Radiation Biology

Radiation Biology
2015
Assist. Prof. Dr. Yekbun Adgzel
stanbul Kemerburgaz University
Faculty of Medicine
MED 122 Cell Tissue and Organ Systems II
Biophysics Lecture
From: On-line lecture notes of Prof. Yair Meiry from University of Debrecen, Hungary.
Some brief highlights:

Nuclei of elements close to Fe in the periodic table are very stable,
as binding energy per nucleon is the highest for these elements.
About radioactive decay;

Radiation associated with high ionization density (ionization density =
LET) is alpha (). Such radiation has a mass number of 4. So, the
mass number of radioactive isotope decreases by 4 during decay.
The mass number decreases by 4 during alpha decay.
Some brief highlights:

Decay that changes the atomic number but not the mass number is
called beta () decay.
The atomic number decreases by one during + decay since
it is the spontaneous transformation of 1 proton to 1 neutron,
along with emission of the positive charge as a + particle.
The atomic number increases by one during - decay.
During K electron capture, a proton is transformed into a neutron
by capturing 1 e- into the nucleus.
The energy spectrum of alpha radiation is discrete (discrete and

line spectrum are synonymous).mma photons and X-ray photons
are considered indirectly ionizing radiations.
In Geiger Muller counter, high energy gamma particles do not
generate a bigger pulse than low energy gamma particles because
the counter is an ionization detector, it does not detect the energy
of the gamma particles.
A detector that uses a crystal and a photomultiplier tube is called
scintillation detector.
A gamma knife is a therapeutic application of radioactive isotopes.
The energy distribution of beta-radiation is continuous because a

neutrino is emitted along with the beta-particle during the decay.
Web-site for the images & the information given below: http://hedberg.web.cern.ch/hedberg/c/nuclear/nuke_sl.htm
The energy spectrum of alpha radiation is discrete (discrete and
line spectrum are synonymous).

The energy distribution of beta-radiation is continuous because a
neutrino is emitted along with the beta-particle during the decay.
Gamma photons and X-ray photons are considered indirectly

ionizing radiations.
In Geiger Muller counter, high energy gamma particles do not

generate a bigger pulse than low energy gamma particles because
the counter is an ionization detector, it does not detect the energy
of the gamma particles.
A detector that uses a crystal and a photomultiplier tube is called
scintillation detector.
A gamma knife is a therapeutic application of radioactive isotopes.
http://www.sprawls.org/ppmi2/RADIOACT/
N0 is the initial quantity of the substance that

will decay (this quantity may be measured in
grams, moles, number of atoms, etc.),
N(t) is the quantity that still remains and has
not yet decayed after a time t,
t12 is the half-life of the decaying quantity,
is a positive number called the mean

lifetime of the decaying quantity,
is a positive number called the decay

constant of the decaying quantity
http://en.wikipedia.org/wiki/Half-life
Physical and biological half-lives
Physical and biological half-lives of a nucleus are NOT directly
proportional with each other, as an undecayed nucleus can leave the

body as a result of metabolism. The latter is related to the rate of
metabolism but physical half-life is to the rate of decay. So, an

undecayed nucleus can leave the body as a result of metabolism.
http://www.sprawls.org/ppmi2/RADIOACT/
N0 is the initial quantity of the substance that

will decay (this quantity may be measured in
grams, moles, number of atoms, etc.),
N(t) is the quantity that still remains and has
not yet decayed after a time t,
t12 is the half-life of the decaying quantity,
is a positive number called the mean

lifetime of the decaying quantity,
is a positive number called the decay

constant of the decaying quantity
http://en.wikipedia.org/wiki/Half-life
Physical and biological half-lives
The effective half-life is combination of the physical half-life and the

biological half-life. So, both work on degradation (metabolism +
decay) of the radioactive isotope, which makes them longer than the
effective half-life, when considered alone. (See decay times in the next slide)
http://biophys.med.unideb.hu/
sites/default/files/course_mate
rial/2010/09/11_radiation_biol
ogy_pn_2010_pdf_29676.pdf
Activity is the property of radionuclides emitting radiation, by

spontaneous transformation of the nuclei. There are two
radioactivity units. These are Curie (Ci) and Becquerel (Bq).
37 000 000 000 Ci = Bq
Physical and Biological Dose

Concepts
Units
The energy amount and dose of the ionizing radiation that is taken
by the human is defined as Gray (Gy) and the unit amount of it is 1
Joule of energy absorbed by 1 kg of mass. The designation rad
was previously used instead of this one.
When Gy is multiplied by a radiation weighting factor, Sievert (Sv)
is obtained. It is the effective dose definition, for the biological
effect of radiation. The designation rem was previously used
instead of this one.
Units
Absorbed dose (unit Gray, Gy): Energy (unit J) absorbed by a
unit of body mass (unit kg)
The information that is not provided above is that Sievert (Sv)
measures damage to the tissues and this is the basic insight one
should gain here. 1 Sv is the damage of 1 Gy of 250 keV X-
ray on the human tissue. So, accordingly, 2 Sv is the damage

of 2 Gy of 250 keV X-ray on the human tissue.
Absorption of 8 Gray by the tissue is fatal, although it does not lead
to a critical increase in temperature (0.002 K calculated by formula:
Q=mcT). Where does the damage arouse from? - Molecular events
http://biophys.med.unideb.hu/sites/default/files/course_material/2010/09/11_radiation_biology_pn_2010_pdf_29676.pdf
The first dose concept that will be taken into account is exposure
(it is the charge, in coulombs, which is generated per unit mass
as a result of being exposed to radiation, unit c/kg). Exposure
is the amount of positive or negative charges generated by Xray or gamma radiation in a body of unit mass during electron
equilibrium. (Electron equilibrium:

The number of electrons entering
or leaving the body volume.)
http://biophys.med.unideb.hu/sites/default/files/course_material/2010/09/11_radiation_bi
ology_pn_2010_pdf_29676.pdf
Exposure
Assume that an ionizing radiation is hitting a body of unit mass,
which can be part of a tissue.

Inherently, ionizing radiation causes ionization of electrons which
causes secondary ionizations.
Electrons move in and out during this primary and secondary

ionization processes.
This results in a charge difference in the mass in question, lets
say the tissue. There is also heat release during these processes.
Exposure
Another dose concept takes heat

release into account as well. This
is KERMA. KERMA is the kinetic
energy released in material and
its unit is also Gray. This is the

sum of the kinetic energy of all
particles that is generated by the

ionizing radiation in an absorbing
material, divided by the mass of
the absorbing material.
(For high energy radiation,

kerma>absorbed dose.)
Kerma
Among all, the biological dose concept is the most commonly
used. Biological dose and equivalent dose are both measured

with the unit Sievert (J/kg). The unit Sievert indicates the
damage that is caused by the ionizing radiation to the tissue.

