Rates and occupational characteristics of international seafarers with mental illness.

BACKGROUND: Seafarers enable 90% of global commerce, working in isolation from social support and medical care. While occupational conditions of isolation may suggest possible excess risk of mental illness and suicide, research on seafarer mental illness is limited. AIMS: To describe seafarers with mental illness and associated incidence rates in a large population of international seafarers. METHODS: We used mental illness claims data from a large international marine insurance provider arising from working seafarers during the years 2007-15. We used descriptive statistics and calculated mental illness incidence rates in this seafarer population. RESULTS: There were 278 seafarer mental illness claims in the study data. Claims were more often reported in deck workers (46%) and ratings (58%). The crude mental illness rate was 3.9 per 100 000 person-years. CONCLUSIONS: Using objective data on a large seafaring population, our analysis highlights the important issue of mental illness in this isolated and underserved international workforce. The low observed mental illness claims rate is likely due to the high threshold for claims reporting.

Skin and respiratory symptoms among workers with suspected work-related disease.

BACKGROUND: Many workers are exposed to chemicals that can cause both respiratory and skin responses. Although there has been much work on respiratory and skin outcomes individually, there are few published studies examining lung and skin outcomes together. AIMS: To identify predictors of reporting concurrent skin and respiratory symptoms in a clinical population. METHODS: Patients with possible work-related skin or respiratory disease were recruited. An interviewer- administered questionnaire collected data on skin and respiratory symptoms, health history, smoking habits, workplace characteristics and occupational exposures. Predictors of concurrent skin and respiratory symptoms were identified using multiple logistic regression models adjusted for age, sex and atopy. RESULTS: In total, 204 subjects participated; 46% of the subjects were female and the mean age was 45.4 years (SD = 10.5). Most subjects (n = 167, 82%) had possible work-related skin disease, compared with 37 (18%) subjects with possible work-related respiratory disease. Subjects with a history of eczema (OR 3.68, 95% CI 1.7-7.8), those from larger workplaces (OR 2.82, 95% CI 1.8-7.4) and those reporting respirator use at work (OR 2.44, 95% CI 1.2-4.8) had significantly greater odds of reporting both work-related skin and respiratory symptoms. Current smoking was also associated with reporting concurrent skin and respiratory symptoms (OR 2.57, 95% CI 1.2-5.8). CONCLUSIONS: Workers reported symptoms in both systems, and this may be under-recognised both in the workplace and the clinic. The association between history of eczema and concurrent skin and respiratory symptoms suggests a role for impaired barrier function but needs further investigation.

Human innate immune responses to hexamethylene diisocyanate (HDI) and HDI-albumin conjugates.

BACKGROUND: Isocyanates, a leading cause of occupational asthma, are known to induce adaptive immune responses; however, innate immune responses, which generally precede and regulate adaptive immunity, remain largely uncharacterized. OBJECTIVE: The aim of the study was to identify and characterize the cellular, molecular and systemic innate immune responses induced by hexamethylene diisocyanate (HDI). METHODS: Human peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with HDI-albumin conjugates or control antigen, and changes in phenotype, gene and protein expression were characterized by flow cytometry, microarray, Western blot and ELISA. Cell uptake of isocyanate was visualized microscopically using HDI-albumin conjugates prepared with fluorescently labelled albumin. In vivo, human HDI exposure was performed via a specific inhalation challenge, and subsequent changes in PBMCs and serum proteins were measured by flow cytometry and ELISA. Genotypes were determined by PCR. RESULTS: Human monocytes take up HDI-albumin conjugates and undergo marked changes in morphology and gene/protein expression in vitro. The most significant (P-values 0.007-0.05) changes in microarray gene expression were noted in lysosomal genes, especially peptidases and proton pumps involved in antigen processing. Chemokines that regulate monocyte/macrophage trafficking (MIF, MCP-1) and pattern-recognition receptors that bind chitin (chitinases) and oxidized low-density lipoprotein (CD68) were also increased following isocyanate-albumin exposure. In vivo, HDI-exposed subjects exhibited a drastic increase in the percentage of PBMCs with the same HDI-albumin responsive phenotype characterized in vitro (HLA-DR(+)/CD11c(+) with altered light scatter properties). An exposure-dependent decrease (46+/-11%; P<0.015) in serum concentrations of chitinase 3-like-1 was also observed in individuals who lack the major (type 1) human chitinase (due to genetic polymorphism), but not in individuals possessing at least one functional chitinase-1 allele. CONCLUSIONS: Previously unrecognized innate immune responses to HDI and HDI-albumin conjugates could influence the clinical spectrum of exposure reactions.

