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ABSTRACT: There is still intensive debate on the variability in the biological activities of different quartz species. Therefore we examined in a rat lung model the inflammatory, fibrogenic and genotoxic characteristics of four commercial quartz flours. The samples, two with probably low activity and two with probably high activity were selected from a panel of 16 samples on the basis of in vitro investigations. Rats were exposed by a single intratracheal injection of 0.6, 1.2 and 2.4 mg quartz samples per lung or with 1.2 mg standard quartz DQ12. After 90 days the inflammatory response was measured in the bronchoalveolar lavage fluid, as well as the content of 8-oxoguanine in the DNA of the lung cells. Additionally mutated p53 protein was determined. The four quartz samples revealed specific differences in all parameters investigated. In good agreement with the in vitro results the two samples expected as lowly active showed only weak inflammatory and no genotoxic reactions in the rat lungs. In contrast the two samples suspected as highly reactive induced a pronounced inflammatory response and for one of the samples genotoxic effects could be proven. The results raised here show a broad spectrum of biological activities dependent on the type of quartz from almost inert to genotoxic and highly inflammatory.
International Journal of Hygiene and Environmental Health 03/2004; 207(2):115-24. · 3.81 Impact Factor
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ABSTRACT: TiO(2) is considered to be toxicologically inert, at least under nonoverload conditions. To study if there are differences in lung effects of surface treated or untreated TiO(2) we investigated the inflammatory and genotoxic lung effects of two types of commercially available TiO(2) at low doses relevant to the working environment. Rats were exposed by instillation to a single dose of 0.15, 0.3, 0.6, and 1.2 mg of TiO(2) P25 (untreated, hydrophilic surface) or TiO(2) T805 (silanized, hydrophobic surface) particles, suspended in 0.2 ml of physiological saline supplemented with 0.25% lecithin. As control, animals were instilled with the vehicle medium only or with a single dose of 0.6 mg quartz DQ12. At days 3, 21, and 90 after instillation bronchoalveolar lavage was performed and inflammatory signs such as cells, protein, tumor necrosis factor-alpha, fibronectin, and surfactant phospholipids were determined. Additionally, 8 microm frozen sections of the left lobe of the lung were cut and stored at -80 degrees C. The sections were used for immunohistochemical detection of 8-oxoguanine (8-oxoGua) by a polyclonal antibody in the DNA of individual lung cells. In the quartz-exposed animals a strong progression in the lung inflammatory response was observed. Ninety days after exposure a significant increase in the amount of 8-oxoGua in DNA of lung cells was detected. In contrast, animals exposed to TiO(2) P25 or TiO(2) T805 showed no signs of inflammation. The amount of 8-oxoGua as a marker of DNA damage was at the level of control. The results indicate that both types of TiO(2) are inert at applicated doses.
Toxicology and Applied Pharmacology 07/2003; 189(2):84-95. · 4.45 Impact Factor
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ABSTRACT: Exposure to quartz and high concentrations of other poorly soluble particles can lead to the development of lung tumors in the rat. The mechanisms involved in particle-induced carcinogenesis seem to include inflammation-associated production of reactive oxygen species (ROS) and DNA damage. ROS induce 8-oxoguanine (8-oxoGua) and a panel of other oxidation products in DNA. In proliferating cells such DNA lesions can lead to various types of mutations, which might be critical for cancer-related genes with respect to tumor formation. Quartz is known to mediate the induction of 8-oxoGua in the nuclear DNA of lung cells when applied to the lung of rats. We have investigated the time- and dose-dependent biologic effects of quartz and, as a control, corundum, on cell proliferation and various pulmonary inflammation and toxicity markers in rat bronchoalveolar lavage fluid (BALF); on the induction of 8-oxoGua in the DNA of rat lung cells; and on the cellular levels of p53 wild-type and p53 mutant (mut) protein. Rats were exposed by intratracheal instillation to various amounts of quartz (0.3, 1.5, or 7.5 mg/rat) or corundum (0.3, 1.5, or 7.5 mg/rat) and measured at Days 7, 21, and 90 after exposure. Corundum had no adverse effects except a slight elevation of 8-oxoGua at a dose of 7.5 mg/rat. However, significant changes in the BALF were detected at all quartz doses. 8-oxoGua was significantly increased only at 1.5 and 7.5 mg quartz/rat. The amount of cells with detectable p53 wild-type protein levels was increased at 1.5 and 7.5 mg quartz/rat at 7 and 21 d. Elevated amounts of cells with enhanced p53 mut protein levels were measured at all time points after instillation of 7.5 mg quartz/rat.
