CIIT Centers for Health Research, P.O. Box 12137, Research Triangle Park, North Carolina 27709-2137
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ABSTRACT |
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Key Words: vitreous fibers; mineral fibers; tumorigenesis; lung; pleural compartment; inflammatory response.
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INTRODUCTION |
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The sequelae of natural mineral fiber exposure in humans have been well documented and comprise a variety of lung and pleural responses, including inflammation, fibrosis, and cancer. Similarly, lung and pleural responses of rodents to inhaled fibers include a generalized inflammation as an immediate consequence, and, with prolonged exposure, fibrosis and cancer of the lung and pleura may develop. It has been suggested that effects in the pleural compartment may be mediated through soluble factors elaborated in the lung rather than by translocated fibers (Adamson et al., 1993). Although this may be true for effects on pleural mesothelial cells adjacent to the alveoli, the physical presence of fibers appears to be necessary for the observed biological pleural responses at sites distant from the lung surface. This conclusion is supported by the translocation of inhaled fibers to the pleural space of humans (Sebastien et al., 1980
) and rodents (Gelzleichter et al., 1996a
), the temporal separation of lung and pleural inflammatory responses following fiber inhalation, and by the induction of inflammation, fibrosis, and mesothelioma following intracavitary injection of fibers (Davis et al., 1991
).
Rats and hamsters demonstrate a differential response to chronic inhalation of the very durable refractory ceramic fiber RCF-1 (Mast et al., 1994). Rats had a significant increase in lung tumors and a low incidence of mesothelioma, whereas hamsters had a high incidence of mesothelioma but no significant increase in lung tumors. Hamsters also developed a high incidence of pleural fibrosis and mesothelioma, but not cancer of the lung, following the inhalation of amosite, an amphibole asbestos fiber (McConnell et al., 1999
), whereas rats developed tumors at both sites (Davis et al., 1986
). The basis for this species difference in response remains unclear, but the possibility that it is partly based on dosimetry considerations has been explored. Our previous work has shown that subchronic inhalation of RCF-1 fibers by rats and hamsters leads to biological responses in the lung that are similar in kind (cell proliferation, inflammation, and fibrosis) and magnitude, whereas pleural responses were greater in hamsters than in rats. Analysis of the fibers translocating to the pleural space showed that total fiber burden adjusted for surface area was similar in rats and hamsters but that there was a significant accumulation of fibers greater than 5 µm long in the hamster (Gelzleichter et al., 1999
).
MMVF 10a is a fibrous glass preparation that is a size-selected fraction, with slightly thinner and longer fiber dimensions, of the material used in a chronic inhalation study with rats. In that study, pulmonary fiber burdens were examined and the fiber dimensions characterized. Chronic inhalation of MMVF 10 did not result in either pulmonary fibrogenic or carcinogenic outcomes in rats (Hesterberg et al., 1993). The pulmonary responses of rats were also studied, following subchronic inhalation of MMVF 10. Results from that study demonstrated that pulmonary inflammation, increased lung-cell proliferation, and decrements in lung clearance of particles in rats exposed to MMVF 10 (Hesterberg et al., 1996a
). More recent studies by the same group entailed the chronic and subchronic inhalation exposure of hamsters to MMVF 10a and the examination of both lung and pleural biological responses. As in the study with rats, MMVF10a-exposed hamsters showed no pulmonary fibrotic or neoplastic responses to the inhalation of these fibers but did exhibit pulmonary inflammation, nonlinear lung burdens, and pleural mesothelial-cell proliferation (Hesterberg et al., 1999
; McConnell et al., 1999
).
In the present study we chose MMVF10a to study because it is a soluble fiber that doesnt lead to fibroproliferative changes but is known to induce pulmonary and pleural inflammation in high-dose exposure scenarios. It should not be forgotten that inflammation of lung and pleura is an important fiber-induced disease state. Our interest has centered on the differences in pleural responses between rat and hamster, and, to date, the rat pleural response to a low-toxicity fiberglass fiber has not been characterized. Moreover, it is of interest to determine whether a component of the pleural toxicity of a fiber is in part determined by the ability to translocate to the pleural compartment. We undertook the present study to determine whether the number and size of inhaled MMVF 10a fibers translocating to the pleural compartment are determinants of the pleural responses in rats and hamsters and to compare the pleural responses in these species.
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MATERIALS AND METHODS |
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Exposures.
