RESUMO
The apoptotic/necrotic changes in isolated human peripheral blood mononuclear cells (MNCs) subjected to hydrogen peroxide (H2O2), cyanate (NaOCN) and their combination were examined. The mitochondrial potential (ΔΨm), the activities of caspases (-2, -3, -6, -8 and -9) and the level of carbonyls and amino groups in proteins were determined and DNA fragmentation. Apoptotic or necrotic cells were identified by fluorescence microscopy using double staining with Hoechst 33258/propidium iodide. Treatment of MNCs with NaOCN (1 mmol/L and 2 mmol/L), alone and in combination with H2O2 (100 µmol/L), led to a significant decrease in the content of amine groups and a significant increase in the carbonyl level of MNCs in comparison with the control. Measurements taken at three time points (30, 60 and 150 min) showed a significant decrease in ΔΨm in MNCs incubated with H2O2, cyanate and their combination. The highest decrease in ΔΨm was observed after 150 min, when a combination of NaOCN and H2O2 was applied. We observed significant increases in the activities of caspases-2 and -3 in cells exposed to H2O2 and the combination of NaOCN and H2O2. An increase in caspase-2 but not in caspase-3 activity was noted in cells incubated with cyanate. A significant increase in caspase-9 activity in MNCs was observed in all arrangements of tested compounds in comparison with the control. In H2O2-treated cells, a higher level of necrotic cells was noted in comparison to apoptotic cells, whereas carbamylation led mainly to apoptotic cell death. The combination of cyanate and H2O2 increased the population of necrotic cells.
Assuntos
Carbamatos/farmacologia , Linfócitos/efeitos dos fármacos , Proteínas/metabolismo , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Cianatos/toxicidade , Ativação Enzimática/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/toxicidade , Leucócitos Mononucleares/efeitos dos fármacos , Microscopia de Fluorescência , Oxirredução , Proteínas/efeitos dos fármacos , Padrões de ReferênciaRESUMO
It is well known that oxidative stress and carbamylation alter macromolecule properties and functions. We evaluated the influence of sodium cyanate (NaOCN) and the combination of cyanate and hydrogen peroxide (H2O2) on nonenzymatic antioxidant capacity (NEAC), total thiols, reduced glutathione (GSH) and hydroperoxide level in mononuclear blood cells (MNCs). We also examined plasma membrane properties of MNCs using the spin labeling method in EPR spectroscopy (electron paramagnetic resonance spectroscopy). We showed that MNCs are resistant to cyanate treatment up to a concentration of 2mM (survival test). On the other hand, a significant loss of antioxidant defense of cells, e.g. NEAC upon NaOCN, H2O2 and the combination of cyanate and hydrogen peroxide was observed. Carbamylation slightly decreased GSH and the free thiol level, but H2O2 and its combination with NaOCN lead to a decrease in their amounts. A markedly higher level of hydroperoxides was only observed in the cells treated with H2O2. We found a significant decrease in lipid membrane fluidity at the depth of 12th and 16th carbon atoms of fatty acids in lymphocytes treated with cyanate or H2O2. The combination of both substances acted synergistically and induced profound changes in comparison to cyanate and hydrogen peroxide used alone.
