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1.  Quantification and Statistical Modeling—Part II: Dermal Concentrations of Monomeric and Polymeric 1,6-Hexamethylene Diisocyanate 
Annals of Occupational Hygiene  2009;53(7):691-702.
We conducted a quantitative dermal and inhalation exposure assessment of monomeric and polymeric 1,6-hexamethylene diisocyanates (HDI) in 47 automotive spray painters from North Carolina and Washington State. We report here the use of linear mixed modeling (LMM) to identify the primary determinants of dermal exposure. Dermal concentrations of HDI, uretidone, biuret, and isocyanurate were significantly higher in 15 painters who did not wear coveralls or gloves (N = 51 paint tasks) than in 32 painters who did wear coveralls and gloves (N = 192 paint tasks) during spray painting. Regardless of whether protective clothing was worn, isocyanurate was the predominant species measured in the skin [geometric mean (GM) = 33.8 ng mm−3], with a 95% detection rate. Other polyisocyanates (GM ≤ 0.17 ng mm−3) were detected in skin during <23% of the paint tasks. According to marginal R2 statistics, mixed models generated in this study described no <36% of the variability in dermal concentrations of the different polyisocyanates measured in painters who did not wear protective clothing. These models also described 55% of the variability in dermal concentrations of isocyanurate measured in all painters (N = 288 paint tasks). The product of analyte-specific breathing-zone concentration (BZC) and paint time was the most significant variable in all the models. Through LMM, a better understanding of the exposure pathways governing individual polyisocyanate exposures may be achieved. In particular, we were able to establish a link between BZC and dermal concentration, which may be useful for exposure reconstruction and quantitatively characterizing the protective effect of coveralls and gloves. This information can be used to reduce dermal exposures and better protect automotive spray painters from potential adverse health effects.
doi:10.1093/annhyg/mep048
PMCID: PMC2758669  PMID: 19635734
dermal exposure; exposure determinants; hexamethylene diisocyanate; isocyanate; statistical modeling
2.  Urine 1,6-Hexamethylene Diamine (HDA) Levels Among Workers Exposed to 1,6-Hexamethylene Diisocyanate (HDI) 
Annals of Occupational Hygiene  2010;54(6):678-691.
Urinary 1,6-hexamethylene diamine (HDA) may serve as a biomarker for systemic exposure to 1,6-hexamethylene diisocyanate (HDI) in occupationally exposed populations. However, the quantitative relationships between dermal and inhalation exposure to HDI and urine HDA levels have not been established. We measured acid-hydrolyzed urine HDA levels along with dermal and breathing-zone levels of HDI in 48 automotive spray painters. These measurements were conducted over the course of an entire workday for up to three separate workdays that were spaced approximately 1 month apart. One urine sample was collected before the start of work with HDI-containing paints and subsequent samples were collected during the workday. HDA levels varied throughout the day and ranged from nondetectable to 65.9 μg l−1 with a geometric mean and geometric standard deviation of 0.10 μg l−1 ± 6.68. Dermal exposure and inhalation exposure levels, adjusted for the type of respirator worn, were both significant predictors of urine HDA levels in the linear mixed models. Creatinine was a significant covariate when used as an independent variable along with dermal and respirator-adjusted inhalation exposure. Consequently, exposure assessment models must account for the water content of a urine sample. These findings indicate that HDA exhibits a biphasic elimination pattern, with a half-life of 2.9 h for the fast elimination phase. Our results also indicate that urine HDA level is significantly associated with systemic HDI exposure through both the skin and the lungs. We conclude that urinary HDA may be used as a biomarker of exposure to HDI, but biological monitoring should be tailored to reliably capture the intermittent exposure pattern typical in this industry.
doi:10.1093/annhyg/meq041
PMCID: PMC2918490  PMID: 20530123
biomarkers; creatinine; dermal exposure; 1,6-hexamethylene diamine; 1,6-hexamethylene diisocyanate; inhalation exposure; urine analysis
3.  Quantitative Plasma Biomarker Analysis in HDI Exposure Assessment 
Annals of Occupational Hygiene  2009;54(1):41-54.
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 ≤0.02–0.92 μg 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 ∼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 ∼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.
doi:10.1093/annhyg/mep069
PMCID: PMC2802519  PMID: 19805392
biomarker; dermal exposure; 1,6-hexamethylene diamine (HDA); 1,6-hexamethylene diisocyanate (HDI); inhalation exposure; plasma
4.  Dermal, inhalation, and internal exposure to 1,6‐HDI and its oligomers in car body repair shop workers and industrial spray painters 
Objectives
To study inhalation and dermal exposure to hexamethylene diisocyanate (HDI) and its oligomers as well as personal protection equipment (PPE) use during task performance in conjunction with urinary hexamethylene diamine (HDA) in car body repair shop workers and industrial spray painters.
