asbestos--amosite and titanium-dioxide

The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO

Topics: Animals; Asbestos, Amosite; Asbestos, Crocidolite; Asbestos, Serpentine; Bronchoalveolar Lavage Fluid; Collagen; Dose-Response Relationship, Drug; Dust; Fibrosis; Inhalation Exposure; Lung; Macrophages, Alveolar; Male; Microscopy, Confocal; Pleura; Rats; Titanium; Toxicity Tests, Subchronic; Traffic-Related Pollution

The dimensions of man-made mineral fiber whiskers are similar to those of some kinds of asbestos. Thus these mineral fibers raise the concern for potential health hazard for workers exposed in the occupational environments. This study was designed to define acute biological effects of intratracheally administered titanium dioxide whiskers (TO1) compared with nonfibrous titanium dioxide (TOP) and UICC amosite (Ams), and their relations to acute lung inflammation in rats. The observed geometric mean length (microm) and width (microm) and geometric standard deviation are: TO1(2.1[2.0], 0.14[1. 53]); Ams (4.3[3.3], 0.31[1.9]); and TOP (50 nm, 1-2 microm aggregates). Ten-week-old Wistar-Jcl male rats received a single tracheal injection of test materials at doses between 0.05 and 1.0 mg/rat. Control animals were injected with the same volume of saline. Lung tissue and bronchoalveolar lavage (BAL) fluid were collected from rats on days 1, 3, and 7 after administration. In the group injected with TO1, total protein, cytokine-induced neutrophil chemoattractant (CINC)/growth-regulated gene product (GRO), interleukin (IL) 1beta, and tumor necrosis factor (TNF) alpha increased on day 1. Subsequently, total elastolytic activity and fucose levels in BAL increased by day 3. All parameters, except for fucose in BAL, recovered to the normal levels. Animals in the Ams group showed increased total protein and CINC/GRO and decreased total elastolytic activity in a dose-dependent manner on day 1. The fucose level increased on day 3 in the Ams group. All parameters returned to their control levels on day 7. Animals in the TOP group did not show significant changes any of parameters during the experimental period. Gene expression of TNF-alpha and monocyte chemoattractant protein (MCP) 3 in the lung increased dose-dependently in the animals treated with the three materials. The mRNAs for eotaxin and MIP-1alpha were overexpressed in the lung of animals treated with Ams and TO1, while RANTES mRNA was overexpressed dose-dependently in the lung of animals treated with Ams on day 1. Onset of inflammatory response was more rapid in the Ams group than the TO1 group. Recovery of the fucose level in BAL was slower in the TO1 group than in the Ams group, though we observed similar histopathological changes in the lung of animals with TO1 or Ams. We conclude that whisker-induced acute biological effects in the lung may be related to the shape of the whiskers and not to their chemical comp

Topics: Administration, Inhalation; Animals; Asbestos, Amosite; Bronchoalveolar Lavage Fluid; Carcinogens; Dust; Elasticity; Fucose; Interleukin-1; Intubation, Intratracheal; Male; Mineral Fibers; Oligonucleotides; Proteins; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Titanium; Tumor Necrosis Factor-alpha

Exposure to mineral dusts is associated with the development of chronic airflow obstruction, probably mediated in part by dust-induced fibrosis of the small airways. To investigate the mechanism of fibrosis, we exposed rat tracheal explants to amosite asbestos, iron oxide, or titanium dioxide. Explants were then maintained in air organ culture, and the expression of genes encoding for various mediators and matrix components assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). At 7 d, all dusts produced significant increases in platelet-derived growth factor-A (PDGF-A) and transforming growth factor-beta1 (TGF-beta1) gene expression compared with control; asbestos and titanium dioxide produced increases in PDGF-B, and titanium dioxide increased TGF-alpha expression. Only asbestos caused increases in procollagen expression. No dust increased expression of tumor necrosis factor-alpha (TNF-alpha), fibronectin, or tropoelastin. Elevations in these factors coincided temporally with transport of particles into the epithelium and then to the subepithelial space. By in situ hybridization, TGF-beta gene expression was found in both the epithelium and subepithelial (interstitial) space, and PDGF-B and procollagen gene expression in the subepithelial space. Chemical analysis showed a small increase in hydroxyproline, a measure of collagen content, in asbestos-treated explants. We conclude that mineral dusts can induce airway wall fibrosis by directly upregulating proliferative and fibrogenic mediators as well as matrix components in the airway epithelium and interstitium, and that neither airspace nor circulating inflammatory cells are required for these effects. Different mineral dusts produce different patterns of reaction.

