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they were taking their walks at lunchtime with their coats on. And with their badges
on and the radiation exposure that they were registering was the radiation from
their outside exposure. It was not dangerous exposure but it was what would
register on our badges as higher than normal inside radiation. Just give you a sense
that there really are natural sources for radiation.
[Slide #6] [Effects of ionizing radiation]
[Dr. Phelan] So what does ionizing radiation do? It produces free radicals. It breaks
chemical bonds. It produces new chemical bonds and cross-linkages between
macromolecules and it damages molecules that regulate vital cell processes such as
DNA, and RNA and proteins. And at low doses, most cells are able to repair damage.
At high doses, the result is cell death. But in the middle, we can end up having tissue
loss of function and we can have permanent changes to the cells that can be
transmitted to future generations of cells, which can end up in situations like cancer.
[Slide #7] [Free Radical Generation diagram]
[Dr. Phelan] If we look at this diagram and we look at the effect on this cell of a
number of different irritantsradiation is one of them. Okay? And here we have
radiation we have some others that, okay? That Dr. Kinnally talked to you about at
the beginning of the year. Inflammation should sound familiar. Reperfusion injury
should sound familiar. Again, because you're getting here an excess amount of
oxygen that is attacking or is the environment for the cell.
And then there is a production of ROS and one possibility is cell injury and the other
possibility is that the cell can neutralize the free radicals and actually have no cell
injury. And so you have a number of possibilities that might occur with free radicals.
[Slide #8] [Acute vs. Delayed Effects]
[Dr. Phelan] And so every damage from radiation or every attack, if you will, or
every exposurethats a better wordevery exposure to radiation is not going to
cause cell death and it may not cause a permanent death of the cell. The problem
youll see as we talk through this lecture, it does not appear that we can identify
where the lowest safety dose is and I think youve heard that over again. And so we
use a term in diagnostic radiation thats called ALARA which means ? As low as
reasonably okay.
So there are some acute effects from radiation exposure and these are the effects
that are seen immediately after large doses of radiation that are delivered over
short periods of time. And then there are delayed effects that appear months later
after a radiation exposure and it depends again, youll see in a little bit, whether or
not the entire body is exposed or only part of the body is exposed. Because we use
radiation in cancer therapy, radiation therapy for cancer, and you will get changes in
the skin over the area being radiated. You get tissue damage around the area in
addition to whatever cancer is being treated. Theres enormous amounts of damage
immediate and then theres also a lot of damage that continues later on after the
radiation treatment is over.
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A single dose, a single whole-body dose, is more lethal than regional doses. And this
is the kind of exposure that people have had nuclear accidents. And Chernobyl, some
of the people that went into clean up were exposed to whole-body radiation. There
is also whole-body radiation that is used in bone marrow transplantation and, again,
usually you would like not for it to be lethal but for it to destroy bone marrow so
that you can replace it with something else.
So those cells that are dividing and are in their G2 phase are the most sensitive to
radiation. And different cell types differ in their response to radiationwhether or
not they can adapt or whether or not they get destroyed.
[Slide #15] [Ionizing Radiation Effects]
[Dr. Phelan] Stem cells are very radiosensitive. So bone marrow stem cells are very
radiosensitive and it is why bone marrow radiation can be used to destroy an
individuals bone marrow and replace it with stem cells. Very interesting that stem
cells both from the individual and from a donor are collected very much like
platelets are collected. Those cells have markers on their surface. This machine
takes an individuals blood and runs it through the machine and picks up all the
stem cells and puts them in a bag. Then those stem cells are given to the individual.
The radiation has been used to eliminate that patients original bone marrow. And
you give the stem cells through peripheral blood and they home to the space in bone
marrow and take up residence again and begin working. But radiation treatment,
whole-body radiation is used to be able to destroy the marrow throughout the body.
That doesnt come with some adverse effects as you can imagine because it affects
multiple other tissues as thats happening. And well see that with some categories
in a bit.
Low metabolic rate decreases radiosensitivity and that kind of makes sense. If the
cells that are turnover are the most sensitive those that arent turning over are the
least sensitive. So those cells that the fast they are turning over, the more
radiosensitive.
[Slide #16] [Ionizing Radiation Effects]
[Dr. Phelan] If we look at this diagram we can see some features of radiation and
radiation exposure. Here, we are forming our hydroxyl radical. And in proliferating
cells, were going to get DNA damage, potentially. They're not able to replicate and
they're dying by apoptosis in this route. Another possibility in those nonproliferating cells, these cells dont have the possibility of repairing and if the
damage or if the radiation exposure is enough, those cellular targets will die by
necrosis, not apoptosis because youre just damaging the cell membrane in the cell
and not triggering apoptosis but just destroying the cell from the outside.
[Slide #17] [Sensitivity of Tissues to Ionizing Radiation: Very Sensitive]
[Dr. Phelan] There are some tissues that are very sensitive to ionizing radiation and
these follow the same rules that I just gave you.
