British Journal of Radiology (2006) 79, 195-200
© 2006 British Institute of Radiology
doi: 10.1259/bjr/21958628
Enhanced biological effectiveness of low energy X-rays and implications for the UK breast screening programme
G J Heyes, PhD
1
A J Mill, PhD
2 and
M W Charles, PhD, DSc
2
1 Department of Medical Physics, University Hospital Birmingham NHS Foundation Trust, Birmingham B15 2TH, 2 Radiation Biophysics Group, School of Physics and Astronomy, The University of Birmingham, Birmingham B15 2TT, UK
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Abstract
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Recent radiobiological studies have provided compelling evidence that the low energy X-rays as used in mammography are approximately four times – but possibly as much as six times – more effective in causing mutational damage than higher energy X-rays. Since current radiation risk estimates are based on the effects of high energy gamma radiation, this implies that the risks of radiation-induced breast cancers for mammography X-rays are underestimated by the same factor. The balance of risk and benefit for breast screening have been re-analysed for relative biological effectiveness (RBE) values between 1 and 6 for mammography X-rays. Also considered in the analysis is a change in the dose and dose-rate effectiveness factor (DDREF) from 2 to 1, women with larger than average breasts and implications for women with a family history of breast cancer. A potential increase in RBE to 6 and the adoption of a DDREF of unity does not have any impact on the breast screening programme for women aged 50–70 years screened on a 3 yearly basis. Situations for which breast screening is not justified due to the potential cancers induced relative to those detected (the detection-to-induction ratio (DIR)) are given for a range of RBE and DDREF values. It is concluded that great caution is needed if a programme of early regular screening with X-rays is to be used for women with a family history of breast cancer since DIR values are below 10 (the lowest value considered acceptable for women below 40 years) even for modest increases in the RBE for mammography X-rays.
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Introduction
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There is increasing evidence from radiobiology studies [1–3] that the low energy X-rays used for mammography breast screening are more effective in inducing biological damage than higher energy X-rays. Risk estimates for radiation-induced cancer – principally derived from the atomic bomb survivor study (ABSS) – are based on the effects of high energy 
-rays and thus the implication is that the risks of radiation-induced breast cancer arising from mammography may be higher than that assumed based on standard risks estimates. As with any clinical examination, the radiological breast screening programme must be justified, in that the risk associated with the exposure must be greatly outweighed by the potential gain to a patient as a result of a the procedure. This is particularly so for breast screening since the large majority of women undergoing mammography are asymptomatic. Thus, while the radiation dose to the breast can be accurately measured and kept as low as reasonably practicable, the risk associated with this dose, and therefore the risk-benefit ratio is less well known.
The most recent and relevant radiobiology studies have utilized the immortalized human cell line designated CGL1 in which the transformation frequencies induced by low energy X-rays were compared with the effects of higher energy X-rays, -rays and electrons. In particular, in one study [1] a direct comparison between 29 kVp X-rays, generated using a clinical mammography unit, and radiation simulating the atomic bomb spectrum at Nagasaki was made. The best estimate of the limiting (low-dose) relative biological effectiveness (RBEM) of 29 kVp X-rays compared with the atomic bomb spectrum radiation was found to be 4.42±2.02. While it is recognized that there can be limitations in directly extrapolating data obtained in vitro to carcinogenesis in vivo, these results provide strong evidence that the radiation risks from mammography may be underestimated by a factor of approximately four, and possibly as high as six. In this paper we re-analyse the balance of risk and benefit for breast screening using the methods of Law and Faulkner [4, 5] based on these higher values of the RBE of mammography energy X-rays.
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The National Health Service Breast Screening Programme
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The National Health Service Breast Screening Programme (NHSBSP) was started in the UK in 1988 in an attempt to reduce mortality from breast cancer. The programme has been largely successful, with the International Agency for Research on Cancer (IARC) concluding that breast screening by mammography of women aged between 50 years and 69 years reduces mortality from breast cancer by 35% [6]. It is clear that a breast screening programme does save lives. However, such a widespread (two million women screened per year in the UK in seven screening rounds) use of a radiological examination in asymptomatic women needs to be treated with some caution. The risks associated with such a programme need to be properly evaluated, especially since there are moves both in the UK and elsewhere to extend the use of mammography to a wider section of the population. Current guidelines for the NHSBSP in the UK are for two-view radiological examinations for women aged between 50 years and 70 years with a frequency of every 3 years [7]. An average mean glandular dose (per two-view screening examination) of 4.5 mGy is used for the purpose of benefit-risk analysis [8]. The UK is considering expanding the screening programme to include younger women (currently considering a minimum age of 40 years). The intention of this NHSBSP "UK Age-trial" with women without family history [8] is to screen women annually from 40 years to 47 years. Such an increase in the screening lifetime will clearly increase the cumulative dose. The frequency of this age trial means that women will in fact receive a higher dose in the age trial (10 screening rounds) than they would in the normal screening programme (seven screening rounds). Just by attending this age trial, women will therefore more than double the lifetime absorbed dose to the breast. The effect is magnified, since the screening of younger, denser breasts can increase the dose required to produce the required film exposure by approximately 15–20% [9]. Since the risks of radiation-induced breast cancer are age-dependent [9], younger breasts are also more susceptible to radiation-induced cancers, thus compounding the increased risk even further.
