IJE Advance Access published online on July 9, 2008
International Journal of Epidemiology, doi:10.1093/ije/dyn122
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Letter to the Editor |
Comments: The non-cancer mortality experience of male workers at British Nuclear Fuels plc, 1946–2005
1Department of Epidemiology and Public Health, Imperial College Faculty of Medicine, Norfolk Place, London W2 1PG, UK.
2University of Central Lancashire, Westlakes Science Park, Moor Row, Cumbria, CA24 3JY, UK.
3Dalton Nuclear Institute, University of Manchester, Pariser Building, PO Box 88, Sackville Street, Manchester, M60 1QD, UK.
4Department of Radiotherapy and Radiation Oncology, University of Leipzig, Stephanstrasse 9a, 04103 Leipzig, Germany.
5Helmholtz Centre Munich, German Research Centre for Environmental Health, Institute of Radiation Biology (ISB), Radiation Proteomics, Ingolstaedter Landstrasse 1, 85764 Oberschleissheim, Germany.
*Corresponding author. Department of Epidemiology and Public Health, Imperial College Faculty of Medicine, Norfolk Place, London W2 1PG. E-mail: mark.little{at}imperial.ac.uk
The study of McGeoghegan et al.1 documents statistically significant positive trends of mortality risk for circulatory disease, as well as various related endpoints (ischaemic heart disease, acute myocardial infarction, stroke, chronic ischaemic heart disease, diabetes) with radiation dose in an important worker cohort. However, there are a number of reasons for caution in interpreting the findings as representing causal associations. The excess risk per unit dose found is rather stronger, by about a factor of four, than that observed in the Japanese A-bomb survivors. For example, McGeoghegan et al.1 document an excess relative risk (ERR) in relation to all circulatory diseases (ICD9 390–438, 440–459) of 0.54 Sv–1 (90% CI 0.30–0.82) for stroke (ICD9 430–438) of 0.66 Sv–1 (90% CI 0.17–1.27) (Table 1), whereas Preston et al.2 document an ERR for heart disease (ICD9 390–429) of 0.17 Sv–1 (90% CI 0.08–0.26) and for stroke (ICD9 430–438) of 0.12 Sv–1 (90% CI 0.08–0.26). Also, the fact that most specific mortality endpoints of non-cancer disease are elevated to a similar extent suggests that there may be bias. As with most other studies of radiation-exposed cohorts (apart from the A-bomb survivors), there is little adjustment for major cardiovascular risk factors, in particular cigarette smoking, diabetes, obesity, blood pressure and blood cholesterol or low density lipoprotein3—only socioeconomic status (a proxy for some of these variables) is adjusted for here, using a crude industrial vs non-industrial classification. Specific occupational factors, in particular stress (e.g. related to shift work, which may well be associated with radiation dose)4 also have the potential to confound, and therefore seriously bias the results. It is of interest that there is significant heterogeneity for certain endpoints by employment type and radiation exposure in the study of McGeoghegan et al.,1 which may reflect confounding by some of these factors.
|
A recent paper systematically reviewed the epidemiological evidence for associations between low and moderate doses (<5 Gy) of ionizing radiation exposure and late occurring cardiovascular disease.3 Risks per unit dose in epidemiological studies varied over at least two orders of magnitude, possibly a result of confounding factors. The paper also reviewed possible biological mechanisms for such low dose effects and indicated that the most likely causative effect of radiation 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.3 However, a role for somatic mutation has been proposed5–7 that would indicate a stochastic effect. In the absence of a convincing mechanistic explanation of epidemiological evidence that is, at present, less than persuasive, the authors concluded that a cause-and-effect interpretation of the reported statistical associations could not be reliably inferred, although neither could it be reliably excluded.3
In comparison even of the lower dose studies summarized in Table 1, a distinction should be made between the acute doses received from radiotherapy and the atomic bombs and the chronic small incremental doses received occupationally. As summarized elsewhere,3,8 it is well recognized that the effect at high acute doses is likely to be deterministic and due to a response to cell killing and tissue damage. Therefore studies of radiotherapy patients, even at doses down to 0.5 Gy, and that are reviewed elsewhere,9 will not address the issue of mechanisms of any potential effect of small incremental doses, since even at 0.5 Gy there will be quite a lot of cell killing. Low dose chronic exposure will not have the same effect. Even if the same total number of cells are killed, the time span over which this occurs is typically tens of years and their loss is unlikely to be detrimental and will probably be accommodated within the normal patterns of cell turnover and renewal.
We compute an aggregate estimate of ERR across this and other studies using standard statistical methodology. For those studies for which an ERR estimate together with a measure of standard deviation is available, we can compute the best linear unbiased estimate (inverse-variance weighted) of ERR, given by:
|
| (1) |
|
| (2) |
|
The results of Table 2 suggest that the aggregate estimate of ERR from all low dose studies excluding the recent study of McGeoghegan et al.1 is 0.02 Sv–1 (95% CI –0.01 to 0.05), and after including it the aggregate estimate of ERR is essentially unchanged at 0.02 Sv–1 (95% CI –0.01 to 0.06). There is significant heterogeneity (p < 0.01) in risk between studies, among all groups considered in Table 2. Further analysis in which each study is removed in turn from the "All studies including McGeoghegan et al." group does not substantially alter the aggregate risk estimate, which increased to at most 0.04 Sv-1 (95% CI 0.01, 0.08) (after exclusion of the Massachusetts study18). Therefore, this analysis suggests that the present paper does little to change the conclusions arrived at in the previous meta-analysis,3 namely that the aggregate low-dose epidemiological data are still only very weakly supportive of a positive trend of cardiovascular disease with dose. As McGeoghegan et al. state: ‘the tentative nature of biological mechanisms ... [and] inhomogeneities in apparent dose–response, mean that the results are not consistent with any simple causal interpretation’.
