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Title: Repetitive Dosing of Fumed Silica Leads to Profibrogenic Effects through Unique Structure–Activity Relationships and Biopersistence in the Lung

Contrary to the notion that the use of fumed silica in consumer products can “generally (be) regarded as safe” (GRAS), the high surface reactivity of pyrogenic silica differs from other forms of synthetic amorphous silica (SAS), including the capacity to induce membrane damage and acute proinflammatory changes in the murine lung. Additionally, the chain-like structure and reactive surface silanols also allow fumed silica to activate the NLRP3 inflammasome, leading to IL-1β production. This pathway is known to be associated with subchronic inflammation and profibrogenic effects in the lung by α-quartz and carbon nanotubes. Different from the latter materials, bolus dose instillation of 21 mg/kg fumed silica did not induce sustained IL-1β production or subchronic pulmonary effects. In contrast, the NLRP3 inflammasome pathway was continuously activated by repetitive-dose administration of 3 × 7 mg/kg fumed silica, 1 week apart. We also found that while single-dose exposure failed to induce profibrotic effects in the lung, repetitive dosing can trigger increased collagen production, even at 3 × 3 mg/kg. The change between bolus and repetitive dosing was due to a change in lung clearance, with recurrent dosing leading to fumed silica biopersistence, sustained macrophage recruitment, and activation of the NLRP3 pathway. These subchronicmore » proinflammatory effects disappeared when less surface-reactive titanium-doped fumed silica was used for recurrent administration. Finally, these data indicate that while fumed silica may be regarded as safe for some applications, we should reconsider the GRAS label during repetitive or chronic inhalation exposure conditions.« less
Authors:
 [1] ;  [2] ;  [1] ;  [2] ;  [2] ;  [3] ;  [4] ;  [1] ;  [1] ;  [5] ;  [6] ;  [1] ;  [3] ;  [7] ;  [8] ;  [8]
  1. Univ. of California, Los Angeles, CA (United States). Division of NanoMedicine
  2. Univ. of California, Los Angeles, CA (United States). California NanoSystems Inst.
  3. Univ. of Bremen (Germany). Foundation Inst. of Materials Science (IWT)
  4. Univ. of California, Los Angeles, CA (United States). Dept. of Ecology and Evoloutionary Biology
  5. Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Chemical and Nuclear Engineering
  6. Univ. of California, Los Angeles, CA (United States). Division of NanoMedicine; Soochow Univ., Suzhou (China). School for Radiological and Interdisciplinary Sciences (RAD-X)
  7. Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Chemical and Nuclear Engineering and Dept. of Molecular Genetics and Microbiology; Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Self-Assembled Materials Dept.
  8. Univ. of California, Los Angeles, CA (United States). Division of NanoMedicine and California NanoSystems Inst.
Publication Date:
OSTI Identifier:
1332917
Report Number(s):
SAND2016--10915J
Journal ID: ISSN 1936-0851; 648694
Grant/Contract Number:
AC04-94AL85000
Type:
Accepted Manuscript
Journal Name:
ACS Nano
Additional Journal Information:
Journal Volume: 10; Journal Issue: 8; Journal ID: ISSN 1936-0851
Publisher:
American Chemical Society
Research Org:
Sandia National Laboratories (SNL-NM), Albuquerque, NM (United States)
Sponsoring Org:
USDOE National Nuclear Security Administration (NNSA)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY biopersistence; dissolution; fumed silica; lung fibrosis; metal doping