Rats and hamsters were exposed to an aerosol of MMVF10a (obtained from the North American Insulation Manufacturers Association, NAIMA) generated as previously described (Gelzleichter et al., 1996a), in open-end, nose-only exposure tubes (Battelle Memorial Institute, WA). Fiber concentrations were continuously monitored using light scatter (RAM, Monitoring Instruments for the Environment, Inc., Billerica, MA). The nominal target mass concentration was 45 mg/m3. Actual fiber mass values were determined from samples captured on open-faced, 0.2 µm polycarbonate filters (Gelman Sciences, Ann Arbor, MI). Table 1
shows the time points and analyses performed. Animals were exposed for 4 h on 5 consecutive days each week for a maximum of 12 consecutive weeks. Air-control and fiber-exposed groups of animals were killed following 4, or 12 weeks of exposure or after a recovery period of 12 weeks. A group of cage-control animals was also sacrificed at the beginning of the experiment to provide background fiber levels.
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BrdU labeling.
Animals to be used for cellular and biochemical analyses were surgically implanted with BrdU-filled (10 mg/ml, Sigma Chemical Co., St. Louis, MO) mini-osmotic pumps (5 µl/h, Alza Corp., Palo Alto, CA) at the end of 4 or 12 weeks of exposure or 12 weeks of recovery. For all time points, these animals were euthanized and lavaged (see below) 6 days after the exposure/recovery interval, inclusive of 3 days labeling.
Pulmonary and pleural free cells.
Six animals, per time point, from each group were anesthetized with pentobarbital and exsanguinated. Bronchoalveolar (BAL) and pleural (PL) lavages were performed using sterile Dulbeccos phosphate-buffered solution (PBS) (Gibco Laboratories, Grand Island, NY) as previously described (Gelzleichter et al., 1996b). Rat and hamster lungs were lavaged twice with 5 and 4 ml, respectively. Pleurae were lavaged twice with 4 (rat) and 3 ml (hamster) PBS. For both pleural and lung lavages, lavage samples were pooled and centrifuged at 200 x g for 10 min at 4°C. Supernatants were separated from the cell pellets and kept on ice. The cell pellets were resuspended in Hams F12 media (Gibco) supplemented with 10% fetal bovine serum (FBS, Hyclone, Logan, UT). Cell densities in these suspensions were determined using a Coulter particle counter (Coulter ZM, Coulter Electronics, Marietta, GA). Differential cell counts were performed on cytospin preparations stained with Wright Geimsa Diff-Quik (Leukostat, Fisher Diagnostics) as previously described (Gelzleichter et al., 1996b
).
Mesothelial cell proliferation.
Following lavage, the lungs and thoracic cavity were fixed in situ with 10% phosphate-buffered formaldehyde. After 24 h the tissues were rinsed and stored in 70% ethanol. Sections of the left intracostal parietal wall, diaphragm, and left lung were cut and embedded in paraffin. Paraffin sections were subsequently cut and stained by established immunohistochemical methods for incorporated BrdU. The labeling indices (LI) for mesothelial cells lining the surface of the lung (visceral), thoracic wall (costal), and the diaphragm in the pleural compartment were determined by counting BrdU-labeled and unlabeled mesothelial cells and expressing the result as a percentage of the total cells counted. The number of cells available for counting in individual cross sections varied, but in all cases, all of the cells present on the section were enumerated. On average, at least 500 cells were counted per section.
Biochemical assays.
Bronchoalveolar lavage fluid (BALF) and pleural lavage fluid (PLF) supernatants were immediately analyzed for lactate dehydrogenase (LDH), N-acetylglucosaminidase (NAG), total protein (TP), and alkaline phosphatase (BALF only), using a COBAS FARA II autoanalyzer (Roche Diagnostic Systems, Inc., Montclair, NJ).
Statistical methods.
