Biomarkers Predicting Isocyanate-Induced Asthma

Three diisocyanates can cause occupational asthma (OA): toluene diisocyanate (TDI), 4,4 diphenylmethane diisocyanate (MDI), and 1,6-hexamethylene diisocyanate (HDI). We analyzed potential biomarkers of isocyanate-induced OA, based on investigated immunologic, genetic, neurogenic, and protein markers, because there is no serological testing method. The prevalence of serum IgG to cytokeratin (CK)18 and CK19 in TDI-OA was significantly higher than in controls, although the prevalence of these antibodies was too low for them to be used as biomarkers. Another candidate biomarker was serum IgG to tissue transglutaminase (tTG), because the prevalence of serum specific IgG to tTG was significantly higher in patients with TDI-OA than in controls. The human leukocyte antigen (HLA) DRB1*1501-DQB1*0602-DPB1*0501 haplotype may be used as a genetic marker for TDI-OA in Koreans via enhanced specific IgE sensitization in exposed subjects. The genetic polymorphisms of catenin alpha 3, alpha-T catenin (CTNNA3) were significantly associated with TDI-OA. Additionally, examining the neurokinin 2 receptor (NK2R) 7853G>A and 11424 G>A polymorphisms, the NK2R 7853GG genotype had higher serum vascular endothelial growth factor (VEGF) levels than the GA or AA genotypes among Korean workers exposed to TDI. To identify new serologic markers using a proteomic approach, differentially expressed proteins between subjects with MDI-OA and asymptomatic exposed controls in a Korean population showed that the optimal serum cutoff levels were 69.8 ng/mL for ferritin and 2.5 microg/mL for transferrin. When these two parameters were combined, the sensitivity was 71.4% and the specificity was 85.7%. The serum cytokine matrix metalloproteinase-9 (MMP-9) level is a useful biomarker for identifying cases of TDI-OA among exposed workers. Despite these possible biomarkers, more effort should be focused on developing early diagnostic biomarkers using a comprehensive approach based on the pathogenic mechanisms of isocyanate-induced OA.

[Evaluation of concentration methylene diphenyl diisocyanate [MDI] in the polyurethane industries of Iran]

MDI [Methylene Diphenyl Diisocyanate] is a high tonnage product, which comprises about 90% of the total diisocyanate in the market. Polyurethanes are produced by reacting diisocyanate with polyols and other chemicals. They are known as respiratory tract and skin sensitizers and are the most common cause of occupational asthma in the world [NIOSH 1994]. On this subject, evaluation of MDI concentration in the polyurethane factories by HPLC, and is worthy to determine its pollution level. All sampling methods have some limitation, therefore, this survey the method of NIOSH 5522 has been used as a standard sampling and analyzing method t then, we utilize SPSS V.13 software, for our data to be analyzed for statistical discussion. Results showed that all of the polyurethane industries under this study have high concentration, rate of more than 80 micro g/m[3]. There was a strong correlation between indoor temperature and high MDI concentration, thus, it implies that various temperatures may be increased, in addition to working time ensuring it has a good correlation with MDI concentration. It also implies that when ever they have more working time comparatively, in turn, they have high exposure rate of MDI pollutant in the workplace. To obtain a better way for determination of MDI concentration in the workplace is using biological monitoring as a standard method to survey the exposure to diisocyanate, by using metabolite determination, it will be easier to collect and analyze more samples as the sampling is not as time-consuming as air monitoring

Effect of Amino Acids and Albumin on Damage Induced by Cyanate in Osteoblast / 대한신장학회지

PURPOSE: Cyanate, known as one of the uremic toxins and derived spontaneously from urea, has several effects on the biologic substances including erythropoietin, antioxidant and ceruloplasmin. To find out the protective materials from the hazardous effect of cyanate in osteoblast, we added twenty amino acids, albumin globulin and hemoglobin in the culture media containing osteoblastic cells with cyanate. METHODS: Osteoblastic ROS 17/2.8 cells, exposed to various concentrations of sodium cyanate, were used to analyze for the cytotoxicity. The cyanate-induced cytotoxicity was assessed by the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay by measuring the absorbance of the reaction solution at 570 nm. Viability of the treated cells was expressed as A570 of sample/A570 of control. The degree of the carbamylation was measured using trinitrobenzenesulphonic acid. The degree of the carbamylation in amino acid was about 50% in average. RESULTS: The degree of the carbamylation in albumin was increased depending on the incubation time with cyanate and the concentration of the cyanate. The degree of the carbamylation in globulin and hemoglobin was nearly zero. Asp, Glu, Leu, Trp and Tyr among the twenty amino acids revealed the protective effect against the damage induced by cyanate. And only albumin among the three proteins revealed the protective effect. CONCLUSION: On the basis of these results, Asp, Glu, Leu, Trp, Tyr and albumin are useful tools for the protection against damages by cyanate carbamylation.

