A-bomb survivors: factors that may lead to a re-assessment of the radiation hazard

Alice M Stewart and George W Kneale

Department of Public Health and Epidemiology, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail: A.Walker{at}bham.ac.uk


    Abstract
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 Results
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Background The study cohort of the survivors of the A-bombs in Japan, used as the basis of the internationally accepted estimates of cancer radiation risk, was collected more than 5 years after the bombing and did not include those who died of bomb-related injuries before that date. This paper tests whether the people who survived, in spite of bomb-related injuries, are homogeneous in respect of variation of cancer risk with age with survivors without such injuries.

Methods Appropriate statistical models are derived and fitted to survivor data by maximum likelihood and the resultant statistics used to test the homogeneity assumption.

Results Significant differences were found between those with no injuries and those with multiple injuries and shown to be largely due to exposures before 10 or after 55 years of age having exceptionally high risks of late effects of radiation for survivors showing early effects, i.e. bomb-related injuries.

Conclusions Certain accepted dogmas about the biology of radiation risks in humans, such as ‘cancer is the only late effect of radiation’ and ‘leukaemia is uniquely radiogenic amongst cancers’, may be significantly in error. These are discussed.

Keywords A-bomb survivors, radiation biology, cancer, age, effects, selection

Accepted 15 January 2000


    Introduction
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 Abstract
 Introduction
 LSS data on disk
 Results
 Discussion
 References
 
After the bombing of Hiroshima and Nagasaki there were thousands of deaths from radiation injuries and devastation effects of the blast.1 These early deaths were a special risk of infection-sensitive people. However, instead of the non-cancer death rate of survivors being lower than normal (and inversely related to the radiation dose) it was close to expectations based on national statistics and showed no signs of being dose related.2 These findings have long been regarded as evidence that the selection effects of the early deaths were so short lived that risk estimates for cancer effects of radiation could be based on a life span study (LSS) cohort consisting of A-bomb survivors still alive on 1 October 1950. Although this method of risk assessment is the basis of the cancer risk coefficients in BEIR V3 and ICRP 60,4 it is far from certain that the LSS cohort is a normal homogeneous population.

For example, the assumption that cancer was the only late effect of the A-bomb radiation ignores the fact that deaths from the only distinctive effect of marrow aplasia (aplastic anaemia) remained common long after 1950.2 Furthermore, the assumption that ‘the survivors, apart from their radiation dose, are representative human beings’,5 ignores the fact that (after the bombing) a normal non-cancer death rate could only be achieved in one of two ways: either there was no selection against infection-sensitive people, or extra deaths of such people were followed (before 1950) by extra deaths of infection-resistant people. Finally, although the use of A-bomb data for risk assessment requires comparable levels of radiosensitivity for survivors and non-survivors (and has repeatedly come to the conclusion that the cancer most likely to be caused by radiation is leukaemia) there has been no attempt to be quite certain that survivors with and without acute radiation injuries had the same mortality experiences.

The discovery that cancer effects of fetal irradiation were less obvious in A-bomb data than in data relating to children who had only had low dose exposures (in the form of prenatal x-rays),6 and the discovery that among the cancers caused by these x-rays there was no excess of leukaemias,7 were regarded by one of us (AMS) as reasons for suspecting that the A-bomb survivors had exceptionally high levels of immunological competence; that cancer was not the only late effect of the A-bomb radiation, and that the special relationship between leukaemia and radiation in A-bomb data might be the result of marrow damage. Only the Radiation Effects Research Foundation (RERF) was in a position to test this hypothesis, but, in 1982, Stewart gave the following reasons for her suspicions:8 (1) For several months after the bombing, deaths from a less obvious effect of marrow aplasia than aplastic anaemia (immune system damage) were numbered in thousands;1 so they too had probably continued after 1950; (2) it would only need deaths from immune system damage to continue after 1950 to leave a false impression of no selection effects of the earlier deaths; and (3) following doses sufficient to cause extensive tissue damage, it would only need a critical leucocytosis to give mutant forms of granulocytosis a unique opportunity to complete the second stage of the cancer process in record time.

