Slide 1

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 2

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 3

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 4

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 5

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 6

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 7

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 8

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 9

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 10

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 11

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 12

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 13

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 14

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 15

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 16

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 17

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 18

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 19

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 20

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 21

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 22

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 23

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 24

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova


Slide 25

Geant4 for Microdosimetry
R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino,
Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia

DNA
MICROS 2005
Venezia, 13-18 November 2005
Maria Grazia Pia, INFN Genova

Object Oriented Toolkit for
the simulation of particle
interactions with matter

also…
An experiment of
distributed software production
and management
An experiment of application of rigorous
software engineering methodologies
and Object Oriented technology
to particle physics environment
Maria Grazia Pia, INFN Genova

Born from the requirements of
large scale HEP experiments

Widely used not only in HEP
• Space science and astrophysics
• Medical physics, medical imaging
• Radiation protection
• Accelerator physics
• Pest control, food irradiation
• Landmining, security
• etc.

• Technology transfer
R&D phase: RD44, 1994 - 1998
1st release: December 1998
2 new releases/year since then

in a nutshell

Geant4 architecture

Rigorous software engineering
Interface to
external
products w/o
dependencies

Domain
decomposition

– spiral software process
– object oriented methods
– quality assurance
– use of standards

Geometry
hierarchical
structure of subdomains

Uni-directional
flow of
dependencies

– multiple solid representations handled through the
same abstract interface (CSG, STEP compliant
solids, BREPs)
– Simple placements, parameterised volumes,
replicas, assembly-volumes etc.
– Boolean operations on solids

Physics independent from tracking
Subject to rigorous, quantitative validation
Electromagnetic physics
– Standard, Low-Energy, Muon, Optical etc.

Hadronic physics
–

Parameterised, data-driven, theory-driven models

Interactive capabilities

Maria Grazia Pia, INFN Genova

– visualisation, UI/GUI
– multiple drivers to external systems w/o
introducing dependencies

~80 members

Geant4 Collaboration

MoU based
Development, Distribution and User Support of Geant4

Major physics laboratories:
CERN, KEK, SLAC, TRIUMF, TJNL
European Space Agency:
ESA
National Institutes:
INFN, IN2P3, PPARC
Universities:

Budker Inst., Frankfurt, Karolinska Inst., Helsinki, Lebedev Inst., LIP, Lund, Northeastern etc.
Maria Grazia Pia, INFN Genova

Dosimetry with Geant4
Wide spectrum of physics coverage, variety of models
Precise, quantitatively validated physics
Accurate description of geometry and materials
Multi-disciplinary
application environment

Space science
Radiotherapy

Maria Grazia Pia, INFN Genova

Effects on components

Dosimetry
in Medical Applications

Courtesy of F. Foppiano et al., IST Genova

Radiotherapy with
external beams, IMRT

Courtesy of P. Cirrone et al., INFN LNS

Radiation
Protection

Maria Grazia Pia, INFN Genova

Courtesy of J. Perl, SLAC

Hadrontherapy

Courtesy of S. Guatelli et al,. INFN Genova

Brachytherapy

Courtesy of L. Beaulieu et al., Laval

Precise dose calculation
Geant4 Low Energy Electromagnetic Physics package
Electrons and photons (250/100 eV < E < 100 GeV)
– Models based on the Livermore libraries (EEDL, EPDL, EADL)
– Penelope models

Hadrons and ions
– Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch
– Nuclear stopping power, Barkas effect, chemical formulae effective charge etc.

Atomic relaxation
– Fluorescence, Auger electron emission, PIXE
Lateral profile
6MV – 10x10 field – 50mm depth

range

D

p-value

-84  -60 mm

0.39

0.23

-59  -48 mm

0.27

0.90

-47  47 mm

0.43

0.19

48  59 mm

0.30

0.82

60 Maria
 84 mm
0.10
Grazia Pia, 0.40
INFN Genova

Percent dose

Kolmogorov-Smirnov Test

Distance (mm)

IMRT Treatment Head

Dosimetry: protons and ions
WHOLE PEAK
(N1=149 N2=66)

