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Biological Effects

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January 2006
Section 2 – Biological Effects of Ionizing Radiation

Principles of Radiation Protection

Section 2

BIOLOGICAL EFFECTS
OF IONIZING RADIATION

Non copyrighted material taken from HEW Publication (FDA) 77-8004

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Section 2 – Biological Effects of Ionizing Radiation

The following section on the Biological Effects of Ionizing Radiation was adapted from a
non-copyrighted document with the same title, produced by the U.S. Food and Drug
Administration, HEW Publication (FDA) 77-8004. Although the document was written over
15 years ago, it still reflects a scientifically accurate overview of radiation effects that are
known to occur in human individuals and populations.

A. Introduction
The fact that ionizing radiation produces biological damage has been known for many
years. The first case of human injury was reported in the literature just a few months
following Roentgen’s original paper in 1895 announcing the discovery of x-rays. As
early as 1902, the first case of x-ray induced cancer was reported in the literature.
Early human evidence of harmful effects as a result of exposure to radiation in large
amounts existed in the 1920s and 1930s, based upon the experience of early
radiologists, miners exposed to airborne radioactivity underground, persons working in
the radium industry, and other special occupational groups. The long-term biological
significance of smaller, repeated doses of radiation, however, was not widely
appreciated until relatively recently, and most of our knowledge of the biological effects
of radiation has been accumulated since World War II.

B. Sequential Pattern of Biological Effects
In general, the sequence of events following radiation exposure may be classified as
follows:

1.

Latent Period
Following the initial radiation event, and before the first detectable effect occurs,
there is a time lag referred to as the latent period. There is a vast time range
possible in the latent period. The biological effects of radiation are arbitrarily
divided into short-term and long-term effects on this basis. Those effects which
appear within a matter of minutes, days, or weeks are called short-term effects
and those which appear years, decades, and sometimes generations later are
called long-term effects.

2.

Period of Demonstrable Effects on Cells and Tissues
During or immediately following the latent period, certain discrete effects can be
observed.
One of the phenomena that is seen most frequently in growing tissues exposed to
radiation is the cessation of mitosis, or cell division. This may be temporary or
permanent, depending upon the radiation dosage. Other effects include breaking
or clumping of chromosomes, and formation of giant cells or other abnormal

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mitoses. It should be pointed out that many of these effects can be duplicated
individually with other types of agents, such as chemicals. However, the entire
gamut of effects cannot be reproduced by any other single agent.

3.

Recovery Period
Following exposure to radiation, recovery can take place to a certain extent. This
is particularly apparent in the case of the short-term effects, i.e., those appearing
within a matter of days or weeks after exposure. However, there may be a
residual damage from which no recovery occurs, and it is this irreparable injury
which can give rise to later long-term effects.

C. Determinants of Biological Effects
1.

The Dose Response Curve
For any biologically harmful agent, it is useful to correlate the dosage
administered with the response of damage produced, in order to establish
acceptable levels of exposure. “Amount of damage” in the case of radiation might
be the frequency of a given abnormality in the cells of an irradiated animal, or the
incidence of some chronic disease in an irradiated human population. In plotting
these two variables, a dose-response curve is produced. With radiation, an
important question has been the nature and shape of this curve. Two possibilities
are illustrated in figures 1 and 2.
Figure 1 is a typical “threshold” curve. The point at which the curve intersects the
abscissa is the threshold dose, i.e., the dose below which there is no response. If
an easily observable radiation effect, such as reddening of the skin, is taken as
“response,” then this type of curve is applicable. The first evidence of the effect
does not occur until a certain minimum dose is reached, although unobserved
effects may exist.
Figure 2 represents a linear, non-threshold relationship, in which the curve
intersects the abscissa at the origin. Here it is assumed that any dose, no matter
how small, involves some degree of response. There is some evidence that the
genetic effects of radiation constitute a non-threshold phenomenon, and one of the
underlying (and prudent) assumptions in the establishment of radiation
protection guides and in radiation control activities in public health programs has
been the existence of a non-threshold effect. Thus some degree of risk is assumed
when large populations of people are exposed to even very small amounts of
radiation. This assumption often makes the establishment of guidelines for
acceptable radiation exposure a complex task, since the concept of “acceptable
risk” comes into play, in which the benefit to be accrued from a given radiation
exposure must be weighed against its hazard.

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2.

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Section 2 – Biological Effects of Ionizing Radiation

Rate of Absorption
The rate at which the radiation is administered or absorbed is important in the
determination of what effects will occur. Since a considerable degree of recovery
occurs from the radiation damage, a given dose will produce less effect if divided
or prolonged (thus allowing time for recovery between dose increments) than if it
were given as a single exposure.

3.

Area Exposed
The portion of the body irradiated is an important parameter because the larger
the area exposed, other factors being equal, the greater the overall damage to the
organism. Even partial shielding of the highly radiosensitive blood-forming
organs such as the spleen and bone marrow can mitigate the total effect
considerably. An example of this phenomenon is in radiation therapy, in which
doses which would be lethal if delivered to the whole body are commonly delivered
to very limited areas; e.g., to tumor sites.
Generally when expressing external radiation exposure without qualifying the
area of the body involved, whole-body irradiation is assumed.

4.

Variation in Species and Individual Sensitivity
There is a wide variation in the radiosensitivity of various species. Lethal doses
for plants and microorganisms, for example, are usually hundreds of times larger
than those for mammals. Even among different species of rodents, it is not
unusual for one to demonstrate three or four times the sensitivity of another.
Within the same species, individuals vary in sensitivity. For this reason the
lethal dose for each species is expressed in statistical terms, usually as the LD50/30
for that species, or the dose required to kill 50 percent of the individuals in a large
population in a thirty-day period. For man, the LD50/30 is estimated to be
approximately 450 rads for whole-body irradiation.

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5.