According to RERF the extra deaths from aplastic anaemia were really cases of leukaemia; the association between childhood cancers and prenatal x-rays was of doubtful significance, and A-bomb data was not alone in showing that the cancer most likely to be caused by radiation was leukaemia. Therefore, the Stewart hypothesis was brushed aside. This remained the position until after release of a limited amount of data, in the form of LSS data on disk.9 This concession by RERF was followed by a paper describing the result of comparing three causes of death (neoplasms, cardiovascular diseases and other causes)10 and a second paper describing the results of comparing LSS data on disk, with published data relating to an ‘in utero cohort’ consisting of those who had survived in utero exposures to the A-bomb radiation and been included in studies of teratogenic and carcinogenic effects of fetal irradiation).11

These independent analyses of LSS data showed that in the in utero cohort there was under-representation of exposures before 8 weeks of fetal age, and in the LSS cohort there was under-representation of exposures before or after 50 years of age among the high dose survivors. They also showed that in the LSS cohort the rate for the residual group of deaths (other causes) was lower in the middle of the dose range than at either extreme. These findings stressed the need for more information about the survivors with and without acute injuries, and finally led to the release of a new version of LSS data on disk, specially prepared for the present research by RERF, which showed how many of the survivors who were interviewed after the 1950 census had claimed or denied any of the following injuries: burns, purpura, oropharyngeal lesions and epilation. With these data it was possible to test the usual assumption of LSS cohort homogeneity.


    LSS data on disk
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 LSS data on disk
 Results
 Discussion
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In their original form ‘LSS data on disk’ had, for 75 991 survivors who were still alive on 1 October 1950, the following specifications: sex (2), city (2), exposure age (6), DS86 dose (7), calendar years of 1950–1985 deaths, and six causes of these deaths, viz: leukaemia (including chronic lymphatic leukaemia), malignant tumours, benign tumours, cardiovascular diseases, other non-neoplastic diseases and trauma. In the enlarged data set there were, for each of the four injuries listed in Table 1Go, three alternatives, namely: claimed, denied or no record. The enlarged data set is available from RERF or from the present authors who have permission from RERF to circulate it.


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Table 1 Specifications of 5-year survivors with injury data
 
Statistical analysis
The basic data consisted of a standard description of each cell of a stratified table of dose-levels (referred to by d). The strata (referred to by s) were the cross-classification of standard factors (sex, city, age at time of bomb and interval to death) and the 81 levels formed by the cross-classification of four types of injury each at three levels (claimed, denied, no record). The data for each of the 29 484 cells defined in this way consisted of the number (nsd) of deaths with specific diagnoses, the number (Psd) of person-years of observation in the cell, and person-year weighted averages of dose (xsd), age at exposure (asd) and latency (tsd).

The relative risk model consisted of a function, (r(xsd, asd, tsd, {theta})) of the cell specific averages and a vector of parameters ({theta}), giving the average relative risk (Rsd) in the cell. Provided the death rate at zero dose in stratum s was given by {lambda}s, the expectation (esd) of nsd was given by RsdPsd{lambda}s. {lambda}S could then be estimated by making the sum of the esd over all dose levels equal to the corresponding sum of the nsd. The log-likelihood (L({theta})) corresponding to a particular value of {theta} for a particular relative risk model was given by the sum over all strata and dose levels of nsd.ln (esd/nsd), where ln (x) is the natural logarithm of x. The maximum likelihood estimate of {theta} ({theta}*) was then obtained by maximizing L({theta}). The statistic approximately distributed as {chi}2 in the null case, with degrees of freedom equal to the dimension of {theta}, was then twice the difference between L({theta}*) and the corresponding value for the null relative risk model (with all Rsd equal to one).

As in the BEIR V analysis of LSS data3 the relative risk was assumed to be Rsd = 1 + ßaxsd, where ßa is the age-specific increase in excess relative risk per unit dose. Maximum likelihood {chi}2 approximations were calculated for a total cohort and three subgroups, and in the final Table the {chi}2 for the three subgroups were combined to produce a test of cohort homogeneity (with 12 d.f. in the present situation).


