Respiratory Disease: Study on Silica Dust in Cats
Detection of Silica Particles in Lung Wash Fluid From Cats With and Without Respiratory Disease
Peter L. Borchelt, Ph.D.
Animal Behavior Consultants, Inc.
Brooklyn, New York
Objective: To identify characteristics of silica material from a variety of popular cat litters using electron-microscopy (EM) and x-ray spectroscopy (XS), and then apply these techniques to analyze tracheal washings (TW) and bronchoalveolar lavage (BAL) fluid to identify, charac-terize and quantify silica particles in cats with and without signs of lower airway disease.
Design: Prospective study.
Animals: Twelve client-owned cats; six with and six without clinical signs of respiratory disease.
Procedure: Samples of dust particles from four clumping and three non-clumping clay litters were submitted for EM and XS analysis. Six client-owned cats presented for evaluation of their respiratory disease underwent either an endotracheal TW or endotracheal BAL. Six healthy client-owned cats from a single household underwent a bronchoscopic BAL. Samples from each cat were analyzed cytologically, bacteriologically and by EM and XS. All cats used clay litter exclusively.
Results: Dust particles obtained from seven commercial cat litters have an identifiable appearance and elemental ratio (primarily aluminum and silica). The same pattern is observed in particles obtained from lung wash wash fluid of cats, and significantly more silica particles were obtained from cats with respiratory disease than cats without respiratory disease.
Conclusions: The most conservative conclusion from the present study is that silica may act as an airway irritant in those cats with airway disease and is not the initiator of a primary disorder.
Clinical Relevance: The higher numbers of silica dust particles found in cats with respiratory disease suggest an association, but it is unknown whether dust particles contribute to respiratory disease or accumulate because of interference with normal lung ciliary function.
Inhaled silica dust has been implicated as a cause of lung cancer and other respiratory diseases in humans and several animal species. Electron microscopy and x-ray spectroscopy were used to identify and characterize dust particles from seven brands of commercially available clay cat litters and to identify, characterize and quantify particles in the lung wash fluid of six cats with and six cats without signs of respiratory disease. Dust particles from clay cat litter have an identifiable appearance and elemental ratio (primarily aluminum and silica) and the same pattern was observed in particles obtained from lung wash fluid. Significantly more silica particles were obtained from cats with than without respiratory disease. This suggests an association between presence of silica particles and respiratory disease, but it is unknown whether silica dust particles contribute to respiratory disease or accumulate because of interference with normal lung ciliary function.
Exposure to silica has been implicated as a cause of lung cancer and other respiratory diseases in humans, rats, mice and hamsters (1,2,3,4,5,6,7,8). Diseases caused by inhalation of silica include silicotic nodules, alveolar proteinosis, interstitial cell infiltrates and interstitial fibrosis (9). Pathological changes include diffuse fibrosis, nodular lesions, lymph node enlargement, and pleural fibrosis which together can result in airflow obstruction and impaired gas exchange (1,10). Inhaled silica particles initially are phagocytized by alveolar macrophages and can be.found in the respiratory mucus of affected patients (11). In addition, alveolar macrophages can leave the bronchial tract and translocate to the interstitium. When the silica laden macrophage dies, it incites an inflammatory reaction and pulmonary fibrosis, silicotic nodules and lymph node enlargement; respiratory failure ensues. Damage to the ciliary apparatus destroys the defense mechanism that functions to remove mucus, inflammatory debris, inhaled particles and infectious agents which colonize the airway. Through these mechanisms, chronic exposure to silica leads to respiratory failure (1,2,3,4,5,6,7,8) and impaired resistance to bacterial infections. In 1997, the International Agency for Research on Cancer classified silica as a human carcinogen (6).
In cats, respiratory diseases such as bronchial asthma, chronic bronchitis, viral, bacterial and pyogranulomatous pneumonia, and pulmonary neoplasia are commonly diagnosed (12). The incidence of primary lung tumors in cats is rare. It is estimated that 1-2% of the general cat population has asthma or chronic bronchitis, however, in some pure breeds, such as the Himalayan and Siamese it may be as high as 5% (13). Despite treatment, these problems may progress and can lead to life-threatening episodes and chronic respiratory disease. In the United States, the majority most of household cats are exposed to silica dust on a daily basis since more than 95% of cat litter is a form of silica (6). Although dusty cat litter has been suggested as exacerbating respiratory problems in cats, no research to date has demonstrated the presence of inhaled silica in airway secretions in cats or the presence of silica in primary lung tumors. The study reported here used scanning electron microscopy and x-ray spectroscopy (14) to analyze particles obtained from tracheal washings (TW) and bronchoalveolar lavage (BAL) fluid of 6 cats with and 6 cats without signs of respiratory disease. Respiratory secretions rather than lung biopsies were chosen to document the presence of silica because it is an accepted method in diagnosing human cases (11) and lung biopsies were not warranted for workup of the respiratory signs.