Cramer –
von Mises test

Anderson –
Darling test

Test statistics

0.06

0.499375

p-value

0.79

0.747452

Electromagnetic only

0.52

agreement with data
better than 3%

0.443831

Inventory of Geant4 hadronic models

Maria Grazia Pia, INFN Genova

Radiation protection for
interplanetary manned missions

Maria Grazia Pia, INFN Genova

Doubling the shielding
thickness decreases the
energy deposit by ~10%
10 cm water
5 cm water

rigid/inflatable
habitats are equivalent
2.15 cm Al

e.m. physics + Bertini set
5 cm water

10 cm water

Maria Grazia Pia, INFN Genova

4 cm Al

shielding
materials
e.m.
physics
only

10 cm water
10 cm polyethylene

A major concern in radiation protection is the

dose accumulated in organs at risk

Anthropomorphic
Phantoms

Development of anthropomorphic
phantom models for Geant4
– evaluate dose deposited in critical organs

Original approach

– analytical and voxel phantoms in
the same simulation environment

Analytical phantoms
Geant4 CSG, BREPS solids

Voxel phantoms
Geant4 parameterised volumes

GDML
Maria Grazia Pia, INFN Genova

for geometry description storage

Effects of external shielding
Self-body shielding

Maria Grazia Pia, INFN Genova

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Skull
Upper spine
Lower spine
Arm bones
Leg bones
Womb
Stomach
Upper intestine
Lower intestine
Liver
Pancreas
Spleen
Kidneys
Bladder
Breast
Overies
Uterus

Radiation exposure
of astronauts
5 cm water shielding

10 cm water shielding

Dose calculation in critical organs

Geometry objects
(solids, logical volumes, physical volumes)

are handled transparently by
Geant4 kernel through

So why not describing
DNA?

abstract interfaces

Processes are handled
transparently by Geant4 kernel
through an

abstract interface

So what about
mutagenesis as a
process?

DNA

Object Oriented technology
+
Geant4 architecture
Maria Grazia Pia, INFN Genova

Biological models in Geant4

Relevance for space:
astronaut and aircrew radiation hazards

Maria Grazia Pia, INFN Genova

DNA

The concept of “dose” fails at cellular
and DNA scales
It is desirable to gain an understanding
to the processes at all levels
(macroscopic vs. microscopic)

“Sister” activity to Geant4 Low-Energy Electromagnetic Physics
– Follows the same rigorous software standards

International (open) collaboration
– ESA, INFN (Genova, Torino), IN2P3 (CENBG, Univ. Clermont-Ferrand), Univ. of Lund

Simulation of nano-scale effects of radiation at the DNA level
– Various scientific domains involved
 medical, biology, genetics, physics, software engineering

– Multiple approaches can be implemented with Geant4
 RBE parameterisation, detailed biochemical processes, etc.

First phase: 2000-2001
– Collection of user requirements & first prototypes

Second phase: started in 2004
– Software development & public, open source release
Maria Grazia Pia, INFN Genova

Multiple domains in the
same software environment
Macroscopic level
– calculation of dose
– already feasible with Geant4
– develop useful associated tools

Complexity of

software, physics and biology

Cellular level

addressed with an iterative and
incremental software process

– 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.

Maria Grazia Pia, INFN Genova

Parallel development
at all the three levels
(domain decomposition)

http://www.ge.infn.it/geant4/dna

Maria Grazia Pia, INFN Genova

Biological processes

Physical
processes

Biological
processes

Known,
available

Courtesy A. Brahme (KI)

Unknown,
not available

Courtesy A. Brahme
Maria Grazia
Pia, INFN Genova
(Karolinska
Institute)

E.g. generation
Chemical of free rad
icals
processes in the cell

Cellular level

Theories and models for cell survival
TARGET THEORY MODELS
 Single-hit model
 Multi-target single-hit model
 Single-target multi-hit model

Geant4 approach: variety of
models all handled through
the same abstract interface

MOLECULAR THEORY MODELS
 Theory of radiation action
 Theory of dual radiation action
 Repair-Misrepair model
 Lethal-Potentially lethal model

Critical evaluation of the models

Requirements
Problem domain analysis
Maria Grazia Pia, INFN Genova

in progress

Analysis & Design
Implementation
Test
Experimental validation of
Geant4 simulation models

Target theory models
Extension of single-hit model

No hits: cell survives
One or more hits: cell dies

Single-hit
model

Multi-target
single-hit
model

Cell survival equations
based on
model-dependent
assumptions
PSURV(q,b,n,D) = B(b)

(e-qD)(n-b)

(1-

b! (n -b)!