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The commonest injury was flash burns (with 5551 claims) followed by purpura (3613), oropharyngeal lesions (2443) and epilation (1308) (Table 1Go). For 1949 of the 75 991 survivors there were no injury data. However, among the remaining survivors there were 2601 who claimed more than one injury (multiple injury or test group), 63 072 who denied all four injuries (nil injury or controls); and 8369 who either claimed only one injury (6683) or had an incomplete set of denials (residue of a ‘total cohort’ of 74 042 survivors).

When classified by cause of death, exposure age or DS86 dose (Table 2Go) the residual group usually occupied an intermediate position between the controls, who included 85% of the total cohort but only had 0.3% of high doses (>1 Gy), and the test group, which included less than 4% of the total cohort but had nearly 30% of high doses. For causes of death other than neoplasms there was virtually no difference between the test group (27.8%) and the controls (28.5%). For all neoplasms the corresponding proportions were 13.5% and 7.7% and for leukaemia they were 1.6% and 0.2%. Finally, both for exposures before 10 years of age and for exposures after 55 years, the proportions were lower for the test group (13.7% and 6.6%) than for the control group (23.3% and 10.5%).


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Table 2 Distribution of acute injuries by cause of death, DS86 dose, and exposure age
 
As a result of the regression analysis recognizing four cohorts, eight causes of death and six exposure ages there were 192 estimates of excess relative risk per Gray (ERR) each with its own {chi}2 test of statistical significance (Table 3Go). Also included in this Table are 32 {chi}2 each with 6 d.f. since they are sums of the {chi}2 for the separate ages. These additional {chi}2 were needed for tests of whether overall (for each cohort and each cause of death) there were any significant radiation associations.


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Table 3  Poisson regression analysis: excess relative risk (ERR) per Gray (Gy)
 
For the two large cohorts (total cohort and controls) and for the small test group there was evidence of radiation associations for three groups of cancer deaths (leukaemia, malignant tumours and all neoplasms). However, only for the test group was there also evidence of radiation associations for three groups of non-cancer deaths (trauma, cardiovascular disease and other). The analysis was hampered by the small numbers of total leukaemia deaths (201) and cancer deaths following exposures before 10 years of age (141), but there were sufficient numbers to show that, whereas in the control group the ERR for malignant tumours and all neoplasms were higher for exposures before 35 years of age than for later exposures, in the case group they were higher for the youngest and oldest exposure ages than for the four intervening ages (Figure 1Go).



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Figure 1 Excess relative risk (ERR) for three causes of death and five exposure ages. Excluding exposures before 10 years of age (see Table 3Go)

 
How much weight to attach to the differences between the total cohort and the three subgroups can be seen in Table 4Go where the additional {chi}2 from Table 3Go are used as tests of cohort homogeneity. If the usual assumption of uniform levels of radiosensitivity for all survivors of the same age and sex was correct then for each cause of death the sum of the additional {chi}2 for three subgroups of the total cohort (test group, controls and residue) would have had roughly the same value as the single {chi}2 for the total cohort. However, for each cause of death, the single additional {chi}2 for the total cohort had a lower value than the sum of the additional {chi}2 for the three subgroups (with 18 d.f.). For two causes of death the difference between the two {chi}2 (with 12 d.f.) was significant at the P < 0.01 level (malignant tumours and all causes of death), and for a further two it was significant at the P < 0.05 level (all neoplasms and all causes of death other than cardiovascular diseases and neoplasms).


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Table 4 Tests of cohort homogeneity
 

    Discussion
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 Abstract
 Introduction
 LSS data on disk
 Results
 Discussion
 References
 
As a result of the thousands of bomb-related deaths before 1950 there was no question of the LSS cohort being a normal, unselected population.1 Nevertheless, for more than 40 years this cohort maintained a normal non-cancer death rate and showed a steeper dose-response curve for leukaemia than for solid tumours. Consequently, ‘the use of A-bomb data for risk assessment is generally predicated on the assumption that the survivors, apart from their radiation dose, are representative human beings’;5 and on two further assumptions, namely, that cancer is the only late effect of radiation, and the cancer most likely to be caused by radiation is leukaemia.

