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Small Airway-Centered Granulomatosis Caused by Long-term Exposure to PolytetrafluoroethylenePolytetrafluoroethylene-Induced Lung Granulomatosis FREE TO VIEW

Won-Il Choi, MD, PhD; Hye Ra Jung, MD; Esmeralda Shehu, MD; Byung Hak Rho, MD; Mi-Young Lee, MD, PhD; Kun Young Kwon, MD, PhD
Author and Funding Information

From the Department of Internal Medicine (Drs Choi and Shehu) and Department of Pathology (Drs Jung and Kwon), Keimyung University School of Medicine, Daegu, South Korea; Department of Internal Medicine (Dr Shehu), Regional Hospital of Durres, Durres, Albania; and Department of Radiology (Dr Rho) and Preventive Medicine (Dr Lee), Keimyung University School of Medicine, Daegu, South Korea.

Correspondence to: Mi-Young Lee, MD, PhD, Department of Preventive Medicine, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Daegu 704-701, South Korea; e-mail: mylee@dsmc.or.kr


Drs Choi and Jung contributed equally to this work.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(6):1397-1402. doi:10.1378/chest.13-1997
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Published online

To date, there have been no reports of chronic pulmonary granulomatosis associated with exposure to polytetrafluoroethylene (PTFE). Here, we report three cases of small airway-centered granulomatous lesions in workers employed at facilities that apply coatings to pans and other utensils. The workers were repeatedly exposed to PTFE particles that were probably generated by the drying process when PTFE coatings are dried in a convection oven at high temperatures (380-420°C). The duration of inhalational PTFE exposure was between 7 and 20 years. We found granulomatous lung lesions around the small airways in lung biopsy specimens obtained from the workers. Scanning electron microscopy/energy-dispersive x-ray spectroscopy analysis was performed focusing on areas where the PTFE particles were suspected to be located in macrophages. The scanning electron microscopy/energy-dispersive x-ray spectroscopy analyses revealed fluorine in the particles. Lung tissue samples from all cases were analyzed using a fully automated Fourier transform infrared spectrometer. Analysis of the spectrum extracted from the position of the foreign particles enabled precise identification of the foreign bodies as PTFE. Fourier transform infrared revealed that all of the lung tissue samples had bands at 1,202 to 1,148 cm−1 and 1,202 to 1,146 cm−1, which are characteristic of the asymmetric and symmetric stretching vibrations of the C-F bonds of PTFE. These cases suggest that recurrent inhalational exposure to PTFE particles causes chronic pulmonary granulomatosis.

Figures in this Article

Polytetrafluoroethylene (PTFE) is the most important of the fluoropolymers, which are technical polymers with very special properties and applications. PTFE is an opaque white material that has a high melting point, approximately 342°C; therefore, the key feature of PTFE is its thermal stability, which facilitates its use in high-temperature applications.1

The highest toxicity associated with PTFE may occur when it is decomposed under nonflaming conditions over a temperature range of 400 to 650°C.1 However, degradation of PTFE can begin at temperatures above 360°C.2 PTFE fumes may be produced in oven temperatures higher than 300°C,3 and it has been suggested that heating PTFE above 350 to 400°C risks illness in nearby workers.4 Polymer-fume fever may develop even when PTFE is heated at temperatures lower than 200°C.5 Taken together, these study findings suggest that PTFE fumes generated at temperatures lower than 400°C may cause respiratory diseases without acute toxic respiratory symptoms.

The rate of market growth for PTFE has been 3% to 5% per year over the past 30 years. The worldwide production capacity of PTFE was > 55,000 tonnes in 1990, and it has since increased to more than twice this figure.6 PTFE is currently the dominant fluoropolymer and has approximately 70% of the total fluoropolymer market worldwide.6 Fluorinated polymers are widely used as engineering plastics owing to their particular combination of mechanical properties, chemical inertness, heat resistance, and low coefficient of friction.7

Previous reports have shown that inhalation exposure to PTFE particles may cause acute lung diseases such as pulmonary fume fever, pulmonary edema, and interstitial pneumonia.4 In addition, the formation of foreign body granulomas has been reported following the injection of large particles of Teflon (eg, for vocal cord paralysis) or from particles shed from Teflon mesh implants.8 However, the effects of chronic inhalation of PTFE remain to be elucidated.

