Total Body Irradiation

1. Lecture 16 Total Body Irradiation • Prodromal radiation syndrome • Cerebrovascular syndrome • Gastrointestinal syndrome • Hematopoietic syndrome • Mean letha dose and dose/time responses • Immunological effects • Assessment and treatment of radiation accidents or • terrorism • Bone marrow transplantation

2. Prodromal Radiation Syndrome • Early symptoms that appear after exposure to whole body radiation: • gastrointestinal: nausea, vomiting, diarrhea, anorexia • neuromuscular: easy fatigability • Effect is dose dependent: • Varies in time of onset • Severity • Duration

3. Early Lethal Effects Cerebrovascular syndrome: • Identified at doses >100 Gy of gamma-rays. • Death occurs within hours from cardiovascular and neuromuscular complications. • Clinical manifestations include severe nausea, vomiting within minutes of exposure, disorientation, loss of muscular co-ordination, respiratory distress, seizures, coma and death.

4. Early Lethal Effects Gastrointestinal syndrome: • Occurs at dose >10 Gy of gamma-rays or its equivalence. • Death usually occurs within 3 to 10 days. • Symptoms due largely to depopulation of the epithelial lining of the GI tract by radiation. • No human has survived radiation dose >10 Gy. • Clinical symptoms include nausea, vomiting, and prolong diarrhea, dehydration, loss of weight, complete exhaustion, and eventually death.

5. Early Lethal Effects Hematopoietic syndrome: • Cause of death at doses <8 Gy. • Peak incidence of death occurs at about 30 days post-irradiation, and continues for up to 60 days. • Suppresses normal bone marrow and spleen functions. • Symptoms associated with hematopoietic syndrome are: chill, fatigue, hemorrhages, ulceration, infection and anemia. Death usually result unless receive bone marrow transplant.

6. Mean lethal dose and dose/time responses

7. Mean lethal dose and dose/time responses

8. Mean lethal dose and dose/time responses

9. Immunological effects The dose-response relationship of the changes in different cell types of the immune system after whole-body irradiation has been analyzed on the basis of measured systemic data and recent reports in the literature. For T lymphocytes, J or inverted J-shaped curves are usually observed after irradiation. For macrophages, dose-response curves of chiefly stimulation with irregular patterns are often observed. Different doses of radiation facilitate different pathways of signal transduction, the expression of different surface molecules and secretion of different cytokines in the antigen presenting cells and T lymphocytes in the immunological synapse.

10. Immunological effects Phenomenon of low doses-short-term stimulation (doses in the range of 0.01-0.50 Gy), and high-dose suppression of immunity is generally observed. Low-dose total body irradiation (TBI) could enhance the immune response through (1) augmenting the proliferative reactive response of the T cells to mitogenic stimulation; (2) altering cytokine release, particularly the activation of interferon gamma and IL-2 production; (3) increasing the expression of IL-2 receptors on the T-cell surface; (4) facilitating signal transduction in T lymphocytes; (5) increasing splenic catecholamine content and lowering the serum corticosterone level; and (6) eliminating a particularly radiosensitive subset of the suppressor T cells.

11. Immunological effects

12. Immunological effects

13. Assessment and treatment of radiation accidents The long shadow of Chernobyl Twenty years ago, operators committed a fatal series of errors in the control room of reactor number four. The explosion that followed still blights land and lives. The fallout, 400 times more radioactivity than was released at Hiroshima, drove a third of a million people from their homes and triggered an epidemic of thyroid cancer in children. The genetic damage done 20 years ago is slowly taking a toll: the authoritative report estimated last year that the cancer fuse lit by Chernobyl will claim 4,000 lives. Yet Chernobyl’s most insidious legasy may be the psychological wounds borne by those who fled blighted homes, and by several million who continue to live on contaminated land. The psychological effects have been devastating. Many women feel they will give birth to unhealthy babies with no future. Many people feel they will die from Chernobyl.

14. The long shadow of Chernobyl A report last year from the Chernobyl Forum, a group of experts convenedby the International Atomic Energy Agency, the WHO, and other United Nations agencies estimated that among millions exposed to Chernobyl radioactive cloud, nearly 4,000 will ultimately die from leukemia and other radiation-induced cancers. Starting in 1990 the sharp rise in childhood thyroid cancer has been observed. Before Chernobyl, Belarus had two or three cases a year in children under 15. In 1995 there were 90 cases. To date about 4,000 children and teenagers in Belarus, Russia, and Ukraine have been diagnosed with the cancer. The impact of Chernobyl doesn’t end with cancer deaths. The scientists have never anticipated the psychological toll on survivors. Believing they are doomed, some live in fear, while others persue a devil-may-care lifestyle: eating mushrooms and berries from contaminated soil, abusing alcohol, or engaging in unprotected promiscuous sex.

