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. .

Ventilation rates and health: multidisciplinary review of the scientific literature.

UNLABELLED: The scientific literature through 2005 on the effects of ventilation rates on health in indoor environments has been reviewed by a multidisciplinary group. The group judged 27 papers published in peer-reviewed scientific journals as providing sufficient information on both ventilation rates and health effects to inform the relationship. Consistency was found across multiple investigations and different epidemiologic designs for different populations. Multiple health endpoints show similar relationships with ventilation rate. There is biological plausibility for an association of health outcomes with ventilation rates, although the literature does not provide clear evidence on particular agent(s) for the effects. Higher ventilation rates in offices, up to about 25 l/s per person, are associated with reduced prevalence of sick building syndrome (SBS) symptoms. The limited available data suggest that inflammation, respiratory infections, asthma symptoms and short-term sick leave increase with lower ventilation rates. Home ventilation rates above 0.5 air changes per hour (h(-1)) have been associated with a reduced risk of allergic manifestations among children in a Nordic climate. The need remains for more studies of the relationship between ventilation rates and health, especially in diverse climates, in locations with polluted outdoor air and in buildings other than offices. PRACTICAL IMPLICATIONS: Ventilation with outdoor air plays an important role influencing human exposures to indoor pollutants. This review and assessment indicates that increasing ventilation rates above currently adopted standards and guidelines should result in reduced prevalence of negative health outcomes. Building operators and designers should avoid low ventilation rates unless alternative effective measures, such as source control or air cleaning, are employed to limit indoor pollutant levels.

Global economic and health benefits of tobacco control: part 2.

Although the risks of tobacco smoking have been known for decades, the pandemic of tobacco use continues. There are an estimated 1.3 billion smokers worldwide, along with millions more using various oral tobacco products. Recent global estimates place the mortality burden from tobacco use at over 6 million annually, with nearly two-thirds of these deaths occurring in developing countries. If current patterns persist, there will be an estimated 1 billion deaths from tobacco during the twenty-first century. Part 1 of this two-part paper provides an overview of the tobacco pandemic, the scope of the pandemic, and its economic and health consequences. Part 2 reviews the history of tobacco control to date and addresses the current global strategy, based on the World Health Organization's (WHO's) Framework Convention on Tobacco Control and the MPOWER package of interventions. Part 2 ends with a consideration of scenarios for the future of the pandemic.

Global economic and health benefits of tobacco control: part 1.

Although the risks of tobacco smoking have been known for decades, the pandemic of tobacco use continues. There are an estimated 1.3 billion smokers worldwide, along with millions more using various oral tobacco products. Recent global estimates place the mortality burden from tobacco use at over 6 million annually, with nearly two-thirds of these deaths occurring in developing countries. If current patterns persist, there will be an estimated 1 billion deaths from tobacco during the twenty-first century. Part 1 of this two-part paper provides an overview of the tobacco pandemic, the scope of the pandemic, and its economic and health consequences. Part 2 reviews the history of tobacco control to date and addresses the current global strategy, based on the World Health Organization's (WHO's) Framework Convention on Tobacco Control and the MPOWER package of interventions. Part 2 ends with a consideration of scenarios for the future of the pandemic.

Modelling the health benefits of smoking cessation in Japan.

BACKGROUND: In Japan, tobacco smoking is one of the main avoidable causes of disease and death. Although the benefits of smoking cessation for reducing disease risk and increasing longevity have been extensively documented, a relatively low proportion of Japanese smokers currently express a willingness to quit. This study attempted to quantify future reduction in the burden of smoking-attributable disease that could result from increases in smoking cessation. METHODS: A simulation model was developed to project changes in mortality in Japan associated with increased quit attempts and use of nicotine replacement therapy (NRT) among smokers, incorporating data on smoking prevalence, cause-specific mortality rates, quitting behaviour and NRT use and effectiveness. RESULTS: Approximately 46 000 lung cancer deaths and 56 000 cardiovascular disease deaths could be avoided over 20 years if the proportion of smokers making a quit attempt per year gradually increased to current US levels over 20 years. If each of these quit attempts were aided by NRT, the estimates of avoidable deaths would increase to 64 000 for lung cancer and 78 000 for cardiovascular disease. In this model, negligible deaths were avoided due to decreased smoking initiation over the 20-year simulation. CONCLUSION: Smoking cessation can have measurable short-term impacts on the smoking-related mortality burden in Japan. However, to achieve these gains, tobacco control policies should focus both on increasing smokers' willingness to quit and providing the support and therapies to increase the likelihood that smoking cessation attempts will succeed.