American Journal of Respiratory Cell and Molecular Biology 05/2001; 24(4):492-8. · 5.13 Impact Factor
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ABSTRACT: Exposure of rats to high doses of quartz and other insoluble isometric particles can produce lung tumors. In contrast, after exposure of such particles in hamsters no tumor outcome has been observed. Recent studies have demonstrated that the tumorigenic effect of particles is closely linked to the induction of inflammatory processes and the subsequent formation and persistence of mutagenic oxidative DNA-modifications. Species-specific differences in sensitivity to particles should therefore be reflected in the molecular reaction of the lung cells. We exposed rats and hamsters to two different doses of quartz (0.3 mg, 1.2 mg/100 g body weight) by intratracheal instillation and characterized the dose-related pattern of pulmonary inflammation (neutrophil recruitment, TNF), toxicity (protein content, surfactant phospholipids), antioxidant defence (glutathione content), mutagenicity (8-oxoguanine, p53) and proliferation. Our results clearly demonstrate a significantly higher response of the rat to quartz exposure for all determined molecular and cellular parameters. Therefore the examination of these parameters in humans would contribute to the evaluation of the relevance of rats or hamsters as models to predict particle-induced human lung cancer risk.
Toxicology Letters 03/2001; 119(1):11-9. · 3.23 Impact Factor
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ABSTRACT: Exposure to silica can lead to fibrosis and the development of lung tumors in the rat. Based on these animal studies and on epidemiological data, silica has been classified as a human carcinogen. The initial mechanisms have not been finally clarified, but particle-induced tumor formation is at least closely associated with inflammation, the production of reactive oxygen species (ROS) and DNA damage. We investigated the dose-dependent effects of silica on the formation of the major DNA oxidation product 8-oxoguanine (8-oxo-Gua) in rat lung cells, on p53 (p53) and p53 mutant protein (p53 mut) synthesis, as well as on the amount of the surfactant phospholipids phosphatidylinositol (PI) and phosphatidylglycerol (PG) in the bronchoalveolar lavage fluids (BALF) as indicators of fibrotic processes in the lung. Rats were exposed by intratracheal instillation to various amounts of DQ12 quartz (0.15, 0.3, 0.6, 1.2, 2.4 mg/animal) and lungs were investigated after 21 and 90 days. PG decreased and PI increased quartz dose dependently. 8-oxoGua was significantly increased only after 1.2 and 2.4 mg quartz/animal. Cells expressing p53 protein were increased at 1.2 and 2.4 mg, p53 mutant protein only at 2.4 mg/animal. This indicates a no-effect level for mutagenicity at a low, but still fibrogenic quartz exposure.
Archive für Toxikologie 02/2001; 74(11):716-9. · 4.67 Impact Factor
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W. Popp,
U. Plappert,
W.-U. Müller, B. Rehn,
J. Schneider,
A. Braun,
P. C. Bauer,
C. Vahrenholz,
P. Presek,
A. Brauksiepe,
G. Enderle,
T. Wüst,
J. Bruch,
T. M. Fliedner,
N. Konietzko,
Christian Streffer,
H.-J. Woitowitz,
K. Norpoth
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ABSTRACT: Former East German uranium miners who are known to have been exposed to radon are estimated to be at high risk for lung carcinogenesis.
