01 Biological Effects of Ionizing Radiation 08

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01 Biological Effects of Ionizing Radiation 08 Powered By Docstoc
					Unit 1. 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
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
   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
 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
 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
 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
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
Chromosome Breaks
       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
        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
 Somatic effects
 Genetic effects
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
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
 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
    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.
    Variables in Somatic Effects
   Species variability. The phenomenon of
    species variability is well known. The reason
    is not well-understood.
    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
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.
    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
Variables in Somatic Effects
   Specific area protection
    Variables in Somatic Effects
   Total dose: The higher the dose of radiation,
    the greater is the probability and severity of
    occurrence of biological effects.
    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
 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
    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.
    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.
    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)
    Variables in Somatic Effects
The female is more radioresistant in some
 species possibly due to high levels of
 estrogens, some of which have
 radioprotective properties. (Arena, p. 463)
    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.
    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.
    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).
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
       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.
       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.
        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.
       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.
    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
    Radiation Effect on Oral Tissues : Teeth
 Adult teeth:
   very resistant to the direct effect of radiation
   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
 <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
 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
   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
 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
       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.
       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.
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
 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
 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.
Acute Radiation Syndrome
    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.
    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.
    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.
    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.
          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
 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.
    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.
    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.
    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
    Stochastic Effects- Evidence
   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
    Stochastic Effects- Evidence
   Increased incidence of leukemia in
    radiologists (as compared to non- radiologic
    physicians) who practiced before the
    radiation protection methods were
   Bone tumors in radium dial painters.
    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
    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
    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
              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
             Stochastic Effects
 Thyroid cancer: The incidence of thyroid
  carcinoma increases following radiation
 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
 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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