Anti-tumour promoting activity of diphenylmethyl selenocyanate against two-stage mouse skin carcinogenesis.

Epidemiological, clinical and experimental evidence collectively suggests that Se in different inorganic and organic forms provides a potential cancer chemopreventive agent, active against several types of cancer. It can exert preventive activity in all the three stages of cancer: initiation, promotion and progression. Literature reports revealed that organoselenocyanates have more potential as chemopreventive agents than inorganic forms due to their lower toxicity. In our previous report we showed chemopreventive efficacy of diphenylmethyl selenocyanate during the initiation and pre- plus post-initiation phases of skin and colon carcinogenesis process. The present study was undertaken to explore the anti-tumour promoting activity of diphenylmethyl selenocyanate in a 7,12-dimethylbenz (a) anthracene (DMBA)-croton oil two-stage skin carcinogenesis model. The results obtained showed significant (p<0.01) reduction of the incidence and number of skin papillomas, precancerous skin lesions, along with significant (p<0.01) elevation of phase II detoxifying enzymes (GST, Catalase and SOD) and inhibition of lipid peroxidation in liver and skin. Thus, the present data strongly suggest that diphenylmethyl selenocyanate also has the potential to act as anti-tumour promoter agent in a two-stage skin carcinogenesis mouse model, pointing to possible general efficacy.

Thiocyanate degradation by pure and mixed cultures of microorganisms

Uma cultura mixta e uma linhagem bacteriana pura foram isoladas de um bioreator para tratamento de tiocianato. As culturas removeram 5mM de tiocianato do meio em 36 horas. A cultura mixta foi capaz de tolerar concentrações superiores a 60mM. A eficiência da degradação de tiocianato diminuiu quando as células foram imobilizadas.

Inhibition of DMBA-croton oil two-stage mouse skin carcinogenesis by diphenylmethyl selenocyanate through modulation of cutaneous oxidative stress and inhibition of nitric oxide production.

Selenium, an essential micronutrient, plays important roles against different diseases, including several types of cancer. In the present study, antioxidative and chemopreventive properties of a synthetic organoselenium compound, diphenylmethyl selenocyanate, were evaluated with a 7,12-dimethylbenz (a) anthracene - croton oil induced two-stage mouse skin carcinogenesis model. The compound was administered orally to carcinogen-treated mice at two different non-toxic doses, 2mg/kg. b.w. and 3mg/kg. b.w. Significant inhibition in the incidence of papilloma formation (53-80%) as well as in the cumulative numbers of papillomas per papilloma bearing mouse were observed in the treated groups as compared to the carcinogen control group. The compound was also found to upregulate significantly different phase II detoxifying enzymes such as glutathione-S-transferase (p<0.01) and superoxide dismutase (p<0.01) in skin cytosol when measured after 15 days and also after 12 weeks of the first 7,12-dimethylbenz (a) anthracene treatment. Lipid peroxidation measured with reference to thiobarbituric acid reactive substances in skin microsomes was significantly inhibited (p<0.05) in a dose dependent manner by diphenylmethyl selenocyanate. Considerable inhibition of the level of nitric oxide production in peritoneal macrophages was observed after 12 weeks (p<0.05). Thus the compound appears to exert chemopreventive activity in terms of papilloma formation, which may be through modulation of cutaneous lipid peroxidation, the phase II detoxifying enzyme system and nitric oxide production.

Sodium cyanate: from a promising therapeutic agent to a research tool in high altitude physiology

Sodium cyanate (NaOCN) first appeared on the biomedical scene as a potential therapeutic agent for sickle-cell disease. Although it did not fulfill its early promise in the clinic, it proved to be useful as a pharmacological tool in physiological research, particularly in the physiology of oxygen transport. NaOCN has been especially valuable in the area of investigation which is reviewed here: the study of oxygen transport, both in normoxic and in hypoxic conditions, in experimental models in which NaOCN was used to induce a shift to the left of the oxygen dissociation curve. The classical idea is that a low Hb-O2 affinity is of adaptive value for life at high altitudes but it has been challenged by several pieces of evidence. One of them is the demonstration of increased survival in hypoxic hypoxia of animals with a high Hb-O2 affinity induced by NaOCN. We also discuss the advantages and potentially confounding factors which should be taken into consideration when interpreting results of studies in which the oxygen dissociation curve has been modified by administration of NaOCN

In vivo effect of cyanate on serum and eye lens in rat.