So, 1 Sv is the damage of 1 Gy of 250 keV X-ray radiation that
is caused in human tissue. It is calculated by the equivalent

dose formula:
(Explained in the next slide)
Biological dose and equivalent dose
each type of radiation (e.g. alpha, beta, and gamma) has different
LET values and penetration capabilities. Therefore, different
radiation types individual contribution to the absorbed

dose is calculated by multiplying the absorbed dose of the
given radiation, by the weighting factor. In the end, all

the present radiation types are summed to calculate the
final equivalent dose, which is formulated as above.
What the above formula for equivalent dose (HT) indicates is that
European Nuclear Society www.euronuclear .org
Radiation weighting factors of different radiation types are

shown in the following table, where the beta-negative (-)
particles are electrons. Alpha () particles have a high
weighting factor.
Radiation weighting factor for equivalent dose
The biological dose concept that is formulated as below is

effective dose concept and it makes more sense as it takes tissue
variations for radiation sensitivity into account. Its unit is also Sv.
This concept is based on the fact that different tissues exhibit

different radiation sensitivities (remember that sensitivity of
different tissue types to radiation are not the same).
Effective dose
absorbed dose is calculated by multiplying the absorbed dose
of the given radiation, by the weighting factor of the tissue of

concern.
In the end, the results are summed for all the present radiation
and tissue types, to calculate the final effective dose, which is
formulated as shown in the previous slide. The basic difference

is that the tissue weighting factors come to stage in case of the
effective dose, contrary to the equivalent dose concept.
Different radiation types individual contribution to the
European Nuclear Society www.euronuclear .org
Organ
Tissue weighting factor T
Gonads
0.20
Colon
0.12
Bone marrow (red)
0.12
Lung
0.12
Stomach
0.12
Bladder
0.05
Chest
0.05
Liver
0.05
Thyroid gland
0.05
Oesophagus
0.05
Skin
0.01
Bone surface
0.01
Adrenals, brain, small intestine, kidney, muscle,

pancreas, spleen, thymus, uterus
0.05
(the weighting factor 0.05 is applied to the average dose

of these organs)
The second table, which is shown below, lists the tissue

weighting factors of some organs.
Target and Molecular Theories
Dose response curve (also called survival curve), which is

shown below, is explained by target theory and molecular
theory.
It shows the fraction of surviving (i.e. non-inactivated, not
damaged) individuals (objects) as a function of dose
Dose response curve
Shape of survival curve for mammalian cells exposed to

radiation. The fraction of cells surviving is plotted on a
logarithmic scale against on a linear scale. For -particles or
low energy neutrons (said to be densly ionizing), the doseresponse curve is a straight line from the origin (i.e., survival is
an exponential function of dose). The survival curve can be
described by just one parameter, the slope. (ref. is on the next slide)
-particles
or low
energy
neutrons
Dose response curve
For X- or -rays (said to be sparsely ionizing), the doseresponse curve has an initial slope, followed by a shoulder; at
higher dose, the curve tends to become straight again.
X- or -rays
Chul-Seung Kay and Young-Nam Kang. Curative Radiotherapy in Metastatic

Disease: How to Develop the Role of Radiotherapy from Local to Metastases
DOI: 10.5772/56556 Web-site: http://cdn.intechopen.com/pdfs-wm/45395.pdf
Dose response curve
graph that is shown in the previous slide are target theory and
molecular theory.
Target theory is basically saying that each molecule has a very

sensitive part which leads to the destruction of whole
molecule when that part is destroyed.
The theories that describe why we observe the relation in the
of whole molecules is random, probabilistic, or whole

molecular destruction is stochastic. The destruction
probability of a molecule is relevant to the number of hits by

the radioactive isotope that it receives. This is a discrete, non-
negative integer value.
Target theory explains the graph as it states that destruction
Survivability curve combined with the probabilistic concept

The concept that deals statistically with discrete variables is Poisson
distribution.
The probability of getting n number of hits is calculated by the formula P(n)
that is shown on the next slide.
To calculate the surviving fraction of organisms, probability of receiving no

hits in the one hit one inactivation situation is used, because only the
organisms that receive no hit will be surviving.

Another relevant concept is D37, which refers to the applied dose that leads
to the percent of surviving organisms to be 37.
D is the applied dose and
Survivability curve combined with the probabilistic concept

mentioned in the previous slide states that the molecules that
require higher number of hits to be destroyed will have a
graph with a longer shoulder, as shown in the figure below.
This is because the shoulder lengthening is due to the
requirement of multiple hits to render the molecules inactive.
Molecular theory of
radiation damage
attempts to explain radiation damage to the organism.

Some molecules are more critical for the survival of the organism
and target theory doesnt account this case.
Molecular theory considers the radiation sensitivity of DNA
that is critical for cell survival. When single strand DNA break
occurs due to ionizing radiation, it can be repaired by cellular
mechanisms but a double strand break cannot be repaired
and causes damage to the cell. This is what the molecular
theory mainly considers.
Molecular theory is the other theory that
Molecular theory considers the radiation sensitivity of DNA

that cant be repaired and is critical for cell survival. .
The DNA double strand break can be caused due to

a single hit, directly, by breaking of the bonds on both
DNA strands, or
indirectly, by breaking of the bond at one strand and
causing the second break at the other strand through a
radical that is generated by this hit.
DNA double strand breaks can also occur as a result of
two (multiple) hits.
Molecular theory
From: On-line lecture notes of Prof. Yair Meiry from Univ ersity of Debrecen, Hungary
Model
Expression describing surviving fraction of cells (equation below)contains 2 terms

(one linear and one quadratic function of D), with regard to the molecular model
of radiation sensitivity.
In this formula,the 1st term in the brackets is

due to the contribution of 1 hit 1 inactivation
case and the 2nd term in the brackets is due
to 2 hits 1 inactivation cases contribution.
Minus sign in front of the bracket leads to
the higher contribution of the 1st term.
From: On-line lecture notes of Prof. Yair Meiry from Univ ersity of Debrecen, Hungary
Model
Expression describing surviving fraction of cells (equation below)contains 2 terms

(one linear and one quadratic function of D), with regard to the molecular model
of radiation sensitivity.
In this formula, the 1st term in the

brackets is due to the contribution of
1 hit 1 inactivation case and the 2nd
term in the brackets is due to 2 hits 1
inactivation cases contribution.
http://eamos.pf.jcu.cz/amos/kra/externi/kra_409/program_02.ppt
The most
important types
of radiation
induced lesions
in DNA
Base damage
Single-strand breaks
Double strand breaks
Possible radiation induced DNA damage in a cell:
Type of lesion
Double strand breaks (dsb)
Single strand breaks (ssb)
Base damage
Sugar damage
DNA-DNA crosslinks
DNA-protein crosslinks
Alkali-labile sites
Number per Gray

40
500-1000
1000-2000
800-1600
30
150
200-300
http://eamos.pf.jcu.cz/amos/kra/externi/kra_409/progr
am_02.ppt
Failure of DNA Repair Mechanisms

Active enzymatic repair processes exist for the repair of both
DNA base damage and strand breaks. Yet, these mechanisms
can fail, and:
Residual unrejoined double strand breaks are lethal to the cell,
whereas incorrectly rejoined breaks may produce important
Incorrect repair
mutagenic lesions.
of DNA damage
In many cases, this DNA misrepair apparently

leads to DNA deletion and rearrangement.
Such large scale changes in DNA structure are Mutations

Unrejoined characteristic of most radiation induced mutations.
DNA
double strand
breaks
Cytotoxic effect
Toxic effects at low to moderate doses (cell killing,

mutagenesis, and malignant transformation) appear
to result from damage to cellular DNA.
Other radiation damages: Radiation induced

membrane damage
Plasma membrane, endoplasmic reticulum, golgi, lysosomes, and
peroxisomes of the cells are all composed of membranes.

