Radiation Biology

Radiation Biology

2015Assist. Prof. Dr. Yekbun Adıgüzel

İstanbul Kemerburgaz University

Faculty of Medicine

MED 122 Cell Tissue and Organ Systems II

Biophysics Lecture

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 (α). Such radiation has a mass number of 4. So, the

mass number of radioactive isotope decreases by 4 during α decay.

The mass number decreases by 4 during alpha decay.

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Some brief highlights:

Decay that changes the atomic number but not the mass number is

called beta (β) decay.

The atomic number decreases by one during β+ decay since

it is the spontaneous transformation of 1 proton to 1 neutron,

along with emission of the positive charge as a β+ particle.

The atomic number increases by one during β- decay.

During K electron capture, a proton is transformed into a neutron

by capturing 1 e- into the nucleus.

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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 notgenerate 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.

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Web-site for the images & the information given below: http://hedberg.web.cern.ch/hedberg/c/nuclear/nuke_sl.htm

The energy distribution of beta-radiation is continuous because a neutrino is emitted along with the beta-particle during the decay.

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.

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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.

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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.Fro

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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,

•t1⁄2 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 htt

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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)

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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,

•t1⁄2 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 htt

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http://biophys.med.unideb.hu/sites/default/files/course_material/2010/09/11_radiation_biology_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

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=mcΔT). Where does the damage arouse from?

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- Molecular events


Units

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 X-

ray or gamma radiation in a body of unit mass during electron

equilibrium. (Electron equilibrium:

The number of electrons entering

or leaving the body volume.)

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fExposure

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, let’s

say the tissue. There is also heat release during these processes.

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fExposure

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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

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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

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What the above formula for equivalent dose (HT) indicates is that

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.

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Radiation weighting factors of different radiation types are shown in the following table, where the beta-negative (β-) particles are electrons. Alpha (α) particles have a high weighting factor.

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Radiation weighting factor for equivalent dose

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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

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fDifferent radiation types’ individual contribution to the

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.

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fThe second table, which is shown below, lists the tissue weighting factors of some organs.

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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

(the weighting factor 0.05 is applied to the average dose of these organs)

0.05

Target and Molecular Theories

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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

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«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 α-particles or

low energy neutrons (said to be densly ionizing), the dose-

response 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)

Dose response curve

α-particles or low energy neutrons

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… For X- or γ-rays (said to be sparsely ionizing), the dose-

response curve has an initial slope, followed by a shoulder; at

higher dose, the curve tends to become straight again.

Dose response curve

X- or γ-rays

Chul-Seung Kay and Young-Nam Kang. Curative Radiotherapy in Metastatic Disease: How to Develop the Role of Radiotherapy from Local to MetastasesDOI: 10.5772/56556 Web-site: http://cdn.intechopen.com/pdfs-wm/45395.pdf

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The theories that describe why we observe the relation in the

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.

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Target theory explains the graph as it states that destruction

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.

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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.

Survivability curve combined with the probabilistic concept

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D is the applied dose and

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fSurvivability 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


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Molecular theory is the other theory that

attempts to explain radiation damage to the organism.

Some molecules are more critical for the survival of the organism

and target theory doesn’t 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.

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fMolecular theory

Molecular theory considers the radiation sensitivity of DNA

that can’t 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.

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of radiation sensitivity.


In this formula,the 1st term in the brackets isdue to the contribution of 1 hit 1 inactivationcase and the 2nd term in the brackets is dueto 2 hits 1 inactivation case’s contribution.Minus sign in front of the bracket leads tothe higher contribution of the 1st term.

Model


In this formula, the 1st term in thebrackets is due to the contribution of1 hit 1 inactivation case and the 2nd

term in the brackets is due to 2 hits 1inactivation case’s contribution.

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.

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t The most important types

of radiation induced lesions

in DNASingle-strand breaks Double strand breaks

Base damage

Possible radiation induced DNA damage in a cell:

Type of lesion Number per GrayDouble strand breaks (dsb) 40Single strand breaks (ssb) 500-1000Base damage 1000-2000Sugar damage 800-1600DNA-DNA crosslinks 30DNA-protein crosslinks 150Alkali-labile sites 200-300

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Failure of DNA Repair MechanismsActive 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 mutagenic lesions.