Among these miners over 200 occupationally caused lung cancer cases are expected to occur each year, resulting in a total
of 7,000–24,000 excess lung cancer cases in the coming years. It is still unknown whether there is a correlation between biomarkers
and the exposure of the uranium miners to ionizing radiation that might enable us to trace those miners with high lung cancer
risk. The primary aim of this pilot study was to test the possibility of performing a biomarker study in this unique cohort
of former uranium miners in spite of several limitations that had to be taken into consideration when comparing them with
healthy controls, such as old age, age-dependent diseases and potential confounding artefacts from dissimilar smoking patterns.
The second aim was to test a range of biomarkers for DNA damage and inflammation in leukocytes and bronchoalveolar fluid for
their ability to detect biological effects. In this cohort of miners we found an increased frequency of chromosomal aberrations
in blood lymphocytes and an increased prevalence of both fibronectin and tumour necrosis factor α in the bronchoalveolar fluid.
Biophysik 11/2000; 39(4):275-282. · 1.70 Impact Factor
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ABSTRACT: Exposure of rats to quartz (or various other particles) can lead to the development of lung tumors. At the moment, the mechanisms involved in particle-induced tumor formation are not clarified. However, it is suggested that inflammation, in conjunction with the production of reactive oxygen species (ROS) and an enhancement of epithelial cell proliferation, may play a key role in the development of lung tumors. ROS induces 8-oxoguanine (8-oxoGua) and other mutagenic DNA oxidation products, which can be converted to mutations in proliferating cells. Mutation formation in cancer-related genes is a critical event with respect to tumor formation. In this study we investigated the effects of quartz (DQ12) and of the nontumorigenic dust corundum on the induction of 8-oxoGua in the DNA of rat lung cells, as well as on cell proliferation and pulmonary inflammation. Wistar rats were exposed by intratracheal instillation to quartz (2.5 mg/rat) or corundum (2.5 mg/rat) suspended in physiological saline; control animals exposed to physiological saline or left untreated. Measurements were carried out 7, 21, and 90 days after the exposures. 8-oxoGua levels were determined in lung tissue sections at the single cell level by immunocytological assay using a rabbit anti-8-oxoGua antibody. After exposure to quartz, 8-oxoGua levels were significantly increased at all time points of investigation. Additionally, we observed inflammation and an enhanced cell proliferation. Exposure to corundum had no adverse effects on the lung; neither increased 8-oxoGua levels nor enhanced cell proliferation or inflammation were detected. These observations support the suggestion that inflammation associated with increased 8-oxoGua levels in lung cells and increased cell proliferation is an important determinant for particle-induced development of lung tumors in the rat.
Environmental Health Perspectives 10/1997; 105 Suppl 5:1291-6. · 7.04 Impact Factor
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Experimental and Toxicologic Pathology 12/1996; 48(6):477-80. · 2.78 Impact Factor
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Experimental and Toxicologic Pathology 12/1996; 48(6):520-2. · 2.78 Impact Factor
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Experimental and Toxicologic Pathology 12/1996; 48(6):544-7. · 2.78 Impact Factor
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ABSTRACT: Whilst alterations in surfactant components of bronchoalveolar lavage fluid (BALF) have been described in a variety of pulmonary diseases in adults, no information is available on the surfactant composition in children beyond the neonatal period. In order to obtain reference values for the paediatric age group, we have studied phospholipid profiles of BALF in children without pulmonary disease. The study population consisted of 38 children aged 3-15 yrs (mean +/- SD 8 +/- 4 yrs) undergoing elective surgery for nonpulmonary illnesses. Surfactant composition was analysed by high pressure liquid chromatography using both an ultraviolet and a light-scattering detector. Total phospholipid concentration was higher in children under 8 yrs of age and decreased with age. In contrast, the total protein concentration remained constant throughout the age range. No age-related changes in the relative composition of phospholipid fractions could be observed. Surfactant protein A concentrations were highly variable in all age groups. This study provides the first data on surfactant components in bronchoalveolar lavage fluid of healthy children and will be the basis for future studies of children with pulmonary diseases.
