The history and fundamental of radiation biology us presented in this presentation. Topics including basic human biology and response to radiation, Law of Bergonie and Tribondeau, Physical factors that affect radiation response, Biologic factors that affect radiation response, Radiation dose-response relationships and 6R's of radiobiology are discussed in this presentation. Topics like Linear energy transfer (LET), Relative Biologic Effectiveness (RBE), Protraction and fractionation, age, oxygen enhancement, hormesis, repair, repopulation, re-oxygenation, redistribution, remote (bystander) cellular effects radio sensitivity etc. are included in concise and comprehensive manner.

2. Outlines
 Introduction
 History
 Human Biology
 Radiobiology Fundamentals
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3. Introduction
 Radiobiology is a branch of science which combines the basic principles of physics and biology and is
concerned with the action of ionizing radiation on biological tissues and living organisms.
 It studies the action of ionizing radiation on healthy and diseased tissue
 Radiation biologists seek to understand the nature and sequence of events that occur following the absorption
of energy from ionizing radiation, the biological consequences of any damage that results, and the
mechanisms that enhance, compensate for, or repair the damage.
 The ultimate goal of radiobiologic research is to accurately describe the effects of radiation on humans so that
radiation can be used more safely in diagnosis and more effectively in therapy.
 Most radiobiologic research seeks to develop radiation dose-response relationships so the effects of planned
doses can be predicted and the response to accidental exposure managed.
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4. Radiobiology History
 The beginning of radiobiology was marked by three significant events:
 Wilhelm Conrad Roentgen’s discovery of X-rays in 1895
 Antoine Henri Becquerel’s observance of rays being given off by a uranium-containing substance in 1896; and
 The discovery of radium by Pierre and Marie Curie in 1898.
 In the late 1890s, the dean at Vanderbilt University sat for a skull radiograph. His hair fell out three weeks post-
exposure.
 At around this same time, other documented signs and symptoms involving X-rays included cases of skin redness,
body part numbness, infection, desquamation, epilation, and pain.
 It was not until the death of Clarence Dally (1865–1904), Thomas Edison’s assistant in the manufacture of X-ray
apparatus, and the documentation of his struggle with burns, serial amputations, and extensive lymph node
involvement, that medical observers took seriously the notion that the rays could prove fatal
 He died in 1904 from mediastinal cancer. Following this, Thomas Edison abandoned his research on X-rays.
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5. Radiobiology History
 Another of the early radiology pioneers, Mihran
Kassabian (1870–1910), kept a detailed journal and
photographs of his hands while suffering from necrosis and
subsequent amputations.
 His intention was that the data he collected would be of
importance after his death.
 The early observations of Roentgen, Becquerel, the Curies,
Edison, and early radiologists sparked research about the
effects of radiation exposure on biological processes.
 From the early 1900s through the 1960s, many theories
were developed to define and explain these effects.
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6. Human Biology

7. Human radiation response
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 At its most basic level, the human body is composed of
atoms; radiation interacts at the atomic level.
 The atomic composition of the body determines the
character and degree of the radiation interaction that
occurs.
 When an atom is ionized due to radiation, its chemical
binding properties change.

8. Human radiation response
 Radiation interaction at the atomic level results in
molecular change, which can produce a cell that is
deficient in terms of normal growth and metabolism.
 The abnormal molecule may function improperly or cease
to function, which can result in serious impairment or
death of the cell.
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9. Human radiation response
 Radiation interaction at the atomic level results in
molecular change, which can produce a cell that is
deficient in terms of normal growth and metabolism.
 The abnormal molecule may function improperly or cease
to function, which can result in serious impairment or
death of the cell.
 However, at nearly every stage in the sequence, it is
possible to repair radiation damage and recover.
 Checkpoints are located at specific points within the cell
cycle.
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10. Human radiation response
 When the critical macromolecular cellular components are irradiated by themselves, a dose of
approximately 10 kGyt (1 Mrad) is required to produce a measurable change in any physical
characteristic of the molecule.
