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D B Warheit

Publications and source records attributed to D B Warheit.

At least 19 recordsLinked to original sources
PubMed2006

Pulmonary toxicity screening studies in male rats with TiO2 particulates substantially encapsulated with pyrogenically deposited, amorphous silica.

The aim of this study was to evaluate the acute lung toxicity in rats of intratracheally instilled TiO2 particles that have been substantially encapsulated with pyrogenically deposited, amorphous silica. Groups of rats were intratracheally instilled either with doses of 1 or 5 mg/kg of hydrophilic Pigment A TiO2 particles or doses of 1 or 5 mg/kg of the following control or particle-types: 1) R-100 TiO2 particles (hydrophilic in nature); 2) quartz particles, 3) carbonyl iron particles. Phosphate-buffered saline (PBS) instilled rats served as additional controls. Following exposures, the lungs of PBS and particle-exposed rats were evaluated for bronchoalveolar lavage (BAL) fluid inflammatory markers, cell proliferation, and by histopathology at post-instillation time points of 24 hrs, 1 week, 1 month and 3 months. The bronchoalveolar lavage results demonstrated that lung exposures to quartz particles, at both concentrations but particularly at the higher dose, produced significant increases vs. controls in pulmonary inflammation and cytotoxicity indices. Exposures to Pigment A or R-100 TiO2 particles produced transient inflammatory and cell injury effects at 24 hours postexposure (pe), but these effects were not sustained when compared to quartz-related effects. Exposures to carbonyl iron particles or PBS resulted only in minor, short-term and reversible lung inflammation, likely related to the effects of the instillation procedure. Histopathological analyses of lung tissues revealed that pulmonary exposures to Pigment A TiO2 particles produced minor inflammation at 24 hours postexposure and these effects were not significantly different from exposures to R-100 or carbonyl iron particles. Pigment A-exposed lung tissue sections appeared normal at 1 and 3 months postexposure. In contrast, pulmonary exposures to quartz particles in rats produced a dose-dependent lung inflammatory response characterized by neutrophils and foamy (lipid-containing) alveolar macrophage accumulation as well as evidence of early lung tissue thickening consistent with the development of pulmonary fibrosis. Based on our results, we conclude the following: 1) Pulmonary instillation exposures to Pigment A TiO2 particles at 5 mg/kg produced a transient lung inflammatory response which was not different from the lung response to R-100 TiO2 particles or carbonyl iron particles; 2) the response to Pigment A was substantially less active in terms of inflammation, cytotoxicity, and fibrogenic effects than the positive control particle-type, quartz particles. Thus, based on the findings of this study, we would expect that inhaled Pigment A TiO2 particles would have a low risk potential for producing adverse pulmonary health effects.

Journal Article↗
PubMed2005

Biodegradability of para-aramid respirable-sized fiber-shaped particulates (RFP) in human lung cells.

Using both in vivo (inhalation) and in vitro (cell culture) studies, we previously reported that p-aramid respirable fibers (RFP--defined as respirable-sized fiber-shaped particulates) are biodegraded in lungs and lung cells of rats following exposures. The current studies were undertaken to determine whether shortening mechanisms of p-aramid RFP biodegradability are also operative in human lung cells. Cultures of human A549 lung epithelial cells (A549), primary alveolar macrophages (HBAL) (collected via bronchoalveolar lavage [BAL]) from volunteers), and co-cultures (Co) of the A549 and HBAL were incubated with p-aramid RFP for either 1 h, 1 day, or 1 week to assess RFP shortening. Lengths of RFP were measured using scanning electron microscopy (SEM) following fixation, digestion of culture tissue components, and processing. Similar to findings using rat lung cells, only slight RFP shortening was measured in A549 cultures at 1-day and 1-week post-incubation. More importantly, in HBAL and Co groups, greater transverse cleavage of p-aramid RFP was measured at 1-day and 1-week postexposure compared to 1-h HBAL or Co groups, or in any A549 groups. In contrast, cellulose RFP, a biopersistent reference control fiber, were not measurably shortened under similar circumstances. Second, p-aramid RFP were incubated either with phosphate-buffered saline (PBS), or acellular BAL fluids from human volunteers or rats and processed for SEM analysis of RFP lengths. Mean lengths of p-aramid RFP incubated with human or rat BAL fluids were substantially decreased compared to PBS. Similar to our findings with rat lung cells, components of human lung fluids coat the p-aramid RFP as a prerequisite for subsequent enzymatic cleavage by human phagocytic lung cells and this finding reinforces the concept that inhaled p-aramid RFP are likely to be biodegradable in the lungs of humans.

