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Radiobiology
Course content
• Physical effect of radiation
- ionization and excitations
- interaction between moving charged particle
and stationary electron
- stopping power and range of radiation in the
medium
• Radiation chemistry
- physical events
- radiolysis of water
• Effect of radiation on DNA molecules and
chromosomes
• Cell survival curve
- cell death
- intrinsic cellular radiosensitivity
- cell survival and repair
• Radiation effect on normal tissue
- from cellular effect to tissue damage
- late effect
• The effect of radiation on tumors, the biological
bases of radiotherapy
• Hypoxic cells and their importance in
radiotherapy
- the oxygen effect
- the hypoxic cells
- methods of selectively attaching hypoxic cells
Introduction
• Scientists have studied radiation for over 100
years and a great deal of information is known
about it.
• Radiation is part of nature. All living creatures,
from the beginning of time, have been, and are still
being, exposed to radiation.
We Live (And Have Always Lived) in a
“Sea of Radiation”
Definition of Radiation
• “Radiation is an energy in the form of
electro-magnetic waves or particulate
matter, traveling in the air.”
Ionizing Radiation
• Definition:
“ It is a type of radiation that is able
to disrupt atoms and molecules on
which they pass through, giving rise
to ions and free radicals”.
Basic Model of a Neutral Atom.
• Electrons (-) orbiting
nucleus of protons (+) and
neutrons. Same number of
electrons as protons; net
charge = 0.
• Atomic number (number of
protons) determines
element.
• Mass number (protons +
neutrons)
Radioactivity
• If a nucleus is unstable for any reason, it will
emit and absorb particles. There are many
types of radiation and they are all pertinent to
everyday life and health as well as nuclear
physical applications.
Ionization
- Ionizing radiation is produced by unstable
atoms. Unstable atoms differ from stable
atoms because they have an excess of
energy or mass or both.
- Unstable atoms are said to be radioactive. In
order to reach stability, these atoms give off,
or emit, the excess energy or mass. These
emissions are called radiation.
TYPES OF RADIATIONS
Types of Radiation
Absorbed Dose
Depends on:
• Whether material is inside or outside body
• How long material remains in the body
• How much radioactive material there is
• The type of radiation it emits
• What its half-life is
Natural and Man-Made
Radiation Sources
Natural Background Radiation
• Cosmic Radiation
• Terrestrial Radiation
• Internal Radiation
Cosmic Radiation
• The earth, and all living things on it, are constantly being
bombarded by radiation from outer space (~ 80%
protons and 10% alpha particles).
• Charged particles from the sun and stars interact with
the earth’s atmosphere and magnetic field to produce a
shower of radiation.
• The amount of cosmic radiation varies in different
parts of the world due to differences in elevation and to
the effects of the earth’s magnetic field.
Terrestrial Radiation
(Uranium, Actinium, Thorium decay series)
• Radioactive material is found throughout nature in
soil, water, and vegetation.
• Important radioactive elements include uranium and
thorium and their radioactive decay products which
have been present since the earth was formed billions
of years ago.
• Some radioactive material is ingested with food and
water. Radon gas, a radioactive decay product of
uranium is inhaled.
• The amount of terrestrial radiation varies in different
parts of the world due to different concentrations of uranium and
thorium in soil.
Internal Radiation
• People are exposed to radiation from radioactive material inside their
bodies. Besides radon, the most important internal radioactive
element is naturally occurring K-40, but uranium and thorium are also
present as well as H-3 and C-14.
• The amount of radiation from potassium-40 does not vary much from
one person to another. However, exposure from radon varies
significantly from place to place depending on the amount of uranium
in the soil.
• On average, in the United States radon contributes 55% or all
radiation exposure from natural and man-made sources. Another
11% comes from the other radioactive materials inside the body.
Man-Made Radiation
Radioactive material is used in:
• Medicine - diagnostic (X-ray, CAT)
• Medicine - therapeutic (Co-60, Linac)
• Medical research (radio-pharmaceuticals, accel.)
• Industry - (X-ray density gauges, well logging)
Radiation in Medicine
• Radiation used in medicine is
the largest source of manmade radiation.
• Most exposure is from
diagnostic x-rays.
Man-Made Radiation Sources
• Exposure of selected groups of the public:
– diagnostic radiology (X-rays)
– nuclear medicine
(radiopharmaceuticals)
– radiotherapy (Co-60)
Interaction of radiation with
matter
Elastic Scattering
Outgoing photon
Incoming photon
No loss of photon
energy
hnin = hnout
Elastic Scattering
•
Elastic scattering is also known as called “Coherent” or “Rayleigh”
scattering
•
Photon scattering angle depends on Z and hn*
hn
Al
Pb
0.1 MeV
15o
30o
1 MeV
2o
4o
10 MeV
0.5o
1.0o
•
Occurs mainly at low energies
•
Large Z materials
•
Contributes nothing to KERMA or dose, no energy transferred, no
e/r  Z2/(hn)2
ionisation, no excitation
•
No real importance in radiotherapy
* F.
H. Attix, Introduction to Radiological Physics and Radiation Dosimetry
The Photoelectric Effect
Incoming
photon
Outgoing
electron
Ee = hn - W
Ee: maximum kinetic energy of the outgoing electron
W: energy needed to remove electron
The Photoelectric Effect
Characteristic X-ray
Auger electron
• Photoelectron emitted leaving atom in unstable, excited state
• Atom relaxes by
• X-ray emission
• Auger electron emission (The Auger Effect)
The Photoelectric Effect
•
Process = attenuation and absorption
•
Interaction of a photon with bound atomic electrons
•
Total absorption of photon energy
•
Photoelectron emitted , max. kinetic energy: Ee = hn - W
•
Produces characteristic X-rays and/or Auger electrons
•
Predominates at low energies
•
Is highly Z dependent
•
Example: tPb/rPb is 300 times greater than tbone/rbone
t/r  Z3/(hn)3
The Photoelectric Effect
• If the photon energy is
slightly higher than the
energy required to remove an
electron form a particular shell
(e.g. K, L, M) around the
nucleus, there is a sharp
increase in t/r.
• This increase is called an
absorption edge.
The Photoelectric effect
Mass absortpion
coefficient
Absorption edges important:
1. In radiology because it influences the choice of material used
in intensifying screens, photographic film, contrast agents
K-
edge for La
Z=57
K-
Example
edge for W
Z=74
CaWO4 Intensifying Screen
LaOBr Intensifying Screen
20
40 60 80
Photon energy keV
2. In radiation protection because it influences the choice of
shielding materials
3.
In radiotherapy because it influences the choice of filtering
material
The Photoelectric Effect
•
Number of X-rays produced/no. of vacancies = Fluorescent Yield (w)
•
Fluorescent Yield is high for high Z, low for low Z
•
Low Z materials give low energy X-rays => X-rays absorbed locally
•
For low Z materials, Auger electrons more probable
Fluorescent yield (K-shell vacancy)*
Z
10
15
20
25
30
35
wK
Z
0
0.05
0.19
0.30
0.50
0.63
40
45
50
55
60
65
wK
0.74
0.80
0.84
0.88
0.89
0.90
Z
70
75
80
85
90
* H. Johns & J. Cunningham, The Physics of Radiology, 4th Edition
wK
0.92
0.93
0.95
0.95
0.97
The Compton Effect
Incoming
photon
Outgoing
electron
f
q
Outgoing
photon
The Compton Effect

Interaction of photon with unbound atomic electrons

Scatter + partial absorption of photon energy

Scattered electron + scattered photon

Change in photon wavelength depends on angle of scattered photon
lout- lin = constant x (1- Cos q)
lin: wavelength of the outgoing electron, lout: energy of incoming photon
•
If photon makes a direct hit:
1.
