Cell and Molecular Responses to ionizing Radiation in Normal tissues : Impact on Radiation Risk

Cell and Molecular Responses to ionizing Radiation in Normal tissues : Impact on Radiation Risk Antone L. Brooks WSU-Tricities International Conference on July 13-14, 2007 Normal Tissue Radiation Effects Las Vegas, NV

acute exposure = all at once; chronic = hours, days, years Ionizing Radiation Dose Ranges ( Sievert ) Ionizing Radiation Dose Ranges ( Sievert ) Cancer Radiotherapytotal dose to tumor Cancer Radiotherapytotal dose to tumor Whole body, acute: G-I destruction; lung damage; cognitive dysfunction (death certain in 5 to 12 days)* Whole body, acute: cerebral/ vascular breakdown (death in 0-5 days)* 0 10 20 30 40 50 60 70 80 90 100 Sv 0 10 20 30 40 50 60 70 80 90 100 Sv Total Body Irradiation (TBI) Therapy Total Body Irradiation (TBI) Therapy Life Span Study (A-bomb survivor epidemiology) Whole body, acute: circulating blood cell death; moderate G-I damage (death probable 2-3 wks)* Acute Radiation Syndromes Acute Radiation Syndromes Whole body, acute: marked G-I and bone marrow damage (death probable in 1-2 wks)* Solar flare dose on moon, no shielding *Note: Whole body acute prognoses assume no medical intervention.) 0 1 2 3 4 5 6 7 8 9 10 Sv 0 1 2 3 4 5 6 7 8 9 10 Sv Human LD50range, acute exposurewith medical intervention Human LD50 range, acute exposure with no medical intervention (50% death in 3-6 weeks)* Human LD50 range, acute exposure with no medical intervention (50% death in 3-6 weeks)* Estimated dose for 3-yr Mars mission (current shielding) Evidence for small increases in human cancer above 0.1 Sv acute exposures, 0.2 Sv chronic exposure Cancer Epidemiology Cancer Epidemiology 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Sv 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Sv Typical mission doses on Intl. Space Station (ISS) Medical Diagnostics, mSv A- Chest x-ray (1 film) 0.1 B- Dental oral exam 1.6 C- Mammogram 2.5 D- Lumbosacral spine 3.2 E- PET 3.7 F- Bone (Tc-99m) 4.4 G- Cardiac (Tc-99m) 10 H- Cranial CT (MSAD) 50 (multiple scan average dose) I- Barium contrast G-I 85 fluoroscopy (2 min scan) J- Spiral CT- full body 30-100 Medical Diagnostics, mSv A- Chest x-ray (1 film) 0.1 B- Dental oral exam 1.6 C- Mammogram 2.5 D- Lumbosacral spine 3.2 E- PET 3.7 F- Bone (Tc-99m) 4.4 G- Cardiac (Tc-99m) 10 H- Cranial CT (MSAD) 50 (multiple scan average dose) I- Barium contrast G-I 85 fluoroscopy (2 min scan) J- Spiral CT- full body 30-100 EPA guideline for lifesaving: 0.25 Sv Natural bkg /yr Ramsar, Iran DOE Low Dose Program DOE Low Dose Program EPA radiological emergency guideline for public relocation H H I I J J “Storefront” full-body CT screening (one scan) “Storefront” full-body CT screening (one scan) 0 10 20 30 40 50 60 70 80 90 100 mSv 0 10 20 30 40 50 60 70 80 90 100 mSv DOE, NRC Dose Limit for Workers: 5 rem/yr = 50 mSv/yr Natural bkg /yr Kerala coast, India DOE administrative control: 20 mSv/yr = 2 rem/yr Medical Diagnostics (A-J) Medical Diagnostics (A-J) Typical annual doses for commercial airline flight crews A A B B F F G G C C D D E E 0 1 2 3 4 5 6 7 8 9 10 mSv 0 1 2 3 4 5 6 7 8 9 10 mSv NRC cleanup criteria for site decommissioning / unrestricted use: 0.25 mSv/yr Natural bkg /yr Yangjiang, China Natural background, U.S. average  3 mSv/yr (includes radon) Natural background, U.S. average  3 mSv/yr (includes radon) Regulations & Guidelines Regulations & Guidelines Max releases DOE facilities Round-trip NY to London LD50 = Lethal Dose to 50% (the acute whole body dose that results in lethality to 50% of the exposed individuals) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 mSv 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 mSv EPA dose limit applicable to public drinking water systems: 0.04 mSv/yr ANSI standard N43.17 Personnel scans max dose for total scans in 1 yr: 0.25 mSv DOE, NRC Dose Limit for Public: 1 mSv/yr = 100 mrem/yr (ICRP, NCRP) EPA dose limit from releases in air: 0.10 mSv/yr Absorbed dose: 1 Gray = 100 rad Dose equivalent: 1 Sievert = 100 rem 1 mSv = 100 mrem (1 Sv = 1 Gy for x- and gamma-rays) Note: This chart was constructed with the intention of providing a simple, user-friendly, “order-of-magnitude” reference for radiation