Effects of radiation and lifestyle factors on risks of urothelial carcinoma in the Life Span Study of atomic bomb survivors

Among the Life Span Study (LSS) of Atomic-bomb survivors, recent estimates showed that unspecified bladder cancer had high radiation sensitivity with a notably high female-to-male excess relative risk (ERR) per radiation dose ratio and were the only sites for which the ERR did not decrease with attained age. These findings, however, did not consider lifestyle factors, which could potentially confound or modify the risk estimates. This study estimated the radiation risks of the most prevalent subtype of urinary tract cancer, urothelial carcinoma, while accounting for smoking, consumption of fruit, vegetables, alcohol and level of education (a surrogate for socioeconomic status). Eligible study subjects included 105,402 (males = 42,890) LSS members who were cancer-free in 1958 and had estimated radiation doses. Members were censored due to loss of follow-up, incident cancer of another type, death, or the end of calendar year 2001. Surveys (by mail or clinical interview) gathered lifestyle data periodically for 1963-1991. There were 63,827 participants in one or more survey. Five hundred seventy-three incident urothelial carcinoma cases occurred, of which 364 occurred after lifestyle information was available. Analyses were performed using Poisson regression methods. The excess relative risk per weighted gray unit (the gamma component plus 10 times the neutron component, Gy(w)) was 1.00 (95% CI: 0.43-1.78) but the risks were not dependent upon age at exposure or attained age. Lifestyle factors other than smoking were not associated with urothelial carcinoma risk. Neither the magnitude of the radiation ERR estimate (1.00 compared to 0.96), nor the female-to-male (F:M) ERR/Gy(w) ratio (3.2 compared to 3.4) were greatly changed after accounting for all lifestyle factors. A multiplicative model of gender-specific radiation and smoking effects was the most revealing though there was no evidence of significant departures from either the additive or multiplicative joint effect models. Among the LSS cohort members with doses greater than 0.005 Gy(w) (average dose 0.21 Gy(w)), the attributable fraction of urothelial carcinoma due to radiation was 7.1% in males and 19.7% in females. Among current smokers, the attributable fraction of urothelial carcinoma due to smoking was 61% in males and 52% in females. Relative risk estimates of smoking risk were approximately two for smokers compared to nonsmokers. After adjustment for lifestyle factors, gender-specific radiation risks and the F:M ERR/Gy(w), the ratios of excess urothelial carcinoma risk were similar to the estimates without adjusting for lifestyle factors. Smoking was the primary factor responsible for excess urothelial carcinoma in this cohort. These findings led us to conclude that the radiation risk estimates of urothelial carcinoma do not appear to be strongly confounded or modified by smoking, consumption of alcohol, fruits, or vegetables, or level of education.     

Calculation of the 1995 lung cancer incidence in the Netherlands and Sweden caused by smoking and radon: risk implications for radon

A two-mutation carcinogenesis model was used to calculate the expected lung cancer incidence caused by both smoking and exposure to radon in two populations, i.e. those of the Netherlands and Sweden. The model parameters were taken from a previous analysis of lung cancer in smokers and uranium miners and the model was applied to the two populations taking into account the smoking habits and exposure to radon. For both countries, the smoking histories and indoor radon exposure data for the period 1910-1995 were reconstructed and used in the calculations. Compared with the number of lung cancer cases observed in 1995 among both males and females in the two countries, the calculations show that between 72% and 94% of the registered lung cancer cases may be attributable to the combined effects of radon and smoking. In the Netherlands, a portion of about 4% and in Sweden, a portion of about 20% of the lung cancer cases (at ages 0-80 years) may be attributable to radon exposure, the numbers for males being slightly lower than for females. In the Netherlands, the proportions of lung cancers attributable to smoking are 91% for males and 71% for females; in Sweden, the figures are 70% and 56%, respectively. The risk from radon exposure is dependent on gender and cigarette smoking: the excess absolute risk for continuous exposure to 100 Bq m-3 ranges between 0.003 and 0.006 and compares well with current estimates, e.g. 0.0043 of the International Commission on Radiological Protection (ICRP). The excess relative risk for continuous exposure to 100 Bq m-3 shows a larger variation, ranging generally between 0.1 for smokers and 1.0 for non-smokers. The results support the assumption that exposure to (indoor) radon, even at a level as low as background radiation, causes lung cancer proportional to the dose and is consistent with risk factors derived from the miners data.     

