| 1. |
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| 2. |
- 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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| 3. |
- Ekman, Eva, et al.
(författare)
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Determination of 5-hydroxythiabendazole in human urine as a biomarker of exposure to thiabendazole using LC/MS/MS.
- 2014
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Ingår i: Journal of Chromatography. B. - : Elsevier BV. - 1873-376X .- 1570-0232. ; 973, s. 61-67
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Tidskriftsartikel (refereegranskat)abstract
- Thiabendazole (TBZ) is widely used as a pre-planting and post-harvest agricultural fungicide and as an anthelminthic in humans and animals. TBZ is of toxicological concern, since adverse effects including nephrogenic, hepatogenic, teratogenic and neurological effects have been reported in mammals. Occupational exposure can occur among agricultural workers and the general public may be environmentally exposed to TBZ through the diet. The metabolite 5-hydroxythiabendazole (5-OH-TBZ) was chosen as biomarker of exposure to TBZ and a LC/MS/MS method for the quantification of 5-OH-TBZ in human urine was developed. The method includes enzyme hydrolysis, as 5-OH-TBZ is conjugated to glucuronide and sulphate in urine. Sample through put was optimised using 96-well plates for sample handling as well as for solid phase extraction (SPE). The method has excellent, within-run, between-run and between-batch precision between 4 and 9%. The limit of detection (LOD) of 0.05 and a limit of quantification (LOQ) of 0.13ng 5-OH-TBZ/mL urine enable detection in environmentally exposed populations. When applying the method in a general Swedish population, 52% had levels above LOD. The method was also applied in one oral and one dermal human experimental exposure study in two individuals. After oral exposure, the excretion of 5-OH-TBZ in urine was described by a two-compartment model and both the first rapid and the second slower elimination phase followed first-order kinetics, with estimated elimination half-life of 2h and 9-12h. The recoveries in urine were between 21 and 24% of the dose. Dermal exposure was described by a one compartment model and followed first order kinetics, with estimated elimination half-life of 9-18h. The recovery in urine was 1% of the administrated dose of TBZ. Although these studies are limited to two individuals, the data provide new basic information regarding the toxicokinetics of TBZ after oral and dermal exposure.
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| 4. |
- Ekman, Eva, et al.
(författare)
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High-throughput method for the analysis of ethylenethiourea with direct injection of hydrolysed urine using online on-column extraction liquid chromatography and triple quadrupole mass spectrometry.
- 2013
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Ingår i: Journal of Chromatography. B. - : Elsevier BV. - 1873-376X .- 1570-0232. ; 934:Jul,5, s. 53-59
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Tidskriftsartikel (refereegranskat)abstract
- Ethylenethiourea (ETU) is of major toxicological concern, since in experimental animal studies, ETU has shown a large spectrum of adverse effects. High occupational exposure can be found among agricultural workers or during manufacturing of ethylenbisdithiocarbamates (EBDC). For the general public, sources of environmental exposure may be residues of ETU in commercial products, food and beverages. For the determination of ETU in human urine we present a high-throughput online on-column extraction liquid chromatography triple quadrupole mass spectrometry method using direct injection of hydrolysed urine samples. This method is simple, user- and environmentally friendly and all sample preparation is performed in 96-well plates. A labelled ETU internal standard was used for quantification. The method showed a good sensitivity with a limit of quantification (LOQ) of 0.5ng ETU/mL urine and the calibration curve was linear in the range 0.25-200ng ETU/mL urine. The within-run, between-run and between-batch precision was between 6% and 13%. Alkaline hydrolysis considerably increased the levels of ETU indicating a potential conjugate. The method was applied in an experimental dermal exposure study in humans, with sample concentrations ranging from 0.4 to 5.0ng ETU/mL urine. The excretion in urine was 10% of the applied dose. The elimination profile seemed to differ between the two individuals. The results show an estimated half-life of ETU between 34 and 72h. Although the experiment is limited to two individuals, the data provide valuable and new information regarding the toxicokinetics of ETU after dermal exposure.
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| 5. |
- Faniband, Moosa, et al.
(författare)
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LC-MS-MS Analysis of Urinary Biomarkers of Imazalil Following Experimental Exposures.
- 2015
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Ingår i: Journal of Analytical Toxicology. - : Oxford University Press (OUP). - 1945-2403 .- 0146-4760. ; 39:9, s. 691-697
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Tidskriftsartikel (refereegranskat)abstract
- Imazalil (IMZ) is a fungicide used in the cultivation of vegetables, such as cucumbers, in green houses or post-harvest on fruit to avoid spoilage due to fungal growth. Agricultural workers can be occupationally exposed to IMZ and the general public indirectly by the diet. The purpose of this study was to develop and validate an LC-MS-MS method for the analysis of IMZ in human urine. The method used electrospray ionization and selected reaction monitoring in the positive mode. Excellent linearity was observed in the range 0.5-100 ng/mL. The limit of detection of the method was 0.2 ng/mL, and the limit of quantitation 0.8 ng/mL. The method showed good within-run, between-run and between-batch precision, with a coefficient of variation <15%. The method was applied to analyze urine samples obtained from two human volunteers following experimental oral and dermal exposure. The excretion of IMZ seemed to follow a two-compartment model and first-order kinetics. In the oral exposure, the elimination half-life of IMZ in the rapid excretion phase was 2.6 and 1.9 h for the female and the male volunteer, respectively. In the slower excretion phase, it was 7.6 and 13 h, respectively. In the dermal exposure, the excretion seemed to follow a single-compartment model and first-order kinetics. The elimination half-life was 10 and 6.6 h for the female and the male volunteer, respectively. Although the study is limited to two volunteers, some information on basic toxicokinetics and metabolism of IMZ in humans is presented.