Electron will be scattered straight on with maximum energy
2.
Photon will be scattered backwards i.e. q = 180o with minimum energy
3.
Scattered photon energy
The Compton Effect
Energy of Compton Scattered Electrons versus Photon Scatter Angle
20
18
16
0.1 MeV
14
Energy (MeV)
1 MeV
4 MeV
12
6 MeV
10 MeV
10
12 MeV
8
15 MeV
20 MeV
6
4
2
0
0
20
40
60
80
100
Angle ( o)
120
140
160
180
The Compton Effect
Energy of Compton Scattered Photons versus Angle
20
0.1 MeV
18
1 MeV
4 MeV
16
6 MeV
Energy (MeV)
14
10 MeV
12
12 MeV
10
15 MeV
20 MeV
8
6
4
2
0
0
20
40
60
80
100
Angle (o )
120
140
160
180
The Compton Effect
•
Dominates over a wide range of X-ray energies
•
Depends on electron density (re)
•
Independent of Z
/r  re / hn
Pair Production – Type 1
Outgoing
Electron, E-
Incoming
Photon, hn
Outgoing
Positron, E+
•
hn  1.022 MeV
•
hn – 1.022 = E- + E+
•
E-, E+ are the kinetic energies of the electron and positron resp.
Pair Production – Type 1
•
Photon interacts with Coulomb field of atomic nucleus and is absorbed
•
Electron/Positron pair produced if hn  1.022 MeV
•
Example of conversion of energy into mass: E = mc2
– Energy equivalent of one electronic mass is 0.511 MeV
– As e+ & e- produced, incoming photon must have energy: 2 x 0.511 MeV
– e+ and e- can receive any fraction of photon energy
•
Dominates at high photon energies
•
Dependent on Z
k/r  Z2 / ln(hn)
Pair Production – Type 1
•
e+ produced in Pair Production dissipates energy locally
•
Energy lost through excitation and ionisation of atoms along its track until it
comes to rest
•
It is annihilated by combining with a free electron producing two photons of energy
0.511 MeV
0.511 MeV photon
slow e+
free electron
0.511 MeV photon
Pair production –Type 2
Outgoing Electron, E2Original Electron, E1Incoming Photon
hn > 2.04 MeV
Outgoing Positron, E+
hn=1.022 MeV+E1-+E2-+E+
• Otherwise called Triplet Production
• Incident photon interacts with Coulomb field of atomic electrons & is absorbed
• Incident photon transfers energy to Host e- and e-/e+ pair produced
• Conservation of momentum => threshold energy for this process is 4mc2
Summary
Pb, W
Sn
Zr
Ca
Al
H
Photonuclear Interactions
•
High energy photon interacts with atomic nucleus resulting in
emission of a proton (p) or a neutron (n)
•
Occurs for incident photons with energy > few MeV
•
If p emitted, effect can contribute to dose. But relative importance
is low
•
If n emitted, there can be consequences for radiation protection
–
–
–
–
must take account in shielding designs
n can escape shielding more readily than photons
n may activate accelerator hardware e.g. in target
Biological effect in radiotherapy patient negligible compared with
effects of photons
The Auger Effect (Revisited)
Auger e-
X-ray
hole
hole
K
K
K
L
L
K
L
M
M
Initial state:
hole in K-shell
hole
hn = EK-EL
L
M
E = hn - EM
E = EK – EL - EM
M
holes in L- and
M-shell
•
Mono-energetic Auger electrons will carry away any surplus energy of
excited atom
•
Multiple Auger electrons can be emitted resulting in an Auger shower.
•
Vacancies continue to move to less tightly bound shells until they are
eventually filled by conduction band (free) electrons
Scattered Radiation
• = By-product of the interaction
of radiation with matter
• Scattered radiation = radiation
(particulate or EM radiation)
that has changed direction with
or without a change in energy
during its passage through
intervening matter.
V
• EXAMPLE: In radiotherapy,
scattered radiation comes from
the interaction of the primary
beam with the flattening filters,
primary and secondary
collimators, monitor chamber,
the patient.
Scattered Radiation
If energy of incoming radiation high  scatter mostly in forward •
direction. Example: Therapy range (MV)
If energy of incoming radiation low  scatter in backwards direction •
(= backscatter) increases. Example: Therapy range (50 – 160 kV) or
Diagnostic Imaging (typically 40 – 80 kVp)
10 keV
100 keV
Scattering point
Not to scale
Spatial distribution of
scattered x-rays
Scattered Radiation
Effects of Scattered Radiation:
• In imaging it acts as a mask over the image.
film, fluorescent screen or
image intensifier
bone
soft
tissue
primary
radiological
image
bone
air
primary
diaphragm
grid
intensity at
detector
scattered
radiation
• In radiotherapy, adds to patient dose and has radiation protection
issues for staff
Secondary Electrons
• When primary radiation interacts with matter, electrons may be
produced – these electrons are called “secondary electrons”
• Secondary electrons are emitted close to the original point of
interaction.
• If the secondary electron is given enough energy, it can create its own
separate track depositing energy along the way – d-ray
•
d-rays do not deposit energy in the immediate vicinity
 consequences for determining Absorbed Dose
• NOTE: Electrons follow tortuous paths undergoing many
interactions before coming to a stop.
Photons travel in straight lines.
Range versus Energy
• The furthest distance radiation travels in a
medium is called “the range”.
An electron follows a tortuous path undergoing
many interactions before coming to a stop
Medium
Incoming
Radiation
A
B
Range
A: starting point for
secondary eB: stopping point for
secondary e-
Range versus Energy
• The range depends on:
– the type and energy of the radiation
– the density of the traversing medium
1.6
1.4
Range (cm)
1.2
1
0.8
Bone
Muscle
Water
Fat
EXAMPLE: Electron range in tissues
0.6
0.4
0.2
0
0.5
1
1.5
Initial Electron Energy (MeV)
Data from: F. Attix, Introduction to Radiological Physics and Radiation Dosimetry
2.5
Linear Energy Transfer
• The LET is the rate at which energy is transferred to the medium
and therefore the density of ionisation along the track of the
radiation.
• LET also referred to as “restricted stopping power” (LD)
• LET is expressed in terms of keV per micron
dE
LET  dX
Radiation
1 MeV g-rays
dE = energy lost by radiation 100 kV X-rays
p
dX = length of track
20 keV b-particles
5 MeV neutrons
• Radiation that is easily
5 MeV a-particles
stopped has a high LET and
vice versa
LET keV/mm
0.5
6
10
20
50
Interaction of Charged Particles
with Matter - General
• charged particles (e-, protons, a-, b-particles) lose energy in a manner
very different from uncharged radiation (X-rays, g-rays, neutron).
• charged-particles are surrounded by an electrostatic field (= Coulomb
field)
• they interact with electrons/nuclei of practically every atom they pass
• The force between two particles is  Ze2/r2
• probability of charged particle passing through a medium without
interaction is ZERO
• Example: a 1 MeV charged-particle typically undergoes 105
interactions before losing all its kinetic energy (K.E.)
Interaction of Charged Particles with
Matter – Energy Loss
HOW?
1. “soft collision” when b >> a
Collisional Energy Loss
2. “hard collision” when b ~ a
3. “Coulomb-force interactions with
Radiative Energy Loss
the external nuclear field” when b << a
Undisturbed
trajectory
Charged
particle
b
a
Interactions characterised by:
“impact parameter, b” vs “atomic radius, a”
Interaction of Charged Particles with Matter – Energy Loss
Soft Collisions (b >> a): Excitation and Ionisation
The electric field of the charged particle interacts with atomic electrons
causing them to accelerate and gain energy.