Assuntos
Cianatos/toxicidade , Peróxido de Hidrogênio/toxicidade , Linfócitos/efeitos dos fármacos , Estresse Oxidativo , Processamento de Proteína Pós-Traducional , Membrana Celular/efeitos dos fármacos , Membrana Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Sinergismo Farmacológico , Glutationa/metabolismo , Humanos , Linfócitos/metabolismo , Linfócitos/fisiologia , Fluidez de Membrana/efeitos dos fármacos , Compostos de Sulfidrila/metabolismoRESUMO
Diisocyanates, reactive chemicals used to produce polyurethane products, are the most common causes of occupational asthma. The aim of this study is to identify susceptibility gene variants that could contribute to the pathogenesis of diisocyanate asthma (DA) using a Genome-Wide Association Study (GWAS) approach. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed in 74 diisocyanate-exposed workers with DA and 824 healthy controls using Omni-2.5 and Omni-5 SNP microarrays. We identified 11 SNPs that exceeded genome-wide significance; the strongest association was for the rs12913832 SNP located on chromosome 15, which has been mapped to the HERC2 gene (p = 6.94 × 10(-14)). Strong associations were also found for SNPs near the ODZ3 and CDH17 genes on chromosomes 4 and 8 (rs908084, p = 8.59 × 10(-9) and rs2514805, p = 1.22 × 10(-8), respectively). We also prioritized 38 SNPs with suggestive genome-wide significance (p < 1 × 10(-6)). Among them, 17 SNPs map to the PITPNC1, ACMSD, ZBTB16, ODZ3, and CDH17 gene loci. Functional genomics data indicate that 2 of the suggestive SNPs (rs2446823 and rs2446824) are located within putative binding sites for the CCAAT/Enhancer Binding Protein (CEBP) and Hepatocyte Nuclear Factor 4, Alpha transcription factors (TFs), respectively. This study identified SNPs mapping to the HERC2, CDH17, and ODZ3 genes as potential susceptibility loci for DA. Pathway analysis indicated that these genes are associated with antigen processing and presentation, and other immune pathways. Overlap of 2 suggestive SNPs with likely TF binding sites suggests possible roles in disruption of gene regulation. These results provide new insights into the genetic architecture of DA and serve as a basis for future functional and mechanistic studies.
Assuntos
Asma/genética , Cianatos/toxicidade , Estudo de Associação Genômica Ampla , Doenças Profissionais/genética , Asma/induzido quimicamente , HumanosRESUMO
BACKGROUND: Cyanate is a uremic toxin formed principally via spontaneous urea biodegradation. Its active isoform, isocyanate, is capable of reaction with proteins by N and S carbamoylation, which influences their structure and function. Sulfurtransferases implicated in anaerobic cysteine transformation and cyanide detoxification belong to the enzymes possessing SH groups in their active centers. The present studies aimed to demonstrate the effect of cyanate and lipoic acid on the activity of these enzymes as well as on the level of antioxidants and prooxidants in the rat heart. METHODS: Wistar rats, which received intraperitoneal injections of cyanate and lipoic acid alone and in combination were sacrificed 2.5 h after the first injection. The hearts were isolated and homogenized in phosphate buffer and next biochemical assays were performed comprising determination of the level of glutathione, malondialdehyde and sulfane sulfur and the activity of antioxidant enzymes as well as glutathione S-transferase and gamma glutamyl transferase. RESULTS: Sulfurtransferases and glutathione S-transferase were deactivated by cyanate treatment. It was accompanied by the decreased level of glutathione and sulfane sulfur and the increased level of reactive oxygen species and malondialdehyde. In parallel, antioxidant enzymes: catalase, glutathione peroxidase and gamma glutamyl transferase were activated under such circumstances. Lipoic acid, administered in combination with cyanate prevented the decrease in the level of glutathione and reduction of a pool of sulfane sulfur-containing compounds, concomitantly preserving the activity of antioxidant enzymes. CONCLUSIONS: Since uremia, characterized by the elevated cyanate/isocyanate level, is accompanied by frequent cases of cardiovascular diseases, the addition of lipoic acid to the therapy seems promising in prophylaxis of heart diseases in uremic patients.
Assuntos
Cianatos/toxicidade , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Ácido Tióctico/farmacologia , Animais , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Masculino , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
Diisocyanates, commonly used in the production of polyurethane foams, paints, elastomers, varnishes, and coatings, are considered among the most hazardous inhalation toxicants. The present report describes 2 unusual cases of mortality in pigeon chicks associated with nesting material contaminated by diisocyanates. Case 1 was submitted by a racing pigeon breeder who had lost all the hatchlings (n = 125) following replacement of the nesting material with a different lot. All adult birds appeared healthy, and hatchability was not significantly affected, but hatchlings became lethargic and dyspneic after a day of hatch. At necropsy, dark wet lungs were found in the hatchlings. Case 2 was submitted by a show-roller pigeon breeder. In this case, the owner reported lower hatchability, and all hatchlings (approximately 100) died within 2 days of hatching with clinical signs similar to the first case. Necropsy did not reveal any significant findings. For both cases, nesting materials were screened for toxic compounds using gas chromatography-mass spectrometry. Toluene-2,4-diisocyanate (approximately 190-290 ppm) and 4,4'-methylene diphenyl diisocyanate (unquantified) were detected in the nesting pads. While there is very limited information on toxicosis in birds, there are reports of inhalant exposure of diisocyanates causing pulmonary edema and death in various mammalian species. Although cause-effect relationship of mortality and the nesting material was not established in the present cases, the presence of toxic compounds in the nesting materials is a cause for concern. Further investigation is needed to determine the prevalence and toxicity of diisocyanates-contaminated nesting material in avian species.
