The Effects of Pleural Plaques on Longitudinal Lung Function in Vermiculite Miners of Libby, Montana.

BACKGROUND: This study was conducted to assess associations of pleural plaques (PP) and longitudinal lung function in vermiculite miners of Libby, Montana who are occupationally exposed to asbestos. High-resolution computed tomography (HRCT) was used to identify asbestos-related findings in former Libby vermiculite miners. We investigated annual lung function decline in miners with PP only and compared them to miners with normal HRCT findings. MATERIALS AND METHODS: HRCTs from 128 miners were categorized into the following 4 diagnostic groups: (1) normal computed tomography scan (n = 9); (2) PP only (n = 72); (3) PP and interstitial fibrosis (n = 26) and (4) additional HRCT abnormalities (n = 21) such as rounded atelectasis, diffuse pleural thickening, pleural effusions or pulmonary nodules or tumor >1cm in diameter. Random intercept and slope linear mixed-effect regression models identified differences in lung function decline between miners with asbestos-associated outcomes and those with normal HRCT. Models were adjusted for follow-up time, body mass index, smoking status, latent exposure period and employment years. Interactions for smoking status with age and smoking status with pleural plaque severity were examined. RESULTS: Miners with PP only did not have an accelerated decline in lung function between 40 and 80 years. Miners with PP and additional HRCT abnormalities displayed significantly accelerated declines in forced expiratory volume in 1 second and diffusing capacity of the lungs for carbon monoxide (P = 0.05 and P < 0.01, respectively). Plaque severity did not affect lung function decline. However, smokers with extensive plaques displayed accelerated loss in diffusing capacity of the lungs for carbon monoxide and forced expiratory volume in 1 second when compared to nonsmoking miners with mild plaque formation. CONCLUSIONS: PP alone did not significantly affect lung function decline in vermiculite miners of Libby, Montana.

Lung Function before and after a Large Chlorine Gas Release in Graniteville, South Carolina.

RATIONALE: On January 6, 2005 a train derailment led to an estimated 54,915-kg release of chlorine at a local textile mill in Graniteville, South Carolina. OBJECTIVES: We used the employee health spirometry records of the textile to identify enduring effects of chlorine gas exposure resulting from the incident on the lung function of workers employed at the textile mill. METHODS: Spirometry records from 1,807 mill workers (7,332 observations) were used from 4 years before and 18 months after the disaster. Longitudinal analysis using marginal regression models produced annual population mean estimates for FEV1, FVC, and FEV1/FVC ratio. Covariate adjustment was made for sex, age, smoking, height, season tested, technician, obesity, season × year interactions, and smoker × year interactions. The increased prevalence of mill workers having accelerated FEV1 decline was also evaluated after the chlorine spill. MEASUREMENTS AND MAIN RESULTS: In the year of the accident, we observed a significant reduction in mean FEV1 (-4.2% predicted; P = 0.019) when compared with the year before the incident. In the second year, partial recovery in the mean FVC % predicted level was seen, but the cohort's average FEV1/FVC ratio continued to decrease over time. Severe annual FEV1 decline was most prevalent in the year of the accident, and independent of mill worker smoking status. CONCLUSIONS: The Graniteville mill worker cohort revealed significant reductions in lung function immediately after the chlorine incident. Improvement was seen in the second year; but the proportion of mill workers experiencing accelerated FEV1 annual decline significantly increased in the 18 months after the chlorine incident.

Reduced lung function in children associated with cesium 137 body burden.