Responses measured in the exhaled breath of human volunteers acutely exposed to ozone and diesel exhaust.

Exhaled breath collection is used to identify and monitor inflammatory or oxidative components in breath. Exhaled breath sample collection is noninvasive and would greatly benefit human pollutant exposure research. We demonstrate the efficacy of exhaled breath collection and analysis in two human exposure studies to ozone (O(3)) and diesel exhaust, respectively. O(3) study: we collected exhaled breath (gas phase) from healthy human volunteers (age 18-35 years, 12 subjects) immediately before and after exposure to filtered air or 0.4 ppm O(3) for 2 h with and without intermittent exercise. Six subjects received antioxidant supplementation for 2 weeks before their O(3) exposure, while the remaining six subjects received placebo treatments. We demonstrate increased amounts of non-polar carbonyls exhaled immediately post O(3) exposure. The O(3)-induced increase in exhaled carbonyl concentrations was attenuated in the group receiving antioxidants. Our data demonstrate that exhaled exposure biomarkers can be measured in the breath gas phase in humans exposed to O(3). Diesel study: we collected exhaled breath condensate (EBC; liquid phase) from healthy human volunteers (age 18-40 years; 10 subjects) immediately before, immediately after and 20 h post filtered air or diesel exhaust (106 ± 9 µg m(-3)) exposure. Clean air and diesel exposures were separated by 3 weeks to 6 months. We obtained reproducible intra-subject EBC volumes and total protein concentrations across our six collection time points. Diesel exposure did not affect either EBC volume or total protein concentrations. Our data demonstrated EBC volume and total protein reproducibility over several months. Volume and total protein concentration may serve as normalizing factors for other EBC constituents.

Inhibition of protein tyrosine phosphatase activity mediates epidermal growth factor receptor signaling in human airway epithelial cells exposed to Zn2+.

Epidemiological studies have implicated zinc (Zn2+) in the toxicity of ambient particulate matter (PM) inhalation. We previously showed that exposure to metal-laden PM inhibits protein tyrosine phosphatase (PTP) activity in human primary bronchial epithelial cells (HAEC) and leads to Src-dependent activation of EGFR signaling in B82 and A431 cells. In order to elucidate the mechanism of Zn2+-induced EGFR activation in HAEC, we treated HAEC with 500 microM ZnSO4 for 5-20 min and measured the state of activation of EGFR, c-Src and PTPs. Western blots revealed that exposure to Zn2+ results in increased phosphorylation at both trans- and autophosphorylation sites in the EGFR. Zn2+-mediated EGFR phosphorylation did not require ligand binding and was ablated by the EGFR kinase inhibitor PD153035, but not by the Src kinase inhibitor PP2. Src activity was inhibited by Zn2+ treatment of HAEC, consistent with Src-independent EGFR transactivation in HAEC exposed to Zn2+. The rate of exogenous EGFR dephosphorylation in lysates of HAEC exposed to Zn2+ or V4+ was significantly diminished. Moreover, exposure of HAEC to Zn2+ also resulted in a significant impairment of dephosphorylation of endogenous EGFR. These data show that Zn2+-induced activation of EGFR in HAEC involves a loss of PTP activities whose function is to dephosphorylate EGFR in opposition to baseline EGFR kinase activity. These findings also suggest that there are marked cell-type-specific differences in the mechanism of EGFR activation induced by Zn2+ exposure.

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.

Adverse effects of smoke exposure on the upper airway.

OBJECTIVE: This paper reviews secondhand smoke (SHS) exposure and diseases and symptoms of the upper airway, including the sinuses. Risks to flight attendants, who were occupationally exposed until smoking was banned on all flights, are emphasised. DATA SOURCES: A systematic database search was conducted; the US Surgeon General's reports and other major reviews were evaluated. Literature summarised by National Research Council (NRC) reports on the airline cabin environment are included. STUDY SELECTION: A limited number of research publications on adults were identified; these are included. Many studies cited by the NRC were never published and information is taken directly from the reports. DATA EXTRACTION: Data from observational studies of cabin crews and the general public were extracted from surveys; exposure monitoring of cabin crews is reported. Data from controlled exposure studies are included; most are challenge studies using volunteers screened for sensitivity to SHS. DATA SYNTHESIS: Evidence shows that active and passive smoking cause upper airway diseases, including sinonasal and laryngeal cancers in adult active smokers. Experimental studies indicate that brief exposures to SHS result in nasal mucosa inflammation. However, direct evidence on sinusitis is limited. CONCLUSIONS: Evidence does not show a strong connection between active smoking and sinusitis, and active smokers have substantial exposures to SHS. However, extrapolation of these studies to cabin crews needs to be cautious, as other environmental conditions may increase risk for upper airway disease and symptoms. Surveys of cabin crews, while flawed, consistently indicate high rates of upper airway symptoms.