Assuntos
Doenças das Aves/induzido quimicamente , Columbidae , Cianatos/toxicidade , Comportamento de Nidação , Animais , Doenças das Aves/mortalidadeRESUMO
OBJECTIVES: To identify possible cases of occupational asthma and assess accidental skin and inhalation exposures to aliphatic diisocyanates. METHODS: Seventy-three employees from two plants, manufacturing or producing aliphatic diisocyanates, were surveyed using a detailed respiratory history questionnaire with additional questions on accidental skin and inhalation exposures. Further reviews of medical records and interviews were used to determine whether any of 15 employees with questionable responses had developed occupational asthma. RESULTS: No cases of occupational asthma were identified. Nevertheless, many employees reported occasional accidental unprotected skin exposures and/or detecting the odor of 1,6-hexamethylene diisocyanate or isophorone diisocyanate. CONCLUSIONS: Consistent with a previous study, no cases of occupational asthma were identified from exposure to 1,6-hexamethylene diisocyanate, isophorone diisocyanate, methylene bis(4-cyclohexyl isocyanate), or their polyisocyanates even though many employees reported detection of odors (93%) or skin exposures (53%).
Assuntos
Asma Ocupacional/diagnóstico , Exposição por Inalação/efeitos adversos , Isocianatos/toxicidade , Exposição Ocupacional/efeitos adversos , Poluentes Ocupacionais do Ar/toxicidade , Asma Ocupacional/etiologia , Indústria Química , Estudos Transversais , Cianatos/toxicidade , Feminino , Humanos , Masculino , Anamnese , Odorantes , Pele , Inquéritos e QuestionáriosRESUMO
Food (cassava) linamarin is metabolized into neurotoxicants cyanide and cyanate, metabolites of which we sought to elucidate the differential toxicity effects on memory. Young 6-8 weeks old male rats were treated intraperitoneally with either 2.5 mg/kg body weight (bw) cyanide (NaCN), or 50 mg/kg bw cyanate (NaOCN), or 1 µl/g bw saline, daily for 6 weeks. Short-term and long-term memories were assessed using a radial arm maze (RAM) testing paradigm. Toxic exposures had an influence on short-term working memory with fewer correct arm entries (F(2, 19) = 4.57 p < 0.05), higher working memory errors (WME) (F(2, 19) = 5.09, p < 0.05) and longer RAM navigation time (F(2, 19) = 3.91, p < 0.05) for NaOCN relative to NaCN and saline treatments. The long-term working memory was significantly impaired by cyanide with fewer correct arm entries (F(2, 19) = 7.45, p < 0.01) and increased working memory errors (F(2, 19) = 9.35 p < 0.05) in NaCN relative to NaOCN or vehicle treated animals. Reference memory was not affected by either cyanide or cyanate. Our study findings provide an experimental evidence for the biological plausibility that cassava cyanogens may induce cognition deficits. Differential patterns of memory deficits may reflect the differences in toxicity mechanisms of NaOCN relative to NaCN. Cognition deficits associated with cassava cyanogenesis may reflect a dual toxicity effect of cyanide and cyanate.
