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RADIATION PROTECTION IN NUCLEAR MEDICINE
PART1. BIOLOGICAL EFFECTS OF IONIZING RADIATION
1.
BASIC CONCEPTS, CELLULAR EFFECTS
Since the basic structure of living matter is the cell, the interaction of ionizing
radiation with living matter is basically an interaction with the cell or more specifically
with structures and molecules in the different cell components. There is substantial
evidence that the most important target in the irradiated cell is the DNA molecule.
Damage to DNA can lead to irreversible cell damage, such as inhibition of its ability
to divide, or structural changes with altered cell function.
The DNA can be damaged by direct energy deposition in the molecule
leading to breakage of chemical bonds and to structural changes of the molecule.
This is called direct action. Damage can, however, also be rendered by indirect
action of the radiation. In this case the energy deposited in the surroundings of the
molecule leads to the production of free radicals and other highly oxidizing agents
which chemically attack DNA resulting in chemical changes to the molecule. Several
kinds of primary damage to DNA are possible: Single and double strand breaks,
base changes, breakage of hydrogen bonds between bases, etc.
It is important to realize that not every type of damage to DNA or other target
molecules of the cell will result in irreversible damage to the cell. A biological system
has a repair capability which is generally very efficient.
If the repair mechanism fails, the result will be biochemical changes in the cell
leading to cell modification or cell killing. The cell modification process can lead to a
transformation of the cell into a tumor cell or if the modification appears in a germ
cell, to mutations observable as hereditary effects.
In the laboratory the response of cells to ionizing radiation at different doses
is generally described by cell survival curves giving the surviving fraction of a cell
population at different absorbed doses. Several factors will affect the shape of the
cell survival curves:
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radiation quality
absorbed dose rate
dose fractionation
types of cells
radioprotectors/radiosensitizers
temperature
The radiation quality, or the type of ionizing radiation and its energy, is a very
important factor. A general rule is that the surviving fraction of a certain cell
population at a given absorbed dose will decrease with increasing LET of the
radiation. The reason for this effect is that the probability of creating irreversible
damage to the target molecule is much higher if the absorbed dose to the cell is
delivered along a dense track of a particle compared to a more random distribution of
ionizations in the whole cell as in the case of photons
The radiosensitivity of cells and tissues varies considerably. It depends upon
cell differentiation and proliferation which has been known since the beginning of
this century, but several exceptions to this general rule have been found. For most
cells the radiosensitivity will vary during the cell cycle with a maximum sensitivity
during mitosis. Eye lens, gonads and lymphocytes are examples of tissues and cells
that have high radiosensitivity, while bone, muscle and nerve cells have low
radiosensitivity
Since the deposition of energy by ionizing radiation is a random process,
even at very low doses there is a certain probability that sufficient energy is
deposited into the critical target molecule in the cell resulting in cell modification or
even cell killing. If one cell or a small number of cells are killed by the radiation there
will be no consequences for the irradiated tissue or the organism. If, however, the
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cell is modified in a way leading to genetic changes or changes resulting in
malignancy the result may have serious consequences for the irradiated organism
and for future generations. Such effects are called stochastic effects. Even at very
low doses, there is a very small but finite probability that such effects occur. If the
dose is increased the frequency of stochastic effects will increase, but the severity of
the effect will remain constant (the irradiated individual will either get cancer or not).
At very high doses the number of cells destroyed will increase and at a
certain level, damage to the irradiated organ can be detected clinically. Above this
threshold the severity of the effect will increase by increasing absorbed dose until the
whole organ or the whole organism is destroyed or killed. Such effects are called
deterministic effects.
Both stochastic and deterministic effects are important in radiation protection.
The main objective in radiation protection must be to avoid deterministic effects and
to reduce the probability of stochastic effects to a level as low as reasonably
achievable.
2.
DETERMINISTIC EFFECTS
By observation, deterministic effects must have a threshold dose below which the
loss of cells in an organ will be compensated and clinically undetectable. Above this
threshold the severity of the damage will increase when the absorbed dose is
increased. In a population the dose-frequency relationship will generally be of
sigmoid shape, where the steepness in the curve reflects the spread of individual
dose-severity relationships.
