Whole Body Irradiation

1
Whole Body Irradiation

• Experience with bomb and powerplant incidents.
• Experimental exposure of animals
• Refers to complete irradiation of body
• Particulate radiation (except neutrons) and
  internal emitters are not usually uniform
• Survival figures usually expressed as in
  lethality assays i.e. LDx/y

2
Whole Body Radiation Syndromes

• Stages of response
• Prodromal Stage
• Latent Stage
• Manifest Illness Stage
• Following the manifest illness stage the patient
  either recovers or dies.
• Long term health issues may remain

3
Total Body Irradiation Syndromes

• Prodromal Stage
• Initial reaction to irradiation
• immediate response
• Characterized by
• Nausea
• Vomiting
• Diarhea
• Lasts from a few minutes to few days
• Happens at low doses but increases with dose

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Total Body Irradiation Syndromes

• Latent Stage
• Characterized by apparent lack of signs
• Changes are occurring at the cellular level
• Patient has false sense of well being
• Lasts for a few days to a week or so

5
Total Body Irradiation Syndromes

• Manifest illness stage
• Time during which clinical illness is evident.
• Depending on the dose received this stage may
  last from a few minutes to several weeks
• Signs are referable to the type of syndrome being
  manifest.
• Ends in recovery or death

6
Total Body Irradiation Syndromes

• Bone marrow Syndrome
• Occurs at doses of 2-10 Gray.
• The LD50/60 is in the 4-6 Gy range
• The prodromal stage is characterized by nausea
• Cause of the nausea is not well understood.
• The latent period can be from a few days to 3
  weeks
• Manifest illness is due to signs of bone marrow
  stem cell depletion.

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Total Body Irradiation Syndromes

• Bone marrow depletion leads to a drop in
  circulating platelets and white blood cells.
• Allows increase in infections and hemorrhage
• Blunts response to new environmental antigens
• With supportive care the patient may recover
• If sufficient stem cells remain recovery may be
  spontaneous
• Bone marrow transplants may improve survival

8
Total Body Irradiation Syndromes

• GI syndrome
• Occurs at doses above 8-10 gray
• This dose is equal to 4-5 time D0
• Prodromal signs begin a few hours after exposure
  and last a day or so.
• Latent period generally last 3-4 days
• Less with higher exposures
• Manifest illness stage lasts a few days
• Diarhea returns and systemic infections ensue

9
Total Body Irradiation Syndromes

• GI syndrome
• Signs are d/t combination of Bone Marrow syndrome
  and GI irradiation
• In GI tract there is a loss of the intestinal
  villi which absorb nutrients and fluid from the
  bowel
• The villi also form a barrier between the blood
  and bacteria in the gut lumen.
• Fluid from the body is lost into the bowel lumen
• Intensive medical therapy effective only at lower
  dose range
• Above 10 gray death is virtually certain by 14
  days

10
Total Body Irradiation Syndromes

• GI syndrome
• Even if patient survives the GI disease there is
  still the effects of the bone marrow depletion to
  deal with.
• Signs and effects will be seen even with just
  irradiation of the abdomen but bone marrow
  depletions would not occur so LD is higher

11
Total Body Irradiation Syndromes

• Central Nervous System Syndrome
• Can occur with just irradiation of the CNS or
  with whole body irradiation
• Occurs at doses of 60-100 Gy.
• Prodromal phase as usual but with nervousness and
  hyperesthesia
• Latent period lasts for a few hours
• Manifest illness stage lasts up to a day and
  consists of severe diarrhea and convulsions

12
Total Body Irradiation Syndromes

• Central Nervous System Syndrome
• Death invariably occurs in 2-3 days
• Signs are probably related to brain edema or
  dysfunction of critical cells in the CNS
• There are few microscopic changes seen
• Bone marrow and GI syndromes do not have time to
  be manifest
• At doses above 100 Gy death can be immediate

13
Irradiation of Embryo and Fetus

• The embryo arises from the fertilized ovum
• Ovum is the parent cell of the entire body
• The term embryo refers the morula of cells
  present in the uterus prior to implantation
• Does not have attachment to the uterine wall
• Does not have a blood supply
• Essentially a rapidly dividing ball of stem cells

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Irradiation of Embryo and Fetus

• After 5-6 generations the division early
  differentiation begins to occur
• Irradiation of the embryo can kill a single cell
  which gives rise to entire cell lines or organs
• For irradiation at this stage even very low dose
  result in a high incidence of fetal loss.
• If the embryo survives then there are few
  consequences of the irradiation
• Remaining cells make up for loss

15
Irradiation of Embryo and Fetus

• Following implantation in the uterine wall the
  embryo is considered to be a fetus.
• Following implantation there is a period of rapid
  differentiation and development of the major
  organ systems.
• This is called the period of organogensis
• Begins at about 2 weeks and lasts to 42 days in
  humans.

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Irradiation of Embryo and Fetus

• Irradiation during this time can cause growth
  delay in the fetus
• During this time the organs develop at different
  times.
• For each organ there are intense bursts of growth
  nearly constant mitosis
• Very radiation sensitive
• Irradiation during one of these bursts can
  destroy or severely damage the developing organ
  system

17
Irradiation of Embryo and Fetus

• The central nervous system is a special case
• Developing constantly not only during
  organogensis but throughout gestation and often
  beyond.
• Doses of 1 Gy have been shown to result in a
  reduction in cognition
• In humans CNS development lasts up to about 12
  years of age.