Surveillance for isocyanate asthma: a model based cost effectiveness analysis.

AIMS: Because logistical and financial obstacles impede using large prospective cohort studies, surveillance decisions in occupational settings must often be made without evidence of relative benefits and costs. Using the example of isocyanate induced asthma, the most commonly reported immune mediated occupational asthma, the authors developed a model based approach to evaluate the costs and benefits of surveillance from both an employer and a societal perspective. METHODS: The authors used a mathematical simulation model of isocyanate asthma to compare annual surveillance to passive case finding. Outcome measures included symptom free days (SFD), quality adjusted life years (QALY), direct costs, productivity losses, and incremental cost effectiveness ratio (CER), measured from the employer and the societal perspectives. Input data were obtained from a variety of published sources. RESULTS: For 100,000 exposed workers, surveillance resulted in 683 fewer cases of disability over 10 years. Surveillance conferred benefits at an incremental cost of 24,000 dollars/QALY (employer perspective; 13.33 dollars/SFD) and was cost saving from the societal perspective. Results were sensitive to assumptions about sensitisation rate, removal rates, and time to diagnosis, but not to assumptions about therapy costs and disability rates. CONCLUSIONS: Baseline results placed the CER for surveillance for isocyanate asthma within the acceptable range. Costs from the societal and employer perspective differed substantially with a more attractive CER from the societal perspective, suggesting opportunities for employer/societal cost sharing. The analysis demonstrates the value of a model based approach to evaluate the cost effectiveness of surveillance programmes for isocyanate asthma, and to inform shared decision making among clinicians, patients, employers, and society. Such a modeling approach may be applicable to surveillance programmes for other work related conditions.

Changes in cholesterol and triglyceride concentrations in the Vanguard population of the Carotene and Retinol Efficacy Trial (CARET).

BACKGROUND: The Beta-Carotene and Retinol Efficacy Trial (CARET) was terminated 21 months ahead of schedule due to an excess of lung cancers. Deaths from cardiovascular disease also increased (relative risk=1.26 (95% confidence interval (CI) 0.99-1.61)) in the group assigned to a combination of 30 mg beta-carotene and 25 000 IU retinyl palmitate (vitamin A) daily. The basis for increased cardiovascular mortality is unexplained. DESIGN: We analyzed data on serum lipids, available for 1474 CARET Vanguard participants who were enrolled in the two CARET pilot studies and transitioned to the Vanguard study. Total cholesterol and triglycerides were measured 2 months prior to, 4 and 12 months following randomization, and annually thereafter for up to 7 y. INTERVENTION: In the asbestos-exposed pilot (N = 816), participants were assigned to beta-carotene and retinol or to placebo; in the smokers pilot (N = 1029), participants were assigned to beta-carotene, retinol, a combination, or placebo. RESULTS: Serum cholesterol showed a decline over time in both arms; serum triglycerides had a continuous decline over time in the placebo arm, but an initial increase that persisted in the active arm. Both serum cholesterol concentrations (P < 0.0003) and serum triglycerides (P < 0.0001) were significantly higher in the participants receiving vitamin A and/or a combination of vitamin A and beta-carotene (n = 863) as compared to the placebo group (n = 611). Those in this active intervention group had an average cholesterol concentration 5.3 mg/dl (0.137 mmol/l) higher than those in the placebo arm. CONCLUSION: The differences in cholesterol and triglyceride concentrations between the groups following randomization may account in part for the unexpected excess in cardiovascular deaths seen in the active intervention arm of CARET.

