Post on 13-Feb-2022
Introduction to Radiation ChemistryIntroduction to Radiation Chemistry
Mike Robbins, PhDMike Robbins, PhDRadiation Biology SectionRadiation Biology Section
Department of Radiation OncologyDepartment of Radiation OncologyWake Forest University School of MedicineWake Forest University School of Medicine
Ionizing Radiation Can Dissipate Its Ionizing Radiation Can Dissipate Its Energy By Two MethodsEnergy By Two Methods
EXCITATIONEXCITATION
IONIZATIONIONIZATION
ExcitationExcitation
Amount of energy absorbed raises an electron in Amount of energy absorbed raises an electron in an atom/molecule to a higher energy level an atom/molecule to a higher energy level without ejection of the electron. without ejection of the electron.
Occurs following exposure to nonOccurs following exposure to non--ionizing ionizing radiation e.g., UVradiation e.g., UV
IonizationIonization
Occurs when the absorbed radiation has Occurs when the absorbed radiation has enough energy to eject one or more orbital enough energy to eject one or more orbital electrons from the atom/molecule.electrons from the atom/molecule.
Radiation with such energy called ionizing Radiation with such energy called ionizing radiation, e.g., X rays, radiation, e.g., X rays, γγ raysrays
Examples: X rays Examples: X rays ((extranuclearextranuclear) and ) and γγ rays rays ((intranuclearintranuclear))
Can view as either a wave Can view as either a wave of electrical and of electrical and mechanical energy or as mechanical energy or as photons (packets of photons (packets of energy) energy)
Electromagnetic SpectrumElectromagnetic Spectrum
Electromagnetic RadiationElectromagnetic Radiation
Irradiating biological material leads to unequal Irradiating biological material leads to unequal distribution of energy in tissues and cellsdistribution of energy in tissues and cells
With ionizing radiation photons contain With ionizing radiation photons contain sufficient energy to break chemical bonds sufficient energy to break chemical bonds leading to biological effectsleading to biological effects
Ionization and Radical FormationIonization and Radical Formation
Ionization of water leads to generation of an ion pairIonization of water leads to generation of an ion pair
HH22O + radiation O + radiation →→ HH22OO++•• + e+ e--
HH22OO++•• is an ion radical: ion is an atom/molecule that is is an ion radical: ion is an atom/molecule that is electrically charged since has lost an electron.electrically charged since has lost an electron.
Free radical is atom/molecule that possesses one or more Free radical is atom/molecule that possesses one or more unpaired electrons; highly reactiveunpaired electrons; highly reactive
Ionization and Radical FormationIonization and Radical Formation
HH22O O ++•• →→ HH++ + HO+ HO••
ee-- + H+ H22O O →→ ee--aqaq
A hydrogen free radical can also be produced, together with someA hydrogen free radical can also be produced, together with somehydrogen peroxide:hydrogen peroxide:
ee--aqaq + H+ H++ →→ HH••
HOHO•• + HO+ HO•• →→ HH22OO22
Ionization and Radical FormationIonization and Radical Formation
Radiolysis of water:Radiolysis of water:
HH22O + radiation O + radiation →→ ee--aqaq + HO+ HO•• +H+H•• + H+ H22OO22
G values G values 2.63 2.72 0.55 0.682.63 2.72 0.55 0.68
G value: measured yield of molecules produced by absorption of G value: measured yield of molecules produced by absorption of 100 eV X rays. For low LET, highest yields are 100 eV X rays. For low LET, highest yields are ee--aqaq and HOand HO••..
Direct and Indirect Effects of RadiationDirect and Indirect Effects of Radiation
Direct effect: target molecule itself reacts Direct effect: target molecule itself reacts directly with radiationdirectly with radiation
RH RH →→ RHRH++
RHRH++ →→ RR•• + H+ H++
Direct and Indirect Effects of RadiationDirect and Indirect Effects of Radiation
Indirect effect: ionizing radiation generates free radicals Indirect effect: ionizing radiation generates free radicals from the radiolysis of waterfrom the radiolysis of water
These can indirectly form radicals with the target These can indirectly form radicals with the target moleculemolecule
RH + HORH + HO•• →→ RR•• + H+ H22OO
RH + HRH + H++ →→ RR•• + H+ H22
““FixationFixation”” of Biological Injuryof Biological Injury
In the presence of In the presence of oxygen, an organic oxygen, an organic peroxyl radical is peroxyl radical is formed. This cannot formed. This cannot easily be repaired, and easily be repaired, and so acts to so acts to ““fixfix”” the the biological injurybiological injury
RR•• + O+ O22 →→ ROOROO••
TARGET THEORYTARGET THEORYFor bacteria, viruses and For bacteria, viruses and somesome mammalian cell lines, semimammalian cell lines, semi--log log plot of SF vs. dose gives a straight lineplot of SF vs. dose gives a straight line
Unit increase in dose produces a corresponding fractional Unit increase in dose produces a corresponding fractional decrease in survivaldecrease in survival
Shape of curve explained in terms of Target Theory: certain Shape of curve explained in terms of Target Theory: certain critical sites in cells must be hit if the cell is to be killedcritical sites in cells must be hit if the cell is to be killed
Single hit in a single target would give an exponential survivalSingle hit in a single target would give an exponential survivalcurvecurve
SingleSingle--target Single Hit Modeltarget Single Hit Modelprobability of survival probability of survival pp ==
pp (0 hits) = e(0 hits) = e--D/DoD/Do
D = dose applied; DD = dose applied; D00 = dose that = dose that gives an average of 1 hit/targetgives an average of 1 hit/target
A dose of DA dose of D00 will reduce survival will reduce survival from 1 to 0.37 i.e., efrom 1 to 0.37 i.e., e--11, or from 0.1 , or from 0.1 to 0.037, etc.to 0.037, etc.
