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Ziel dieses Projektes war es, verschiedene Aerosole im Expositionslabor des Instituts für Prävention und Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung (IPA) mit einem geeigneten Probenahmesystem direkt auf einen Probenträger abzuscheiden. Mittels Rasterelektronenmikroskopie-Aufnahmen sollte analysiert werden, welche morphologische Beschaffenheit ein Aerosol hat, unmittelbar bevor Probanden einer toxikologischen Studie luftgetragene Partikel in verschiedenen Größen inhalieren. Dabei sollten die experimentellen Umgebungsbedingungen identisch mit den Zielbedingungen des beabsichtigten bzw. bereits durchgeführten Studiendesigns sein. Zusätzlich sollte die Frage beantwortet werden, welches Partikelgeneratorsystem für zukünftige Inhalationsstudien im Expositionslabor für eine gewünschte Substanz zur Anwendung kommen kann. Die Untersuchungen umfassten nano-Zinkoxid, mikro-Zinkoxid, mikro-Bariumsulfat und zwei unterschiedliche nano-Titandioxid-Atmosphären. Begleitende Messungen bestätigten, dass es kaum Unterschiede zwischen Soll- und Zielkonzentrationen gab. Auch die zu erwartenden Partikelgrößenverteilungen wurden erreicht – mit Ausnahme eines der beiden Titandioxid-Materialien. Zusätzlich konnte die Frage beantwortet werden, ob es mit einem Suspensionsvernebler-System möglich ist, nanofeine Materialien in die Atmosphärenluft unter Erhalt der ursprünglichen Partikelgröße zu resuspendieren. Allerdings funktionierte diese Methode nicht.

Background Most threshold limit values are based on animal experiments. Often, the question remains whether these data reflect the situation in humans. As part of a series of investigations in our exposure lab, this study investigates whether the results on the inflammatory effects of particles that have been demonstrated in animal models can be confirmed in acute inhalation studies in humans. Such studies have not been conducted so far for barium sulfate particles (BaSO4), a substance with very low solubility and without known substance-specific toxicity. Previous inhalation studies with zinc oxide (ZnO), which has a substance-specific toxicity, have shown local and systemic inflammatory respones. The design of these human ZnO inhalation studies was adopted for BaSO4 to compare the effects of particles with known inflammatory activity and supposedly inert particles. For further comparison, in vitro investigations on inflammatory processes were carried out. Methods Sixteen healthy volunteers were exposed to filtered air and BaSO4 particles (4.0 mg/m3) for two hours including one hour of ergometric cycling at moderate workload. Effect parameters were clinical signs, body temperature, and inflammatory markers in blood and induced sputum. In addition, particle-induced in vitro-chemotaxis of BaSO4 was investigated with regard to mode of action and differences between in vivo and in vitro effects. Results No local or systemic clinical signs were observed after acute BaSO4 inhalation and, in contrast to our previous human exposure studies with ZnO, no elevated values of biomarkers of inflammation were measured after the challenge. The in vitro chemotaxis induced by BaSO4 particles was minimal and 15-fold lower compared to ZnO. Conclusion The results of this study indicate that BaSO4 as a representative of granular biopersistent particles without specific toxicity does not induce inflammatory effects in humans after acute inhalation. Moreover, the in vitro data fit in with these in vivo results. Despite the careful and complex investigations, limitations must be admitted because the number of local effect parameters were limited and chronic toxicity could not be studied.

In this study, 24 subjects (20-58 years) were exposed to carbon dioxide (CO2 ) at 770 ppm and 20 000 ppm in an exposure laboratory for 4-h, including 2 × 15 min of cycling to investigate the effects on acid-base balance, physiological responses, cognitive performance and acute health. Capillary blood analysis, heart rate, respiratory rate, divided attention, flexibility, and sustained attention from the Test Battery for Attentional Performance (TAP), critical flicker fusion frequency (CFF), and self-reported symptoms were measured before, during, and after the 4-h exposure. Blood pH decreased and partial pressure of carbon dioxide (pCO2 ) increased significantly when exposed to 20 000 ppm CO2 compared to 770 ppm. However, the values remained within the normal range. In addition, respiratory rate increased slightly but significantly at 20 000 ppm CO2 . No significant changes in heart rate, CFF, task performance or acute health were found. In sum, the findings suggest that the observed changes in acid-base balance and ventilation can be classified as physiological adaptation responses. Impairment of cognitive performance is not expected from exposure to 20 000 ppm CO2 , neither as direct effect on central nervous system function nor as a distraction related to perception of health effects.

The ubiquitous use of phthalates in various materials and the knowledge about their potential adverse effects is of great concern for human health. Several studies have uncovered their role in carcinogenic events and suggest various phthalate-associated adverse health effects that include pulmonary diseases. However, only limited information on pulmonary toxicity is available considering inhalation of phthalates as the route of exposure. While in vitro studies are often based on submerged exposures, this study aimed to expose A549 alveolar epithelial cells at the air-liquid interface (ALI) to unravel the genotoxic and oxidative stress-inducing potential of dibutyl phthalate (DBP) with concentrations relevant at occupational settings. Within this scope, a computer modelling approach calculating alveolar deposition of DBP particles in the human lung was used to define in vitro ALI exposure conditions comparable to potential occupational DBP exposures. The deposited mass of DBP ranged from 0.03 to 20 ng/cm2 , which was comparable to results of a human lung particle deposition model using an 8 hours workplace threshold limit value (TLV) of 580 μg/m3 proposed by the Scientific Committee on Occupational Exposure Limits (SCOEL) for the European Union. Comet and Micronucleus assay revealed that DBP induced genotoxicity at DNA and chromosome level in sub-cytotoxic conditions. Since genomic instability was accompanied by increased generation of the lipid peroxidation marker malondialdehyde (MDA), oxidative stress might play an important role in phthalate-induced genotoxicity. The results highlight the importance of adapting in vitro studies to exposure scenarios relevant at occupational settings and reconsidering occupational exposure limits for DBP.