15. The long shadow of Chernobyl Chernobyl’s deadly footprint Windblown fallout like the plume shown below fell thick near reactor, forcing evacuation of more than a thousand square miles straddling Ukraine- Belarus border. High-altitude winds swept radioactive smoke and ash across a wider area (map on the right), which scientists traced from soil levels of cesium 137, a long-lived isotope.

16. The long shadow of Chernobyl After 10 years of negotiations, work is expected to start later this year on a new sarcophagus designed as a giant steel arch. Longer than football field, taller than statue of Liberty, costing perhaps 800 million dollars

17. Radiation accidents in the United States The United States operates 103 nuclear power reactors-that’s a quarter of the world’s total. The hopes of a burgeoning nuclear industry imploded 27 years ago after the partial meltdown at one of the Three Mile Island reactors in Pennsylvania.

18. Survivors of the serious radiation accidents in the United States • The number involved in the United States is about 70 workers • in 13 separate accidents. • The long-term survivors have been exhaustively studied over • the years: • the medical history of the heavily irradiated persons is the same • as that of any aging population; • shortened lifespan, early malignancies and rapidly progressing • lenticular opacities have not been observed; • several malignancies, cataracts, and degenerative diseases are • no more than is expected in a similar group of unirradiated • persons of the same age.

19. Assessment and treatment of radiation accidents

20. Assessment and treatment of radiation accidents

21. Assessment and treatment of radiation accidents

22. Assessment and treatment of radiation accidents terrorism In the context of radiation accidents, it should be noted that the Medical Sciences Division of the Oak Ridge Institute for Science and Education operates a radiation Emergency Assistance Center/ Training Site (REAC/TS) on behalf of the U.S. Department of Energy. REAC/TS provides 24-hour assistance with medical and health physics problems associated with radiation accidents in local, national and international incidents. The resources of REAC/TS consist of expertise in cytogenetics for dose assessment, calculation of doses from internally deposited radionuclides, and laboratory facilities that include total-body counting capabilities.

23. Assessment and treatment of radiation accidents terrorism Recommendations available on following Websites: http://www.afrri.usuhs.mil/www/outreach/biodostools.htm http://www.arpansa.gov.au/rempan.htm http://www.doeal.gov/opa/Emergency%20Public%20 Information/REACTS_Final_June2002.pdf • Radiation emergency assistance training • Casualty management guidance • Terrorism with Ionizing Radiation Guide • Medical Management of Radiological casualties • Exposure assessment software (BAT, • biodosimetry assessment tool) • Radiation Biological Dosimetry Tools for • Emergency Responders • Manual on the Medical Management • of Individuals Involved in Radiation Accidents

24. Acute Radiation Syndrome • Signs and symptoms experienced by individuals exposed to acute whole body irradiation. • Data collected largely through Japanese atomic bomb survivors at Hiroshima and Nagasaki. • Limited number of accidents at nuclear instillations. • Clinical radiotherapy. • Well-characterized animal data base. • LD50 dose of human is ~4 Gy.

25. Radiation-induced Mutagenesis • Radiation DOES NOT produce new, unique mutations, but increases the incidence of the same mutations that occur spontaneously. • Mutation incidence in humans is DOSE and DOSE-RATE dependent. • A dose of 1 rem (10 mSv) per generation increases background mutation rate by 1%. • Information on the genetic effects of radiation comes almost entirely from animal and IN VITRO studies. • Children of A-bomb survivors from Hiroshima and Nagasaki fail to show any significant genetic effects of radiation.

26. Radiation Carcinogenesis • A stochastic late effect. • No threshold, an all or none effect. • Severity is not dose related. • Probability of carcinogenesis is dose dependent. • Leukemia has the shortest latency period of ~5 years. Solid tumors have a latency period of ~20 to 30 years. • Total cancer risk for whole body irradiation is one death per 104 individuals exposed to 1 rem. • For every leukemia induced there are 3 to 4 sarcoma induced in the same irradiated population.

28. Bone marrow transplantation Bone marrow rescue “dose”-the number of transplanted bone-marrow cells that are required for a person to recover from a supralethal dose.

29. Bone marrow transplantation