Three men were referred to our outpatient clinic because of abnormalities observed on chest radiography during a routine personal check-up. There was no occupational health regulation at the PTFE facility. Two did not have any respiratory symptoms except for an occasional dry cough, but the third presented with cough and mucoid sputum that had developed over the preceding 6 months.

Cases 1-3

Each patient had worked in a different small factory that produced various cooking utensils using aluminum (Al) as a raw material. There were about five to 10 workers in each factory. Their main job was to spray PTFE coatings onto pans. The pan surface was washed with a detergent and rinsed with water in preparation for the PTFE coating, which was applied in the same liquid form in one or two layers. The base coating was usually started with a primer. The ingredients of the primer dispersion were as follows: PTFE (58%-62%), octyl-phenoxypolyethoxylethanol (0%-5%), nonyl-phenoxypolyethoxylethanol (0%-5%), ammonium perfluorooctanoate (0.5%), and water (33%-40%). After the primer was applied, the pan was dried for a few minutes in a convection oven. Once all of the coatings had been used, the pan was dried again in an oven at 380 to 420°C for about 5 min, and then it was ready to assemble and package. They used sandpaper to make the outside of the pans smooth for painting, but there were no ventilation duct systems present in the facilities. Nevertheless, the patients had regularly worn facial paper masks while working. The rooms they worked in, which were about 3.3×3.3 m in similar size at each factory, were generally kept closed. Initial chest radiographs (Fig 1A) and high-resolution CT scan images of case 3 showed bilateral ground-glass opacities and numerous centrilobular nodules (Fig 1B). No endobronchial lesion was detected by fiber-optic bronchoscopy. BAL identified numerous alveolar macrophages containing translucent fine granular and amorphous materials in the cytoplasm. The lavage samples of all cases were negative for Gram/acid-fast bacilli staining and TB polymerase chain reaction. Bacterial and acid-fast bacilli cultures were negative of lavage fluid in all cases. Pulmonary function tests revealed an unremarkable pattern (Table 1).

Figure Jump LinkFigure 1. A, Case 3 chest radiograph shows multiple bilateral tiny nodules in the lung fields. B, Case 3 high-resolution CT scan of the chest, demonstrates numerous bilateral centrilobular small nodules.Grahic Jump Location
Table Graphic Jump Location
Table 1 —Characteristics of the Patients Who Developed Small Airway Granulomatosis Following Long-term Exposure to PTFE

Al = aluminum; C = carbon; Ca = calcium; Dlco = diffusing capacity of the lung for carbon monoxide; EM/EDS = electron microscopy/energy-dispersive x-ray spectroscopy analysis; F = fluorine; FT-IR = Fourier transform infrared spectroscopy; HRCT = high-resolution CT; O = oxygen; P = phosphorus; PTFE = polytetrafluoroethylene; Si = silicon; TLC = total lung capacity.

a 

Representing EDS spectrum.

Predicted values of pulmonary function tests were based on our national data.9 All cases underwent a video-assisted thoracoscopic lung wedge resection. Histologic features of cases 1 and 2 showed multiple peribronchiolar granulomatous nodules with dystrophic calcification and fibrotic conglomeration (Figs 2A-C), but case 3 showed relatively early peribronchiolar granulomatous lesions with lymphangitic distribution (Fig 2D panels D1-D3). The most common histopathologic findings of all cases show small airway-centered granulomatous lesion (Fig 2E). Amorphous transparent cytoplasmic materials were identified in the granulomatous lesions (Figs 2F, 2G). The transparent material had an irregular birefringent pattern on polarizing microscope (Fig 2G inset). For the transmission electron microscope analysis, the dissected lung tissues (about 1 mm3) were fixed for 2 h with 2.5% glutaraldehyde using 0.1M phosphate buffer, pH 7.4. Postfixation was performed for 2 h in 1% osmium tetraoxide at 4°C. After several washing steps with 0.1M phosphate buffer, the sample was dehydrated in a graded ethanol series (70%, 80%, 90%, 95%, and 100% volumes). It was then embedded in Epon using a technique described elsewhere.10 Ultrathin sections were cut at 40 to 60 nm on an MT-XL microtome (RMC) and mounted on 200-mesh copper grids. They were then stained with uranyl acetate and lead citrate and imaged with a transmission electron microscope (H-7100; Hitachi, Ltd). Electron microscopic findings revealed intermediate electron-dense amorphous materials and scattered electron-dense particles in the cytoplasm of multinucleated giant cells (Figs 3A-C). We marked areas of deposition of amorphous materials in hematoxylin and eosin-stained tissue slides that were gold-coated for backscattered electron imaging. Two or more backscattered electron images were prepared for each case.

