TY  - JOUR
AB  - Context: Inhaled hygroscopic aerosols will absorb water vapor from the warm and humid air of the human lung, thus growing in size and consequently changing their deposition properties. Objective: The objectives of the present study are to study the effect of a stochastic lung structure on individual particle growth and related deposition patterns and to predict local deposition patterns for different hygroscopic aerosols. Materials and methods: The hygroscopic particle growth model proposed by Ferron et al. has been implemented into the stochastic asymmetric lung deposition model IDEAL. Deposition patterns were calculated for sodium chloride (NaCl), cobalt chloride (CoCl26H2O), and zinc sulfate (ZnSO4-7H2O) aerosols, representing high, medium and low hygroscopic growth factors. Results: Hygroscopic growth decreases deposition of submicron particles compared to hydrophobic particles with equivalent diameters due to a less efficient diffusion mechanism, while the more efficient impaction and sedimentation mechanisms increase total deposition for micron-sized particles. Due to the variability and asymmetry of the human airway system, individual trajectories of inhaled particles are associated with individual growth factors, thereby enhancing the variability of the resulting deposition patterns. Discussion and conclusions: Comparisons of model predictions with several experimental data for ultrafine and micrometer-sized particles indicate good agreement, considering intersubject variations of morphometric parameters as well as differences between experimental conditions and modeling assumptions.
AU  - Winkler-Heil, R.*
AU  - Ferron, G.A.
AU  - Hofmann, W.*
C1  - 30666
C2  - 33975
CY  - London
SP  - 193-206
TI  - Calculation of hygroscopic particle deposition in the human lung.
JO  - Inhal. Toxicol.
VL  - 26
IS  - 3
PB  - Informa Healthcare
PY  - 2014
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Context: Once inhaled, nanoparticles (NP) deposit on the lung surface and have first contact with the epithelial lung lining fluid (ELF) rich in proteins, which may bind to NP. Objective: In this study, we investigate the parameters that influence the binding between NP and proteins. Materials and methods: We used the proteins albumin, transferrin (TF), and apolipoprotein A-1 (all known as proteins from ELF) and different NP (polystyrene NP with negative, positive, and neutral surface coatings, Printex G and Printex 90) as models. Results: In all cases, a linear correlation of the added NP amount and the amount of bound proteins was found and was described quantitatively by binding indices. Bovine serum albumin (BSA), TF, and apo A-1 were bound to the largest extent to hydrophobic NP, which shows the extraordinary importance of the NP's surface properties. Discussion: The binding index indicates the relevance of primary particle size and surface properties, including hydrophobicity. Conclusion: Size and surface modifications of NP determine their protein binding. Our results suggest that the formation of conjugates of BSA, TF, and Apo A-1 with NP may play an important role in their translocation across the air-blood-barrier and subsequent biokinetics.
AU  - Fertsch-Gapp, S.
AU  - Semmler-Behnke, M.
AU  - Wenk, A.
AU  - Kreyling, W.G.
C1  - 6436
C2  - 28682
SP  - 468-475
TI  - Binding of polystyrene and carbon black nanoparticles to blood serum proteins.
JO  - Inhal. Toxicol.
VL  - 23
IS  - 8
PB  - Informa Healthcare
PY  - 2011
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Context: The aerosol components responsible for the adverse health effects of the exposure to particulate matter (PM) have not been conclusively identified, and there is especially little information on the role of particulate organic compounds (POC). Objective: This study evaluated the role of PM and POC with regard to daily symptoms. Methods: One hundred and fifty-three myocardial infarction survivors from Augsburg, Germany, recorded daily occurrence of different symptoms in winter 2003/2004. Ambient concentrations of PM with a diameter <2.5 μm (PM(2.5)), particle number concentration (PNC), PM(2.5)-bound hopanes, and polycyclic aromatic hydrocarbons (PAH) were quantified. Data were analyzed using generalized estimating equations adjusting for meteorological and other time-variant confounders. Results: The odds for avoidance of physically demanding activities due to heart problems increased immediately associated with most POC measures (e.g. 5% per 1.08 ng/m(3) increase in benzo[a]pyrene, 95%-confidence interval (CI):1-9%) and tended to a delayed decrease. After a 2-day delayed decrease associated with hopanes, the odds for shortness of breath increased consistently after 3 days with almost all POC measures (e.g. 4% per 0.21 ng/m(3) increase in 17α(H), 21β(H)-hopane, CI: 1-8%). The odds for heart palpitations marginally increased immediately in association with PNC (8% per 8146 cm(-3) increase in PNC, CI: 0-16%). Conclusions: The study showed an association between PM, particle-bound POC, and daily symptoms. The organic compounds may be causally related with cardiovascular health or act rather as indicators for traffic- and combustion-related particles.
AU  - Kraus, U.
AU  - Breitner-Busch, S.
AU  - Schnelle-Kreis, J.
AU  - Cyrys, J.
AU  - Lanki, T.*
AU  - Rückerl, R.
AU  - Schneider, A.E.
AU  - Brüske, I.
AU  - Gu, J.W.
AU  - Devlin, R.*
AU  - Wichmann, H.-E.
AU  - Zimmermann, R.
AU  - Peters, A.
C1  - 6384
C2  - 28547
SP  - 431-447
TI  - Particle-associated organic compounds and symptoms in myocardial infarction survivors.
JO  - Inhal. Toxicol.
VL  - 23
IS  - 7
PB  - Informa Healthcare
PY  - 2011
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - no abstract
AU  - Rückerl, R.
AU  - Schneider, A.E.
AU  - Breitner-Busch, S.
AU  - Cyrys, J.
AU  - Peters, A.
C1  - 6532
C2  - 28915
SP  - 555-592
TI  - Health effects of particulate air pollution: A review of epidemiological evidence.
JO  - Inhal. Toxicol.
VL  - 23
IS  - 10
PB  - Informa Healthcare
PY  - 2011
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Epidemiologic studies report associations between particulate air pollution and increased mortality from pulmonary diseases. This study was performed to examine whether the exposure to ambient gaseous and particulate air pollution leads to an alteration of the differential white blood cell count in patients with chronic pulmonary diseases like chronic bronchitis, chronic obstructive pulmonary disease, and asthma. A prospective panel study was conducted in Erfurt, Eastern Germany, with 12 repeated differential white blood cell counts in 38 males with chronic pulmonary diseases. Hourly particulate and gaseous air pollutants and meteorological data were acquired. Mixed models with a random intercept adjusting for trend, meteorology, weekday, and other risk variables were used. In this explorative analysis, we found an immediate decrease of polymorphonuclear leukocytes in response to an increase of most gaseous and particulate pollutants. Lymphocytes increased within 24 h in association with all gaseous pollutants but showed only minor effects in regard to particulate air pollution. Monocytes showed an increase associated with ultrafine particles, and nitrogen monoxide. The effect had two peaks in time, one 0-23 h before blood withdrawal and a second one with a time lag of 48-71 h. The increase of particulate and gaseous air pollution was associated with multiple changes in the differential white blood cell count in patients with chronic pulmonary diseases.
AU  - Brüske, I.
AU  - Hampel, R.
AU  - Socher, M.M.*
AU  - Rückerl, R.
AU  - Schneider, A.E.
AU  - Heinrich, J.
AU  - Oberdörster, G.*
AU  - Wichmann, H.-E.
AU  - Peters, A.
C1  - 5974
C2  - 27685
SP  - 245-252
TI  - Impact of ambient air pollution on the differential white blood cell count in patients with chronic pulmonary disease.
JO  - Inhal. Toxicol.
VL  - 22
IS  - 3
PB  - Informa Healthcare
PY  - 2010
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - This study presents different research techniques linked together to improve our understanding of the particulate matter (PM) impacts on health. PM samples from the exhaust of different vehicles were collected by a versatile aerosol concentration enrichment system (VACES). Waterborne PM samples were collected with this technique, thus retaining the original physicochemical characteristics of aerosol particles. PM samples originated from a gasoline Euro 3 car and two diesel cars complying with the Euro 2 and Euro 4 standards, respectively. The Euro 2 diesel car operated consecutively on fossil diesel and biodiesel. The Euro 4 car was also retrofitted with a diesel particle filter. In total, five vehicle configurations and an equal number of samples were examined. Each sample was intratracheally instilled to 10 mice at two different dose levels (50 and 100 μL). The mice were analyzed 24 h after instillation for acute lung inflammation by bronchoalveolar lavage and also for hematological changes. Results show that a moderate but still significant inflammatory response is induced by PM samples, depending on the vehicle. Several organic and inorganic species, including benz(a)anthracene, chrysene, Mn, Fe, Cu, and heavy polycyclic aromatic hydrocarbons (PAHs), as well as the reactive oxygen species content of the PM suspensions are correlated to the observed responses. The study develops conceptual dose-response functions for the different vehicle configurations. These demonstrate that inflammatory response is not directly proportional to the mass dose level of the administered PM and that the relative toxicity potency depends on the dosage level.
