INT . J . RADIAT . BIOL .,
1992,
VOL .
61,
NO .
5, 565-566
Letter Causality of relationship between paternal radiation exposure and leukaemia incidence in the children of Sellafield workers
Int J Radiat Biol Downloaded from informahealthcare.com by Mcgill University on 11/14/14 For personal use only.
(Received 25 November 1991)
In his recent analysis, Baverstock (1991) makes a strong case against the likelihood of a causal relationship between reported leukaemia incidence and paternal radiation dose in the children of Sellafield workers . This conclusion is important, since paternal doses reported in the study of Gardner et al . (1990) (e.g. > 10 mSv over 6 months) are not unique to Sellafield workers and the reported association might imply a leukaemogenic risk in the offspring of all male workers exposed to comparable doses . Baverstock's analysis reinforces the view that such dose levels would not be likely to present a significant hazard to the offspring of exposed individuals . However, the analysis does not dispose of some mechanisms which could be peculiar to the Sellafield situation . Most obviously, the reported association with externally measured dose may be serving as a marker for much higher dose levels from ingested radionuclides, or for exposure to leukaemogenic chemicals in the workplace . As an extreme possibility, fortuitous combination of a short-range particleemitting radionuclide (e.g. an Auger emitter) with an organic or biochemical molecule having affinity for cellular DNA provides an example of a situation not covered by the Baverstock analysis . This possibility is implicitly recognized by Baverstock when he states that `what is important in the present context is that there is no selective absorption in DNA, or in any of its bases, or indeed in any base sequence' (Baverstock 1991) . Though such a possibility might seem rather contrived, it cannot be readily dismissed on theoretical grounds and remains a mechanism which could be consistent with the reported observations . Further studies of childhood leukaemia in the vicinity of Sellafield might reasonably include a search for molecular species to be found in the context of nuclear fuel reprocessing which might be capable of vectoring short-range emitters to DNA . Another interesting aspect of Baverstock's analysis is the role played by dose-rate . It is concluded that doses below 0 .05 Gy/min induce single-strand breaks in DNA at lower frequency than occurs sponta-
neously, and are therefore unlikely to perturb the equilibrium between DNA degradation and repair . Higher dose-rates might induce such a perturbation, and Baverstock suggests that the experimental findings of Nomura (1982, 1986), showing raised cancer incidence in the offspring of irradiated mice, might result from a generalized repair defect induced at higher radiation doses (" 5 Gy) and dose-rate (- 0 .7 Gy/min) . It may be of relevance that for the reported doses to Sellafield workers (e.g. > 100 mSv over 10 years, > 10 mSv over 6 months) the seeming low dose-rates are only by inference . Precise data on the time-pattern of dose accumulation are not available, and it may be premature to conclude that all incidents resulting in dose accumulation involved only low dose-rate irradiation . These considerations emphasize the desirability of devising approaches to experimental test of the germ-line damage hypothesis, as well as the a priori evaluation of its plausibility as undertaken by Baverstock . One unambiguous prediction is that the age distribution of childhood leukaemia should be leftshifted to younger ages in the patient group hypothesized to have inherited a predisposing gene (Wheldon et al. 1989) . This hypothesis has been tested and confirmed by Gardner and Snee (1990) for the relevant group of patients at Sellafield . It would be of great interest to know whether a similar perturbation of age distribution has occurred at other locations where leukaemia `clusters' have been reported . Analysis of existing epidemiological databases should provide the answer . Another prediction results from the two-hit induction model for childhood acute leukaemia (Greaves and Chan 1986) also invoked by Baverstock in his analysis . Inheritance of the first of two leukaemogenic alleles by all somatic cells implies the possibility of multiple leukaemic transformations by independent somatic (second) mutation in a large number of predisposed haemopoietic cells . Recently we have developed a mathematical model to explore this possibility, and have concluded (Wheldon et al.
0020-7616/92 $3.00 © 1992 Taylor & Francis Ltd
Int J Radiat Biol Downloaded from informahealthcare.com by Mcgill University on 11/14/14 For personal use only.