Hematopoietic cells--rapidly dividing cells. Lymphoid cellsrapidly dividing cells.
Spermatogonia are dividing cells. And ovarian cells have the potential to be dividing
cells. So these are very sensitive to ionizing radiation. They will very often be
destroyed for a high dose but might be injured in a lower dose.
[Slide #18] [Sensitivity of Tissues to Ionizing Radiation: Sensitive]
[Dr. Phelan] And then there are cells that are sort of in the middle and these are
considered tissues that are sensitive. Gastrointestinal mucosa. In a patient that has
radiation treatment even to the oral region, the mucosa sloughs and becomes
damaged. In whole body radiation the entire GI system might be damaged during
radiation. It will renew but its damaged as a result of the exposure to radiation.
Endothelial cellsso blood vessels can be affected by radiation. Hair follicles, breat
tissue, pancreas, bladder, heart, and lungs are sensitive but not as sensitive as these.
I think we could also fit probably salivary gland tissue in the sensitive tissues as a
tissue in our area that would fall in the sensitive area. The question on salivary
glandswe know that if a person has radiation treatment that affects the salivary
glands, that the salivary glands stop producing saliva immediately. One hypothesis
is that the first area or the first tissue that gets affected by radiation is actually the
endothelial cells, even faster than the parotid acinar cells. And by messing up or
destroying the endothelial cells you cause necrosis in the salivary glands because
you get an ischemic necrosis if you destroy the endothelial cells and the
microcirculation. So it's not really clear what comes first in salivary glands but we
know that as soon as you hit them with radiation exposure and radiation treatment
that person loses within a very short amount of time the functioning of those
salivary glands. So people that have radiation treatment to the head and neck very
often are left with very, very dry mouth.
[Slide #19] [Sensitivity of Tissues to Ionizing Radiation: Least Sensitive]
[Dr. Phelan] And then there are some tissues that are pretty insensitive. Bone and
cartilage that dont change much with radiation exposure. Skeletal muscle doesnt.
heart is a little bit more sensitive than skeletal muscle. Nervous tissue, again, is not
turning over very rapidly and so these tissues are much less sensitive. So you can
kind of think of these categories in relationship to how tissue reacts when it is
exposed to radiation treatment.
[Slide #20] [Developing embryo/fetus]
[Dr. Phelan] Okay, a developing embryo or fetus is most, it would make sense, its
most sensitive during the earliest stages of differentiation because thats the time,
when even later the embryo or fetus, or the fetus rather has still rapidly dividing
cells but not nearly as much as early in development. And again, first semester, first
trimester is the most sensitive when compared to second and third.
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[Slide #21] [Whole body radiation exposure vs. localized radiation exposure]
[Dr. Phelan] Another concept that Id like you to think about is whole body
radiation exposure versus localized. In treatment, we usually use localized. Not
always, but usually. Bone marrow transplant you would use whole body but in most
other treatments of cancers, the use of radiation is localized.
[Slide #22] [Whole Body Radiation]
[Dr. Phelan] And so a whole body radiation is going to come through in bone
marrow transplantation, as I just mentioned, in industrial accidents, and in
explosion of nuclear weapons and thats when the whole body gets radiated.
[Slide #23] [Acute Radiation Syndrome (Radiation Sickness)]
[Dr. Phelan] And in partial exposure, its usually in radiation treatment. There is
something called radiation sickness that occurs when a person has been exposed to
whole-body radiation and there are different syndromes that fall under radiation
sickness.
[Slide #14] [Acute Radiation Sickness]
[Dr. Phelan] And if you look at this well spend a couple of minutes with this so I
can try to explain to you whats going on here. Were looking at different responses
to whole-body radiation. Hematopoietic, which is usually bone marrow, or mostly
bone marrow. Intestinal which is GI and brain, okay? And if you're looking at the
dose here, it goes along this section. And so at a lower dose, because that tissue is
more sensitive, the hematopoietic or bone marrow is going to be affected. As you get
higher dose we will also see bone marrow affected but then you begin to see GI
effects.
And then we can get very high dose and you can have brain effects but youre still
going to get hematopoietic and intestinal responses as well as brain. So if you look at
the way the amount of radiation increases, we get increasing effects onhere we
have very sensitive here we have moderately sensitive and here we have pretty
insensitive but we still can affect the central nervous system if the exposure is high
enough. And that's what happens in accidental exposures or what happened in the
explosion of nuclear bombs.
[Slide #25] [Fetal Effects of Whole Body Radiation]
[Dr. Phelan] The fetal effects of whole body radiation have been identified and they
are developmental abnormalities that youve seen before. Reduced head size,
diminished overall growth, mental retardation, hydrocephaly, microopthalmia and I
can read the rest of them but so can you. Do you think that these are monotopic or
polytopic?
[Student]Both?
[Dr. Phelan]Okay, thats a good answer because you might be right, okay?