Ziel dieser Untersuchung war es, verschiedene Messgeräte und Analysentechniken zur Ermittlung der Stickoxidkonzentrationen (NOx-Konzentrationen) so zu vergleichen, wie sie zurzeit in Messstellen eingesetzt werden. Dazu wurden sie verschiedenen Prüfgaskonzentrationen ausgesetzt, die sich an den aktuellen Arbeitsplatzgrenzwerten (AGW) orientierten. Ein Nebenaspekt betraf NOx-Prüfgase aus Druckgasflaschen, um Aussagen zur Abweichung zwischen Soll- und Istwerten zu treffen. Zum Einsatz kamen mehrere Chemolumineszenz-Analysatoren, direktanzeigende Warngeräte auf Basis elektrochemischer Sensorik und elektrochemische Sensorelemente, die nicht in einem Gerät verbaut waren. Die Vergleichsmessungen fanden 2019 im Institut für Prävention und Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung (IPA) statt. Während die Messergebnisse der Chemolumineszenz-Geräte geringe Abweichungen zeigten, ergaben sich bei den elektrochemischen Sensoren teilweise erhebliche Spannbreiten. Die Messergebnisse der Warngeräte können als orientierende Konzentrationsbestimmungen im AGW-Bereich verwendet werden. Zusätzlich wurde gezeigt, dass die gemessenen NOx-Konzentrationen der Prüfgasflaschen teilweise deutlich von den zertifizierten Werten abwichen.

Occupational exposure limits (OELs) are derived for protection from health hazards, assuming that exposed subjects are healthy adult workers. Whether differences in susceptibility to sensory irritation effects from airborne chemicals have to be taken into account is currently under discussion. Thus, we chose atopics as a healthy but possibly susceptible subpopulation that can be identified with a clinical test. To investigate the influence of sex or atopy on sensitivity to airborne chemicals, 22 subjects were exposed for 4 h to ethyl acrylate at three concentrations: 0.05 ppm (odor threshold; sham), 5 ppm (constant), and varying exposure between 0 and 10 ppm. Odor intensity decreased and eye irritation ratings increased in a dose-dependent manner, reflecting the time course of the exposure scenarios. The reports of moderate-to-strong eye irritation were verified by significant increases in eye blink frequency. Our results show that women reported subjective eye irritation to an increasing degree. However, these sex-related differences in ratings could not be verified by objective assessment of eye blink frequency. Atopic subjects reported higher odor intensity than non-atopic subjects, but only during the sham (odorous but not irritating) exposure condition. Differences in ratings on annoyance, and eye or nose irritation were not found. Furthermore, the study revealed that atopic subjects might belong to a group of subjects with frequent eye blink activity. Although the relative increase in blink rates was more pronounced in non-atopic subjects, atopic subjects had significant higher blink rates at the end of the exposure to varying ethyl acrylate concentrations. Our results do not support that atopy enhances chemosensory effects if only the increase of blink rates and not the absolute height are considered as adverse effect. Nevertheless, the results indicate that individuals with frequent eye blink activity should be distinguished from those with normal eye blink activity while investigating blink rates as objective parameter of eye irritation.

Biopersistent pro-inflammatory fibers are suspected human carcinogens. Cytotoxicity and transcription of pro- and anti-inflammatory mediators of different fibers were investigated in functional relationship to chemotaxis in vitro as a model for fiber-induced inflammation of the lung. We challenged NR8383 rat macrophages with multi-walled carbon nanotubes (MWCNT) and various asbestos fibers. The resulting cell supernatants were than studied using the Particle-induced Cell Migration Assay (PICMA) and cytotoxicity was determined using the LDH test. Expression of inflammatory mediators was analyzed with qPCR and verified by ELISA. Chrysotile A and the rigid, needle-shaped NM-401 caused the strongest cytotoxic effects and the largest number of migrated cells. In contrast, the MWCNT NM-400, NM-402, and NM403 were apparently non-cytotoxic but induced pronounced cell migration showing a very steep dose response. However, the strength of cell migration and cytotoxicity of the asbestos fibers were correlated. The expression profile of inflammatory mediators was comparable, although cytotoxicity of the MWCNT NM-401 and NM-403 differed strongly. Induction of the corresponding proteins was confirmed for CCL2, CCL3, CXCL1, CXCL3, IL1RA (IL1RN), CSF1, GDF15 and TNFa. Chrysotile A and NM-401 induced much stronger chemotaxis than the non-fibrous particles reported in our previous study. Cytotoxic and chemotactic effects correspond to the induction of inflammatory mediators.

Background Exposure to airborne zinc oxide (ZnO) particles occurs in many industrial processes, especially in galvanizing and welding. Systemic inflammation after experimental inhalation of ZnO particles has been demonstrated previously, but little is known about the impact on the cardiovascular system, particularly on the autonomic cardiac system and the risk of arrhythmias. In this study we investigated the short-term effects of ZnO nanoparticles on heart rate variability (HRV) and repolarization in healthy adults in a concentration-dependent manner at rest and during exercise in a controlled experimental set-up. Methods Sixteen healthy subjects were exposed to filtered air and ZnO particles (0.5, 1.0 and 2.0 mg/m3) for 4 h, including 2 h of cycling at low workloads. Parameters were assessed before, during, immediately after, and about 24 h after each exposure. For each subject, a total number of 46 10-min-sections from electrocardiographic records were analyzed. Various parameters of HRV and QT interval were measured. Results Overall, no statistically significant effects of controlled ZnO inhalation on HRV parameters and QT interval were observed. Additionally, a concentration-response was absent. Conclusion Inhalation of ZnO nanoparticles up to 2.0 mg/m3 for 4 h does not affect HRV and cardiac repolarization in healthy adults at the chosen time points. This study supports the view that cardiac endpoints are insensitive for the assessment of adverse effects after short-term inhalation of ZnO nanoparticles.