Glutathione protects human airway proteins and epithelial cells from isocyanates.

BACKGROUND: Glutathione (GSH), one of the major anti-oxidants of the lung, has been linked to the human response to isocyanate exposure. However, the ability of GSH to modulate key chemical reactions, thought to be central to the development of human isocyanate allergy, has not been directly analyzed under biologic exposure conditions. OBJECTIVE: To better understand the potential role of GSH in the response to occupational isocyanate exposure, we evaluated its effects on two processes thought to be involved in the development of isocyanate allergy, isocyanate-protein conjugation and epithelial cell toxicity. METHODS: The effects of GSH on (1) isocyanate conjugation with albumin, its major target in the airway fluid and (2) isocyanate-induced toxicity to human airway epithelial cell lines, A549 and NCI-H292, were tested using two different in vitro models. For protein conjugation studies, a newly described vapour exposure system was used to model the air/liquid interface at the surface of the epithelial fluid in the airways. Epithelial cell exposures were performed in fluid phase to mimic the in vivo exposure of airway cells covered by epithelial lining fluid. RESULTS: Reduced GSH prevented hexamethylene diisocyanate (HDI) conjugation to albumin in a dose-dependent manner, while oxidized GSH (GSSG) conversely increased conjugation rates. GSH levels equivalent to those found in normal human airway fluid (100 microm) provided >90% protection against HDI-protein conjugation when albumin was exposed to HDI vapour levels 10-fold above permissible occupational limits. Physiologic levels of GSH, but not GSSG, also reduced HDI toxicity to human airway epithelial cells in a dose-dependent manner, when present extracellularly, however, drugs that modulate intra-cellular GSH levels did not significantly alter isocyanate toxicity. CONCLUSIONS: Together with previously reported genetic and toxicity studies, the data suggest that airway GSH plays an important role in protection against HDI exposure and may help prevent the development of allergic sensitization and asthma.

Determinants of isocyanate exposures in auto body repair and refinishing shops.

As part of the Survey of Painters and Repairers of Auto bodies by Yale (SPRAY), the determinants of isocyanate exposure in auto body repair shops were evaluated. Measurements (n = 380) of hexamethylene diisocyanate-based monomer and polyisocyanate and isophorone diisocyanate-based polyisocyanate were collected from 33 auto body shops. The median total reactive isocyanate concentrations expressed as mass concentration of the NCO functional group were: 206 microg NCO/m3 for spray operations; 0.93 microg NCO/m3 for samples collected in the vicinity of spray operations done on the shop floor (near spray); 0.05 microg NCO/m3 for office or other shop areas adjacent to spray areas (workplace background); 0.17 microg NCO/m3 for paint mixing and gun cleaning operations (mixing); 0.27 microg NCO/m3 for sanding operations. Exposure determinants for the sample NCO mass load were identified using linear regression, tobit regression and logistic regression models. For spray samples in a spray booth the significant determinants were the number of milliliters of NCO applied, the gallons of clear coat used by the shop each month and the type of spray booth used (custom built crossdraft, prefabricated crossdraft or downdraft/semi-downdraft). For near spray (bystander) samples, outdoor temperature >65 degrees F (18 degrees C) and shop size >5000 feet2 (465 m2) were significant determinants of exposure levels. For workplace background samples the shop annual income was the most important determinant. For sanding samples, the shop annual income and outdoor temperature >65 degrees F (18 degrees C) were the most significant determinants. Identification of these key exposure determinants will be useful in targeting exposure evaluation and control efforts to reduce isocyanate exposures.

Diisocyanate-exposed auto body shop workers: a one-year follow-up.