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Variation in Cell Sensitivity
Within the same individual, a wide variation in susceptibility to radiation damage
exists among different types of cells and tissues. In general, those cells which are
rapidly dividing or have a potential for rapid division are more sensitive than
those which do not divide. Further, cells which are non-differentiated (i.e.,
primitive or non-specialized) are more sensitive than those which are highly
specialized. Within the same cell families, then, the immature forms, which are
generally primitive and rapidly dividing, are more radiosensitive than the older,
mature cells which have specialized in function and have ceased to divide.
Based upon these factors, it is possible to rank various kinds of cells in descending
order of radiosensitivity. Most sensitive are the white blood cells called
lymphocytes, followed by immature red blood cells. Epithelial cells, which line
and cover body organs, are of moderately high sensitivity; in terms of injury from
large doses of whole-body external radiation, the epithelial cells which line the
gastrointestinal tract are often of particular importance. Cells of low sensitivity
include muscle and nerve, which are highly differentiated and do not divide.

D. Short Term Effects
An acute dose of radiation is one which is delivered to the body during a very short
time. If the amount of radiation involved is large enough, acute doses may result in
effects which can manifest themselves within a period of hours or days. Here the
latent period, or time elapsed between the radiation insult and the onset of effects, is
relatively short and grows progressively shorter as the dose level is raised. When the
radiation is delivered to the whole body, the signs and symptoms which comprise these
short-term effects are collectively known as the Acute Radiation Syndrome.

1.

Stages in the Acute Radiation Syndrome
a.

Prodrome
This is the initial phase of the syndrome, and is usually characterized by
nausea, vomiting and malaise.

b.

Latent Stage
During this phase, which may be likened to the incubation period of a viral
infection, the subjective symptoms of illness may subside, and the individual
may feel well. Changes, however, may be taking place within the bloodforming organs and elsewhere which will subsequently give rise to the next
aspect of the syndrome.

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c.

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Manifest Illness Stage
This phase reflects the clinical picture specifically associated with the
radiation injury. Among the possible signs and symptoms are loss of hair
(epilation), fever, infection, hemorrhage, severe diarrhea, prostration,
disorientation, and cardiovascular collapse. Observation of the foregoing
phenomena in a given individual is largely dependent upon the radiation dose
received.

d.

2.

Recovery or Death

Relation of Dose to Type of Acute Radiation Syndrome
Recalling the different sensitivities of various kinds of cells, one can predict
roughly the biological systems which will be affected as radiation dose increases.
At relatively low doses, for example, the most likely cells to be injured are those
with greatest sensitivity, i.e., immature white blood cells of lymph and bone
marrow, so that the observable effects during the manifest illness stage would
relate to these cells; one would thus expect to observe fever, infection and
hemorrhage. This is known as the hematopoietic form of the acute radiation
syndrome.
At higher doses, usually over 600 rads, cells of somewhat lower sensitivity will
also be injured. Of particular importance are the epithelial cells which line the
gastrointestinal tract, for when these are destroyed a vital biological barrier is
broken down. As a result, there may be fluid loss, overwhelming infection and
severe diarrhea in this gastrointestinal form of the acute radiation syndrome.
In the cerebral form, which may result from doses of 10,000 rads or more, the
relatively resistant cells of the central nervous system are damaged, and the
affected individual undergoes a rapid illness, characterized by disorientation and
shock.
Considering the large degree of individual variation which exists with respect to
radiation injury, it is difficult to assign a precise dose range to each of the above
forms of the syndrome. The following generalizations, however, may serve to
provide a rough indication of the kinds of doses involved. At 50 rads or less,
ordinary laboratory or clinical methods will show no indications of injury from
whole-body irradiation. At 100 rads, most individuals show no symptoms,
although a small percentage may show mild blood changes. At 200 rads, most
persons show definite signs of injury; this dose level may prove fatal to those
individuals most sensitive to the effects of radiation. At 450 rads, the median
lethal dose has been reached, and 50 percent of exposed individuals will succumb.
Approximately 600 rads usually marks the threshold of the gastrointestinal form
of the acute radiation syndrome, with a very poor prognosis for all individuals
involved; a fatal outcome may well be certain at 800 to 1,000 rads. (For a detailed

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account of the Acute Radiation Syndrome, including symptomatology, laboratory
findings, diagnosis and patient management, see: Thoma, George E., and Wald,
Neil, “The Diagnosis and Management of Accidental Radiation Injury,” Journal of
Occupational Medicine, 1: 421-427, August 1959.)

3.

Summary
The Acute Radiation Syndrome represents the signs and symptoms which result
from large doses of radiation, generally over 100 rads, delivered to a major portion
of the body; it is important to recall that this type of injury occurs only when the
dose is received over a short period of time. The total effect may vary from mild
and transient illness to death.
Because of the variation in susceptibility to radiation injury which exists among
different individuals, it is extremely difficult to predict with accuracy the degree of
effect in a given person, even when the dose is known. Within certain broad
ranges, however, certain effects may be correlated with various dose levels on a
population basis.
The course of the syndrome may vary from hours to several weeks. This time
element is generally related to the radiation dose; other factors being equal, the
duration of the various phases of the syndrome is inversely proportional to the
amount of radiation received, with a rapid, illness being characteristic of very high
doses.
The following graphical representation of the above information attempts to
summarize the Acute Radiation Syndrome.

Acute Radiation Syndrome

Effects

0

100

Exposure (Roentgens)
400
600

1000

//

5000

Organs Affected

Nil

Hemopoiesis

GI Tract

CNS

Signs

Nil

Leukopenia
Hemorrhages
Infection

Diarrhea,
Electrolyte
Imbalance

Convulsions,
Tremors,
Ataxia

Critical Period

4-6 weeks

1-2 weeks

0-2 days

Cause and Time
of Death

Hemorrhage,
Infection,
2 months

Circulatory
Collapse,
2 weeks

Respiratory Failure
Cerebral Edema
2 days

Prognosis

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Good

50% Deaths

100% Deaths

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E. Long Term Effects
1.

