cancer in childhood and Clare Hardiman outlined the dosimetry in this session. ... diagnostic radiology, the Paper by Adrian Levy projected the lifetime risk of ...
Effects of low-dose ionizing radiation: implications for human health - Conference summary W. Atkinson* D. Goodheadt G. Harte** M. Little+ K. Rose* B. Wade* In May 1987, The British Nuclear Energy Society (BNES) held a conference in London on the subject of the human health effects of radiation at doses of practical· concern. Bringing together a diverse range of biological and epidemiological interests on an international scale provided the basis for a stimulating and productive conference. Five years later, BNES judged that it would be timely to repeat the formula. The second BNES international conference was held in Bournemouth, UK on 18-20 May 1992. The programme (Annex 1) included twelve keynote Papers reviewing the main aspects relevant to human radiation health effects, as well as over 30 contributed Papers. It attracted some 160 participants from 14 countries. In his opening address, Sir Richard Doll spoke on the theme of The Known, the Unknown and the Unknowable. He pointed out that we know more about the effect of ionizing radiations in humans than we do about the effects of any other environmental hazard, except perhaps for tobacco smoke. The time may not be very far off when the law of diminishing returns will seriously discourage further financial and intellectual investment in the subject. However, Sir Richard then proceeded to demonstrate that we are some way from approaching this position. He summarized the principal gaps in our knowledge of five outstanding problem areas. The carcinogenic effect oflow-LET radiation at low doses rests on a variety of assumptions such as time dependence, extrapolation to other populations and dose-rate effectiveness factors, some or all of which may be seriously in error. Similar uncertainties apply to cancer induction by high-LET radiation. The models for lung cancer induction by radon *AEA Environment & Energy, Harwell, UK tMRC, Radiobiology Unit, Chilton, UK **Nuclear Electric, Bedminster Down, UK :j:NRPB, Chilton, UK Nucl. Energy, 1992, 31, No.4, Aug., 247-259
are so uncertain as to make it imperative to try to assess the effects of radon in houses by direct observation. As for genetic damage, Sir Richard will continue to consider that the Gardner findings were due to chance or to some unsuspected confounding factor until follow-up of the children of the many other radiation workers provides convincing validation. Other areas where there are substantial uncertainties in our knowledge include damage to the fetus and the clustering of childhood leukaemias in the vinicity of nuclear installations. Sir Richard looked forward to at least the partial filling of some of these gaps in the course of the conference. Session 1 - Mechanisms underlying cellular response to radiation In the first keynote Paper, Mort Elkind summarized data on neoplastic transformation of a cultured mouse-cell line (C3H 1OT ~ by fission spectrum neutrons and proposed a model to explain the surprising finding that the frequency of transformed cells increased with decreasing dose rate of high-LET radiation, provided that the overall dose was not too great. This 'inverse' dose-rate effect had first been reported by his group in 1982 and it had been confirmed subsequently by others as well as by themselves, and extended to transformation of Syrian hamster embryo cells and expression of surface antigen in a human/hamster hybrid cell line. Similar trends for fission neutrons and a-particles had also been reported for induction of some tumours in rodents and in humans. But at least two other studies with C3H lOT cells had found no such effect, for: fission neutrons or for 2 · 7 MeV a-particles. Professor Elkind proposed a model that might explain this inverse dose-rate phenomenon, as well as its absence in some situations. He proposed that cells in or near mitosis were particularly sensitive to transformation and to cell killing by high-LET radiations. These cells were of little overall
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W. ATKINSON ET AL.