quantities of interest to scientists, managers, and the general public. In that spirit, most quantities were expressed in the more commonly used radiation protection unit, the rem (or Sievert, 2nd page), and medical doses are not in “effective” dose. It is acknowledged that the decision to use one set of units does not address everyone’s needs. (NRC—US Nuclear Regulatory Commission; EPA—US Environmental Protection Agency) Disclaimer: Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information disclosed. Chart compiled by NF Metting, Office of Science, DOE/BER “Orders of Magnitude” revised March 2006 Chart compiled by NF Metting, Office of Science, DOE/BER “Orders of Magnitude” revised March 2006 acute exposure = all at once; chronic = hours, days, years Ionizing Radiation Dose Ranges ( Sievert ) Cancer Radiotherapytotal dose to tumor Whole body, acute: G-I destruction; lung damage; cognitive dysfunction (death certain in 5 to 12 days)* Whole body, acute: cerebral/ vascular breakdown (death in 0-5 days)* 0 10 20 30 40 50 60 70 80 90 100 Sv Total Body Irradiation (TBI) Therapy Life Span Study (A-bomb survivor epidemiology) Whole body, acute: circulating blood cell death; moderate G-I damage (death probable 2-3 wks)* Acute Radiation Syndromes Whole body, acute: marked G-I and bone marrow damage (death probable in 1-2 wks)* Solar flare dose on moon, no shielding *Note: Whole body acute prognoses assume no medical intervention.) 0 1 2 3 4 5 6 7 8 9 10 Sv Human LD50range, acute exposurewith medical intervention Human LD50 range, acute exposure with no medical intervention (50% death in 3-6 weeks)* Estimated dose for 3-yr Mars mission (current shielding) Evidence for small increases in human cancer above 0.1 Sv acute exposures, 0.2 Sv chronic exposure Cancer Epidemiology 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Sv Typical mission doses on Intl. Space Station (ISS) Medical Diagnostics, mSv A- Chest x-ray (1 film) 0.1 B- Dental oral exam 1.6 C- Mammogram 2.5 D- Lumbosacral spine 3.2 E- PET 3.7 F- Bone (Tc-99m) 4.4 G- Cardiac (Tc-99m) 10 H- Cranial CT (MSAD) 50 (multiple scan average dose) I- Barium contrast G-I 85 fluoroscopy (2 min scan) J- Spiral CT- full body 30-100 EPA guideline for lifesaving: 0.25 Sv Natural bkg /yr Ramsar, Iran DOE Low Dose Program EPA radiological emergency guideline for public relocation H I J “Storefront” full-body CT screening (one scan) 0 10 20 30 40 50 60 70 80 90 100 mSv DOE, NRC Dose Limit for Workers: 5 rem/yr = 50 mSv/yr Natural bkg /yr Kerala coast, India DOE administrative control: 20 mSv/yr = 2 rem/yr Medical Diagnostics (A-J) Typical annual doses for commercial airline flight crews A B F G C D E 0 1 2 3 4 5 6 7 8 9 10 mSv NRC cleanup criteria for site decommissioning / unrestricted use: 0.25 mSv/yr Natural bkg /yr Yangjiang, China Natural background, U.S. average  3 mSv/yr (includes radon) Regulations & Guidelines Max releases DOE facilities Round-trip NY to London LD50 = Lethal Dose to 50% (the acute whole body dose that results in lethality to 50% of the exposed individuals) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 mSv EPA dose limit applicable to public drinking water systems: 0.04 mSv/yr ANSI standard N43.17 Personnel scans max dose for total scans in 1 yr: 0.25 mSv DOE, NRC Dose Limit for Public: 1 mSv/yr = 100 mrem/yr (ICRP, NCRP) EPA dose limit from releases in air: 0.10 mSv/yr Absorbed dose: 1 Gray = 100 rad Dose equivalent: 1 Sievert = 100 rem 1 mSv = 100 mrem (1 Sv = 1 Gy for x- and gamma-rays) Note: This chart was constructed with the intention of providing a simple, user-friendly, “order-of-magnitude” reference for radiation quantities of interest to scientists, managers, and the general public. In that spirit, most quantities were expressed in the more commonly used radiation protection unit, the rem (or Sievert, 2nd page), and medical doses are not in “effective” dose. It is acknowledged that the decision to use one set of units does not address everyone’s needs. (NRC—US Nuclear Regulatory Commission; EPA—US Environmental Protection Agency) Disclaimer: Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information disclosed. Chart compiled by NF Metting, Office of Science, DOE/BER “Orders of Magnitude” revised March 2006

