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Leena A Nylanderfrench - One of the best experts on this subject based on the ideXlab platform.

  • influence of genetic variance on biomarker levels after occupational exposure to 1 6 Hexamethylene Diisocyanate monomer and 1 6 Hexamethylene Diisocyanate isocyanurate
    Frontiers in Genetics, 2020
    Co-Authors: Laura W Taylor, John E French, Zachary Robbins, Jayne C Boyer, Leena A Nylanderfrench
    Abstract:

    We evaluated the impact of genetic variance on biomarker levels in a population of workers in the automotive repair and refinishing industry who were exposed to respiratory sensitizers 1,6-Hexamethylene Diisocyanate (HDI) monomer and one of its trimers, HDI isocyanurate. The exposures and respective urine and plasma biomarkers 1,6-diaminohexane (HDA) and trisaminohexyl isocyanurate (TAHI) were measured in 33 workers; and genome-wide microarrays (Affymetrix 6.0) were used to genotype the workers' single-nucleotide polymorphisms (SNPs). Linear mixed model analyses have indicated that interindividual variations in both inhalation and skin exposures influenced these biomarker levels. Using exposure values as covariates and a false discovery rate < 0.10 to assess statistical significance, we observed that seven SNPs were associated with HDA in plasma, five were associated with HDA in urine, none reached significance for TAHI in plasma, and eight were associated with TAHI levels in urine. The different genotypes for the 20 significant SNPs accounted for 4- to 16-fold changes observed in biomarker levels. Associated gene functions include transcription regulation, calcium ion transport, vascular morphogenesis, and transforming growth factor beta signaling pathway, which may impact toxicokinetics indirectly by altering inflammation levels. Additionally, in an expanded analysis using a minor allele cutoff of 0.05 instead of 0.10, there were biomarker-associated SNPs within three genes that have been associated with isocyanate-induced asthma: ALK, DOCK2, and LHPP. We demonstrate that genetic variance impacts the biomarker levels in workers exposed to HDI monomer and HDI isocyanurate and that genetics can be used to refine exposure predictions in small cohorts when quantitative personal exposure and biomarker measurements are included in the models.

  • dna methylation modifies urine biomarker levels in 1 6 Hexamethylene Diisocyanate exposed workers a pilot study
    Toxicology Letters, 2014
    Co-Authors: Leena A Nylanderfrench, John E French, Jayne C Boyer, Lisa Smeester, Alison P Sanders, Rebecca C Fry
    Abstract:

    Abstract DNA methylation may mediate inter-individual responses to chemical exposure and, thus, modify biomarker levels of exposure and effects. We analyzed inter-individual differences in inhalation and skin exposure to 1,6-Hexamethylene Diisocyanate (HDI) and urine biomarker 1,6-Hexamethylene diamine (HDA) levels in 20 automotive spray-painters. Genome-wide 5-methyl cytosine (CpG) DNA methylation was assessed in each individual’s peripheral blood mononuclear cells (PBMC) DNA using the Illumina 450K CpG array. Mediation analysis using linear regression models adjusted for age, ethnicity, and smoking was conducted to identify and assess the association between HDI exposure, CpG methylation, and urine HDA biomarker levels. We did not identify any CpGs common to HDI exposure and biomarker level suggesting that CpG methylation is a mediator that only partially explains the phenotype. Functional significance of genic- and intergenic-CpG methylation status was tested using protein–protein or protein–DNA interactions and gene-ontology enrichment to infer networks. Combined, the results suggest that methylation has the potential to affect HDI mass transport, permeation, and HDI metabolism. We demonstrate the potential use of PBMC methylation along with quantitative exposure and biomarker data to guide further investigation into the mediators of occupational exposure and biomarkers and its role in risk assessment.