Inhalation of high concentrations of zinc oxide (ZnO) particles may cause metal fume fever. A useful tool to characterize the reactivity of innate immune cells of an individual, e.g., after in vivo exposure, is the whole blood assay (WBA). The measurable outcome of WBA is the release of cytokines, especially pro-inflammatory and pyrogenic cytokines induced by stimulation in vitro. The aim of the study was to evaluate whether inhalation of nano-sized zinc oxide particles modifies the results of WBA from healthy blood donors. Sixteen healthy subjects were exposed to filtered air and ZnO particles (0.5, 1.0, and 2.0 mg/m

Atopic, allergic, and especially asthmatic subjects might be particularly susceptible to sensory irritation induced by airborne chemicals compared to healthy individuals. Therefore, a good characterization of subjects is essential in inhalation exposure studies on sensory irritants. A total of 105 volunteers, 87% of whom reported to be non-allergic, participated in a medical examination that included skin prick test (SPT), measurements of total IgE, specific IgE (sIgE) to an ubiquitous allergen mix (sx1), and fractionated exhaled nitric oxide (FeNO), as well as pulmonary function and methacholine test. The median value of sIgE to sx1 was 0.20 kU/L (0.07–91.3 kU/L) and correlated significantly with total IgE (28.8 kU/L (2–756 kU/L)) and FeNO (14 ppb (5–100 ppb)). Forty-three subjects (41%) had sIgE to sx1 ≥ 0.35 kU/L and were classified as atopic. Thirty-five subjects, all also sx1-positive, were positive in SPT. Obstruction, small airway disease, and/or bronchial hyperreactivity were diagnosed in 18 subjects. Receiver operating characteristics (ROC) were performed to check whether signs of sensitization are useful to discriminate subjects with and without airway diseases. However, sx1, total IgE, FeNO, and SPT reached only low areas under the curve (AUC: 0.57–0.66). Although predominantly young and, according to their own statements, mostly non-allergic subjects participated in the study, almost half of them were atopic, and 10% had airway disease or bronchial hyperreactivity. This indicates that the validity of self-reported data might be inaccurate. In summary, diversified investigations of the allergy-related health status appear necessary for a thorough characterization of subjects for exposure studies on sensory irritants.

Background Workers in the zinc production and processing of galvanized sheet steel are exposed to a complex mixture of particles and gases, including zinc oxide (ZnO) that can affect human health. We aimed to study the effects of short-term controlled exposure to nano-sized ZnO on airway inflammatory markers in healthy volunteers. Methods Sixteen subjects (8 females, 8 men; age 19–42, non-smokers) were exposed to filtered air and ZnO nanoparticles (0.5, 1.0 and 2.0 mg/m3) for 4 h, including 2 h of cycling with a low workload. Induced sputum samples were collected during a medical baseline and a final examination and also about 24 h after each exposure. A number of inflammatory cellular and soluble markers were analyzed. Results Frequency and intensity of symptoms of airway irritation (throat irritation and cough) were increased in some subjects 24 h after ZnO exposures when compared to filtered air. The group comparison between filtered air and ZnO exposures showed statistically significant increases of neutrophils and interleukin-8 (IL-8), interleukin-6 (IL-6), matrix metalloproteinase (MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1) in sputum starting at the lowest ZnO concentration of 0.5 mg/m3. However, a concentration-response relationship was absent. Effects were reversible. Strong correlations were found between neutrophil numbers and concentrations of total protein, IL-8, MMP-9, and TIMP-1. Conclusions Controlled exposures of healthy subjects to ZnO nanoparticles induce reversible airway inflammation which was observed at a concentration of 0.5 mg/m3 and higher. The lack of a concentration-response relationship warrants further studies.

Potash miners can become exposed to carbon dioxide (CO

The whole-blood assay (WBA) with human fresh blood may provide insight into the features of an individual's innate immunity. To assess this, ex vivo cytokine release is measured after stimulation of whole blood with various stimuli, for instance, endotoxin in vitro. The aim of the present study was to evaluate WBA reproducibility with fresh blood using different calculation models. The blood was collected from 16 healthy volunteers on 6 different days. Ex vivo stimulation was performed in each individual's blood sample for 22 h, using different endotoxin concentrations. Interleukin (IL)-1β and IL-8 release were quantified using specific immunoassays in the cell-free supernatant. We found that a dose-response relationship between endotoxin and cytokine concentration could be verified for all blood donors in all tests. The median coefficient of variation of the repeated tests was 29% for IL-1β and 52% for IL-8. Upon stimulation with 40 pg/mL endotoxin, a confidence interval of 60-140% was calculated for IL-1β and 70-271% for IL-8 regarding test reproducibility. Furthermore, the classification into high or low responder was reproducible. We conclude that repeated blood collection offers an opportunity to evaluate the variability of WBA. Considering a high intragroup variability, an individual range assessment has been suggested to evaluate exposure effects.

A large number of occupational exposure limit values (OELs) are based on avoiding of sensory irritation of the eyes and the upper respiratory tract. In order to investigate the chemosensory effect range of a chemical, odor and sensory irritation thresholds (lateralization thresholds, LTs) can be assessed. Humidity affects olfactory function and thus influences odor thresholds; however, a similar effect has not been shown for sensory irritation thresholds. The purpose of the present study was to explore whether LTs for ammonia vapor vary depending on the water vapor content of the inspired stimulus. Eight healthy nonsmoking volunteers were simultaneously exposed to ammonia vapor through one nostril and clean air through the other and were asked to determine which nostril received the chemical. Within experimental runs, ascending ammonia concentrations (60–350 ppm) that were either dry or humidified were administered at fixed time intervals. Geometric mean LTs obtained at wet (181 ppm) or dry (172 ppm) conditions did not differ significantly (P= 0.19) and were within the range of those reported by previous studies. These results suggest that humidity is not a critical factor in determining sensory irritation thresholds for ammonia, and future studies will examine if these findings are transferable to sensory irritation thresholds for other chemicals.