Biological membranes serve as highly specific mediators between the cell (or its
organelles) 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 membranes structure can

cause changes in its permeability to various molecules, i.e. electrolytes.
Other radiation damages: Radiation induced

membrane damage
In the case of nerve cells, alterations of its membrane proteins would affect
their ability to conduct electrical impulses.
Also, unregulated release of lysosomes catabolic enzymes into the cell could
be disastrous. Ionizing radiation has been suggested to be playing a role in
plasma membrane damage, which may be an important factor in cell death.
Direct and Indirect Effects of

Radiation

Radiation
The stages of action of ionizing radiation:
Physical, physic-chemical, chemical, biological
Effect of radiation on atom and molecules: Excitation, ionization.
(Ionization is the basic mechanism to trigger the events that cause
radiation damage to living tissues.)
Mechanisms of damage at molecular level: Direct and indirect actions.

Direct effect is the predominant cause of damage in reactions involving high LET
radiation, such as alpha particles, neutrons and heavy ions. Absorption of energy
sufficient to remove an electron can result in bond breaks.
Indirect action is predominant with low LET radiation such as X and gamma rays.

Radiation
The stages of action of ionizing radiation:
Physical, physic-chemical, chemical, biological
Effect of radiation on atom and molecules: Excitation, ionization.
(Ionization is the basic mechanism to trigger the events that cause
radiation damage to living tissues.)
Mechanisms of damage at molecular level: Direct and indirect actions.

Ionization is the major direct action, but excitation of atoms in key molecules can
also occur resulting in bond breaks. In this case energy can be transferred along
the molecule to a weak bond site and cause break. Tautomeric shifts can also
occur by the energy of excitation sourced predominance of one molecule form.
Indirect action takes effect by radiolysis of water and its attacks on biomolecules.
the radiosensitive volume and/or causes double strand DNA breaks.

The biological molecule is directly hit and inactivated by the radiation
It is the only mechanism taking place when irradiating dried samples
Its probability is much smaller than that of hitting a solvent molecule
when irradiating solutions
Tautomeric shifts
Direct effects of radiation are observed when the radiation hits
effects are considered, formation of radicals in
aqueous solutions is meant. Different factors such as radiation quality,

relative biological effectiveness (RBE), cell cycle, fractionation, and O2
effects also influence radiation sensitivity.
In dilute aqueous solutions, the probability that the radiation hits a
water molecule is much larger than probability of hitting a target (e.g.
enzyme molecule).
Radiation leads to
the generation of
free radicals from
water which reach
and inactivate the
target.
When indirect
of radiation on water molecules lead to the
formation of radicals that have free electron pairs on their orbital.

These radicals seek aggressively for molecules to share their electrons
with, and ionize them, which can lead to inactivation of those other
molecules.
So, in dilute aqueous solutions, the molecule of interest may not be hit
by the radiation, directly, but still be inactivated by such indirect effects.
As a result, the targets in dilute aqueous solutions are effectively larger
in size.
The impact
From: On-line lecture notes of Prof. Yair Meiry from

University of Debrecen, Hungary.
The targets in dilute aqueous solutions are effectively larger in size.

Effect of this relation on enzyme activity is shown in the below graph.
Relevance of Free Radicals Lifetimes

HO2o
RO2o
OHo
OHo
3nm
Ho
Because short life of simple free radicals (10-10sec), only those formed in
water column of 2-3 nm around DNAre able to participate in indirect effect
While generally highly reactive, these simple free radicals do not exist long
enough to migrate from the site of formation to the cell nucleus. However,
O2 derived species such as hydroxyperoxy free radical does not readily
recombine into neutral forms. These more stable forms have a lifetime
long enough to migrate to nucleus, where serious damage can occur.
Factors influencing radiation sensitivity
A. The quality of radiation

Among the factors effecting radiation sensitivity, radiation
quality includes LET (linear energy transfer, ionization density)
and penetrability. These are relevant to the weighting factor
concept. There is also relative biological effectiveness (RBE).

This is showing the effectiveness of a specific dose of radiation
radiation (Dtest) with respect to the standardized dose of a 250
keV X-ray radiation (Dx-ray).
So, RBE = Dx-ray / Dtest

The extent of radiation damage depends on ionization
density (LET).
LET is characterized by the relative biological effectiveness
(RBE), a constant similar to the quality factor (QR) and the
radiation weighing factor (wR).
Penetrability: alpha and beta radiation cannot penetrate

the skin They can only generate systemic effects, if they
can, in the organism.

Relative biological effectiveness (RBE)
RBE is similar, but not identical to quality factor (QR) and
radiation weighing factor (wR).
B. Biological variability
1. Cells display different radiation sensitivity in different parts
of the cell cycle (implications for radiation therapy of cancer:
in cancer a higher fraction of cells is in the M phase than in
normal tissue.)
1. Cells display different radiation sensitivity in different parts
of the cell cycle (implications for radiation therapy of cancer:
in cancer a higher fraction of cells is in the M phase than in
normal tissue.)
Within the tissues, cells are the major units that are considered for being
affected by radiation since they are the basic units showing viability.
The cell is of course damaged through the damage in its components such
as proteins, DNA, and enzymes.
Within a cell division cycle, the M and the G2 phases are the most radiation
sensitive phases.
2. The less differentiated the cells are, the higher their
radiation sensitivity is (implications for radiation therapy of
cancer: cancer cells are less differentiated than normal cells)
The radiation sensitivity of tissues based on the dependence of
radiation sensitivity on cell cycle and differentiation:

tissue
tissue
Lympathic tissue
Blood vessels
White blood cells, immature

erythrocytes in bone marrow
Glands, liver
Mucous membrane of stomach

and intestine
Connective tissue
Gametes
Muscle tissue
Proliferating cell layer of the skin
10
Nervous tissue
those cell types that are less differentiated like stem cells are
more radiosensitive than the more differentiated cells like
muscle and nerve cells.

As a generalized rule, the tissue becomes less radiosensitive as
it gets more differentiated.

A list of tissues types starting from more radiosensitive going
down to less radiosensitive were shown in the table within the
previous slide.
The other factors influencing radiation sensitivity are:
C. Time factor (Fractionation)

Fractionation influences surviving fraction curve by applying radiation
dose over a period of time so that time would be allowed for the single
strand DNA breaks to be repaired, which would increase surviving
fraction number and decrease radiation damage.
D. Metabolism and temperature and

E. The effect of O2
C. Time factor
The remaining factors influencing radiation sensitivity to be mentioned

are D. metabolism and temperature and E. the effect of oxygen
In case of D, the former one, metabolism is directly proportional with
temperature and the radiation sensitivity.
The latter one, E. the effect of oxygen, is obviously relevant to the
radical formation, which is directly proportional with the presence of
oxygen. So, tissue oxygenation levels are thus influencing the
radiosensitivity levels of those tissues.
C. Metabolism and temperature

Cells with a higher metabolic rate usually have higher radiation
sensitivity.
Since the rate of metabolism increases with temperature, a

temperature increase usually leads to higher radiation sensitivity.

E. The effect of oxygen
Oxygen can modify the reaction by enabling creation of other
free radical species with greater stability and longer lifetimes
H + O2 HO2 (hydroperoxy free radical)

R + O2 RO2 (organic peroxy free radical)
The transfer of the free radical to a biological molecule can be sufficiently
damaging to cause bond breakage or inactivation of key functions.
In addition, the organic peroxy free radical can transfer the radical
from molecule to molecule causing damage at each encounter.
Thus, a cumulative effect can occur, greater than a single
ionization or broken bond.