Investigation of glutathione S-transferase M1 and T1 deletions in lung cancer

Glutathione S-transferases (GSTs) M1 and T1 are known to be polymorphic in humans. Both polymorphisms are due to gene deletions which are responsible for the existence of null genotypes. Previous studies have suggested that GST genotypes may play a role in determining susceptibility to a number of unrelated cancers, including lung cancer. The GSTM1 and GSTT1 polymorphisms were determined by PCR-based analysis in 75 lung cancer patients and 55 controls. The unconditional logistic regression analysis was used to calculate ORs and 95% CI. The frequencies of GSTM1 and GSTT1 null genotypes were 37.3 and 22.7% in lung cancer patients and 27.3 and 16.4% in controls, respectively. When analyzed by histology the GSTM1 null genotype was more prevalent in squamous-cell carcinoma and adenocarcinoma patients. Whereas, GSTT1 null genotype frequency was lower in small-cell lung cancer patients than controls. But these differences were not statistically significant. According to smoking status, null genotype for both gene are associated with an increase in risk for lung cancer. Our results suggest that GSTM1 and GSTT1 polymorphisms may play a role in the development of lung cancer for some histological subtypes and modifies the risk of smoking-related lung cancer.     

CCND1 G870A polymorphism interaction with cigarette smoking increases lung cancer risk: meta-analyses based on 5008 cases and 5214 controls

Evidence indicates CCND1 G870A polymorphisms as a risk factor for a number of cancers. Increasing studies have been conducted on the association of CCND1 G870A polymorphism with lung cancer risk. However, the results were controversial. The aim of the present study was to derive a more precise estimation of the relationship. Meta-analyses examining the association between CCND1 G870A polymorphism and lung cancer were performed. Subgroup analyses regarding ethnicity, smoking status, histological types and source of controls were also implemented. All eligible studies for the period up to May 2012 were identified. The overall data from ten case–control studies including 5,008 cases and 5,214 controls indicated that variant A allele may have an association with increased lung cancer risk (AA vs GG: OR = 1.21; 95 % CI = 1.08–1.36, dominant model: OR = 1.09; 95 % CI = 1.00–1.19, recessive model: OR = 1.23; 95 % CI = 1.01–1.49). In the subgroup analysis by ethnicity, A allele may elevate lung cancer risk among Asians but not Caucasians or Mixed ethnicities. In smoking status subgroup, A allele was shown to associate with increased lung cancer risk among smokers but not non-smokers. In the subgroup analysis by histological types, increased cancer risks were shown in adenocarcinoma but not squamous cell carcinoma, under the homozygote comparison and recessive models. Collectively, the results of the present study suggest that CCND1 G870A polymorphism might be a low-penetrant risk factor for lung cancer, particularly among Asians and smokers. Moreover, homozygous AA alleles might have a correlation with increased lung adenocarcinoma susceptibility.     

Lung cancer risks of underground miners: cohort and case-control studies

All underground mines have higher radon levels than are found in surface air. Ventilation is the primary method of controlling radon levels. Fourteen cohort and seven case-control studies done on underground miners are reviewed; they include many types of ore. Only five of the studies deal with more than 100 lung cancer deaths. Variations in the attributable risk are given. Some generalizations can be drawn from these studies: the longer the follow-up, the greater is the attributable risk, even though the relative risk is reasonably constant. The induction-latent period is quite variable but is shortened by high exposure rates, by cigarette smoking, and by increasing age at start of mining. The predominant histological type of lung cancer among miners changed from small-cell undifferentiated for short follow-up time to epidermoid after long follow-up times. With short follow-up time, a multiplicative interaction between smoking and radiation was indicated, but, with long follow-up time, the two factors appear to be simply additive. This difference is probably due to the shortened latent period among cigarette smokers, not to synergism.     

Factors significant in the diagnostic accuracy of lung cytology in bronchial washing and sputum samples. I. Bronchial washings