Materials and Methods:
Cats: TW or BAL fluid from a total of twelve client-owned cats was obtained. Six cats (4 MC, 2 FS, between 3-16 years of age, 3 DSH, 2 Abyssinians, 1 DLH) with lower airway disease were evaluated at the Bobst Hospital of The Animal Medical Center between October 1998 and December 1999. Six cats (4 FS, 2 MC, between 2-9 years of age, 3 DSH, 2 DLH, 1 Siamese) without respiratory disease were identified as controls and evaluated at Michigan State University Veterinary Teaching Hospital from November - December 1999. The six cats with respiratory disease used various brands of clumping and non-clumping clay litter. The six healthy cats used Premium Choice clumping clay litter exclusively.
The presence of respiratory disease was based on the clinical signs described by the owners, radiographic changes, physical examination findings and TW-BAL results. The absence of respiratory disease was determined by the lack of observed clinical signs by owners, absence of radiographic abnormalities, normal physical examination findings and BAL results.
TW and BAL Procedure: The determination of whether to perform a TW or BAL was made by the clinician or based on radiographic findings (15).
Cats with Respiratory Disease: Bobst Hospital of The Animal Medical Center.
Thoracic Radiology: Thoracic radiographs (lateral and ventrodorsal) were performed on each cat and evaluated by a single member of the radiology staff.
Endotracheal TW: The cats were anesthetized with intravenous ketamine and diazepam. A sterile endotracheal tube was passed through the larynx into the trachea avoiding oral cavity contamination. A sterile polyethylene tube was passed through the end of the endotracheal tube. One ml/kg (0.45 ml/lb.) of 0.9% saline solution (pH=5.0) was flushed through the tube and immediately aspirated. Washings were repeated when necessary to collect an adequate sample.
Endotracheal BAL: Bronchoalveolar lavage was performed in a standard method using an endotracheal tube. The cats were anesthetized with intravenous ketamine and diazepam for the procedure (16).
Sample Handling: For each cat, samples were submitted as either prepared slides of mucus secretions or in a sterile EDTA blood collection tubeboth a sterile EDTA blood collection tube for cytological analysis and in a Copan-Type Aimes culturette for submission for bacterial culture and sensitivity testing. All samples from theSamples submitted as slides from TW were stained with Wright stain and evaluated cytologically under light microscopy. All samples from the BAL were collected in sterileSamples submitted in EDTA tubes were first prepared using a cytospin technique prior to Wright stain and evaluated cytologically under light microscopy. All samples from the BAL were collected in sterile EDTA tubes and submitted to Idexx Laboratories (Totowa, New Jersey) for fluid analysis and cell count differential. Slides were also prepared using a cytospin technique and Wright stain for evaluation under light microscopy. Samples for bacterial culture were plated onto Maconkey Agar and Blood Agar and placed in Thiobroth and incubated at 37º C (98.6º F) for 5 days. Two mls of lung wash fluid from each cat was placed in a sterile non-citrated blood collection tube and stored at -70º C (-94º F) until analyzed by EM and XS.
Cats Without Respiratory Disease: Michigan State University Veterinary Teaching Hospital:
Thoracic Radiology: Thoracic radiographs (lateral and ventrodorsal) were performed on each cat and evaluated by a board certified veterinarymember of the radiologistradiology staff.
Bronchoscopic BAL: Control cats were anesthetized with intravenous propofol. Intubation was not performed; oxygen was delivered via an 8 french red rubber catheter advanced to the level of the carina. BAL samples were obtained by fiberoptic bronchoscopy (Olympus). The bronchoscope was advanced to the deepest level of fit (3.5mm diameter). A bolus of 10 ml Balanced Salt Solution (Baxter laboratory) was infused through the endoscope port. Coupage was performed and suction employed to collect the BAL sample in the sterile collection receptacle.