E. The effect of oxygen
EFFECTS OF IONIZING RADIATION

ON TISSUES, ORGANS AND
SYSTEMS
Ionizing radiation
Cell
If the damage is too severe, the cell

may die.
Repair
Mitotic
cell
death
When cells come into contact with

ionizing radiation sufficient to
cause cellular damage, one of three
possible actions will occur.
Damaged
normal cell
If the cell is not severely damaged,

it might be able to repair itself and
continue functioning, but could
lose its ability to divide. This is
known as reproductive (mitotic) cell
death.
A damaged normal cell might

mutate, which may cause cancer or
genetic effects.
Types of cellular damage
Remember from the previous slides that the less differentiated

the cells are, the higher their radiation sensitivity is
(implications for radiation therapy of cancer: cancer cells are
less differentiated than normal cells)
The radiation sensitivity of tissues based on the dependence of
radiation sensitivity on cell cycle and differentiation:

tissue
tissue
Lympathic tissue
Blood vessels
White blood cells, immature

erythrocytes in bone marrow
Glands, liver
Mucous membrane of stomach

and intestine
Connective tissue
Gametes
Muscle tissue
Proliferating cell layer of the skin
10
Nervous tissue
http://biophys.med.unideb.hu/sites/default/files/course_material/2010/09/11_radiation_biolo
gy_pn_2010_pdf_29676.pdf, http://eamos.pf.jcu.cz/amos/kra/externi/kra_409/program_03.ppt
Tissue radiosensitivity
Highly radiosensitive
Lymphoid
While all cellstissue
can be
Bone
marrow
destroyed
by a high enough
Gastrointestinal
radiation dose, highly
epithelium
radiosensitive
cells or
tissue
Gonads (testis
and
exhibit
ovary)deleterious effects
at
much lower (foetal)
doses than
Embryonic
others.
tissues
Moderately radiosensitiveLeast radiosensitive

Skin
Central
nervous
The least radiosensitive
tissue,
although
Vascular endothelium
system (CNS)
radioresistant, is less capable
of cell renewal than
Lung
Endocrine (except
highly sensitive tissue. Some - especially
Kidney
gonad) neurons, glial
Liver
Thyroid
adults no
cells of the brain, and muscle cells
- has in
essentially
Lens
(eye)
Muscle
ability
to regenerate. Once these
cells are killed, the
Thyroid in childhood
Bone and cartilage
area is repairedConnective
by fibrosis ortissue
scarring.
Highly radiosensitive Moderately radiosensitiveLeast radiosensitive

Lymphoid tissue
Bone marrow
Gastrointestinal
epithelium
Gonads (testis and
ovary)
Embryonic (foetal)
tissues
Skin
Vascular endothelium
Lung
Kidney
Liver
Lens (eye)
Thyroid in childhood
Central nervous
system (CNS)
Endocrine (except
gonad)
Thyroid in adults
Muscle
Bone and cartilage
Connective tissue
http://biophys.med.unideb.hu/sites/default/files/course_material/2010/09/11_radiation_biolo
gy_pn_2010_pdf_29676.pdf, http://eamos.pf.jcu.cz/amos/kra/externi/kra_409/program_03.ppt
Tissue radiosensitivity
Organs
Relative radio
sensitivity
Chief mechanism of parenchymal

hypoplasia
High
Destruction of parenchymal cells, especially

the vegetative or differentiating cells
Skin; cornea & lens of eyes;

gastrointestinal organs:
cavity, esophagus,
stomach, rectum
Fairly high
Destruction of vegetative and differentiating

cells of the stratified epithelium
Growing cartilage; the

vasculature; growing bones
Medium
Destruction of proliferating chondroblasts or

osteoblasts; damage to the endothelium;
destruction of connective tissue cells &
chondroblasts or osteoblasts
Mature cartilage or bone;

lungs; kidneys; liver;
pancreas; adrenal gland;
pituitary gland
Fairly low
Hypoplasia (incomplete or defective

development, underdevelopment) secondary
damage to the fine vasculature and
connective tissue elements
Muscle; brain; spinal cord
Low
Hypoplasia secondary damage to the fine

vasculature and connective tissue elements,
with little contribution by the direct effects on
parenchymal tissues
Lymphoid organs; bone

marrow, testis & ovaries;
small intestines
Embryonic tissue
Relative radiosensitivity of various organs based on

parenchymal hypoplasia (incomplere or underdevelopment)
Hierarchical organization of haematopoiesis
Most radiosensitive are the stem cells of the bone marrow, which
give rise to all circulating blood cells and platelets, and the lymphoid
tissue found in the spleen, liver, lymph nodes and thymus.
CFU : Colony forming unit
BFU: Burst forming unit
GM: Granulocyte-Macrophage
MK: Megakaryocyte
BFU-E
BFU-MK
CFU-GEMM
CFU-GM
CFU-E
CFU-MK
CFU-M
CFU-G
Stem cell
L: Lymphoid
BL: B lymphoid
TL: T lymphoid
CFU-L
E: Erythroid
Ba: Basophil
Eo: Eosinophil
GEMM: Granulocyte erytrocyte
megakaryocyte monocyte
red blood cell

platelets
monocytes
neutrophils
CFU-Ba
basophils
CFU-Eo
eosinophils
CFU-BL
B lymphocytes
Thymus
CFU-TL T lymphocytes
Proliferation Bone marrow Differentiation
Haematopoietic system
Blood
Normal physiological situation

Resting
stem cells
Proliferating
compartment:
stem cell and
progenitors
activation
Differentiating Mature
Blood
compartment:
cells
precursors
exit
differentiation
proliferation, differentiation
Stem cells: immature cells with autorenewal capability
Progenitors: primitive cells, high proliferative potential
Mature cells: no proliferative capability
Bone marrow kinetics
The bone marrow contains three cell renewal systems:

1.
the erythropoietic (red cell),
2.
the myelopoietic (white cell), and
3.
the thrombopoietic (platelet).
The time cycles and cellular distribution patterns and postirradiation

responses of these three systems are quite different.
Morphological and functional studies have shown that each cell line, i. e.
erythrocyte, leukocyte, and platelet, has its own unique renewal kinetics.
The time related responses evident in each of these cell renewal systems
after irradiation are integrally related to the normal cytokinetics of each

cell system.
Bone marrow kinetics
Normal physiological situation

Resting
stem cells
Proliferating
compartment:
stem cell and
progenitors
activation
Differentiating Mature
Blood
compartment:
cells
precursors
exit
differentiation
proliferation, differentiation
I
R
R
A
D Block of
I
Depletion by absence of renewal
proliferation,
A
T cell death
Depletion of
I The main effect of ionizing radiation is to
BLOOD
O induce the death of proliferating cells within proliferating
APLASIA
compartment
N the stem cell and progenitor compartment.
Effects of radiation on haematopoiesis
http://biophys.med.unideb.hu/sites/default/files/course_material/2010/09/11_radiation_biology_pn_2010_pdf_29676.pdf
Normal bone marrow cellularity appears in

this photomicrograph as clear spaces that
are fat cells, pink-stained angular bodies
that are spicules on normal bone, and
diffuse haematopoietic tissue.
Normal bone
Irradiated bone marrow lacks all

marrow precursor haematopoietic cells
Within 48 hours after a lethal dose of radiation, peak cell degeneration,

consisting of massive destruction and necrosis of bone marrow stem cells,
occurs.
Effect of radiation on bone marrow
Normal bone marrow Irradiated bone marrow lacks all

precursor haematopoietic cells
Within 48 hours after a lethal dose of radiation, peak cell degeneration,

consisting of massive destruction and necrosis of bone marrow stem cells,
occurs.
In the irradiated bone marrow shown on the right hand side, the precursor
haematopoietic cells are no longer present. Four days after 9 Gy of cobalt-60
irradiation, all that is left in the irradiated canine bone marrow shown is a fine
network of reticular stroma. The red areas are vascular sinusoids engorged with
red blood cells and occasional plasma cells. The clear areas indicate where the
haematopoietic tissues were. The plasma cells, being differentiated cells, are
relatively radioresistant at this stage.
Effect of radiation on bone marrow
Cell pools in normal steady state

