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An earlier analysis examined the possibility of bias in the Life Span Study (LSS) cohort by studying Japanese A-bomb survivors with bomb-related acute injuries and those without such injuries. The authors reported significantly higher radiation risks, both for cancers and non-cancers, among those survivors with acute injuries compared with those without. The risks were reported to be particularly large among survivors aged <10 or > or =55 years of age at the time of bombings. The aim of this paper is to examine these findings more closely using the LSS acute effects data. All the analyses were carried out using Poisson regression. Relative risk models were fitted with adjustment for sex and other factors. Significant differences in relative risk between survivors with epilation and burns and those without epilation and burns are found for leukaemia. There is also some evidence for heterogeneity in the leukaemia risk between survivors with two or more acute injuries and those with no injuries, but the evidence is disappeared when survivors with one or more injuries are compared with those without injuries. For solid cancers, cardiovascular disease and all deaths combined, the risks do not differ to a statistically significant extent between survivors with and without injuries. There is no statistically significant heterogeneity in risk across age-at-exposure categories for survivors with injuries. For all deaths combined, relative risk estimates and their uncertainties are significantly higher for survivors exposed at ages <10 years when compared with other exposure ages, but risks are not significantly raised for survivors exposed at > or =55 years of age. With the exception of leukaemia, the findings from the present work are inconsistent with those of Stewart and Kneale.

Statistically significant increases in non-cancer disease mortality with radiation dose have been observed among survivors of the atomic bombings of Hiroshima and Nagasaki. The increasing trends arise particularly for diseases of the circulatory, digestive, and respiratory systems. Rates for survivors exposed to a dose of 1 Sv are elevated by about 10%, a smaller relative increase than that for cancer. The aetiology of this increased risk is not yet understood. Neither animal nor human studies have found clear evidence for excess non-cancer mortality at the lower range of doses received by A-bomb survivors. In this paper, we examine the age and time patterns of excess risks in the A-bomb survivors. The results suggest that the excess relative risk of non-cancer disease mortality might be highest for exposure at ages 30-49 years, and that those exposed at ages 0-29 years might have a very low excess relative risk compared with those exposed at older ages. The differences in excess relative risk for different age-at-exposure groups imply that the dose response relationships for non-cancer disease mortality need to be modelled with adjustment for age-at-exposure.

An epidemiological study was set up in the 1980s of UK participants in the UK atmospheric nuclear weapons testing programme. A large cohort of test participants was established along with a closely matched comparison or control group. Three analyses of mortality and cancer incidence have been carried out. This review describes the development of the evidence on possible effects on test participants with especial emphasis on the most recent analysis. Other sources of evidence, particularly from studies of other groups of test participants, are also considered. It was concluded that overall levels of mortality and cancer incidence in UK nuclear weapons test participants were similar to those in a matched control group, and overall mortality was lower than expected from national rates. There was no evidence of an increased raised risk of multiple myeloma among test participants in recent years, and the suggestion in the first analysis of this cohort of a raised myeloma risk relative to controls is likely to have been a chance finding. There was some evidence of a raised risk of leukaemia other than chronic lymphatic leukaemia among test participants relative to controls, particularly in the early years after the tests. Whilst this could be a chance finding, the possibility that test participation caused a small absolute risk of leukaemia other than chronic lymphatic leukaemia cannot be ruled out.

This review gives a general account of how and why epidemiological studies of UK participants in the nuclear weapons test programme were set up. There is a short description of the circumstances in which the tests were planned and executed and a discussion of the general considerations involved in designing studies to show whether the health of test participants suffered as a result of the tests. The companion review article summarises the results of the epidemiological studies.

