not only me when dropped into hurn when dropped into of course close to that of equires oxygen, water, xygen condenses into a emarkable property: it This property of heing aramagnetism, is found ontains unpaired elecs about the behavior of whether the bonding n the diatomic molecule Flgve 1. Energy level diagram of the O2 molecule (ground state blplet form. 3Z)drawnto scale, wlth wbltal energies measuredby photmlecbonspectroccopy. Note the two unpaired electrons of parallel spin that occupy the two w' antibonding wbltals (AB). (Energies are In k J I m l X 100). del for diatomic mole- 1shows the energy level f electrons are assigned orbitals (BO), and one wo r* antihondine orbiving their spins p&allel e two electrons obev the energy" rule, andthey he 0 2 molecule has two tic. This explanation of he great triumph of the ing the two electrons to Figwe 2. (lefl) Schematle energy level dlagam of me oxygen molecule in the more stable slnglet state, 'A. This form lies 94.7 kj (7882 cm-', 1269 nm) in energy above the blplet ground state. Figure 3. (rlgm) Smematloenergy level diagram of the oxygen molecule In the Edoardo Milotti - Radiobiology second (and less sable) singlet state '2.This state lies 158 kj (13120 cm-'. 34

35 The superoxide anion is highly reactive and toxic Human cells use the superoxide anion to kill bacteria. The enzymes of the complex NADPH oxidase (NOX) produce superoxide. The absence of NADPH oxidase leads to the chronic granulomatous diseases. The superoxide anion is toxic to human cells, and this requires mechanisms to get rid of it, like the enzyme superoxide dismutase. Edoardo Milotti - Radiobiology 35

36 Main types of ROS Electron structures of common reactive oxygen species. Each structure is provided with its name and chemical formula. The designates an unpaired electron. Edoardo Milotti - Radiobiology 36

37 Physical stage (time < s) This involves the ionization and the excitation of water molecules Edoardo Milotti - Radiobiology 37

38 Physico-chemical stage (time s s) The ionized and excited molecules produced in the physical stage are highly unstable, and they transfer their energy by dissipating it on neighboring molecules and by breaking chemical bonds. Proton transfer to a neighboring water molecule leads to the production of OH radicals (i.e., and ion with an unpaired electron; radicals are usually quite reactive). + + H 2 O + H 2O OH + H 3O Edoardo Milotti - Radiobiology 38

39 Physico-chemical stage (time s s) /ctd. Moreover there are several channels for the dissociation or the deexcitation of the excited water molecule + H O * 2 H * H 2 O H 2 + * H O 2 H 2 + OH 1 O ( D ) 3 O ( P ) atomic oxygen, singlet state atomic oxygen, triplet state * 2 H O H 2O de-excitation by heat loss Edoardo Milotti - Radiobiology 39

40 Physico-chemical stage (time s s) /ctd. Secondary electrons also behave as a new individual species and they become hydrated e e th e tr e aq Edoardo Milotti - Radiobiology 40

41 Non-homogeneous chemical stage (time s 10-6 s) At the end of the physico-chemical stage, the species H, OH, H 2, H 2 O 2 are created in very high concentration in the spurs. Other species such as O( 3 P) may also be present in small quantity. They diffuse in the medium and eventually encounter chemical species created in other spurs, which gives them the opportunity to react. In general, the radicals such as H, OH and e -aq react in 1 μs to form the molecular species H 2 and H 2 O 2. For example, H 2 O 2 is formed by the reaction OH + OH H 2 O 2 Another important reaction is H + OH H 2 O, which forms water. Edoardo Milotti - Radiobiology 41

42 Chemical reactions table Reactions H. +H. H 2. OH+. OH H 2 O 2 H 2 O 2 +e aq OH +. OH H + +O.. 2 HO 2 H. +. OH H 2 O. OH+H 2 O 2 HO. 2 +H 2 O H 2 O 2 +OH HO 2 +H 2 O H + +HO 2 H 2 O 2 H. +H 2 O 2 H 2 O+. OH. OH+H 2 H. +H 2 O H 2 O 2 +O( 3 P) HO OH H + +O.. OH H. +e aq H 2 +OH. OH+e aq OH H 2 O 2 +O. HO. 2 +OH OH +HO. 2 O. 2 +H 2 O H. +OH H 2 O+e aq. OH+OH O. +H 2 O H 2 +O( 3 P) H. +. OH OH +O( 3 P) HO 2 H.. +O 2 HO 2. OH+HO. 2 O 2 +H 2 O H 2 +O. H. +OH HO. 2 +O( 3 P) O 2 +. OH H. +HO. 2 H 2 O 2. OH+O. 2 O 2 +OH e aq+e aq H 2 +2OH. HO. 2 +HO. 2 H 2 O 2 +O 2 H. +O. 2 HO 2. OH+HO 2 HO. 2 +OH e aq+h + H. HO. 2 +O. 2 HO 2 +O 2 H. +O( 3 P). OH. OH+O( 3. P) HO 2 e. aq+o 2 O 2 HO 2 +O( 3 P) O OH H. +O. OH. OH+O. HO 2 e aq+ho. 2 HO 2 O( 3 P)+O( 3 P) O 2 The end result of the radiolysis of water leads to radiochemical species Edoardo Milotti - Radiobiology 42