Assuntos
Cianatos/toxicidade , Transtornos da Memória/induzido quimicamente , Cianeto de Sódio/toxicidade , Animais , Cianatos/administração & dosagem , Cianatos/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Masculino , Manihot/efeitos adversos , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Plantas Tóxicas/efeitos adversos , Ratos , Ratos Sprague-Dawley , Cianeto de Sódio/administração & dosagem , Cianeto de Sódio/farmacologia , Aumento de Peso/efeitos dos fármacosRESUMO
Hexamethylene diisocyanate (HDI) is a reactive chemical used in the commercial production of polyurethanes. Toxic effects in rodents exposed to HDI vapor primarily occur in the nasal passages, yet some individuals exposed occupationally to concentrations exceeding current regulatory limits may experience temporary reduction in lung function and asthma-like symptoms. Knowledge of interspecies differences in respiratory tract dosimetry of inhaled HDI would improve our understanding of human health risks to this compound. HDI uptake was measured in the upper respiratory tract of anesthetized Fischer-344 rats. Nasal uptake of HDI was >90% in rats at unidirectional flow rates of 150 and 300 ml/min and a target air concentration of 200 ppb. Uptake data was used to calibrate nasal and lung dosimetry models of HDI absorption in rats and humans. Computational fluid dynamics (CFD) models of the nasal passages were used to simulate inspiratory airflow and HDI absorption. Transport of HDI through lung airways was simulated using convection-diffusion based mass transport models. HDI nasal uptake of 90% and 78% was predicted using the rat and human nasal CFD models, respectively. Total respiratory tract uptake was estimated to be 99% in rats and 97% in humans under nasal breathing. Predicted human respiratory uptake decreased to 87% under oral breathing conditions. Absorption rates of inhaled HDI in human lung airways were estimated to be higher than the rat due to lower uptake in head airways. Model predictions demonstrated significant penetration of HDI to human bronchial airways, although absorption rates were sensitive to breathing style.
Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Cianatos/toxicidade , Pulmão/efeitos dos fármacos , Mucosa Respiratória/efeitos dos fármacos , Poluentes Ocupacionais do Ar/farmacocinética , Animais , Cianatos/farmacocinética , Relação Dose-Resposta a Droga , Humanos , Exposição por Inalação , Isocianatos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Modelos Biológicos , Ratos , Ratos Endogâmicos F344 , Mucosa Respiratória/metabolismo , Especificidade da Espécie , VolatilizaçãoRESUMO
Diisocyanates are a common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants of antioxidant defense genes, glutathione S-transferases (GSTM1, GSTT1, GSTM3, GSTP1), manganese superoxide dismutase (SOD2), and microsomal epoxide hydrolase (EPHX1) are associated with increased susceptibility to diisocyanate-induced asthma (DA). The main study population consisted of 353 Caucasian French-Canadians from among a larger sample of 410 diisocyanate-exposed workers in three groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95); symptomatic diisocyanate workers with a negative SIC (DA(-), n = 116); and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5'-nuclease PCR assay. The SOD2 rs4880, GSTP1 rs1695, and EPHX1 rs2740171 variants were significantly associated with DA in both univariate and multivariate analyses. In the first logistic regression model comparing DA(+) and DA(-) groups, SOD2 rs4880, GSTM1 (null), GSTP1 rs762803, and EPHX1 rs2854450 variants were associated with DA (p = 0.004, p = 0.047, p = 0.021, p <0.001, respectively). Genotype combinations GSTT1*GSTP1 rs762803, GSTM1*EPHX1 rs2854450, EPHX1 rs2740168*EPHX1 rs1051741, and GSTP1 rs762803*EPHX1 rs2740168 were also associated with DA in this model (p = 0.027, p = 0.002, p = 0.045, p = 0.044, respectively). The GSTP1 rs1695 and EPHX1 rs1051741 and rs2740171 variants showed an association with DA in the second model comparing DA(+) and AW groups (p = 0.040, p = 0.019, p = 0.002, respectively). The GSTM3 rs110913*EPHX1 rs1051741 genotype combination was also associated with DA under this model (p = 0.042). The results suggest that variations in SOD2, GST, and EPHX1 genes and their interactions contribute to DA susceptibility.
