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Health Effects of Alpha Emitters (Mechanistic Basis) Antone L. Brooks Washington State University Tri-Cities Health Physics Society Spokane WA July 10-14, 2005 Past Assumptions About Exposure to Alpha Emitters Hit cell has large radiation dose and effect

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Health effects of alpha emitters mechanistic basis l.jpg

Health Effects of Alpha Emitters (Mechanistic Basis)

Antone L. BrooksWashington State University Tri-Cities

Health Physics SocietySpokane WA July 10-14, 2005


Past assumptions about exposure to alpha emitters l.jpg
Past Assumptions About Exposure to Alpha Emitters

  • Hit cell has large radiation dose and effect

  • Hit cells killed mutated and transformed as a function of hit number

  • No dose-rate effect for exposure to alpha emitters.

  • Linear-no-threshold dose-response for many biological endpoints including cancer.


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Health Effects from Alpha Emitting Radioactive Material

  • Radium dial painters

  • Thorotrast patients

  • Uranium miners

  • Workers in the production of Nuclear Weapons


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70

60

50

Percent tumor cumulative incidence

40

30

20

10

10

100

1000

10000

100000

Dose Response For human cancer

Bone sarcoma in Radium dial painters

Evans 1981



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Relative Risks calculated from:

Indoor studies (case control)

Miner studies (cohort)

5

1

0.3

0 100 200 300 400

Radon-induced lung cancer

Relative Risk

Relative Risk=1

Radon Concentration (Bq/m3)

BEIR VI


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Distribution of Attributable Risk(BEIR VI Model)

Exposure (Bq/m3) % Homes AR

0-150 94.3 70%

150-600+ 5.7 30%


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How do Animal studies Help?

  • Little information available on many of the alpha emitting isotopes (239Pu, 241Am, 238Pu)

  • Lifespan dose-response studies help link to human data

  • Address specific problems like influence of dose distribution, age or dose patterns.

  • Ya, but what if? “Hot Particle Hypothesis”.


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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

  • Hypothesis suggests that risk from inhaled plutonium particles too low by a factor of 100,000-200,000.

  • Studies demonstrated that this was false.



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The Influence of 239PuO2 Particle Size on the Dose-Distribution in the Liver of Chinese Hamsters

Citrate

0.44µm

0.84µm

0.17µm


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

Aberrations/Cell

Brooks et al


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Influence of dose distribution on risk

  • There is no evidence that organs outside of the target organ are at increased risk from the internal emitter.

  • For tissue, the more uniform the distribution of dose, the higher the risk.

  • For cells, the more cells that are hit, the higher the risk.

  • Concentrated “hot spots” produce less risk of cancer than uniform dose-distribution.


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Biological parameters that influence responses from Alpha emitters

  • Biological endpoint

  • Species

  • Genetic background and repair capability

  • Tissue and organ type


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Radon- induced lung cancer in rats emitters

Nasal +

Trachea 0

Deep lung fibroblasts +

Deep lung epithelial cells ++++


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32.8 emitters+ 2.4 Tracheal epithelial cells

?

76.2 + 7.9 Deep lung fibroblasts

92.2 + 9.2 Deep lung epithelial cells

34.5 + 4.3 Nasal epithelium

Radon in RatsInduction of micronuclei(micronuclei/1000 cells/Gy


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Relationships between insults using Cellular Biodosimetry emitters

Alpha Hits/ dose (mGy)

Alpha Hits/exposure (WL)

Dose (mGy)/exposure (WL)


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Key Research Areas emitters

  • Technological Advances

  • Biological Advances


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Key Research Areas emitters

Technological Advances


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Viewing Light emitters

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



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Selection of Target emitters

  • Cell

  • Nucleus

  • Cytoplasm


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Control Distribution of Energy emitters

  • Distribution of energy

  • Distribution of damage


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Key Research Areas emitters

Biological Advances


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Cellular Changes emitters

  • 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


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Relationship between biological responses to radiation emitters

AdaptiveResponse

Genomic Instability

Bystander Effects


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Bystander Effects emittersin vitro


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Microbeam emitters

10 % of cells hit with 1 alpha particles

Each cell hit by one particle

Sawant et al. 2000


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Cell Transformation emitters

Sawant et al.2000


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Relationship between biological responses to radiation emitters

AdaptiveResponse

Genomic Instability

Bystander Effects


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Adaptive Response and alpha particles emitters.

  • Low-LET radiation produces marked adaptive responses at low total doses.

  • Low-LET radiation results in a decrease in risk at low doses relative to that predicted by the LNTH.

  • Low doses of low-LET produce an adaptive response seen in bystander cells following high-LET radiation.

  • There is little evidence for alteration of dose-response by adaptive mechanisms following high-LET radiation.


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Relationship between biological responses to radiation emitters

AdaptiveResponse

Genomic Instability

Bystander Effects


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Radiation-induced Genetic Damage emitters

Old Paradigm

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

Mutation is a rare event


Genomic instability l.jpg

Micronuclei emitters

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.


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Radiation-induced Genomic Instability emitters

  • 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


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Summary emitters

  • Internally deposited alpha emitting radioactive materials are more effective in producing cellular changes and cancer than low-LET radiation.

  • There are many alpha induced non-linear dose-response relationships for cellular changes and cancer.

  • Extensive evidence exists for changes in biological mechanisms as a function of dose.

  • These mechanisms support non-linear dose-response functions.


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Adaptive Response emitters

High-LET exposure

Bystander

Acute Low-LET exposure

Direct Effects

Bystander and direct effects

Biological paradigm for dose-response relationships

Chromosome Aberrations

Background

0 20 40 60 80

Dose (cGy)


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