AU  - Tzamkiozis, T.*
AU  - Stöger, T.
AU  - Cheung, K.*
AU  - Ntziachristos, L.*
AU  - Sioutas, C.*
AU  - Samaras, Z.*
C1  - 6133
C2  - 28085
SP  - 59-69
TI  - Monitoring the inflammatory potential of exhaust particles from passenger cars in mice.
JO  - Inhal. Toxicol.
VL  - 22
IS  - SUPPL. 2
PB  - Informa Healthcare USA, Inc.
PY  - 2010
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Sixteen beagle dogs were housed in four large chambers under minimum restraint. They were exposed for 16 months to clean air and individual baseline data of markers were obtained. For 13 months, eight dogs were further exposed to clean air and eight dogs for 6 h/d to 1-μm MMAD (mass median aerodynamic diameter) acidic sulfate particles carrying 25 μmol H+ m−3 into their lungs. To establish functional responses (lung function, cell and tissue integrity, redox balance, and non-specific respiratory defense capacity), each exposed animal served as its own control. To establish structural responses, the eight non-exposed animals served as controls. Acidic particles were produced by nebulization of aqueous sodium hydrogen sulfate at pH 1.5. Only subtle exposure-related changes of lung function and structure were detected. A significant increase in respiratory burst function of alveolar macrophages points to a marginal inflammatory response. This can be explained by the significant production of prostaglandin E2, activating cyclooxygenase-dependent mechanisms in epithelia and thus inhibiting lung inflammation. The non-specific defense capacity was slightly affected, giving increased tracheal mucus velocity and reduced in vivo dissolution of moderately soluble test particles. Hypertrophy and hyperplasia of bronchial epithelia were not observed, but there was an increase in volume density of bronchial glands and a shift from neutral to acidic staining of epithelial secretory cells in distal airways. The acidic exposure had thus no pathophysiological consequences. It is therefore unlikely that long-term inhalation of acidic particles is associated with a health risk.
AU  - Heyder, J.
AU  - Beck-Speier, I.
AU  - Ferron, G.A.
AU  - Josten, M.
AU  - Karg, E.W.
AU  - Kreyling, W.G.
AU  - Lenz, A.-G.
AU  - Maier, K.L.
AU  - Reitmeir, P.
AU  - Ruprecht, L.
AU  - Takenaka, S.
AU  - Wohland, T.
AU  - Ziesenis, A.
AU  - Schulz, S.
C1  - 1335
C2  - 26626
CY  - UK
SP  - 920-932
TI  - Long-term responses of canine lungs to acidic particles.
JO  - Inhal. Toxicol.
VL  - 21
IS  - 11
PB  - Informa Healthcare
PY  - 2009
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - We have previously reported that outdoor levels of fine particles (PM(2.5), diameter <2.5 microm) are associated with urinary CC16, a marker for lung damage, in Helsinki, Finland, but not in the other two ULTRA cities (Amsterdam, The Netherlands, and Erfurt, Germany). We here evaluated whether PM(2.5) from specific source categories would be more strongly associated with CC16 than (total) PM(2.5). In addition, we compared two source apportionment methods. METHODS: We collected biweekly spot urinary samples over 6 months from 121 subjects with coronary heart disease for the determination of CC16 (n = 1251). Principal component analysis (PCA) was used to apportion daily outdoor PM(2.5) between different source categories. In addition, the multilinear engine (ME) was used for the source apportionment in Amsterdam and Helsinki. We analyzed associations of source category-specific PM(2.5) and PM(2.5) absorbance, an indicator for combustion originating particles, with logarithmized values of CC16 adjusting for urinary creatinine using multivariate mixed models in STATA. RESULTS: In the pooled analyses, CC16 was increased by 0.6% (standard error 0.3%) per 1 x 10(-5) m(-1) increase in the same-day levels of PM(2.5) absorbance. Source category-specific PM(2.5) concentrations were not consistently associated with the levels of CC16 in the three cities. Correlations between source category-specific PM(2.5) determined using either PCA or ME were in general high. Associations of source category-specific PM(2.5) with CC16 in Amsterdam and Helsinki were statistically less significant when ME was used. CONCLUSIONS: The present results suggest that PM(2.5) from combustion sources increases epithelial barrier permeability in lungs.
AU  - Jacquemin, B.*
AU  - Lanki, T.
AU  - Yli-Tuomi, T.*
AU  - Vallius, M.*
AU  - Hoek, G.*
AU  - Heinrich, J.
AU  - Timonen, K.*
AU  - Pekkanen, J.*
C1  - 1173
C2  - 26490
CY  - England
SP  - 1068-1076
TI  - Source category-specific PM2.5 and urinary levels of Clara cell protein CC16. The ULTRA study.
JO  - Inhal. Toxicol.
VL  - 21
IS  - 13
PB  - Informa Healthcare
PY  - 2009
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Currently, translocation of inhaled insoluble nanoparticles (NP) across membranes like the air-blood barrier into secondary target organs (STOs) is debated. Of key interest are the involved biological mechanisms and NP parameters that determine the efficiency of translocation. We performed NP inhalation studies with rats to derive quantitative biodistribution data on the translocation of NP from lungs to blood circulation and STOs. The inhaled NP were chain aggregates (and agglomerates) of either iridium or carbon, with primary particle sizes of 2–4 nm (Ir) and 5–10 nm (C) and aggregate sizes (mean mobility diameters) between 20 and 80 nm. The carbon aggregates contained a small fraction ( < 1%) of Ir primary particles. The insoluble aggregates were radiolabeled with 192Ir. During 1 h of inhalation, rats were intubated and ventilated to avoid extrathoracic NP deposition and to optimize deep lung NP deposition. After 24 h, 192Ir fractions in the range between 0.001 and 0.01 were found in liver, spleen, kidneys, heart, and brain, and an even higher fraction (between 0.01 and 0.05) in the remaining carcass consisting of soft tissue and bone. The fractions of 192Ir carried with the carbon NP retained in STOs, the skeleton, and soft tissue were significantly lower than with NP made from pure Ir. Furthermore, there was significantly less translocation and accumulation with 80-nm than with 20-nm NP aggregates of Ir. These studies show that both NP characteristics—the material and the size of the chain-type aggregates—determine translocation and accumulation in STOs, skeleton, and soft tissue.
AU  - Kreyling, W.G.
AU  - Semmler-Behnke, M.
AU  - Seitz, J.
AU  - Scymczak, W.
AU  - Wenk, A.
AU  - Mayer, P.
AU  - Takenaka, S.
AU  - Oberdörster, G.*
C1  - 1918
C2  - 26501
SP  - 55-60
TI  - Size dependence of the translocation of inhaled iridium and carbon nanoparticle aggregates from the lung of rats to the blood and secondary target organs.
JO  - Inhal. Toxicol.
VL  - 21
IS  - S1
PB  - Informa Healthcare, UK
PY  - 2009
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - The aim of this study was to investigate the potential cytotoxicity of solid lipid nanoparticles (SLN) for human lung as a suitable drug delivery system (DDS). Therefore we used a human alveolar epithelial cell line (A549) and murine precision-cut lung slices (PCLS) to estimate the tolerable doses of these particles for lung cells. A549 cells (in vitro) and precision-cut lung slices (ex vivo) were incubated with SLN20 (20% phospholipids in the lipid matrix of the particles) and SLN50 (50% phospholipids in the lipid matrix of the particles) in increasing concentrations. The cytotoxic effects of SLN were evaluated in vitro by lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Vitality of lung slices was controlled by staining with calcein AM/ethidium homodimer 1 using confocal laser scanning microscopy and followed by quantitative image analysis with IMARIS software. A549 cell line revealed a middle effective concentration (EC(50)) for MTT assay for SLN20 of 4080 microg/ml and for SLN50 of 1520 microg/ml. The cytotoxicity in terms of LDH release showed comparable EC(50) values of 3431 microg/ml and 1253 microg/ml for SLN20 and SLN50, respectively. However, in PCLS we determined only SLN50 cytotoxic values with a concentration of 1500 microg/ml. The lung slices seem to be a more sensitive test system. SLN20 showed lower toxic values in all test systems. Therefore we conclude that SLN20 could be used as a suitable DDS for the lung, from a toxicological point of view.
