Acute Biological Effects of Intratracheally Instilled Titanium Dioxide Whiskers Compared With Nonfibrous Titanium Dioxide and Amosite in Rats

Abstract

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 composition or surface crystal structure, showing biological effects similar to those of UICC amosite.

Effects of Surface Characteristics of Potassium Titanate Whisker Samples on Acute Lung Injury Induced by a Single Intratracheal Administration in Rats

“…These observations correlated well with the changes of cellularity in BAL fluid. We previously observed overexpression of eotaxin mRNA concomitant with eosinophils infiltration in the lungs of rats treated with TO1 or UICC amosite (Ishihara et al, 1999). Overexpression of eotaxin mRNA, as well as increased BAL eosinophils, was also observed in this study.…”

Pulmonary Inflammatory and Fibrotic Responses in Fischer 344 Rats After Intratracheal Instillation Exposure to Libby Amphibole

“…Markers of cellular permeability and damage were also augmented at most of the time points both in the amosite and in the high-dose LA groups. Increased protein in BAL fluid, likely due to increased epithelial permeability, was reported previously in rats exposed to amphibole asbestos by inhalation (Petruska et al 1991) and IT instillation (Ishihara et al 1999;Adamis et al 2001). LDH was elevated in both FIGURE 9.…”

“…In our study, both lung tissue mRNA and BAL fluid protein levels of TNF-α were elevated at 1 d in animals exposed to the amosite and high-dose LA. Prior studies also reported increases in TNF-α mRNA expression after amosite exposure in rats, but no changes in BAL fluid protein levels (Ishihara et al 1999). Persistently lower levels of BAL fluid IL-1β were observed in the high-dose LA group, while tissue mRNA levels were unchanged over time.…”

“…TNF-α, IL-1β, and IL-6 are generally increased in BAL fluid of humans exposed to asbestos (Zhang et al 1993;Simeonova et al 1997) and in rodent models (Li et al 1993;Ishihara et al 1999). TNF-α is an important mediator of the proinflammatory process and pulmonary fibrogenesis due to asbestos exposure (Mossman and Churg 1998).…”

In Vivo Studies of Man-Made Mineral Fibers. Fibrosis-Related Factors.

“…Ishihara et al 21) studied gene expression in lung tissue after intratracheal instillation of mineral fibers in rats. Exposure to fibrous titanium dioxide whiskers or amosite increased in total protein and expression of cytokine-induced neutrophil chemoattractant / growth-regulated gene, but exposure to nonfibrous titanium dioxide did not.…”