Introduction
Long-term effects of radiation are those which may manifest themselves years
after the original exposure. The latent period, then, is much longer than that
associated with the acute radiation syndrome. Delayed radiation effects may
result from previous acute, high-dose exposures or from chronic low-level
exposures over a period of years. From the standpoint of public health
significance, the possibility of long-term effects on the large number of people
receiving low, chronic exposures is cause for greater concern than the short-term
radiation effects from acute exposures which involve only a few individuals.
It should be emphasized that there is no unique disease associated with the longterm effects of radiation; these effects express themselves in human populations
simply as a statistical increase in the incidence of certain already-existing
conditions. Because of the low normal incidence of these conditions, it is usually
necessary to observe large populations of irradiated persons in order to measure
this kind of increase, and employ biostatistical and epidemiologic methodology. In
addition to the large numbers of people needed for human studies of long-term
radiation effects, the situation is further complicated by the latent period; in some
cases, a radiation-induced increase in a disease may go unrecorded unless the
study is continued for many years.
It should also be noted that although it is possible to perform true experiments
with animal populations, in which all factors with the exception of radiation
exposure are kept identical in study populations, human data is limited to
“second-hand” information, accrued from populations which have been irradiated
for reasons other than radiobiological information. It is often the special
characteristics of irradiated human populations, e.g., the presence of some preexisting disease, which makes for caution in drawing meaningful conclusions
when these groups are compared with non-irradiated ones.
Despite the above difficulties, many epidemiologic investigations of irradiated
human beings have provided convincing evidence that ionizing radiation may
indeed result in an increased risk of certain diseases long after the initial
exposure. This information supplements and corroborates that gained from
animal experimentation which demonstrates these same effects.
Among the long-term effects thus far observed have been somatic damage, which
may result in an increased incidence of cancer, embryological defects, cataracts,
and life span shortening; and genetic mutations, which may have an adverse effect
for generations after the original radiation damage.

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2.

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Carcinogenic Effects

With proper selection of animal species and strains, and of dose, ionizing radiation
may be shown to exert an almost universal carcinogenic action, resulting in
tumors in a great variety of organs and tissues. There is human evidence as well
that radiation may contribute to the induction of various kinds of neoplastic
diseases.
a.

Possible Carcinogenic Mechanisms
It should be made clear that even with high doses of radiation, most
irradiated individuals will not suffer long-term consequences despite the fact
that the incidence of certain diseases, such as leukemia and other forms of
cancer, may be increased manyfold. The explanation may lie in the fact that
most diseases are probably “caused” by the simultaneous interaction of
several factors, and that the presence of some of these factors without the
others may not be sufficient to induce the disease. Radiation, like other
chemical and physical agents which are considered carcinogenic, may be only
one of a number of interacting factors which, in a given individual, must be
present in order to result in the disease.
Among the tentative explanations thus far proposed for the carcinogenic
action of radiation are the following:
1)

Activation of a Latent Carcinogenic Virus
The essential factor in the production of cancers may be a virus which
attacks normal cells by injecting itself into the cell nucleus. The genetic
material of the virus, now within the host cell, stimulates the cell to
reproduce wildly, thus initiating the neoplastic growth. The virus, it
would seem, is ubiquitous, and even may be passed from mother to fetus
during prenatal life. It would follow, then, that normal cells have a
natural mechanism whereby the action of these viruses is resisted; it is
possible that radiation and other carcinogenic agents may activate the
latent virus or interfere with the cell’s resistance. In this case, the
presence of the virus in the cell would be the primary, initiating event,
and the radiation would act as a promoting (catalytic) agent.

2)

Damage of Chromosomes
Certain diseases, among them leukemia, have been associated with
specific chromosome aberrations. It may be that radiation damage can
produce these abnormalities in the chromosomes and that these changes
in turn initiate the disease.

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3)

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Mutations in Somatic Cells
Radiation can produce mutations in many kinds of cells in the body
including those in the reproductive organs (germ cells) as well as those
in other parts of the body (somatic cells). It may be that a sufficient
accumulation of mutations in a colony of cells can result ultimately in
the kind of uncontrolled growth which results in cancer. The somatic
mutation concept is an attractive one since it provides a means by which
to relate both the carcinogenic effects of radiation and aging. Somatic
mutations probably occur constantly at a low rate in all organisms and
the resultant damage accumulates gradually in the affected tissues.
When the level of malfunction or damage reaches a critical point, cell
death or carcinogenesis could occur. Radiation, like other harmful
agents, may accelerate the rate at which these mutations occur, thus
hastening the death of the organism or the production of cancers.
When radiation doses are large enough to destroy a portion of the cells in
an organ, the surviving cells, many of which may have undergone
mutations as a result of the radiation exposure, are stimulated to rapid
division in order to replace the missing ones. This resulting rapid
division may be a concomitant factor in cancer production. In the
somatic chromosome aberration or mutation processes, the radiationinduced change may be the primary or initiating event, with other
factors playing a contributory or promoting role.

4)

Formation of Free Radicals
As a result of the irradiation of water molecules, which are abundant in
all living cells, certain short-lived but potent damaging agents called
“free radicals” are formed and may play an important role in both cancer
and aging. There is some evidence that these radicals are generated
continually at a low rate as a byproduct of certain normal biochemical
reactions in living cells, and that radiation simply accelerates their
formation.
None of the above speculations need exclude the others. For example,
free radicals are formed wherever living cells are irradiated, and so this
takes place during all of the above processes. That cancer, mutations,
and aging are interrelated seems reasonably clear, but the precise
mechanisms involved have yet to be elucidated.

b.

Human Evidence for Radiation Carcinogenesis
Both empirical observations and epidemiologic studies of irradiated
individuals have more or less consistently demonstrated the carcinogenic
properties of radiation. Some of these findings are summarized below.

