Publications by authors named "Zdenka Fenclova"

41 Publications

Three-Year Study of Markers of Oxidative Stress in Exhaled Breath Condensate in Workers Producing Nanocomposites, Extended by Plasma and Urine Analysis in Last Two Years.

Nanomaterials (Basel) 2020 Dec 6;10(12). Epub 2020 Dec 6.

J. Heyrovský Institute of Physical Chemistry CAS, Dolejškova 3, 182 23 Prague 8, Czech Republic.

Human data concerning exposure to nanoparticles are very limited, and biomarkers for monitoring exposure are urgently needed. In a follow-up of a 2016 study in a nanocomposites plant, in which only exhaled breath condensate (EBC) was examined, eight markers of oxidative stress were analyzed in three bodily fluids, i.e., EBC, plasma and urine, in both pre-shift and post-shift samples in 2017 and 2018. Aerosol exposures were monitored. Mass concentration in 2017 was 0.351 mg/m during machining, and 0.179 and 0.217 mg/m during machining and welding, respectively, in 2018. In number concentrations, nanoparticles formed 96%, 90% and 59%, respectively. In both years, pre-shift elevations of 50.0% in EBC, 37.5% in plasma and 6.25% in urine biomarkers were observed. Post-shift elevation reached 62.5% in EBC, 68.8% in plasma and 18.8% in urine samples. The same trend was observed in all biological fluids. Individual factors were responsible for the elevation of control subjects' afternoon vs. morning markers in 2018; all were significantly lower compared to those of workers. Malondialdehyde levels were always acutely shifted, and 8-hydroxy-2-deoxyguanosine levels best showed chronic exposure effect. EBC and plasma analysis appear to be the ideal fluids for bio-monitoring of oxidative stress arising from engineered nanomaterials. Potential late effects need to be targeted and prevented, as there is a similarity of EBC findings in patients with silicosis and asbestosis.
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http://dx.doi.org/10.3390/nano10122440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762143PMC
December 2020

Markers of oxidative stress after three days of nanoTiO sunscreen use in humans: a pilot study.

Cent Eur J Public Health 2020 10;28 Suppl:S17-S21

Department of Occupational Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

Objective: Recent experimental studies point to a high reactivity of nanoparticles and the potential of sunscreens to penetrate the skin. We measured 20 markers of oxidative stress and inflammation to find out whether skin exposure to nanoTiO sunscreen may elevate the level of the markers in exhaled breath condensate (EBC) and urine of exposed subjects, as was suggested by our earlier study.

Methods: Six volunteers (3 males and 3 females), with a mean age of 48.0 ± 6.7 years, used commercial sunscreen for three days continuously. The first samples were collected before the test. The second samples were collected on day 4, before the sunscreen was washed off, and the third samples on day 11. The following biomarkers were measured: malondialdehyde, 4-hydroxy-trans-hexenal, 4-hydroxy-trans-nonenal, aldehydes C6-C12, 8-isoProstaglandin F2α, o-tyrosine, 3-chlorotyrosine, 3-nitrotyrosine, 8-hydroxy-2-deoxyguanosine, 8-hydroxyguanosine, 5-hydroxymethyl uracil, and leukotrienes B4, C4, D4, and E4, using liquid chromatography-electrospray ionisation-tandem mass spectrometry.

Results: In the urine, 4-hydroxy-trans-hexenal was significantly higher in post-exposure sample 2, and the same trend was seen in all urinary markers. In EBC, no difference was seen between the mean values of 20 post-test markers as compared with pre-test samples.

Conclusion: This study suggests potential side effects of the sunscreen - borderline elevation of markers of oxidative stress/inflammation - which may relate to the absorption of the nanoTiO, and the non-significant difference may be explained by the small number of subjects. The effect was not seen in EBC, where nanoTiO was not found. A larger study is needed, as according to our previous study, the beneficial effect of the sunscreen to suppress oxidative stress caused by UV radiation may be questioned.
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http://dx.doi.org/10.21101/cejph.a6158DOI Listing
October 2020

The genotoxic effects in the leukocytes of workers handling nanocomposite materials.

Mutagenesis 2020 09;35(4):331-340

Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska, Prague, Czech Republic.

The extensive development of nanotechnologies and nanomaterials poses a number of questions to toxicologists about the potential health risks of exposure to nanoparticles (NP). In this study, we analysed DNA damage in the leukocytes of 20 workers who were long-term exposed (18 ± 10 years) to NP in their working environment. Blood samples were collected in September 2016, before and after a shift, to assess (i) the chronic effects of NP on DNA (pre-shift samples) and (ii) the acute effects of exposure during the shift (the difference between pre- and post-shift samples). The samples from matched controls were taken in parallel with workers before the shift. Leukocytes were isolated from heparinised blood on a Ficoll gradient. The enzyme-modified comet assay (DNA formamido-pyrimidine-glycosylase and endonuclease III) demonstrated a considerable increase of both single- and double-strand breaks in DNA (DNA-SB) and oxidised bases when compared with the controls (2.4× and 2×, respectively). Acute exposure induced a further increase of DNA-SB. The welding and smelting of nanocomposites represented a higher genotoxic risk than milling and grinding of nanocomposite surfaces. Obesity appeared to be a factor contributing to an increased risk of oxidative damage to DNA. The data also indicated a higher susceptibility of males vs. females to NP exposure. The study was repeated in September 2017. The results exhibited similar trend, but the levels of DNA damage in the exposed subjects were lower compared to previous year. This was probably associated with lower exposure to NP in consequence of changes in nanomaterial composition and working operations. The further study involving also monitoring of personal exposures to NP is necessary to identify (i) the main aerosol components responsible for genotoxic effects in workers handling nanocomposites and (ii) the primary cause of gender differences in response to NP action.
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http://dx.doi.org/10.1093/mutage/geaa016DOI Listing
September 2020

DNA Methylation Profiles in a Group of Workers Occupationally Exposed to Nanoparticles.

Int J Mol Sci 2020 Mar 31;21(7). Epub 2020 Mar 31.

Department of Machining and Assembly, Department of Engineering Technology, Department of Material Science, Faculty of Mechanical Engineering, Technical University in Liberec, Studentska 1402/2 Liberec, Czech Republic.

The risk of exposure to nanoparticles (NPs) has rapidly increased during the last decade due to the vast use of nanomaterials (NMs) in many areas of human life. Despite this fact, human biomonitoring studies focused on the effect of NP exposure on DNA alterations are still rare. Furthermore, there are virtually no epigenetic data available. In this study, we investigated global and gene-specific DNA methylation profiles in a group of 20 long-term (mean 14.5 years) exposed, nanocomposite, research workers and in 20 controls. Both groups were sampled twice/day (pre-shift and post-shift) in September 2018. We applied Infinium Methylation Assay, using the Infinium MethylationEPIC BeadChips with more than 850,000 CpG loci, for identification of the DNA methylation pattern in the studied groups. Aerosol exposure monitoring, including two nanosized fractions, was also performed as proof of acute NP exposure. The obtained array data showed significant differences in methylation between the exposed and control groups related to long-term exposure, specifically 341 CpG loci were hypomethylated and 364 hypermethylated. The most significant CpG differences were mainly detected in genes involved in lipid metabolism, the immune system, lung functions, signaling pathways, cancer development and xenobiotic detoxification. In contrast, short-term acute NP exposure was not accompanied by DNA methylation changes. In summary, long-term (years) exposure to NP is associated with DNA epigenetic alterations.
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http://dx.doi.org/10.3390/ijms21072420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177382PMC
March 2020

The repeated cytogenetic analysis of subjects occupationally exposed to nanoparticles: a pilot study.

