2.3 Biological (Tissue, Organ and Systemic) Effects of Ionizing Radiation

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2.3 Biological (Tissue, Organ and Systemic)
Effects of Ionizing Radiation

• Hanaa A. Hassan

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Development of Radiation Injury
Ionizing Particles (alpha, beta, protons, etc.)
Gamma and x-rays
IONIZATION EXCITATION
CHEMICAL CHANGE (free radical formation)
BIOLOGIC CHANGE (DNA damage)
MALIGNANT TRANSFORMATION OF CELLS
INHIBITION of CELL DIVISION (cell death)
MUTATIONS
ACUTE SOMATIC AND TERATOGENIC EFFECTS
GENETIC EFFECTS
CANCER
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THE EFFECTS OF RADIATION ON BIOLOGICAL SYSTEMS
TISSUES
Hematopoietic System

• Highly sensitive to radiation killing are the
  cells of the hematopoietic system and related
  lymphoid system.
• Most sensitive are the stem cells of the bone
  marrow, which give rise to all circulating blood
  cells and platelets, as well as the lymphoid
  tissues found in the spleen, liver, lymph nodes
  and thymus.

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Hematopoietic System

• Circulating lymphocytes are quite sensitive to
  radiation and a measurable drop in the normal
  titre (about 21,000/dl) can meter radiation
  exposure and indicate dose levels.
• As little as 10 cGy can show a measurable drop
  in the circulating small lymphocyte population.
• Of particular resistance are the mature
  circulating red blood cells and platelets this
  is probably due to their lack of a nucleus.

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Hematopoietic System

• Within the blood-forming organs are precursor
  cells that are killed by radiation. The
  subsequent effect on circulating cell levels is
  not seen for days to weeks because resistant
  mature cells in circulation remain viable. Only
  after these begin to diminish by natural turnover
  does the decrease in cell levels become evident,
  because the damaged bone marrow has made no
  replacements.

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Hematopoietic System

• The effect is pan-cytopenia (depression of all
  cell types), resulting in hemorrhage (platelet
  reduction), infection (white-cell depression),
  and the effect of anemia from plummeting red
  cells.

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Reproductive System

• The cells of the reproductive system are highly
  sensitive to radiation effects
• In the human male, stem cells and proliferating
  spermatogonia are highly sensitive. However,
  spermatids and mature sperm show considerable
  resistance. Also resistant are the interstitial
  cells of the testis, which control hormone
  production and secondary sexual characteristics.
  Therefore at sterilizing doses of 6 Gy, potency,
  fluid production of the prostate and seminal
  vesicles, as well as voice, beard and male social
  behavior are not affected.

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Reproductive System

• With a turnover time for spermatogenesis (stem
  cell to mature sperm) of 64 to 72 days, sterility
  is never seen immediately after the radiation
  dose, because mature sperm are resistant to the
  killing effects of radiation. They can sustain
  heritable genetic damage, however.
• Doses of about 6 Gy are required to permanently
  sterilize males (sterility occurs after several
  months). Although lower doses can also cause
  sterility after several months, the effect is
  temporary. Fertility and near-normal sperm counts
  return after 1 to 2 years.

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Reproductive System

• Dose rate has an unusual effect on the incidence
  of sterility in males. In animals it was found
  that dose protraction and fractionation were more
  effective in causing permanent sterility. This
  may be a result of synchronizing the sperm stem
  cells. Proliferating stem cells in the G2 phase
  or M phase of the cell cycle are killed by
  radiation. But since the dose is protracted at a
  constant low rate, resistant S and G1 cells
  eventually progress to the sensitive phases and
  are killed.

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Reproductive System-Female

• Rradiation destroys both ovum and maturing
  follicules. This reduces hormon production.
  Therefore radiogenic sterility in females can be
  accompanied by artificial menopause, with
  significant effects on sexual characteristics and
  secondary genitalia.

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Reproductive System-Female

• Total dose, dose rate, and age are important
  factors in the final effect. Younger women seems
  better able to recover fertility than do older
  women.
• A dose of 2 Gy permanently sterilizes women over
  40 but causes temporary sterility in women age 35
  and under.
• Menopouse was caused in 50 of younger women
  exposed to doses of 1,5 to 5 Gy. Women over 40
  showed 90 menapouse at 1,5 Gy.