AU  - Nassimi, M.*
AU  - Schleh, C.
AU  - Lauenstein, H.D.*
AU  - Hussein, R.*
AU  - Lübbers, K.*
AU  - Pohlmann, G.*
AU  - Switalla, S.*
AU  - Sewald, K.*
AU  - Müller, M.*
AU  - Krug, N.*
AU  - Müller-Goymann, C.C.*
AU  - Braun, A.*
C1  - 1974
C2  - 26102
SP  - 104-109
TI  - Low cytotoxicity of solid lipid nanoparticles in in vitro and ex vivo lung models.
JO  - Inhal. Toxicol.
VL  - 21
PB  - Informa Healthcare
PY  - 2009
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Since the mid-1990 s, the number of studies linking air pollutants to preterm and low birth weight, as well as to cardiac birth defects, has grown steadily each year. The critical period in the development of mouse embryos begins with the commencement of gastrulation at day 7.5 of gestation. Our aim is to examine the role of particles size and surface modification in particle translocation during this early embryonic development. Fluorescent polystyrene particles (PS) were employed because they offer an efficient and safe tracking method. Pregnant female mice were sacrificed at 7.5 days of gestation. After cutting open the deciduas, the parietal endoderm was carefully separated and removed. Different sizes of amine- and carboxyl-modified PS beads were injected via the extraembryonic tissue. The embryos were incubated for 12 h, and were investigated under fluorescent microscopy, confocal microscopy, and mesoscopic fluorescence tomography. The results show that 20-nm carboxylic PS distribute in the embryonic and extraembryonic germ layers of ectoderm, mesoderm, and endoderm. Moreover, when the particles are bigger than 100 nm, PS accumulate in extraembryonic tissue, but nevertheless 200-nm amine-modified particles can pass into the embryos. Interestingly, a growth inhibition was observed in the embryos containing nanoparticles. Finally, the stronger translocation effect is associated with amine-modified PS beads (200 nm) instead of the smaller (20 nm, 100 nm) carboxyl ones.
AU  - Tian, F.
AU  - Razansky, D.
AU  - Estrada, G.G.
AU  - Semmler-Behnke, M.
AU  - Beyerle, A.
AU  - Kreyling, W.G.
AU  - Ntziachristos, V.
AU  - Stöger, T.
C1  - 2464
C2  - 26466
SP  - 92-96
TI  - Surface modification and size dependence in particle translocation during early embryonic development.
JO  - Inhal. Toxicol.
VL  - 21
IS  - SUPPL. 1
PB  - Informa Healthcare
PY  - 2009
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - The mechanisms underlying the association between air pollution and cardiovascular morbidity and mortality are unknown. This study aimed to determine whether controlled exposure to elemental carbon ultrafine particles (UFP) affects electrocardiogram (ECG) parameters describing heart rate variability; repolarization duration, morphology, and variability; and changes in the ST segment. Two separate controlled studies (12 subjects each) were performed using a crossover design, in which each subject was exposed to filtered air and carbon UFP for 2 hours. The first protocol involved 2 exposures to air and 10 g/m3 ( 2 106 particles/cm3, count median diameter 25 nm, geometric standard deviation 1.6), at rest. The second protocol included 3 exposures to air, 10, and 25 g/m3 UFP ( 7 106 particles/cm3), with repeated exercise. Each subject underwent a continuous digital 12-lead ECG Holter recording to analyze the above ECG parameters. Repeated measures analysis of variance (ANOVA) was used to compare tested parameters between exposures. The observed responses to UFP exposure were small and generally not significant, although there were trends indicating an increase in parasympathetic tone, which is most likely also responsible for trends toward ST elevation, blunted QTc shortening, and increased variability of T-wave complexity after exposure to UFP. Recovery from exercise showed a blunted response of the parasympathetic system after exposure to UFP in comparison to air exposure. In conclusion, transient exposure to 10-25 g/m3 ultrafine carbon particles does not cause marked changes in ECG-derived parameters in young healthy subjects. However, trends are observed indicating that some subjects might be susceptible to air pollution, with a response involving autonomic modulation of the heart and repolarization of the ventricular myocardium.
AU  - Zareba, W.*
AU  - Couderc, J.P.*
AU  - Oberdörster, G.*
AU  - Chalupa, D.*
AU  - Cox, C.*
AU  - Huang, L.-S.*
AU  - Peters, A.
AU  - Utell, M.J.*
AU  - Frampton, M.W.*
C1  - 2402
C2  - 26184
SP  - 223-233
TI  - ECG parameters and exposure to carbon ultrafine particles in young healthy subjects.
JO  - Inhal. Toxicol.
VL  - 21
IS  - 3
PB  - Informa Healthcare
PY  - 2009
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Epidemiological studies have shown an association between ambient particle inhalation and adverse respiratory heath effects. Inhalation of ultrafine particles (UFP, diameter <100 nm) has been suggested to contribute to exacerbation of allergic airway inflammation. Here we analyze the potential effects of allergen sensitization and challenge on total and regional deposition of UFP in the lung. Ovalbumin (OVA)-sensitized and nonsensitized mice were exposed for 1 h to ultrafine iridium particles radiolabeled with (192)Ir (UF-Ir) (0.2 mg m(-3)) at 2 different time points either before or after allergen (OVA) challenge. Additional sensitized and nonsensitized mice were exposed to UF-Ir without allergen challenge. Lung total and regional UF-Ir deposition were calculated according to the distribution of radioactivity in the body and in the excreta during 3 days following UF-Ir inhalation. OVA-sensitized mice showed a 21% relative increase of total UF-Ir deposited fraction compared to nonsensitized mice. When UF-Ir inhalation was performed after allergen challenge, no difference in total UF-Ir deposited fraction between sensitized and nonsensitized mice was detectable. Furthermore, no differences in extrathoracic deposition or in regional particle deposition were detected between all experimental groups. This study indicates that allergen sensitization alone can affect UFP deposition in the lungs. Whether higher UFP deposition in sensitized individuals compared to nonsensitized individuals or whether other factors, like alterations in long-term clearance kinetics, contribute substantially to the susceptibility of allergic individuals to particle exposure has yet to be elucidated.
AU  - Alessandrini, F.
AU  - Semmler-Behnke, M.
AU  - Jakob, T.*
AU  - Schulz, S.
AU  - Behrendt, H.
AU  - Kreyling, W.G.
C1  - 1263
C2  - 25315
SP  - 585-593
TI  - Total and regional deposition of ultrafine particles in a mouse model of allergic inflammation of the lung.
JO  - Inhal. Toxicol.
VL  - 20
IS  - 6
PB  - Informa Healthcare
PY  - 2008
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - In this article, we review and analyze different modes of exposure to ultrafine particles in order to assess particle-induced inflammatory responses and the underlying mechanisms in vitro and in vivo. Based on results from monocytic cells cultured under submerged conditions, we discuss (1) the impact of particle properties such as surface area and oxidative potential on lipid metabolism as a highly sensitive regulatory pathway and (2) the interference of diesel exhaust particles with toll-like receptor-mediated inflammatory responses. Furthermore, new developments of air-liquid interface exposure used as an alternative approach to simulate cell particle interactions are presented. In addition to the in vitro approaches, animal exposure studies are described that apply selected mouse models to elucidate potential allergic and inflammatory pulmonary responses and mast-cell-related mechanisms after particle exposure. Long-term inhalation of ultrafine particles might lead to irreversible changes in lung structure and function. Clinical studies addressing the characteristics of inflammatory airway cells are a promising approach to understand underlying pathophysiological mechanisms in chronic obstructive pulmonary disease. Finally, a potential outcome of human particle exposure is chronic cough in children. Here, discrimination between asthmatic and nonasthmatic cough by means of immunological parameters appears to be an important step toward improving diagnosis and therapy.
AU  - Maier, K.L.
AU  - Alessandrini, F.
AU  - Beck-Speier, I.
AU  - Hofer, T.P.
AU  - Diabaté, S.*
AU  - Bitterle, E.*
AU  - Stöger, T.
AU  - Jakob, T.*
AU  - Behrendt, H.
AU  - Horsch, M.
AU  - Beckers, J.
AU  - Ziesenis, A.*
AU  - Hültner, L.
AU  - Frankenberger, M.
AU  - Krauss-Etschmann, S.
AU  - Schulz, S.