Methods
Personal task based inhalation samples (n = 95) were collected from six car body repair shops and five industrial painting companies using impingers with di‐n‐butylamine (DBA) in toluene. In parallel, dermal exposure was assessed using nitril rubber gloves. Gloves were submerged into DBA in toluene after sampling. Analysis for HDI and its oligomers was performed by LC‐MS/MS. Urine samples were collected from 55 workers (n = 291) and analysed for HDA by GC‐MS.
Results
Inhalation exposure was strongly associated with tasks during which aerosolisation occurs. Dermal exposure occurred during tasks that involve direct handling of paint. In car body repair shops associations were found between detectable dermal exposure and glove use (odds ratio (OR) 0.22, 95% confidence interval (CI) 0.09 to 0.57) and inhalation exposure level (OR 1.34, 95% CI 0.97 to 1.84 for a 10‐fold increase). HDA in urine could be demonstrated in 36% and 10% of car body repair shop workers and industrial painting company workers respectively. In car body repair shops, the frequency of detectable HDA was significantly elevated at the end of the working day (OR 2.13, 95% CI 1.07 to 4.22 for 3–6 pm v 0–8 am). In both branches HDA was detected in urine of ∼25% of the spray painters. In addition HDA was detected in urine of a large proportion of non‐spray painters in car body repair shops.
Conclusion
Although (spray) painting with lacquers containing isocyanate hardeners results in the highest external exposures to HDI and oligomers, workers that do not perform paint related tasks may also receive a considerable internal dose.
doi:10.1136/oem.2005.023226
PMCID: PMC2078164  PMID: 16728504
isocyanate; oligomers; dermal; biomonitoring; spray painting
5.  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 ⩽ 0.05). The prevalence of specific IgE sensitization was low (up to 4.2% in spray painters). Nevertheless, IgE to N100 (oligomeric HDI)–HSA was associated with exposure and work-related chest tightness. The prevalence of specific IgG was higher (2–50.4%) and strongly associated with exposure.
Conclusions: The results provide evidence of exposure–response relationships for both work-related and non–work-related respiratory symptoms and specific sensitization in a population exposed to oligomers of HDI. Specific IgE was found in only a minority of symptomatic individuals. Specific IgG seems to be merely an indicator of exposure.
doi:10.1164/rccm.200702-215OC
PMCID: PMC2176099  PMID: 17656675
oligomer; isocyanate; asthma; spray painter; sensitization
6.  Biomonitoring Hexamethylene Diisocyanate (HDI) Exposure Based on Serum Levels of HDI-Specific IgG 
Annals of Occupational Hygiene  2012;56(8):901-910.
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.
doi:10.1093/annhyg/mes024
PMCID: PMC3471419  PMID: 22449630
biomarker; exposure; HDI; hygiene; occupational
7.  Development of immunoassays for biomonitoring of hexamethylene diisocyanate exposure. 
Environmental Health Perspectives  2001;109(11):1103-1108.
Hexamethylene diisocyanate (HDI) is used widely to manufacture polyurethanes for paints and coatings. It is an irritant and a chemical asthmagen. The U.S. Occupational Safety and Health Administration time-weighted average permissible exposure limit is 5 ppb and the ceiling limit is 20 ppb. We sought to develop a sensitive and specific immuno-bioassay to supplement workplace air monitoring and detect recent HDI exposure. For this, we produced rabbit antiserum to HDI-adducted keyhole limpet hemocyanin (HDI-KLH). The specificity of the antiserum was demonstrated by its reaction with a variety of HDI-conjugated proteins and the absence of reactions with conjugates of other diisocyanates, namely toluene diisocyanate and diphenyl methylene diisocyanate. Four immunoassays were developed and compared for their ability to detect decreasing quantities of HDI-adducted human serum albumin (HSA) containing 2 mol HDI adduct per mol HSA (HDI(2)-HSA) as determined by matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry. The sensitivities of some of the assays are within the range (0.82-45 nM) of current analytic methods. A Western analysis procedure has a sensitivity of 600 nM HDI adduct on HSA. ELISA inhibition assay, in which microtiter plates are coated with the HDI(2)-HSA antigen, has a sensitivity of 300 nM HDI adduct. An immunoblot assay has a sensitivity of 9 nM HDI adduct. The most sensitive bioassay (1.8 nM HDI adduct) is a three-antibody sandwich ELISA in which wells of microtiter plates are coated with the IgG fraction of the anti-HDI-KLH antisera. Compared with analytic methods for HDI biomonitoring, the immunoassays are faster and less costly and accommodate numerous samples simultaneously. The assays have the potential to affect industrial biomonitoring programs significantly.
