Computer modeling of radiation effects

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Darrell Hood
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1 Computer modeling of radiation effects 20th International CODATA Conference 25 October 2006, Beijing Noriyuki B. Ouchi and Kimiaki Saito Radiation Effects Analysis Research Group, Nuclear Science and Engineering Directorate, Japan Atomic Energy Agency

2 Table of Contents 1. Introduction 2. Simulation of DNA strand breaks by ionizing radiation 3. Molecular dynamical study of the DNA lesion repair 4. Modeling and simulation of the cellular level tumorigenesis 5. Conclusion 2

3 1. Introduction Radiation Effects? Deterministic effect -- organ/tissue damage (or death) Late time (stochastic) effect -- radiation induced cancer High Dose effect At low dose region, quantitative risk estimation are not so easily obtained. Low dose radiation risk risk = probability of cancer incidence 3

4 Dose-Response Cancer incidence Low dose Assessment by extrapolation Dose Risk estimation at low dose radiation needs further study based on the Biological mechanisms. 4

5 What is low dose? Experimental viewpoint < 100mSv Limit of the observation of radiation effects. Average annual effective dose of radiation workers = ~15mSv Various suggestions: 10mSv 100mSv The definition of low dose is physically and operationally ambiguous, only some effect-based guidelines have been suggested. 5

6 Scale of the++ cm mm (10-3 ) μm (10-6 ) Initial process of the DNA damage Cellular level simulation Gene-mutation Carcinogenesis Tumorigenesis nm (10-9 ) A (10-10 ) Radical reactions ionization DNA damage DNA Repair Basis of risk estimation DNA lesion repair s 10-9 s 10-6 s sec. min. hour day year 6

7 Check point #1 7

8 2. Initial process of radiation induced DNA Damage Radiation to the cell nucleus causes damage to DNA Biologically important damage Single Strand Break (SSB) Double Strand Break (DSB) Question: What kind of radiation with what type of track generate how much damages? To clarify the relations between track structure and DNA strand breaks. 8

9 Simulation method Track structure Radical production Radical diffusion 1. Track structure calculation 2. Radical production 3. DNA modeling 4. Calculating DNA and radical reactions Target DNA modeling Track structure: spatial distribution of energy deposition of ionizing radiation 9

10 Simulation example DNA damage induction simulation (proton + solenoid DNA) 10

Indicator of complexity of DNA damage 35 Result [SSB/DSB ratio] Ratio (SSB/DSB) 30 25 20 15 10 5 60 Co 10keV photon linear nucleosome proton α 1MeV 135keV 344keV 1MeV 0 10-1 10 0 10 1 10 2

11 Indicator of complexity of DNA damage 35 Result [SSB/DSB ratio] Ratio (SSB/DSB) Co 10keV photon linear nucleosome proton α 1MeV 135keV 344keV 1MeV LET (kev/um) linear model nucleosome model LET [Linear Energy Transfer] - energy deposition by the charged particle per unit path length DSB yield increasing with LET up to 100 kev/µm 11

12 Check point #2 12

13 3. Molecular dynamical study of the DNA Molecular Dynamics simulation lesion repair O F i = V ( r r i i ) = m i 2 ri ( t) 2 t H H ri Position of each atoms (i) mi F i mass Force acting on atom i V ( r i ( i i ) Potential energy of the system r (0), r& (0)) Initial condition (configuration) To clarify a dependency between damaged DNA structural change and capability of the DNA repair. 13

14 Simulation example 14

15 Shape change of damaged DNA Damaged DNA: 8oxo-G + AP site 1.3 ns Native DNA (no damage) 2.0 ns AP site 8-oxoG Clustered damage Damaged DNA shows bending movement at leisioned site Dynamic analysis of DNA structure is ongoing. 15

16 Check point #3 16

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.

17 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 system Can study colony formation or tumorigenesis. Can introduce dynamical based group effect Easily comparable with the experiments. Molecular biologically based model. 17

18 Intracellular dynamics Cell transformation τ1 PI τ2 Ppm τ3 PC τ4 kd1 kd2 kd3 kd4 k d : Prob. of cell death P I, P pm, P c : prob. of cell state change (genetic) cell state τ : normal, initiation, promotion, cancer Cell division If a(s) > a c then cell division occur 18

19 Details of the model Intracellular state change affects the physical parameters (cell adhesion molecule, cell membrane) τ 1 (J1, a1, l1 ) τ 2 (J2, a2, l2 ) τ 3 (J3, a3, l3 ) τ 4 (J4, a4, l4 ) 19

20 Spatial patterns (cell sorting) Initial 500steps 3000steps 8000steps 20

21 Simulation example Medium Normal cell τ 1 Initiated cell τ 2 Progressed cell τ 3 Cancer cell τ 4 Large mutation rates are used for the time limitation. 21

22 Mutation rate vs. Cancer cell production NO cancer Cancer emergence Mutation rate of normal cell 22

23 Conclusion Our 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. 23

24 Thanks! JAEA Dr. Ritsuko Watanabe : Dr. Miroslav Pinak : Dr. Julaj Kotulic Bunta : Dr. Mariko Higuchi : NIID Dr. Hideaki Maekawa : Dr. Hirofumi Fujimoto : NIRS Dr. Manabu Koike : Simulation of DNA damage induction Simulation of DNA repair Simulation of Ku70/80 binding Simulation of multiple lesioned DNA DNA damage induction experiment DNA repair simulation DNA repair experiment 24

25 JAEA J-PARC JAEA 25

26 Divider 26

LET, RBE and Damage to DNA

LET, RBE and Damage to DNA Linear Energy Transfer (LET) When is stopping power not equal to LET? Stopping power (-de/dx) gives the energy lost by a charged particle in a medium. LET gives the energy absorbed