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| 6. |
- Jönsson, Lena S, et al.
(författare)
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N-nitrosamines in the southern Swedish rubber industries - exposure, health effects, and immunologic markers
- 2009
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Ingår i: Scandinavian Journal of Work, Environment and Health. - : Scandinavian Journal of Work, Environment and Health. - 0355-3140 .- 1795-990X. ; 35:3, s. 11-203
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim of this study was twofold: (i) to evaluate the air levels of N-nitrosamines in the Swedish rubber industry and (ii) to estimate the risk of symptoms and changed levels of immunologic markers in relation to these levels.METHODS: Using adsorption tubes, we collected samples of N-nitrosamines in the breathing zone of 96 rubber workers and analyzed them with liquid chromatography tandem mass spectrometry. Of these 96 workers, 66 were included in a medical examination and blood analysis together with an additional 106 rubber workers and 118 unexposed subjects. Medical and occupational histories were obtained in structured interviews, symptoms were recorded and immunologic markers analyzed in blood.RESULTS: The sum of N-nitrosamines ranged from less than the limit of detection to 36 microg/m (3)and differed with the vulcanization (ie, curing process) method used. Workers vulcanizing with a salt bath had the highest levels (median 4.2 microg/m (3)). Compared to the unexposed subjects, the rubber workers had an increased risk of nosebleeds, eye and throat symptoms, hoarseness, cough, nausea, headache, and changed levels of eosinophils and total immunoglobulin G (IgG). However, we found no clear exposure-response relationship with the symptoms or the immunologic markers studied.CONCLUSIONS: High levels of N-nitrosamines were found and must be lowered considerably in order to decrease the risk of cancer. There is a need for an occupational exposure limit for N-nitrosamines in Sweden. The lack of exposure-response relationships with the subacute symptoms examined in this study may be due to a healthy-worker selection or to the possibility that the symptoms are caused by an exposure not co-varying with N-nitrosamines.
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| 7. |
- Krais, Annette M, et al.
(författare)
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Detection of the fungicide transformation product 4-hydroxychlorothalonil in serum of pregnant women from Sweden and Costa Rica
- 2024
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Ingår i: Journal of Exposure Science & Environmental Epidemiology. - 1559-064X. ; 34:2, s. 270-277
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: 4-hydroxychlorothalonil (HCT, R182281), a transformation product of the fungicide chlorothalonil, was recently identified in human serum and breast milk. There are indications that HCT may be more toxic and environmentally persistent than chlorothalonil.OBJECTIVE: Our aim was to investigate serum concentrations of HCT in pregnant women in Sweden and Costa Rica.METHODS: We developed a quantitative analytical method for HCT using liquid chromatography tandem mass spectrometry. We measured HCT in 1808 serum samples from pregnant women from the general population in Sweden (1997-2015) and in 632 samples from 393 pregnant women from an agricultural population in Costa Rica (2010-2011). In Swedish samples, we assessed time trends and investigated seasonality. In the Costa Rican samples, we evaluated variability between and within women and explanatory variables of HCT concentrations.RESULTS: HCT was detected in all serum samples, and the limit of detection was 0.1 µg/L. The median HCT concentration in the Swedish samples was 4.1 µg/L (interquartile range [IQR] of 2.9 - 5.8 µg/L), and 3.9 times higher in the Costa Rican samples (median: 16.1 µg/L; IQR: 10.6 - 25.0 µg/L). We found clear seasonal variation with higher concentrations in the first half of each year among Swedish women. In the Costa Rican study, women working in agriculture and living near banana plantations had higher HCT concentrations, whilst higher parity and having a partner working in agriculture were associated with decreased HCT, and no clear seasonal pattern was observed.IMPACT STATEMENT: For the first time, this study quantifies human exposure to the fungicide chlorothalonil and/or its transformation product 4-hydroxychlorothalonil (HCT, R182281) and finds higher serum concentrations in women from a tropical agricultural setting as compared with women from the general population in Sweden.
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| 8. |
- Lindh, Christian, et al.
(författare)
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Analysis of 3,5-dichloroaniline as a biomarker of vinclozolin and iprodione in human urine using liquid chromatography/triple quadrupole mass spectrometry.