Statistical analysis was performed as previously described (Gelzleichter et al., 1999). Fiber length and diameter were assumed to follow a bivariate lognormal distribution (Cheng, 1986
; Moss et al., 1994
; Siegrist et al., 1980
; WHO, 1988
). Size distributions were described by the means and variances of the natural logarithms of fiber length and diameter and the correlation between ln (length) and ln (diameter). With the data collected from 6 animals per group, estimates were made of the 5 parameters of the bivariate distribution: the geometric mean length (GML), the geometric standard deviation of length (GSD [L]), the geometric mean diameter (GMD), the geometric standard deviation of diameter (GSD [D]), and the correlation between ln (length) and ln (diameter) (tau). Small numbers of objects were recovered for analysis in some of the animals, and therefore comparisons between species and groups were made using the total estimated number of fibers in each animal fitting in either 4 or 2 length intervals (1 < L ≤ 3, 3 < L ≤ 5, 5 < L ≤ 8, L > 8 or L ≤ 5, L > 5). There were insufficient numbers of fibers, particularly from the pleura, to create diameter classes. Standard counting rules (WHO, 1988
) were applied for weighting and scaling up the total count represented by each observed fiber. For each length interval, the mean value ± standard error of the mean (SEM) is reported (n = 6). The weighted fiber counts were then scaled up on a per-lung or per-pleura basis and normalized by the surface area. Lung surface areas for the hamster (2800 cm2) and rat (6600 cm2) were obtained from the literature (Sahebjami, 1992
; Valberg et al., 1992
). Pleural surface area for the rat (24.5 cm2) was determined empirically (R. R. Mercer, personal communication). The pleural surface area for the hamster (14.1 cm2) was estimated by calculating the surface area of a sphere with a volume equivalent to the volume (5 ml) of agarose necessary to fill the pleural space. For cellular and biochemical assays, all results are expressed as mean values ± 1 SD. Significant differences between groups were determined by a Students t-test; p values of less than 0.05 were considered statistically significant.
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RESULTS |
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Analyses of Pulmonary and Pleural Fiber Burdens
Samples were collected after 0, 4, and 12 weeks of exposure and 12 weeks postexposure for the characterization of lung and pleural fiber burdens. Fibers were present in very low numbers (less than 1% of the number in exposed animals) in the lungs of control animals, presumably resulting from environmental contaminants (Table 2). The fibers recovered from the lungs of rats and hamsters were shorter (GML 6.9 µm and 6.9 µm versus 12.5 µm) and thinner (GMD 0.71 µm and 0.68 µm versus 0.93 µm) than fibers of the aerosol. The total number of fibers per lung was calculated based on the fibers counted and, when averaged over the three time points, were eightfold greater in rats (hamsters; 6.4 x 106, rats; 50.1 x 106). When these data were normalized on a surface area basis, the lung burdens in rats (7.6 x 103/cm2) remained significantly greater (p < 0.05) than those of hamsters (2.3 x 103/cm2). The ratio of short (< 5 µm) to long (>5 µm) fibers in the rat lung remained relatively constant over time at approximately 1:2, with a decrease in the total number of fibers with time postexposure to 56% of peak values (Table 2
). Similarly, the ratio of short to long fibers in the hamster lung was approximately 1:2, but there was a shift to shorter, thinner fibers with time postexposure (approximate short-to-long ratio of 1:1) and the total number of fibers decreased to approximately 10% of peak values (Table 2
).
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Cellular and Biochemical Analyses of Pulmonary and Pleural Lavage Fluid
Control ranges for the number of cells recovered from the rat lung were 5.66.6 x 105, 1.59.8 x 103, and 1.97.6 x 103 for macrophages, neutrophils, and lymphocytes, respectively. In the control animals, the macrophages were at least 97% of the recovered cells. There was a mild inflammatory response in the lungs of the rats characterized by a significant increase in the number of neutrophils and increases in biochemical indicators of toxicity. The number of neutrophils increased with exposure to values that were significantly elevated over concurrent controls (Fig. 1). The percentage of the cells identified as neutrophils rose to a maximum of 15% of the cells and subsequently declined, after 12 weeks of recovery, to 3%. Lymphocytes also increased significantly during the exposure period (Fig. 1
) but returned to control values by 12-weeks postexposure. Control values for the biochemical markers in rat BALF ranged from 24 to 29 units/l, 2.32.9 units/l, 92134 µg/ml, and 5464 units/l for LDH, NAG, TP, and alkaline phosphatase, respectively. All of the biochemical markers examined in rat BALF were elevated after 4 weeks of exposure (Fig. 2
). LDH and alkaline phosphatase levels remained elevated and unchanged through 12 weeks of recovery, whereas TP decreased with time postexposure but remained significantly greater than concurrent controls.
