Keywords

1 Introduction

Silicon is the second most prevalent element in the earth’s crust existing primarily as oxygen-containing silica and silicates and accounting for around 27% of elemental mass with oxygen comprising approximately 45% [1–3]. Silica is omnipotent being present in almost all of the earth’s minerals, rocks, sands, and clays and exists in myriad chemical forms expressed as quartz, emerald, feldspar, serpentine, mica, talc, clay, asbestos, and glass all of which have different uses [4,5]. Overall, quartz and aluminosilicates are the two most predominant silicates [6]. As an element, silicon has found widespread use in industrial applications often as a component of fabricated steel, a component of abrasives (silicon carbide), a building block of transistors (along with boron, gallium, arsenic, etc.), solar cells, rectifiers, and other electronic solid-state devices [7]. Industrial applications also include synthesis of glass when derived from sand-based silica, production of computer chips, and as a filler for paint and rubber ceramics, in lubricants, concrete and bricks, as well as being used for medical devices such as silicone implants [5]. Although silicon is used frequently for technical applications, its exposure to humans is fairly limited and largely in chemical forms that are not readily absorbed nor bioavailable.

Silica is used widely in the food and beverage industry as a food additive, i.e., anti-caking agent in foods, clarifying agent in beverages, viscosity controlling agent, as an anti-foaming agent, dough modifier, and as an excipient in drugs and vitamins [5]. Thus, silicon as silica is a dietary component although largely assumed to be inert when provided in forms typically used in the aforementioned applications. Nonetheless, humans are exposed to diet-derived forms of silica suggesting potential capacity for absorption and ultimate bioavailability, which raises the question of whether silicon as a molecular component can exert beneficial, biological effects in humans. Currently, silicon is not recognized as a nutrient in humans although emerging research suggests benefit from consumption of water-soluble forms. To that end, there is renewed growing interest in the potential beneficial effects of silica on human health.

Regarding inadvertent environmental exposure, previous research, in large part, has explored the toxic effects of inhaled crystalline silica and silica-derived asbestos. In fact, silicon has long been recognized as a pulmonary carcinogen with resultant silicosis or asbestosis developing upon prolonged and/or heavy exposure to airborne material [8]. Silicosis is a disease of the lungs caused by continued inhalation of the dust of minerals that contain silica and is characterized by progressive fibrosis and a chronic shortness of breath [9]. Asbestosis is similar in etiology and pathology but distinct as an exposure. While there are intrinsic dangers associated with inhalation of crystalline silica, there are multiple forms of silica in nature that are not toxic. Although non-toxic, the question remains as to the relative water-solubility of different compounds, relative amounts ingested, efficiency of absorption and overall bioavailability. Low-molecular-weight silica can dissolve in water as silicic acid rendering it bioavailable and potentially a beneficial component in humans. Collectively, the lack of understanding of the relative dependence of the physicochemical structure of silica and silicates on water-solubility for absorption has limited overall research interest in aqueous silica. As a result, a clearer understanding of the chemistry of silica, specifically of aqueous orthosilicic acid, is critical to fostering much needed research on potential health benefits.

2 Silicon Biochemistry

2.1 Silicon Distribution and Prevalence in Nature

Chemically, silica is an oxide of silicon and represented by silicon dioxide (SiO2). Silicon itself is a tetravalent metalloid with chemical properties somewhere in between that of a metal and non-metal element. Its presence is second only to oxygen in its abundance on earth comprising almost a third of the earth’s crust. In its pure form, silicon typically does not exist in a natural elemental state due to its extreme propensity to undergo reactions with ambient oxygen and water. For example, silica, SiO2, and other oxides, are ubiquitously found in polymerized combinations with metals and embedded in geologic rock formations. Given its omnipotence, overall prevalence and reactivity with other elements, it clearly exists in myriad forms with differing physicochemical properties with some that are toxic and others that are seemingly critical for health.

Silica is largely present in geographical formations and not readily released from these substrates except through natural, but significant, weathering of these structures. Overall, the forms and resultant molecular sizes of polymers and aggregates are dependent on pH and concentrations in aqueous matrices [10]. For example, at low concentrations (<2 mM) silicon exists in a monomeric acidic form (pK a 9.6) as orthosilicic acid, which imparts a fair degree of water solubility and certainly more than the higher-molecular-weight forms. As concentrations increase, polymerization will occur to form oligomers and eventually colloids, then aggregates and solid amorphous precipitates with a clear concentration dependence on solubility. As one might surmise, the increasing molecular weight and structural complexity restricts water solubility and, as a result, limits potential absorption by humans and animals.

2.1.1 Dietary Sources

Silica exists in the food chain with concentrations tending to be much higher in plant-based foods, i.e., phytolithic, than animal foods [11]. Beverages, however, are the major contributor to dietary silica, or silicon, and include water, coffee, and beer (due to barley, hops, etc.) where fluid ingestion alone can account for ≥20% of intake [12–14]. Beer is the major source of bioavailable silicon for males with concentrations of 9–39 mg/L [14–16]. Silica is also prevalent in municipal water supplies but is particularly high in bottled spring and artesian waters depending on the respective geological source [17]. In fact, beverages alone contribute up to 55% of total dietary intake of silicon as water-soluble silica. Dietary grains and grain products including cereals, oats, barley, wheat flour, pasta, pastries, and polished rice contribute 14% of ingested silicon and vegetables contribute 8% [18]. In the Western diet, major sources of silicon are cereals (30%) followed by fruits, beverages, and vegetables, which together make up 75% of total silicon intake [19]. Processing and refinement of grains remove silicon during the processes but silica-derived food additives can replace the stripped silicon and increase the content although the relative absorptivity of added silicon is questionable. Overall, estimation of dietary intake from all sources is approximately 20–50 mg silicon/day for Western populations but up to ~200 mg/day for populations consuming a more plant-based diet such as populations from India and China [12,18,20–22].