The whole-blood assay (WBA) with human fresh blood may provide insight into the features of an individual’s innate immunity. To assess this, ex vivo cytokine release is measured after stimulation of whole blood with various stimuli, for instance, endotoxin in vitro. The aim of the present study was to evaluate WBA reproducibility with fresh blood using different calculation models. The blood was collected from 16 healthy volunteers on 6 different days. Ex vivo stimulation was performed in each individual’s blood sample for 22 h, using different endotoxin concentrations. Interleukin (IL)-1β and IL-8 release were quantified using specific immunoassays in the cell-free supernatant. We found that a dose-response relationship between endotoxin and cytokine concentration could be verified for all blood donors in all tests. The median coefficient of variation of the repeated tests was 29% for IL-1β and 52% for IL-8. Upon stimulation with 40 pg/mL endotoxin, a confidence interval of 60–140% was calculated for IL-1β and 70–271% for IL-8 regarding test reproducibility. Furthermore, the classification into high or low responder was reproducible. We conclude that repeated blood collection offers an opportunity to evaluate the variability of WBA. Considering a high intragroup variability, an individual range assessment has been suggested to evaluate exposure effects.

Potash miners can become exposed to carbon dioxide (CO2) during the blasting of basalt intrusions or loading and transporting the blasted salt. In a cross-shift study, we compared physiological effects of acute exposure to elevated CO2 concentrations in miners after long-term exposure to evaluate the possible health risks. A group of 119 miners was assessed by clinical examination, lung function tests, and blood gas content directly before and after the shift. A cumulative CO2 exposure was measured using personal monitors. The miners were categorized as low ( 0.5 vol.%, n = 10) CO2 exposed subjects. We found no significant differences among the three groups. Lung function testing revealed no conspicuous findings, and chronic health effects were not observed in the miners either. In conclusion, no significant adverse effects could be found in potash miners exposed to elevated CO2 concentrations. Therefore, the mining authorities allow potash mining operations for 4 h at ambient CO2 up to 1.0 vol.% and for 2 h at CO2 not exceeding 1.5 vol.% per shift.

There is an interest in assessing changes in nasal NO (nNO) levels as an effect marker of upper airways. In this study, we examined methodologic influences on short and long term repeatability of nNO levels assessed by a portable electrochemical analyzer. Nine atopic and eighteen healthy subjects were exposed for 4 h to ethyl acrylate concentration of 0.05 ppm (sham) and mean concentrations of 5 ppm (either constant 5 ppm or variable 0 to 10 ppm). Sampling of nNO was performed by using passive aspiration during both breath-holding (634 ppb) or calm tidal breathing (364 ppb, p < 0.0001). The intra-session (between-session) repeatability in terms of coefficient of variation was 16.4% (18.5%) using the tidal-breathing and 8.6% (13.0%) using the breath-holding method, respectively. Atopic subjects demonstrated a significant increase in nNO (breath-holding mean 16%, tidal-breathing mean 32%) after applying a constant ethyl acrylate concentration (5 ppm). Our findings suggest that the less elaborate tidal-breathing method might be sufficient to detect significant changes at a group level. Given a lower coefficient of variation of breath-holding we assume there is an advantage of that approach at an individual level. Further research is needed to validate the usefulness of nNO in the evaluation of irritative, non-allergic responses.

Exposure to air contaminants, such as chemical vapors and particulate matter, poses important health hazards at workplaces. Short-term experimental exposure of human subjects to chemical vapors and particles is a promising attempt to investigate acute effects of such hazards. In the EU, there is an increasing need for regulatory agencies to derive health-based threshold limits based on human inhalation studies. Ethyl 2-cyanoacrylate (ECA) is the most widely used adhesive, both in industrial and domestic applications. ECA-containing vapors are irritating to the skin, eyes and respiratory system. In Germany, no occupational threshold limit value has been derived for ECA. A necessary prerequisite for inhalation challenge tests is the development of a suitable method to generate and characterize ECA test atmospheres for human whole-body inhalation studies. To address this, we developed a method to evaporate pretreated ECA with the help of a calibration gas generator. Experimental proof of the quantitative evaporation process was attained with a wipe test. The determination of airborne ECA concentrations in our exposure unit was established using chemical ionization real time mass spectroscopy taking into account temporal stability, different relative humidities and the presence of subjects in the chamber. Finally, we also developed a 5-step ECA inhalation challenge test.

Challenge studies in humans have shown considerable interindividual variability in pulmonary impairment across ozone exposure.Since previous results suggested effect modulation by neural mechanism, we investigated sensory C-fiber reactivity in relationship to ozone-triggered response pattern.Cough reflex thresholds reflecting C-fiber sensitivity were evaluated by capsaicin single breath dose-response method. Capsaicin concentrations triggering, respectively, two and five or more coughs (C2, C5) were recorded. Sixteen healthy subjects were randomly exposed in an intermittent exercise protocol to ozone concentrations of 240 and 40 ppb (sham exposure). Ozone responsiveness was defined by a decrease in forced expiratory volume in 1 s (FEV(1)) of more than 5%.Based on a dichotomous classification, subjects with enhanced reactivity to ozone had lower cough thresholds than non-responders (C2, p = 0.035; C5, p = 0.086). Over all, we could demonstrate relationships between capsaicin sensitivity and ozone-triggered changes in FEV(1), peak expiratory flow and maximal expiratory flow at 50% vital capacity but not in specific airway resistance.Our results suggest that capsaicin challenge tests might be useful to characterize subjects with enhanced pulmonary function response towards inhalant irritants.

In a potash mine in the center of Germany, stationary measurements 40 cm above ground level have revealed occasional increases in the carbon dioxide (CO2) levels that exceed the 0.5 vol.% German occupational exposure limit (OEL). This study, therefore, aimed to examine the individual exposures of potash miners to CO2 at their underground workplaces. 119 miners were equipped with personal CO2 detectors to log the individual CO2 exposures during underground work. We decided to use electrochemical monitors due to their compactness and minimal mass. Furthermore, generated CO2 measurements with precipitated overshooting and false positive CO2 values were studied using diverse CO2 test gases and different fumigation times. The personal detectors showed short-term CO2 peak exposures at very high concentrations in a limited number of workers. Twenty-two threshold limit value violations were observed according to the present OEL, and the personal CO2 monitoring allowed categorization into three exposure groups, low (n = 83), moderate (n = 26) and high burdens (n = 10) of CO2. The electrochemical sensors used have numerous properties that can potentially influence the assessment of exposures. The current findings suggest that assessing similar exposure scenarios, with respect to elevated and strongly fluctuating CO2 concentrations, the behavior of electrochemical sensors should be taken into consideration.

