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

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 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 Free radical formation Present Bystander effects Cell-cell communication Cell-matrix communication

Microbeam Alpha Hits for Cell Transformation Each cell hit by one particleAverage 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 Shadley and Wolff 1987 Aberrations Dose cGy

7K Microarray Results for “Stress Chip” Clone Selection Fornace

Normal Initiation Promotion Progression Mutation Theory Tissue Theory Tissues suppress cancer. Gene Mutation and Expression in Cancer Gene Mutation- a rare eventGene 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 Number Responding

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 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.