zom703biologicaleffectsofionizingradiation-221228102135-accdae82.pdf

Biological effects of Ionizing
Radiations

Dominion Dental Journal, 1897
Excerpts: “Danger in X-rays”
“So as to better diagnose the dental troubles of
which Miss Josie McDonald of New York
complained, Drs. Nelson T. Shields and George
F. Jernignan a month ago decided to have an X-
ray photograph taken of the young woman’s
face.
The picture was taken by Mr. J. O’Connor, and as a
result of the exposure to the strong mysterious
light, Ms. McDonald is now suffering from
burns.

A few days after being photographed. The
skin on the young woman’s face, neck,
shoulder, left arm and breast became blistered
and finally peeled off.
One ear swelled to three times its natural
size and it is said there has been no hearing in
it since.

The first picture taken of the young woman,
O’Connor admits, was unsatisfactory, and a
second and successful attempt was made. The
first exposure lasted eight minutes and the last
one thirteen minutes. Besides the burns, large
patches of Miss McDonald’s hair have fallen out”

Biological Effects
 First case of radiation-induced human injury
was reported in the literature in 1896.
 Who discovered X rays and when?
 First case of X-ray induced cancer was
reported in 1902

Biological Effects
 X-radiation energy is transferred to the
irradiated tissues primarily by Photoelectric and
Compton’s processes which produce ionizations
and excitations of essential cell molecules such
as DNA, enzymes, ATP, coenzymes, etc.
 The functions of these molecules are altered.
 The cells with damaged molecules can not
function normally.

Biological Effects
 The severity of biological effect is related to
the type of molecule absorbing radiation.
 Effect on DNA molecule is more harmful
than on cytoplasmic organelles

Mechanism of Action
 Two mechanisms of radiation damage, mostly on
DNA:
 Direct action: Damage or mutation occurs at the site
where the radiation energy is deposited.
 Indirect action: The radiation initially acts on water
molecules to cause ionization. The water is
abundantly present in the body (approx. 70 % by
weight)
 Indirect effect accounts for 2/3rd of the damage,
direct effect is responsible for the remainder.

Indirect Action
 The ions, H2O+ and H2O-, are very
unstable and break up into free radicals.

Indirect Action
 Free radicals:
 highly reactive atoms and molecules
 react with and alter essential molecules
that come in contact with them.
 These altered molecules have different
chemical and biologic properties from the
original molecules. This translates to
biologic damage.

Indirect Action
 Free radicals may also combine with each
other to produce hydrogen peroxide
OH• + OH•-------> H2O2
 Hydrogen peroxide is a cell poison which may
contribute to biological damage

Radiation Effects at Cellular Level
 Point mutations: Effect of radiation on
individual genes is referred to as point
mutation.
 The effect can be loss or mutation in a gene
or a set of genes.
 The implication of such a change is that the
cell may now exhibit an abnormal pattern of
behavior.

Radiation Effects at Cellular Level
 Chromosome alterations: Several kinds of
alterations in the chromosomes have been
described. Most of these are clearly visible
under the microscope.
 The effect upon chromosomes can result in the
breaking of one or more chromosomes. The
broken ends of the chromosome seem to
possess the ability to join together again after
separation.

Chromosome Breaks
 Such damage may be repaired rapidly in an
error-free fashion by cellular repair
processes (restitution) using the intact
second strand as a template.
 However, if the separation between broken
fragments is great, the chromosome may
lose part of its structure (deletion).

Chromosome Breaks
 If more than one break, the broken fragments
may join in different combinations.
 inversion of the middle segment followed by
recombination

Chromosome Breaks
 Double-strand breakage: when both strands
of a DNA molecule are damaged. Sections of
one broken chromosome may join sections
of another, broken chromosome.

Chromosome Breaks
 A large proportion of damage will result in
misrepair which can result in the formation
of gene and chromosomal mutations that
may cause malignant development.

Arrested Mitosis
 Ionizing radiations also affect cell division,
resulting in arrested mitosis and, consequently,
in retardation of growth. This phenomenon is
the basis of radiotherapy of neoplasms.
 The extent of arrested mitosis varies with the
phase of the mitotic cycle that a cell is in at the
time of irradiation. Cells are most sensitive to
radiation during the last part of resting phase
and the early part of prophase.

Cytoplasmic Changes
 Cytoplasmic changes probably play a minor
role in arrested mitosis and cell death.
 Swelling of mitochondria and changes in cell
wall permeability have been observed.