BACKGROUND: Diisocyanates currently are the most commonly identified cause of occupational asthma in industrialized countries. Auto body shops, a common hexamethylene diisocyanate (HDI) exposure setting, are difficult to study due to their small size and episodic exposures. OBJECTIVES: A 1-year follow-up was undertaken as an adjunct to the cross-sectional SPRAY study (Survey of Painters & Repairers of Auto bodies by Yale) to investigate the effects of HDI on auto body shop workers over time and whether or not the healthy worker effect may exist in this industry. METHODS AND RESULTS: Forty-eight workers from seven shops were re-contacted. Thirty-four subjects who stayed at the same shop and 11 who left their original shop participated. No statistically significant changes in physiology, symptoms, and immunologic responses from baseline to follow-up were noted. However, significant differences between those who left the shops and those who stayed were noted. Those who left were younger, less experienced in the industry, and more likely to have a history of asthma (23 vs. 3%; P < 0.05), bronchial hyper-responsiveness (23 vs. 9%), HDI-specific IgG (64 vs. 29%; P < 0.05), and HDI-specific proliferation (S.I. 2.0 vs. 1.3; P < 0.05). CONCLUSIONS: The differences in workers who stayed at their shop compared to those who left, combined with the low asthma prevalence and high job turnover rate, all suggest that a healthy worker effect may exist in the auto body industry, and may in part account for the low prevalence of asthma noted in SPRAY and other cross-sectional studies of diisocyante workers.

Development of immunoassays for biomonitoring of hexamethylene diisocyanate exposure.

Hexamethylene diisocyanate (HDI) is used widely to manufacture polyurethanes for paints and coatings. It is an irritant and a chemical asthmagen. The U.S. Occupational Safety and Health Administration time-weighted average permissible exposure limit is 5 ppb and the ceiling limit is 20 ppb. We sought to develop a sensitive and specific immuno-bioassay to supplement workplace air monitoring and detect recent HDI exposure. For this, we produced rabbit antiserum to HDI-adducted keyhole limpet hemocyanin (HDI-KLH). The specificity of the antiserum was demonstrated by its reaction with a variety of HDI-conjugated proteins and the absence of reactions with conjugates of other diisocyanates, namely toluene diisocyanate and diphenyl methylene diisocyanate. Four immunoassays were developed and compared for their ability to detect decreasing quantities of HDI-adducted human serum albumin (HSA) containing 2 mol HDI adduct per mol HSA (HDI(2)-HSA) as determined by matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry. The sensitivities of some of the assays are within the range (0.82-45 nM) of current analytic methods. A Western analysis procedure has a sensitivity of 600 nM HDI adduct on HSA. ELISA inhibition assay, in which microtiter plates are coated with the HDI(2)-HSA antigen, has a sensitivity of 300 nM HDI adduct. An immunoblot assay has a sensitivity of 9 nM HDI adduct. The most sensitive bioassay (1.8 nM HDI adduct) is a three-antibody sandwich ELISA in which wells of microtiter plates are coated with the IgG fraction of the anti-HDI-KLH antisera. Compared with analytic methods for HDI biomonitoring, the immunoassays are faster and less costly and accommodate numerous samples simultaneously. The assays have the potential to affect industrial biomonitoring programs significantly.

Subclinical immunologic and physiologic responses in hexamethylene diisocyanate-exposed auto body shop workers.

