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Stillbirths among offspring of male radiation workers
CORRESPONDENCE
To support their suggestion that anencephaly can result from paternal preconceptional irradiation, Parker and colleagues cite a mouse experiment4 in which they state that anencephaly was seen in the offspring of male irradiated mice. Unfortunately, a mistake has crept in because this paper makes no mention of anencephaly. Some limitations of the study of radiation workers seem important. For example, there was no consideration of many possible factors in the mothers that would seem to be much more likely to affect stillbirth rates than paternal preconceptional irradiation. Paul B Selby Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830-6480, USA (e-mail: [email protected]) 1
2
3
4
Parker L, Pearce MS, Dickinson HO, et al. Stillbirths among offspring of male radiation workers at Sellafield nuclear reprocessing plant. Lancet 1999; 354: 1407–14. United Nations. Sources and effects of ionizing radiation. United Nations scientific committee on the effects of atomic radiation UNSCEAR 1993 Report to the General Assembly, with scientific annexes. New York: United Nations, 1993. Selby PB, Russell WL. First-generation litter-size reduction following irradiation of spermatogonial stem cells in mice and its use in risk estimation. Environ Mutagen 1985; 7: 451–69. Kirk KM, Lyon MF. Induction of congenital malformations in the offspring of male mice treated with x-rays at pre-meiotic and postmeiotic stages. Mutat Res 1984; 125: 75–85.
Authors’ reply Sir—In response to Pat Doyle and colleagues, as we reported, the crude stillbirth rates in the two groups are higher than those in the radiation workers largely because the children tended to be born in earlier years, when rates were higher, and to men of lower social classes. In comparison with the non-Sellafield cohort there were significantly more stillbirths than expected for the radiation worker cohort (115·0 stillbirths predicted [95% CI 100·6–129·3]; 130 observed). Our analysis was of stillbirth risk to radiation workers defined as men who had received an occupational radiation exposure in the time before conception. When moving from annual dose records (in the cohort study) to film badge records (in the case-control study), six births (five liveborn and one stillborn) included in the cohort study proved not to have had a dose in the preconception period and so were excluded from the study. Doyle and colleagues are mistaken in suggesting that men with a zero 90 day dose were excluded from the analyses. There were four men who each had two stillborn babies and, as reported, we looked at
THE LANCET • Vol 355 • February 5, 2000
familial effects by means of a variance components model, which showed little effect. We were concerned about the misclassification of birth order, especially in early years, and we have done several subanalyses and none suggested an undue influence. The results of the post 1961 analysis, in which misclassification of birth order was less of a difficulty, were very similar to those including the 1950s data (see table 5). Doyle and colleagues are concerned about identification of children. Respondents to the validation questionnaire included both past and present employees from Sellafield. The error rate, as reported, was less than 2%. This error rate was achieved by a careful process which included comparison of spouse information, occupation and, for parents born after 1969, place of birth. There were 278 mothers (501 liveborn children, six stillbirths) who were radiation workers before conception (dose range 0·08–159·9 mSv). With such small numbers and low exposure, we were unable to show a significant effect (odds ratio at 100 mSv 5·13 [95% CI 0·083–31·77], likelihoodratio-test statistic p=0·136). Paul Selby suggests that we claim the paternal preconceptional irradiation at Sellafield has led to a substantial increase in stillbirths. We reported a robust statistical association between father’s paternal preconceptional irradiation and stillbirth risk in radiation workers in whom there is a significant excess of stillbirths in comparison with the rest of Cumbria. Direct comparison of the human situation with animal models is extremely complicated, especially since there is no animal model in which the exposure pattern observed in long-term workers in the nuclear industry has been adequately replicated. The extrapolation of the association we have observed, over a dose range up to 910 mSv, to a dose of 5000 mSv is meaningless. We agree that we had little data on mothers, but consider that our careful consideration of social class, father’s age, and birth order did contribute to a consideration of some maternal factors to the analysis. To affect our results, any remaining maternal risk factor would need to be highly correlated with father’s radiation exposure independent of social class and the other covariates we considered. *Louise Parker, Alan W Craft, Mark S Pearce, Heather O Dickinson Department of Child Health, The Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK
Sir—The report by Louise Parker and colleagues1 of a dose-response relation between fathers’ preconception radiation dose and the subsequent risk of stillbirth is unusual and would be easier to assess if we knew whether or not there had been a significant excess of stillbirths among the radiation workers. We are told that the model they used, based on 3468 stillbirths of 235 316 total births in Cumbria to non-Sellafield workers, predicted 18·1 stillbirths to non-radiation workers at Sellafield against 21 observed and 99·9 stillbirths among children conceived before their fathers’ employment at Sellafield against 96 observed. However, we do not know how many stillbirths were predicted for the radiation workers whose babies were conceived after first employment against an observed number of 130. It would be helpful to know what the predicted number was and the 95% confidence limit of the resultant stillbirth ratio. Richard Doll CTSU, Harkness Building, Radcliffe Infirmary, Oxford OX2 6HE, UK 1
Parker L, Pearce MS, Dickinson HO, et al. Stillbirths among the offspring of male radiation workers at the Sellafield nuclear reprocessing plant. Lancet 1999; 354: 1407–14.