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Ranges for the number of cells recovered from the pleural space of control rats were 5.0 to 6.8 x 106, 0.3 to 2.3 x 104, and 2.9 to 10.8 x 104 for macrophages, neutrophils, and lymphocytes, respectively. Similar to the lung, the majority of the cells recovered were macrophages but comprised a smaller fraction (76-80%). Pleural cellular responses in rats consisted of increased numbers of macrophages following 4 and 12 weeks of exposure (Fig. 1) and mast cells after 12 weeks of recovery (data not shown). Control values for the biochemical markers in rat PLF ranged from 28 to 46 units/l, 0.7 to 0.8 units/l, and 210 to 330 µg/ml for LDH, NAG, and TP, respectively. Of the biochemical markers of toxicity, only LDH was elevated in the rat PLF and only after 12 weeks of exposure to MMVF10a.
Ranges for the number of cells recovered from the pleural space of control hamsters were 2.5 to 3.4 x 106, 2.2 to 5.3 x 104, and 5.6 to 6.4 x 105 for macrophages, neutrophils, and lymphocytes, respectively. Macrophages accounted for at least 89% of the cells recovered from the pleural space of controls. Pleural macrophages were increased in fiber-exposed hamsters but (unlike rats) remained significantly elevated at the end of the 12-week recovery period. Similarly, lymphocytes were increased after 4 weeks of exposure and were still significantly greater than concurrent controls after 12 weeks of recovery. Mast cell numbers were significantly greater than controls following 4 weeks of exposure but returned to control values by 12 weeks of exposure (data not shown). Control values for the biochemical markers in hamster PLF ranged from 37 to 59 units/l, 0.7 to 0.8 units/l, and 196 to 275 µg/ml for LDH, NAG, and TP, respectively. There were no significant increases in the biochemical markers of toxicity in PLF of hamsters exposed to MMVF10a.
BrdU Labeling of Pleural Mesothelium
DNA replication in mesothelial cells was detected as the incorporation of BrdU and quantified for three distinct pleural sites: left lung visceral, left costal wall, and diaphragm. The only site in rats where there was significantly increased DNA synthesis was at the diaphragm, and this was limited to animals that had been exposed to fibers for 4 weeks (Fig. 3). Significantly increased DNA synthesis was found in hamsters at the costal wall after 4 weeks of fiber exposure and at the diaphragm after 12 weeks of fiber exposure (Fig. 3
).
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DISCUSSION |
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Lung burdens in the present study differed between rats and hamsters. After 12 weeks of exposure, total lung burdens in rats were approximately eight-fold greater than in hamster. These differences have been observed in other studies with inhaled fibers (Gelzleichter et al., 1999; Hesterberg et al., 1993
, 1999
) and are probably due to the inherent species differences in lung size and surface area, physiological parameters (e.g., min volume), and the ability to clear fibers. Attained lung burdens in hamsters in the present study, after adjusting for total exposure hours, are in good agreement with those found in a study with the same species and aerosol mass concentration of MMVF 10.1, a preparation with a slightly higher fluorine content than MMVF 10a, but with approximately the same dissolution rate in vitro (Hesterberg et al., 1999
). The species difference in the ability to remove fibers from the lung is evident upon examination of lung fiber burdens following 12 weeks of postexposure recovery. Hamster lung burdens decreased approximately 90% in the 12 weeks of recovery, whereas lung burdens in rats only decreased approximately 44%. The ability of hamsters to efficiently clear particles from the lung has been previously noted (Bermudez et al., 2002
; Creutzenberg, et al., 1998
), as have differences in how alveolar macrophages handle fibers (Dorger et al., 2000
).
Although pulmonary inflammation was observed in rats and hamsters, the character of the responses differed. Rats had significant increases in neutrophils and a concomitant increase in biochemical markers of toxicity that remained elevated through the end of the recovery period. Hamsters, on the other hand, had a mild pulmonary inflammatory response limited to increased neutrophils after 12 weeks of exposure, and decreased alkaline phosphatase levels after 4 weeks of exposure. In the case of the rats, but not hamsters, the mean neutrophil response correlated (r2 = 0.9792) with the measured lung fiber burdens. The extent of the pulmonary inflammatory response observed in the present study is in good agreement with the work of Hesterberg et al.(1999), where hamsters were exposed to MMVF 10.1 fibers for 13 weeks. In comparison with the pulmonary response elicited by the inhalation of RCF-1 fibers, the response seen here was of a much lesser magnitude. Neutrophils in the lung, following exposure for 90 days to RCF-1, comprised approximately 50% (unpublished data) of the recovered cells, whereas approximately 12% were neutrophils following MMVF 10a inhalation. This difference is probably due to the greater lung fiber burdens observed in rats and hamsters exposed to the more durable RCF-1 fibers.
