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British Journal of Radiology (2005) 78, 8-10
© 2005 British Institute of Radiology
doi: 10.1259/bjr/51173413
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UKRC 2004 debate

Radiation risk is linear with dose at low doses

K H Chadwick, PhD1 and H P Leenhouts, PhD2

1 Ellerbank, Cowan Head, Kendal, Cumbria LA8 9HX, UK and 2 FredBantinglaan, 6721 BC Bennekom, The Netherlands

Abstract

This paper presents a brief argument, based on a mechanistic approach, to show that radiation risk is linear with radiation dose from zero dose up. Similarities in cellular effects lead to the assumption of a common mechanism and the DNA double strand break is identified as the crucial radiation-induced lesion. A cancer model extends the cellular effects to the main radiation risk providing confirmation of the dose effect for cancer at low doses.

The question of radiation risk, i.e. radiation induced cancer, and the shape of its dose–effect relationship at very low doses is the subject of intense debate in the radiological protection community, especially because the International Commission on Radiological Protection (ICRP) is currently preparing a revision of its Recommendations [1]. The recent article by Brenner et al [2] makes it very clear that in order to quantify a risk of radiation for doses of lower than 10 mSv, impossibly large epidemiological studies would be necessary and the authors suggest that at lower doses inferences on risk need to be based on an understanding of the mechanisms of radiation action. This paper briefly presents a pathway of linkage using experimentally derived cellular and human data which associates a basic molecular lesion with the occurrence of cancer and which implies, on a mechanistic basis, that radiation risk is linear with dose from zero dose upwards. It is not possible to illustrate all the experimental evidence mentioned and readers should consult the quoted references for confirmation of the claims made [3, 4].

Theoretical background

Cellular effects
The induction of chromosomal aberrations, the induction of somatic mutations and the induction of cell killing can all be described by a linear-quadratic dose–effect relationship i.e.Go


{780008E001}

where "Effect" can be yield of chromosomal aberrations (Y), mutation frequency (M) or the negative of the logarithm of cell survival (-lnS). Indeed, Gillespie et al [5, 6] have shown that the linear-quadratic equation fits cell survival data as well as can be expected.

The three different cellular effects show the same systematic behaviour with dose rate changes and with radiation quality changes. As the dose rate is reduced all three effects decrease reflecting a reduction of the {beta}-coefficient in the linear-quadratic equation and at very low dose rates {beta} becomes zero. As the quality of radiation is increased, e.g. from gamma rays to alpha particles the dose–effect relationships for all three effects become more linear and the {alpha}-coefficient increases.

The common dose–effect relationship and the similarities in response to changes in exposure conditions imply that a common mechanism may be the origin of the three different cellular effects. If this is the case it may be expected that when different effects are measured in the same experiments direct correlations should be found with relationships such as –lnS=KY and –lnS=qM where K and q are constants.

Several examples of these correlations have been determined [7–14] and we conclude that a common radiation induced lesion may be at the origin of each of the three cellular effects. The chromosomal aberrations and mutations imply that the common lesion involves damage to the DNA and we continue by examining correlations between cell survival and the induction of DNA double strand breaks.

The molecular lesion
Radford [15–17] was the first to measure the induction of DNA double strand breaks at doses of radiobiological relevance and make the correlation with cell survival determined in the same experiment using different exposure conditions. The single straight line correlation in accordance with the equation: Go


{780008E002}

where N is the number of DNA double strand breaks and p is a constant, led him to conclude that the DNA double strand break was the lethal radiation induced lesion. Two other laboratories have also measured the correlation between DNA double strand breaks and cell survival [18–20].

Figure 1Go presents, schematically, the way in which DNA double strand breaks might be induced by ionizing radiation.



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  		Figure 1. Schematic presentation of the way in which DNA double strand breaks might be induced by ionizing radiation.

 
Radiation may break both strands in the passage of an ionizing particle track or two independent particle tracks may break each strand of the DNA double helix. The number (N) of double strand breaks is:Go


{780008E003}

and we have a basis for the linear-quadratic equation.

