Unit 1. Biological Effects of Ionizing Radiations

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• Unit 1. Biological Effects of Ionizing Radiations

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• 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 womans face.
• The picture was taken by Mr. J. OConnor, and as
  a result of the exposure to the strong mysterious
  light, Ms. McDonald is now suffering from burns.

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• A few days after being photographed. The skin on
  the young womans 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.

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• The first picture taken of the young woman,
  OConnor 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 McDonalds hair have fallen out

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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

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Biological Effects

• X-radiation energy is transferred to the
  irradiated tissues primarily by Photoelectric and
  Comptons 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.

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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

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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.

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Indirect Action

• The ions, H2O and H2O-, are very unstable and
  break up into free radicals.

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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.

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Indirect Action

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

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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.

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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.

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Chromosome Breaks
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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).

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Chromosome Breaks

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

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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.

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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.

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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.

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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.

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Radiation Effects at Tissue Level

• Two types of biological effects may appear in
  tissues after exposure to ionizing radiation.
• Somatic effects
• Genetic effects

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Radiation Effects at Tissue Level

• 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.

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Radiation Effects at Tissue Level

• 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.

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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

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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.

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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)

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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

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Variables in Somatic Effects

• 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.

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Variables in Somatic Effects

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

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Variables in Somatic Effects

• 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.

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Bergonie and Tribondeus 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.

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Variables in Somatic Effects

• 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

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Variables in Somatic Effects

• Specific area protection

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Variables in Somatic Effects

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

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Variables in Somatic 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.

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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.

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Variables-Dose Rate

• Local somatic effect (Alexander, p.149 Revised
  Edition)

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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

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Dose-effect Relationships

• 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.

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Dose-effect Relationships

• 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.

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Variables in Somatic Effects

• 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)

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Variables in Somatic Effects

• 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)

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Variables in Somatic Effects

• 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.

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Variables in Somatic Effects

• 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.

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Variables in Somatic Effects

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

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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.

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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.

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Deterministic Effects

• 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.

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Deterministic Effects

• 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.

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Deterministic Effects

• 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.

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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.

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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.

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Radiation Effect on Oral Tissues Developing
teeth

• lt10 Gy has very little or no visible effect.
• Effects to an infant may include destruction of
  tooth bud, tooth malformation and delay in
  eruption.

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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.

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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.

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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.

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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.

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Deterministic Effects

• 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.

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Deterministic Effects

• 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.

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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.

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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.

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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.

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Acute Radiation Syndrome
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Acute Radiation Syndrome

• 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.

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Acute Radiation Syndrome

• 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.

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Acute Radiation Syndrome

• 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.

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Acute Radiation Syndrome

• 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.

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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.

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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.

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Stochastic Effects

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

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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.

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Stochastic Effects- Evidence

• 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.

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Stochastic Effects- Evidence

• 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.

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Stochastic Effects- Evidence

• 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.

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Stochastic Effects- Evidence

• Until the 1950s, 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.

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Stochastic Effects- Evidence

• 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.

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Stochastic Effects- Evidence

• 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

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Stochastic Effects- Evidence

• 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.

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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.

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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.

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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.

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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.

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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.

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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).

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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.

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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

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Risk Estimation

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

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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