Radiation and Environmental Biophysics

, Volume 49, Issue 2, pp 139–153 | Cite as

Review and meta-analysis of epidemiological associations between low/moderate doses of ionizing radiation and circulatory disease risks, and their possible mechanisms

  • M. P. Little
  • E. J. Tawn
  • I. Tzoulaki
  • R. Wakeford
  • G. Hildebrandt
  • F. Paris
  • S. Tapio
  • P. Elliott


Although the link between high doses of ionizing radiation and damage to the heart and coronary arteries has been well established for some time, the association between lower-dose exposures and late occurring cardiovascular disease has only recently begun to emerge, and is still controversial. In this paper, we extend an earlier systematic review by Little et al. on the epidemiological evidence for associations between low and moderate doses of ionizing radiation exposure and late occurring blood circulatory system disease. Excess relative risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well-known (but unobserved) risk factors, and there is statistically significant (p < 0.00001) heterogeneity between the risks. This heterogeneity is reduced, but remains significant, if adjustments are made for the effects of fractionated delivery or if there is stratification by endpoint (cardiovascular disease vs. stroke, morbidity vs. mortality). One possible biological mechanism is damage to endothelial cells and subsequent induction of an inflammatory response, although it seems unlikely that this would extend to low-dose and low-dose-rate exposure. A recent paper of Little et al. proposed an arguably more plausible mechanism for fractionated low-dose effects, based on monocyte cell killing in the intima. Although the predictions of the model are consistent with the epidemiological data, the experimental predictions made have yet to be tested. Further epidemiological and biological evidence will allow a firmer conclusion to be drawn.


Excess Relative Risk Vascular Smooth Muscle Cell Proliferation Circulatory Disease Life Span Study Thorotrast 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors are grateful for the detailed and helpful comments of the editor and two referees. This work was funded partially by the European Commission under contracts FI6R-CT-2003-508842 (RISC-RAD) and FP6-036465 (NOTE). The Mayak worker analysis by Drs. Azizova and Muirhead was conducted with support from the European Commission’s Euratom Nuclear Fission and Radiation Protection Programme as part of the SOUL project; more details of this analysis can be found in separate papers by the study investigators.