  • penetration patterns of monomeric and polymeric 1 6 Hexamethylene Diisocyanate monomer in human skin
    Chemical Hazards in Industry, 2012
    Co-Authors: Jennifer M Thomasen, Leena A Nylanderfrench
    Abstract:

    The authors investigated penetration patterns of monomeric and polymeric 1,6-Hexamethylene Diisocyanate (HDI), experimentally and as part of commercial products, in excised full-thickness human skin at 5, 10, 30, or 60 min after exposure. They observed that both monomeric and polymeric HDI were readily absorbed into the skin and that the clearcoat composition affects the penetration rate of the individual isocyanates. The short-term absorption rates for HDI monomer, biuret, and isocyanurate were determined and used to estimate the exposure time required to reach a body burden equal to the American Conference of Governmental Industrial Hygienists (ACGIH) inhalation threshold limit value (TLV) or Oregon State occupational exposure limit (OEL). Oregon is the only government entity in the United States to promulgate a short-term exposure limit (STEL) for HDI-based polyisocyanates biuret and isocyanurate. Based on these absorption rates for a slow-drying clearcoat after 10 min (1.33 µg/cm2/h) or 60 min (0.219 µg/cm2/h), They calculated that 6.5 and 40 min dermal exposure, respectively, is required to achieve a dose of HDI equivalent to the ACGIH TLV. For biuret, the time to achieve a dose equivalent to the Oregon OEL for slow-drying clearcoat was much shorter (<31 min) than that for fast-drying clearcoat (618 min). Isocyanurate had the shortest skin absorption times regardless of clearcoat formulation (14 s-1.7 min). These results indicate that the dose received through dermal exposure to HDI-containing clearcoats has a significant potential to exceed the dose equivalent to that received through inhalation exposure at established regulatory limits. A critical need exists to monitor dermal exposure quantitatively in exposed workers, to use proper protective equipment to reduce dermal exposure, and to re-evaluate regulatory exposure limits for isocyanates.

  • development of a sampling patch to measure dermal exposures to monomeric and polymeric 1 6 Hexamethylene Diisocyanate a pilot study
    Journal of Occupational and Environmental Hygiene, 2011
    Co-Authors: Jennifer M Thomasen, Kenneth W. Fent, Leena A Nylanderfrench
    Abstract:

    The purpose of this study was to develop and evaluate a patch sampler to monitor dermal exposures to monomeric and polymeric 1,6-Hexamethylene Diisocyanate (HDI) in the automotive refinishing industry. Different patch materials were used to construct the patches, and patches impregnated with a derivatizing solution were compared with those that were not impregnated. We observed that impregnated felt patches measured significantly more HDI monomer (p = 0.04) than non-impregnated patches in a controlled experiment. Both impregnated and non-impregnated patches were compared with the tape-strip method by monitoring three spray painters’ dermal exposure to monomeric and polymeric HDI. Isocyanurate was the predominant species measured by all three sampler types with detectable levels in >86% of samples. Overall, tape-strips of exposed skin measured lower levels of monomeric and polymeric HDI than impregnated patch samplers at the same sampling site on the skin. Unlike tape-strips, impregnated patches are not as...

  • hemoglobin adducts in workers exposed to 1 6 Hexamethylene Diisocyanate
    Biomarkers, 2011
    Co-Authors: Sheila L Flack, Stephen G Whittaker, Linda Trelles G Gaines, Jennifer M Thomasen, Kenneth W. Fent, Louise M. Ball, Leena A Nylanderfrench
    Abstract:

    We investigated the utility of 1,6-Hexamethylene diamine (HDA) hemoglobin adducts as biomarkers of exposure to 1,6-Hexamethylene Diisocyanate (HDI) monomer. Blood samples from 15 spray painters applying HDI-containing paint were analyzed for hemoglobin HDA (HDA-Hb) and N-acetyl-1,6-Hexamethylene diamine (monoacetyl-HDA-Hb) by GC-MS. HDA-Hb was detected in the majority of workers (≤1.2–37 ng/g Hb), whereas monoacetyl-HDA-Hb was detected in one worker (0.06 ng/g Hb). The stronger, positive association between HDA-Hb and cumulative HDI exposure (r2 = 0.3, p < 0.06) than same day exposure (p ≥ 0.13) indicates long-term elimination kinetics for HDA-Hb adducts. This association demonstrates the suitability of HDA-Hb adducts for further validation as a biomarker of HDI exposure.

