Lung Cancer In Uranium Miners Research Articles

Radon Exposure, IL-6 Promoter Variants, and Lung Squamous Cell Carcinoma in Former Uranium Miners

Background:High radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology observed in former uranium miners. Radon exposure can cause oxidative stress, leading to pulmonary inflammation. Interleukin-6 (IL-6) is a pro-carcinogenic inflammatory cytokine that plays a pivotal role in lung cancer development.Objectives:We assessed whether single nucleotide polymorphisms (SNPs) in the IL6 promoter are associated with lung cancer in former uranium miners with high occupational exposure to radon gas.Methods:Genetic associations were assessed in a case–control study of former uranium miners (242 cases and 336 controls). A replication study was performed using data from the Gene Environment Association Studies (GENEVA) Genome Wide Association Study (GWAS) of Lung Cancer and Smoking. Functional relevance of the SNPs was characterized using in vitro approaches.Results:We found that rs1800797 was associated with squamous cell carcinoma in miners and with a shorter time between the midpoint of the period of substantial exposure and diagnosis among the cases. Furthermore, rs1800797 was also associated with lung cancer among never smokers in the GENEVA dataset. Functional studies identified that the risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity. Furthermore, fibroblasts with the risk allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo[a]pyrene diolepoxide treatments.Conclusions:An IL6 promoter variant was associated with lung cancer in uranium miners and never smokers in two external study populations. The associations are strongly supported by the functional relevance that the IL6 promoter SNP affects basal expression and carcinogen-induced IL-6 secretion.Citation:Leng S, Thomas CL, Snider AM, Picchi MA, Chen W, Willis DG, Carr TG, Krzeminski J, Desai D, Shantu A, Lin Y, Jacobson MR, Belinsky SA. 2016. Radon exposure, IL-6 promoter variants, and lung squamous cell carcinoma in former uranium miners. Environ Health Perspect 124:445–451; http://dx.doi.org/10.1289/ehp.1409437

Is the radon risk overestimated? Neglected doses in the estimation of the risk of lung cancer in uranium underground miners.

Only the exposure to inhaled radon decay products is usually taken into account in the determination of the risk of radiogenic lung cancer in uranium miners. However, the elevated lung cancer risk in uranium miners is due to the total dose of radiation received by that organ, not to the dose from inhaled radon-222 decay products (222Rn D.P.) alone. Lung doses from sources other than 222Rn D.P. may reach 25% to 75% of total effective dose, absorbed dose or equivalent lung dose, are correlated to 222Rn D.P. doses and are quite variable between facilities. Therefore, to neglect these doses leads to a systematic overestimation of the risk of lung cancer per unit 222Rn D.P. exposure, both through dose underestimation and dose misclassification. Correction for neglected doses and dose misclassification would pull the risk per unit radon exposure downward by a factor of at least two or three and bring the overall dose-effect relationship towards the no-effect null hypothesis, thereby increasing the likelihood of thresholds for lung cancer risk at indoor and today's uranium mine exposures.

Modelling lung tumour risk in radon-exposed uranium miners using generalizations of the two-mutation model of Moolgavkar, Venzon and Knudson

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 threemutation models radon daughters and cigarette smoke were assumed to act on the first mutation rate. In the optimal twomutation 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.

An analysis of bone and head sinus cancers in radium dialpainters using a two-mutation carcinogenesis model