Sir—The radiation workers in Louise Parker and colleagues’ study1 had total cumulative external preconceptional doses in the range 0·01–911 mSv with a median of 30·1 mSv. Of the 9208 births to the partners of these men, 130 were stillborn and the statistical models derived by the researchers predict that up to 31·9 of these might be attributable to the radiation exposure received by the fathers. By contrast, studies on the offspring of the Japanese atomic bomb survivors have failed to find any significant association with parental radiation exposure for a range of adverse pregnancy outcomes and other measures of possible genetic effects.2 In the atomic bomb studies, stillbirths alone, with maternal age and parity taken into account, were analysed and no association with paternal dose was shown. Studies of somatic mutations in Sellafield workers, who received low dose chronic exposure, consistently indicate lower yields in comparison with similar studies on the acutely exposed Japanese atomic bomb survivors.3,4 Chromosome analysis of peripheral blood lymphocytes for stable aberrations revealed frequencies per unit dose a factor of six lower than those seen in atomic bomb survivors.3
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To support their suggestion that anencephaly can result from paternal preconceptional irradiation, Parker and colleagues cite a mouse experiment4 in which they state that anencephaly was seen in the offspring of male irradiated mice. Unfortunately, a mistake has crept in because this paper makes no mention of anencephaly. Some limitations of the study of radiation workers seem important. For example, there was no consideration of many possible factors in the mothers that would seem to be much more likely to affect stillbirth rates than paternal preconceptional irradiation. Paul B Selby Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830-6480, USA (e-mail: [email protected]) 1
2
3
4
Parker L, Pearce MS, Dickinson HO, et al. Stillbirths among offspring of male radiation workers at Sellafield nuclear reprocessing plant. Lancet 1999; 354: 1407–14. United Nations. Sources and effects of ionizing radiation. United Nations scientific committee on the effects of atomic radiation UNSCEAR 1993 Report to the General Assembly, with scientific annexes. New York: United Nations, 1993. Selby PB, Russell WL. First-generation litter-size reduction following irradiation of spermatogonial stem cells in mice and its use in risk estimation. Environ Mutagen 1985; 7: 451–69. Kirk KM, Lyon MF. Induction of congenital malformations in the offspring of male mice treated with x-rays at pre-meiotic and postmeiotic stages. Mutat Res 1984; 125: 75–85.
