Hormesis by Low Dose Radiation Effects: Low-Dose Cancer Risk Modeling Must Recognize Up-Regulation of Protection

  • Ludwig E. Feinendegen
  • Myron Pollycove
  • Ronald D. Neumann
Chapter
Part of the Medical Radiology book series (MEDRAD)

Abstract

Ionizing radiation primarily perturbs the basic molecular level proportional to dose, with potential damage propagation to higher levels: cells, tissues, organs, and whole body. There are three types of defenses against damage propagation. These operate deterministically and below a certain impact threshold there is no propagation. Physical static defenses precede metabolic-dynamic defenses acting immediately: scavenging of toxins;—molecular repair, especially of DNA;—removal of damaged cells either by apoptosis, necrosis, phagocytosis, cell differentiation-senescence, or by immune responses,—followed by replacement of lost elements. Another metabolic-dynamic defense arises delayed by up-regulating immediately operating defense mechanisms. Some of these adaptive protections may last beyond a year and all create temporary protection against renewed potentially toxic impacts also from nonradiogenic endogenous sources. Adaptive protections have a maximum after single tissue absorbed doses around 100–200 mSv and disappear with higher doses. Low dose-rates initiate maximum protection likely at lower cell doses delivered repetitively at certain time intervals. Adaptive protection preventing only about 2–3 % of endogenous lifetime cancer risk would fully balance a calculated-induced cancer risk at about 100 mSv, in agreement with epidemiological data and concordant with an hormetic effect. Low-dose-risk modeling must recognize up-regulation of protection.