References
1 McGeoghegan D, Binks K, Gillies M, Jones S, Whaley S. The non-cancer mortality experience of male workers at British Nuclear Fuels plc, 1946-2005. Int J Epidemiol (2008) 37:506–18.
2 Preston DL, Shimizu Y, Pierce DA, Suyama A, Mabuchi K. Studies of mortality of atomic bomb survivors. Report 13: solid cancer and noncancer disease mortality: 1950–1997. Radiat Res (2003) 160:381–407.[CrossRef][Web of Science][Medline]
3 Little MP, Tawn EJ, Tzoulaki I, et al. A systematic review of epidemiological associations between low and moderate doses of ionizing radiation and late cardiovascular effects, and their possible mechanisms. Radiat Res (2008) 169:99–109.[CrossRef][Web of Science][Medline]
4 Tüchsen F, Hannerz H, Burr H. A 12 year prospective study of circulatory disease among Danish shift workers. Occup Environ Med (2006) 63:451–55.
5 Andreassi MG, Botto N. DNA damage as a new emerging risk factor in atherosclerosis. Trends Cardiovasc Med (2003) 13:270–75.[CrossRef][Web of Science][Medline]
6 Botto N, Berti S, Manfredi S, et al. Detection of mtDNA with 4977 bp deletion in blood cells and atherosclerotic lesions of patients with coronary artery disease. Mutat Res (2005) 570:81–88.[Web of Science][Medline]
7 Mahmoudi M, Mercer J, Bennett M. DNA damage and repair in atherosclerosis. Cardiovasc Res (2006) 71:259–68.
8 Schultz-Hector S, Trott K-R. Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data? Int J Radiat Oncol Biol Phys (2007) 67:10–18.[Web of Science][Medline]
9 McGale P, Darby SC. Commentary: a dose–response relationship for radiation-induced heart disease - current issues and future prospects. Int J Epidemiol (2008) 37:518–23.
10 Ashmore JP, Krewski D, Zielinski JM, Jiang H, Semenciw R, Band PR. First analysis of mortality and occupational radiation exposure based on the National Dose Registry of Canada. Am J Epidemiol (1998) 148:564–74.
11 Johnson P, Atkinson WD, Nicholls JL. 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 Century (1999) London: Society for Radiological Protection.
12 Richardson DB, Wing S. Radiation and mortality of workers at Oak Ridge National Laboratory: positive associations for doses received at older ages. Environ Health Perspect (1999) 107:649–56.[Web of Science][Medline]
13 Atkinson WD, Law DV, Bromley KJ, Inskip HM. Mortality of employees of the United Kingdom Atomic Energy Authority, 1946-97. Occup Environ Med (2004) 61:577–85.
14 Vrijheid M, Cardis E, Ashmore P, et al. 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 (2007) 36:1126–35.
15 Yamada M, Wong FL, Fujiwara S, Akahoshi M, Suzuki G. Noncancer disease incidence in atomic bomb survivors, 1958–1998. Radiat Res (2004) 161:622–32.[CrossRef][Web of Science][Medline]
16 Carr ZA, Land CE, Kleinerman RA, et al. Coronary heart disease after radiotherapy for peptic ulcer disease. Int J Radiat Oncol Biol Phys (2005) 61:842–50.[CrossRef][Web of Science][Medline]
17 Darby SC, Doll R, Gill SK, Smith PG. Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis. Br J Cancer (1987) 55:179–90.[Web of Science][Medline]
18 Davis FG, Boice JD Jr, Hrubec Z, Monson RR. Cancer mortality in a radiation–exposed cohort of Massachusetts tuberculosis patients. Cancer Res (1989) 49:6130–36.
19 Ivanov VK, Maksioutov MA, Chekin SY, et al. The risk of radiation-induced cerebrovascular disease in Chernobyl emergency workers. Health Phys (2006) 90:199–207.[CrossRef][Web of Science][Medline]
20 Bolotnikova MG, Koshurnikova NA, Komleva NS, Budushchev EB, Okatenko PV. Mortality from cardiovascular diseases among male workers at the radiochemical plant of the ‘Mayak’ complex. Sci Total Environ (1994) 142:29–31.[CrossRef][Medline]
21 Kreuzer M, Kreisheimer M, Kandel M, Schnelzer M, Tschense A, Grosche B. Mortality from cardiovascular diseases in the German uranium miners cohort study, 1946-1998. Radiat Environ Biophys (2006) 45:159–66.[CrossRef][Web of Science][Medline]
22 Talbott EO, Youk AO, McHugh-Pemu KP, Zborowski JV. Long-term follow-up of the residents of the Three Mile Island accident area: 1979-1998. Environ Health Perspect (2003) 111:341–48.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||