Radiation Effects at Tissue Level
 Two types of biological effects may appear
in tissues after exposure to ionizing
radiation.
 Somatic effects
 Genetic effects

 Somatic effects include responses of all
irradiated body cells except the germ cells
of the reproductive system.
 Somatic effects are deleterious to the
person irradiated.
 Somatic effects may be stochastic or
deterministic.

 Genetic effects. Include responses of
irradiated reproductive cells.
 Genetic effects become primarily important
when they are passed on to future
generations.
 Genetic effects are of no consequence in
persons who do not procreate or who are in
the post-reproductive period of life.

Somatic Effects
 Somatic tissues do not always react to doses
of ionizing radiation so as to give immediate
clinically observable effects. There may be a
time-lapse before any effects are seen.
 Basically, somatic effects are classified in
two categories:
 Acute or immediate effects
 Delayed or chronic (latent) effects

Acute Somatic Effects
 Appear rather soon after exposure to a
single massive dose of radiation or after
several smaller doses of radiation delivered
within a relatively short period of time.
 In general, effects which appear within 60
days of exposure to radiation are classified
as acute effects.

Delayed Somatic Effects
 Delayed effects may occur anywhere from
two months to as late as 20 years or more
after exposure to radiation. The time lapse
between the exposure to radiation and the
appearance of effects is referred to as the
"latent period."
 In radiobiology, the term “latent period” is
usually used only in relation to stochastic
effects (malignancy)

Variables in Somatic Effects
 The magnitude of somatic effects depend
on the following variables:
 Individual
 Species
 Cellular and tissue
 Extent of exposure (full or partial body)
 Total dose
 Dose rate

 Individual Variability. Certain individuals
are more sensitive or resistant than others
in their response to radiation.
 The expression, “LD50 (30 days)”, is
frequently used in radiobiology which
means that a certain dose kills 50% of the
exposed animals within 30 days.
 The 50% who survive are due to the
individual variability.

 Species variability. The phenomenon of
species variability is well known. The reason
is not well-understood.

 Cellular and tissue variability. In 1907
Bergonie and Tribondeu advanced the first
generalization in radiobiology by stating that
"cells are sensitive to radiation in proportion
to their proliferative activity and in inverse
proportion to their degree of differentiation.“
 Simply stated, it means that the rapidly
dividing cells are more sensitive to radiation
than more differentiated, slowly dividing
cells.

Bergonie and Tribondeu’s Axiom
 One of the most notable exceptions to this
generalization is the lymphocyte, not
capable of proliferative activity, is a
differentiated cell, and is one of the most
radiosensitive cells in the body.

 Total-body vs localized-area exposure. A
single radiation dose of 4.5-5.0 Gy may
produce only erythema of the skin if given to
a localized part of the body.
 However, if the same dose is given to the
entire body, it will cause the death of 50
percent of the people exposed.
 This quantity of radiation is identified as LD50,
the lethal dose for 50 percent of the people
thus exposed

 Specific area protection

 Total dose: The higher the dose of radiation,
the greater is the probability and severity of
occurrence of biological effects.

 Dose rate dependence: radiation dose that would
be lethal if given in a short time, such as a few
hours, may result in no detectable effects if given
in small increments during a period of several
years.
 This is due to the ability of somatic cells to repair
damage caused by exposure to radiation. However,
tissues do not return to their original state
following radiation damage, as there are some
irreparable alterations produced.

Variables-Dose Rate
 In general, it may be stated that four-fifths of
somatic damage is repaired. But the
irreparable damage is cumulative. When this
cumulative damage reaches a high level,
clinical manifestations may appear.

Variables-Dose Rate
 Local somatic effect (Alexander, p.149
Revised Edition)

Dose-effect Relationships
 Threshold response: An increase in radiation
dose may not produce an observable effect
until the tissue has received a minimal level of
exposure called the threshold dose.
 Once the threshold dose has been exceeded,
increasing dose will demonstrate exceeding
observable tissue damage.
 Cataract and erythema of skin are well-known
threshold responses

 Linear response: A linear dose-response
suggests that all exposure carries a certain
probability of harm and that the effects of
multiple small doses are additive.
 The dose response curve for most radiation-
induced tumors is linear which implies that
there is no "safe" dose, i.e., no dose below
which there is absolutely zero risk.
 Every exposure carries some risk.

 Linear-quadratic response (curve)
A linear-quadratic response implies lesser
risk at lower dose rate than linear response
or when the exposure is fractionated.
However, there is no safe dose.

