| 1. |
- Broström, Julia, et al.
(författare)
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Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and its association with airways symptoms.
- 2015
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 1096-0333 .- 0041-008X. ; 287:3, s. 222-231
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Tidskriftsartikel (refereegranskat)abstract
- Diisocyanates are industrial chemicals which have a wide range of applications in developed and developing countries. They are notorious lung toxicants and respiratory sensitizers. However, the mechanisms behind their adverse effects are not adequately characterized. Autotaxin (ATX) is an enzyme producing lysophosphatidic acid (LPA), and the ATX-LPA axis has been implicated in lung related inflammatory conditions and diseases, including allergic asthma, but not to toxicity of environmental low-molecular-weight chemicals. We investigated effects of toluene diisocyanate (TDI) on ATX induction in human lung epithelial cell models, and we correlated LPA-levels in plasma to biomarkers of TDI exposure in urine collected from workers exposed to <5ppb (parts per billion). Information on workers' symptoms was collected through interviews. One nanomolar TDI robustly induced ATX release within 10min in vitro. A P2X7- and P2X4-dependent microvesicle formation was implicated in a rapid ATX release and a subsequent protein synthesis. Co-localization between purinergic receptors and ATX was documented by immunofluorescence and confocal microscopy. The release was modulated by monocyte chemoattractant protein-1 (MCP-1) and by extracellular ATP. In workers, we found a dose-response relationship between TDI exposure biomarkers in urine and LPA levels in plasma. Among symptomatic workers reporting "sneezing", the LPA levels were higher than among non-symptomatic workers. This is the first report indicating induction of the ATX-LPA axis by an environmental low-molecular-weight chemical, and our data suggest a role for the ATX-LPA axis in TDI toxicity.
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| 2. |
- Hamada, Haneen, et al.
(författare)
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Assessment of dermal uptake of diphenylmethane-4,4'-diisocyanate using tape stripping and biological monitoring
- 2018
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Ingår i: EJD. European journal of dermatology. - : John Libbey Publishing. - 1167-1122 .- 1952-4013. ; 28:2, s. 143-148
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Tidskriftsartikel (refereegranskat)abstract
- Very little is known about the dermal uptake of isocyanates, and dermal exposure to isocyanates has been discussed as a factor involved in the induction of respiratory diseases. To investigate the dermal uptake of diphenylmethane-4,4'-diisocyanate (4,4'-MDI). Four volunteers were dermally exposed to 10, 25, 49 and 50 mg 4,4'-MDI, respectively, for eight hours. The exposed areas were tape stripped. Urine and blood were biologically monitored for 48 hours. Tape strips, plasma, and urine were analysed by liquid chromatography-mass spectrometry. In total, 35-70% of the applied dose of 4,4'-MDI was absorbed by the skin. Very low fractions of applied dose were found in the tape strips. The 4,4'-MDA concentration in plasma and urine was low, but peaked in urine at 10-14 hours and plasma at 8-32 hours after exposure. 4,4'-MDI is readily absorbed by human skin. Only small fractions of 4,4'-MDI remain as such in the superficial skin layers. The amounts found in blood and urine were only small fractions of the total applied doses which indicates that very small amounts of 4,4'-MDI penetrate the skin and reach the blood stream. The dermal uptake and distribution of 4,4'-MDI is much slower compared to that associated with airway uptake. Our data strongly indicate that formation of 4,4'-MDA from 4,4'-MDI upon reacting with water in the skin can only occur to a very limited extent.
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| 3. |
- Lindh, Christian, et al.
(författare)
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Biological monitoring of toluene diisocyanate (TDI) exposure by analysis of urine from exposed workers
- 2002
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Ingår i: Proceedings 50th ASMS Conference on Mass Spectrmetry and Allied Topics. ; , s. 655-656
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Konferensbidrag (refereegranskat)abstract
- A gas chromatography-negative ion chemical ionization-selected ion monitoring-mass spectrometry (GC-NICI-SIM-MS) method was used to quantitate the metabolite toluene diamine (TDA) in urine samples of toluene diisocyanate (TDI) exposed workers. In order to validate the biological monitoring method, air samples were collected and analyzed using a liquid chromatography tandem mass spectrometry (LC-MS) method. The urine samples were treated with liquid-liquid extraction to retrieve the toluene diamine (TDA). It was observed that urinary TDA levels were applicable fro biological monitoring of TDI exposure.