The NHSBSP report [8] also highlights a "high dose subgroup" population: a proportion of women who receive a higher than average mean glandular dose. This increase in dose may be due to the use of difficulties with imaging equipment or to higher than average breast tissue thickness under compression. The mean glandular dose for this subgroup is 21.4 mGy per two-view examination [8]. This high dose subgroup is estimated to account for 0.1% of the screened population. However, this figure is set to increase with increasing breast size of the UK population. Over the course of the screening programme (seven two-view sessions) a woman in the high dose subgroup can expect to receive a mean glandular dose of more than 170 mGy. It is likely that an age trial will be targeted at women who are judged to be at an increased risk of breast cancer. Such women are identified if (amongst other reasons) there is a family history of breast cancer (thought to be the most important factor) or if they are obese (and are therefore also likely to be in the high-dose subgroup). Women with a family history of breast cancer are thought most at risk of developing the disease, since about 10% of breast cancers are thought to have a genetic basis. These women may be deficient in one of the known breast cancer suppressor genes, BRCA1 and BRCA2. Such a gene deficiency may well increase the susceptibility of a woman to develop a radiation-induced tumour, since the number of targets in each cell requiring damage is reduced. The radiation risk for this sensitive subgroup may therefore be significantly greater than the risks associated with the average UK population. Currently these risks are poorly understood, and this paper seeks to highlight the need for caution if mammography breast screening is to be used in this subgroup.
In the NHSBSP, the risks associated with mammography doses are calculated from various epidemiological sources [8]. The source includes data from North American women who were given high doses of radiation for medical reasons (e.g. X-ray therapy for acute post-partum mastitis and multiple sessions of direct fluoroscopy for tuberculosis, mostly during the 1930s and 1940s). In addition to being a high-dose population, the North American women were exposed to therapy energies of X-rays, highlighting the importance of calculating the efficacy in inducing cell damage by lower energy X-ray radiation. ABSS data are considered, but not used in the calculations of risk. The justification for the omission of the ABSS is [8] that since Japanese women "have a markedly lower natural incidence of breast cancer than women from western counties such as the UK and USA..." it is "difficult to transfer radiation risks between these two populations." Published risk figures for potential cancer inductions varying with age of exposure to X-rays are available [4]. Using these data, with the published values of breast cancers detected in the UK screening programme (NHS report) the ratio of cancers detected to those induced by the mammography dose (detection to induction ratio (DIR)) can be calculated. The use of the DIR is not a true measure of the benefit-risk ratio, but it is an indication of its likely magnitude. An examination of the relationship of these two ratios [4] has shown that the difference between them is likely to be as little as 15–20%. A DIR of 100 is considered to be ample, whilst a ratio of 10 is considered to be sufficient in terms of justifying the use of a radiological exposure [5].
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The effect of a higher RBE for mammography X-rays
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The in vitro cell transformation data from Heyes and Mill [1] suggest a best estimate for the RBE of mammography X-rays of approximately 4 with 90% confidence intervals in the range 2 to 6. Table 1
presents the cancer induction-rates for the UK population that are assumed in the NHSBSP. Table 2 then presents the number of induced cancers for a range of RBE values from 1 (as assumed in the NHSBSP) to 6 (an approximate upper limit based on the latest in vitro data). In Table 3 the DIR values are given. The data given in Tables 2 and 3 are for women screened once every 3 years in the UK NHSBSP and include those in the high dose sub group as well as the "normal" group of women. Using an RBE of 1 for mammography X-rays, as used by the NHSBSP, the DIR falls below 100 only when the screening age is below 55 years. With an RBE value of 2, the DIR falls below 100 for all screening ages below 65 years. For higher values of the RBE, all values of DIR lie below 100. For women in the high dose sub group DIR values are clearly much lower.