Keywords

Low-dose cancer risk Adaptive protections Hormesis 

References

  1. Azzam EI, de Toledo SM, Raaphorst GP, Mitchel REJ (1996) Low-dose ionizing radiation decreases the frequency of neoplastic transformation to a level below the spontaneous rate in C3H 10T1/2 cells. Radiat Res 146:369–373PubMedCrossRefGoogle Scholar
  2. Barcellos-Hoff MH, Brooks AL (2001) Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis; bystander effects, and genomic instability. Radiat Res 156:618–627PubMedCrossRefGoogle Scholar
  3. Bond VP, Fiedner TM, Archambeau JO (1966) Mammalian Radiation Lethality: a Disturbance in Cellular Kinetics. Academic Press, New YorkGoogle Scholar
  4. Bond VP, Benary V, Sondhaus CA, Feinendegen LE (1995) The meaning of linear dose-response relations, made evident by use of absorbed dose to the cell. Health Phys 68:786–792PubMedCrossRefGoogle Scholar
  5. Brenner DJ, Hall EJ (2007) Computed tomography–an increasing source of radiation exposure. N Engl J Med 357:2277–2284PubMedCrossRefGoogle Scholar
  6. Calabrese EJ, Baldwin LA (2003) Toxicology rethinks its central belief. Nature 421:691–692PubMedCrossRefGoogle Scholar
  7. Cardis E et al (2007) The 15-country collaborative study of cancer risk among radiation workers in the nuclear workers in the nuclear industry: estimates of radiation-related cancer risks. Radiat Res 167:396–416PubMedCrossRefGoogle Scholar
  8. Chandra J, Samali A, Orrenius S (2000) Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med 29:323–333PubMedCrossRefGoogle Scholar
  9. Day TK, Zeng G, Hooker AM, Bhat M, Scott BR, Turner DR, Sykes PJ (2006) Extremely low priming doses of X radiation induce an adaptive response for chromosomal inversions in pKZ1 mouse prostate. Radiat Res 166:757–766PubMedCrossRefGoogle Scholar
  10. Dziegielewski J, Baulch JE, Goetz W, Coleman MC, Spitz DR, Murley JS, Grdina DJ, Morgan WF (2008) WR-1065, the active metabolite of amifostine, mitigates radiation-induced delayed genomic instability. Free Radic Biol Med 45:1674–1681PubMedCentralPubMedCrossRefGoogle Scholar
  11. Elmore E, Lao X-Y, Kapadia R, Redpath JL (2009) Threshold-type dose response for induction of neoplastic transformation by 1 GeV/nucleon iron ions. Radiat Res 171:764–770PubMedCrossRefGoogle Scholar
  12. Feinendegen LE (2002) Reactive oxygen species in cell responses to toxic agents. Hum Exp Toxicol 21:85–90PubMedCrossRefGoogle Scholar
  13. Feinendegen LE (2005) Evidence for beneficial low level radiation effects and radiation hormesis. Brit J Radiol 78:3–7PubMedCrossRefGoogle Scholar
  14. Feinendegen LE, Neumann RD (2005) Physics must join with biology in better assessing risk from low-dose irradiation. Rad Prot Dosim 117:346–356CrossRefGoogle Scholar
  15. Feinendegen LE, Muehlensiepen H, Lindberg C, Marx J, Porschen W, Booz J (1984) Acute and temporary inhibition of thymidine kinase in mouse bone marrow cells after low-dose exposure. Intern J Radiat Biol 45:205–215CrossRefGoogle Scholar
  16. Feinendegen LE, Loken MK, Booz J, Muehlensiepen H, Sondhaus CA, Bond VP (1995) Cellular mechanisms of protection and repair induced by radiation exposure and their consequences for cell system responses. Stem Cells 13(1):7–20PubMedGoogle Scholar
  17. Feinendegen LE, Bond VP, Sondhaus CA, Muehlensiepen H (1996) Radiation effects induced by low doses in complex tissue and their relation to cellular adaptive responses. Mutat Res 358:199–205PubMedCrossRefGoogle Scholar
  18. Feinendegen LE, Bond VP, Sondhaus CA, Altman KI (1999) Cellular signal adaptation with damage control at low doses versus the predominance of DNA damage at high doses. C.R Acad Sci Paris, Life Sciences 322:245–251Google Scholar
  19. Feinendegen LE, Neumann RD (eds) (2000) Cellular responses to low doses of ionizing radiation. Workshop of the US department of energy (DOE), Washington, and the national institutes of health (NIH), Bethesda, held on 27–30 April 1999 at the Mary Woodward Lasker Center, Cloister, NIH DOE Report Publication SC-047Google Scholar