Administration, Inhalation↗
PubMed2005

Comparative pulmonary toxicity inhalation and instillation studies with different TiO2 particle formulations: impact of surface treatments on particle toxicity.

Most pigment-grade titanium dioxide (TiO(2)) samples that have been tested in pulmonary toxicity tests have been of a generic variety-i.e., generally either uncoated particles or TiO(2) particles containing slightly hydrophilic surface treatments/coatings (i.e., base TiO(2)). The objectives of these studies were to assess in rats, the pulmonary toxicity of inhaled or intratracheally instilled TiO(2) particle formulations with various surface treatments, ranging from 0-6% alumina (Al(2)O(3)) or alumina and 0-11% amorphous silica (SiO(2)). The pulmonary effects induced by TiO(2) particles with different surface treatments were compared to reference base TiO(2) particles and controls. In the first study, groups of rats were exposed to high exposure (dose) concentrations of TiO(2) particle formulations for 4 weeks at aerosol concentrations ranging from 1130-1300 mg/m(3) and lung tissues were evaluated by histopathology immediately after exposure, as well as at 2 weeks and 3, 6, and 12 months postexposure. In the second study, groups of rats were intratracheally instilled with nearly identical TiO(2) particle formulations (when compared to the inhalation study) at doses of 2 and 10 mg/kg. Subsequently, the lungs of saline-instilled and TiO(2)-exposed rats were assessed using both bronchoalveolar (BAL) biomarkers and by histopathology/cell proliferation assessment of lung tissues at 24 h, 1 week, 1 and 3 months postexposure. The results from these studies demonstrated that for both inhalation and instillation, only the TiO(2) particle formulations with the largest components of both alumina and amorphous silica surface treatments produced mildly adverse pulmonary effects when compared to the base reference control particles. In summary, two major conclusions can be drawn from these studies: (1) surface treatments can influence the toxicity of TiO(2) particles in the lung; and (2) the intratracheal instillation-derived, pulmonary bioassay studies represent an effective preliminary screening tool for inhalation studies with the identical particle-types used in this study.

Administration, Inhalation↗
PubMed2003

Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats.

The aim of this study was to evaluate the acute lung toxicity of intratracheally instilled single-wall carbon nanotubes (SWCNT) in rats. The lungs of rats were instilled either with 1 or 5 mg/kg of the following control or particle types: (1) SWCNT, (2) quartz particles (positive control), (3) carbonyl iron particles (negative control), (4) phosphate-buffered saline (PBS) + 1% Tween 80, or (5) graphite particles (lung tissue studies only). Following exposures, the lungs of PBS and particle-exposed rats were assessed using bronchoalveolar lavage (BAL) fluid biomarkers and cell proliferation methods, and by histopathological evaluation of lung tissue at 24 h, 1 week, 1 month, and 3 months postinstillation. Exposures to high-dose (5 mg/kg) SWCNT produced mortality in ~15% of the SWCNT-instilled rats within 24 h postinstillation. This mortality resulted from mechanical blockage of the upper airways by the instillate and was not due to inherent pulmonary toxicity of the instilled SWCNT particulate. Exposures to quartz particles produced significant increases versus controls in pulmonary inflammation, cytotoxicity, and lung cell parenchymal cell proliferation indices. Exposures to SWCNT produced transient inflammatory and cell injury effects. Results from the lung histopathology component of the study indicated that pulmonary exposures to quartz particles (5 mg/kg) produced dose-dependent inflammatory responses, concomitant with foamy alveolar macrophage accumulation and lung tissue thickening at the sites of normal particle deposition. Pulmonary exposures to carbonyl iron or graphite particles produced no significant adverse effects. Pulmonary exposures to SWCNT in rats produced a non-dose-dependent series of multifocal granulomas, which were evidence of a foreign tissue body reaction and were nonuniform in distribution and not progressive beyond 1 month postexposure (pe). The observation of SWCNT-induced multifocal granulomas is inconsistent with the following: (1) lack of lung toxicity by assessing lavage parameters, (2) lack of lung toxicity by measuring cell proliferation parameters, (3) an apparent lack of a dose response relationship, (4) nonuniform distribution of lesions, (5) the paradigm of dust-related lung toxicity effects, (6) possible regression of effects over time. In addition, the results of two recent exposure assessment studies indicate very low aerosol SWCNT exposures at the workplace. Thus, the physiological relevance of these findings should ultimately be determined by conducting an inhalation toxicity study.