In many cases, this DNA misrepair apparently leads to DNA deletion and rearrangement.

Such large scale changes in DNA structure are

characteristic of most radiation induced mutations.

Toxic effects at low to moderate doses (cell killing, mutagenesis, and malignant transformation) appear to result from damage to cellular DNA.

Unrejoined

DNA

double strand

breaks

Cytotoxic effect

Incorrect repair

of DNA damage

Mutations

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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 membrane’s structure can

cause changes in its permeability to various molecules, i.e. electrolytes.

Other radiation damages: Radiation induced membrane damage

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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


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.

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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.

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Direct effects of radiation are observed when the radiation hits

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

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When indirect 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.

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The impact 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.

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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

3nm

Because short life of simple free radicals (10-10sec), only those formed in

water column of 2-3 nm around DNA’re able to participate in indirect effect

Ho

OHo Ho

OHo

HO2o RO2

o

While generally highly reactive, these simple free radicals do not exist longenough to migrate from the site of formation to the cell nucleus. However,O2 derived species such as hydroxyperoxy free radical does not readilyrecombine into neutral forms. These more stable forms have a lifetimelong enough to migrate to nucleus, where serious damage can occur.

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Factors influencing radiation sensitivity

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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


A. The quality of radiation

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fFactors influencing radiation sensitivity


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.

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Relative biological effectiveness (RBE)

RBE is similar, but not identical to quality factor (QR) and

radiation weighing factor (wR).

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B. Biological variability1. 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.)

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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.

Factors influencing radiation sensitivityB. Biological variability1. 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.)

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B. Biological variability

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

1 Lympathic tissue 6 Blood vessels

2 White blood cells, immature erythrocytes in bone marrow

7 Glands, liver

3 Mucous membrane of stomach and intestine

8 Connective tissue

4 Gametes 9 Muscle tissue

5 Proliferating cell layer of the skin 10 Nervous tissue

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… 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.


B. Biological variability

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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


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C. Time factor

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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.


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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.


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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

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Factors influencing radiation sensitivityE. The effect of oxygen

EFFECTS OF IONIZING RADIATION ON TISSUES, ORGANS AND

SYSTEMS

Types of cellular damage

Ionizing radiation

Cell

Repair

Damaged

normal cell

Mitotic cell death

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When cells come into contact with

ionizing radiation sufficient to

cause cellular damage, one of three

possible actions will occur.

• If the damage is too severe, the cell

may die.

• 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.

Tissue radiosensitivityh

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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

1 Lympathic tissue 6 Blood vessels

2 White blood cells, immature erythrocytes in bone marrow

7 Glands, liver

3 Mucous membrane of stomach and intestine

8 Connective tissue

4 Gametes 9 Muscle tissue

5 Proliferating cell layer of the skin 10 Nervous tissue

Highly radiosensitive•Lymphoid tissue•Bone marrow •Gastrointestinal epithelium•Gonads (testis andovary)•Embryonic (foetal)tissues

Moderately radiosensitive•Skin•Vascular endothelium•Lung•Kidney•Liver•Lens (eye)•Thyroid in childhood

Least radiosensitive•Central nervous system (CNS)•Endocrine (except gonad) •Thyroid in adults•Muscle•Bone and cartilage•Connective tissue

While all cells can be destroyed by a high enough radiation dose, highly radiosensitive cells or tissue exhibit deleterious effects at much lower doses than others.

The least radiosensitive tissue, although radioresistant, is less capable of cell renewal than

highly sensitive tissue. Some - especially neurons, glialcells 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.