Stem
cell
Dividing
&
maturing
Maturing
only
Blood
Relative
Number of Cells
Changes after irradiation
Time
After Irradiation
1 hour
1 day
2 days
3 days
4 1/4 days
5 days
Model of blood renewal system
Erythrocytes changes as a dose function - 1
1 Gy
3 Gy
Erythrocytes changes as a dose function
1 Gy
3 Gy
The function of cell renewal system is to produce mature erythrocytes for the
circulation. The transit time from the stem cell stage in the bone marrow to
the mature red cell ranges from 4 to 7 days, after which the life span of the
red cell is approximately 120 days.
The immature forms, i.e. erythroblast and proerythroblast, undergo mitosis
as they progress through the dividing and differentiating compartment.
Because of their rapid proliferating characteristics, they are markedly
sensitive to cell killing by ionizing radiation. Cell stages within the maturing
(non-dividing) and functional compartments, i.e. normoblast, reticulocyte, red
cell, are not significantly affected by mid-lethal to lethal doses.
1 Gy
3 Gy
The death of stem cells and of those within the next compartment is
responsible for the depression of erythropoietic marrow and, if sufficiently

severe, is responsible together with haemorrhage for subsequent radiation
induced anaemia.
Because of the relatively slow turnover rate, e.g. approximately 1% loss

of red cell mass per day, in comparison with leukocytes and platelets,
evidence of anaemia is manifested subsequent to the depression of the
other cell lines, provided that significant haemorrhage has not occurred.
1 Gy
3 Gy
The erythropoietic system has a marked propensity for regeneration following
irradiation from which survival is possible.
After sublethal exposures, marrow erythropoiesis normally recovers slightly
earlier than granulopoiesis and thrombopoiesis and occasionally overshoots
the base-line level before levels at or near normal are reached.
Reticulocytosis, occasionally evident in peripheral blood smears during the
early intense regenerative phase occurring after maximum depression, often
closely follows the temporal pattern of marrow erythropoietic recovery.
Although anaemia may be evident in later stages of the bone marrow
syndrome, it should not be considered a survival limiting sequalae
Leukocytes changes as a function of dose

-1
Normal
<1Gy
1-2 Gy
2-5 Gy
>5-6 Gy
Time after
exposure,
days
Leukocytes changes as a function of dose
Normal
<1Gy
1-2 Gy
>5-6 Gy
2-5 Gy
Time after
exposure,
days
Stem cells and those developing stages within the dividing and differentiating
compartment are the most radiosensitive. These are myeloblast, progranulocyte
and myelocyte stages. As with the erythropoietic system, cell stages within the
maturing (non-dividing) compartment and the mature functional compartment,
i.e. granulocytes, are not significantly affected by radiation doses within the mid-
lethal range. 3-7 days are normally required for the mature circulating neutrophil
granulocyte to form from its stem cell precursor stage in bone marrow.
Leukocytes changes as a function of dose - 1
Normal
<1Gy
1-2 Gy
2-5 Gy
Time after
>5-6 Gy
exposure,
days
An ionizing radiation dose of 2 Gy or less usually causes a very gradual depression
of counts to 50% or less with a nadir at more than 40 days. Doses greater than 2
Gy cause an initial paradoxical rise in counts, a rise that lasts only hours or days
and is followed by a precipitous drop. This is caused by prompt demargination of
white cells into the circulation. Any CBC taken during this paradoxical rise may be
misinterpreted as evidence of infection. Doses greater than 5 Gy usually cause the
precipitous drop to continue relentlessly to a nadir of zero or near zero in 3-4
weeks. Doses of 2-5 Gy cause a second abortive rise, which interrupts the
precipitous drop in counts for several days and possibly as long as a week.
Normal
<1Gy
1-2 Gy
2-5 Gy
Time after
>5-6 Gy
exposure,
days
This 2nd abortive rise is caused by products of final differentiation and entry into
circulation of marrow PMN (polymorphic nucleated cell) precursor cells, which do
not need to undergo further mitotic divisions. Extent and duration of this 2nd rise
varies; but classically, it lasts for about a week with a rise from ~ 50% to ~ 75% of
normal. Then neutrophil count continues dropping to a nadir of near zero to 20%
of normal at ~25-35 days after exposure. Recovery of myelopoiesis lags slightly
behind erythropoiesis and is accompanied by rapid increases in differentiating and
dividing forms number in the marrow. Prompt recovery is occasionally manifest
and is indicated by increased band cell numbers in the peripheral blood.
Thrombocytes changes as a dose function

-1
Normal
<1Gy
2-5 Gy
>5-6 Gy
1-2 Gy
Time after
exposure,
days
Thrombocytes changes as a dose function
Normal
<1Gy
1-2 Gy
>5-6 Gy
2-5 Gy Time after

exposure, days
The thrombopoietic cell renewal system is responsible for the production of

platelets (thrombocytes) for the peripheral circulating blood. Platelets along with
granulocytes constitute two of the most important cell types in the circulation, the
levels of which during the critical phase after mid-lethal doses markedly influence
the survival or non-survival of irradiated persons. Platelets are produced by
megakaryocytes in the bone marrow. Both platelets and mature megakaryocytes

