Overview of diisocyanate occupational asthma

doi:10.1016/0300-483X(96)03375-6

Toxicology

Volume 111, Issues 1–3, 17 July 1996, Pages 181-189

https://doi.org/10.1016/0300-483X(96)03375-6 Get rights and content

Abstract

Surveillance programs established around the world have determined that diisocyanate chemicals are the most common cause of occupational asthma. In the United States approximately 100000 workers are exposed to these chemical compounds in the workplace each year and 5–10% of these workers will develop occupational asthma. There are no known reliable risk factors or biomarkers which can be used to predict which exposed worker will develop diisocyanate-occupatonal asthma. Diisocyanate-occupational asthma workers manifest characteristic physiologic responses after specific bronochoprovocation which correlate with pathologic changes in their airways. However, the mechanism(s) for diiocyanate-occupational asthma remains unclear. Specific IgE antibody production to diisocyanates is found in only 10–30% of these workers. Bronchial biopsies and bronchoalveolar lavage have confirmed the presence of T-lymphocytes and eosinophils in the airways of these workers suggesting that T-cell mediated immune responses are more likely to play a central role in this disease. It is essential to diagnose diisocyanate-occupational asthma as early as possible in order to prevent or reduce the significant asthma morbidity associated with continuous long term exposure to these chemicals. Treatment of choice is removal of the worker from further exposure. Prospective studies evaluating larger populations of diisocyanate-exposed workers is essential for a better understanding of the pathogenesis and natural course of diisocyanate-occupational asthma.