Kenneth W. Fent - One of the best experts on this subject based on the ideXlab platform.

  • development of a sampling patch to measure dermal exposures to monomeric and polymeric 1 6 Hexamethylene Diisocyanate a pilot study
    Journal of Occupational and Environmental Hygiene, 2011
    Co-Authors: Jennifer M Thomasen, Kenneth W. Fent, Leena A Nylanderfrench
    Abstract:

    The purpose of this study was to develop and evaluate a patch sampler to monitor dermal exposures to monomeric and polymeric 1,6-Hexamethylene Diisocyanate (HDI) in the automotive refinishing industry. Different patch materials were used to construct the patches, and patches impregnated with a derivatizing solution were compared with those that were not impregnated. We observed that impregnated felt patches measured significantly more HDI monomer (p = 0.04) than non-impregnated patches in a controlled experiment. Both impregnated and non-impregnated patches were compared with the tape-strip method by monitoring three spray painters’ dermal exposure to monomeric and polymeric HDI. Isocyanurate was the predominant species measured by all three sampler types with detectable levels in >86% of samples. Overall, tape-strips of exposed skin measured lower levels of monomeric and polymeric HDI than impregnated patch samplers at the same sampling site on the skin. Unlike tape-strips, impregnated patches are not as...

  • hemoglobin adducts in workers exposed to 1 6 Hexamethylene Diisocyanate
    Biomarkers, 2011
    Co-Authors: Sheila L Flack, Stephen G Whittaker, Linda Trelles G Gaines, Jennifer M Thomasen, Kenneth W. Fent, Louise M. Ball, Leena A Nylanderfrench
    Abstract:

    We investigated the utility of 1,6-Hexamethylene diamine (HDA) hemoglobin adducts as biomarkers of exposure to 1,6-Hexamethylene Diisocyanate (HDI) monomer. Blood samples from 15 spray painters applying HDI-containing paint were analyzed for hemoglobin HDA (HDA-Hb) and N-acetyl-1,6-Hexamethylene diamine (monoacetyl-HDA-Hb) by GC-MS. HDA-Hb was detected in the majority of workers (≤1.2–37 ng/g Hb), whereas monoacetyl-HDA-Hb was detected in one worker (0.06 ng/g Hb). The stronger, positive association between HDA-Hb and cumulative HDI exposure (r2 = 0.3, p < 0.06) than same day exposure (p ≥ 0.13) indicates long-term elimination kinetics for HDA-Hb adducts. This association demonstrates the suitability of HDA-Hb adducts for further validation as a biomarker of HDI exposure.

  • field comparison of air sampling methods for monomeric and polymeric 1 6 Hexamethylene Diisocyanate
    Journal of Occupational and Environmental Hygiene, 2011
    Co-Authors: Jennifer M Thomasen, Stephen G Whittaker, Kenneth W. Fent, Carolyn K Reebwhitaker, Leena A Nylanderfrench
    Abstract:

    This study was to critically compared 13 different air samplers for their ability to monitor air exposures to monomeric and polymeric 1,6-Hexamethylene Diisocyanate (HDI) in the automotive refinishing industry. Using both fast- and slow-drying clearcoat, we tested the following types of samplers: single- and dual-stage 37-mm polypropylene (PP) and polystyrene (PS) samplers (open- and closed-face), IOM (with plastic and stainless steel inserts), OSHA42, IsoChek, and WA-DOSH samplers. Midget impingers with frit were used as reference samplers. We observed the PP, PS, and IOM samplers to measure greater levels of HDI monomer and biuret when a fast-drying clearcoat was applied compared with a slow-drying clearcoat. When a slow-drying clearcoat was applied, the open-face PP and PS samplers measured significantly more monomeric and polymeric HDI (2-fold; p < 0.003) than the closed-face PP and PS samplers. We determined that significantly more monomeric and polymeric HDI were measured by impingers (1.3–1.9-fold)...