Mutagenesis 2019 09;34(3):253-263

Department of Machining and Assembly, Technical University in Liberec, Liberec, Czech Republic.

The application of nanomaterials has been rapidly increasing during recent years. Inhalation exposure to nanoparticles (NP) may result in negative toxic effects but there is a critical lack of human studies, especially those related to possible DNA alterations. We analyzed pre-shift and post-shift a group of nanocomposite researchers with a long-term working background (17.8 ± 10.0 years) and matched controls. The study group consisted of 73.2% males and 26.8% females. Aerosol exposure monitoring during a working shift (involving welding, smelting, machining) to assess the differences in exposure to particulate matter (PM) including nanosized fractions <25-100 nm, and their chemical analysis, was carried out. A micronucleus assay using Human Pan Centromeric probes, was applied to distinguish between the frequency of centromere positive (CEN+) and centromere negative (CEN-) micronuclei (MN) in the binucleated cells. This approach allowed recognition of the types of chromosomal damage: losses and breaks. The monitoring data revealed differences in the exposure to NP related to individual working processes, and in the chemical composition of nanofraction. The cytogenetic results of this pilot study demonstrated a lack of effect of long-term (years) exposure to NP (total frequency of MN, P = 0.743), although this exposure may be responsible for DNA damage pattern changes (12% increase of chromosomal breaks-clastogenic effect). Moreover, short-term (daily shift) exposure could be a reason for the increase of chromosomal breaks in a subgroup of researchers involved in welding and smelting processes (clastogenic effect, P = 0.037). The gender and/or gender ratio of the study participants was also an important factor for the interpretation of the results. As this type of human study is unique, further research is needed to understand the effects of long-term and short-term exposure to NP.
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http://dx.doi.org/10.1093/mutage/gez016DOI Listing
September 2019

NanoTiO Sunscreen Does Not Prevent Systemic Oxidative Stress Caused by UV Radiation and a Minor Amount of NanoTiO is Absorbed in Humans.

Nanomaterials (Basel) 2019 Jun 17;9(6). Epub 2019 Jun 17.

Czech University of Life Sciences, Kamycka 129, 165 00 Prague 6, Czech Republic.

The present pilot study tested the efficiency of nanoTiO sunscreen to prevent the oxidative stress/inflammation caused by ultraviolet (UV) radiation using biomarkers in subjects' blood, urine, and exhaled breath condensate (EBC). In addition, the skin absorption of nanoTiO was studied. Six identical subjects participated in three tests: (A) nanoTiO sunscreen, (B) UV radiation, and (C) sunscreen + UV. The first samples were collected before the test and the second after sunscreen application and/or UV exposure. On day 4, the third samples were collected, and the sunscreen was washed off, and the fourth samples were collected on day 11. The following biomarkers were measured: malondialdehyde, 4-hydroxy--hexenal, 4-hydroxy--nonenal, aldehydes C6-C12, 8--Prostaglandin F2α, o-tyrosine, 3-chlorotyrosine, 3-nitrotyrosine, 8-hydroxy-2-deoxyguanosine, 8-hydroxyguanosine, 5-hydroxymethyl uracil, and leukotrienes, using liquid chromatography-electrospray ionisation-tandem mass spectrometry. Titania was measured using inductively coupled plasma mass spectrometry and TiO nanoparticles by transmission and scanning electron microscopy. Sunscreen alone did not elevate the markers, but UV increased the biomarkers in the plasma, urine, and EBC. The sunscreen prevented skin redness, however it did not inhibit the elevation of oxidative stress/inflammatory markers. Titania and nanoTiO particles were found in the plasma and urine (but not in the EBC) in all sunscreen users, suggesting their skin absorption.
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http://dx.doi.org/10.3390/nano9060888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631994PMC
June 2019

Leukocyte telomere length is not affected by long-term occupational exposure to nano metal oxides.

Ind Health 2019 Nov 28;57(6):741-744. Epub 2019 Mar 28.

Institute of Chemical Process Fundamentals CAS, Czech Republic.

The aim of this study was to ascertain whether long-term occupational exposure to nanoparticles would affect relative leukocyte telomere length (LrTL). We analysed occupational exposure to size-resolved aerosol particles, with special emphasis on nanoparticles at two workshops: i/ the production of nanocomposites containing metal oxides; ii/ laboratory to test experimental exposure of nano-CuO to rodents. Thirty five exposed researchers (age 39.5 ± 12.6 yr; exposure duration 6.0 ± 3.7 yr) and 43 controls (40.4 ± 10.5 yr) were examined. LrTL did not significantly (p=0.14) differ between the exposed researchers (0.92 ± 0.13) and controls (0.86 ± 0.15). In addition, no significant correlation (r=-0.22, p=0.22) was detected between the duration of occupational exposure and LrTL. The results remained non-significant after multiple adjustments for age, sex and smoking status. Our pilot results suggest that relative leukocyte telomere length is not affected by occupational exposure to nanoparticles.
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http://dx.doi.org/10.2486/indhealth.2018-0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885603PMC
November 2019

Deep Airway Inflammation and Respiratory Disorders in Nanocomposite Workers.

Nanomaterials (Basel) 2018 Sep 16;8(9). Epub 2018 Sep 16.

UMass, Lowell, Department of Biomedical and Nutritional Sciences, Zuckerberg College of Health Sciences, Lowell, MA 01854, USA.

Thousands of researchers and workers worldwide are employed in nanocomposites manufacturing, yet little is known about their respiratory health. Aerosol exposures were characterized using real time and integrated instruments. Aerosol mass concentration ranged from 0.120 mg/m³ to 1.840 mg/m³ during nanocomposite machining processes; median particle number concentration ranged from 4.8 × 10⁴ to 5.4 × 10⁵ particles/cm³. The proportion of nanoparticles varied by process from 40 to 95%. Twenty employees, working in nanocomposite materials research were examined pre-shift and post-shift using spirometry and fractional exhaled nitric oxide (FeNO) in parallel with 21 controls. Pro-inflammatory leukotrienes (LT) type B4, C4, D4, and E4; tumor necrosis factor (TNF); interleukins; and anti-inflammatory lipoxins (LXA4 and LXB4) were analyzed in their exhaled breath condensate (EBC). Chronic bronchitis was present in 20% of researchers, but not in controls. A significant decrease in forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) was found in researchers post-shift ( ˂ 0.05). Post-shift EBC samples were higher for TNF ( ˂ 0.001), LTB4 ( ˂ 0.001), and LTE4 ( ˂ 0.01) compared with controls. Nanocomposites production was associated with LTB4 ( ˂ 0.001), LTE4 ( ˂ 0.05), and TNF ( ˂ 0.001), in addition to pre-shift LTD4 and LXB4 (both ˂ 0.05). Spirometry documented minor, but significant, post-shift lung impairment. TNF and LTB4 were the most robust markers of biological effects. Proper ventilation and respiratory protection are required during nanocomposites processing.
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http://dx.doi.org/10.3390/nano8090731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164906PMC
September 2018

Markers of Oxidative Stress in the Exhaled Breath Condensate of Workers Handling Nanocomposites.

Nanomaterials (Basel) 2018 Aug 10;8(8). Epub 2018 Aug 10.

Department of Biomedical and Nutritional Sciences, Zuckerberg College of Health Sciences, Lowell, MA 01854, USA.