Cell and Molecular Responses to ionizing Radiation in Normal tissues : Impact on Radiation Risk • Understand the differences in the mechanisms of action for low vs high doses of radiation • Evaluate the LNT hypothesis and the DDREF for low dose radiation exposure • To provide a scientific basis for radiation standards in the low dose region • Provide up-to-date information to researchers and public on low dose effects http://www.lowdose.energy.gov

Mechanistic Studies • How can the research in the low dose region move from observations to mechanisms? • What is a mechanistic study? • New and more sensitive techniques to detect radiation induced changes? • New models? • Different application of data i.e. molecular epidemiology? • Systems biology? • Understanding the responses at the level that make it possible to predict and potentially modify the outcome of radiation exposure!!!

Biological Responses Induced by Low Doses of Radiation AdaptiveResponse Genomic Instability Bystander Effects Genetic Sensitivity

Adaptive response induced in prostate by very low radiation doses Day et al. 2006

Radiation induced changes in gene expression: adaptive and non-adaptive cells At 50 mGy Radiation Exposure 12,000 Genes Non-adaptive Cells All Cells Adaptive Cells 57 47 45 Coleman et al 2005

50mGy NA A A Group 1 Genes up-regulated by radiation in all cells Group 2 Genes down-regulated by radiation in all cells Group 3 Genes up-regulated by radiation in adaptive cells, but down regulated in non-adaptive Group 4 Genes down -regulated by radiation in adaptive cells, but up-regulated in non-adaptive Adaptive vs non-adaptive radiosensitive genes

Gene Response Adaptive Non-Adaptive vs DNA Repair Stress Response Apoptosis Cell Cycle Coleman et al 2005

Low Dose-induced Apoptosis of Transformed Cells Transformed cell - O2: - O2: HO Cl- - O2: - O2: - O2: PO Cl- Cl- PO - O2: -NO -NO TGFβ TGFβ LTGFβ LTGFβ Non-transformed cell Non-transformed bystander cell OH- APOPTOSIS ONOO- Cl- Cl- Georg Bauer

Bystander Effects in vitro

Micronuclei in Non-Exposed Cells Geard

Bystander EffectAll-or-none dose response Fraction of cells damaged One cell targeted per dish Four cells targeted per dish Numbers of particles per targeted cell Belyakov et al. 2001

Calcium fluxes as bystander signals (24 h post-irradiation with 5 alpha particles) 10 % cells Nuclear 100 % cells Cytoplasmic 100% cells 10% cells treated with DMSO Control Shao et al 2006

Genomic instability is modified by adaptive response GFP+/- Colonies Genomic Instabiilty 1 2 3 10 1 2 3 10 Dose (cGy) Huang et al. 2007

Dose-rate modification of radiation responses • Molecular understanding of dose-rate effects • Tissue studies • Whole Animal Studies • What is the appropriate value of DDREF?

γH2AX Ishizaki et al. 2004

Influence of dose-rate on DNA damage de Toledo et al. 2006

Transformation frequency as a function of radiation dose and dose-rate Elmore et al. 2006

It takes a tissue to make a tumor... Normal mammary epithelial cells (milk production) CANCER Normal matrix Artificial substrate Mammary epithelial cells Normal matrix Irradiated matrix CANCER Barcellos-Hoff et al. 2000

2.0 0.5 1. 0 1.5 A-Bomb Experience LNT High Dose High Dose-Rate 5%/Sv increase in Cancer Mortality 35 DDREF DOE Low Dose Radiation Research Program %Cancer Mortality 30 LNT Low Dose Low Dose-Rate 25 23 ? Background Cancer Mortality ? 0.1 Background Radiation in 70 years Dose (Sv)

Radiation-induced Cancer • Public Perception Each and every ionization causes cancer. (LNTH and BEIR VII) • Scientific Data The risk for radiation induced cancer is small. (LNTH and BEIR VII) It takes very large amounts of radiation, delivered to a large population, to produce a detectable increasein cancer frequency.