  • factors affecting variability in the urinary biomarker 1 6 Hexamethylene diamine in workers exposed to 1 6 Hexamethylene Diisocyanate
    Journal of Environmental Monitoring, 2011
    Co-Authors: Linda Trelles G Gaines, Stephen G Whittaker, Jennifer M Thomasen, Sheila L Flack, Kenneth W. Fent, Leena A Nylanderfrench
    Abstract:

    Although urinary 1,6-Hexamethylene diamine (HDA) is a useful biomarker of exposure to 1,6-Hexamethylene Diisocyanate (HDI), a large degree of unexplained intra- and inter-individual variability exists between estimated HDI exposure and urine HDA levels. We investigated the effect of individual and workplace factors on urine HDA levels using quantitative dermal and inhalation exposure data derived from a survey of automotive spray painters exposed to HDI. Painters' dermal and breathing-zone HDI-exposures were monitored over an entire workday for up to three separate workdays, spaced approximately one month apart. One urine sample was collected before the start of work with HDI-containing paints, and multiple samples were collected throughout the workday. Using mixed effects multiple linear regression modeling, coverall use resulted in significantly lower HDA levels (p = 0.12), and weekday contributed to significant variability in HDA levels (p = 0.056). We also investigated differences in urine HDA levels stratified by dichotomous and classification covariates using analysis of variance. Use of coveralls (p = 0.05), respirator type worn (p = 0.06), smoker status (p = 0.12), paint-booth type (p = 0.02), and more than one painter at the shop (p = 0.10) were all found to significantly affect urine HDA levels adjusted for creatinine concentration. Coverall use remained significant (p = 0.10), even after adjusting for respirator type. These results indicate that the variation in urine HDA level is mainly due to workplace factors and that appropriate dermal and inhalation protection is required to prevent HDI exposure.

  • urine 1 6 Hexamethylene diamine hda levels among workers exposed to 1 6 Hexamethylene Diisocyanate hdi
    Annals of Occupational Hygiene, 2010
    Co-Authors: Linda Trelles G Gaines, Stephen G Whittaker, Jennifer M Thomasen, Sheila L Flack, Kenneth W. Fent, Kai Ding, Louise M. Ball, David B Richardson, Leena A Nylanderfrench
    Abstract:

    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.

Sebastien Gagne - One of the best experts on this subject based on the ideXlab platform.

  • quantitative determination of Hexamethylene Diisocyanate hdi 2 4 toluene Diisocyanate 2 4 tdi and 2 6 toluene Diisocyanate 2 6 tdi monomers at ppt levels in air by alkaline adduct coordination ionspray tandem mass spectrometry
    Journal of Environmental Monitoring, 2005
    Co-Authors: Jacques Lesage, Yves Cloutier, Sebastien Gagne, Claude Ostiguy, Huu Van Tra
    Abstract:

    Occupational exposures to isocyanates can lead to occupational asthma. Once sensitized, some workers could react to isocyanate monomers at concentrations below 1% of the Permissible Exposure Limit of 5 ppb in air. Currently available methods are not sufficiently sensitive to adequately evaluate isocyanates present at these levels in workplace air. This article describes a novel method for isocyanate determination allowing the ultratrace quantification in workplace air of Hexamethylene Diisocyanate, 2,4-toluene Diisocyanate and 2,6-toluene Diisocyanate monomers. Sampling is performed during a complete workshift at a flow rate of 1 L min−1 with a cassette containing a 1-(2-methoxyphenyl)piperazine-impregnated 25 mm filter. Analysis is performed using liquid chromatography hyphenated with coordination ionspray tandem mass spectrometry. The analytical method’s linearity was measured for a concentration range varying from the limit of detection of 0.04–0.13 ng mL−1, depending on the monomer, up to approximately 32 ng mL−1 for every isocyanate monomer, all with correlation coefficients (R2) greater than 0.999. The analytical method’s lower limit of quantification combined with an adapted sampling strategy allow the quantification of isocyanate monomers down to 0.04 ppt for an 8 h work shift when a lithium adduct is used, which is more than 300 times lower than the most sensitive method currently available. This novel method can be used to confirm the very low level of isocyanate monomers for the safe reassignment of sensitized workers and it is also useful for charting the isocyanate dispersion tail in workplace environments.