RATIONALE: We previously reported that obstructive and restrictive lung function findings were associated with radioactive Cesium 137 ((137)Cs) soil contamination from the 1986 Chernobyl disaster in a pediatric cohort residing in the Narodichesky district of Ukraine from 1993 to 1998. OBJECTIVES: To determine whether these associations persist, we repeated the study and refined the exposure by measuring individual radiation concentration with a whole-body counter. METHODS: Basic and post-bronchodilator spirometry measurements were made for 517 children aged 8 to 17 years born in and living within this differentially contaminated study area during 2008 to 2010. MEASUREMENTS AND MAIN RESULTS: A γ-spectrometer equipped with a collimator was used for the measurement of whole-body radiation and adjusted for weight. General linear and logistic regression models were used to estimate the association between spirometry measures and the weight-adjusted (137)Cs whole-body burden (Bq/kg) while controlling for potential confounders. The geometric median weight-adjusted radiation concentration was 65.96 Bq/kg (95% confidence interval, 14.98-240.9 Bq/kg), equivalent to a geometric mean internal dose estimate of 0.165 mSv/yr (95% confidence interval, 0.037-0.602 mSv/yr). Decrements in percentage predicted FEV1/FVC and an increased odds of bronchodilator responsiveness, restrictive impairment, and FVC less than lower limit of normal were associated with a log increase in weight-adjusted (137)Cs whole-body burden after adjusting for potential confounders. CONCLUSIONS: Our previous study of soil (137)Cs exposure and reduced lung function was corroborated herein with individual (137)Cs whole-body burden, although low, and annual internal dose data. Children in a region just outside of the closed Chernobyl contamination zone continued to have respiratory health deficits associated with (137)Cs whole-body burden as recently as 2010.

Pleural plaques and their effect on lung function in Libby vermiculite miners.

BACKGROUND: Multiple studies have investigated the relationship between asbestos-related pleural plaques (PPs) and lung function, with disparate and inconsistent results. Most use chest radiographs to identify PPs and simple spirometry to measure lung function. High-resolution CT (HRCT) scanning improves the accuracy of PP identification. Complete pulmonary function tests (PFTs), including spirometry, lung volumes, and diffusing capacity of the lung for carbon monoxide, provide a more definitive assessment of lung function. The goal of this study was to determine, using HRCT scanning and complete PFTs, the effect of PPs on lung function in Libby vermiculite miners. METHODS: The results of HRCT scanning and complete PFTs performed between January 2000 and August 2012 were obtained from the medical records of 166 Libby vermiculite miners. Multivariate regression analyses with Tukey multivariate adjustment were used to assess statistical associations between the presence of PPs and lung function. Adjustments were made for age, BMI, smoking history, duration of employment, and years since last occupational asbestos exposure. RESULTS: Nearly 90% of miners (n = 149) had evidence of PPs on HRCT scan. No significant differences in spirometry results, lung volumes, or diffusing capacity of the lung for carbon monoxide were found between miners with PPs alone and miners with normal HRCT scans. Miners with both interstitial fibrosis and the presence of PPs had a significantly decreased total lung capacity in comparison with miners with normal HRCT scans (P = .02). Age, cumulative smoking history, and BMI were significant covariates that contributed to abnormal lung function. CONCLUSIONS: Asbestos-related PPs alone have no significant effect on lung function in Libby vermiculite miners.

Respiratory symptoms and lung function 8-10 months after community exposure to chlorine gas: a public health intervention and cross-sectional analysis.

BACKGROUND: We implemented a community based interventional health screening for individuals located within one mile of a 54 metric tons release of liquid chlorine following a 16 tanker car train derailment on 6 January, 2005 in Graniteville, South Carolina, USA. Public health intervention occurred 8-10 months after the event, and provided pulmonary function and mental health assessment by primary care providers. Its purpose was to evaluate those exposed to chlorine for evidence of ongoing impairment for medical referral and treatment. We report comparative analysis between self-report of respiratory symptoms via questionnaire and quantitative spirometry results. METHODS: Health assessments were obtained through respiratory symptom and exposure questionnaires, simple spirometry, and physical exam. Simple spirometry was used as the standard to identify continued breathing problems. Sensitivity, specificity, positive and negative predictive values were applied to evaluate the validity of the respiratory questionnaire. We also identified the direction of discrepancy between self-reported respiratory symptoms and spirometry measures. Generalized estimation equations determined prevalence ratios for abnormal spirometry based on the presence of participant persistent respiratory symptoms. Covariate adjustment was made for participant age, sex, race, smoking and educational status. RESULTS: Two hundred fifty-nine people participated in the Graniteville health screening; 53 children (mean age = 11 years, range: <1-16), and 206 adults (mean age = 50 years, range: 18-89). Of these, 220 (85%) performed spirometry maneuvers of acceptable quality. Almost 67% (n = 147) displayed abnormal spirometry, while 50% (n = 110) reported persistent new-onset respiratory symptoms. Moreover, abnormal spirometry was seen in 65 participants (29%) who did not report any discernible breathing problems. This represented a net 16.8% underreporting of symptoms. Sensitivity and specificity of questionnaire self-report of symptoms were low at 55.8% and 61.6%, respectively. Persistent cough (41%) and shortness of breath (39%) were the most frequently reported respiratory symptoms. CONCLUSION: Eight to ten months after acute chlorine exposure, the Graniteville health screening participants under-reported respiratory symptoms when compared to abnormal spirometry results. Sensitivity and specificity were low, and we determined that relying upon the self-report questionnaire was not adequate to objectively assess the lung health of our population following irritant gas exposure.