We (Gelzleichter et al., 1999), and others (Sebastien et al., 1980
; Suzuki et al., 1991
), have previously demonstrated that fibers translocate from the lung to the pleural space, but that these fibers are relatively few in number. This observation holds for MMVF 10a in the present study, where the total number of fibers in the pleural compartment was at least a thousand times lower than in the lung. A shift in the distribution of fiber length toward longer fibers was noted in the pleural compartment, relative to the lung, such that the majority of fibers were of lengths greater than 5 µm. This may be a result of more rapid clearance of "short" fibers in the lung, as has been observed in rats exposed to crocidolite (Hesterberg et al., 1996b
). Burdens in the pleural compartment increased with time of exposure in both species. The measured burdens are approximately proportional to those measured by Hesterberg and colleagues (Hesterberg et al., 1999
) in hamsters exposed for 78 weeks to MMVF 10a, demonstrating the continued accumulation of fibers with exposure. Pleural burdens in the hamster only differed from rats after 12 weeks of exposure and in the accumulation of fibers greater than 5 µm. We previously noted this apparent accumulation of longer fibers in the hamster as compared to the rat (Gelzleichter et al., 1999
). After 12 weeks of recovery, pleural fiber burdens equalized between rats and hamsters and probably reflect the rapidly declining lung burdens and clearance of this very soluble fiber from the pleural space of the hamster.
In our previous studies where rats and hamsters were exposed for 12 weeks to RCF-1 the pleural fiber burdens for all size categories were on the order of 6 to 28-fold greater than in the present study, however the number of fibers of length greater than 5 µm was approximately the same in both studies (Gelzleichter et al., 1999). This finding suggests that the movement of fibers with lengths greater than 5 µm from the lung to the pleural compartment is more restricted than the movement of shorter fibers and that this process is independent of the fiber type. Also worth noting is that in the current study the number of fibers in the pleural space of the rat did not change with 12 weeks of recovery whereas in hamsters there was an approximate decrease of 50% in the number of fibers. This may be a reflection of the slower removal of fibers from the rat lung with a continued translocation of fibers to the pleural space where the sequestration of fibers, the ability of macrophages to engulf particles, and the dissolution of fibers may differ between species.
The pleural inflammatory response, though present, was minimal in both species. Rats exhibited elevated LDH levels, cell replication of the diaphragmatic mesothelium, and increased numbers of macrophages, but only during the exposure phase of the experiment. Hamsters had increased macrophage and lymphocyte numbers through the end of the postexposure recovery period and cell replication of costal and diaphragmatic mesothelium during exposure, however there were no significant increases in soluble markers of inflammation. By comparison, the pleural responses elicited by the inhalation of RCF-1 in rats and hamsters reflected the higher attained pleural fiber burdens and the negligible clearance of a more durable fiber and included increases in the levels of soluble markers of inflammation, persistent mesothelial cell turnover at all sites, and increases in macrophage, neutrophil, and eosinophil populations (Gelzleichter et al., 1999). The pattern of pleural responses observed in the present study has been noted in hamsters exposed to similar concentrations of MMVF 10a (Hesterberg et al., 1999
) and is in keeping with the low fiber burdens and the low toxicity of this particular fiber.
It should be emphasized that the present study examined the effects of a single, high exposure concentration and thus cannot discern species differences in the kinetics of fiber accumulation or clearance and the lung and pleural responses that may become evident if a multiple dose study design incorporating high and low doses is used.
In summary, inhalation of MMVF 10a for 12 weeks resulted in species differences in pulmonary and pleural fiber burdens. Pleural burdens at the end of exposure were greatest in hamsters and in particular those fibers with lengths greater than 5µm. Clearance of fibers from the lung and pleural space was more evident in hamsters than in rats. Coincident with pleural fiber burdens were differences in cellular reaction and inflammatory responses. Inflammatory responses to the presence of fibers were evident in both species but were of a lesser degree than observed with more toxic fibers. Species differences in pleural reaction were limited to increased macrophage numbers after 12 weeks of recovery and cell proliferation of both costal and diaphragmatic mesothelial cells. Taken together, it is evident that the species differences observed following the subchronic inhalation of MMVF 10a are due not only to retained fiber burdens and the physical properties of the fiber, but on differences in the kinetics of fiber translocation, macrophage function, mesothelial cell reactivity, and other biological differences.
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ACKNOWLEDGMENTS |
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NOTES |
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2 Present address: GlaxoSmithKline, Research Triangle Park, NC 27709.
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