C1  - 3386
C2  - 25158
SP  - 319-337
TI  - Health effects of ambient particulate matter - biological mechanisms and inflammatory responses to in vitro and in vivo particle exposures.
JO  - Inhal. Toxicol.
VL  - 20
IS  - 3
PB  - Informa Healthcare
PY  - 2008
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Ambient air pollution has been associated with an increased risk of hospital admission and mortality in potentially susceptible subpopulations, including myocardial infarction (MI) survivors. The multicenter epidemiological study described in this report was set up to study the role of air pollution in eliciting inflammation in MI survivors in six European cities, Helsinki, Stockholm, Augsburg, Rome, Barcelona, and Athens. Outcomes of interest are plasma concentrations of the proinflammatory cytokine interleukin 6 (IL-6) and the acute-phase proteins C-reactive protein (CRP) and fibrinogen. In addition, the study was designed to assess the role of candidate gene polymorphisms hypothesized to lead to a modification of the short-term effects of ambient air pollution. In total, 1003 MI survivors were recruited and assessed with at least 2 repeated clinic visits without any signs of infections. In total, 5813 blood samples were collected, equivalent to an average of 5.8 repeated clinic visits per subject (97% of the scheduled 6 repeated visits). Subjects across the six cities varied with respect to risk factor profiles. Most of the subjects were nonsmokers, but light smokers were included in Rome, Barcelona, and Athens. Substantial inter- and intraindividual variability was observed for IL-6 and CRP. The study will permit assessing the role of cardiovascular disease risk factors, including ambient air pollution and genetic polymorphisms in candidate genes, in determining the inter- and the intraindividual variability in plasma IL-6, CRP, and fibrinogen concentrations in MI survivors.
AU  - Peters, A.
AU  - Schneider, A.E.
AU  - Greven, S.
AU  - Bellander, T.*
AU  - Forastiere, F.*
AU  - Ibald-Mulli, A.
AU  - Illig, T.
AU  - Jacquemin, B.*
AU  - Katsouyanni, K.*
AU  - Koenig, W.*
AU  - Lanki, T.*
AU  - Pekkanen, J.*
AU  - Pershagen, G.*
AU  - Picciotto, S.*
AU  - Rückerl, R.
AU  - Schaffrath Rosario, A.
AU  - Stefanadis, C.*
AU  - Sunyer, J.*
AU  - AIRGENE Study Group (*)
C1  - 4127
C2  - 24923
SP  - 161-175
TI  - Air pollution and inflammatory response in myocardial infarction survivors: Gene-environment interactions in a high-risk group.
JO  - Inhal. Toxicol.
VL  - 19
IS  - SUPPL. 1
PB  - Informa Healthcare
PY  - 2007
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Diesel exhaust particles (DEPs) have been implicated in the worldwide increased incidence of allergic airway diseases over the past century. There is growing evidence that DEP-associated polycyclic aromatic hydrocarbons (PAHs) participate in the development and maintenance of immunoglobulin (Ig) E-mediated allergic diseases. To address this issue we investigated the impact of U.S. Environmental Protection Agency (EPA) priority PAHs as well as of PAH-containing airborne extracts on antigen-induced CD63 upregulation and mediator release from human basophils. Whole blood samples from birch pollen allergic and control subjects were incubated in the presence of organic extracts of urban aerosol (AERex) or EPA-PAH standard with or without rBet v 1. Basophils were analyzed for CD63 expression as a measure of basophil activation by using multiparameter flow cytometry. In addition, purified basophils from birch pollen allergic donors were incubated for 2 h in the presence of 1 muM benzo[a]pyrene (BaP) or phenanthrene (Phe) and then stimulated with rBet v 1 for 45 min. Supernatants were assayed for histamine, interleukin (IL)-4, and IL-8 by means of enzyme-linked immunosorbent assay (ELISA). Basophils exposed in vitro simultaneously to AERex or EPA-PAH standard and rBet v 1 expressed CD63 significantly more than with antigen alone. PAHs synergized with rBet v 1 dose dependently, but did not activate basophils from nonallergic donors. BaP and Phe significantly enhanced cytokine secretion (IL-4, IL-8) and histamine release from purified basophils without antigen added, and secretion was not further enhanced by rBet v 1 stimulation. In conclusion, PAHs from roadside emissions can directly activate sensitized basophils to cytokine secretion and drive proallergic processes through enhanced Fcepsilon RI-coupled mediator release from human basophils.
AU  - Schober, W.
AU  - Lubitz, S.
AU  - Belloni, B.
AU  - Gebauer, G.
AU  - Lintelmann, J.
AU  - Matuschek, G.
AU  - Weichenmeier, I.
AU  - Eberlein-König, B.
AU  - Buters, J.
AU  - Behrendt, H.
C1  - 4125
C2  - 24737
SP  - 151-156
TI  - Environmental polycyclic aromatic hydrocarbons (PAHs) enhance allergic inflammation by acting on human basophils.
JO  - Inhal. Toxicol.
VL  - 19
IS  - SUPPL. 1
PB  - Informa Healthcare
PY  - 2007
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Diesel motor emission is a complex mixture of hundreds of constituents in either gas or particle form. Diesel particulate matter (DPM) is composed of a center core of elemental carbon and adsorbed organic compounds including PAHs and nitro-PAHs, and small amounts of sulfate, nitrate, metals, and other trace elements. DPM consists of fine particles including a high number of ultrafine particles. These particles are highly respirable and have a large surface area where organics can adsorb easily. Exposure to DPM can cause acute irritation and neurophysiological, respiratory, and asthma-like symptoms and can exacerbate allergenic responses to known allergens. Consistently, lung cancer risk is elevated among workers in occupations where diesel engines have been used. However, quantification of the cancer risk with respect to DPM concentrations is not possible. Furthermore, ambient fine and ultrafine particles, of which DPM is an important component, contribute to cardiopulmonary morbidity and mortality and lung cancer. In conclusion, diesel exhaust poses a cancer risk greater than that of any other air pollutant, as well as causing other short- and long-term health problems. One effective way to effectively reduce emission of DPM is the use of particle traps.
AU  - Wichmann, H.-E.
C1  - 4126
C2  - 24921
SP  - 241-244
TI  - Diesel exhaust particles.
JO  - Inhal. Toxicol.
VL  - 19
IS  - SUPPL. 1
PB  - Informa Healthcare
PY  - 2007
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - The effect of banning bituminous coal sales on the black-smoke concentration and the mortality rates in Dublin, Ireland, has been analyzed recently. Based on the application of standard epidemiological procedures, the authors concluded that, as a result of the ban, the total nontrauma death rate was reduced strongly (-8.0% unadjusted, -5.7% adjusted). The purpose of this study was to reanalyze the original data with the aim of clarifying the three most important aspects of the study, (a) the effect of epidemics, (b) the trends in mortality rates due to advances in public health care, and (c) the correlation between mortality rates and black-smoke concentrations. Particular attention has been devoted to a detailed evaluation of the time dependence of mortality rates, stratified by season. Death rates were found to be strongly enhanced during three severe pre-ban winter-spring epidemics. The cardiovascular mortality rates exhibited a continuous decrease over the whole study period, in general accordance with trends in the rest of Ireland. These two effects can fully account for the previously identified apparent correlation between reduced mortality and the very pronounced ban-related lowering of the black-smoke concentration. The third important finding was that in nonepidemic pre-ban seasons even large changes in the concentration of black smoke had no detectable effect on mortality rates. The reanalysis suggests that epidemiological studies exploring the effect of ambient particulate matter on mortality require improved tools allowing proper adjustment for epidemics and trends. Aspects of harvesting and more recent results derived from a distributed lag model covering the effects of black smoke and temperature are also discussed.
AU  - Wittmaack, K.
C1  - 4176
C2  - 25054
SP  - 343-350
TI  - The big ban on bituminous coal sales revisited: Serious epidemics and pronounced trends feign excess mortality previously attributed to heavy black-smoke exposure.
JO  - Inhal. Toxicol.