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1)

Principles of Radiation Protection

Radium Dial Painters
Early in this century, when long-term radiation effects were little
recognized, luminous numerals on watches and clocks were painted by
hand with fine sable brushes, dipped first in the radium-containing paint
and then often tipped on the lips or tongue. Young girls commonly were
employed in this occupation. Years later, studies of these individuals
who had ingested radium paint have disclosed an increased incidence of
bone sarcomas and other malignancies, resulting from the burdens of
radium which had accumulated in their bones.

2)

Radiologists and Dentists
Some early medical and dental users of x-rays, largely unaware of the
hazards involved, accumulated considerable doses of radiation. As early
as the year 1910, there were reports of cancer deaths among physicians,
presumably attributable to x-ray exposure. Skin cancer was a notable
finding among these early practitioners; dentists, for example, developed
lesions on the fingers with which they repeatedly held dental films in
their patients’ mouths.
Of course, the excesses associated with the very early use of x-rays have
diminished. Nonetheless, a more recent study comparing radiologists of
various ages with physicians who do not use x-rays has shown that some
groups of radiologists have a significantly higher incidence of leukemia
than their non-radiologist counterparts. This difference seems to be
largely confined to older radiologists who presumably received much of
their exposure in the 1930’s through 1950’s when protective measures
were not as widely employed as they are today.

3)

Uranium Miners
Early in this century, certain large mines in Europe were worked for
pitchblende, a uranium ore. Lung cancer was highly prevalent among
the miners as a result of the inhalation of large quantities of airborne
radioactive materials. It was estimated that the risk of lung cancer in
the pitchblende miners was at least 50 percent higher than that of the
general population.
Modern mining conditions have greatly improved. Nonetheless, recent
studies have indicated a slight but statistically significant excess risk of
lung cancer even among contemporary American uranium miners.

4)

Atomic Bomb Survivors
One of the strongest supports for the concept that radiation is a
luekemogenic agent in man comes from the epidemiologic studies of the

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survivors of the atomic bombing of Hiroshima. Survivors exposed to
radiation above an estimated dose of approximately 100 rem showed a
significant increase in the incidence of leukemia. In addition, leukemia
incidence correlated well with the estimated dose, thus strengthening
the hypothesis that the excess leukemia cases were indeed attributable
to the radiation exposure. Thyroid and breast cancers have also shown
an increase among the heavily irradiated survivors. The latent period
for these cancers appears to have been longer than that for the radiationinduced leukemias, ranging from approximately 10 to more than 20
years.
5)

Ankylosing Spondylitis Patients
Ankylosing spondylitis, a progressively disabling arthritic disease of the
spine, has been treated with large x-ray doses delivered to the vertebrae
to slow the progress of the disease and to relieve its symptoms. Persons
thus treated accumulated large doses of radiation to the bone marrow. A
study of a large population of such persons revealed a much higher
incidence of leukemia than might be expected in the general population.
It is generally agreed that radiation received by these patients was a
major factor in producing the excess leukemias. However, since a control
group of spondylitis patients who had not been treated with x-rays was
not available for comparison in the study, it is possible that a part of the
observed increase in leukemia might have been caused by (a) a possible
predisposition to leukemia on the part of ankylosing spondylitis patients,
and/or, (b) a possible carcinogenic effect from the drug therapy which the
patients may have received along with the x-ray treatments.

6)

Children Irradiated for Thymus Enlargement
Many young children with respiratory distress were diagnosed in former
years as having enlarged thymus glands and were treated with
therapeutic doses of x-rays to the thymic region. A number of follow-up
studies were performed on these children, and although results varied, it
is generally agreed that these persons have experienced a significantly
increased incidence of thyroid cancer and other malignancies of the head
and neck. Such findings are not limited to thymic irradiation; further
studies have demonstrated excess thyroid cancers and other head and
neck malignancies as a result of childhood irradiation to this area of the
body for the treatment of a wide variety of benign conditions such as
enlarged tonsils and adenoids, acne, etc.

7)

Tinea Capitis Patients
X-ray epilation was a widely used treatment for children with tinea
capitis (ringworm of the scalp). A study of a group of such children in

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New York City, and a similar investigation in Israel, indicate an
increased incidence of thyroid cancer and leukemia in the irradiated
children, as well as the possibility of functional changes in the central
nervous system.
8)

Patients Receiving Breast Irradiation
A link between high doses of radiation to the chest and breast cancer was
discovered in a survey of women who had been treated for tuberculosis
by artificial pneumothorax, a procedure which consisted of intentionally
collapsing the affected lung for a period of time and then reinflating it.
This was accomplished with the assistance of the fluoroscope, and in
many cases the pneumothorax treatment was repeated, sometimes more
than 100 times. The patient was often positioned in the vertical
fluoroscope machine facing the x-ray tube, so that the largest radiation
dose was delivered to the anterior surface of the chest. The incidence of
breast cancer among these heavily irradiated patients was found to be 4
to 8 times the expected rate for this disease. Further, the investigators
were able to show a correlation between the side of the chest receiving
the treatment and the affected breast. A similar increase in breast
cancer incidence was found in a group of women who had received x-ray
treatment of the breast for postpartum mastitis.

9)

Children Whose Mothers Were Irradiated During Pregnancy
A pioneering study in this area purported to show an increased risk of
leukemia among young children if they had been irradiated in utero as a
result of pelvic x-ray examination of the mother. Mothers of leukemic
children were questioned as to their radiation histories during pregnancy
with the child in question, and these responses were compared with
those of a control group, consisting of mothers of healthy playmates of
the leukemic children. Originally this work received much criticism,
based partly on the questionnaire technique used to elicit the
information concerning the radiation history. It was believed that the
differences in recall between the two groups of mothers might have
biased the results. A larger subsequent study designed to correct for the
objections to the first one corroborated its essential findings.
It should be noted the investigations presented thus far which
demonstrate the carcinogenic properties of radiation involve large doses,
such as those received in therapeutic x-ray procedures, with the
exception of these childhood leukemia investigations. Here, doses of
radiation are low, in the diagnostic radiographic range. Such findings
bear out the high sensitivity of embryonic tissues to radiation damage.