are relatively radioresistant; however, the stem cells and immature stages are very
radiosensitive. During their developmental progression through the bone marrow,
megakaryocytic precursor cells undergo nuclear division without cell division.
Thrombocytes changes as a dose function - 1
Normal
<1Gy
1-2 Gy
>5-6 Gy
2-5 Gy Time after
exposure, days
The transit time through the megakaryocyte proliferating compartment in humans
ranges from 4 to 10 days. Platelets have a lifespan of 8-9 days. Although platelet
production by megakaryocytes may be reduced by a high dose of ionizing
radiation, the primary effect is on the stem cells and immature megakaryocyte
stages in the bone marrow. As with the erythropoietic and myelopoietic systems,
the time of beginning depression of circulating platelets is influenced by the
normal turnover kinetics of cells within the maturing and functional
compartments. Early platelet depression, reaching thrombocytopenic levels by 34 weeks after mid-lethal range doses, occurs from killing of stem cells and
immature megakaryocyte stages and from maturation depletion of maturing and
functional megakaryocytes.
Normal
<1Gy
1-2 Gy
>5-6 Gy
2-5 Gy Time after
exposure, days
Regeneration of thrombocytopoiesis after sublethal irradiation normally lags
behind both erythropoiesis and myelopoiesis. Supranormal platelet numbers which
overshoot the preirradiation level have occurred during the intense regenerative
phase in human nuclear accident victims. The mechanism of the prompt rapid
recovery of platelet numbers after acute sublethal irradiation may be explained by
the response of the surviving and regenerating stem cell pool to a human feedback
stimulus from the acute thrombocytopenic condition, and marked increases in size
of megakaryocytes contribute to the intense platelet production and eventual
restoration of steady state levels. Blood coagulation defects with concomitant
haemorrhage constitute important clinical sequalae during the thrombocytopenic
phase of bone marrow and gastrointestinal syndromes.
Effects of radiation on lymphatic tissue1
A
Normal monkey
lymph node
B
Germinal centre of
normal monkey
lymph node
C
D
9 Gy CO-60 40-60 Gy
Germinal centre of
irradiated human
lymph node
Lymphoid cells
depleted
in cortex of canine
lymph node
A. Normal lymph node from monkey. Normal architectural features include the
capsule, cortex, paracortical regions, germinal centres, and medulla. The clear,
sharp cortical-medullary delineation is evident. The medulla, cortex, germinal
centres, and paracortical areas are well defined.
Effects of radiation on lymphatic tissue-1
A
Normal monkey
lymph node
B
Germinal centre of
normal monkey
lymph node
C
D
9 Gy CO-60 40-60 Gy
Germinal centre of
irradiated human
lymph node
Lymphoid cells
depleted
in cortex of canine
lymph node
B. Normal germinal centre The germinal centre of a normal monkey lymph node
is shown magnified. The centre of the follicle, which stains light pink, is an area of
predominantly B cell proliferation. A mantel zone of mixed T and B cells surrounds
this central area. The paracortical regions, which are deep and lateral to the
follicles, are predominantly T lymphocyte regions within the lymph node.
A
Normal monkey
lymph node
B
Germinal centre of
normal monkey
lymph node
C
D
9 Gy CO-60 40-60 Gy
Germinal centre of
irradiated human
lymph node
Lymphoid cells
depleted
in cortex of canine
lymph node
C. Depleted lymph node The depleted lymph node shown is from a canine that
received 9 Gy of cobalt-60 gamma irradiation. It shows moderate edema in the
subcapsular sinuses. The sharp cortical-medullary functional architecture is not
well defined because of the overall depletion of lymphoid cells within the cortex.
A
Normal monkey
lymph node
B
Germinal centre of
normal monkey
lymph node
C
D
9 Gy CO-60 40-60 Gy
Germinal centre of
irradiated human
lymph node
Lymphoid cells
depleted
in cortex of canine
lymph node
D. Irradiated germinal centre Shown is a section of a germinal centre from a

lymph node of a human who received 40 to 60 Gy of whole body irradiation. There
is extensive necrosis of lymphocytes, characterized by pyknotic and karyorrhectic
nuclei. Necrotic debris is being phagocytized, or cleaned up, by macrophages. Such
destruction occurs within hrs of irradiation. This patient died 35 h after exposure.
Early changes in peripheral blood lymphocyte

counts depending on the dose of acute whole
body exposure
Circulating lymphocytes are quite sensitive to

radiation and a measurable drop in the normal titre
0.251.0 Gy
1.0-2.0Gy
2-4 Gy
4-6 Gy
>6 Gy
(1500-3000/mm3) can meter radiation exposure

and indicate the dose levels.
Lymphocyte counts are usually the first blood
counts to drop after exposure to ionizing
radiation.
A drop in lymphocytes occurs 24 to 48 hrs after the
injury.
The speed and extent of the lymphocyte drop is
linearly proportional to the severity of the dose to
the bone marrow.
Early changes in peripheral

blood lymphocyte counts
A minor drop is noted after doses of 0.25 to 1 Gy. At

about 1.5 Gy, the drop is around 20%. At 3 Gy, the
count drops to 700/mm3; at 4 to 5 Gy, it drops to
0.251.0 Gy
1.0-2.0Gy
2-4 Gy
4-6 Gy
>6 Gy
less than 500/mm3. A drop to zero (within 2 days)

implies a dose greater of 6 Gy.
Thus, the drop in lymphocyte count is a crude but
simple and sensitive, and therefore important,
estimation of severity of injury within 48 hrs of
exposure. A patient whose lymphocyte count stays
above 1500/mm3 after 48 h may have received a

clinically significant dose, but the overall prognosis
is quite good. On the other hand, a patient whose
count drops to less than 500/mm3 in 24 h
demonstrates a profound life threatening injury.
Early changes in peripheral Early changes in peripheral blood lymphocyte

counts depending on the dose of acute whole body
blood lymphocyte counts
exposure
<1 Gy
1-2 Gy
2-5 Gy
>5-6 Gy
Time after exposure, days
The first detectable sign of whole body exposure is a decrease in blood
lymphocytes. This decrease appears a few hours or days after irradiation and is
related to the dose received, but also to the volume of irradiated bone marrow.
This is due to the direct effect of ionizing radiation on lymphocytes, but also to
the radiation induced death of proliferating haematopoietic cells that are not
able to ensure the renewal of blood cells.
Lymphocytes changes as a function of dose
Effect of radiation on gastrointestinal tract
The vulnerability of the small intestine to radiation is primarily in the cell

renewal kinetics of the intestinal villi. The renewal system is in the crypt and
villus structures, where epithelial cell formation, migration and loss occur. The
four cell renewal compartments are: stem cell and proliferating cell
compartment, maturation compartment, functional compartment, and the
extrusion zone. Stem cells and proliferating cells move from crypts into a
maturing only compartment at the neck of the crypts and base of the villi.
Functionally mature epithelial cells than migrate up the villus wall and are
extruded at the villus tip. The overall transit time from stem cell to extrusion
on the villus for man is estimated as being 7 to 8 days.

Image from Wikimedia Commons
Because of the high turnover rate occurring within the

stem cell and proliferating cell compartment of the
crypt, marked damage occurs in this region by
whole-body radiation doses above the mid-lethal

range. Destruction as well as mitotic inhibition occurs
cell compartments within hours after high doses.

Maturing and functional epithelial cells continue to
migrate up the villus wall and are extruded albeit the
process is slowed.
Image from Wikimedia Commons
within the highly radiosensitive crypt and proliferating
Shrinkage of villi and morphological changes in mucosal cells, i.e., columnar to

cuboidal to squamoid, occur as new cell production is diminished within the
crypts. Continued extrusion of epithelial cells in the absence of cell production

can result in denudation of the intestinal mucosa. Concomitant injury to the
microvasculature of the mucosa and submucosa in combination with epithelial
cell denudation results in hemorrhage and marked fluid and
electrolyte loss contributing to shock.
These events normally occur within 1 to 2 weeks after irradiation. A second

mechanism of injury has recently been
detected at the lower range of the gastrointestinal syndrome,

or before major denudation occurs at higher doses of
radiation. This response is a functional increase in fluid
and electrolyte secretion on the epithelial cells without
visible cell damage. This 2nd mechanism may have
important implications for fluid replacement therapy.
Denuding of sections of bowel, in
Depletion of the epithelial
turn, causes a host of

pathophysiological sequelae. They
cells lining lumen of
include invasion of lumenal bacteria
gastrointestinal tract
into the circulation, loss of fluid and