The presence of large amounts of silica in geological formations contributes greatly to the silica content of water. For example, in the United Kingdom, silicon concentrations are ≤2.5 mg/L in north and west Britain but up to 14 mg/L in south and east Britain [23–25]. Silica is found in fresh water at concentrations of 1–100 mg/L depending on the geographical location, e.g., soil content. Typical municipal water supplies can provide 4–11 mg/L of aqueous silica as noted in a study of the large cities of France. Levels of around 18–20 mg/L occur in the water of large cities of the United States. Bottled waters also contain modest concentrations of silica ranging from 8 to 36 mg/L as noted for the French brands Badoit, Vichy Celestian, and Volvic [26]. Interestingly, bottled water from Malaysia contains 30–40 mg/L silica and from the Fiji Islands contains 85 mg/L silica, more than four times the levels found in fresh water and municipal supplies and over twice that of other bottled waters, presumably due to the leaching of water-soluble silica from volcanic rock. Collectively, aqueous sources provide a wide range of concentrations of water-soluble, bioavailable silica.

There are other dietary sources of silicon including primarily food additives and dietary supplements. For foods, silicon may be added to processed, manufactured, and distributed foods as anticaking agents, thickeners, stabilizers, and clarifying agents, significantly increasing the overall silicon concentration [27]. However, silicates are generally considered to be inert and, as a result, not absorbed to any great extent by humans. In particular, polymeric silicic acids and amorphous silicon dioxide are poorly absorbed. Dietary supplements are an alternative silicon source containing orthosilicic acid or other forms that are presumably modified to a form that is water-soluble, absorbed, and bioavailable although this does not universally apply [28,29]. The estimated overall bioavailability of silicon from supplements ranges from <1 to >50%, a remarkably wide range, and depends on the formulation and concentration [6].

Silica is prevalent in the typical human diet at around 10–25 mg/day and generally considered safe, even if indigestible and non-absorbable. Although a biomarker of silicon status has yet to be developed, approximately 41% of ingested silicon is excreted in urine, which is significantly correlated with dietary consumption of silicon [20,30]. The lack of clear understanding of the myriad of chemical forms of silica and significant, widely communicated likelihood of increased risk of cancer has unduly overshadowed the study of the potential protective effects of silica on human health. It is the intent of this review to provide insight into the chemical properties of silica that may render it bioavailable and beneficial to human health.

Although there are dietary sources of silicon which are thought to exert beneficial effects in humans, there is no recommended dietary allowance (RDA) for silicon and, in fact many do not recognize silicon as a micronutrient essential for life, although 1–2 g is present in the human body [31,32]. However, if one considers the risk assessment of amorphous silicon dioxide as a common silicon source, although non-absorbed, the safe tolerable upper intake level (TUL), a component of the Dietary Reference Intakes (DRIs), is estimated to be 700 mg/day for adults, which is equivalent to 12 mg silicon/kg body weight/day for a 60 kg adult [33]. However, only minimal amounts of silicon become water-soluble and ultimately absorbed, thus the systemic plasma concentration does not increase significantly. The mean dietary silicon intake reported for a Finnish population was 29 mg silicon/day and for a typical British diet 20–50 mg/day corresponding to 0.3–0.8 mg silicon/kg body weight/day [14,18,34,35]. The estimated dietary intake in the US is 24–33 mg silicon/day with males generally consuming more [20].

2.1.2 Non-dietary Sources

Given the relative prevalence and widespread use of silica, it seems reasonable that there are myriad, diverse sources of and exposures to non-dietary silica/silicon. These occur primarily from exposure to dust, pharmaceuticals, cosmetics, medical implants, and medical devices. Often the forms of silicon occur as silicates or “silicones,” synthetic organosilicon compounds that, for the most part, are sparse in the human diet and contribute little silicon overall. Moreover, the forms that do result in exposure are not readily absorbed or biologically useful. For example, some pharmaceuticals can increase exposure of silicon to >1 g/d but the molecular species are largely inert and not absorbed to any significant extent. Examples of silicates include talc, kaolin, and magnesium, calcium, and sodium salts. This seems to be the case with other non-dietary sources such as toiletries, e.g., toothpaste, lipstick, etc., and detergents, tissue implants, etc. [6].

2.2 Silicon Chemical Speciation as Silicates

Silicon is the second most abundant element on earth with properties that are a mixture of both metals and non-metals resulting in classification as an elemental metalloid. As stated previously, silicon is rarely found in its elemental form but rather complexed with oxygen and/or other elements forming silica and silicates. Silicon dioxide, SiO2, is the oxide of silicon most commonly found in nature as sand or quartz. Generally, a silicate is any compound containing silicon and oxygen as an anion, SiO 2 −4 , with most in nature existing as oxides although the non-oxygen containing hexafluorosilicate anion, [SiF6]2−, is also often included as a silicate. Chemically, silicate anions can form compounds with numerous, diverse cations, thus this chemical class of compounds is large with formation of aluminosilicates being the most prevalent in nature [36]. Aluminum is the third most prevalent element in the earth’s crust and exists in combination with >270 other minerals.