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c. Significance of Human Studies on Radiation Carcinogenesis
1)

Considerations in Epidemiologic Studies
In evaluating human studies of the kind described above, two important
concepts should be borne in mind. Because the studies were not
designed as radiobiological experiments in which all factors are held
constant with the exception of radiation exposure, caution is required
before the association between radiation and some later disease can be
labeled as a cause-effect relationship. This is particularly true when the
study group consists of patients irradiated for some disease or
abnormality, since the question arises as to whether the abnormality
itself might not account for the later disease rather than the irradiation.
Sometimes further studies or the selection of a proper control group with
which to compare the irradiated subjects can help to resolve these
doubts. For example, in the spondylitis investigation, a valid question
arose as to whether the disease itself might predispose the patient to
develop leukemia later. A follow-up study which ascertained the
leukemia incidence among non-irradiated rheumatic patients, helped to
answer this question. Doubts concerning the studies of children with
thymic irradiation could have been forestalled, had the control group
consisted of children with diagnosed thymic enlargement who had not
been treated with x-rays. It was not possible, however, to select such a
control group; instead healthy siblings or cancer incidence from general
population statistics were employed. Thus, although the weight of
evidence in these studies points toward true radiation carcinogenesis,
there is room for speculation as to whether the infants with enlarged
thymus glands might not have been at least somewhat predisposed to
the development of malignant diseases.
Even the studies of the relationship of prenatal x-ray examinations to
childhood leukemias have been subject to the same kind of question, e.g.,
whether the special characteristics of the mothers and children in
question which necessitated the pelvic x-rays in the first place might not
be a predisposing factor in the development of leukemia, irrespective of,
or in addition to, the radiation received. Despite these reservations, all
of the above studies, when taken together, comprise an impressive
accumulation of evidence indicating that ionizing radiation is a true
carcinogen in man.

2)

Risk Versus Benefit
Assuming that studies such as these are valid, the question arises as to
their practical implications. Even in investigations such as the
spondylitis studies in which roughly a ten-fold increase in leukemia was
observed, the additional risk to an irradiated individual remains small
because of the relatively low normal incidence of leukemia. The small

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but real increase in risk to the individual calls for an intelligent
balancing in each case of the benefits to be accrued from the radiation
exposure and techniques which are of great benefit to patients cannot be
abandoned because of the risk of delayed harmful effects. On the other
hand, if the same diagnostic information or therapeutic results can be
obtained using techniques which reduce radiation exposure to the
patient, or if equally effective non-radiologic procedures which do not
involve such risk are available, such methods should be used.

3.

Embryological Effects
Considering the fact that immature, undifferentiated and rapidly dividing cells
are highly sensitive to radiation, it is not surprising that embryonic and fetal
tissues are readily damaged by relatively low doses of radiation. It has been
shown in experiments with mice that deleterious effects may be produced with
doses of only 10 rads delivered to the embryo during the period of organogenesis.
There is no reason to doubt that the human embryo is equally susceptible. It
should be emphasized that radiation is not unique in producing embryological
effects and that a growing body of evidence exists which indicates that a host of
external insults, including certain drugs, chemicals, and viral infections also can
damage the highly sensitive embryo and fetus.
a.

Embryological Effect vs. Stage of Pregnancy
The majority of the anomalies produced by prenatal irradiation involve the
central nervous system, although the specific type of damage is related to the
dose and to the stage of pregnancy during which irradiation takes place. In
terms of embryonic death, the very earliest stages of gestation, perhaps the
first few weeks of pregnancy in the human being, are most radiosensitive.
For the production of congenital anomalies in the newborn, irradiation during
the period of organogenesis is of greatest importance. This period occurs
during approximately the second through the sixth week of human gestation,
when pregnancy could still be unsuspected. During the period, embryonic
death is less likely than in the extremely early stage, but the production of
morphological defects in the newborn is the major consideration.
During later stages of pregnancy, fetal tissue is more resistant to gross and
easily observable damage. However, functional changes, particularly those
involving the central nervous system, may result from such late exposures
and would be difficult to measure or evaluate at birth. They usually involve
subtle alterations in such phenomena as learning patterns and development
and may have a considerable latent period before they manifest themselves.
There is some evidence that the decreasing sensitivity of the fetus to gross
radiation damage as pregnancy progresses may not apply for the
leukemogenic effects of prenatal irradiation. Another important factor to be

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considered in evaluating the radiation hazard during late pregnancy is that
irradiation may produce true genetic mutations in the immature germ cells of
the fetus for which no threshold dose has been established.
b.

Human Evidence for Embryological Effects
Human evidence for embryological damage has been found among persons
exposed in utero at the time of the atomic bombing of Hiroshima. Data
obtained from their follow-up through childhood and adolescence into
adulthood, in which groups exposed during gestation were compared with
each other and with non-exposed controls on the basis of distance from the
detonation and stage of pregnancy, shows a growth stunting effect among the
exposed, particularly with regard to head size, and an increased incidence of
mental retardation. The risk of these developmental defects correlates well
with proximity to the bomb and thus with estimated dose; also, the results
further corroborate the increased sensitivity to embryological damage during
the first trimester of pregnancy.

c.

The Problem of Unsuspected Pregnancy
The increased susceptibility to radiation damage during very early gestation,
when pregnancy may still not be apparent, underscores the importance of
taking possible pregnancy status into account when a physician is
considering pelvic, abdominal or lower back x-rays for a woman of
childbearing age. It is important to ascertain whether she is or may be
pregnant, and to take this information into account in deciding on the
necessity of the x-ray examination.

4.