  1. Adams MJ, Hardenbergh PH, Constine LS, Lipshultz SE (2003) Radiation-associated cardiovascular disease. Critical Rev Oncol Hematol 45:55–75CrossRefGoogle Scholar
  2. Ashmore JP, Krewski D, Zielinski JM, Jiang H, Semenciw R, Band PR (1998) First analysis of mortality and occupational radiation exposure based on the National Dose Registry of Canada. Am J Epidemiol 148:564–574Google Scholar
  3. Atkinson WD, Law DV, Bromley KJ, Inskip HM (2004) Mortality of employees of the United Kingdom Atomic Energy Authority, 1946–97. Occup Environ Med 61:577–585CrossRefGoogle Scholar
  4. Azizova TV, Muirhead CR (2009) Epidemiological evidence for circulatory diseases—occupational exposure. EU Scientific Seminar 2008. “Emerging evidence for radiation induced circulatory diseases”. Proceedings of a scientific seminar held in Luxembourg on 25 November 2008. Radiation Protection 158:33–46 (downloadable from
  5. Benditt EP, Benditt JM (1973) Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Natl Acad Sci USA 70:1753–1756CrossRefADSGoogle Scholar
  6. Bobik A, Agrotis A, Kanellakis P, Dilley R, Krushinsky A, Smirnov V, Tararak E, Condron M, Kostolias G (1999) Distinct patterns of transforming growth factor-β isoform and receptor expression in human atherosclerotic lesions. Colocalization implicates TGF-β in fibrofatty lesion development. Circulation 99:2883–2891Google Scholar
  7. Braganza DM, Bennett MR (2001) New insights into atherosclerotic plaque rupture. Postgrad Med J 77:94–98CrossRefGoogle Scholar
  8. Burns DM (2003) Epidemiology of smoking-induced cardiovascular disease. Prog Cardiovasc Disease 46:11–29CrossRefGoogle Scholar
  9. Carr ZA, Land CE, Kleinerman RA, Weinstock RW, Stovall M, Griem ML, Mabuchi K (2005) Coronary heart disease after radiotherapy for peptic ulcer disease. Int J Radiat Oncol Biol Phys 61:842–850Google Scholar
  10. Chung I-M, Schwartz SM, Murry CE (1998) Clonal architecture of normal and atherosclerotic aorta. Implications for atherogenesis and vascular development. Am J Pathol 152:913–923Google Scholar
  11. Clark KJ, Cary NR, Grace AA, Metcalfe JC (2001) Microsatellite mutation of type II transforming growth factor-β receptor is rare in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 21:555–559Google Scholar
  12. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, Godwin J, Gray R, Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y, Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 366:2087–2106Google Scholar
  13. Clarke MC, Littlewood TD, Figg N, Maguire JJ, Davenport AP, Goddard M, Bennett MR (2008) Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration. Circ Res 102:1529–1538CrossRefGoogle Scholar
  14. Danesh J, Whincup P, Lewington S, Walker M, Lennon L, Thomson A, Wong Y-K, Zhou X, Ward M (2002) Chlamydia pneumoniae IgA titres and coronary heart disease. Prospective study and meta-analysis. Eur Heart J 23:371–375CrossRefGoogle Scholar
  15. Darby SC, Doll R, Gill SK, Smith PG (1987) Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis. Br J Cancer 55:179–190Google Scholar
  16. Darby S, McGale P, Taylor CW, Peto R (2005) Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300 000 women in US SEER cancer registries. Lancet Oncol 6:557–565CrossRefGoogle Scholar
  17. Davis FG, Boice JD Jr, Hrubec Z, Monson RR (1989) Cancer mortality in a radiation—exposed cohort of Massachusetts tuberculosis patients. Cancer Res 49:6130–6136Google Scholar
  18. dos Santos Silva I, Malveiro F, Jones ME, Swerdlow AJ (2003) Mortality after radiological investigation with radioactive Thorotrast: a follow-up study of up to fifty years in Portugal. Radiat Res 159:521–534CrossRefGoogle Scholar
  19. Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695CrossRefGoogle Scholar
  20. Howe GR, Zablotska LB, Fix JJ, Egel J, Buchanan J (2004) Analysis of the mortality experience amongst U.S. nuclear power industry workers after chronic low-dose exposure to ionizing radiation. Radiat Res 162:517–526CrossRefGoogle Scholar
  21. Ivanov VK, Maksioutov MA, Chekin SY, Petrov AV, Biryukov AP, Kruglova ZG, Matyash VA, Tsyb AF, Manton KG, Kravchenko JS (2006) The risk of radiation-induced cerebrovascular disease in Chernobyl emergency workers. Health Phys 90:199–207CrossRefGoogle Scholar
  22. Johnson P, Atkinson WD, Nicholls JL (1999) Updated analysis of mortality in workers at UK atomic weapons establishments. In: Proceedings of the SRP Sixth International Symposium: Achievements & challenges: advancing radiation protection into the 21st centuryGoogle Scholar
  23. Kreuzer M, Kreisheimer M, Kandel M, Schnelzer M, Tschense A, Grosche B (2006) Mortality from cardiovascular diseases in the German uranium miners cohort study, 1946–1998. Radiat Environ Biophys 45:159–166CrossRefGoogle Scholar
