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Cell and Molecular Effects of Low Doses of Radiation Antone L. Brooks Washington State University Tri-Cities Richland WA, 99352 Health Physics Meeting Portland, Oregon July 8-12, 2007 Overview of Presentation Frame the problem Low Dose Radiation Research at the Cell and molecular level

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cell and molecular effects of low doses of radiation
Cell and Molecular Effects of Low Doses of Radiation

Antone L. Brooks

Washington State University Tri-Cities

Richland WA, 99352

Health Physics Meeting Portland, Oregon

July 8-12, 2007

overview of presentation
Overview of Presentation
  • Frame the problem
  • Low Dose Radiation Research at the Cell and molecular level
  • Low Dose-Rate Radiation Effects (DDREF)
  • Data for Standard Setting
  • Communicating Radiation Risks
lnth assumption with dose
LNTH Assumption with Dose

Low dose x large number of subjects

High dose x small number of subjects

Energy to system

radiation dose response models

LNTH

Linear

Hypersensitive response

Threshold

Adaptive response

Radiation Dose-Response Models

Data and radiation-induced cancer

No data

Cancer Frequency

Background Cancer Rate

Dose

a bomb experience

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)

dose response curve following low dose exposures
Dose-Response Curve Following Low Dose Exposures
  • DDREF non-linear extrapolation from high dose region
  • BEIR VII Linear after the DDREF
  • Model one-hit, one DNA Damage, one mutation, one cancer
  • New Data suggest that it is non-Linear at low doses after applying DDREF
doe low dose radiation research program
DOE Low-Dose Radiation Research Program
  • A 10 year program
  • Focused on biological mechanisms of low-dose (< 0.1 Gy) and low dose-rate (< 0.1 Gy / Yr) radiation
  • International in scope (currently about 80projects)
  • To develop a scientific basis for radiation standards

http://www.lowdose.energy.gov

why now
Why now?
  • Standards 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 for mechanistic studies of low dose effects
key research areas
Key Research Areas
  • Technological Advances
  • Biological Advances
focused x ray microbeam

CCD camera

Lamp

Epi-fluorescent

microscope

Micropositioning

stage

Optical shutter

Zone-plate

assembly

X-ray mirror

Carbon target

Electron gun

Focused X-ray Microbeam

Spatial Resolution of the

Microfocus

Source

Cell

OSA

9mm

Apodized

Spot

Zone-plate

200µm

Michael et al.

Gray Laboratory

alpha particle radiation system

Viewing Light

Scintillation Detector

Scintillation Plastic

Piezoelectric Shutter

Manually Adjustable Collimeter

Faraday Cup

Beam Control Slits

Beam from Accelerator

Vertical Bending Magnet

Alpha-Particle Radiation System

Video Camera

Microscope Objective Lens

Newport Positioning Stage

Mylar Bottom Petri Dish

Texas A&M

slide13

Microbeams- Recent findings

Localized DNA damage observed after both focussed soft X-ray production and charged particle induction using gH2AX

Single

3 MeV

Helium ion

Focused CK

X-rays

5 mm

cellular changes
Cellular Changes
  • Adaptive Response
    • Small dose alters response to large dose
    • Small dose decreases spontaneous damage
  • Bystander Effects
    • Cells respond without energy deposition
    • Cell-cell communication
    • Materials into the media
  • Genomic Instability
    • Loss of genetic control many cell generations after the radiation exposure
biological responses induced by low doses of radiation
Biological Responses Induced by Low Doses of Radiation

AdaptiveResponse

Genomic Instability

Bystander Effects

Genetic Sensitivity

dna damage and signaling
DNA Damage and Signaling
  • Alterations in gene expression
  • Changing redox status of the cells
  • Modifying signaling pathways
  • Modification of cell cycle
  • Induction of apoptosis
  • Alterations in differentiation
role of dna damage and epigenetics in bystander effects
Role of DNA Damage and Epigenetics in Bystander Effects
  • DNA damage in “hit cells” is not the trigger to induce bystander responses
  • DNA damage and repair is important in the “bystander cells” for the induction of bystander endpoints. (Prise et al. 2006)
  • Epigenetic changes in “bystander tissue”: increase in some types of DNA methyl-transferase and a decrease in other types
  • Methyl-binding proteins known to be involved in transcriptional silencing increased in “bystander tissue”. (Koturbash et al. 2006)
calcium fluxes as bystander signals 24 h post irradiation with 5 alpha particles
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

bystander effects in vivo
Bystander Effects in vivo
  • Bystander effects after single, high-dose, acute radiation exposure.
    • Tissue exposed
    • Non-exposed organs or tissues
  • Bystander effects following internally deposited radioactive materials.
    • Tissues exposed
    • Non-exposed organs or tissues
the influence of communication on radiation induced micronuclei in lung

