Personal exposure and long-term health effects in survivors of the union carbide disaster at bhopal. (25/207)

Nine years after the Bhopal methyl isocyanate disaster, we examined the effects of exposures among a cross-section of current residents and a subset of those with persistent symptoms. We estimated individual exposures by developing exposure indices based on activity, exposure duration, and distance of residence from the plant. Most people left home after the gas leak by walking and running. About 60% used some form of protection (wet cloth on face, splashing water). Mean and median values of the exposure indices showed a declining trend with increasing distance from the plant. For those subjects reporting any versus no exposure, prevalence ratios were elevated for most respiratory and nonrespiratory symptoms. We examined exposure-response relationships using exposure indices to determine which were associated with health outcomes. The index total exposure weighted for distance was associated with most respiratory symptoms, one measure of pulmonary function in the cross-sectional sample [mid-expiratory flow (FEF)(25-75), p = 0.02], and two measures of pulmonary function in the hospitalized subset [forced expiratory volume (FEV)(1), p = 0.02; FEF(25-75), p = 0.08). Indices that correlated with FEV(1) and forced vital capacity in the hospitalized subset did not correlate with the cross-sectional sample, and most indices (except total exposure) that correlated with the hospitalized subset did not correlate with the cross-sectional sample. Incorporation of distance into every index increased the number of symptoms associated; an improvement was also noted in the strength of the association for respiratory symptoms, but not for pulmonary function. The sum of duration (p = 0.02) and total exposure (p = 0.03) indices independently demonstrated stronger associations with percent predicted FEF(25-75) than the distance variable (p = 0.04). The results show that total exposure weighted for distance has met the criteria for a successful index by being associated with most respiratory symptoms as well as FEF(25-75), features of obstructive airways disease.  (+info)

Effects of thermal degradation products from polyurethane foams based on toluene diisocyanate and diphenylmethane diisocyanate on isolated, perfused lung of guinea pig. (26/207)

OBJECTIVES: The composition of thermal degradation products from two types of polyurethane foams, one based on toluene diisocyanate (TDI) and the other on diphenylmethane diisocyanate (MDI), was analyzed and their toxic lung effects were compared. METHODS: Isolated perfused lungs of guinea pig were subjected to thermal decomposition products of polyurethane foams from an aerosol generator with compartments for diluting, mixing, and sampling. RESULTS: Thermal degradation of MDI-based polyurethane foams released MDI, phenyl isocyanate, and methyl isocyanate. The emitted particulate fraction was 75% for MDI, whereas that for TDI from TDI-based polyurethane foam was 3%. Thermal degradation products from MDI-based foam caused a pronounced dose-dependent decrease in the measured lung function parameters (conductance and compliance). In contrast, the thermal degradation products from TDI-based foam did not cause any decrease in lung function. CONCLUSIONS: Thermal degradation products generated from MDI-based polyurethane foam were more toxic to the lung than those generated from TDI-based polyurethane foam. This difference was probable due to MDI in the particle phase.  (+info)

Requirement of a carbon spacer in benzyl isothiocyanate-mediated cytotoxicity and MAPK activation in head and neck squamous cell carcinoma. (27/207)

Cruciferous vegetable-derived isothiocyanates (ITCs; chemical structure: R-N=C=S) are highly effective in affording protection against chemically induced cancers in animal models. Here, we studied the antitumor effects of benzyl isothiocyanate (BITC; Ph-CH2-N=C=S), the predominant ITC compound in broccoli, on head and neck squamous cell carcinoma (HNSCC) cell lines. Proliferation, apoptosis and immunoblotting assays were used to determine the effects and mechanism of several ITCs on HNSCC cells. The IC50 for BITC (24 h treatment) in two of the HNSCC cell lines was approximately 22 and 17 micro M, respectively. Interestingly, phenyl isothiocyanate (PITC; Ph-N=C=S), which is a close structural analog of BITC but lacks a -CH2- spacer that links the aromatic ring to N=C=S moiety, did not result in significant killing of the HNSCC cells in this dose range. BITC (but not PITC) caused activation of caspase 3 and PARP cleavage. Within 20 min of treatment, BITC (but not PITC) induced a rapid activation of p38 MAPK. In addition, BITC (but not PITC) treatment resulted in the activation of p44/42 MAPK. Co-treatment with a specific p38 MAPK inhibitor, SB203580, or an inhibitor of the MEK/MAPK pathway, U0126, partially rescued cells from BITC-induced killing. Our results show that minor structural differences in ITCs can be crucial for the antiproliferative activity of ITCs and that BITC may be a promising chemopreventive as well as therapeutic agent in HNSCC.  (+info)

Cytokine mRNA expression in isocyanate-induced hypersensitivity pneumonitis. (28/207)

BACKGROUND: Diisocyanate is widely used as a polymerizing agent for manufacturing many products. However, repeated inhalation exposure to diisocyanates in the workplace can cause bronchial asthma, hypersensitivity pneumonitis (HP), and neoplasia. OBJECTIVES: In the current study, immunological tests were conducted to explore the mechanisms involved in the pathogenesis of diisocyanate-induced HP. METHODS: Evaluations included 4 patients with diisocyanate-induced HP, 4 volunteers with current occupational exposure to diisocyanates and 4 normal volunteers without a history of exposure to diisocyanates. IgG and IgA antibody levels to diisocyanates were determined by ELISA in sera and BAL fluids. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence or in the absence of 10 microg/ml MDI-HSA (4, 4' diphenylmethane diisocyanate)-HSA (human serum albumin). (3)H-thymidine uptake, mRNA expression by RT-PCR (beta-actin, IL-1beta, IL-2R, IL-4, IL-5, IL-6, IL-10, IFN-gamma, TNF-alpha, TGF-beta) were estimated. RESULTS: Patients with diisocyanate-induced HP had detectable IgG and IgA antibodies to diisocyanates. In addition, PBMCs from HP patients proliferated in the presence of diisocyanates and showed enhanced expression of mRNA of proinflammatory cytokines. In contrast, normal volunteers with current occupational exposure showed elevated levels of mRNA expression of IL-10 and IL-2R, suggesting the presence of sensitized cells and protection from pathology as a result of enhanced IL-10 production. CONCLUSIONS: Patients with diisocyanate-induced HP are likely to override the protective effects of IL-10 as they express lower levels of this cytokine.  (+info)