PMCID: PMC1240469  PMID: 11712993
8.  Effects of hexamethylene diisocyanate exposure on human airway epithelial cells: in vitro cellular and molecular studies. 
Environmental Health Perspectives  2002;110(9):901-907.
In this study we developed an in vitro exposure model to investigate the effects of hexamethylene diisocyanate (HDI) on human airway epithelial cells at the cellular and molecular level. We used immunofluorescence analysis (IFA) to visualize the binding and uptake of HDI by airway epithelial cell lines (A549 and NCI-NCI-H292) and microarray technology to identify HDI sensitive genes. By IFA, we observed that subcytotoxic concentrations of HDI form microscopic micelles that appear to be taken up by cells over a 3-hr period postexposure. Microarray analysis (4.6K genes) of parallel cultures identified four genes (thioredoxin reductase, dihydrodiol dehydrogenase, TG interacting factor, and stanniocalcin) whose mRNA levels were up-regulated after HDI exposure. Northern analysis was used to confirm that HDI increased message levels of these four genes and to further explore the dose dependence and kinetics of the response. The finding that HDI exposure increases thioredoxin reductase expression supports previous studies suggesting that HDI alters thiol-redox homeostasis, an important sensor of cellular stress. Another of the HDI-increased genes, a dihydrodiol dehydrogenase, encodes a protein previously shown to be specifically susceptible to HDI conjugation, and known to detoxify other hydrocarbons. Together, the data describe a novel approach for investigating the effects of HDI binding and uptake by human airway epithelial cells and begin to identify genes that may be involved in the acute response to exposure.
PMCID: PMC1240990  PMID: 12204825
9.  Hexamethylene diisocyanate (HDI) vapor reactivity with glutathione and subsequent transfer to human albumin 
INTRODUCTION
Airway fluid glutathione (GSH) reactivity with inhaled vapors of diisocyanate, a common occupational allergen, is postulated to be a key step in exposure-induced asthma pathogenesis.
METHODS
A mixed (vapor/liquid) phase exposure system was used to model the in vivo reactivity of inhaled HDI vapor with GSH in the airway fluid. HDI-GSH reaction products, and their capacity to transfer HDI to human albumin, were characterized through mass spectrometry and serologic assays, using HDI-specific polyclonal rabbit serum.
RESULTS
HDI vapor exposure of 10 mM GSH solutions resulted in primarily S-linked, bis(GSH)-HDI reaction products. In contrast, lower GSH concentrations (100 μM) resulted in mainly mono(GSH)-HDI conjugates, with varying degrees of HDI hydrolysis, dimerization and/or intra-molecular cyclization, depending upon the presence/absence of H2PO4-/HPO42- and Na+/Cl- ions. The ion composition and GSH concentration of the fluid phase, during HDI vapor exposure, strongly influenced the transfer of HDI from GSH to albumin, as did the pH and duration of the carbamoylating reaction. When carbamoylation was performed overnight at pH 7, twenty-five of albumin's lysines were identified as potential sites of conjugation with partially hydrolyzed HDI. When carbamoylation was performed at pH 9, more rapid (within 3 hours) and extensive modification was observed, including additional lysine sites, intra-molecular cross-linkage with HDI, and novel HDI-GSH conjugation.
CONCLUSIONS
The data define potential mechanisms by which the levels of GSH, H2PO4-4/HPO42-, and/or other ions (e.g. H+/OH-, Na+, Cl-) affect the reactivity of HDI vapor with self-molecules in solution (e.g. airway fluid), and thus, might influence the clinical response to HDI respiratory tract exposure.
doi:10.1016/j.tiv.2012.11.013
PMCID: PMC3587365  PMID: 23178851
hexamethylene diisocyanate (HDI); vapor; aliphatic; albumin; carbamoylation; glutathione (GSH); glutathione; diisocyanate; HDI; GSH
10.  Occupational Exposure to HDI: Progress and Challenges in Biomarker Analysis 
1,6-hexamethylene diisocyanate (HDI) is extensively used in the automotive repair industry and is a commonly reported cause of occupational asthma in industrialized populations. However, the exact pathological mechanism remains uncertain. Characterization and quantification of biomarkers resulting from HDI exposure can fill important knowledge gaps between exposure, susceptibility, and the rise of immunological reactions and sensitization leading to asthma. Here, we discuss existing challenges in HDI biomarker analysis including the quantification of N-acetyl-1,6-hexamethylene diamine (monoacetyl-HDA) and N,N′-diacetyl-1,6-hexamethylene diamine (diacetyl-HDA) in urine samples based on previously established methods for HDA analysis. In addition, we describe the optimization of reaction conditions for the synthesis of monoacetyl-HDA and diacetyl-HDA, and utilize these standards for the quantification of these metabolites in the urine of three occupationally exposed workers. Diacetyl-HDA was present in untreated urine at 0.015 – 0.060 μg/l. Using base hydrolysis, the concentration range of monoacetyl-HDA in urine was 0.19 – 2.2 μg/l, 60-fold higher than in the untreated samples on average. HDA was detected only in one sample after base hydrolysis (0.026 μg/l). In contrast, acid hydrolysis yielded HDA concentrations ranging from 0.36 to 10.1 μg/l in these three samples. These findings demonstrate HDI metabolism via N-acetylation metabolic pathway and protein adduct formation resulting from occupational exposure to HDI.
