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. In addition, 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. However, 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 subchronic proinflammatory effects disappeared when less surface-reactive titanium-doped fumed silica was used for recurrent administration. All considered, 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.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Sun
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Yu-Pei
authors.initials: YP
authors.lastname: Liao
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Ji
authors.forename: Chong Hyun
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Foundation Institute of Materials Science (IWT), Department of Production Engineering, University of Bremen , 28359 Bremen, Germany.
authors.forename: Suman
authors.initials: S
authors.lastname: Pokhrel
authors.forename: Justine
authors.initials: J
authors.lastname: Ku
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Liu
authors.forename: Meiying
authors.initials: M
authors.lastname: Wang
authors.forename: Darren R
authors.initials: DR
authors.lastname: Dunphy
authors.affiliation: School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University , Suzhou 215123, China.
authors.forename: Ruibin
authors.initials: R
authors.lastname: Li
authors.forename: Huan
authors.initials: H
authors.lastname: Meng
authors.affiliation: Foundation Institute of Materials Science (IWT), Department of Production Engineering, University of Bremen , 28359 Bremen, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Mädler
authors.affiliation: Self-Assembled Materials Department, Sandia National Laboratories , P.O. Box 5800 MS1349, Albuquerque, New Mexico 87185, United States.
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Brinker
authors.forename: André E
authors.initials: AE
authors.lastname: Nel
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
mesh_terms: D000818:Animals; D058847:Inflammasomes; D008168:Lung / Q000737:chemistry*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology; D037742:Nanotubes, Carbon; D012822:Silicon Dioxide / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D037742:Nanotubes, Carbon; C492716:Nlrp3 protein, mouse; D012822:Silicon Dioxide
keywords: biopersistence; dissolution; fumed silica; lung fibrosis; metal doping