chapter 34 principles of radiobiology in 1906, two french scientists, bergonie and tribondeau,...
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Chapter 34 Principles of Radiobiology
• In 1906, two French scientists, Bergonie and Tribondeau, theorized and observed that radiosensitivity was a function of the metabolic state of the tissue being irradiated. There observations became the
• Law of Bergonie & Tribondeau
Law of Bergonie & Tribondeau
• Stem cells are radiosensitive; mature cells are radio-resistant.
• Younger tissues and organs are radiosensitive.
• Tissues with high metabolic activity are radiosenstive.
• High proliferation rate for cells and high growth rate for tissues result in increased radiosensitivity.
Law of Bergonie & Tribondeau
• Basically it states that radiosensitivity of living tissue varies with maturity and metabolism.
• In diagnostic imaging the law serves to remind us that a fetus is considerably more sensitive to radiation exposure than a child or mature adult.
Physical factors Affecting Radiosensitivity
• When tissue is irradiated, the response of the tissue is determined principally by the amount of energy deposited per unit of mass: the dose in Rads (Gy).
• Even under controlled conditions, the response to like exposure may be different.
Physical factors Affecting Radiosensitivity
• Physical property factors
• Linear energy transfer (LET)
• Relative Biological Effectiveness (RBE)
• Fractionation and Protraction
Linear Energy Transfer
• The rate which energy is transferred from ionization to soft tissue is the (LET).
• It is another method of expressing radiation quality and determining the value of the tissue weight factor used in radiation protection.
• It is expressed in the units of kiloelectron volts of energy transferred per micrometer in soft tissue.
Linear Energy Transfer
• The ability of ionizing radiation to produce a biologic response increases as the LET of the radiation increases.
• The LET of diagnostic x-rays is approximately 3 keV/µm.
Relative Biologic Effectiveness
• As the LET of the radiation increases, the ability to produce biologic damage also increases. This quantification is referred to as the Relative Biologic Effects (RBE).
• The RBE of diagnostic x-ray is 1. • Radiations with a lower LET will have a
RBE of less than 1.• Radiations with a higher LET will have a
RBE greater than 1.
The LET & RBE of Various Radiations
Type of Radiation LET RBE
25 MV x-rays 0.2 0.860Co gamma rays 0.3 0.9
1MeV electrons 0.3 0.9
Diagnostic X-ray 3.0 1.0
10 MeV protons 4.0 5.0
Fast Neutrons 50.0 10
5 MeV Alpha Particles
100.0 20
LET & RBE Graph
• As the LET increases, the RBE also increases but a maximum level is reached followed by a reduction due to overkill.
Fractionation & Protraction
• If the dose is administered over a long time rather than quickly, the effects of that dose will be less.
• If the time of irradiation is lengthened, a higher dose is required to produce the same effect.
• Dose protraction and fractionation cause less effect allowing time for intracellular repair and tissue recovery.
Protraction
• If we give an exposure of 600 rads at 300 rads/minute, the effects will be less than if the same exposure is given at 600 rads/ minute. This us called protraction.
Fractionation
• If that 600 rads is given at 150 rad per day over 4 days, the effects would be less than 600 rads given over 1 day.
• This is called fractionation.
Biologic Factors Affecting Radiosensitity
• Oxygen Effect: Tissue is more sensitive to radiation if the tissue is oxygenated or aerobic state than when irradiated in the anoxic ( w/o oxygen) or hypoxic state (low oxygen) state.
• The characteristic of tissue is described numerically as the Oxygen Enhancement Ratio. (OER)
Biologic Factors Affecting Radiosensitity
• Oxygen Enhancement Effect for diagnostic x-ray is full oxygenation.
• The OER is LET dependent. The OER for highest for low LET radiation having a maximum value of approximately 3, decreasing to 1 for high LET radiation.
Oxygen Enhancement Ratio
• The OER is high for low LET radiation and decreases as the LET increases.
Biologic Factors Affecting Radiosensitity
• Age affects the biologic structure’s radiosensitivity. Humans are most sensitive before birth.
• Sensitivity decreases until maturity.
• In old age, sensitivity increases again.
Biologic Factors Affecting Radiosensitity
Recovery: If the dose of radiation is sufficient to kill the cell before its next division, interphase death will occur.
• If the dose is sub lethal, the cell may recover from the damage.
• Some cell types are more capable of recovery.
