Compendium of the most significant studies with reference to properties, intake, effects.

Dai C, Huang Y, Zhou Y. Research progress about the relationship between nanoparticles silicon dioxide and lung cancer. Zhongguo Fei Ai Za Zhi. 2014 Oct 20;17(10):760-4. doi: 10.3779/j.issn.1009-3419.2014.10.09. 

Abstract. Nano-silicon dioxide widely distributed in plastic, rubber, ceramics, paint, adhesives, and many other fields, and it is the product of coal combustion. A growing evidence shows that nano-silicon dioxide has certain correlation with respiratory system disease. In this paper, we synthesized existing researches of domestic and abroad, summarized the lung toxicity of nanoparticles. This article are reviewed from the physical and chemical properties of nanoparticles silicon dioxide, exposure conditions and environment, and the pathogenic mechanism of nano-silicon dioxide.

Yoo NK, Jeon YR, Choi SJ. Determination of Two Differently Manufactured Silicon Dioxide Nanoparticles by Cloud Point Extraction Approach in Intestinal Cells, Intestinal Barriers and Tissues. Int J Mol Sci. 2021 Jun 29;22(13):7035. doi: 10.3390/ijms22137035.

Abstract. Food additive amorphous silicon dioxide (SiO2) particles are manufactured by two different methods-precipitated and fumed procedures-which can induce different physicochemical properties and biological fates. In this study, precipitated and fumed SiO2 particles were characterized in terms of constituent particle size, hydrodynamic diameter, zeta potential, surface area, and solubility. Their fates in intestinal cells, intestinal barriers, and tissues after oral administration in rats were determined by optimizing Triton X-114-based cloud point extraction (CPE). The results demonstrate that the constituent particle sizes of precipitated and fumed SiO2 particles were similar, but their aggregate states differed from biofluid types, which also affect dissolution properties. Significantly higher cellular uptake, intestinal transport amount, and tissue accumulation of precipitated SiO2 than of fumed SiO2 was found. The intracellular fates of both types of particles in intestinal cells were primarily particle forms, but slowly decomposed into ions during intestinal transport and after distribution in the liver, and completely dissolved in the bloodstream and kidneys. These findings will provide crucial information for understanding and predicting the potential toxicity of food additive SiO2 after oral intake.

Dekkers S, Krystek P, Peters RJ, Lankveld DP, Bokkers BG, van Hoeven-Arentzen PH, Bouwmeester H, Oomen AG. Presence and risks of nanosilica in food products. Nanotoxicology. 2011 Sep;5(3):393-405. doi: 10.3109/17435390.2010.519836.

Abstract. This study uniquely describes all steps of the risk assessment process for the use of one specific nanomaterial (nanosilica) in food products. The aim was to identify gaps in essential knowledge and the difficulties and uncertainties associated with each of these steps. Several food products with added silica (E551) were analyzed for the presence, particle size and concentration of nanosilica particles, using experimental analytical data, and the intake of nanosilica via food was estimated. As no information is available on the absorption of nanosilica from the gastrointestinal tract, two scenarios for risk assessment were considered. The first scenario assumes that the silica is absorbed as dissolved silica, while the second scenario assumes that nanosilica particles themselves are absorbed from the gastrointestinal tract. For the first scenario no adverse effects are expected to occur. For the second scenario there are too many uncertainties to allow proper risk assessment. Therefore, it is recommended to prioritize research on how nanosilica is absorbed from the gastrointestinal tract.

Fruijtier-Pölloth C. The safety of nanostructured synthetic amorphous silica (SAS) as a food additive (E 551). Arch Toxicol. 2016 Dec;90(12):2885-2916. doi: 10.1007/s00204-016-1850-4. 

