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The risk of childhood leukaemia with preconceptual exposure to ionising radiation
Radiography
(1999) 5, 39-44
REVIEW
The risk of childhood leukaemia with preconceptual exposure to ionising radiation Linda Tutty and Patrick C. Brennan U. C. D. Sciwoi qf Diq.y~ost~cImz~~in~. Sf A~itimy’s, Hwb~rt An~~te. D~hh 4.
lrelilllri ilZ&md 19 Ortuber
2 ]111y 1997; nccrptcd 199x1
words: parental; paternal; Sellafield; epidemiology; genetics.
Key
The purpose of this article is to review the current literature on the association between parental irradiation and an excess risk of childhood leukaemia. The risk of childhood leukaemia resulting from paternal pre-conceptional radiation exposure found among children from the Sellafield workforce is compared with the risk in a number of other epidemiological studies. Specifically, the extent of a cluster of leukaemia cases in Seascale is incompatible with: parental exposure risks of other offspring of workers in Scottish, Canadian, French and other English nuclear stations; data collected from Japanese bomb survivors; available information following the Chernobyl accident. It is also proposed that the Sellafield hypothesis is in conflict with what is known regarding familial pattern of childhood leukaemia and the level of radiation dose necessary to increase mutation rates. It is concluded that the original association found by Gardner has been confined to children in Seascale and is largely inconsistent with other scientific evidence.
Introduction The 1983 television documentary ‘Windscale: the Nuclear Laundry’ led to a much increased interest in the link between local community health risks and radioactive emissions from nuclear power stations. This television programme suggested that leukaemia, a relatively rare disease, seemed to occur at an unusually high rate in the village of Seascale which is on the coast about 3 km south of the nuclear waste reprocessing operation at Sellafield. Shortly after this programme was broadcast, an Independent Advisory Group chaired by Sir Douglas Black was set up by the British government to establish whether this proposed increased incidence of leukaemia could be supported by examining death certificates and cancer registrations [I]. The Black enquiry demonstrated that within the Millom rural district a raised leukaemia mortality rate was evident for the under 25-year-olds during 1968-78 [2]. When mortality ratios were standardized and compared with 151 1078-8174/99/010039+06
$18.00
similar rural districts in England and Wales, Millom was seen to be second highest. This group did not examine any link between the effect of radioactive discharge and leukaemia, but recommended further research.
The Gardner
hypothesis
In 1987, Gardner and his colleagues undertook a cohort study comparing the incidence of leukaemia in 1068 children born in Seascale with 1546 children who were born elsewhere but attended school in Seascale [3, 41. The results backed up the findings of the Black enquiry with a IO-fold excess for leukaemia in those children born in Seascale. Three years later, Gardner published the findings of a case-controlled study examining all cases of leukaemia in the West Cumbria Health Authority diagnosed before the 25th year [5, 61. The most notable finding was a strong dose-dependent statistical association between relatively high levels 0 1999 The College of Radiographers
40
of paternal preconceptional irradiation (PPI) received occupationally at Sellafield and the incidence of childhood leukaemia in their offspring. In particular, fathers who were exposed to doses of 100 millisieverts (mSv) or greater were at risk. Gardner suggested that this association was sufficient to explain the excess of leukaemia cases in Seascale [5, 71. The findings of Gardner fuelled a lengthy court case heard in the High Court in London during 1992-1993 [8].
United Kingdom Since 1990 a number of other studies have investigated the possible link between PPI and leukaemia. An excess of childhood leukaemia was reported near the Dounreay nuclear installation in Northern Scotland. Results of a case-control study of under 15-year-olds [9] reported that the excess could not be explained by factors associated with parental employment in the nuclear industry before conception, including radiation exposure. However, the authors of this study acknowledge that the numbers were small and the results should be treated with some degree of caution. A larger case-controlled study by Kinlen et al., again in Scotland, examined all leukaemias diagnosed in Scotland before the age of 25 [lo]. Fathers in the workforce of a variety of nuclear installations were identified. The results offered no support for the Gardner hypothesis. Kinlen, in a further study, also found that the excess of leukaemia in Seascale was not limited to children born there, but also extended to children born elsewhere but living in Seascale [II]. This does not correlate with Gardner’s findings and may be attributed to the fact that three cases of leukaemia in Kinlen’s study were not included by Gardner and of the three, only one of the children’s father had received any occupational dose before the child’s conception. In 1993 results of a larger case-control study examining the excess of childhood leukaemia in young children living near Aldermaston and Burghfield nuclear weapons facilities in West Berkshire established a weak association of childhood leukaemia and PI’1 [12]. Unlike Gardner’s findings, however, the doses were low and risks were not dependent on dose. It is interesting that clusters of leukaemia have been found at six potential nuclear sites in United Kingdom and two nuclear installations which were constructed but never operated [x3], suggesting a factor other than radiation to be responsible.
