Transcript Overview of Basic Radiation Biology

Linear-No-Threshold HypothesisScientific Evidence?
Dr. Antone Brooks
Washington State University Tri-cities
Richland, Washington
My Background
• Early interest in radiation
(Watching atomic weapons in southern Utah)
• MS in radiation ecology (Chasing fallout)
• PhD in radiation biology in genetics
(Trying to discover what radiation is actually doing inside people)
• Investment of my life in research on health
effects of low doses of radiation
DOE Low-Dose Radiation
Research Program
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A 10 year program at $21 million/year
International in scope
To fund the best scientist (currently 46 projects/year)
To understand biological mechanisms
To develop radiation standards based on risk
http://lowdose.org
Why now?
• Standards have been set from high dose
effects, but low dose effects have not been
measurable until now
• New technological developments and
biological discoveries have made it possible
to study low dose effects
Problems Associated with
Estimating Health Risks
• Background radiation (dose)
• Background cancer (response)
Normal annual exposure from natural radiation
300 mrem/year
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Radon gas
Human body
Rocks, soil
Cosmic rays
200 mrem
40 mrem
28 mrem
27 mrem
Normal annual exposure from man-made radiation
70 mrem/yr
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Medical procedures
Consumer products
One coast to coast airplane flight
Watching color TV
Sleeping with another person
Weapons test fallout
Nuclear industry
53 mrems
10 mrems
2 mrems
1 mrem
1 mrem
less that 1 mrem
less than 1 mrem
mrem / year
Exposure at Different Elevations
140
120
100
80
60
40
20
0
Sea Level
Death
Valley
Richland Denver
Ledville
1 mrem/year = 200 feet of altitude
4 mrem/year = 800 feet
500 mrem/year = some isolated populations
Background Cancer
Over 30 % of us will develop cancer
About 25 % will die of cancer
Cancer is variable as a function of
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Genetic Background
Environmental Exposures
Diet
Lifestyle
Key Research Areas
• Technological Advances
• Biological Advances
Major Paradigm Shifts
• Hit Theory vs. Bystander Effects
• Mutation vs. gene induction
• Genomic instability vs. multiple steps in
carcinogenesis
How Does Radiation Interact
with Cells?
Past
Present
Hit theory
Bystander effects
• Direct ionization
• Cell-cell
communication
• Free radical
formation
• Cell-matrix
communication
Microbeam
Alpha Hits for Cell Transformation
Each cell hit by one particle
Average of one particle/cell
Miller et al.1999
Bystander Effects
Normal
10 cGy
3 cGy
Biological Changes Detected in
Non-hit Cells
• Gene induction
• Mutations
• Chromosome aberrations
• Apoptosis and cell killing
• Cell transformation
Adaptive Response
Radiation-induced Chromatid Aberrations
90
80
70
60
50
40
30
20
10
0
Observed
Expected
0
0.5
1
150
150 + .5 150 + 1
Dose cGy
Shadley and Wolff 1987
7K Microarray Results for
“Stress Chip” Clone Selection
Dose (Gy) Time (Hr) Induced Repressed
Genes
Genes
2.5
24
62
8
0.2
24
114
11
.02
24
55
6
Fornace
Gene Mutation and Expression in Cancer
Single cell origin of cancer
Normal
Gene Activation
Normal
Initiation
Down
Regulation
Promotion
Progression
Gene Mutation- a rare event
Progression
Gene Expression- a common event
LNTH Assumption with Dose
Low dose x large number of
subjects
High dose x small number of
subjects
Energy to system
Absorbed Dose-Imparted
Energy
Biological
Response
Barrier
B
A
B
Background Energy
Level
Imparted Energy (J) in System
Low-Dose Research Program
Goals
Understand mechanisms of biological
response to low-dose radiation on a cellular
and molecular level
Evaluate appropriate and adequate risk from
low doses and dose-rates of radiation
Adequate Protection
• Control Contamination
• Minimize Exposure
• Reduce Dose
How low is low enough? “Zero”?
Adequate Protection
Adequate Protection
Adequate Protection
Adequate Protection
Adequate Protection
Adequate and Appropriate?
Questions and Problems
Associated with Dose-Response
Relationships
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Ratios:
Energy/Mass=Dose
Damage/Mass=Response
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What is the appropriate mass?
Is there a “free lunch”?
Is the biological response unique at low radiation doses?
Is extrapolation possible?
Do New Paradigms Impact Standards?
NON-LINEAR
Tissue
Multiple Independent
Events
Gene
Expression
vs.
vs.
vs.
Cell
Genomic Instability
Mutation
LINEAR
Summary
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Radiation risks from low levels of radiation exposure cannot be
predicted with epidemiological studies.
Combining advances in technology with those in cell and
molecular biology make it possible to detect biological changes
after low levels of radiation exposure.
These low level changes have required changes in basic radiation
paradigms.
Understanding the role of these biological changes in cancer risk
may or may not impact radiation protection standards, but will
help ensure that the standards are both adequate and appropriate.