  20. Feinendegen LE, Bond VP, and Sondhaus CA (2000) The dual response to low-dose irradiation: induction versus prevention of DNA damage. In: Yamada T, Mothersill C, Michael BD, Potten CS (eds), Biological effects of low dose radiation, Excerpta Medica, International Congress Serie 1211. Elsevier, Amsterdam pp 3–17Google Scholar
  21. Feinendegen LE, Pollycove M, Sondhaus CA (2004) Responses to low doses of ionizing radiation in biological systems. Nonlinearity in Biol Toxicol Med 2:143–171CrossRefGoogle Scholar
  22. Feinendegen LE, Pollycove M, Neumann RD (2007a) Whole body responses to low-level radiation exposure: new concepts in mammalian radiobiology. Exp Hematol 35:37–46PubMedCrossRefGoogle Scholar
  23. Feinendegen LE, Paretzke HG, Neumann RD (2007b) Damage propagation in complex biological systems following exposure to low doses of ionizing radiation. AFP: Int J 1:336–354CrossRefGoogle Scholar
  24. Feinendegen LE, Paretzke HG, Neumann RD (2008) Response to Comments by Dr. de Saint Georges: damage propagation in complex biological systems following exposure to low doses of ionizing radiation. AFP: Int J 2:206–210CrossRefGoogle Scholar
  25. Feinendegen LE, Brooks AL, Morgan WF (2011) Biological consequences and health risks of low-level exposure to ionizing radiation: commentary on the workshop. Health Phys 100:247–259PubMedCrossRefGoogle Scholar
  26. Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of aging. Nature 408:239–247PubMedCrossRefGoogle Scholar
  27. Fliedner TN, Dörr H, Meineke V (2005) Multi-organ involvement as a pathogenic principle of the radiation syndromes: a study involving 110 case histories documented in SEARCH and classified as the bases of haematopoetic indicators of effect. Brit J Radiol Suppl 27:1–8CrossRefGoogle Scholar
  28. Franco N, Lamartine J, Frouin V, Le Minter P, Petat C, Leplat JJ, Libert F, Gidrol X, Martin MT (2005) Low-dose exposure to gamma rays induces specific gene regulations in normal human keratinocytes. Radiat Res 163:623–635PubMedCrossRefGoogle Scholar
  29. Fujita K, Ohtomi M, Ohyama H, and Yamada T (1998) Biphasic induction of apoptosis in the spleen after fractionated exposure of mice to very low doses of ionizing g radiation. In: Yamada T, Hashimoto Y (eds), Apoptosis, its role and mechanism, Business Center for Academic Societies Japan, Tokyo, pp 201–218Google Scholar
  30. Guyton AC, Hall JE (2005) Textbook of medical physiology, 11th edn. WB Saunders Company, PhiladelphiaGoogle Scholar
  31. Hall EJ, Giaccia AJ (2005) Radiobiology for the Radiologist, 6th edn. Lippincott Williams & Wilkins, New YorkGoogle Scholar
  32. Harder D (2008) Ionisierende Strahlung and die Dosiabhängigkeit ihrer Wirkung. Nova Acta Leopoldina NF 96(355):21–44Google Scholar
  33. Heidenreich WF, Hoogenweem R (2001) Limits of applicability for the deterministic approximation of the two-step cloncal expansion model. Risk Anal 21:103–105PubMedCrossRefGoogle Scholar
  34. Heidenreich WF, Paretzke HG, Jacob P (1997) No evidence for increased tumour rates below 200 mSv in atomic bomb survivors. Radiat Environ Biophys 36(3):205–207PubMedCrossRefGoogle Scholar
  35. Hohn-el-Karim K, Muehlensiepen H, Altman KI, Feinendegen LE (1990) Modification of effects of radiation on thymidine kinase. Intern J Radiat Biol 58:97–110CrossRefGoogle Scholar
  36. ICRP (International Commission on Radiation Protection) (1977) Recommendations of the international commission on radiological protection, ICRP Publication 26, Annals of the ICRP 1 No. 3Google Scholar
  37. ICRU (International Commission on Radiation Units and Measurements) (1983) Microdosimetry. Report 36, ICRU, BethesdaGoogle Scholar