Abstract. Synthetic amorphous silica (SAS) meeting the specifications for use as a food additive (E 551) is and has always been produced by the same two production methods: the thermal and the wet processes, resulting in E 551 products consisting of particles typically in the micrometre size range. The constituent particles (aggregates) are typically larger than 100 nm and do not contain discernible primary particles. Particle sizes above 100 nm are necessary for E 551 to fulfil its technical function as spacer between food particles, thus avoiding the caking of food particles. Based on an in-depth review of the available toxicological information and intake data, it is concluded that the SAS products specified for use as food additive E 551 do not cause adverse effects in oral repeated-dose studies including doses that exceed current OECD guideline recommendations. In particular, there is no evidence for liver toxicity after oral intake. No adverse effects have been found in oral fertility and developmental toxicity studies, nor are there any indications from in vivo studies for an immunotoxic or neurotoxic effect. SAS is neither mutagenic nor genotoxic in vivo. In intact cells, a direct interaction of unlabelled and unmodified SAS with DNA was never found. Differences in the magnitude of biological responses between pyrogenic and precipitated silica described in some in vitro studies with murine macrophages at exaggerated exposure levels seem to be related to interactions with cell culture proteins and cell membranes. The in vivo studies do not indicate that there is a toxicologically relevant difference between SAS products after oral exposure. It is noted that any silicon dioxide product not meeting established specifications, and/or produced to provide new functionality in food, requires its own specific safety and risk assessment.

Casey TR, Bamforth CW. Silicon in beer and brewing. J Sci Food Agric. 2010 Apr 15;90(5):784-8. doi: 10.1002/jsfa.3884.

Abstract. Background: It has been claimed that beer is one of the richest sources of silicon in the diet; however, little is known of the relationship between silicon content and beer style and the manner in which beer is produced. The purpose of this study was to measure silicon in a diversity of beers and ascertain the grist selection and brewing factors that impact the level of silicon obtained in beer. Results: Commercial beers ranged from 6.4 to 56.5 mg L(-1) in silicon. Products derived from a grist of barley tended to contain more silicon than did those from a wheat-based grist, likely because of the high levels of silica in the retained husk layer of barley. Hops contain substantially more silicon than does grain, but quantitatively hops make a much smaller contribution than malt to the production of beer and therefore relatively less silicon in beer derives from them. During brewing the vast majority of the silicon remains with the spent grains; however, aggressive treatment during wort production in the brewhouse leads to increased extraction of silicon into wort and much of this survives into beer. (c) 2010 Society of Chemical Industry.

Givens BE, Diklich ND, Fiegel J, Grassian VH. Adsorption of bovine serum albumin on silicon dioxide nanoparticles: Impact of pH on nanoparticle-protein interactions. Biointerphases. 2017 May 3;12(2):02D404. doi: 10.1116/1.4982598. 

Abstract. Bovine serum albumin (BSA) adsorbed on amorphous silicon dioxide (SiO2) nanoparticles was studied as a function of pH across the range of 2 to 8. Aggregation, surface charge, surface coverage, and protein structure were investigated over this entire pH range. SiO2 nanoparticle aggregation is found to depend upon pH and differs in the presence of adsorbed BSA. For SiO2 nanoparticles truncated with hydroxyl groups, the largest aggregates were observed at pH 3, close to the isoelectric point of SiO2 nanoparticles, whereas for SiO2 nanoparticles with adsorbed BSA, the aggregate size was the greatest at pH 3.7, close to the isoelectric point of the BSA-SiO2 complex. Surface coverage of BSA was also the greatest at the isoelectric point of the BSA-SiO2 complex with a value of ca. 3 ± 1 × 1011 molecules cm-2. Furthermore, the secondary protein structure was modified when compared to the solution phase at all pH values, but the most significant differences were seen at pH 7.4 and below. It is concluded that protein-nanoparticle interactions vary with solution pH, which may have implications for nanoparticles in different biological fluids (e.g., blood, stomach, and lungs).

Kim JH, Kim CS, Ignacio RM, Kim DH, Sajo ME, Maeng EH, Qi XF, Park SE, Kim YR, Kim MK, Lee KJ, Kim SK. Immunotoxicity of silicon dioxide nanoparticles with different sizes and electrostatic charge. Int J Nanomedicine. 2014 Dec 15;9 Suppl 2(Suppl 2):183-93. doi: 10.2147/IJN.S57934. 

