Transcript Lecture 16 - Biology of Cancer

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
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
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.
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.
Early Lethal Effects
Hematopoietic syndrome:
• Cause of death at doses <8 Gy.
• Peak incidence of death occurs at about 30 days postirradiation, 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.
Mean lethal dose and dose/time responses
Mean lethal dose and dose/time responses
Mean lethal dose and dose/time responses
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.
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.
Immunological effects
Immunological effects
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.
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.
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 UkraineBelarus 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.
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
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.
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.
Assessment and treatment of radiation
accidents
Assessment and treatment of radiation
accidents
Assessment and treatment of radiation
accidents
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.
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
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.
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.
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.
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.
Bone marrow transplantation