Aims: To extend and analyse follow up of mortality and cancer incidence among men who took part in the UK's atmospheric nuclear weapon tests and experimental programmes 40-50 years ago, with particular reference to multiple myeloma and leukaemia., Methods: A total of 21,357 servicemen and male civilians from the UK who participated in the tests and a control group of 22,333 male controls were followed over the period 1952-98. Analyses were conducted of mortality from various causes, and of mortality and incidence for 27 types of cancer., Results: Rates of mortality from all causes continued to be similar among test participants and controls with the longer follow up, with standardised mortality ratios (SMRs) of 89 and 88 respectively over the full follow up period. For all cancers, the corresponding SMRs were 93 for participants and 92 for controls. Mortality from multiple myeloma was consistent with national rates both for participants and controls, and the relative risk (RR) of myeloma incidence among participants relative to controls was 1.14 (90% CI 0.74 to 1.74) over the full follow up period and 0.79 (90% CI 0.45 to 1.38) during the extended period of follow up (1991-98). Over the full follow up period, leukaemia mortality among participants was consistent with national rates, while rates among controls were significantly lower, and there was a suggestion of a raised risk among test participants relative to controls (RR 1.45, 90% CI 0.96 to 2.17); the corresponding RR for leukaemia incidence was 1.33 (90% CI 0.97 to 1.84). After excluding chronic lymphatic leukaemia (CLL), which is not thought to be radiation inducible, the RR of leukaemia mortality increased to 1.83 (90% CI 1.15 to 2.93), while that for incidence was little changed. Analysis of subgroups of participants with greater potential for exposure provided little evidence of increased risks, although the numbers of men involved were smaller and the statistical power was therefore less. Among other types of cancer, only for liver cancer incidence was there evidence of differences in rates between participants and controls in both the earlier and in the additional period of follow up. Mortality rates among test participants from causes other than cancer were generally similar to those among the controls., Conclusions: Overall levels of mortality and cancer incidence in UK nuclear weapons test participants have continued to be similar to those in a matched control group, and overall mortality has remained lower than expected from national rates. There was no evidence of an increased raised risk of multiple myeloma among test participants in recent years, and the suggestion in the first analysis of this study of a raised myeloma risk is likely to have been a chance finding. There was some evidence of a raised risk of leukaemia other than CLL among test participants relative to controls, particularly in the early years after the tests, although a small risk may have persisted more recently. This could be a chance finding, in view of low rates among the controls and the generally small radiation doses recorded for test participants. However, the possibility that test participation caused a small absolute risk of leukaemia other than CLL cannot be ruled out.

Epidemiological studies of the survivors of the atomic bombings of Hiroshima and Nagasaki have been conducted over many years. These studies have examined, inter alia, mortality and cancer incidence among the survivors. This paper summarises the form of the studies undertaken, outlines the main findings and describes how these results can be used in deriving estimates of radiation risks. In doing so, some areas of uncertainty and open issues are highlighted, such as the magnitude of lifetime cancer risks and the evidence for raised risks of non-cancer diseases at low doses. Continued follow-up of the survivors will be important in shedding further light on these issues.

Purposes: To assess the degree of overestimation in low-dose cancer risk when models linear in dose are fitted to cancer data., Materials and Methods: Examination of the quadratic and the linear coefficients (in dose) in the Japanese atomic bomb survivor cancer incidence data, based on follow-up to 1987 and taking separate account of random errors in DS86 neutron and DS86 gamma dose estimates and systematic errors in Hiroshima DS86 neutron dose estimates., Results: When the 0-4Gy dose range is used, the low-dose extrapolation factor for all solid tumours, assessing the degree to which low-dose cancer risks are overestimated by fitting a model linear in dose, is 1.06 (95% CI 0.78, 1.62) and so is not significantly different from 1; the associated ratio of the quadratic to the linear coefficients is 0.06 Sv(-1) (95% CI -0.22, 0.67). The best estimate of the low-dose extrapolation factor for leukaemia is 2.47 (95% CI 1.24, > 1,000). The ratio of the quadratic to the linear coefficients is 1.81 Sv(-1) (95% CI 0.21, > 1,000). When various types and groupings of solid tumours are considered there is not generally any strong evidence for upward curvature; for only two out of the six solid tumour groupings are there indications of appreciable upward curvature in the dose response, and in no instance is this statistically significant. Consideration of a lower dose range (0-2Gy rather than 0-4 Gy) results in the low-dose extrapolation factor for solid tumours increasing to 1.21 (95% CI 0.81, 2.45), with corresponding increases for solid tumour subtypes; the corresponding quantity for leukaemia decreases to 1.73 (95% CI 0.79, 147.67). Three out of the six solid tumour subtypes now show appreciable upward curvature. If there is additional adjustment of the Hiroshima neutron dose estimates over the 0-2 Gy dose range, the low-dose extrapolation factor for all solid tumours increases still further, to 1.43 (95% CI 0.97, 2.72), whereas for leukaemia this quantity is further reduced, to 1.58 (95% CI 0.90, 10.58)., Conclusions: There is marked upward curvature in the dose response for leukaemia. For solid tumours there is little indication of upward curvature in the dose response over the 0-4 Gy dose range, although over the 0-2 Gy dose range and after adjustment of Hiroshima DS86 neutron dose estimates the upward curvature is more pronounced. Uncertainties in the likely adjustments to the Hiroshima DS86 neutron dose estimates imply that these findings should be treated with caution.