2.3 Silicon Chemistry and Effects on Bioavailability

Silica, SiO2, is a silicic acid anhydride of monomeric orthosilicic acid (H4SiO4) which is water-soluble and stable in aqueous solutions when relatively dilute. Several other low-molecular-weight, but hydrated forms, of silicic acid exist in aqueous solutions and include metasilicic acid (H2SiO3), lower-molecular-weight oligomers such as disilicic acid (H2Si2O5) and trisilicic acid (H2Si3O7), as well as their hydrated forms pentahydro- and pyrosilicic acids [1]. Depending on the environmental conditions (temperature, pH, and presence of other ions), concentrations, and exposure time, formation of numerous potential polymerized silicic acids is possible through chemical condensation and cross-linking resulting in colloids and gels [37]. It is the lower molecular weight forms, especially the orthosilicic acid that is of the greatest research interest in exerting beneficial effects since this form is preferentially absorbed [38]. In fact, a small human study showed that ingestion of polymeric forms of silicic acid did not increase urinary levels suggesting little absorption, but 53% of ingested orthosilicic acid did increase urinary output indicating absorption [39]. Interestingly, most aqueous silica, i.e., seawater, freshwater, soil water, etc., occurs as orthosilicic acid (H4SiO4) making it an important environmental exposure in the context of biological systems due both to its water-solubility and bioavailability [4,40].

As previously noted, orthosilicic acid is water-soluble at relatively low concentrations but polymerizes readily at higher concentrations in excess of 100–200 ppm to form colloids and gels, which are less bioavailable. However, more concentrated solutions of orthosilicic acid can be stabilized to avoid polymerization. In fact, choline-stabilized orthosilicic acid, a liquid formulation, has been developed and approved for human consumption. It is considered non-toxic at high doses with a lethal dose exceeding 5,000 mg/kg body weight in humans and 6,640 mg/kg body weight in animals [41,42]. For a 70 kg human, this translates to a safe level of consumption of 350 g. This stabilized form currently represents the most bioavailable source of supplemental silicon.

3 Silicon and Its Potential Health Benefits

Silicon is the third most abundant trace element in the human body [20,43]. It is present at 1–10 ppm in hair, nails, the epidermis, and epicuticle of hair [44–46]. Considering the natural abundance, presence of bioavailable chemical forms, exposure to humans through diet, it seems more than plausible that there could, and likely is, potential benefit to humans. Whether silicon is an essential micronutrient continues to be debated. It has, however, been reported in the peer-reviewed literature that silicon is actively involved, and perhaps integral, in bone mineralization and prevention of osteoporosis, collagen synthesis, and prevention of the aging of skin, overall condition of hair and nails, reduced risk of atherosclerosis and Alzheimer’s disease, as well as other biological effects [47–51].

Interestingly, serum levels are similar to other trace elements and appear to be dependent on life stage, age, and sex with levels of 11–31 μg/dL depending on population assessed and means of analysis [23,52]. A recent study by Jugdaohsingh et al. evaluated host factors potentially influencing the absorption and excretion of dietary silicon. Serum and urine samples were collected from 26 participants followed by a single ingestion of 17 mg orthosilicic acid. Analyses of samples over the subsequent 6 hours indicated that participant age, sex, and estrogen status did not influence absorption or excretion suggesting more research is needed to better understand the effects of host factors on disposition of dietary silica [53].

3.1 Bone Health and Skeletal Development

Osteoporosis is a leading cause of morbidity and mortality in the elderly and markedly affects overall quality of life, as well as life expectancy. As a result, there is considerable interest in elucidation and use of specific nutrients, non-nutritive dietary components, and/or bioactive compounds of natural origin singly or in combination as a means of mitigating or preventing disease, as well as for maintenance of bone health. Calcium and vitamin D have largely been the primary focus of nutritional prevention of osteoporosis, however, supplementation with other vitamins including B, C, and K has been an area of increased research as well as the use of silicon for maintenance of bone health [54,55].