Assuntos
Antioxidantes/metabolismo , Asma/induzido quimicamente , Cianatos/toxicidade , Predisposição Genética para Doença , Variação Genética , Isocianatos/toxicidade , Tolueno 2,4-Di-Isocianato/toxicidade , Adulto , Asma/genética , Canadá , Feminino , Humanos , MasculinoRESUMO
The vast majority of long-term complications in transplanted patients are associated with cardiovascular disease. Previously, an alternative and dominant mechanism for cyanate formation in atherosclerotic lesions has been discovered. This study was designed to determine the effect of cyanate on insulin secretion in cultured pancreatic ß cells (INS-1 cells). The cytotoxicity of cyanate was determined by 3-(4,5-Desethyithiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Insulin secretion was measured by ELISA in cyanate-treated INS-1 cells. Reactive oxygen species (ROS) generation was also determined by measuring the fluorescent oxidized product of 2,7-dichlorefluorescein in cyanate-treated INS-1 cells. FACS analysis was carried out to determine the effect of cyanate on the apoptosis of INS-1 cells. Firstly, we found that cyanate, within concentration ranges in which no cytotoxic effect was observed (0.01, 0.1 and 1.0 mM), decreased insulin secretion dose-dependently in both non-glucose-stimulated and glucose-stimulated INS-1 cells. Cyanate at a 1.0 mM concentration inhibited insulin secretion by more than 50% in non-glucose-stimulated cells and glucose (5 and 10 mM)-stimulated cells. Cyanate, however, did not affect ROS generation. Furthermore, no pro- or anti-apoptotic effect was observed in cyanate-treated INS-1 cells. The results in this study suggest the possible inhibitory effect of cyanate on insulin secretion in INS-1 pancreatic ß cells. The inhibitory effect was not mediated either by ROS generation or by apoptosis. Further studies to determine the underlying mechanisms will be of benefit.
Assuntos
Cianatos/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Cianatos/toxicidade , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Occupational diisocyanate-induced extrinsic allergic alveolitis (EAA) is a rare and probably underestimated diagnosis. Two acute occupational EAA cases have been described in this context, but neither of them concerned hexamethylene diisocyanate (HDI) exposure. AIMS: To investigate the cause of a life-threatening EAA arising at work in a healthy 30-year-old female paint quality controller. METHODS: Occupational medical assessment, workplace evaluation, airborne and biological monitoring and immunodermatological tests. RESULTS: Diagnosis of EAA relied on congruent clinical and radiological information, confirmed occupational HDI exposure and positive IgG antibodies and patch tests. The patient worked in a small laboratory for 7 years, only occasionally using HDI-containing hardeners. While working with HDI for 6 h, she developed breathlessness, rapidly progressing to severe respiratory failure. Workplace HDI airborne exposure values ranged from undetectable levels to 4.25 p.p.b. Biological monitoring of urinary hexamethylene diamine in co-workers ranged from <1.0 to 15.4 µg/g creatinine. Patch tests 8 months later showed delayed skin reaction to HDI at 48 h. Subsequent skin biopsy showed spongiotic dermatitis with infiltration of CD4(+) and CD8(+) T cells. CONCLUSIONS: We believe this is the first reported case of acute life-threatening EAA following exposure to HDI. Low concentrations of airborne HDI and relatively high urinary hexamethylene diamine suggest significant skin absorption of HDI could have significantly contributed to the development of this acute occupational EAA.
Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Alveolite Alérgica Extrínseca/induzido quimicamente , Cianatos/toxicidade , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Pintura/toxicidade , Adulto , Diagnóstico Diferencial , Feminino , Humanos , IsocianatosRESUMO
We investigated the utility of 1,6-hexamethylene diamine (HDA) hemoglobin adducts as biomarkers of exposure to 1,6-hexamethylene diisocyanate (HDI) monomer. Blood samples from 15 spray painters applying HDI-containing paint were analyzed for hemoglobin HDA (HDA-Hb) and N-acetyl-1,6-hexamethylene diamine (monoacetyl-HDA-Hb) by GC-MS. HDA-Hb was detected in the majority of workers (≤1.2-37 ng/g Hb), whereas monoacetyl-HDA-Hb was detected in one worker (0.06 ng/g Hb). The stronger, positive association between HDA-Hb and cumulative HDI exposure (r(2) = 0.3, p < 0.06) than same day exposure (p ≥ 0.13) indicates long-term elimination kinetics for HDA-Hb adducts. This association demonstrates the suitability of HDA-Hb adducts for further validation as a biomarker of HDI exposure.