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Irradiation of Embryo and Fetus

• Period of fetal growth
• Begins following the period of organogensis
• Lasts throughout rest of gestation
• All of the major organ systems are present and
  enlarging
• Eyes are part of CNS and severe ocular effects
  are expected following irradiation.
• Humans are particularly sensitive due to the
  advanced CNS development.

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Irradiation of Embryo and Fetus

• Other effects
• Mutation induction gtgtgt cancer
• May not be seen for years after birth
• Single cells may require years to grow to
  noticeable size.
• Ovum and spermatigonia may have mutations which
  can be passed on to subsequent generations

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Irradiation of Embryo and Fetus

• Dose limiting tissue for radiation workers
• 500 millirem for duration of pregnancy
• Fetal monitors often required if radiation in
  area
• Accidental exposure of pregnant women not
  generally at risk is a problem.
• Mother may feel no ill effects
• Damage to fetus may still be significant

21
Irradiation of Embryo and Fetus

• One of few instances where diagnostic x-rays are
  considered a hazard.
• Abdominal radiograhs in pregnant women could
  result in a dose of 1-3 cGy to the fetus.
• Ultrasound is generally used except in cases of
  emergency.

22
Effects of Moderate (0.5-1.0 Gy) Whole Body
Irradiation

• Immunologic effects
• As always, severity of effect increases w/ dose
• Macrophages and other white blood cells in the
  spleen, liver and circulating blood are an
  important part of the bodies immune system
• Macrophages are resistant but their stem cells
  are not
• Many white blood cells are short lived
• Major function is destruction of infective
  microbes

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Effects of Moderate (0.5-1.0 Gy) Whole Body
Irradiation

• White blood cell (wbcs) effects
• WBCs engulf and destroy microbes which get into
  the blood stream.
• There is a constant shower of these from the gut,
  skin, eyes, lungs etc.
• If the influx of microbes is to great the wbcs
  can be overwhelmed.
• Following irradiation there is a decrease in wbc
  numbers
• There may also be a decrease in functional
  capability

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Effects of Moderate (0.5-1.0 Gy) Whole Body
Irradiation

• Cytokines and other chemicals in the body that
  attack microbes are products of wbcs and their
  levels or activity may also be affected.

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Effects of Moderate (0.5-1.0 Gy) Whole Body
Irradiation

• Humoral defense mechanism (antibodies) effects.
• Plasma cells (derived from lymphocytes) produce
  antibodies
• Antibodies are derived from immunologically
  sensitized cells.
• They attach to foriegn protiens and microbes
• Attract macrophages to engulf and destroy foreign
  material.

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Antibody Production Effects

• Plasma cells must first be sensitized
• Requires a few days between sensitization and the
  onset of antibody production.
• Once antibodies begin to attack foreign materials
  the macrophages will eliminate it relatively
  quickly.
• Long lived lymphocytes and plasma cells
  remember the foreign agent so a second response
  occurs more quickly and vigorously

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Antibody Production Effects

• Phases of antibody stimulation
• Preinduction
• Recognition of foreign protien
• Induction period
• Antibody production mechanisms are set in place
• Production period
• Large amounts of antibodies released into
  circulation

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Antibody Production Effects

• Preinduction period
• Circulating lymphocytes detect the foreign
  protiens, this takes 1-4 hours
• Sensitized lympocytes divide and migrate out of
  the blood stream into the tissues.
• Once in tissues they mature into plasma cells.
• Due to cell division, this stage is highly
  radiosensitive and irradiation at this time
  results in severe blunting of antibody response
• Low wbc s d/t prior irradiation has same effect

29
Antibody Production Effects

• Induction period
• Plasma cells differentiate from the sensitized
  lymphocytes
• Antibody production mechanisms initiated
• Moderately radiosensitive period
• Irradiation at this time delays response but
  antibody levels will reach normal levels.

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Antibody Production Effects

• Production period
• Antibody production occurs and high levels
• Plasma cells are resistant FPM cells
• The phase is highly radiation resistant
• Some studies have suggested that moderate
  irradiation during this period may actually
  increase production of antibodies.
• Because the induction phase is skipped in a
  secondary response there is little response
  blunting.

31
Antibody Production Effects

• If antibody response is blunted then foreign cell
  killing by radioresistant macrophages and
  neutrophils can still occur but is less efficient
  and takes longer.

32
Carcinogenisis

• It has been shown that radiation is a relatively
  potent carcinogen
• This is a cumulative effect
• Increased dose increases the effect.
• The effect is not mitigated by dose rate as it is
  associated with non-repairable DNA damage.
• Since chromosomal effects are associated with
  cell reproduction it may take years for them to
  manifest in slowly dividing cells.

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Carcinogenisis

• The effect is a stochastic effect
• Increased dose increases probability
• But, the creation of a cancer is all or none
  effect
• Effect is to increase the incidence in synch with
  the natural background occurrence.
• Seen in post radiation therapy patients but
  oncology patients have higher incidence of second
  cancers anyway.