1. Riccardo Capra 1, Stéphane Chauvie 2, Ziad Francis 3, Sebastien Incerti 4, Barbara Mascialino 1, Gerard Montarou 3, Philippe Moretto 4, Petteri Nieminen 5, Maria Grazia Pia 1 TheCollaboration 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)

2. Radiobiological models implementation inToolkit 14th Symposium on Microdosimetry November 13-18, 2005 – Venezia, Italy

3. Abstract 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.

4. 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.

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

6. Physical processes Biological processes Chemical processes Process requirements Courtesy Nature Known, available Unknown, not available E.g. generation of free rad icals in the cell User requirements on geometry and visualisation Collection of User Requirements

7. Software process guidelines Unified Processtailored Unified Process, specifically tailored to the project RUP –practical guidance and tools from the RUP –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 component fractional survival of a population of cells irradiated with photons or charged particles

8. Courtesy A. Brahme (KI) Courtesy A. Brahme (Karolinska Institute) Biological processes Complexity Multiple disciplines involved –physics –chemistry –biology Still object of active research –not fully known –no general models, only partial/empirical ones

9. Uncertainties Physics Radiobiology Extrapolations to human beings Particles / Fluence rates LOW (cells, tissues, animals) LARGE LARGE LARGER Shielding MODERATE Acute exposure Chronic exposure Space radiation effects

10. Scope Goal: 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 biology addressed with an iterative and incremental software process Parallel development at all the three levels (domain decomposition)

11. Different biological endpoints Cell survival Cell transformation Chromosome aberrations Low dose hypersensitivity Inverse dose rate effect Dose rate effect Sublethal damage repair Cell cycle Temperature Courtesy Blakely Courtesy Hall Fractionation

12. Requirements Problem domain analysis Models for cell survival SURVIVAL 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 & Design Implementation Test Experimental validation of Geant4 simulation models Critical evaluation of the models done in progress future Cellular level The flexible design adopted makes it open to further extension to implement other cell survival models.

13. Primary and secondary particles deposit energyPROBLEM: 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 fraction On the basis of the model selected Retrieve the biological outcome of the targeted cells

14. Low 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 level Elastic scattering Excitation Electrons exchange Ionisation processes

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