Risk

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  • Irradiation set up for shielded irradiation. (A) Neonatal Ptch1+/− and Ptch1+/+ mice placed in polystyrene boxes were irradiated with heads and upper body shielded by individual custom-built lead cylinders. (B) Demarcation between exposed and shielded regions at P10 due to hair-growth delay in exposed skin. (C) Characteristics of the lead shields.
  • Radiation damage by expected scatter dose in exposed vs. bystander EGL. (A and B) γ-H2AX positivity in the outer EGL of SH-8.3 Gy mice at 6h postirradiation compared with undetectable staining after exposure to the scatter dose (0.1 Gy). (D and E) Increased apoptosis in EGL of SH-8.3Gy mice at 6 h postirradiation compared with very rare apoptosis after a 0.1 Gy dose. (C and F) Percentage of γ-H2AX-positive and apoptotic cells in cerebellum at 3, 4.5, 6, and 18 h post-8.3-Gy (SH) and 0.1 Gy (WB) irradiation. *, P = 0.0139; **, P = 0.0015; ***, P = 0.0001. (Scale bars, 20 μm.)
  • Risk

    1. 1. 放射線健康リスク - その認知・受容・制御 長崎大学先導生命科学研究支援センター (大学院医歯薬学総合研究科) 放射線生物・防護学分野 松田 尚樹  2009.3.2  岡山大
    2. 2. Two general categories of adverse health effects of radiation from biological aspects of radiation protection <ul><li>Deterministic effects </li></ul><ul><ul><li>killing/malfunction of cells following doses higher than the threshold </li></ul></ul><ul><ul><li>harmful tissue reactions </li></ul></ul><ul><li>Stochastic effects </li></ul><ul><ul><li>mutation of somatic or germ cells </li></ul></ul><ul><ul><li>cancer and heritable effects </li></ul></ul>10 5 0 radiation dose frequency (%) 100 50 0 threshold risk (%) radiation dose
    3. 3. Primary target for radiation DNA 3 billion (3x10 9 ) nucleotides / cell cell 60 trillion (6x10 13 ) / body
    4. 4. Radiation-induced chromosomal aberration
    5. 5. double-strand DNA Radiation single-strand break double-strand break repair enzymes repair unrepaired damage incorrect repair biological effect base damage NHEJ/HR type naturally occurring ( /cell/day ) radiation-induced ( /cell/Gy ) base damage 20,000 300 single-strand break 50,000 1,000 double-strand break 10 300
    6. 6. <ul><li>unable to replicate DNA </li></ul><ul><ul><li>cell growth arrest </li></ul></ul><ul><li>unable to transcript DNA </li></ul><ul><ul><li>no protein synthesis </li></ul></ul><ul><li>induction of apoptosis </li></ul><ul><li>changes to the nucleotide sequence </li></ul><ul><ul><li>incorrect genetic information </li></ul></ul>DNA damage cell death mutation unrepaired repaired incorrectly Cellular outcome of DNA damage
    7. 7. cell death mutation loss of structural and functional integrity of tissue genetic instability ・ cancer ・ heritable effect deterministic effects stochastic effects DNA damage is completely repaired within the repair capacity of cells biological effect occurs at doses higher than the threshold incorrect repair takes place regardless of repair capacity of the cells biological effect occurs even at very low doses
    8. 8. Effective Dose Limit ( Public ) <ul><li>1 m Sv/year </li></ul>ICRP recommendations (Publication 103), pp99 (Table 6), 2007