Tissue radiosensitivity

Highly radiosensitive•Lymphoid tissue•Bone marrow •Gastrointestinal epithelium•Gonads (testis andovary)•Embryonic (foetal)tissues

Moderately radiosensitive•Skin•Vascular endothelium•Lung•Kidney•Liver•Lens (eye)•Thyroid in childhood

Least radiosensitive•Central nervous system (CNS)•Endocrine (except gonad) •Thyroid in adults•Muscle•Bone and cartilage•Connective tissue

http

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Relative radiosensitivity of various organs based on parenchymal hypoplasia (incomplere or underdevelopment)

Organs Relative radio

sensitivity

Chief mechanism of parenchymal

hypoplasia

Lymphoid organs; bone

marrow, testis & ovaries;

small intestines

Embryonic tissue

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 bonesMedium 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

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Haematopoietic systemMost radiosensitive are the stem cells of the bone marrow, whichgive rise to all circulating blood cells and platelets, and the lymphoidtissue found in the spleen, liver, lymph nodes and thymus.

red blood cell

platelets

monocytes

neutrophils

basophils

eosinophils

B lymphocytes

T lymphocytes

BloodBone marrowProliferation Differentiation

Thymus

CFU-E

CFU-MK

CFU-M

CFU-G

CFU-Ba

CFU-Eo

CFU-BL

CFU-TL

Stem cell

CFU-L

CFU-GEMM

BFU-E

BFU-MK

CFU-GM

Hie

rarc

hic

al o

rgan

izat

ion

of

hae

mat

op

oie

sis CFU : Colony forming unit

BFU: Burst forming unitGM: Granulocyte-MacrophageMK: Megakaryocyte

L: LymphoidBL: B lymphoidTL: T lymphoidE: ErythroidBa: BasophilEo: EosinophilGEMM: Granulocyte erytrocytemegakaryocyte monocyte

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Bone marrow kinetics

Resting

stem cells

Proliferating

compartment:

stem cell and

progenitors

Differentiating

compartment:

precursors

Mature

cellsBlood

Normal physiological situation

activation

proliferation, differentiation

differentiation

exit

Stem cells: immature cells with autorenewal capability

Progenitors: primitive cells, high proliferative potential

Mature cells: no proliferative capability

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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.

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Effects of radiation on haematopoiesis

Resting

stem cells

Proliferating

compartment:

stem cell and

progenitors

Differentiating

compartment:

precursors

Mature

cellsBlood

Normal physiological situation

activation

proliferation, differentiation

differentiation

exit

Block of

proliferation,

cell deathDepletion of

proliferating

compartment

Depletion by absence of renewal

BLOOD

APLASIA

I

R

R

A

D

I

A

T

I

O

N

The main effect of ionizing radiation is to induce the death of proliferating cells within the stem cell and progenitor compartment.


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Irradiated bone marrow lacks all precursor haematopoietic cells

Effect of radiation on bone marrow

Within 48 hours after a lethal dose of radiation, peak cell degeneration,consisting of massive destruction and necrosis of bone marrow stem cells,occurs.

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 marrow

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Irradiated bone marrow lacks all precursor haematopoietic cells

Effect of radiation on bone marrow

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 precursorhaematopoietic cells are no longer present. Four days after 9 Gy of cobalt-60irradiation, all that is left in the irradiated canine bone marrow shown is a finenetwork of reticular stroma. The red areas are vascular sinusoids engorged withred blood cells and occasional plasma cells. The clear areas indicate where thehaematopoietic tissues were. The plasma cells, being differentiated cells, arerelatively radioresistant at this stage.

Normal bone marrow

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Model of blood renewal system

Cell pools in normal steady state

Stem

cell

Dividing&

maturing

Maturing

onlyBlood

Changes after irradiation

Time

After Irradiation

1 hour

1 day

2 days

3 days

4 1/4 days

5 daysRela

tive

Nu

mb

er o

f C

ells

Erythrocytes changes as a dose function - 1

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Erythrocytes changes as a dose function

1 Gy

3 Gy

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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.

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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.

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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

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Leukocytes changes as a function of dose

Normal

<1Gy

1-2 Gy

2-5 Gy

>5-6 Gy Time after exposure, days

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Normal<1Gy

1-2 Gy

2-5 Gy>5-6 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.

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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>5-6 Gy


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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.