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Gastrointestinal System

• The gastrointestinal (GI) tract is highly
  sensitive to radiation. Following irradiation,
  the first changes seen occur in the epithelium
  lining of the small intestine containing millions
  of convolutions called villi. The crypt cells of
  the villi are highly proliferative, supplying
  cells that continue to differentiate and migrate
  to the terminal villus. There they eventually
  slough off into the intestinal contents.
• Radiation causes mitotic arrest of the crypt
  cells followed by eventual denudation of the
  villi, ulceration of the wall, and septic
  infiltration.

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Gastrointestinal System

• Effects on the large intestine cause functional
  impairment resulting in fluid and electrolyte
  loss, and diarrhea.
• Effects on the upper GI tract include vomiting,
  depression of acid, and pepsin secretion.
  Destruction of the epithelium lining of the
  phrynx and esophagus results in dryness,
  soreness, and petechia (capillary rupture).

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Skin

• Skin is relatively radiosensitive.
• The radiobiologic end-points in skin are
  dependent on the total dose, the dose rate, and
  the radiation quality.
• Radiobiologic effects in skin include erythema
  (skin reddening), and temporary epilation (hair
  loss).
• At very high doses, permanent epilation and
  destruction of suborgans, including the
  vasculature, sebaceous and sweat gland, occur.

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Skin

• The response of the skin to ionizing radiation is
  called radiation dermatitis. This effect follows
  a temporal as well as dose response depending on
  damage to the suborgans and connective tissue.
  Skin responses include
• 1. Initial erythema. Redness occurs within days
  due to capllary dilatation caused by histamine
  releases. Threshold dose is 2 Gy from beta
  radiation or 1000 R from x-ray radiation.

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Skin

• 2. Dry desquamation. After several days the
  epidermis scales and peels as a result of
  reduction in sebaceous and sweat gland secretion,
  and vascular damage.
• 3. Erythema proper. After the third or fourth
  week redness with soreness and burning and edema
  results. This is caused by obstructive changes in
  the fine vasculature in the dermis.
• 4. Moist desquamation. At high doses of 2000 R,
  blisters form in the epidermis, permanent
  epilation results and edema with macrophage
  infiltration occurs. Severe damage to the
  vasculature and connective tissue is the cause.

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Skin

• 5. Necrosis. At very high doses, dermal necrosis
  may result after erythema proper as a result of
  dermis destruction, or later because of
  obstructive changes in arterioles, infection, and
  subcutaneous-fat-cell destruction.
• 6. Late effects. After one year, at high doses
  dermal atrophy, deep fibrosis, hyperpigmentation
  and general dryness are seen. At very high doses
  (several tens Gy), necrotic damage as a result of
  obliterative endarteritis may cause the eventual
  loss of limbs or large areas of the skin.

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TIME OF ONSET OF CLINICAL SIGNS OF SKIN INJURY
DEPENDING ON DOSE OF RADIATION EXPOSURE
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Skin

• Chronic exposure at lower doses results in
  hyperkeratosis, characterized by thickening of
  the epidermis, weekening of the strata with
  frequent ulceration, poor healing, and decreased
  vascularization.
• Chronic exposure is also associated with
  radiogenic carcinoma, primarily squamous cell
  carcinoma

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Mucous Membranes

• Mucous membranes are also radiosensitive,
  particularly those in the mouth, pharynx, and
  esophagus.
• After considerable doses, dryness, soreness, and
  petechial ulceration of the mouth occur within 2
  weeks.
• In the third week this progresses to swelling of
  the tongue with hypersecretion of the mucus,
  which eventually becomes a thick pseudomembrane
  that covers the buccal area, throat, and tongue.
• Later, fibrosis, ulceration, and poor vasculature
  accompanies skin effects.

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Central Nervous System

• Generally, the CNS is resistant to radiation
  effects. Very high doses are required to cause
  substantial effects on the brain and nervous
  system.
• The vasculature is the limiting factor in
  radiation effects to the CNS. Effects on the
  vessels cause breakdown of the capillary
  circulation with rupture of the walls,
  interstitial edema, meningitis, encephalitis, and
  the breakdown of the blood-brain barrier.