Researchers in nanocomposite processing may inhale a variety of chemical agents, including nanoparticles. This study investigated airway oxidative stress status in the exhaled breath condensate (EBC). Nineteen employees (42.4 ± 11.4 y/o), working in nanocomposites research for 18.0 ± 10.3 years were examined pre-shift and post-shift on a random workday, together with nineteen controls (45.5 ± 11.7 y/o). Panels of oxidative stress biomarkers derived from lipids, nucleic acids, and proteins were analyzed in the EBC. Aerosol exposures were monitored during three major nanoparticle generation operations: smelting and welding (workshop 1) and nanocomposite machining (workshop 2) using a suite of real-time and integrated instruments. Mass concentrations during these operations were 0.120, 1.840, and 0.804 mg/m³, respectively. Median particle number concentrations were 4.8 × 10⁴, 1.3 × 10⁵, and 5.4 × 10⁵ particles/cm³, respectively. Nanoparticles accounted for 95, 40, and 61%, respectively, with prevailing Fe and Mn. All markers of nucleic acid and protein oxidation, malondialdehyde, and aldehydes C₆⁻C were elevated, already in the pre-shift samples relative to controls in both workshops. Significant post-shift elevations were documented in lipid oxidation markers. Significant associations were found between working in nanocomposite synthesis and EBC biomarkers. More research is needed to understand the contribution of nanoparticles from nanocomposite processing in inducing oxidative stress, relative to other co-exposures generated during welding, smelting, and secondary oxidation processes, in these workshops.
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http://dx.doi.org/10.3390/nano8080611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116291PMC
August 2018

Diabetes, Cardiovascular Disorders and 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Body Burden in Czech Patients 50 Years After the Intoxication.

Basic Clin Pharmacol Toxicol 2018 Sep 7;123(3):356-359. Epub 2018 May 7.

Department of Occupational Medicine, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.

The correlation between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication and the parameters of metabolic impairment was examined in the last eight male survivors of 80 workers exposed to TCDD during the production of herbicides in a chemical factory in 1965-1967. Their median TCDD blood level was 112 (46-390) pg/g lipids, and the median TCDD body deposit was 3.9 (0.8-11.7) μg. This puts these patients into the most severely intoxicated group of subjects, according to back-calculated levels of TCDD. The median TCDD blood level in eight controls was 12 pg/g (<0.10 to 22.2 pg/g). Markers of metabolic impairment - diabetes, dyslipidaemia, arterial hypertension, carotid artery plaque, skin microvascular reactivity, eye fundus hypertensive angiopathy and history of coronary heart disease - were assessed and compared to a general male population of comparable age. Measured parameters compared with a population of comparable age were as follows: prevalence of diabetes (62.5% versus 17.6%), arterial hypertension (87.5% versus 71.8%), dyslipidaemia (87.5% versus 88.8%), history of coronary heart disease (62.5% versus 26.0%) and eye fundus hypertension angiopathy (50% versus 14%). All eight patients (100% versus 43%) developed plaques in carotid arteries, six had stenosis >50% and two had a carotid intervention (stenting or endarterectomy). Total cholesterol levels decreased compared to the earlier study this patient group in 2008, most likely due to a more intensive use of lipid-lowering drugs. Several metabolic parameters were higher (diabetes as much as 3.5-fold) in the group of severely TCDD-intoxicated subjects than in a general population of comparable age. This suggests that TCDD plays a role in the development of metabolic impairment and vascular changes.
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http://dx.doi.org/10.1111/bcpt.13013DOI Listing
September 2018

Neurological and Neurophysiological Findings in Workers with Chronic 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Intoxication 50 Years After Exposure.

Basic Clin Pharmacol Toxicol 2018 Feb 27;122(2):271-277. Epub 2017 Sep 27.

Department of Occupational Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

The last eight survivors of 80 workers accidentally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during production of herbicides based on trichlorophenoxyacetic acid in 1965-1967 in a chemical factory were followed. All were men, mean age 72.4 ± 1.3 years. Their current median TCDD blood level was 112 (46-390) pg/g lipids. Neurological examination revealed central nervous system impairment in all individuals and signs of polyneuropathy in 87.5%, which was confirmed by a nerve conduction study (NCS) in 75%. A Lanthony test demonstrated acquired dyschromatopsia in 87.5% of the patients, with deterioration of mean colour confusion index (CCI) from 1.52 ± 0.39 in 2010 to 1.73 ± 0.41 in 2016. Single-photon emission computer tomography (SPECT) of the brain showed focal reduction of perfusion in various brain locations in all patients and worsening in six patients. Visual-evoked potentials (VEP) was abnormal in 62.6% of individuals. Most patients complained of psychological problems. The neuropsychological test battery showed most positive impairments in the Trail Making Test evaluating processing speed (average level in the range of mild neurocognitive impairment), which correlated with mean CCI (p < 0.05).

Conclusion: Fifty years after exposure, blood levels of TCDD are still 10 times higher than the general population. NCS, VEP, Lanthony test and SPECT findings deteriorated from examination of these patients in 2004 and in 2010. The total of abnormal tests per patient in 2016 is very high. Minor differences among patients and their reduced count may explain why the number of impairments in 2016 does not correlate with TCDD blood level.
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http://dx.doi.org/10.1111/bcpt.12899DOI Listing
February 2018

Markers of nucleic acids and proteins oxidation among office workers exposed to air pollutants including (nano)TiO2 particles.

Neuro Endocrinol Lett 2016 Dec;37(Suppl1):13-16

Charles University and General University Hospital in Prague, 1st Faculty of Medicine, Department of Occupational Medicine, Prague, Czech Republic.

Objectives: Experimental studies using nanoscale TiO2 have documented lung injury, inflammation, oxidative stress, and genotoxicity. Human health data are extremely scarce.

Methods: In exhaled breath condensate (EBC) and urine of 22 office employees occupationally exposed to TiO2 during their visit in the production workshops for average 14±9 min/day a panel of biomarkers of nucleic acids and proteins oxidation was studied, specifically 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), 5-hydroxymethyl uracil (5-OHMeU), o-tyrosine (o-Tyr), 3-chlorotyrosine (3-ClTyr), and 3-nitrotyrosine (3-NOTyr). Examination was performed also in 14 comparable controls.

Results: The median respirable TiO2 mass concentration in the workshops was 0.40 mg/m3, median number concentration was 2.32×104 particles/cm3 with 80% of the particles being <100 nm in diameter. All 6 markers of oxidation were elevated in EBC in factory office employees relative to controls (p<0.01). Significant association was found between their job in TiO2 production plant and 5 markers of oxidation (except 3-NOTyr) in the EBC in multivariate analysis. No elevation of markers was detected in the urine.

Conclusion: This pilot study suggests that even short nanoTiO2 exposure may lead to pulmonary oxidative stress; however this effect may be short-term and reversible. The clinical significance of these findings is unclear and more studies are needed.
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December 2016

Markers of lipid oxidative damage in the exhaled breath condensate of nano TiO production workers.

Nanotoxicology 2017 02 9;11(1):52-63. Epub 2016 Dec 9.

h UMass Lowell, Department of Public Health , College of Health Sciences , Lowell, MA , USA.