Shielded Cells

400

No Cells Evaluated

Micronuclei/1000 Cells

800

Lower half of lungs irradiated with 10 Gy

The Influence of Communication on Radiation-induced Micronuclei in Lung

Exposed Cells

Khan et al 1998

clastogenic factors
Clastogenic Factors
  • A-bomb survivors
  • Chernobyl clean-up
  • Radiation therapy
  • Experimental animals
induction of clastogenic factors in experimental animals

Radiation Exposure

Induction of Clastogenic Factors in Experimental Animals

Blood Sample

Blood Sample

Plasma

Blood Lymphocytes

Culture for chromosome analysis

Morgan 2003

bystander effects in vivo following low dose rate exposures
Bystander Effects in vivo Following Low Dose-rate Exposures
  • Exposure to non-uniform radiation fields
  • Exposure to internally deposited radioactive materials that target selected organs
  • Exposure to internally deposited radioactive particles
hot particle hypothesis
Hot Particle Hypothesis
  • Cellular dose and response are linked
  • Non-uniform dose distribution results in increased risks
  • Large doses to a few cells result in large risks
  • Risk from inhaled plutonium particles too low by a factor of 100,000-200,000.
  • Studies undertaken to test this hypothesis
the influence of 239 puo 2 particle size on the dose distribution in the liver of chinese hamsters
The Influence of 239PuO2 Particle Size on the Dose-Distribution in the Liver of Chinese Hamsters

Citrate

0.44µm

0.84µm

0.17µm

slide30

The Influence of 239Pu Dose-Distribution on Chromosome Aberration Frequency

Aberrations/Cell

Brooks et al

low dose rate exposures no bystander effects in unexposed tissues or organs
Low Dose Rate Exposures: No Bystander Effects in Unexposed Tissues or Organs
  • Cancer from internal emitters are at the site of radionuclide deposition
  • Secondary cancers from radio-therapy located at the exposure site
  • At low dose rates there is little evidence for cancer in non-exposed tissues
biological responses induced by low doses of radiation33
Biological Responses Induced by Low Doses of Radiation

AdaptiveResponse

Genomic Instability

Bystander Effects

Genetic Sensitivity

what genes are responsible for the adaptive response
What Genes are Responsible for the Adaptive Response ?

90

80

70

60

Aberrations

50

Observed

40

Expected

30

20

10

0

0

0.5

150

0.5 + 150

Dose cGy

Shadley and Wolff 1987

radiation induced changes in gene expression adaptive and non adaptive cells
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

adaptive vs non adaptive radiosensitive genes

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
Gene Response

Adaptive

Non-Adaptive

vs

DNA Repair

Stress Response

Apoptosis

Cell Cycle

Coleman et al 2005

adaptive response sub linear dose response

Intervention

Adaptive ResponseSub-linear Dose Response

Transformation Frequency

0

10

20

30

40

50

60

70

80

90

100

Dose (cGy)

Redpath et al. 2001

dna damage from low dose exposures reduced by changing oxidative metabolism
DNA damage from low-dose exposures reduced by changing oxidative metabolism

de Toledo et al. 2006

biological responses induced by low doses of radiation42
Biological Responses Induced by Low Doses of Radiation

AdaptiveResponse

Genomic Instability

Bystander Effects

Genetic Sensitivity

radiation induced genetic damage
Radiation-induced Genetic Damage

Old Paradigm

After a cell is mutated by radiation, all of its prodigy are mutated

Mutation is a rare event

genomic instability

Micronuclei

Cell death

Gene mutation

Mitotic failure-aneuploidy

Chromosome aberration

Genomic Instability

New Paradigm

After a cell is exposed to radiation, different things can happen

…sometimes after many cell divisions. This is a frequent event.