Acute effects of ethyl acrylate exposure at 5 ppm for 4 h include changes of pH in exhaled breath condensate (EBC-pH) and exhaled nitric oxide (FeNO). So far, few data have been reported for atopic persons or the impact of the exposure conditions on biomarkers, e.g., constant versus variable application of irritants. Nine atopic and eighteen healthy volunteers without bronchial hyperresponsiveness were exposed for 4 h to ethyl acrylate concentrations of 0.05 ppm (sham), 5 ppm (constant concentration), and 0–10 ppm (variable, mean concentration of 5 ppm) in an exposure laboratory. A positive atopic status was defined according to specific IgE concentrations to common inhalant allergens (sx1 ≥ 0.35 kU/L). Biomarker levels were assessed before and after challenge and adjusted for levels after sham exposure (net response). Ethyl acrylate at constant, but not at variable concentrations induced a significant change in the net responses of EBC-pH and FeNO. Concerning FeNO, this could be observed only for atopic persons. The changes of biomarker levels were related to their baseline values. Biomarker responses to challenge with ethyl acrylate may be influenced by the patterns of application as well as baseline airway inflammation and atopic status of the volunteers.

Exposures to air contaminants, such as chemical vapors and particulate matter, pose important health hazards at workplaces. Short-term experimental exposures to chemical vapors and particles in humans are a promising attempt to investigate acute effects of such hazards. However, a significant challenge in this field is the determination of effects of co-exposures to more than one chemical or mixtures of chemical vapors and/or particles. To overcome such a challenge, studies have to be conducted under standardized exposure characterization and real time measurements, if possible. A new exposure laboratory (ExpoLab) was installed at IPA, combining sophisticated engineering designs with new analytical techniques, to fulfill these requirements. Low-dose as well as high-dose exposure scenarios are achieved by means of a calibration-gas-generator. Exposure monitoring can be carried out with a high performance real time mass spectrometer and other suitable analyzers (e.g. gas chromatograph). Numerous automated security facilities guarantee the physical integrity of the volunteers, and the waste atmosphere is removed using either charcoal filtration or catalytic post-combustion. Measurements of sulfur hexafluoride, carbon dioxide, aniline and carbon black are presented to demonstrate the performance of the exposure unit with respect to the temporal and spatial stability of generated atmospheres. The variations of generated contents in the atmospheres at steady state are slightly higher than the measurement precision of the analyzers (the typical standard deviation of generated atmospheres is2%). The technical components of ExpoLab and its monitoring systems ensure high quality standards in validity and reliability of generating and measuring exposure atmospheres.

Summary Background: Presently, percutaneous absorption of potentially hazardous chemicals in humans can only be assessed in animal experiments, in vitro, or predicted mathematically. Our aim was to demonstrate the proof-of-principle of a novel quantitative in vivo assay for percutaneous absorption: confocal Raman micro-spectroscopy (CRS). The advantages and limitations of CRS for health risk assessments are discussed. Patients and Methods: 2-butoxyethanol, toluene, and pyrene were applied in pure form, diluted in water, or in ethanol on the skin of three healthy volunteers. CRS measurements were done following application for 15 min and 3 hours. The concentrations of the three substances as a function of distance to the skin surface were calculated and further analyzed with regard to mass transport into the stratum corneum (μg/cm2) and the flux through the stratum corneum (μg/cm2h). The results were compared with the available data from literature. Results: Considering the preliminary nature of these data, good accordance with data from the literature was observed. In addition, we observed that 2-butoxyethanol penetrates markedly faster when dissolved in water as compared to ethanol. This observation is also in agreement with previous results. Conclusions: CRS has the potential to provide fast, accurate and reliable results for advanced studies of in vivo percutaneous absorption kinetics of hazardous substances in human skin. This will require further research with other substances and under differing conditions.

Hintergrund Eine Vitiligo der Haut ist meist idiopathisch; allerdings konnen Berufsstoffe diese ebenfalls auslosen. Fuhrt beruflicher Kontakt mit p-tert.-Butylphenol (ptBP) zu einer Vitiligo, kann eine Berufskrankheit der Nr. 1314 anerkannt werden. Neben ptBP existieren Substanzen, die sowohl zu lokalisierten als auch zu Vitiligo-artigen Veranderungen mit symmetrischer Verteilung und Genitalbefall fuhren und deren Auftreten die atiologische Differenzierung erschwert. Liegt eine Vitiligo durch andere Chemikalien vor, kann dies nach § 9 Abs. 2 der Berufskrankheitenverordnung behandelt werden.

Ethyl acrylate is an irritant known to affect the upper airways and eyes. An increase of the eye blink frequency in humans was observed during exposure to 5 ppm. Studies on the lower airways are scant and our study objective was the evaluation of pH in exhaled breath condensate (EBC-pH) and nitric oxide in exhaled breath (FeNO) as markers of inflammation. Sixteen healthy volunteers were exposed for 4 h to ethyl acrylate at a concentration of 5 ppm and to sham (0.05 ppm) in an exposure laboratory. Clinical irritation symptoms, EBC-pH (at a pCO2 of 5.33 kPa) and FeNO were assessed before and after exposure. Differences after ethyl acrylate exposure were adjusted for those after sham exposure. 5 ppm ethyl acrylate induced clinical signs of local irritation in the nose and eyes, but not in lower airways. Exposure produced a subtle, but statistically significant, decrease in breathing frequency (1 breath/min; p = 0.017) and a lower EBC-pH (by 0.045 units; p = 0.037). Concerning FeNO, we did not observe significant changes compared to sham exposure. We conclude that local effects induced by 5 ppm ethyl acrylate consist of sensory irritation of eyes and nose. In addition, acute ethyl acrylate exposure to 5 ppm resulted in a net decrease of EBC-pH. Whether that can be interpreted in terms of additional lower airway irritation or already inflammatory alterations set in needs further investigations.