Assuntos
Poluentes Ocupacionais do Ar/sangue , Cianatos/sangue , Hemoglobinas/análise , Exposição Ocupacional , Poluentes Ocupacionais do Ar/toxicidade , Biomarcadores/sangue , Cianatos/toxicidade , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Isocianatos , Pintura/toxicidadeRESUMO
Chronic renal failure (CRF) patients have an increased plasma level of urea, which can be a source of cyanate. This compound can cause protein carbamoylation thereby changing biological activity of proteins. Therefore, in renal failure patients, cyanate can disturb metabolism and functioning of the liver. This work presents studies demonstrating that the treatment of rats with cyanate alone causes the following changes in the liver: (1) inhibition of rhodanese (TST), cystathionase (CST) and 3-mercaptopyruvate sulfotransferase (MPST) activities, (2) decrease in sulfane sulfur level (S*), (3) lowering of nonprotein sulfhydryl groups (NPSH) group level, and (4) enhancement of prooxidant processes (rise in reactive oxygen species (ROS) and malondialdehyde (MDA) level). This indicates that cyanate inhibits anaerobic cysteine metabolism and shows prooxidant action in the liver. Out of the above-mentioned changes, lipoate administered with cyanate jointly was able to correct MDA, ROS and NPSH levels, and TST activity. It had no significant effect on MPST and CST activities. It indicates that lipoate can prevent prooxidant cyanate action and cyanate-induced TST inhibition. These observations can be promising for CRF patients since lipoate can play a dual role in these patients as an efficient antioxidant defense and a protection against cyanate and cyanide toxicity.
Assuntos
Antioxidantes/uso terapêutico , Cianatos/toxicidade , Cisteína/metabolismo , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/uso terapêutico , Uremia/prevenção & controle , Animais , Sulfeto de Hidrogênio/metabolismo , Falência Renal Crônica/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Terapia de Alvo Molecular , Oxidantes/toxicidade , Venenos/toxicidade , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/metabolismo , Tiossulfato Sulfurtransferase/metabolismo , Uremia/induzido quimicamente , Uremia/metabolismoRESUMO
Cyanate and its active form isocyanate are formed mainly in the process of nonenzymatic urea biodegradation. Cyanate is capable of protein S- and N-carbamoylation, which can affect their activity. The present studies aimed to demonstrate the effect of cyanate on activity of the enzymes implicated in anaerobic cysteine metabolism and cyanide detoxification and on glutathione (GSH) level and peroxidative processes in the kidney. In addition, we examined whether a concomitant treatment with lipoate, a dithiol that may act as a target of S-carbamoylation, can prevent these changes. The studies were conducted in Wistar rats. The animals were assigned to four groups, which received injections of physiological saline, cyanate (200 mg/kg), cyanate (200 mg/kg) + lipoate (100 mg/kg) and lipoate alone (100 mg/kg). The animals were killed 2 h after the first injection, the kidneys were isolated and kept at -80°C until biochemical assays were performed. Cyanate inhibited rhodanese (TST) and mercaptopyruvate sulfotransferase (MPST) activity, decreased GSH level and enhanced peroxidative processes in the kidney. All these changes were abolished by cyanate treatment in combination with lipoate.
Assuntos
Antioxidantes/farmacologia , Cianatos/toxicidade , Rim/efeitos dos fármacos , Ácido Tióctico/farmacologia , Animais , Cisteína/metabolismo , Glutationa/metabolismo , Rim/metabolismo , Peroxidação de Lipídeos , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Enxofre/metabolismo , Sulfurtransferases/metabolismo , Tiossulfato Sulfurtransferase/metabolismoRESUMO
BACKGROUND: Aliphatic polyisocyanates based on hexamethylene 1,6-diisocyanate (HDI) are components of lacquers, coatings, and spray paints. They are mainly composed of HDI trimers, but also contain larger oligomers, and minute amounts of HDI monomers (<1%). HDI trimers occur as biuret, isocyanurate and asymmetrical types. OBJECTIVES: We report on 4 patients with allergic contact dermatitis/contact allergy resulting from HDI-based polyisocyanates in polyurethane paints. METHODS: The patients were examined at the Finnish Institute of Occupational Health in 2000-2009. The first two patients were diagnosed by testing with their own polyurethane hardeners and ingredients of the hardeners. In 2002, HDI isocyanurate (HDI-IC) trimer was added to our isocyanate series, and the last two patients were screened with the series. RESULTS: Patient no. 1 was exposed and sensitized to HDI biuret trimer, patient no. 2 to HDI-IC trimer, and patient no. 4 to HDI asymmetrical trimer. Patient no. 3 was positive with HDI-IC trimer. He had been handling several paint hardeners containing HDI-based polyisocyanates, but the subtypes of the trimers remained unidentified. All 4 patients were negative with HDI monomer. CONCLUSIONS: HDI trimers are novel contact allergens in workers who handle polyurethane paints. The allergic reactions cannot be explained by sensitization to HDI monomer.