consequence in a cycling cell population irradiated at high dose-rate because there were very few of them. The passage of cells through this window of sensitivity results in enhanced transformation when small doses are protracted, but not at large doses because of cell killing. He suggested that the absence of a dose-rate effect in two reported studies was due in one case to mechanical loss of mitotic cells due to transportation before irradiation and in the other to the limited range of the a-particles (- 15 ~-tm after entering the cell monolayer) inadequately irradiating the rounded mitotic cells. In the later discussion Professor Elkind explained that his model differed substantially from previous sensitive window models because of his inclusion of cell killing and of radiation induced delay of cells entering the sensitive window. He suggested that the magnitude of the inverse dose-rate effect was less informative for mechanistic guidance than was the existence of the effect itself. Using the same C3H lOT cell line, Andy Mill later presented results that had been obtained for transformation by 2 · 5 MeV monoenergetic neutrons and by 3 · 2 MeV a-particles. For the neutrons they obtained only a small enhancement factor of about 1 · 3, which was barely significantly different from unity. He suggested that when all the available neutron data in the world is considered together, it is seen that most give factors of only 1-2, with the most notable exceptions being the earlier results from Elkind's group where factors up to about 8 were reported. For transformation by a-particles, Dr. Mill et al. found no significant dose-rate effects. There was some indication of a reduction for cycling cell cultures and a smaller indication of an enhancement for stationary cultures, but neither were significant despite the large scale of the experiments, which had used a total of 32m2 culture vessel surface! He presented survival curves and measurements of the sizes of individual cells as irradiated to argue that all cells, including the mitotics, were fully irradiated by the a-particles (of range 19 ~-tm). An additional interesting feature of their data was that stationary cultures were 2-3 fold less sensitive to transformation by a-particles than were cycling cultures. In his keynote paper Michael Fry considered the risks and mechanisms of radiation-induced cancer. Current estimates of risk have come essentially from studies of the atomic bomb survivors. Despite this impressive basis, important concerns remain regarding: projection of lifetime risks, as 60% of the exposed Japanese population are still alive and many more cancers are expected with advancing years; transference of risk from Japanese to other populations in which distribution of types, and age dependence, of cancer are different; and extrapolation from high doses and high dose-rates to the low dose-rates of main relevance. He discussed whether experimental studies can be undertaken to give guidance to answering these concerns. Experimental studies, mainly in female mice, despite radiation perturbations of hormone status, have shown that cancer risk may be affected by diverse factors including age
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dependence, latent period, dose-dependence, protraction, risk projection models and interaction with other agents. Concentrating on the low dose problem, what can be done? There are clearly widely differing shapes of dose response for different cancers - for example, a threshold for overt skin cancer (although not for the initial event) and near linearity for breast cancer, and different turn-over points and LET-dependencies. Little is known of the reasons. If chromosome aberrations are the initiating events, how do subsequent factors affect the tumour response, changing the expectation of a linear-quadratic dose dependence to near linear for the solid cancers in the bomb survivors? The low dose response can be probed with data from multiple fractions. Many data from large studies and many tissues are needed. There are some human data after fluoroscopy that suggest no fractionation effect for breast but a significant amount for lung. However, rodent experiments suggest that the limit may be reached only with very small doses per fraction, possibly lower than the fluoroscopy doses. Dr. Fry raised two often overlooked aspects of the low dose and low dose-rate problems. Apart from reducing cancer incidence, do they alter the spectrum of cancer types and can they alter the degree of malignancy of some tumours, in conflict with the standard definition of cancer as a stochastic effect? As evidence for such possibilities he suggested that low dose effects are dominated by late life tumours rather than leukaemias as at high dose and that radiation workers show a different spectrum compared to the bomb survivors. There are very few data on degree of malignancy versus dose, but Harderian gland tumours do show histological and metastatic dependence on dose as well as on LET. The implications could be substantial because no account of degree of malignancy is currently allowed for in dose-rate or RBE dependence. An alternative way to approach the problem of radiationinduced cancer might be to analyse individual tumours and seek their causes rather than to seek their rare occurrence. Specific histologic, mutation or other molecular markers might be found for ionizing radiation or its different types. For example, carcinoma of the mastoid occurs only after radium exposure, and recent data suggests agent specificity of mutations in the P53 gene, with identified differences for aflotoxins, ultraviolet light, radon, a-particles and tobacco smoke. If adequate profiles are built up, then low dose estimates could be improved. In the third keynote Paper, Ged Adams raised the possibility that mechanisms of radiation carcinogenesis may exist that are relevant only at low doses or, alternatively, that are optimum at low doses. This. would question the common assumption that the mechanisms that apply at high doses also do so at low doses, and that differences in dose only govern the probability of cancer induction, not its mechanisms. The cellular adaptive, or stress, response may be one relevant example. The generality of this phenomenon