S(ρ,Δ) = PSURV (ρ0, h=0, Δ) = (1- ρ0)Δ = exp[Δ ln (1- ρ0)]

Single-target
multi-hit
model

No assumption on:
• Time
• Enzymatic repair of DNA

2

S= e-ßD

two hits

Maria Grazia Pia, INFN Genova

n!

e-qD)b

S=

Joiner & Johns
model
- D/DC

e-αR [1 + ( αS / αR -1) e

]D–ßD

Molecular models for cell death
More sophisticated models
Molecular theory
of radiation action
(linear-quadratic model)

Chadwick and Leenhouts (1981)

Repair or misrepair
of cell survival

Tobias et al. (1980)
Maria Grazia Pia, INFN Genova

Theory of dual
radiation action

Kellerer and Rossi (1971)

Lethal-potentially
lethal model

Curtis (1986)

TARGET
THEORY

SINGLE-HIT

TARGET
THEORY

MULTI-TARGET
SINGLE-HIT

S= e-D / D0
REVISED MODEL

MOLECULAR RADIATION ACTION
THEORY

S = 1- (1- e-qD)n
S = e –p ( αD + ßD

S = e-q1D [ 1- (1- e-qn D)n ]
2

)

In progress:
evaluation of
model
parameters
from clinical
data

MOLECULAR DUAL RADIATION
ACTION
THEORY

S = S0 e

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / QUADMIS

S = e-αD[1 + (αDT / ε)]ε

MOLECULAR REPAIR-MISREPAIR
THEORY
LIN REP / MIS

S = e-αD[1 + (αD / ε)]εΦ

MOLECULAR LETHAL-POTENTIALLY
LETHAL
THEORY

NPL
S = exp[ - NTOT[1 + ε (1 – e- εBAtr) ]ε ]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LOW DOSE
THEORY

S = e-ηAC D

MOLECULAR LETHAL-POTENTIALLY
LETHAL – HIGH DOSE
THEORY

- ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)]

MOLECULAR LETHAL-POTENTIALLY
LETHAL – LQ APPROX
THEORY

- ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Maria Grazia Pia, INFN Genova

2

- k (ξ D + D )

Low Energy Physics extensions

DNA level

Specialised processes down to the eV scale
– at this scale physics processes depend on material, phase etc.
– In progress: Geant4 processes in water at the eV scale, release winter 2006

Details: see poster presentation
Processes for other material than water to follow
Electrons
Elastic

Brenner (7.5 - 200 eV)
Emfietzoglou (> 200 ev)

Protons (H+) Hydrogen (H) Alpha (He++)
Negligible effect

Negligible effect

He+

He

Negligible effect

Negligible effect

Negligible effect

Miller and Green

Miller and Green

Miller and Green

(1 keV – 15 MeV)

(1 keV – 15 MeV)

(1 keV – 15 MeV)

In progress

In progress

Not pertinent to this
particle

Excitation

Emfietzoglou

Miller and Green

Born (7 ev – 10 keV)

Born (100 eV – 10 MeV)

Charge decrease

Not pertinent to this
particle

Dingfelder
(100 eV – 2 MeV)

Not pertinent to this
particle

Charge increase

Not pertinent to this
particle

Not pertinent to this
particle

Miller and Green
Dingfelder
(0.1 Kev – 100 MeV)

Not pertinent to this
particle

In progress

In progress

Rudd (0.1 – 100 MeV)

In progress

In progress

In progress

Ionization

In progress

Maria Grazia Pia, INFN Genova

Rudd (0.1 - 500 keV)
In progress (> 500 keV)

Negligible effect

Scenario
for Mars (and Earth…)
Geant4 simulation
space
environment
treatment
source
+
spacecraft,from
shielding
etc.
geometry
CT image
+
or
anthropomorphic phantom

Dose in organs
at risk

Geant4 simulation
with biological
processes at cellular
level (cell survival,
cell damage…)

Oncological risk to
astronauts/patients
Risk of nervous
system damage
Phase-space input
to nano-simulation

Maria Grazia Pia, INFN Genova

Geant4 simulation with
physics at eV scale
+
DNA processes

Conclusions
Geant4 offers powerful geometry and physics modelling in an advanced
computing environment
Wide spectrum of complementary and alternative physics models

Multi-disciplinary applications of dosimetry simulation
Precision of physics, validation against experimental data
Geant4-DNA: extensions for microdosimetry
– physics processes at the eV scale
– biological models

Multiple levels addressed in the same simulation environment
– conventional dosimetry
– processes at the cellular level
– processes at DNA level

OO technology in support of physics versatility: openness to extension,
without affecting Geant4 kernel

Maria Grazia Pia, INFN Genova