Marjo Tuppurainen - One of the best experts on this subject based on the ideXlab platform.

  • long term follow up of Hexamethylene Diisocyanate diphenylmethane Diisocyanate and toluene Diisocyanate induced asthma
    American Journal of Respiratory and Critical Care Medicine, 2000
    Co-Authors: Päivi Piirilä, Suvipaivikki Salo, Helena Keskinen, Timo Tuomi, Ritva Luukkonen, Henrik Nordman, Marjo Tuppurainen
    Abstract:

    In 1976–1992 245 new cases of asthma induced by Diisocyanates were diagnosed, caused by Hexamethylene Diisocyanate (HDI) in 39%, diphenylmethane Diisocyanate (MDI) in 39%, and toluene Diisocyanate (TDI) in 17% of the cases. Our aim was to study the clinical outcome of Diisocyanate-induced asthma. A questionnaire was sent to the 235 patients alive in 1995, and validated by reexamining clinically 91 of them. The study was carried out on average 10 (3-19) yr after the diagnosis. Of the patients 82% experienced symptoms of asthma, 34% used no medication, and 35% were on regular medication. The patients having displayed immunoglobulin E (IgE) antibodies to isocyanates used less medication (OR 0.273; CI 0.098, 0.758) and had fewer symptoms of asthma (OR 0.329; CI 0.124, 0.875) than the IgE-negative ones. They also had a significantly shorter duration of symptoms (p = 0.0025), latency period (p = 0.0249), and duration of exposure (p = 0.0008) than the IgE-negative patients. This did not, however, entirely explai...

  • long term follow up of Hexamethylene Diisocyanate diphenylmethane Diisocyanate and toluene Diisocyanate induced asthma
    American Journal of Respiratory and Critical Care Medicine, 2000
    Co-Authors: Päivi Piirilä, Suvipaivikki Salo, Helena Keskinen, Timo Tuomi, Ritva Luukkonen, Henrik Nordman, Marjo Tuppurainen
    Abstract:

    In 1976-1992 245 new cases of asthma induced by Diisocyanates were diagnosed, caused by Hexamethylene Diisocyanate (HDI) in 39%, diphenylmethane Diisocyanate (MDI) in 39%, and toluene Diisocyanate (TDI) in 17% of the cases. Our aim was to study the clinical outcome of Diisocyanate-induced asthma. A questionnaire was sent to the 235 patients alive in 1995, and validated by reexamining clinically 91 of them. The study was carried out on average 10 () yr after the diagnosis. Of the patients 82% experienced symptoms of asthma, 34% used no medication, and 35% were on regular medication. The patients having displayed immunoglobulin E (IgE) antibodies to isocyanates used less medication (OR 0.273; CI 0.098, 0.758) and had fewer symptoms of asthma (OR 0.329; CI 0.124, 0.875) than the IgE-negative ones. They also had a significantly shorter duration of symptoms (p = 0.0025), latency period (p = 0.0249), and duration of exposure (p = 0.0008) than the IgE-negative patients. This did not, however, entirely explain the more favourable outcome of the IgE-positive patients. Patients with HDI-induced asthma used less medication (OR 0.412; CI 0.229, 0.739) than patients with MDI- and TDI-induced asthma. The results confirm the generally rather poor medical outcome of Diisocyanate-induced asthma; the persistence of symptoms and unspecific bronchial reactivity were pronounced in TDI-induced asthma. A more favourable outcome was associated with IgE mediation and HDI inducement.

Carrie A Redlich - One of the best experts on this subject based on the ideXlab platform.