Sequential respiratory, psychologic, and immunologic studies in relation to methyl isocyanate exposure over two years with model development. (29/207)

Of 113 methyl isocyanate (MIC)-exposed subjects studied initially at Bhopal, India, 79, 56, 68, and 87 were followed with clinical, lung function, radiographic, and immunologic tests at 3, 6, 12, 18, and 24 months. Though our cohort consisted of subjects at all ages showing a varied severity of initial illness, fewer females and young subjects were seen. Initially all had eye problems, but dominant symptoms were exertional dyspnea, cough, chest pain, sputum, and muscle weakness. A large number showed persistent depression mixed with anxiety, with disturbances of personality parameters. The early radiographic changes were lung edema, overinflation, enlarged heart, pleural scars, and consolidation. The persistent changes seen were interstitial deposits. Lung functions showed mainly restrictive changes with small airway obstruction; there was impairment of oxygen exchange. Oxygen exchange improved at 3-6 months, and spirometry improved at 12 months, only to decline later. The expiratory flow rates pertaining to large and medium airway function improved, but those for small airways remained low. There were changes of alveolitis in bronchoalveolar lavage fluid on fiber optic bronchoscopy, and in 11 cases positive MIC-specific antibodies to IgM, IgG, and IgE were demonstrated. On follow up, only 48% of the subjects were clinically stable, while 50% showed fluctuations. Thirty-two percent of the subjects had lung function fluctuations. Detailed sequential behavior over 2-4 years was predicted for dyspnea, forced vital capacity, maximum expiratory flow rate (0.25-0.75), peak expiratory flow rate, VO2, and depression score. A model for clinical behavior explained a total variance of 52.4% by using the factors of cough, PCO2 and X-ray zones in addition to above five parameters. The behavior of the railway colony group (1640 patients) revealed a similar pattern of illness. When this observed pattern of changes was transferred to the affected Bhopal city sections (with an equitable age-sex distribution), our model results were again validated. Thus the picture of MIC-induced disease seems similar despite the differences for age-sex and initial severity of illness in our cohort and in the population of Bhopal city as predicted by our model.  (+info)

Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. (30/207)

Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct-ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.  (+info)

Exaggerated bronchoconstriction due to inhalation challenges with occupational agents. (31/207)

Inhalation challenges with occupational agents are used to confirm the aetiology of occupational asthma. It has been proposed that using closed-circuit equipment rather than the realistic challenge method would improve the methodology of these tests. Changes in forced expiratory volume in one second (FEV1) were examined in 496 subjects with "positive specific inhalation challenges", i.e. changes in FEVI of > or = 20% after exposure to an occupational agent, including 357 subjects exposed by the realistic method, 108 using the closed-circuit method and 31 by both methods. For immediate reactions, 18 of 95 (19%) showed changes in FEV1 of > or = 30% with the closed-circuit method, whereas a significantly larger proportion, i.e. 77 of 200 (38.5%), showed such changes using the realistic method. As regards nonimmediate reactions, changes in FEV1 of > or = 30% occurred in 16 of 43 (37%) cases with the closed-circuit method as compared to a larger proportion, i.e. 87 of 180 (48%) cases, using the realistic method. This favourable effect was significantly more pronounced in workers with higher levels of bronchial hyperresponsiveness to methacholine. It is concluded that, for agents that can be generated using the closed-circuit method, use of such apparatus results in a smaller proportion of exaggerated bronchoconstriction than does the realistic method, this being particularly true for low-molecular weight agents.  (+info)

Cancer incidence and mortality of isocyanate exposed workers from the Swedish polyurethane foam industry: updated findings 1959-98. (32/207)

AIMS: To assess whether cancer incidence and mortality in chronic obstructive lung diseases were increased in the Swedish polyurethane foam industry cohort, updated with 11 more years of follow up. METHODS: The mortality and cancer incidence (1959-98) experienced by a cohort of 4175 male and female employees employed for at least one year in the period 1959-87 at one of nine Swedish polyurethane foaming plants were investigated. Comparisons were based on calendar year, sex, and five-year age group specific mortality and incidence rates for Sweden. Workplaces and job tasks were categorically assessed for exposure to toluene diisocyanate (TDI) and methylene diphenyldiisocyanate (MDI) by occupational hygienists. RESULTS: Fewer cancer cases than expected were observed, but the lung cancer incidence was enhanced in women. Women with "apparent exposure" to TDI or MDI did not, however, have a higher lung cancer incidence than those with "no or low exposure". Moreover, a nested case referent study did not find that polyurethane dust exposure had been more prevalent among the female lung cancer cases than among referents. No increased mortality in chronic obstructive lung diseases was observed in the cohort. CONCLUSIONS: Results support the findings from two other cohort studies of an increased lung cancer risk among female workers in the polyurethane foam manufacturing industry. Chance or confounding from smoking are not obvious explanations for the coherent findings. However, the study was not able to link isocyanate exposed employment with lung cancer risk.  (+info)