Tutty and Brent&
Parker and his colleagues proposed that if a statistical association exists between preconceptional doses received by fathers working in Sellafield and the increased incidence of childhood leukaemia, then radiation doses should be concentrated in fathers of children born in Seascale [14]. This is particularly relevant since no excess of leukaemia in the rest of Cumbria has been observed, despite the fact that over 90% of births to Sellafield employees occurred outside Seascale [15-181. No such concentration was shown to exist, in fact 93% of the total preconceptional dose is delivered to those fathers with children born outside Seascale [19]. This dose distribution is highly inconsistent with the proportion of risk accounting for the Seascale excess. In Gardner’s work, a 6-8-fold increased risk of childhood leukaemia was reported in children of fathers who received a total recorded external dose of > 100 mSv in the 6 months preceding conception [7]. These figures were obtained by halving the preceding annual dose summaries [19]. The Health and Safety Executive (HSE) also found a significant association of cumulative PPI with leukaemia in Sellafield workers, which shows some agreement with the Gardner study [IT]. However, the HSE findings must be treated with some caution because when one individual with a very large dose was omitted from the study the significant trend was ‘almost entirely lost’ [17]. The HSE did not, however, show any association with the 6 month pre-conceptional dose, nor did they find any link with the dose received in the more biologically appropriate 12 week period immediately before conception [a]. A case-controlled study, very recently published by the National Radiological Protection Board (NRPB) in the UK, tested the Gardner hypothesis [20]. This large study gathered data from the National Registry for Radiation Workers, National Registry of Childhood Tumours, Oxford Survey of Childhood Cancers and Office of Population Censuses and Surveys. For each child with cancer a control was selected matched on sex and place and date of birth. The study established that fathers of children with leukaemia, when compared with the fathers of controls, were significantly more likely to be radiation workers. However, no dose response relationship was shown for any of the exposure periods examined; instead the association was most notable for those with doses below the level of detection. No significant increase in risk was noted for fathers who had lifetime exposures greater than
Parental exposures
and childhood
41
leukaemia
100 mSv, doses of 10 mSv or greater in the 6 months prior to conception, or doses of 5 mSv or more in the 3 months before conception. Maternal radiation work was not associated with a significantly elevated risk of childhood leukaemia. It was concluded by the authors of this study that no support could be offered for the Gardner hypothesis. It was judged that the observed association was either a chance finding or resulted from an alternative cause.
absence of an increased incidence of leukaemia among 263 offspring conceived shortly after the bombings, whose fathers received a dose 2 10 mSv, is inconsistent with the findings of Gardner. No inverse dose-rate effect has been hypothesized which would be necessary to explain the disparity between the Gardner and the atomic bomb survivors’ data.
Chernobyl Ontario A study carried out further afield investigating leukaemia in children (under the age 15 years) born to mothers living near nuclear stations in Ontario failed to suggest any excess risk of leukaemia arising from occupational pre-conceptional exposure, irrespective of the pre-conception dose period used 1211.
La Hague La Hague has one of the world’s three remaining nuclear reprocessing plants operating on an industrial level. Research carried out by Pobel and Vie1 [22] in the La Hague did not support an association between fathers’ exposure to radiation and childhood leukaemia, since the fathers of children diagnosed with leukaemia did not receive any radiation dose before conception. They did, however, find evidence for a causal link between leukaemia and environmental radiation exposure resulting from recreational activities on local beaches. Other authors have questioned the study design and are not convinced by this association [23-251.
Japanese
data
The Sellafield findings also suggest sensitivities to ionising radiation, with regard to the induction of leukaemia, to be at least 50 times greater than results drawn from Japanese data [26]. The absence of any excess of childhood leukaemia among over 30 000 children of Japanese survivors of the atomic bombings of Hiroshima and Nagasaki has been confirmed, with fathers receiving a preconceptional dose in excess of 10 mSv, with an average dose of 418 mSv [8]. In addition, the
On the 26 April 1986, the accident at the nuclear reactor in Chernobyl, in the former Soviet Union, released large amounts of radioactivity into the atmosphere [27]. The dissemination of radioactive isotopes, principally Iodine-131 and Caesium-137 occurred across a wide area of Europe [28]. Outside Chernobyl, contamination resulting from the accident was highest in Greece, with high levels recorded in the Scandinavian countries [29-311. All cases of childhood leukaemia diagnosed throughout Greece since the accident have been documented. Petridou and colleagues found that preconceptional irradiation has no significant effect on leukaemia incidence at any of the age groups studied [29]. Other workers studying the incidence of leukaemia in Finland [31] and in Sweden [32] excluded any link with leukaemia and increased levels of radiation associated with Chernobyl.