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Citation Excerpt :
Diisocyanates such as toluene diisocyanate (usually a mixture of 2,4-toluene diisocyanate (24TDI) and 2,6-toluene diisocyanate (26TDI)), 4,4′-methylenediphenyl diisocyanate (MDI), 1,6-hexamethylene diisocyanate (HDI) and their oligomers, are increasingly used in e.g. polyurethane foam, paints, adhesives, elastomers, coatings, insecticides and for consolidation of loose rock zones in coal mining or tunneling (Munn et al., 2005). Diisocyanates are one of the main causes of occupational asthma (Baur et al. 1994; Bernstein 1996; Grunewalder and Karol 1986). The predominant routes of occupational exposure is through inhalation and dermal absorption (Liljelind et al. 2010).
Humans are potentially exposed to a large amount of chemicals present in the environment and in the workplace. In the European Human Biomonitoring initiative (Human Biomonitoring for the European Union = HBM4EU), acrylamide, mycotoxins (aflatoxin B1, deoxynivalenol, fumonisin B1), diisocyanates (4,4′-methylenediphenyl diisocyanate, 2,4- and 2,6-toluene diisocyanate), and pyrethroids were included among the prioritized chemicals of concern for human health. For the present literature review, the analytical methods used in worldwide biomonitoring studies for these compounds were collected and presented in comprehensive tables, including the following parameter: determined biomarker, matrix, sample amount, work-up procedure, available laboratory quality assurance and quality assessment information, analytical techniques, and limit of detection. Based on the data presented in these tables, the most suitable methods were recommended. According to the paradigm of biomonitoring, the information about two different biomarkers of exposure was evaluated: a) internal dose = parent compounds and metabolites in urine and blood; and b) the biologically effective = dose measured as blood protein adducts. Urine was the preferred matrix used for deoxynivalenol, fumonisin B1, and pyrethroids (biomarkers of internal dose). Markers of the biological effective dose were determined as hemoglobin adducts for diisocyanates and acrylamide, and as serum-albumin-adducts of aflatoxin B1 and diisocyanates. The analyses and quantitation of the protein adducts in blood or the metabolites in urine were mostly performed with LC-MS/MS or GC-MS in the presence of isotope-labeled internal standards. This review also addresses the critical aspects of the application, use and selection of biomarkers. For future biomonitoring studies, a more comprehensive approach is discussed to broaden the selection of compounds.
Chemical characteristics and sources of nitrogen-containing organic compounds at a regional site in the North China Plain during the transition period of autumn and winter
2022, Science of the Total Environment
Citation Excerpt :
Nevertheless, urea is usually found to be the dominant contributor to NOCs (Booyens et al., 2019; Ho et al., 2016). Isocyanates are harmful to the respiratory system (Lesage et al., 2001), which are generally emitted from industry (Bernstein, 1996; Redlich and Karol, 2002) and derived from biomass burning (Priestley et al., 2018). The average mass concentration of isocyanates was 24.0 ng m−3 (Table 1).
Organic nitrogen constitutes a significant fraction of the nitrogen budget in particulate matter (PM). However, the composition and sources of nitrogen-containing organic compounds (NOCs) in PM remain unclear currently in North China Plain (NCP), China. Rare local or regional studies on NOCs were conducted. In this study, ambient fine particles (PM_2.5) were collected in Xianghe, a regional background site in NCP, from 26 October to 26 December 2017. The insights from this study include NOC molecule identification, concentration level, and NOC sources and origins. Specifically, we have identified and quantified >90 NOC species, with urea being the most abundant, accounting for 39.7 ± 4.7% of the total NOC followed by free amino acids (FAAs; 21.9 ± 1.5%), cyclic NOCs (15.3 ± 4.5%), amines (14.8 ± 1.5%), alkyl amides (5.8 ± 0.5%), isocyanates (1.7 ± 0.2%), and nitriles (1.1 ± 0.2%). The time series of FAAs was well correlated (r = 0.51–0.68, p < 0.01) with the organic marker of levoglucosan and was moderately correlated with O_x (r = 0.29–0.41, p < 0.01), suggesting biomass burning and secondary formation were important FAAs sources. We also show that amines can be oxidized and/or reacted by aqueous-phase processing to form secondary aerosols, which are further enhanced by the involvement of iron in the catalytic process. Using the receptor model of positive matrix factorization (PMF), six factors were identified including coal combustion, crustal sources, biomass burning, industry-related sources, traffic emissions, and secondary aerosols. Source apportionment of NOC shows biomass burning was the dominant factor, accounting for 31.8% of the total NOCs. This study provides a unique dataset of NOCs at this regional background site in the NCP, with the insights of NOC chemical composition and sources gained in this study being important for future NOC modeling as well as NOC health effects studies.
Trisaminohexyl isocyanurate, a urinary biomarker of HDI isocyanurate exposure
2018, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Citation Excerpt :
Exposures in the general population can occur from contact with isocyanate-containing consumer goods, from slow-curing isocyanate coatings or materials used in housing construction, in outdoor areas near industrial sites where isocyanates are used in manufacturing, or in neighborhoods surrounding auto-refinishing businesses [5–11]. Exposures to aerosols and vapors of HDI monomer and oligomers, including HDI isocyanurate, are associated with a high risk of contact dermatitis and asthma [12–16]. Acute exposure can cause shortness of breath, rhinitis, irritation of the skin, eyes, and mucous membranes, and pulmonary edema [8,9,14,17].
