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RTE 2385Radiation Biology
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Interactions with radiation
Although it is impossible to determinewhether ionizations of molecules occur
through direct vs. indirect effects, asthe human body is ~75% water it istheorized that most radiation actionswith humans are indirect.
The dose to cell irradiation is alsodetermined by dose in rads.
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Radiolysis of water
With the human body being ~75%water, it follows that the irradiation of
water is involved in the majority ofinteractions involving
DNA is the most critical target ofradiation and it is the irradiation of
water that causes indirect effects If water is irradiated, the water is
ionzied and separates into other
molecular products
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Water cont’d…
When at atom of water is irradiatedthis ionizes the water and produces afree radical, this makes it chemically
unstable & highly reactive The end result of radiolysis of water is
the development of an ion pair and twofree radicals
These ions can recombine & form anormal water molecule or they can reactchemically & damage other cellmacromolecules
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Irradiation of macromolecules
Solution: a suspension of particles ormolecules in a fluid; when you mix fluidsyou get a solution
When macromolecules are irradiated in vitro, three things happen: main chainscission, crosslinking and point lesions
Definition of scission: dividing, splittingor cutting
Definition of macromolecule: a largemolecule
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Main chain scission
The breakage of the backbone of thelong-chain macromolecule
When this happens, the long, singlemolecule becomes many molecules
What would happen if this was amacromolecule that was not in
abundance?
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Crosslinking
Some molecules have small, spur-likestructures extending off the main chain
Others produce these spurs due toirradiation
Sometimes these side structuresbehave as if there was a sticky
substance on their end, they attach toanother macromolcule or to anothersegment of their macromolcule
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Point lesions
A disruption of single, chemical bonds inthe macromolecule as a result ofirradiation
This type of lesion can cause the cell tonot function correctly
At low doses of radiation, these lesions
are regarded to be the cellular radiationdamage responsible for late effectradiation damage observed at the whole-body level
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The major effect of all ofthese is:
Genetic code being incorrectlytransferred to daughter cells
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Single-hit aberrations
When chromosomes are irradiated, theinteraction can be direct or indirect
The result of either interaction is called a “hit”
These chromosomal hits are the cause ofvisible chromosome change
Such a hit would mean that numerous molecularbonds had been interfered with and that
several chains of DNA had been severed Chromosome hits represent critical DNA
damage
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Single-hit aberrations
Figure 3-9
If there is a breakage of the chromatid, thisis termed a chromatid deletion
There is low probability that ionizing radiationwill pass through sister chromatids to produceisochromatids
The radiation normally causes a chromatid
deletion in just one arm of the chromosomeresulting in a chromosome that is missingchromatid fragment and subsequently ismissing genetic material
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Multi-hit chromosomeaberrations
It is theorized that human chromosomes havemore than a single target
It is feasible for a single chromosome to
receive more than one hit These multi-hit aberrations are not that
unusual
Multi-hit aberrations are rare, they require
that the same chromosome be hit two or moretimes or that neighboring chromosomes are hitand join together
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Multi-hit aberrations
Multi-hit aberrations arerepresentative of major cell damage
The results of this aberrations is thatone or both daughter cells is missingsignificant genetic information
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Reciprocal translocations
Multi-hit aberrations
If chromosomes experience this, they
do not lose genetic material The genes become rearranged
Results in all genetic codes beingavailable but sequenced incorrectly
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At the doses received in diagnosticradiology, only single-hit types ofchromosome aberrations are seen
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Dose-response relationships
Also called dose-response curves
Graphic relationship between observedeffects (response) from radiation anddose of radiation received
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Dose-response curves differ in two ways: They are either linear or nonlinear
They are either threshold or nonthreshold
Linear means that the observed response isdirectly proportional to the dose
Nonlinear means that an observed response isnot directly proportional to the dose
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Threshold assumes that there is noradiation level reached below whichthere would be no effects observed
Nonthreshold assumes that anyradiation dose causes an effect
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Linear dose response relationships
All linear dose response relationshipsexhibit an effect regardless of thedose
Leukemia, breast cancer and geneticdamage are believed to follow the
linear dose response relationship
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Linear, quadratic dose responsecurves
At low doses, the curve is linear and at highdoses the curve becomes curvilinear
The portion where the curve increases indose shows little to no increase is called the“toe” and the “shoulder” is considered thearea of the curve in which the leveling off
occurs (demonstrating little to no increase ineffect)
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Nonlinear dose responserelationships
The sigmoid dose response curve is
applied predominantly for use in thehigh dose effects observed inradiotherapy
There is normally a threshold belowwhich no observable effects occur
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Danger of this model:
it underestimates the low dose effect ofradiation, as the linear part of the curveis somewhat leveled off or flattened
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Using high LET radiation, ionizationdistances are so close together that
there is a high probability that a directhit will take place
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Target theory
Some molecules do not have a lot of“back-up” which could cause seriousproblems if the radiation damage wereto occur on those molecules
According to target theory, for a cellto die after radiation exposure, its
target molecule must be inactivated DNA is the target molecule
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According to target theory, there willbe cell death only if the cell’s targetmolecule is inactivated
The going theory is that DNA is thecritical molecular taget
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Cell survival curves
Cellular sensitivity studies began in themiddle 1950’s with Puck and Marcus
They performed in vitro studies using HeLa
cells Cell survival curves deal with the percentage
of cells not killed by various doses ofradiation
In complex cells like those found in humans,it is thought that at least one hit to at leasttwo targets is needed to kill the cell
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Because humans have two of eachchromosome, it is believed that both ofthese chromosomes or target must bedamaged for the damage to kill the cell
The cell survival curve for humans has
a shoulder at low doses if you were tograph it
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As the amount of radiation increases,the number of cells with no targets hitwill decrease until for all practicalpurposes, all cells have at least onetarget hit.
Up until that point, the response curve
would be quadratic or flattened, fromthat point on the curve would be linear
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The shoulder of the cell survival curveshows that some damage must accruebefore there can be cell death
The accumulated damage is calledsublethal damage
The wider the shoulder the more
sublethal damage the cell can endure