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Correspondence |
We would like to thank Redpath and Mitchel for their comments, which focus primarily on radiobiological aspects of in vitro transformation. We have contributed to this field of study ourselves in earlier work which pre-dates some of the articles to which they refer [1]. Our BJR paper on which they are commenting was written from a somewhat different standpoint – that of the application of detailed scientific findings to the broader issues of practical applications to radiological protection. While we ourselves are involved in detailed scientific investigations of low dose cellular radiobiology, we would like to note the recent findings of reviews from the most influential international organizations in this field that have the responsibility of converting basic scientific findings into workable radiation protection guidelines.
In the last 5 years there have been a number of international reviews dealing with cancer risks at low doses. The summary of the United Nations Scientific Committee on Ionising Radiation (UNSCEAR) 2000 report [2] concluded:
"...as far as is known, even at low doses radiation may act as a mutational initiator of tumorigenesis and that anti-tumorigenic defences are unlikely to show low-dose dependency. In general, tumorigenic response does not therefore appear to be a complex function of increasing dose. The simplest representation is a linear relationship, which is consistent with most of the available mechanistic and quantitative data."
In 2001 the National Council on Radiation Protection and Measurements, NCRP, published NCRP Report No. 136 [3] which presents an evaluation of the existing data on the dose–response relationships and current understanding of the health effects of low doses of ionizing radiation. The conclusion of the report, in short, comes out in support of the continued use of a linear-no-threshold (LNT) dose response for cancer induction for radiological protection purposes.
In April 2005, the International Commission on Radiological Protection (ICRP) put the draft of a new Foundation Document for consultation on its website [4]. This is intended to replace ICRP 60. In July 2005, a preliminary version of the BEIR (The Committee on the Biological Effects of Lonizing Radiation) VII report by the US National Academy of Sciences [5] became available that deals with "Health risks from exposure to low levels of ionizing radiation". In brief – the ICRP and BEIR maintain the established use of LNT. They are, however, rather more guarded than in earlier reports. The ICRP, for example, conclude:
"Although the available data do not exclude the existence of a universal low dose threshold, the evidence as a whole, as summarised in this report, does not favour this proposition. It may be that the long standing question on the true validity of the linear-no threshold (LNT) hypothesis will provide to be beyond definitive scientific resolution and that "weight of evidence" arguments and practical judgements will continue to apply in the foreseeable future."
In the midst of these consensual reports from UNSCEAR, NCRP, ICRP and BEIR, a diametrically opposed view emerged from the French Academy of Sciences and the National Academy of Medicine [6] who published a report on "Dose–effect relationships and estimation of the carcinogenic effects of low doses of ionizing radiation" in French in late 2004 and in English (on the French Academy of Sciences website) in March 2005. In both reports the Academies come to conclusions on low dose radiation risks that are in contrast to NCRP, ICRP and BEIR. They favour threshold dose responses or significantly reduced risks at low doses. They believe that epidemiological studies have been unable to detect a significant increase of cancer incidence in humans for doses below about 100 mSv and state that the use of LNT for assessing the risks of doses below 20 mSv is unjustified and should be discouraged.
Differences between the views of the French Academies and proponents of LNT have recently been debated by Tubiana et al [7] and Brenner and Sachs [8]. Brenner and Sachs argue in support of LNT, against French criticisms based on grounds of microdosimetry, cell biology and immune suppression. Their conclusions are however guarded:
"...even if there are significant deviations from linearity in the relevant dose range, potentially caused by the effects of intercellular interactions or immune surveillance, we know almost nothing quantitatively about these effects. Consequently, we do not know the magnitude, nor even the direction of any such deviations from linearity—the risks could indeed be lower than those predicted by a linear extrapolation, but they could well be higher."
There are clearly understandable differences of opinion on what pragmatic, rather than purely scientific, assumptions should be made regarding the dose response relationship at low doses for radiological protection purposes. It seems probable therefore that in the short term the formal evaluation of the health impact of mammography screening is likely to be on the basis of LNT. For example, we understand that breast cancer risks are currently being reviewed by the Advisory Group on Ionising Radiation (AGIR) of the Health Protection Agency (HPA) as part of a review of solid cancer risks (http://www.hpa.org.uk/radiation/advisory_groups/agir/index.htm). While we are not privy to those considerations, it would be surprising if LNT was not adopted. It is to be hoped that these complex considerations will be published in detail so that the bases of derived risk figures are patent. This is particularly important in the case of radiation induced breast cancer where factors such as the dose and dose rate effectiveness factor (DDREF), relative biological effectiveness (RBE) and the dependence of RBE on photon energy are so intimately related [9–11].
The use of a DDREF of two in the UK breast screening programme [12], and used in our calculations already, accounts for the fact that a simple linear extrapolation to zero dose may overestimate the risk of cancer induction. In addition to this we also examine the effect of using a DDREF of unity, therefore assuming a fully linear extrapolation. The US Environmental Protection Agency [13] advocates a DDREF of unity for the specific case of breast cancer.
We are indeed aware of the J-shaped model for the dose–response relationship at low doses as advocated by Ko et al [14]. However, the interpretation of Ko et al's data depends crucially on the spontaneous transformation frequency observed in their assay. In Table 1
we have listed the spontaneous transformation frequencies observed using the CGL1 transformation assay from a number of laboratories world-wide over the past 10 years or so. As can be seen, the value reported in Ko et al's work is significantly higher – by a factor of 3 to 4 times – than that measured by ourselves and others.
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The fundamental under-pinning science should not be lost sight of amidst the pragmatism that is radiological protection. Our BJR paper was addressed to the pragmatists. We of course fully support Redpath and Mitchel's concerns that all the data from cell radiobiology at low doses should inform the process.
Yours etc.,
1 Medical Physics, University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, B15 2TH2 Radiation Biophysics Group, School of Physics and Astronomy, The University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
References
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  B M Moores Relative biological effectiveness and exposure of the female breast Br. J. Radiol., February 1, 2007; 80(950): 141 - 142. [Full Text] [PDF]
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