    9. 9. <ul><li>100 m Sv/ 5 years </li></ul><ul><ul><li>not exceed 50mSv in any single year </li></ul></ul><ul><ul><li>additional restrictions apply to the pregnant women </li></ul></ul>Effective Dose Limit ( Occupational ) ICRP recommendations (Publication 103), pp99 (Table 6), 2007
    10. 10. Detriment-adjusted nominal risk coefficients after exposure to radiation at low dose rate ICRP recommendations (Publication 103), pp53 (Table 1), 2007 Exposed population Cancer Heritable effects Total Whole population 5.5 x 10 -2 /Sv 0.2 x 10 -2 /Sv 5.7 x 10 -2 /Sv Adult workers 4.1 x 10 -2 /Sv 0.1 x 10 -2 /Sv 4.2 x 10 -2 /Sv
    11. 11. リスクの比較 (人口 10 万人あたりの年間死亡者概数) いろいろな事項についての 10 万人あたりの年間死亡数、体質研究会、 http://www.taishitsu.or.jp/risk/risk2006.html リスクのモノサシ、中谷内一也、 NHK ブックス 全死因 848.5 放射線発がん (放射線業務従事者) 4.1 がん 255.1 水難事故 0.70 心疾患 135.4 インフルエンザ 0.55 脳血管疾患 103.9 他殺 0.52 喫煙発がん(現状) 80.0 自然災害 0.10 喫煙発がん ( 1000 円) 30.0 HIV 0.04 自殺 23.9 食中毒 0.004 交通事故 9.1 落雷 0.002 放射線発がん (一般公衆) 5.5 BSE 感染牛による クロイツフェルトヤコブ病 0.0009
    12. 12. Brenner et al., PNAS 100, 13761-137661, 2003 Cancer risks of atomic bomb survivors Estimated excess relative risk (+/- 1SE) of mortality (1950-1997) from solid cancers among groups of survivors who were exposed to low doses (<500mSv) of radiation
    13. 13. a linear non-threshold (LNT) b downwardly curving c upwardly curving d threshold e hormetic Radiation risks down to very low doses All of these possible extrapolations could be consistent with higher-dose epidemiological data Brenner et al., PNAS 100, 13761-137661, 2003
    14. 14. Lobrich and Jeggo, Nature Rev Cancer 7: 861 - 869 , 2007 Encounters with radiation and risk estimation
    15. 15. from Madurai to Nagercoil, Tamilnadu, India
    16. 16. Tirunelveri District, Tamilnadu, India
    17. 17. Chinnavilai in Manavalakurichi Town Panchayath, Kanyakumari District, Tamilnadu, India
    18. 18. Chinnavilai in Manavalakurichi Town Panchayath, Kanyakumari District, Tamilnadu, India
    19. 19. Chinnavilai in Manavalakurichi Town Panchayath, Kanyakumari District, Tamilnadu, India
    20. 20. Chinnavilai in Manavalakurichi Town Panchayath, Kanyakumari District, Tamilnadu, India
    21. 21. St.Joseph’s Primary School, Chinnavilai, Kanyakumari District, Tamilnadu, India
    22. 22. Kudankulam Nuclear Power Project, Tirunelveli district, Tamiunadu, India
    23. 23. World Nuclear Association, February 2009 Nuclear Power Plant in India Reactor State Type Mwe net, each Commercial operation Tarapur 1&2 Maharashtra BWR 150 1969 Kaiga 1&2 Karnataka PHWR 202 1999-2000 Kaiga 3 Karnataka PHWR 202 2007 Kakrapar 1&2 Gujarat PHWR 202 1993-1995 Kalpakkam 1&2 Tamil Nadu PHWR 202 1984-1986 Narora 1&2 Uttar Pradesh PHWR 202 1991-1992 Rawatbhata 1 Rajasthan PHWR 90 1973 Rawatbhata 2 Rajasthan PHWR 187 1981 Rawatbhata 3&4 Rajasthan PHWR 202 1999-2000 Tarapur 3&4 Maharashtra PHWR 490 2005-2006 17 reactors operating 3,779 Kaiga 4 Karnataka PHWR 202 2009 Rawatbhata 5&6 Rajasthan PHWR 202 2009 Kudankulam 1&2 Tamil Nadu PWR (VVER) 950 Sep-Dec 2009 Kalpakkam Tamil Nadu FBR 470 2011 9 reactors under construction 2,976
    24. 24. Annual terrestrial radiation doses in the world http://www.taishitsu.or.jp/genshiryoku/gen-1/1-ko-shizen-2.html Area Mean (mGy/year) Maximum (mGy/year) Ramsar, Iran 10.2 260 Guarapari, Brazil 5.5 35 Kerala, India 3.8 35 Yangiang, China 3.5 5.4 World Average 0.50 Japan 0.43 1.26