Figure Jump LinkFigure 2. A-D, Histologic features of three cases of pulmonary granulomatous lesions induced by polytetrafluoroethylene (PTFE) exposure. A-C, Case 1 and 2 show mainly small airway-centered granulomatous micronodular lesions (arrows) with central dystrophic calcification. A, Case 1. B, Case 2. C, Higher magnification image of case 2 shows peribronchiolar conglomerated granulomatous nodules with central dystrophic calcification (arrows). D, Case 3. D1-D3, Higher magnification images of case 3 (D) show multiple scattered early granulomatous lesions (arrowheads) with a characteristic lymphangitic distribution (arrows) (D1, interlobular; D2, subpleural; and D3, peribronchiolar distributed granulomatous lesions). E, Typical finding of peribronchiolar granulomatous lesion. F, Multinucleated giant cells contain amorphous transparent materials (arrows). G, Amorphous semitransparent materials (arrows) are associated with black pigments in the granulomatous lesion. G, Inset, Polarizing microscopic examination shows semitransparent birefringence in the same hematoxylin-eosin (H&E) finding of panel G. (H&E, original magnification: A, B, D, × 5; C, × 20; D1, D2, and E, × 40; D3, × 100; F-G, × 400).Grahic Jump Location
Figure Jump LinkFigure 3. Electron microscopic findings show intracytoplasmic electron-lucent amorphous materials (asterisks) in histiocytes. A, Case 1. B, Case 2. C, Case 3. N = nucleus. Arrows indicate scattered electron-dense material. (Original magnification: A, × 3,500; B, × 5,000; C, × 4,000).Grahic Jump Location

For elemental analysis via scanning electron microscopy (EM), 4-μm-thick paraffin sections were embedded on glass slides without any conductive coating. The sections were analyzed in a scanning electron microscope (Zeiss SUPRA 55VP) with an energy-dispersive x-ray spectroscopy (EDS) analysis system (UltraDay; Thermo Fisher Scientific Inc). The entire lift was scanned by scanning EM at a 20 keV accelerating voltage with a 34.3° takeoff angle; four squares (4 μm2) containing suspicious intracytoplasmic particles in the backscattered electron images were analyzed by the EDS system. Scanning EM/EDS was performed, focusing on the area where the PTFE particles were suspected to be located in the macrophages. We found an increased peak for fluorine at 0.68 keV, but this was also associated with carbon, oxygen, Al, and silicon (Si) (Fig 4A). We confirmed the presence of PTFE in the tissue specimen by Fourier transform infrared (FT-IR) spectrometry analysis. The lung tissue samples were placed in a solution of perchloric acid and nitric acid (ratio 1:4). The acid in the solution removed all organic components such as proteins and lipids. The samples were maintained at 120°C for 10 days in the solution to generate an aqueous state. They were then dehydrated for several days. The preparations were then sectioned and analyzed using a fully automated FT-IR spectrometer over the range 750 ± 4,000 cm−1 at a resolution of 4 cm−1. High signal-to-noise spectra were obtained, and infrared maps were built by integrating each spectrum. FT-IR analysis of the tissues showed a peak with the characteristic symmetric and asymmetric stretching vibrations of the C-F bonds of PTFE in the 1,148 to 1,202 cm−1 region, which corresponded to the C-F bonds characteristic of the spray material used in the factory (Fig 4B).

Figure Jump LinkFigure 4. A, Energy-dispersive x-ray spectroscopy spectrum of a particle in a multinucleated giant cell shows: a prominent peak for F as well as other associated elements, including Si, C, O, Al, Ca, Na, Mg, and Fe. B, Fourier transform infrared spectroscopy analysis of a lung tissue specimen demonstrates a peak at 1,148 to 1,202 cm−1, which is characteristic of the C-F bond vibrations of PTFE. Al = aluminum; C = carbon; Ca = calcium; F = flourine; Fe = iron; Mg = magnesium; Na = sodium; O = oxygen; Si = silicon. See Figure 2 legend for expansion of other abbreviation.Grahic Jump Location

We here described three cases of small airway-centered granulomatous lesions in workers repeatedly exposed to PTFE for 7 to 20 years. Pulmonary granulomatous disease may occur in response to a variety of infectious agents and may be due to the inhalation of both organic and inorganic substances. In many cases, identifying the specific agent responsible for pulmonary granulomatous disease is very difficult.11,12 In the present cases, the granulomatous nodules were characteristically developed in areas with lymphangitic distribution. FT-IR analysis of the lung specimens supported our hypothesis that the granulomatous lung lesions were induced by long-term inhalation exposure to PTFE particles.