Normal<1Gy

1-2 Gy

2-5 Gy>5-6 Gy


Thrombocytes changes as a dose function - 1

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Thrombocytes changes as a dose functionNormal

<1Gy

1-2 Gy2-5 Gy

>5-6 Gy Time after exposure, days

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Thrombocytes changes as a dose function - 1Normal

<1Gy

1-2 Gy

2-5 Gy>5-6 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.

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<1Gy

1-2 Gy


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 3-

4 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.

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<1Gy

1-2 Gy


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 tissue-1

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Normal monkey

lymph nodeGerminal centre of

normal monkey

lymph node

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.

A B C D9 Gy CO-60 40-60 Gy

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Normal monkey


normal monkey

lymph node

Germinal centre of

irradiated human

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 B C D9 Gy CO-60 40-60 Gy

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Normal monkey


normal monkey

lymph node

Germinal centre of

irradiated human

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 B C D9 Gy CO-60 40-60 Gy

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Normal monkey


normal monkey

lymph node

Germinal centre of

irradiated human

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.

A B C D9 Gy CO-60 40-60 Gy

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Early changes in peripheral blood lymphocyte counts

0.25-1.0 Gy

1.0-2.0Gy

2-4 Gy

4-6 Gy

>6 Gy

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

(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.

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Early changes in peripheral blood lymphocyte counts

0.25-1.0 Gy

1.0-2.0Gy

2-4 Gy

4-6 Gy

>6 Gy

Early changes in peripheral blood lymphocyte

counts depending on the dose of acute whole body

exposure

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

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.

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Lymphocytes changes as a function of dose

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.

<1 Gy

1-2 Gy

>5-6 Gy

2-5 Gy


Effect of radiation on gastrointestinal tract

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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

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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

within the highly radiosensitive crypt and proliferating

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. Ima

ge

fro

mW

ikim

edia

Co

mm

on

s

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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.

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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.

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Pathogenesis of the gastrointestinal syndrome

Depletion of the epithelial

cells lining lumen of

gastrointestinal tract

Intestinal bacteria gain free

access to body

Haemorrhage through

denuded areas

Loss of absorptive capacity

Denuding of sections of bowel, in

turn, causes a host of

pathophysiological sequelae. They

include invasion of lumenal bacteria

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.

Reproductive cell kinetics and sterility

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Reproductive cell kinetics and sterility - maleThe 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.

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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.

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Reproductive cell kinetics and sterility - femaleRadiation 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.

Effect of radiation on skin

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Human skin structure

Cellularity

Normal human skin exhibits a uniform layered appearance of cellularity, beginning with the basal layer.

Epidermis – its average thickness is 70 µm, but basal cells are located in hair follicles at a depth of 200 µm.

Derma - its average thickness is 1-3 mm

Image modified from: http://www.gold-collagen.com/wp-content/uploads/2014/01/SKIN-ILLUSTRATION-FINAL-VERSION.jpg

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Alpha radiation is absorbed in

superficial layers of dead cells

within the stratum corneum

Beta radiation damages epithelial

basal stratum. High energy ß-

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

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Skin layers

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.

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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.

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Effect of radiation on skin

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.

Norm

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Irrad

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Pulmonary effects

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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.

../MEIR/images/05/G_ars23l.jpg

../MEIR/images/05/G_ars23l.jpg

EFFECTS OF IONIZING RADIATION ON TISSUES, ORGANS AND

SYSTEMS - SUMMARYBone 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

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Use of Isotopes in Medicine

2015Assist. Prof. Dr. Yekbun Adıgüzel

İstanbul Kemerburgaz University

Faculty of Medicine

MED 122 Cell Tissue and Organ Systems II

Biophysics Lecture

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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.

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PRODUCTION OF ISOTOPESBY USING ACCELERATORS

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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.

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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.

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fAs 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.

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•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.F

rom

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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.

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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.

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For measuring the volumes of bodily compartments, again a

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.

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If the radiopharmacon is absorbed specifically by a tissue, the amount

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.

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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

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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.

Gamma Camera

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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.

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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.

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Radiation Biology

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