Department of Public Health and Epidemiology, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail: A.Walker{at}bham.ac.uk
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Abstract |
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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
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Introduction |
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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.
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LSS data on disk |
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The relative risk model consisted of a function, (r(xsd, asd, tsd, )) of the cell specific averages and a vector of parameters (
), giving the average relative risk (Rsd) in the cell. Provided the death rate at zero dose in stratum s was given by
s, the expectation (esd) of nsd was given by RsdPsd
s.
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(
)) corresponding to a particular value of
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
(
*) was then obtained by maximizing L(
). The statistic approximately distributed as
2 in the null case, with degrees of freedom equal to the dimension of
, was then twice the difference between L(
*) 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 2 approximations were calculated for a total cohort and three subgroups, and in the final Table the
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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Results |
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When classified by cause of death, exposure age or DS86 dose (Table 2) 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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Discussion |
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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 ageswhich 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
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Acknowledgments |
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References |
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