Genetics Familial patterns of childhood leukaemia are uncommon [19]. From the U.K. National Childhood Cancer Register, it is estimated that the true proportion of genetically determined leukaemia is about 5%. This low proportion, along with the fact that the disease presents in approximately I in 2000 children, suggests that a recessive mutation with a low degree of penetrance contributes to the disease. This is in contrast to the dominant mutation with a high degree of penetrance that would be necessary to be responsible for the Sellafield data reported by Gardner [33]. In addition, the Gardner hypothesis does not agree with what is known of mutation rates by radiation. Tawn maintains ‘there is no evidence that radiation can induce fragile sites in germ cells or preferentially damage pre-existing heritable fragile sites’ [I]. A study on children of atomic bomb survivors found no increased frequency of mutations [19]. These
42 Table
Tutty and Brennan 1. A summary of some of the risk ratios for childhood
Author(s) of study and reference
Description
“Gardner et al. [5] Kinlen et al. [lOI
Kinlen et al. [II]
Roman el al. [12]
Wakeford et al. [18]
McLaughlin
et al. [?,I]
Auvinen et al. [31]
leukaemia described in the literature
of data
Data
Risk ratio
Risk ratio of childhood leukaemia for children of fathers receiving preconceptual irradiation at Sellafield Risk of ratio of childhood leukaemia for children of fathers who received preconceptual irradiation exposure from the Scottish Nuclear industry
BC (3 100 mSv) 6 months BC (3 10 mSv) BC ( 2 50 mSv) 6 months BC (2 5 mSv) 3 months BC (2 2.5 mSv)
Risk ratio of childhood leukaemia for children born in Seascale compared with those born elsewhere
Seascale Elsewhere
Risk ratio for childhood leukaemia & non-Hodgkin’s lymphoma in West Berkshire and North Hampshire for parents employed in a nuclear establishment before conception
Father Mother
2.8
Risk ratios for all types of leukaemias within West Cumbria excluding the Sellafield Ward
O-4 years
0.93
O-14 years
0.85
O-24 years
0.95
Risk ratio of childhood leukaemia in Ontario with fathers having detectable radiation exposures Risk ratio of childhood leukaemia in Finland following Chernobyl accident
the
6.24 7.17 1.04 1.26 1.27 15.8 6.7
0.0
0.87
1986-M
0.95
1989-92
1.01
“indicates a study which demonstrated a statistically significant finding Risk ratios were calculated by dividing the observed number of cases by the expected number. BC = before conception; mSv=milliSieverts.
authors suggest that for an acute exposure a dose of 2 Sv is required to double the mutation rate in humans and 4 Sv for chronic exposure. These levels are far in excess of those received by Seascale workers. The association at the doses indicated by Gardner would suggest that children of radiologists would be vulnerable to an increased risk of leukaemia, which was not found to be the case [M]. If heritable genetic effects are to play a major role following radiation exposure, increased common congenital malformations would be anticipated to occur at a higher rate than leukaemia [17]. However, no study to date has demonstrated such an incidence in atomic bomb survivors or in Seascale offspring [17, 351.
Alternative
explanations
Since the majority of the literature seems to suggest parental exposure is not responsible for the increase in leukaemia, it is interesting to consider
other possibilities. According to Tawn, the incidence of leukaemia is associated with the country of residence rather than ethnic origin, thus indicating an environmental rather than a heritable determinant [I]. An infective basis brought about by an increase in population mixing in previously isolated areas has been proposed as an explanation for the clusters of excess leukaemia [la]. In particular, large scale mixing of rural and urban groups of people leads to an increased incidence in the disease [36-381. Although the route and nature of infection remains unclear [36, 391, it has been established that specific viruses can cause leukaemia in animals, as HTLV-1 does in humans [36]. In Seascale the continual influx of new-comers from urban backgrounds may explain the excess of leukaemia incidence highlighted by the village’s isolation [38].
Conclusion The Gardner hypothesis states that parental, in particular occupational radiation exposure, prior to
P?wental exposures
and childhood
leukaemia
conception, can lead to mutations in their sperm which significantly increases the risk of the development of childhood leukaemia (Table I). Observations sustained by studies in the neighbourhood of other nuclear installations in the U.K., Canada and France, on the offspring of atomic bomb survivors and on exposed persons following the Chernobyl accident do not support the hypothesis (Table 1). Knowledge of radiation genetics and hereditability of the leukaemia suggests that radiation cannot be accountable for Sellafield’s high incidence of the disease in children. Kinlen has produced compelling evidence in favour of unusual forms of population mixing accounting for the raised risk of childhood leukaemia, which is consistent with an infective basis for the disease. In the lengthy court case previously referred to [8], with the evidence before him, the judge concluded: ‘the scales tilt decisively in fiwot4~ of &e Defendants, and fhe Plaintiffs, therefure, have failed to safisfy me on fhe lhaf PPI zuas a material conbbalance of p&abilikies hfoty came of the Seascale excess’[Ft-erzch, the Hon. MY
43
Sellafield nuclear plant. Environ Henifh Perspecf 1991; 94: 5-7.