Biological monitoring of occupational exposure to 1,6-hexamethylene diisocyanate (HDI)-containing spray-paints is limited to analysis of metabolites of HDI monomer although polymeric HDI isocyanurate constitutes the predominant inhalation and skin exposure for workers in the automotive paint industry. A novel method using nanoflow ultra-performance liquid chromatography coupled to nano-electrospray ionization tandem mass spectrometry (nano-UPLC-ESI-MS/MS) was developed to quantify trisaminohexyl isocyanurate (TAHI), a hydrolysis product of HDI isocyanurate, in the urine of spray-painters. Analytical and internal standards were synthesized in-house and weighted linear regression calibration curves were generated using spiked control urine from non-exposed persons (0.06–7.98 μg/L; N = 13; w = x⁻²; r = 0.998). Urine samples collected from 15 exposed workers (N = 111) were subjected to acid hydrolysis and extracted with dichloromethane, then derivatized with acetic anhydride. The derivatized product, trisacetamidohexyl isocyanurate (TAAHI), was analyzed using nano-UPLC-ESI-MS/MS. The protocol was sensitive and specific for analysis of TAHI in the urine of exposed workers with a method detection limit at 0.03 μg/L. TAHI was detected in 33 of 111 urine samples and in 11 of 15 workers. This biomarker for HDI isocyanurate is critical to determine the relative potency and dose-relationships between the monomer and oligomer exposure on the development of diisocyanate induced health effects in future studies.
Polymerization of hexamethylene diisocyanate in solution and a 260.23 m/z [M+H]<sup>+</sup> ion in exposed human cells
2018, Analytical Biochemistry
Citation Excerpt :
Hexamethylene (and related) diisocyanate compounds are widely used and are among the best-recognized chemical causes of occupational asthma [1].
Hexamethylene diisocyanate (HDI) is an important industrial chemical that can cause asthma, however pathogenic mechanisms remain unclear. Upon entry into the respiratory tract, HDI's N=C=O groups may undergo nucleophilic addition (conjugate) to host molecules (e.g. proteins), or instead react with water (hydrolyze), releasing CO₂ and leaving a primary amine in place of the original N=C=O. We hypothesized that (primary amine groups present on) hydrolyzed or partially hydrolyzed HDI may compete with proteins and water as a reaction target for HDI in solution, resulting in polymers that could be identified and characterized using LC-MS and LC-MS/MS. Analysis of the reaction products formed when HDI was mixed with a pH buffered, isotonic, protein containing solution identified multiple [M+H]⁺ ions with m/z's and collision-induced dissociation (CID) fragmentation patterns consistent with those expected for dimers (259.25/285.23 m/z), and trimers (401.36/427.35 m/z) of partially hydrolyzed HDI (e.g. ureas/oligoureas). Human peripheral blood mononuclear cells (PBMCs) and monocyte-like U937, but not airway epithelial NCI-H292 cell lines cultured with these HDI ureas contained a novel 260.23 m/z [M+H]⁺ ion. LC-MS/MS analysis of the 260.23 m/z [M+H]⁺ ion suggest the formula C₁₃H₂₉N₃O₂ and a structure containing partially hydrolyzed HDI, however definitive characterization will require further orthogonal analyses.
Determination of albumin adducts of 4,4′-methylenediphenyl diisocyanate after specific inhalative challenge tests in workers
2016, Toxicology Letters
Citation Excerpt :
Exposure to diisocyanate vapors is associated with various pulmonary ailments, such as eosinophilic airway inflammation, bronchial hyperresponsiveness, early and late onset asthma, exogenous allergic alveolitis and direct toxic responses at high concentrations (Baur, 1990; Karol, 1986; Mapp et al., 1994; Redlich and Karol, 2002). Diisocyanates are one of the main causes of occupational asthma (Baur et al., 1994; Bernstein, 1996; Karol, 1986). Occupational isocyanate exposure is through inhalation and dermal absorption (Liljelind et al., 2010).
4,4′–Methylenediphenyl diisocyanate (MDI) is the most important isocyanate used in the industry. Lung sensitization with bronchial asthma is the main disorder in exposed workers. Albumin adducts of MDI might be involved in specific immunological reactions. MDI adducts with lysine (MDI-Lys) of albumin have been found in MDI-workers and construction workers. MDI-Lys is an isocyanate-specific adduct of MDI with albumin. In the present study, we report MDI-adducts in workers undergoing diagnostic MDI challenge tests. The workers were exposed for 2 h to 5 ppb of MDI. The adduct levels increase significantly after the exposure to MDI in the challenge chamber. About 0.6% of the dose was bound to albumin. So far, only urinary metabolites of MDI were measured to monitor isocyanate workers. However, such urinary metabolites are not isocyanate specific. Therefore, we propose to measure albumin adducts for monitoring MDI exposed subjects.
Effect of Ipomea carnea Jacq. flowers on hematological changes in toluene diisocyanate-induced inflammation in Wistar rats
2014, Chinese Journal of Natural Medicines
To investigate the active chloroform fraction of the ethanol extract of Ipomoea carnea flowers on hematological changes in toluene diisocyanate-induced inflammation in Wistar rats.
Except for the control group, all of the rats were sensitized with intranasal application of 5 μL of 10% toluene diisocyanate (TDI) for 7 days. One week after second sensitization, all of the rats were provoked with 5 μL of 5% TDI to induce airway hypersensitivity. After the last challenge, blood and bronchoalvelor lavage (BAL) fluid were collected and subjected to total and differential leucocytes count. Flash chromatography was performed on the most active chloroform fraction to isolate an individual component.
Treatment with the ethanolic extract and its chloroform fraction at an oral dose of 200 mg·kg⁻¹ showed a significant decrease in circulating neutrophil and eosinophil in blood and BAL as compared with standard dexamethasone (DEXA). The structure of the compound obtained from chloroform fraction of Ipomea carnea was elucidated as stigmast-5, 22-dien-3β-ol on the basis of spectral data analysis.
The chloroform fraction was found to be more effective to suppress airway hyper reactivity symptoms, and decreased count of both total and differential inflammatory cells.

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Session IV. Occupational and environmental exposure case studiesOverview of diisocyanate occupational asthma

Abstract

J. Allergy Clin. Allergy

Toxicol. Appl. Pharmacol.

J. Allergy Clin. Immunol.

Immunological investigation of individuals with toluene diisocyanate asthma

Clin. Exp. Immunol.

Prevalence and determinants

Clinical assessment and management of occupational asthma

Surveillance and prevention

Occupational asthma

Clin. Allergy

Definition and classification of asthma

V-beta gene segment expression in diisocyanate-occupational asthma

Asthma: Theory to Treatment

Reactive airways dysfunction syndrome (RADS)

Dpictions

Occupational asthma. “My job is making me sick”

Postgrad. Med.

Session IV. Occupational and environmental exposure case studies
Overview of diisocyanate occupational asthma