Geant4 for Microdosimetry DNA Geant4 for Microdosimetry R. Capra, S. Chauvie, Z. Francis, S. Guatelli, S. Incerti, B. Mascialino, Ph. Moretto, G. Montarou, P. Nieminen, Maria Grazia Pia MMD 2005 Wollongong, 5-8 November 2005

Born from the requirements of large scale HEP experiments Object Oriented Toolkit for the simulation of particle interactions with matter 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 also… An experiment of distributed software production and management An experiment of application of rigorous software engineering methodologies and object oriented technology to the particle physics environment R&D phase: RD44, 1994 - 1998 1st release: December 1998 2 new releases/year since then

in a nutshell Domain decomposition hierarchical structure of sub-domains Geant4 architecture Uni-directional flow of dependencies Interface to external products w/o dependencies in a nutshell Rigorous software engineering Iterative-incremental software process Object oriented methods Quality assurance Geometry Powerful and versatile geometry modelling 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 Visualisation, UI/GUI Multiple drivers to external systems

Geant4 Collaboration ~100 members 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.

Dosimetry with Geant4 Wide spectrum of physics coverage, variety of physics models Precise, quantitatively validated physics Accurate description of geometry and materials Multi-disciplinary application environment Radfet #2 Radfet #4 Radfet #1#3 S300/50 G300/50 D300/50 D690/15 DG300/50 G690/15 S690/15 DG690/15 Bulk Diode Space science Radiotherapy 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 Hadrontherapy Courtesy of S. Guatelli et al,. INFN Genova Brachytherapy Radiation Protection Courtesy of J. Perl, SLAC 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 Fe lines GaAs lines Atomic relaxation Fluorescence Auger effect shell effects ions

A medical accelerator for IMRT p-value = 1 depth dose profile Simulation Exp. data lateral dose profile Simulation Exp. data tumour healthy tissue Kolmogorov-Smirnov test Rigorous software engineering is important in the medical physics domain to be maintainable over a large time scale to be extensible, to accommodate new user requirements (thanks to the OO technology) range D p-value -84  -60 mm 0.385 0.23 -59  -48 mm 0.27 0.90 -47  47 mm 0.43 0.19 48  59 mm 0.30 0.82 60  84 mm 0.40 0.10

MicroSelectron-HDR source Endocavitary brachytherapy Interstitial brachytherapy MicroSelectron-HDR source Superficial brachytherapy Bebig Isoseed I-125 source

Dosimetry: protons and ions agreement with data better than 3% Further validation tests in progress 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 0.443831 Inventory of Geant4 hadronic models

Exotic Geant4 applications… FAO/IAEA International Conference on Area-Wide Control of Insect Pests: Integrating the Sterile Insect and Related Nuclear and Other Techniques Vienna, May 9-13, 2005 K. Manai, K. Farah, A.Trabelsi, F. Gharbi and O. Kadri (Tunisia) Dose Distribution and Dose Uniformity in Pupae Treated by the Tunisian Gamma Irradiator Using the GEANT4 Toolkit

Radiation protection for interplanetary manned missions

habitats are equivalent Doubling the shielding thickness decreases the energy deposit by ~10% 10 cm water 5 cm water S. Guatelli et al., Geant4 Simulation for interplanetary manned missions, to be submitted December 2005 2.15 cm Al 10 cm water 5 cm water 4 cm Al rigid/inflatable habitats are equivalent 10 cm water 10 cm polyethylene e.m. physics + Bertini set e.m. physics only shielding materials

Anthropomorphic Phantoms A major concern in radiation protection is the dose accumulated in organs at risk Development of anthropomorphic phantom models for Geant4 evaluate dose deposited in critical organs Original approach analytical and voxel phantoms in the same simulation environment Anthropomorphic Phantoms Analytical phantoms Geant4 CSG, BREPS solids Voxel phantoms Geant4 parameterised volumes GDML for geometry description storage

Radiation exposure of astronauts 5 cm water shielding Skull Upper spine Lower spine Arm bones Leg bones Womb Stomach Upper intestine Lower intestine Liver Pancreas Spleen Kidneys Bladder Breast Overies Uterus Preliminary 10 cm water shielding Skull Upper spine Lower spine Arm bones Leg bones Womb Stomach Upper intestine Lower intestine Liver Pancreas Spleen Kidneys Bladder Breast Overies Uterus Dose calculation in critical organs Effects of external shielding self-body shielding

DNA Object Oriented technology + Geant4 architecture Geometry objects (solids, logical volumes, physical volumes) are handled transparently by Geant4 kernel through abstract interfaces So why not describing DNA? Processes are handled transparently by Geant4 kernel through an abstract interface So what about mutagenesis as a process? Object Oriented technology + Geant4 architecture

Biological models in Geant4 Relevance for space: astronaut and aircrew radiation hazards

Physics From the Minutes of LCB (LHCC Computing Board) meeting on 21 October, 1997: “It was noted that experiments have requirements for independent, alternative physics models. In Geant4 these models, differently from the concept of packages, allow the user to understand how the results are produced, and hence improve the physics validation. Geant4 is developed with a modular architecture and is the ideal framework where existing components are integrated and new models continue to be developed.”