8. Wakeford R. The risk of childhood cancer from intrauterine and preconceptional exposure to ionizing radiation. Environ Healfh Perspecf 1995; 103: 1018-25. 9. Urquhart JD, Black RJ, Muirhead MJ ef ai. Case-control study of leukaemia and non-Hodgkin’s lymphoma in children in Caithness near the Dounreay nuclear installation. Br Med ] 1991; 302: 687-92. 10. Kinlen LJ, Clarke K, Balkwill A. Paternal preconceptional radiation exposure in the nuclear industry and leukaemia and non-Hodgkin’s lymphoma in young people in Scotland. Br Med] 1993; 306: 1153-8. 11. Kinlen LJ. Can paternal preconceptional radiation account for the increase of leukaemia and non-Hodgkin’s lymphoma in Seascale? Br Med 1 1993; 306: 1718-21. 12. Roman E, Watson A, Beral V ef ill. Case-control study of leukaemia and non-Hodgkin’s lymphoma among children aged 0-4 years living in West Berkshire and North Hampshire health districts, Br Med ] 1993; 306: 615-21. 13. Smart RC. What 14.
]r4sfice, 19931.
In conclusion, an association between parental pre-conceptional exposure radiation and an excess of childhood leukaemia is unlikely, and the cluster of cases of childhood leukaemia in Seascale currently remains an enigma.
15.
16.
17.
References 18. I. Tawn EJ. Leukaemia and Sellafield: is there a heritable link? / Med Genrf 1995; 32: 2.51-6. 2. Black D. Investigation of the possible increased incidence of cancer in West Cumbria. Report of the Independent Advisory Group (Ch. Sir Douglas Black). London: HMSO, 1984. 3. Gardner MJ, Hall AJ, Downes S, Terre11 JD. Follow-up study of children born to mothers resident in Seascale. Br Med ] 1987; 29.5: 8222-7. 4. Gardner MJ, Hall AJ, Downes S, Terre11 JD. Follow-up study of children born elsewhere but attending schools in Seascale, West Cumbria (schools cohort). Br Med ] 1987; 295:
819-22.
5. Gardner MJ, Snee Ml’, Hall AJ, Powell CA, Downes S, Terre11 JD. Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. Br Med ] 1990; 300: 423-9. 6. Gardner MJ, Hall AJ, Snee Ml’, Downes S, Powell CA, Terre11 JD. Methods and basic data of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. Br Med J 1990; 300:
329-34.
7. Gardner MJ. Father’s occupational exposure to radiation and the raised level of childhood leukaemia near the
19.
20.
21.
are the risks of diagnostic medical radiation? Med J Ausfrnl 1997; 166: 589-91. Parker L, Craft AW, Smith J ef ni. Geographical distribution of preconceptional radiation doses to fathers employed at the Sellafield nuclear installations, West Cumbria. Br Med ] 1993; 307: 966-71. Draper GJ, Stiller CA, Cartwright RA, Craft AW, Vincent TJ. Cancer in Cumbria and in the vicinity of the Sellafield nuclear installation. Br Med ] 1993; 306: 89-94. Berry RJ. Preconception paternal occupational radiation exposure and the risk of childhood leukaemia: a paradox within an enigma. OCCURS Med 1995; 45: 5-10. Little MP, Charles MW, Wakeford R. A review of the risks of leukaemia in relation to paternal pre-conceptional exposure to radiation. Heu/fh Phys 1995; 68: 299-310. Wakeford R, Parker L. Leukaemia and non-Hodgkin’s lymphoma in young persons resident in small areas of West Cumbria in relation to paternal pre-conceptional irradiation. Br ] Cmcer 1996; 73: 672-79. Doll R, Evans JH, Darby SC. Paternal exposure not to blame. Nafwe 1994; 367: 678-80. Draper GJ, Little Ml’, Sorahan T ef ul. Cancer in the offspring of radiation workers-a record linkage study. Chilton: NRPB-R298 1997; l-72. McLaughlin JR, King WD, Anderson TW, Clarke EA, Ashmore JP. Paternal radiation exposure and leukaemia in offspring: the Ontario case-control study. Br Med ] 1993; 307:959-66.
22. Pobel D, Vie1 JF. Case-control study of leukaemia among young people near La Hague nuclear reprocessing plant: the environmental hypothesis revisited. Br Med J 1997; 314:
101-6.
