biological effects of ionizing radiations..what every physician must know

Biological effects of ionizing radiations

Dr/Ahmed bahnassy

Consultant radiologist

PSMMC

what every physician must know

Aims of lecture

• To become familiar with the mechanisms of different types of biological effects following exposure to ionizing radiation.

• To be aware of the models used to derive risk coefficients for estimating the detriment.

Radiation injury from an industrial source

Ionizing RadiationIonizing Radiation

Ionizing Radiation is Ionizing Radiation is the the removal of an removal of an electronelectron

from an atom leaving from an atom leaving an an unstable molecule unstable molecule which may then which may then break apart to form break apart to form free radicals.free radicals.

http://www.paradigmlink.com/ionrad.shtml

The weapon

Linear Energy Transfer (LET)Linear Energy Transfer (LET)

The average energy deposited per unit The average energy deposited per unit

length of track.length of track.

Measured in kiloelectron volts per Measured in kiloelectron volts per micronmicron

(10(10-6-6 m) m)

Low LET / High LETLow LET / High LET

Low LETLow LETLow mass, increased Low mass, increased

travel distance (gamma rays, travel distance (gamma rays, x-rays).x-rays).

Sparsely ionizing with Sparsely ionizing with

random interactions. random interactions.

Causes damage primarily Causes damage primarily

through indirect action or through indirect action or

may cause single strand may cause single strand

breaks (which are repairable). breaks (which are repairable).

http://staff.jccc.net/PDECELL/biochemistry/dna.gif

e-

Low LET / High LETLow LET / High LET

High LETHigh LET– Large mass, decreased Large mass, decreased

travel distance (alpha travel distance (alpha particles, protons, low particles, protons, low energy neutrons).energy neutrons).

– Causes dense Causes dense ionization ionization

along its path with a along its path with a high probability of high probability of interacting directly with interacting directly with DNA.DNA.

http://staff.jccc.net/PDECELL/biochemistry/dna.gif

α++


Alpha particlesAlpha particles The alpha particle has a large mass and consists of two The alpha particle has a large mass and consists of two

protons, two neutrons and no electrons (+2)protons, two neutrons and no electrons (+2) The alpha particle deposits a large amount of energy in a short The alpha particle deposits a large amount of energy in a short

distance of travel (about 1-2 inches)distance of travel (about 1-2 inches) Most alpha particles are stopped by a few centimeters of air, a Most alpha particles are stopped by a few centimeters of air, a

sheet of paper, or the dead layer (outer layer) of skin. sheet of paper, or the dead layer (outer layer) of skin.

Beta particlesBeta particles The beta particle has a small mass and is negatively charged (-The beta particle has a small mass and is negatively charged (-

1) 1) Beta radiation causes ionization by displacing electrons from Beta radiation causes ionization by displacing electrons from

their orbits.their orbits. Because of its negative charge, the beta particle has a limited Because of its negative charge, the beta particle has a limited

penetrating ability. Range in air is about 10 feet. penetrating ability. Range in air is about 10 feet.

The following are the most common types of ionizing radiation:The following are the most common types of ionizing radiation:



Gamma rays/x raysGamma rays/x rays Gamma/ x ray radiation is an electromagnetic wave or Gamma/ x ray radiation is an electromagnetic wave or

photon and has no electrical chargephoton and has no electrical charge Gamma/ x ray radiation can ionize as a result of direct Gamma/ x ray radiation can ionize as a result of direct

interactions with orbital electrons and is transmitted interactions with orbital electrons and is transmitted directly to its target. Because Gamma/ x ray radiation directly to its target. Because Gamma/ x ray radiation have no charge and no mass, it has a very high have no charge and no mass, it has a very high penetrating power. penetrating power.

Neutron particlesNeutron particles Neutron radiation consists of neutrons that are ejected Neutron radiation consists of neutrons that are ejected

from the nucleus and have no electrical chargefrom the nucleus and have no electrical charge Due to their neutral charge, neutrons interact with matter Due to their neutral charge, neutrons interact with matter

either directly or indirectly either directly or indirectly Because of the lack of a charge, neutrons have a Because of the lack of a charge, neutrons have a

relatively high penetrating ability and are difficult to relatively high penetrating ability and are difficult to stop. stop.



The reactions caused by ionizing The reactions caused by ionizing radiation occur rapidly, they are radiation occur rapidly, they are nonselective and nonselective and

random.random.The majority of damage caused by The majority of damage caused by

radiation is due to chemical radiation is due to chemical reactions with water within the cell.reactions with water within the cell.