When, in 1997, Shimizu et al. found evidence of an excess risk for non-cancer deaths at high dose levels,12 they were inclined to suspect an artefact caused by ‘erroneous attribution of radiation-related cancer deaths to other causes’. Even so, they finally concluded that the ‘increase does not appear to be fully explicable in terms of errors in classification’. By showing that the extra non-cancer deaths were restricted to those who claimed at least two acute injuries, the present analysis has strengthened the impression of a genuine excess of non-cancer deaths caused by non-stochastic effects of the radiation.

The assumption that A-bomb survivors are ‘representative human beings’ requires comparability not only between those who died before or after the LSS cohort was assembled, but also between survivors with or without acute injuries. By revealing significant differences between survivors with and without epilation, a 1989 analysis of LSS data by Neriishi et al.13 provided some support to the idea that the normal non-cancer death rate might be an artefact caused by diametrically opposite effects of marrow damage and selection.8 They finally decided that such differences ‘would be expected as an artefact of dosimetry errors’. However, by focusing on survivors who either denied all four injuries or claimed at least two injuries, the present analysis has minimized the effects of faulty reporting (of dose levels in injuries) and revealed significant differences between two groups of 5-year survivors. This non-homogeneity of the LSS cohort is alone sufficient to show that the 5-year survivors are not representative of the original exposed population, and there are further reasons for doubting the validity of all risk estimates based on A-bomb survivors.

By recognizing six exposure ages the regression analysis made it possible to compare survivors whose risk of dying before 1950 was above average (vulnerable ages or the youngest and oldest age groups) or below average (resistant ages or the four remaining age groups). Among 27 130 survivors who died during the follow-up period, there was better representation of vulnerable ages among 22 807 people who denied all acute injuries (31.2%) than among the 1072 people with multiple claims (15.5%). Furthermore, in the large group, most of the extra cancers affected resistant ages, and in the small group most of them affected vulnerable ages—which is exactly what would be expected if the bomb-related deaths before 1950 had caused selective loss of radiosensitive people. Finally, in the enlarged data base it was possible to see that it was only among the survivors who had claimed any acute injuries that leukaemia deaths were at all common.

The last observation made it reasonable to suspect that the different findings for myeloid and lymphatic leukaemia in A-bomb data (and in the ankylosing spondylitis survey)14 were the result of high doses causing both an immediate lymphocytopenia and a short-lived granulocytosis.15 As a result of these reactions the number of malignant stem cells at risk of stochastic effects would be exceptionally large for one part of the reticulo-endothelial system (red marrow) and exceptionally small for another part of the same cell system (lymph nodes). Loss of immunological competence would ensure short latency for any extra (radiogenic) leukaemias, and a prolonged lymphocytopenia would reduce the risk of idiopathic as well as radiogenic cases of lymphatic leukaemia. Finally, the different findings for lymphocytes and granulocytes could be a sign that outright destruction of red marrow is less easily achieved by external penetrating radiation than outright destruction of more superficially placed lymph nodes.

Since there was no separate identification of myeloid leukaemia, lymphatic leukaemia or other blood diseases in our data base, there was no possibility of testing this hypothesis. But it would explain why, in all high-dose studies, the association between radiation and leukaemia was so strong; and why in children whose extra cancers were the result of prenatal x-rays (and in nuclear workers whose extra cancers were the result of occupational exposure to small doses of gamma radiation) there was no evidence of any special association between radiation and leukaemia.7,16,17

By showing that, among the survivors with signs of acute radiation effects, levels of radiosensitivity were higher at the beginning and end of the life span than during the intervening period, the present analysis has found one reason for there being a wide diversity of radiosensitivity levels in all large populations.18 It has also made it reasonable to suspect that this diversity is the result of immune system control of radiosensitivity as well as infection sensitivity. With such control there would be a good reason why, in all diseases where there is unequivocal evidence of extreme radiosensitivity (ataxia telangiectasia, Down's syndrome, xeroderma pigmentosa and Friedreich's ataxia) there is also extreme infection sensitivity. There would also be a good chance of identifying, in A-bomb data, some of the factors which determine individual levels of radiosensitivity. The observed association between exposure age and cancer risk is unlikely to be an artefact; and there has been continuous monitoring of three survivor populations (i.e. the LSS cohort of 5-year survivors together with their not-in-city controls; the cohort of in utero children, and the F1 cohort).19 Therefore, Japanese epidemiologists should be in a uniquely good position to discover some of the reasons why radiotherapists are now quite certain that ‘individuals vary widely in the susceptibility of their body tissues to the damaging effects of ionizing radiation’.18