Alkaline Phosphatase↗
PubMed2003

Pulmonary toxicity studies in rats with triethoxyoctylsilane (OTES)-coated, pigment-grade titanium dioxide particles: bridging studies to predict inhalation hazard.

The aim of this study was to assess and compare the acute lung toxicities of intratracheally instilled hydrophobic relative to hydrophilic surface-coated titanium dioxide (TiO(2)) particles using a pulmonary bridging methodology. In addition, the results of these instillation studies were bridged with data previously generated from inhalation studies with hydrophilic, pigment-grade (base) TiO(2) particles, using the base, pigment-grade TiO(2) particles as the inhalation/instillation bridge material. To conduct toxicity comparisons, the surface coatings of base pigment-grade TiO(2) particles were made hydrophobic by application of triethoxyoctylsilane (OTES), a commercial product used in plastics applications. For the bioassay experimental design, rats were intratracheally instilled with 2 or 10 mg/kg of the following TiO(2) particle-types: (1) base (hydrophilic) TiO(2) particles; (2) TiO(2) with OTES surface coating; (3) base TiO(2) with Tween 80; or (4) OTES TiO(2) with Tween 80. Saline instilled rats served as controls. Following exposures, the lungs of sham- and TiO(2)-exposed rats were assessed both using bronchoalveolar lavage (BAL) biomarkers and by histopathology of lung tissue at 24 hours, 1 week, 1 month, and 3 months post exposure. The results demonstrated that only the base, high-dose (10 mg/kg) pigment-grade TiO(2) particles and those with particle-types containing Tween 80 produced a transient pulmonary inflammatory response, and this was reversible within 1 week postexposure. The authors conclude that the OTES hydrophobic coating on the pigment-grade TiO(2) particle does not cause significant pulmonary toxicity.

Animals↗
PubMed2002

Biodegradability of inhaled p-aramid respirable fiber-shaped particulates (RFP): mechanisms of RFP shortening and evidence of reversibility of pulmonary lesions.

These studies elucidated mechanisms of inhaled p-aramid respirable fiber-shaped particulates (RFP) biodegradation in the lungs of exposed rats and hamsters. We postulate that lung fluids coat/activate inhaled p-aramid RFP which deposits in the lung and promote enzymatic attack and consequent shortening. p-Aramid or cellulose (biopersistent control) RFP were instilled into the lungs of rats and the lungs digested 24 h later using two different (KOH or enzymatic) digestion techniques. In vivo, the enzyme but not the KOH solution produced shortening of p-aramid but not cellulose RFP recovered from the lungs. For in vitro studies, the two RFP-types were incubated with BAL fluids and underwent simulated digestions; also rat lung epithelial cells, macrophages or co-cultures were incubated with p-aramid and digested at 1, 24, or 168 h postexposure. The results of in vitro acellular studies demonstrated that only p-aramid RFP incubated in BAL fluids and digested by the enzyme method were shortened. In vitro cellular studies demonstrated a shortening of p-aramid RFP in macrophages and co-cultures but not in lung epithelial cells at 24 h and 1 week postexposure. These results demonstrate that lung fluids coat and catalyze the p-aramid RFP as a prelude for shortening and describe a likely mechanism for the biodegradability of inhaled p-aramid RFP in the lungs of exposed animals.

Administration, Inhalation↗
PubMed2001

Biodegradability of inhaled para-aramid respirable-sized fiber-shaped particulates: mechanistic in vivo and in vitro studies.