Nanoscale titanium dioxide (nanoTiO) is a commercially important nanomaterial. Animal studies have documented lung injury and inflammation, oxidative stress, cytotoxicity and genotoxicity. Yet, human health data are scarce and quantitative risk assessments and biomonitoring of exposure are lacking. NanoTiO is classified by IARC as a group 2B, possible human carcinogen. In our earlier studies we documented an increase in markers of inflammation, as well as DNA and protein oxidative damage, in exhaled breath condensate (EBC) of workers exposed nanoTiO. This study focuses on biomarkers of lipid oxidation. Several established lipid oxidative markers (malondialdehyde, 4-hydroxy-trans-hexenal, 4-hydroxy-trans-nonenal, 8-isoProstaglandin F2α and aldehydes C-C) were studied in EBC and urine of 34 workers and 45 comparable controls. The median particle number concentration in the production line ranged from 1.98 × 10 to 2.32 × 10 particles/cm with ∼80% of the particles <100 nm in diameter. Mass concentration varied between 0.40 and 0.65 mg/m. All 11 markers of lipid oxidation were elevated in production workers relative to the controls (p < 0.001). A significant dose-dependent association was found between exposure to TiO and markers of lipid oxidation in the EBC. These markers were not elevated in the urine samples. Lipid oxidation in the EBC of workers exposed to (nano)TiO complements our earlier findings on DNA and protein damage. These results are consistent with the oxidative stress hypothesis and suggest lung injury at the molecular level. Further studies should focus on clinical markers of potential disease progression. EBC has reemerged as a sensitive technique for noninvasive monitoring of workers exposed to engineered nanoparticles.
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http://dx.doi.org/10.1080/17435390.2016.1262921DOI Listing
February 2017

Markers of lipid oxidative damage among office workers exposed intermittently to air pollutants including nanoTiO2 particles.

Rev Environ Health 2017 Mar;32(1-2):193-200

Nanoscale titanium dioxide (nanoTiO2) is a commercially important nanomaterial used in numerous applications. Experimental studies with nanotitania have documented lung injury and inflammation, oxidative stress, and genotoxicity. Production workers in TiO2 manufacturing with a high proportion of nanoparticles and a mixture of other air pollutants, such as gases and organic aerosols, had increased markers of oxidative stress, including DNA and protein damage, as well as lipid peroxidation in their exhaled breath condensate (EBC) compared to unexposed controls. Office workers were observed to get intermittent exposures to nanoTiO2 during their process monitoring. The aim of this study was to investigate the impact of such short-term exposures on the markers of health effects in office workers relative to production workers from the same factory. Twenty-two office employees were examined. They were occupationally exposed to (nano)TiO2 aerosol during their daily visits of the production area for an average of 14±9 min/day. Median particle number concentration in office workers while in the production area was 2.32×104/cm3. About 80% of the particles were <100 nm in diameter. A panel of biomarkers of lipid oxidation, specifically malondialdehyde (MDA), 4-hydroxy-trans-hexenal (HHE), 4-hydroxy-trans-nonenal (HNE), 8-isoprostaglandin F2α (8-isoprostane), and aldehydes C6-C12, were studied in the EBC and urine of office workers and 14 unexposed controls. Nine markers of lipid oxidation were elevated in the EBC of office employees relative to controls (p<0.05); only 8-isoprostane and C11 were not increased. Significant association was found in the multivariate analysis between their employment in the TiO2 production plant and EBC markers of lipid oxidation. No association was seen with age, lifestyle factors, or environmental air contamination. The EBC markers in office employees reached about 50% of the levels measured in production workers, and the difference between production workers and office employees was highly significant (p<0.001). None of these biomarkers were elevated in urine. The approach presented here seems to be very sensitive and useful for non-invasive monitoring of employees exposed to air pollutants, including gases, organic aerosols, and nanoTiO2, and may prove useful for routine biomonitoring purposes. Among them, aldehydes C6, C8, C9, and C10 appear to be the most sensitive markers of lipid oxidation in similar occupational cohorts. One major challenge with sensitive biomonitoring techniques, however, is their non-specificity and difficulty in interpreting the meaning of their physiological values in the context of chronic disease development and damage-repair kinetics.
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http://dx.doi.org/10.1515/reveh-2016-0030DOI Listing
March 2017

Leukotrienes in exhaled breath condensate and fractional exhaled nitric oxide in workers exposed to TiO2 nanoparticles.

J Breath Res 2016 06 30;10(3):036004. Epub 2016 Jun 30.

Department of Occupational Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Na Bojišti 1, 128 00 Prague 2, Czech Republic.

Human health data regarding exposure to nanoparticles are extremely scarce and biomonitoring of exposure is lacking in spite of rodent pathological experimental data. Potential markers of the health-effects of engineered nanoparticles were examined in 30 workers exposed to TiO2 aerosol, 22 office employees of the same plant, and 45 unexposed controls. Leukotrienes (LT) B4, C4, E4, and D4 were analysed in the exhaled breath condensate (EBC) and urine via liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Fractional exhaled nitric oxide (FeNO) and spirometry was also measured. The median particle number concentration of the aerosol in the production ranged from 1.98  ×  10(4) to 2.32  ×  10(4) particles cm(-3); about 80% of the particles were  <100 nm in diameter. Median total mass concentration varied between 0.4 and 0.65 mg m(-3). All LT levels in workers' EBC were elevated relative to the controls (p  <  0.01). LTs in the EBC sample were correlated with titanium levels. Urinary LTs were not elevated in the workers and office employees. Office workers had higher LTB4 in EBC (p  <  0.05), and higher levels of FeNO (p  <  0.01). FeNO was higher in office employees with allergic diseases and was negatively correlated with smoking (p  <  0.01). In spirometry significant impairment in the workers was seen only for %VCIN and %PEF (both p  <  0.01). Multiple regression analysis confirmed a significant association between production of TiO2 and all cysteinyl LTs in EBC (p  <  0.01) and impaired %VCIN and %PEF (both p  <  0.01). LTB4 was also associated with smoking (p  <  0.01). LT levels complemented our earlier findings of DNA, protein, and lipid damage in the EBC of workers with nanoTiO2 exposures. Cysteinyl LTs in EBC analysis suggest inflammation and potential fibrotic changes in the lungs; they may be helpful for monitoring the biological effect of (nano)TiO2 on workers. Spirometry was not sensitive enough.
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http://dx.doi.org/10.1088/1752-7155/10/3/036004DOI Listing
June 2016

Evaluation of Lumbar Spine Load by Computational Method in Order to Acknowledge Low-back Disorders as Occupational Diseases.

Cent Eur J Public Health 2016 Mar;24(1):58-67

Department of Occupational Medicine, First Medical Faculty, Charles University and General University Hospital, Prague, Czech Republic.

Aim: The aim of the study was to develop a computational module for the prediction of compressive force on the L4/L5 disc suitable for use in field settings.

Method: The value of compressive force is intended to be used as a proxy measure of the mechanical burden of low-back when performing work activities. The compressive force predicted by the module in a particular worker should be compared with the NIOSH limit value of 3,400 N for the assessment of lumbar spine load during manual lifting tasks. Exceeding the limit will be considered as the fulfilment of "hygienic criterion" that should be met to acknowledge low-back disorder as an occupational disease. To develop the computational module we used the ergonomic software TECNOMATIX Classic Jack taking into account the anthropometric parameters of a worker and ergonomic parameters of his/her work activity.

Results: We calculated compressive forces on the L4/L5 disc in about 1,300 simulated combinations of various factors influencing compressive force. Parameters which turned out to be crucial for the compression of L4/L5 disc were included in the computational algorithm.