EFFECTS OF LOW DOSE IONIZING RADIATION: CONFERENCE SUMMARY
suggests that it may be part of an evolutionary defence mechanism in which low doses of the damaging agent induce resistance to the same, or some other, agent. The stress response can be induced by heat, ultraviolet light, ionizing radiation, various drugs and other cytotoxic chemicals, oxygen deficiency or depletion of nutrients. At the sub-cellular level, various biochemical changes that have been induced by low levels of ionizing radiation have been observed in different cell types. These include changes in the expression level of various proteins, such as upregulation of transcription at the RNA level of protein kinase C and of various oncogenes and other genes that appear to be involved in signalling mechanisms as an early event in proliferative response. These include the genes c-fos and cjun which are involved in stimulation of other genes relevant to growth regulation and control. Evidence that radiation stress responses may be relevant to carcinogenesis is still sparse and indirect. However, their involvement in regulatory processes concerned with proliferation is suggestive. Further, there is increasing evidence that some tumour cells subjected to stress agents, including radiation, become more tumourogenic or show accelerated proliferation. One of the reasons for interest in radiation effects on growth control mechanisms is experimental evidence from Nomura et al. that risk factors for tumour induction in mice following parental irradiation are exceptionally high compared with those for non-malignant mutations as assessed from specific locus mutation data. The Gardner finding, of an association between leukaemia incidence in Seascale and parental employment in the nearby reprocessing plant, may be relevant to this. Cellular mechanisms controlling growth and differentiation include the 'suppressor' genes. A dominant-like change, or inactivation, of any one of these numerous control mechanisms could confer sufficient growth advantage to constitute a malignant change. This could imply large target sizes and large risk factors. There is considerable evidence that radiation produces large DNA deletions. For example, Thacker et al. have found that most hprt mutations in cultured cells are deletions of much or all of the gene, and Cattanach et al. find many large deletions in viable and fertile mice, including up to 43 Mbase loss (or 20% of chromosome 1) in the case of Dmh-1. This mutation retains fertility but carries major developmental abnormalities. Three contributed Papers dealt with radiation effects on the haemopoietic system. In adult mammals the maintenance of cells in the peripheral blood is achieved by proliferation and differentiation of progenitor cells, all derived from a small self-maintaining population of multipotential stem cells. Effects on the stem cells are implicated in many of the most serious consequences, including certain leukaemias. Eric Wright presented data on the ability of CBA/H murine bone marrow stem cells to proliferate to form colonies after being irradiated with a parallel beam of a-particles of energy 3·3 MeV (121 keV t-tm- 1 ) at doses corresponding to 0·5, 1 · 0 and 2 · 0 a-particles per cell. The probability of a stem
cell surviving the passage of an a-particle was low ( ~ 10%) and it might then carry viable genetic damage that is very much greater, at both the cell and chromatin-levels, than would ever be received from low doses oflow-LET radiation. To investigate such changes individual cells within individual colonies were subjected to karyotypic analysis. The frequency of chromosome damage was high, with 40-60% of the colonies containing abnormalities, predominantly of the chromatid type. But the most surprising observation was that the individual scorable cells in a given colony carried non-identical (i.e. non-clonal) aberrations, suggesting that they had occurred many cell generations after irradiation. By contrast, the results from 3 Gy of X-rays followed conventional expectations, producing only a few clonal aberrations above control levels. Thus the two types of radiation are significantly different in their qualitative as well as quantitative effects. But, most strikingly, the pattern of a-particle induced abnormalities suggests that the exposed, surviving stem cells transmit to their daughter cells some chromosomal instability that may result in one or more visible aberrations many cell cycles later. The longer-term consequences of this instability are under study. Bryn Bridges presented data of frequencies of hprt mutations in peripheral T-lymphocytes in fresh human blood and compared these with household radon concentrations. First he provided background information that the average frequency is very low at birth and then rises by about an order of magnitude by age 20 and thereafter at around 1 · 3% per year. In smokers the average frequency is about 1 · 5 fold greater. A one-month survey of radon levels in houses in Street, Somerset, with plastic track detectors had shown values from 30-1200 Bq m- 3 , in comparison with the UK average levels of about 20 Bq m- 3 . Blood samples from 20 nonsmokers in these houses showed frequencies of hprt mutations that correlated significantly with the radon levels, even when allowance was made for age and the single highest mutation point was ignored. After subsequent 3-monthly radon measurements and repeat mutation assays on the original blood samples, the correlation remained. The correlation was not present for cumulative exposure (dose x years). If the correlation is not a statistical fluke or due to unknown confounding factors, the data imply an estimated mutation doubling dose of about 2 mSv/a- 1 (220 Bq m- 3 ) for recent exposures. Professor Bridges emphasized the need for caution in interpretation until the observations have been independently confirmed. Their own studies are seeking further suitable houses and blood donors in Street and are extending to invitro induction of hprt mutations in T-lymphocytes by defined a-particle tracks. Andrew Silver addressed the role of specific chromosome breakage in the mechanism of radiation-induced CBA/H murine acute myeloid leukaemia (AML). About 90% of 249