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| 4. |
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| 5. |
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| 6. |
- Sennbro, Carl Johan, et al.
(författare)
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Biological monitoring of exposure to toluene diisocyanate.
- 2004
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Ingår i: Scandinavian Journal of Work, Environment and Health. - 0355-3140. ; 30:5, s. 371-378
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES :Toluene diisocyanate (TDI) is used in the manufacture of polyurethane and is a potent inducer of diseases of the airways. In this study, 2,4- and 2,6-toluenediamine in hydrolyzed urine and plasma were evaluated as biomarkers of exposure to 2,4- and 2,6-TDI, respectively. METHODS: For 81 exposed workers from nine different plants, the personal 8-hour time-weighted-average exposure to TDI was monitored by a filter method with 1-(2-methoxyphenyl)piperazine. In parallel, urinary samples (U1) were collected during the last 4 hours of the workshift. On a different occasion, blood samples and additional urinary samples (U2) were collected from the exposed workers, and also from a reference group consisting of 121 unexposed workers. The biomarker levels were determined in urine and plasma by the use of alkaline hydrolysis. RESULTS: There were strong associations between the personal air and biomarker levels, with correlation coefficients in the range of 0.75-0.88 for the U1 samples and in the range of 0.50-0.78 for the plasma samples. By weighted linear regression, the relations were calculated between the air and biomarker levels. The slopes of the obtained regression curves ranged from 1.8 to 2.7 m3/1 for air-urine and from 2.2 to 2.9 m3/1 for air-plasma, and the intercepts were all close to the origin of the coordinates. Through the extrapolation of these regression curves, biological exposure limits were calculated. CONCLUSIONS: The biological monitoring methods and strategies presented in this report are useful for assessing exposure to TDI in practice.
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| 7. |
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| 8. |
- Sennbro, Carl Johan, et al.
(författare)
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Development, validation and characterization of an analytical method for the quantification of hydrolysable urinary metabolites and plasma protein adducts of 2,4-and 2,6-toluene diisocyanate, 1,5-naphthalene diisocyanate and 4,4 '-methylenediphenyl diisocyanate
- 2003
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Ingår i: Biomarkers. - : Informa UK Limited. - 1366-5804 .- 1354-750X. ; 8:3-4, s. 204-217
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Tidskriftsartikel (refereegranskat)abstract
- Occupational exposure to diisocyanates within the plastic industry causes irritation and disorders in the airway. The aim of this study was to develop, validate and characterize a method for the determination of 2,4-toluenediamine (2,4-TDA), 2,6-toluenediamine (2,6-TDA), 1,5-diaminonaphthalene (1,5-NDA) and 4,4'-methylenedianiline (4,4'-MDA) in hydrolysed urine and plasma, and to study the correlation between the plasma and urinary levels of these potential biomarkers of 2,4-toluene diisocyanate (2,4-TDI), 2,6-toluene diisocyanate (2,6-TDI), 1,5-naphthalene diisocyanate (1,5-NDI) and 4,4'-methylenediphenyl diisocyanate (4,4'-MDI), respectively. Samples were hydrolysed with 0.3 M NaOH at 100degreesC for 24 h. The diamines were extracted, derivatized with pentafluoropropionic acid anhydride, and quantified by selected ion monitoring on gas chromatography-mass spectrometry. The repeatability and reproducibility of the method were 7-18% and 7-19%, respectively. Dialysis experiments showed that the metabolites of 2,4-TDI, 2,6-TDI, 1,5-NDI and 4,4'-MDI in plasma were exclusively protein adducts. No free diamines were found in urine, indicating that all diisocyanate-related metabolites were in a conjugated form. For each diisocyanate-related biomarker, there were strongly significant correlations (p < 0.001) between individual levels of metabolites in plasma and urine, with Spearman's rank correlation coefficient (r(s)) values of 0.74-0.90. The methods presented here will be valuable for the development of biological monitoring methods for diisocyanates.