 Age.
"The radiosensitivity is very high in new-born
mammals; it decreases until full adulthood is
reached and then remains constant; old mice
(about 600 days) are again more radiosensitive."
(Bacq and Alexander, P.299)
"The embryo is . . . most sensitive during the period
of most active organ development, which lasts
from the second to the sixth week after
conception." (Alexander, p. 156 Revised Edition)

 Sex
The female is more radioresistant in some
species possibly due to high levels of
estrogens, some of which have
radioprotective properties. (Arena, p. 463)

 Metabolism. The lower the metabolic rate
and the lower the state of nutrition, the
higher the resistance of the organism to the
effects of radiation. Higher metabolic rate
seems to magnify the radiation effect.

 Linear Energy Transfer (LET)
The dose required to produce a certain
biological effect is reduced as the LET of the
radiation increases. Thus alpha particles are
more efficient in causing biological damage
than low LET radiations.

 Oxygen effect
The radioresistance of many biological tissues
increases 2 to 3 times when irradiation is
conducted with reduced oxygen (hypoxia).

Types of Biological Responses
 Chronic deterministic effects:
 These effects are observed after large
absorbed doses of radiation. Doses required
to produce deterministic effects are, in most
cases, in excess of 1-2 Gy.
 There is usually a threshold dose below which
the effects are not manifested.
 With increasing dose the severity of the effect
increases.

Deterministic Effects
 Skin. Excessive exposure of the skin to ionizing
radiation may result in erythema or reddening
of the skin, which is produced by dilatation of
small blood vessels beneath the skin.
 The dose of radiation required to produce
erythema of the skin is between 1.65-3.5 Gy.
 Higher doses are associated with dermatitis.

 Hair. Epilation, or loss of hair, results from
exposure of the skin to 2.0-6.0 Gy. A latent
period of about 3 weeks ensues before the
hair is lost.
 The hair usually grows back in a few weeks.
 For permanent epilation, considerably
higher doses are required.

 Sterility.
 Sterility results from destruction by X-radiation
of gonadal tissues which produce mature
sperm or ova.
 A single dose of 4.0 Gy to the male gonads is
necessary to produce permanent sterility.
 The dose required to produce permanent
sterility in the female may be 6.25 Gy or more.

 Cataract. Exposure of the lens of the eye to
radiation can cause cataract (opacification of
the lens).
 The threshold for cataract induction is 2.0-5.0
Gy for a single exposure and approximately
10.0 Gy or more for exposures protracted
over a period of months or years.

Therapeutic Radiation to Oral Tissues
 Standard therapeutic radiation dose for
treating cancer is approximately 50 to 60 Gy.
 Administered over a period of 10 to 14 weeks
at the rate of approximately 2.5 Gy twice
weekly.

Radiation Effect on Oral Tissues : Teeth
 Adult teeth:
 very resistant to the direct effect of radiation
exposure.
 no effect on the crystalline structure of
enamel, dentin and cementum.
 Radiation caries: in individuals whose salivary
glands have been damaged resulting in
xerostomia. Secondary to changes in saliva; i.e.,
reduced flow, pH and buffering capacity and
increased viscosity.

Radiation Effect on Oral Tissues : Developing
teeth
 <10 Gy has very little or no visible effect.
 Effects to an infant may include: destruction
of tooth bud, tooth malformation and delay
in eruption.

Radiation Effect on Oral Tissues : Bone
 The most serious complication: jaw
osteoradionecrosis.
 This is primarily due to damage to the blood
vessels of the jaw and consequent decreased
capacity of the bone to resist infection.
 Tooth extraction or other injury: possibility of
bone infection and necrosis becomes very high.
 More common in the mandible than in maxilla.

Radiation Effect on Oral Tissues : Salivary
glands
 Xerostomia: marked and progressive loss of
salivary secretion.
 The mouth becomes dry (xerostomia) and tender.
 The pH of saliva falls below normal (5.5 as
compared to 6.5 in normal saliva).
 The salivary changes influence oral microflora, and,
secondarily contribute to the formation of
radiation caries.
 Whether xerostomia is temporary or permanent
depends upon the volume of glands exposed.

Radiation Effect on Oral Tissues : Mucosa
 Mucositis. At 3rd or 4th week, oral mucosa
becomes red and inflamed (mucositis). As the
therapy continues, mucosa forms yellow
pseudomembrane.
 Secondary infection by Candida albicans is a
common complication. Mucositis is most severe at
the end of the treatment period.
 Healing begins soon after treatment and is usually
complete in about two months after therapy. The
mucosa tends to become atrophic, thin and
relatively avascular permanently. Dentures may
frequently cause oral ulceration.