W. ATKINSON ET AL.
AMLs are characterized by rearrangements and/or deletions in chromosome (ch)2, with non-random clustering of breakpoints. By analysing karyotypes of in-vitro x-irradiated (3 Gy) bone marrow cells repopulating radiation ablated mice, (ch)2 changes were found at an unexpectedly high frequency starting as early as 3-5 days post transplantation. The breakpoints were non-random, clustering significantly in 6 sub-regions of (ch)2, three of which also had highly significant concordance with the breakpoints in AMLs. These results suggest that (ch)2 may contain multiple radiationsensitive sites some of which are involved as initiating events for AML. In seeking molecular probes for these regions, Dr. Silver noted that the F region has a human genetic homologue that is possibly an interstitial telomere-like repeat (TLR) array. Telomere repeats are found at the end of all mammalian chromosomes. However, TLRs are also present at district interstitial chromosome sites and, although their biological role remains uncertain, they may represent sites of ancestral chromosome fusion and may be fragile sites to chemical mutagens and radiation. Polymerase chain reaction methods were used to isolate a TLR sequence clone from the murine DNA which turned out to contain an inverted repeat structure that may facilitate looping out DNA between adjacent or distant TLR arrays. These may predispose particular sites to deletion or rearrangement, as seen in the radiation-sensitive sites of (ch)2 that may be associated with initiation of AML by loss of critical genes. Joe Lucas discussed the methodology that had been developed at the Lawrence Livermore National Laboratory for chromosome 'painting' and evaluated its usefulness for biological dosimetry at low levels of ionizing radiation. Selective staining of one or more complete chromosomes can be achieved by hybridizing to it a sufficiently large number of specific DNA probes that are fluorescently labelled. With this fluorescent in situ hybridization (FISH) technique, interchromosomal exchanges are readily visible as bicoloured chromosomes under a fluorescent microscope. These can be rapidly detected and scored. For recently irradiated blood, a very similar dose response was found for translocations and dicentrics. The stability of reciprocal translocations was confirmed for one worker who had accidentally incorporated tritiated water 6 years previously and shortly thereafter been assessed for frequency of dicentrics. Stability is also illustrated by measurements of reciprocal translocations in 20 survivors of the atomic bombs in Japan. The data were scattered around the acute dose-response calibration curve for recent irradiation - the wide scatter may indicate uncertainties in the dose estimates for individual survivors. The FISH technique for scoring reciprocal translocations was further validated by comparing the measured frequencies with those obtained by the much more laborious G-banding method. Differences in response of individual patients to clinical radiotherapy have long been recognized in the clinic, 250
including a minority of patients who develop abnormally severe normal tissue reactions. Neil Burnet addressed the question of whether such variation is due to differences in intrinsic cellular radiosensitivity and whether this could be predicted for improved treatment of both the more sensitive few and the remaining majority. To investigate this, fibroblast cell strains from patients were irradiated with 6°Co )'-rays at high and low (0 · 01 Gy min -I) dose rates and subsequent survival measured by clonogenic assays, for comparison with the clinical responses of these patients. It was found that the recovery factor, shown as increased survival at low doserates, cannot be predicted or inferred from the high doserate survival curve. There was generally little or no curvature in the dose responses, yet most showed significant recovery indicating that there was repair of sub-lethal damage. Fibroblast sensitivity at low dose-rate correlated with clinical normal tissue response both for acute and for late effects, opening the door to predictive testing. The fibroblasts of some of the over-reacting patients showed no recovery at low dose-rate. Dr. Burnet suggested the possibility that differences in intrinsic radiosensitivity may apply also at low levels of exposure, calling into question the accuracy of biological dosimetry for individuals and assessment of individual risks. This session highlighted the significant advances in the understanding of biological mechanisms which have occurred during the five years since the previous BNES conference. New approaches have been identified to tackle long-standing questions on the underlying mechanisms of carcinogenesis. It has now become possible to clarify and probe more of the subtle cellular and sub-cellular effects of radiation at low doses, including specific early and final changes that