Dr. Antone Brooks Washington State University Tri-cities Richland, Washington
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Transcript of Dr. Antone Brooks Washington State University Tri-cities Richland, Washington
Dr. Antone Brooks
Washington State University Tri-cities
Richland, Washington
Linear-No-Threshold Hypothesis- Scientific Evidence?
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
• 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)
70 mrem/yr Medical procedures 53 mrems Consumer products 10 mrems One coast to coast airplane flight 2 mrems Watching color TV 1 mrem Sleeping with another person 1 mrem Weapons test fallout less that 1 mrem Nuclear industry less than 1 mrem
Normal annual exposure from man-made radiation
Normal annual exposure from natural radiation
300 mrem/year Radon gas 200 mrem Human body 40 mrem Rocks, soil 28 mrem Cosmic rays 27 mrem
Exposure at Different Elevations
0
20
40
60
80
100
120
140
Sea Level DeathValley
Richland Denver Ledville
mre
m /
year
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 • 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?
PastHit theory
• Direct ionization
• Free radical formation
PresentBystander effects
• Cell-cell communication
• Cell-matrix communication
CCD camera
epi-fluorescent microscope
lamp
micropositioning stage
electron gun
zone-plate assembly
optical shutter
carbon target
X-ray mirror
CCD camera
epi-fluorescent microscope
lamp
micropositioning stage
electron gun
zone-plate assembly
optical shutter
carbon target
X-ray mirror
MicrobeamAlpha 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
0102030405060708090
0 0.5 1 150 150 + .5 150 + 1
ObservedExpected
Shadley and Wolff 1987
Abe
rrat
ions
Dose cGy
7K Microarray Results for “Stress Chip” Clone Selection
Dose (Gy) Time (Hr) InducedGenes
RepressedGenes
2.5 24 62 8
0.2 24 114 11
.02 24 55 6
Fornace
Normal
Initiation
Promotion
Progression
Tissue TheoryTissues suppress
cancer.
Gene Mutation and Expression in Cancer
Gene Mutation- a rare event Gene Expression- a common event
Gene Activation
Down Regulation
Single cell origin of cancer
Normal
Progression
LNTH Assumption with Dose
Energy to system
High dose x small number of subjects
Low dose x large number of subjects
Absorbed Dose-Imparted Energy
Background Energy Level
Biological Response Barrier
B
A
B
Imparted Energy (J) in System
Nu
mb
er R
esp
ond
ing
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
• Ratios:Energy/Mass=Dose
Damage/Mass=Response
• 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
Multiple Independent Events
vs.
Genomic Instability
LINEAR
Gene Expression
vs.
Mutation
Tissue
vs.
Cell
Summary
• 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.