Are nearly free silanols a unifying structural determinant of silica particle toxicity?

Due to the abundance of and potential exposure to crystalline and amorphous silica dusts (Fig. 1 A ), silica toxicity has been investigated for over 100 y, and currently the International Agency for Research on Cancer classifies cristobalite and quartz as group 1 (carcinogenic to humans) (1, 2). In contrast, amorphous silica is classified as having inadequate evidence for carcinogenicity (group 3) and is considered as generally recognized as safe for use in food additives and packaging by the Food and Drug Administration (2, 3). However, all amorphous silica is not created equal, and there is mounting evidence that pyrolytic or so-called fumed silica is significantly more toxic than colloidal amorphous silica (e.g., precipitated, Stober, or mesoporous silica) (4). The synthesis processes of these two classes of amorphous silicas are significantly different and may account for the observed differences in toxicity. Pyrolytic silica is synthesized via flame pyrolysis of SiCl4 at high temperature ( ca . 1,300 °C) according to the net reaction SiCl 4 + 2 H 2 + O 2 → SiO 2 + 4 HCl followed by rapid thermal quenching, whereas colloidal amorphous silica is formed by the condensation of soluble silicates under low-temperature aqueous conditions according to the net reaction Si ( OH ) 4 → SiO 2 + 2 H 2 O . The most common toxicity pathway identified for both crystalline and amorphous silica particles is inflammasome activation. The Nalp3–inflammasome activation pathway, which underlies asbestosis and silicosis (5), is a cellular defense mechanism requiring two signals. Signal 1 (priming) results from toll-like receptor 4 activation causing nuclear factor κB activation and pro-interleukin 1β (pro-IL-1β) production. Signal 2 (activation) is provided by a plethora of stimuli, such as pore-forming toxins, viral RNA, and particulate matter and activates the NLRP3 inflammasome, resulting in generation of the proinflammatory … \n\n[↵][1]1To whom correspondence may be addressed. Email: jbrinker{at}unm.edu.\n\n [1]: #xref-corresp-1-1