genomic instability can be demonstrated in some strains of mice

Sensitive BALB/c mice

Resistant C57BL/6 mice

Genomic Instability can be Demonstrated in Some Strains of Mice

0.35

0.3

0.25

0.2

Aberrations/Cell

0.15

0.1

0.05

0

4

8

12

16

20

24

28

Population Doublings

B. Ponnaiya & R.L. Ullrich, 1998

radiation induced genomic instability
Radiation-induced Genomic Instability
  • High frequency event
    • 3%/Sv low LET
    • 4%/Sv high LET
  • Independent of dose rate at high total dose
  • Related to inflammation and the Redox status of the cell
  • Produced both in vitro and in vivo
genomic instability is modified by adaptive response
Genomic Instability is Modified by Adaptive Response

GFP+/- Colonies

Genomic Instability

1

2

3

10

1

2

3

10

Dose (cGy)

Huang et al. 2007

mechanisms for cancer induction
High Doses

Cancer

Changes in gene expression

Mutations

Chromosome aberrations

Genomic instability

Cell killing

Stimulate cell proliferation

Tissue and matrix disruption

Inflammation

Change in ROS status of cells

Low Doses

Cancer?

Changes in gene expression

Mutations

Chromosome aberrations

Adaptive response

Bystander effects

Differential apoptosis

Mechanisms for Cancer Induction
mechanisms involved in new phenomena
Mechanisms Involved in New Phenomena
  • Altered gene expression
  • Impact of oxidative status of the cell
  • Radiation-induced changes in apoptosis
  • Cell/cell, cell/matrix interactions
  • Nutrition and radioprotectants
slide50

Numbers of Genes

Differentially Regulated

in HLB Cells 4 hr after IR

703 Genes with

Significant

F-ratio

245

Up-regulated at 2Gy

135

Down-regulated at 2Gy

182

Up-regulated at 0.1Gy

Down-regulated at 0.1Gy

187

Yin 2003

DIFFERENCES IN TRANSCRIPTION PROFILES

BETWEEN LOW AND HIGH DOSE IRRADIATION IN

MURINE BRAIN CELLS

0.1 Gy

2Gy

191

299

213

Total gene set contains nearly 10,000 genes

slide51

Cluster 1

Cluster 2

Cluster 3

Cluster 4

Are the mechanisms the same at low vs. high doses?

Three lines of evidence point to a transitionin transcript expression profiles in the range of 10-25 cGy

Cluster analyses

Filter for differential expression (FDR < 0.10)

All gene data

(n = 22283)

Combine into one dataset

N=420 genes

Self Organizing Maps

Near neighbor analyses

Unique genes

(Wyrobek, et al., LLNL)

In collaboration with D. Nelson, K. Krishnan

radiation induced changes in gene expression

Radiation-induced Changes in Gene Expression

Low Dose Genes

High Dose Genes

0 10 100 1000

Dose (cGy)

Wyrobek

radiation related gene induction
Radiation-related Gene Induction

It has been shown that certain genes are

inappropriately induced, or “turned on” or

“turned off” by radiation. The effect of the

gene induction sometimes shows up more

frequently several generations after the

initial radiation exposure. Experiments on

the CDKN1A gene provide a good example.

radiation and the redox status of cells
Radiation and the Redox Status of Cells
  • Radiation produces free radical and reactive oxygen species (ROS)
  • Radiation triggers signals that alter the level of ROS and RNS for long periods of time (frequent event)
  • Redox status regulates cell cycle, differentiation, and apoptosis
  • Physiological factors can be used to modify redox signaling pathways induced by radiation
  • These represent potential methods for intervention to modify radiation-induced damage and risk
dna damage from low dose exposures reduced by changing oxidative metabolism55
DNA Damage from Low-dose Exposures Reduced by Changing Oxidative Metabolism

de Toledo et al. 2006

slide56

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

cell matrix interactions
Cell/Matrix Interactions
  • Cell/Matrix communication and signaling
  • Cell/matrix tension
  • Signaling molecules and pathways
  • Exposed matrix can produce transformation in non-exposed cells
  • Change phenotype with matrix
  • Frequent non-mutagenic event
it takes a tissue to make a tumor
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

dietary intervention supplements reduce oxidative stress levels after radiation
Dietary InterventionSupplements reduce Oxidative Stress Levels after Radiation

Guan, et al 2004

linking cellular events to cancer
Linking Cellular Events to Cancer

CANCER RESISTANT

SENSITIVE TO CANCER

impact of dose rate
Impact of Dose-Rate
  • All levels of biological organization show “repair” after low dose-rate exposure.
  • Slope is reduced following low-dose rate exposure.
  • Essential to have a DDREF that is realistic especially following accidents or terrorist acts since total dose may be high and dose-rate low
slide63
γH2AX