doi:10.1016/j.jchromb.2010.01.012
PMCID: PMC2889189  PMID: 20176515
1,6-hexamethylene diamine (HDA); biomarker; 1,6-hexamethylene diisocyanate (HDI); diisocyanate-induced asthma
11.  Biological monitoring to assess exposure from use of isocyanates in motor vehicle repair 
OBJECTIVES: To develop a method for the measurement of a metabolite of hexamethylene diisocyanate (HDI), an isocyanate, and use it to assess the exposure of sprayers employed in motor vehicle repair shops. METHODS: Urine samples were taken from sprayers wearing personal protective equipment and spraying in booths or with local exhaust ventilation, from bystanders, and from unexposed subjects. Samples were analyzed for a metabolite of HDI, hexamethylene diamine (HDA), by gas chromatography-mass spectrometry (GC-MS). RESULTS: HDA was detected in four sprayers and one bystander out of 22 workers. No HDA was detected in the urine of unexposed subjects. CONCLUSIONS: Exposure to isocyanates still occurs despite the use of personal protective equipment and the use of a booth or extracted space. Health surveillance is likely to be required to provide feedback on the adequacy of controls even if such precautions are used and to identify cases of early asthma. Biological monitoring can provide a useful additional tool to assess exposure and the adequacy of controls in this group of exposed workers.
 
PMCID: PMC1757787  PMID: 10615291
12.  Effects within the week on forced vital capacity are correlated with long term changes in pulmonary function: reanalysis of studies on car painters exposed to isocyanate. 
OBJECTIVES--To examine if car painters who work with polyurethane paints that contain hexamethylenediisocyanate (HDI) and hexamethylenediisocyanate biuret trimer (HDI-BT) develop acute as well as chronic impairment of lung function. METHODS--In this study data were reanalysed from two earlier studies on a group of car painters to see if a decrease in lung function within the week is a marker of vulnerability in those workers. Data on changes in forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) within the week were available for 20 car painters who were also examined six years later. RESULTS--10 men showed a decline in FVC within the week. There were no significant differences in age, duration of employment, exposures during the follow up period, or smoking between car painters who had decline in lung function within the week and car painters who had not. A significant correlation was found between the change in FVC within the week and the long term (six year) change in FVC, standardised for the effects of aging and smoking, and adjusted for the number of peak exposures. CONCLUSIONS--The results suggest that the decrease in FVC within the week might serve as a guide to identify car painters at risk of a further decrement in lung function above the effects of aging, smoking, and exposure.
PMCID: PMC1128186  PMID: 7735393
13.  Development of Photocrosslinkable Urethane-Doped Polyester Elastomers for Soft Tissue Engineering 
Finding an ideal biomaterial with the proper mechanical properties and biocompatibility has been of intense focus in the field of soft tissue engineering. This paper reports on the synthesis and characterization of a novel crosslinked urethane-doped polyester elastomer (CUPOMC), which was synthesized by reacting a previously developed photocrosslinkable poly (octamethylene maleate citrate) (POMC) prepolymers (pre-POMC) with 1,6-hexamethylene diisocyanate (HDI) followed by thermo- or photo-crosslinking polymerization. The mechanical properties of the CUPOMCs can be tuned by controlling the molar ratios of pre-POMC monomers, and the ratio between the prepolymer and HDI. CUPOMCs can be crosslinked into a 3D network through polycondensation or free radical polymerization reactions. The tensile strength and elongation at break of CUPOMC synthesized under the known conditions range from 0.73±0.12MPa to 10.91±0.64MPa and from 72.91±9.09% to 300.41±21.99% respectively. Preliminary biocompatibility tests demonstrated that CUPOMCs support cell adhesion and proliferation. Unlike the pre-polymers of other crosslinked elastomers, CUPOMC pre-polymers possess great processability demonstrated by scaffold fabrication via a thermally induced phase separation method. The dual crosslinking methods for CUPOMC pre-polymers should enhance the versatile processability of the CUPOMC used in various conditions. Development of CUPOMC should expand the choices of available biodegradable elastomers for various biomedical applications such as soft tissue engineering.