Sample Handling: Since cytologic examination (Michigan State University Clinical Pathology Laboratory) was performed on site immediately following the collection, preservative was not added to the sample. Slides were prepared using a cytospin technique and Wright stain and evaluated by a board certified clinical pathologistunder light microscopy. The BAL sample was also cultured for bacterial growth. Bacterial culture was performed on site (Michigan State University Department of Microbiology) immediately after collection. Samples were plated onto Maconkey Agar and Blood Agar and placed in Thiobroth and incubated at 37º C (98.6º F)for 72 hours. One ml of BAL fluid was placed in a 3 ml serum tube, stored at 4º C (39º F) , and shipped to The Bobst Hospital of The Animal Medical Center for EM and XS analysis in a manner identical to samples of cats with respiratory disease.
Electron Microscopy and X-Ray Spectroscopy
Dry cat litter dust from seven brands of cat litter was transferred to filters by passing the filter above each cat litter sample immediately after it was shaken vigorously in a vial. For each TW or BAL sample, 3 drops (approximately 30µl) of fluid were gently filtered in a dust-free environment onto a polycarbonate filter (pore size = 0.45µm). All filters were dried in a 60ºC (140º F) incubator for 24 hours, mounted on aluminum SEM stubs using double coated carbon tabs, and carbon coated at 70kv using a Denton Desk II carbon yarn coating system. Observations of all samples were made over a one month period using a Hitachi Digital Scanning Electron Microscope fitted with an x-ray Spectral Analysis System. Each stub was observed for about 1 hour and all particles containing silica found in each sample were photographed and the x-ray spectrum recorded.
Statistical Analysis: The total number of silica particles in each sample from healthy cats and from cats with respiratory disease were tabulated and the two groups compared using students t-test.
EM and XS Analyses
Dry Samples of Clay Litter Dust:
Photomicrographs and spectral analyses were obtained from dust samples from 7 popular brands of clay cat litter. The photomicrographs depict particles mostly in the 5-20µm size range and spectral analyses of all the litter dust samples indicated minor differences between brands of clay cat litter in the ratios of different elements (particularly aluminum and silica). These results provide a baseline for identifying clay cat litter particles in lung wash samples.
The cats without respiratory disease used Premium Choice clay clumping litter exclusively and a representative photomicrograph and spectral analysis is presented in Figure 1A and B.
Figure 1BThe cats with respiratory disease used several brands of clumping and non-clumping clay litters (mostly Fresh Step) and a representative photomicrograph and spectral analysis is shown in Figure 2A and B.
Figure 2BLung Wash Samples: The photomicrographs and spectral analyses of the lung wash samples from cats both with and without respiratory disease indicated that clay cat litter dust collects in lungs of cats. Representative photomicrographs and spectral analyses are presented in Figure 3A and B and 4A and B.
Figure 4BThese data show that the identified particles in TW and BAL samples have a very similar appearance and x-ray spectrum as dust particles obtained from common brands of clay cat litter. Particles from two cats had higher aluminum peaks than observed from our the seven dry dust samples. These cats at one time used commercial litters which were not included in the baseline samples. A tabulation of the number of identified clay litter particles in lung wash samples for each group is shown in Table 1.
1 All cats without respiratory disease underwent bronchoscopic BAL.Particles identified as other than clay cat litter (wool fibers, plant material, insect parts, diatoms) were excluded from the table. A statistical comparison between the two groups indicated significantly more silica particles among cats with respiratory disease as compared to cats without respiratory disease (t=4.7678, df=10, p<.000759).
Cats With Respiratory Disease: The thoracic radiographs of five of the six cats had an abnormal bronchial pattern ranging in description from slight bronchial wall thickening to severe bronchial wall thickening and a marked miliary nodular interstitial pattern. In one of these cats (Number 8), scant pleural effusion was also noted. The sixth cat (Number 11) had moderate right and left ventricular enlargement and congested lung lobes in addition to a scant pleural effusion.
Four of the six cats presented for respiratory evaluation at The Bobst Hospital of The Animal Medical Center had TW performed and the remaining two cats had endotracheal BAL performed (Table 1). The cytological results of the TW demonstrated inflammatory cells including degenerative and non-degenerative neutrophils, lymphocytes, eosinophils and macrophages. The BAL fluid contained between 495 and 7970 nucleated cells per cubic millimeter which consisted primarily of neutrophils (range 59% of 495 cells to 96% of 7970 cells) and macrophages (range 38% of 495 cells and 2% of 7970 cells). These two cats had blue green material resembling hemosiderin in their macrophages. None of the six cats’ samples contained litter particles that were identified with light microscopy.