Osteoporosis is defined as a progressive, debilitating skeletal disorder characterized by low bone mass and deterioration of the microarchitecture of bone [56,57]. Indeed, several key animal studies dating back four decades clearly showed that dietary silicon deficiency caused abnormalities and dysfunction in connective tissues and bone function [58–62]. Numerous human studies have supported a role for dietary silicon in bone health including reduction of the risk for osteoporosis. In a retrospective, clinical study by Eisinger and Clairet, dietary silicon administration induced significant increases in bone mass and bone mineral density of the femur in human females [47]. Moukarzel et al. have also shown a direct relationship between silicon intake and bone mineral density [63]. In osteoporotic participants, supplementation with silicon increased trabecular bone volume and femoral bone mineral density [47,64]. Spector et al. showed in osteopenic and osteoporotic study participants an increase in bone formation markers, i.e., collagen synthesis, and significant increases in femoral bone mineral density [65]. Maehira et al. [66] have shown in mice fed five different calcium sources with differing silicon concentrations that soluble silicate and coral sand, with the highest silicon content, significantly improved bone biochemical and mechanical properties through induced gene expression encouraging correction of the imbalance between bone-forming osteoblastogenesis and suppression of bone-resorbing osteoclastogenesis [66–68]. Others have shown in human osteoblasts that orthosilicic acid-releasing zeolites could induce osteoblastogenesis, formation of extracellular matrix, induced synthesis of ostecalcin and activity of alkaline phosphatase both produced by osteoblasts and reflecting biosynthetic activity of bone formation [69–71]. It has also been shown that silicon supplementation increased hip bone mineral density in men and pre-menopausal, but not post-menopausal, women although a subsequent study showed increased bone mineral density in the spine and femur of both pre- and post-menopausal women currently taking hormone replacement therapy [15,72]. Compelling evidence demonstrates that silicon localizes to bone and that dietary silicon can strengthen bones and, as a result, reduce the risk of osteoporosis [73].

As mentioned before, stabilized preparations of silicic acid have been developed, e.g., choline-stabilized orthosilicic acid, permitting water-soluble preparations with higher concentrations and also markedly enhanced bioavailability. In a randomized controlled animal study, long-term treatment with choline-stabilized orthosilicic acid prevented partial femoral bone loss and exerted a positive, beneficial effect on bone turnover and ultimately bone mineral density [74]. In this study, ovariectomized aged rodents were used suggesting a potential interrelationship between estrogen and bone health and silicon metabolism. A subsequent study by Macdonald et al. found that dietary silicon interacts with estrogen to beneficially affect bone health [72]. Silicon has previously been shown to significantly enhance the rate of bone mineralization and calcification much like vitamin D, although functioning independently [75]. There are potentially conflicting reports since Jugdaohsingh et al. found that silicon supplementation in drinking water did not significantly alter silicon concentrations in the bones of rodents suggesting an additional nutritional cofactor might be absent such as vitamin K in rodents fed a low silicon diet [76].

3.2 Vascular Disease and Atherosclerosis

It has been reported that there are higher incidences of sudden death, cerebrovascular diseases, arterial hypertension, and coronary heart disease in soft water areas of the United States suggesting, in part, that the absence of components presence in hard water, i.e., minerals, may be contributors. As a result, a major research effort has been devoted to identifying potential protective factors in hard water including calcium, magnesium, manganese, and silicon, as examples, all of which are considered potentially beneficial [77].

Silicon is recognized by epidemiologic and biochemical studies as a protective trace element in atherosclerosis. Moreover, the observed decrease in silicon concentrations with increasing age has been suggested to contribute to chronic diseases such as atherosclerosis. The highest concentrations of silica in the human occur in connective and elastic tissues and especially the normal human aorta where it appears to function as a crosslinking agent that stabilizes collagen and presumably strengthens the vasculature [49,78]. Atherosclerosis significantly decreases silicon levels in arterial walls. Moreover, silicon levels decrease just prior to plaque development, which may indicate that silicon deficiencies cause inherent weaknesses in blood vessel walls.

In a study by Trinca et al., the antiatheromatous effect of sodium silicate was tested in rabbits given a standard control diet, an atherogenic diet, and a sodium silicate-supplemented atherogenic diet. Levels of total lipids, cholesterol, triglycerides, free fatty acids, and phospholipids remained unchanged in sodium silicate supplemented rabbits fed an atherogenic diet [79]. In a subsequent study, silicon administered orally or intravenously in rabbits inhibited experimental atheromas normally induced by an atheromatous diet, decreasing the number of atheromatous plaques and lipid deposits. It was proposed that the preservation of elastic fiber architecture, as well as of ground substance and the lack of free fatty acid accumulation in the aortic intima decreased plaque formation [80]. In a study by Maehira et al. using soluble silica and coral sand, as a natural silicon-containing material, the effect on hypertension, a contributing factor to atherosclerosis, was evaluated in spontaneously hypertensive rats. In rats fed 50 mg/kg dietary silicon for 8 weeks, systolic blood pressure was significantly lowered by 18 mmHg. Provision of soluble dietary silica also suppressed the aortic gene expression of angiotensinogen and growth factors related to vascular remodeling. Silicon also stimulated the expression of peroxisome proliferator-activated receptor-γ, which has antiinflammatory and antihypertensive effects on vascular cells [81]. In a study by Oner et al., dietary silica modified the characteristics of endothelial dilation in aortic rings from rats with modulation of endothelial relaxants and attenuation of smooth muscle cell responsiveness to nitric oxide [82].

Silicon has also been suggested to exert a protective role in atherosclerosis through its effects on blood vessel-associated glycosaminoglycans and collagen integrity and function via its crosslinking capacity [19]. Glycosaminoglycans are long unbranched (linear) polysaccharides consisting of repeating disaccharide units including hyaluronan, chondroitin, dermatan, heparan, and keratan. Silicon is also a constituent of the enzyme prolyl hydroxylase, which synthesizes collagen and glycosaminoglycans. Dietary silicon may facilitate the formation of glycosaminoglycans and collagen and/or serve a structural role as a component of glycosaminoglycans where it crosslinks, and strengthens, polysaccharide chains. Nakashima et al. have noted that the glycosaminoglycan content of the aorta was inversely correlated with the severity of atherosclerosis. Interestingly, they showed that the silicon content in fatty streaks and/or atheroma was significantly higher than in normal human aortic intimal regions suggesting that the increase of silicon in the aortic intima is related to the occurrence and/progression of atherosclerosis [83].