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Table 1. Total number of breast cancers induced per million women screened per mGy absorbed for women of different ages(after Law et al [4])
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Table 2. Estimated numbers of cancers detected and induced for women in the normal(N) and high dose (H) groups screened three-yearly in the NHSBSP
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Table 3. Estimated ratio of cancer detection to induction(DIR) for women in the normal (N) and high dose (H) groups screened 3 yearly in the NHSBSP
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Dose and dose-rate effectiveness and the breast screening programmes in the UK and USA
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According to the dual action theory of radiation damage, the dose response should be linear at low doses. At higher doses and dose-rates, multiple track events become important, thereby bending the dose response upwards. As a result, the response per unit dose at low doses will be overestimated if a linear extrapolation is made from observations at high doses. The degree of overestimation is expressed in terms of a dose and dose-rate effectiveness factor (DDREF). A DDREF of 2 is used in the NHSBSP [6]. However, the US Environmental Protection Agency (EPA) advocates a DDREF value of 1 for breast cancer [10] and risks based on a DDREF of 1 are twice those calculated by the NHSBSP. The EPA states that there is epidemiological evidence that dose-fractionation has little or no effect on risk to the breast [10], and that a DDREF of unity should be adopted.
If the DDREF for breast cancer is unity, as advocated by the American EPA, the DIR falls below 100 with an RBE of 1 for all screening ages below 65 years. If the RBE is increased, the DIR is below 100 for all ages, and would even fall below 10 for a screening age of 50–54 years if a "worst case scenario" RBE of 6 is considered. DIR values for a DDREF of unity are exactly one half of the values given in Table 3
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Screening of women with a family history of breast cancer
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The National Institute for Clinical Excellence (NICE) [11] considers the efficacy of early screening of women with a family history of breast cancer. Whilst most of the studies listed as research literature evidence (section 7.2.2 of [11]) conclude regular, early screening sessions would lead to an increase in tumour detection, very little mention is made to the potential of women with a genetic disorder being more susceptible to radiation-induced breast tumour. One study [12] even concluded that mammography was relatively insensitive to detecting tumours in women with BRCA1/2 mutations, and that other forms of detection were likely to be more beneficial to this high risk group.
Law et al [4] have published the detection/incidence ratio for younger women (aged 25–49 years) with a family history of breast cancer screened annually with two-view mammography. The cancer induction-rates upon which these values are calculated are shown here in Table 4. The DIR for women with two index ages are given in Table 5. When the index patient (mother, sister, daughter) age is 30–39 years, the ratio of detection to induction falls below 10 for women with such a family history if they are screened below the age of 30 years using an RBE of 2, and below 35 years when the RBE is 4. The screening age of a woman with a family history (index age 30–39 years) where the DIR falls below 10 is 45 years for an RBE of 6.
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Table 4. Estimated cancer induction for women in the age range 25–49 years with a family history of breast cancer (after Law et al [4]). Annual 2-view screening
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Table 5. Effect of an increase in RBE on the cancer detection/induction ratio for UK women screened annually (two views) with a family history of breast cancer (values in parenthesis are for a DDREF of 1)
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If benefit is to exceed radiation risk in a screening programme, the ratio of detection to induction (DIR) should exceed a factor of about 5 [13]. This may not apply to women below the age of 40 years, for whom the DIR should exceed 10.
If the index patient is 40–49 years old the detection-rate is less, and this means the DIR falls below 10 at higher ages than for the index patient age of 30–39 years. The DIR falls below 10 in this case if the screening age is less than 30 years for an RBE of 1, an age less than 35 years for an RBE of 2 and does not exceed 10 for any screening age if the RBE is greater than or equal to 4. These results therefore imply that the caution should be used when considering mammography screening for women with a history of breast cancer, especially if the index patient age is greater than 40 years old. Such women may be carriers of BRCA1 and BRCA2 gene mutations, and as such may be more susceptible to a radiation induced tumour.
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Discussion
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Using a DDREF of 2 and an RBE of unity in the normal screening programme, only women aged between 50 years and 54 years will have a DIR of less than 100. If an RBE of 2 is used then the DIR for women in the 50–54 year range falls to 45 years, and women up to and including the 60–64 year age range have a DIR of less than 100. If an RBE of 4 is considered (as suggested from the in vitro radiobiology results [1]), the DIR is below 100 for women of all ages considered, and has a minimum value of 22 for women aged between 50 years and 54 years.