VL  - 19
IS  - 4
PB  - Informa Healthcare
PY  - 2007
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - The role of alveolar macrophages in the fate of ultrafine particles in the lung was investigated. Male Wistar-Kyoto rats were exposed to ultrafine gold particles, generated by a spark generator, for 6 h at a concentration of 88 mu g/m 3 (4 x 10(6)/cm(3) , 16 nm modal mobility diameter). Up to 7 days, the animals were serially sacrificed, and lavaged cells and lung tissues were examined by transmission electron microscopy. The gold concentration/content in the lung, lavage fluid, and blood was estimated by inductively coupled plasma-mass spectrometry. Gold particles used were spherical and electron dense with diameters of 5-8 nm. The particles were individual or slightly agglomerated. By inductively coupled plasma-mass spectrometry analysis of the lung, 1945 +/- 57 ng (mean +/- SD) and 1512 +/- 184 ng of gold were detected on day 0 and on day 7, respectively, indicating that a large portion of the deposited gold particles was retained in the lung tissue. In the lavage fluid, 573 +/- 67 ng and 96 +/- 29 ng were found on day 0 and day 7, respectively, which means that 29% and 6% of the retained gold particles were lavageable on these days. A low but significant increase of gold (0.03 to 0.06% of lung concentration) was found in the blood. Small vesicles containing gold particles were found in the cytoplasm of alveolar macrophages. In the alveolar septum, the gold particles were enclosed in vesicles observed in the cytoplasm of alveolar type I epithelial cells. These results indicate that inhaled ultrafine gold particles in alveolar macrophages and type I epithelial cells are processed by endocytotic pathways, though the uptake of the gold particles by alveolar macrophages is limited. To a low degree, systemic particle translocation took place.
AU  - Takenaka, S.
AU  - Karg, E.W.
AU  - Kreyling, W.G.
AU  - Lentner, B.
AU  - Möller, W.
AU  - Behnke-Semmler, M.
AU  - Jennen, L.
AU  - Walch, A.K.
AU  - Michalke, B.
AU  - Schramel, P.
AU  - Heyder, J.
C1  - 4876
C2  - 23858
SP  - 733-740
TI  - Distribution pattern of inhaled ultrafine gold particles in the rat lung.
JO  - Inhal. Toxicol.
VL  - 18
IS  - 10
PB  - Informa Healthcare
PY  - 2006
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Human pulmonary retention of 35 nm 99mTc-labeled carbonaceous particles, produced with a modified Technegas generator, was followed for 24 h using a gamma camera imaging technique. Nine healthy subjects and four asthmatics inhaled the test particles. Particle labeling stability was tested in vitro during 48 h. We also measured in vivo leaching in blood and in urine for 24 h. One additional subject was exposed to particles with unstable labeling. There were no significant differences between healthy and asthmatic subjects in any of the parameters studied. Particle retention after 24 h was 102% (SD +/- 4.7). Cumulative in vitro leaching of 99mTc activity from the particles was 1.7% (+/-1.1) after 24 h. In blood samples, 80 min after exposure, 1.1% (+/- 0.4) of initially deposited activity was detected and 91% of the activity was not bound to particles. In urine sampled during the first 24 h after exposure, 3.6% (+/- 0.9) of lung deposited activity was detected. Lung retention was 30% after 1 h in the subject exposed to the leaching aerosol (n = 1). Thirty-one percent of the deposited activity was detected in the blood after 80 min and 80% was not bound to particles. Fifty percent of the activity was excreted with urine within 24 h. On gamma camera images the activity visibly translocated from lungs to thyroid and gastrointestinal tract. In conclusion, over a 24-h period there was no significant translocation of inhaled 35-nm particles to the systemic circulation.
AU  - Wiebert, P.*
AU  - Sanchez-Crespo, A.*
AU  - Falk, R.*
AU  - Philipson, K.*
AU  - Lundin, A.*
AU  - Larsson, S.*
AU  - Möller, W.
AU  - Kreyling, W.G.
AU  - Svartengren, M.*
C1  - 4097
C2  - 23767
SP  - 741-747
TI  - No significant translocation of inhaled 35-nm carbon particles to the circulation in humans.
JO  - Inhal. Toxicol.
VL  - 18
IS  - 10
PB  - Informa Healthcare
PY  - 2006
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Harder, V.
AU  - Gilmour, P.S.*
AU  - Lentner, B.
AU  - Karg, E.W.
AU  - Takenaka, S.
AU  - Ziesenis, A.
AU  - Stampfl, A.
AU  - Kodavanti, U.P.*
AU  - Heyder, J.
AU  - Schulz, S.
C1  - 5292
C2  - 22500
SP  - 29-42
TI  - Cardiovascular responses in unrestrained WKY rats to inhaled ultrafine carbon particles.
JO  - Inhal. Toxicol.
VL  - 17
PB  - Informa Healthcare
PY  - 2005
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Oberdörster, G.*
AU  - Sharp, Z.*
AU  - Atudorei, V.*
AU  - Elder, A.*
AU  - Gelein, R.*
AU  - Kreyling, W.G.
AU  - Cox, C.*
C1  - 3694
C2  - 22069
SP  - 437-445
TI  - Translocation of inhaled ultrafine particles to the brain.
JO  - Inhal. Toxicol.
VL  - 16
PB  - Informa Healthcare
PY  - 2004
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Semmler, M.
AU  - Seitz, J.
AU  - Erbe, F.
AU  - Mayer, P.
AU  - Heyder, J.
AU  - Oberdörster, G.*
AU  - Kreyling, W.G.
C1  - 3801
C2  - 21949
SP  - 453-459
TI  - Long-term clearance kinetics of inhaled ultrafine insoluble iridium particles from the rat lung, including transient translocation into secondary organs.
JO  - Inhal. Toxicol.
VL  - 16
PB  - Informa Healthcare
PY  - 2004
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Takenaka, S.
AU  - Karg, E.W.
AU  - Kreyling, W.G.
AU  - Lentner, B.
AU  - Schulz, S.
AU  - Ziesenis, A.
AU  - Schramel, P.
AU  - Heyder, J.
C1  - 4324
C2  - 21885
SP  - 83-92
TI  - Fate and toxic effects of inhaled ultrafine cadmium oxide particles in the rat lung.
JO  - Inhal. Toxicol.
VL  - 16
PB  - Informa Healthcare
PY  - 2004
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Alessandrini, F.
AU  - Ziesenis, A.
AU  - Takenaka, S.
AU  - Karg, E.W.
AU  - Heyder, J.
AU  - Ring, J.*
AU  - Behrendt, H.
C1  - 9650
C2  - 21474
SP  - 343-356
TI  - Effects of inhaled CdO particles on the sphingolipid synthesis of rat lungs.
JO  - Inhal. Toxicol.
VL  - 15
PB  - Taylor & Francis
PY  - 2003
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Peters, A.
AU  - Perz, S.
AU  - Döring, A.
AU  - Stieber, J.
AU  - Koenig, W.*
AU  - Wichmann, H.-E.
C1  - 21576
C2  - 19702
SP  - 51-61
TI  - Activation of the autonomic nervous system and blood coagulation in association with an air pollution episode.
JO  - Inhal. Toxicol.
VL  - 12 (Suppl.2)
PB  - Taylor & Francis
PY  - 2000
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Takenaka, S.
AU  - Karg, E.W.
AU  - Möller, W.
AU  - Roth, C.
AU  - Ziesenis, A.
AU  - Heinzmann, U.
AU  - Schramel, P.
AU  - Heyder, J.
C1  - 9649
C2  - 22564
SP  - 291-299
TI  - A morphologic study on the fate of ultrafine silver particles : Distribution pattern of phagocytized metallic silver in vitro and in vivo.
JO  - Inhal. Toxicol.
VL  - 12
PB  - Taylor & Francis
PY  - 2000
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - The motivation of simulating real-world environmental exposure in a number of long-term studies with dogs was to address the question of whether or not perpetual inhalation of air pollutants can initiate diseases in healthy lungs and can thus contribute to the increasing prevalence of respiratory diseases in industrialized countries. The major conclusion of this article is that this question has to be answered in the negative for the simultaneous inhalation of the major constituents of combustion-related air pollution, particle-associated sulfur(IV), and particle-associated hydrogen ions. Over 13 mo, 8 healthy beagle dogs were exposed in 2 whole-body chambers daily for 16.5 h to 1 microm neutral sulfite [sulfur(IV)] particles at a mass concentration of 1.5 mg m-3 and for 6 h to 1.1 microm acidic sulfate particles carrying 15 micromol m-3 hydrogen ions into the canine lungs. This longitudinal study was characterized by repeated observations of individual respiratory response patterns. To establish baseline data the dogs were repeatedly examined preexposure while the chambers were ventilated over 16 mo with clean air. Each individual served thus as its own control. Another eight dogs served as additional controls. They were housed in 2 chambers ventilated with clean air over the entire study period of 29 mo. To assess response patterns, respiratory lung function tests were performed pre- and postexposure, segmental lung lavages were repeatedly performed to obtain epithelial lining fluid from the lungs for analysis of cell content, cell function, and biochemical indicators of lung injury, and radiolabeled test particles were used to study pathways of intrapulmonary particle elimination. At the end of the study, the lungs of all animals were morphologically and morphometrically examined. Functional and structural responses were finally compared to those observed previously as a result of a sole exposure of canine lungs to neutral sulfite particles over 10 mo (Heyder et al., 1992). Interactions between responses induced by neutral sulfite and acidic sulfate particles occurred, but antagonism rather than synergism was observed. The responses induced by sulfur(IV) were less pronounced, not detectable, or even reversed when hydrogen ions were also delivered to the lungs. On the other hand, responses not induced by the sole exposure to sulfur(IV) were observed: The activity of alkaline phosphatase was elevated and type II pneumocytes proliferated. It can, however, be concluded that long-term exposure of healthy lungs to particle-associated neutral sulfur(IV) and hydrogen ions at concentration close to ambient levels causes subtle respiratory responses but does not initiate pathological processes in the lungs. In other words, the perpetual inhalation of sulfur(IV) and hydrogen ions from the atmospheric environment presents no health risk to the healthy lungs. It is thus also very unlikely that respiratory diseases can be initiated by the inhalation of these pollutants.