1.
Excitation: If the gain in electron energy
is equal to the difference in energy
between its own energy level and a
higher energy level, then the electron is
excited to the higher energy level.
2. Ionisation: If the gain in energy is
greater than the binding energy for the
electron, then an electron is removed
from its orbital. The atom is “ionised”.
Passing charged particle
1.
Ejected electron
Net effect: transfer of a small amount of
energy (few eV) to atom of absorbing medium
2.
Interaction of Charged Particles with
Matter – Energy Loss
Soft Collisions (b >> a)
Large b more probable than small b
 “soft” collisions more likely than any other type of interaction
 approx. 1/2 particle energy transferred to absorbing medium
Two additional effects:
1. Polarisation of atoms in
absorbing medium
2. Cerenkov radiation = emission of
bluish light (< 0.1 % of particle
energy spent in this way.
Cerenkov radiation
in the core
of a reactor
Interactions of Charged Particles with Matter – Energy Loss
Hard Collisions (b ~ a): Ionisation, d-rays, char. X-rays + Auger eWhen b ~ a, more likely for CP to interact with single atomic e “hard” collisions result in ejection of e e- emitted with large K.E. = d-ray
 d-rays have sufficient energy to ionise other atoms
 d-rays dissipate energy along separate track = spur
Ejected electron
Bremsstrahlung
Incoming
radiation
Main e- track
d-ray
Interactions of Charged Particles with Matter – Energy Loss
Hard Collisions (b ~ a): Ionisation, d-rays, char. X-rays + Auger e char. X-rays and Auger electrons also emitted
 some energy transferred to medium by d-rays, char. x-rays and
Auger e- transported away from primary particle track
 no. of hard collisions is small
 BUT fraction of energy spent in hard + soft collision comparable
K radiation
Incoming charged
particle
Ejected
electron
K
L
M
E - hnk
L-shell to K-shell = Ka radiation
M-shell to K-shell = Kb radiation
Interaction of Charged Particles with
Matter – Energy Loss
Mean Energy Expended per Ion Pair, W
In measuring the energy absorbed extensive use is
made of ionisation.
Mean energy expended to form an ion pair:
W = E/N
where
E = initial K.E. of the charged particle
N = mean no. of ion pairs formed when all
energy is used
EXAMPLE: W for dry air is 34 eV
Interaction of Charged Particles with Matter – Energy Loss
Coulomb-force interactions with the external nuclear field” (b << a):
Bremsstrahlung
When charged particle comes very close to nucleus, its electric field interacts with that of the
nucleus.
–
Most important for electrons because: Prob.  Z2 , 1/m2
–
Most cases, elastic scattering results i.e. electron changes direction
but loses no energy
–
2-3% of cases, charged particle decelerates thereby losing energy and
changing direction
–
Up to 100 % particle energy lost as X-rays = Bremsstrahlung
 continuous spectrum of Bremsstrahlung radiation
Incoming charged
particle
Bremsstrahlung,
hn
E - hn
Interaction of Charged Particles with Matter – Energy Loss
Electrons
The interaction of electrons with matter is different from other
charged particles because the electron is very small:
me = 9.11 e-31 kg
mp = 1.67 e-27 kg
Therefore, two important effects observed for electrons:
•Relativistic effects  large changes in energy and angle
•Rapid deceleration  Bremsstrahlung
Stopping Power, S
•
Stopping Power, S: The rate of energy loss per unit path length by a
charged particle having K.E. in a medium of atomic number Z
•
Units: MeV/cm
•
Mass Stopping Power = S/r (independent of density)
•
Total Stopping Power  collision losses + radiative losses
Scoll
Srad
S


r
r
r
• Stopping Power depends on the absorbing medium, the
particle charge, the particle energy, and the particle mass
BIOLOGICAL EFFECTS
OF IONIZING RADIATION
AT MOLECULES AND CELLS
The stage of action
of ionizing radiation
Physical stage
The transfer of kinetic energy from ionizing
radiation to atoms or molecules leads to
excitation and ionization of these atoms or
molecules
10 – 16 –
10 – 15
seconds
Physic-chemical
stage
The displace of absorbed energy of ionizing
radiation into molecules and between them.
Formation of free radicals
10 – 14 –
10 – 11
seconds
Chemical stage
Reactions between free radicals, reactions
between free radicals and intact molecules.
Formation of molecules with abnormal
structure and function
10 – 6 –
10 – 3
seconds
Biological stage
Formation of injures on all levels – from
cellular structures to organism and
population.
Development of processes of biological
damage and reparative processes
Seconds
– years
Effect of radiation
on atom and molecules
Effects of ionizing radiation
at atomic level
Excitation
Ionization
Mechananisms of damage
at molecular level
Direct action
of ionizing radiation
Ionizing radiation + RH
R- + H +
Bond breaks
a
OH
I
R – C = NH
imidol (enol)
b
Tautomeric shifts
O
II
R – C = NH2
amide (ketol)
Indirect action
of ionizing radiation
P+
H
X ray
g ray
e-
O
H
OHH+
Ho
OHo
Radiolysis of H2O molecule
Shared electron
Shared electron
H-O-H  H+ + OH- (ionization)
H-O-H  H0 + OH0 (free radicals)
Reaction of H2O molecule radiolysis
Н2О + hn  Н2О+ + ео
о
*
Н2О + hn  Н2О  Н + НО
о
Н2О + е  е  Н + НОо
о
Н2О + е-  Н2О*  Н + ОН
Н2О  Н+ + ОНо
е- + Н+  Но
о
+
Н2О + ОН  Н2О + ОН
о
+
+
Н2О + Н2О  Н3О + ОН
о
+
Н3О + е  Н2О + Н
Effects of oxygen
on free radical formation
Oxygen can modify the reaction by
enabling creation of other free radical
species with greater stability and longer
lifetimes
H0 + O2  HO20 (hydroperoxy free radical)
R0 + O2  RO20 (organic peroxy free radical)
Reactions with free radicals
H0 + OH0  H2O
H0 + H0  H2
OH0 + OH0  H2O2
RH + OH0  R0 + H2O
RH + H0  R0 + H2
R0 + OH  ROH
R0 + H  RH
R0 + O2  ROO0
ROO0 + RH  ROOH + R0
Lifetimes of free radicals
HO2o
H
o
OHo
RO2o
OHo
3nm
Ho
Because short life of simple free radicals (10-10sec),
only those formed in water column of 2-3 nm around
DNA are able to participate in indirect effect
Relation between linear energy transfer (LET)
and type of action
Direct action is predominant cause of
damage with high LET radiation, e.g.
alpha particles and neutrons
Indirect action is predominant with low
LET radiation, e.g. X and gamma rays
Effects of Ionizing Radiation on DNA
• Single strand break
• Double-Strand Break
• Double-Strand Break in Same Rung of
DNA
• Mutation
Single-Strand Break
If ionizing radiation interacts with a DNA macromolecule, the
energy transferred can rupture one of its chemical bonds,
possibly severing one of the sugar-phosphate chain side rails or
strands of the ladderlike molecular structure (single-strand
break). This type of injury to DNA is called a point mutation.
Gene mutations may result from a single alteration along the
sequence of nitrogenous bases. Point mutations commonly occur
with low-LET radiations. Repair enzymes, however, are capable of
reversing this damage.