Biopersistence represents an important health-related issue in fiber toxicology. These studies were undertaken to elucidate the mechanism(s) through which inhaled p-aramid respirable-sized fiber-shaped particulates (RFP) are biodegraded in the lungs of exposed rats and hamsters. Previously, we and others have reported that, following deposition in the lung, long p-aramid RFPs are cleaved into shorter fibrous fragments. To investigate the mechanisms of RFP biodegradation, we have postulated that lung fluids coat/activate p-aramid RFP following deposition in the alveolar regions of the lung, thus predisposing the RFP to enzymatic attack and consequent shortening. This process enhances the rate of clearance of the inhaled RFP. To test this hypothesis, we have conducted both in vivo and in vitro cellular and noncellular investigations. First, p-aramid or cellulose RFP were instilled into the lungs of rats and the lungs were digested 24 h postexposure using two different digestion techniques: (1) a conventional ethanolic KOH method and (2) an enzymatic method that simulates the action of lung enzymes. Cellulose RFP were utilized as a control organic fiber-type that is known to be biopersistent. The results demonstrated that the enzymatic but not the KOH method resulted in transverse cleavage of the p-aramid RFP; the lengths of cellulose RFP recovered from rat lungs were not reduced by either method. Next, standardized preparations of p-aramid RFP or cellulose RFP were incubated with saline or lung fluids and then processed by one of two tissue digestion techniques. Mean lengths of p-aramid RFP incubated with saline and processed with KOH or the enzyme method were not found to be altered. Indeed, only the preparation of p-aramid RFP that had been incubated with bronchoalveolar lavage (BAL) fluids and processed with the enzyme solution resulted in cleavage of p-aramid RFP. Moreover, when the BAL fluids were autoclaved to denature proteins, the length dimensions of p-aramid RFP were intermediate between saline controls and RFP incubated with normal BAL fluids and processed via the enzymatic technique. In contrast to the in vitro noncellular studies with p-aramid RFP, the combination of BAL fluid incubation and enzyme digestion method had no measurable effect on shortening of cellulose RFP, indicating that the results with p-aramid were specific to that fiber-type. In a final set of in vitro cellular studies, cultures of rat lung epithelial cells, alveolar macrophages, or co-cultures of epithelial cells and macrophages were treated with p-aramid RFP for 1 h, 1 day, or 1 week to determine whether RFP shortening occurs directly in the phagocytic cells. The lengths of fibrils were measured using scanning electron microscopy techniques. The results demonstrated that (1) no shortening occurred in the epithelial cell cultures at any time point; however, (2) in the macrophage and cocultures, cleavage of p-aramid RFP was observed at 1 day and 1 week postexposure. Our data suggest that components of lung fluids coat and catalyze the p-aramid RFP as a prerequisite for enzymatic cleavage. This process could play a significant role in facilitating the transverse cleavage or shortening of inhaled p-aramid RFP in the lungs of exposed rats and hamsters.

Administration, Inhalation↗
PubMed2001

p-Aramid RFP do not induce chromosomal aberrations in a standardized in vitro genotoxicity assay using human lymphocytes.

Genotoxicity evaluations have been proposed as regulatory requirements for establishing German MAK values for inhaled fibrous dusts. The objective of this in vitro assay was to assess the potential for para-aramid (p-aramid) respirable-sized, fiber-shaped particulates (RFP) to induce chromosomal aberrations in cultured human peripheral blood lymphocytes without metabolic activation. The highest concentration tested in this assay was limited by the physical characteristics of p-aramid RFP. The test substance was suspended in fully supplemented RPMI culture medium with 1% Pluronic F68. All dosing was achieved using a dosing volume of 90% (900 microl/ml), and the vehicle control cultures were treated with 900 microl/ml of fully supplemented RPMI culture medium with 1% Pluronic F68. In the chromosomal aberrations assay, the treatments were either 3 or 19 h without metabolic activation. Cultures were harvested 22 h from the initiation of treatment. Replicated cultures of human whole blood lymphocytes were incubated with p-aramid RFP concentrations of 6.30, 12.6, 25.2, 50.4, 101, 201, and 401 microg/ml. Cultures treated with concentrations to 50.4 microg/ml for 3 h and 6.30, 12.6, 25.2, and 201 microg/ml for 19 h were analyzed for structural and numerical chromosomal aberrations. No significant increase in cells with chromosomal aberrations, polyploidy, or endoreduplication was observed in the cultures analyzed. The results demonstrated that p-aramid RFP was negative for inducing chromosomal aberrations in cultured human peripheral blood lymphocytes without metabolic activation. In addition, we conclude that the utility of these tests for evaluating the genotoxicity of fibrous or particulate materials is questionable.