Bone and head sinus cancer incidence after ingestion of226Ra and 228Ra by radium dial painters isanalysed using a two-mutation clonal expansion model forradiation carcinogenesis, taking into account the retention andradiation patterns of these nuclides in the body. The best fit isobtained for compact bone retention and efficient diffusion of222Rn to the bone cavities and radiation action on bothmutation rates of the cancer model, as found in a similar analysisof bone sarcomas after 226Ra injection in beagles. Themodel parameters of the best fit are consistent with cellularradiobiological data and a previous analysis of lung cancer inuranium miners. Due to the low background incidence of bone andhead sinus cancer, the resulting dose-effect relationships forthese cancers are linear-quadratic with radium ingestion and alpharadiation dose. These results do not support a threshold doseconcept, but the risks at low doses calculated by the model comeout to about a factor 10 lower than using a linear extrapolation ofthe data to low doses, a procedure currently applied by ICRP andEPA. Furthermore, the model results indicate radiation risks atlow doses to be related with background cancer incidencebetween relative and absolute radiation risk projections. Theresults, which are dependent on the model assumptions, might bemore generally applicable for bone seekers and will thereforeneed further study to arrive at better radiation risk estimations.

Deposition of Ultrafine Particles in Human Tracheobronchial Airways

Ultrafine particles smaller than 200 nm in diameter are produced by combustion, radioactive decay and gas-to-particle conversion in the urban air. Inhalation of ultrafine particles in both outdoor and indoor environments is a health concern. Exposure to radioactive radon progeny in the size range of 1-200 nm causes lung cancer in uranium miners and may have similar health effects in people exposed indoors. In the ambient air, ultrafine particles have a higher number concentration and may be more toxic than larger particles. Ultrafine particles deposit in the respiratory tract primarily by diffusion with increased deposition of smaller particles. Total lung deposition of ultrafine particles measured in human volunteers confirms diffusion as the mechanism (Schiller etal., 1988). Higher deposition in the extrathoracic region has been determined in human nasal/oral casts and in human volunteers (Cheng etal., 1993, in press). Deposition in the human tracheobronchial airways has been measured in an adult cast for particle sizes between 40 and 200 nm (Cohen etal., 1990). Their data indicated higher deposition in the tracheobronchial airway than predicted by diffusional deposition in a tube, assuming a fully developed flow profile. The purpose of our study was to determine the tracheobronchial deposition in wider size range of particles using airway casts of adults and children. The deposition data were compared with theoretical predictions of both parabolic and plug flows.

Radon and lung carcinogenesis: mutability of p53 codons 249 and 250 to 238Pu alpha-particles in human bronchial epithelial cells.

Radon-222, a decay product of uranium-238 and a source of high linear energy transfer (LET) alpha-particles, has been implicated in the increased risk of lung cancer in uranium miners as well as non-miners. p53 mutation spectrum studies of radon-associated lung cancer have failed to show any specific mutational hot spot with the exception of a single study in which 31% of squamous cell and large cell lung cancers from uranium miners showed a p53 codon 249 AGGarg --> ATGmet mutation. Although the results of laboratory studies indicate that double-strand breaks and deletions are the principal genetic alterations caused by alpha-particles, uncertainty still prevails in the description of DNA damage in radon-associated human lung cancer. In the present study, we have evaluated the mutability of p53 codons 249 and 250 to alpha-particles in normal human bronchial epithelial (NHBE) cells using a highly sensitive genotypic mutation assay. Exposure of NHBE cells to a total dose of 4 Gy (equivalent to approximately 1460 working level months in uranium mining) of high LET alpha-radiation induced codon 249 AGG --> AAG transitions and codon 250 CCC --> ACC transversions with absolute mutation frequencies of 3.6 x 10(-7) and 3.8 x 10(-7) respectively. This mutation spectrum is consistent with our previous report of radon-associated human lung cancer.

Clinical measures, smoking, radon exposure, and risk of lung cancer in uranium miners.