    25. 25. Jiang T et al., J Radiat Res 41S: 63 - 68 , 2000 Increase in unstable-type chromosome aberrations in inhabitants of high background radiation areas in China
    26. 26. Relative risk for cancer in high background radiation areas in China during 1979-1995 Tao Z et al., J Radiat Res 41S: 31 - 41 , 2000 Variable Low Medium High Subtotal Follow-up period 1979-86 1.10 (0.86-1.42) 1.02 (0.79-1.32) 0.98 (0.75-1.29) 1.04 (0.85-1.28) 1987-95 1.04 (0.83-1.30) 0.98 (0.78-1.22) 0.86 (0.68-1.10) 0.96 (0.80-1.15) Sex Male 1.02 (0.83-1.26) 1.09 (0.89-1.34) 0.93 (0.74-1.16) 1.02 (0.86-1.20) Female 1.14 (0.87-1.51) 0.82 (0.61-1.11) 0.89 (0.65-1.21) 0.95 (0.76-1.20) Age 0-59 0.99 (0.80-1.24) 0.98 (0.79-1.22) 0.90 (0.71-1.13) 0.96 (0.80-1.15) 60+ 1.18 (0.91-1.53) 1.02 (0.78-1.32) 0.94 (0.71-1.25) 1.05 (0.85-1.29)
    27. 27. Boffetta P et al., Am J Epidemiol 165: 36 - 43 , 2006 Kaplan-Meier curve for total cancer incidence by frequency of chromosomal aberrations in central Europe during 1978-2002
    28. 28. Nagercoil, Tamilnadu, India
    29. 29. Meals with Chapati ( चपाती ) Meals with Chapati ( चपाती ) Vegetable Uthappam ( தோசை , Dosa) Sambar Ghee Idly ( இட்லி )
    30. 30. <ul><li>No direct evidence from in vitro and in vivo study </li></ul><ul><li>The lower limit of cancer risk at doses around 100mSv from epidemiological study </li></ul><ul><li>Increased chromosome aberrations but no elevation of cancer risk in high background radiation areas </li></ul>Uncertainty on health effects at low doses
    31. 31. Chernobyl ●  チェルノブイリ ウクライナ ゴメリ州 ● ベラルーシ共和国 ●  クリンシー(ブリヤンスク州) ロシア連邦 ●  チェルノブイリ ウクライナ ゴメリ州 ● ベラルーシ ●  クリンシー(ブリヤンスク州) ロシア連邦
    32. 32. チェルノブイリ原子力発電所事故 <ul><li>1986 年 4 月 26 日に発生。 </li></ul><ul><li>原子炉内の多量の放射性物質が大気中に放出。 </li></ul><ul><li>現在のウクライナ、ベラルーシ共和国及びロシア連邦に及ぶ地域が汚染。 </li></ul><ul><li>急性放射線障害による死者は 28 名。 </li></ul><ul><li>2004 年までの間に 19 名ががんで死亡。被ばくとの因果関係は不明。 </li></ul><ul><li>周辺地区において小児甲状腺がんが有意に増加。 </li></ul>
    33. 33. 朝日新聞  2006 年 4 月 27 日
    34. 34. チェルノブイリ原子力発電所事故によるがん死のリスク * 生涯: 95 年、初期: 10 年    **Cs-137>37kBq/m 3 Cardis et al. 1996 3,960 4,970 対象 人口 平均被ばく線量 がんの 種類 期間 * 自然発がん死 事故による発がん死 発生数 発生率 発生数 発生率 寄与率 事故処理 作業者 1986-1987 200,000 100mSv 固形がん 生涯 415,000 21 2,000 1 5 白血病 生涯 800 0.4 200 0.1 20 初期 40 0.02 150 0.08 79 避難住民 半径 30km 135,000 10mSv 固形がん  生涯 215,000 16 150 0.1 0.1 白血病 生涯 500 0.3 10 0.01 2 初期 65 0.05 5 0.004 7 高度汚染 地区住民 270,000 50mSv 固形がん 生涯 43,500 16 1,500 0.5 3 白血病 生涯 1,000 0.3 100 0.04 9 初期 130 0.05 60 0.02 32 その他の 汚染地区 ** 住民 6,800,000 7mSv 固形がん 生涯 800,000 16 4,600 0.05 0.6 白血病 生涯 24,000 0.03 370 0.01 1.5 初期 3,300 0.05 190 0.003 5.5
    35. 35. チェルノブイリ原子力発電所事故によるがん発生死 International Agency for Research on Cancer/WHO, 2006 5.6 人 /10 万人 /mSv 対象 人口 平均被ばく線量 事故による発がん死 発生数 寄与率 事故処理作業者 避難住民 高度汚染地区住民 600,000 66mSv 4,000 3.5 事故処理作業者 避難住民 高度汚染地区住民 その他の地区住民 ~ 6,000,000 14mSv 9,000 0.9 ヨーロッパ全土 ~ 570,000,000 0.5mSv 16,000 0.01
    36. 36. 放射線作業者
    37. 37. BMJ 2005;331;77-
    38. 38. 解析対象集団  15 ヶ国  407,391 人 平均個人累積線量  19.4mSv
    39. 40. A cumulative dose of 100mSv would lead to 9.7% increased mortality from cancers excluding leukaemia. The corresponding figure is 19% for mortality from leukaemia excluding CLL. 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation.