The threshold dose is dependent on the deterministic effect studied. For
instance, the threshold dose for skin erythema is 3-5 Gy while for skin necrosis about
50Gy. The threshold doses may seem very high and far above the doses that can be
received by a worker in nuclear medicine. It is, however, possible to identify
situations where the exposure can reach above the threshold dose. One such
situation is the prolonged handling of vials and syringes with radiopharmaceuticals
without using any shields.
Some accidents can lead to high enough whole body doses that the irradiated
individual will die. The cause of death is generally severe cell depletion in vital
organs. The X- and Y-ray threshold whole body dose for lethality is about 1 Gy. The
number of surviving individuals will decrease when the absorbed dose is increased
and without medical intervention it is less than one percent at 6 Gy.
The cause of death for whole body doses below 5 Gy is loss of bone marrow
stem cells. It might be possible to improve the chances of survival by substituting
new cells from a suitable donor. The treatment of the victims of the Chernobyl
accident revealed that the use of bone marrow growth stimulating factors is a
possible method to improve survival. At doses higher than 5 Gy additional effects
caused by gastrointestinal damage will occur causing death within 1-2 weeks after
the exposure. At very high doses, radiation effects on the central nervous system
and the cardiovascular system will cause death within a few days.
The period of early development is characterized by rapid cell proliferation
and it was noticed early on that irradiation in utero could result in damage to the
embryo and fetus. It is now generally accepted that irradiation of an embryo or fetus
can cause lethal effects, or deterministic effects such as malformations and mental
retardation as well as stochastic effects (leukemia, cancer, and hereditary effects).
The biological effects in the embryo and fetus are related to the postconception time of exposure. Extensive animal studies have shown that the effect of
high doses of ionizing radiation during the implantation period (0-14 d for humans)
will be a prenatal death of the embryo. Exposure during organogenesis, when most
of the embryonic cells are in a differentiation stage will cause lethal effects and
malformations. During the fetus period, which for humans lasts from the sixth week
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until birth and which is mainly a growing period, the effects will primarily be related to
the central nervous system.
Observations among human populations include A-bomb survivors and
women who have received radiotherapy during pregnancy. The most commonly
reported abnormalities are microcephaly and growth reduction. The threshold dose
for these deterministic effects is supposed to be >100 mSv. The microcephaly is
often combined with severe mental retardation. Recent observations show that the
frequency of severe mental retardation depends on the time of exposure during
pregnancy and it is assumed that IQ will be shifted downwards by 30 units per Gy for
exposure during 8-15 weeks of gestation
As a general conclusion we can state that the probability of inducing radiation
effects in individuals exposed in utero will be larger than for the same whole body
dose in exposed adults. The risk of severe mental retardation is probably the most
important factor to take into consideration in establishing recommendations about
medical exposure of pregnant women.
3.
STOCHASTIC EFFECTS
Two types of stochastic effects are generally recognized. The first will occur in
somatic cells and may result in development of cancer. The second will occur in
germ cells and can result in hereditary effects.
There is no doubt that ionizing radiation can cause hereditary effects. It has
been demonstrated in extensive animal studies. In fact, in the absence of human
data, estimates of mutation rates from animal studies form the principal basis for
estimating the probability of radiation-induced hereditary effects in humans.
In the case of cancer induction, for which extensive experimental data exists,
calculations of risks to humans must be based on careful observations of populations
that have been exposed to ionizing radiation at doses higher than those of direct
interest in radiation protection. The most well known of these groups is the A-bomb
survivors in Hiroshima and Nagasaki. Several other groups have, however, also
been studied, including radium dial painters, miners, populations living in areas of
increased natural background radiation and populations therapeutically and
diagnostically irradiated.
Induction of cancer is a multi-stage process. The first stage is the initiation
which is the primary modification of one or a small number of cells. The further
stages include promotion, a process by which a modified cell grows to a detectable
cancer and progression. The number of cells in a detectable cancer is aprox. one
billion. The different stages can be separated by long periods of time, which partly
explains the long latency period which can be observed between the exposure to the
carcinogenic agent and the development of a cancer. The shortest mean latency
period is observed for leukemia (7-10 year) while cancers in organs such as brain,
breast, lung and thyroid have mean latency periods in the range of 20-30 years or
even more. These long latency periods must be considered when an exposed human
population is observed as a basis for risk evaluations. The observation time must be
very long in order to get reliable data.