Occupational exposures to diisocyanates may cause allergic asthma. Inhalation challenges are the most important tool for the diagnosis of occupational asthma due to diisocyanates. Various diisocyanate atmospheres can be generated at IPA. A multi-steps exposure protocol is used, the dosage is constantly monitored and adjusted if necessary. The quasi-online monitoring of concentrations of airborne diisocyanates in the laboratory is done with a paper-tape monitor, which is widely used in laboratories that perform inhalation challenges worldwide, but also for monitoring of threshold limits at workplaces. The analyzer MDA 7100 (Zellweger Analytics, Inc., Lincolnshire, USA) is no longer supported by the producer. It was replaced by the successor model Single Point Monitor (Honeywell Analytics, Inc., Lincolnshire, USA), but comparative measurements are not available. It was the aim of this study to compare both paper-tape monitors with a discontinuous standard procedure. Comparative measurements between the two paper-tape monitors showed that the newer model yielded lower concentrations than the old device. Both paper-tape monitors yielded lower values than the reference method at concentrations > 10 ppb. The old monitor detected 68%, the new device 38% of the average concentration of the standard method at 36.7 ppb. We conclude that the differences between the measurements with the new paper-tape monitor and the standard method are important above concentrations of about 10 ppb. For monitoring of diisocyanate concentrations < 5 ppb at workplaces, the deviations are negligible.

The P + -transfer abilities of 1,1,1,3,3,3-hexakis(dimethylamino)-triphosphenium tetraphenylborate were investigated. Reaction with Schwartz reagent lead to the first planar tetracoordinated phosphonium salt P[ZrCp 2 H] 4 + BPh 4 + . The theoretical background of this unusual planar geometry at the phosphorus atom is discussed. The first arsenic analogue [As(P(NMe 2 ) 3 )2] + BPh 4 m of the respective triphosphenium salt was prepared, which surprisingly can act as a P + - and As + -transfer reagent at the same time. Furthermore, the synthesis of perstannylated ([(Me 3 Sn) 4 E]OSO 2 CF 3 , E = N, P) and persilylated ([(Me 3 Si) 4 E] + B(C 6 F 5 ) 4 m , E = P, As) onium ions of nitrogen, phosphorus, and arsenic are reported, which are potential starting materials for an independent access to E[ZrCp 2 X] 4 salts.

The Al3P3 heterocycle 1 is formed in 94% yield by the reaction of the primary silylphosphane 6a with Me3Al in toluene at 70 degrees C. While 1 crystallizes in an isomerically pure form, in which the six-membered Al3P3 ring prefers the chair conformation and the P-H hydrogen atoms adopt exo positions, it isomerizes in solution to give different diastereomers as shown by 1H and 31P NMR spectroscopy. Intermolecular cyclocondensation of 1 at 110 degrees C in toluene leads, under liberation of methane, to the distorted hexameric-prismatic (AlP)6 cluster 2 in 98% yield. The capability of 1 to function as a building block was further used for the synthesis of the solvent-separated ion pair [Li(thf)2]+ [(Me2Al)4(PR)3]- (3) which was prepared by a one-pot reaction of 1 with nBuLi and Me2AlCl in 15% yield. The structure of 3 was established by an X-ray diffraction analysis. Double deprotonation at phosphorus in 1 with RPLi2 (R = iPr3Si) (molar ratio 1:2), and subsequent transformation of the reaction mixture with Me3Al afforded the novel donor-solvent-free cluster 4 in 62% yield. The latter consists of a rhombododecahedral Al4Li4P6 framework, in which the Li centers are three-coordinate. The reaction of the silylphosphane 6b with the trimethylamine adduct of alane furnishes not only the hexamer (RPAIH)6 (R = (iPrMe2C)-Me2Si) but also the corresponding heptamer 5, which has a nonregular polyhedral (AIP)7 framework and represents the first cluster of this type.

The title compound (1) was obtained by salt-metathesis reaction of iPr3SiPLi2 with two molar equiv. of iPr3SiOTf (OTf = OSO2CF3) in 34% yield. Surprisingly, (1) consists of an 4 : 1 mixture of the two diastereomers (1 a) and (1 b), which do not interconvert to each other even at their decomposition temperature (> 70 °C). They represent different iPr-rotational isomers which are separated by an unusual high rotational barrier (> 25 kcal mol–1), resulting from hindered rotations around the Si–C and C–C bonds. The unexpectedly small magnitude of the 1J(Si, P) coupling constant of (1 a) (9.4 Hz) and (1 b) (9.0 Hz) reflects unusual electronic properties of the Si3P skeleton. Hitherto only (1 a) could be isolated in the form of single-crystals and its structure was determined by X-ray diffraction analysis. The P-atom in (1 a) is almost planar coordinated (sum of bond angles = 359.789(3)°), but the Si–P-distance (2.264(7) A) resembles those values of related silylphosphanes with pyramidally coordinated P atoms. Although MNDO calculations revealed two other iPr-rotational isomers with similar energy, they prove that the Si3P skeleton prefers the trigonal-planar arrangement due to steric congestion. P(SiiPr3)3: Das erste Trisilylphosphanderivat mit einem fast planar dreifachkoordinierten Phosphoratom Die Titelverbindung (1) wurde durch Salzmetathesereaktion von iPr3SiPLi2 mit zwei Molaquivalent iPr3SiOTf (OTf = OSO2CF3) in 34% Ausbeute erhalten. Uberraschenderweise besteht (1) aus einer 4 : 1 Mischung der zwei Diastereomere (1 a) und (1 b), die sich auch bis zu ihrer Zersetzungstemperatur (70 °C) nicht ineinander umwandeln. Sie reprasentieren verschiedene iPr-Rotamere, die durch eine ungewohnlich hohe Rotationsbarriere (> 25 kcal · mol–1) voneinander getrennt sind und die von gehinderten Rotationen um die Si–C- und C–C-Bindungen herruhren. Der unerwartet kleine Betrag der 1J(Si, P)-Kopplungskonstante von (1 a) (9.4 Hz) und (1 b) (9.0 Hz) spiegelt die ungewohnlichen elektronischen Eigenschaften des Si3P-Gerusts wider. Bisher konnte nur (1 a) in einkristalliner Form isoliert werden, und seine Struktur wurde durch Rontgenbeugungsanalyse bestimmt. Das P-Atom in (1 a) ist annahernd planar koordiniert (Summe der Bindungswinkel = 359.789(3)°), aber der Si–P-Abstand (2.264(7) A) gleicht den Werten von verwandten Silylphosphanen mit pyramidal-koordinierten P-Atomen. Obwohl MNDO-Berechnungen zwei andere Rotamere ergaben, beweisen sie, dass das Si3P-Gerust die trigonal-planare Anordnung wegen der sterischen Uberladung bevorzugt.

