: Dr. Antone Brooks Washington State University Tri-cities Richland, Washington Linear-No-Threshold Hypothesis- Scientific Evidence?


My Background :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 :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? :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 :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


Exposure at Different Elevations :Exposure at Different Elevations 1 mrem/year = 200 feet of altitude 4 mrem/year = 800 feet 500 mrem/year = some isolated populations


Background Cancer :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 :Key Research Areas Technological Advances Biological Advances


Major Paradigm Shifts :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? :How Does Radiation Interact with Cells? Past Hit theory Direct ionization Free radical formation Present Bystander effects Cell-cell communication Cell-matrix communication


Slide 13:Schematic of the Gray Laboratory Microfocus X-ray source


Microbeam :Microbeam Alpha Hits for Cell Transformation Each cell hit by one particle Average of one particle/cell Miller et al.1999


Bystander Effects :Bystander Effects Normal 10 cGy 3 cGy


Biological Changes Detected in Non-hit Cells :Biological Changes Detected in Non-hit Cells Gene induction Mutations Chromosome aberrations Apoptosis and cell killing Cell transformation


Adaptive Response Radiation-induced Chromatid Aberrations :Adaptive Response Radiation-induced Chromatid Aberrations Shadley and Wolff 1987 Aberrations Dose cGy


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


Slide 19:Normal Initiation Promotion Progression Mutation Theory Tissue Theory Tissues 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 :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 :Absorbed Dose-Imparted Energy Background Energy Level Biological Response Barrier Imparted Energy (J) in System Number Responding


Low-Dose Research Program Goals :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 :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 Protection


Adequate Protection :Adequate Protection


Adequate Protection :Adequate Protection Adequate and Appropriate?


Questions and Problems Associated with Dose-Response Relationships :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? :Do New Paradigms Impact Standards? NON-LINEAR Multiple Independent Events vs. Genomic Instability LINEAR Gene Expression vs. Mutation Tissue vs. Cell


Summary :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.