doi:10.4018/ijbre.2011010102
PMCID: PMC3615254  PMID: 23565318
Biodegradable Elastomer; Polyester; Soft Tissue Engineering; Thermo-Crosslinking; UV-Crosslinking
14.  Modeling of hexamethylene diisocyanate and psychrometric parameters and other effective factors in the polyurethane factories 
Background:
Diisocyanates are widely used in surface coatings, polyurethane (PUR) foams, adhesives, resins, elastomers, binders, and sealants. Isocyanate exposure is irritative to the skin, mucous membranes, eyes, and respiratory tract. The most common adverse health outcome associated with isocyanate exposure is asthma due to sensitization.
Objective:
The goal of this study is to find statistical predictive model to determine the relationship between airborne hexamethylene diisocyanate (HDI) and selective psychrometric variables.
Materials and Methods:
All air samplers (by midget impinger) were collected by mini personal sampler pump fixed to work stations near the source of pollution. The air samples and psychrometric parameters were separately collected and determined in a working shift for three periods of 2 h, each at a flow rate of 2 l/min in an impinger containing a solution of reagent of dimethyl sulfoxide in tryptamine [US National Instituteof Occupational Safety and Health (NIOSH), 1994].
Results:
There was a significant correlation between HDI concentration and relative humidity and dry bulb temperature (P < 0.05). No significant correlation was seen between altitude and dimension of PUR factories (P > 0.05).
Conclusions:
The finding of the study may be a useful initial tool in estimating possible HDI pollution situation in the PUR workplaces, based on simple psychrometric factors (indoor air temperature and relative humidity).
doi:10.4103/0019-5278.75693
PMCID: PMC3062018  PMID: 21461158
Diisocyanate; dry bulb temperature; hexamethylene diisocyanate concentration; regression; relative humidity
15.  N-halamine-based rechargeable antimicrobial and biofilm-controlling polyurethane 
Acta Biomaterialia  2011;8(4):1498-1506.
An N-halamine precursor, 5, 5-dimethyl hydantoin (DMH), was covalently linked to the surface of polyurethane (PU) with 1,6-hexamethylene diisocyanate (HDI) as a coupling agent. The reaction pathways were investigated using propyl isocyanate (PI) as a model compound, and the results suggested that the imide and amide groups of DMH had very similar reactivity toward the isocyanate groups on PU surfaces activated with HDI. After bleach treatment, the covalently bound DMH moieties were transformed into N-halamines. The new N-halmaine-based PU provided potent antimicrobial effects against Staphylococcus aureus (S. aureus, Gram-positive), Escherichia coli (E. coli, Gram-negative), methicillin-resistant staphylococcus aureus (MRSA, drug resistant Gram-positive bacteria), vancomycin-resistant enterococcus (VRE, drug resistant Gram-positive bacteria), and Candida albicans (C. ablicans, fungi), and successfully prevented bacterial and fungal biofilm formation. The antimicrobial and biofilm-controlling effects were stable for longer than 6 months under normal storage in open air. Furthermore, if the functions were lost due to prolonged use, they could be recharged by another chlorination treatment. The recharging could be repeated as needed to achieve long-term protection against microbial contamination and biofilm-formation.
doi:10.1016/j.actbio.2011.12.027
PMCID: PMC3289718  PMID: 22244984
Antimicrobial; Biofilm-controlling; N-halamine; Chlorination; Rechargeable; Polyurethane
16.  Asthma-like symptoms, atopy, and bronchial responsiveness in furniture workers 
OBJECTIVES: To study the role of individual and occupational risk factors for asthma in furniture workers. METHODS: 296 workers were examined (258 men, 38 women) with a questionnaire of respiratory symptoms and diseases, baseline spirometry, bronchial provocative test with methacholine, and skin prick tests. Non-specific bronchial hyperreactivity was defined as when a provocative dose with a fall of 20% in forced expiratory volume in 1 second (PD20FEV1) was < 0.8 mg and atopy in the presence of at least one positive response to skin prick tests. Workers were subdivided into spray painters (exposed to low concentrations of diisocyanates and solvents), woodworkers (exposed to wood dusts), and assemblers (control group). RESULTS: The prevalences of attacks of shortness of breath with wheezing and dyspnoea were higher in spray painters (13.5% and 11.5% respectively) than in woodworkers (7.7% and 6.3%) or in assemblers (1.6% and 1.6%); prevalences of chronic cough, asthma, and rhinitis were also slightly but not significantly higher in spray painters and in woodworkers than in assemblers. The difference in the prevalence of respiratory symptoms among the job titles was due to the atopic subjects, who showed a higher prevalence of chronic cough, wheeze, shortness of breath with wheeze, dyspnoea, and asthma in spray painters than in the other groups. The prevalence of non-specific bronchial hyperreactivity in subjects who performed bronchial provocative tests was 17.7%, with no significant difference among groups. Asthma symptoms were significantly associated with non-specific bronchial hyperreactivity. Asthma-like symptoms plus non-specific bronchial hyperreactivity was found in 4% of assemblers, 10% of woodworkers, and 13.3% of spray painters (chi 2 = 2.6, NS). Multiple logistic analysis taking into account individual (smoke, atopy, age) and occupational (job titles) risk factors confirmed that spray painters had higher prevalence of chronic cough than assemblers, and a trend in increasing the prevalence of shortness of breath with wheeze, dyspnoea, and asthma. CONCLUSIONS: Painters in the furniture industry, particularly atopic subjects, are at higher risk of asthma-like symptoms than other job titles. In these workers asthma-like symptoms are more sensitive than non-specific bronchial hyperreactivity in detecting a negative effect of the occupational exposure.
