Sensitization and cross-reactivity patterns of contact allergy to diisocyanates and corresponding amines: investigation of diphenylmethane-4,4'-diisocyanate, diphenylmethane-4,4'-diamine, dicyclohexylmethane-4,4'-diisocyanate, and dicylohexylmethane-4,4'-diamine.

BACKGROUND: Isocyanates are used in polyurethane production. Dermal exposure to isocyanates can induce contact allergy. The most common isocyanate is diphenylmethane diisocyanate used for industrial purposes. The isomer diphenylmethane-4,4'-diisocyanate (4,4'-MDI) is used in patch testing. Diphenylmethane-4,4'-diamine (4,4'-MDA) is its corresponding amine. Concurrent reactions to 4,4'-MDI and 4,4'-MDA have been reported, as have concurrent reactions to 4,4'-MDI and dicyclohexylmethane-4,4'-diisocyanate (4,4'-DMDI). OBJECTIVES: To investigate the sensitization capacities and the cross-reactivity of 4,4'-MDI, 4,4'-MDA, 4,4'-DMDI, and dicyclohexylmethane-4,4'-diamine (4,4'-DMDA). METHODS: The guinea-pig maximization test (GPMT) was used. RESULTS: The GPMT showed sensitizing capacities for all investigated substances: 4,4'-MDI, 4,4'-MDA, 4,4'-DMDI, and 4,4'-DMDA (all p < 0.001). 4,4'-MDI-sensitized animals showed cross-reactivity to 4,4'-MDA (p < 0.001) and 4,4'-DMDI (all p < 0.05). 4,4'-MDA-sensitized animals showed cross-reactivity to 4,4'-DMDA (p = 0.008). CONCLUSION: All of the investigated substances were shown to be strong sensitizers. Animals sensitized to 4,4'-MDI showed cross-reactivity to 4,4'-MDA and 4,4'-DMDI, supporting previous findings in the literature. The aromatic amine 4,4'-MDA showed cross-reactivity to the aliphatic amine 4,4'-DMDA.

Skin symptoms in bakery and auto body shop workers: associations with exposure and respiratory symptoms.

PURPOSE: Despite the importance of skin exposure, studies of skin symptoms in relation to exposure and respiratory symptoms are rare. The goals of this study were to describe exposure-response relationships for skin symptoms, and to investigate associations between skin and respiratory symptoms in bakery and auto body shop workers. METHODS: Data from previous studies of bakery and auto body shop workers were analyzed. Average exposure estimates for wheat allergen and isocyanates were used. Generalized linear models were constructed to describe the relationships between exposure and skin symptoms, as well as between skin and respiratory symptoms. RESULTS: Data from 723 bakery and 473 auto body shop workers were analyzed. In total, 5.3% of bakery and 6.1% of auto body shop workers were female; subjects' mean age was 39 and 38 years, respectively. Exposure-response relationships were observed in auto body shop workers for itchy or dry skin (PR 1.55, 95% CI 1.2-2.0) and work-related itchy skin (PR 1.97, 95% CI 1.2-3.3). A possible exposure-response relationship for work-related itchy skin in bakery workers did not reach statistical significance. In both groups, reporting skin symptoms was strongly and significantly associated with reporting respiratory symptoms, both work-related and non-work-related. CONCLUSIONS: Exposure-response relationships were observed for skin symptoms in auto body shop workers. The lack of significant exposure-response associations in bakery workers should be interpreted cautiously. Workers who reported skin symptoms were up to four times more likely to report respiratory symptoms. Improved awareness of both skin and respiratory outcomes in exposed workers is needed.

Biomonitoring Hexamethylene diisocyanate (HDI) exposure based on serum levels of HDI-specific IgG.

