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Pulmonary Toxicity of Expancel^® Microspheres in the Rat

¹ National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Morgantown, West Virginia 26505
² Division of Applied Research and Technology, Cincinnati, Ohio 45226

Correspondence: Address correspondence to: Dale W. Porter, Ph.D., M/S 2015, NIOSH, 1095 Willowdale Road, Morgantown, WV 26505. E-mail:DPorter{at}cdc.gov

Expancel^® microspheres are thermoplastic microspheres enclosing hydrocarbon. These microspheres expand when heated, producing many applications. Because they have unknown biological persistence and toxicity, we investigated the toxicity of two unexpanded (11.1 and 15.4 µm mean diameter) and two expanded (3.1 and 5.5 µm mass median aerodynamic diameter) Expancel^® microspheres in intratracheally-instilled, male, Sprague–Dawley rats. Pulmonary histopathology was evaluated at 28 days postexposure. Bronchoalveolar lavage fluid was evaluated at days 1, 7, 14, and 28 days postexposure. Crystalline silica was the positive control. By histopathology, both unexpanded and expanded microspheres caused granulomatous bronchopneumonia characterized by macrophages and giants cells, suggesting a persistent foreign body response. Expanded, but not unexpanded microspheres, also caused eosinophilic bronchitis and bronchiolitis, mucous metaplasia of airways and organized granulomatous inflammation with associated fibrosis and frequent airway obstruction. In contrast, alveolar macrophage activation, polymorphonuclear leukocytes, LDH and albumin in bronchoalveolar laveage fluid were initially elevated but returned to near control levels at 28 days, and did not reflect the persistent granulomatous bronchopneumonia caused by Expancel^® microspheres. These findings emphasize the importance of histopathology for evaluating pulmonary toxicity, suggest that Expancel^® microspheres are a potential occupational hazard, and indicate a need for additional studies on their potential pulmonary toxicity.

[Supplementary materials are available for this article. Go to the publisher’s online edition of Toxicology Pathology for the following free supplemental resources: motion within unexpected microspheres in H&E-stained lung (supplementary Figure 1); broncholar epithelium 28 days following exposure to 551 DE 20 microspheres (supplementary Figure 2); membrane ruffling and some instances of phagocytosis within the microspheres (supplementary Figure 3)]

View larger version (20K): [in this window] [in a new window]   Figure 1 Bronchoalveolar lavage alveolar macrophages and polymorphonuclear leukocytes. (A) Bronchoalveolar lavage macrophages and (B) polymorphonuclear leukocyte numbers were determined at 1, 7, 14, and 28 days post-IT exposure. For each post-IT exposure time, an "a" indicates a significant difference versus saline control group, and a "b" indicates a significant difference versus silica-exposed group. Values represent mean ± SE, n = 7–8 per group. Significance was set at p 0.05.

View larger version (18K): [in this window] [in a new window]   Figure 2 Bronchoalveolar lavage fluid albumin and lactate dehydrogenase. (A) Bronchoalveolar lavage fluid albumin concentrations and (B) bronchoalveolar lavage fluid lactate dehydrogenase activities were determined at 1, 7, 14, and 28 days postexposure. For each postexposure time, an "a" indicates a significant difference versus saline control group, and a "b" indicates a significant difference versus silica-exposed group. Values represent mean ± SE, n = 7–8 per group. Significance was set at p 0.05.

View larger version (15K): [in this window] [in a new window]   Figure 3 Alveolar Macrophage Chemiluminescence. (A) Total alveolar macrophage chemiluminescence and (B) 1400W-sensitive alveolar macrophage chemiluminescence was determined at 1, 7, 14, and 28 days postexposure. For each postexposure time, an "a" indicates a significant difference versus saline control group, and a "b" indicates a significant difference versus silica-exposed group. Values represent mean ± SE, n = 7–8 per group. Significance was set at p 0.05.

Key Words: Microspheres • Lung • Bronchoalveolar Lavage • Pulmonary inflammation • Occupational respiratory disease • Granulomatous pneumonia

Abbreviations: IT, intratracheal • BAL, bronchoalveolar lavage • INSPEC, Inertial Spectrometer • PBS, Ca²⁺ and Mg²⁺-free phosphate-buffered saline • AM, alveolar macrophage • PMN, polymorphonuclear leukocyte • LDH, lactate dehydrogenase • AM CL, alveolar macrophage chemiluminescence • NBF, neutral-buffered formalin • NO, nitric oxide • SEM, scanning electron microscopy • H&E, hematoxylin and eosin • EMEM, Eagle’s Minimal Essential Medium

Toxicologic Pathology, Vol. 35, No. 5, 702-714 (2007)
DOI: 10.1080/01926230701481915


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