566
Letter
1992) that inheritance of a single predisposing allele would lead to the development of a large number (e.g. 101-10 3 ) of independent leukaemic events in each affected individual . Possibilities exist for the detection of the implied multiclonality of leukaemia in these patients . Feasible approaches include the use of X-linked molecular polymorphisms in female patients, immunoglobulin gene rearrangements in B-lineage leukaemia patients and T-cell receptor gene rearrangements in T-lineage leukaemia patients (Wainscoat and Fey 1990) . Though investigations of historical cases may be precluded by lack of biological material, clonality studies on any new cases in the vicinity of Sellafield or other `leukaemia cluster' sites where germ-cell injury is a candidate causative mechanism may prove instructive . T. E . WHELDONtl, R. J . MAIRSt, A. BARRETTt§ tRadiation Oncology Research Group, CRC Beatson Laboratories, University of Glasgow, Garscube Estate, Glasgow G11 6NT, UK I Department of Clinical Physics and Bio-Engineering, West of Scotland Health Boards, 11 West Graham Street, Glasgow G4 9LF, UK §Beatson Oncology Centre, Western Infirmary, Glasgow G 11 6NT, UK
References 1991, DNA instability, paternal irradiation and leukaemia in children around Sellafield . International Journal of Radiation Biology, 60, 581-596 . GARDNER, M . J . and SNEE, M. P ., 1990, Leukaemia and lymphoma among young people near Sellafield . British Medical Journal, 300, 678 . GARDNER, M . J ., SNEE, M . P ., HALL, A. J ., POWELL, C . A ., DOWNES, S . and TERRELL, D., 1990, Results of a case control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria . British Medical Journal, 300, 423-429 . GREAVES, M . F. and CHAN, L. C ., 1986, Is spontaneous mutation the major cause of childhood acute lymphoblastic leukaemia? British Journal of Haematology, 64, 1-13 . NOMURA, T ., 1982, Parental exposure to X-rays and chemicals induces heritable tumours and anomalies in mice . Nature, 296, 575-577 . NOMURA, T., 1986, Further studies on X-ray and chemicallyinduced germ-line alterations causing tumours and malformations in mice . Genetic Toxicology of Environmental Chemicals, Part B, edited by C . Ramel et al., Alan R . Liss, New York, pp . 13-20 . WAINSCOAT, J . S . and FEY, M . F., 1990, Assessment of clonality in human tumours - a review. Cancer Research, 50, 1355-1360 . WHELDON, T. E ., MAIRS, R . and BARRETT, A., 1989, Germ cell injury and childhood leukaemia clusters . Lancet, 1, 792-793 . WHELDON, T . E ., MAIRS, R . J ., BARRETT, A., WHELDON, E . G. and GIBSON, B . E ., 1992, Alternative models for early onset of childhood leukaemia . British Journal of Cancer (In press) . BAVERSTOCK, K . E .,
1992,
VOL .
61,
NO .
5, 565-566
Letter Causality of relationship between paternal radiation exposure and leukaemia incidence in the children of Sellafield workers
Int J Radiat Biol Downloaded from informahealthcare.com by Mcgill University on 11/14/14 For personal use only.
(Received 25 November 1991)
In his recent analysis, Baverstock (1991) makes a strong case against the likelihood of a causal relationship between reported leukaemia incidence and paternal radiation dose in the children of Sellafield workers . This conclusion is important, since paternal doses reported in the study of Gardner et al . (1990) (e.g. > 10 mSv over 6 months) are not unique to Sellafield workers and the reported association might imply a leukaemogenic risk in the offspring of all male workers exposed to comparable doses . Baverstock's analysis reinforces the view that such dose levels would not be likely to present a significant hazard to the offspring of exposed individuals . However, the analysis does not dispose of some mechanisms which could be peculiar to the Sellafield situation . Most obviously, the reported association with externally measured dose may be serving as a marker for much higher dose levels from ingested radionuclides, or for exposure to leukaemogenic chemicals in the workplace . As an extreme possibility, fortuitous combination of a short-range particleemitting radionuclide (e.g. an Auger emitter) with an organic or biochemical molecule having affinity for cellular DNA provides an example of a situation not covered by the Baverstock analysis . This possibility is implicitly recognized by Baverstock when he states that `what is important in the present context is that there is no selective absorption in DNA, or in any of its bases, or indeed in any base sequence' (Baverstock 1991) . Though such a possibility might seem rather contrived, it cannot be readily dismissed on theoretical grounds and remains a mechanism which could be consistent with the reported observations . Further studies of childhood leukaemia in the vicinity of Sellafield might reasonably include a search for molecular species to be found in the context of nuclear fuel reprocessing which might be capable of vectoring short-range emitters to DNA . Another interesting aspect of Baverstock's analysis is the role played by dose-rate . It is concluded that doses below 0 .05 Gy/min induce single-strand breaks in DNA at lower frequency than occurs sponta-
