The production of pyrogenic (fumed)
silica is increasing worldwide at
a 7% annual growth rate, including expanded use in food,
pharmaceuticals, and other industrial products. Synthetic amorphous
silica, including fumed
silica, has been generally recognized as safe for use in food products by the Food and Drug Administration. However, emerging evidence from experimental studies now suggests that fumed
silica could be hazardous due to its
siloxane ring structure, high
silanol density, and "string-of-pearl-like" aggregate structure, which could combine to cause membrane disruption, generation of
reactive oxygen species, pro-inflammatory effects, and
liver fibrosis. Based on this structure-activity analysis (SAA), we investigated whether calcination and
rehydration of fumed
silica changes its hazard potential in the lung due to an effect on
silanol density display. This analysis demonstrated that the accompanying change in surface reactivity could indeed impact
cytokine production in macrophages and acute
inflammation in the lung, in a manner that is dependent on
siloxane ring reconstruction. Confirmation of this SAA in vivo, prompted us to consider safer design of fumed
silica properties by
titanium and
aluminum doping (0-7%), using flame spray pyrolysis. Detailed characterization revealed that increased Ti and Al doping could reduce surface
silanol density and expression of three-membered
siloxane rings, leading to dose-dependent reduction in
hydroxyl radical generation, membrane perturbation,
potassium efflux, NLRP3
inflammasome activation, and cytotoxicity in THP-1 cells. The reduction of NLRP3
inflammasome activation was also confirmed in bone-marrow-derived macrophages. Ti doping, and to a lesser extent Al doping, also ameliorated acute
pulmonary inflammation, demonstrating the possibility of a safer design approach for fumed
silica, should that be required for specific use circumstances.