Double-Strand Break
Further exposure of the affected DNA macromolecule to ionizing radiation may
result in additional breaks in the sugar-phosphate molecular chain(s). These
breaks might also be repaired, but double-strand breaks (one or more breaks in
each of the two sugar-phosphate chains) are not repaired as easily as singlestrand breaks. If repair does not take place, further separation may occur in the
DNA chains, threatening the life of the cell. Double-strand breaks occur more
commonly with densely ionizing (high-LET) radiations and often are associated
with the loss or gain of one or more nitrogenous bases. When high-LET radiation
interacts with DNA molecules, the ionization interactions may be so closely
spaced that, by chance, both strands of the DNA chain are broken. If both
strands are broken at the same nitrogenous base “rung,” the result is the same
as if both side rails of the ladder were cut at the same step or rung—the ladder
would be cut into two pieces. If the DNA is cut into two pieces, the
chromosome, which is composed of a long chain of twisted strands of DNA
ladders, is itself broken. Thus some types of chromosomal damage that are
particularly associated with high-LET radiation are related to double-strand
breaks of DNA. Because the chance of repairing this damage is much slighter,
the possibility of inducing a lethal alteration of nitrogenous bases within the
genetic sequence is far greater.
Double-Strand Break in Same Rung of DNA
When two interactions (hits), one on each of the two sugarphosphate chains, occur within the same rung of the DNA ladder
like configuration, the result is a cleaved or broken chromosome,
with each new portion containing an unequal amount of genetic
material. If this damaged chromosome divides, each new daughter
cell will receive an incorrect amount of genetic material. This will
culminate in the death or impaired functioning of the new daughter
cell.
Mutation
In general, the interaction of high-energy radiation with a DNA molecule causes either
a loss of or change in a nitrogenous base on the DNA chain. The direct consequence
of this damage is an alteration of the base sequence. Because the genetic information
to be passed on to future generations is contained in the strict sequence of these
bases, the loss or change of a base in the DNA chain is a mutation. It may not be
reversible and may cause acute consequences for the cell but, more important, if the
cell remains viable, incorrect genetic information will be transferred to one of the two
daughter cells when the cell divides.
Covalent Cross-Links
Covalent cross-links are chemical unions created
between atoms by the single sharing of one or
more pairs of electrons. Covalent cross-links
involving DNA are another effect initiated by highenergy radiation. At low energies, however,
covalent cross-links are probably caused by the
process of indirect action. Following irradiation,
some molecules can produce small, spurlike
molecules that become very interactive (“sticky”)
when exposed to radiation. This can cause these
molecules to attach to other macromolecules or to
other segments of the same macromolecule chain.
Cross-linking can occur in many different patterns.
For example, a cross-link can form between two
places on the same DNA strand. This joining is
termed an intrastrand cross-link. Cross-linking may
also occur between complementary DNA strands
or between entirely different DNA molecules.
These joinings are termed interstrand cross-links.
Finally, DNA molecules also may become
covalently linked to a protein molecule. All these
linkages are potentially fatal to the cell if they are
not properly repaired.
Biochemical reactions with ionizing radiation
DNA is primary target for cell
damage from ionizing radiation
Radiation induced
DNA damage
The most important types of radiation
induced lesions in DNA
Base damage: 1000-2000 per 1 Gy
Single-strand breaks
500-1000 per 1 Gy
Double strand breaks
40-50 per 1 Gy
Mechanisms of base excision and
nucleotide excision repair
Mechanism of single-strand breaks
DNA repair
Endonuclease
1
2
DNA polymerase
3
Exonuclease
4
DNA ligase
5
DNA restoration failure
Unrejoined DNA
double strand breaks
Cytotoxic effect
Incorrect repair
of DNA damage
Mutations
Radiation induced membrane damage
• Biological membranes serve as highly specific
mediators between the cell and the environment.
Radiation changes within the lipid bilayers of the
membrane may alter ionic pumps. This may be due to
changes in the viscosity of intracellular fluids
associated with disruptions in the ratio of bound to
unbound water. Such changes would result in an
impairment of the ability of the cell to maintain
metabolic equilibrium and could be very damaging
even if the shift in equilibrium were quite small.
• Alterations in the proteins that form part of a
membrane’s structure can cause changes in its
permeability to various molecules, i.e. electrolytes.
Effect of radiation
on cells
Types of cellular damage
Norma
Mutation
repair
Interphase
cell death
Mitotic
cell death
Changes of
metabolism
& function
Cell cycle
Mitotic death
NORMAL
IRRADIATED
Bergonié and Tribondeaus’ ‘law’ (1906)
The most ‘radiosensitive’
cells are
 actively proliferating (dividing) at
the time of exposure
 undifferentiated (non-specialized
in structure and function)
Morphological forms of cell death
 Pyknosis: The nucleus becomes contracted, spheroidal, and
filled with condensed chromatin.
 Karyolysis: The nucleus swells and loses its chromatin.
 Protoplasmic Coagulation: Irreversible gelatin formation
occurs in both the cytoplasm and nucleus.
 Karyorrhexis: The nucleus becomes fragmented and
scattered throughout the cell.
 Cytolysis: Cells swell until they burst and then slowly
disappear.
 Apoptosis: Programmed cell death, usually be
fragmentation
Changes of cell metabolism and function
 Block of Mitotic Cycle: Mitosis may be delayed or inhibited
following radiation exposure.
 Disruptions in Cell Growth: Cell growth may also be
retarded, usually after a latent period.
 Permeability Changes: Irradiated cells may show both
increased and decreased permeability.
 Changes in Cell Motility: The motility of a cell may be
decreased following irradiation.
Radiation induced chromosome damage
Chromosomes
Effects of Ionizing Radiation on Chromosomes
Large-scale structural changes in a chromosome
brought about by ionizing radiation may be as
grave for the cell as are radiation-induced
changes in DNA. When changes occur in the DNA
molecule, the chromosome exhibits the
alteration. Because DNA modifications are
discrete, they do not inevitably result in
observable structural chromosome alterations.
Radiation-Induced Chromosome Breaks
After irradiation and during cell division,
some radiation-induced chromosome breaks
may be viewed microscopically. These
alterations manifest themselves during the
metaphase and anaphase of the cell division
cycle, when the length of the chromosomes
is visible.
Because the events that have happened
before these phases of cell division are not
visible, they can only be assumed to have
occurred. What can be seen, however, is the
effect of these events—the gross or visible
alterations in the structure of the
chromosome. Both somatic cells and
reproductive cells are subject to
chromosome breaks induced by radiation.
Chromosomal Fragments
After chromosome breakage, two or more
chromosomal fragments are produced. Each of
these fragments has a fractured extremity.
These broken ends appear sticky and have the
ability to adhere to another such sticky end.
The broken fragments may rejoin in their
original configuration, fail to rejoin and create
an aberration (lesion or anomaly), or rejoin
other broken ends and create new
chromosomes that may not look structurally
altered compared with the chromosome before
irradiation
Chromosome Anomalies
Two types of chromosome anomalies have been
observed at metaphase. They are called (1)
chromosome aberrations and (2) chromatid
aberrations. Chromosome aberrations result when
irradiation occurs early in interphase, before DNA
synthesis takes place. In this situation, the break
caused by ionizing radiation is in a single strand of
chromatin; during the DNA synthesis that follows,
the resultant break is replicated when this strand
of chromatin lays down an identical strand
adjacent to itself if repair is not complete before
the start of DNA synthesis.
This leads to a chromosome aberration in which
both chromatids exhibit the break. This break is
visible at the next mitosis. Each daughter cell
generated will have inherited a damaged
chromatid as a consequence of a failure in the
repair mechanism. Chromatid aberrations, on
the other hand, result when irradiation of
individual chromatids occurs later in interphase,
after DNA synthesis has taken place. In this
situation, only one chromatid of a pair might
suffer a radiation-induced break. Therefore only
one daughter cell is affected.