Cataractogenic Effects
The fibers which comprise the lens of the eye are specialized to transmit light.
Damage to these, and particularly to the developing immature cells which give
rise to them, can result in opacities in the lens called “cataracts,” which, if they
are large enough, can interfere with vision. Radiation in sufficiently high doses
can induce the formation of cataracts; the required dose for humans, which is
difficult to ascertain, probably is in the order of several hundred rads for x- or
gamma rays, and 1/5 to 1/10 of this for neutron irradiation.
Human evidence for radiation cataractogenesis is derived mainly from a relatively
small number of workers inadvertently exposed to large doses of radiation to the
eye, including several nuclear physicists working with cyclotrons; patients
exposed to therapeutic radiation (sometimes from radium plaques applied to the
eye); and Japanese atomic bomb survivors who were heavily irradiated.

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5.

Principles of Radiation Protection

Life Span Shortening
In a number of animal experiments, repeated large doses of radiation have been
demonstrated to have a life span shortening effect. The aging process per se is
complex and largely obscure, and the exact mechanisms involved in this effect are
as yet uncertain. Irradiated animals in these investigations appear to die of the
same diseases as the non-irradiated control animals, but they do so at an earlier
age. How much of the total effect is due to premature aging and how much to an
increased incidence of radiation-induced diseases is still unresolved.
a.

Mechanisms
A number of theories have been proposed to account for the phenomenon of
aging in general, and for the aging effects of radiation in particular. One
theory is that a variety of extrinsic insults produce tissue damage in
organisms, some of which is reparable and some of which is irreparable. The
irreparable, or residual components of various insults to the organism
(infections, trauma, etc) are additive and cumulative, and when a certain
critical amount of injury has accumulated, the organism dies. Because
irradiation is one of the agents which can produce such injury, irradiated
animals arrive at a lethal accumulation sooner than do the non-irradiated
controls. Another theory proposes that radiation exerts its life span
shortening effect by producing somatic mutations in the cells, which lower the
organism’s ability to function properly. It further states that organs having
cells which seldom, if ever, divide are affected most by these mutations, and
play a major part in the aging process.

b.

Human Evidence
A study in which death rates from various causes were established for
radiologists and for two control groups, consisting of physicians who used
radiation occasionally and those who did not use it at all, seems to show a
true life span shortening effect among the radiologists. An association, of
course, between two phenomena (in this case, being a radiologist and having
a shorter life span than a non-radiologist) does not necessarily indicate that
one is a cause of the other, and, recalling the caution with which
epidemiologic studies must be interpreted, one might propose explanations
for the association other than that the radiation causes the shortened life
span. It is conceivable, for example, that those individuals choosing radiology
as a specialty could be somewhat less healthy as a group than those selecting
other fields, and thus a slightly shorter life span among the former would not
necessarily relate to their radiation exposure. The investigators have
considered such alternative explanations of the data, however, and because of
certain strengthening factors in their findings, they nonetheless hold that a
true life span-shortening effect was operative. An important finding in this
study, which helps to support the general adequacy of current occupation
radiation protection guidelines, is that the excess risk

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of death among the radiologists is largely confined to those who practiced
during the earlier years of x-ray use when safety practices were more lax and
occupational exposures among radiologists were presumably much higher
than today.

6.

Genetic Effects
a.

Background
The fertilized egg, which is a single cell resulting from the union of sperm and
egg, and which after millions of cell divisions results in a new organism,
contains all of the genetic information necessary to produce all of the organs
and tissues of the new individual. This information is carried in the nucleus
of the fertilized egg on rod-shaped structures called chromosomes, arranged
in 23 pairs in man. In each pair, one member is contributed by the mother
and the other by the father. With each cell division which the rapidly
developing embryonic tissue undergoes, all of this information is faithfully
duplicated, so that the nucleus in each cell of the new organism contains
essentially all of the information. This, of course, includes those germ cells in
the new organism which are destined to become sperm and egg, and thus the
information is transmitted from one generation to the next. This hereditary
information is often likened to a template, or to a code, which is reproduced
millions of times over with remarkable accuracy. It is possible to damage the
hereditary material in the cell nucleus by means of external influences, and
when this is done the garbled or distorted genetic information will be
reproduced just as faithfully when the cell divides as was the original
message. When this kind of alteration occurs in those cells of the ovaries or
testes which will become mature sperm and egg, it is referred to as genetic
mutation; if the damaged sperm or egg cell is then utilized in conception, the
defect is reproduced in all of the cells of the new organism which results from
this conception, including those which will become sperm or egg, and thus
whatever defect resulted from the original mutation can be passed on for
many generations.
Most geneticists agree that the great preponderance of genetic mutations are
harmful. By virtue of their damaging effects, they can be gradually
eliminated from population by natural means, since individuals afflicted with
this damage are less likely to reproduce themselves successfully than normal
individuals. The more severe the deficit produced by a given mutation, the
more rapidly it will be eliminated, and vice-versa; mildly damaging mutations
may require a great many generations before they gradually disappear.
As a balance to this natural elimination of harmful mutations, fresh ones are
constantly occurring. A large number of agents have mutagenic properties,
and it is probable that our current knowledge includes just a fraction of these.
In addition, it may be that mutations can arise with the germ cells of

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Principles of Radiation Protection

an organism without external insult; free radicals, which may be produced as
a natural byproduct of normal metabolic reactions in the body, may have a
mutational effect. Among the various external influences which have been
found to be mutagenic are a wide variety of chemicals, certain drugs, and
physical factors such as elevated temperatures and ionizing radiation.
Natural background radiation probably accounts for a small proportion of
naturally occurring mutations. For man, it has been estimated that
background radiation probably produces less than ten percent of these.
Manmade radiation, of course, if delivered to the gonads, can also produce
mutations, over and above those which occur spontaneously. Radiation, it
should be noted, is not unique in this respect, and is probably one of a
number of manmade environmental influences that is capable of increasing
the mutation rate.
b.