Some factors influencing the diagnostic accuracy for primary lung cancer in bronchial washings were studied in 276 consecutive cases seen between 1959 and 1974. Diagnostic accuracy increased during the years under study; the reasons included increasing expertise of the laboratory staff, better documentation of cytologic criteria and improved collection techniques. The overall accuracy was 74%. Detection of malignant cells was highest for squamous-cell and adenosquamous carcinomas (81%), small-cell carcinoma, adenocarcinoma and large-cell carcinoma (70%) and lowest for bronchioloalveolar-cell carcinoma (47%). Accuracy was 84% for central tumors as compared to 30% for peripheral lesions. Tumors of less than 2 cm in diameter yielded very poor results (15%) while those greater than 2 cm yielded 82% accuracy. The specificity of diagnosis of cell type in those specimens with malignant cells was over 93% for squamous-cell carcinoma, small-cell carcinoma and adenocarcinoma, 77% for large-cell carcinoma and below 50% for adenosquamous carcinoma, bronchioloalveolar carcinoma and the uncommon tumors. Two bronchial washings per case gave an appreciably better result (92%) than one per case (68%). The percentage of unsatisfactory specimens from those with cancer was 13.5 and from a control group was 29.9. Reasons for unsatisfactory specimens included limited cellular material, excessive blood and/or leukocytes and drying artifacts.     

Joint effects of radiation and smoking on lung cancer risk among atomic bomb survivors

Results are given on the joint effect of radiation exposure and cigarette smoking on lung cancer risks among A-bomb survivors, based on 592 cases through 1994. Information on smoking was derived from mail surveys and clinical interviews of 45113 persons in the Radiation Effects Research Foundation cohort. Radiation and smoking effects on lung cancer are found to be significantly sub-multiplicative and quite consistent with additivity. The smoking relative risk, previously very low in studies of this cohort, is now similar to that found in Western populations. This increase is likely to be related to the scarcity of cigarettes during and after the war. The smoking relative risk depends little on sex. After adjusting for smoking, the radiation-related risks relative to background rates for nonsmokers are similar to those for other solid cancers: a sex-averaged ERR/Sv of about 0.9 with a female:male sex ratio of about 1.6. Adjusting for smoking removes a spuriously large female:male ratio in radiation relative risk due to confounding between sex and smoking level. The adjustment also removes an artifactual age-at-exposure effect in the radiation relative risk, opposite in direction to other cancers, which is due to birth cohort variation in lung cancer rates.     

Lung cancer in Mayak workers: interaction of smoking and plutonium exposure

Lung cancer mortality among 5058 male workers of the Mayak Production Association has been analyzed with emphasis on the interaction of smoking and radiation exposure by using the two-step clonal expansion (TSCE) model of carcinogenesis. The cohort consists of all Mayak workers with known smoking status, who were employed in the period 1948–1972, and who either had the plutonium concentration in urine measured or who worked in the reactors, where plutonium exposure was negligible. Those who died during the first two years after the first urine sampling were excluded. The follow-up extended until the end of 1998. During this time, 2176 workers died, including 244 lung cancer cases. Mayak workers were exposed to external (gamma and neutron) radiation, and in the radiochemical and plutonium plants to plutonium. In the preferred TSCE model, internal radiation and smoking act on the clonal expansion of pre-carcinogenic clones. Assuming a plutonium radiation weighting factor of 20, the excess relative risk per lung dose was estimated to be 0.11 (95% CI: 0.08; 0.17) Sv⁻¹. Most of the lung cancer deaths are found to be due to smoking. The second main factor is the interaction of smoking and internal radiation. The model is sub-multiplicative in relative risks due to smoking and radiation. In a multiplicative version of the TSCE model, internal radiation acts on initiation and transformation rates. This model version agrees with conventional epidemiological risk models, because it also suggests a higher risk estimate than the preferred TSCE model. However, it fits the data less well than the preferred model. An erratum to this article can be found at     

Mortality in relation to smoking: 22 years' observations on female British doctors.

A total of 6194 female doctors who in 1951 replied to a questionnaire about their smoking habits were followed up prospectively for 22 years. During that time 1094 died. Ischaemic heart disease, lung cancer, and chronic obstructive lung disease were all significantly (p < 0.001) related to smoking, though the absolute excess risks were lower than in male doctors smoking equivalent amounts. Female smokers born before the first world war were less likely to describe themselves as inhalers or as having started to smoke while young than were female smokers who were born later. In these respects this younger group resembled male smokers, and as they move into their 60s and 70s their absolute risk of lung disease and relative risk of ischaemic heart disease will probably come to resemble the risks for men smoking the same numbers of cigarettes. These findings show only that cigarette smoking causes lung cancer, chronic obstructive lung disease, and heart disease in women as in men. Whether the proportional increase in mortality from these diseases is as great in women as in men might be estimated directly from new case-control studies on men and women born since 1920.     