 
PMCID: PMC1757531  PMID: 9924457
17.  The role of exhaust ventilation systems in reducing occupational exposure to organic solvents in a paint manufacturing factory 
This paper presents the successful design and implementation of several exhaust ventilation systems in a paint manufacturing factory. The ventilation systems were designed based on American Conference of Governmental Industrial Hygienists recommendations. The duct works, fans, and other parts were made and mounted by local manufacturers. The concentrations of toluene and xylene as the common solvents used in paint mixing factories were measured to evaluate the role of ventilation systems in controlling the organic solvents. Occupational exposure to toluene and xylene as the major pollutants was assessed with and without applying ventilation systems. For this purpose, samples were taken from breathing zone of exposed workers using personal samples. The samples were analyzed using Occupational Safety and Health Administration analytical method No.12. The samples were quantified using gas chromatography. The results showed that the ventilation systems successfully controlled toluene and xylene vapors in workplace, air well below the recommended threshold limit value of Iran (44.49 and 97.73 ppm, respectively). It was also discovered that benzene concentration in workplace air was higher than its allowable concentrations. This could be from solvents impurities that require more investigations.
doi:10.4103/0019-5278.43266
PMCID: PMC2796753  PMID: 20040984
Exhaust ventilation systems; occupational exposure; paint manufacturing; ventilation standard
18.  Exposure Assessment Suggests Exposure to Lung Cancer Carcinogens in a Painter Working in an Automobile Bumper Shop 
Safety and Health at Work  2013;4(4):216-220.
A 46-year-old man who had worked as a bumper spray painter in an automobile body shop for 15 years developed lung cancer. The patient was a nonsmoker with no family history of lung cancer. To determine whether the cancer was related to his work environment, we assessed the level of exposure to carcinogens during spray painting, sanding, and heat treatment. The results showed that spray painting with yellow paint increased the concentration of hexavalent chromium in the air to as much as 118.33 μg/m3. Analysis of the paint bulk materials showed that hexavalent chromium was mostly found in the form of lead chromate. Interestingly, strontium chromate was also detected, and the concentration of strontium chromate increased in line with the brightness of the yellow color. Some paints contained about 1% crystalline silica in the form of quartz.
doi:10.1016/j.shaw.2013.09.002
PMCID: PMC3889078  PMID: 24422178
exposure assessment; hexavalent chromium; lung cancer; painting
19.  Occupational Exposure to Organic Solvents during Bridge Painting 
Annals of Occupational Hygiene  2010;54(4):417-426.
Exposure to volatile organic compounds (VOCs) from bridge painting was measured in New York City and New Jersey during the summer and fall seasons from 2005 to 2007. The effect of painting activities (paint coating layer, confinement setup, and application method) and meteorological conditions (temperature, humidity, and wind speed) on solvent exposure to aromatic, ketone, ester, and alkane compounds were individually evaluated. Mixed-effect models were used to examine the combination effects of these factors on the air concentration of total VOCs as the individual compound groups were not present in all samples. Air concentration associated with spraying was not affected by meteorological conditions since spraying was done in a confined space, thus reducing their impact on solvent air concentration. The mixed models for brushing and rolling samples included two fixed factors, i.e. application method and temperature, and one random factor, i.e. sampling day. An independent dataset (daily air samples) was used to validate the mixed model constructed for brushing and rolling samples. The regression line of the predicted values and actual measurements had a slope of 1.32 ± 0.15 for daily brushing and rolling samples, with almost all points being within the 95% confidence bands. The constructed model provides practical approaches for estimating the solvent exposure from brushing and rolling activities among construction painters. An adjusted mean air concentration derived from the activity-specific spray samples was the best estimate for that painting application.