3.3 Neurodegenerative Disease (Alzheimer’s Disease)

Metals that can cross the blood brain barrier and generate directly or indirectly oxidative stress can cause significant damage to the neuronal structure of the brain. Aluminum is abundant in the environment but is not a micronutrient. However, ingestion and/or exposures can cause deposition and accumulation in the body, e.g., brain, where it can cause considerable damage. Aluminum, a nonredox-active metal, is a well-known toxicant and its salts can accelerate oxidative damage of neurons. Oxidative stress is one of the critical features in the pathogenesis of Alzheimer’s disease and has been demonstrated in brain tissue from Alzheimer’s patients. Aluminum is a contributing factor to oxidative stress, as it generates reactive oxygen species (ROS) shown to cause oxidative damage to neurons through interaction with iron, a redox-active metal, and promotion of free radical-generating Fenton reactions, which can increase hallmark aggregation and accumulation of β-amyloid. Collectively, studies clearly indicate that aluminum promotes oxidative stress capable of damaging neuronal cell death [84].

The molecular pathogenesis of Alzheimer’s disease includes many risk factors including extracellular deposition of β-amyloid, accumulation of intracellular neurofibrillary tangles, oxidative neuronal damage and activation of inflammatory cascades [85]. Although the subject of continuing scientific debate, aluminum has been detected in neurofibrillary tangles in the brains of both Alzheimer’s and Parkinson’s disease patients with dementia and is proposed to play crucial roles as a crosslinker in β-amyloid oligomerization [86–88].

Although the neurotoxicity of aluminum is well-documented, the association with neurodegenerative disorders is the subject of debate as is the potential benefit of consuming silica [89]. Some epidemiological studies, but not all, suggest that silica could be protective against aluminum damage, because silica reduces oral absorption of aluminum and/or enhances its excretion [90–92]. Studies have suggested that oligomeric but not monomeric, viz., orthosilicic acid, silica can prevent aluminum absorption through the gastrointestinal (GI) tract reinforcing the importance of chemical speciation [39]. Silicon readily complexes with aluminum and, in fact, aluminosilicates are the most prevalent silicates in nature. A silicate is any of numerous compounds containing silicon, oxygen, and one or more metals forming essentially a salt of silicic acid. Aluminum silicates are water-insoluble and although the processes involved in aluminum bioavailability are unclear regarding its transport into the central nervous system, numerous reports show that silicic acid can, in fact, reduce aluminum absorption and ultimately deposition and accumulation within the brain. In an epidemiological study, Rondeau et al. examined associations between exposure to aluminum or silica from drinking water and risk of cognitive decline, dementia, and Alzheimer’s disease among 1,925 elderly subjects followed for 15 years. The authors concluded that cognitive decline with time was greater in subjects with a higher daily intake or geographic exposure to aluminum from drinking water. An increase of 10 mg/day in silica intake was significantly associated with a reduced risk of dementia [93]. Thus, it appears that the relative concentration of both aluminum and silica in drinking water are important in determining benefit or detriment regarding the risk and/or exacerbation of Alzheimer’s disease [94]. Interestingly, soft water contains less silica acid and more aluminum while the converse is true for hard water [25]. In a study by Exley et al. introduction of hard water rich in silica significantly reduced overall aluminum levels in the body presumably through reduced absorption of aluminum as supported by reduced urinary concentrations [95]. A subsequent study showed that drinking up to 1 L of a silicon-rich mineral water daily for 12 weeks fostered urinary removal of aluminum in both control and Alzheimer patient groups without increasing urinary excretion of the micronutrients iron and copper [96]. Moreover, there were clinically relevant increases in cognitive performance in 20% of participants. Gonzalez-Munoz et al. have shown that beer consumption, a rich bioavailable source of silicic acid, can reduce cerebral oxidation caused by aluminum toxicity by, interestingly, modulating gene expression of pro-inflammatory cytokines and antioxidative enzymes [51].

3.4 Diabetes

Type 2 diabetes is a disorder of glycemia based largely on the development of insulin resistance. It has been noted that micronutrients can regulate metabolism and gene expression associated with glycemia thereby potentially influencing the development and progression of diabetes [97]. In a report by Oschilewski et al., administration of silica to BB-rats, prone to spontaneous diabetic syndrome, completely prevented the development of diabetes [98]. Rats were treated with 100 mg silica/kg body weight via intraperitoneal and intravenous routes and observed for weight changes, glycosuria, and ketonuria. The authors showed nearly complete inhibition of the development of diabetes (1 of 31 in treated group versus 9 of 31 for control group) and attribute the protection of silica to reduced infiltration of pancreatic islets by macrophages. Kahn and Zinman showed in a previous study exploring bone health that dietary silicon suppressed bone marrow-derived peroxisome-proliferator receptor-γ, which regulates bone metabolism, but also regulates glucose metabolism where it is a ligand-activated transcription factor and a molecular target of a class of insulin-sensitizing drugs referred to as thiazolidinediones [99].