Solid cancer incidence in atomic bomb survivors: 1958-1998

This is the second general report on radiation effects on the incidence of solid cancers (cancers other than malignancies of the blood or blood-forming organs) among members of the Life Span Study (LSS) cohort of Hiroshima and Nagasaki atomic bomb survivors. The analyses were based on 17,448 first primary cancers (including non-melanoma skin cancer) diagnosed from 1958 through 1998 among 105,427 cohort members with individual dose estimates who were alive and not known to have had cancer prior to 1958. Radiation-associated relative risks and excess rates were considered for all solid cancers as a group, for 19 specific cancer sites or groups of sites, and for five histology groups. Poisson regression methods were used to investigate the magnitude of the radiation-associated risks, the shape of the dose response, how these risks vary with gender, age at exposure, and attained age, and the evidence for inter-site variation in the levels and patterns of the excess risk. For all solid cancers as a group, it was estimated that about 850 (about 11%) of the cases among cohort members with colon doses in excess of 0.005 Gy were associated with atomic bomb radiation exposure. The data were consistent with a linear dose response over the 0- to 2-Gy range, while there was some flattening of the dose response at higher doses. Furthermore, there is a statistically significant dose response when analyses were limited to cohort members with doses of 0.15 Gy or less. The excess risks for all solid cancers as a group and many individual sites exhibit significant variation with gender, attained age, and age at exposure. It was estimated that, at age 70 after exposure at age 30, solid cancer rates increase by about 35% per Gy (90% CI 28%; 43%) for men and 58% per Gy (43%; 69%) for women. For all solid cancers as a group, the excess relative risk (ERR per Gy) decreases by about 17% per decade increase in age at exposure (90% CI 7%; 25%) after allowing for attained-age effects, while the ERR decreased in proportion to attained age to the power 1.65 (90% CI 2.1; 1.2) after allowing for age at exposure. Despite the decline in the ERR with attained age, excess absolute rates appeared to increase throughout the study period, providing further evidence that radiation-associated increases in cancer rates persist throughout life regardless of age at exposure. For all solid cancers as a group, women had somewhat higher excess absolute rates than men (F:M ratio 1.4; 90% CI 1.1; 1.8), but this difference disappears when the analysis was restricted to non-gender-specific cancers. Significant radiation-associated increases in risk were seen for most sites, including oral cavity, esophagus, stomach, colon, liver, lung, non-melanoma skin, breast, ovary, bladder, nervous system and thyroid. Although there was no indication of a statistically significant dose response for cancers of the pancreas, prostate and kidney, the excess relative risks for these sites were also consistent with that for all solid cancers as a group. Dose-response estimates for cancers of the rectum, gallbladder and uterus were not statistically significant, and there were suggestions that the risks for these sites may be lower than those for all solid cancers combined. However, there was emerging evidence from the present data that exposure as a child may increase risks of cancer of the body of the uterus. Elevated risks were seen for all of the five broadly classified histological groups considered, including squamous cell carcinoma, adenocarcinoma, other epithelial cancers, sarcomas and other non-epithelial cancers. Although the data were limited, there was a significant radiation-associated increase in the risk of cancer occurring in adolescence and young adulthood. In view of the persisting increase in solid cancer risks, the LSS should continue to provide important new information on radiation exposure and solid cancer risks for at least another 15 to 20 years.     

Involuntary smoking and the risk of head and neck cancer in an East Asian population

BackgroundAlthough tobacco involuntary smoking is an established risk factor for lung cancer, the association with head and neck cancer (HNC) is not established. We aimed to investigate this potential association in an East Asian population.MethodsWe conducted a multicenter case-control study in East Asia including eight centers. We restricted our analysis to never tobacco smokers (303 cases and 459 controls) and to never tobacco smokers/never alcohol drinkers (243 cases and 403 controls).ResultsAmong never tobacco smokers, involuntary smoking was associated with a 1.47-fold increase in risk of HNC (95%CI = 1.02, 2.13) and a 1.8-fold increase in the risk of oral cavity cancer (95%CI = 1.14, 2.92). Among never tobacco smokers who were also never alcohol drinkers, increased risks were detected for more than 3 h per day of involuntary smoking exposure and for 15 or more years of exposure. A dose-response relation was suggested for frequency of exposure (p for trend = 0.014) and for years of exposure (p for trend = 0.010) for oral cavity cancer. We did not detect strong increases in the risk of the other HNC subsites.ConclusionsOur study supports the association between involuntary smoking and the risk of HNC. The association may be stronger for oral cavity cancer than for other HNC subsites.     