  24. Kreuzer M, Grosche B, Schnelzer M, Tschense A, Dufey F, Walsh L (2009) Radon and risk of death from cancer and cardiovascular diseases in the German uranium miners cohort study—follow-up 1946–2003. Radiat Environ Biophys: doi: 10.1007/s00411-009-0249-5
  25. Lauk S, Rüth S, Trott K-R (1987) The effects of dose-fractionation on radiation-induced heart disease in rats. Radiother Oncol 8:363–367CrossRefGoogle Scholar
  26. Little MP, Tawn EJ, Tzoulaki I, Wakeford R, Hildebrandt G, Paris F, Tapio S, Elliott P (2008) A systematic review of epidemiological associations between low and moderate doses of ionizing radiation and late cardiovascular effects, and their possible mechanisms. Radiat Res 169:99–109CrossRefGoogle Scholar
  27. Little MP, Tawn EJ, Tzoulaki I, Wakeford R, Hildebrandt G, Tapio S, Elliott P (2009a) Comments. The non-cancer mortality experience of male workers at British Nuclear Fuels plc, 1946–2005 (letter to the editor). Int J Epidemiol 38:1159–1164CrossRefGoogle Scholar
  28. Little MP, Gola A, Tzoulaki I (2009b) A model of cardiovascular disease giving a plausible mechanism for the effect of fractionated low-dose ionizing radiation exposure. PLoS Comput Biol 5(10):e1000539. doi: 10.1371/journal.pcbi.1000539
  29. Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P, Ritchie A, Goddard M, Bennett M (2006) Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis. Effects of telomerase and oxidative stress. Circ Res 99:156–164CrossRefGoogle Scholar
  30. McCaffrey TA, Du BH, Consigli S, Szabo P, Bray PJ, Hartner L, Weksler BB, Sanborn TA, Bergman G, Bush HL (1997) Genomic instability in the type II TGF-β1 receptor gene in atherosclerotic and restenotic vascular cells. J Clin Invest 100:2182–2188CrossRefGoogle Scholar
  31. McCullagh P, Nelder JA (1989) Generalized linear models, 2nd edn. Chapman & Hall, LondonGoogle Scholar
  32. McGale P, Darby SC (2005) Low doses of ionizing radiation and circulatory diseases: a systematic review of the published epidemiological evidence. Radiat Res 163:247–257,711CrossRefGoogle Scholar
  33. McGeoghegan D, Binks K, Gillies M, Jones S, Whaley S (2008) The non-cancer mortality experience of male workers at British Nuclear Fuels plc, 1946–2005. Int J Epidemiol 37:506–518CrossRefGoogle Scholar
  34. Morgan WF (2003) Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects. Radiat Res 159:581–596CrossRefGoogle Scholar
  35. Muirhead CR, O’Hagan JA, Haylock RGE, Phillipson MA, Willcock T, Berridge GLC, Zhang W (2009) Mortality and cancer incidence following occupational radiation exposure: third analysis of the National Registry for Radiation Workers. Br J Cancer 100:206–212CrossRefGoogle Scholar
  36. Pai JK, Pischon T, Ma J, Manson JE, Hankinson SE, Joshipura K, Curhan GC, Rifai N, Cannuscio CC, Rimm EB (2004) Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 351:2599–2610CrossRefGoogle Scholar
  37. Preston DL, Shimizu Y, Pierce DA, Suyama A, Mabuchi K (2003) Studies of mortality of atomic bomb survivors. Report 13: solid cancer and noncancer disease mortality: 1950-1997. Radiat Res 160:381–407CrossRefGoogle Scholar
  38. Richardson RB (2008a) Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries—Part A: Dose from radon and thoron. Int J Radiat Biol 84:838–848CrossRefADSGoogle Scholar
  39. Richardson RB (2008b) Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries—Part B: Modeling oxygen diffusion into vessel walls. Int J Radiat Biol 84:849–857CrossRefADSGoogle Scholar
  40. Richardson RB (2008c) Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries—Part C: Oxygen effect and its implications on high- and low-LET dose. Int J Radiat Biol 84:858–865CrossRefADSGoogle Scholar
  41. Richardson DB, Wing S (1999) Radiation and mortality of workers at Oak Ridge National Laboratory: positive associations for doses received at older ages. Environ Health Perspect 107:649–656CrossRefGoogle Scholar
  42. Ridker PM (1998) Inflammation, infection, and cardiovascular risk. How good is the clinical evidence? Circulation 97:1671–1674Google Scholar
  43. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000a) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101:1767–1772Google Scholar
  44. Ridker PM, Hennekens CH, Buring JE, Rifai N (2000b) C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836–843CrossRefGoogle Scholar
  45. Schultz-Hector S, Trott K-R (2007) Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data? Int J Radiat Oncol Biol Phys 67:10–18Google Scholar