Structural Changes in Biologic Tissue Caused by Ionizing Radiation
Ionizing radiation interacts randomly with matter. Because of this
phenomenon, exposure to radiation produces a variety of structural changes
in biologic tissue. Some of these changes are as follows:
•A single-strand break in one chromosome
•A single-strand break in one chromatid
•A single-strand break in separate chromosomes
•A strand break in separate chromatids
•More than one break in the same chromosome
•More than one break in the same chromatid
•Chromosome stickiness, or clumping together
Consequences to the Cell from Structural Changes in
Biologic Tissue:
1.Restitution, whereby the breaks rejoin in their original
configuration with no visible damage . In this case no
damage to the cell occurs because the chromosome has
been restored to the condition it was in before irradiation.
The process of healing by restitution is believed to be the
way in which 95% of single-chromosome breaks mend.
2.Deletion, whereby a part of the chromosome or
chromatid is lost at the next cell division, creating an
aberration known as an acentric fragment.
3.Broken-end rearrangement, whereby a grossly
misshapen chromosome may be produced. Ring
chromosomes, dicentric chromosomes, and anaphase
bridges are examples of such distorted chromosomes.
4.Broken-end rearrangement without visible damage to
the chromosomes, whereby the chromosome's genetic
material has been rearranged even though the
chromosome appears normal. Translocations are an
example of such rearrangements. Changes such as these
inevitably result in mutation because the positions of the
genes on the chromosomes have been rearranged, thus
altering the heritable characteristics of the cell.
Restitution
Deletion
The process of broken-end rearrangement may result
in no visible damage to the chromosome, although
the chromosome's genetic material has been
rearranged—a result that will drastically alter its
function within the cell, probably leading to cell
death or failure to replicate.
Target Theory
Amid the many different types of molecules that
lie within the cell, a master, or key, molecule that
maintains normal cell function also is believed to
be present. This master molecule is necessary for
the survival of the cell. Because this molecule is
unique in any given cell, no similar molecules in
the cell are available to replace it; if the master
molecule is inactivated by exposure to radiation,
the cell will die. Experimental data strongly
support this concept and indicate that DNA is the
irreplaceable master, or key,
molecule that serves as the vital target.
Destruction of some of the molecules that are
plentiful in the cell does not result in cell death.
The reason for this is simply that cells have an
abundance of similar molecules to take over and
perform necessary functions for them in the
event of their demise. If only a few non-DNA cell
molecules are destroyed by radiation exposure,
the cell will probably not show any evidence of
injury after irradiation.
CELLULAR EFFECTS OF IRRADIATION
Ionizing radiation can adversely affect the cell. Damage
to the cell's nucleus reveals itself in one of the
following ways:
1.Instant death
2.Reproductive death
3.Apoptosis, or programmed cell death (interphase
death)
4.Mitotic, or genetic, death
5.Mitotic delay
6.Interference of function
7.Chromosome breakage
SURVIVAL CURVES FOR MAMMALIAN CELLS
Cells vary in their radiosensitivity. This fact is
particularly important in determining the type
of cancer cells that will respond to radiation
therapy. A classic method of displaying the
sensitivity of a particular type of cell to
radiation is the cell survival curve. A cell
survival curve is constructed from data
obtained by a series of experiments. First, the
cells are made to grow “in culture,” meaning in
a laboratory environment such as a Petri dish.
Then the cells are exposed to a specified
dose of radiation. After radiation exposure,
the ability of the cells to divide, or form new
“colonies” of cells, is measured. The fraction
of cells that are able to form new colonies
through cell division is then reported as the
fraction of cells that have survived
irradiation. The process is repeated for a
range of radiation doses, and the results are
graphed with the logarithm of the surviving
fraction on the vertical axis and the dose on
the horizontal axis.
Relative cellular radiosensitivity
 Vegetative Cells: these cells, comprising differentiated functional cells of a
large variety of tissues, are generally the most radiosensitive.
 Differentiating Cells: these cells are somewhat less sensitive to radiation;
they are relatively short-lived and include the first generation produced by
division of the vegetative mitotic cells.
 Totally Differentiated Cells: these cells are relatively radioresistant; they
normally have relatively long lifespans and do not undergo regular or
periodic division in the adult stage, except under abnormal conditions such
as following damage to or destruction of a large number of their own kind.
 Fixed Nonreplicating Cells: these cells are most radioresistant; they are
highly differentiated morphologically and highly specialized in function.
Radiosensitivity varies in different types of tissue. While all cells can be
destroyed by a high radiation dose, highly radiosensitive cells or tissue
exhibit deleterious effects at much lower doses than others, rapidly
dividing, undifferntiated cells in tissue are the most sensitive to radiation
effects.
Highly radiosensitive tissue - lymphoid, bone marrow elements,
gastrointestinal epithelium, gonads (testis and ovary), and foetal tissue.
Moderately radiosensitive tissue - skin, vascular endothelium, lung,
kidney, liver, lens and thyroid in childhood.
Least radiosensitive tissue - central nervous system, endocrine (except
gonad), thyroid in adults, muscle, bone and cartilage, and connective
tissue. The least radiosensitive tissue, although radioresistant, is less
capable of cell renewal than highly sensitive tissue. Some - especially
neurons, glial cells of the brain, and muscle cells - has essentially no
ability to regenerate. Once these cells are killed, the area is repaired by
fibrosis or scarring.
Factors affecting cell radiosensitivity
1- cell maturity and specialization: immature
cells are nonspecialized and undergo rapid cell
division so they are radiosensitive
2- amount of radiation energy transferred to
biologic tissue (LET)
3- oxygen enhancement effect: oxygen increases
the cell radiosensitivity, more free radicals are
formed in the presence of oxygen
4- Low of Beronie’ and Tribondeau: the
radiosensitivity is a function of the metabolic
state of the cell receiving the exposure. It
state that the radiosensitivity of the cells is
directly proportional to their reproductive
activity and inversely proportional to their
degree of differentiation.
Effect of ionizing radiation on
human cells
• Blood cells
- hematologic depression: ionizing radiation
affect blood cells by depressing the number of
cells in the peripheral circulation a whole body
dose of 25 rad produce measurable
hematologic depression.
- Depletion of immature blood cells: most blood
cells are produced in the bone marrow
radiation causes decrease in the number of
immature blood cells
• If the bone marrow cells have not been
destroyed by exposure they can repopulate
after a period of recovery, the recovery time
depend on the magnitude of the radiation
dose received ( repopulation).
• Effect on stem cells of the hematopoietic
system: radiation affects primarily the stem
cells of the hematopoietic ( blood forming)
system erythrocytes are among the most
sensitive of human tissue, as with all cells that
transform from an immature, undifferentiated
state to a mature functional state
• The mature red blood cells are less
radiosensitive. Because the population of
circulating RBCs is high and their life span is
long depletion of red cells is not usually the
cause of death in high dose, death is more
typically caused by infection that cannot be
overcome by the immune system because of
destruction of myeloblasts (type of WBCs) and
internal bleeding resulting from destruction of
magakaryoblasts ( precursors of platelets)
• Whole body dose in excess of 5 Gy (500 rad)
- Body exposure more than 5 Gy might result in
death within 30-60 days because of effect
related to initial depletion of stem cells of
hematopoietic system. The use of antibiotics or
isolation from pathogens in the environment
feeding only sterilized food has been shown to
limit these effects in animals and humans.
- Lethal dose in animals is usually specified as
LD50/30 ( dose that produce s death of 50% of
exposed group in 30 days
• The lethal dose in human beings is usually
given as LD 50/60 because humans recovery is
slower than that of the laboratory animals.
• The lethal dose for human beings estimated to
be 3-4 GY without treatment and higher if
medical intervention is available.