Turning science into junk: the tobacco industry and passive smoking.

In this issue, Glantz and Ong offer a powerful analysis of the tobacco industry's attempt to discredit the scientific evidence on passive smoking, particularly the industry's use of the label "junk science." Environmental epidemiologic studies in other arenas have also been targets for the "junk science" label. Lessons for researchers involved in high-stakes issues in the public policy arena include a need for awareness of competing interests, for transparency concerning funding, and for adherence to rigorous quality assurance and peer review practices. The goal of "sound science" seems an admirable one; it should not, however, be used to dismiss available but uncertain evidence in order to delay action.

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.

Comorbidity and survival of elderly head and neck carcinoma patients.

BACKGROUND: Alcohol and tobacco, the primary etiologic agents for head and neck carcinoma (HNCA), cause other chronic diseases and may contribute to the high prevalence of comorbid conditions and generally poor survival of persons with HNCA. METHODS: The authors explored the prognostic role of comorbidity in persons with HNCA using Health Care Finance Administration Medicare (HCFA) files linked with the appropriate files of the Surveillance, Epidemiology, and End Results (SEER) Program. The Charlson comorbidity index was applied to in-patient data from the HCFA files. The SEER data were used to ascertain survival and identify persons with HNCA diagnosed from 1985 to 1993 (n = 9386). RESULTS: In a proportional hazards regression model adjusted for age and historic stage at diagnosis, race, gender, marital status, socioeconomic status, histologic grade, anatomic site, treatment, and pre-1991 diagnosis, Charlson index scores of 0, 1, and 2+ had estimated relative hazards (RHs) with 95 confidence intervals (CIs) of 1.00, 1.33 (95% CI, 1.21-1.47), and 1.83 (95% CI, 1.64-2.05), respectively (P value for trend < 0.0001). The adjusted RH for a Charlson index score of 1 or more compared with 0, using stratified models, was found to be greater in whites (RH, 1.55; 95% CI, 1.43-1.67) than blacks (RH, 1.24; 95% CI, 0.96-1.60), local (RH, 1.72; 95% CI, 1.50-1.96) versus distant stage (RH, 1.25; 95% CI, 1.00-1.56), and age 65-74 years (RH, 1.53; 95% CI, 1.38-1.69) versus age 85+ years (RH, 1.42; 95% CI, 1.09-1.84). CONCLUSIONS: This study establishes comorbidity as a predictor of survival in an elderly HNCA population and lends support to the inclusion of comorbidity assessment in prognostic staging of patients with HNCA diagnosed after 65 years of age.

Ethnic differences in asthma and associated phenotypes: collaborative study on the genetics of asthma.

BACKGROUND: In the Collaborative Study on the Genetics of Asthma, 314 families with 2584 subjects were characterized for asthma and allergy. OBJECTIVE: The purpose of this investigation was to examine clinical heterogeneity observed in asthma and allergic characteristics among 3 ethnic groups (African American, white, and Hispanic family members). METHODS: Pulmonary function parameters and asthma associated phenotypes were compared among the ethnic groups. RESULTS: In comparison with the other groups, African American sibling pairs had a significantly lower baseline FEV(1) percent of predicted (P =.0001) and a higher rate of skin test reactivity to cockroach allergen (P =.0001); Hispanic sibling pairs had significantly more skin reactivity overall (P =.001); and white sibling pairs had significantly lower total serum IgE (P <.05). In addition, there were significantly more relatives with asthma among the African American families than among the white and the Hispanic families (P =.001). CONCLUSION: Although different environmental backgrounds should be considered, these clinical differences could be due to differences in genetic susceptibility among the ethnic groups, such as those suggested by our previous genome screen.

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.