Killed outright by the bomb or acute radiation effects. Survived for lifespan study More than 100,000 people 86,572 people Effects of Atomic Bomb

5% less cancer than total controls 2.45 Km (5 mSv) 3 Km (2 mSv) 46,249 “Exposed” 5 Km 10,159 “Controls” A-BOMB SURVIVOR STUDIES Pierce and Preston 2000

A-BOMB SURVIVOR STUDIES Preston et al. 2004 3 Km CONTROL AREA 2. Km Excess Excess Solid Tumors Leukemias 1 Km 113 116 99 41 44 2 28.2 27.7 18.9 10.4 4.7 4.0 0.1 64 572 Total Excess Cancers 479 Total 93 Total

Atomic Bomb Survivor Excess Cancer Population of Survivors Studied86,572 40% of these people are still alive 60 years after the bomb Cancer Mortality observed after the Bomb 10,127 Cancers Mortality Expected without Bomb 9,555 Total Cancer Mortality Excess572 Excess Tumor 479 Excess Leukemia 94 + = 572

U.S Dose Rates from Fallout and Natural Background

acute exposure = all at once; chronic = hours, days, years Ionizing Radiation Dose Ranges ( Sievert ) Ionizing Radiation Dose Ranges ( Sievert ) Cancer Radiotherapytotal dose to tumor Cancer Radiotherapytotal dose to tumor Whole body, acute: G-I destruction; lung damage; cognitive dysfunction (death certain in 5 to 12 days)* Whole body, acute: cerebral/ vascular breakdown (death in 0-5 days)* 0 10 20 30 40 50 60 70 80 90 100 Sv 0 10 20 30 40 50 60 70 80 90 100 Sv Total Body Irradiation (TBI) Therapy Total Body Irradiation (TBI) Therapy Life Span Study (A-bomb survivor epidemiology) Whole body, acute: circulating blood cell death; moderate G-I damage (death probable 2-3 wks)* Acute Radiation Syndromes Acute Radiation Syndromes Whole body, acute: marked G-I and bone marrow damage (death probable in 1-2 wks)* Solar flare dose on moon, no shielding *Note: Whole body acute prognoses assume no medical intervention.) 0 1 2 3 4 5 6 7 8 9 10 Sv 0 1 2 3 4 5 6 7 8 9 10 Sv Human LD50range, acute exposurewith medical intervention Human LD50 range, acute exposure with no medical intervention (50% death in 3-6 weeks)* Human LD50 range, acute exposure with no medical intervention (50% death in 3-6 weeks)* Estimated dose for 3-yr Mars mission (current shielding) Evidence for small increases in human cancer above 0.1 Sv acute exposures, 0.2 Sv chronic exposure Cancer Epidemiology Cancer Epidemiology 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Sv 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Sv Typical mission doses on Intl. Space Station (ISS) Medical Diagnostics, mSv A- Chest x-ray (1 film) 0.1 B- Dental oral exam 1.6 C- Mammogram 2.5 D- Lumbosacral spine 3.2 E- PET 3.7 F- Bone (Tc-99m) 4.4 G- Cardiac (Tc-99m) 10 H- Cranial CT (MSAD) 50 (multiple scan average dose) I- Barium contrast G-I 85 fluoroscopy (2 min scan) J- Spiral CT- full body 30-100 Medical Diagnostics, mSv A- Chest x-ray (1 film) 0.1 B- Dental oral exam 1.6 C- Mammogram 2.5 D- Lumbosacral spine 3.2 E- PET 3.7 F- Bone (Tc-99m) 4.4 G- Cardiac (Tc-99m) 10 H- Cranial CT (MSAD) 50 (multiple scan average dose) I- Barium contrast G-I 85 fluoroscopy (2 min scan) J- Spiral CT- full body 30-100 EPA guideline for lifesaving: 0.25 Sv Natural bkg /yr Ramsar, Iran DOE Low Dose Program DOE Low Dose Program EPA radiological emergency guideline for public relocation H H I I J J “Storefront” full-body CT screening (one scan) “Storefront” full-body CT screening (one scan) 0 10 20 30 40 50 60 70 80 90 100 mSv 0 10 20 30 40 50 60 70 80 90 100 mSv DOE, NRC Dose Limit for Workers: 5 rem/yr = 50 mSv/yr Natural bkg /yr Kerala coast, India DOE administrative control: 20 mSv/yr = 2 rem/yr Medical Diagnostics (A-J) Medical Diagnostics (A-J) Typical annual doses for commercial airline flight crews A A B B F F G G C C D D E E 0 1 2 3 4 5 6 7 8 9 10 mSv 0 1 2 3 4 5 6 7 8 9 10 mSv NRC cleanup criteria for site decommissioning / unrestricted use: 0.25 mSv/yr Natural bkg /yr Yangjiang, China Natural background, U.S. average  3 mSv/yr (includes radon) Natural background, U.S. average  3 mSv/yr (includes radon) Regulations & Guidelines Regulations & Guidelines Max releases DOE facilities Round-trip NY to London LD50 = Lethal Dose to 50% (the acute whole body dose that results in lethality to 50% of the exposed individuals) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 mSv 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 mSv EPA dose limit applicable to public drinking water systems: 0.04 mSv/yr ANSI standard N43.17 Personnel scans max dose for total scans in 1 yr: 0.25 mSv DOE, NRC Dose Limit for Public: 1 mSv/yr = 100 mrem/yr (ICRP, NCRP) EPA dose limit from releases in