Observing Mutations
1)

The Difficulties of the Task
Measuring changes in the normal mutation rate in humans is extremely
difficult for several reasons. First, the majority of mutations are
recessive, that is, their full effects do not manifest themselves in an
individual unless he or she carries the same mutational defect in the
same location of a given pair of chromosomes, i.e., unless both the
mother and father were afflicted with the same kind of genetic damage.
It can be seen from this that it might take many generations after a
genetically damaging event occurred in a population before enough
individuals carrying the recessive mutation mated with one another to
produce offspring who would demonstrate overt damage. Secondly,
contrary to popular impression, the damage produced by most mutations
is subtle in its effects and difficult to measure. Mutations, for example,
may result in a slightly altered metabolism, in which there is a less
efficient utilization of certain nutritional elements, or a slightly greater
predisposition to a given disease, or a slightly lower intelligence than
would otherwise have been attained. Adding to this is the difficulty
encountered in extricating true genetic phenomena from other influences
which may produce the same results. It would be most difficult, for
example, to determine whether an individual’s predisposition to heart
disease were due to a subtle genetic defect in his cardiovascular system,
or to environmental stresses such as diet or occupation, or to personality
and developmental factors in childhood, etc.

2)

Indicators of Change in the Mutation Rate
Despite these difficulties, it is possible to observe fluctuations in the
mutation rate if large enough populations are available for close study.
Certain diseases, for example, have been linked to specific genetic
defects, and an increase or decrease in the incidence of these diseases

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would indicate a concomitant change in the mutations rate. Certain
mutations are lethal; they are highly damaging and result in
intrauterine death. Other factors being equal, significant fluctuations in
the incidence of these deaths in a population might serve as a rough
barometer for changing mutation rates. Observing a population for
evidence of genetic mutations can be likened to watching an iceberg;
most of the iceberg is invisible, with only a small portion above the
water. Changes in the size of the observable part serve to give some
indication of the more significant changes taking place beneath the
surface. (For a discussion of the difficulties and techniques in finding
and evaluating genetic radiation damage, see Chapter 7, “The
Quantitative Assessment of Hereditary Damage Induced by Radiation,”
by James and Newcombe, in Progress in Medical Genetics, Vol. 3, Grune
and Stratton, Inc., New York, 1964.
3)

What Can Be Observed in the First Generation
Even in the first generation after a population has been exposed to a
possibly mutagenic event, it is possible to observe the effects of certain
kinds of mutations. Dominant mutations, i.e., those which manifest
their full effects even when only one parent carries the mutation, may be
evident in the offspring. Those which are also lethal will appear as an
increase in intrauterine deaths. There is a particular kind of recessive
mutation which can also be observed in the first generation, the sexlinked mutation. Of the 23 pairs of chromosomes in the fertilized egg,
one pair determines the sex of the offspring. In this pair, females carry
two full-sized chromosomes, called X chromosomes, while males carry
one X chromosome and one Y chromosome, which is much smaller and
which probably does not carry a full complement of genetic information.
If a recessive mutation arises on one of the X chromosomes of the
mother, female offspring who inherit it, but now have the benefit of the
matching normal X chromosome of the father, will not demonstrate this
recessive characteristic. Male offspring, however, to whom the mother
has contributed this defective X chromosome, have only the small Y
chromosome contributed by the father to offset the deficit, and as a
result the damage will appear in these males, despite its having been
produced by a recessive mutation. Recessive sex-linked mutations of this
kind which are also lethal will thus show up as an increase in the
number of intrauterine deaths among boys, and not among girls. This
provides a useful yardstick for assessing genetic damage in an irradiated
population, for if a sub-population is selected in which mothers have
been irradiated and fathers have not, then a lowering in the percentage
of boys born versus girls, i.e., a reduction in the sex-ratio, might be an
indicator of genetic damage.

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c.

Principles of Radiation Protection

Animal Evidence of Genetic Effects
The mutagenic properties of ionizing radiation were first discovered in 1927,
using the fruit fly as the experimental animal. Since that time, experiments
have been extended to include other species, and a great deal of recent
investigation has been carried out on the mouse. Animal experimentation
remains our chief source of information concerning the genetic effects of
radiation, and as a result of the intensive experimentation which has been
carried out during recent years, certain generalizations may be made. Among
those of health significance are (1) that there is no indication of a threshold
dose for the genetic effects of radiation, i.e., a dose below which genetic
damage does not occur, and (2) that the degree of mutational damage which
results from radiation exposure seems to be dose-rate dependent, so that a
given dose is less effective in producing damage if it is protracted or
fractionated over a long period of time.

d.

Human Evidence of Genetic Effects
1)

Atomic Bomb Survivors (Prenatal Exposure)
A major human study on genetic effects has concerned the Japanese
atomic bomb survivors. As the index of a possible increase in the
mutation rate, the sex-ratio in the offspring of certain irradiated groups
(families, for example, in which the mother had been irradiated but the
father had not) was observed, using the approach described earlier.
Although early reports showed a shift in the ratio of boys versus girls in
these families, later evaluation of more complete data did not bear out
the original suggestion of an effect on the sex-ratio.

2)

Cancer in Children Exposed In Utero to Diagnostic X-rays
The pre-conception radiation histories of the parents of leukemic
children as compared with those of normal children was a part of the
subject of another investigation. From the results, it appears that there
may be a statistically significant increase in leukemia risk among
children whose mothers had received diagnostic x-rays during this
period. The effect here is apparently a genetic rather than an
embryologic one, since the irradiation occurred prior to the conception of
the child. This finding remains to be confirmed with further study.

A somewhat similar study ascertained the radiation exposure histories of the
parents of children with Down’s Syndrome; most of this exposure too, was
prior to the conception of the child. A significantly greater number of the
mothers of children with Down’s Syndrome reported receiving diagnostic
fluoroscopy and x-ray therapy prior to the birth of the Down’s child than did
mothers of normal children comprising a control group.