In this paper the radiation-associated relative risks of second primary cancer incidence in groups treated for first primary cancer by radiotherapy are compared with radiation-associated relative risk estimates in the Japanese atomic bomb survivor cancer incidence data. For four cancer sites, namely lung cancer, bone cancer, ovarian cancer and leukaemia, the relative risks in the comparable (age at exposure, time since exposure, sex matched) subsets of the Japanese data are significantly greater than those in the majority of second cancer studies. Even when the differences between the relative risks in the Japanese atomic bomb survivors and the medical series do not approach conventional levels of statistical significance, relative risks tend to be higher in the Japanese data than in the second cancer studies. At least for leukaemia, the discrepancy between the Japanese and second cancer risks can be largely explained by cell-sterilisation effects. There are few indications of modification of radiation-associated second cancer relative risk among those treated with adjuvant chemotherapy, nor are there strong indications of modification of radiation-associated relative risk by heritable genetic factors. If anything, there is evidence that second cancer relative excess risks are lower among those patients with cancer-prone disorders than among non-susceptible patients. However, the higher underlying cancer risk in some of these medically exposed populations should also be considered, in particular for those with cancer-prone conditions, so that the absolute excess risk is sometimes higher than in the Japanese data.

The dose-response relationship for radiation-induced leukemia was examined in a pooled analysis of three exposed populations: Japanese atomic bomb survivors, women treated for cervical cancer, and patients irradiated for ankylosing spondylitis. A total of 383 leukemias were observed among 283,139 study subjects. Considering all leukemias apart from chronic lymphocytic leukemia, the optimal relative risk model had a dose response with a purely quadratic term representing induction and an exponential term consistent with cell sterilization at high doses; the addition of a linear induction term did not improve the fit of the model. The relative risk decreased with increasing time since exposure and increasing attained age, and there were significant (P < 0.00001) differences in the parameters of the model between datasets. These differences were related in part to the significant differences (P = 0.003) between the models fitted to the three main radiogenic leukemia subtypes (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia). When the three datasets were considered together but the analysis was repeated separately for the three leukemia subtypes, for each subtype the optimal model included quadratic and exponential terms in dose. For acute myeloid leukemia and chronic myeloid leukemia, there were reductions of relative risk with increasing time after exposure, whereas for acute lymphocytic leukemia the relative risk decreased with increasing attained age. For each leukemia subtype considered separately, there was no indication of a difference between the studies in the relative risk and its distribution as a function of dose, age and time (P > 0.10 for all three subtypes). The nonsignificant indications of differences between the three datasets when leukemia subtypes were considered separately may be explained by random variation, although a contribution from differences in exposure dose-rate regimens, inhomogeneous dose distribution within the bone marrow, inadequate adjustment forcell sterilization effects, or errors in dosimetry could have played a role.

Purposes: To investigate the evidence for a threshold in the cancer dose-response curve., Materials and Methods: Japanese atomic bomb survivor cancer mortality data, based on follow-up to 1990, was used, taking account of random errors in DS86 dose estimates., Results: For all solid cancers analysed together, there is a significant positive dose response (two-sided p<0.05) if all survivors who received <0.5 Sv are considered, but the significance vanishes if doses of <0.2 Sv are considered; the same is also true for leukaemia. For solid cancer mortality there is no indication of curvilinearity in the dose response: no statistically significant improvement in fit to a linear relative risk model is provided by addition of quadratic or threshold dose terms. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to solid cancer mortality data, the best estimate of the threshold is < 0.00 Sv (95% CI <0.00-0.13). If a linear-quadratic-threshold model is used the best estimate of the threshold is < 0.00 Sv (95% CI < 0.00-0.15). For leukaemia mortality there is highly statistically significant upward curvature in the dose response. In particular, if a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to the leukaemia data, the best estimate of the threshold is 0.16 Sv (95% CI 0.05-0.40) (two-sided p=0.001 for test of departure of threshold from 0). However, there is no evidence for a threshold effect (two-sided p = 0.16) when a quadratic term is included in the dose response: the best estimate of threshold in this case is 0.09Sv (95% CI <0.00-0.29). Moreover, addition of a quadratic term improves the fit of a linear-threshold model at borderline levels of statistical significance (two-sided p = 0.07). Therefore, the most parsimonious description of the leukaemia dose response is provided by a linear-quadratic function of dose., Conclusions: There is no evidence of threshold-type departures from the linear-quadratic dose response either for solid tumours or for leukaemia in the Japanese atomic bomb survivor mortality data.