Considering that these workers were exposed to other toxic chemicals, it was difficult to attribute the respiratory findings to PTFE alone. Differential diagnoses included silicosis and Al-induced pulmonary granulomatosis.

An elemental analysis was performed for more than four regions as small as 4 μm3 in each case. This semiquantitative EDS analysis may not be representative of the whole tissue. Although about 15% Si was identified by scanning EM/EDS in these three cases, the pathology did not support Si-related disease. Silica particles are very weakly birefringent and are usually tetrahedral or round. Unlike silica particles, some irregular translucent birefringent particles were seen in multinucleated giant cells, and other tiny birefringent particles were also noted in the cases. Nothing resembling classic silicotic nodules was observed by light microscopy. Furthermore, in the chest CT scans, the typical nodule size of simple silicosis is < 5 mm. Over time, small nodules may conglomerate and develop large fibrotic nodules.13 In silicosis, nodules are usually variable in size, but in the present cases, the size of the nodules was more uniform. Silicosis is also usually accompanied by enlargement of the hilar or mediastinal lymph nodes, and often by calcification of the lymph nodes.14 In the present study, none of the patients had enlarged mediastinal lymph nodes. Finally, the glass slides used for embedding the lung tissue sample in scanning EM could be a source of Si spectrum in EDS analysis. That is, the Si component could be a contaminant from the glass slides used during EDS analysis.

Occasionally, chronic lung diseases are attributed to exposure to Al dust. The EDS finding of Al peaks in association with the other elements indicated that the presence of Al silicates was more likely than Al metal or oxide. Sandpaper was used to sand down the exterior surfaces of the aluminum pans for painting, and the cases may have been exposed to Al particles during this process. Considering that these patients heated their Al instruments at 380 to 420°C and that the melting point of Al is around 660.3°C, it is quite improbable that they were exposed to Al fumes. Moreover, examination by polarizing light microscopy also showed that the particles observed in the granulomas were birefringent, whereas Al particles are not.15 These findings suggest that Al likely did not contribute to the granulomatous disease observed in the small airways in these cases.

The iron and phosphorus observed in the EDS spectrum may be components of hemosiderin. EDS analysis was performed based on square area (4 μm2) and not on individual particles in macrophages. Single macrophages often contain many different particles related to smoking history and environmental conditions. Light microscopy did not show typical findings of mixed dust pneumoconiosis, diatomaceous earth pneumoconiosis, or Langerhans cell histiocytosis.

Experimental studies in animals have confirmed the potential toxicity of PTFE fumes.16,17 The tiny particulates that evolve from PTFE when it is heated at 450°C are the highly toxic component, and they are responsible for the pulmonary edema reported in rats.16 Another animal study reported that gas or particle-phase fumes alone did not cause significant acute toxicity in the lungs of rats. However, the combination of gas and particle-phase fumes caused significant lung injury.17 The investigators reported that the harmful PTFE particles ranged in size from 0.02 to 5 μm.16 Small amounts of repeated exposure to PTFE particles can lead to adaptation to its toxicity.17 Therefore, the different toxicity noted in these experiments and in the present cases could be related to PTFE fumes arising from temperatures below or above the 450°C required to pyrolize PTFE.

There were two possible stages during which the workers could have been exposed to PTFE particles. The first was during the spraying of the PTFE coating onto pans, and the second was during exposure to fumes containing PTFE particles arising from pans drying in the ovens. However, the primer containing PTFE was applied in a liquid formulation and it was maintained at room temperature. Because PTFE is stable at room temperature, we may exclude the possibility of PTFE particle exposure during spraying. Although there was organic compound present in the coating primer, ammonium perfluorooctanoate constituted < 0.5% of the total. Therefore, we can also exclude the possibility of other irritants arising from the pans drying in the ovens.