  • polymerization of Hexamethylene Diisocyanate in solution and a 260 23 m z m h ion in exposed human cells
    Analytical Biochemistry, 2018
    Co-Authors: Adam V Wisnewski, Carrie A Redlich, Jian Liu, Ala F Nassar
    Abstract:

    Abstract Hexamethylene Diisocyanate (HDI) is an important industrial chemical that can cause asthma, however pathogenic mechanisms remain unclear. Upon entry into the respiratory tract, HDI's N=C=O groups may undergo nucleophilic addition (conjugate) to host molecules (e.g. proteins), or instead react with water (hydrolyze), releasing CO2 and leaving a primary amine in place of the original N=C=O. We hypothesized that (primary amine groups present on) hydrolyzed or partially hydrolyzed HDI may compete with proteins and water as a reaction target for HDI in solution, resulting in polymers that could be identified and characterized using LC-MS and LC-MS/MS. Analysis of the reaction products formed when HDI was mixed with a pH buffered, isotonic, protein containing solution identified multiple [M+H]+ ions with m/z's and collision-induced dissociation (CID) fragmentation patterns consistent with those expected for dimers (259.25/285.23 m/z), and trimers (401.36/427.35 m/z) of partially hydrolyzed HDI (e.g. ureas/oligoureas). Human peripheral blood mononuclear cells (PBMCs) and monocyte-like U937, but not airway epithelial NCI-H292 cell lines cultured with these HDI ureas contained a novel 260.23 m/z [M+H]+ ion. LC-MS/MS analysis of the 260.23 m/z [M+H]+ ion suggest the formula C13H29N3O2 and a structure containing partially hydrolyzed HDI, however definitive characterization will require further orthogonal analyses.

  • Articles Effects of Hexamethylene Diisocyanate Exposure on Human Airway Epithelial Cells: In Vitro Cellular and Molecular Studies
    2013
    Co-Authors: Adam V Wisnewski, Nadine Magoski, Qing Liu, Jing-jing Miller, Carrie A Redlich
    Abstract:

    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 HDIincreased 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. Key words: exposure, Hexamethylene Diisocyanate, human airway epithelial cell, redox, thiol, thioredoxin reductase. Environ Health Perspect 110:901–907 (2002). [Online 25 July 2002

  • biomonitoring Hexamethylene Diisocyanate hdi exposure based on serum levels of hdi specific igg
    Annals of Occupational Hygiene, 2012
    Co-Authors: Adam V Wisnewski, Meredith H Stowe, Abby Nerlinger, Paul Opareaddo, David Decamp, Christopher R Kleinsmith, Carrie A Redlich
    Abstract:

    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 5 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 5 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.

  • human innate immune responses to Hexamethylene Diisocyanate hdi and hdi albumin conjugates
    Clinical & Experimental Allergy, 2008
    Co-Authors: Adam V Wisnewski, Qing Liu, Jian Liu, Carrie A Redlich
    Abstract:

    Summary 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 The aim of the study was to identify and characterize the 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 labelled albumin. In vivo, human HDI exposure was performed via a 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-values 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 a drastic 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 who 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.

  • urinary hexane diamine to assess respiratory exposure to Hexamethylene Diisocyanate aerosol a human inhalation study
    International Journal of Occupational and Environmental Health, 2004
    Co-Authors: Youcheng Liu, Michele Berode, Carole Holm, Meredith H Stowe, Frank X Walsh, Martin D Slade, Mark F Boeniger, Carrie A Redlich
    Abstract:

    AbstractThe use of urinary hexane diamine (HDA) as a biomarker to assess human respiratory exposure to Hexamethylene Diisocyanate (HDI) aerosol was evaluated. Twenty-three auto body shop workers were exposed to HDI biuret aerosol for two hours using a closed exposure apparatus. HDI exposures were quantified using both a direct-reading instrument and a treated-filter method. Urine samples collected at baseline, immediately post exposure, and every four to five hours for up to 20 hours were analyzed for HDA using gas chromatography and mass spectrometry. Mean urinary HDA (μg/ g creatinine) sharply increased from the baseline value of 0.7 to 18.1 immediately post exposure and decreased rapidly to 4.7, 1.9 and 1.1, respectively, at 4,9, and 18 hours post exposure. Considerable individual variability was found. Urinary HDA can assess acute respiratory exposure to HDI aerosol, but may have limited use as a biomarker of exposure in the workplace.