 However, when a macromolecule is incorporated into the apparatus of a living cell, only a few mGy
are necessary to produce a measurable biologic response.
 The lethal dose in some single-cell organisms, such as bacteria, is measured in Gyt, but human cells
can be killed with a dose of less than 1 Gyt
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11. COMPOSITION OF THE BODY
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12. Cell proliferation
 Cell proliferation is the act of a single cell
or group of cells to reproduce and
multiply in number.
 Ionizing events at a particularly sensitive
site of a critical target molecule are thought
to be capable of disrupting cell
proliferation.
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13. Cell types and Radiosensitivity
 The cells of a tissue system are identified by their rate
of proliferation and their stage of development.
 Immature cells are called undifferentiated cells,
precursor cells, or stem cells.
 As a cell matures through growth and proliferation, it
can pass through various stages of differentiation into
a fully functional and mature cell.
 The sensitivity of the cell to radiation is determined
somewhat by its state of maturity and its functional
role.
 Stem cells are more sensitive to radiation than mature
cells.
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14. Cell types and Radiosensitivity
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15. Cell types and Radiosensitivity
 Cell radiosensitivity depends upon what part of the cell cycle the
cell is in.
 Mitosis, and the passage from late G1 into early S-phase, are
judged the most radiosensitive phases of the cell cycle whereas,
Mid- to late S-phase is considered to be the most radioresistant
cell cycle phase.
 Numerous experiments have determined that the nucleus of a cell
is considerably more radiosensitive than is the cytoplasm of the
cell.
 DNA is the most radiosensitive part of the cell whereas, RNA
radiosensitivity is intermediate between that of DNA and protein.
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16. Radiobiology Fundamentals
1. Law of Bergonie and Tribondeau.
2. Physical factors that affect radiation response.
3. Biologic factors that affect radiation response.
4. Radiation dose-response relationships.

17. Law of Bergonie and Tribondeau
 In 1906, radiologist Jean Bergonie and histologist Louis Tribondeau observed the effects of radiation by
exposing rodent testicles to X-rays.
 The testes were selected because they contain both mature (spermatozoa) and immature
(spermatogonia and spermatocytes) cells.
 These cells have different cellular functions and their rate of mitosis also differs. The spermatogonia cells
divide frequently, whereas the spermatozoa cells do not divide.
 After irradiating the testes, Bergonie and Tribondeau noticed the immature cells were injured at lower
doses than the mature cells.
 Supported by their observations, they proposed a law describing radiation sensitivity for all body cells.
 Their law maintains that actively mitotic and undifferentiated cells are most susceptible to damage from
ionizing radiation.
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18. Law of Bergonie and Tribondeau
The law of Bergonie and Tribondeau states that:
1. Stem or immature cells are more radiosensitive than mature cells.
2. Younger tissues and organs are more radiosensitive than older tissues and organs.
3. The higher the metabolic cell activity, the more radiosensitive it is.
4. The greater the proliferation and growth rate for tissues, the greater the radiosensitivity.
In diagnostic imaging, the law serves to remind us that fetuses are considerably more sensitive to radiation
exposure as are children compared with the mature adults.
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19. Ancel and Vitemberger
 In 1925, embryologists Paul Ancel and P. Vitemberger modified the law of Bergonie and Tribondeau.
 They suggested that the intrinsic susceptibility of damage to any cell by ionizing radiation is identical, but that
the timing of manifestation of radiation-produced damage varies according to the cell type.
 Their experiments on mammals demonstrated that there are two factors that affect the manifestation of
radiation damage to the cell:
1. The amount of biologic stress the cell receives.
2. Pre- and post-irradiation conditions to which the cell is exposed.
 They theorized that the most significant biologic stress on the cell is the need for cell division.
 They determined that a given dose of radiation will cause the same degree of damage to all cells, but only if
and when the cell divides will damage be demonstrated.