The Immediate Pulmonary Disease Pattern following Exposure to High Concentrations of Chlorine Gas.

Background. Classification of pulmonary disease into obstructive, restrictive, and mixed patterns is based on 2005 ATS/ERS guidelines and modified GOLD criteria by Mannino et al. (2003), but these guidelines are of limited use for simple spirometry in situations involving mass casualties. Aim. The purpose of this study was to apply these guidelines to patients who underwent simple spirometry following high concentration of chlorine gas inhalation after a train derailment in Graniteville, South Carolina. Methods. We retrospectively investigated lung functions in ten patients. In order to classify pulmonary disease pattern, we used 2005 ATS/ERS guidelines and modified GOLD criteria along with our own criteria developed using available simple spirometry data. Results. We found predominant restrictive pattern in our patients with both modified GOLD and our criteria, which is in contrast to other chlorine exposure studies where obstructive pattern was more common. When compared to modified GOLD and our criteria, 2005 ATS/ERS guidelines underestimated the frequency of restrictive disease. Conclusion. Diagnosis of pulmonary disease patterns is of importance after irritant gas inhalation. Acceptable criteria need to be developed to evaluate pulmonary disease through simple spirometry in events leading to mass casualty and patient surge in hospitals.

137Cesium exposure and spirometry measures in Ukrainian children affected by the Chernobyl nuclear incident.

BACKGROUND: After the Chernobyl accident in 1986, children of the contaminated Narodichesky region of Ukraine were obliged to participate in a yearly medical screening. They have been exposed to 137cesium (137Cs; half-life = 30 years) in contaminated soils, air, and food. OBJECTIVE: Using a "natural experiment" approach and a longitudinal prospective cohort study design, we investigated the association of soil 137Cs and spirometry measures for 415 children using 1,888 repeated measurements from 1993 to 1998. METHODS: Mean baseline village soil 137Cs measurements, which varied from 29.0 to 879 kBq/m2, were used as exposure indicators. A standardized spirometry protocol and prediction equations specific to Ukrainian children were used by the same pulmonologist in all screenings. RESULTS: Children living in villages with the highest quintile of soil 137Cs were 2.60 times more likely to have forced vital capacity (FVC) < 80% of predicted [95% confidence interval (CI), 1.07-6.34] and 5.08 times more likely to have a ratio of forced expiratory volume in 1 sec (FEV1) to FVC% < 80% (95% CI, 1.02-25.19). We found statistically significant evidence of both airway obstruction (FEV1/FVC%, peak expiratory flow, and maximum expiratory flow at 25%, 50%, and 75% of FVC) and restriction (FVC) with increasing soil 137Cs. CONCLUSIONS: These findings are unique and suggest significant airway obstruction and restriction consequences for children chronically exposed to low-dose radioactive contaminants such as those found downwind of the Chernobyl Nuclear Power Plant.

Lung, liver and bone cancer mortality after plutonium exposure in beagle dogs and nuclear workers.

The Mayak Production Association (MPA) worker registry has shown evidence of plutonium-induced health effects. Workers were potentially exposed to plutonium nitrate [(239)Pu(NO(3))(4)] and plutonium dioxide ((239)PuO(2)). Studies of plutonium-induced health effects in animal models can complement human studies by providing more specific data than is possible in human observational studies. Lung, liver, and bone cancer mortality rate ratios in the MPA worker cohort were compared to those seen in beagle dogs, and models of the excess relative risk of lung, liver, and bone cancer mortality from the MPA worker cohort were applied to data from life-span studies of beagle dogs. The lung cancer mortality rate ratios in beagle dogs are similar to those seen in the MPA worker cohort. At cumulative doses less than 3 Gy, the liver cancer mortality rate ratios in the MPA worker cohort are statistically similar to those in beagle dogs. Bone cancer mortality only occurred in MPA workers with doses over 10 Gy. In dogs given (239)Pu, the adjusted excess relative risk of lung cancer mortality per Gy was 1.32 (95% CI 0.56-3.22). The liver cancer mortality adjusted excess relative risk per Gy was 55.3 (95% CI 23.0-133.1). The adjusted excess relative risk of bone cancer mortality per Gy(2) was 1,482 (95% CI 566.0-5686). Models of lung cancer mortality based on MPA worker data with additional covariates adequately described the beagle dog data, while the liver and bone cancer models were less successful.

