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. LD x/y

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

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

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

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

Total Body Irradiation Syndromes

 Bone marrow Syndrome – Occurs at doses of 2-10 Gray. – The LD 50/60 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.

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

Total Body Irradiation Syndromes

 GI syndrome – Occurs at doses above 8-10 gray  This dose is equal to 4-5 time D 0  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

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

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

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

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

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

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

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.

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

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.

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.

Irradiation of Embryo and Fetus

 Other effects – Mutation induction >>> 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

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

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.

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

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

 White blood cell (wbc’s) effects – WBC’s 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 wbc’s can be overwhelmed.  Following irradiation there is a decrease in wbc numbers  There may also be a decrease in functional capability

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

 Cytokines and other chemicals in the body that attack microbes are products of wbc’s 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.

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

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

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

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.

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.

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.

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.

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.