The injury mechanism

H2O HOH+

e-

water

electron

Positively charged water

molecule

Radiation reacts with water to produce an electron and a positively charged water molecule.

H2O HOH+

e- + H2O HOH-

water

negatively charged water

molecule

electron water


molecule

The electron reacts with another water molecule to produce a negatively charged water molecule

H2O HOH+

H+

OH*

e- + H2O HOH-

water


molecule

Hydrogen ion

Hydroxyl radical

electronwater


molecule

The positively charged water molecule dissociates into a hydrogen ion and a hydroxyl radical.

H2O HOH+

H+

OH*

H* OH-

e- + H2O HOH-

water


molecule

Hydrogen ion

Hydroxyl radical

electron water


molecule

hydrogen radical

Hydroxyl ion

The negatively charged water molecule dissociates into a hydrogen radical and a hydroxyl ion.

ReactionsReactions

The previous reactions produce free The previous reactions produce free

electrons (eelectrons (e--), the ions H), the ions H-- and OH and OH--, ,

the free radicals H* and OH*.the free radicals H* and OH*.The fate of these products are…….The fate of these products are…….

H2O HOH+

H+

OH*

H* OH-

e- + H2O HOH-

HOH+ + e- H2O

The positively charged water molecule and the electron recombine to form water.

H2O HOH+

H+

OH*

H* OH-

e- + H2O HOH-

H+ + OH- H2O

The ions combine to form water.

H2O HOH+

H+

OH*

H* OH-

e- + H2O HOH-

H* + OH* H2O

The radicals combine to form water.

H2O HOH+

H+

OH*

H* OH-

e- + H2O HOH-

OH*

OH* + OH* H2O2

The hydroxyl radical reacts with another hydroxyl radical to form hydrogen peroxide.

Free RadicalsFree Radicals

A free radical is an atom or A free radical is an atom or molecule that has an molecule that has an unpaired unpaired

electron in its valence shell.electron in its valence shell. These free radicals are These free radicals are

non-selective when pairing non-selective when pairing up up

with electrons from otherwith electrons from other

atoms, including those that atoms, including those that make up the DNA molecule.make up the DNA molecule.

Direct Action / Indirect Direct Action / Indirect ActionActionDirect ActionDirect Action

Causes damage directly to DNA or other Causes damage directly to DNA or other important important

molecules in the cell.molecules in the cell.More likely when the beam of charged particles More likely when the beam of charged particles consist of alpha particles, protons, or electrons consist of alpha particles, protons, or electrons

Indirect ActionIndirect ActionCauses damage by interacting with the cellular Causes damage by interacting with the cellular medium producing free radicals which then medium producing free radicals which then

damage the DNA molecule.damage the DNA molecule.More likely when x-rays or gamma-rays compose More likely when x-rays or gamma-rays compose

the beam.the beam.

Direct Action / Indirect Direct Action / Indirect ActionAction

DNA DamageDNA Damage

The arrangement of The arrangement of nitrogenous bases nitrogenous bases provide a blueprint for DNA for the provide a blueprint for DNA for the synthesis of specific proteins necessary synthesis of specific proteins necessary for individual cell function.for individual cell function.

In the event of a In the event of a loss or change loss or change of one of one or more of the nitrogenous or more of the nitrogenous bases....base sequence and bases....base sequence and normal functioning of the cell is altered.normal functioning of the cell is altered.

Another form of DNA damage due to Another form of DNA damage due to radiation involves a radiation involves a breakbreak in the in the hydrogen bonds between the Adenine hydrogen bonds between the Adenine – Thymine and Cytosine – Guanine – Thymine and Cytosine – Guanine base pairs. These bonds function to base pairs. These bonds function to keep the DNA strands togetherkeep the DNA strands together

Bonds can also break between Bonds can also break between deoxyribose sugar and the phosphate deoxyribose sugar and the phosphate groups which can lead togroups which can lead to cross-linking cross-linking of DNAof DNA

The target

Chromosome AberrationsChromosome Aberrations If the chromosome fragments are If the chromosome fragments are

near one another they have a high near one another they have a high chance of reattaching in their chance of reattaching in their original position – causing no future original position – causing no future damage to the cell.A process damage to the cell.A process known as known as restitution.restitution.

In In translocationstranslocations and inversions, no and inversions, no genetic information is lost, but the genetic information is lost, but the rearrangement of gene sequence rearrangement of gene sequence will alter protein synthesis.will alter protein synthesis.