Considering a change in DDREF to unity, such as that used by the American system, the DIR would fall to 11 for the youngest women with an RBE of 4. In the worst case scenario (RBE = 6) the DIR falls below 10 for women between 50 years and 59 years (Table 3).
If the risk of radiation induced tumours can be justified in terms of maintaining the DIR above 5 for women over 40 years, then an increase in RBE, even to 6 and a DDREF of unity, would not therefore have an impact on the use of mammography as a breast screening tool for the normal 3 yearly screened population of women aged between 50 years and 70 years since the lowest DIR calculated in these cases is 7.4 for women aged between 50 years and 54 years. Younger (50–54 years) women in the high-dose subgroup are likely to have a DIR less than 5 if the RBE is significantly increased from unity. Unfortunately, there are no cancer detection data upon which to accurately calculate the DIR for this population. In these calculations the detection-rates for the high dose subgroup population have been assumed to be the same as those in the normal screened population.
In the cases of women with a family history of breast cancer, women screened annually with two-views from the age of 25 years are considered. The DIR for such a population is already reduced, even with a DDREF of 2 and an RBE of unity. The lowest DIR is 6 for the youngest age range (25–29 years). The effect on a change to the RBE is most dramatic in this screening group. For these younger women, the DIR should exceed 10 if the benefit is to exceed the radiation risk [13]. In fact, an increase in the RBE to just 2 means that women aged 25–34 years have a DIR less than 10 (with a DDREF of 2). If the RBE of mammography X-rays is 4, then the entire age range (25–49 years) of women with a family history of breast cancer (index age 40–49 years) will have a DIR less than 10 (DDREF = 2). In this case, the youngest women (age range 25–29 years) have a DIR of less than 2.0. It is still only 3.0 (i.e. not justifiable) for this age range if the RBE is decreased to 2.0.
These comments are summarized in Table 6, where a DIR of 5 is chosen to be a cut-off, below which a screening programme could not be justified due to the potential cancers induced relative to those detected. (For women under the age of 40 years, a DIR of 10 is used as the cut-off [13]).
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Table 6. Situations when breast screening should not be carried out for different RBE and DDREF values– based on a cut-off DIR value of 5 (10 for women aged 40 years and under) below which screening should not occur
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Conclusion
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This work suggests great caution should be exercised if a programme of early, regular screening using X-rays, is to be used in women with a family history of breast cancer. The effect of an increase in RBE or DDREF is most pronounced in younger women screened due to a family history and women in the high-dose subgroup.
Other methods for detecting tumours at an early stage are available, and have been considered by NICE [11]. Many studies [14–16] have shown that MRI is more accurate than mammography in screening young women with a family history of breast cancer. Such a widespread use of MRI would, however, place a high burden on limited NHS resources in the UK, due to the significant increase in screening cost. A number of studies [12, 17] have observed that mammography surveillance is less sensitive in younger women, women with a family history and BRCA1/2 mutant carrier, a point noted by NICE [11].
It is recognized that in vitro radiobiological experiments using immortalized cell lines cannot be considered in isolation or used directly as a basis for reviewing the breast screening programme. The recently observed high values of RBE for cancer-related in vitro end-points do, however, strengthen the long accepted evidence, based largely on non-cancer end-points, that low energy X-radiations have larger RBE values than higher energy photons. Such findings have long been accepted by the International Commission on Radiological Protection (ICRP). For general radiological protection situations the ICRP has, however, maintained a radiation weighting factor of 1 for all low LET radiations (including electrons and photons of all energies). In specific situations the ICRP recommends the use of more appropriate assumptions. The possibility of RBE values for mammography exposures which are in excess of the ICRP radiation weighting factors focuses attention on the results of related epidemiology studies. It widens the range of possible assumptions which can be used in cost-benefit analyses to inform the debate regarding extensions to existing screening programmes.
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Footnotes
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This work was supported by EPSRC grant RRAH07673. 
Received for publication April 19, 2005.
Revision received June 23, 2005.
Accepted for publication June 24, 2005.
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References
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- Goggelmann W, Jacobsen C, Panzer W, Walsh L, Roos H, Schmid E. Re-evaluation of the RBE of 29 kV x-rays (mammography x-rays) relative to 220 kV x-rays using neoplastic transformation of human CGL1-hybrid cells. Radiat Environ Biophys 2003;42:175–82.[CrossRef][Medline]
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Abstract
Introduction