BACKGROUND: Diisocyanates are potent sensitizing agents and currently the most commonly identified cause of occupational asthma in industrialized countries. However, diisocyanate asthma is difficult to diagnose and exposure and host risk factors are unclear. Auto body shops, one of the most common hexamethylene diisocyanate (HDI) exposure settings, are particularly difficult to study due to their small size and episodic exposures. Surveillance studies of such workers are limited. OBJECTIVES: We have initiated a cross-sectional field epidemiologic study, Survey of Painters and Repairers of Auto bodies by Yale (SPRAY), to characterize the effects of diisocyanate exposures on actively employed auto body shop workers. Methods and Results We present here questionnaire, physiologic, immunologic, and exposure data on 75 subjects enrolled in the study. No overt cases of clinically apparent diisocyanate asthma were identified based on spirometry, methacholine challenge, peak flows, and symptoms. HDI-specific lymphocyte proliferation was present in 30% of HDI-exposed workers and HDI-specific IgG in 34% of HDI-exposed workers, but they were not associated. HDI-specific IgE was detected in two workers. HDI-specific lymphocyte proliferation, increased methacholine responsiveness, and symptoms of chest tightness and shortness of breath were more common in the most heavily HDI-exposed workers, the painters. More long-term follow-up of this cohort should clarify the significance of these HDI-specific immunologic responses, physiologic changes, and symptoms. CONCLUSIONS: These findings demonstrate the presence of HDI-specific immune responses in a large proportion of healthy HDI-exposed workers.

Human gamma/delta T-cell lines derived from airway biopsies.

gamma/delta T cells have been postulated to play an important role in the immune response at epithelial boundaries, but have not been well described in human lung tissue. We have identified and characterized gamma/delta T-cell lines from human airway biopsies and compared them with T-cell lines from paired peripheral blood samples. Airway-derived T-cell lines stimulated with tetanus toxoid (TT) contained a greater proportion of gamma/delta T cells compared with T-cell lines stimulated with mitogens, other antigens, or without antigen. TT-stimulated airway T cells expressed different T-cell receptors (TCRs) than did blood- derived T cells, and used predominantly variable region (V)gamma I family genes rather than V gamma II family genes. Airway-derived gamma/delta T cells produced high levels of interferon-gamma and were associated with T helper 1--like cytokine profiles. This study describes the presence and antigen-dependent proliferation of gamma/delta T cells from human airway tissue, and demonstrates differences in lung-derived gamma/delta TCRs compared with gamma/delta T cells derived from peripheral blood. The data suggest that gamma/delta T cells may be functionally enriched in human airways relative to peripheral blood.

Serum hepatic biochemical activity in two populations of workers exposed to styrene.

OBJECTIVE: To determine whether hepatic biochemical changes, as measured by routinely available tests indicative of hepatocellular necrosis, cholestasis, or altered hepatic clearance of bilirubin, occur in association with low to moderate exposure to styrene commonly experienced in industrial production. METHODS: Two independent cross sectional studies were performed comparing serum hepatic transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), cholestatic enzymes (alkaline phosphatase (AP) and gamma glutamyl transpeptidase (GGT)), and bilirubin in (a) 47 workers of fibreglass reinforced plastics who were exposed to styrene and (b) 21 boat and tank fabricators, with separate referent groups of unexposed workers. Exposure to styrene was assessed in air by dosimetry, and in venous blood by headspace analysis. Hepatic biochemical variables were assessed across strata of exposure to styrene defined as 25 ppm in air, or 0.275 mg/l in blood, adjusting for age, sex, body mass index, and ethanol consumption. RESULTS: A consistent and significant linear trend for increasing direct bilirubin and direct/total bilirubin ratio was found in association with increasing exposure to styrene, by both air and blood monitoring, in both studies. Mean direct bilirubin concentrations increased from 0.05-0.08 mg% in referents to 0.12-0.19 in workers exposed above 25 ppm, with a significant exposure-response trend (p<0.005). Significantly increased direct/total bilirubin ratios, ranging from 0.22 to 0.35 were associated with exposure to styrene (p<0.001), indicating diminished hepatic clearance of conjugated bilirubin. Also, a significant linear association between the hepatic transaminases ALT and AST and exposure to styrene was found in pooled regression analyses, with an increase in AP of about 10 IU/ml in workers exposed above 25 ppm air or 0.275 mg/l blood styrene in pooled analyses from both studies. CONCLUSIONS: The consistent finding of increased direct bilirubin and AP concentrations in these two independent studies provides evidence for diminished hepatic clearance of conjugated bilirubin with associated cholestasis in workers exposed to styrene. The finding of a significant linear association between hepatic transaminase concentrations and exposure to styrene in pooled analyses is consistent with mild hepatic injury and associated metabolic dysfunction.