European Respiratory Journal 03/1996; 9(2):328-33. · 5.89 Impact Factor
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ABSTRACT: Quartz was injected into a hind food of BALB/c and DBA/2 mice and on days 40, 90, and 180 the progressive response ensuing in the draining popliteal lymph node (PLN) was investigated by histopathology and immunohistopathology. The area of silicotic nodules (ASN) was measured by morphometry, and, by this parameter, strain BALB/c proved to be a high responder to quartz, and strain DBA/2 a low responder, albeit both strains showed a similar degree of reactive lymphoid hyperplasia in the draining PLN. Both strains also showed a similar quartz content in the draining PLN but in BALB/c mice quartz particles were concentrated in the ASN, whereas in DBA/2 mice they were evenly dispersed over the PLN. Because the silicotic response of athymic BALB/c nu/nu mice was even stronger than that of euthymic BALB/c mice, T cells are not required for the development of silicotic nodules. This fits the notion that quartz is not an antigen and that high and low responder strains are MHC-identical. Because quartz-treated BALB/c, but not DBA/2 mice, showed a persistent expression of the macrophage differentiation markers MRP8 and MRP14, phenotypically the observed strain difference in silicotic responsiveness seems to be expressed at the level of macrophages.
Journal of Leukocyte Biology 03/1996; 59(2):178-88. · 4.99 Impact Factor
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Clinica Chimica Acta 01/1995; 231(2):193-204. · 2.54 Impact Factor
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ABSTRACT: The question of lung damage as a result of exposure to silicon carbide (SiC) was investigated by inhalation experiments to obtain information on the qualitative response of lung tissue to the test substance (SiC). For comparison, quartz, kaolinite, and tempered clay dusts were used. The indices for the effects of the dusts studied were organ weights, numbers of bronchoalveolar cells, lung surfactant phospholipid concentrations including subfractions, and lung clearance. Exposure to the test samples was carried out according to the Essen inhalation model in two independent series. The results of the two series were similar: Compared with sham controls, exposure to SiC did not affect the indices studied. Even at a low dose (a quarter of the SiC dose) quartz gave pronounced deviations in all indices. In particular, an increase in granulocytes indicated toxic properties of the dust. The long term elimination of quartz from the lung was worse than that of SiC. The kaolinite and tempered clay dusts were intermediate between SiC and quartz based on several of the indices studied. It is concluded that SiC is deposited practically inert in the lung.
British journal of industrial medicine 10/1993; 50(9):797-806.
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ABSTRACT: Silicon carbide (SiC) dust and other dusts for comparison were injected intratracheally at a high dose (50 mg) into rats and the response of the lungs and the lymph nodes was studied after an appropriate experimental period. The indices studied were: histological changes in the lung and lymph nodes, organ weights, the formation of collagenous fibres, and the appearance of quartz typical areas. According to several epidemiological investigations and previous experimental animal studies, SiC produces silicogenic (fibrogenic) effects. No changes in the tissues studied in terms of damaging fibrogenic effects could be found after eight months (first series) and three and 12 months (second series). In particular, the histological findings and the absence of quartz typical areas as well as the quantitative determination of collagen fibres show that SiC had no harmful effects on tissues. Based on these results, the extent to which other exposures during the production of SiC can be responsible for the established radiological alterations is discussed. Without doubt the following may be confounders: SiC fibres, crystalline SiO2 (quartz, cristobalite, tridymite), and possibly gaslike emissions (SO2). From the hygienic medical point of view the workplaces during SiC manufacture should be examined carefully. The substance SiC dust as such can be considered as inert from the experimental results based on qualitative and extremely sensitive procedures. A revision of the present threshold value for SiC in ther German MAK list is called for.