Trichloroethylene risk assessment: a review and commentary.

Trichloroethylene (TCE) is a widespread environmental contaminant that is carcinogenic when given in high, chronic doses to certain strains of mice and rats. The capacity of TCE to cause cancer in humans is less clear. The current maximum contaminant level (MCL) of 5 ppb (microg/L) is based on an US Environment Protection Agency (USEPA) policy decision rather than the underlying science. In view of major advances in understanding the etiology and mechanisms of chemically induced cancer, USEPA began in the late 1990s to revise its guidelines for cancer risk assessment. TCE was chosen as the pilot chemical. The USEPA (2005) final guidelines emphasized a "weight-of-evidence" approach with consideration of dose-response relationships, modes of action, and metabolic/toxicokinetic processes. Where adequate data are available to support reversible binding of the carcinogenic moiety to biological receptors as the initiating event (i.e., a threshold exists), a nonlinear approach is to be used. Otherwise, the default assumption of a linear (i.e., nonthreshold) dose-response is utilized. When validated physiologically based pharmacokinetic (PBPK) models are available, they are to be used to predict internal dosimetry as the basis for species and dose extrapolations. The present article reviews pertinent literature and discusses areas where research may resolve some outstanding issues and facilitate the reassessment process. Key research needs are proposed, including role of dichloroacetic acid (DCA) in TCE-induced liver tumorigenesis in humans; extension of current PBPK models to predict target organ deposition of trichloroacetic acid (TCA) and DCA in humans ingesting TCE in drinking water; use of human hepatocytes to ascertain metabolic rate constants for use in PBPK models that incorporate variability in metabolism of TCE by potentially sensitive subpopulations; measurement of the efficiency of first-pass elimination of trace levels of TCE in drinking water; and assessment of exogenous factors' (e.g., alcohol, drugs) ability to alter metabolic activation and risks at such low-level exposure.

Hypoxia during air travel in adults with pulmonary disease.

At the present time, commercial aircraft cabins are required to be pressurized to the equivalent of 8,000 feet or less. Although in-flight medical emergencies are infrequent, some adults with pulmonary disease may experience significant physiological stress, exacerbation of their underlying illness, and severe hypoxemia during air travel. A careful preflight medical evaluation is essential to determine which patients with pulmonary disease can fly safely, which patients require supplemental oxygen, and which patients should not fly at all. All adults with pulmonary disease who have a preflight arterial oxygen tension of less than 70 mm Hg or a preflight pulse oximetry saturation of less than 92% should receive supplemental oxygen during air travel. The hypoxia altitude simulation test and the 6-minute walk test are useful when additional evaluation for supplemental in-flight oxygen is needed. Patients with an unstable condition, an acute exacerbation of their pulmonary disease, severe pulmonary hypertension (Class III and Class IV), or an active pneumothorax should not fly.

Application of cryopreserved human hepatocytes in trichloroethylene risk assessment: relative disposition of chloral hydrate to trichloroacetate and trichloroethanol.