electrolytes, loss of absorptive
capability, significant
gastrointestinal haemorrhage and
loss of blood, and dysfunctional
bowel motility, resulting in severe
bloody diarrhoea, anaemia, ileus,
severe electrolyte disturbances, and
malnutrition.
Intestinal bacteria gain free

access to body
Haemorrhage through
denuded areas
Loss of absorptive capacity
Pathogenesis of the gastrointestinal syndrome
Reproductive cell kinetics and sterility
The cells of the reproductive system are highly sensitive to radiation effects. In the
human male, stem cells and proliferating spermatogonia are highly sensitive.
However, spermatids and mature sperm show considerable resistance. Also resistant
are the interstitial cells of the testis, which control hormone production and
secondary sexual characteristics. Therefore at sterilizing doses of 6 Gy, potency, fluid
production of the prostate and seminal vesicles, as well as voice, beard and male
social behaviour are not affected.
With a turnover time for spermatogenesis (stem cell to mature sperm) of 64 to 72
days, sterility is never seen immediately after the radiation dose, because mature
sperm are resistant to the killing effects of radiation. They can sustain inheritable
genetic damage, however.
Reproductive cell kinetics and sterility - male
Doses of about 6 Gy are required to permanently sterilize males (sterility occurs after
several months). Although lower doses can also cause sterility after several months,
effect is temporary. Fertility and near-normal sperm counts return after 1 to 2 years.
Dose rate has an unusual effect on the incidence of sterility in males. In animals it
was found that dose protraction and fractionation were more effective in causing
permanent sterility. This may be a result of synchronizing the sperm stem cells.
Proliferating stem cells in the G2 phase or M phase of the cell cycle are killed by
radiation. But since the dose is protracted at a constant low rate, resistant S and G1
cells eventually progress to the sensitive phases and are killed.
Reproductive cell kinetics and sterility - male
Radiation destroys both ovum and maturing follicles. This reduces hormone
production. Therefore radiogenic sterility in females can be accompanied by
artificial menopause, with significant effects on sexual characteristics and
secondary genitalia.
Total dose, dose rate, and age are important factors in the final effect. Younger
women seem better able to recover fertility than do older women.
A dose of 2 Gy permanently sterilizes women over 40 but causes temporary
sterility in women aged 35 and under. Menopouse was caused in 50% of
younger women exposed to doses of 1.5-5 Gy. Women over 40 showed 90%
menapouse at 1.5 Gy.
Reproductive cell kinetics and sterility - female
Effect of radiation on skin
Image modified from:

http://www.gold-collagen.com/wpcontent/uploads/2014/01/SKINILLUSTRATION-FINAL-VERSION.jpg
Cellularity
Normal human skin exhibits a uniform layered appearance of cellularity,
beginning with the basal layer.
Epidermis its average thickness is 70 m, but basal cells are located in hair
follicles at a depth of 200 m.
Derma - its average thickness is 1-3 mm
Human skin structure
Alpha radiation is absorbed in

superficial layers of dead cells
within the stratum corneum
Beta radiation damages epithelial
basal stratum. High energy radiation may affect vascular layer
of derma, with lesion like thermal
burn
Gamma
radiation
damages
underlying tissues and organs
Penetration of radiation
through skin stuctures
The tissue of the skin most sensitive to radiation is the rapidly developing
germinal or basal layer of epithelial cells. In the normal epidermal layer of
skin, the cells that make up the basal germinal layer through the superficial
layers are uniform in appearance and are well differentiated.
Irradiation damages the moderately radiosensitive basal germinal cells. It
disrupts the normal cellular appearance, causes atypical and bizarre cells in
the upper layers, and results in a general loss of cohesiveness at the
intercellular junction.
Skin layers
Cellularity
Normal human skin exhibits a uniform layered appearance of cellularity,
beginning with the basal layer. The irradiated human skin (figure on the rigth, in
the next slide) is from the back of the hand of a patient exposed to 100 to 150
Gy of X rays. There is a decrease in the number of cells in the basal layer, and
the remaining cells are irregular in shape and size. Some are separated,
exhibiting acantholysis. There are occasional bizarre mitotic figures. In this
condition, the entire epithelial layer will eventually ulcerate and slough.
Irradiated
Normal
The irradiated human skin is from the back of the hand of a patient exposed to
100 to 150 Gy of X-rays. There is a decrease in the number of cells in the basal
layer, and the remaining cells are irregular in shape and size.
Some are
separated, exhibiting acantholysis. There are occasional bizarre mitotic figures.
In this condition, the entire epithelial layer will eventually ulcerate and slough.
Effect of radiation on skin
Pulmonary effects
Irradiated lung tissue Pulmonary fibrosis
Radiation doses in the 10-30 Gy also produce potentially life threatening

pulmonary effects of respiratory insufficiency and pneumonitis, which will be
seen 14-30 days after exposure. Pneumonitis is likely to be caused by a complex
of factors, including breakdown of vascular permeability, fluid imbalance, free
radical tissue interactions, infectious agent, biological and chemical toxin damage,
and inhalation injury from heat, smoke, and fumes.
Pulmonary effects
Bone marrow consists of progenitor and stem cells, the most

radiosensitive cells in the human body and the most important
in controlling infection
Doses in tens of gray produce central nervous system syndrome,
causing death before appearance of the haematopoietic or
gastrointestinal syndromes
The latter syndromes may occur after doses of as low as 2.5 and
8 Gy, respectively. Lesions in the brain are usually caused by
damage to the vascular endothelium
Lung lesions do not usually appear at radiation doses less than
10 Gy. Significant concern in partial-body irradiation and in
radiation therapy
EFFECTS OF IONIZING RADIATION

ON TISSUES, ORGANS AND
SYSTEMS - SUMMARY
Use of Isotopes in
Medicine
2015
Assist. Prof. Dr. Yekbun Adgzel
stanbul Kemerburgaz University
Faculty of Medicine
MED 122 Cell Tissue and Organ Systems II
Biophysics Lecture
http://biophys.med.unideb.hu/sites/default/files/course_material/2010/09/12_isotopes_kg
_2010_pdf_12915.pdf
_2010_pdf_12915.pdf
Meselson-Stahl experiment proves semiconservative DNA replication by
the use of nitrogen isotopes.

The bacteria that are reproducing in a medium containing only the
15N
isotope will have only the 15N isotope in their DNA.

When these bacteria are transferred into a medium containing only the
14N
isotope, the first generation during replication will have exactly equal
amounts of
15N
and
14N
isotopes and exactly one fourth of the DNA will
have 15N isotopes in their DNA. This is observed experimentally.

So, the Meselson-Stahl experiment is an example of the employment of a
stable isotope,
15N,
for research purposes, namely the demonstration of
semiconservative replication of DNA.
PRODUCTION OF ISOTOPES
BY USING ACCELERATORS
_2010_pdf_12915.pdf
Particle accelerators are generally used to accelerate charged particles in

an electrical field, by using alternating radiofrequency pulses. They can
be linear or cyclic and can be used to make 13C isotopes.
DIAGNOSTIC USE
C14 DATING
_2010_pdf_12915.pdf
_2010_pdf_12915.pdf
The second example of the applications of isotopes is determination of

small concentrations.
When the target molecule of interest can be bound by antibodies, they can
be immobilized onto surface and used for detection of small amount of the
target antigens inside any sample. Then binding can be confirmed by

washing the surface and sending radioactively labeled antibodies, as a
detectable tracer for determination of the surface-bound antigens. This is
the direct manner of determination.
Y. Meiry from University of Debrecen, Hungary
_2010_pdf_12915.pdf
As the indirect manner,

the unoccupied binding
regions on the surface
can be measured by a
detectable tracer, in
comparison to the
control signal.
Control signal would be

received from measuring
the detectable tracer
after binding it to all the
sites over the surface.
_2010_pdf_12915.pdf
As the third applications of isotopes, 14C dating is discussed.