Recent developments in diisocyanate asthma.

Despite recent advances in our understanding of diisocyanate-induced asthma, this disease remains a perplexing phenomenon. Studies reported in the past year have focused on: (i) diisocyanate antigens; (ii) the role of airway and skin epithelium; (iii) human immune responses to exposure; (iv) neurogenic pathways; and (v) genetic factors that may confer susceptibility. These studies support the hypothesis that diisocyanate asthma results from the host immune response to these chemicals, and may represent a mixed T helper type 1/2 response. A better understanding of the pathogenesis of diisocyanate asthma should facilitate the development of better diagnostic tests and strategies for disease surveillance and intervention.

Pulmonary function tests at work.

Occupational exposures remain an important cause of lung disease. A number of PFTs are used in the occupational setting, including spirometry, PEF recordings, methacholine challenge testing, lung volume, and DL(CO). These tests are used in a number of situations, including the clinical evaluation and management of patients with possible occupational lung disorders, preplacement and fitness-for-duty examinations, medical screening of exposed workers, impairment and disability evaluations, and research. The diagnosis of occupational lung disease has serious consequences for a worker and, in addition to a careful occupational history, usually requires objective assessment using PFTs. Serial PFTs are useful in following such patients and screening exposed populations of workers for respiratory conditions.

Identification of human lung and skin proteins conjugated with hexamethylene diisocyanate in vitro and in vivo.

Diisocyanates are asthma-causing chemicals used in the commercial production of polyurethane. We have previously shown that human lung epithelial cell proteins can become conjugated with hexamethylene diisocyanate (HDI) and may be biologically important in diisocyanate-induced asthma. The objective of this study was to identify specific human lung and skin proteins that become conjugated with diisocyanate after in vitro and in vivo exposure. Following in vitro exposure of human airway epithelial cells (A549), keratin 18, the 78-kD glucose-regulated protein, trans-1, 2-dihyrobenzene-1,2-diol dehydrogenase, and actin were identified as prominent diisocyanate-conjugated proteins through use of a combination of immunocytochemical and mass spectrometric techniques. Following in vivo inhalation of an HDI aerosol, keratin 18 was also identified as the predominant diisocyanate-conjugated protein in human endobronchial biopsy samples, whereas albumin was the predominant diisocyanate-conjugated protein in bronchoalveolar lavage fluid. Keratin was also identified as a predominant diisocyanate-conjugated protein in human skin biopsy samples after epicutaneous exposure to liquid-phase HDI, although the major skin diisocyanate-conjugated protein (56-kD) differed from the predominant lung diisocyanate-conjugated keratin (47-kD). The data from this study identify keratin and other proteins as potential "carriers" for diisocyanates in vivo, and suggest that HDI conjugation of these proteins may play a role in the pathogenesis of diisocyanate-induced asthma.

Qualitative assessment of isocyanate skin exposure in auto body shops: a pilot study.

BACKGROUND: Little is known about the extent of human isocyanate skin exposure in auto body shops and the effectiveness of personal protective equipment. Animal studies have suggested that skin exposure to isocyanates may be an important risk factor for respiratory sensitization leading to asthma. This study provides initial data on hexamethylene diisocyanate skin exposure in three auto body shops. METHODS: Three auto body shops of different size which use different paint systems were examined for the presence of aliphatic isocyanates on environmental surfaces and workers' skin and for breakthrough of personal protective equipment. Qualitative detection of contamination by isocyanates was conducted using a wipe-sampling technique. Assessment focused on the painters and their tasks, although other auto body repairers were also evaluated. RESULTS: Environmental surfaces such as painters' workbenches, spray equipment, and cleaning tools were found contaminated with isocyanates. Painters had frequent contact with contaminated surfaces, often without wearing gloves. Moderate to heavy contamination of some skin surfaces was found with painters from two of the three auto body shops. Latex gloves used for skin protection showed significant penetrations by isocyanates even after a single painting session. CONCLUSIONS: Contaminated environmental surfaces and skin exposure to isocyanates were documented in several auto body shops. Latex gloves were not adequate protection for workers using isocyanate paints. Further research which would better quantify skin exposure, and its potential relationship to respiratory sensitization and asthma is warranted.