From four of the six cats (66%), bacteria was isolated from culture media; two positive culture results were from BAL samples and two from TW samples (Table 1). The organisms isolated included Pseudomonas stutzeri, Bordetella bronchiseptica and Pasturella multocida each as single organisms from three cats and one cat had three organisms isolated including Serratea marcescens, Pasturella multocida and a non-pathogenic alpha strep.
Cats Without Respiratory Disease: Thoracic radiographs were considered within normal limits for the age of each cat. Cytologic analysis of bronchoscopic BAL fluid from these cats showed that one cat (Number 2) was normal, three cats (Numbers 1, 3 and 4) showed mild eosinophilic inflamation, and two cats (Numbers 5 and 6) had a mixed population of cells. All cats’ BAL fluid contained blue green pigments assumed to be hemosiderin within the macrophages.
Four of the six cats (66%) had negative bacterial cultures. Pasturella sp. and alpha hemolytic strep were cultured for two cats (Numbers 3 and 6). Cat number 3 also cultured a gram negative bacillus which most closely resembles Bergeyella (weeksella) sp. This cat’s BAL cytology suggested oropharyngial contamination.
Respiratory disorders in cats are commonly diagnosed. Cats are known to develop chronic bronchitis, bronchial asthma and occasionally lung tumors. Respiratory diseases have many causes including bacterial, viral and fungal infections. In addition, it is known that airborne pollutants and dust particles can aggravate or initiate respiratory problems (17). Many occupational or industrial lung diseases in people are caused by inhaled dusts, including asbestos and silica (18). For example, one specific study suggests that there may be a relation between inhalation of a form of aluminum silicate and pulmonary fibrosis in workers who bagged this material for cat litter. (19). The clearance of these deposited particles from the lungs is by two major mechanisms: the mucociliary apparatus and the alveolar macrophage. Both of these mechanisms are impaired by silica dust deposition.
The normal function and operation of the mucociliary system is affected by pollutants and disease. They alter function by increasing the amount of mucus material and overwhelming ciliary motion by denuding the respiratory epithelium or by altering mucus composition to a more tenacious consistency (17). Regardless of mechanism, the result is mucus plugging of the airways, airflow restriction and loss of this important pulmonary defense. In the cat, it is known that asthma and bronchitis are associated with an increase of mucus volume, that respiratory infections (viruses and mycoplasma) may affect the degradation of substance P (a protein capable of causing airway constriction and edema) (13), and that eosinophils release cationic proteins from their granules which cause epithelial cell sloughing, ciliary stasis, and increased airway smooth muscle contraction (20). If the mucociliary system does not trap inhaled dust particles for clearance by the cough reflex, the particles will gain entrance into the alveolar region of the lung where the alveolar macrophage then takes over as the most important arm of the defense mechanism.
In man, the alveolar macrophages phagocytose the foreign particles, migrate to the small airway region where they become deposited on the mucus layer and are cleared by the mucociliary apparatus. In some cases, the alveolar macrophage migrates instead into the peribronchial tissue and deposits the dust there. If a dust is toxic, such as silica, the alveolar macrophage may be destroyed and a severe fibrosing reaction occurs in the lung where the dust accumulates. This results in dense collagen fibers around respiratory bronchioles, inside alveoli, and along lymphatics. Silica particles can also be observed within the nodules that are formed. These silicotic nodules are initially localized around bronchioles and arterioles. With advanced disease, the surrounding fibrosis destroys the lung tissue and the nodules enlarge and become confluent. Calcified perihilar lymphadenopathy may also occur (20).
The consequence of parenchymal fibrosis is decreased lung compliance due to increased elastic recoil and the increased work of breathing. If small airways are involved, there is concomitant air flow obstruction. Pleural plaques can also be seen. Evidence supports a relationship between silicosis and lung cancer (21). Because of diminished function of the alveolar macrophages which have engulfed silica, humans are, in addition to the above problem, also predisposed to Mycobacterium tuberculosis infections (22).
In man, the likelihood that a particle within the lung will cause a respiratory problem is related to three important components of the particle: the composition of the particle, the deposition of the particle, and the total tissue burden of inhaled particles. Tissue burden relates to particle size, particle concentration in the inhaled airstream, duration and frequency of exposure, clearance ability at various levels of respiratory tract obstruction, and other factors. Two important host factors include genetic variability and the presence of respiratory disease at the time of exposure (1).