Assuntos
Dermatite Alérgica de Contato/etiologia , Dermatite Ocupacional/etiologia , Pintura/toxicidade , Poliuretanos/toxicidade , Adulto , Cianatos/toxicidade , Dermatite Alérgica de Contato/diagnóstico , Feminino , Humanos , Isocianatos , Masculino , Pessoa de Meia-Idade , Exposição OcupacionalRESUMO
OBJECTIVE: To identify if 1,6-hexamethylene diisocyanate (HDI) workers demonstrated an increased prevalence of occupational asthma or accelerated decline in pulmonary function. METHODS: Employees from two plants manufacturing or producing 1,6-HDI monomer and/or HDI polyisocyanates were matched to a control population by age, gender, race, and smoking status. A random coefficient regression analysis compared the decline in pulmonary function test values over time. Retrospective medical review was used to identify potential cases of occupationally induced asthma. RESULTS: No significantly accelerated annual decline in force expiratory volume after 1 second in the HDI exposure group compared to the matched control group was observed. No cases of adult onset asthma, beyond those present at time of hire, and no cases of occupational asthma were identified. CONCLUSIONS: This study provides support for the current American Conference of Governmental Industrial Hygienists threshold limit value time-weighted average of 5 ppb.
Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Asma/epidemiologia , Cianatos/toxicidade , Exposição Ocupacional/efeitos adversos , Respiração , Adulto , Asma/induzido quimicamente , Estudos de Coortes , Feminino , Humanos , Isocianatos , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
The polyisocyanates of 1,6-hexamethylene diisocyanate (HDI) find widespread commercial use as components of paints and in the formulation of light-stable polyurethane coating materials. This 2-year study assessed the oncogenicity of the diisocyanate monomer HDI in male and female Fischer-344 rats exposed 6 h/day, 5 days/week to mean analytical air concentrations of 0, 0.005, 0.025, and 0.164 ppm HDI. During the in-life phase, transient eye irritation was observed in 0.164 ppm males, and a slight body weight decrease (5%) in the 0.164 ppm females during the second year of exposure. There were no exposure-related effects on mortality. Compound-related, non-neoplastic histopathologic changes were limited to the respiratory tract and changes were characterized by epithelial tissue reaction to the acute irritant properties of HDI vapor. For tissues of the nasal cavity, the major histopathologic findings were degeneration of the olfactory epithelium characterized by destruction of the epithelial architecture often with narrowing or atrophy and occasional focal erosion or ulceration. In addition, there was variable degeneration of the respiratory epithelium with hyperkeratosis of the epithelium, epithelial and mucus secretory cell hyperplasia, squamous metaplasia, chronic-active inflammation, and errosive or ulcerative changes. These tissue effects along with a statistically significant decrease in body weight of female rats demonstrated attainment of a maximum tolerated dose. There was no evidence of progression of these changes in the nasal epithelium to neoplasia nor evidence of any compound-related neoplastic lesions for any of the other tissues examined. Therefore, it is concluded that HDI did not show a carcinogenic potential in this study.