Recently released data on cancer incidence in Japanese atomic bomb survivors are analyzed using a variety of relative risk models that take account of errors in estimates of dose to assess the dose response at low doses. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to solid cancer data, a threshold of more than about 0.2 Sv is inconsistent with the data, whereas these data are consistent with there being no threshold. Among solid cancer subtypes there is strong evidence for a possible dose threshold only for nonmelanoma skin cancer. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to the leukemia data, a threshold of more than about 0.3 Sv is inconsistent with the data. In contrast to the estimates for the threshold level for solid cancer data, the best estimate for the threshold level in the leukemia data is significantly different from zero even when allowance is made for a possible quadratic term in the dose response, albeit at borderline levels of statistical significance (p = 0.04). There is little evidence for curvature in the leukemia dose response from 0.2 Sv upwards. However, possible underestimation of the errors in the estimates of the dose threshold as a result of confounding and uncertainties not taken into account in the analysis, together with the lack of biological plausibility of a threshold, makes interpretation of this finding questionable.

The recently released data on cancer incidence in the Japanese atomic bomb survivors are analysed using a variety of relative risk models which take account of errors in estimates of dose to assess the dose-response at low doses. For all solid cancers analysed together there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the solid cancer data, a threshold of more than about 0.2 Sv is inconsistent with the data, whereas these data are consistent with there being no threshold. Linear-quadratic models and linear-quadratic models with an exponential cell-sterilization term provide no better fit than the linear model. For the three main radiation-inducible leukaemia subtypes analysed together (acute lymphatic leukaemia, acute myeloid leukaemia and chronic myeloid leukaemia) there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the leukaemia data, a thresh-old of more than about 0.3 Sv is inconsistent with the data. In contrast with the solid cancer data, the best estimate for the threshold level in the leukaemia data is significantly different from zero, even when allowance is made for a possible quadratic term in the dose-response, albeit at borderline levels of statistical significance (p = 0.04). There is little evidence for curvature in the leukaemia dose-response from 0.2 Sv upwards. However, the possible underestimation of the errors in the estimates of the dose threshold as a result of confounding and uncertainties not taken into account in the analysis, together with the lack of biological plausibility of a threshold, makes the interpretation of this finding questionable.

Altogether 22,347 men who participated in the United Kingdom's atmospheric nuclear weapon tests and experimental programmes in Australia and the Pacific Ocean between 1952 and 1967 were identified from the archives of the Ministry of Defence and followed up. Their mortality and incidence of cancer were compared with those in 22,326 matched controls selected from the same archives. The risk of mortality in the participants relative to that in the controls was 1.01 for all causes and 0.96 for all neoplasms. Thirty eight causes of death were examined separately. Significant differences in mortality were found for leukaemia, multiple myeloma, and other injury and poisoning, with higher rates in the participants, and for cancers of the prostate and kidney and chronic bronchitis, with higher rates in the controls. The mortality from leukaemia and multiple myeloma in the participants was slightly greater than would have been expected from national values (standardised mortality ratios of 113 and 111, respectively), but in the controls it was substantially lower (standardised mortality ratios of 32 and 0, respectively). Examination of the rates of leukaemia and multiple myeloma in groups of participants showed very little difference between groups characterised by recorded doses of external radiation or type of test participation and failed to indicate any specific hazard. Evidence obtained from participants who reported themselves voluntarily (or were reported by relatives or friends) suggested that 17% of participants may have been omitted from the main study group but that any resulting bias was small. Most of the differences observed between the participants and controls were interpreted as due to chance, but some may be due to differences in smoking habits. Participation in the test programme did not seem, in itself, to have caused any detectable effect on the participants' expectation of life, apart from possibly causing small risks of developing leukaemia and multiple myeloma.