Biologic Factors Affecting Radiosensitity
• Recovery: At the whole body level, recovery is assisted by repopulation by the surviving cells.
• If the tissue or organ receives a sufficient dose, it will respond by shrinking in size. This is called atrophy.
• Atrophy happens because cells die, disintegrate and are carried away as waste.
Recovery
• Recovery = Intracellular Repair+ Repopulation
• Some chemical agents can modify radiation response.– Radiosensitizers enhance the effects– Radioprotectors reduce the effects
Radiosensitizers
• Agents that enhance the effects of radiation are radiosensitizers. Example include:– Halogenated pyrimidines that become
incorporated in the cell DNA and effectively double the effect of the radiation.
– Vitamin K
• Must be present at the time of irradiation.
Radioprotectors
• Radio protector agents exist but have not found any human application. They must be given in toxic levels to be effective.
• The protective agent can be worse than the radiation.
Hormesis
• There is a growing body of radiobiologic evidence that suggest that a little bit of radiation is good for you.
• Studies have shown that animals live longer lives when they receive low radiation doses.
Hormesis
• The prevailing explanation is that a little radiation stimulates hormonal and immune responses to toxic environmental agents.
• Regardless of Hormesis, we still practice ALARA as a known safe response to radiation safety.
Radiation Dose-Response Relationships
• Radiobiology is a relatively new science. Interest increased in the 1940’s with the advent of the atomic age.
• The object of nearly all of the research is the establishment of radiation dose-response relationships.
Radiation Dose-Response Relationships
• Radiation Dose-Response Relationships have two important functions.– Designing therapeutic treatment routines for
patients with cancer.– Provide information on the effects of low dose
irradiation.
Radiation Dose Response Relationship Characteristics
• Every exposure has two characteristics. It is either:– Linear
• Threshold or• Non-Threshold
– Non-Linear• Threshold or• Non-Threshold
Linear Dose-Response Relationship
• Radiation-induced cancer and genetic effects follow a linear, nonthreshold dose response relationship.
• Any exposure above zero is expected to cause some response.
• Exposure can also be a linear threshold type where the dose axis is greater than zero.
Linear Dose-Response Relationship
• Linear dose graphs have a straight line graph starting at zero for nonthreshold exposures or at a point greater than zero for threshold exposures.
Non-Linear Dose Response
• All other radiation dose response relationships are defined as non-linear.
• If the dose response curve starts at zero, it has a nonthreshold.
• The shape of the curve will determine the rate of response.
Non-Linear Dose Response
• Radiation death and skin effects of high dose fluoroscopy follow a sigmoid-type dose relationship.
• At exposure levels below where the graph threshold, no effect had been identified.
• The point where the curve stops bending up is the inflection point.
Non-linear Dose Response
• Above the inflection point, the incremental dose increase becomes less effective.
• Dose response graphs are used to discuss the type and degree of radiation injury.
Non-Linear Dose Response
• In diagnostic exposures it is most exclusively concerned with late effects and therefore with linear non-threshold dose response relationships.
• The principle interest in diagnostic responses to very low level exposures.
Linear Non-threshold Dose Response
• Since this cannot be done directly, the dose response is extrapolated from known high dose exposures using the linear response graphs.
Exposure to Diagnostic X-ray
• Diagnostic x-ray is usually and primarily concerned with the late effects of radiation exposure.
• The existence of radiation hormesis is highly controversial. Regardless of it’s existence, no human response has been observed following doses less than 10 rad (100 mGy).
Chapter 35 Molecular & Cellular Radiobiology
• When macromolecules are irradiated in vitro( outside the body) it take a considerable amount of radiation to produce a measurable effect.
• Irradiation in vivo (inside the body) in a living cell in solution, macromolecules are considerably more radiosensitive in their natural state.
Results of irradiation of macro-molecules.
• There are three major results of irradiation of macro-molecules in solution:– A-Main chain Scission– B- Cross linking– C- Point lesions
Main Chain Scission
• Main-chain scission is the breakage of the backbone of the long chain macro-molecules.
• This results in many smaller molecules which still may be macro-molecules.
Main Chain Scission
• This not only changes the size of the molecule but the viscosity of the solution also increases.
• Measurement of the viscosity determines the degree of main chain scission.
Cross Linking
• B- Cross Linking• Some macro-molecules
have small spur like side structures extending off the main chain.
• Other produce the spurs as a result of irradiation.