  46. Schultz-Hector S, Sund M, Thames HD (1992) Fractionation response and repair kinetics of radiation-induced heart failure in the rat. Radiother Oncol 23:33–40CrossRefGoogle Scholar
  47. Schwartz SM, Murry CE (1998) Proliferation and the monoclonal origins of atherosclerotic lesions. Annu Rev Med 49:437–460CrossRefGoogle Scholar
  48. Stamler J, Neaton JD, Garside DB, Daviglus ML (2005) Current status: six established major risk factors—and low risk. In: Marmot M, Elliott P (eds) Coronary heart disease epidemiology: from aetiology to public health, 3rd edn. Oxford University Press, Oxford, pp 32–70Google Scholar
  49. Talbott EO, Youk AO, McHugh-Pemu KP, Zborowski JV (2003) Long-term follow-up of the residents of the Three Mile Island accident area: 1979–1998. Environ Health Perspect 111:341–348Google Scholar
  50. Travis LB, Land CE, Andersson M, Nyberg U, Goldman MB, Knudson Gaul L, Berger E, Storm HH, Hall P, Auvinen A, Janower ML, Holm L-E, Monson RR, Schottenfeld D, Boice JD Jr (2001) Mortality after cerebral angiography with or without radioactive Thorotrast: an international cohort of 3,143 two-year survivors. Radiat Res 156:136–150CrossRefGoogle Scholar
  51. Trott K-R, Kamprad F (1999) Radiobiological mechanisms of anti-inflammatory radiotherapy. Radiother Oncol 51:197–203CrossRefGoogle Scholar
  52. Tüchsen F, Hannerz H, Burr H (2006) A 12 year prospective study of circulatory disease among Danish shift workers. Occup Environ Med 63:451–455CrossRefGoogle Scholar
  53. Tzoulaki I, Murray GD, Lee AJ, Rumley A, Lowe GD, Fowkes FG (2005) C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population. Edinburgh Artery Study. Circulation 112:976–983CrossRefGoogle Scholar
  54. United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) (2000) Sources and effects of ionizing radiation. UNSCEAR 2000 report to the general assembly, with scientific annexes. Volume II: Effects. United Nations, New YorkGoogle Scholar
  55. Vasan RS (2006) Biomarkers of cardiovascular disease. Molecular basis and practical considerations. Circulation 113:2335–2362CrossRefGoogle Scholar
  56. Villeneuve PJ, Lane RSD, Morrison HI (2007) Coronary heart disease mortality and radon exposure in the Newfoundland fluorspar miners’ cohort, 1950–2001. Radiat Environ Biophys 46:291–296CrossRefGoogle Scholar
  57. Vrijheid M, Cardis E, Ashmore P, Auvinen A, Bae J-M, Engels H, Gilbert E, Gulis G, Habib RR, Howe G, Kurtinaitis J, Malker H, Muirhead CR, Richardson DB, Rodriguez-Artalejo F, Rogel A, Schubauer-Berigan M, Tardy H, Telle-Lamberton M, Usel M, Veress K (2007) Mortality from diseases other than cancer following low doses of ionizing radiation: results from the 15-Country Study of nuclear industry workers. Int J Epidemiol 36:1126–1135CrossRefGoogle Scholar
  58. Wakeford R, Little MP (2009) Epidemiological evidence for circulatory diseases—non-occupational exposure. EU Scientific Seminar 2008. “Emerging evidence for radiation induced circulatory diseases”. Proceedings of a scientific seminar held in Luxembourg on 25 November 2008. Radiation Protection 158:21–31 (downloadable from
  59. Whincup P, Danesh J, Walker M, Lennon L, Thomson A, Appleby P, Hawkey C, Atherton J (2000) Prospective study of potentially virulent strains of Helicobacter pylori and coronary heart disease in middle-aged men. Circulation 101:1647–1652Google Scholar
  60. Wilson PWF, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB (1998) Prediction of coronary heart disease using risk factor categories. Circulation 97:1837–1847Google Scholar
  61. Wong FL, Yamada M, Sasaki H, Kodama K, Akiba S, Shimaoka K, Hosoda Y (1993) Noncancer disease incidence in the atomic bomb survivors: 1958–1986. Radiat Res 135:418–430CrossRefGoogle Scholar
  62. Yamada M, Wong FL, Fujiwara S, Akahoshi M, Suzuki G (2004) Noncancer disease incidence in atomic bomb survivors, 1958–1998. Radiat Res 161:622–632CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • M. P. Little
    • 1
  • E. J. Tawn
    • 2
  • I. Tzoulaki
    • 1
  • R. Wakeford
    • 3
  • G. Hildebrandt
    • 4
  • F. Paris
    • 5
  • S. Tapio
    • 6
  • P. Elliott
    • 1
  1. 1.Department of Epidemiology and Public HealthImperial College Faculty of MedicineLondonUK
  2. 2.Westlakes Research InstituteUniversity of Central LancashireMoor Row, CumbriaUK
  3. 3.Dalton Nuclear InstituteUniversity of ManchesterManchesterUK
  4. 4.Department of Radiotherapy and Radiation OncologyUniversity of RostockRostockGermany
  5. 5.INSERM U 601, Department of Cancer ResearchUniversity of NantesNantes Cedex 01France
  6. 6.Radiation Proteomics, Institute of Radiation Biology (ISB)Helmholtz Zentrum München, German Research Centre for Environmental HealthOberschleissheimGermany

Personalised recommendations