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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

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
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.
health effects from alpha emitting radioactive material
Health Effects from Alpha Emitting Radioactive Material
  • Radium dial painters
  • Thorotrast patients
  • Uranium miners
  • Workers in the production of Nuclear Weapons
dose response for human cancer

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

radon induced lung cancer

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

distribution of attributable risk beir vi model
Distribution of Attributable Risk(BEIR VI Model)

Exposure (Bq/m3) % Homes AR

0-150 94.3 70%

150-600+ 5.7 30%

how do animal studies help
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”.
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
  • Hypothesis suggests that risk from inhaled plutonium particles too low by a factor of 100,000-200,000.
  • Studies demonstrated that this was false.
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

slide12

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

Aberrations/Cell

Brooks et al

influence of dose distribution on risk
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.
biological parameters that influence responses from alpha emitters
Biological parameters that influence responses from Alpha emitters
  • Biological endpoint
  • Species
  • Genetic background and repair capability
  • Tissue and organ type
radon induced lung cancer in rats
Radon- induced lung cancer in rats

Nasal +

Trachea 0

Deep lung fibroblasts +

Deep lung epithelial cells ++++

radon in rats induction of micronuclei micronuclei 1000 cells gy

32.8 + 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
relationships between insults using cellular biodosimetry
Relationships between insults using Cellular Biodosimetry

Alpha Hits/ dose (mGy)

Alpha Hits/exposure (WL)

Dose (mGy)/exposure (WL)

key research areas
Key Research Areas
  • Technological Advances
  • Biological Advances
key research areas19
Key Research Areas

Technological Advances

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

selection of target
Selection of Target
  • Cell
  • Nucleus
  • Cytoplasm
control distribution of energy
Control Distribution of Energy
  • Distribution of energy
  • Distribution of damage
key research areas24
Key Research Areas

Biological Advances

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
relationship between biological responses to radiation
Relationship between biological responses to radiation

AdaptiveResponse

Genomic Instability

Bystander Effects

microbeam
Microbeam

10 % of cells hit with 1 alpha particles

Each cell hit by one particle

Sawant et al. 2000

cell transformation
Cell Transformation

Sawant et al.2000

relationship between biological responses to radiation30
Relationship between biological responses to radiation

AdaptiveResponse

Genomic Instability

Bystander Effects

adaptive response and alpha particles
Adaptive Response and alpha particles.
  • 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.
relationship between biological responses to radiation32
Relationship between biological responses to radiation

AdaptiveResponse

Genomic Instability

Bystander Effects

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.

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
summary
Summary
  • 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.
biological paradigm for dose response relationships

Adaptive Response

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)