In a In a deletiondeletion, a chromosome , a chromosome fragment is not replicated during fragment is not replicated during the next mitosis, the genetic the next mitosis, the genetic information is lost. The effects this information is lost. The effects this has on the cell depends on the has on the cell depends on the amount and type of information amount and type of information lost.lost.

Translocation

Inversion

Deletion

The effects

Chromosome deletion

Chromosome translocation

IAEA 3 : Biological effects of ionizing radiation

Outcomes after cell exposure

DAMAGEREPAIRED

CELL DEATH(APOPTOSIS)

TRANSFORMED CELL

DAMAGE TO DNA

DNA Mutation

Cell survives but mutated

Cancer ?

Cell death

Mutation repaired

Unviable Cell

Viable Cell


Repair of DNA damage

• RADIOBIOLOGISTS ASSUME THAT THE REPAIR SYSTEM IS NOT 100% EFFECTIVE.

Cancer initiationCancer initiation

NORMAL TISSUE

CELL INITIATION

An initiating event

creates a mutation in

one of the basal cells

DYSPLASIA

More mutations occurred.

The initiated cell has

gained proliferative

advantages.

Rapidly dividing cells

begin to accumulate

within the epithelium.

BENIGN TUMOR

More changes within

the proliferative cell line lead

to full tumor development.

MALIGNANT TUMOR

The tumor breaks trough

the basal lamina.

The cells are irregularly

shaped and the cell line is

immortal. They have an increased

mobility and invasiveness.

METASTASIS

Cancer cells break through

the wall of a lymphatic

vessel or blood capillary.

They can now migrate

throughout the body and

potentially seed new tumors.

A simple generalized scheme for multistage oncogenesis

Damage to chromosomal DNAof a normal target cell

Failure to correctDNA repair

Appearance of specificneoplasia-initiating mutation

Promotional growthof pre-neoplasm

Conversion to overtlymalignant phenotype

Malignant progression and tumour spread

RadiosensitivityRadiosensitivity

Actively reproducing Actively reproducing cells are more cells are more radiosensitive than mature cells.radiosensitive than mature cells.

During During mitosismitosis, the cell is in a , the cell is in a stressed stressed state and shows an increase in damage state and shows an increase in damage caused by radiation.caused by radiation.Cells that have Cells that have decreased decreased levels of levels of differentiation are more radiosensitive differentiation are more radiosensitive than specialized cells.than specialized cells.

The Cell Cycle

An ordered set of events, culminating in cell growth and division into two daughter cells

Tc, full mitotic cycle

G2

(2nd gap)

M(mitosis)

S(DNA Synthesis phase)

G1

(1st gap)

Cells that cease division

Radiosensitivity & Mitotic Cycle Cell cycle components

M, G1, S, G2

Cell cycles times vary largely due to G1 crypt cells, 9 - 10 hours stem cells (mouse skin) 200 hr

Sensitivity Cells most sensitive close to mitosis Resistance greatest in latter part of S For long G1’s, there is an early resistance period followed by

sensitive one at the end of G1 G2 ~ M in sensitivity


Radiosensitivity

Muscle

Bones

Nervous system

Skin

Mesoderm organs (liver, heart, lungs…)

Bone Marrow

Spleen

Thymus

Lymphatic nodes

Gonads

Eye lensLymphocytes (exception to the RS laws)

Low RSMedium RSHigh RS

Fractionation in Fractionation in radiotherapyradiotherapy Instead of a single treatment Instead of a single treatment consisting of a high dose, consisting of a high dose,

fractionation divides the dose fractionation divides the dose to be delivered over a period to be delivered over a period of time, usually 6-8 weeks.of time, usually 6-8 weeks.

At low doses of radiation, At low doses of radiation, normal cells normal cells have an increased have an increased

survival rate because of their survival rate because of their ability to repair sublethal ability to repair sublethal damage before the next damage before the next fraction of radiation is fraction of radiation is delivered.delivered.