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| 9. |
- Tinnerberg, Håkan, et al.
(författare)
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Biomarkers of exposure in Monday morning urine samples as a long-term measure of exposure to aromatic diisocyanates.
- 2014
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 1432-1246 .- 0340-0131. ; 87:4, s. 365-372
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Exposure to diisocyanates is a known occupational hazard. One method for monitoring occupational exposure is by analyzing biomarkers in hydrolyzed urine and plasma. The half-life of the biomarkers in plasma is about 3 weeks, and the urinary elimination is divided into one fast (hours) and one slow phases (weeks). Polymorphism in glutathione S-transferase enzymes (GST) is earlier shown to modify the metabolism. The aim of the study was to assess whether biomarkers of exposure in urine collected after two non-exposed days correlate with levels in plasma and whether they can be used as a measure for long-term exposure to aromatic diisocyanates and further whether polymorphisms in GST influenced the correlations. METHODS: Biomarkers of exposure was analyzed in urine and blood samples collected from 24 workers, exposed to at least one of toluene-, methylenediphenyl- or naphthalene diisocyanate, on a Monday morning after at least two unexposed days. Moreover, genotype was determined for 19 of the workers. RESULTS: The corresponding specific gravity-adjusted biomarkers in urine and plasma levels for the different diisocyanates correlated well (r between 0.689 and 0.988). When taking all samples together, the correlation coefficient was 0.926. Polymorphism in the GSTM1 genotype seemed to modify the association. CONCLUSION: Urine collected after two unexposed days can possibly be used as long-term biomarker of exposure for aromatic diisocyanates.
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| 10. |
- Wahlberg, K., et al.
(författare)
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Filaggrin variations are associated with PAH metabolites in urine and DNA alterations in blood
- 2019
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Ingår i: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 177
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Tidskriftsartikel (refereegranskat)abstract
- Dermal chemical exposure is common in many professions. The filaggrin protein is important for the skin barrier and variations in the filaggrin gene (FLG) may influence the uptake of chemicals via the skin, and consequently, the degree of systemic effects. The aim of this study was to investigate, in chimney sweeps with occupational exposure to polycyclic aromatic hydrocarbons (PAH) from soot, the influence of variation in FLG on internal PAH dose and DNA alterations, including epigenetic, previously linked to cancer and cardiovascular disease. We used TaqMan PCR to genotype 151 chimney sweeps and 152 controls for four FLG null variants (R501X, R2447X, S3247X and 2282del4) which cause impaired skin barrier, and FLG copy number variation (12th repeat, CNV12) which potentially is beneficial for the skin barrier. The internal dose of PAH was represented by urinary PAH metabolites (e.g. 1-hydroxypyrene and 3-hydroxybenzo[a]pyrene) that we measured by LC-MS/MS. We measured epigenetic alterations (methylation of AHRR and F2RL3) in blood by pyrosequencing; and DNA alterations (telomere length and mitochondrial DNA copy number) by real-time PCR. Hypomethylation of AHRR or F2RL3 is a risk factor for lung cancer and shorter telomere length a risk factor for cardiovascular disease. The frequencies of FLG null were 8.6 and 11.8% (p = 0.35), and CNV12 27.8 and 19.7% (p = 0.09) in chimney sweeps and controls, respectively. We found that among chimney sweeps working predominately with soot sweeping (high PAH exposure), CNV12 carriers had lower concentrations of PAH metabolites in urine compared with non-carriers (median 1-hydroxypyrene = 0.37 vs 0.86 μg/g creatinine respectively; p = 0.025 by linear regression models adjusted for age, BMI and smoking) compared to sweeps not carrying CNV12. Further, FLG null was associated with approximately 2.5% higher methylation of F2RL3 (cg03636183, p = 0.019 after adjustment for exposure group, age, BMI and smoking). FLG null was associated with approximately 7% shorter telomere length (p = 0.015, adjusted model). Our results suggest that FLG variations may influence the dose of PAH in highly exposed workers, possibly via dermal uptake. It also suggests that FLG variation may influence the degree of (epi)genotoxicity in the body. FLG variation is common in the working population and should be considered in risk assessment. © 2019
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