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Radiological Science in the Context of
Radiological Terrorism
Basics of
Ionizing Radiation
Effects
Charles R. Geard
Center for Radiological Research
Columbia University
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Radiation and Life
In the context of this conference αparticles are important only when
radioactive material is inhaled or
ingested.
β-rays – only when ingested or skin
X- and γ-rays – external radiation
Neutrons – nuclear explosion
Quantities and Units
Dose – Measured Physical Quantity
Old unit – rad
New unit – Gray (Gy)
1 Gy = 100 rad
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Quantities and Units
Equivalent Dose – Calculated Quantity
The same dose of different radiations does
not produce the same biological effect.
Equivalent dose = dose x radiation weighting
factor (WR).
WR = 20 for α-particles and some neutrons.
Old unit – rem
New unit – Sievert (Sv)
1 Sv = 100 rem
Quantities and Units
Effective Dose – Calculated Quantity
Different organs vary in radiosensitivity;
e.g., thyroid, breast and colon are more
sensitive than extremities.
Old unit – rem
New unit – Sievert (Sv)
1 Sv = 100 rem
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Doses to the
U.S. Population
Exposure to
Natural Radiation
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Radiation
Exposure Due
to Human
Activity
Average Effective Dose in U.S. (3.6 mSv/yr)
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Ionizing Radiation(s)
Able to ionize atoms – i.e., knock an
electron out of orbit.
Able to break chemical bonds and
disrupt the large molecules that living
things are made of.
Ionizing Radiation
The biological effect results, not from
the total energy absorbed, but from
the energy of the individual charged
particle or photons of
γ-rays.
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Total Body Irradiation
Mass = 70 kgm.
LD/50/60 = 4 Gy.
Energy absorbed =
70 x 4 = 280 Joules
= 280 = 67 calories.
4.18
Drinking Hot Coffee
Excess temperature (°C) = 60° - 37° = 23°
Volume of coffee consumed to equal the
energy in the LD/50/60 = 67 = 3 ml = 1 sip
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Chain of Events
Time Scale
incident x-ray photon
↓
fast electron
↓
ion radical
↓
chemical changes due to
the breakage of bonds
↓
biological effects
10-15 sec


↓
-5
10 sec


↓
days, years or
generations
RADIATION BIODOSIMETRY
Dose Predictive Assays
How much radiation has a person/cell received?
Center for High-Throughput Minimally-Invasive Radiation Biodosimetry
Radiation Dose
Home Land Security – Dirty Bombs!
Biological Response
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BIOLOGICAL RESPONSES TO IONIZING RADIATION
Cell Death
Apoptosis
Gene Mutation
Chromosomal Aberrations
Micronuclei
A
N
D
!
e
g
a
m
a
D
Changes in Levels of Specific Gene Products
Others………
Direct and Indirect Action
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DNA –
Double
Strand
Break
Biological Effects of Radiation
Cell Killing – division of damaged
chromosomes
– Relevant to radiotherapy.
– Cause of some effects on the embryo & fetus at
low doses, and to adults at high doses.
Mutation in Germ Cells - altered
chromosomes
– Hereditary consequences expressed in later
generations.
Carcinogenesis or Leukemogenesis
– Chromosomal changes and/or mutations in
dividing somatic cells.
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Cell Killing
Conventional Radiology
– Doses too small to cause discernible
cell killing (<10 cGy).
Radiological event
– Doses sufficient to cause erythema and
possibly necrosis need to be greater
than 1 Gy (e.g. an atomic bomb).
Cellular consequences of radiation exposure
Cell cycle arrest (cells stop dividing)
• Temporary or permanent
• Changes in gene products
DNA repairNo change
AlterationsViable or lethal
Cell Death
• Apoptosis or necrosis
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Damaged Chromosome Reproduction Errors
Dicentric Chromosome in a Peripheral Lymphocyte
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Chromosome Translocation in Chronic Myeloid Leukemia
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Complex inter-chromosomal translocation
multiplex FISH
Combined
FITC
SPECTRUM O
TEXAS RED
Cy5
DEAC
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Radiation and Cell Damage
Radiation breaks chromosomes.
DNA breaks repair or mis-repair.
Mis-repaired chromosomes can lead to
abnormal cell division
Cells die and are removed when they attempt to
divide – micronuclei and nucleoplasmic bridges
Carcinogenic change only expresses in dividing
cells – translocations and small deletions
Until then cells are present and can function.
Radiation Dose
Dose Response
Biological Response
Larger the Dose – Greater the Biological Response
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Radiation Biodosimetry
Irradiation of human peripheral blood
lymphocytes
• Separate lymphocytes from whole blood
• Split culture: process for micronucleated
cells, DNA damage foci, gene expression
• Harvest RNA after 24 hours,
compare on microarray
• Follow-up of induced genes
•
ALL ENDPOINTS
• Reproducibility in multiple donors
• Time-course of response
• Dose-response relationship
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Aberrations per Cell
Based on DNA Damage
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γ-H2AX foci per cell
γ-H2AX foci
• Radiation causes gene expression changes
• Gene expression changes underlie many
cellular responses
• We can now study changes in gene
expression across the whole genome
• Gene expression profiles may soon
provide useful information for biodosimetry
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Stress Signaling Pathways
cytokine
receptors
ionizing
radiation
cell surface
cera
cytokines and
bystander signals
mide
activation
PKC
Protein modifications
plasma
membrane
NFκB
MAPK (p38, JNK)
c-Abl
caspases
DNA-PK
Gene expression
changes
(Functional Genomics)
ATM
p53
DNA
DNA damage
ionizing
radiation
Altered cellular
function
nucleus
Relative Expression
Gene induction in PBL persists at least two days
24 hours
post-irradiation
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48 hours
post-irradiation
8
DDB2
6
4
CDKN1A
6
XPC
4
2
DDB2
CDKN1A
XPC
2
0
0
50
100
150
200
Dose (cGy)
0
0
50
100
150
200
Dose (cGy)
Amundson et al., (2000)
Radiation Research, 154 (3): 342-346
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Developing gene expression for biodosimetry
Blood sample
Array Profile
Integrated
profiling cassette
Dose Assessment
- triage
Informatic
Analysis
Compare Profile
To Database
Radiation biodosimetry
in the event of population radiation exposure.
Requirements:
Speed Accuracy Longevity
DNA damage and cytogenetic assays
DNA based foci
Chromosomal domain alterations
Micronuclei and nucleoplasmic bridges
Chromosomal aberrations
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