Abstract. Silicon dioxide (SiO2) nanoparticles (NPs) have been widely used in the biomedical field, such as in drug delivery and gene therapy. However, little is known about the biological effects and potential hazards of SiO2. Herein, the colloidal SiO2 NPs with two different sizes (20 nm and 100 nm) and different charges (L-arginine modified: SiO2 (EN20[R]), SiO2 (EN100[R]); and negative: SiO2 (EN20[-]), SiO2 (EN100[-]) were orally administered (750 mg/kg/day) in female C57BL/6 mice for 14 days. Assessments of immunotoxicity include hematology profiling, reactive oxygen species generation and their antioxidant effect, stimulation assays for B- and T-lymphocytes, the activity of natural killer (NK) cells, and cytokine profiling. In vitro toxicity was also investigated in the RAW 264.7 cell line. When the cellularity of mouse spleen was evaluated, there was an overall decrease in the proliferation of B- and T-cells for all the groups fed with SiO2 NPs. Specifically, the SiO2 (EN20(-)) NPs showed the most pronounced reduction. In addition, the nitric oxide production and NK cell activity in SiO2 NP-fed mice were significantly suppressed. Moreover, there was a decrease in the serum concentration of inflammatory cytokines such as interleukin (IL)-1β, IL-12 (p70), IL-6, tumor necrosis factor-α, and interferon-γ. To elucidate the cytotoxicity mechanism of SiO2 in vivo, an in vitro study using the RAW 264.7 cell line was performed. Both the size and charge of SiO2 using murine macrophage RAW 264.7 cells decreased cell viability dose-dependently. Collectively, our data indicate that different sized and charged SiO2 NPs would cause differential immunotoxicity. Interestingly, the small-sized and negatively charged SiO2 NPs showed the most potent in vivo immunotoxicity by way of suppressing the proliferation of lymphocytes, depressing the killing activity of NK cells, and decreasing proinflammatory cytokine production, thus leading to immunosuppression.

Silicon dioxide 

is a very common chemical compound, silicon oxide. The term 'silicon dioxide' is derived from its constituent elements:

• "dioxide" indicates that there are two oxygen atoms for every silicon atom in the compound. The prefix 'di-' comes from the Greek word 'two' and 'oxide' refers to the oxygen component of the compound.
• "Silicon" is a chemical element with the symbol Si and the atomic number 14. It is a hard, brittle crystalline solid with a blue-grey metallic lustre, and is a tetravalent metalloid and semiconductor.

The synthesis of silicon dioxide can occur naturally or be produced industrially. Here are some common methods:

• Natural formation: silicon dioxide forms naturally over time through geological processes. It is the main component of sand and quartz and is also found in many types of rock.
• From silicon: silicon dioxide can be produced from silicon through oxidation. When silicon is exposed to oxygen (in the air), it reacts to form silicon dioxide. This is the principle behind the formation of a thin layer of silicon dioxide on the surface of silicon wafers used in the semiconductor industry.
• From sodium silicate: Silicon dioxide can also be produced from sodium silicate, also known as water glass. 
• From tetraethylorthosilicate (TEOS): In the sol-gel process, a common method for producing silica gels and aerogels, silicon dioxide is synthesised from a silicon alkoxide, such as tetraethylorthosilicate (TEOS). When TEOS is hydrolysed and then condensed, it forms silicon dioxide.

It appears in the form of a white powder with a native particle size of 5nm to 40nm with functions of filling, thickening, strengthening and thixotropy of various materials. 

In industry, it is used in the form of "Fumed silica" synthesized by pyrolysis method in which halogenated silanes (hydrolyzed chlorosilane) react with oxygen and hydrogen at high temperature. 

