Lifetime excess absolute risk for lung cancer due to exposure to radon: results of the pooled uranium miners cohort study PUMA.

The Pooled Uranium Miners Analysis (PUMA) study is the largest uranium miners cohort with 119,709 miners, 4.3 million person-years at risk and 7754 lung cancer deaths. Excess relative rate (ERR) estimates for lung cancer mortality per unit of cumulative exposure to radon progeny in working level months (WLM) based on the PUMA study have been reported. The ERR/WLM was modified by attained age, time since exposure or age at exposure, and exposure rate. This pattern was found for the full PUMA cohort and the 1960 + sub-cohort, i.e., miners hired in 1960 or later with chronic low radon exposures and exposure rates. The aim of the present paper is to calculate the lifetime excess absolute risk (LEAR) of lung cancer mortality per WLM using the PUMA risk models, as well as risk models derived in previously published smaller uranium miner studies, some of which are included in PUMA. The same methods were applied for all risk models, i.e., relative risk projection up to <95 years of age, an exposure scenario of 2 WLM per year from age 18-64 years, and baseline mortality rates representing a mixed Euro-American-Asian population. Depending upon the choice of model, the estimated LEAR per WLM are 5.38 × 10-4 or 5.57 × 10-4 in the full PUMA cohort and 7.50 × 10-4 or 7.66 × 10-4 in the PUMA 1960 + sub-cohort, respectively. The LEAR per WLM estimates derived from risk models reported for previously published uranium miners studies range from 2.5 × 10-4 to 9.2 × 10-4. PUMA strengthens knowledge on the radon-related lung cancer LEAR, a useful way to translate models for policy purposes.

Diabetes mellitus and tuberculosis in Korean adults: impact on tuberculosis incidence, recurrence and mortality.

The prevalence of diabetes mellitus (DM) worldwide is increasing markedly, and many countries with rising rates also have a high incidence rate of tuberculosis (TB). To investigate the relationships of fasting serum glucose (FSG) and DM with TB incidence, recurrence and mortality risk in a prospective cohort study in South Korea. Our study comprised 1 267 564 Koreans who received health insurance from the National Health Insurance System, had an initial medical evaluation between 1997 and 2000 and were prospectively followed biennially. Participants with DM had a higher risk for incident TB (hazard ratio [HR] 1.81, 95%CI 1.71-1.91 in males, HR 1.33; 95%CI 1.20-1.47 in females) than those without DM. There was a strong positive trend for TB risk with rising FSG among males. The risk for recurrent TB among those with previous TB was significantly higher in males (HR 1.58, 95%CI 1.43-1.75) and in females with DM (HR 1.38, 95%CI 1.08-1.76). The increased risk of death from TB during follow-up was also significant in men (HR 1.91, 95%CI 1.87-1.95) and in women (HR 1.71, 95%CI 1.65-1.77). A diagnosis of DM is a risk factor for TB, TB recurrence and death from TB. Screening for TB should be considered among people living with DM in Korea, particularly those with severe DM. .

Plasma and lung macrophage responsiveness to carotenoid supplementation and ozone exposure in humans.

OBJECTIVE: To examine the effect of ozone exposure and vegetable juice supplementation on plasma and lung macrophage concentrations of carotenoids. DESIGN: A randomized trial. SETTING: Subjects were exposed to ambient air prior to antioxidant supplementation and to ozone after antioxidant supplementation or placebo. Exposures occurred while exercising intermittently in a controlled metabolic chamber at the Human Studies Division, US EPA. SUBJECTS: In all, 23 healthy subjects between ages of 18 and 35 y. INTERVENTIONS: Subjects consumed a low fruit and vegetable diet for 3 weeks. After the first week, subjects underwent a sham exposure to filtered air with exercise, followed by bronchoalveolar lavage (BAL). Subjects were randomly assigned into supplement (one can vegetable juice, vitamins C and E daily) or placebo (orange soda, placebo pill daily) groups for 2 weeks. After the 2-week intervention, subjects were exposed to 0.4 ppm (784 microg/m(3)) ozone for 2 h with exercise followed by BAL. Blood samples were drawn before, immediately after and 3 h postexposure on each exposure day. The concentrations of nine carotenoids were determined by HPLC in BAL macrophages and plasma samples. RESULTS: Plasma concentrations of all the carotenoids that were present in the vegetable juice (except cis-beta-carotene) increased significantly in the supplemented group. Lung macrophage alpha-carotene concentrations increased significantly, lycopene isomers increased slightly, and all other carotenoids decreased (nonsignificantly) in the supplementation group following the intervention. Ozone exposure resulted in decreases in several carotenoids in plasma of the placebo group, but not in the supplemented group. CONCLUSIONS: Lung macrophage concentrations of carotenoids can be manipulated by diet. Ozone is a potent environmental oxidant that appears to reduce plasma carotenoids in nonsupplemented individuals.