The present study in cats with and without lung disease was initiated to determine whether silica can be detected in airway secretions, and if so, to determine if a quantitative difference between groups could be found. It was found that cats with respiratory disease had a greater number of particles retrieved than those without lung disease. The questions that need to be answered are, (i) why did it accumulate more in cats with lung disease, and (ii) whether the presence of silica causes changes in cat lungs similar to those in man. It is suggested that cat litter induces pulmonary disease in workers who bagged aluminum silica used in cat litter (19). None of the cats in the present study had pulmonary function tests or post-mortems performed so no conclusion can could be drawn regarding alteration in pulmonary structure and function. The radiographic changes of cats with lung disease were not interpreted as consistent with pulmonary fibrosis, a common finding in radiographs from humans with silicosis. Some of the cats’ radiographs were interpreted as having a nodular pattern. This pattern may be consistent with mucus accumulation in airways and not necessarily the pulmonary silicotic nodules seen in humans. Radiographically, none of the cats had intrathoracic nodal enlargement, pleural placques, or calcification of their lymph nodes. None of the cats had pulmonary neoplasia.
The cats with an increased number of particles were not the oldest, those with the longest history of symptoms, those with the longest exposure, those with positive airway cultures, those with more severe signs, or those with the most inflammatory exudate. The cats with the greatest number of particles did not have a BAL performed versus a TW. In addition, the presence of hemosiderin-like particles in macrophages was noted only in those cats who had undergone BAL and may not represent hemosiderin but rather silica in the airways and its engulfment by macrophages. Hence, it is impossible to know from the present study whether the presence of respiratory disease and/or altered pulmonary defenses predispose cats to particle accumulation, or whether, as in man, silicosis predisposes to respiratory tract disease.
In man, exposure to fibrogenic dusts such as silica causes pulmonary dysfunction. Subsequent exposure to otherwise harmless substances then can cause the lungs to overreact and create a state of sensitization and asthma (23). Also in man, respiratory tract infections and the associated neutrophil recruitment causes denudation of bronchial epithelium, reduction of ciliary beating and stimulation of mucus secretion, all of which impair the pulmonary defense system (24). Chronic urban air pollutants affected the mucociliary clearance and pulmonary function testing in an experimental study on rat lungs (17). Perhaps in cats with lung disease, silica presence may further impair an already altered mucus clearance, incite a neutrophilic response and predispose the respiratory tract to hyperreactivity or infection. Although the number of particles of silica did not correlate with the degree of inflammation, cats with respiratory signs had a greater number of neutrophils in the lung wash fluid than did cats without respiratory disease.
The most conservative conclusion from the present study is that silica may act as an airway irritant in cats with airway disease and is not the initiator of a primary disorder. The increase in number of particles in the airways of cats with lung disease may reflect that an altered lung defense system was already present and further hindered by the presence of silica.
The authors recognize that only a small number of cats were evaluated in this study and that further research is necessary. The questions that need to be answered are, (i) why did silica accumulate more in cats with lung disease, and (ii) whether the presence of silica causes changes in cat lungs similar to those in man. Suggested future research should include pulmonary function testing that compares normal cats with no exposure to silica-based cat litter, normal cats with documented silica deposition in their lungs, and cats with respiratory disease and silica deposition. Post-mortem or histology is needed, as well as studies on ciliary apparatus motion and mucus composition. Additional studies should include the clinical courses of cats with respiratory disease that have access to alternative litter compared to control cats with continued use of clay litter.
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Figure and TableLegends
Figure 1A A representative photomicrograph of a silica particle from clumping clay litter used by the cats without respiratory disease.
Figure 1B An x-ray spectral analysis of the particle shown in Figure 1A.
Figure 2A A representative photomicrograph of a silica particle from clumping clay litter used by many of the cats with respiratory disease.
Figure 2B An x-ray spectral analysis of the particle shown in Figure 2A.
Figure 3A A representative photomicrograph of a silica particle from lung wash fluid of a cat without respiratory disease.
Figure 3B An x-ray spectral analysis of the particle shown in Figure 3A.
Figure 4A A representative photomicrograph of a silica particle from lung wash fluid of a cat with respiratory disease.
Figure 4B An x-ray spectral analysis of the particle shown in Figure 4A.