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.
biomarker; dermal exposure; 1,6-hexamethylene diamine (HDA); 1,6-hexamethylene diisocyanate (HDI); inhalation exposure; plasma
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.
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.
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.
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.
isocyanate; oligomers; dermal; biomonitoring; spray painting
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.
1,6-hexamethylene diamine (HDA); biomarker; 1,6-hexamethylene diisocyanate (HDI); diisocyanate-induced asthma
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.
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.
dermal exposure; exposure determinants; hexamethylene diisocyanate; isocyanate; statistical modeling
We conducted a repeated exposure-assessment survey for task-based breathing-zone concentrations (BZCs) of monomeric and polymeric 1,6-hexamethylene diisocyanate (HDI) during spray painting on 47 automotive spray painters from North Carolina and Washington State. We report here the use of linear mixed modeling to identify the primary determinants of the measured BZCs. Both one-stage (N = 98 paint tasks) and two-stage (N = 198 paint tasks) filter sampling was used to measure concentrations of HDI, uretidone, biuret, and isocyanurate. The geometric mean (GM) level of isocyanurate (1410 μg m−3) was higher than all other analytes (i.e. GM < 7.85 μg m−3). The mixed models were unique to each analyte and included factors such as analyte-specific paint concentration, airflow in the paint booth, and sampler type. The effect of sampler type was corroborated by side-by-side one- and two-stage personal air sampling (N = 16 paint tasks). According to paired t-tests, significantly higher concentrations of HDI (P = 0.0363) and isocyanurate (P = 0.0035) were measured using one-stage samplers. Marginal R2 statistics were calculated for each model; significant fixed effects were able to describe 25, 52, 54, and 20% of the variability in BZCs of HDI, uretidone, biuret, and isocyanurate, respectively. Mixed models developed in this study characterize the processes governing individual polyisocyanate BZCs. In addition, the mixed models identify ways to reduce polyisocyanate BZCs and, hence, protect painters from potential adverse health effects.
air sampling; exposure determinants; hexamethylene diisocyanate; isocyanate; statistical modeling
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.
oligomer; isocyanate; asthma; spray painter; sensitization
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.
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.
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.
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.
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.
biomarker; exposure; HDI; hygiene; occupational
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.
diisocyanate; immunology; genotoxicity; carcinogenicity; review
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.
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.
Identify and characterize cellular, molecular and systemic innate immune responses induced by hexamethylene diisocyanate (HDI).
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.
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.
Previously unrecognized innate immune responses to HDI and HDI-albumin conjugates could influence the clinical spectrum of exposure reactions.
Isocyanate; Innate; Monocyte; Macrophage; Chitinase; CD68; Albumin; MIF; Cathepsin; Exposure; Asthma
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.
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].
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).
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).
Diisocyanate; dry bulb temperature; hexamethylene diisocyanate concentration; regression; relative humidity
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
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.
isocyanates; diisocyanate; review; diagnosis; prevention
Single strand breaks in DNA were monitored in leucocytes from 17 men occupationally exposed to styrene. Personal air monitoring was carried out during one workday with two diffusion samplers and a portable photoionisation detector placed in the breathing zone. Exposure to styrene was also monitored by analysing styrene in blood and urine and mandelic acid in urine. Single strand breaks were measured in leucocytes by the alkaline elution technique. The biological samples were collected before a shift, at the end of a shift, and the next morning, before the next shift. An exposure dependent increase in single strand breaks was seen at the end of a shift but not before a shift or the next morning. Linear regression analysis indicated that the amount of DNA damage was roughly doubled after eight hours of exposure to 18 ppm styrene or at a urine concentration of 240 mg mandelic acid/g creatinine compared with the damage in non-exposed men. This study indicates that monitoring of single strand breaks with the alkaline elution technique may be a sensitive marker of genotoxic effects. To our knowledge, this is the first time that such a marker has been shown to correlate with exposure to less than 20 ppm styrene.