To conclude, chronic occupational exposure to PTFE particles can cause small airway-centered granulomatosis, and more attention should be paid to occupational exposure to PTFE.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Al

aluminum

EDS

energy-dispersive x-ray spectroscopy

EM

electron microscopy

FT-IR

Fourier transform infrared spectroscopy

PTFE

polytetrafluoroethylene

Si

silicon

Purser DA. Recent developments in understanding the toxicity of PTFE thermal decomposition products. Fire Mater. 1992;16(2):67-75.
 
Harris DK. Polymer-fume fever. Lancet. 1951;258(6692):1008-1011.
 
Bowler RG, Buckell M, et al. The risk of fluorosis in magnesium foundries. Br J Ind Med. 1947;4(4):216-222.
 
Shusterman DJ. Polymer fume fever and other fluorocarbon pyrolysis-related syndromes. Occup Med. 1993;8(3):519-531.
 
Albrecht WN, Bryant CJ. Polymer-fume fever associated with smoking and use of a mold-release spray containing polytetrafluoroethylene. J Occup Med. 1987;29(10):817-819.
 
Teng H. Overview of the development of the fluoropolymer industry. Appl Sci. 2012;2(2):496-512.
 
Dobkowski Z, Zielecka M. Thermal analysis of the poly(siloxane)-poly(tetrafluoroethylene) coating system. J Therm Anal Calorim. 2002;68(1):147-158.
 
Varvares MA, Montgomery WW, Hillman RE. Teflon granuloma of the larynx: etiology, pathophysiology, and management. Ann Otol Rhinol Laryngol. 1995;104(7):511-515.
 
Choi JK, Paek D, Lee JO. Normal predictive values of spirometry in Korean population. Tuberc Respir Dis. 2005;58(3):230-242.
 
Luft JH. Improvements in epoxy resin embedding methods. J Biophys Biochem Cytol. 1961;9:409-414.
 
Rybicki BA, Iannuzzi MC, Frederick MM, et al; ACCESS Research Group. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med. 2001;164(11):2085-2091.
 
Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med. 1997;336(17):1224-1234.
 
Bergin CJ, Müller NL, Vedal S, Chan-Yeung M. CT in silicosis: correlation with plain films and pulmonary function tests. AJR Am J Roentgenol. 1986;146(3):477-483.
 
Chong S, Lee KS, Chung MJ, Han J, Kwon OJ, Kim TS. Pneumoconiosis: comparison of imaging and pathologic findings. Radiographics. 2006;26(1):59-77.
 
Hull MJ, Abraham JL. Aluminum welding fume-induced pneumoconiosis. Hum Pathol. 2002;33(8):819-825.
 
Lee KP, Zapp JA Jr, Sarver JW. Ultrastructural alterations of rat lung exposed to pyrolysis products of polytetrafluoroethylene (PTFE, Teflon). Lab Invest. 1976;35(2):152-160.
 
Johnston CJ, Finkelstein JN, Mercer P, Corson N, Gelein R, Oberdörster G. Pulmonary effects induced by ultrafine PTFE particles. Toxicol Appl Pharmacol. 2000;168(3):208-215.
 

Figures

Figure Jump LinkFigure 1. A, Case 3 chest radiograph shows multiple bilateral tiny nodules in the lung fields. B, Case 3 high-resolution CT scan of the chest, demonstrates numerous bilateral centrilobular small nodules.Grahic Jump Location
Figure Jump LinkFigure 2. A-D, Histologic features of three cases of pulmonary granulomatous lesions induced by polytetrafluoroethylene (PTFE) exposure. A-C, Case 1 and 2 show mainly small airway-centered granulomatous micronodular lesions (arrows) with central dystrophic calcification. A, Case 1. B, Case 2. C, Higher magnification image of case 2 shows peribronchiolar conglomerated granulomatous nodules with central dystrophic calcification (arrows). D, Case 3. D1-D3, Higher magnification images of case 3 (D) show multiple scattered early granulomatous lesions (arrowheads) with a characteristic lymphangitic distribution (arrows) (D1, interlobular; D2, subpleural; and D3, peribronchiolar distributed granulomatous lesions). E, Typical finding of peribronchiolar granulomatous lesion. F, Multinucleated giant cells contain amorphous transparent materials (arrows). G, Amorphous semitransparent materials (arrows) are associated with black pigments in the granulomatous lesion. G, Inset, Polarizing microscopic examination shows semitransparent birefringence in the same hematoxylin-eosin (H&E) finding of panel G. (H&E, original magnification: A, B, D, × 5; C, × 20; D1, D2, and E, × 40; D3, × 100; F-G, × 400).Grahic Jump Location
Figure Jump LinkFigure 3. Electron microscopic findings show intracytoplasmic electron-lucent amorphous materials (asterisks) in histiocytes. A, Case 1. B, Case 2. C, Case 3. N = nucleus. Arrows indicate scattered electron-dense material. (Original magnification: A, × 3,500; B, × 5,000; C, × 4,000).Grahic Jump Location
Figure Jump LinkFigure 4. A, Energy-dispersive x-ray spectroscopy spectrum of a particle in a multinucleated giant cell shows: a prominent peak for F as well as other associated elements, including Si, C, O, Al, Ca, Na, Mg, and Fe. B, Fourier transform infrared spectroscopy analysis of a lung tissue specimen demonstrates a peak at 1,148 to 1,202 cm−1, which is characteristic of the C-F bond vibrations of PTFE. Al = aluminum; C = carbon; Ca = calcium; F = flourine; Fe = iron; Mg = magnesium; Na = sodium; O = oxygen; Si = silicon. See Figure 2 legend for expansion of other abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Characteristics of the Patients Who Developed Small Airway Granulomatosis Following Long-term Exposure to PTFE