OBJECTIVES: Isocyanate chemicals essential for polyurethane production are widely used industrially, and are increasingly found in consumer products. Asthma and other adverse health effects of isocyanates are well-documented and exposure surveillance is crucial to disease prevention. Hexamethylene diisocyanate (HDI)-specific serum immunoglobulin G (IgG) was evaluated as an exposure biomarker among workers at a US Air Force Air Logistics Center, which includes a large aircraft maintenance facility. METHODS: HDI-specific IgG (HDI-IgG) titers in serum samples (n = 74) were measured using an enzyme-linked immunosorbent assay based upon the biuret form of HDI conjugated to human albumin. Information on personal protective equipment (PPE), work location/tasks, smoking, asthma history, basic demographics, and HDI skin exposure was obtained through questionnaire. RESULTS: HDI-specific serum IgG levels were elevated in n = 17 (23%) of the workers studied. The prevalence and/or end-titer of the HDI-IgG was significantly (P < 0.05) associated with specific job titles, self-reported skin exposure, night-shift work, and respirator use, but not atopy, asthma, or other demographic information. The highest titers were localized to specific worksites (C-130 painting), while other worksites (generator painting) had no or few workers with detectable HDI-IgG. CONCLUSIONS: HDI-specific immune responses (IgG) provide a practical biomarker to aid in exposure surveillance and ongoing industrial hygiene efforts. The strategy may supplement current air sampling approaches, which do not assess exposures via skin, or variability in PPE use or effectiveness. The approach may also be applicable to evaluating isocyanate exposures in other settings, and may extend to other chemical allergens.

Occupational contact allergy to monomeric isocyanates.

BACKGROUND: The monomeric isocyanates diphenylmethane diisocyanate (MDI), 2,4-toluene diisocyanate (TDI), isophorone diisocyanate (IPDI) and 1,6-hexamethylene diisocyanate (HDI) are used in polyurethane products and sometimes cause contact allergy. OBJECTIVES: To describe patients with isocyanate contact allergy in an occupational dermatology clinic. METHODS: Test files were screened for allergic reactions to isocyanates and 4,4'-diaminodiphenylmethane (MDA). Patients with allergic reactions to some of the allergens were analysed for occupation, exposure, concomitant reactions to other allergens, and diagnosis. RESULTS: Over a period of almost 13 years, 54 patients reacted to isocyanates (9 to IPDI, 12 to MDI, 6 to TDI, and 1 to HDI) or MDA (44 patients). The motor vehicle, electronics and paint industries, and painting and construction work, were among the most significant occupational fields. An in-house polymeric MDI (PMDI) test substance was superior to commercial MDI preparations. About half of the occupational cases related to MDI products were diagnosed by testing MDA. The most prominent cause of IPDI allergy comprised polyurethane paint hardeners. Some of the IPDI reactions could be explained by cross-allergy to isophoronediamine in epoxy products. Specific exposure to MDA was difficult to trace. CONCLUSIONS: MDA and PMDI test substances were significant in the diagnosis of MDI contact allergy.

Effect of 1,6-hexamethylene diisocyanate exposure on peak flowmetry in automobile paint shop workers in Iran.

The aim of this study was to investigate the effects of occupational exposure to 1,6-hexamethylene diisocyanate (HDI) on peak flowmetry in automobile body paint shop workers in Iran. We studied a population of 43 car painters exposed to HDI at their workplaces. Peak expiratory flow was tested for one working week, from the start to the end of each shift. Air was sampled and HDI analysed in parallel, according to the OSHA 42 method. Daily and weekly HDI exposure averages were (0.42+/-0.1) mg m(-3) and (0.13+/-0.05) mg m(-3), respectively. On painting days, 72 % of workers showed more than a 10 % variation in peak expiratory flow. Inhalation exposure exceeded the threshold limit value (TLV) ten times over. This strongly suggests that HDI affected the peak flowmetry in the studied workers.

Sequential sensitization to different occupational compounds in a young woman.

BACKGROUND: Very few authors have reported sensitization to two or more different occupational sensitizers in a single patient. OBJECTIVE: To describe a subject with occupational asthma caused by sensitization to two different agents, exposure to which occurred in dierent time periods. METHODS: We studied a young woman with asthma-like symptoms predominantly in relationship to a sequential occupational exposure, first to methylene diisocyanate (MDI) and later to flour dust. In the first and second periods of occupational exposure, the patient was subjected to metbacholine challenge test (MCT), sputum analysis, and specific challenge test (SCT). RESULTS: At the first observation, MCT (PD20FEV1: 0.109 mg) and SCT with MDI were positive and induced sputum analysis showed a high percentage of eosinophils (32%). The patient reduced exposure to MDI but symptoms worsened with continuing occupational exposure. After one year, she started another job exposed to flour dust. After four years, asthma symptoms persisted despite treatment with inhaled corticosteroids and bronchodilators, and bronchial byperreactivity and sputum eosinophbilia were still present (PD2OFEV1: 0.067 mg; sputum eosinophils: 5.3%). The patient also developed rhinitis symptoms associated with dermatitis. A SCT with flour dust showed an immediate response (deltaFEV1: 33%). The subject left work and a year later was still symptomatic:pulmonary function was within normal limits under regular therapy and induced sputum showed absence of eosinophilia. CONCLUSIONS: This was an unusual case of double sensitization to different occupational compounds to which the patient was exposed in different time periodsj suggesting the role of a pre-existing occupational aSthma in the development and/or worsening of sensitization to other occupational agents.

