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Overview of Basic Radiation Biology

VIEWS: 3 PAGES: 31

									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
• • • • • 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
    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
       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

Exposure at Different Elevations
140 120 100 80 60 40 20 0
mrem / year

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
• • • • 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
Hit theory
• Direct ionization

Present
Bystander effects
• 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

3 cGy

10 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 0 0.5 1 150 150 + .5 150 + 1

Observed Expected

Dose cGy
Shadley and Wolff 1987

7K Microarray Results for “Stress Chip” Clone Selection
Dose (Gy) Time (Hr) Induced Repressed Genes Genes 2.5 0.2 .02 24 24 24 62 114 55 8 11 6
Fornace

Gene Mutation and Expression in Cancer
Single cell origin of cancer

Normal Gene Activation

Normal Initiation Promotion Progression Gene Mutation- a rare event

Down Regulation

Progression Gene Expression- a common event

LNTH Assumption with Dose

High dose x small number of subjects Energy to system

Low dose x large number of subjects

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 • • • • •
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

Tissue

Multiple Independent Events

Gene Expression

vs.
Cell

vs.
Genomic Instability

vs.
Mutation

LINEAR

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.


								
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