Computer modeling of radiation effects Noriyuki B. Ouchi and Kimiaki SaitoRadiation Effects Analysis Research Group,Nuclear Science and Engineering Directorate,Japan Atomic Energy Agency20th International CODATA Conference 25 October 2006, Beijing

Table of ContentsIntroductionSimulation of DNA strand breaks by ionizing radiationMolecular dynamical study of the DNA lesion repairModeling and simulation of the cellular level tumorigenesisConclusion

1. IntroductionRadiation Effects ?Deterministic effect -- organ/tissue damage (or death)Late time (stochastic) effect-- radiation induced cancer

Low dose radiation riskrisk = probability of cancer incidenceAt low dose region, quantitative risk estimation are not so easily obtained.

Dose-Response DoseCancer incidenceLow doseRisk estimation at low dose radiation needs further study based on the Biological mechanisms.

What is low dose?Experimental viewpoint < 100mSvLimit of the observation of radiation effects.Average annual effective dose of radiation workers = ~15mSvVarious suggestions: 10mSv 100mSvThe definition of low dose is physically and operationally ambiguous,only some effect-based guidelines have been suggested.

Scale of the++RadicalreactionsCarcinogenesisTumorigenesis10-15s10-9s10-6ssec.min.hourdayyearGene-mutationDNAdamageionization cm

mm(10-3)

m(10-6)

nm(10-9)

(10-10)Basis of risk estimationDNA RepairInitial process of theDNA damageDNA lesion repairCellular level simulation

Check point #11

2. Initial process of radiation induced DNA DamageTo clarify the relations between track structure and DNA strand breaks.Radiation to the cell nucleus causes damage to DNAWhat kind of radiation with what type of track generate how much damages ? Question:Biologically important damage

Simulation methodTrack structure calculation Radical productionDNA modelingCalculating DNA and radical reactionsTrack structure: spatial distribution of energy deposition of ionizing radiation

Simulation exampleDNA damage induction simulation (proton + solenoid DNA)

1MeVResult [SSB/DSB ratio] nucleosome modellinear modelLET [Linear Energy Transfer] - energy deposition by the charged particle per unit path length DSB yield increasing with LET up to 100 keV/m

Check point #22

3. Molecular dynamical study of the DNA lesion repair Molecular Dynamics simulationTo clarify a dependency between damaged DNA structural change and capability of the DNA repair.

Simulation example

Shape change of damaged DNA 2.0 nsDamaged DNA: 8oxo-G + AP site Native DNA (no damage)Damaged DNA shows bending movement at leisioned siteDynamic analysis of DNA structure is ongoing.

Check point #33

3. Modeling and simulation of the cellular level tumorigenesis The dynamics of the carcinogenesis is studied by the simulation of the cell group in the cell level.Same configuration with Cell culture systemCan study colony formation or tumorigenesis.Can introduce dynamical based group effectEasily comparable with the experiments.Molecular biologically based model.

43Intracellular dynamicskd1kd2kd3kd4PCPIPpmCell divisionIf a(s) > ac then cell division occurkd : Prob. of cell deathcell state t : normal, initiation, promotion, cancer PI, Ppm, Pc : prob. of cell state change (genetic) 2Cell transformation1

Details of the modelIntracellular state change affects the physical parameters (cell adhesion molecule, cell membrane)

Spatial patterns (cell sorting)Initial500steps3000steps8000steps

Simulation exampleMediumInitiated cell 2Normal cell1Cancer cell 4Progressed cell 3Large mutation rates are used for the time limitation.

Mutation rate vs. Cancer cell productionMutation rate of normal cell

ConclusionOur ongoing study about initial to cellular level biological radiation effects using computer modeling and simulations is showed.LET dependency of the DNA damage complexity is studied.Relationship between structural change of damaged DNA and its repair is studied.Cellular level dynamics of the carcinogenesis is modeled and parameter (mutation rates) dependency is examined.

Thanks!JAEA Dr. Ritsuko Watanabe :Simulation of DNA damage inductionDr. Miroslav Pinak :Simulation of DNA repairDr. Julaj Kotulic Bunta :Simulation of Ku70/80 bindingDr. Mariko Higuchi : Simulation of multiple lesioned DNA

NIIDDr. Hideaki Maekawa :DNA damage induction experimentDr. Hirofumi Fujimoto :DNA repair simulation

NIRSDr. Manabu Koike :DNA repair experiment

JAEAJ-PARC

DividerX

We know that the radiation effects have two identified categories. One is a deterministic effect, organ/tissue damage, or death. Another occur at late time after exposure, that is known as radiation induced cancer.

SSB/DSB ratio by direct effect Indicator of complexity of DNA damage DSB yield increases for increasing LET up to 100 keV/m

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