Adult↗
PubMed2001

Potential pulmonary effects of man-made organic fiber (MMOF) dusts.

In the first half of the twentieth century epidemiologic evidence linked elevated incidences of pulmonary fibrosis and cancer with inhalation of chrysotile and crocidolite asbestos, a family of naturally occurring inorganic fibrous materials. As the serpentine and amphibole forms of asbestos were phased out, synthetic vitreous fibers (SVFs; fiber glass, mineral wool, and refractory fiber) became increasingly utilized, and concerns were raised that they too might cause adverse health effects. Extensive toxicological research on SVFs has demonstrated that their pulmonary effects are directly related to fiber dose in the lung over time. This is the result of deposition (thin fibers deposit in the lower lung more efficiently than thick fibers) and lung-persistence ("biopersistence" is directly related to fiber length and inversely related to dissolution and fragmentation rates). In rat inhalation studies, asbestos was determined to be 7- to 10-fold more biopersistent in the lung than SVFs. Other than its effect on biopersistence, fiber composition did not appear to play a direct role in the biological activity of SVFs. Recently, the utilization of man-made organic fibers (MMOFs) (also referred to by some as synthetic organic fibers) has increased rapidly for a variety of applications. In contrast to SVFs, research on the potential pulmonary effects of MMOFs is relatively limited, because traditionally MMOFs were manufactured in diameters too thick to be respirable (inhalable into the lower lung). However, new developments in the MMOF industry have resulted in the production of increasingly fine-diameter fibers for special applications, and certain post-manufacturing processes (e.g., chopping) generate respirable-sized MMOF dust. Until the mid-1990s, there was no consistent evidence of human health affects attributed to occupational exposure to MMOFs. Very recently, however, a unique form of interstitial lung disease has been reported in nylon flock workers in three different plants, and respirable-sized nylon shreds (including fibers) were identified in workplace air samples. Whether nylon dust or other occupational exposures are responsible for the development of lung disease in these workers remains to be determined. It is also unknown whether the biological mechanisms that determine the respirability and toxicity of SVFs apply to MMOFs. Thus, it is appropriate and timely to review the current data regarding MMOF workplace exposure and pulmonary health effects, including the database on epidemiological, exposure assessment, and toxicology studies.

Administration, Inhalation↗
PubMed2001

Man-made respirable-sized organic fibers: what do we know about their toxicological profiles?

Man-made organic fibers (MMOFs) have been manufactured for over 50 years. Until recently, there have been few concerns raised regarding the safety of organic fiber dusts. This is due, in large part, to the perception that the dimensions of most, if not all, of these products were too large to be inhaled into the distal lungs of workers, i.e., were considered to be nonrespirable. A brief review of some of the issues related to organic fiber toxicology is presented herein. Some of the organic fiber-types used in commerce are identified and some fundamental tenets of fiber toxicology are discussed. In addition, the European Union, in their recent consideration for banning chrysotile asbestos fibers, evaluated some organic fiber substitutes and compared them to the hazards of asbestos. A brief review of their conclusions is described below. Finally, the results of some recent studies assessing the mechanisms of biodegradability of para-aramid respirable-sized, fiber-shaped particulates (RFP) are presented. Para-aramid (p-aramid) RFP are the most extensively-studied respirable organic fiber-type and RFP is the new term which describes respirable-sized organic fibers (ECETOC, 1996) (1). The results of these studies provide clues regarding the mechanism(s) of p-aramid RFP shortening in the lungs of exposed animals, and may be relevant for humans.

Administration, Inhalation↗
PubMed2001

Inhaled amorphous silica particulates: what do we know about their toxicological profiles?