may be involved in cancer mutation. Session 2 - Effects of pre-conceptual irradiation Eva Alberman opened this session with a partial survey (omitting all but tangential reference to the Gardner study) of the observed effects of pre-conceptual radiation in human populations. The difficulty of separating events early in pregnancy (which would generally lead to teratogenic effects) and pre-conceptual effects (which are mutational in nature) was discussed. The latter could lead to infertility or very early loss of the embryo, which would have no serious public health implications (although with possibly serious implications for the individual). More serious public health consequences could result from the embryo surviving to term and being born with a handicap or other obvious birth defect, or possibly with some predisposition to malignant disease. It is a theoretical possibility that excess abnormalities could result from an impaired ability to abort an abnormal fetus. The problems of using the A-bomb survivors as a basis for deriving risks of pre-conceptual radiation were dwelt on at some length. In particular the lower rates of infant mortality than the national average were highlighted, so that although no significant effects had been observed (either positively
EFFECTS OF LOW DOSE IONIZING RADIATION: CONFERENCE SUMMARY
,
;,;,
or negatively) caution in extrapolating from this cohort was perhaps in order. Professor Alberman concluded with a discussion of problems affecting other studies linking pre-conceptual radiation with disease in offspring, and in particular the problems of recall bias in studies of medical diagnostic radiation. Problems of differential ascertainment over time were also a problem with studies that had been (or might be) undertaken of those with significant exposure resulting from the Chernobyl accident. Roger Cox was concerned largely with some possible explanations for the extremely low doubling doses for parental pre-conception radiation for certain tumours in offspring suggested by the studies of Nomura and Gardner. The tone was speculative as to the mechanisms that might be involved and he elaborated four sorts of phenomena that might have a role. Clearly the 1 Sv doubling dose recommended by ICRP represents an average for all of the human genes and it is likely that there might be considerable variation in sensitivity. Higher sensitivity is perhaps to be expected, particularly for phenotypes involving complex genomic re-arrangement. The second possibility was of indirect mutagenesis resulting, for example, from so-called transposons. These are mobile DNA elements that can result in the multiplication of particular mutations. These have been implicated in human haemophilia A and various other conditions, although very little is known as to the radiosensitivity of these mutations. Heritable fragile sites were then discussed as a potential contributor to enhanced radiosensitivity. Various cases involving such sites are known for tumours in both mice and humans, including the ~:-fra site in some leukaemias observed in Japanese populations. The last possibility was of epigenetic effects, that is to say those of a non-mutational nature, and in particular the phenomenon of genomic imprinting. This last was most lucidly explained as the process whereby certain genes are differentially expressed depending on whether they are inherited from the father or mother. This is known to have a role in certain tumour suppressor genes, for example retinoblastoma, but it is not known whether it contributes in any way to leukaemia. In conclusion, it was stressed that what is known about unconventional mechanisms of genetic damage ought to make one cautious about dismissing 'outliers' such as the Gardner and Nomura studies. Brian Lord presented some preliminary results of experiments looking at haemopoiesis in offspring of male DBA2 mice injected with plutonium-239 prior to conception. Numbers of bone marrow Colony Forming Units (CFU) seemed to be significantly increased, particularly in the group in which the longest period (three months) elapsed between the administration of plutonium and mating. For Spleen CFUS, if anything the opposite pattern was seen: there was a significant excess in the mice that were administered plutonium in the shortest period (14 days) before mating but
