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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.

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Cell and molecular responses to ionizing radiation in normal tissues impact on radiation risk l.jpg
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


Slide2 l.jpg

acute exposure = all at once; chronic = hours, days, years tissues : Impact on Radiation Risk

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 risk3 l.jpg
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 l.jpg
Mechanistic Studies tissues : Impact on Radiation Risk

  • 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 l.jpg
Biological Responses Induced by Low Doses of Radiation tissues : Impact on Radiation Risk

AdaptiveResponse

Genomic Instability

Bystander Effects

Genetic Sensitivity



Radiation induced changes in gene expression adaptive and non adaptive cells l.jpg
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 l.jpg

50mGy non-adaptive cells

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 l.jpg
Gene Response non-adaptive cells

Adaptive

Non-Adaptive

vs

DNA Repair

Stress Response

Apoptosis

Cell Cycle

Coleman et al 2005


Slide10 l.jpg

Low Dose-induced Apoptosis of Transformed Cells non-adaptive 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


Biological responses induced by low doses of radiation11 l.jpg
Biological Responses Induced by Low Doses of Radiation non-adaptive cells

AdaptiveResponse

Genomic Instability

Bystander Effects

Genetic Sensitivity


Bystander effects in vitro l.jpg
Bystander Effects non-adaptive cellsin vitro


Micronuclei in non exposed cells l.jpg
Micronuclei in Non-Exposed Cells non-adaptive cells

Geard


Bystander effect all or none dose response l.jpg
Bystander Effect non-adaptive cellsAll-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 l.jpg
Calcium fluxes as bystander signals non-adaptive cells (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


Biological responses induced by low doses of radiation16 l.jpg
Biological Responses Induced by Low Doses of Radiation non-adaptive cells

AdaptiveResponse

Genomic Instability

Bystander Effects

Genetic Sensitivity


Genomic instability is modified by adaptive response l.jpg
Genomic instability is modified by adaptive response non-adaptive cells

GFP+/- Colonies

Genomic Instabiilty

1

2

3

10

1

2

3

10

Dose (cGy)

Huang et al. 2007


Dose rate modification of radiation responses l.jpg
Dose-rate modification of radiation responses non-adaptive cells

  • Molecular understanding of dose-rate effects

  • Tissue studies

  • Whole Animal Studies

  • What is the appropriate value of DDREF?


Slide19 l.jpg
γ non-adaptive cellsH2AX

Ishizaki et al. 2004


Influence of dose rate on dna damage l.jpg
Influence of dose-rate on DNA damage non-adaptive cells

de Toledo et al. 2006



It takes a tissue to make a tumor l.jpg
It takes a tissue to make a tumor... dose-rate

Normal mammary epithelial cells (milk production)

CANCER

Normal matrix

Artificial substrate

Mammary epithelial cells

Normal matrix

Irradiated matrix

CANCER

Barcellos-Hoff et al. 2000


A bomb experience l.jpg

2.0 dose-rate

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 l.jpg
Radiation-induced Cancer dose-rate

  • 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.


Effects of atomic bomb l.jpg

Killed outright by the bomb or acute radiation effects dose-rate.

Survived for lifespan study

More than 100,000 people

86,572 people

Effects of Atomic Bomb


A bomb survivor studies l.jpg

5% less cancer than total controls dose-rate

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 studies27 l.jpg
A-BOMB SURVIVOR STUDIES dose-rate

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 l.jpg
Atomic Bomb Survivor Excess Cancer dose-rate

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



Slide31 l.jpg

acute exposure = all at once; chronic = hours, days, years dose-rate

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


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Medical Radiation Exposures dose-rate

  • 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


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LNTH Assumption with Dose dose-rate

Low dose x large number of subjects

High dose x small number of subjects

Energy to system


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Impact on Dose-response dose-rate

  • 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


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Linking Cellular Events to Cancer dose-rate

CANCER RESISTANT

SENSITIVE TO CANCER


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Energy deposited in the nucleus dose-rate

Ionizations produced

DNA broken

Mutations

Chromosomal Aberrations

Cell Death

Cell Transformation

CANCER

Low Dose Radiation Responses(Old Paradigm)


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GENETIC SENSITIVITY dose-rate

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


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Accomplishments: dose-rate

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.


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