    40. 41. 喫煙・アルコール摂取量と累積線量の関係 2000.12  放射線影響協会
    41. 42. Because of the uncertainty on health effects at low doses, the Commission judges that it is not appropriate , for the purposes of public health planning, to calculate the hypothetical number of cases of cancer or heritable disease that might be associated with very small radiation doses received by large numbers of people over very long periods of time . ICRP recommendations (Publication 103), pp51(paragraph 66), 2007
    42. 43. <ul><li>Radiation effect is observed in non-irradiated cells </li></ul><ul><ul><li>Bystander-effect / Non-Targeted effect </li></ul></ul><ul><li>Survived cells mutate after cell divisions </li></ul><ul><ul><li>Genetic instability / Delayed responses </li></ul></ul><ul><li>Unrepairable DNA damage exists by very low doses </li></ul><ul><ul><li>Low-dose hypersensitivity </li></ul></ul>Uncertainty on health effects at low doses mysterious biological responses
    43. 44. The bystander effect of radiation Damage signals may be transmitted from irradiated to non-irradiated cells in a population, leading to the occurrence of biological effects that receive no radiation exposure. irradiated cells non-irradiated cells damage signals biological effect Gap Junctional Intercellular Communication Extracellular Soluble Factors Gene expressions Genetic effects - DNA damage, cell killing, mutation, transformation
    44. 45. The bystander effect of low LET radiation Technical approaches Authors Radiation source Method Mothersill & Seymour 1997- 60 Co γ -irradiation medium transfer Balajee et al. 2004 137 Cs γ -irradiation Prise et al. 2003 278eV C K soft X-ray microbeam Yang et al. 2005 250kVp X-ray co-culture
    45. 46. Localization of phosphorylated ATM in irradiated nucleus unirradiated 0.5 Gy 1.0 Gy Confocal observation by Zeiss LSM 510 META
    46. 47. Phosphorylated ATM in bystander cells before medium transfer 2h after medium transfer from 1Gy-irradiated cells
    47. 48. Focus of phosphorylated ATM and g-H2AX Red : phosphorylated ATM Green : g-H2AX
    48. 49. unirradiated culture Number of gamma-H2a.X foci in inirradiated cells 0 0.1 0.2 0.3 0.4 Induction of DNA damage in unirradiated cells co-culture of unirradiated and irradiated cells
    49. 50. Micronucleus formation mitosis (telophase) binuclear cell micronucleus
    50. 51. 0 50 100 150 200 250 300 350 Induction of micronucleus in unirradiated cells Number of micronucleus in 2000 unirradiated cells unirradiated culture co-culture of unirradiated and irradiated cells co-culture in the presence of an anti-oxidant
    51. 52. 0 5 9 Induction of mutation in unirradiated cells Mutation frequency at HPRT locus (10 -6 ) unirradiated culture co-culture of unirradiated and irradiated cells
    52. 53. Irradiation set up for shielded irradiation Mancuso M. et.al. PNAS 2008;105:12445-12450 © 2008 by The National Academy of Sciences of the USA
    53. 54. Radiation damage by expected scatter dose in exposed vs. bystander EGL Mancuso M. et.al. PNAS 2008;105:12445-12450 © 2008 by The National Academy of Sciences of the USA Radiation damage by expected scatter dose in exposed vs. bystander EGL. (A and B) γ-H2AX positivity in the outer EGL of SH-8.3 Gy mice at 6h postirradiation compared with undetectable staining after exposure to the scatter dose (0.1 Gy). (D and E) Increased apoptosis in EGL of SH-8.3Gy mice at 6 h postirradiation compared with very rare apoptosis after a 0.1 Gy dose. (C and F) Percentage of γ-H2AX-positive and apoptotic cells in cerebellum at 3, 4.5, 6, and 18 h post-8.3-Gy (SH) and 0.1 Gy (WB) irradiation. *, P = 0.0139; **, P = 0.0015; ***, P = 0.0001. (Scale bars, 20 μm.)