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The finding of these two studies would seem to provide evidence that ionizing
radiation is a mutational agent in man. On the other hand, they can be
viewed with the same kind of reservations as were explained previously, i.e.,
there could be significant differences to begin with between populations of
people requiring x-rays and those not requiring x-rays. These differences
alone might account for a slightly higher incidence of leukemia or Down’s
Syndrome in the offspring of the former group, irrespective of the radiation
received; however, when viewed in conjunction with available evidence
concerning the mutagenic nature of ionizing radiation, the most reasonable
and prudent interpretation of studies such as these is that the effects
observed are due at least in part to the x-rays received by the children.
e.

Health Significance of Genetic Mutations
Recalling the previous discussion concerning the natural elimination of
harmful mutations and the simultaneous introduction of fresh ones into a
population, the total number of mutations present may be likened to the
water in a tank, in which in-flow at the top represents new mutations and
out-flow at the bottom represents the elimination of old mutations. The
water level does not necessarily remain constant; if the rate at which new
mutations are produced exceeds that at which old ones are discarded, the pool
of mutations grows larger. The reverse is true if the output exceeds the
input, with a resultant lowering of the pool. With contemporary human
populations, it is highly desirable to keep the level of the mutational pool as
low as possible, since the pool largely represents diseases and defects which
tend to lower overall biological fitness. However, two factors unique to
modern life may tend to increase the level. First, human populations are
being exposed to a greater and greater number of potential mutagens as a
result of a progressive increase in the variety and quantity of manmade
chemical and physical agents which are a product of our technological
advances. Secondly, modern medical knowledge and techniques result in the
salvage of more and more individuals with genetic defects so that they may
reproduce themselves, thus distributing these defects to an ever-larger
number of people. In the face of these factors which tend to increase the
mutational load in the world’s population, it is all the more important, if the
level of the pool is to be kept at a minimum, to make every effort to maintain
the influx of new mutations as small as possible. Considering the potent
mutagenic properties of ionizing radiation, the goal, then, is clear: to avoid
any unnecessary irradiation of the gonads.

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Principles of Radiation Protection

Suggested General References
Advisory Committee on the Biological Effects of Ionizing Radiations (BEIR), Report V:
Health Effects of Exposure to Low Levels of Ionizing Radiation, Commission on Life
Sciences, National Academy of Sciences, National Research Council, Washington,
D. C., 1990.
Frankel, Radiation Protection for Radiologic Technologists, McGraw-Hill, New York, 1976.
Fullerton, Gary D., David T Kopp, Robert G Waggener, and Edward W Webster, Biological
Risks of Medical Irradiations, American Association of Physicists in Medicine by the
American Institute of Physics, New York, 1980.
Hall, Eric J., Radiobiology for the Radiologist, Harper and Row, New York, 1973.
National Council on Radiation Protection and Measurements, Basic Radiation Protection
Criteria, Washington, D. C., 1971.
Pizzarello and Witcofski, Medical Radiation Biology, Lea and Febiger, Philadelphia, 1972.
Prasad, Kedar N., CRC Handbook of Radiobiology, CRC Press, Boca Raton, Fl., 1984.
Travis, Elizabeth Latorre, Primer of Medical Radiobiology, by, Year Book Medical
Publishers, Inc., Chicago, 1975.
United Nations Scientific Committee on the Effects of Atomic Radiation to the General
Assembly (UNSCEAR 2000), Sources and Effects of Ionizing Radiation, A Report of
the, Volume II: Effects, New York, 2000.

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Glossary
abscissa: Coordinate representing the distance of a point from the y-axis in a plane
Cartesian coordinate system, measured along a line parallel to the x-axis.
acute radiation syndrome: A term used to refer to the signs and symptoms which
comprise short-term effects after radiation is delivered to the whole body.
ankylosing spondylitis: Progressively disabling arthritic disease of the spine.
biological: Of, pertaining to, caused by, or affecting life or living organisms.
carcinogenic: Cancer causing substance.
cerebral: Of or pertaining to the brain or cerebrum.
chromosome: A DNA-containing linear body of the cell nuclei of plants and animals,
responsible for the determination and transmission of hereditary characteristics.
dose response curve: The curve plotted by correlating the dosage administered with the
response of damage produced, in order to establish acceptable levels of radiation
exposure.
Down’s Syndrome: A congenital disorder characterized by moderate to severe mental
retardation, a short flattened skull, and slanting eyes.
free radicals: An atom or group of atoms having at least one unpaired electron.
fluoroscope: A fluorescent screen on which the internal structure of an optically opaque
object, as of the human body, may be continuously viewed by transmission of x-rays
through the object.
gastrointestinal: Of or pertaining to the stomach and the intestines.
hematopoietic: The formation of blood in the body.
in utero: Within the uterus.
irradiate: To expose to radiation.
latent period: Time lag between the initial radiation event and occurrence of the first
detectable effect.
leukemia: Any of a group of usually fatal diseases of the reticuloendothelial system
involving uncontrolled proliferation of leukocytes.

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long-term effects: Effects which appear years, decades, and sometimes generations after
an event.
mastitis: Inflammation of the breast.
mutation: An alteration or change.
neoplasm: An abnormal new growth of tissue in animals or plants; tumor.
non-threshold phenomenon: In the dose response curve, where the curve intersects the
abscissa at the origin, it is assumed that any dose, no matter how small, involves some
degree of response.
organogenesis: The origin and development of biological organs.
pitchblende: Principal ore of uranium, a brownish-black mineral of uraninite and
uranium trioxide with small amount of water and uranium decay products.
pneumothorax: Accumulation of air or gas in the pleural cavity, occurring as a result of
disease or injury, or sometimes induced to collapse the lung in the treatment of
tuberculosis and other lung diseases.
prodrome: A symptom of the onset of a disease.
rad: Unit of energy absorbed from ionizing radiation, equal to 100 ergs per gram of
irradiated material.
radiosensitive: Sensitive to radiation.
short-term effects: Effects which appear within a matter of minutes, days, or weeks.
somatic cell: A bodily cell other than a germ cell.
tinea capitis: Ringworm of the scalp.

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