Authors’ reply Sir—In response to Pat Doyle and colleagues, as we reported, the crude stillbirth rates in the two groups are higher than those in the radiation workers largely because the children tended to be born in earlier years, when rates were higher, and to men of lower social classes. In comparison with the non-Sellafield cohort there were significantly more stillbirths than expected for the radiation worker cohort (115·0 stillbirths predicted [95% CI 100·6–129·3]; 130 observed). Our analysis was of stillbirth risk to radiation workers defined as men who had received an occupational radiation exposure in the time before conception. When moving from annual dose records (in the cohort study) to film badge records (in the case-control study), six births (five liveborn and one stillborn) included in the cohort study proved not to have had a dose in the preconception period and so were excluded from the study. Doyle and colleagues are mistaken in suggesting that men with a zero 90 day dose were excluded from the analyses. There were four men who each had two stillborn babies and, as reported, we looked at
THE LANCET • Vol 355 • February 5, 2000
familial effects by means of a variance components model, which showed little effect. We were concerned about the misclassification of birth order, especially in early years, and we have done several subanalyses and none suggested an undue influence. The results of the post 1961 analysis, in which misclassification of birth order was less of a difficulty, were very similar to those including the 1950s data (see table 5). Doyle and colleagues are concerned about identification of children. Respondents to the validation questionnaire included both past and present employees from Sellafield. The error rate, as reported, was less than 2%. This error rate was achieved by a careful process which included comparison of spouse information, occupation and, for parents born after 1969, place of birth. There were 278 mothers (501 liveborn children, six stillbirths) who were radiation workers before conception (dose range 0·08–159·9 mSv). With such small numbers and low exposure, we were unable to show a significant effect (odds ratio at 100 mSv 5·13 [95% CI 0·083–31·77], likelihoodratio-test statistic p=0·136). Paul Selby suggests that we claim the paternal preconceptional irradiation at Sellafield has led to a substantial increase in stillbirths. We reported a robust statistical association between father’s paternal preconceptional irradiation and stillbirth risk in radiation workers in whom there is a significant excess of stillbirths in comparison with the rest of Cumbria. Direct comparison of the human situation with animal models is extremely complicated, especially since there is no animal model in which the exposure pattern observed in long-term workers in the nuclear industry has been adequately replicated. The extrapolation of the association we have observed, over a dose range up to 910 mSv, to a dose of 5000 mSv is meaningless. We agree that we had little data on mothers, but consider that our careful consideration of social class, father’s age, and birth order did contribute to a consideration of some maternal factors to the analysis. To affect our results, any remaining maternal risk factor would need to be highly correlated with father’s radiation exposure independent of social class and the other covariates we considered. *Louise Parker, Alan W Craft, Mark S Pearce, Heather O Dickinson Department of Child Health, The Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK
Sir—The report by Louise Parker and colleagues1 of a dose-response relation between fathers’ preconception radiation dose and the subsequent risk of stillbirth is unusual and would be easier to assess if we knew whether or not there had been a significant excess of stillbirths among the radiation workers. We are told that the model they used, based on 3468 stillbirths of 235 316 total births in Cumbria to non-Sellafield workers, predicted 18·1 stillbirths to non-radiation workers at Sellafield against 21 observed and 99·9 stillbirths among children conceived before their fathers’ employment at Sellafield against 96 observed. However, we do not know how many stillbirths were predicted for the radiation workers whose babies were conceived after first employment against an observed number of 130. It would be helpful to know what the predicted number was and the 95% confidence limit of the resultant stillbirth ratio. Richard Doll CTSU, Harkness Building, Radcliffe Infirmary, Oxford OX2 6HE, UK 1
Parker L, Pearce MS, Dickinson HO, et al. Stillbirths among the offspring of male radiation workers at the Sellafield nuclear reprocessing plant. Lancet 1999; 354: 1407–14.
Sir—The radiation workers in Louise Parker and colleagues’ study1 had total cumulative external preconceptional doses in the range 0·01–911 mSv with a median of 30·1 mSv. Of the 9208 births to the partners of these men, 130 were stillborn and the statistical models derived by the researchers predict that up to 31·9 of these might be attributable to the radiation exposure received by the fathers. By contrast, studies on the offspring of the Japanese atomic bomb survivors have failed to find any significant association with parental radiation exposure for a range of adverse pregnancy outcomes and other measures of possible genetic effects.2 In the atomic bomb studies, stillbirths alone, with maternal age and parity taken into account, were analysed and no association with paternal dose was shown. Studies of somatic mutations in Sellafield workers, who received low dose chronic exposure, consistently indicate lower yields in comparison with similar studies on the acutely exposed Japanese atomic bomb survivors.3,4 Chromosome analysis of peripheral blood lymphocytes for stable aberrations revealed frequencies per unit dose a factor of six lower than those seen in atomic bomb survivors.3
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