In the subsequent study, the antidiabetic effects of silicon were investigated in obese diabetic KKAy mice prone to hyperleptinemia, hyperinsulinemia, and hyperlipidemia (50 ppm silicon for 8 weeks). Interestingly, silicon and coral sand, a rich source of silicon, displayed antidiabetic effects through blood glucose reductions and increases in insulin responsiveness, as well as improvement in the responses to the adipokines leptin and adiponectin [100]. The authors report this as a novel function of anti-osteoporotic silicon and suggest use of silicon as a potential antidiabetic agent capable of reducing plasma glucose and reducing the risk of diabetic glomerulonephropathy. There is clearly a need for research into the potential novel therapeutic applications of silicon, as silica, for prevention and management of diabetes.

3.5 Wound Healing

Silica already finds widespread use in medical and surgical applications including tissue engineering for regeneration of tissues, e.g., wound repair and organs. This typically is in the form of collagen scaffolds, which are used as sponges, thin sheets or gels. Collagen, as a long fibrous structural protein, possesses the appropriate properties for tissue regeneration including optimal pore structure, permeability, hydrophilicity and stability in vivo. As a result, collagen scaffolds permit deposition and growth of cells, e.g., osteoblasts and fibroblasts, promoting normal tissue growth and restoration [101]. There are studies that suggest that dietary silicon can also exert beneficial effects on wound repair.

The successful healing of wounds requires local synthesis of significant amounts of collagen with its high hydroxyproline content drawing upon amino acid precursors such as proline and ornithine [102]. In animal studies, silica-deficient diets result in poor formation of connective tissues including collagen and ultimate structural damage. Silica maintains the health of connective tissues due, in part, to its interaction with the formation of glycosaminoglycans where silicon is consistently found and presumed to have an active role. As a result, a deficiency in silica could result in reduced skin elasticity and wound healing due to its role in collagen and glycosaminoglycan formation. Seaborn and Nielsen have reported that silicon deprivation decreases collagen formation in wounds and bone, and decreases ornithine transaminase enzyme activity in liver [103]. In a rodent study, silicon deprivation affected collagen formation at several different stages of bone development, the activities of collagen-forming enzymes, and consequent collagen deposition on other tissues. This has major implications suggesting that silicon is important in wound healing and supports that dietary silicon, as silicic acid, can exert therapeutic effects for this use.

4 Toxicology of Silicon and Silica

4.1 Chemical Forms Contributing to Toxicity

As previously discussed, elemental silicon exists primarily as an oxide largely in the form of silicon dioxide. Silica, SiO2, is a silicic acid anhydride of monomeric orthosilicic acid (H4SiO4), which is water-soluble and stable in aqueous solutions when relatively dilute but can polymerize and complex with numerous minerals to form silicates with aluminum silicate being the most prevalent. Several other low-molecular-weight, but hydrated forms, of silicic acid exist in aqueous solutions and are non-toxic. Forms of silicon that are toxic include long fibrous crystalline forms such as asbestos. Asbestos is a group of crystalline 1:1 layer hydrated silicate fibers that are classified into six types based on different physicochemical features [104]. These include chrysotile [Mg6Si4O10(OH)8], the most common and economically important asbestos in the Northern Hemisphere, and the amphiboles: crocidolite [Na2(Fe3+)2(Fe2+)3Si8O22(OH)2], amosite [(Fe,Mg)7Si8O22(OH)2], anthophyllite [(Mg,Fe)7Si8O22(OH)2], tremolite [Ca2Mg5Si8O22(OH)2], and actinolite [Ca2(Mg,Fe)5Si8O22(OH)2].

Silica occurs in both non-crystalline and crystalline forms where crystalline silica is a basic component of soil, sand, granite, and many other minerals. Crystalline forms technically are physical states in which the silicon dioxide molecules are arranged in a repetitive pattern with unique spacing, lattice structure and angular relationship of the atoms. Crystalline silica forms, viz., polymorphs, include quartz, cristobalite, tridymite, keatite, coesite, stishovite, and moganite. Silicosis largely occurs due to inhalation of one of the forms of crystalline silica, most commonly quartz. All three forms may become respirable size particles when workers chip, cut, drill, or grind objects that contain crystalline silica.

4.2 Routes of Exposure and Safety

The most noted toxicity associated with silica and asbestos are silicosis and asbestosis, respectively. The key route of exposure leading to toxicity is respiratory with progressive, debilitating damage from lengthy and/or heavy inhalation of the dust of silica. In fact, the International Agency for Research on Cancer (IARC) classifies silica as a “known human carcinogen” based on inhalation as a route of exposure. Regarding dietary exposure, there is no evidence of carcinogenesis when silica was fed to rodents for ~2 years (effectively the whole life span) supporting that the route of exposure is more critical than the chemical form. There are reports that magnesium trisilicate (6.5 mg elemental silicon) when used as an antacid in large amounts for years may be associated with the development of urolithiasis due to formation, in vivo, of silicon-containing stones although fewer than 30 cases have been reported in the last 80 years [105].

