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

Abstract

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:

Sun, Bingbing ^[1]; Wang, Xiang ^[2]; Liao, Yu-Pei ^[1]; Ji, Zhaoxia ^[2]; Chang, Chong Hyun ^[2]; Pokhrel, Suman ^[3]; Ku, Justine ^[4]; Liu, Xiangsheng ^[1]; Wang, Meiying ^[1]; Dunphy, Darren R. ^[5]; Li, Ruibin ^[6]; Meng, Huan ^[1]; Mädler, Lutz ^[3]; Brinker, C. Jeffrey ^[7]; Nel, André E. ^[8]; Xia, Tian ^[8]

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+ Show Author Affiliations

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:

Tue Aug 02 00:00:00 EDT 2016

Research Org.:

Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

Sponsoring Org.:

USDOE National Nuclear Security Administration (NNSA)

OSTI Identifier:

1332917

Report Number(s):

SAND2016-10915J
Journal ID: ISSN 1936-0851; 648694; TRN: US1700176

Grant/Contract Number:  

AC04-94AL85000

Resource 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

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