Tumor cells Tumor cells do not possess do not possess the repair enzymes the repair enzymes necessary to necessary to

keep up with the repairs and keep up with the repairs and as a result the cell is as a result the cell is overwhelmed and is overwhelmed and is

destroyed.destroyed. http://www.usoncology.com/CompanyInfo/PhotoLibrary.asp

Two effects of radiation exposure: deterministic (threshold) stochastic: cancer

Radiation Standards set below threshold set to limit stochastic risk

Dose-Response Relationships

Non-Stochastic (Deterministic) Effects Occurs above threshold

dose Severity increases with

dose Alopecia (hair loss) Cataracts Erythema (skin reddening) Radiation Sickness Temporary Sterility

Stochastic (Probabilistic) Effects

Occurs by chance Probability increases with dose

Carcinogenesis Mutagenesis Teratogenesis


Radiation health effects

DETERMINISTICSomaticClinically attributable in the exposed individual

CELL DEATH

STOCHASTICsomatic & hereditaryepidemiologically attributable in large populations

ANTENATALsomatic and hereditary expressed in the foetus, in the live born or descendants

BOTH

TYPEOF

EFFECTS

CELL TRANSFORMATION

Radiation effects and Syndromes


Injury

Threshold

Dose to

Skin (Sv)

Weeks to

Onset

Early transient erythema 2 <<1Temporary epilation 3 3

Main erythema 6 1.5Permanent epilation 7 3Dry desquamation 10 4Invasive fibrosis 10Dermal atrophy 11 >14Telangiectasis 12 >52

Moist desquamation 15 4Late erythema 15 6-10

Dermal necrosis 18 >10Secondary ulceration 20 >6

Skin damagefrom prolongedfluoroscopicexposure

Skin reactions


Skin injuries


Effects in eye

• Eye lens is highly RS.

• Coagulation of proteins occur with doses greater than 2 Gy.

• There are 2 basic effects:

From “Atlas de Histologia...”. J. Boya

Histologic view of eye:

Eye lens is highly RS, moreover, it is surrounded by highly RS cuboid cells. > 0.155.0

Visual impairment (cataract)

> 0.10.5-2.0Detectable opacities

Sv/year for many years

Sv single brief exposure

Effect

IAEA 3 : Biological effects of ionizing radiation 49

Whole body response: adult

Acute irradiation syndrome Chronic irradiation

syndrome

Sur

viva

l tim

e

Dose

Steps:

1. Prodromic (onset of disease)

2. Latency

3. Manifestation

Lethal dose 50 / 30

BONE MARROW GASTRO

INTESTINAL

CNS(central nervous

system)

1-10 Gy

10 - 50 Gy

> 50 Gy

•Mechanism: Neurovegetative disorder

•Similar to a sick feeling

•Quite frequent in fractionated radiotherapy

Threshold Doses for Deterministic Effects

• Cataracts of the lens of the eye 2-10 Gy

• Permanent sterility

• males 3.5-6 Gy

• females 2.5-6 Gy

• Temporary sterility

• males 0.15 Gy

• females 0.6 Gy

Severity ofeffect

dose

threshold

Symptoms of Acute Radiation Sickness

Three categories (E. Hall, 1994) Hemopoietic: 3-8 Gy LD50/60

radiation damages precursors to red/white blood cells & platelets

prodromal may occur immediately symptoms: septicemia, survival mixed examples include Chernobyl personnel (203 exhibited

symptoms, 13 died)

Symptoms, continued Gastrointestinal : >10 Gy

radiation depopulates GI epithelium (crypt cells) abdominal pain/fever, diarrhea, dehydration death 3 to 10 days (no record of human survivors above 10

Gy) examples include Chernobyl firefighters

Cerebrovascular : > 100 Gy death in minutes to hours

Delayed Effects

SOMATIC: they affect the health of the irradiated person. They are mainly different kinds of cancer (leukemia is the most common, with a delay period of 2-5 years, but also colon, lung, stomach cancer…)

GENETIC: they affect the health of the offspring of the irradiated person. They are mutations that cause malformation of any kind (such as mongolism)

Summary Effects of ionizing radiation may be

deterministic and stochastic, immediate or delayed, somatic or genetic

Some tissues are highly radiosensitive Each tissue has its own risk factor Risk from exposure may be assessed

through such factors

IAEA 3 : Biological effects of ionizing radiation 56

Where to Get More Information (1)

• The 2007 Recommendations of the International Commission on Radiological Protection, ICRP 103, Annals of the ICRP 37(2-4):1-332 (2007)

• UNSCEAR 2008 Report to the General Assembly, with scientific annexes, United Nations Scientific Committee on the Effects of Atomic Radiation, United Nations, Vienna, Austria, 2008

• Avoidance of radiation injuries from medical interventional procedures. ICRP Publication 85. Ann ICRP 2000;30 (2). Elsevier

Avoidance of radiation injuries from medical interventional procedures. ICRP Publication 85. Ann ICRP 2000;30 (2). Pergamon

biological effects of ionizing radiations..what every physician must know

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