43 Time-dependent cross sections of the nonhomogeneous spatial distributions of the main radiolytic species (e aq,.oh, H., H 2, and H 2 O 2 ) in liquid water exposed to 24-MeV 4 He 2+ ions from 1 ps to 10 µs. Adapted from I. Plante and J.-P. Jay-Gerin: Monte-Carlo step-by-step simulation of the early stages of liquid water radiolysis: 3D visualization of the initial radiation track structure and its subsequent chemical development, Journal of Physics: Conference Series 56 (2006) Edoardo Milotti - Radiobiology 43

44 Chemical development of a 4-keV electron track in liquid water, calculated by Monte Carlo simulation. Each dot in these stereo views gives the location of one of the active radiolytic species, OH, H 3 O +, e aq, or H, at the times shown. Note structure of track with spurs, or clusters of species, at early times. After 10 7 s, remaining species continue to diffuse further apart, with relatively few additional chemical reactions. (Adapted from James E. Turner: Atoms, Radiation, and Radiation Protection, 3 rd ed. Wiley 2007) Edoardo Milotti - Radiobiology 44

45 Chemical development of a 4-keV electron track in liquid water, calculated by Monte Carlo simulation. Each dot in these stereo views gives the location of one of the active radiolytic species, OH, H 3 O +, e aq, or H, at the times shown. Note structure of track with spurs, or clusters of species, at early times. After 10 7 s, remaining species continue to diffuse further apart, with relatively few additional chemical reactions. (Adapted from James E. Turner: Atoms, Radiation, and Radiation Protection, 3 rd ed. Wiley 2007) Edoardo Milotti - Radiobiology 45

46 Chemical development of a 4-keV electron track in liquid water, calculated by Monte Carlo simulation. Each dot in these stereo views gives the location of one of the active radiolytic species, OH, H 3 O +, e aq, or H, at the times shown. Note structure of track with spurs, or clusters of species, at early times. After 10 7 s, remaining species continue to diffuse further apart, with relatively few additional chemical reactions. (Adapted from James E. Turner: Atoms, Radiation, and Radiation Protection, 3 rd ed. Wiley 2007) Edoardo Milotti - Radiobiology 46

47 Chemical development of a 4-keV electron track in liquid water, calculated by Monte Carlo simulation. Each dot in these stereo views gives the location of one of the active radiolytic species, OH, H 3 O +, e aq, or H, at the times shown. Note structure of track with spurs, or clusters of species, at early times. After 10 7 s, remaining species continue to diffuse further apart, with relatively few additional chemical reactions. (Adapted from James E. Turner: Atoms, Radiation, and Radiation Protection, 3 rd ed. Wiley 2007) Edoardo Milotti - Radiobiology 47

48 Track of a 300 MeV 12 C 6+ ion, from ~10-12 to ~10-6 s, front view Each dot represents a radiolytic species. The changes in color indicate chemical reactions. from Edoardo Milotti - Radiobiology 48

49 Track of a 300 MeV 12 C 6+ ion, from ~10-12 to ~10-6 s, side view Each dot represents a radiolytic species. The changes in color indicate chemical reactions. from Edoardo Milotti - Radiobiology 49

50 G value: number of a given species produced per 100 ev of energy loss by the original charged particle and its secondaries, on the average, when it stops in the water. Table extracted from Turner: Atoms, Radiation, and Radiation Protection Edoardo Milotti - Radiobiology 50

51 G value: number of a given species produced per 100 ev of energy loss by the original charged particle and its secondaries, on the average, when it stops in the water. Table extracted from Turner: Atoms, Radiation, and Radiation Protection Edoardo Milotti - Radiobiology 51

52 Exercise: If a 20-keV electron stops in water and an average of 352 molecules of H 2 O 2 are produced, what is the G value for H 2 O 2 for electrons of this energy? G value: number of a given species produced per 100 ev of energy loss by the original charged particle and its secondaries, on the average, when it stops in the water. Edoardo Milotti - Radiobiology 52

53 Exercise: If a 20-keV electron stops in water and an average of 352 molecules of H 2 O 2 are produced, what is the G value for H 2 O 2 for electrons of this energy? Answer: 20 kev/100 ev = 200 therefore G = 352/200 = 1.76 G value: number of a given species produced per 100 ev of energy loss by the original charged particle and its secondaries, on the average, when it stops in the water. Edoardo Milotti - Radiobiology 53

54 Electrons, protons, and alpha particles all produce the same species in local track regions at s: H 2 O +, H 2 O, and subexcitation electrons. The chemical differences that result at later times are presumably due to the different spatial patterns of initial energy deposition that the particles have. Edoardo Milotti - Radiobiology 54

55 Table 13.3 G Values (Number per 100 ev) for Various Species in Water at 0.28 µsforelectronsatseveralenergies Electron Energy (ev) Species ,000 20,000 OH H 3 O e aq H H H 2 O Fe Edoardo Milotti - Radiobiology 55

56 Homework A 50 cm 3 sample of water is given a dose of 50 mgy from 10-keV electrons. If the yield of H 2 O 2 is G = 1.81 per 100 ev, how many molecules of H 2 O 2 are produced in the sample? Edoardo Milotti - Radiobiology 56

57 The radiolysis of water damages metals, what do the radiolytic species do to cells and organisms? Radiobiology is a branch of science which combines basic principles of physics and biology and is concerned with the action of ionizing radiation on biological tissues and living organisms. Ionizing radiation acts at the molecular and cellular level, while in this Master s course we are interested in the medical issues: in this Radiobiology course we try to understand how the action of radiation at the microscopic level affects human health Edoardo Milotti - Radiobiology 57

58 Next step, study the effects of ionizing radiation on individual cells. To this end we need to know cells first. Edoardo Milotti - Radiobiology 58