Bridge painters are exposed to lead during several job tasks performed during the workday, such as sanding, scraping, and blasting. After the Occupational Safety and Health Administration standard was passed in 1993 to control lead exposures among construction workers including bridge painters, this study was conducted among 84 bridge painters in the New England area to determine the significant predictors of blood lead levels. Lead was measured in personal air and hand wipe samples that were collected during the 2-week study period and in blood samples that were collected at the beginning and at the end of the study period. The personal air and hand wipe data as well as personal behaviors (i.e., smoking, washing, wearing a respirator) and work site conditions were analyzed as potential determinants of blood lead levels using linear mixed effects models. Our results show that the mean air lead levels over the 2-week period were the most predictive exposure measure of blood lead levels. Other individual-level significant predictors of blood lead levels included months worked on bridge painting crews, education, and personal hygiene index. Of the site-level variables investigated, having a containment facility on site was a significant predictor of blood lead levels. Our results also indicate that hand wipe lead levels were significantly associated with higher blood lead levels at the end of the study period compared with the beginning of the study period. Similarly, smoking on site and respirator fit testing were significantly associated with higher blood lead levels at the end of the study period. This study shows that several individual-level and site-level factors are associated with blood lead levels among bridge painters, including lead exposure through inhalation and possible hand-to-mouth contact, personal behaviors such as smoking on site, respirator fit testing, and work site conditions such as the use of better containment facilities. Accordingly, reduction in blood lead levels among bridge painters can be achieved by improving these workplace practices.
air lead levels; blood lead levels; bridge painters; hand wipes; lead; work site conditions
Isocyanates are some of the leading occupational causes of respiratory disorders, predominantly asthma. Adequate exposure monitoring may recognize risk factors and help to prevent the onset or aggravation of these aliments. Though, the biomonitoring appears to be most suitable for exposure assessment, the sampling time is critical, however. In order to settle the optimal time point for the sample collection in a practical biomonitoring approach, we aimed to measure the elimination of isocyanate urine metabolites.
A simple biomonitoring method enabling detection of all major diamine metabolites, from mono-, poly- and diisocyanates in one analytical step, has been established. Urine samples from 121 patients undergoing inhalative challenge tests with diisocyanates for diagnostic reasons were separated by gas chromatography and analyzed with mass spectrometry (GC-MS) at various time points (0-24 h) after the onset of exposure.
After controlled exposures to different concentrations of diisocyanates (496 ± 102 ppb-min or 1560 ± 420 ppb-min) the elimination kinetics (of respective isocyanate diamine metabolites) revealed differences between aliphatic and aromatic isocyanates (the latter exhibiting a slower elimination) and a dose-response relationship. No significant differences were observed, however, when the elimination time patterns for individual isocyanates were compared, in respect of either low or high exposure or in relation to the presence or absence of prior immunological sensitization.
The detection of isocyanate metabolites in hydrolyzed urine with the help of gas chromatography combined with mass spectrometric detection system appears to be the most suitable, reliable and sensitive method to monitor possible isocyanate uptake by an individual. Additionally, the information on elimination kinetic patterns must be factored into estimates of isocyanate uptake before it is possible for biomonitoring to provide realistic assessments of isocyanate exposure. The pathophysiological elimination of 1,6-hexamethylene diamine, 2,4-diamine toluene, 2,6-diamine toluene, 1,5-naphthalene diamine, 4,4'-diphenylmethane diamine and isophorone diamines (as respective metabolites of: 1,6-hexamethylene diisocyanate, 2,4-toluene diisocyanate and 2,6 toluene diisocyanate, 1,5-naphthalene diisocyanate, 4,4'-diphenylmethane diisocyanate and isophorone diisocyanates) differs between individual isocyanates' diamines.
