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 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 ( 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 ( 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 ( 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.

Effects of Moderate ( 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.