Riccardo CapraRiccardo Capra11, , Stéphane ChauvieStéphane Chauvie22 , ,

Ziad FrancisZiad Francis33, Sebastien Incerti, Sebastien Incerti44, Barbara , Barbara MascialinoMascialino11, Gerard Montarou, Gerard Montarou33, Philippe Moretto, Philippe Moretto44, ,

Petteri NieminenPetteri Nieminen55, Maria Grazia Pia, Maria Grazia Pia11

TheThe Collaboration Collaboration 1 INFN Sezione di Genova (Italy)

2 Azienda Ospedaliera Santa Croce e Carle Cuneo; INFN Sezione di Torino (Italy)3 Université Blaise Pascal, Laboratoire de Physique Corpusculaire; IN2P3 (France)

4 Centre d’Etudes Nucléaires de Bordeaux-Gradignan and Université Bordeaux; IN2P3 (France)5 European Space Agency (The Netherlands)

Radiobiological models implementationRadiobiological models implementation

in in ToolkitToolkit

14th Symposium on Microdosimetry14th Symposium on Microdosimetry

November 13-18, 2005 – Venezia, Italy November 13-18, 2005 – Venezia, Italy

AbstractAbstract

A project is in progress to extend the Geant4 simulation toolkit to model the effects of radiation with biological systems, both at cellular and DNA level. For the first time a general-purpose Monte Carlo system is equipped with functionality specific to radiobiological simulations.The object oriented technology adopted by Geant4 allows providing an ample set of models to simulate the response of a cell line to irradiation, leaving the option to users to choose among them the most appropriate ones for their simulation study. The project follows an iterative and incremental software process; the first component implemented describes a primary biological endpoint: the fractional survival of a population of cells irradiated with photons or charged particles. It provides the user the option to choose among a wide set of cell survival models, such as models based on the target theory of cell killing, the repair-misrepair model, the lethal-potentially lethal model, and the Scholz and Kraft model. The flexible design adopted makes it open to further extension to implement other cell survival models.We present the architecture of the new Geant4 component for radiobiological modeling, the detailed design of the cell survival models implemented and preliminary results of application in some specific cell lines. The simulation tool developed for the study of radiation interaction with biological matter would have a wide domain of application in several fields: from oncological radiotherapy to the radiation protection of astronauts.

is a simulation toolkit for the simulation of the passage of particles through matter.

A project is in progress to extend the simulation toolkit to model the effects of radiation with biological systems, both at cellular and DNA level. For the first time a general-purpose Monte Carlo system is equipped with functionality specific to radiobiological simulations.

object-oriented design and component architecture allows the extension of the toolkit functionality without affecting its kernel.

Biological models in Geant4 Biological models in Geant4

Relevance for space: Relevance for space: astronaut and aircrew radiation hazardsastronaut and aircrew radiation hazards

PhysicalPhysicalprocessesprocesses

BiologicalBiologicalprocessesprocesses

ChemicalChemicalprocessesprocesses

Process Process requirementsrequirements

Cou

rtes

y N

atur

e

Known, available

Unknown, not available

E.g. generation E.g. generation of free radof free rad

icals icals in the cellin the cell

User requirements on User requirements on geometry and geometry and visualisationvisualisation

Collection of User RequirementsCollection of User Requirements

Software process guidelinesSoftware process guidelines

Unified ProcessUnified Process, specifically tailoredtailored to the project– practical guidance and tools from the RUPRUP– both rigorous and lightweight– mapping onto ISO 15504

Incremental and iterative life-cycle mandatory in such a complex, evolving research field

Realistic, concrete objectives– code release with usable functionality

SPIRAL APPROACH

First componentfractional survival of

a population of cells irradiated with

photons or charged particles

Cou

rtes

y A

. Bra

hme

(KI)

Courtesy A. Brahme (Karolinska Institute)

Biological processesBiological processes

Complexity

Multiple disciplines involved– physics– chemistry– biology

Still object of active research– not fully known– no general models, only

partial/empirical ones

UncertaintiesUncertainties

Physics

Radiobiology

Extrapolations to human beings

Particles / Fluence rates LOWLOW

(cells, tissues, animals)

LARGELARGE

LARGELARGE

LARGERLARGER

Shielding MODERATEMODERATE

Acute exposure

Chronic exposure

Space radiation effects

ScopeScopeGoal: provide capabilities to study the biological effects of radiation at multiple levels

Macroscopic – calculation of dose– already feasible with Geant4– develop useful associated tools

Cellular level– cell modelling– processes for cell survival, transformation etc.

DNA level– DNA modelling– physics processes at the eV scale– processes for DNA strand breaks, chromosome aberrations etc.

Complexity of

software, physics and biologysoftware, physics and biology

addressed with an iterative and incremental software process

Parallel development at all the three levels

(domain decomposition)

Different biological endpointsDifferent biological endpoints

Cell survival

Cell transformation

Chromosomeaberrations

Low dose hypersensitivity

Inverse dose rate effect

Dose rate effect

Sublethal damage repair

Cell cycle Temperature

Courtesy BlakelyCourtesy Hall

Fractionation

RequirementsProblem domain analysis

Models for cell survivalModels for cell survival

SURVIVAL MODELSSURVIVAL MODELS Single-hit model Multi-target single-hit model Single-target multi-hit model Theory of radiation action Theory of dual radiation action Repair-Misrepair model Lethal-Potentially lethal model Scholz-Kraft model

Analysis & DesignImplementation

Test

Experimental validation of Geant4 simulation models

Critical evaluation of the models

done

in progress

future

Cellular level Cellular level Cellular level Cellular level

The flexible design adopted makes it open to further extension to implement other cell survival models.

Primary and secondary particles deposit energy

PROBLEM:PROBLEM:Describe the surviving fraction of cells starting from alternative theoretical models

- Repair-misrepair model- Lethal – potentially lethal model- Scholz-Kraft model- Target theory models- Radiation action model- Dual radiation action model

Incident radiation

Cell line

(electromagnetic and hadronic interactions)

Retrieve the dose in the cell

Model the cell in terms of geometry and materials

Cell nucleus

Cell cytoplasm

Describe the surviving fractionOn the basis of

the model selected

Retrieve the biological outcomeof the targeted cells

Low Energy Physics extensionsLow Energy Physics extensions

Current Geant4 low energy electromagnetic processes: down to 250/100 eV (electrons and photons)

– not adequate for application at the DNA level

Specialised processes down to the eV scale– at this scale physics processes depend on material, phase etc.– some models exist in literature (Dingfelder et al., Emfietzoglou et al. etc.)

In progress: Geant4 processes in water at the eV scale

DNA levelDNA levelDNA levelDNA level

Elasticscattering Excitation Electrons

exchangeIonisation processes

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