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.