Enhancement of mast cell survival: a novel function of some secretory phospholipase A(2) isotypes.

This study tested the hypothesis that certain secretory phospholipase A(2) (sPLA(2)) isotypes act in a cytokine-like fashion through cell surface receptors to influence mast cell survival. Initial experiments revealed that sPLA(2) activity and sPLA(2) receptor expression are increased, and mast cells lost their capacity to maintain membrane asymmetry upon cytokine depletion. Groups IB and III, but not group IIA PLA(2), prevented the loss of membrane asymmetry. Similarly, group IB prevented nucleosomal DNA fragmentation in mast cells. Providing putative products of sPLA(2) hydrolysis to cytokine-depleted mast cells did not influence survival. Furthermore, catalytic inactivation of sPLA(2) did not alter its capacity to prevent apoptosis. Inhibition of protein synthesis using cycloheximide or actinomycin reversed the antiapoptotic effect of sPLA(2). Additionally, both wild-type and catalytically inactive group IB PLA(2) induced IL-3 synthesis in mast cells. However, adding IL-3-neutralizing Ab did not change Annexin V(FITC) binding and only partially inhibited thymidine incorporation in sPLA(2)-supplemented mast cells. In contrast, IL-3-neutralizing Ab inhibited both Annexin V(FITC) binding and thymidine incorporation in mast cells maintained with IL-3. sPLA(2) enhanced phosphoinositide 3'-kinase activity, and a specific inhibitor of phosphoinositide 3'-kinase reversed the antiapoptotic effects of sPLA(2). Likewise, sPLA(2) increased the degradation of I-kappaBalpha, and specific inhibitors of nuclear factor kappa activation (NF-kappaB) reversed the antiapoptotic effects of sPLA(2). Together, these experiments reveal that certain isotypes of sPLA(2) enhance the survival of mast cells in a cytokine-like fashion by activating antiapoptotic signaling pathways independent of IL-3 and probably via sPLA(2) receptors rather than sPLA(2) catalytic products.

Effect of antioxidant supplementation on ozone-induced lung injury in human subjects.

To determine whether antioxidants can influence human susceptibility to ozone (O(3))-induced changes in lung function and airway inflammation, we placed 31 healthy nonsmoking adults (18 to 35 yr old) on a diet low in ascorbate for 3 wk. At 1 wk, subjects were exposed to filtered air for 2 h while exercising (20 L/min/m(2)), and then underwent bronchoalveolar lavage (BAL) and were randomly assigned to receive either a placebo or 250 mg of vitamin C, 50 IU of alpha-tocopherol, and 12 oz of vegetable cocktail daily for 2 wk. Subjects were then exposed to 0.4 ppm O(3) for 2 h and underwent a second BAL. On the day of the O(3) exposure, supplemented subjects were found to have significantly increased levels of plasma ascorbate, tocopherols, and carotenoids as compared with those of the placebo group. Pulmonary function testing showed that O(3)-induced reductions in FEV(1) and FVC were 30% and 24% smaller, respectively, in the supplemented cohort. In contrast, the inflammatory response to O(3) inhalation, as represented by the percent neutrophils and the concentration of interleukin-6 recovered in the BAL fluid at 1 h after O(3) exposure was not different for the two groups. These data suggest that dietary antioxidants protect against O(3)-induced pulmonary function decrements in humans.