not in the two groups given the dose before this time. Dr. Lord admitted that there were clearly still many gaps in this data but a tentative explanation is that there might be delayed post-natal development of haemopoietic tissue followed by a shift to more primitive cell types. In the discussion it emerged that no measurements of plutonium had been made in the sperm of the mice, but that the male mice had not been in the same environment as the female mice except in the days surrounding mating, limiting the possibility for contamination. Tom Wheldon outlined some consequences of the Greaves model of acute lymphoblastic leukaemia. This model supposes that leukaemia results from two mutations, the first of which typically occurs during embryogenesis (although it could be inherited) and the second as a result of antigenic stimulation of the lymphoblast population. It predicts that leukaemias resulting from an in-utero mutation (or one in the germ line) would occur earlier than for the general population and that they would tend to be multiclonal, with between 10 and 1000 leukaemic clones typically. Two tests were proposed of the latter prediction, the first applicable only to females and the second only to children with B-cell lineage leukaemia (the majority of early leukaemias), and tests on all Scottish infants developing leukaemia will now be carried out. In the discussion afterwards it became clear that multiclonality would be principally detected by following children surviving initial treatment for leukaemia and examining relapses. Michael Hawkins presented results of a study of offspring of UK childhood cancer survivors, testing for possible germcell mutagenic effects. This was done by looking at the endpoints of miscarriage, still-birth, low birth weight, congenital abnormalities and sex ratio. Survivors of cancer had been treated both with chemotherapy and with radiotherapy (involving direct exposure of abdomen or gonads), and a control group of childhood cancer survivors who had not received such potentially mutagenic therapy was also examined. The only significant effects were found in the female survivors in whom a slight deficit of males in the firstborn was seen and of miscarriages and other terminations (again particularly among first pregnancies). The excess of miscarriage was particularly marked in those treated with radiotherapy. Neither of these effects was felt likely to be a result of germ cell mutation (because of the lack of the effect in subsequent pregnancies), fibrotic effects being a more likely culprit. The results of this study therefore lend weight to the parallel findings of absence of such effects in the offspring of the Japanese bomb survivors, as the childhood cancer survivors were exposed to generally very high doses and the study was of sufficient power to be able to detect with 80% probability a trebling of risk. Florent de Vathaire gave some preliminary results of a similar French study examining offspring of women treated for thyroid cancer with 131 1. The results of this study also seemed to show an increase in the frequency of miscarriage 251
W. ATKINSON ET AL.
and a slight reduction in birth weight in offspring of those women receiving higher doses of 131 I, but no dose-related effects were seen for other end-points e.g. congenital abnormalities, thyroid pathologies, other cancers or mortality before 1 year of age. The frequency of miscarriage was highest in those women with the shortest gap between termination of 131 I therapy and the beginning of pregnancy (and indeed was only elevated at all in those for whom this gap was less than a year). These results therefore reinforce the previous ones in suggesting that 131 I therapy has no large mutagenic effect on female germ cells. Richard Wakeford presented some observations on the most recent study of Gardner and colleagues, which linked paternal pre-conception doses of radiation with leukaemia in the offspring of the survivors. Most of the excess leukaemia cases seen in the highest dose groups in the Gardner study were born in the village of Seascale, but, as far as can be inferred from presently available information on the geographical and dose distribution of the Sellafield work-force, this is not where one would have expected the cases to occur (most heavily exposed workers live in villages to the north of the site). This would appear to suggest that paternal pre-conception radiation cannot account for the geographical distribution of leukaemia cases in the offspring of the Sellafield workforce, but until data collection is complete these results must remain tenative. Mark Little followed this with some observations on the compatibility of the leukaemia paternal pre-conception exposure risks observed in the Gardner study, those in the Dounreay workforce and those seen in the 70 000 offspring of the Japanese bomb survivors. A variety of relative risk models were fitted to each data set and the relative risk coefficients compared. It was clear that the leukaemia relative risk coefficients of the models fitted to the Japanese and Sellafield data sets were not statistically compatible, particularly for risks in terms of doses received up to six months prior to conception. The Dounreay study is of such low power that the relative risk coefficients were compatible with those of the Sellafield and Japanese data sets. Dr. Little discussed a number of factors that might account for the discrepancy between the Sellafield and Japanese data, including chance,- incorrect dosimetry used at Sellafield, dose fractionation and of a viral or other mutagen perhaps acting synergistically with radiation. The possibility of 'missing' leukaemia cases was only a problem for those children conceived within six months of the bombings, but analyses of the mortality of this group did not suggest that leukaemias might have been mis-diagnosed. Session 3 - Epidemiology of malignant and genetic disease in children This session produced several items of new information, several reviews and accounts of two studies still in progress. New information came from Aileen Clarke concerning the imminent publication of a Canadian study having sufficient
