Biological effects of ionizing radiations..what every physician must know
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Transcript of 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++
Ionizing RadiationIonizing Radiation
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:
http://www.paradigmlink.com/ionrad.shtml
Ionizing RadiationIonizing 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.
http://www.paradigmlink.com/ionrad.shtml
Ionizing RadiationIonizing Radiation
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
Positively charged water
molecule
The electron reacts with another water molecule to produce a negatively charged water molecule
H2O HOH+
H+
OH*
e- + H2O HOH-
water
negatively charged water
molecule
Hydrogen ion
Hydroxyl radical
electronwater
Positively charged water
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
negatively charged water
molecule
Hydrogen ion
Hydroxyl radical
electron water
Positively charged 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
IAEA 3 : Biological effects of ionizing radiation
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
IAEA 3 : Biological effects of ionizing radiation
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
IAEA 3 : Biological effects of ionizing radiation
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
IAEA 3 : Biological effects of ionizing radiation
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
IAEA 3 : Biological effects of ionizing radiation
Skin injuries
IAEA 3 : Biological effects of ionizing radiation
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