Rapid development of allergic contact dermatitis from dicyclohexylmethane-4,4'-diisocyanate.

Isocyanates are widely used in the manufacturing of rigid and flexible foams, fibers, and coatings such as paints, varnishes, and elastomers but are rarely reported as contact sensitizers. The aliphatic diisocyanate dicyclohexylmethane-4,4'-diisocyanate (DMDI) is known to be a strong cutaneous sensitizer. We report a 27-year-old woman who developed a severe eczematous eruption on the arms, trunk, and abdomen within 2 weeks of employment at a company using the product Chem-Dec 808 isocyanate (containing 40-70% weight per weight DMDI). Patch testing was performed with the North American screening series, an isocyanate series, and 1% Chem-Dec 808 isocyanate. At day 7, a +++ reaction to Chem-Dec 808 isocyanate and a ++ reaction to the aromatic isocyanate diphenylmethane-4,4'-diisocyanate were observed. DMDI has strong sensitizing potential and requires rigorous safety monitoring in the workplace.

Respiratory symptoms and lung function in foundry workers exposed to low molecular weight isocyanates.

BACKGROUND: This study investigated the prevalence of ocular and respiratory symptoms and lung function in foundry workers exposed to isocyanic acid (ICA) and methyl isocyanate (MIC). METHODS: Foundry workers (n = 64) using the Hot Box binder technique and referents (n = 134) completed two questionnaires and a spirometry before and after a day shift. Findings were analyzed relating to exposure measurements of ICA, MIC, and formaldehyde. RESULTS: Exposed workers reported more frequently ocular irritation and coughing. Pre-shift lung function was lower than predicted in both groups of workers, and was not associated with exposure duration. Decrease in lung function over shift was more pronounced in exposed workers, but this was not associated with quantitative measures of the exposures. CONCLUSIONS: An increased prevalence of ocular and respiratory symptoms, as well as a small decrease in lung function over shift, was observed among exposed workers. No associations with exposure to monoisocyanates and formaldehyde were seen, thus suggesting that other irritants in the foundry environment might be the cause. The effects seemed to be small and not clinically relevant on an individual level. Further studies using a follow-up design may be warranted.

Contact sensitization to 4,4'-diaminodiphenylmethane and to isocyanates among general dermatology patients.

BACKGROUND: Diisocyanates and 4,4'-diaminodiphenylmethane (MDA) are industrial sensitizers. Occupational asthma is a risk among workers exposed to diisocyanates. Exposure may also lead to contact sensitization and allergic contact dermatitis. OBJECTIVE: The aim of this study was to determine the occurrence of contact sensitization to MDA and to diisocyanates among general dermatology patients. PATIENTS AND METHODS: Patch testing with MDA was carried out in 1595 patients. Diphenylmethane-4,4'-diisocyanate (MDI) and toluene-2,4-diisocyanate (TDI) were tested in 1023 patients and isophorone diisocyanate (IPDI) and 1,6-hexamethylene diisocyanate (HDI) in 433 patients. The clinical data and sources of exposure are analysed. RESULTS: MDA reactions were seen in 17 (1.1%) patients and MDI reactions in 4 patients. Six MDA-positive patients reacted to p-phenylenediamine and two to epoxy chemicals. 5/10 of the TDI reactions were seen concurrently with reactions to MDI, MDA, HDI, or to IPDI. IPDI reactions were seen in eight patients and HDI reactions in two patients. Possible sources of exposure were traced in most patients, although the association with the current dermatitis was not apparent in all cases. CONCLUSION: (Di)isocyanates may induce contact sensitization with or without allergic contact dermatitis.

Respiratory symptoms, sensitization, and exposure response relationships in spray painters exposed to isocyanates.