Cancers induced by ionizing radiation are indistinguishable from those
occurring from other causes. Cancer may be induced in almost all tissues of the
human body although the frequency of fatal cancer will vary considerably between
the different tissues and organs. Bone marrow is highly sensitive to the leukemia
induction. Among organs the stomach, colon and lung are very sensitive while bone,
thyroid and skin have low sensitivities. These variations in sensitivity must also be
taken into account when calculating the probabilities of cancer induced by ionizing
radiation. However, a distinction must be made between cancer incidence and fatal
cancer incidence. Lung cancer has, for instance, a very high lethality while thyroid
and skin cancers are less fatal.
Another important factor is the age of the victim at exposure. Generally, the
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probability of fatal cancer is higher for people exposed at a young age.
4.
RISK ESTIMATES
In order to allow calculation of the quantitative risk of stochastic effects, an
epidemiologic observation, such as the follow up of the A-bomb survivors, must fulfill
certain requirements. It must include a representative population and a large number
of individuals. It must also, as carefully as possible, describe the exposure of each
individual including age at exposure, sex and irradiated organs. The radiation quality
and absorbed dose of each individual must also be known.
If these criteria are fulfilled, the study can be used to estimate the risks of
radiation hazard. However, some other factors must also be considered such as a
projection in time if the observation is limited in time and the transformation of data to
a general population of all ages
Many observations, both in experiments and in studies of human populations,
indicate that the probability of cancer induction for low LET radiation is 2 or 3 times
higher per unit of dose in the case of high doses and high dose rates compared to
low doses and low dose rates. Thus, a simple linear extrapolation of the radiation
risks from high to low doses is not acceptable for all cancers. It is now generally
accepted that the dose-response curve for most cancers is of linear-quadratic form:
P = AD + BD2
where P is the probability of cancer induction, D is the absorbed dose and A and B
are constants. The relationship is valid for doses lower than the threshold of
significant cell killing. For low doses the linear part (A*D) will dominate and for high
doses the quadratic term will dominate. A low dose is <50 mGy and a low dose rate
<100 mGy/h. The quotient A/B is called DDREF (Dose and Dose Rate Effectiveness
Factor) and has been assigned by ICRP the value 2 for low LET radiation. Thus, in a
radiation protection situation where individuals are exposed to low doses of low LET
radiation the probability of cancer induction per unit dose would be expected to be
about half that observed among the highly exposed A-bomb survivors. The
probability will also increase linearly with the absorbed dose with a slope determined
by the constant A. This is called the linear no-threshold hypothesis
Summary of ICRP's estimates of probabilities of effects of exposure to ionizing
radiation.
Effect
Population
Exposure period
Probability
Hereditary effects
whole population
Lifetime
1% per Sv (all
generations)
Fatal cancer
"
Lifetime
5% per Sv
Fatal cancer
working population
age 18-65
4% per Sv
Health detriment
whole population
Lifetime
7.3% per Sv
Health detriment
working population
age 18-65
5.6% per Sv
The higher risks for a population of all ages compared to the working population
depends exclusively upon the high risks for young people. This in turn is a
combination of the general higher radiosensitivity observed in children and their
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expected long life time making it possible for cancers with long mean latency period
to develop.
5.
REFERENCES
1. WORLD HEALTH ORGANIZATION and INTERNATIONAL ATOMIC ENERGY
AGENCY. Manual on Radiation Protection in Hospital and General Practice. Vol.
1. Basic requirements (in press)
2. INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION. 1990
Recommendations of the International Commission on Radiological Protection,
ICRP Publication No. 60. Oxford, Pergamon Press, 1991 (Annals of the ICRP 21,
1-3).
3. INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION.
Nonstochastic effects of ionizing radiation, ICRP Publication No. 41. Oxford,
Pergamon Press, 1984 (Annals of the ICRP 14, 3).
4. ALPEN E.L Radiation Biophysics. Academic Press, 1998
5. OTAKE M, OSHIMARO H, SCHULL WJ. Otake M. Severe mental retardation
among the prenatally exposed survivors of the atomic bombings of Hiroshima
and Nagasaki: A comparison of the T65DR and DS86 dosimetry system. Tokyo,
1987 (Radiation Effects Research Foundation Report RERF TR 16-87).
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