D/DD/D00 is the average number of is the average number of hits/targethits/target
MultiMulti--event Modelsevent Models
Mammalian cells tend to show a different Mammalian cells tend to show a different responseresponse
At low doses see a shoulder, only see At low doses see a shoulder, only see exponential response at higher dosesexponential response at higher doses
Various multiVarious multi--event models have been event models have been proposedproposed
MultiMulti--target singletarget single--hit Modelhit ModelProposes 2 or more targets in a cell; each Proposes 2 or more targets in a cell; each
must receive a single hit before the cell must receive a single hit before the cell is killed. is killed.
Model is described by the following Model is described by the following equation:equation:
SF SF = 1= 1--(1(1-- ee--D/D0D/D0))nn
where SF is the surviving fraction after a where SF is the surviving fraction after a dose Ddose D
DD00 is the dose needed to reduce cell SF to is the dose needed to reduce cell SF to 1/e (37%) of its initial value on the 1/e (37%) of its initial value on the exponential portion of the survival exponential portion of the survival curve. Also the reciprocal slope of the curve. Also the reciprocal slope of the survival curve, survival curve,
nn is the extrapolation number. is the extrapolation number.
MultiMulti--target singletarget single--hit Modelhit Model
Has proved useful for describing the response of Has proved useful for describing the response of mammalian cells at high dosesmammalian cells at high doses
However, does not describe survival response at However, does not describe survival response at lower more clinically relevant doseslower more clinically relevant doses
Imply zero slope at very low doses; most data show Imply zero slope at very low doses; most data show finite or nonfinite or non--zero initial slopezero initial slope
Two Compartment ModelTwo Compartment ModelCombines the simple multiCombines the simple multi--target target
model with a singlemodel with a single--target target component. component.
This model fits the majority of This model fits the majority of mammalian cell survival curves, mammalian cell survival curves, implies the possibility of both implies the possibility of both single and multisingle and multi--hit events. hit events.
f f = e= e--D/D1D/D1 [1[1--(1(1-- ee--D/D2D/D2)])]nn
where Dwhere D11 and Dand D22 refer to the initial refer to the initial and final slopesand final slopes..
Two Compartment ModelTwo Compartment Model
Disadvantages:Disadvantages:
Changes in cell survival over the range 0Changes in cell survival over the range 0--DDqq occur occur almost linearlyalmost linearly
Implies no sparing of damage at doses per fraction Implies no sparing of damage at doses per fraction less than ~ 2 Gy less than ~ 2 Gy
LinearLinear--Quadratic ModelQuadratic Model
Gives a better description of the Gives a better description of the radiation response of cells in radiation response of cells in the low dose region (0the low dose region (0--3 Gy)3 Gy)
f f = e= e--((ααD +D +ββD2)D2)
Gives a continuously bending Gives a continuously bending survival curve with no straight survival curve with no straight portion at high radiation doses portion at high radiation doses
Shape or bendiness of the curve is Shape or bendiness of the curve is determined by the determined by the αα//ββ ratio; ratio; represents the dose (Gy) at represents the dose (Gy) at which linear contribution to which linear contribution to cell kill equals quadratic cell kill equals quadratic contribution.contribution.
Lethal, potentially Lethal Damage (LPL) ModelLethal, potentially Lethal Damage (LPL) Model
Ionizing radiation produces 2 kinds of lesions: repairable (poteIonizing radiation produces 2 kinds of lesions: repairable (potentially lethal) ntially lethal) lesions and nonlesions and non--repairable (lethal) lesions. repairable (lethal) lesions.
The nonThe non--repairable lesions produce single hit lethal events; linear comrepairable lesions produce single hit lethal events; linear component ponent of cell kill. of cell kill.
The effect of the repairable lesions depends on the competing prThe effect of the repairable lesions depends on the competing processes of ocesses of repair and binary misrepair; leads to quadratic component.repair and binary misrepair; leads to quadratic component.
At higher doses the probability of binary interaction of potentAt higher doses the probability of binary interaction of potentially lethal ially lethal lesions increases.lesions increases.
DNA Damage is the Critical Event in DNA Damage is the Critical Event in RadiationRadiation--induced Cell deathinduced Cell death
Microirradiation studies indicate that to kill cells by irradiatMicroirradiation studies indicate that to kill cells by irradiation the ion the cytoplasm requires much greater doses than the nucleus; >250 Gy cytoplasm requires much greater doses than the nucleus; >250 Gy compared with ~2 Gycompared with ~2 Gy
Isotopes such as Isotopes such as 33H and H and 125125I that emit short range I that emit short range ββ particles, when particles, when incorporated intercellular DNA, efficiently produce radiation ceincorporated intercellular DNA, efficiently produce radiation cell kill ll kill and DNA damageand DNA damage
The incidence of chromosomal aberrations following irradiation iThe incidence of chromosomal aberrations following irradiation is s closely linked to cell kill.closely linked to cell kill.
Thymidine analogues such as IUdr and Thymidine analogues such as IUdr and BrUdrBrUdr when specifically when specifically incorporated into DNA modify radiosensitivity. Substituted incorporated into DNA modify radiosensitivity. Substituted deoxyuridines, which are not incorporated into DNA, have no suchdeoxyuridines, which are not incorporated into DNA, have no suchaffect on cellular radiosensitivity. affect on cellular radiosensitivity.