There are other reports of toxicity from oral ingestion of crystalline and amorphous silicates. For example, nephropathy can result from finely ground silicates and nephritis from long-term use of high dose, silica-containing medications as well as kidney damage and kidney stones [106]. There are some reports of increased risk of cancer (esophagus and skin) from silica-rich materials such as millet and seeds [14,107,108]. It is proposed that the overall limitation in absorption of silicon, regardless of level of dietary intake, coupled with efficient elimination significantly limits the potential toxicity of silica. Circumventing this defense mechanism via peritoneal injections of silicon as shown in animals can easily exceed expected urinary output beyond that associated with presumed silicon adequacy [30,109].

4.2.1 Inhalation and Asbestosis

When asbestos fibers are inhaled, most fibers are expelled, but some can become lodged in the lungs and remain there throughout life increasing the risk of asbestosis. Asbestosis is a chronic inflammatory and fibrotic disease affecting the parenchymal tissue of the lungs, referred to as interstitial fibrosis, caused by the inhalation and deposition of fibrous asbestos. Manifestation of the disease occurs typically after high intensity and/or long-term exposure to asbestos as a specific group of airborne crystalline silicate fibers. Asbestos fibers are invisible without magnification because their size is approximately 3–20 μm wide but as small as 0.01 μm. For reference, human hair has a width of ~20–180 μm. Given the omnipotence of asbestosis in technical applications, it is considered an occupational lung disease.

4.2.2 Inhalation and Silicosis

Silicosis is also a form of irreversible occupational lung disease, technically a type of pneumoconiosis that is caused by inhalation of small particles of crystalline silica dust. Inhaling finely divided crystalline silica dust even in small quantities (the Occupational Safety and Health Administration (OSHA) allows 0.1 mg/m3) over time can lead to silicosis, bronchitis, or cancer, as the dust becomes lodged in the lungs causing chronic irritation with reduced lung capacity. It is marked by inflammation, pulmonary edema, scarring of the lungs, and formation of nodular lesions in the upper lobes of the lungs with resultant difficulty in breathing. There are several different clinical and pathologic varieties of silicosis, including simple (nodular) silicosis, acute silicosis (silicoproteinosis), complicated pneumoconiosis (progressive massive fibrosis), and true diffuse interstitial fibrosis [110].

4.3 Mechanisms of Toxicity

The molecular mechanism of silica and asbestos-induced carcinogenesis is complex and unclear. Clearly, inhalation is the primary route of exposure leading to toxicity and depends on the shape and size of silica fibers, duration of exposure, and relative dose, as well as lung clearance capacity and individual genetics [111,112]. Several mechanisms have been proposed including the adsorption, chromosome tangling, and oxidative stress hypotheses.

The adsorption theory posits that the surface of asbestos has a high natural affinity for proteins and other biomolecules and presumably disrupts cell function. The chromosome tangling hypothesis argues that asbestos can interact with chromosomes and “tangle” them during cellular division causing clastogenic damage. Probably the most compelling mechanism at this time is the oxidative stress theory, which purports that iron associated with asbestos fibers, once internalized, can contribute to Fenton chemistry with generation of reactive, damaging free radicals and reactive oxygen species. Moreover, deposition of asbestos and silica particles in the lungs can initiate chronic inflammation via involvement of phagocytic macrophages, which also produces copious ROS. Although discussed separately, oxidative stress and inflammation are intimately linked and often occur concurrently, thus both occur concomitantly in lung disease.

4.3.1 Oxidative Stress

Cumulative supporting evidence suggests a role for ROS and reactive nitrogen species in the pathogenesis of asbestos- and silica-induced diseases [110,113]. Oxidative damage to the lungs can occur directly through highly reactive hydroxyl radical formation via the Fenton and Haber-Weiss reactions with fiber surface iron, and indirectly through inflammation [114–116]. This route involves the recruitment and activation of ROS-producing inflammatory cells, such as macrophages. Other cell types also participate in the process including mesothelial cells and lung fibroblasts, which also produce ROS species in response to silica and/or asbestos.

Numerous in vitro studies have shown the involvement of oxidative stress in damage caused by silica. For example, Liu et al. tested the effects of silica nanoparticles on endothelial cells by measuring ROS generation, apoptosis and necrosis, proinflammatory and prothrombic properties and the levels of the apoptotic signaling proteins and the transcription factors after exposure to silica nanoparticles (25–200 μg/mL) for 24h [117]. Silica nanoparticles markedly induced ROS production, mitochondrial depolarization and apoptosis in endothelial cells. Others have shown similar results with primary endothelial cells exposed to silica nanoparticles with activation and dysfunction of endothelial cells shown by release of von Willebrand factor and necrotic cell death [118]. In a study of mesothelial cells, exposure to crocidolite asbestos induced oxidative stress, caused DNA damage and induced apoptosis demonstrating that phagocytosis was important for asbestos-induced injury to mesothelial cells [119].

Several human studies have been conducted to determine if oxidative stress results from asbestos exposure using a relatively new biomarker of exposure. Measurement of exhaled breath condensate for markers of oxidative stress is one of the most promising methods available for determining pulmonary damage from environmental exposures [120]. An increase in the exhaled breath condensate concentrations of 8-isoprostane, an oxidative stress marker, has been observed in patients with idiopathic pulmonary fibrosis and in a limited study with asbestos-exposed subjects. Pelclova et al. measured 8-isoprostane, in 92 former asbestos workers with an average exposure of 24 years [114]. The results indicated higher levels of 8-isoprostane in exposed subjects compared to control subjects (69.5 versus 47.0 pg/mL) supporting asbestos-induced oxidative stress. In a study involving 83 patients (45 with asbestosis and hyalinosis and 37 with silicosis), concentrations of 8-isoprostane and hydroxynonenal, an oxidative degradation product, were measured in urine and exhaled breath condensate. The results indicated that most markers correlated positively and significantly with lung function impairment [121]. These markers as well as others have been effectively developed to detect and confirm oxidative stress in patients with asbestosis and silicosis [122,123].