Radiation Effect on Oral Tissues: Taste buds
 Taste acuity is reduced or lost in about 4 weeks
into the radiation treatment.
 In general, bitter and acid flavors are more
severely affected when posterior third of the
tongue is irradiated and salt and sweet when
anterior third is irradiated.
 Complete recovery of taste usually occurs in
two to four months following treatment
completion.

 Life span shortening. Life span of small
laboratory animals can be shortened by
exposure to repeated large doses of radiation.
 If this phenomenon occurs among the human
beings is inconclusive.

 Embryological and developmental effects.
therapeutic doses of radiation delivered to
the pelvic region of a pregnant woman can
result in the death of the fetus or in the
birth of an abnormal child.
 The developmental effects on the embryo
are strongly related to the stage at which
the exposure occurs.

Embryological and developmental
 The first 2 weeks of pregnancy: most critical
period. If the dose is high, the fetus will die.
The congenital anomalies are rare at this stage.
 The highest incidence of malformations is the
period of organogenesis (3-8 weeks of
pregnancy).
 The threshold doses are relatively low: 100-200
mGy for most malformations and 200 mGy for
brain damage.

Embryological and developmental
 After organogenesis, effect is at the tissue and
cellular level rather, than at the organ level; so
that gross, congenital anomalies are not to be
expected.
 In general, a dose as small as 100 mGy may
cause gross defects. In Denmark, a therapeutic
abortion is recommended once it is
determined that the fetus has received 100
mGy (or 100 mSv) of radiation.

Acute Radiation Syndrome
 Radiation Sickness.
 Symptom complex that occurs after the
exposure of the entire body, or a major portion
of the body to a large dose of radiation (above
1.0 Sv) within a short period of time. The effect
may vary from a transient illness to death.
 A radiation dose of this magnitude is not
expected in any diagnostic procedure,
especially in dentistry.

 Prodromal Syndrome. 1.0 - 2.0 Gy exposure.
 Individual usually develops G.I. symptoms
such as nausea, vomiting, weakness,
fatigue, and anorexia. These symptoms
usually disappear soon.

 Hematopoietic Syndrome. 2.0 - 7.0 Gy.
 Severe injury to hematopoietic system of
the bone marrow, irreversible damage to
the proliferative capacity of the of the
spleen and bone marrow.
 Rapid fall in the number of circulating
granulocytes, platelets and erythrocytes
 Rampant infection, due in part from
lymphopenia, granulopenia, and anemia.
The death occurs in 10 to 30 days.

 Gastrointestinal syndrome. 7.0 to 15.0 Gy.
 Extensive damage to GI system: anorexia, nausea,
vomiting, severe diarrhea and malaise in a few
hours after exposure. Basal epithelial cells of the
intestinal villi are destroyed.
 Loss of plasma and electrolytes into the intestines,
hemorrhages and ulcerations. Results in
dehydration and loss of weight. The denuded
surface gets rapidly infected; septicemia and
death is an invariable consequence.

 Cardiovascular and CNS syndrome. Excess of
50 Gy.
 Death occurs within 1 or 2 days. Common
symptoms are: uncoordination, disorientation
and convulsions. This is due to damage to the
neurons and brain vasculature.

Stochastic Effects
 The most important effect of ionizing radiation
on human mortality is judged to be neoplasia and
leukemia . Radiation in this regard is considered a
two-edged sword. It cures cancer and it also
causes cancer.
 The probability of carcinogenic effect increases
with dose.
 It is currently judged that there is NO THRESHOLD
below which the effect will not occur. Severity of
the effect is independent of the radiation dose.

Stochastic Effects
 There is no controversy relative to relationship of
ionizing radiation exposure and neoplasia
production.
 It is universally accepted that such exposure
increases incidence of tumors in a great variety of
tissues and organs.
 It is important to appreciate that in the U.S.,
almost 20 percent of deaths are attributable to
cancer (400,000 annually) and a very small fraction
of this total number is due to radiation exposure.

Stochastic Effects
 A statistically significant increase in cancer
has not been detected in populations
exposed to doses less than 50 mSv.

Stochastic Effects- Evidence
 The largest group of individuals studied are the
Japanese atomic bomb survivors.
 In the cohort of 86,572, there were 9,335
deaths from solid cancer between 1950 and
1997. Only 440 deaths were estimated to be
excess over spontaneous incidence and were
considered radiation-induced cancer deaths
(NCRP Report # 145).
 During the same period, 87 leukemia deaths
can be attributed to radiation exposure.

 Other studies have followed over 14,000
British patients who received spinal
irradiations for ankylosing spondylitis
between 1935-1954.
 36 cases of leukemia and 563 cases of
cancer of other types have been reported in
these patients.