23. Clavel G, Roman E. Leukaemia near La Hague nuclear
plant: bias could have been introduced into study. Br Med ] 1997; 314:
1553.
24. Law G, Roman E. Leukaemia near La Hague nuclear
plant: study design is questionable. Bv Med 1 1997; 314: 1553. 25. Wakeford
R. Leukaemia near La Hague nuclear plant: Scientific context is needed. Br Med J 1997; 314: 1553-4.
44
Tutty and BrennBn
26. Olshan AF. Lessons learned from epidemiological studies of environmental exposure and genetic disease. Environ Mol Mutagen 1995; 26: 74-80. 27. Boice J, Linet M. Chernobyl, childhood cancer, and chromosome 21. Br Med ] 1994; 309: 139-40. 28. Parkin DM, Clayton D, Black RJ ef al. Childhood leukaemia in Europe after Chernobyl: 5 year follow-up. Br ] Cancer 1996; 73: 1006-12.
29. Petridou E, Trichopoulos D, Dessypris N et a/. Infant leukaemia after in utero exposure to radiation from Chernobyl. Nahre 1996; 382: 352-3. 30. Darby S, Roman E. Links in childhood leukaemia. Naltrre 1996; 382:
303-304.
31. Auvinen A, Hawama M, Arvela H et al. Fallout from Chernobyl and incidence of childhood leukaemia in Finland, 1976-92. Br Med ] 1994; 309: 1151-4. 32. Waller LA, Turnbull BW, Gustafsson G, Hjalmars U, Andersson B. Detection and assessment of clusters of disease: an application to nuclear power plant facilities and childhood leukaemia in Sweden. Slat Med 1995; 14: 3-16.
33. Watson GM. Leukaemia and paternal radiation exposure. MIA 1991; 154: 483-87.
34. Sorahan T, Roberts PJ. Childhood cancer and paternal exposure to ionizing radiation: preliminary findings from the Oxford Survey of Childhood Cancers. Am ] Ind Med 1993; 23:343-54.
35. Hawkins MM, Draper GJ, Winter DL. Cancer in the offspring of survivors of childhood leukaemia and non-Hodgkin’s lymphomas. Br ] Cancer 1995; 71: 1335-9.
36. Kinlen LJ, O’Brien F, Clarke K. Balkwill A, Matthews F. Rural population mixing and childhood leukaemia: effects of the North Sea oil industry in Scotland, including the area near Dounreay nuclear site. Br Med ] 1993; 306: 743-8.
37. Kinlen LJ. Epidemiological evidence for an infective basis in childhood leukaemia. Br ] Cancer 1995; 71: 1-5. 38. Kinlen LJ, Dickson M, Stiller CA. Childhood leukaemia and non Hodgkin’s lymphoma near large rural construction sites, with a comparison with Sellafield nuclear site. Br Med] 1995; 310: 763-68. 39. Alexander FE. Viruses, clusters and clustering of childhood leukaemia: a new perspective? Eur J Cancer 1993;
29A: 1424-43
(1999) 5, 39-44
REVIEW
The risk of childhood leukaemia with preconceptual exposure to ionising radiation Linda Tutty and Patrick C. Brennan U. C. D. Sciwoi qf Diq.y~ost~cImz~~in~. Sf A~itimy’s, Hwb~rt An~~te. D~hh 4.
lrelilllri ilZ&md 19 Ortuber
2 ]111y 1997; nccrptcd 199x1
words: parental; paternal; Sellafield; epidemiology; genetics.
Key
The purpose of this article is to review the current literature on the association between parental irradiation and an excess risk of childhood leukaemia. The risk of childhood leukaemia resulting from paternal pre-conceptional radiation exposure found among children from the Sellafield workforce is compared with the risk in a number of other epidemiological studies. Specifically, the extent of a cluster of leukaemia cases in Seascale is incompatible with: parental exposure risks of other offspring of workers in Scottish, Canadian, French and other English nuclear stations; data collected from Japanese bomb survivors; available information following the Chernobyl accident. It is also proposed that the Sellafield hypothesis is in conflict with what is known regarding familial pattern of childhood leukaemia and the level of radiation dose necessary to increase mutation rates. It is concluded that the original association found by Gardner has been confined to children in Seascale and is largely inconsistent with other scientific evidence.