AU  - Heyder, J.
AU  - Beck-Speier, I.
AU  - Busch, B.*
AU  - Dirscherl, P.
AU  - Heilmann, P.
AU  - Ferron, G.A.
AU  - Josten, M.
AU  - Karg, E.W.
AU  - Kreyling, W.G.
AU  - Lenz, A.-G.
AU  - Maier, K.L.
AU  - Miaskowski, U.
AU  - Platz, S.*
AU  - Reitmeir, P.
AU  - Schulz, S.
AU  - Takenaka, S.
AU  - Ziesenis, A.
C1  - 24058
C2  - 31432
SP  - 343-359
TI  - Health effects of sulfur-related environmental air pollution. I. Executive summary.
JO  - Inhal. Toxicol.
VL  - 11
IS  - 5
PB  - Informa Healthcare
PY  - 1999
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Recently concern has been raised about health effects related to environmental sulfur and/or acidic aerosols. To assess long-term effects on respiratory lung function, 8 beagle dogs were exposed over a period of 13 mo for 16.5 h/day to 1.0 microm neutral sulfite aerosol with a particle associated sulfur(IV) concentration of 0.32 mg m(-3) and for 6 h/day to 1.1 microm acidic sulfate aerosol providing an hydrogen ion concentration of 15.2 micromol m(-3) for inhalation. Prior to exposure the dogs were kept under clean air conditions for 16 mo to establish physiological baseline values for each dog. A second group of eight dogs (control) was kept for the entire study under clean air conditions. Nonspecific defense mechanisms in the airways and in the peripheral lung were studied during chronic exposure of the combination of neutral sulfur(IV) and acidic sulfur(VI) aerosols. No functional changes of tracheal mucus velocity were found, in agreement with unchanged morphometry of the airways. However, the exposure resulted in changes of several alveolar macrophage (AM) mediated particle clearance mechanisms: (1) Based on in vivo clearance analysis and cultured AM studies using moderately soluble cobalt oxide particles, intracellular particle dissolution was significantly reduced since phagolysosomal proton concentration was decreased. We deduce exposure-related malfunction of proton pumps bound to the phagolysosomal membrane as a result of an increase of cytosolic proton concentration. (2) Based on in vivo clearance analysis using insoluble polystyrene particles, AM-mediated particle transport from the lung periphery toward ciliated terminal bronchioli and further to the larynx was significantly reduced. Activation of epithelial type II cells at the entrance of alveoli was inferred from observed type II cell proliferation at those alveolar ridges and enhanced secretion of alkaline phosphatase in the fluid of bronchoalveolar lavages. As a result, hypersecretion of chemotactic mediators by activated type II cells at these loci led to the observed decrease of particle transport toward ciliated bronchioli. (3) Based on in vivo clearance analysis using insoluble polystyrene particles, particle transport from the alveolar epithelium into interstitial tissues was increased and (4) particle transport to the tracheobronchial lymph nodes was significantly enhanced. Particle transport into interstitial tissues is the most prominent clearance pathway from the canine alveolar epithelium. We conclude that the deteriorated particle transport toward ciliated terminal bronchioli resulted in an enhanced particle transport across the epithelial membrane into interstitial tissues and the lymphatic drainage. The observed alterations in alveolar macrophage-mediated clearance mechanisms during chronic exposure of these air pollutants indicate an increased risk of health.
AU  - Kreyling, W.G.
AU  - Dirscherl, P.
AU  - Ferron, G.A.
AU  - Heilmann, P.
AU  - Josten, M.
AU  - Miaskowski, U.
AU  - Neuner, M.
AU  - Reitmeir, P.
AU  - Ruprecht, L.
AU  - Schumann, G.
AU  - Takenaka, S.
AU  - Ziesenis, A.
AU  - Heyder, J.
C1  - 24062
C2  - 31434
SP  - 391-422
TI  - Health effects of sulfur-related environmental air pollution. III. Nonspecific respiratory defense capacities.
JO  - Inhal. Toxicol.
VL  - 11
IS  - 5
PB  - Informa Healthcare
PY  - 1999
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Airway epithelial surface is the primary target of airborne pollutants. To estimate the distribution of xenobiotic-metabolizing enzymes in the respiratory tract of dogs, epithelia from different airway sites of four animals were analyzed for metabolism of sulfite (sulfite oxidase) and formaldehyde (formaldehyde dehydrogenase and aldehyde dehydrogenase). In addition, glutathione S-transferases were assayed using several model substrates. Enzyme activities were compared with those found in liver parenchyma. The activity of sulfite oxidase was found to be comparable in nose, trachea, and proximal and medium bronchi, but appeared to be lower in lung parenchyma of most animals. In contrast, hepatic sulfite oxidase activity of these animals was substantially higher compared to that in airway epithelia. The activity of glutathione-dependent formaldehyde dehydrogenase (FDH) appeared to be highest in nose and lowest in distal bronchi, lung, and liver parenchyma. The distribution pattern of the glutathione-independent aldehyde dehydrogenase (AldDH) in the respiratory tract was different from that of FDH. Levels of AldDH were about 5- to 10-fold lower than those of FDH, suggesting that AldDH is of minor importance for pulmonary formaldehyde detoxification. With regard to ethanol detoxification by a class I alcohol dehydrogenase (ADH), no measurable enzyme activity could be detected at most respiratory sites contrary to the high activity found in liver parenchyma. Regarding glutathione S-transferases (GSTs), different distributions of enzyme activities were found in the large and small airways when using three substrates. The 1-chloro-2,4-dinitrobenzene (CDNB)-related activities in the cytosolic fraction of the upper (nose, trachea) and lower airways (proximal, medium and distal bronchi) were higher than those in the microsomal fraction. Interestingly, there was no difference between CDNB-related activities in the cytosolic and microsomal fraction of the liver. Highest cytosolic activities were found in the nose, and were comparable to those detected in the liver parenchyma. The cytosolic 1,2-dichloro-4-nitrobenzene (DCNB)-related activities in the nose, proximal bronchi, and lung parenchyma were appeared to be markedly higher than those in trachea and medium and distal bronchi, while the microsomal activities were not detectable at most respiratory sites. In contrast, distinctly higher activities were measured in both fractions of liver tissue. Cytosolic 1, 2-epoxy-3-(p-nitrophenoxy)-propane (EPNP)-related activities were present in upper and lower airways including lung parenchyma at comparable levels, while in liver tissue the mean activities were distinctly lower. No EPNP-related activities were found in the microsomal fractions. In conclusion, most xenobiotic-metabolizing enzymes investigated in this study could be detected in epithelia of various respiratory sites. The most outstanding result revealed higher levels of FDH activity in the nose and downstream to the medium bronchi in comparison to those found in the small airways, lung, and liver tissue. Similarly, the EPNP-related GST exhibited a distinctly higher activity at all respiratory sites compared to the activity in liver tissue, suggesting a different regulation of this enzyme in lung and liver.
AU  - Maier, K.L.
AU  - Wippermann, U.
AU  - Leuschel, L.
AU  - Josten, M.
AU  - Pflugmacher, S.
AU  - Schröder, P.
AU  - Sandermann, H.
AU  - Takenaka, S.
AU  - Ziesenis, A.
AU  - Heyder, J.
C1  - 23283
C2  - 31150
SP  - 19-35
TI  - Xenobiotic-metabolizing enzymes in the canine respiratory tract.
JO  - Inhal. Toxicol.