Conclusion: Our study was primarily aimed at the assessment of lumbar disorders as occupational diseases. Moreover, the study can contribute to the recommendation of preventive measures to decrease health risks in occupations associated with the overload of low-back region. The graphic maps generated by the computational module enable a fast and exact analysis of particular job.
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http://dx.doi.org/10.21101/cejph.a4332DOI Listing
March 2016

Oxidative stress markers are elevated in exhaled breath condensate of workers exposed to nanoparticles during iron oxide pigment production.

J Breath Res 2016 Feb 1;10(1):016004. Epub 2016 Feb 1.

Charles University in Prague and General University Hospital in Prague, First Faculty of Medicine, Department of Occupational Medicine, Na Bojišti 1, 128 00 Prague 2, Czech Republic.

Markers of oxidative stress and inflammation were analysed in the exhaled breath condensate (EBC) and urine samples of 14 workers (mean age 43  ±  7 years) exposed to iron oxide aerosol for an average of 10  ±  4 years and 14 controls (mean age 39  ±  4 years) by liquid chromatography-electrospray ionization-mass spectrometry/mass spectrometry (LC-ESI-MS/MS) after solid-phase extraction. Aerosol exposure in the workplace was measured by particle size spectrometers, a scanning mobility particle sizer (SMPS) and an aerodynamic particle sizer (APS), and by aerosol concentration monitors, P-TRAK and DustTRAK DRX. Total aerosol concentrations in workplace locations varied greatly in both time and space. The median mass concentration was 0.083 mg m(-3) (IQR 0.063-0.133 mg m(-3)) and the median particle concentration was 66 800 particles cm(-3) (IQR 16,900-86,900 particles cm(-3)). In addition, more than 80% of particles were smaller than 100 nm in diameter. Markers of oxidative stress, malondialdehyde (MDA), 4-hydroxy-trans-hexenale (HHE), 4-hydroxy-trans-nonenale (HNE), 8-isoProstaglandin F2α (8-isoprostane) and aldehydes C6-C12, in addition to markers of nucleic acid oxidation, including 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), 5-hydroxymethyl uracil (5-OHMeU), and of proteins, such as o-tyrosine (o-Tyr), 3-chlorotyrosine (3-ClTyr), and 3-nitrotyrosine (3-NOTyr) were analysed in EBC and urine by LC-ESI-MS/MS. Almost all markers of lipid, nucleic acid and protein oxidation were elevated in the EBC of workers comparing with control subjects. Elevated markers were MDA, HNE, HHE, C6-C10, 8-isoprostane, 8-OHdG, 8-OHG, 5-OHMeU, 3-ClTyr, 3-NOTyr, o-Tyr (all p  <  0.001), and C11 (p  <  0.05). Only aldehyde C12 and the pH of samples did not differ between groups. Markers in urine were not elevated. These findings suggest the adverse effects of nano iron oxide aerosol exposure and support the utility of oxidative stress biomarkers in EBC. The analysis of urine oxidative stress biomarkers does not support the presence of systemic oxidative stress in iron oxide pigment production workers.
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http://dx.doi.org/10.1088/1752-7155/10/1/016004DOI Listing
February 2016

LOW-BACK PAIN DISORDERS AS OCCUPATIONAL DISEASES IN THE CZECH REPUBLIC AND 22 EUROPEAN COUNTRIES: COMPARISON OF NATIONAL SYSTEMS, RELATED DIAGNOSES AND EVALUATION CRITERIA.

Cent Eur J Public Health 2015 Sep;23(3):244-51

Aim: Low-back pain diseases (LBPD) belong to the most frequent diagnoses determined by general practitioners, and constitute one of the most common reasons for sick leave and permanent disability pension in the Czech Republic and other European countries. Epidemiological studies have shown a statistically significant association between LBPD and certain types of occupational burden. However, in the Czech Republic, LBPD caused by overload and/or whole-body vibrations have not yet been included in the list of occupational diseases. The aim of this study was to collect and compare the systems, criteria and diagnoses used to recognize LBPD as occupational diseases in other European countries.

Methods: A questionnaire focused on LBPD was distributed and answered by specialists in occupational diseases in European countries. It included items concerning LBPD in the national list of occupational diseases, and work-related and diagnostic criteria that need to be fulfilled for recognizing LBPD as occupational diseases and possible awarding compensations to the patients.

Results: In 13 countries out of the 23 countries studied, LBPD caused by overload can be recognized as occupational, providing that the diagnosis is sufficiently proven and exposure criteria and/or listed occupation are met and duration of exposure is confirmed (Belgium, Denmark, France, Germany, Hungary, Italy, Lithuania, Macedonia, Netherlands, Romania, Slovakia, Sweden, and Switzerland). LBPD due to vibrations can be also recognized as occupational in 14 countries. In 8 countries LBPD are not accepted as occupational unless they are caused by an injury at work. Specific criteria to evaluate occupational exposure of patients with LBPD were set in Belgium, Denmark, France, Germany, Lithuania, Macedonia, Netherlands, and Slovakia. In other countries, the evaluation is done at an individual basis.

Conclusions: In practice, the assessment of occupational overload and its contribution to the development of LBPD as well as its inclusion in the compensation system are important for several reasons. Firstly, it may be considered essentially preventable. Secondly, cases with a significant contribution of occupational aetiology may be viewed as occupational diseases for which compensation may be claimed, as it is the case in many European countries. Importantly, inclusion of LBPD in the list of occupational diseases or another system of compensation may be viewed as a preventive measure as it increases the visibility of this problem not only for the workers, but especially for the employers.
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http://dx.doi.org/10.21101/cejph.a4185DOI Listing
September 2015

Asthma caused by potassium aluminium tetrafluoride: a case series.

Ind Health 2015 23;53(6):562-8. Epub 2015 Jul 23.

Department of Occupational Medicine, First Medical Faculty, Charles University in Prague, Czech Republic.

The objective of this study is to describe a case-series of potassium aluminium tetrafluoride (KAlF(4))-induced occupational asthma (OA) and/or occupational rhinitis (OR). The study involves five patients from a heat-exchanger production line who were examined (including specific inhalation challenge tests) for suspected OA and/or OR caused by a flux containing almost 100% KAlF(4) - with fluorides' workplace air concentrations ranging between 1.7 and 2.8 mg/m(3). No subject had a previous history of asthma. All five patients had a positive specific challenge test (three patients were diagnosed with OA alone, one with OR and one with both OR and OA). At the follow-up visit, after three years on average, all patients needed permanent corticosteroid therapy (four topical, one oral). After elimination from the exposure, only one of the observed subjects gave an indication of an improvement, two subjects stabilized and two worsened. Our case series focuses on the correlation between patients' exposure to fluorides in air-conditioner production and the subsequent occurrence of OR/OA. Currently, it is uncertain whether these OR/OA were caused by hypersensitivity or irritation.
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http://dx.doi.org/10.2486/indhealth.2014-0094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667047PMC
December 2016

Raman microspectroscopy of exhaled breath condensate and urine in workers exposed to fine and nano TiO2 particles: a cross-sectional study.

J Breath Res 2015 Jul 14;9(3):036008. Epub 2015 Jul 14.

Charles University in Prague and General University Hospital in Prague, First Faculty of Medicine, Department of Occupational Medicine, Na Bojisti 1, 128 00 Prague 2, Czech Republic.