Introduction The 1983 television documentary ‘Windscale: the Nuclear Laundry’ led to a much increased interest in the link between local community health risks and radioactive emissions from nuclear power stations. This television programme suggested that leukaemia, a relatively rare disease, seemed to occur at an unusually high rate in the village of Seascale which is on the coast about 3 km south of the nuclear waste reprocessing operation at Sellafield. Shortly after this programme was broadcast, an Independent Advisory Group chaired by Sir Douglas Black was set up by the British government to establish whether this proposed increased incidence of leukaemia could be supported by examining death certificates and cancer registrations [I]. The Black enquiry demonstrated that within the Millom rural district a raised leukaemia mortality rate was evident for the under 25-year-olds during 1968-78 [2]. When mortality ratios were standardized and compared with 151 1078-8174/99/010039+06
$18.00
similar rural districts in England and Wales, Millom was seen to be second highest. This group did not examine any link between the effect of radioactive discharge and leukaemia, but recommended further research.
The Gardner
hypothesis
In 1987, Gardner and his colleagues undertook a cohort study comparing the incidence of leukaemia in 1068 children born in Seascale with 1546 children who were born elsewhere but attended school in Seascale [3, 41. The results backed up the findings of the Black enquiry with a IO-fold excess for leukaemia in those children born in Seascale. Three years later, Gardner published the findings of a case-controlled study examining all cases of leukaemia in the West Cumbria Health Authority diagnosed before the 25th year [5, 61. The most notable finding was a strong dose-dependent statistical association between relatively high levels 0 1999 The College of Radiographers
40
of paternal preconceptional irradiation (PPI) received occupationally at Sellafield and the incidence of childhood leukaemia in their offspring. In particular, fathers who were exposed to doses of 100 millisieverts (mSv) or greater were at risk. Gardner suggested that this association was sufficient to explain the excess of leukaemia cases in Seascale [5, 71. The findings of Gardner fuelled a lengthy court case heard in the High Court in London during 1992-1993 [8].
United Kingdom Since 1990 a number of other studies have investigated the possible link between PPI and leukaemia. An excess of childhood leukaemia was reported near the Dounreay nuclear installation in Northern Scotland. Results of a case-control study of under 15-year-olds [9] reported that the excess could not be explained by factors associated with parental employment in the nuclear industry before conception, including radiation exposure. However, the authors of this study acknowledge that the numbers were small and the results should be treated with some degree of caution. A larger case-controlled study by Kinlen et al., again in Scotland, examined all leukaemias diagnosed in Scotland before the age of 25 [lo]. Fathers in the workforce of a variety of nuclear installations were identified. The results offered no support for the Gardner hypothesis. Kinlen, in a further study, also found that the excess of leukaemia in Seascale was not limited to children born there, but also extended to children born elsewhere but living in Seascale [II]. This does not correlate with Gardner’s findings and may be attributed to the fact that three cases of leukaemia in Kinlen’s study were not included by Gardner and of the three, only one of the children’s father had received any occupational dose before the child’s conception. In 1993 results of a larger case-control study examining the excess of childhood leukaemia in young children living near Aldermaston and Burghfield nuclear weapons facilities in West Berkshire established a weak association of childhood leukaemia and PI’1 [12]. Unlike Gardner’s findings, however, the doses were low and risks were not dependent on dose. It is interesting that clusters of leukaemia have been found at six potential nuclear sites in United Kingdom and two nuclear installations which were constructed but never operated [x3], suggesting a factor other than radiation to be responsible.
Tutty and Brent&
Parker and his colleagues proposed that if a statistical association exists between preconceptional doses received by fathers working in Sellafield and the increased incidence of childhood leukaemia, then radiation doses should be concentrated in fathers of children born in Seascale [14]. This is particularly relevant since no excess of leukaemia in the rest of Cumbria has been observed, despite the fact that over 90% of births to Sellafield employees occurred outside Seascale [15-181. No such concentration was shown to exist, in fact 93% of the total preconceptional dose is delivered to those fathers with children born outside Seascale [19]. This dose distribution is highly inconsistent with the proportion of risk accounting for the Seascale excess. In Gardner’s work, a 6-8-fold increased risk of childhood leukaemia was reported in children of fathers who received a total recorded external dose of > 100 mSv in the 6 months preceding conception [7]. These figures were obtained by halving the preceding annual dose summaries [19]. The Health and Safety Executive (HSE) also found a significant association of cumulative PPI with leukaemia in Sellafield workers, which shows some agreement with the Gardner study [IT]. However, the HSE findings must be treated with some caution because when one individual with a very large dose was omitted from the study the significant trend was ‘almost entirely lost’ [17]. The HSE did not, however, show any association with the 6 month pre-conceptional dose, nor did they find any link with the dose received in the more biologically appropriate 12 week period immediately before conception [a]. A case-controlled study, very recently published by the National Radiological Protection Board (NRPB) in the UK, tested the Gardner hypothesis [20]. This large study gathered data from the National Registry for Radiation Workers, National Registry of Childhood Tumours, Oxford Survey of Childhood Cancers and Office of Population Censuses and Surveys. For each child with cancer a control was selected matched on sex and place and date of birth. The study established that fathers of children with leukaemia, when compared with the fathers of controls, were significantly more likely to be radiation workers. However, no dose response relationship was shown for any of the exposure periods examined; instead the association was most notable for those with doses below the level of detection. No significant increase in risk was noted for fathers who had lifetime exposures greater than
Parental exposures
and childhood
41
leukaemia
100 mSv, doses of 10 mSv or greater in the 6 months prior to conception, or doses of 5 mSv or more in the 3 months before conception. Maternal radiation work was not associated with a significantly elevated risk of childhood leukaemia. It was concluded by the authors of this study that no support could be offered for the Gardner hypothesis. It was judged that the observed association was either a chance finding or resulted from an alternative cause.