 Patients receiving repeated fluoroscopic
examinations during treatment of
tuberculosis and women treated with
radiation for postpartum mastitis between
1930-1956 demonstrated a higher risk of
breast cancer.

 Increased incidence of thyroid cancer has
been observed in children who received
radiation therapy for enlarged thymus.
Breast cancer was also elevated in these
individuals.

 Until the 1950’s, X rays were used to
epilate children with tinia capitis
(ringworm infection of the scalp) in Israel.
Over 10, 000 children were exposed.
 These children showed a higher incidence
of thyroid cancer as well as brain tumors,
salivary gland tumors, skin cancer and
leukemia.

 Increased incidence of leukemia in
radiologists (as compared to non- radiologic
physicians) who practiced before the
radiation protection methods were
established.
 Bone tumors in radium dial painters.

 Higher incidence of lung cancer in miners in
Saxony who dug out the ore from which the
radium was extracted.
 Higher incidence of lung cancer was also
reported in uranium miners in central
Colorado

 All patients in above studies received
exposures well above diagnostic range.
 The probability of diagnostic-dose radiation-
induced cancer occurrence can only be
estimated by extrapolating from cancer
rates observed following exposures to larger
doses.

Stochastic Effects- Generalizations
 Cancers other than leukemia typically start to
appear 10 years following exposure (5 years for
leukemia) and the increased risk remains for
the lifetime of the exposed individuals.
 The risk from exposure during fetal life,
childhood and adolescence is estimated to be
about 2-3 times as large as the risk during
adulthood.

Stochastic Effects
 Leukemia: The incidence of leukemia (other
than chronic lymphocytic) rises following
exposure of red marrow. Wave of leukemia
appear within 5 years of exposure, and return
to base line rates within 40 years.
 Children under 20 are more at risk than adults.
 The mortality data for leukemia are compatible
with a linear quadratic dose response
relationship.

Stochastic Effects
 Thyroid cancer: The incidence of thyroid
carcinoma increases following radiation
exposure.
 The susceptibility is greater early in
childhood that later in life.
 Females are 3 times more susceptible than
males to both radiation induced and
spontaneous thyroid cancer.

Stochastic Effects
 Bone cancer: Patients treated for childhood
cancer demonstrate an increasing risk of bone
sarcomas.
 Brain and nervous system cancer: Ionizing
radiation exposure can induce tumors of the
CNS. Most tumors are benign such as
neurilemommas and meningiomas (average
mid-brain dose of 1 Gy). Malignant brain
tumors have also been demonstrated, but only
at radiation therapy doses.

Stochastic Effects
 Esophageal cancer: The data regarding
esophageal cancer is sparse. Excess cancers
are found in the Japanese A-bomb survivors
as well as in patients treated with X-rays for
ankylosing spondylitis.

Stochastic Effects
 Salivary-gland cancer: An increased
incidence of salivary gland tumors has been
demonstrated in patients therapeutically
irradiated for the diseases of head and neck,
in the Japanese A-bomb survivors and in
persons exposed to diagnostic levels of x-
radiation (cumulative parotid dose of 0.5 Gy
or more).

Stochastic Effects
 Skin: Association between ionizing radiation
exposure and development of basal cell
carcinoma is well documented in the literature.
There is minimal indication of association with
malignant melanoma.
 Other organs: Excess cases of multiple
myeloma as well as malignancy of paranasal
sinuses have also been demonstrated in
patients receiving radiation doses.

Risk Estimation
 Four agencies or bodies comprehensively
review, assess, or estimate the radiation risk
to humans from exposure to ionizing
radiation and periodically publish their
findings in the form of reports. These
agencies are:

Risk Estimation
1. The Biological Effects of Ionizing Radiations
(BEIR) Committee of the U.S. National
Research Council
2. International Commission on Radiological
Protection (ICRP)
3. National Council on Radiation Protection and
Measurements (NCRP)
4. United Nations Scientific Committee on the
Effects of Atomic Radiation (UNSCEAR).

Risk Estimation
 Radiation induced tumors are clinically, morphologically
and biochemically indistinguishable from those which
occur spontaneously.
 This implies that carcinogenic effects of radiation may be
demonstrated on statistical basis only; that is, one may
infer such action by the demonstration of an excess in the
number of cancers in the irradiated population over the
natural incidence.
 Alternately, the probability of the cancer incidence from a
small dose is estimated by extrapolating from cancer
rates observed following exposure to large doses.
 Risk vs benefit

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