The health effects of engineered nanoparticles in humans are not well-understood; however experimental data support the theory of oxidative stress promoting fibrogenesis and carcinogenicity. The aim of this study was to detect TiO2 particles in exhaled breath condensate (EBC) and urine samples to ascertain their presence and potential persistence and excretion in urine.EBC and urine samples were collected from 20 workers exposed to TiO2 aerosol; among them, 16 had a higher risk level of exposure (production workers) and four had medium risk level (research workers); in addition to 20 controls. Titanium levels in EBC and urine were analysed using the inductively coupled plasma mass spectrometry (ICP-MS) method. A Raman microspectroscopic analysis was performed in EBC and urine to identify the phase composition of TiO2 particles observed. Aerosol exposure in the workplaces was measured using SMPS and APS spectrometers and P-TRAK and DustTRAK DRX monitors.The median concentration of TiO2 aerosol was 1.98 × 10(4) particles cm(-3), the interquartile range (IQR) was 1.50 × 10(4) - 3.01 × 10(4) particles cm(-3) and the median mass concentration was 0.65 mg m(-3) (IQR 0.46-.0.83 mg m(-3)); 70-82% of the particles were smaller than 100 nm in diameter. In any part of the plant, the median TiO2 air concentration did not exceed the national airborne exposure limit of 10 mg m(-3) for inert dust. Particles of rutile and/or anatase were found in the EBC of exposed workers in 8/20 (40%) of the pre-shift and 14/20 (70%) of the post-shift samples. In the urine of workers, TiO2 particles were detected in 2/20 post-shift urine samples only. The mean concentration of titanium in the EBC in production workers was 24.1 ± 1.8 µg/l. In the research workers the values were below the limit of quantitation; LOQ = 4.0 ± 0.2 µg/l), as well as in the controls. In the urine samples of all of the subjects, titanium was under the limit of detection (LOD = 1.2 µg/l). Raman microanalysis of EBC in the workers confirmed the presence of TiO2 anatase and/or rutile crystal phases in the pre-shift samples and their persistence from previous shifts in the workers.
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http://dx.doi.org/10.1088/1752-7155/9/3/036008DOI Listing
July 2015

Czech mass methanol outbreak 2012: epidemiology, challenges and clinical features.

Clin Toxicol (Phila) 2014 Dec 25;52(10):1013-24. Epub 2014 Oct 25.

Department of Occupational Medicine,Toxicological Information Center, First Faculty of Medicine, Charles University in Prague and General University Hospital , Prague , Czech Republic.

Objectives: Methanol poisonings occur frequently globally, but reports of larger outbreaks where complete clinical and laboratory data are reported remain scarce. The objective of the present study was to report the data from the mass methanol poisoning in the Czech Republic in 2012 addressing the general epidemiology, treatment, and outcomes, and to present a protocol for the use of fomepizole ensuring that the antidote was provided to the most severely poisoned patients in the critical phase.

Methods: A combined prospective and retrospective case series study of 121 patients with confirmed methanol poisoning.

Results: From a total of 121 intoxicated subjects, 20 died outside the hospital and 101 were hospitalized. Among them, 60 survived without, and 20 with visual/CNS sequelae, whereas 21 patients died. The total and hospital mortality rates were 34% and 21%, respectively. Multivariate regression analysis found pH < 7.0 (OR 0.04 (0.01-0.16), p < 0.001), negative serum ethanol (OR 0.08 (0.02-0.37), p < 0.001), and coma on admission (OR 29.4 (10.2-84.6), p < 0.001) to be the only independent parameters predicting death. Continuous hemodialysis was used more often than intermittent hemodialysis, but there was no significant difference in mortality rate between the two [29% (n = 45) vs 17% (n = 30), p = 0.23]. Due to limited stockpiles of fomepizole, ethanol was administered more often; no difference in mortality rate was found between the two [16% (n = 70) vs. 24% (n = 21), p = 0.39]. The effect of folate administration both on the mortality rate and on the probability of visual sequelae was not significant (both p > 0.05).

Conclusions: Severity of metabolic acidosis, state of consciousness, and serum ethanol on admission were the only significant parameters associated with mortality. The type of dialysis or antidote did not appear to affect mortality. Recommendations that were issued for hospital triage of fomepizole administration allowed conservation of valuable antidote in this massive poisoning outbreak for those patients most in need.
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http://dx.doi.org/10.3109/15563650.2014.974106DOI Listing
December 2014

Rare alleles within the CYP2E1 (MEOS system) could be associated with better short-term health outcome after acute methanol poisoning.

Basic Clin Pharmacol Toxicol 2015 Feb 19;116(2):168-72. Epub 2014 Sep 19.

Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Genetic polymorphisms influence the metabolism of ethanol and methanol, but the potential effects of genetic predisposition on the clinical course, outcome and short-term health sequelae of acute methanol poisoning are unknown. To evaluate the role of the MEOS system in methanol poisoning, we analysed the effect of three polymorphisms (RsaI - rs2031920; PstI - rs3813867; insertion/deletion I/D) within the CYP2E1 enzyme (MEOS system) in 50 adult survivors of methanol poisoning and compared their genotype frequencies with 460 controls. The minor allele frequencies of all three polymorphisms were below 5% in both groups. We did not detect significant differences in the genotype frequencies between survivors of methanol poisoning and controls (p = 0.34 for the RsaI variant; p = 0.59 for the PstI variant and p = 0.21 for the I/D polymorphism). The carriers of at least one minor allele in the CYP2E1 gene had less severe clinical symptoms and better short-term outcome after acute poisoning. Variants within the CYP2E1 gene are likely not significant genetic determinants of acute methanol poisoning (if survivors are analysed), but they may influence the severity of methanol poisoning and its visual/central nervous system (CNS) outcome.
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http://dx.doi.org/10.1111/bcpt.12310DOI Listing
February 2015

Occupational asthma follow-up--which markers are elevated in exhaled breath condensate and plasma?

Int J Occup Med Environ Health 2014 Apr 19;27(2):206-15. Epub 2014 Mar 19.

Department of Occupational Medicine of the First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic,

Objectives: To search for optimal markers in the exhaled breath condensate (EBC), plasma and urine that would reflect the activity/severity of occupational asthma (OA) after the withdrawal from the exposure to the allergen.

Material And Methods: Markers of oxidative stress: 8-iso-prostaglandin F2α (8-isoprostane, 8-ISO), malondialdehyde (MDA), 4-hydroxy-trans-2-nonenale (HNE), cysteinyl leukotrienes (LT) and LTB4 were determined using liquid chromatography and mass spectrometry in 43 subjects with immunological OA (49.3 ± 11.8 years), removed from the exposure to the sensitizing agent 10.5 ± 6.5 years ago; and in 20 healthy subjects (49.0 ± 14.9 years). EBC was harvested both before and after the methacholine challenge test. In parallel, identical markers were collected in plasma and urine. The results were analyzed together with forced expiratory volume in one second (FEV1), blood eosinophils, immunoglobulin E (IgE) and eosinophilic cationic protein (ECP) and statistically evaluated (Spearman rank correlation rS, two- or one-sample t tests and alternatively Kruskal Wallis or pair Wilcoxon tests).

Results: Several parameters of lung functions were lower in the patients (FEV1% predicted, MEF25% and MEF50%, Rtot%, p < 0.001). Shorter time interval since the removal from the allergen exposure correlated with higher ECP (rS = 0.375) and lower FEV1%, MEF25% and MEF50% after methacholine challenge (rS = -0.404, -0.425 and -0.532, respectively). In the patients, IgE (p < 0.001) and ECP (p = 0.009) was increased compared to controls. In EBC, 8-ISO and cysteinyl LTs were elevated in the asthmatics initially and after the challenge. Initial 8-ISO in plasma correlated negatively with FEV1 (rS = -0.409) and with methacholine PD20 (rS = -0.474). 8-ISO in plasma after the challenge correlated with IgE (rS = 0.396).