VL  - 11
IS  - 1
PB  - Informa Healthcare
PY  - 1999
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Recently, concern has been raised about effects related to environmental sulfur and/or acidic aerosols. To assess long-term effects on nonrespiratory lung function, 8 beagle dogs were exposed over a period of 13 mo for 16.5 h/day to a neutral sulfite aerosol at a sulfur(IV) concentration of 0.32 mg m(-3) and for 6 h/day to an acidic sulfate aerosol providing a hydrogen concentration of 15.2 micromol m(-3) for inhalation. Prior to exposure the dogs were kept under clean air conditions for 16 mo to establish physiological baseline values for each animal. A second group of eight dogs (control) was kept for the entire study under clean air conditions. No clinical symptoms were identified that could be related to the combined exposure. Biochemical and cellular parameters were analyzed in sequential bronchoalveolar lavage (BAL) fluids. The permeability of the alveolo-capillary membrane and diethylenetriaminepentaacetic acid (DTPA) clearance was not affected. Similarly, oxidant burden of the epithelial lining fluid evaluated by levels of oxidation products in the BAL fluid protein fraction remained unchanged. Both the lysosomal enzyme beta-N-acetylglucosaminidase and the alpha-1-AT were increased (p <.05). In contrast, the cytoplasmic marker lactate dehydrogenase remained unchanged, indicating the absence of severe damages to epithelial cells or phagocytes. Various surfactant functions were not altered during exposure. Three animals showed elevated levels of the type II cell-associated alkaline phosphatase (AP), indicating a nonuniform response of type II cells. Significant correlations were found between AP and total BAL protein, but not between AP and lactate dehydrogenase, suggesting proliferation of alveolar type II cells. Absolute and relative cell counts in the BAL fluid were not influenced by exposure. Alveolar macrophages showed no alterations with regard to their respiratory burst upon stimulation with opsonized zymosan. The percentage of alveolar macrophages capable of phagocytozing latex particles was significantly decreased (p<.05), while the phagocytosis index was not altered. In view of the results of this and previous studies, we conclude that there is no synergism of effects of these two air pollutants on nonrespiratory lung functions. It is hypothesized that antagonistic effects of these air pollutants on phospholipase A2-dependent pathways account for compensatory physiological mechanisms. The results emphasize the complexity of health effects on lung functions in response to the complex mixture of air pollutants and disclose the precariousness in the risk assessment of air pollutants for humans.
AU  - Maier, K.L.
AU  - Beck-Speier, I.
AU  - Dayal, N.
AU  - Dirscherl, P.
AU  - Griese, M.*
AU  - Heilmann, P.
AU  - Hinze, H.
AU  - Josten, M.
AU  - Karg, E.W.
AU  - Kreyling, W.G.
AU  - Lenz, A.-G.
AU  - Leuschel, L.
AU  - Meyer, B.
AU  - Miaskowski, U.
AU  - Reitmeir, P.
AU  - Ruprecht, L.
AU  - Schumann, G.
AU  - Ziesenis, A.
AU  - Heyder, J.
C1  - 24060
C2  - 31433
SP  - 361-389
TI  - Health effects of sulfur-related environmental air pollution. II. Cellular and molecular parameters of injury.
JO  - Inhal. Toxicol.
VL  - 11
IS  - 5
PB  - Informa Healthcare
PY  - 1999
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Recently concern has been raised about health effects related to environmental sulfur and/or acidic aerosols. To assess long-term effects on respiratory lung function, 8 beagle dogs were exposed over a period of 13 mo for 16.5 h/day to 1-microm neutral sulfite aerosol with a particle-associated sulfur(IV) concentration of 0.32 mg m(-3) and for 6 h/day to 1.1-microm acidic sulfate aerosol providing an hydrogen ion concentration of 15.2 micromol m(-3) for inhalation. Prior to exposure the dogs were kept under clean air conditions for 16 mo to establish physiological baseline values for each dog. A second group of eight dogs (control) was kept for the entire study under clean air conditions. Before and at the end of exposure, respiratory lung function was evaluated in both groups in anesthetized and mechanically ventilated animals. Lung volumes as well as static and dynamic lung compliances were measured. Series dead-space volumes and slopes of the alveolar plateau for respiratory (O2, CO2) and inert test gases (He, SF6) were determined from single-breath washout tracings. Monodisperse 0.9-microm DEHS droplets were used to assess convective mixing in the lungs and to evaluate airway dimensions in vivo. Gas exchange across the alveolar-capillary layer was characterized by membrane diffusing capacity for carbon monoxide and alveolar-arterial pressure differences for respiratory gases. A bronchial challenge with carbachol was used to assess airway responsiveness. In comparison to the control group, dogs exposed to sulfur(IV) and acidic aerosol exhibited no significant changes in any respiratory lung function parameter. Also the responsiveness of the bronchial airways to carbachol was not affected. In view of the results obtained in this and previous studies, we conclude that anticipated synergistic effects of the two air pollutants on pulmonary lung function were not observed. It is hypothesized that antagonistic effects of the air pollutants on the activity of phospholipase A2 play an important role and account for counteracting physiological compensatory mechanisms. The results emphasize the complexity of health effects on lung function in response to the complex mixtures of ambient air pollutants and witness the precariousness in the risk assessment of air pollutants for humans.
AU  - Schulz, S.
AU  - Eder, G.
AU  - Heilmann, P.
AU  - Karg, E.W.
AU  - Meyer, T.
AU  - Schulz, A.
AU  - Ziesenis, A.
AU  - Heyder, J.
C1  - 24064
C2  - 31435
SP  - 423-438
TI  - Health effects of sulfur-related environmental air pollution. IV. Respiratory lung function.
JO  - Inhal. Toxicol.
VL  - 11
IS  - 5
PB  - Informa Healthcare
PY  - 1999
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - The lungs of 8 male beagle dogs were examined morphologically and morphometrically after exposure for 13 mo to a respirable sulfur(IV) aerosol at a mass concentration of 1.53 mg m(-3) (16.5 h/day), and to an acidic sulfate aerosol carrying 15.2 micromol m(-3) hydrogen ions into the lungs (6 h/day). An additional eight dogs served as unexposed controls. Standard morphometric analyses of both the surface epithelia of the conducting airways and the alveolar region were performed. These analyses showed no difference between the exposure group and control group. However, there was a tendency to an increase in the volume density of bronchial glands in the exposure group. Five of eight exposed animals showed thickened ridges (knob-like structures) at the entrance to alveoli in the alveolar duct and alveolar sac. Transmission electron microscopy revealed that the thickening was mainly due to type II cell proliferation. As the previous experiment using sulfite aerosol only showed no alterations in the proximal alveolar regions, the changes observed may be considered as effects of acidic sulfate aerosol alone or in combination with sulfite. These findings suggest that sulfur aerosols have the potential to induce epithelial alterations in the proximal alveolar region, which is a primary target for air pollutants.
AU  - Takenaka, S.
AU  - Godleski, J.J.*
AU  - Heini, A.
AU  - Karg, E.W.
AU  - Kreyling, W.G.
AU  - Ritter, B.
AU  - Schulz, S.
AU  - Ziesenis, A.
AU  - Heyder, J.
C1  - 24066
C2  - 31436
SP  - 439-454
TI  - Health effects of sulfur-related environmental air pollution. V. Lung structure.
JO  - Inhal. Toxicol.
VL  - 11
IS  - 5
PB  - Informa Healthcare
PY  - 1999
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Patrick, G.
AU  - Stirling, C.
AU  - Kreyling, W.G.
AU  - Poncy, J.-L.
AU  - Duserre, C.
AU  - Colliuer, C.G.
AU  - Godelski, J.
AU  - Brein, J.D.
C1  - 20553
C2  - 13759
SP  - 225-240
TI  - Interspecies Comparison of the Celarance of Ionic Cobalt from the Lungs.
JO  - Inhal. Toxicol.
