Models of biological effects of radiation in the Geant4 Toolkit

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Models of biological effects of radiation in the
Geant4 Toolkit

• S. Chauvie, Z. Francis, S. Guatelli, S. Incerti,
  B. Mascialino,
• Ph. Moretto, G. Montarou, P. Nieminen, M.G. Pia

IEEE Nuclear Science Symposium San Diego, 30
October 4 November 2006
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for radiation biology

• Several specialized Monte Carlo codes have been
  developed for radiobiology/microdosimetry
• Typically each one implementing models developed
  by its authors
• Limited application scope
• Not publicly distributed
• Legacy software technology (FORTRAN, procedural
  programming)
• Geant4-DNA
• Full power of a general-purpose Monte Carlo
  system
• Toolkit multiple modeling options, no overhead
  (use what you need)
• Versatility from controlled radiobiology setup
  to real-life ones
• Open source, publicly released
• Modern software technology
• Rigorous software process

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International (open) collaboration ESA INFN
(Genova, Torino) - IN2P3 (CENBG, Univ.
Clermont-Ferrand) -
Sister activity to Geant4 Low-Energy
Electromagnetic Physics Follows the same rigorous
software standards

• Simulation of Interactions of Radiation with
  Biological Systems at the Cellular and DNA level
• Various scientific domains involved
• medical, biology, genetics, physics, software
  engineering
• Multiple approaches can be addressed with Geant4
• RBE parameterisation, detailed biochemical
  processes, etc.

For the first time a general-purpose Monte Carlo
system is equipped with functionality specific to
the simulation of biological effects of radiation
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http//www.ge.infn.it/geant4/dna
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Toolkit
MULTIDISCIPLINARY STUDY
OO technology
Strategic vision

• A set of compatible components
• each component is specialised for a specific
  functionality
• each component can be refined independently to a
  great detail
• components can be integrated at any degree of
  complexity
• it is easy to provide (and use) alternative
  components
• the user application can be customised as needed

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Multiple domains in the same software environment

• Macroscopic level
• calculation of dose
• already feasible with Geant4
• develop useful associated tools
• Cellular level
• cell modelling
• processes for cell survival, damage etc.
• DNA level
• DNA modelling
• physics processes at the eV scale
• bio-chemical processes
• processes for DNA damage, repair etc.

Complexity of SOFTWARE PHYSICS
BIOLOGY addressed with an iterative and
incremental software process
Parallel development at all the three
levels (domain decomposition)
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The biological effects of radiation can be
manifold, from cell killing, to mutation in germ
cells, up to carcinogenesis or leukemogenesis
Cellular level
Before irradiation Normal Cell
SOME OF THE MOST STUDIED CELL LINES HeLa cells,
derived from human cervical cancer V79 cells,
derived from hamster lung CHO cells, derived from
ovary 9L cells, derived from rat gliosarcoma T1
cells, derived from human kidney
Radiation
Damage to chromosome
CELL DEATH
Broken or changed chromosome (mutation)
REPAIR
After irradiation Abnormal Cell
VIABLE CELL (BUT MODIFIED)
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Biological outcome cell survival
DOSE-RESPONSE RELATIONSHIP

• A cell survival curve describes the relationship
  between the radiation dose and the proportion of
  cells that survive.
• What do we mean with cell death?
• loss of the capacity for sustained proliferation
  or loss of reproductive integrity.
• A cell still may be physically present and
  apparently intact, but if it has lost the
  capacity to divide indefinitely and produce a
  large number of progeny, it is by definition
  dead.

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Theories and models for cell survival

• TARGET THEORY MODELS
• Single-Hit model
• Multi-Target Single-Hit model
• Single-Target Multi-Hit model
• MOLECULAR THEORY MODELS
• Theory of Radiation Action
• Theory of Dual Radiation Action
• Repair-Misrepair model
• Lethal-Potentially lethal model

in progress
Analysis Design Implementation Test
Requirements Problem domain analysis
Experimental validation of Geant4 simulation
models
Incremental-iterative software process
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Prototype design
STRATEGY PATTERN Biological
models are encapsulated and made interchangeable.
Concrete radiobiological models derive from the
abstract interface
The flexible design adopted makes the system open
to further extension to other radiobiological
models available in literature.
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SURVIVAL OF A POPULATION OF RADIATED CELLS
LINEAR-QUADRATIC MODEL
DOSE OF RADIATION TO WHICH THE CELLS WERE EXPOSED
Low doses DSBs are generated by the same particle
SINGLE-HIT MULTI-TARGET

• Two component of cell killing by radiation, one
  dependent by the dose and the other one
  proportional to the square of the dose
• - cell survival curve is continuously bending

• - n targets in the cell, all with the same volume
• - one or more of these targets must be
  inactivated
• - each target has the same probability of being
  hit
• one hit is sufficient to inactivate each target
  (but not the cell)

High doses DSBs are generated by different
electrons
Courtesy E. Hall
LETHAL-POTENTIALLY LETHAL
eAB
?AB
?AC

• Based on
• radiation induced lethal and potentially lethal
  lesions
• the capacity of the cell to repair them

eBC
B and C lesions are linearly related to dose
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Cell survival models verification
Monolayer
Data points Geant4 simulation results
V79-379A cells
Proton beam E 3.66 MeV/n
Continuous line LQ theoretical model with
Folkard parameters
LQ model
a 0.32 ß -0.039
Folkard et al, Int. J. Rad. Biol., 1996
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Wide and complex problem domain
Geant4 simulation with biological processes at
cellular level (cell survival, cell damage)
Dose in sensitive volumes
Biological systems responses to irradiation
exposure are of critical concern both to
radiotherapy and to risk assessment
WIDE DOMAIN OF NOVEL APPLICATIONS IN
RADIOBIOLOGY AND OTHER FIELDS
Phase space input to nano-simulation
Geant4 simulation with physics at eV scale
DNA processes
ADVANCED FUNCTIONALITIES OFFEREND BY GEANT4
IN OTHER SIMULATION DOMAINS (GEOMETRY, PHYSICS,
INTERACTIVE TOOLS)
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Conclusions

• The Geant4-DNA project is in progress to extend
  the Geant4 simulation toolkit to model the
  effects of radiation with biological systems at
  cellular and DNA level
• According to the rigorous software process
  adopted, a variety of radiobiological models has
  been designed, implemented and tested in Geant4
• The flexible design adopted makes the system
  open to further extension to other
  radiobiological models available in literature
• For the first time a general-purpose Monte Carlo
  system is equipped with functionality specific to
  the simulation of biological effects of radiation

Rigorous software engineering Advanced object
oriented technology in support of Geant4
modelling versatility