252
power to test the Gardner hypothesis on childhood leukaemia: also Bernd Grosche provided information about two childhood leukaemia clusters in Lower Saxony not associated with a nuclear facility. The reviews concerned Bavarian, Canadian and Norwegian studies of childhood leukaemia, the last being interpreted to predict the likely childhood leukaemia incidence resulting from Chernobyl fallout. Finally, Eve Roman described a study of genetic effects of irradiation based on the offspring of UK radiation workers and Florent de Vathaire outlined a study of secondary cancers following radiation therapy for childhood leukaemia. The importance of geographic data to radiation epidemiology was discussed by John Bithell. The recent interest in geographical data has resulted in several new methods of analysis, particularly for cluster testing. Such methods are easy to derive but are not necessarily powerful in a statistical sense. It is important to know the power of the test when interpreting p values. A model for non-uniformity of risk, based on Monte Carlo analyses, using the concept of relative risk function, was described. It contained the reasonable assumption that radiation acts individually. It can be adapted for risk either in populations or in case-control studies. The model was illustrated by reference to Cumbria where the distribution of 36 childhood leukaemia cases (four in Seascale) was compared to that of the controls. A threedimensional plot showed the peak at Seascale and few other 'bumps'. However, the peak only just reached statistical significance (p' 0 ·03-0 ·04). This illustrated that the model provides a convincing picture even with only a few cases. It was considered to be an improvement on the GAM technique. Two Canadian studies were described by Dr A. Clarke, both initiated because of findings at Seascale near Sellafield. However, it was acknowledged that the nature of the radioactivity discharged from the five Canadian nuclear facilities was different to that from Sellafield. In the first study the incidence and mortality of leukaemia among children up to the age of 14 years, born within a radius of about 25 km from five different types of nuclear facilities, were compared with the provincial average. The leukaemia data, both incidence and mortality, were obtained from the cancer records maintained by the Ontario Cancer Registry. The actual number of leukaemias (Table 1) among children of 0-14 years of age, and born within 25km radius of a given facility was determined for the period from the year of startup of the facility to 1987. The expected number of childhood leukaemias (Table 1) for the same area, and for the same period, was calculated from the provincial average, matched for age and sex of the study population. The ratio of 0/E, at 95% confidence intervals, was used to determine the significance of the occurrence of any excess childhood leukaemia around the five nuclear facilities. The names of the five facilities and the results are summarized in Table 1. None of the increases or decreases
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EFFECTS OF LOW DOSE IONIZING RADIATION: CONFERENCE SUMMARY
Table 1. Childhood leukaemia around five Canadian nuclear facilities* Facility CRNL, Chalk River NPD, Rolphton UCF, Port Hope UMMF, Elliot Lake PNGS, Pickering
Observed (0)
Expected (E)
Ratio (0/E)
2
6·1
0·33
0·04-1·19
(2) 12 (13) 4 (4) 33
(0·32) 1·20
3
(6·3) 10·0 (11·7) 4·4 (5·0) 24·6 (62 ·8) 1·1
0·92 (0·80) 1·34 (1·15) 2·78
(0·04-1·14) 0·62-2·09 (0·59-1·91) 0·25-2·35 (0·22-2·05) 0·92-1·89 (0·90-1·44) 0 ·56-8. 13
(4)
(2·6)
(1·57)
(0·42-4·01)
(72)
BNPD and Douglas Point Bruce Peninsula
95% CI
(l·ll)
*The data were obtained from INF0-0300-2, a report prepared for the Atomic Energy Control Board of Canada by Dr A. Clarke et at. at the Ontario Cancer Treatment and Research Foundation. The quantities without brackets refer to leukaemia mortality data for the period from the year of start-up of the facility to 1978. In Ontario, the leukaemia mortality data is available only for the period 1950-87. The quantities within brackets refer to leukaemia incidence data for the period from the year of start-up the facility or 1964, whichever is later, to 1986. In Ontario, the leukaemia incidence data is available for the period 1964-86.
