title: Pulmonary exposures to Sepiolite nanoclay particulates in rats: resolution following multinucleate giant cell formation.
abstract: Sepiolite is a magnesium silicate-containing nanoclay mineral and is utilized as a nanofiller for nanocomposite applications. We postulated that lung exposures to Sepiolite clay samples could produce sustained effects. Accordingly, the pulmonary and extrapulmonary systemic impacts in rats of intratracheally instilled Sepiolite nanoclay samples were compared with quartz or ultrafine (uf) titanium dioxide particle-types at doses of 1mg/kg or 5mg/kg. All particulates were well characterized, and dedicated groups were evaluated by bronchoalveolar lavage, lung cell proliferation, macrophage functional assays and full body histopathology at selected times postexposure (pe). Bronchoalveolar lavage results demonstrated that quartz particles produced persistent, dose-dependent lung inflammatory responses measured from 24h through 3 months pe. Exposures to uf TiO(2) particles or Sepiolite samples produced transient neutrophilic responses at 24-h pe; however, unlike the other particle-types, Sepiolite exposures produced macrophage-agglomerates or multinucleate giant cells at 1 week, 5 weeks and 3 months pe. In vitro alveolar macrophage functional studies demonstrated that mononuclear cells recovered from quartz but not Sepiolite or uf TiO(2)-exposed rats were deficient in their chemotactic capacities. Moreover, lung parenchymal cell proliferation rates were increased in rats exposed to quartz but not Sepiolite or uf TiO(2) particles. Histopathological evaluation of lung tissues revealed that pulmonary exposures to Sepiolite nanoclay or quartz samples produced inflammation in centriacinar regions at 24-h pe but the effects decreased in severity over time for Sepiolite and increased for quartz-exposed rats. The quartz-induced lesions were progressive and were characterized at 3 months by acinar foamy alveolar macrophage accumulation and septal thickening due to inflammation, alveolar Type II cell hyperplasia and collagen deposition. In the Sepiolite nanoclay group, the finding of multinucleated giant cell accumulation associated with minor collagen deposition in acinar regions was rarely observed. Exposures to ultrafine TiO(2) produced minimal effects characterized by the occurrence of phagocytic macrophages in alveolar ducts. Full body histopathology studies were conducted at 24h and 3 months post particle exposures. Histopathological evaluations revealed minor particle accumulations in some mediastinal or thoracic lymph nodes. However, it is noteworthy that no extrapulmonary target organ effects were observed in any of the particle-exposed groups at 3 months postexposure.
authors.affiliation: DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, DE 19714-0050, USA. david.b.warheit@usa.dupont.com
authors.forename: David B
authors.initials: DB
authors.lastname: Warheit
authors.forename: Christie M
authors.initials: CM
authors.lastname: Sayes
authors.forename: Steven R
authors.initials: SR
authors.lastname: Frame
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Reed
mesh_terms: D000538:Aluminum Silicates / Q000494:pharmacology; D000818:Animals; D018893:Bronchoalveolar Lavage; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D000077215:Clay; D004305:Dose-Response Relationship, Drug; D015726:Giant Cells / Q000187:drug effects* / Q000502:physiology; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000502:physiology; D017633:Magnesium Silicates / Q000009:adverse effects*; D008297:Male; D057139:Nanofibers / Q000009:adverse effects*; D011791:Quartz / Q000009:adverse effects; D051381:Rats
chemical_list: D000538:Aluminum Silicates; D017633:Magnesium Silicates; D011791:Quartz; C001671:magnesium trisilicate; D000077215:Clay