Primarily, they are polytopic because the fetus is going to be hit at one point,
usually. Trying to find a way to expose that fetus to radiation over a long period of
time would be difficult. So its usually the fetus is exposed at one time. It is possible
I can make you explain this. Who said monotopic? Somebody want to who was it
that said monotopic? Huh? Somebody did. Okay. If we were thinking about
monotopic somebody wont admit it because youre afraid of what Im going to
ask you. But youre going to actually come up with a way of explaining a monotpic
effect. That somehow the radiation mostly damaged one developing part and
because of that one developing part that didnt develop correctly that there was a
sequence anomaly so you had multiple other effects. I dont know that I could give
you a good example of that in radiation but I can see where if you came up with a
good example that you might be right on the potential for a monotopic effect. But for
the most part, its a polytopic effect but its everything thats being developed at that
time is whats being affected by the radiation.
[Slide #26] [Fetal Effects of Whole Body Radiation]
[Dr. Phelan] The information that we have about whole body radiation in a
population mostly comes from the experience when the US dropped bombs in Japan.
And were getting some more information now out of accident in Chernobyl. There
was also an accident in Pennsylvania a while back from which there is some
information emerging.
And so from Japan, pregnant women who are exposed to doses of 25 rads or greater,
did give birth to infants with developmental effects. So again, you're looking at the
effects on the fetus and the effect on development and you there were effects.
From that experience, the time for growth retardation and microcephaly seemed to
be between the 3rd and the 20th week. Major congenital malformations were
unlikely if they occurred after day 14, so it was very early exposure of the
developing embryo or fetus. It's possible that some low doses may make some
subtle effects that werent so easily identified.
[Slide #27] [Genetic Effects of Whole Body Radiation]
[Dr. Phelan] Then theres some questions about whether or not you get permanent
genetic damage that is transmitted in inherited diseases. And it appears that that did
not happenthat there really has not been evidence of genetic damage over that
has been inherited and passed onto other subsequent generations from changes
from exposure to radiation.
[Slide #28] [Aging Effects of Whole Body Radiation]
[Dr. Phelan] It didnt also appear that they could identify premature aging but
there clearly is identified increased or excess mortalitymore people died. And
why people died is because of malignant neoplasms and malignancies clearly
increased as a result of that radiation exposure.
procedures that we want to do. There are animal experiments. There are
occupational exposures. There is radiation treatment for non-neoplastic conditions
and a number of ways that we have actually learned that ionizing radiation is
associated with the potential development for cancer.
An example Ill give you here, we have seen a case of a patient with a disease called
fibrous dysplasia that we talked a little bit about in developmental abnormalities
completely benign, okay? But it is disfiguring. It is a cosmetic issue, particularly in
the jaws when particularly a young person has an expanding jaw, either maxilla or
mandible. And initially, there were attempts to treat that with radiation treatment.
The problem was, years later, that bone then transformed into an osteosarcoma. So
there were a number of cases that made it clear that there was association between
radiation treatment for fibrous dysplasia and the development of bone cancer in
those lesions. We actually saw a case in one of our oral pathology meetings where
there had been a patient that had acne and had undiagnosed fibrous dysplasia. The
acne was treated with very low dose radiation treatment and as a 40-year-old
individual twenty years later, she developed a osteosarcoma in the maxilla in the
environment of the fibrous dysplasia. So we know there are certain kinds of nonneoplastic conditions that should no be treated with radiation because they have the
potential for transforming.
[Slide #37] [Ionizing Radiation and Cancer]
[Dr. Phelan] Early days of taking dental x-rays--the way they were taken is the
dentist or the dental assistant held the x-ray film in the patients mouth. Or before
there was really an understanding of the dangers of radiation. In order to test the
beam, the radiologist would test their equipment by placing their hand in the path of
the beam. There was also a time when you went to shoe stores and you can find this
if you hunt around on your if you good it, there was a time when shoe stores in
the United States in order to see if your shoes fit, there was a piece of equipment
that looks something like a podium and it was actually a fluoroscope. You put your
feet in the bottom part of it and looked in the eyepieces and you pushed the button
and you radiated your feet to see if your feet fit in the shoes. There was a time when
we really didnt understand the potential for radiation damage to human tissue.
And so there are a number of dentists and dental assistants who developed either
squamous cell carcinoma or basal cell carcinoma on their hands because they held
the x-ray film in the patients mouth. Its a lot easier to take x-rays that way,
however, its not a good idea.
[Slide #38] [Ionizing radiation and Cancer]
[Dr. Phelan] There is an episode of osteoscarcoma and other carcinomas in the
paranasal sinuses from people who used radium to paint on watch dials at a time,
again, when it wasnt clear how dangerous this was. And what they would do is, in
order to paint the watch dials, they had to have a very thin brush in one or two
bristles, and they would take a brush and put it in their mouths and make the point
on the brush as pointy as they could and then they would paint the dials. There was
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studies that come up to see what you get. And we finished one minute over. So have
a nice weekend.
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