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 acute membrane damage and acute pro-inflammatory 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 sub-chronic inflammation and pro-fibrogenic 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 sub-chronic pulmonary effects. In contrast, the NLRP3 inflammasome pathway was continuously activated by repetitive dose administration of 3×7 mg/kg fumed silica, one week apart. We also found that while single-dose exposure failed to induce pro-fibrotic 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 sub-chronic pro-inflammatory 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.

Structure activity relationships of engineered nanomaterials in inducing NLRP3 inflammasome activation and chronic lung fibrosis

“…70 Single bolus dose instillation of 21 mg/kg fumed silica did not induce sustained IL-1β production or sub-chronic pulmonary effects, due to the comparatively high rate of dissolution and clearance of fumed silica from the lung. In contrast, repetitive dosing could lead to biopersistence with a change in lung toxicity, and the NLRP3 inflammasome pathway was continuously activated by repetitive dose administration of 3 × 7 mg/kg fumed silica, one week apart.…”

Pro-Inflammatory and Pro-Fibrogenic Effects of Ionic and Particulate Arsenide and Indium-Containing Semiconductor Materials in the Murine Lung

“…71 It is also important to consider that the release of arsenic from III-V arsenides at chronic low exposures might induce lung cancer. 14, 71 In spite of using what may currently constitute an unrealistic high-dose in our studies, it is important to be aware of dosimetry considerations when assessing exposures to III-V particulates in the semiconductor industry, particularly in the maintenance areas. Successful technology has been implemented to assess the airborne spread of nanoparticles contained in the primary CMP slurries.…”

Facilitating Translational Nanomedicine via Predictive Safety Assessment

“…Although these findings have improved our understanding with respect to the correlation between Si-NPs physicochemical characteristics and their toxicity, further in vivo analyses are needed to facilitate their application in translational nanomedicine. A finding by Sun et al 29 indicated that although a single high-dose exposure of fumed Si-NPs to pulmonary system did not induce a profibrogenic effect, repetitive exposure at a lower dose led to a significant subchronic inflammatory response in the murine lungs. Though this study was focused on pulmonary toxicity of fumed silica, repetitive administration of colloidal Si-NPs might show similar pro-inflammatory effects in the long-term.…”