This type of silica is used in many industries:

• Glass
• Rubber
• Optics
• Construction
• Food
• Medicine

Where it comes from

It is found in the earth's crust, in rocks in crystalline or amorphous form.

What it is used for and where

Food

In particular, in food can be used in foods, food supplements and other as anti-caking agent. Labelled as food additive thickener E551 in the European Food Additives List,  its function is to avoid clumping in sauces, food supplements, cooking salt, dry foods. "Anti-caking agents" are substances that reduce the tendency of individual particles of a food product to adhere to each other.

Chillproofing agent in beer.

Pharmaceuticals

In the pharmaceutical industry, colloidal silica improves powder flow as it acts on breaking the interparticle force of silica particles adhering to the product surface. It is a thickening agent. Food thickeners are normally used to facilitate the ingestion of drugs in tablet form. Some thickeners directly influence the dissolution and disintegration of tablets and may even delay their dissolution.

It should not exceed 2% of the total weight of the product in which it is inserted.

Cosmetics

• Abrasive agent. It contains abrasive particles to remove stains or biofilm that accumulate on the stratum corneum or teeth. Baking soda, kieselguhr, silica and many others have abrasive properties. Peeling or exfoliating products used in dermatology or cosmetic applications contain abrasive agents in the form of synthetic microspheres, however these microspheres or abrasive particles are not biodegradable and create pollution in aquatic ecosystems.
• Absorbent. Absorbs substances dispersed or dissolved in aqueous solutions, water/oil, oil/water.
• Anticaking agent. This compound facilitates free flow and prevents aggregation or clumping of substances in a formulation by reducing the tendency of certain particles to stick together. 
• Bulking agent. It regulates the water content, dilutes other solids, can increase the volume of a product for better flow, acts as a buffer against organic acids, helps to keep the pH of the mixture within a certain level.
• Opacifying agent. It is useful into formulations that may be translucent or transparent to make them opaque and less permeable to light.
• Viscosity control agent. It controls and adapts, Increasing or decreasing, viscosity to the required level for optimal chemical and physical stability of the product and dosage in gels, suspensions, emulsions, solutions.

Other uses

• controls the rheology and thixotropy of binder systems, polymers, liquids, etc.
• reinforces HTV- and RTV- 2K silicone rubber
• absorbent and carrier in ink-jet printing coatings
• filling for dental materials
• low-temperature and high-temperature insulation as a carrier catalyst, with significant thermal insulation.

Safety

Regarding its toxicity, we must refer to nanoparticles, rather than milligrams (2) since its presence derives, mainly in the environment, from plastics, rubber, ceramics, paints, adhesives and others and it is also the product of coal combustion (3).

The potential risk of nanoparticles from air pollution has recently attracted a great deal of attention. Although the toxicology of nanoparticles has been extensively studied, little work has been reported on the combined effect of silicon dioxide (SiO₂) nanoparticles and cold exposure at the cellular level. 

The haze problem has a major impact on public health, and has been a widespread concern in recent years. Studies have shown that ultrafine particulate matter (PM 0.1 ), which is equivalent to nanoparticles, is harmful to humans. The increasing use of nanoparticles for a wide range of commercial, industrial, and biomedical applications has led to safety concerns (4).

In this study, the genotoxic effects of SiO₂^EN20(-) and SiO₂^EN100(-) were elucidated using four genotoxicity assays in standardized Good Laboratory Practice system protocols. Although the different exposure routes in this study may induce genotoxicity from SiO₂^EN20(-) and SiO₂^EN100(-) in different organs in in vivo systems, the data suggest that SiO2 are not genotoxic substances based on OECD test guidelines (5).

The results of this research confirmed that the addition of colloidal silica in microemulsion simultaneously loaded with vitamins C and E improved the skin bioavailability of the vitamins due to its dual influence on the delivery characteristics of the microemulsion and the properties of the skin (6).

Silicon dioxide studies

General features:

• refractive index    n20/D 1.46 (lit.)
• surface area    395 m2/g±25 m2/g
• density    2.3 lb/cu.ft at 25 °C (bulk density)(lit.)