It is important to note that at low doses (and low dose rates) the linear-quadratic equation reduces to N={alpha}D, which is linear with dose from zero dose up. So we conclude at this point that radiation induced cellular effects can all be ascribed to the induction of DNA double strand breaks and exhibit a dose–effect relationship which is linear with dose from zero dose up.

Cancer
Figure 2Go presents a schematic representation of a two mutation clonal expansion model of cancer development.



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  		Figure 2. A two mutation clonal expansion model of cancer development. For explanation see text.

 
Briefly, a population of normal stem cells (S) are targets for a mutation (µ1), which converts the cell to an intermediate state (I). With time the intermediate cell divides ({varepsilon}) and eventually forms a large population of cells which are targets for a second mutation (µ2) which converts the cell to a malignant state. The malignant cell divides and in time (tlag) produces a detectable tumour (T). Time, a large part of lifetime, is an important parameter in this model.

It has been possible to fit several sets of human radiation induced cancer data to this cancer model [21–25].

Spontaneous tumours arise from spontaneous mutations, radiation adds to the spontaneous mutations but does not affect clonal expansion, at least at low doses. The model calculates the age dependent increase in cancer for spontaneous cancers and after radiation exposure. It should be obvious that a single acute exposure may affect the first or the second mutation step but not both so that the radiation induced mutation in one of the steps relies on a spontaneous mutation in the other step to make the cell malignant and the radiation effect depends on the spontaneous mutations or the spontaneous cancer incidence. The same situation occurs with a protracted exposure and the radiation induced mutation will usually rely on a spontaneous mutation to create a malignant cell because spontaneous mutations are much more common. Thus the radiation effect on cancer induction reflects the radiation induction of mutations which is linear-quadratic, in general, but linear with dose at low doses and dose rates.

Conclusion

We conclude that the DNA double strand break is the critical lesion leading to cellular effects and that a radiation induced mutation or aberration arising from a double strand break can ultimately lead to cancer so that the dose–effect for cancer induction is linear-quadratic, in general, but at low doses and low dose rates it is linear with dose from zero dose up.

Audience participation

The question put to the audience based on this contribution was "Taking the spontaneous levels of cancer into account, do you think it will ever be possible to determine low dose radiation effects at doses just above background levels using experimental or epidemiological methods?"

Responses: Yes 21%; no 66%; don't know 13%.