Supplementation of cyanate in rats caused a significant decrease in serum GSH and increase in calcium and phosphate level both in serum and lens. Consequently, these changes led to induce acidosis uremia in serum and hypercalcemia and hyperphosphatemia in lens which may be possible causing factor for cataract.

Inhalation toxicity of methylisocyanate: assessment of germ cell mutagenicity and reproductive effects in rats.

Adult male Wistar rats were exposed to methylisocyanate (MIC, 3.2 mg/l, single inhalation exposure for 8 min under static condition) or ethyl methanesulphonate (EMS, 150 mg/kg, single ip dose) for the assessment of germ cell mutagenicity and reproductive effects. Sequential matings of treated males with normal females on days 1-7, 8-14 and 15-21 post-exposure did not indicate any induction of dominant lethal mutation (increased frequency of preimplantation losses and early fetal deaths) by MIC but it was significantly induced by EMS as compared to respective controls. Males, necropsied after 21 days of exposure, showed no effect of MIC on epididymal sperm density and morphology. EMS also had no effect on sperm density but it significantly induced morphological abnormalities in sperm as compared to untreated controls. There was an acute and transitional reduction in reproductive performance (10-21%) of MIC-exposed males during days 1-14 post-exposure followed by recovery to the normal level during days 15-21 post-exposure. The progeny of MIC-exposed males was also normal in terms of litter size, litter weight, neonatal survival and body weight gain in litters up to 10 days post-partem. It is concluded with the evidence at hand that the observed failure of MIC to cause germ cell mutagenicity is related to its poor biodistribution to the target site(s) and a transient reduction in the reproductive performance of MIC-exposed males is a result of general stress and disconsolate copulation.

Pregnancy outcome in women exposed to toxic gas at Bhopal.

A study was undertaken to compare the effects of exposure to the toxic gas in pregnant women in Bhopal with pregnant women in a similar, unexposed area. A high incidence of spontaneous abortions (24.2%) in the pregnant women exposed to the toxic gas was observed as compared to those in the control area (5.6%). Other indices of adverse reproductive outcome, such as the rate of still birth and congenital malformation were not found to be different. The perinatal and neonatal mortalities were significantly higher in the affected area (6.9 and 6.1% respectively), as compared to the control area (5.0 and 4.5% respectively).

Bronchoalveolar lavage study in victims of toxic gas leak at Bhopal.

Bronchoalveolar lavage using flexible fibreoptic bronchoscope was carried out in 50 patients 1-2 1/2 yr after exposure to the 'toxic gas' at Bhopal. Thirty six patients in the analysis were categorised into 3 groups (viz., mild, moderate and severe), depending upon the severity of exposure. There was an increase in cellularity in the lower respiratory tract (alveolitis) of the severely exposed patients (in both smokers and non-smokers), compared to normals (P less than 0.05). The increase in cellularity in severely exposed non-smokers was due to abnormal accumulation of macrophages (P less than 0.01), and in severely exposed smokers, to macrophages (P less than 0.01) and neutrophils (P less than 0.05). Mild and moderately exposed patients did not show significant change in cellularity in lower respiratory tract, compared to normal individuals (P greater than 0.2). There was a trend towards increasing cellularity, as the severity increased (P less than 0.0001) and higher numbers of total cells were seen in severely exposed smokers, suggesting that smoking is a risk factor. It appears, therefore, that subjects severely exposed to the toxic gas at Bhopal may have a subclinical alveolitis characterised by accumulation and possibly activation of macrophages in the lower respiratory tract. Smokers, who were exposed to the gas had in addition, accumulation of neutrophils.

Effect of subacute exposure to methyl isocyanate on testicular histomorphology in mice.

Mice exposed to methyl isocyanate (MIC; 134 mg.m-3 for 30 min = 4020 mg.min-1.m-3) showed a marked loss of body weight after 24 hr and the mean body weight of the exposed group was significantly less than the control, even 15 days after the exposure. No significant change was observed on relative testicular weight. Spermatozoa in the seminiferous tubules disappeared 3 days post exposure. Primary and secondary spermatocytes were hypertrophied. Normalization occurred after 15 days.