Durch Einleiten von PH3 in eine Losung von Diisobutylaluminiumhydrid in Hexan entsteht unter Bildung von H2 die Titelverbindung [iBu2AlPH2]3 (4). Das Alan 4 ist in nichtkoordinierenden Solventien wie in Kohlenwasserstoffen vermutlich trimer aufgebaut und zeigt in solchen Losungen nur eine geringe Tendenz zur Dissoziation. Eine nucleophile Ubertragung der PH2-Gruppe von 4 auf E–X-Verbindungen der 14. Gruppe (E = Si, Ge; X = Cl) gelingt erst in Gegenwart von THF, das 4 in das koorespondierende monomere, THF-solvatisierte Alan 5 uberfuhrt. Letzteres ist ein bemerkenswert mildes Phosphanylierungsreagens, das einen effizienteren Zugang zu Si(PH2)4 (1), Ge(PH2)4 (2), MeSi(PH2)3 (6) und EtSi(PH2)3 (7) ermoglicht. Diisobutyl(phosphaneyl)alane: a Simple PH2-Transfer Reagent for the Synthesis of Polyphosphaneyl Compounds of Silicon and Germanium Introduction of PH3 into a solution of diisobutylaluminium hydride in hexane furnishes, under evolution of H2, the title compound [iBu2AlPH2]3 (4). The alane 4 is probably trimer in noncoordinating solvents such as hydrocarbons and shows only a marginal tendency in such solutions to undergo dissociation. A nucleophilic transfer of the PH2 group in 4 onto E–X-compounds of group 14 elements (E = Si, Ge; X = Cl) succeeds only in the presence of THF which transforms 4 to the corresponding monomeric, THF-solvated alane 5. The latter is a remarkable mild phosphaneylation reagent, which facilitates access to Si(PH2)4 (1), Ge(PH2)4 (2), MeSi(PH2)3 (6), and EtSi(PH2)3 (7) more efficiently.

With the synthesis of new perfluoroalkyltellurocarbonyls, their precursors and cyclic dimers additional valuable information about these classes of compounds has become available. They were prepared via pyrolysis of Me3SnTeCF(CF3)2 and the novel compounds Me3SnTeR (R = n-C3F7, n-C4F9). The monomer (CF3)2CTe could not be detected as it dimerises quantitatively to the corresponding 1,3-ditelluretane. It was possible to isolate R(F)CTe (R = C2F5, n-C3F7) at −196 °C, but slightly above this temperature, these compounds cyclise to mixtures of cis/trans 1,3-ditelluretanes. The tellurocarbonyls undergo [4 + 2]-cycloaddition reactions with 2,3- dimethylbutadiene providing the corresponding tellurins. The reaction between RTeTeR and mercury yielded Hg(TeR)2 which have been converted with iodine in CH2Cl2 solution to RTeI. With AgCN the in situ prepared iodides form RTeCN (R = CF(CF3)2, n-C3F7, n-C4F9) in good yields. A new type of compound has been synthesized by chlorination of tetrafluoro-1,3-ditelluretane: 1,3-dichloro-2,2,4,4-tetrafluoro-1λ4,3λ4-ditellurabicyclo[1.1.0]butane. It is only stable below −20 °C and rearranges almost quantitatively at room temperature to ClF2CTeTeCF2Cl.

Aniline is an important starting material in the manufacture of polyurethane-based plastic materials. Aniline-derived methemoglobinemia (Met-Hb) is well described in exposed workers although information on the dose-response association is limited. We used an experimental design to study the association between aniline in air with the formation of Met-Hb in blood and the elimination of aniline in urine. A 6-h exposure of 2 ppm aniline in 19 non-smoking volunteers resulted in a time-dependent increase in Met-Hb in blood and aniline in urine. The maximum Met-Hb level in blood (mean 1.21 ± 0.29 %, range 0.80-2.07 %) and aniline excretion in urine (mean 168.0 ± 51.8 µg/L, range 79.5-418.3 µg/L) were observed at the end of exposure, with both parameters rapidly decreasing after the end of exposure. After 24 h, the mean level of Met-Hb (0.65 ± 0.18 %) returned to the basal level observed prior to the exposure (0.72 ± 0.19 %); whereas, slightly elevated levels of aniline were still present in urine (means 17.0 ± 17.1 vs. 5.7 ± 3.8 µg/L). No differences between males and females as well as between slow and fast acetylators were found. The results obtained after 6-h exposure were also comparable to those observed in four non-smoking volunteers after 8-h exposure. Maximum levels of Met-Hb and aniline in urine were 1.57 % and 305.6 µg/L, respectively. Overall, our results contribute to the risk assessment of aniline and as a result, the protection of workers from aniline-derived adverse health effects at the workplace.

Study objective was the evaluation of pH in exhaled breath condensate (EBC-pH) and nitric oxide in exhaled breath (FeNO) as biomarkers of ozone induced inflammation. We recently demonstrated that an ozone exposure of 240 ppb is sufficient to reduce lung function indices. We enrolled ten healthy subjects exposed in an intermittent exercise protocol to ozone concentrations of 240 ppb and 40 ppb (sham exposure). EBC-pH and FeNO were assessed before (pre), immediately post (post), and 16 h after exposure (16 h). Findings are that compared to baseline, EBC-pH was significantly higher immediately after sham and ozone exposures, but not 16 h later. There was a negative net change in EBC-pH after adjusting for effects after sham exposure (net-ΔpHpost −0.38 %, net-ΔpH16h −0.23 %). Concerning FeNO, we observed no changes of values after sham exposure compared to baseline, but measured a significant lower net response at the end of exposure (net-ΔFeNOpost −17.5 %) which was transient within 16 h (net-ΔFeNO16h −9.4 %). We conclude that exercise known to enhance EBC-pH may compensate for EBC acidification associated with inflammation resulting in diminished change of this biomarker. Ozone imposes an oxidative burden and reactions between reactive oxygen species and NO might be an explanation for reduced FeNO levels.