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20. Physical Factors That Affect Radiosensitivity
 The response of the tissue is determined principally by the amount of energy deposited per unit mass—the
radiation dose in Gyt (rad).
 However, even under controlled experimental conditions, when equal doses are delivered to equal
specimens, the response may not be the same because of other modifying factors.
 A number of physical factors affect the degree of radiation response, some of them are:
 Linear Energy Transfer (LET)
 Relative Biologic Effectiveness (RBE)
 Protraction and fractionation
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21. Linear Energy Transfer
 Specific Ionization: For charged particles, we can define the specific ionization as the number of ion pairs
formed per unit path length
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22. Linear Energy Transfer
 LET is the product of the average energy transferred per ion pair and the specific ionization (number of ion
pairs per unit length)
 It is the energy transferred by radiation per unit path length in soft tissue
 It is a physical quantity that is useful for defining the quality of an ionizing radiation beam
 The LET of a charged particle is proportional to the square of the charge and inversely proportional to the
particle’s kinetic energy (i.e., LET ∝ Q2 /Ek )
 The unit used for the LET is keV/µm.
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23. Linear Energy Transfer
 The specific ionization is greatest for heavy
charged particles and deposit a relatively large
amount of energy per unit length. Alphas and
neutrons being heavy charged particles are
considered high LET radiations.
 On the other hand, betas and photons (which
liberate electrons) leave a sparsely ionized particle
track. The amount of energy deposited per unit
path length is relatively low, so beta particles and
X-rays/gamma rays are considered low-LET
radiations.
 The demarcation value between low and high LET
is at about 10 keV/µm.
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24. Relative Biological Effectiveness
 Although all ionizing radiations are capable of producing the same types of biologic effects, the magnitude
of the effect per unit dose differs.
 To evaluate the effectiveness of different types and energies of radiation and their associated LETs,
experiments are performed that compare the dose required for the test radiation to produce the same
specific biologic response produced by a particular dose of a reference radiation (typically, x-rays
produced by a potential of 250 kV).
 The term relating the effectiveness of the test radiation to the reference radiation is called the relative
biological effectiveness (RBE).
 The RBE is defined, for identical exposure conditions, as follows:
𝑅𝐵𝐸 =
Dose of standard radiation necessary to produce a given effect
Dose of test radiation necessary to produce the same effect.
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25. Relative Biological Effectiveness
 Example:
 When rats are irradiated with 250 kVp X-rays, 300 rad are required to cause death. If these rats are
irradiated with heavy nuclei, only 100 rad are necessary.
 RBE for the heavy nuclei= RBE =
300 rad
100 rad
= 3
 In the case discussed, it can be said that the heavy nuclei is 3 times more damaging to rats than 250-
kVp X-rays.
 Diagnostic x-rays have an RBE of 1
 Whereas radiations with lower LET than diagnostic x-rays have an RBE less than 1, radiations with
higher LET have a higher RBE
 The RBE is an essential element in establishing the radiation weighting factors (wR )
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26. LET vs RBE
 Generally, the RBE increases with increasing
LET.
 However, the RBE increases with increasing
LET only up to some maximum value.
 The maximum RBE occurs when the LET is
approximately 100 keV/μm.
 Beyond this value, higher LET does not
contribute to more cell damage. LET values
greater than 100 keV/μm are said to produce
“overkill or wasted dose”
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27. LET vs RBE
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28. Protraction and Fractionation
 If a dose of radiation is delivered over a long period of time rather than quickly, the effect of that dose is less.
 If the dose is delivered continuously but at a lower dose rate, it is said to be protracted
 If the dose is delivered at the same dose rate, in equal fraction, all separated by similar time interval, the dose is
said to be fractionated.
 Dose protraction and fractionation cause less effect because time is allowed for intracellular repair and tissue
recovery.
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29. Protraction and Fractionation
Fractionation Theory:
 Biggest dose (tolerated), given as fast as possible, was the best treatment?