• Molecular Formula : SiO₂  O₂Si
• Molecular Weight : 60.08
• CAS : 112926-00-8   7631-86-9

• UNII  ETJ7Z6XBU4
• EC Number  215-683-2
• DSSTox Substance ID  DTXSID1029677      DTXSID4029852     DTXSID5041801 e molti altri
• MDL number  MFCD00011232
• PubChem Substance ID 24866359
• InChI=1S/O2Si/c1-3-2
• InChI Key    VYPSYNLAJGMNEJ-UHFFFAOYSA-N
• SMILES    O=[Si]=O
• IUPAC dioxosilane
• ChEBI 30563
• MDL number  MFCD00011232
• PubChem Substance ID   57654622
• ISC    0248   0807    0808    0809 
• RTECS    VV7325000    VV7330000    VV7335000
• NCI    C29853
• RXCUI    9771    314826    1362874

Synonyms: 

• Silicon dioxide
• Silicon dioxide amorphous
• Silicic anhydride

References_______________________________________________________________________

(1) Tran DT, Majerová D, Veselý M, Kulaviak L, Ruzicka MC, Zámostný P. On the mechanism of colloidal silica action to improve flow properties of pharmaceutical excipients. Int J Pharm. 2019 Feb 10;556:383-394. doi: 10.1016/j.ijpharm.2018.11.066.

(2) Petrick L, Rosenblat M, Paland N, Aviram M. Silicon dioxide nanoparticles increase macrophage atherogenicity: Stimulation of cellular cytotoxicity, oxidative stress, and triglycerides accumulation. Environ Toxicol. 2016 Jun;31(6):713-23. doi: 10.1002/tox.22084.

(3) Dai C, Huang Y, Zhou Y. Research progress about the relationship between nanoparticles silicon dioxide and lung cancer. Zhongguo Fei Ai Za Zhi. 2014 Oct 20;17(10):760-4. Chinese. doi: 10.3779/j.issn.1009-3419.2014.10.09.

Hassankhani R, Esmaeillou M, Tehrani AA, Nasirzadeh K, Khadir F, Maadi H. In vivo toxicity of orally administrated silicon dioxide nanoparticles in healthy adult mice. Environ Sci Pollut Res Int. 2015 Jan;22(2):1127-32. doi: 10.1007/s11356-014-3413-7.

(4) Zhang Y, Li X, Lin Y, Zhang L, Guo Z, Zhao D, Yang D. The combined effects of silicon dioxide nanoparticles and cold air exposure on the metabolism and inflammatory responses in white adipocytes. Toxicol Res (Camb). 2017 Jul 6;6(5):705-710. doi: 10.1039/c7tx00145b.

(5) Kwon JY, Kim HL, Lee JY, Ju YH, Kim JS, Kang SH, Kim YR, Lee JK, Jeong J, Kim MK, Maeng EH, Seo YR. Undetactable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests. Int J Nanomedicine. 2014 Dec 15;9 Suppl 2(Suppl 2):173-81. doi: 10.2147/IJN.S57933. Erratum in: Int J Nanomedicine. 2015;10:4621. 

(5) Kwon JY, Kim HL, Lee JY, Ju YH, Kim JS, Kang SH, Kim YR, Lee JK, Jeong J, Kim MK, Maeng EH, Seo YR. Undetactable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests. Int J Nanomedicine. 2014 Dec 15;9 Suppl 2(Suppl 2):173-81. doi: 10.2147/IJN.S57933. Erratum in: Int J Nanomedicine. 2015;10:4621. 

(6) Rozman B, Gosenca M, Gasperlin M, Padois K, Falson F. Dual influence of colloidal silica on skin deposition of vitamins C and E simultaneously incorporated in topical microemulsions. Drug Dev Ind Pharm. 2010 Jul;36(7):852-60. doi: 10.3109/03639040903541187.