• Effect of radiation on lymphocytes: white
blood cells are called leukocytes, lymphocytes
are subgroup of WBCs these cells defend the
body against antigens by forming antibodies
to fight the disease, they live only for 24 hours
• Lymphocytes manufactured in the bone
marrow are the most sensitive blood cells in
the human body, a radiation dose of 0.25 GY
(25 rad) is sufficient to depress the number of
cells present in the circulating blood, when
significant number of lymphocytes are
damaged the body loses its natural ability to
fight infection and become more susceptible
to infection by bacteria and viruses. This also
applied to neutrophils and granulocytes
• Effect of ionizing radiation on thrombocytes
(platelets): platelets initiate blood clotting and
prevent hemorrhage they have life span of 30
days a dose of radiation greater than 0.5 Gy
lessens the number of platelets in the circulating
blood, death from internal bleeding might occur.
• Radiation exposure during diagnostic imaging
procedures: diagnostic procedures should not
result in high exposure to blood forming organs,
however studies indicate chromosomal abrasion
in lymphocytes that receive radiation dose during
diagnostic procedure,
• Patients with high level fluoroscopic procedures
like cardiac catheterization.
• Occupational radiation exposure monitoring: film
badge or TLD can be used to detect exposures in
mSv and can be used to discover potentially
hazardous working conditions, a periodic blood
count is not recommended as a method of
monitoring occupational exposure because
biologic damage has already been sustained when
irregulatory is seen in the blood counts
• Muscle tissue: these tissues are highly
specialized and do not divide they are
relatively insensitive to radiation
• Nervous tissue: in adults nerve cells are highly
specialized and perform specific functions, in
the nucleus of one of these cells is destroyed
the cell will die and never restored. If axon or
dendrites damaged by radiation control and
communication with some areas of the body
may be disrupted.
• Nerve tissue in the embryo-fetus: developing
nerve cells in the embryo-fetus are more
radiosensitive than mature nerve cells of the
adult, irradiation of the embryo may lead to
CNS anomalies, microcephaly and mental
retardation, maximum sensitivity extends
from 8-15 weeks after gestation during this
period exposure of 0.1 Sv (10 rem) fetal EqD is
associated with as much as 4% risk of mental
retardation
• Reproductive cells:
• Spermatogonia: human germ cells are relatively
radiosensitive, the male testes contain both mature
and immature Spermatogonia, the mature
spermatogonia are specialized and do not divide they
are relatively insensitive to radiation, the immature
spermatogonia are rapidly dividing they are extremely
radiosensitive, radiation dose of 2Gy may cause
temporary sterility for 12 months and 5-6 Gy exposure
may cause permanent sterility, small doses 0.1 Gy may
depress male sperm population. Male reproductive
cells that have been exposed to 0.1 Gy or more may
cause genetic mutation in future generation.
• Ova: is the mature female germ cells that do not divide
constantly, radiosensitivity of ova varies considerably
throughout the life time of the germ cells immature ova
are very radiosensitive, after irradiation a mature ovum
can still unit with a male germ cell, these irradiated cells
may contain damaged chromosomes, genetic damage
may be passed on to the offspring resulting in
congenital anomalies. During diagnostic imaging
gonadal shielding is essential to limit radiation damage
to the reproductive organs.
• Radiation exposure also may cause female sterility
depending on the age of the subject the ovaries of
female fetus and young child are very radiosensitive
because they contain large number of stem cells.
Summary
• Cells going through the division phase (M and S) are
generally the most sensitive to ionizing radiation.
Exceptions: lymphocytes and some bone marrow stem cells,
which exhibit interphase death
• Bone marrow consists of progenitor and stem cells, the
most radiosensitive cells in the human body and the
most important in controlling infection
• Early and late effect of radiation
1- early effect: when biologic effects of
radiation occur relatively soon after
human exposure to a high does of
radiation
Early Somatic Effects
• This appears within minutes,
hours, days, or weeks, of the
time of radiation exposed
• A sever amount of dose can
cause a pattern of symptoms
which referred to as radiation
syndrome.
• Nausea, Fatigue, Erythema, and
Blood Disorder
• The amount Somatic and genetic damage
depends on
1- the quantity of ionizing radiation to which the
body is exposed
2- the ability of ionizing radiation to cause
ionizations of human tissue
3- the amount of body area exposed
4- the specific body part exposed
• Somatic effects: when human body exposed
to radiation experience biological damage, the
effects of this exposure is classified as somatic
effect. Depending on the length of time from
the exposure to the first appearance of
symptoms of radiation damage. The effects
are classified as either early or late somatic
effects
• If these effects are cell-killing and directly related to
the dose received they are called deterministic
somatic effects, as dose increased the severity of
early effects are also increased. A substantial dose
of ionizing radiation is required to produce
biological effect soon after exposure, the severity of
these effects is dose dependent the higher the dose
the more severe is the damage
• Acute radiation syndrome (ARS): occur in
human after whole body exposure to large
doses of ionizing radiation in short period of
time.
• Symptoms of ARS: three separate dose related
syndromes occur as part of the total body
syndrome
- Hematopoietic syndrome
- Gastrointestinal syndrome
- Cerebrovascular syndrome
• Response stages of ARS
- prodromal
- Latent period
- Manifest illness
- Recovery or death
• Prodromal or initial stage occur within hours
after whole body absorbed dose of 1 Gy or
more this stage is characterized by nausea,
vomiting, diarrhea, fatigue, and leukopenia
>5000/ cubic mm.
• Latent period: occur about 1 week after exposure
during which no visible symptoms occur, during this
period either recovery or lethal effects begin
• Manifest illness: the period when symptoms that
affect the hematopoietic, gastrointestinal, and
Cerebrovascular systems become visible. Some of
these symptoms are apathy, confusion, decrease in
the number of RBCs and WBCs and platelets in the
circulating blood, dehydration, epilation, exhaustion,
vomiting , severe diarrhea, infection hemorrhage,
and cardiovascular collapse.
• Lethal dose LD: LD 50/30 means the whole
body dose of radiation that can kill 50% of the
exposed population within 30 days. The LD
50/30 for adult human is estimated to be 3-4
Gy without medical support, for x-ray and
gamma ray this is equal to an equivalent dose
of 3-4 Sv, whole body does greater than 6 Gy
may cause the death of the entire population
in 30 days.
LD 50/30
Hematologic Syndrome
Radiation doses in the range of approximately 200 to 1000
rad (2 to 10 Gyt) produce the hematologic syndrome. The
patient initially experiences mild symptoms of the
prodromal syndrome, which appear in a matter of a few
hours and may persist for several days.
The latent period that follows can extend as long as 4
weeks and is characterized by a general feeling of
wellness. There are no obvious signs of illness, although
the number of cells in the peripheral blood declines during
this time.
The period of manifest illness is characterized by
possible vomiting, mild diarrhea, malaise, lethargy,
and fever. Each of the types of blood cells follows a
rather characteristic pattern of cell depletion. If the
dose is not lethal, recovery begins in 2 to 4 weeks,
but as long as 6 months may be required for full
recovery.
If the radiation injury is severe enough, the reduction
in blood cells continues unchecked until the body's
defense against infection is nil. Just before death,
hemorrhage and dehydration may be pronounced.
Death occurs because of generalized infection,
electrolyte imbalance, and dehydration.
Gastrointestinal (GI) Syndrome
Radiation doses of approximately 1000 to 5000 rad (10 to 50
Gy) result in the GI syndrome. The prodromal symptoms of
vomiting and diarrhea occur within hours of exposure and
persist for hours to as long as a day. A latent period of 3 to 5
days follows, during which no symptoms are present.
The manifest illness period begins with a second wave of
nausea and vomiting, followed by diarrhea. The victim
experiences a loss of appetite (anorexia) and may become
lethargic. The diarrhea persists and becomes more severe,
leading to loose and then watery and bloody stools.