  38. ICRU (International Commission on Radiation Units and Measurements) (2005) Patient dosimetry of X-rays used in medical imaging, Report 74, J ICRU; Oxford J, Oxford University Press, OxfordGoogle Scholar
  39. ICRU (International Commission on Radiation Units and Measurements) (2011) Quantification and reporting of low-dose and other heterogeneous exposures. Report 86, J ICRU; Oxford University Press, OxfordGoogle Scholar
  40. ICRU (Internationalö Comnission on Radiaiton Units and Measurements) (1998) Fundamental quanititis and units for ionizting radiaiton, report 60. ICRU, BethesdaGoogle Scholar
  41. ICRU (International Commission on Radiation Units and Measurements) (2002) Acsorbed dose specification in nuclerar medicine, Report 67, J thw ICRU; Oxford J, Oxford University Press, OxfordGoogle Scholar
  42. Ishizaki K, Hayashi Y, Nakamura H, Yasui Y, Komatsu K, Tachibana A (2004) No induction of p53 phosphorylation and few focus formation of phosphorylated H2AX suggest efficient repair of DNA damage during chronic low-dose-rate irradiation in human cells. J Radiat Res 45:521–525PubMedGoogle Scholar
  43. James SJ, Makinodan T (1990) T-cell potentiation by low dose ionizing radiation: possible mechanisms. Health Phys 59:29–34PubMedCrossRefGoogle Scholar
  44. Kadhim MA, Hill MA, Moore SR (2006) Genomic instability and the role of radiation quality. Radiat Prot Dosimetry 122:221–227PubMedCrossRefGoogle Scholar
  45. Kondo S (1988) Altruistic cell suicide in relation to radiation hormesis. Intern J Radiat Biol 53:95–102CrossRefGoogle Scholar
  46. Leonard BE (2007) Adaptive response and human benefit: Part I—a microdosimetric dose dependent model. Intern J Radiat Biol 83:115–131CrossRefGoogle Scholar
  47. Liu SZ, Zhang YC, Mu Y, Su X, Liu JX (1996) Thymocyte apoptosis in response to low-dose radiation. Mutat Res 358:185–191PubMedCrossRefGoogle Scholar
  48. Mitchel REJ, Jackson JS, Morrison DP, Carlisle SM (2003) Low doses of radiation increase the latency of spontaneous lymphomas and spinal osteosarcomas in cancer prone, radiation sensitive Trp53 heterozygous mice. Radiat Res 159:320–327PubMedCrossRefGoogle Scholar
  49. Mitchel RE, Burchart P, Wyatt H (2008) A lower dose threshold for the in vivo protective adaptive response to radiation. Tumorigenesis in chronically exposed normal and Trp53 heterozygous C57BL/6 mice. Radiat Res 170:765–775PubMedCrossRefGoogle Scholar
  50. Morgan WF, Sowa MB (2009) Non-targeted effects of ionizing radiation: Implications for risk assessment and the radiation dose response profile. Health Phys 97:426–432PubMedCrossRefGoogle Scholar
  51. Mothersill C, Seymour CB (2006) Radiation-induced bystander effects and the DNA paradigm: an “out of field” perspective. Mutat Res 59:5–10CrossRefGoogle Scholar
  52. Mullenders L, Atkinson M, Paretzke H, Sabatier L, Bouffler S (2009) Assessing cancer risk of low-dose radiation. Nat Rev/Cancer 9:596–604CrossRefGoogle Scholar
  53. Nair RR, Rajan B, Akiba S, Jayalekshmi P, Nair MK, Gangadharan P, Koga T, Morishima H, Nakamura S, Sugahara T (2009) Background radiation and cancer incidence in Kerala, India-Karanagappally cohort study. Health Phys 96:55–66PubMedCrossRefGoogle Scholar
  54. National Research Council, Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation (2006) Health risks from low levels of ionizing radiation: BEIR VII, Phase 2. The National Academies Press, WashingtonGoogle Scholar
  55. Neumaier T, Swenson J, Pham C, Polyzos A, Lo AT, Yang PA, Dyball J, Asaithamby A, Chen DJ, Bissell MJ, Thalhammer S, Costes SV (2012) Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells. Proc Nat Acad Sci US 109:443–448CrossRefGoogle Scholar
  56. Nikjoo H, O’Neill P, Terrissol M, Goodhead DT (1999) Quantitative modelling of DNA damage using Monte-Carlo track structure method. Radiat Envrion Biophys 38:31–38CrossRefGoogle Scholar