RATIONALE: Associations between oligomeric isocyanate exposure, sensitization, and respiratory disease have received little attention, despite the extensive use of isocyanate oligomers. OBJECTIVES: To investigate exposure-response relationships of respiratory symptoms and sensitization in a large population occupationally exposed to isocyanate oligomers during spray painting. METHODS: The prevalence of respiratory symptoms and sensitization was assessed in 581 workers in the spray-painting industry. Personal exposure was estimated by combining personal task-based inhalatory exposure measurements and time activity information. Specific IgE and IgG to hexamethylene diisocyanate (HDI) were assessed in serum by ImmunoCAP assay and enzyme immunoassays using vapor and liquid phase HDI-human serum albumin (HDI-HSA) and HSA conjugates prepared with oligomeric HDI. MEASUREMENTS AND MAIN RESULTS: Respiratory symptoms were more prevalent in exposed workers than among comparison office workers. Log-linear exposure-response associations were found for asthmalike symptoms, chronic obstructive pulmonary disease-like symptoms, and work-related chest tightness (prevalence ratios for an interquartile range increase in exposure of 1.2, 1.3 and 2.0, respectively; P

Diisocyanate conjugate and immunoassay characteristics influence detection of specific antibodies in HDI-exposed workers.

BACKGROUND: The structural characteristics of diisocyanate chemical protein antigens vary depending upon the methods of production, and may influence diisocyanate antigen immunoassays. The impact of different antigen preparation methods on immunoassay sensitivity, specificity, and predictive value for identifying workers with diisocyanate asthma (DA) has not been systematically evaluated. OBJECTIVE: Evaluate the influence of preparation methodology of hexamethylene diisocyanate human serum albumin (HDI-HSA) conjugates on the performance of specific antibody assays for identifying workers with confirmed HDI asthma. METHODS: Asthmatic reactions to HDI exposure were assessed in 80 autobody shop workers by specific inhalation challenge (SIC). HDI-specific IgE and IgG in serum were measured by RAST and ELISA with seven different HDI-HSA conjugates prepared in liquid phase with monomeric or polymeric HDI, or vapour-phase monomeric HDI. The HDI : HSA substitution ratios were determined by mass spectrometry. RESULTS: DA was confirmed by SIC in 23 subjects. The maximal sensitivity for detecting specific IgE among workers with positive SIC results was higher with RAST and with polymeric vs. monomeric HDI-albumin conjugates (21.7% vs. 8.7%) with a generally high specificity (>or=95%). HDI-HSA specific IgG antibody was also detected in 22-43% of HDI asthmatics depending upon the conjugate used. The specificity of specific IgG varied from 88% to 96%, and it was higher for monomeric (vs. polymeric) HDI-albumin conjugates with low (vs. high) substitution ratios. CONCLUSION: The test performance of specific IgE and IgG immunoassays for identifying a positive SIC response varied with different HDI-HSA conjugates. Standard test antigens and common immunoassays must be used to minimize inter-laboratory variability.

[Work-related asthma caused by IgE-verified allergy to methylene di-isocynate]. / Arbejdsbetinget astma udløst af immunglobulin E-verificeret diisocyanatallergi.

A 44-year-old blacksmith periodically exposed to methylene di-isocynate (MDI) from foaming processes over the course of eight years developed an acute episode of asthma shortly after high exposure to MDI. The respiratory symptoms declined gradually over some months. A year later the specific IgE to MDI was still high (23.92 KU/l), but lung function (FEV1, PEF and FVC) was normal and no bronchial hyperreactivity was observed. He is still working at the same factory under respiratory health surveillance.

Work, unemployment and life satisfaction among patients with diisocyanate induced asthma--a prospective study.

Occupational asthma has been found to be associated with lowered socio-economic outcomes, an increased unemployment rate and a decreased quality of life. The compensation of occupational diseases is comparatively favourable in Finland. Our aim was to follow-up the working status and life satisfaction of patients with diisocyanate-induced asthma in 245 cases diagnosed during 1976-1992. A questionnaire was sent out on average 10 (3-19) yr after the diagnosis to the surviving 235 patients. The questionnaire was validated by re-examining 91 of them clinically, and with spirometry, histamine challenge test and peak flow surveillance. Of the 213 responding patients, 14% were unemployed, and for 50% of them unemployment was caused by asthma. Unemployment was associated with nocturnal asthma symptoms (OR 10.93; CI 2.69-44.452), increased PEF variability (OR 8.46; CI 1.52-46.97) and with the use of short-acting beta-sympathomimetic medication (p=0.045). Satisfaction with life was associated with present working (OR 3.50; CI 1.73-7.06) and with good condition of asthma as assessed by the use of asthma medication (OR 0.49; CI 0.27-0.89) and objective measurements of the asthma condition, e.g. PEF variability (OR 0.21; CI 0.08-0.59). As a conclusion, unemployment was remarkably low as compared with earlier reports and related to the period of simultaneous economic recession. Unemployment, as well as dissatisfaction with life were associated with poor conditions of asthma. Unemployment was associated with improper asthma care favouring the use of short-acting beta-sympathomimetic medication. Proper follow-up of asthma is essential for minimizing the social complaints of occupational asthma, as well as for enhancing life satisfaction.