Conclusions: The improvement in OA is very slow and objective impairments persist years after removal from the exposure. Cysteinyl LTs and 8-ISO in EBC and 8-ISO in plasma might enrich the spectrum of useful objective tests for the follow-up of OA.
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http://dx.doi.org/10.2478/s13382-014-0243-2DOI Listing
April 2014

Intermittent hemodialysis is superior to continuous veno-venous hemodialysis/hemodiafiltration to eliminate methanol and formate during treatment for methanol poisoning.

Kidney Int 2014 Jul 12;86(1):199-207. Epub 2014 Mar 12.

Department of Acute Medicine, The Norwegian Center for NBC Medicine, Oslo University Hospital, Ullevaal, Norway.

During an outbreak of methanol poisonings in the Czech Republic in 2012, we were able to study methanol and formate elimination half-lives during intermittent hemodialysis (IHD) and continuous veno-venous hemodialysis/hemodiafiltration (CVVHD/HDF) and the relative impact of dialysate and blood flow rates on elimination. Data were obtained from 11 IHD and 13 CVVHD/HDF patients. Serum methanol and formate concentrations were measured by gas chromatography and an enzymatic method. The groups were relatively comparable, but the CVVHD/HDF group was significantly more acidotic (mean pH 6.9 vs. 7.1 IHD). The mean elimination half-life of methanol was 3.7 and formate 1.6 h with IHD, versus 8.1 and 3.6 h, respectively, with CVVHD/HDF (both significant). The 54% greater reduction in methanol and 56% reduction in formate elimination half-life during IHD resulted from the higher blood and dialysate flow rates. Increased blood and dialysate flow on the CVVHD/HDF also increased elimination significantly. Thus, IHD is superior to CVVHD/HDF for more rapid methanol and formate elimination, and if CVVHD/HDF is the only treatment available then elimination is greater with greater blood and dialysate flow rates.
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http://dx.doi.org/10.1038/ki.2014.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080337PMC
July 2014

Occupational viral hepatitis in the Slovak and the Czech Republic.

Cent Eur J Public Health 2013 Jun;21(2):92-7

Department of Public Health, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia.

Background: The proportion of occupational infectious diseases (ID) in the total number of occupational diseases reported in the Slovak Republic (SR) and the Czech Republic (CR) was decreasing from 1973 to 2010. Our study presents a longitudinal analysis of the occurrence of occupational infectious diseases in the Slovak Republic and the Czech Republic in the period from 1973-2010 with special focus on viral hepatitis.

Methods: The sources of data were national health statistics of Czechoslovakia, the Czech Republic and the Slovak Republic. Descriptive statistical methods were used for data analysis. Incidence rate of reported diseases was calculated per 100,000 general population or per 100,000 people insured.

Results: During the studied period, a total of 2,931 and 8,318 cases of occupational viral hepatitis (VH) were reported in the Slovak Republic and the Czech Republic, respectively. The incidence culminated in the late 1970s when hepatitis represented almost 50% of all reported occupational infectious diseases. Most cases of occupational hepatitis occurred in health and social services. Since the early 1980s, a steep decrease in the incidence of hepatitis has been observed due to the gradual implementation of mandatory vaccination against hepatitis A and B in risk groups. In SR in 1973, the incidence rate of occupational infectious diseases and that of occupational viral hepatitis was 10.85/100,000 and 1.86/100,000, respectively. In 2010, these rates decreased to 0.74/100,000 and 0.20/100,000, respectively. In CR, the incidence rates of occupational infectious diseases and that of occupational viral hepatitis reported in 1973 were 11.75/100,000 and 3.69/100,000. In 2010, reported incidence rates were 1.71/100,000 and 0.10/100,000, respectively.

Conclusion: Although the incidence of occupational viral hepatitis has dramatically decreased in the Slovak and the Czech Republic as well as in other Visegrad group countries during the studied period, we emphasize the necessity of continuing epidemiological surveillance of hepatitis, especially with regard to the recent incidence increase of viral hepatitis C.
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http://dx.doi.org/10.21101/cejph.a3790DOI Listing
June 2013

Leukotrienes B4, C4, D4 and E4 in the exhaled breath condensate (EBC), blood and urine in patients with pneumoconiosis.

Ind Health 2012 13;50(4):299-306. Epub 2012 Jun 13.

Department of Occupational Medicine of the 1st Faculty of Medicine, Charles University in Prague, Czech Republic.

Leukotrienes (LTs) are involved in the pathogenesis of lung fibrosis and were increased in exhaled breath condensate (EBC) of the patients with pneumoconiosis. However the possible influence of extra-pulmonary disorders on the EBC markers is not known. Therefore in parallel with EBC, LTs' levels in the plasma and urine were measured in patients with pneumoconiosis (45 × asbestos exposure, 37 × silica exposure) and in 27 controls. Individual LTs B4, C4, D4 and E4 were measured by liquid chromatography - electrospray ionization - tandem mass spectrometry (LC-ESI-MS/MS). In EBC, LT D4 and LT E4 were increased in both groups of patients (p<0.001 and p<0.05), comparing with the controls. Both LT B4 and cysteinyl LTs were elevated in asbestos-exposed subjects (p<0.05). Asbestosis with more severe radiological signs (s1/s2-t3/u2) and lung functions impairment has shown higher cysteinyl LTs and LT C4 in the EBC (p<0.05) than mild asbestosis (s1/s0-s1/s1). In addition, in the subjects with asbestosis, cysteinyl LTs in EBC correlated with TLC (-0.313, p<0.05) and TLCO/Hb (-0.307, p<0.05), and LT C4 with TLC (-0.358, p<0.05). In pneumoconioses, EBC appears the most useful from the 3 fluids studied.
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http://dx.doi.org/10.2486/indhealth.ms1274DOI Listing
February 2013

Increased oxidative/nitrosative stress markers measured non- invasively in patients with high 2,3,7,8-tetrachloro-dibenzo-p-dioxin plasma level.

Neuro Endocrinol Lett 2011 ;32 Suppl 1:71-6

Department of Occupational Medicine of the First Faculty of Medicine and General University Hospital, Charles University Prague, Czech Republic.

Objectives: 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) is a highly toxic persistent environmental contaminant, classified as a human carcinogen affecting any target organ. The mechanism of carcinogenesis by TCDD is unclear as TCDD shows a lack of direct genotoxicity. Experimental studies also support the role of oxidative stress in TCDD neurotoxicity and vascular dysfunction. The aim was to investigate markers of oxidative/nitrosative stress and inflammation using non-invasive methods in subjects who got ill due to severe occupational exposure to TCDD in the years 1965-1968.

Methods: In 11 TCDD-exposed patients, and 16 controls, the analysis of following oxidative products of lipids, proteins and nucleic acids in plasma, urine and exhaled breath condensate (EBC) was performed: 8-iso-prostaglandin F2α (8-isoprostane), 4-hydroxy-trans-2-nonenale (HNE), malondialdehyde (MDA), o-tyrosine (o-Tyr), 8-hydroxyguanosine (8-OHG), 8-hydroxy-2´-deoxy-guanosine (8-OHdG), 5-hydroxymethyluracil (5-OHMeU). In addition, nitric-oxide-tyrosine (NO-Tyr) and leukotriene (LT) B4, C4, D4, and E4 were detected by liquid chromatography-mass spectrometry/mass spectrometry (LC-ESI-MS/MS). TCDD was measured by HRGC/HRMS, body lipid content by densitometry. Single-photon emission spectrometry (SPECT) of the brain was performed and compared with the findings of the patients in 2008.