In the EU there is an increasing need for regulatory agencies to derive health based threshold limits based on human inhalation studies with airborne particles. A necessary prerequisite for such projects is the development of a suitable generator system to produce nanoparticle test aerosols for human whole-body inhalation studies. We decided to use a generator with flame-based heating of aqueous precursor solutions. Validation of the test system was done by generating zinc oxide (ZnO) nanoparticles with minimal contamination of trace gases, i.e., nitric oxides or carbon monoxide that could confound the effects seen in exposed subjects. ZnO was selected based on the uncertainties surrounding its health effects after exposure at the workplace. The generation process of the developed flame generator yields ZnO nanoparticles with monomodal size distribution and very good temporal stability. The maximum target exposure mass concentration of 2 mg/m3 ZnO, with a resulting median particle diameter of 57 nm, is attainable in our human exposure laboratory. The morphological examination shows typical agglomerates and aggregates formed by high temperature processes. Overall, the performed experiments confirm that a constant exposure can be provided for all subjects at all times. Copyright 2014 American Association for Aerosol Research

Inhalative challenges are important in the diagnosis of occupational asthma due to diisocyanates. As existing protocols are time-consuming and costly, it was the aim of this study to develop a short duration whole body exposure protocol. Ninety three subjects with suspected occupational diisocyanate-induced asthma and verified current or previous occupational exposure to diisocyanates and ten control subjects without diisocyanate exposure but with bronchial hyperresponsiveness were investigated. After baseline examination on the first day, subjects underwent a standardized whole body multiple-steps-1-day challenge with exposures of up to four times 30 min to concentrations of 5, 10, 20, and 30 ppb of the dominant diisocyanate used at work on the second day. Common spirometric and body plethysmographic parameters were used as positivity criteria. Overall, 14 subjects demonstrated a positive diisocyanate challenge, 19 were considered doubtful, and 60 were negative. All controls had negative challenges. Positive reactions occurred during the challenge (n = 10) or during follow-up (n = 4). Eight subjects showed >40 % fall of FEV1. These severe reactions occurred after 5 ppb (n = 2) or 10 ppb (n = 3), while isolated late reactions after 2 h of follow-up were not observed. Multivariate analysis showed an association between a positive challenge and both the degree of previous occupational exposure and the presence of baseline bronchial hyperresponsiveness. In summary, the proposed 4-steps-1-day diisocyanate challenge protocol induced pronounced bronchial reactions in a small number of subjects. As these reactions were more likely to occur after low concentrations, it is recommended to shift the initial concentration/dose step to lower exposures.

The hallmark of sensory hyperreactivity is an enhanced capsaicin induced cough reflex. The cough reflex can be modified by activation of nociceptive (capsaicin-sensitive) nerve terminals. The aim of our study was to assess the influence of exposure to CO2 concentrations up to 2.0 vol% on capsaicin induced cough reflex on four different occasions. Sixteen healthy volunteers were exposed to CO2 concentrations of 0.5, 1.0, and 2.0 vol% for 4 h and to clean air in a repeated measures cross-over design. After exposure the capsaicin induced cough reflex was assessed by the single breath dose–response method according to ERS 2007 guidelines. After blank solutions, capsaicin doses (n=12, range 0.49 to 1000 μM) were administrated from a nebulizer combined with a provocation system (Masterscope, software APS version 5.02). Doses were doubled every minute and the concentration causing five or more coughs (C5) was fixed as the end point. The inter-individual C5 capsaicin responsiveness reflected a representative range (0.95–1000 μM). On an intra-individual basis, a good reproducibility could be demonstrated for four tests within 3 weeks. There was no influence of CO2 challenge on the cough reflex. The first capsaicin test demonstrated a lower C5 threshold independent of the CO2 concentration applied. In conclusion, assessing the capsaicin cough reflex by single breath inhalation is reliable. However, the at cough sensitivity might be overestimated at the first test occasion. Exposure to CO2 in concentrations of up to 2.0 vol% has no effect on sensory reactivity.

Only strong Lewis acidic, arene-solvated Me3 Si+ ions react with E(SiMe3 )3 compounds (E=P, As) to give the crystallographically characterized E(SiMe3 )4+ onium ions 1 (left hand picture), which contain highly negative polarized P and As atoms, respectively. The masked Me3 Si+ ions in 1 can be easily transferred to Et2 O, to give the first structurally characterized planar silyloxonium ion [Et2 (Me3 Si)O]+ 2 (right hand picture).

Human odor and mucosal membrane irritation thresholds are used as criteria for assessing air quality in occupational and environmental settings. Unfortunately, reported threshold values still differ by several orders of magnitude rendering most standard compilations of little practical utility. Thus, in view of the need to repeat odor threshold measurements with a reliable methodology, a new technical approach based on original equipment manufacturer integrated solutions is presented. To test applicability, a calibration gas generator was used to continuously generate a fixed odor vapor concentration. Different dilution steps were realized by coupling to a purchasable olfactometer. Comparison with the "standard," that is, odor stimulus supply via sample bags revealed good correspondence. As a second step, the calibration gas generator was used to generate rapid changes in stimulus concentration between consecutive trials. Irritation thresholds were measured with an ascending series of ammonia concentrations generated from an aqueous solution. The obtained thresholds lay within the range previously reported. The introduced technology enables quick and reliable odor stimulus generation and provides flexibility in choosing the optimal start concentration, the step-size between dilutions, and the range of stimulus concentrations. Errors from usage of rotameters or sample bags can be avoided.

The complex LiAl(PH2)4 functions as an excellent nucleophilic transfer reagent for the phosphanyl group (PH2), as was shown by its reaction with SiCl4 and GeCl4 to give tetraphosphanylsilane and tetraphosphanylgermane, resp. Tetraphosphanylsilane was characterized by 1H, 31P and 29Si NMR spectroscopy and x-ray crystallog. (monoclinic, space group P21/c, R1 = 0.0479).