VL  - 6
PY  - 1994
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - The present study was designed to investigate the effect of chronic inhalation of a low concentration of airborne sulfur(IV) on mammalian lungs. Eight beagle dogs were continuously exposed in whole-body chambers for 290 d to a respirable S(IV) aerosol with a mass median aerodynamic diameter of 0.6 μm (geometric standard deviation about 2) at a concentration of 0.3 mg m-3, equivalent to a sulfur dioxide concentration of 0.6 mg m-3. Three dogs served as sentinels. To establish baseline data for lung parameters, the dogs were first housed in the chambers for 400 d under clean air conditions. Biochemical and cellular parameters in the lung lavage fluids were evaluated repeatedly for each dog. During exposure, each lung parameter was again measured repeatedly for each dog and the values obtained were compared with the baseline values. Thus each individual served as its own control. Parameters of respiratory lung function and lung morphology were only evaluated at the end of the study The three sentinal dogs were used as controls for these parameters. The most pronounced effects-were seen in the increased permeability of the alveolar membrane for proteins, in macrophage function like release of Iysosomal components, and in the decline in bacterial defense capacity as indicated by a reduced phagocytic capacity and a decreased formation of oxygen radicals. Macrophage-mediated particle clearance from the lung periphery was enhanced. In addition, there seemed to be some early indications of allergic and immunological reactions to the sulfur(IV) aerosol, reflected in an increase in eosinophils and lymphocytes. Postmortem morphologic examination of the respiratory system revealed hyperplastic changes in the nasal cavity and disturbance of ciliated cell development in the trachea. Morphometric analysis indicated early peripheral airspace enlargement, resulting in a significant decrease in the surface area available for gas exchange in the exposed lungs. The lungs also showed a tendency to impairment in the membrane diffusing capacity. The results show that chronic exposure to a sulfur(IV) aerosol at a low dose can initiate pathophysiological and pathobiochemical pathways in the lungs, thus indicating a potential health hazard. © 1992 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
AU  - Heyder, J.
AU  - Beck-Speier, I.
AU  - Ferron, G.A.
AU  - Heilmann, P.
AU  - Karg, E.W.
AU  - Kreyling, W.G.
AU  - Lenz, A.-G.
AU  - Maier, K.L.
AU  - Schulz, S.
AU  - Takenaka, S.
AU  - Tuch, T.
C1  - 19027
C2  - 12069
SP  - 159-174
TI  - Early Response of the Canine Respiratory Tract Following Long-Term Exposure to a Sulfur(IV) Aerosol at Low Concentration: I. Rationale, Design, Methodology and Summary.
JO  - Inhal. Toxicol.
VL  - 4
IS  - 3
PY  - 1992
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - After a control period of 400 d in filtered, contaminant-free air, eight dogs were exposed continuously for 290 d to a respirable sulfur(IV) aerosol at an S(IV) concentration of 0.3mg-3, equivalent to a sulfur dioxide concentration of 0.6 mg m-3. Long-term particle clearance from the lungs was tested with uniform, moderately soluble cobalt oxide (Co3O4)particles and nearly insoluble fused aluminosilicate particles (FAP) after short-term inhalation. The former were used to analyze translocation of dissolved particle mass from the lungs to blood, and the latter to study mechanical particle transport from the lungs to the larynx and into the gastrointestinal tract, and via lymphatics to the lung-associated lymph nodes. The in vivo translocation rate of moderately soluble test particles was significantly increased (by a factor of 7.8) in three dogs during S(IV) exposure compared to the rate during the control period. The results were confirmed by in vitro measurements of intracellular dissolution of moderately soluble Co3O4 particles in alveolar macro-phages obtained from serial bronchoalveolar lavages of the dogs. Moreover, the in vitro studies showed a significant increase on average in intracellular particle dissolution in macrophages (by a factor of 1.3) from 2 mo until the end of exposure, indicating changes in alveolar macrophage function leading to enhanced particle clearance by translocation. Long-term mechanical particle transport (MPT) from the lungs to the larynx was a very slow clearance mechanism in the dogs, starting with a rate of 0.002 day-1 of the retained particles, which decreased exponentially. Thus the nearly insoluble FAP were in fact more effectively cleared by translocation than by MPT In five dogs, MPT during exposure was more effective by a factor of five than expected from the MPT during the control period. In contrast, MPT in two dogs was reduced by a factor of 0.3. The mechanical particle transport to the lung-associated lymph nodes during the entire period of the study showed a substantial intersubject variability of between 0.02 and 0.13 of the long-term retained FAP. The results indicate early changes in long-term particle clearance in the lungs following continuous exposure to S(IV). Since both clearance mechanisms are alveolar macrophage mediated, the alterations indicate the presence of functional changes in the phagolysosomal vacuole and in factors affecting the motility of alveolar macrophages on the epithelial surface.
AU  - Kreyling, W.G.
AU  - Ferron, G.A.
AU  - Fürst, G.M.
AU  - Heilmann, P.
AU  - Neuner, M.
AU  - Ruprecht, L.*
AU  - Schumann, G.
AU  - Takenaka, S.
AU  - Heyder, J.
C1  - 33001
C2  - 38669
SP  - 197-233
TI  - Early response of the canine respiratory tract following long-term exposure to a sulfur(IV) aerosol at low concentration. III. Macrophage-mediated long-term particle clearance.
JO  - Inhal. Toxicol.
VL  - 4
IS  - 3
PY  - 1992
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Maier, K.L.
AU  - Beck-Speier, I.
AU  - Dayal, N.
AU  - Heilmann, P.
AU  - Hinze, H.
AU  - Lenz, A.-G.
AU  - Leuschel, L.
AU  - Matjekova, E.
AU  - Miaskowski, U.
AU  - Heyder, J.
AU  - Ruprecht, L.
C1  - 19028
C2  - 12070
SP  - 175-195
TI  - Early Response of the Canine Respiratory Tract Following Long-Term Exposure to a Sulfur(IV) Aerosol at Low Concentration: II. Biochemistry and Cell Biology of Lung Lavage Fluid.
JO  - Inhal. Toxicol.
VL  - 4
PY  - 1992
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Schulz, S.
AU  - Eder, G.
AU  - Heilmann, P.
AU  - Ruprecht, L.
AU  - Schumann, G.
AU  - Takenaka, S.
AU  - Heyder, J.
C1  - 19030
C2  - 12072
SP  - 235-246
TI  - Early Response of the Canine Respiratory Tract Following Long-Term Exposure to a Sulfur(IV)  Aerosol at Low Concentration: IV. Respiratory Lung Function.
JO  - Inhal. Toxicol.
VL  - 4
PY  - 1992
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Takenaka, S.
AU  - Fürst, G.
AU  - Heilmann, P.
AU  - Heini, A.
AU  - Heinzmann, U.
AU  - Kreyling, W.G.
AU  - Murray, A.B.
AU  - Schulz, S.
AU  - Heyder, J.
C1  - 19031
C2  - 12073
SP  - 247-272
TI  - Early Response of the Canine Respiratory Tract Following Long-Term Exposure to a Sulfur(IV)  Aerosol at Low Concentration: V. Morphology and Morphometry.
JO  - Inhal. Toxicol.
VL  - 4
PY  - 1992
SN  - 0895-8378
ER  - 

TY  - JOUR
AU  - Kreyling, W.G.
AU  - Nyberg, N.
AU  - Nolibé, D.
AU  - Collier, C.G.
AU  - Camner, P.
AU  - Heilmann, P.
AU  - Lirsac, P.
AU  - Lundborg, M.
AU  - Matejkova, E.
C1  - 18536
C2  - 11695
SP  - 91-100
TI  - Interspecies Comparison of Phagolysosomal pH in Alveaolar Macrophages.
JO  - Inhal. Toxicol.
VL  - 3
PY  - 1991
SN  - 0895-8378
ER  - 

TY  - JOUR
AB  - Differences in the translocation of dissolved particle mass from the lungs to the blood were found in a recent large interspecies comparison of long-term lung clearance after inhalation of uniform 57Co3O4 particles. Since the particles were dissolved most prominently in phagolysosornes of alveolar macrophages, the differences may have been due to differences in pH in these vacuoles. The phagolysosomal pH was measured in alveolar macrophages obtained by bronchoalveolar lavage from baboons, dogs, guinea pigs, and rabbits using fluorescein-labeled amorphous silica particles as a probe. In the alveolar macrophages from the 4 species pH was on average 4.8 or 4.9 with small variations among and within animals. The results indicate that it is unlikely that differences in phagolysosomal pH are responsible for the differences in translocation observed previously.
AU  - Kreyling, W.G.
AU  - Nyberg, K.*
AU  - Nolibé, D.*
AU  - Collier, C.G.*
AU  - Camner, P.*
AU  - Heilmann, P.
AU  - Lirsac, P.N.*
AU  - Lundborg, M.*
AU  - Matejkova, E.
C1  - 40699
C2  - 40236
SP  - 91-100
TI  - Interspecies comparison of phagolysosomal ph in alveolar macrophages.
JO  - Inhal. Toxicol.
VL  - 3
IS  - 1
PY  - 1991
SN  - 0895-8378
ER  -