doi:10.1093/annhyg/meq021
PMCID: PMC2902363  PMID: 20354053
construction; occupational exposure; oil-based paints; painting; solvents
20.  Diagnosis and prevention of diseases induced by isocyanate 
Isocyanates are among the most frequent causes of occupational asthma in industrialized countries. Early diagnosis of diisocyanate asthma followed by prompt termination of chemical exposure can prevent chronic morbidity due to persistent asthma. Chronic exposure to isocyanates also induces hypersensitivity pneumonitis (HP). The accurate diagnosis of diisocynate asthma requires a systematic approach that combines information obtained from the occupational history, immunologic tests and physiologic studies. The prevention of health problems from toluene diisocyanate (TDI), 4,4′-methylenediphenyl diisocyanate (MDI) and 1,6′-hexamethylene diisocyanate (HDI) is essential for all those handling the chemicals. Regulatory exposure limits should be observed. However, wheezing, coughing or even asthmatic attacks may occur after exposure much below the regulatory exposure limits especially in sensitive individuals. Preventing or minimizing exposure is of prime importance and should be supported by the installation of engineering controls, by education of the workforce, by regular monitoring of the workplace exposure and by medical surveillance. To prevent such asthma it is suggested that workers should be tested airway sensitivity and should avoid working in areas that have dust containing specific-IgE. Such tests must be periodically performed after working. Symptoms induced by isocyanate need earlier discover and early isolation of the associated individuals.
doi:10.1007/BF02897329
PMCID: PMC2723398  PMID: 21432263
isocyanates; diisocyanate; review; diagnosis; prevention
21.  Review of the occupational exposure to isocyanates: Mechanisms of action 
Polyurethanes are useful polymers in a large variety of technical and consumer products that are generally made from diisocyanates and polyols or similar compounds. Toluene diisocyanate (TDI), 4,4′-methylenediphenyl diisocyanate (MDI) and 1,6′-hexamethylene diisocyanate (HDI) are useful for polyurethane products. Isocyanates are reactive chemicals that can be handled without problems in manufacturing or technical environments. In general, consumers may only have contact with these chemicals on rare occasions. The objective of this study was to review the mechanisms of action of inhalation of isocyanates. This paper describes, in summary, the potential occupational exposure to isocyanates, the chemistry and reactivity of isocyanates, the results from genotoxicity studies, investigative toxicity studies, metabolism and results from epidemiology studies on isocyanate-exposed workers. The overall conclusion is that because humans are not exposed to high levels of respiratory isocyanate particles, concerns over the possible development of lung tumors should not be relevant. There are many mechanisms of action induced by isocyanates, but those entities are unclear. This is because these mechanisms act simultaneously and are complex.
doi:10.1007/BF02898058
PMCID: PMC2723231  PMID: 21432282
diisocyanate; immunology; genotoxicity; carcinogenicity; review
22.  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 µg/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.
doi:10.4168/aair.2011.3.1.21
PMCID: PMC3005314  PMID: 21217921
Isocyanate; toluene diisocyanate; biomarkers; 4,4-diphenylmethane diisocyanate; occupational asthma
23.  Human Innate Immune Responses to Hexamethylene Diisocyanate (HDI) and HDI-Albumin Conjugates 
Background
Isocyanates, a leading cause of occupational asthma, are known to induce adaptive immune responses; however, innate immune responses, which generally precede and regulate adaptive immunity, remain largely uncharacterized.
Objective
Identify and characterize cellular, molecular and systemic innate immune responses induced by hexamethylene diisocyanate (HDI).
Methods
Human peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with HDI-albumin conjugates or control antigen, and changes in phenotype, gene, and protein expression were characterized by flow cytometry, microarray, Western blot and ELISA. Cell uptake of isocyanate was visualized microscopically using HDI-albumin conjugates prepared with fluorescently-labeled albumin. In vivo, human HDI exposure was performed via specific inhalation challenge, and subsequent changes in PBMCs and serum proteins were measured by flow cytometry and ELISA. Genotypes were determined by PCR.