absence of an increased incidence of leukaemia among 263 offspring conceived shortly after the bombings, whose fathers received a dose 2 10 mSv, is inconsistent with the findings of Gardner. No inverse dose-rate effect has been hypothesized which would be necessary to explain the disparity between the Gardner and the atomic bomb survivors’ data.
Chernobyl Ontario A study carried out further afield investigating leukaemia in children (under the age 15 years) born to mothers living near nuclear stations in Ontario failed to suggest any excess risk of leukaemia arising from occupational pre-conceptional exposure, irrespective of the pre-conception dose period used 1211.
La Hague La Hague has one of the world’s three remaining nuclear reprocessing plants operating on an industrial level. Research carried out by Pobel and Vie1 [22] in the La Hague did not support an association between fathers’ exposure to radiation and childhood leukaemia, since the fathers of children diagnosed with leukaemia did not receive any radiation dose before conception. They did, however, find evidence for a causal link between leukaemia and environmental radiation exposure resulting from recreational activities on local beaches. Other authors have questioned the study design and are not convinced by this association [23-251.
Japanese
data
The Sellafield findings also suggest sensitivities to ionising radiation, with regard to the induction of leukaemia, to be at least 50 times greater than results drawn from Japanese data [26]. The absence of any excess of childhood leukaemia among over 30 000 children of Japanese survivors of the atomic bombings of Hiroshima and Nagasaki has been confirmed, with fathers receiving a preconceptional dose in excess of 10 mSv, with an average dose of 418 mSv [8]. In addition, the
On the 26 April 1986, the accident at the nuclear reactor in Chernobyl, in the former Soviet Union, released large amounts of radioactivity into the atmosphere [27]. The dissemination of radioactive isotopes, principally Iodine-131 and Caesium-137 occurred across a wide area of Europe [28]. Outside Chernobyl, contamination resulting from the accident was highest in Greece, with high levels recorded in the Scandinavian countries [29-311. All cases of childhood leukaemia diagnosed throughout Greece since the accident have been documented. Petridou and colleagues found that preconceptional irradiation has no significant effect on leukaemia incidence at any of the age groups studied [29]. Other workers studying the incidence of leukaemia in Finland [31] and in Sweden [32] excluded any link with leukaemia and increased levels of radiation associated with Chernobyl.
Genetics Familial patterns of childhood leukaemia are uncommon [19]. From the U.K. National Childhood Cancer Register, it is estimated that the true proportion of genetically determined leukaemia is about 5%. This low proportion, along with the fact that the disease presents in approximately I in 2000 children, suggests that a recessive mutation with a low degree of penetrance contributes to the disease. This is in contrast to the dominant mutation with a high degree of penetrance that would be necessary to be responsible for the Sellafield data reported by Gardner [33]. In addition, the Gardner hypothesis does not agree with what is known of mutation rates by radiation. Tawn maintains ‘there is no evidence that radiation can induce fragile sites in germ cells or preferentially damage pre-existing heritable fragile sites’ [I]. A study on children of atomic bomb survivors found no increased frequency of mutations [19]. These
42 Table
Tutty and Brennan 1. A summary of some of the risk ratios for childhood
Author(s) of study and reference
Description
“Gardner et al. [5] Kinlen et al. [lOI
Kinlen et al. [II]
Roman el al. [12]
Wakeford et al. [18]
McLaughlin
et al. [?,I]
Auvinen et al. [31]
leukaemia described in the literature
of data
Data
Risk ratio
Risk ratio of childhood leukaemia for children of fathers receiving preconceptual irradiation at Sellafield Risk of ratio of childhood leukaemia for children of fathers who received preconceptual irradiation exposure from the Scottish Nuclear industry
BC (3 100 mSv) 6 months BC (3 10 mSv) BC ( 2 50 mSv) 6 months BC (2 5 mSv) 3 months BC (2 2.5 mSv)
Risk ratio of childhood leukaemia for children born in Seascale compared with those born elsewhere
Seascale Elsewhere
Risk ratio for childhood leukaemia & non-Hodgkin’s lymphoma in West Berkshire and North Hampshire for parents employed in a nuclear establishment before conception
Father Mother
2.8
Risk ratios for all types of leukaemias within West Cumbria excluding the Sellafield Ward
O-4 years
0.93
O-14 years
0.85
O-24 years
0.95
Risk ratio of childhood leukaemia in Ontario with fathers having detectable radiation exposures Risk ratio of childhood leukaemia in Finland following Chernobyl accident
the
6.24 7.17 1.04 1.26 1.27 15.8 6.7
0.0
0.87
1986-M
0.95
1989-92
1.01
“indicates a study which demonstrated a statistically significant finding Risk ratios were calculated by dividing the observed number of cases by the expected number. BC = before conception; mSv=milliSieverts.