Topics: Airway Obstruction; Animals; Asbestos, Amosite; Culture Techniques; Dust; Epithelium; Extracellular Matrix Proteins; Ferric Compounds; Fibronectins; Gene Expression Regulation; Hydroxyproline; Inflammation Mediators; Irritants; Lung; Male; Mineral Fibers; Minerals; Platelet-Derived Growth Factor; Procollagen; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-sis; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Titanium; Transforming Growth Factor beta; Tropoelastin; Tumor Necrosis Factor-alpha; Up-Regulation

The factors that determine whether an exogenous mineral particle will be taken up by tracheobronchial epithelial cells are unclear. We have previously proposed that active oxygen species play a role in this process, most likely through iron-catalyzed formation of hydroxyl radical and subsequent lipid peroxidation of cell membranes. To further examine this hypothesis, we prepared rat tracheal explant cultures and exposed them for 1 h to suspensions of amosite asbestos or titanium dioxide (rutile) that had been preincubated with varying concentrations of a mixture of ferrous and ferric chloride. Explants were then maintained in organ culture in air/CO2 for 1 wk to allow particle or fiber uptake to occur. Particles or fibers in the tracheal epithelium were determined by light microscopic morphometry. Similarly treated explants were assayed for malondialdehyde as a measure of lipid peroxidation in the epithelial cells. Asbestos fibers without added iron caused lipid peroxidation, but this was not true of titanium dioxide particles. For both types of dust, increasing adsorbed iron concentrations were associated with increasing particle uptake and increasing lipid peroxidation. These observations suggest that cationic iron may play a major role in particle uptake by tracheobronchial epithelia, and that particle uptake is also related to iron-mediated lipid peroxidation.

Topics: Adsorption; Animals; Asbestos, Amosite; Chlorides; Dust; Epithelial Cells; Epithelium; Female; Ferric Compounds; Ferrous Compounds; Iron; Lipid Metabolism; Malondialdehyde; Organ Culture Techniques; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Titanium; Trachea

The effects of mixed dust exposure on pulmonary clearance during chronic exposure has been investigated using rats exposed to combinations of toxic and relatively nontoxic dusts: quartz (at respirable dust concentrations of 1 and 10 mg/m3) plus titanium dioxide (at 30 and 20 mg/m3, respectively), and amosite asbestos (2.5 mg/m3) plus titanium dioxide (15 mg/m3). The rats were exposed for 5 days per week, and for up to 16 weeks (for quartz) or up to 32 weeks (for asbestos). The lung burdens were compared with previously published results for exposure to single dusts under the same exposure regimens. The main feature of all these comparisons was the absence of significant differences between the lung burdens (at 3, 10, and 38 days postexposure) for single-dust and mixed-dust exposures. There was, however, some reduction in the postexposure clearance (as shown by the lung burdens at 94, 150, and 260 days postexposure) of titanium dioxide which appeared to be due to the presence of quartz in the lung. For the quartz plus titanium dioxide experiments, the lymph nodes were dissected and analyzed separately. These results showed that transfer to lymph nodes accounted for most of the postexposure clearance for titanium dioxide, and almost all for the quartz.

Topics: Animals; Asbestos; Asbestos, Amosite; Atmosphere Exposure Chambers; Chronic Disease; Dose-Response Relationship, Drug; Drug Interactions; Lung; Male; Minerals; Pneumoconiosis; Quartz; Rats; Rats, Inbred Strains; Specific Pathogen-Free Organisms; Time Factors; Titanium