The International Agency for Research on Cancer (IARC) recently published a monograph on the evaluation of carcinogenic risks to humans of exposure to crystalline and amorphous silica particles. The IARC Working Group concluded that crystalline silica, in the form of quartz or cristobalite, from occupational sources posed a carcinogenic risk to humans (Category 1). IARC also determined that amorphous silica particles were not classifiable as to its carcinogenicity to humans (Category 3). With regard to amorphous silica, the evaluation was based primarily on the lack of toxicological and epidemiological data for these materials and this was noted in the IARC document. This manuscript is designed to provide a brief summary of the limited inhalation toxicity database related to amorphous silica particulates and to cite a few studies wherein the pulmonary toxicological effects of inhaled crystalline and amorphous silica particles were compared.

Air Pollutants, Occupational↗
PubMed2000

Biodegradability of inhaled p-aramid respirable fibre-shaped particulates: representative of other synthetic organic fibre-types?

OBJECTIVES: Biopersistence, or alternatively, biodegradability (i.e., low biopersistence) represents an important concept in fibre toxicology. The studies described below were undertaken to investigate the mechanisms through which inhaled para-aramid (p-aramid) respirable, fibre-shaped particulates (RFP) are biodegraded in the lungs of exposed rats and hamsters; in contrast, cellulose fibres, another organic fibre-type, are known to be biopersistent. To investigate the mechanisms of RFP biodegradation, we have hypothesized that lung fluids activate p-aramid RFP following deposition, and the RFP are then vulnerable to enzymatic attack in the lungs. METHODS: To test the hypothesis, p-aramid RFP or cellulose RFP were instilled into the lungs of rats and the lungs digested 24 h post-exposure using two different digestion techniques: (1) a conventional ethanolic KOH method, and (2) an enzymatic method which simulates lung enzymes. RESULTS: The enzymatic but not the KOH method artificially cleaved the p-aramid RFP recovered from rat lungs. Next, p-aramid RFP or cellulose RFP were incubated with saline or lung fluids and then processed by one of the two digestion techniques. Mean lengths of p-aramid RFP processed with KOH and evaluated by SEM were 13.4 microm; in contrast, mean lengths of p-aramid RFP samples, incubated in lung fluids and treated with the enzymatic method were 8.8 microm. The enzymatic digestion method had no discernible effect on shortening of cellulose RFP, indicating that the results with p-aramid were specific. CONCLUSIONS: Our data indicate that components of lung fluids coat and catalyze the p-aramid, thereby predisposing the RFP to enzymatic cleavage. This could play a significant mechanistic role in facilitating the transverse cleavage or shortening of inhaled p-aramid RFP in the lungs of exposed rats and hamsters.

Air Pollutants, Occupational↗
PubMed1997

Inhalation of high concentrations of low toxicity dusts in rats results in impaired pulmonary clearance mechanisms and persistent inflammation.

This study was carried out to assess the time course of pulmonary clearance impairment and persistence of inflammation following high-dose inhalation exposures to titanium dioxide (TiO2) or carbonyl iron (CI) particles. Male rats were exposed to air, TiO2 or CI particles 6 hr/day, 5 days/week, for 4 weeks at concentrations of 5, 50, and 250 mg/m3 and evaluated at selected intervals through 6 months postexposure. Indices of pulmonary inflammation as well as alveolar macrophage clearance functions (i.e., morphology, in vivo and in vitro phagocytosis, and chemotaxis), cell proliferation, and histopathology endpoints were measured at several postexposure time periods through 6 months. In addition, amounts of TiO2 or CI in lungs and tracheobronchial lymph nodes were measured to allow an evaluation of particle clearance and translocation patterns. Four-week exposures to TiO2 or CI particles at concentrations of 250 mg/m3 resulted in lung burdens of 12 mg titanium and 17 mg iron, respectively, with particle retention half-times ranging from 68 days for 5 mg/m3 TiO2 to approximately 330 days for 250 mg/m3. The impact of this TiO2 dust load and similar lung burdens of CI particles produced a sustained pulmonary inflammatory response measured through a period of 3-6 months postexposure concomitant with increases in BrdU cell labeling of terminal airway and pulmonary parenchymal cells. The impairment of particle clearance mechanisms was accounted for by deficits in in vitro phagocytic and chemotactic potential of alveolar macrophages recovered from the lungs of high-dose, TiO2- or CI-exposed rats. Free granular pigment (TiO2 or CI) was present on the hypertrophic mucosal surfaces of bronchioles and bronchi, and particle-laden macrophages, found individually, were numerous throughout alveoli and within lymphoid tissues immediately after exposure. Aggregates of particle-laden macrophages were present within alveoli and alveolar ducts from 1 week postexposure through the entire 6-month recovery period. Macrophage accumulations increased in size and number from 1 week through 1 month postexposure and then appeared to remain constant through the remaining 5-month postexposure period. Minimal cellular hypertrophy and hyperplasia were evident at alveolar duct bifurcations adjacent to macrophage aggregates, and this effect was most prominent at 3 to 6 months postexposure. The results of this study clearly demonstrate that exposure to high dust concentrations of two different innocuous particle types produced sustained pulmonary inflammation, enhanced proliferation of pulmonary cells, impairment of particle clearance, deficits in macrophage function, and the appearance of macrophage aggregates at sites of particle deposition. In addition, the mass deposition rate determination appears to be a less sensitive indicator of "overload" when compared to biomarkers of pulmonary toxicity, such as macrophage function and cellular inflammation and proliferation indices.