    54. 55. The commission recognizes that these biological factors, together with possible tumor-promoting effects of protracted irradiation, and immunological phenomena, may influence radiation cancer risk, but current uncertainties on their mechanisms and tumorigenic consequences of the above processes are too great for the development of practical judgments. ICRP recommendations (Publication 103), pp51(paragraph 67), 2007
    55. 56. Debate on the Topic “Does Scientific Evidence Support a Change from the LNT Model for Low-Dose Radiation Risk Extrapolation?” <ul><li>D. Averbeck (France) </li></ul><ul><ul><li>Living cells and tissues react differently to radiation insults from high to low dose exposures. </li></ul></ul><ul><ul><li>Some protection mechanisms are especially active at low doses, including protection against ROS, signaling activation of DNA repair, and elimination of damaged cells. </li></ul></ul><ul><ul><li>At high doses, DNA repair is fully activated, which can be in part error-prone giving rise to chromosomal damage and mutations. </li></ul></ul><ul><ul><li>Unirradiated preneoplastic cells effectively undergo apoptosis. </li></ul></ul><ul><li>D. J. Brenner (USA) </li></ul><ul><ul><li>There is no direct evidence for different damage response pathways at very low doses. </li></ul></ul><ul><ul><li>Even if there were such evidence from in vitro studies, we would not be able to predict the consequences in terms of low dose cancer risks in humans. </li></ul></ul><ul><ul><li>We don’t know if deviations from the predictions of LNT will be large or small, nor even whether they will increase or decrease the cancer risk. </li></ul></ul><ul><ul><li>It is more than premature to be advocating changes in policy or practice of radiation protection. </li></ul></ul>NCRP 44 th Annual Meeting “Low Dose and Low Dose-Rate Radiation Effects and Models”, 2008
    56. 57. Issues that may prompt the NRC to reexamine radiation protection standards <ul><ul><li>Potential gender and age differences in radiation sensitivity </li></ul></ul><ul><ul><li>Threshold for cataracts formation </li></ul></ul><ul><ul><li>Ability to identify genetic markers in people who may be abnormally sensitive to radiation exposure </li></ul></ul><ul><ul><li>Possible existence of a real or practical threshold in radiation dose response </li></ul></ul>U.S. Nuclear Regulatory Commission Perspective, 2008
    57. 58. Report of High Level and Expert Group on European Low Dose Risk Research, Jan 2009 <ul><li>Shape of dose response </li></ul><ul><li>LNT (linear non-threshold) </li></ul><ul><li>- Dose rate </li></ul><ul><li>Tissue sensitivities </li></ul><ul><li>Tissue weightning factors </li></ul><ul><li>Radiation quality </li></ul><ul><li>Radiation quality factors </li></ul><ul><li>Internal emitters </li></ul><ul><li>Biokinetic models </li></ul><ul><li>Dosimetric models </li></ul><ul><li>Individual sensitivities </li></ul><ul><ul><li>Genetics </li></ul></ul><ul><ul><li>Age </li></ul></ul><ul><ul><li>Gender </li></ul></ul><ul><ul><li>Lifestyle </li></ul></ul><ul><ul><li>Other exposures </li></ul></ul><ul><li>Non-cancer effects </li></ul><ul><ul><li>Circulatory diseases </li></ul></ul><ul><ul><li>Cognitive functions </li></ul></ul><ul><ul><li>Lens opacities </li></ul></ul>Radiation Protection System Dose limits Constraints Optimisation Dose as surrogate for risk Addtivity Cancer and hereditary effects ? ? The main issues where judgements are made in the current system of radiation protection. The four upper boxes denote judgements that fall directly within the main ICRP dosimetric system, while the two lower boxes include issues that are at present included only to a relatively minor degree.
    58. 59. 国際放射線 保健医療研究 原爆医療研究 放射線基礎 生命科学研究 『社会と個人の安全と安心確保のための技術開発と     地球規模の教育研究拠点構築の必要性』 <ul><li>高齢化する原爆被爆者医療 </li></ul><ul><li> (進行がん、多重がん、精神心理影響) </li></ul><ul><li>在外被爆者・海外ヒバクシャ問題 </li></ul> 「被ばく医療学」の確立 1 2 3 Nagasaki University Global COE Program Global Strategic Center for Radiation Health Risk Control
    59. 60. Division of Radiation Biology and Protection Center for Frontier Life Sciences, Nagasaki University Domestic projects Yoshida M, Morita N, Takao H, Miura M, Hayashida R, Kaneko M, Takemoto T, Okimura Y Indian projects Selvasekarapandian S, Brahmanandhan GM, Hakkim FL, Takamura N, Suyama A + terrific students in Kalasalingam, Bharathiar, and Nagasaki University நன்றி nandri

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