Ishizaki et al. 2004

beagle lifespan inhalation study
Beagle Lifespan Inhalation Study

Low LET Radiation 90Sr, 137Cs, 144Ce, 90Y, 91Y

Days until Death

15 years

10 years

5 years

Cancers in exposed= 60/116 or 52%

Cancer in controls= 38/90 or 42%

Acute Exposure

Lovelace

target cancers

15 years

10 years

5 years

Target Cancer in Controls = 8/90 9%

Target Cancer in Exposed = 5/116 4%

Target Cancers
non uniform exposure cancer frequency
Non-uniform Exposure: Cancer Frequency

(107)

(72)

(38)

(80)

(67)

Number of dogs in group

(137)

impact on dose response
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

low dose radiation responses old paradigm

Energy deposited in the nucleus

Ionizations produced

DNA broken

Mutations

Chromosomal Aberrations

Cell Death

Cell Transformation

CANCER

Low Dose Radiation Responses(Old Paradigm)
low dose radiation responses new 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

slide72

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.

basis for radiation risks
Basis for Radiation Risks
  • Genetic Risks from radiation
  • Cancer Risks from radiation
slide74

Mega Mouse Study

Mega Mouse Study

Mega Mouse Study

AA

aa

Wild type homogenous

Mutant homogenous

AA

AA

aa

aa

Male was irradiated with a very large dose (3 Gy + 3 Gy)

Wild type homogenous

Wild type homogenous

Mutant homogenous

Mutant homogenous

Male was irradiated with a very large dose (3 Gy + 3 Gy)

Male was irradiated with a very large dose (3 Gy + 3 Gy)

Most offspring were without mutations

aa

There were occasional offspring with mutations

Most offspring were without mutations

Most offspring were without mutations

Aa

aa

aa

There were occasional offspring with mutations

There were occasional offspring with mutations

Aa

Aa

Male Mice were irradiated, there were 119,326 offspring and 111 of them had mutations.

Russell

After many thousands of mice were irradiated, there were very few mutations in the offspring.

After many thousands of mice were irradiated, there were very few mutations in the offspring.

Russell

Russell

calculation of radiation induced genetic risk

Calculation of Radiation-Induced Genetic Risk

Risk= 1/DD x P x MC x PRCF

DD = doubling dose

(mouse data)

P = Incidence of the genetic disease

(human data)

MC = Mutation Component of the disease

(combined data)

PRCF = Potential Recoverability Correction Factor

(molecular biology)

what about genetic load
What about Genetic Load?
  • Genetic load is number of bad mutations that we each carry
  • How does radiation influence genetic load?
  • Will the genetic load increase with radiation to the point that we will become unable to reproduce
slide77

Multiple Generation Mouse Study (Genetic Load)

Mega Mouse Study

Mega Mouse Study

AA

AA

aa

aa

Spaulding irradiated male mice, bred to non irradiated female, then took female F1 offspring and bred them to a different irradiated males. Litters were evaluated for signs of genetic damage.

After 20 generations, no change in sex ratio, litter size or other indications of cumulative genetic damage were seen.

Wild type homogenous

Wild type homogenous

Mutant homogenous

Mutant homogenous

Male was irradiated with a very large dose (3 Gy + 3 Gy)

Male was irradiated with a very large dose (3 Gy + 3 Gy)

Most offspring were without mutations

Most offspring were without mutations

20 Generations

aa

aa

There were occasional offspring with mutations

There were occasional offspring with mutations

Aa

Aa

Spaulding

After many thousands of mice were irradiated, there were very few mutations in the offspring.

After many thousands of mice were irradiated, there were very few mutations in the offspring.

Russell

Russell

regulatory summaries
Regulatory Summaries

For the working population , ICRP estimates

probability of radiation-induced hereditary defects 0.6 x10-2 per Sv

Human studies show no significant radiation induced increase in genetic disease….1993 NCRP

problems with low dose epidemiology
Problems with Low Dose Epidemiology
  • Background radiation
  • Background cancer
  • High signal to noise ratio

Radiation is a poor mutagen/carcinogen, but a very good cell killer

slide81

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
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
cancer rate is highly variable
Race

White 136/100,000

Black 294/100,000

Sex

Males 60.6%

Females 39.4%

Geographic Distribution

Areas with top 10 percentile of cancer= 231-892 cancers/100,000 person-years

Areas with lowest 10 percentile of cancer= 93-168 cancers/100/000 person-years

Cancer Rate is Highly Variable
effects of the atomic bomb
Killed outright by the bomb or acute radiation effects.