Double primary lung cancers: with special reference to their exfoliative cytology and to the rare, malignant "mixed" tumor of the salivary-gland type

Two autopsy cases are reported in which double primary cancers of the lung had been strongly or definitely suspected before death by demonstration of two different types of malignant cells in the sputum as well as in smears of aspirates from pleural fluid and/or mediastinal tumor. By exfoliative cytology, one case was characterized by carcinoma cells of the small-cell type plus the large-cell and/or adenocarcinoma type; the other displayed small-cell-type and squamous-cell-type malignant cells. The autopsies definitely revealed in the first case an anaplastic carcinoma of the small-cell type in the left bronchus and a salivary-gland-type malignant "mixed" tumor in the right lower lobe and in the second case an anaplastic carcinoma of the small-cell type in the right upper lobe and a squamous-cell carcinoma in the left upper lobe. The frequence of occurrence and pathologic diagnosis of double primary lung cancers are reviewed and discussed. A rare type of lung cancer, salivary-gland-type malignant "mixed" tumor, is given special reference.     

Job strain and risk of esophageal and cardia cancers

BackgroundFew studies have investigated work-related stress in relation to esophageal or cardia cancers.MethodsOur nationwide Swedish population-based case-control study included 189 and 262 esophageal and cardia adenocarcinoma cases respectively, 167 esophageal squamous-cell carcinoma cases and 820 controls. We derived each study participant's occupation of longest duration from occupational histories and applied a psychosocial job-exposure matrix. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional logistic regression, in multivariable models.ResultsJob strain was positively associated with risk of esophageal adenocarcinoma (OR 3.2, 95% CI 1.0–9.8) and squamous-cell carcinoma (OR 4.0, 95% CI 1.6–10.5), but not with cardia adenocarcinoma. No associations regarding demands, control, social support or iso strain were observed, except for a positive association between high control and risk of esophageal squamous-cell carcinoma (OR 1.5, 95% CI 1.0–2.3).ConclusionJob strain seems to increase the risk of both histological types of esophageal cancer.     

Classification of lung carcinoma by means of digital nuclear image analysis

An investigation was performed of the maximum discriminating efficiency for each subgroup of digital nuclear image features and of the overall classification of nuclei from three types of human lung carcinomas in histologic sections: adenocarcinoma, small-cell carcinoma and squamous-cell carcinoma. The results indicate that, for each subgroup of features, the nuclei of the small-cell carcinomas are generally "correctly" classified in a higher percentage (80% to 100%) than are the nuclei of the adenocarcinomas (46% to 74%) and squamous-cell carcinomas (29% to 68%). The discriminant analysis for the overall classification selected features from most of the subgroups, suggesting that it is useful to perform nuclear image analysis with many subgroups having different properties. The overall classifications for the nuclei of the adenocarcinomas, small-cell carcinomas and squamous-cell carcinomas were, respectively, 81.4%, 93.2% and 74.7%. Before this technique can be applied to histopathologic diagnosis, a larger number of unselected lung carcinomas must be evaluated.     

Modulation of human dUTPase using small interfering RNA

Analyzing the CYP2A6 gene of subjects who showed a poor metabolic phenotype toward SM-12502, we discovered a novel mutant allele (CYP2A6*4C) lacking the whole CYP2A6 gene. Using genetically engineered Salmonella typhimurium expressing a human CYP, we found that CYP2A6 was involved in the metabolic activation of a variety of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contained in tobacco smoke. Taking these results into consideration, we hypothesized that the subjects carrying the CYP2A6*4C allele had lower risk of tobacco-related lung cancer. In accordance with our hypothesis, our epidemiological studies indicated that smokers homozygous for the CYP2A6*4C allele showed much lower odds ratios toward cancer risk. Other mutant alleles reducing the CYP2A6 activity, besides CYP2A6*4C, also reduced the risk of lung cancer in smokers, particularly of squamous-cell carcinoma and small-cell carcinoma, both smoking-related cancers. 8-Methoxypsoralen, an inhibitor of CYP2A6, efficiently prevented the occurrence of adenoma caused by NNK in A/J mice.     