Supportive therapy cannot prevent the rapid progression of
symptoms that ultimately leads to death within 4 to 10 days
of exposure.
Intestinal cells are normally in a rapid state of
proliferation and are continuously being replaced by
new cells. The turnover time for this cell renewal
system in a normal person is 3 to 5 days.
Radiation exposure kills the most sensitive cells—stem
cells; this controls the length of time until death. When
the functional cells are completely removed from
intestinal lining, fluids pass uncontrollably across the
intestinal membrane, electrolyte balance is destroyed,
and conditions promote infection.
Central Nervous System (CNS) Syndrome
After a radiation dose in excess of approximately 5000 rad
(50 Gyt) is received, a series of signs and symptoms occur
that lead to death within a matter of hours to days. First,
severe nausea and vomiting begins, usually within a few
minutes of exposure.
During this initial onset, the patient may become extremely
nervous and confused, may describe a burning sensation in
the skin, may lose vision, and can even lose consciousness
within the first hour. This may be followed by a latent period
that lasts up to 12 hours, during which earlier symptoms
subside or disappear.
The latent period is followed by the period of
manifest illness, during which symptoms of the
prodromal stage return but are more severe. The
person becomes disoriented; loses muscle
coordination; has difficulty breathing; may go into
convulsive seizures; experiences loss of equilibrium,
ataxia, and lethargy; lapses into a coma; and dies.
Regardless of the medical attention given to the
patient, the symptoms of manifest illness appear
rather suddenly and always with extreme severity. At
radiation doses high enough to produce CNS
effects, the outcome is always death within a few
days of exposure.
The ultimate cause of death in CNS syndrome is
elevated fluid content of the brain.
The CNS syndrome is characterized by increased
intracranial pressure, inflammatory changes in the
blood vessels of the brain (vasculitis), and
inflammation of the meninges (meningitis). At doses
sufficient to produce CNS damage, damage to all
other organs of the body is equally severe. The
classic radiation-induced changes in the GI tract and
the hematologic system cannot occur because there
is insufficient time between exposure and death for
them to appear.
Acute radiation lethality follows a nonlinear,
threshold dose-response relationship.
At the lower dose of approximately 100 rad (1
Gyt), no one is expected to die.
Above approximately 600 rad (6 Gyt), all those
irradiated die unless vigorous medical support is
available. Above 1000 rad (10 Gyt), even vigorous
medical support does not prevent death.
As the whole-body radiation dose increases, the
average time between exposure and death
decreases. This time is known as the
mean survival time.
•All early radiation responses—local tissue
damage is a good example—follow a thresholdtype dose-response relationship. This is
characteristic of a deterministic radiation
response. A minimum dose is necessary to
produce a deterministic response. Once that
threshold dose has been exceeded, the severity
of the response increases with increasing dose.
• local tissues that can be affected immediately
by the radiation are:
skin, gonads, and bone marrow.
Radiation effects
Early
(deterministic only)
Late
Local
Deterministic
Common
Radiation injury of
Radiation dermatitis
Acute
radiation
disease
individual organs:
Radiation cataract
Acute
radiation
syndrome
functional and/or
Teratogenic effects
morphological
changes within
hrs-days-weeks
Stochastic
Tumours
Leukaemia
Genetic effects
Late effect of radiation
• High radiation doses can induce cancer in
human, low radiation doses such as those
received in occupationally exposed individuals
are not known to cause malignancy, however
the risk for radiation induced cancer in
radiation workers is not really measurable at
low doses encountered in diagnostic radiology
Radiation Dose-Response
Relationship
• Also known as the dose response
curves, which is graphically determined
by a curve that diagrams the observed
effects of radiation exposure in relation
to the dose of the radiation given.
Dose-Response curves different in
two ways:
1. They can either be linear or non
linear
linear (straight line)
nonlinear (curved to some degree)
2. They can also be either threshold or
nonthreshold
Nonlinear
• Nonlinear can be described as a
relationship or function that is not exactly
proportional.
• For Example: An observed response that is
not directly proportional to the dose.
• Doubling the dose of radiation, does not
double the response.
Threshold
• Threshold is the point at
which something begins
or changes. (Starting
Point)
• In this case, it assumes
that there is a radiation
level reached below
which no effects can be
observed.
Nonlinear Dose-Response
• Also known as the Sigmoid Dose
Response Curve.
• Sigmoid meaning S-shaped (curve)
• This curve is mainly applied to the high
dose effects observed in radiotherapy.
• There is usually a Threshold below
which no visible effects happen.
Nonthreshold
• Means that any radiation dose will produce
biologic effect, no radiation dose is believed to
be absolutely safe, some biologic response will
be caused in living organisms by even the
smallest dose of ionizing radiation, A linearquadratic dose response is a relationship
between dose and biological response that is
curved. This implies that the rate of change in
response is different at different doses. The
response may change slowly at low doses, for
example, but rapidly at high doses
Dose Response Relationship
• Threshold assumes that there is a radiation
level reached below which there would be no
effects observed.
• Nonthreshold assumes that any radiation dose
produces an effect.
A. Linear Quadratic Dose
Response
B. Linear Nonthreshold Dose
Response
C. Linear Threshold Dose
Response
D. Nonlinear Dose Response
(sigmoid curve)
Factors Effecting the Dose Models and
Theories
• The time period over which the dose is
delivered
• Age of the exposed individual
• State of health of the exposed individual
• The time period between multiple exposures
• Somatic effect : when living organisms that
have been exposed to radiation sustain
biologic damage the effects of the exposure
are classified as somatic effects.
• Late somatic effects : are effects that appear
months or years after exposure to ionizing
radiation, these effects may result from
previous whole or partial body acute high
radiation doses, or may be due to individual
low level doses sustained over several years.
• Late effects that can be directly related to the
dose received and occur months or years after
high level radiation exposure are classified as
late deterministic somatic effects ( cataract,
fibrosis, organ atrophy, reduced fertility,
sterility).
• Late effects that do not have threshold occur
in an arbitrary or probabilistic manner have a
severity that does not depend on dose, and
occur months or years after high level
radiation exposure
• Are classified as late stochastic somatic
effects ( cancer, embryonic effects( birth
defects)).
Long Term Effects
•
•
•
•
•
•
Malignant disease
Induction of cataracts of the eye lenses
Local tissue damage
Life-span shortening
Genetic damage
Potential effects to fetus
Bone Cancer
•
•
•
•
Radium dial painters
Ingested radium
Radium deposited in bones
Increased incidence of osteogenic sarcoma
and osteoporosis
• Radon is very high LET radiation
• Alpha and Beta particles emitted
Studies Showing Evidence Of
Carcinogenesis In Humans
• Atomic Bomb Survivors
– Leukemia, Thyroid,
Breast
• Marshall Islanders
– Some thyroid cancer
• Radium Dial Painters
– Bone cancer
• Early Radiologists
– Leukemia, skin cancer
• Multiple Chest Fluoroscopy
– Breast cancer
• Infants W/Enlarged Thymus
– Thyroid cancer
• Thorotrast
– Leukemia, Liver cancer
• In Utero Exposures
– Leukemia
• Iodine 131 Therapy
ForThyroid
– Some leukemia
• Uranium Miners
– Lung cancer
Conclusions About RadiationInduced Cancer
• Single exposure can be enough to
elevate cancer incidence several
years later
• There is no radiounique cancer
• Almost all cancers are associated
with radiation
• Breast, bone marrow, and thyroid
are especially radiosensitive
• The most prominent radiogenic
tumor is leukemia
• Solid tumors have a latent period of
10 years
• Leukemia’s latent period is
thought to be about 5 - 7
years
• Age of irradiated individual
is most important factor
• Percentage increase in
cancer incidence/rad varies
between organs and types
of cancers
• Dose-effect curves are best
assumed to be linear
Cytogenetic damage
• Increased spontaneous
abortions or still birth
• Altered sex ratios
• Leukemia and other
neoplasms
• Increased infant
mortality
• Increased congenital
effects
• Decreased life expectancy
• Dominant inherited
diseases
– Dwarfism, Polydactly,
Huntington’s Chorea
• Recessive inherited
diseases
– Cystic fibrosis, TaySachs, hemophilia,
albinism
Skin
• Highly vascular organ
• Basal layer is constantly regenerating
– Most radiosensitive layer
• Late changes in skin
– sunburn, aging
– atrophy
– fibrosis
– change in pigmentation
– ulceration
– necrosis
Skin Cancer
Skin cancer usually begins with the development of a
radiodermatitis. Significant data have been developed
from several reports of skin cancer induced in radiation
therapy recipients treated with orthovoltage (200 to 300
kVp) or superficial x-rays (50 to 150 kVp).