isocyanates; biomonitoring; biological monitoring; exposure assessment, occupational asthma; hypersensitivity pneumonitis; specific inhalation challenge
Recently, a genome-wide association study (GWAS) conducted in Korean subjects identified four CTNNA3 (alpha-T catenin) single nucleotide polymorphisms (SNPs) (rs10762058, rs7088181, rs1786929, and rs4378283) associated with diisocyanate-induced occupational asthma (DA). The CTNNA3 gene codes for a cadherin involved in formation of stretch-resistant cell-cell adhesions. We conducted a candidate gene association study to replicate these findings in Caucasian workers. Genotyping was performed on DNA using a 5′ nuclease PCR assay collected from 410 diisocyanate-exposed and predominantly Canadian workers including 132 workers with DA confirmed by a specific inhalation challenge (DA+); 131 symptomatic workers in whom DA was excluded by a negative challenge (DA−); and 147 hexamethylene diisocyanate–exposed asymptomatic workers (AWs). As in the Korean study, highly linked CTNNA3 rs7088181 and rs10762058 SNPs (but not rs4378283 and rs1786929) were significantly associated with DA+ when compared with AWs but not in comparison with DA− workers (p ≤ 0.05). After adjusting for potentially confounding variables of age, smoking status, and duration of exposure, minor allele homozygotes of rs7088181 and rs10762058 SNPs were at increased risk for DA compared with AWs (OR = 9.05 [95% CI: 1.69, 48.54] and OR = 6.82 [95% CI: 1.65, 28.24], respectively). In conclusion, we replicated results from the only reported GWAS study of DA demonstrating an association between two closely linked CTNNA3 gene SNPs and DA. These findings lend further support to the clinical relevance of these genotypes in predicting susceptibility to DA and the potential importance of catenins in the disease process.
diisocyanate asthma; CTNNA3; alpha-T catenin; occupational asthma
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.
Antimicrobial; Biofilm-controlling; N-halamine; Chlorination; Rechargeable; Polyurethane
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.
Biodegradable Elastomer; Polyester; Soft Tissue Engineering; Thermo-Crosslinking; UV-Crosslinking
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.
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.
Isocyanate; toluene diisocyanate; biomarkers; 4,4-diphenylmethane diisocyanate; occupational asthma
A novel polyurethane was successfully synthesized by chain-extension of biodegradable poly (l-lactide) functionalized phosphatidylcholine (PC) with hexamethylene diisocyanate (HDI) as chain extender (PUR-PC). The molecular weights, glass transition temperature (Tg) increased significantly after the chain-extension. The hydrophilicity of PUR-PC was better than the one without PC, according to a water absorption test. Moreover, the number of adhesive platelets and anamorphic platelets on PUR-PC film were both less than those on PUR film. These preliminary results suggest that this novel polyurethane might be a better scaffold than traditional biodegradable polyurethanes for tissue engineering due to its better blood compatibility. Besides, this study also provides a new method to prepare PC-modified biodegradable polyurethanes.
polyurethanes; phosphatidylcholine; biodegradable; blood compatibility; polymer; surface
Urine samples were collected from 152 workers (64 men, 88 women) who had been exposed to benzene, 53 workers (men only) exposed to a mixture of benzene and toluene, and 213 non-exposed controls (113 men, 100 women). The samples were analysed for 1,2,4-benzentriol (a minor metabolite of benzene) by high performance liquid chromatography. The time weighted average solvent exposure of each worker was monitored by diffusive sampling technique. The urinary concentration of 1,2,4-benzentriol related linearly to the intensity of exposure to benzene both in men and women among workers exposed to benzene, and was suppressed by toluene co-exposure among male workers exposed to a mixture of benzene and toluene. A cross sectional balance study in men at the end of the shift of a workday showed that only 0.47% of benzene absorbed will be excreted into urine as 1,2,4-benzenetriol, in close agreement with previous results in rabbits fed benzene. The concentration of 1,2,4-benzenetriol in urine was more closely related to the concentration of quinol than that of catechol. The fact that phenol and quinol, but not catechol, are precursors of 1,2,4-benzentriol in urine was further confirmed by the intraperitoneal injection of the three phenolic compounds to rats followed by urine analysis for 1,2,4-benzenetriol.