Exposure to the radioactive daughters of radon is associated with increased risk of lung cancer in mining populations. An investigation of incidence of lung cancer following a clinical survey of Ontario uranium miners was undertaken to explore whether risk associated with radon is modified by factors including smoking, radiographic silicosis, clinical symptoms, the results of lung function testing, and the temporal pattern of radon exposure. Miners were examined in 1974 by a respiratory questionnaire, tests of lung function, and chest radiography. A random selection of 733 (75%) of the original 973 participants was followed up by linkage to the Ontario Mortality and Cancer Registries. Incidence of lung cancer was increased threefold. Risk of lung cancer among miners who had stopped smoking was half that of men who continued to smoke. There was no interaction between smoking and radon exposure. Men with lung function test results consistent with airways obstruction had an increased risk of lung cancer, even after adjustment for cigarette smoking. There was no association between radiographic silicosis and risk of lung cancer. Lung cancer was associated with exposures to radon daughters accumulated in a time window four to 14 years before diagnosis, but there was little association with exposures incurred earlier than 14 years before diagnosis. Among the men diagnosed with lung cancer, the mean and median dose rates were 2.6 working level months (WLM) a year and 1.8 WLM/year in the four to 14 year exposure window. Risk of lung cancer associated with radon is modified by dose and time from exposure. Risk can be substantially decreased by stopping smoking.

The Biological Effectiveness of Radon-Progeny Alpha Particles. II. Oncogenic Transformation as a Function of Linear Energy Transfer

Epidemiological studies have established an association between exposure to radon and carcinoma of the lung. However, based on data for either lung cancer in uranium miners exposed to radon or bronchial epithelial carcinomas in Japanese A-bomb survivors, it has not been possible to assign estimates of risk of lung cancer for the general population exposed to radon in their homes. Based on past success with the excellent quantitative properties of the C3H 10T1/2 in vitro oncogenic transformation assay system, the relative biological effectiveness (RBE) for radiation-induced transformation for charged particles of defined LET has been determined. As the LET of the radiation was increased, the rate of induction of oncogenic transformation increased and the RBEm approached 20. At higher LETs, RBE dropped precipitously. The rapid drop in effectiveness for alpha particles with LETs between 120 and 265 keV/microns implies a lower quality factor than the 20-25 currently considered appropriate when estimating lung cancer mortality.

Reproducibility of major diagnoses in a binational study of lung cancer in uranium miners and atomic bomb survivors : Keehn R, Auerbach O, Nambu S, Carter D, Shimosato Y, Greenberg SD et al. Radiation Epidemiology Branch, 6130 Executive Boulevard, Bethesda, MD 20852. Am J Clin Pathol 1994; 101: 478-82

Reproducibility of major diagnoses in a binational study of lung cancer in uranium miners and atomic bomb survivors : Keehn R, Auerbach O, Nambu S, Carter D, Shimosato Y, Greenberg SD et al. Radiation Epidemiology Branch, 6130 Executive Boulevard, Bethesda, MD 20852. Am J Clin Pathol 1994; 101: 478-82

Mortality in uranium miners in west Bohemia: a long-term cohort study.

A cohort of 4320 uranium miners in West Bohemia who started work at the mines during 1948 to 1959 and worked there for at least four years were followed up to the end of 1990 to determine cause specific mortality risks in relation to exposures in the mines. The miners had experienced high radon exposures, on average 219 working level months during their uranium mining careers, for which detailed measurements were available. They had also been exposed to high arsenic levels in one of the two major mines, and to dust. New follow up methods, not previously used for occupational cohorts in Czechoslovakia, were utilised. By the end of follow up 2415 (56%) of the cohort were known to have died. Overall mortality was significantly raised compared with that in the general population (relative risk (RR) = 1.56, 95% confidence interval (95% CI) 1.50-1.63), with significantly raised risks of lung cancer (RR = 5.08, 95% CI 4.71-5.47), accidents (RR = 1.59, 95% CI 1.34-1.87), homicide (RR = 5.57, 95% CI 2.66-10.21), mental disorders (RR = 5.18, 95% CI 2.83-8.70), cirrhosis (RR = 1.51, 95% CI 1.16-1.94), and non-rheumatic circulatory diseases (RR = 1.16, 95% CI 1.08-1.25). The relative risk of lung cancer was greatest four to 14 years after entry to the mines. Relative risks for homicide and accidents were raised up to 25 years from entry but not after this. Substantial significantly raised risks at 15 to 24 years after entry occurred for cirrhosis, non-rheumatic circulatory diseases,a nd pneumonia and other respiratory infections. Sizeable significantly raised risks at 25 and more years after entry, but not earlier, were present for mental disorders, tuberculosis, and non-malignant non-infectious respiratory conditions. No specific causes showed risks significantly related to age at entry to mining. Risk of lung cancer was significantly positively related to radon exposure, estimated arsenic exposure, and duration of work in the mines, but no other cause was significantly positively related to these variables. The raised risk of lung cancer in uranium miners, which is well established, is related aetiologically to radon exposure, and in the present cohort it may also in part have been due to exposure to arsenic. The raised risks of accidents, tuberculosis, and non-infectious respiratory diseases have also been seen in other uranium mining cohorts, and are likely to reflect the dangerous and dusty working conditions and the confined spaces in which work occurred. The cirrhosis and homicide deaths probably related to the lifestyle associated with mining. The raised risk of circulatory diseases does not seem to be related to radon or arsenic exposure; its causes are unclear. The use of multiple follow up methods was found to be mortality in the cohort.