authors suggest that for an acute exposure a dose of 2 Sv is required to double the mutation rate in humans and 4 Sv for chronic exposure. These levels are far in excess of those received by Seascale workers. The association at the doses indicated by Gardner would suggest that children of radiologists would be vulnerable to an increased risk of leukaemia, which was not found to be the case [M]. If heritable genetic effects are to play a major role following radiation exposure, increased common congenital malformations would be anticipated to occur at a higher rate than leukaemia [17]. However, no study to date has demonstrated such an incidence in atomic bomb survivors or in Seascale offspring [17, 351.
Alternative
explanations
Since the majority of the literature seems to suggest parental exposure is not responsible for the increase in leukaemia, it is interesting to consider
other possibilities. According to Tawn, the incidence of leukaemia is associated with the country of residence rather than ethnic origin, thus indicating an environmental rather than a heritable determinant [I]. An infective basis brought about by an increase in population mixing in previously isolated areas has been proposed as an explanation for the clusters of excess leukaemia [la]. In particular, large scale mixing of rural and urban groups of people leads to an increased incidence in the disease [36-381. Although the route and nature of infection remains unclear [36, 391, it has been established that specific viruses can cause leukaemia in animals, as HTLV-1 does in humans [36]. In Seascale the continual influx of new-comers from urban backgrounds may explain the excess of leukaemia incidence highlighted by the village’s isolation [38].
Conclusion The Gardner hypothesis states that parental, in particular occupational radiation exposure, prior to
P?wental exposures
and childhood
leukaemia
conception, can lead to mutations in their sperm which significantly increases the risk of the development of childhood leukaemia (Table I). Observations sustained by studies in the neighbourhood of other nuclear installations in the U.K., Canada and France, on the offspring of atomic bomb survivors and on exposed persons following the Chernobyl accident do not support the hypothesis (Table 1). Knowledge of radiation genetics and hereditability of the leukaemia suggests that radiation cannot be accountable for Sellafield’s high incidence of the disease in children. Kinlen has produced compelling evidence in favour of unusual forms of population mixing accounting for the raised risk of childhood leukaemia, which is consistent with an infective basis for the disease. In the lengthy court case previously referred to [8], with the evidence before him, the judge concluded: ‘the scales tilt decisively in fiwot4~ of &e Defendants, and fhe Plaintiffs, therefure, have failed to safisfy me on fhe lhaf PPI zuas a material conbbalance of p&abilikies hfoty came of the Seascale excess’[Ft-erzch, the Hon. MY
43
Sellafield nuclear plant. Environ Henifh Perspecf 1991; 94: 5-7.
8. Wakeford R. The risk of childhood cancer from intrauterine and preconceptional exposure to ionizing radiation. Environ Healfh Perspecf 1995; 103: 1018-25. 9. Urquhart JD, Black RJ, Muirhead MJ ef ai. Case-control study of leukaemia and non-Hodgkin’s lymphoma in children in Caithness near the Dounreay nuclear installation. Br Med ] 1991; 302: 687-92. 10. Kinlen LJ, Clarke K, Balkwill A. Paternal preconceptional radiation exposure in the nuclear industry and leukaemia and non-Hodgkin’s lymphoma in young people in Scotland. Br Med] 1993; 306: 1153-8. 11. Kinlen LJ. Can paternal preconceptional radiation account for the increase of leukaemia and non-Hodgkin’s lymphoma in Seascale? Br Med 1 1993; 306: 1718-21. 12. Roman E, Watson A, Beral V ef ill. Case-control study of leukaemia and non-Hodgkin’s lymphoma among children aged 0-4 years living in West Berkshire and North Hampshire health districts, Br Med ] 1993; 306: 615-21. 13. Smart RC. What 14.
]r4sfice, 19931.
In conclusion, an association between parental pre-conceptional exposure radiation and an excess of childhood leukaemia is unlikely, and the cluster of cases of childhood leukaemia in Seascale currently remains an enigma.
15.
16.
17.
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