Radiation-induced skin cancer follows a
threshold dose-response relationship.
Eyes
• Cataractogenesis
• Latent period may take up to 30 years
– About 200 rads
– All will develop cataracts at 1000 rads
– The dose-response relationship for
radiation induced cataracts is nonlinear,
threshold.
If the lens dose is high enough, in excess of approximately 1000 rad
(10 Gyt), cataracts develop in nearly 100% of those who are irradiated.
The precise level of the threshold dose is difficult to assess.
Most investigators would suggest that the threshold after an acute xray exposure is approximately 200 rad (2 Gyt). The threshold after
fractionated exposure, such as that received in radiology, is probably in
excess of 1000 rad (10 Gyt). Occupational exposures to the lens of the
eye are too low to require protective lens shields for radiologic
technologists. It is nearly impossible for a medical radiation worker to
reach the threshold dose.
Radiation administered to patients who are undergoing head and neck
examination by fluoroscopy or computed tomography can be
significant. In computed tomography, the lens dose can be 5 rad (50
mGyt) per slice. In this situation, however, usually no more than one or
two slices intersect the lens. In either case, protective lens shields are
not normally required. However, in computed tomography, it is
common to modify the examination to reduce the dose to the eyes
LIFE-SPAN SHORTENING
Many experiments have been conducted with animals after both
acute and chronic exposures that show that irradiated animals
die young. Figure below, shows that the relationship between
life span shortening and dose is apparently linear, nonthreshold.
When all animal data are considered collectively, it is difficult to
attempt a meaningful extrapolation to humans
The theory of radiation hormesis suggests that
very low radiation doses are beneficial.
Some evidence supports the principle of radiation
hormesis. Radiation hormesis suggests that low
levels of radiation—less than approximately 10 rad
(100 mGyt)—are good for you! Such low doses may
provide a protective effect by stimulating molecular
repair and immunologic response mechanisms.
Nevertheless, radiation hormesis remains a theory
at this time, and until it has been proved, we will
continue to practice ALARA—as low as reasonably
achievable.
Genetically Significant Dose
• The dose equivalent to the reproductive
organs that would bring about genetic injury
to the population if received by the total
population
• The estimated GSD for the US is about 20
mrem
Radiation Effects On Fetal Development
• Three basic stages in fetal development
– Preimplantation
• Conception to 10 days post conception
– Organogenesis
• Cells implanted in uterine wall
• Cells begin differentiating into organs
– Fetal or growth stage
• Sixth week after conception
• Growth rather than new development
Principle Effects Of Radiation On Embryo
Or Fetus
• Embryonic or fetal
death
• Malformations
• Growth retardation
• Congenital defects
• Cancer induction
• Doses of less than 10 rad
– No indication to
terminate a pregnancy
• Doses between 10 and 25
rad
– Gray area for
terminating pregnancy
• Doses above 25 rad
– Termination should be
considered
Radiation Damage In Terms Of
When Irradiated
• Cataracts
– 0-6 gestation days
• Herniation of the brain
– 0 - 37 days
• Embryonic death
• Anophthalmia
– 16 - 32 days
• Cleft palate
– 20 - 37 days
• Skeletal disorders
– 4 - 11 days
– 25 - 85 days
• Anencephaly or
microcephaly
• Growth disorders
– 9 - 90 days
– 54 +
Doses To Embryo Per Procedure
• Based on overhead films only
• Average number of films/examination
– Barium Enema - 800 mrad
– Cholecystrogram - 80 mrad
– IVP - 800 mrad
– Pelvis - 200 mrad
– UGI - 50 mrad
Objective of radiation protection
• 1- to prevent any clinically important radiation
induced deterministic effect from occurring by
adhering to dose limits that are below
threshold level
• 2- to limit the risk of stochastic response to a
conservative level as weighted against societal
needs, values, benefits acquired, and
economic consideration
• ALARA concept: national council on radiation
protection and measurements (NCRP) put this
principle that radiation exposure should be
kept as low as reasonably achievable with
consideration for economic and social factors.
• The continuation of good radiation protection
program and practices which traditionally
have been effective in keeping the average
and individual exposures for monitored
workers well below the limit.
• For the radiographer and the radiologist the
ALARA concept should serve as a guide for
the selection of technical radiographic and
fluoroscopic exposure factors for all patient
imaging procedure.
• The reason for this concept in radiologic
practice is to keep radiation exposure and
consequent dose to the lowest possible level.
Responsibility for Maintaining
ALARA
• It is the responsibility of the employer to provide the
necessary resources and appropriate environment in
which to execute an ALARA program.
• To determine that proper lowered radiation exposure
are being applied, management should perform
periodic exposure audits.
• Radiation workers with appropriate education and
work experience must function with awareness of
rules governing the work situations.
EQUIVALENT DOSE AND EFFECTIVE DOSE
Equivalent Dose (EqD)– A quantity that attempts to take
into account the variation in biologic harm that is produced
by different types of radiation.
• Equivalent Dose (Eqd) enables the calculation of the
Effective Dose (EfD)
Effective Dose (EfD) – A quantity that attempts to
summarize the overall potential for biologic damage to a
human due to exposure to ionizing radiation
• Effective dose takes into account organ weighting factors
and represents the whole body dose that would give an
equivalent biologic response.
• EfD and EqD are both expressed in sieverts (Sv), used by
the International System of Units (SI), or rem, which adopts
the traditional measuring system
NCRP Recommendations
• Annual occupational effective dose limits
should not exceed 50mSv (5 rem) for whole
body dose
• Cumulative effective dose limits refers to
lifetime effective dose age in years multiplied
by 10mSv for whole body dose
• Collective effective dose in description with
population or group exposure using an
averaging the effective dose
NCRP Recommendations (cont)
• Limits of nonoccupationally exposed individuals are set at
1mSv annually for medical exposure and 5mSv for natural
exposure
• Limits for pregnant female radiation workers are 0.5mSv per
month and entire pregnancy dose limit of 5mSv
• Limits for education and training purpose for individuals under
18years of age is 1mSv annually
• Negligible individual dose is 0.01mSv
• Limits for tissue and organs are set differently depending on
sensitivity of the organ or tissue.
– Lens of the eye 150mSv(15rem)
– Localized skin 500mSv(50rem)
Occupational Dose Limits
• Action limits are set by health care facilities to
ensure radiographers do not reach a dose limit
that can be harmful
• Effective dose limits for radiation workers are
20mSv (2 rem) annually
• Special limits are set for highly sensitive areas
of the body such as the lens of the eye and
localized areas of the skin, hands, and feet to
prevent nonstochastic effects