Effect of long-term beta-carotene and vitamin A on serum cholesterol and triglyceride levels among participants in the Carotene and Retinol Efficacy Trial (CARET)

OBJECTIVE: The Carotene and Retinol Efficacy Lung Cancer Chemoprevention Trial (CARET) ended prematurely due to the unexpected findings that the active treatment group on the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate had a 46% increased lung cancer mortality and a 26% increased cardiovascular mortality compared with placebo. This study was designed when the CARET intervention was halted to evaluate the effects of long-term supplementation with beta-carotene and retinol on serum triglyceride and cholesterol levels, in an attempt to explore possible explanations for the CARET result. METHODS: Serum triglyceride levels, and total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol levels were determined in a subgroup of 52 CARET participants. Baseline and mid-trial levels were available on 23 participants on placebo and 29 on active treatment who were then serially followed for 10 months after trial termination. RESULTS: Triglyceride, and total, HDL and LDL cholesterol levels were similar in the two groups at baseline. After a mean of 5 years on the intervention there was a small nonsignificant increase in serum triglyceride levels in the active group, but no difference in total, HDL, or LDL cholesterol levels. After stopping the intervention there was a decrease in triglyceride levels in the active intervention group, and no change in the other parameters. CONCLUSION: Based on a small convenience sample, CARET participants in the active treatment arm had a small nonsignificant increase in serum triglyceride levels while on the intervention, and a decrease in serum triglyceride levels after the intervention was discontinued. No significant changes in total or HDL cholesterol were noted. These results argue against a major contribution of treatment-induced changes in serum lipid and lipoprotein levels to the increased cardiovascular mortality in the active treatment group.

Isocyanate-conjugated human lung epithelial cell proteins: A link between exposure and asthma?

BACKGROUND: Isocyanates are a group of highly reactive cross-linking chemicals that cause airway inflammation and asthma in exposed individuals. Isocyanates have been detected along the airway epithelia of exposed workers and animals, prompting the hypothesis that isocyanates can directly bind to epithelial cell proteins. OBJECTIVE: We tested the hypothesis that hexamethylene diisocyanate (HDI) binds directly to lung epithelial cell proteins and initiated studies to evaluate the immunostimulatory potential of HDI-conjugated lung epithelial cell proteins. METHODS: Human lung epithelial cell lines were exposed to vapor- and liquid-phase HDI, and the cellular proteins were analyzed for HDI conjugation by Western blotting and tested for the ability to induce lymphocyte proliferation in vitro. RESULTS: A number of epithelial cell polypeptides, ranging from 25 to 110 kd in apparent molecular weight, were conjugated with HDI after exposure of the human lung epithelial cell lines (A549 and NCI-H292) to HDI concentrations greater than 0.005% (vol/vol) in the liquid phase. Vapor-phase HDI exposure resulted in a more restricted HDI conjugation pattern, with major HDI-conjugated polypeptides migrating at 47, 71, and 91 kd. HDI-conjugated epithelial cell proteins specifically stimulated proliferation of PBMCs from subjects with isocyanate-induced asthma but not HDI-exposed nonasthmatic individuals or atopic subjects with nonisocyanate-related asthma. CONCLUSIONS: The data demonstrate that epithelial cell proteins readily react with HDI and that HDI-conjugated epithelial cell proteins can stimulate lymphocyte proliferation. Further characterization and evaluation of HDI-conjugated epithelial cell proteins will elucidate their potential role in the pathogenesis of isocyanate-induced asthma.