British journal of industrial medicine 10/1993; 50(9):807-13.
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Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 02/1993; 130:133-43.
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ABSTRACT: This study presents results of bronchoalveolar lavage (BAL) after irradiation to the lungs in mice as well as clinical data. The number of BAL cells, mainly macrophages, lymphocytes, and granulocytes, changed in a time-dependent manner. The phagocytic activity of the macrophages measured as the phagocytosis of microbeads and measured as the esterase activity also showed a strong time-dependent increase during the acute phase up to 21 days after irradiation. The contents of surfactant phospholipids (SF) and sphingomyelin (SPH; as a parameter for cell death) were quantified by HPLC. Both were significantly changed between day 2 and 21 after irradiation. Three BALs of a patient with idiopathic interstitial pneumonitis, who had received an allogenic bone marrow graft after total body irradiation with 10 Gy, showed similar effects in the cellular and surfactant parameters. These data indicate that there are positive interactions between the number of different BAL cells, macrophage activity, and SF and SPH content in the preclinical model of the mouse as well as in the clinical situation after lung irradiation.
Environmental Health Perspectives 08/1992; 97:171-5. · 7.04 Impact Factor
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ABSTRACT: When rat (female Wistar) lungs were lavaged (bronchoalveolar lavage, BAL) six times with physiological saline, approximately the same number of alveolar macrophages (AM) were found in the first and second BAL, whereas in the third fourth, fifth, and sixth BAL, the number of AM decreased exponentially. Morphometric counting of the number of AM in histological sections of lung tissue showed that only 14% of the AM population had been recovered by BAL. Although additives to the BAL fluid such as lidocaine and/or fetal calf serum increased the AM count in the first washing considerably, the total number of AM washed out remained unaltered. Addition of the phagocytosis stimulant zymosan increased the AM count in BAL by a factor of more than 2. On stimulation of the lungs with an inert dust (silicon carbide), the AM count in the BAL and the lung was only slightly increased 8 weeks after intratracheal instillation. In contrast, after exposure to fibrogenic and cytotoxic quartz, the AM count in BAL and lung was significantly increased, and the recovery of AM had also increased by a factor of approximately 2. The experiments show that it is the micromilieu of the alveoli and the condition of the AM (certain physiological activation states, such as phagocytic activity) that essentially determine the degree of recovery.
Environmental Health Perspectives 08/1992; 97:11-6. · 7.04 Impact Factor
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ABSTRACT: This study presents results of morphometric investigations of mouse lungs after single irradiation. An automatic image analyser was used to monitor pathological changes in morphological structure, especially the size and distribution of collagen fibres, the thickness of the septa and the diameters of alveoli in the lung. Radiation-induced changes in the area of alveoli and septa as well as collagen content were seen 11 weeks after irradiation. A dose-dependent increase in tissue and decrease in alveolar surface as well as a quantifiable increase in radiation oedema were seen. The septa were thickened and the total collagen content increased in a dose-dependent manner. The morphometric methods used here are suitable for determining changes in lung structure, particularly those in collagen content in the early phase of a pathological response after thorax or total body irradiation for conditioning in bone marrow transplantation.
Journal of Cancer Research and Clinical Oncology 02/1991; 117(1):27-32. · 2.56 Impact Factor
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ABSTRACT: The Golgi technique was used to study the development of spines on the external dendrites of granule cells in the olfactory bulbs of young rats that had been continuously exposed to cyclohexanone vapor, deodorized air, or rat odors. Exposure to deodorized air for 3 weeks from postnatal day 1 reduced spine density on the medial and lateral sides of the bulb, whilst exposure to cyclohexanone reduced spine density on the lateral side only. These reductions were evident in other animals exposed for 7 weeks. With all treatments, spine density reached a maximum at postnatal day 21 and decreased markedly during the next month.
Brain Research 06/1988; 468(1):143-7. · 2.73 Impact Factor