Strategic vision OO technology Toolkit Openness to extension and evolution new implementations can be added w/o changing the existing code Robustness and ease of maintenance protocols and well defined dependencies minimize coupling Strategic vision Toolkit A set of compatible components each component is specialised for a specific functionality each component can be refined independently to a great detail components can be integrated at any degree of complexity it is easy to provide (and use) alternative components the user application can be customised as needed

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 & open source release

Multiple domains in the same software environment Macroscopic level calculation of dose already feasible with Geant4 develop useful associated tools Cellular level cell modelling processes for cell survival, damage etc. DNA level DNA modelling physics processes at the eV scale bio-chemical processes processes for DNA damage, repair etc. Complexity of software, physics and biology addressed with an iterative and incremental software process Parallel development at all the three levels (domain decomposition)

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

Biological processes Known, available Unknown, not available Physical processes Biological processes Known, available Unknown, not available Courtesy A. Brahme (KI) E.g. generation of free radicals in the cell Chemical processes Courtesy A. Brahme (Karolinska Institute)

Theories and models for cell survival Cellular level Theories and models for cell survival TARGET THEORY MODELS Single-hit model Multi-target single-hit model Single-target multi-hit model MOLECULAR THEORY MODELS Theory of radiation action Theory of dual radiation action Repair-Misrepair model Lethal-Potentially lethal model Geant4 approach: variety of models all handled through the same abstract interface in progress Critical evaluation of the models Analysis & Design Implementation Test Requirements Problem domain analysis Experimental validation of Geant4 simulation models

Target theory models Multi-target single-hit model Single-hit model No hits: cell survives One or more hits: cell dies Extension of single-hit model Multi-target single-hit model Single-hit model Cell survival equations based on model-dependent assumptions PSURV(q,b,n,D) = B(b) (e-qD)(n-b) (1- e-qD)b n! 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 Joiner & Johns model S= e-ßD 2 S = e-αR [1 + ( αS / αR -1) e ] D – ß D - D/DC two hits

Molecular models for cell death More sophisticated models Molecular theory of radiation action (linear-quadratic model) Theory of dual radiation action Chadwick and Leenhouts (1981) Kellerer and Rossi (1971) Lethal-potentially lethal model Repair or misrepair of cell survival Tobias et al. (1980) Curtis (1986)

In progress: evaluation of model parameters from clinical data TARGET THEORY SINGLE-HIT MULTI-TARGET MOLECULAR RADIATION ACTION DUAL RADIATION ACTION REPAIR-MISREPAIR LIN REP / QUADMIS LIN REP / MIS LETHAL-POTENTIALLY LETHAL LETHAL-POTENTIALLY LETHAL – LOW DOSE LETHAL-POTENTIALLY LETHAL – HIGH DOSE LETHAL-POTENTIALLY LETHAL – LQ APPROX S= e-D / D0 REVISED MODEL S = 1- (1- e-qD)n S = e-q1D [ 1- (1- e-qn D)n ] S = e –p ( αD + ßD ) 2 In progress: evaluation of model parameters from clinical data S = S0 e - k (ξ D + D ) 2 S = e-αD[1 + (αDT / ε)]ε S = e-αD[1 + (αD / ε)]εΦ S = exp[ - NTOT[1 + ]ε ] ε (1 – e- εBAtr) NPL S = e-ηAC D - ln[ S(t)] = (ηAC + ηAB) D – ε ln[1 + (ηABD/ε)(1 – e-εBA tr)] - ln[ S(t)] = (ηAC + ηAB e-εBAtr ) D + (η2AB/2ε)(1 – e-εBA tr)2 D2]

Low Energy Physics extensions DNA level Low Energy Physics extensions 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 b-release winter 2006 Processes for other material than water to follow interest for radiation effects on components Current status

Development process Complex domain Collaboration with theorists physics software Collaboration with theorists Innovative design introduced in Geant4 Policy-based class design Parameterised classes: policies are cross section models, models for final state calculation etc. Flexibility of modelling + performance optimisation Collaboration with experimentalists for model validation would be helpful Geant4 physics validation at low energies is difficult!

Cross sections Process kinematics Final state generation

Elastic scattering Preliminary Total cross section Brenner Emfietzoglou Phys. Med. Biol. 45 (2000) 3171-3194 Solid line: our model Preliminary Angular distribution 10 eV 100 eV 200 eV 500 eV 1 keV J. Phys. D 33 (2000) 932-944

Excitation Preliminary Testing still in progress p + H20  p + H20* s(m2) E(eV) p + H20  p + H20* Preliminary Rad. Phys. Chem. 59 (2000) 255-275 s(m2) E(eV) e- + H20  e- + H20* Testing still in progress

Excitation Preliminary He + H2O  He + H2O* He+ + H2O  He+ + H2O* Rad. Phys. Chem. 59 (2000) 255-275 s(m2) E(eV) He + H2O  He + H2O* He+ + H2O  He+ + H2O* He++ + H2O  He++ + H2O* s(m2) Preliminary E(eV)

Charge transfer Preliminary p + H20  H + H20+ + E s(m2) Preliminary p + H20  H + H20+ + E H + H20  p + e- + H20 Helium E(eV) Charge transfer by protons/Hydrogen is implemented Charge transfer by Helium is still to be implemented

Ionisation Preliminary H + H20  H + e- + H20+ p + H20  p + e- + H20+ s(m2) Preliminary H + H20  H + e- + H20+ p + H20  p + e- + H20+ ln(E/eV) Proton (< 500 keV) and Hydrogen ionisation implemented Development of remaining ionisation processes still ongoing

Scenario for Mars (and earth…) Geant4 simulation with biological processes at cellular level (cell survival, cell damage…) Geant4 simulation treatment source + geometry from CT image or anthropomorphic phantom Geant4 simulation space environment + spacecraft, shielding etc. anthropomorphic phantom Dose in organs at risk Oncological risk to astronauts/patients Risk of nervous system damage Phase space input to nano-simulation 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