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Central Nervous System

• At higher doses, prompt killing (pynknosis) of
  the cerebellum has been seen.
• At lower doses, reversible changes in neurons can
  occur.
• The spinal cord exhibits radiation effects
  including thickening of the vessels, dissolution
  of white matter, and myelitis after doses in the
  order of 5000 R. This is a delayed effect,
  manifesting one to several years after exposure.
• Peripheral nerves are highly resistant to
  radiation effects. Higher doses and longer latent
  periods are required for expression of effects.

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The Fetus

• Fetal effects are seen at relatively low doses of
  radiation. The fetus is a highly proliferative
  system with many undifferentiated cells.
  Therefore it is extremely sensitive to radiation
  effects.
• The classic triad of effects of radiation upon
  the embryo are
• 1. Intrauterine growth retardation (IUGR)
• 2. Embryonic, fetal, or neonatal death
• 3. Congenital malformation

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EFFECTS OF RADIATION ACCORDING TO GESTATIONAL
STAGE

• Preconception - No statistically significant
  effects noted.
• Preimplantation - All or none
• In the human, implantation of the zygote in the
  wall of the uterus occurs at approximately days
  10 to 12 following conception. Radiation
  delivered exclusively during this stage may cause
  prenatal death with failure of implantation
  otherwise a normal pregnancy ensues.
• Implantation - Transient Intrauterine Growth
  Retardation threshold 10-20 cGy

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EFFECTS OF RADIATION ACCORDING TO GESTATIONAL
STAGE

• Organogenesis 7-13 weeks
• Embryo sensitive to lethal, teratogenic and
  growth-retarding effects because of the
  criticality of cellular activities and the high
  proportion of radiosensitive cells.
• IUGR, gross congenital malformations,
  microcephaly and mental retardation are the
  predominant effects for doses gt 50 rads
• There is no report of external irradiation
  inducing morphologic malformation in humans
  unless the individual also had growth retardation
  or a CNS anomaly

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Specific Radiation Effects on the Fetus

• Mental retardation
• Highest risk during major neuronal migration
  (8-15 weeks). Incidence increases with dose. At
  1 Gy (100 rads), 75 experience severe
  retardation
• At 16-25 weeks, fetus shows no increase in mental
  retardation at doses lt 0.5 Gy(50 rads)
• IQ
• Risk factor associated with diminution of IQ is
  21-33 points at 1 Gy given in the gestational
  period 8-15 weeks.
• Microcephaly Hiroshima Data
• 0 dose - 4 1-9 cGy - 7 10-19 cGy - 11
• 20-29 cGy- 23 30-49 cGy - 36 50-149 cGy 45
• gt 150 cGy - 35

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Considerations for Pregnancy Termination

• Normal rate of preclinical loss - gt 30.
• At 0.1 Gy (10 rads), this is increased by
  0.1-1.
• Consider the lifetime risk factor for induction
  of childhood tumors to be 1 in 2000 per cGy. At
  5 cGy, maximal risk for childhood leukemia is 1
  in 400. Conversely, probability of not having
  childhood cancer is gt 99.
• If the fetal absorbed dose gt 50 cGy in the 7-13
  week window, there is a substantial risk of IUGR
  and CNS damage.
• In the range 25 - 50 rads at 7-13 weeks
  Parental decision with physician guidance.

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Lens of the Eye

• At doses 2-6 Gy, damage to the lens, significant
  to cause eventual cataract formation.
• There is no mechanism for removal of cells from
  the lens. Subsequently, radiation-damaged cells
  migrate to the posterior poles and centrally, as
  an opacity.
• Latent period is from 2-35 years, with a mean
  time of 8 years at single doses of 2.5-6.5 Gy

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Other Organs

• In general the viscera exhibits relative
  radioresistance. Usually the connective tissue
  and vasculature become the limiting structures,
  but functional damage can result from high doses.
• Lung Radiation pneumonitis, an acute
  inflammatory reaction of the functional tissue
  and vasculature with doses of several thousands
  centigray after 4 to 6 months.
• Lung Radiation fibrosis, accumulation of fibrin
  in alveoli and septa, 6 months to years after
  high doses.
• Blood vessels Hemorrhage followed by progressive
  thickening and proliferation of endotelial cells
  known as obliterative endarteritis.
• Kidney Nephrosclerosis, nephritis, hypertension,
  and renal failure 2 to 3 years after doses of 30
  Gy.

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