  57. Olivieri G, Bodycote J, Wolff S (1984) Adaptive response of human lymphocytes to low concentration of radioactive thymidine. Science 223:594–597PubMedCrossRefGoogle Scholar
  58. Pollycove M, Feinendegen LE (2001) Biologic response to low doses of ionizing radiation: detriment versus hormesis. Part 2: dose responses of organisms. J Nucl Med 42:26N–32NPubMedGoogle Scholar
  59. Pollycove M, Feinendegen LE (2003) Radiation-induced versus endogenous DNA damage: possible effect of inducible protective responses in mitigating endogenous damage. Hum Exp Toxicol 22:290–306PubMedCrossRefGoogle Scholar
  60. Preston DL, Pierce DA, Shimizu Y, Cullings HM, Fujita S, Funamoto S, Kodama K (2004) Effect of recent changes in atomic bomb survivor dosimetry on cancer mortality risk estimates. Radiat Res 162:377–389PubMedCrossRefGoogle Scholar
  61. Preston DL, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M, Mabuchi K, Kodama K (2007) Solid cancer incidence in atomic bomb survivors: 1958–1998. Radiat Res 168:1–64PubMedCrossRefGoogle Scholar
  62. Rothkamm K, Löbrich M (2003) Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses’. Proc Natl Acad Sci US 100:5057–5062CrossRefGoogle Scholar
  63. Schöllnberger H, Stewart RD, Mitchel REJ (2005) Low-LET-induced radioprotective mechanisms within a stochastic two-stage cancer model. Dose-Response 3:508–518PubMedCentralCrossRefGoogle Scholar
  64. Scott BR (2004) A biological-based model that.links genomic instability; bystander effects, and adaptive response. Mutat Res 568:129–143PubMedCrossRefGoogle Scholar
  65. Sedelnikova OA, Horikawa I, Zimonjic DB, Popescu NC, Bonner WM, Barrett JC (2004) Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nature Cell Biol 6:168–170PubMedCrossRefGoogle Scholar
  66. Sen K, Sies H, Baeurle P (eds) (2000) Redox regulation of gene expression. Academic Press, San DiegoGoogle Scholar
  67. Tanooka H (2001) Threshold dose-response in radiation carcinogenesis: an approach from chronic beta-irradiation experiments and a review of non-tumour doses. Int J Radiat Biol 77:541–551PubMedCrossRefGoogle Scholar
  68. Tanooka H (2011) Meta-analysis of non-tumour doses for radiation-induced cancer on the basis of dose-rate. Int J Radiat Biol 87:645–652PubMedCentralPubMedCrossRefGoogle Scholar
  69. Tubiana M, Aurengo A, Averbeck D, et al. (2005). Dose-effect relationships and the estimation of the carcinogenic effects of low doses of ionizing radiation. Academy of Medicine (Paris) and Academy of Science (Paris) Joint Report No. 2Google Scholar
  70. Tubiana M, Feinendegen LE, Yang CJM, Kaminski JM (2009) The linear no-threshold relationship is inconsistent with radiation biologic and experimental data. Radiology 251:13–22PubMedCentralPubMedCrossRefGoogle Scholar
  71. Vilenchik MM, Knudson AG (2000) Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates. Proc Natl Acad Sci US 97:5381–5386CrossRefGoogle Scholar
  72. Wolff S, Afzal V, Wienke JK, Olivieri G, Michaeli A (1988) Human lymphocytes exposed to low doses of ionizing radiations become refractory to high doses of radiation as well as to chemical mutagens that induce double-strand breaks in DNA. Intern J Radiat Biol 53:39–49CrossRefGoogle Scholar
  73. Zamboglou N, Porschen W, Muehlensiepen H, Booz J, Feinendegen LE (1981) Low dose effect of ionizing radiation on incorporation of iodo-deoxyuridine into bone marrow cells. Int J Radiat Biol 39:83–93CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg  2012

Authors and Affiliations

  • Ludwig E. Feinendegen
    • 1
    • 2
  • Myron Pollycove
    • 3
  • Ronald D. Neumann
    • 4
  1. 1.Heinrich-Heine-UniversityDüsseldorfGermany
  2. 2.Brookhaven National LaboratoryUptonUSA
  3. 3.School of MedicineUniversity of California San FranciscoSan FranciscoUSA
  4. 4.Radiology and Imaging Sciences, Clinical CenterThe National Institutes of HealthBethesdaUSA

Personalised recommendations