Assuntos
Poluentes Atmosféricos/toxicidade , Carcinógenos/toxicidade , Cianatos/toxicidade , Irritantes/toxicidade , Poluentes Atmosféricos/classificação , Animais , Peso Corporal/efeitos dos fármacos , Testes de Carcinogenicidade , Carcinógenos/classificação , Cianatos/classificação , Traumatismos Oculares/induzido quimicamente , Feminino , Exposição por Inalação , Isocianatos , Longevidade/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Cavidade Nasal/efeitos dos fármacos , Cavidade Nasal/patologia , Ratos , Ratos Endogâmicos F344 , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/patologia , Testes de Toxicidade CrônicaRESUMO
Quantification of amines in biological samples is important for evaluating occupational exposure to diisocyanates. In this study, we describe the quantification of 1,6-hexamethylene diamine (HDA) levels in hydrolyzed plasma of 46 spray painters applying 1,6-hexamethylene diisocyanate (HDI)-containing paint in vehicle repair shops collected during repeated visits to their workplace and their relationship with dermal and inhalation exposure to HDI monomer. HDA was detected in 76% of plasma samples, as heptafluorobutyryl derivatives, and the range of HDA concentrations was < or =0.02-0.92 microg l(-1). After log-transformation of the data, the correlation between plasma HDA levels and HDI inhalation exposure measured on the same workday was low (N = 108, r = 0.22, P = 0.026) compared with the correlation between plasma HDA levels and inhalation exposure occurring approximately 20 to 60 days before blood collection (N = 29, r = 0.57, P = 0.0014). The correlation between plasma HDA levels and HDI dermal exposure measured on the same workday, although statistically significant, was low (N = 108, r = 0.22, P = 0.040) while the correlation between HDA and dermal exposure occurring approximately 20 to 60 days before blood collection was slightly improved (N = 29, r = 0.36, P = 0.053). We evaluated various workplace factors and controls (i.e. location, personal protective equipment use and paint booth type) as modifiers of plasma HDA levels. Workers using a downdraft-ventilated booth had significantly lower plasma HDA levels relative to semi-downdraft and crossdraft booth types (P = 0.0108); this trend was comparable to HDI inhalation and dermal exposure levels stratified by booth type. These findings indicate that HDA concentration in hydrolyzed plasma may be used as a biomarker of cumulative inhalation and dermal exposure to HDI and for investigating the effectiveness of exposure controls in the workplace.
Assuntos
Poluentes Ocupacionais do Ar/metabolismo , Cianatos/metabolismo , Diaminas/sangue , Exposição por Inalação/análise , Exposição Ocupacional/análise , Pintura , Poluentes Ocupacionais do Ar/análise , Poluentes Ocupacionais do Ar/toxicidade , Albuminas/análise , Automóveis , Biomarcadores/sangue , Cianatos/análise , Cianatos/toxicidade , Interpretação Estatística de Dados , Monitoramento Ambiental , Cromatografia Gasosa-Espectrometria de Massas , Hemoglobinas/análise , Humanos , Hidrólise , Isocianatos , Modelos Lineares , Masculino , Equipamentos de Proteção/estatística & dados numéricos , Absorção Cutânea , Fatores de Tempo , Local de Trabalho/normasRESUMO
Today, many raw materials used in factories may have a dangerous effect on the physiological system of workers. One of them which is widely used in the polyurethane factories is diisocyanates. These compounds are widely used in surface coatings, polyurethane foams, adhesives, resins, elastomers, binders, and sealants. Exposure to diisocyanates causes irritation to the skin, mucous membranes, eyes, and respiratory tract. Hexamethylene diamine (HDA) is metabolite of hexamethylene diisocyanate (HDI). It is an excretory material by worker's urine who is exposed to HDI. Around 100 air samples were collected from five defined factories by midget impinger which contained dimethyl sulfoxide absorbent as a solvent and tryptamine as reagent. Samples were analyzed by high-performance liquid chromatography with EC\UV detector using NIOSH 5522 method of sampling. Also, 50 urine samples collected from workers were also analyzed using William's biological analysis method. The concentration of HDI into all air samples were more than 88 microg/m(3), and they have shown high concentration of pollutant in the workplaces in comparison with NIOSH standard, and all of the workers' urine were contaminated by HDA. The correlation and regression test were used to obtain statistical model for HDI and HDA, which is useful for the prediction of diisocyanates pollution situation in the polyurethane factories.