Cross Linking
• These structures can behave as though they had a sticky substance on end.
• They can attach to other macro-molecules or another segment of the same molecule.
• Also increases viscosity of the solution.
Point Lesions
• Radiation interaction can also result in disruption of a single chemical bond.
• Such point lesions are not detectable but can result in minor modifications to the cell that can cause it to malfunction.
Point Lesions
• Radiation interaction can also result in disruption of a single chemical bond.
• Such point lesions are not detectable but can result in minor modifications to the cell that can cause it to malfunction.
Point Lesions
• At low radiation doses, point lesions are considered to be the cellular radiation damage resulting in the late effects observed at the whole body level.
Irradiation of Macro-molecules
• Laboratory experiments have shown that all these types of radiation effects on macro-molecules are reversible through intracellular repair and recovery.
• Radiation damage may result in cell death or late effects.
• DNA is the most radiosensitive molecule. It forms chromosomes and controls cell and human growth and development.
Normal & Radiation Damaged Chromosomes
1. Normal
2. Terminal deletion
3. Dicentrics Formation
4. Ring formation
Radiation Responses of DNA
• Types of damage.
1. One side rail severed.
2. Both side rails severed
3. Cross linking
4. Rung breakage
All are reversible
Point mutation
• A change or a loss of a base is called a point mutation.
• It destroys the triplet code and may not be reversible.
• It is a molecular lesion of the DNA.
• One of the daughter cells will receive incorrect genetic code.
Principle effects of DNA irradiation
• The principle effects are:– Cell death– Malignant disease– Genetic damage
• The latter two conform to the linear, nonthreshold dose response relationship.
Radiolysis of Water
• Because the human body is an aqueous solution containing 80% water molecules, irradiation of water represents the principle radiation interaction with the body.
• When water is irradiated, it dissociates into other molecular products. This is referred to as radiolysis of water.
Radiolysis of Water
• Following ionization, a number of reactions can happen.
• The ion pair can rejoin into a stable water molecule.
• If they don’t rejoin, the negative ion (electron) can join with another water molecule.
Radiolysis of Water
• This results in a third type of ion.
• H2O + e-→HOH-
• HOH+ and HOH- are relatively unstable and can dissociate into still smaller molecules.
Radiolysis of Water
• The final result of the radiolysis of water is the formation of an ion pair, H+ and OH-
and two free radicals.• The ion pairs can
recombine and therefore no biologic damage would occur.
Free Radicals
• A free radical is an uncharged molecule containing a single unpaired electron in the outer shell.
• They are highly reactive and unstable with a lifetime of less than 1 ms.
• They are capable of diffusion through the cell and interaction at a distant site.
Free Radicals
• They contain excess energy that can be transferred to other molecules to disrupt bonds and produce point lesions.
• OH* free radicals can join with similar molecules to form hydrogen peroxide.
• Hydrogen Peroxide is poisonous to the cell and therefore acts as a toxic agent.
Free Radicals
• H* free radicals can react with O2 to form hydroperoxyl.
• Hydroperoxyl and hydrogen peroxide are considered to be the principle damaging products following radiolysis of water.
• Hydroperoxyl free radicals can form Hydrogen peroxide.
Direct & Indirect Effect
• When biologic material is irradiated in vivo, the harmful effects occur because of damage to a particularly sensitive molecule such as DNA.
• If the initial ionization event occurs on the target molecule, the effect of radiation is direct.
• If it occurs on a distant, non critical molecule, which then transfers the energy of ionization to the target molecule, it is an indirect effect.
Direct & Indirect Effect
• The human body is 80% water and less than 1% DNA, the principle effect of radiation on humans is indirect.
• When oxygen is present, as in living tissue, the indirect effect is amplified because of the additional types of free radicals that are formed.
Target Theory
• The cell contains many molecules, most of which exist in overabundance. Radiation damage to such molecules would probably not result in noticeable injury to the cell.
• Some molecules in the cell are considered particularly necessary for normal cell function. They are rare and radiation damage could severely effect the cell function.
Target Theory
• This concept of a key molecule is the basis for the target theory.
• If the target molecule is deactivated by radiation, the cell may die.
• When radiation does interact with the target molecule, it is called a hit.
Target Theory
• Radiation interact with other than the target molecule can result in a hit.
• It is not possible to distinguish between direct and indirect hit.
• When a hit occurs through indirect effect, the size of the target appears to be much larger because of mobility of free radicals.