    Acknowledgments
 
The data described in this report were obtained from the Radiation Effects Research Foundation (RERF) in Hiroshima, Japan. RERF is a private foundation that is funded equally by the Japanese Ministry of Health and Welfare and the US Department of Energy through the US National Academy of Sciences. The conclusions reached in this report are those of the authors and do not necessarily reflect the scientific judgement of RERF or its funding agencies. Alice Stewart is holder of an Emeritus Fellowship from the Leverhulme Trust.


    References
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 Abstract
 Introduction
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 Results
 Discussion
 References
 
1 Ohkita T. Acute effects of the Hiroshima and Nagasaki bombs. J Radiat Res 1975;16(Suppl.):49–66.[Medline]

2 Beebe GW, Land CE, Kato H. The hypothesis of radiation—accelerated ageing and the mortality of Japanese A-bomb victims. In: Late Radiological Effects of Ionizing Radiation 1978;1:3–8.

3 BEIR V. Health Effects of Exposures to Low Levels of Ionizing Radiation. Washington DC: National Academic Press, 1990.

4 International Committee on Radiological Protection (ICRP) 60. Annals of the ICRP. 1990 Recommendations. Pergamon Press, 1990.

5 Radiation Effects Research Foundation. Annual Report of the Scientific Committee for the Period 1975–76. 1976, p.98.

6 Jablon S, Kato H. Childhood cancer in relation to prenatal exposure to A-bomb radiation. Lancet 1980;ii:1000–03.

7 Stewart AM, Webb J, Hewitt D. A survey of childhood malignancies. Br Med J 1958;I:1495–508.

8 Stewart AM. Delayed effects of A-bomb radiation: a review of recent mortality rates and risk estimates for five-year survivors. J Epidemiol Community Health 1992;36:80–86.[Abstract]

9 Radiation Effects Research Foundation. Life span study cancer mortality available on disk. RERF Update 1990;II,Issue I:9.

10 Stewart AM, Kneale GW. A-bomb radiation and evidence of late effects other than cancer. Health Phys 1990;58:729–35.[ISI][Medline]

11 Stewart AM, Kneale GW. A-bomb survivors: further evidence of late effects of early deaths. Health Phys 1993;64:467–72.[ISI][Medline]

12 Shimizu Y, Kato H, Schull W, Hoel D. Studies of the mortality of A-bomb survivors. 9th report on 1950–85 part 3. Noncancer mortality based on the revised doses (DS86). Rad Res 1992;130:249–66.[ISI][Medline]

13 Neriishi K, Stram DO, Vaeth M, Mizuno S, Akiba S. The observed relationship between the occurrence of acute radiation effects and leukaemia mortality among A-bomb survivors. TR 18–89. RERF Hiroshima 1989; also Rad Res 1991;125:206–13.[ISI][Medline]

14 Court Brown W, Doll R. Leukaemia and Aplastic Anaemia in Patients Irradiated for Ankylosing Spondylitis. Medical Research Council Special Report No. 295. London: HMSO, 1957.

15 Langham WH (ed.). Radiobiological Factors in Manned Space Flight. Report of the Space Radiation Study Panel of the Life Sciences Committee. Washington, DC: National Academy of Sciences-National Research Council, 1967.

16 Kneale GW, Stewart AM. Reanalysis of Hanford data: 1944–1986 deaths. Am J Ind Med 1993;23:371–89.[ISI][Medline]

17 Wing S, Shy C et al. Mortality among workers at Oak Ridge National Laboratory. Evidence of radiation effects in follow-up through 1984. JAMA 1991;265:1397–402.[Abstract]

18 Lewis PD. Variation in individual sensitivity to ionizing radiation. In: Jones RR, Southwood R (eds). Radiation and Health. Chichester & New York: John Wiley and Son, 1987.

19 Schull WJ. Effects of Atomic Bomb Radiation. A Half Century of Studies from Hiroshima and Nagasaki. New York: Wiley Liss, 1995.