Estimating lung cancer mortality from residential radon using data for low exposures of miners.

Some recent estimates of lung cancer risk from exposure to radon progeny in homes have been based on models developed from a pooled analysis of 11 cohorts of underground miners exposed to radon. While some miners were exposed to over 10,000 working level months (WLM), mean exposure among exposed miners was 162 WLM, about 10 times the exposure from lifetime residence in an average house and about three times the exposure from lifetime residence at the "action level" suggested by the U.S. Environmental Protection Agency. The extrapolation of lung cancer risk from the higher exposures in the miners to the generally lower exposures in the home is a substantial source of uncertainty in the assessment of the risk of indoor radon. Using the pooled data for the miners, analyses of lung cancer risk were carried out on data restricted to lower exposures, either <50 WLM or <100 WLM. In the pooled data, there were 115 lung cancer cases among workers with no occupational WLM exposure and 2,674 among exposed miners, with 353 and 562 lung cancer cases in miners with <50 WLM and <100 WLM, respectively. Relative risks (RRs) for categories of WLM based on deciles exhibited a statistically significant increasing trend with exposure in each of the restricted data sets. In the restricted data, there was little evidence of departures from a linear excess relative risk model in cumulative exposure, although power to assess alternative exposure-response trends was limited. The general patterns of declining excess RR per WLM with attained age, time since exposure and exposure rate seen in the unrestricted data were similar to the patterns found in the restricted data. Risk models based on the unrestricted data for miners provided an excellent fit to the restricted data, suggesting substantial internal validity in the projection of risk from miners with high exposures to those with low exposures. Estimates of attributable risk for lung cancer (10-14%) in the U.S. from residential radon based on models from the unrestricted data were similar to estimates based on the data for miners receiving low exposures.

Silicosis and lung cancer risk in underground uranium miners.

The presence of radiographic silicosis as a risk factor for lung cancer was assessed in a case-control study conducted within a study cohort of New Mexico underground uranium miners. Chest radiographs were interpreted for the presence of silicosis for 65 lung cancer cases and 216 controls. The presence of silicosis on the chest radiograph taken closest to the start of employment or on the latest radiograph available was not associated with lung cancer risk after adjustment for cumulative exposure to radon progeny. The odds ratio associated with the presence of any type of opacity indicative of pneumoconiosis on the chest x ray closest to the start of employment was 1.33 (95% confidence interval, 0.31-5.72). For the most recent available chest x ray, the corresponding odds ratio was 1.16 (95% confidence interval, 0.35-3.84). Although the findings are limited by the relatively small number of subjects, the lack of association of silicosis with lung cancer suggests that silica exposure should not be regarded as a major uncertainty in extrapolating radon risk estimates from miners to the general population.

Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners.

Radon increases the risk of lung cancer in smoking and non-smoking underground miners. To investigate the mutational spectrum associated with exposure to high levels of radon, we sequenced exons 5-9 of the p53 tumour suppressor gene and codons 12-13 of the Ki-ras protooncogene in 19 lung cancers from uranium miners exposed to radon and tobacco smoke. Mutations were not found in Ki-ras, but 9 p53 mutations, including 2 deletions, were found in 7 patients by direct DNA sequencing after polymerase chain reaction amplification of DNA from formalin-fixed, paraffin-embedded tissue. In tumours from 5 patients, the mutation produced an aminoacid change and an increased nuclear content of p53 protein. The tumours with either a stop codon or frame-shift deletion in the p53 gene were negative by immunohistochemistry. None of the mutations were G:C to T:A transversions in the coding strand of the p53 gene, which are the most frequent base substitutions associated with tobacco smoking, and none were found at the hotspot codons described in lung cancer. The observed differences from the usual lung cancer mutational spectrum may reflect the genotoxic effects of radon.

Lung cancer mortality and exposure to radon progeny in a cohort of New Mexico underground uranium miners.