Survived for lifespan study

More than 100,000 people

86,572 people

Effects of the Atomic Bomb
a bomb survivor studies

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 studies90
A-BOMB SURVIVOR STUDIES

3 Km

Preston et al. 2004

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

slide91

Background Cancer Frequency

Normal

BKG Cancers

Predicted 0.1 Sv Radiation exposure

Beir VII

slide92
A very large number of people would be needed to demonstrate an effect at low doses using cohort methods and life time follow-up…

Brenner et al. 2003

solid cancer risk and radiation exposure

Solid Cancer Risk and Radiation Exposure

A-bomb data

2.0

Excess Risk

Linear fit

Extrapolated Risk

Linear-quadratic

1.5

Cancer Risk

(Background is shown as 1.0)

1.0

Background Cancer risk

0.5

Background dose/yr

0.0

0.0

0.1

0.2

0.3

0.4

0.5

Modified from BEIR VII, McClellan and Brooks

Radiation Dose (Sv)

real risk vs extrapolated risk
Real Risk vs Extrapolated Risk
  • Real Risk (Automobile Accidents)
    • Risk uses measured number of dead bodies or accidents
    • Relate biological change to measurable quantity (miles driven or defined driving conditions
  • Extrapolated Radiation Risk
    • No dead bodies (cannot identify a radiation induced cancer)
    • Difficult to determine or link exposure or dose to deaths
    • Dependent on the model assumptions
    • Requires large indefinable extrapolations
      • Between populations
      • High to low doses
      • High to low dose-rates
slide95

It takes a lot of radiation to produce cancer!!!

How much total radiation?

Yearly background radiation dose

*This is a large lethal amount of radiation given to one person. Cancer can never be detected with this quantity of radiation regardless of population size!!!

**Background low LET dose/person

slide96

It takes a lot of radiation to produce Cancer!!!

Amount per person and the population size is below the level to detect cancer.

Cancer is detectable in this range of population, dose, exposure.

** A-bomb observed response.

*BEIR VII

slide97

Validity Range of Population Dose and Cancer Risk Coefficients in the Determination of Latent Cancer Fatalities

1 mSv/person

Death

10,000 mSv/person

100 mSv/person

10 5

10 4

Cancer Fatality Risk Coefficient Valid

10 3

Cancer Fatality Risk Coefficient Extrapolated

10 2

10 1

Collective Dose (person-sievert)

10 0

10-1

10-2

No Demonstrated Effect

10-3

10-4

Dodd 2006

10-5

1

101

102

103

104

105

106

107

108

Persons

radiation induced cancer
Radiation-induced Cancer
  • Public Perception

Each and every ionization causes cancer.

Most people who are exposed to radiation get cancer.

(LNTH and BEIR VII)

  • Scientific Data

Each and every ionization increases the “risk” for cancer

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 increase in cancer frequency.

radiation is a rather poor mutagen and carcinogen
Radiation is a Rather Poor Mutagen and Carcinogen

It is a very good cell killer

  • Induction of apoptosis
  • Chromosome cell death
  • Necrosis
  • Wide use in radiation therapy
public communication of radiation risk
Public Communication of Radiation Risk
  • How bad is a “dirty bomb” or Improvised Nuclear Device? It is as bad as we perceive it to be.
  • The public will respond to the perception not the scientific data.
  • My message: Radiation is a poor mutagen and carcinogen but is a good cell killer.
  • My Message: It takes a huge amount of radiation delivered to a large population to detect a significant increase in cancer.
  • My Message: If you survive the blast, count your blessings.
potential impact of research on public perception
Potential impact of research on public perception
  • Provide scientific outreach
  • Level of understanding increased
  • Risk and fear put into perspective
  • Scientific basis for standards
slide102

Summary

  • Mechanisms of radiation action change as a function of dose.
  • Mechanistic data support the need for a DDREF
  • Bystander effects, adaptive responses, and genomic instability are interrelated and can be related to mechanisms.
  • Low Dose research suggest the need for paradigm shifts in radiation biology.
  • The risk for radiation induced cancer is low and undetectable at low radiation doses (It takes a lot of radiation to produce an increase in cancer)
  • Linear low dose extrapolation after applying DDREF is not supported by the low dose radiation research