were significant. A number of potential confounding factors (e.g. migration, missing live births) were investigated, none significantly affected the results. The second study tests for correlations between radiation doses received by the male workers at these Canadian nuclear facilities and the subsequent development of leukaemia among their children; despite the fact that no significant excesses were found in childhood leukaemia in the first study. Dr Clarke said that results would be available shortly. It has been calculated that the study has more than 80% power of detecting a relative risk > 7 · 6 due to preconception exposure > 100 mSv (i.e. it will be a reasonable test of the Gardner hypothesis). Dr. B. Grosche reported a childhood leukaemia study around five Bavarian nuclear reactors (the experimental NNP at Kahl (V AK), the research reactor at Garching (FRM), and the commercial NPPs at Gundremmingen (KRB), Isar (KKI), and Grafenrheinfeld (KKG) ), and also mentioned two leukaemia clusters in Lower Saxony. The Bavarian study included the following variables: r-outdoor radiation; ground inversion; at least one community of a district belonging to the vicinity of a reactor; urbanization of a district, derived from some socio-economic variables by factor analysis; and unemployment rate. Leukaemia cases were taken from the childhood cancer registry, which covers the whole of Western Germany. The rest of the data were obtained from a variety of sources. Urbanization was the only variable that showed a significant influence on the incidence of childhood leukaemia: the highest rates being in the urban areas. Table 2 gives 0/E ratios and the number of cases observed within the vicinity regions. One out of 15 ratios (V AK) shows a significant excess. Looking at regional clustering within the 5 km circle, it was found that all five cases occurring here lived in those communities where the reactors are located. This leads to an 0/E ratio of 3 · 92 with confidence intervals of 1 · 43 and 8 · 68. It was concluded that for only one reactor and vicinity area
has a difference in the incidence been found compared to control regions within a radius of 5 and 10 km around five reactors in Bavaria. The fact that all cases within the inner circle occurred in those communities where the reactors are located was not reproducible when data from a prior study were used. This leads to the conclusion that the incidence within the vicinity of the reactors is comparable to that of Bavaria. Turning to the two childhood leukaemia clusters recently reported in Lower Saxony, only one was close to a nuclear reactor. In the Elbmarsch cluster, which was opposite the Krummel reactor, five cases occurred about five years after start-up within a time span of two years. (0/E = 41· 7). For the Sittensen cluster there was no nuclear reactor, but again five cases occurred in about three years (0/E = 13 ·9). A large study starting as a result of the Elbmarsh cluster would investigate about 500 childhood leukaemia cases in Germany during the time span 1987-1993. Methodological issues were discussed by Dr. E. Roman in relation to the effects of pre-natal exposure on childhood health. The importance of defining the type of exposure and separating pre-conception from intra-uterine exposure, if possible, was explained and illustrated by earlier studies. Three UK studies are currently in progress in this area: the UK Childhood Cancer Study, the Linkage Study and the Table 2. OlE ratios in the vicinity of five Bavarian reactors Plant YAK FRM KRB KKI KKG pooled
5 km circle 3·6 0 4·3 0 5·4 2·2
(2) (I)
(2) (5)
5-10 km ring 3·0 0·9 0 0 1·5 1·2
(3) (2)
(6) (II)
10 km circle 3·2 0·7 0·5 0 1·9 1·4
(5)* (2) (I) (8)
(16)
*p