Association between haplotypes of manganese superoxide dismutase (SOD2), smoking, and lung cancer risk

Tobacco smoke contains high concentrations of reactive oxygen species (ROS) that can damage DNA, proteins, and lipids. Manganese superoxide dismutase (SOD2) catalyzes the dismutation of superoxide radicals into hydrogen peroxide and protects against oxidative stress in lung tissues. Three tagSNPs were identified in one block of high linkage disequilibrium that spans the entire SOD2 gene and 5-kb promoter region. These tagSNPs, representing four haplotypes (TAA, TCA, TCG, CCG), were genotyped in 372 lung cancer cases and 605 controls. There was no association between the haplotype frequencies and the overall lung cancer risk. The TCG haplotype (6% in controls) was significantly associated with a lower risk of lung cancer in light smokers (相似文献   

Radon, smoking and lung cancer risk: results of a joint analysis of three European case-control studies among uranium miners

A combined analysis of three case-control studies nested in three European uranium miner cohorts was performed to study the joint effects of radon exposure and smoking on lung cancer death risk. Occupational history and exposure data were available from the cohorts. Smoking information was reconstructed using self-administered questionnaires and occupational medical archives. Linear excess relative risk models adjusted for smoking were used to estimate the lung cancer risk associated with radon exposure. The study includes 1046 lung cancer cases and 2492 controls with detailed radon exposure data and smoking status. The ERR/WLM adjusted for smoking is equal to 0.008 (95% CI: 0.004-0.014). Time since exposure is shown to be a major modifier of the relationship between radon exposure and lung cancer risk. Fitting geometric mixture models yielded arguments in favor of a sub-multiplicative interaction between radon and smoking. This combined study is the largest case-control study to investigate the joint effects of radon and smoking on lung cancer risk among miners. The results confirm that the lung carcinogenic effect of radon persists even when smoking is adjusted for, with arguments in favor of a sub-multiplicative interaction between radon and smoking.     

Risk of lung cancer and leukemia from exposure to ionizing radiation and potential confounders among workers at the Portsmouth Naval Shipyard

Significantly elevated lung cancer deaths and statistically significantly positive linear trends between leukemia mortality and radiation exposure were reported in a previous analysis of Portsmouth Naval Shipyard workers. The purpose of this study was to conduct a modeling-based analysis that incorporates previously unanalyzed confounders in exploring the exposure-response relationship between cumulative external ionizing radiation exposure and mortality from these cancers among radiation-monitored workers in this cohort. The main analyses were carried out with Poisson regression fitted with maximum likelihood in linear excess relative risk models. Sensitivity analyses varying model components and using other regression models were conducted. The positive association between lung cancer risk and ionizing radiation observed previously was no longer present after adjusting for socioeconomic status (smoking surrogate) and welding fume and asbestos exposures. Excesses of leukemia were found to be positively, though not significantly, associated with external ionizing radiation, with or without including potential confounders. The estimated excess relative risk was 10.88% (95% CI -0.90%, 38.77%) per 10 mSv of radiation exposure, which was within the ranges of risk estimates in previous epidemiological studies (-4.1 to 19.0%). These results are limited by many factors and are subject to uncertainties of the exposure and confounder estimates.     

Lung cancer risk of Mayak workers: modelling of carcinogenesis and bystander effect

Lung cancer mortality in the period of 1948-2002 has been analysed for 6,293 male workers of the Mayak Production Association, for whose information on smoking, annual external doses and annual lung doses due to plutonium exposures was available. Individual likelihoods were maximized for the two-stage clonal expansion (TSCE) model of carcinogenesis and for an empirical risk model. Possible detrimental and protective bystander effects on mutation and malignant transformation rates were taken into account in the TSCE model. Criteria for non-nested models were used to evaluate the quality of fit. Data were found to be incompatible with the model including a detrimental bystander effect. The model with a protective bystander effect did not improve the quality of fit over models without a bystander effect. The preferred TSCE model was sub-multiplicative in the risks due to smoking and internal radiation, and more than additive. Smoking contributed 57% to the lung cancer deaths, the interaction of smoking and radiation 27%, radiation 10%, and others cause 6%. An assessment of the relative biological effectiveness of plutonium was consistent with the ICRP recommended value of 20. At age 60 years, the excess relative risk (ERR) per lung dose was 0.20 (95% CI: 0.13; 0.40) Sv(-1), while the excess absolute risk (EAR) per lung dose was 3.2 (2.0; 6.2) per 10(4) PY Sv. With increasing age attained the ERR decreased and the EAR increased. In contrast to the atomic bomb survivors, a significant elevated lung cancer risk was also found for age attained younger than 55 years. For cumulative lung doses below 5 Sv, the excess risk depended linearly on dose. The excess relative risk was significantly lower in the TSCE model for ages attained younger than 55 than that in the empirical model. This reflects a model uncertainty in the results, which is not expressed by the standard statistical uncertainty bands.