A cohort of 3469 males with at least 1 y of underground uranium mining experience in New Mexico was assembled and mortality followed up through 31 December 1985. The mean and median cumulative exposures for the cohort were 0.39 J h m-3 and 0.12 J h m-3 (111.4 and 35.0 Working Level Months [WLM]), respectively. Overall, mortality in the cohort was significantly increased (standardized mortality ratio [SMR] = 1.1, 95% confidence interval [CI] = 1.02-1.2) relative to the general population of the state. By cause, significant increases were observed for lung cancer (SMR = 4.0, 95% CI 3.1-5.1) and for external causes of death (SMR = 1.5, 95% CI 1.3-1.7). The risk of lung cancer increased for exposure categories above 100 WLM; the excess relative risk increased by 0.5% per mJ h m-3, 95% CI 0.2-1.5 (1.8% per WLM, 95% CI 0.7-5.4). Data were consistent with a multiplicative interaction between smoking and exposure to Rn progeny in an exponential relative risk model. The risk of lung cancer varied substantially with age at observation; the odds ratios rose more steeply with exposure to Rn progeny for those less than age 55 y at observation.

Diseases of uranium miners and other underground miners exposed to radon.

Excess lung cancer has been demonstrated in many groups of underground miners exposed to radon, including uranium miners and those mining other substances in radon-contaminated mines. In the United States, most underground uranium mines had shut down by the late 1980s, but occupational exposure to radon progeny remains a concern for many other types of underground miners and other underground workers. Worldwide, uranium mining continues, with documented production in Canada, South Africa and other African countries, and Australia. Thus, radon in underground mines remains a significant occupational hazard as the end of the twentieth century approaches.

High-performance liquid chromatography separation of phospholipid classes and arachidonic acid on cyanopropyl columns.

An HPLC method for the separation and analysis of arachidonic acid and eight phospholipid classes is described: phosphatidylglycerol, phosphatidylinositol, cardiolipin, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, sphingomyelin, and 2-lysophosphatidylcholine. The separation is carried out at 60 degrees C on 2 cyanopropyl columns using a gradient of acetonitrile and 5 mM sodium acetate (pH 5.0). Cyanopropyl columns require a lower proportion of water in the mobile phase to elute the more polar phospholipids than other types of columns and are thus less prone to equilibration problems. The method is highly reproducible (average coefficient of variation for each retention time less than or equal to 3.5%) and permits analysis of peaks by phosphorus content. Data obtained by analyzing lipid extracts from rat alveolar macrophages prelabeled with [G-3H]-arachidonic acid were analyzed by this HPLC method and compared to standard analysis by TLC. There was a significant correlation between the radioactivity profiles obtained with the two chromatographic methods (HPLC versus TLC) by linear regression analysis [HPLC = 0.83 (TLC) + 3.58, n = 25, r = 0.95, P less than 0.001].

Radon and lung cancer.

Radon, an inert gas released during the decay of uranium-238, is ubiquitous in indoor and outdoor air and contaminates many underground mines. Extensive epidemiologic evidence from studies of underground miners and complementary animal data have documented that radon causes lung cancer in smokers and nonsmokers. Radon must also be considered a potentially important cause of lung cancer for the general population, which is exposed through contamination of indoor air by radon from soil, water, and building materials. This review describes radon's sources, levels in U.S. homes, dosimetry, the epidemiologic evidence from studies of miners and the general population, and the principal, recent risk assessments.

Radon progeny exposure and lung cancer risk in New Mexico U miners: a case-control study.

A case-control study was conducted to describe lung cancer risk in a cohort of New Mexico underground U miners. The subjects included 65 cases and 230 age-matched controls, most with exposures below 3.50 J h m-3 (1000 WLM). The risk for lung cancer was increased for all cumulative exposures to Rn progeny of 0.35 J h m-3 (100 WLM) or greater. The odds ratios were unchanged with control for cigarette smoking. With exclusion of subjects with exposures above 3.50 J h m-3 (1000 WLM), the estimated excess relative risk was 0.3% per mJ h m-3 (1.1% per WLM). The risk was greater for younger subjects and the data were consistent with a multiplicative interaction between cigarette smoking and exposure to Rn progeny.

Health implications of radionuclide levels in cattle raised near U mining and milling facilities in Ambrosia Lake, New Mexico.