Al = aluminum; C = carbon; Ca = calcium; Dlco = diffusing capacity of the lung for carbon monoxide; EM/EDS = electron microscopy/energy-dispersive x-ray spectroscopy analysis; F = fluorine; FT-IR = Fourier transform infrared spectroscopy; HRCT = high-resolution CT; O = oxygen; P = phosphorus; PTFE = polytetrafluoroethylene; Si = silicon; TLC = total lung capacity.

a 

Representing EDS spectrum.

References

Purser DA. Recent developments in understanding the toxicity of PTFE thermal decomposition products. Fire Mater. 1992;16(2):67-75.
 
Harris DK. Polymer-fume fever. Lancet. 1951;258(6692):1008-1011.
 
Bowler RG, Buckell M, et al. The risk of fluorosis in magnesium foundries. Br J Ind Med. 1947;4(4):216-222.
 
Shusterman DJ. Polymer fume fever and other fluorocarbon pyrolysis-related syndromes. Occup Med. 1993;8(3):519-531.
 
Albrecht WN, Bryant CJ. Polymer-fume fever associated with smoking and use of a mold-release spray containing polytetrafluoroethylene. J Occup Med. 1987;29(10):817-819.
 
Teng H. Overview of the development of the fluoropolymer industry. Appl Sci. 2012;2(2):496-512.
 
Dobkowski Z, Zielecka M. Thermal analysis of the poly(siloxane)-poly(tetrafluoroethylene) coating system. J Therm Anal Calorim. 2002;68(1):147-158.
 
Varvares MA, Montgomery WW, Hillman RE. Teflon granuloma of the larynx: etiology, pathophysiology, and management. Ann Otol Rhinol Laryngol. 1995;104(7):511-515.
 
Choi JK, Paek D, Lee JO. Normal predictive values of spirometry in Korean population. Tuberc Respir Dis. 2005;58(3):230-242.
 
Luft JH. Improvements in epoxy resin embedding methods. J Biophys Biochem Cytol. 1961;9:409-414.
 
Rybicki BA, Iannuzzi MC, Frederick MM, et al; ACCESS Research Group. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med. 2001;164(11):2085-2091.
 
Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med. 1997;336(17):1224-1234.
 
Bergin CJ, Müller NL, Vedal S, Chan-Yeung M. CT in silicosis: correlation with plain films and pulmonary function tests. AJR Am J Roentgenol. 1986;146(3):477-483.
 
Chong S, Lee KS, Chung MJ, Han J, Kwon OJ, Kim TS. Pneumoconiosis: comparison of imaging and pathologic findings. Radiographics. 2006;26(1):59-77.
 
Hull MJ, Abraham JL. Aluminum welding fume-induced pneumoconiosis. Hum Pathol. 2002;33(8):819-825.
 
Lee KP, Zapp JA Jr, Sarver JW. Ultrastructural alterations of rat lung exposed to pyrolysis products of polytetrafluoroethylene (PTFE, Teflon). Lab Invest. 1976;35(2):152-160.
 
Johnston CJ, Finkelstein JN, Mercer P, Corson N, Gelein R, Oberdörster G. Pulmonary effects induced by ultrafine PTFE particles. Toxicol Appl Pharmacol. 2000;168(3):208-215.
 
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