air: 0.10 mSv/yr Absorbed dose: 1 Gray = 100 rad Dose equivalent: 1 Sievert = 100 rem 1 mSv = 100 mrem (1 Sv = 1 Gy for x- and gamma-rays) Note: This chart was constructed with the intention of providing a simple, user-friendly, “order-of-magnitude” reference for radiation quantities of interest to scientists, managers, and the general public. In that spirit, most quantities were expressed in the more commonly used radiation protection unit, the rem (or Sievert, 2nd page), and medical doses are not in “effective” dose. It is acknowledged that the decision to use one set of units does not address everyone’s needs. (NRC—US Nuclear Regulatory Commission; EPA—US Environmental Protection Agency) Disclaimer: Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information disclosed. Chart compiled by NF Metting, Office of Science, DOE/BER “Orders of Magnitude” revised March 2006 Chart compiled by NF Metting, Office of Science, DOE/BER “Orders of Magnitude” revised March 2006 acute exposure = all at once; chronic = hours, days, years Ionizing Radiation Dose Ranges ( Sievert ) Cancer Radiotherapytotal dose to tumor Whole body, acute: G-I destruction; lung damage; cognitive dysfunction (death certain in 5 to 12 days)* Whole body, acute: cerebral/ vascular breakdown (death in 0-5 days)* 0 10 20 30 40 50 60 70 80 90 100 Sv Total Body Irradiation (TBI) Therapy Life Span Study (A-bomb survivor epidemiology) Whole body, acute: circulating blood cell death; moderate G-I damage (death probable 2-3 wks)* Acute Radiation Syndromes Whole body, acute: marked G-I and bone marrow damage (death probable in 1-2 wks)* Solar flare dose on moon, no shielding *Note: Whole body acute prognoses assume no medical intervention.) 0 1 2 3 4 5 6 7 8 9 10 Sv Human LD50range, acute exposurewith medical intervention Human LD50 range, acute exposure with no medical intervention (50% death in 3-6 weeks)* Estimated dose for 3-yr Mars mission (current shielding) Evidence for small increases in human cancer above 0.1 Sv acute exposures, 0.2 Sv chronic exposure Cancer Epidemiology 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Sv Typical mission doses on Intl. Space Station (ISS) Medical Diagnostics, mSv A- Chest x-ray (1 film) 0.1 B- Dental oral exam 1.6 C- Mammogram 2.5 D- Lumbosacral spine 3.2 E- PET 3.7 F- Bone (Tc-99m) 4.4 G- Cardiac (Tc-99m) 10 H- Cranial CT (MSAD) 50 (multiple scan average dose) I- Barium contrast G-I 85 fluoroscopy (2 min scan) J- Spiral CT- full body 30-100 EPA guideline for lifesaving: 0.25 Sv Natural bkg /yr Ramsar, Iran DOE Low Dose Program EPA radiological emergency guideline for public relocation H I J “Storefront” full-body CT screening (one scan) 0 10 20 30 40 50 60 70 80 90 100 mSv DOE, NRC Dose Limit for Workers: 5 rem/yr = 50 mSv/yr Natural bkg /yr Kerala coast, India DOE administrative control: 20 mSv/yr = 2 rem/yr Medical Diagnostics (A-J) Typical annual doses for commercial airline flight crews A B F G C D E 0 1 2 3 4 5 6 7 8 9 10 mSv NRC cleanup criteria for site decommissioning / unrestricted use: 0.25 mSv/yr Natural bkg /yr Yangjiang, China Natural background, U.S. average  3 mSv/yr (includes radon) Regulations & Guidelines Max releases DOE facilities Round-trip NY to London LD50 = Lethal Dose to 50% (the acute whole body dose that results in lethality to 50% of the exposed individuals) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 mSv EPA dose limit applicable to public drinking water systems: 0.04 mSv/yr ANSI standard N43.17 Personnel scans max dose for total scans in 1 yr: 0.25 mSv DOE, NRC Dose Limit for Public: 1 mSv/yr = 100 mrem/yr (ICRP, NCRP) EPA dose limit from releases in air: 0.10 mSv/yr Absorbed dose: 1 Gray = 100 rad Dose equivalent: 1 Sievert = 100 rem 1 mSv = 100 mrem (1 Sv = 1 Gy for x- and gamma-rays) Note: This chart was constructed with the intention of providing a simple, user-friendly, “order-of-magnitude” reference for radiation quantities of interest to scientists, managers, and the general public. In that spirit, most quantities were expressed in the more commonly used radiation protection unit, the rem (or Sievert, 2nd page), and medical doses are not in “effective” dose. It is acknowledged that the decision to use one set of units does not address everyone’s needs. (NRC—US Nuclear Regulatory Commission; EPA—US Environmental Protection Agency) Disclaimer: Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information disclosed. Chart compiled by NF Metting, Office of Science, DOE/BER “Orders of Magnitude” revised March 2006