 During 1920 to 1930, Claude Regaud argued that the differential effect of X-rays on cancer and normal tissues
could be best obtained by giving the treatment slowly..
 Radiologist Regaud exposed sheep testicles
 They could be sterilized with one large dose, but this quantity of radiation also caused the skin adjacent to the
scrotum to have a reaction.
 It was found that if the original dose was fractionated, or broken up into smaller doses spread out over a period of
time, the animals would still become sterile, but with considerably less damage to their skin. Regaud called this
the fractionation theory.
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30. Protraction and Fractionation
 Six gray (6 Gyt /600 rad) delivered in 3 minutes at a dose of 2 Gyt/min is lethal for a mouse
 However, when 6 Gyt is delivered at the rate of 10 mGyt/hr for a total time of 600 hours, the mouse will survive;
protracted
 If the 6-Gyt dose is delivered at the same dose rate, but in 12 equal fractions of 500 mGyt, all separated by 24
hours, the mouse will survive; fractionated
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31. Biologic Factors That Affect Radiosensitivity
A number of biologic conditions alter the radiation response of tissue.
 Oxygen Effect
 Age
 Recovery
 Chemical Agents
 Hormesis
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32. Oxygen Effect
 The 1940s brought experimentation with oxygen.
 Geneticist Charles Rick determined oxygen to be a radiosensitizer because it increases the cell-killing
effect of a given dose of radiation.
 This occurs as a result of the increased production of free radicals when ionizing radiation is delivered in
the presence of oxygen.
 This was named the oxygen effect.
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33. Oxygen Effect
 Tissue is more sensitive to radiation when irradiated in the oxygenated, or aerobic, state than when irradiated
under anoxic (without oxygen) or hypoxic (low-oxygen) conditions.
 This response is called the oxygen effect and is described numerically by the oxygen enhancement ratio
(OER).
 OER =
Dose necessary under anoxic conditions to produce a given effect
Dose necessary under aerobic conditions to produce the same effect
 For example, in an experiment, we find that 100 cGy will kill 50% of cells in air, while in an oxygen-free
(anoxic) environment, it takes 300 cGy to kill the same fraction of cells. In this case, the OER for the
population would be 3
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34. Oxygen Effect
 The OER is LET dependent.
 The OER is highest for low-LET radiation, with a
maximum value of approximately 3 that decreases to
approximately 1 for high-LET radiation.
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35. Oxygen Effect
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36. Chemical agents
 Some chemicals can modify the radiation response. To be effective, they must be present at the time of
irradiation.
 Radiosensitizers. Agents that enhance the effect of radiation are called sensitizing agents.
 Examples include: Oxygen, halogenated pyrimidines, methotrexate, actinomycin D, hydroxyurea, and
vitamin K.
 They have an effectiveness ratio of approximately 2,
 that is, if 90% of a cell culture is killed by 2 Gyt (200 rad), then in the presence of a sensitizing
agent, only 1 Gyt (100 rad) is required for the same percentage of lethality
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37. Chemical agents
 Radioprotectors. Radioprotective compounds include molecules that contain a sulfhydryl group, such
as cysteine and cysteamine.
 Effectiveness ratio is approximately 2,
 that is, if 6 Gyt (600 rad) is a lethal dose to a mouse, then in the presence of a radioprotective agent,
12 Gyt (1200 rad) would be required to produce lethality
 The most successful synthetic radioprotector is amifostine, which is believed to have been carried by
the Apollo astronauts to protect them in case of a large radiation dose due to a “solar event.”
 Amifostine is Food and Drug Administration (FDA) approved for clinical use, where it has been
successful in reducing side effects from radiation therapy in head and neck cancer patients.
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38. Chemical agents
 Radioprotectors.
 Just as we defined the OER, we can similarly define the dose reduction factor (DRF) for radioprotective
compounds.