References

  1. ICRP. The evolution of the current system of radiological protection: the justification for new ICRP recommendations (a memorandum from the International Commission on Radiological Protection). J Radiol Prot 2003;23:129–42.[CrossRef][Medline]
  2. Brenner DJ, Doll R, Goodhead DJ, Hall EJ, Land CE, Little JB, et al. Cancer risks attributable to low doses of ionizing radiation: Assessing what we really know. Proc Natl Acad Sci USA 2003;100:13761–6.[Abstract/Free Full Text]
  3. Chadwick KH, Leenhouts HP. The molecular theory of radiation biology. Heidelberg: Springer Verlag, 1981.
  4. Chadwick KH, Leenhouts HP, Brugmans MJP. A contribution to the linear no-threshold discussion. J Radiol Prot 2003;23:53–78.[CrossRef][Medline]
  5. Gillespie CJ, Chapman JD, Reuvers AP, Dugle DL. The inactivation of Chinese hamster cells by X-rays: synchronized and exponential cell populations. Radiat Res 1975;64:353–64.[CrossRef][Medline]
  6. Gillespie CJ, Chapman JD, Reuvers AP, Dugle DL. Survival of X-irradiated hamster cells: analysis in terms of the Chadwick-Leenhouts model. In: Alper T, editor. Cell survival after low doses of radiation: theoretical and clinical implications. London: IOPP and John Wiley & Sons Ltd, 1975:25–31.
  7. Dewey WC, Furman SC, Miller HH. Comparison of lethality and chromosome damage induced by X-rays in synchronized Chinese hamster cells in vitro. Radiat Res 1970;43:561–81.[CrossRef][Medline]
  8. Dewey WC, Stone LE, Miller HH, Giblak RE. Radiosensitization with 5-bromodeoxyuridine of Chinese hamster cells irradiated during different phases of the cell cycle. Radiat Res 1971;47:672–88.[CrossRef][Medline]
  9. Dewey WC, Miller HH, Leeper DB. Chromosomal aberrations and mortality of X-irradiated mammalian cells; emphasis on repair. Proc Natl Acad Sci USA 1971;68:667–71.[Abstract/Free Full Text]
  10. Dewey WC, Sapareto SA, Betten DA. Hyperthermic radiosensitization of synchronous Chinese hamster cells: relationship between lethality and chromosomal aberrations. Radiat Res 1978;76:48–59.[Medline]
  11. Bhambhani R, Kuspira J, Giblak RE. A comparison of cell survival and chromosomal damage using CHO cells synchronized with and without colcemid. Can J Genet Cytol 1973;15:605–18.[Medline]
  12. Franken NAP, Ruurs P, Ludwikow G, Van Bree C, Kipp JBA, Darroudi F, et al. Correlation between cell reproductive death and chromosome aberrations assessed by FISH for low and high doses of radiation and sensitization by iodo-deoxyuridine in human SW-1573 cells. Int J Radiat Biol 1999;75:293–9.[CrossRef][Medline]
  13. Goodhead DT, Thacker J, Cox R. Effectiveness of 0.3 keV carbon ultrasoft X-rays for the inactivation and mutation of cultured mammalian cells. Int J Radiat Biol 1979;36:101–14.
  14. Rao BS, Hopwood LE. Modification of mutation frequency in plateau Chinese hamster ovary cells exposed to gamma radiation during recovery from potentially lethal damage. Int J Radiat Biol 1982;42:501–8.
  15. Radford IR. The level of induced DNA double-strand breakage correlates with cell killing after X-irradiation. Int J Radiat Biol 1985;48:45–54.
  16. Radford IR, Hodgson GS. 125I-induced DNA double strand breaks: use in calibration of the neutral filter elution technique and comparison with X-ray induced breaks. Int J Radiat Biol 1985;48:555–66.
  17. Radford IR. Evidence for a general relationship between the induced level of DNA double-strand breakage and cell killing after x-irradiation of mammalian cells. Int J Radiat Biol 1986;49:611–20.
  18. Prise KM, Davies S, Michael BD. The relationship between radiation-induced DNA double-strand breaks and cell kill in hamster V79 fibroblasts irradiated with 250 kVp X-rays, 2.3 MeV neutrons or 238Pu {alpha}-particles. Int J Radiat Biol 1987;52:893–902.
  19. Murray D, Prager A, Miles L. Radioprotection of cultured mammalian cells by amniothiols WR-1065 and WR-255591: correlation between protection against DNA double-strand breaks and cell killing after {alpha}-radiation. Radiat Res 1989;120:154–63.[CrossRef][Medline]
  20. Murray D, Prager A, Vanankeren SC, Altschuler EM, Kerr MS, Terry NHA, Milas L. Comparative effect of the thiols dithiothreitol, cysteamine aand WR-151326 on survival and on the induction of DNA damage in cultured Chinese hamster ovary cells exposed to gamma-radiation. Int J Radiat Biol 1990;58:71–91.[Medline]
  21. Leenhouts HP. Radon-induced lung cancer in smokers and non-smokers: risk implications using a two mutation carcinogenesis model. Radiat Environ Biophys 1999;38:57–71.[CrossRef][Medline]
  22. Leenhouts HP, Chadwick KH. A two-mutation model of radiation carcinogenesis: applications to lung tumours in rodents and implications for risk evaluations. J Radiol Prot 1994;14:115–30.[CrossRef]
  23. Leenhouts HP, Brugmans MJP. An analysis of bone and head sinus cancers in radium dial painters using a two-mutation carcinogenesis model. J Radiol Prot 2000;20:169–88.[CrossRef][Medline]
  24. Leenhouts HP, Brugmans MJP. Calculation of the 1995 lung cancer incidence in the Netherlands and Sweden caused by smoking and radon: risk implications for radon. Radiat Environ Biophys 2001;40:11–21.[CrossRef][Medline]
  25. Leenhouts HP, Brugmans MJP, Chadwick KH. Analysis of thyroid cancer data from the Ukraine after ‘Chernobyl’ using a two-mutation carcinogenesis model. Radiat Environ Biophys 2000;39:89–98.[CrossRef][Medline]




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