This study was conducted to determine radionuclide tissue levels in cattle raised near U mining and milling facilities. Ambrosia Lake, New Mexico, has been the site of extensive U mining for 30 y and contains several underground U mines, a processing mill, and two large U tailings piles. Ten cows were purchased from two grazing areas in Ambrosia Lake and ten control animals were purchased from Crownpoint, New Mexico. Muscle, liver, kidney, and bone tissue taken from these animals, and environmental samples, including water, grasses and soil collected from the animals' grazing areas, were analyzed for 238U, 234U, 230Th, 226Ra, 210Pb, and 210Po. Mean radionuclide levels in cattle tissue and environmental samples from Ambrosia Lake were higher in almost every comparison than those found in respective controls. Liver and kidney tissues were particularly elevated in 226Ra and 210Po. Radiation dose commitments from eating cattle tissue with these radionuclide concentrations were calculated. We concluded that the health risk to the public from eating exposed cattle is minimal, unless large amounts of this tissue, especially liver and kidney, are ingested.

Lung cancer and occupation in New Mexico.

The association between occupation and lung cancer risk was examined in a population-based, case-control study of 506 patients (333 males and 173 females) and 771 control (499 males and 272 females) subjects in New Mexico. A personal interview was used to obtain lifetime occupational and smoking histories and self-reported history of exposures to specific agents. High-risk jobs were identified in advance of data analysis and linked with industrial and occupational codes for hypothesis testing. For females, lung cancer risk was not associated with employment history, but power was limited. For males, elevated risks were found for the uranium mining industry [odds ratio (OR) = 1.9; 95% confidence internal (CI) = 0.8-4.9], underground miners (OR = 2.1; 95% CI = 1.1-3.7), painters (OR = 2.7; 95% CI = 0.8-8.9), and welders (OR = 3.2; 95% CI = 1.4-7.4). For self-reported exposure to any of 18 agents, only the OR for exposure to "other metals" was elevated. The population attributable risk in males was estimated as 14% for employment in any high-risk industry or occupation with an OR above 1 in this study.

Use of quantified and frequency indices of vitamin A intake in a case-control study of lung cancer.

Recent publications have examined the extent of food frequency data needed to estimate nutrient intakes in epidemiological studies. The need for amount (usual portion size) data to supplement information on average frequency of intake has been questioned. In a case-control study of risk factors for lung cancer, we have collected data on frequency, amount and past pattern of intake for common or rich sources of vitamin A. These data have been combined with standard content information to calculate three different types of indices: one based on frequency alone, a quantitative index that included both frequency and amount, and a past-weighted index that combined the frequency, amount and data on relative consumption in the past. Odds ratios by tercile of carotene, retinol and total vitamin A intake varied little between the frequency index and the quantified and past-weighted indices. Higher intakes of carotene and total vitamin A were associated with a lower risk for lung cancer regardless of index type. This consistency of results is explained by a stability of relative intakes regardless of index type. Spearman rank order correlation coefficients between the frequency and quantitative indices exceeded 0.90 for total vitamin A, carotene, and retinol. This stability is attributable to parallel trends of increased frequency of consumption and portion size at higher levels of nutrient intake. Because similar trends were observed in five main food groups included in these analyses, these findings may be generalizable to other nutrients.

Uranium mining and lung cancer in Navajo men.

We performed a population-based case-control study to examine the association between uranium mining and lung cancer in Navajo men, a predominantly nonsmoking population. The 32 cases included all those occurring among Navajo men between 1969 and 1982, as ascertained by the New Mexico Tumor Registry. For each case in a Navajo man, two controls with nonrespiratory cancer were selected. Of the 32 Navajo patients, 72 per cent had been employed as uranium miners, whereas no controls had documented experience in this industry. The lower 95 per cent confidence limit for the relative risk of lung cancer associated with uranium mining was 14.4. Information on cigarette smoking was available for 21 of the 23 affected uranium miners; eight were nonsmokers and median consumption by the remainder was one to three cigarettes daily. These results demonstrate that in a rural nonsmoking population most of the lung cancer may be attributable to one hazardous occupation.