 The DRF is the factor by which the radiation dose must be increased, in the presence of the
radioprotector, in order to achieve the same biological effect:
DRF =
dose of radiation with drug to produce a given effect
dose of radiation without drug to produce the same effect
 The best radioprotectors (amifostine and another synthetic compound, WR-638) attain DRF values of
1.6–2.7 for bone marrow or gut in mice exposed to X-rays
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39. Age
 Humans are most sensitive before birth.
 After birth, sensitivity decreases until maturity, at
which time humans are most resistant to radiation
effects.
 In old age, humans again become somewhat more
radiosensitive.
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40. Recovery
 In vitro experiments show that human cells can recover from
radiation damage
 If the radiation dose is not sufficient to kill the cell before its
next division (interphase death), then given sufficient time,
the cell will recover from the sublethal radiation damage it
has sustained
 This intracellular recovery is attributable to a repair
mechanism inherent in the biochemistry of the cell
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41. Recovery
 If a tissue or organ receives a sufficient radiation dose, it
responds by shrinking. This is called atrophy
 If a sufficient number of cells sustain only sub-lethal damage
and survive, they may proliferate and repopulate the
irradiated tissue or organ.
 The combined processes of intracellular repair and
repopulation contribute to recovery from radiation damage.
 Recovery = Intracellular repair + Repopulation
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42. Hormesis
 A separate and small body of radiobiologic evidence suggests that a little bit of radiation is good.
 Some studies have shown that animals given low radiation doses live longer than controls because a
little radiation stimulates hormonal and immune responses to other toxic environmental agents.
 Regardless of radiation hormesis, we continue to practice ALARA vigorously as a safe approach to
radiation management.
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43. Radiation Dose-response Relationships
 A radiation dose-response relationship is a mathematical relationship between various radiation dose
levels and magnitude of the observed response.
 It has two important applications:
 to design therapeutic treatment routines for patients with cancer
 to yield information on the effects of low-dose irradiation.
 Every radiation dose-response relationship has two characteristics. It is either linear or nonlinear, and it
is either threshold or non-threshold.
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44. Linear Dose-Response Relationships
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• A,B: linear, nonthreshold (LNT) type: any dose,
regardless of its size, is expected to produce a response.
• The level RN, called the natural response level, indicates
that even without radiation exposure, that type of
response, such as cancer, occurs
• C,D: linear, threshold type: At radiation doses below
DT, no response is observed.

45. Nonlinear Dose-Response Relationships
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• A,B: nonlinear, nonthreshold:
• Curve A shows that a large response results from a very
small radiation dose
• Curve B; Incremental doses in the low dose range
produce very little response.
• C: nonlinear, threshold (sigmoid type): At doses below
DT, no response is measured.

46. Constructing a Dose-Response Relationship
 It is nearly impossible to measure low-dose, stochastic effects—the area of greatest interest in
diagnostic imaging.
 Therefore, a limited number of animals are irradiated to very large doses of radiation in the hope of
observing a statistically significant response.
 The principal interest in diagnostic imaging is to estimate response at very low radiation doses.
Because this cannot be done directly, extrapolation of the dose response relationship from the high-
dose, known region into the low-dose, unknown region is done.
 This extrapolation invariably results in a linear, nonthreshold dose-response relationship. Such an
extrapolation, however, may not be correct because of the many qualifying conditions on the
experiment.
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48. Fundamental R’s Of Radiobiology
 Researchers identified many biological factors that can enhance the responses of normal and cancerous cells in
fractionated therapy.
 The most important of them are collectively referred to as “four Rs” of radiation biology.
 In general, success or failure of standard clinical radiation treatment is determined by the 4 R’s of radiobiology:
 Repair of DNA damage,
 Redistribution of cells in the cell cycle,
 Repopulation, and
 Reoxygenation of hypoxic tumor areas.
