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Purpose: To compare quantitative estimates of lifetime cancer risk in humans for exposures to internally deposited radionuclides and external radiation. To assess the possibility that risks from radionuclide exposures may be underestimated., Materials and Methods: Risk estimates following internal exposures can be made for a small number of alpha-particle-emitting nuclides. (1) Lung cancer in underground miners exposed by inhalation to radon-222 gas and its short-lived progeny. Studies of residential (222)Rn exposure are generally consistent with predictions from the miner studies. (2) Liver cancer and leukaemia in patients given intravascular injections of Thorotrast, a thorium-232 oxide preparation that concentrates in liver, spleen and bone marrow. (3) Bone cancer in patients given injections of radium-224, and in workers exposed occupationally to (226)Ra and (228)Ra, mainly by ingestion. (4) Lung cancer in Mayak workers exposed to plutonium-239, mainly by inhalation. Liver and bone cancers were also seen, but the dosimetry is not yet sufficiently good enough to provide quantitative estimates of risks. Comparisons can be made between risk estimates for radiation-induced cancer derived for radionuclide exposure and those derived for the A-bomb survivors, exposed mainly to low-LET (linear energy transfer) external radiation. Data from animal studies, using dogs and rodents, allow comparisons of cancer induction by a range of alpha- and beta-/gamma-emitting radionuclides. They provide information on relative biological effectiveness (RBE), dose-response relationships, dose-rate effects and the location of target cells for different malignancies., Results: For lung and liver cancer, the estimated values of risk per Sv for internal exposure, assuming an RBE for alpha-particles of 20, are reasonably consistent with estimates for external exposure to low-LET radiation. This also applies to bone cancer when risk is calculated on the basis of average bone dose, but consideration of dose to target cells on bone surfaces suggests a low RBE for alpha-particles. Similarly, for leukaemia, the comparison of risks from alpha-irradiation ((232)Th and progeny) and external radiation suggest a low alpha RBE; this conclusion is supported by animal data. Risk estimates for internal exposure are dependent on the assumptions made in calculating dose. Account is taken of the distribution of radionuclides within tissues and the distribution of target cells for cancer induction. For the lungs and liver, the available human and animal data provide support for current assumptions. However, for bone cancer and leukaemia, it may be that changes are required. Bone cancer risk may be best assessed by calculating dose to a 50 micro m layer of marrow adjacent to endosteal (inner) bone surfaces rather than to a single 10 micro m cell layer as currently assumed. Target cells for leukaemia may be concentrated towards the centre of marrow cavities so that the risk of leukaemia from bone-seeking radionuclides, particularly alpha emitters, may be overestimated by the current assumption of uniform distribution of target cells throughout red bone marrow., Conclusions: The lifetime risk estimates considered here for exposure to internally deposited radionuclides and to external radiation are subject to uncertainties, arising from the dosimetric assumptions made, from the quality of cancer incidence and mortality data and from aspects of risk modelling; including variations in baseline rates between populations for some cancer types. Bearing in mind such uncertainties, comparisons of risk estimates for internal emitters and external radiation show good agreement for lung and liver cancers. For leukaemia, the available data suggest that the assumption of an alpha-particle RBE of 20 can result in overestimates of risk. For bone cancer, it also appears that current assumptions will overestimate risks from alpha-particle-emitting nuclides, particularly at low doses.

Purposes: To model radon-induced lung cancer in uranium miners using a quasi-biological model of carcinogenesis., Materials and Methods: Fitting of generalizations of the stochastic two-mutation carcinogenesis model of Moolgavkar, Venzon and Knudson to a case-control dataset nested within the cohort and to the full cohort of lung cancer mortality in the Colorado Plateau uranium miners, taking account of exposure to cigarette smoke and to radon daughters., Results: Models with three mutations gave adequate descriptions of the time and age patterns of radon-daughter-induced excess lung tumour mortality. The overall fit of the two-mutation model to the case-control data was somewhat worse than that of the three-mutation model. For both the optimal two- and three-mutation models radon daughters and cigarette smoke were assumed to act on the first mutation rate. In the optimal two-mutation model, radon daughters also modified the intermediate cell death or differentiation rate. In the optimal three-mutation model, radon daughters modified the second mutation rate. In all models, the action of radon daughters and cigarette smoke was markedly non-linear, particularly in their action on the mutation rates. The optimal two- and three-mutation models fitted to the cohort data were of slightly different form to those fitted to the case-control data. The model fits to the cohort data are preferred to those to the case-control data on grounds of plausibility., Conclusions: Quasi-biological carcinogenesis models with three mutations give adequate descriptions of the time and age patterns of radon-daughter-induced excess lung tumour mortality. The overall fit of the two-mutation model is somewhat worse than that of the three-mutation model.

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.

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.

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.