neously, and are therefore unlikely to perturb the equilibrium between DNA degradation and repair . Higher dose-rates might induce such a perturbation, and Baverstock suggests that the experimental findings of Nomura (1982, 1986), showing raised cancer incidence in the offspring of irradiated mice, might result from a generalized repair defect induced at higher radiation doses (" 5 Gy) and dose-rate (- 0 .7 Gy/min) . It may be of relevance that for the reported doses to Sellafield workers (e.g. > 100 mSv over 10 years, > 10 mSv over 6 months) the seeming low dose-rates are only by inference . Precise data on the time-pattern of dose accumulation are not available, and it may be premature to conclude that all incidents resulting in dose accumulation involved only low dose-rate irradiation . These considerations emphasize the desirability of devising approaches to experimental test of the germ-line damage hypothesis, as well as the a priori evaluation of its plausibility as undertaken by Baverstock . One unambiguous prediction is that the age distribution of childhood leukaemia should be leftshifted to younger ages in the patient group hypothesized to have inherited a predisposing gene (Wheldon et al. 1989) . This hypothesis has been tested and confirmed by Gardner and Snee (1990) for the relevant group of patients at Sellafield . It would be of great interest to know whether a similar perturbation of age distribution has occurred at other locations where leukaemia `clusters' have been reported . Analysis of existing epidemiological databases should provide the answer . Another prediction results from the two-hit induction model for childhood acute leukaemia (Greaves and Chan 1986) also invoked by Baverstock in his analysis . Inheritance of the first of two leukaemogenic alleles by all somatic cells implies the possibility of multiple leukaemic transformations by independent somatic (second) mutation in a large number of predisposed haemopoietic cells . Recently we have developed a mathematical model to explore this possibility, and have concluded (Wheldon et al.
0020-7616/92 $3.00 © 1992 Taylor & Francis Ltd
Int J Radiat Biol Downloaded from informahealthcare.com by Mcgill University on 11/14/14 For personal use only.
566
Letter
1992) that inheritance of a single predisposing allele would lead to the development of a large number (e.g. 101-10 3 ) of independent leukaemic events in each affected individual . Possibilities exist for the detection of the implied multiclonality of leukaemia in these patients . Feasible approaches include the use of X-linked molecular polymorphisms in female patients, immunoglobulin gene rearrangements in B-lineage leukaemia patients and T-cell receptor gene rearrangements in T-lineage leukaemia patients (Wainscoat and Fey 1990) . Though investigations of historical cases may be precluded by lack of biological material, clonality studies on any new cases in the vicinity of Sellafield or other `leukaemia cluster' sites where germ-cell injury is a candidate causative mechanism may prove instructive . T. E . WHELDONtl, R. J . MAIRSt, A. BARRETTt§ tRadiation Oncology Research Group, CRC Beatson Laboratories, University of Glasgow, Garscube Estate, Glasgow G11 6NT, UK I Department of Clinical Physics and Bio-Engineering, West of Scotland Health Boards, 11 West Graham Street, Glasgow G4 9LF, UK §Beatson Oncology Centre, Western Infirmary, Glasgow G 11 6NT, UK
References 1991, DNA instability, paternal irradiation and leukaemia in children around Sellafield . International Journal of Radiation Biology, 60, 581-596 . GARDNER, M . J . and SNEE, M. P ., 1990, Leukaemia and lymphoma among young people near Sellafield . British Medical Journal, 300, 678 . GARDNER, M . J ., SNEE, M . P ., HALL, A. J ., POWELL, C . A ., DOWNES, S . and TERRELL, D., 1990, Results of a case control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria . British Medical Journal, 300, 423-429 . GREAVES, M . F. and CHAN, L. C ., 1986, Is spontaneous mutation the major cause of childhood acute lymphoblastic leukaemia? British Journal of Haematology, 64, 1-13 . NOMURA, T ., 1982, Parental exposure to X-rays and chemicals induces heritable tumours and anomalies in mice . Nature, 296, 575-577 . NOMURA, T., 1986, Further studies on X-ray and chemicallyinduced germ-line alterations causing tumours and malformations in mice . Genetic Toxicology of Environmental Chemicals, Part B, edited by C . Ramel et al., Alan R . Liss, New York, pp . 13-20 . WAINSCOAT, J . S . and FEY, M . F., 1990, Assessment of clonality in human tumours - a review. Cancer Research, 50, 1355-1360 . WHELDON, T. E ., MAIRS, R . and BARRETT, A., 1989, Germ cell injury and childhood leukaemia clusters . Lancet, 1, 792-793 . WHELDON, T . E ., MAIRS, R . J ., BARRETT, A., WHELDON, E . G. and GIBSON, B . E ., 1992, Alternative models for early onset of childhood leukaemia . British Journal of Cancer (In press) . BAVERSTOCK, K . E .,