Reproducibility of major diagnoses in a binational study of lung cancer in uranium miners and atomic bomb survivors.

A binational panel of four Japanese and four American pathologists examined 208 pulmonary neoplasms, according to the World Health Organization (WHO) recommendations, second edition, for the histologic typing of lung tumors. The study design included independent evaluations by pathologists working alone, followed by group reviews. The individual evaluations, and their implications for reproducibility of the WHO recommendations, are reported. Consensus (agreement by six or more pathologists) with respect to major (ie, first digit) diagnosis was obtained for 76.4% of the cases. Consensus was obtained for 72.5% of the cases with any major diagnosis of small cell cancer; the comparable figures for adenocarcinoma and squamous cell carcinoma were 56% and 48%, respectively. American pathologists were twice as likely as Japanese pathologists to diagnose large-cell cancer, the only significant national difference. Consensus was far less frequent with the minor (ie, second digit) diagnosis categories. This study shows that lung cancers continue to be difficult to classify reproducibly.

The epidemiology of primary lung cancer in uranium miners in Ontario.

This paper reviews the epidemiology of lung cancer in uranium miners in northern Ontario whose cumulative exposure was relatively low and who were exposed only for a short period of time. The development of the "epidemic" is demonstrated chronologically and in terms of latency. An apparent difference between the effects of short-term and of more prolonged radiation is shown. A dose-response effect is demonstrated at all levels. Analysis of tumor type suggests that there may be a difference in dose-response between the two principal types encountered. The relationship of the geographic location of exposure to the final residence at death is reviewed.

Estimate of risk from environmental exposure to radon-222 and its decay products.

Consideration of the epidemiological evidence on radiogenic lung cancer in uranium miners and of the incidence of the disease generally leads to an upper estimate for the lifetime risk of 10(-4) cases per working level month for members of the general population.

Lung Cancer in Uranium Miners and Long-term Exposure to Radon Daughter Products

Epidemiological study of lung cancer in Czechoslovak miners discloses an increasing cumulative exposure above 1000 WLM. The course of exposure-to-effect relationship was different in the age subgroups, but was not at variance with linearity in the total followed up population of miners. A comparison of the findings of Czechoslovak and American studies up to 1973 is also presented.

THE CANCER HAZARDS OF INDUSTRIAL AND ACCIDENTAL EXPOSURE TO RADIOACTIVE ISOTOPES

Data are reviewed from studies carried out during the past 27 years on the toxicity of Ra, the incidence of lung cancer in uranium miners, and animal studies on the induction of tumors by inhaled or ingested radioactive materials. The relation between body content and tumor induction in man is discussed. It is pointed out that the sites of tumors induced by Ra are related to the sites of deposition in the skeleton and physical factors concerned with the decay of Ra and Rn in the body. Finally, data on Ra dial painters and U miners constitute all the data available on hazards to man from industrial and accidental exposure to radioactive isotopes.