BACKGROUND: Trichloroethylene (TCE) is a suspected human carcinogen and a common groundwater contaminant. Chloral hydrate (CH) is the major metabolite of TCE formed in the liver by cytochrome P450 2E1. CH is metabolized to the hepatocarcinogen trichloroacetate (TCA) by aldehyde dehydrogenase (ALDH) and to the noncarcinogenic metabolite trichloroethanol (TCOH) by alcohol dehydrogenase (ADH). ALDH and ADH are polymorphic in humans, and these polymorphisms are known to affect the elimination of ethanol. It is therefore possible that polymorphisms in CH metabolism will yield subpopulations with greater than expected TCA formation with associated enhanced risk of liver tumors after TCE exposure. METHODS: The present studies were undertaken to determine the feasibility of using commercially available, cryogenically preserved human hepatocytes to determine simultaneously the kinetics of CH metabolism and ALDH/ADH genotype. Thirteen human hepatocyte samples were examined. Linear reciprocal plots were obtained for 11 ADH and 12 ALDH determinations. RESULTS: There was large interindividual variation in the Vmax values for both TCOH and TCA formation. Within this limited sample size, no correlation with ADH/ALDH genotype was apparent. Despite the large variation in Vmax values among individuals, disposition of CH into the two competing pathways was relatively constant. CONCLUSIONS: These data support the use of cryopreserved human hepatocytes as an experimental system to generate metabolic and genomic information for incorporation into TCE cancer risk assessment models. The data are discussed with regard to cellular factors, other than genotype, that may contribute to the observed variability in metabolism of CH in human liver.

Hypersensitivity pneumonitis.

PURPOSE OF REVIEW: Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a granulomatous, inflammatory disease of the lungs caused by the inhalation of antigenic organic particles or fumes. The disease may present as an acute, subacute, or chronic illness. Episodes of acute and subacute HP usually resolve following cessation of antigen exposure. Chronic HP may be progressive, irreversible, and result in debilitating fibrotic lung disease. This review discusses current concepts regarding the diagnosis, pathogenesis, and treatment of HP. RECENT FINDINGS: The pathogenesis of HP involves both type III and type IV hypersensitivity reactions that are mediated by immune complexes and Th1 T cells, respectively. Proinflammatory cytokines and chemokines activate alveolar macrophages, cause an influx of CD8+ lymphocytes into the lungs, facilitate granuloma formation, and promote the development of pulmonary fibrosis. IFN-gamma is essential for the development of HP and IL-10 appears to modulate the severity of disease. TNF-alpha and TGF-beta have been implicated in development of the pulmonary fibrosis that is seen in chronic HP. It has been shown that pigeon fanciers with HP have an increase in the frequency of HLA-DRB1*1305 and HLA-DQB1*0501 alleles, a decrease in the frequency of the HLA-BRB1*0802 allele, and an increased frequency of the TNF-2 (-308) polymorphism of the TNF-alpha promoter gene. SUMMARY: A careful environmental and occupational history and establishment of exposure to a known inciting antigen are key factors in making the diagnosis of HP. Serum precipitating antibodies, bronchoalveolar lavage, and lung biopsy may be helpful in making the diagnosis. Avoidance of organic antigen exposure is the most important factor in the management of HP. Corticosteroids are indicated for the treatment of severe acute and subacute HP and for chronic HP that is severe or progressive. Long-term corticosteroid therapy for the treatment of chronic HP should be considered only if objective improvement in clinical signs, pulmonary function, or radiographic abnormalities is documented.

Glutathione S-transferase M1 polymorphism and the risk of lung cancer.

Glutathione S-transferases (GSTs) are a family of enzymes that detoxify hydrophobic electrophiles, including polycyclic aromatic hydrocarbon carcinogens that have been implicated in the pathogenesis of lung cancer. The GSTM1 gene within the mu class of human GSTs has been shown to be polymorphic, with individuals who are homozygous for a null allele having the GSTM1-null genotype. Individuals with the GSTM1-null genotype are deficient in both the GSTM1 and GSTM3 isoenzymes in the lung. A number of epidemiological studies have been conducted to assess the association between the GSTM1-null genotype and the risk of lung cancer. Although there have been conflicting reports regarding this relationship, the current weight of evidence indicates that the GSTM1-null genotype is probably associated with a modest increase in the risk of lung cancer. This risk appears to be greater in African-American and Asian populations than in Caucasians. Recent investigations have shown that the GSTM1-null genotype combined with CYP1A1, NAT2, or GSTP1 polymorphisms confers a greater risk of lung cancer than the GSTM1-null genotype alone. Future investigations should focus on assessing the risk of lung cancer related to multiple combinations of genetic polymorphisms that may identify individuals who are at high risk for developing lung cancer with a greater degree of certainty than is currently possible. This could lead to new clinical strategies for counseling, risk reduction and the detection of lung at an early and potentially curable stage.