 The 4 Rs in terms of repair, repopulation, reoxygenation, and redistribution along the cell cycle have been
promoted to 5 Rs with the aid of radiosensitivity and more recently to 6 Rs with the experimental evidence of
remote (bystander) cellular effects.
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49. Fundamental R’s Of Radiobiology
 Repair: the process of rejoining DNA strands.
 Single strand and double strand damage
 Single strand break are usually considered “repairable”
 Double strand breaks are not usually “repairable” if the breaks are close
together, since an intact 2nd strand of the DNA molecule is needed for the
repair of enzymes to be able to copy the genetic information.
 Most repairs occur within 15 minutes to 1 hour. Split-dose experiments
show that repair is completed within about 6 hours.
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50. Fundamental R’s Of Radiobiology
 Repair
 The effect of dose:
 At low doses, both DNA strands are unlikely to be hit; so single
strand breaks will dominate i.e. repair is common
 At high doses, double strand breaks will be common i.e. little
repair
 Cancer cells do not “repair” damage at low doses as well as do
normal tissue cells.
 “window of opportunity” at low dose
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51. Fundamental R’s Of Radiobiology
 Repopulation
 Cancer cells and cells of acutely-reacting normal tissue proliferate during the course of therapy i.e.
“Repopulation”
 Cells of late-reacting normal tissue proliferate little
 Hence the shorter the overall treatment time the better
 But should not be too short otherwise acute reactions will prevent completion of treatment.
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52. Fundamental R’s Of Radiobiology
 Reoxygenation
 Oxygen; powerful radiosensitizer
 Hypoxic tumors can reoxygenate during a course of treatment becoming more sensitive
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53. Fundamental R’s Of Radiobiology
 Redistribution: refers to the change in the fraction of cells in each phase of the cell cycle.
 Cells in different parts of the reproductive cycle have different sensitivities.
 Cells are most sensitive at or close to mitosis
 Resistance is usually greatest in the latter part of the S phase
 Radiation exposure kills more of the cells in the M phase, and more cells in the S phase survive.
 Redistribution in proliferating cell population throughout the cell cycle phases increases the cell
killing from a fractionated treatment
 This effect has not been shown to be advantageous in radiation therapy.
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54. Fundamental R’s Of Radiobiology
 Radiosensitivity was introduced as the fifth R of radiobiology by Steel, McMillan and Peacock in
1989
 It is well known that the response of the tumor or tissues to irradiation basically depends on the
radiosensitivity of the individual cells.
 Radiosensitivity refers to the degree of shrinkage of a tumor/normal tissues following irradiation and
it is expressed based on the law of Bergonie and Tribondeau
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55. Fundamental R’s Of Radiobiology
Radiation-Induced Bystander Effect
 It is a phenomenon in which unirradiated cells exhibit
irradiation effects (such as reduction in cell survival,
cytogenetic damage, mutation, etc.) as a result of molecular
signals received from nearby irradiated cells.
 Bystander effect may play a significant role in optimizing
radiation therapy and radio diagnostic procedures because it
may increase or decrease the clinical outcome depending
upon the types of cells receiving those signals.
 Bystander effects have been evidenced in both tumor and
normal cells, which implies that such remote effects could
have clinical implications.
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56. Fundamental R’s Of Radiobiology
Effect of LET
 Repair decreases as LET increases
 The OER decreases as LET increases
 The cell-cycle effect decreases as LET increases
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57. Summary
 In 1906, two French scientists, Bergonie and Tribondeau first theorized that radiosensitivity was a function
of the metabolic state of tissue being irradiated.
 Physical and biologic factors affect tissue radiosensitivity.
 Radiobiologic research concentrates on radiation dose-response relationships.
 For establishing radiation protection guidelines for diagnostic imaging, the linear, nonthreshold dose-
response model is used.
 Basis of fractionation is rooted in 6 primary biological factors called the 6 Rs of radiobiology; repair,
repopulation, reoxygenation, redistribution, radiosensitivity, remote (bystander) cellular effects
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