Administration, Inhalation↗
PubMed1997

Lung proliferative and clearance responses to inhaled para-aramid RFP in exposed hamsters and rats: comparisons with chrysotile asbestos fibers.

This study compared pulmonary effects of para-aramid respirable-sized, fiber-shaped particles (RFP) (p-aramid fibrils) and chrysotile asbestos fiber exposures in rats. Additional p-aramid inhalation studies were conducted in hamsters to compare species responses. The hamster results are preliminary. The parameters studied were clearance/biopersistence of inhaled p-aramid RFP or size-separated asbestos fibers as well as pulmonary cell proliferation and inflammation indices after 2-week inhalation exposures. Rats were exposed nose only to chrysotile asbestos fibers at concentrations of 459 and 782 fibers/ml or to p-aramid RFP at 419 or 772 fibrils/ml. Hamsters were exposed whole body to p-aramid RFP at concentrations of 358 and 659 fibrils/ml. Subsequently, animals were assessed immediately (time 0) as well as 5 days (10 days for hamsters), 1, 3, 6, and 12 months postexposure. Lung burdens for the p-aramid-exposed rats were 4.8 x 10(7) and 7.6 x 10(7) fibrils/lung, with similar numbers of chrysotile fibers > 5 microns recovered from the lungs of asbestos-exposed rats. In comparison, 1.4 x 10(6) fibrils/lung were recovered in the high-dose hamster group. Biopersistence studies in p-aramid-exposed rats and hamsters demonstrated an initial increase (relative to time 0) in retained p-aramid fibrils during the first month postexposure, which indicated breakage or shortening of inhaled fibrils. This result was associated with a progressive reduction, and increased residence time in the lung, in the mean lengths of the fibrils, which signified biodegradability of inhaled p-aramid fibrils in both species. In contrast, clearance of short chrysotile asbestos fibers was rapid, but clearance of the long chrysotile fibers was slow or insignificant, as evidenced by a progressive increase over time in the mean lengths of fibers recovered from the lungs of exposed rats. Two-week, high-dose exposures to p-aramid in both rats and hamsters produced transient increases in pulmonary inflammatory and cell proliferative responses. In contrast, inhalation of size-separated chrysotile asbestos fibers in rats produced persistent increases in cell labeling indices of airway, alveolar, and subpleural cells measured through a period of 1 to 3 months postexposure. These results suggest that inhaled p-aramid RFP are biodegradable in the lungs of exposed rats and hamsters. In contrast, exposures to chrysotile asbestos fibers in rats resulted in a selective pulmonary retention of long chrysotile fibers.

Administration, Inhalation↗
PubMed1996

Pulmonary effects in rats inhaling size-separated chrysotile asbestos fibres or p-aramid fibrils: differences in cellular proliferative responses.