Atmosphere continuously forms 14C, due to cosmic interactions with nitrogen (14N).
All materials around us contains 14C, but live biological systems continuously
intakes this isotopes, which has a specific half-life.
This 14C uptake ceases after death of the organism or formation of the
material, such as geological formations.
Therefore, 14C can be used for dating non-living materials through
correlating the ages of the materials with the half-life of 14C.
_2010_pdf_12915.pdf
_2010_pdf_12915.pdf
As a brief highlight to start up, a radiopharmacon (radioactive isotope +

biologically relevant molecule) features a radioactive isotope that
diffuses throughout or selectively targets a certain organ or gland in the
body. It is injected into the patient body. There, it emits gamma
radiation.
As the first application of isotopes, tracing radioactivity for measuring

protein interactions in the body, one can couple the radioactive isotope
3H
with the biologically relevant leucine molecule to obtain a
radiopharmacon as the tracer and follow its decay, to see its fate in the
body. For instance, that leucine will be absorbed in the pancreas, to be
secreted. If the pancreas is dissected at different times, the route that
leucine follows during secretion by the pancreas can be learned by

locating the radioactive tracer at each of those different times. So, this
is a means of taking a functional image.
_2010_pdf_12915.pdf
measuring
the
volumes
of
bodily
compartments,
again
radiopharmacon, a biologically relevant molecule coupled to a radioactive

isotope can be used. The principle is basically calculating the volume of
the target tissue through applying a known concentration and volume of
radiopharmacon that will be diluted in a higher volume and the size of the
larger volume can be calculated through the resulting dilution amount.
Blood volume determination can be a good example for this application.
_2010_pdf_12915.pdf
For
of absorption can be measured as well, such as in case of the iodine

uptake by the thyroids. The selected isotopes are preferred to have
short half-lives, in order to diminish the duration of radioactivity
presence in the body and its emission to the environment.
_2010_pdf_12915.pdf
If the radiopharmacon is absorbed specifically by a tissue, the amount
ISOTOPES THAT ARE USED IN IMAGING
_2010_pdf_12915.pdf
_2010_pdf_12915.pdf
Gamma Camera
Gamma Camera
The working principle of gamma cameras is as follows:
Outside the body, the emitted gamma radiation from the radioisotope such
as 99Tc is absorbed through the collimators,

goes by the scintillation detector, and
is interpreted through the current that it induces at the photomultiplier tubes
(PMTs).
Gamma Camera
PMT is responsible for the actual reading of the device.
On the other hand, collimator is responsible for the lateral

resolution since radiation that reaches to the collimator at oblique
angles are blocked by the collimator and radiation at specific

angles are allowed to reach at the scintillation detector.
Also, the exemplified 99Tc is a commonly preferred isotope for its

short half-life, meaning that it decays rather fast and therefore the
adverse effects of long radiation duration is prevented.
_2010_pdf_12915.pdf
http://www.radiologyinfo.org/en/info.cfm?pg=renal
Renal scintigraphy, also known as "renal scanning" or "renal

imaging," refers to several examinations using radioisotopes that
evaluate the function and anatomy of the kidney. Renal scintigraphy
is one of many imaging methods used to evaluate the kidneys.
Different types of renal scans are used to examine different aspects of the
kidneys and kidney functioning by the injection of a radiotracer or

radioisotope, or imaging substance that emits a tiny amount of radioactivity,
into the patient. Because the radiotracer accumulates differently in different

kinds of tissue, it can help physicians determine if something is wrong with the
kidneys. Renal scintigraphy can also be used to evaluate a transplanted kidney.
After injection, the radiotracer eventually accumulates in the kidneys,

where it gives off energy in the form of gamma rays. This energy is
detected by a device called a gamma camera. The camera works with a
computer to measure the amount of radiotracer absorbed by the body
and to produce special pictures offering details on both the structure and
function of organs and tissues. SPECT uses a gamma camera that rotates
around the body to produce more detailed, three-dimensional images.
_2010_pdf_12915.pdf
_2010_pdf_12915.pdf
The application examples of isotopes is

concluded with gamma knife. Gamma knife is
radioactive therapy. So, it is a therapeutic
instrument that uses 60Co to generate gamma
radiation, which can be used to irradiate
tumors in brain with multiple gamma rays
from different sources. Each individual
gamma rays may not be that damaging but
their collective effect are far too effective.
End of the presentation

Radiation Biology

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Radiation Biology

Some brief highlights:

About radioactive decay;

mass number of radioactive isotope decreases by 4 during decay.

The mass number decreases by 4 during alpha decay.

Some brief highlights:

The energy spectrum of alpha radiation is discrete (discrete and

A gamma knife is a therapeutic application of radioactive isotopes.

The energy distribution of beta-radiation is continuous because a

The energy spectrum of alpha radiation is discrete (discrete and

line spectrum are synonymous).

Gamma photons and X-ray photons are considered indirectly

In Geiger Muller counter, high energy gamma particles do not

N0 is the initial quantity of the substance that

is a positive number called the mean

is a positive number called the decay

Physical and biological half-lives

Physical and biological half-lives of a nucleus are NOT directly

proportional with each other, as an undecayed nucleus can leave the

metabolism but physical half-life is to the rate of decay. So, an

N0 is the initial quantity of the substance that

is a positive number called the mean

is a positive number called the decay

Physical and biological half-lives

The effective half-life is combination of the physical half-life and the

Activity is the property of radionuclides emitting radiation, by

37 000 000 000 Ci = Bq

Physical and Biological Dose

should gain here. 1 Sv is the damage of 1 Gy of 250 keV X-

ray on the human tissue. So, accordingly, 2 Sv is the damage

equilibrium. (Electron equilibrium:

or leaving the body volume.)

Assume that an ionizing radiation is hitting a body of unit mass,

which can be part of a tissue.

Electrons move in and out during this primary and secondary

Another dose concept takes heat

its unit is also Gray. This is the

particles that is generated by the

(For high energy radiation,

Among all, the biological dose concept is the most commonly

used. Biological dose and equivalent dose are both measured

damage that is caused by the ionizing radiation to the tissue.

is caused in human tissue. It is calculated by the equivalent

Biological dose and equivalent dose

radiation types individual contribution to the absorbed

given radiation, by the weighting factor. In the end, all

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Radiation weighting factors of different radiation types are

Radiation weighting factor for equivalent dose

The biological dose concept that is formulated as below is

This concept is based on the fact that different tissues exhibit

absorbed dose is calculated by multiplying the absorbed dose

of the given radiation, by the weighting factor of the tissue of

formulated as shown in the previous slide. The basic difference

effective dose, contrary to the equivalent dose concept.

Different radiation types individual contribution to the

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Tissue weighting factor T

Bone marrow (red)

Adrenals, brain, small intestine, kidney, muscle,

(the weighting factor 0.05 is applied to the average dose

The second table, which is shown below, lists the tissue

Target and Molecular Theories

Dose response curve (also called survival curve), which is