Animal models for diisocyanate asthma: answers for lingering questions.

PURPOSE OF REVIEW: Diisocyanates are the leading cause of occupational asthma, the most commonly reported lung disease associated with the workplace. Clinical studies have implicated the immune system in the pathogenesis of occupational asthma, but ethical and moral issues prevent mechanistic investigations in humans. For this reason, the development and characterization of animal models are germane to further understanding of diisocyanate occupational asthma and to identify avenues for therapeutic intervention. This review will highlight important features of existing experimental animal models with emphasis on new developments. RECENT FINDINGS: Experimental animal models of diisocyanate occupational asthma have demonstrated an immunological basis for the disease. Mice can be sensitized by dermal or respiratory exposure, suggesting that either exposure route may be important in the workplace. Recent findings show that sensitized mice develop airway hyperreactivity and inflammation, reflective of human disease. The transfer of lymphocytes or serum from sensitized mice can cause clinical disease in naive mice. Transgenic animals have identified a role for specific immunity, including the involvement of T-helper type 1/2 responses as well as CD4 and CD8 T cells in diisocyanate occupational asthma. Recent animal models have shown that sensitization can occur through subchronic inhalation of vapor-phase diisocyanate at levels as low as 20 ppb. SUMMARY: Recent progress using animal models has been instrumental in furthering current understanding of the involvement of the immune system in disease pathogenesis. The demonstration of diisocyanate occupational asthma in a murine model after sub-chronic inhalation exposure at relevant exposure levels should provide opportunities for more accurate risk assessment data.

[Diisocyanate exposure as a cause of occupational asthma]. / Expozice diizokyanátum jako prícina profesionálního astmatu.

The authors present a summary of current knowledge on asthma caused by diisocyanates in workers under occupational exposure and introduce basic characteristics of these chemicals widely used in industry. Although they represent one of the main causes of occupational bronchial asthma (AB) in developed industrial countries, the number of reported asthma caused by diisocyanates is still relatively low in the Czech Republic--it represents less than ten percent of all reported occupational asthma. One of the possible reasons is demanding diagnostics and assessment of occupational impact of chemical noxae with combined effect mechanism characteristic of low-molecular diisocyanates. Studies concerned with presented topics support the concept that AB caused by diisocyanates shows clinical features of both atopic and nonatopic asthma. AB caused by DI is presented by mixed type of the TH1/TH2 response, influx and regulatory role of CD4+ and CD8+ T lymphocytes. Mixed immunopathological mechanism and toxic effect are combined. For the present, evaluation of elimination and reexposure tests appear as the most valuable of available diagnostic methods, respectively simulated reexposure test in a health care facility and assesment of serum IgG or IgE antibodies against diisocyanates can be used. Data on occurrence of the disease in the Czech Republic and detailed information on the sample of patients with respiratory allergic disease caused by diisocyanates reported by the Clinic of Occupational Diseases of the Faculty Hospital in Hradec Králové in 1994-2003 are presented. The disease was caused by evaporation of diisocyanates released during the production of polyurethanes and evaporation of adhesives containing toluendiisocyanate (TDI). In most cases, there were milder forms of asthma with significant improvement or elimination of difficulties occuring after occupational exposure was interrupted. Knowledge of the pathogenesis of AB caused by diisocyanates should accelerate the development of diagnostic tests and consequent treatment intervention, as early determination of diagnosis and interruption of occupational exposure are essential for following prognosis of disease.

Diisocyanates and nonoccupational disease: a review.

More than 32 million people in the United States suffer from chronic lung diseases; 12 million experienced at least one asthma attack in 2002. The causes of this "epidemic" are complex and uncertain; however, there is a strong possibility that environmental exposures play a role. The most common and well-studied cause of occupational asthma is diisocyanates, but their use in consumer products as a potential cause of respiratory disease in the general population has been overlooked. These substances are found in or are used to produce an array of polyurethane-containing products, including adhesives, sealants, paints, flexible foams, and rigid foams, among others. The world market for polyurethane products has tripled since 1985 to more than 9.3 billion kg in the year 2000. In this article, the author reviews biologically plausible explanations, as well as the epidemiologic, experimental, and clinical evidence for the role of diisocyanates and polyurethanes in the genesis of nonoccupational allergy and respiratory disease.