This study was designed to compare the pulmonary cellular proliferative effects of inhaled, size-separated preparations of chrysotile asbestos fibres with similar aerosol fibre concentrations of para-aramid fibrils. Following fibre preparation, rats were exposed for 2 weeks to aerosols of p-aramid fibrils or chrysotile asbestos fibres at design fibre concentrations of 750 and 400 f/cc. Two week exposures to p-aramid fibrils produced transient pulmonary inflammatory and cell labeling responses in terminal bronchiolar and subpleural regions. Similar to p-aramid, exposure to chrysotile produced a transient increase in neutrophils. In contrast, however, substantial increases compared to controls in pulmonary cell labeling indices were measured on terminal bronchiolar, parenchymal, subpleural, and mesothelial surfaces immediately after exposure, and some increases persisted for 3 months postexposure. In complementary studies we demonstrated that p-aramid is biodegradable in the lungs of exposed rats; in contrast, the clearance of long chrysotile fibres was slow or insignificant, resulting in a pulmonary retention of long chrysotile asbestos fibres. The dimensional changes of asbestos fibres as well as the pulmonary cell labeling data indicate that chrysotile asbestos fibres may produce greater long-term pulmonary effects when compared to inhaled para-aramid fibrils.

Administration, Inhalation↗
PubMed1996

Subchronic inhalation of high concentrations of low toxicity, low solubility particulates produces sustained pulmonary inflammation and cellular proliferation.

Long-term inhalation exposures to high dust burdens can produce tumors or proliferative keratin cysts in the lungs of exposed rats. We hypothesized that dust burdens which overwhelm lung clearance mechanisms are associated with sustained cellular proliferation responses and pulmonary inflammation. Male rats were exposed to titanium dioxide (TiO2) or carbonyl iron (CI) particles for 4 weeks at concentrations of 5, 50 and 250 mg/m3. Following completion of exposure, the lungs of sham and dust-exposed animals were lavaged or assessed for cell proliferation or particle clearance immediately after, as well as 1 week, 1, 3 and 6 months postexposure. Exposures to TiO2 or CI at 250 mg/m3 produced persistent pulmonary inflammatory responses and increased BrdU labeling of terminal airway and pulmonary parenchymal cells. The results of this study clearly demonstrate that exposure to excessive dust concentrations of two low toxicity, low solubility particle-types produced sustained pulmonary inflammation, enhanced pulmonary cell labeling, impairment of particle clearance, and the development of pulmonary lesions.

Administration, Inhalation↗
PubMed1996

Time course of chemotactic factor generation and neutrophil recruitment in the lungs of dust-exposed rats.

The time course of neutrophil recruitment into the lung, neutrophilic chemotactic activity, and the gene expression of neutrophilic chemokines by lavaged cells was determined after intratracheal instillation of various particles. Low-toxicity, low-solubility dusts such as titanium dioxide (TiO2) particles, as well as fibrogenic crystalline silica and nonfibrogenic amorphous silica particles were instilled into the lungs of rats. Results showed that all three dusts induced neutrophilic inflammation as early as 5 h after exposure. Both crystalline and amorphous silica elicited higher degrees of pulmonary inflammation when compared with TiO2 particles. Maximal infiltration of neutrophils into the lungs occurred 5 to 6 h after intratracheal instillation of the dusts. The inflammatory response was transient for TiO2 and amorphous silica, i.e., evident at 2 days after exposure but not different from controls at 10 days after exposure. In contrast, inflammatory effects were sustained through a 10-day period following exposures to crystalline silica. Chemotactic activity for neutrophils was detected directly in bronchoalveolar lavage (BAL) fluids of dust-exposed rats within 2 h after exposure, but not in the BAL fluids of saline- or unexposed rats. The chemotactic activity was correlated with the influx and disappearance of neutrophils into alveolar regions of the lung in TiO2- and amorphous silica-exposed rats. The mRNA expression of two known neutrophil chemotactic cytokines in BAL cells, macrophage inflammatory protein-2 (MIP-2) and KC, also correlated with chemotactic activity and acute and pulmonary inflammatory responses. MIP-2 mRNA was expressed prior to the detection of chemotactic activity in BAL fluids. However, the mRNA expressions of MIP-2 and KC were transient for rats that were exposed to these dusts as KC and MIP-2 message were no longer detectable in BAL cells after 2 days of recovery. Although both neutrophilic chemotactic activity and inflammation remained prominent 10 days after exposure to crystalline silica, MIP-2 expression could not be detected in BAL cells. Thus, we conclude that MIP-2 is likely to be only one of several cytokines involved in mediating neutrophilic inflammation following a single instillation of crystalline silica.

Animals↗