Medical Radiation Exposures • 200 million medical x-rays/year • X-ray 0.1 mGy • 100 million dental x-rays/year • Dental 0.06 mGy • 10 million doses of radiopharmaceuticals/yr • 67 million CT scans/year • Head scan 4-6 mGy/scan • Body scan 40-100 mGy/scan • Large doses from radiation therapy

LNTH Assumption with Dose Low dose x large number of subjects High dose x small number of subjects Energy to system

Impact on Dose-response • Production of damage • Linear processes • Deposition of energy • DNA damage • Processing of damage • Non-linear processes • Induction of Apoptosis • Gene & Protein expression Physics Biology Balancing Act

Linking Cellular Events to Cancer CANCER RESISTANT SENSITIVE TO CANCER

Energy deposited in the nucleus Ionizations produced DNA broken Mutations Chromosomal Aberrations Cell Death Cell Transformation CANCER Low Dose Radiation Responses(Old Paradigm)

GENETIC SENSITIVITY AdaptiveResponse DNA may be broken, or other molecules may be damaged Genomic Instability Bystander Effects Apoptosis (Selective) Cell Killing Micronuclei Mutations Low Dose Radiation Responses(New Paradigm) Energy deposited in the nucleus OR cytoplasm Ionizations produced Epigenetic factors Apoptotic DNA fragmentation factor Other Proteins PCNA, RPA and APE TISSUE RESPONSE Triggers biological processes CANCER? Oxidative Status Upregulation of antioxidant enzymes Inhibition of superoxide anions SIGNALING Direct Cell-cell Indirect –secretive Signaling molecules ++Ca DNA-PKc’s TGF-B Modifies GENE AND PROTEIN EXPRESSIOn

Accomplishments: DOE Low Dose Radiation Research Program • Effectively integrated advances in biological and physical technology to define low dose radiation effects (0.10 Gy or less) which provides a strong scientific basis for radiation standards. • Characterized unique responses that exist after low dose radiation exposure (bystander effects, adaptive response and genomic instability) that can influence the shape of the dose-response at low doses • Defined the unique signaling molecules induced by low doses of radiation • Integrated studies on low-dose-hypersensitivity, apoptosis, gene expression, protein expression, and molecular pathways to help define the mechanisms of action for low dose responses • Determined that low doses of radiation changes the reactive oxygen status of the cell and influence radiation-induced phenotypic changes • Linked cellular and molecular changes to low dose phenotypic changes and determined how these changes influence cancer risk • Defined the role of complex tissue interaction in modification of cancer response following low dose radiation exposure • Recognized and studied the importance of genetic resistance and sensitivity on low dose radiation response 2. Emphasized research on the cellular and molecular mechanisms of action associated with low and high does of radiation to differentiate between these responses 3. The research has resulted in the need for changes in radiation paradigms and challenged models used to extrapolate the cancer and genetic risk from high to low radiation.

Cell and Molecular Responses to ionizing Radiation in Normal tissues : Impact on Radiation Risk