Results: Mean TCDD plasma level in 2010 was 175 ± 162 pg/g lipids (population level about 2 pg/g), total TCDD content in the body 5.16 ± 4.62 mg. Reduction of cerebral blood flow in SPECT progressed in 8 patients, finding was stable in 2 subjects, and improvement occurred in 1 patient. In the EBC, 10 from 12 markers (all except LT D4 and LT E4), were significantly increased in the patients (p<0.05). In the urine, 7 markers were significantly higher than in the controls (p<0.05): 8-isoprostane, MDA, HNE, LT C4, LT E4, o-Tyr and NO-Tyr. In plasma, only NO-Tyr and 8-OHG were elevated (p<0.05).

Conclusion: NO-Tyr was increased in all matrices in dioxin-exposed patients. EBC is not limited to lung disorders as the markers of oxidative stress and inflammation were elevated in EBC of patients with normal lung functions. TCDD-induced oxidative stress and inflammation markers can be detected non-invasively in the EBC and urine in the follow-up of the highly-exposed patients. Their prognostic value, however, needs to be elucidated.
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April 2012

Oxidative stress markers in exhaled breath condensate in lung fibroses are not significantly affected by systemic diseases.

Ind Health 2011 20;49(6):746-54. Epub 2011 Oct 20.

Charles University in Prague, 1st Faculty of Medicine, Department of Occupational Medicine of the 1st Faculty of Medicine, Prague, Czech Republic.

Exhaled breath condensate (EBC) is assumed to reflect processes in the lungs, yet it is unknown whether oxidative stress markers in EBC are affected by systemic disorders (atherosclerosis, hypertension, diabetes) or whether lung diseases increase markers in plasma and urine. 8-isoprostane, 4-hydroxy-trans-2-nonenale (HNE) and malondialdehyde (MDA) were measured using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) in EBC, plasma and urine in 82 patients (45 with asbestosis and hyalinosis, and 37 with silicosis) and in 29 control subjects. 8-isoprostane and HNE in EBC, and HNE in urine were higher in both groups of patients. In addition, 8-isoprostane in plasma and urine, and MDA in urine were higher in asbestos-exposed patients and MDA in plasma in silicotics, with this marker in plasma correlated with the grade of silicosis. In all subjects, 8-isoprostane in EBC correlated with urine (r=0.38, p<0.001) and plasma levels (r=0.28, p=0.003), and HNE and MDA with urine levels (r=0.31, p<0.001; r=0.23, p=0.016, respectively). Most markers positively correlated with lung function impairment, EBC markers negatively with vitamin E supplementation. To conclude: The influence of satisfactorily controlled systemic disorders on markers in EBC in patients with pneumoconioses is not significant. In addition to oxidative stress markers in EBC, lung fibroses may increase oxidative stress markers in plasma and urine.
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http://dx.doi.org/10.2486/indhealth.ms1237DOI Listing
April 2012

Determination of cysteinyl leukotrienes in exhaled breath condensate: method combining immunoseparation with LC-ESI-MS/MS.

J Chromatogr B Analyt Technol Biomed Life Sci 2011 Aug 13;879(23):2220-8. Epub 2011 Jun 13.

Institute of Chemical Technology, Technická 5, 166 28 Prague 6, Czech Republic.

A rapid and precise method for the identification and quantification of cysteinyl leukotrienes (leukotriene C(4), leukotriene D(4) and leukotriene E(4)), essential markers of bronchial asthma, in exhaled breath condensate was developed. The protocol consists of immunoaffinity separation and a detection step, liquid chromatography combined with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). In particular, the selected reaction monitoring mode was used for its extremely high degree of selectivity and the stable-isotope-dilution assay for its high precision of quantification. The developed method was characterized with a high precision (≤ 7.7%, determined as RSD), an acceptable accuracy (90.4-93.7%, determined as recovery), a low limit of detection (≤ 2 pg/ml EBC) and a low limit of quantification (≤ 10 pg/ml EBC). It was compared to other simple, clinically appropriate combinations of pre-treatment methods (solid phase extraction and lyophilization) with LC/MS. Finally, the method (a combination of immunoaffinity separation with LC-MS) was successfully tested in a clinical study where a significant difference was found in the concentration levels of cysteinyl leukotrienes between patients with occupational bronchial asthma and healthy subjects.
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http://dx.doi.org/10.1016/j.jchromb.2011.06.004DOI Listing
August 2011

Chronic health impairment due to 2,3,7,8-tetrachloro-dibenzo-p-dioxin exposure.

Neuro Endocrinol Lett 2009 ;30 Suppl 1:219-24

Department of Occupational Medicine, Charles University Prague, Czech Republic.

Objectives: The aim of this study, performed in 2008, was to evaluate the consequences of severe occupational intoxication with 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) that occurred during production of the herbicide trichlorophenoxyacetic acid in the period 1965-1968.

Design: Examination of 11 men, mean age 64.4+/-1.5 years, included: internal and neurological examination, eye fundus examination, TCDD in plasma, thyroid-stimulating hormone (TSH), testosterone and serum lipids, ultrasonography of the carotid artery, nerve conduction study (NCS), electroencephalography (EEG), visual evoked potential (VEP), Lanthony test of acquired visual impairment, single photon emission computer tomography (SPECT) of the brain, neuropsychological examination and carbohydrate-deficient transferrin (CDT), a marker of chronic ethanol intake.

Results: Mean TCDD level in 2008 was still 274.0+/-181.2 pg/g blood lipids (reference level is 2-3 pg/g). All (100%) patients had residues of chloracne/chloracne consequences, atherosclerotic changes on the eye fundus and plaques in the carotid arteries. Progression of intima-media thickness (IMT) from a mean of 0.84+/-0.14 mm in 2003 to 1.09+/-0.18 mm in 2008 was observed. Ninety-one per cents of patients had impairment in SPECT of the brain; and 55% of patients had hyperfixation of the perfusion indicator as a measure of increased neuronal activity. Additionally, 91 % of patients were treated for hyperlipidaemia, 73 % for hypertension, 55 % for diabetes type 2, 45 % for ischemic heart disease, and 36 % for psychological disorders. The Lanthony test demonstrated acquired dyschromatopsia in 80 % of patients. Mean colour confusion index (CCI) was 1.438, which indicates impairment since 2003, when the index was 1.302. CDT was in the normal range and did not correlate with CCI. Neuropsychological status appeared stabilized in all 8 patients examined, with impairment in one or more parameter (memory, attention, verbal fluency, psychomotor speed, motorics) in comparison to the norm.

Conclusion: Forty years after intoxication, the blood level of TCDD is still 100 times higher than in the general population. Other PCDD/Fs were not elevated. A high percentage of subjects suffer from neurological and vascular disorders. No association of alcohol consumption with neurological impairment was seen, and the highly significant correlation between CCI and TCDD blood concentration suggests that acquired colour impairment was associated with TCDD but not with alcohol consumption. IMT significantly increased during past 5 years. The patients obviously need complex treatment, including intense hypolipidaemic and antidepressant therapy.
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May 2010
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