OER and Target Theory
• With low LET radiation and no O2 the probability of a hit is low.
• When O2 , free radicals are formed the probability is increased.
OER and Target Theory
• With high LET radiation, the distance between ionizations is so close that the probability of a hit by direct effect is high.
• When O2 is added, the added sphere of influence does not result in more hits.
• The maximum hits has already been produced by direct effect.
Single Target, Single Hit Model
• The single target single hit model applies to biologic targets, such as enzymes, viruses or simple cells like bacteria.
• The multitarget, single hit applies to more complicated systems such as human cells.
• Radiation interacts randomly with matter.
• Poisson distribution is used to determine the probability of a hit.
Poisson Distribution
• If there were 100 squares and 100 rain drops, 63% of the squares would be hit and 37% would remain dry.
• If rain fell uniformly, all 100 squares would be wet.
• If the rain drops were x-rays, some of the squares are hit more than once that would result in wasted radiation since they are already killed by the first hit.
D37
• If we used increasing increments of radiation until we reached a level that would kill 63%(37% survival) of the cells, it would be referred to as D37.
• If we doubled the D37 dose, 14% of the cells would survive.
• The lethal effects of radiation are determined by observing cell survival, not cell death.
D37
• A cell with a low D37 is highly radiosensitive.
• A cell with a high D37 represents radio-resistance.
• For these purposes, a hit is not just an ionizing event, but rather ionization that inactivates the target molecule.
• If there was no wasted hits, uniform not random interactions, D37 is the dose that would kill 100% of the cells.
Multitarget, Single Hit Model
• Complex cells such as human cells are said to have more than one critical target.
• As an example if the cell has two target molecules and both had to be hit to deactivate the cell, there would need to be a significant dose to hit both targets since radiation is random.
Multitarget, Single Hit Model
• At very low radiation doses cell survival is nearly 100%. As the dose increases, less survive as more cells get hits in both targets.
• At high radiation doses, all cells that survive have one hit. Therefore at even higher doses, the dose response would appear as the single target, single hit model.
Do
• The Do is called the mean lethal dose and it is a constant related to radiosensitivity of the cell.
• A large Do indicates radio-resistant cells.
• A small Do is characteristic of radiosensitive cells.
DQ
• The DQ is called the threshold dose.
• This is related to the cells ability to recover from sublethal damage.
• It is a measure of the capacity to accumulate sublethal and the ability to recover from sublethal damage.
Dose (DQ) for mammalian cell lines
• Cell Type• Mouse skin• Human Bone Marrow• Human fibroblasts• Human lymphocytes
• Do (rad) DQ (rad)
• 135 350• 137 100• 150 160• 400 100
Split-Dose Irradiation
• This graph illustrates cell recovery from a relatively large dose.
• D0=160rad DQ=110rad• The 1st exposure is
470rad.• The surviving cells are
re-incubated and grow into another large population.
Split-Dose Irradiation
• The second population is subject to additional incremental doses of radiation.
• The second graphs has the same shape at first dose response by the threshold dose.
Recovery
• For full recovery the time between each exposure must be at least as long as the cell generation.
• Experiments have demonstrated that cells that survive an initial radiation insult exhibits the same characteristics as non-irradiated cells.
• The surviving cells have fully recovered from a sublethal dose.
Cell-Cycle Effect
• Human cells replicate by mitosis. The time from one mitosis to the next mitosis is called the Cell-cycle time or generation time.
• Most cells that are in a state of normal proliferation have generation times of 10 to 20 hours.
• The G1 or pre DNA synthesis phase is the most time variable of cell phases
Cell-Cycle Effect
• The change in radiosensitivity as a function of the phase of cell cycle is the age-response function.
• Cells in mitosis are always most sensitive. The fraction of surviving cells is lowest in this phase.
• The G1-S phase is the next most sensitive.• The late S phase is the most radio-
resistant.
LET, RBE and OER
• Many experiments have been done to measure the effect of various types of radiation and to determine the magnitude of various dose modifiers such as oxygen.
• The LET (linear energy transfer) determines the magnitude of RBE and OER.
LET, RBE and OER
• For high LET radiation (alpha particles or neutrons), cell survival follows the single-target, single-hit.
• Low LET radiation (diagnostic x-ray), cell survival follows the multitarget, single hit model.
• Oxygen enhancement is maximizes the effects of low LET radiation.
End of Lecture
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