Results
Human monocytes take-up HDI-albumin conjugates and undergo marked changes in morphology and gene/protein expression in vitro. The most significant (p 0.007 – 0.05) changes in mircoarray gene expression were noted in lysosomal genes, especially peptidases and proton pumps involved in antigen processing. Chemokines that regulate monocyte/macrophage trafficking (MIF, MCP-1), and pattern recognition receptors that bind chitin (chitinases) and oxidized low-density lipoprotein (CD68) were also increased following isocyanate-albumin exposure. In vivo, HDI exposed subjects exhibited an acute increase in the percentage of PBMCs with the same HDI-albumin responsive phenotype characterized in vitro (HLA-DR+/CD11c+ with altered light scatter properties). An exposure-dependent decrease (46±11%; p<0.015) in serum concentrations of chitinase-3-like-1 was also observed, in individuals that lack the major (type 1) human chitinase (due to genetic polymorphism), but not in individuals possessing at least one functional chitinase-1 allele.
Conclusions
Previously unrecognized innate immune responses to HDI and HDI-albumin conjugates could influence the clinical spectrum of exposure reactions.
doi:10.1111/j.1365-2222.2008.02982.x
PMCID: PMC3131007  PMID: 18498542
Isocyanate; Innate; Monocyte; Macrophage; Chitinase; CD68; Albumin; MIF; Cathepsin; Exposure; Asthma
24.  Impact of occupational health hazards on serum markers of bone formation in spray painters of Chennai region in Tamil Nadu 
Context:
The association between spray paint exposure and bone remodeling received little attention despite the high usage of spray paints in automobile industries, steel furniture workshops etc.
Aim:
The present study was aimed at investigating the level of serum markers of bone formation in spray painters. The spray painting subjects were selected from automobile body repair workshops in Chennai region of TamilNadu which constitutes 30% of India's automobile industry.
Setting and Design:
All the study subjects, exposed to spray paint were working in a workshop without standard spraying room and did not wore any aerosol removing respirator. The controls were selected from random population irrespective of occupation. Data relevant to the socioeconomic features and personal history was collected using a questionnaire. The current study included 50 spray painters and 25 control subjects of same age group.
Materials and Methods:
We examined the level of serum calcium, serum phosphorus, serum differentiation markers of bone such as alkaline phosphatase (bone specific) and serum osteocalcin in which these levels were found to be high in serum of spray painters.
Conclusion:
The current study concludes dysregulation in bone remodeling of spray painters exposed to chronic solvents and paint pigments.
doi:10.4103/0019-5278.107084
PMCID: PMC3617514  PMID: 23580840
Bone remodeling; paint pigments; serum markers
25.  Exposure biomarkers and risk from gluing and heating of polyurethane: a cross sectional study of respiratory symptoms 
OBJECTIVES—To define the relation between exposure to polyurethane (PUR) glue, biomarkers of exposure and effect, and work related symptoms that occur at least once a week.
METHODS—In a cross sectional study, 152 workers and 14 clerks in a factory with exposure to sprayed and heated PUR glue containing 4,4'-diphenylmethane (MDI) or 1,6-hexamethylene (HDI) di-isocyanate were examined with gas chromatography-mass spectrometry (GC-MS) for metabolites of MDI in plasma (P-MDX) and urine (U-MDX), 2,4- and 2,6-toluene di-isocyanate (TDI; P-TDX, U-TDX) and HDI in plasma and urine, specific serum IgG (S-IgG-MDI, S-IgG-HDI, and S-IgG-TDI, respectively) and IgE (S-IgE-MDI). Work related symptoms of the eyes and airways (nose or lower airways, or both), and lung function were also evaluated.
RESULTS—P-MDX was detected in 65% of the workers, U-TDX in 47%, HDX in none. Three per cent were positive for S-IgE-MDI, 33% for S-IgG-MDI, 32% for S-IgG-TDI, and 12% for S-IgG-HDI. A few clerks had metabolites, and some had antibodies. Most metabolites and immunoglobulins were slightly correlated—for example, P-MDX v S-IgG-MDI: rs=0.21. Workers who heated glue had increased P-MDX (odds ratio (OR)=12 for a value above the median) and S-IgG-MDI (OR=3.7), sprayers P-2,4-TDX (OR=6.2) and P-2,6-TDX (OR=16). Twenty six per cent of the workers had work related symptoms of the airways, 21% from the nose, 11% from the lower airways. Spraying of glue increased the risk of work related symptoms and slightly decreased lung function. U-MDX was associated with work related symptoms from the airways (OR=3.7) and P-2,6-TDX with work related symptoms from the lower airways (OR=6.6). S-IgG-MDI was related to work related symptoms from the airways (OR=2.6).
CONCLUSIONS—There were relations between exposures to sprayed and heated PUR glue based on MDI and HDI, concentrations of metabolites of MDI and TDI in plasma and urine, specific IgG serum antibodies against MDI, TDI, and HDI, and work related symptoms.


Keywords: isocyanate; metabolites; antibodies
doi:10.1136/oem.57.6.396
PMCID: PMC1739970  PMID: 10810129

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