- 2007
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Ingår i: Rapid Communications in Mass Spectrometry. - : Wiley. - 1097-0231 .- 0951-4198. ; 21:4, s. 536-542
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Tidskriftsartikel (refereegranskat)abstract
- The fungicides vinclozolin and iprodione are widely used in agriculture. These pesticides are dicarboximide fungicides containing the common moiety 3,5-dichloroaniline (3,5-DCA). It ha; been suggested that low-level exposures to such compounds may be associated with adverse health effects such as endocrine disruption. In this study a method using liquid chromatography/triple quadrupole mass spectrometry (LC/MS/MS) was developed for the analysis of 3,5-DCA as a biomarker of exposure to these fungicides in human urine. The urine samples were treated by basic hydrolysis to degrade the fungicides, their metabolites and conjugates to 3,5-DCA. The 3,5-DCA was then extracted using toluene and derivatized using pentafluoropropionic anhydride (PFPA). Analysis of the derivative was carried out using selected reaction monitoring (SRM) in the negative ion mode. Quantification of the derivative was performed using [C-13(6)]-labeled 3,4-DCA as an internal standard with good precision and linearity in the range 0.1-200 ng/mL urine. The limit of detection was determined to be 0.1 ng/mL. The metabolites in urine were found to be stable during storage at -20 degrees C. To validate 3,5-DCA as a biomarker the method was applied in a human experimental exposure to iprodione and vinclozolin. Two healthy volunteers received 200 jig single oral doses of each pesticide followed by urine sampling during 72-120 h post-exposure. Between 78-107% of the dose was recovered as 3,5-DCA in the urine after exposure.
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| 9. |
- Lindh, Christian, et al.
(författare)
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Analysis of chlormequat in human urine as a biomarker of exposure using liquid chromatography triple quadrupole mass spectrometry.
- 2011
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Ingår i: Journal of Chromatography. B. - : Elsevier BV. - 1873-376X .- 1570-0232. ; 879:19, s. 1551-1556
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Tidskriftsartikel (refereegranskat)abstract
- In this study, a method using liquid chromatography triple quadrupole mass spectrometry (LC/MS/MS) is described for the analysis of the plant growth regulator chlormequat (CCC) in human urine. Analysis was carried out using selected reaction monitoring (SRM) in the positive ion mode. [(2)H(4)] labeled CCC as internal standard (IS) was used for quantification of CCC. The limit of detection (LOD) was determined to 0.1ng/mL. The method was linear in the range 0.3-800ng/mL urine and had a within-run precision of 4-9%. The between-run precision was determined at urine levels of 7.0 and 31ng/mL and found to be 5 and 6% respectively. The reproducibility was 3-6%. To validate CCC as a biomarker of exposure, the method was applied in a human experimental oral exposure to CCC. Two healthy volunteers received 25μg/kg b.w. CCC in a single oral dose followed by urine sampling for 46h post-exposure. The CCC was estimated to follow a first order kinetic and a two compartment model with an elimination half-life of 2-3h and 10-14h respectively. One hundred 24h urine samples were collected from non-occupationally exposed individuals in the general population in southern Sweden. All samples had detectable levels above the LOD 0.1ng/mL urine. The median levels were 4ng/mL of CCC in unadjusted urine. The levels found in the population samples are several magnitudes lower than those found in the experimental exposure, which corresponds to an oral exposure of 50% of the ADI for CCC.
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| 10. |
- Lindh, Christian, et al.
(författare)
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Analysis of ethylenethiourea as a biomarker in human urine using liquid chromatography/triple quadrupole mass spectrometry.
- 2008
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Ingår i: Rapid Communications in Mass Spectrometry. - : Wiley. - 1097-0231 .- 0951-4198. ; 22:16, s. 2573-2579
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Tidskriftsartikel (refereegranskat)abstract
- Ethylenebisdithiocarbamates (EBDCs) are widely used fungicides. Ethylenethiourea (ETU), the main metabolite and also a contaminant in the commercially available products, is of major toxicological concern. In this study, a method using liquid chromatography/triple quadrupole mass spectrometry (LC/MS/MS) is described for the analysis of ETU in human urine after a single-step extractive derivatization using pentafluorobenzyl bromide (PFBBr). Analysis was carried out using selected reaction monitoring (SRM) in the positive ion mode. Quantification of ETU was performed using [(2)H(4)]-labeled ETU as internal standard (IS). The limit of detection (LOD) was determined to 0.05 ng/mL. The method was linear in the range 0.1-54 ng/mL urine and had a within-run precision of 3-5%. The between-run precision was determined at an average urine level of 2 and 10 ng/mL urine and found to be 9%. The inter-batch precision was 6%. To validate ETU as a biomarker of exposure, the method was applied in a human experimental oral exposure to the commercial fungicide Ridomil Gold, containing 64% mancozeb and 4.5% ETU. Two healthy volunteers received 8.9 microg/kg body weight (b.w.) Ridomil Gold in a single oral dose followed by urine sampling for 104 h post-exposure. The elimination half-life of ETU was estimated to 17-23 h.
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