4.3.2 Inflammation

There is growing evidence that amorphous silica can cause an inflammatory response in the lung. These crystalline silicates are phagocytozed by macrophages that then release cytokines that attract and stimulate other immune cells including fibroblasts, which are responsible for the excessive production of collagen (fibrotic tissue) that is characteristic of silicosis [10]. In a study by McCarthy et al., exposure of human lung submucosal cells to SiO2 nanoparticles (10–500 nm) for up to 24 hours increased cyotoxicity and cell death, induced pro-inflammatory gene expression and release of pro-inflammatory IL-6 and IL-8, and upregulation of pro-apoptotic genes indicating oxidative stress-associated injury [124]. Bauer et al. also showed that silica nanoparticles caused dysfunction and cytoxicity through exocytosis of von Willebrand factor and necrotic cell death in primary human endothelial cells [118]. In the study by Liu et al., incubation of endothelial cells with 200 μg/mL silica caused increased cell death and the release of numerous, diverse pro-inflammatory mediators (TNF, IL-6, IL-8, and MCP-1) by remaining viable cells [117].

Silica nanoparticles also activated pro-inflammatory gene expression, e.g., NF-κB, and suppressed antiinflammatory gene expression, e.g., Bcl-2. The study collectively showed that silica nanoparticles damaged endothelial cells through oxidative stress via changes in gene expression associated with inflammation. Others have shown the role of IFN-γ in the development of murine bronchus-associated lymphoid tissues induced by silica and activation of NF-κB in silica-induced IL-8 production by bronchial epitehelial cells [125]. Clearly, silicosis is characterized by mononuclear cell aggregation and lymphocytes are abundant in these lesions [126].

Ironically, short-term studies in rodents exposed to crystalline quartz suggested that silicon exposure stimulated the immune system and respiratory defense through activation of neutrophils, T lymphocytes, and NK cells with subsequent increased production of ROS [127–129]. This is thought to enhance the pulmonary clearance of microbes. Intriguingly, silica was shown, at least in rats, to activate and increase proliferation of CD8+ and CD4+ T cells suggesting potential therapeutic use in the future as an immunostimulant for pulmonary disorders. Recently a supplemental anionic alkali mineral complex containing sodium silicate (60% of mass) has been developed and is currently used as immunostimulant in animals including horses, pigs, etc. [130]. The mechanism of action is not known, however, it has been suggested that orthosilicic acid-generating sodium silicate is the bioactive agent responsible for the immunostimulation. Sodium metasilicate has also been shown to be immunostimulatory [131]. The seemingly dichotomous actions of silica represent a conundrum with excessive immunostimulation in silicosis and asbestosis clearly being detrimental but an apparent capacity of silica to also beneficially boost the immune system with consequent ROS production.

5 Potential Medicinal Uses of Silicon and Silicates

The potential medicinal uses of silicon in the form of silica have only recently been recognized particularly with respect to bone health and prevention of neurodegenerative diseases. Data are preliminary yet supportive of potential roles in reducing the occurrence of type 2 diabetes and preserving and producing collagen, e.g., wound repair. Silicon is environmentally prevalent representing the second most abundant element yet the biological availability of silica is limited and distributed unevenly based largely on geographic location and source. As discussed previously, it is the orthosilicic acid that is water-soluble and bioavailable yet overall intake and absorption could be improved. Thus, orthosilicic acid will likely be a prominent therapeutic medicinal agent and, in fact, many potential therapeutic applications have already been presented. For example, silicon appears to play a significant role in maintaining bone health through increased bone formation and increased bone mineral density and maintenance of connective tissues. Silicon, as dietary silica, also inhibits absorption of toxic aluminum, which may contribute to the development of Alzheimer’s disease. This occurs at a time when there is increased prevalence of osteoporosis and Alzheimer’s disease as populations worldwide become older. Other potential uses include enhancement of immune function, preservation and health of skin, hair, and nails, and use as potential antidiabetic and anticancer agents.

The development of new formulations of orthosilicic acid or orthosilicic acid-releasing compounds is a promising means of delivering increased concentrations of bioavailable and safe silicon. Choline-stabilized orthosilicic acid is a newly developed, concentrated solution of orthosilicic acid in a choline and glycerol matrix and is promoted as biologically active and the most bioavailable form of silicon. Moreover, choline-stabilized orthosilicic acid has been approved for human consumption and is considered relatively non-toxic with a tolerable upper limit exceeding 5 g/kg body weight [28,41]. There are many other silicon supplements available including extracts of horsetail, which contains 12 mg silicon per tablet of which 85% is suggested to be bioavailable [28,29,65,74,132]. Overall, results of the NHANES III study indicate a median intake of silicon from supplements to be 2 mg/d, but with preparations such as the aforementioned could markedly increase.

A particularly interesting area of research and development has been the emergence and/or use of orthosilicic acid-releasing compounds. Specifically, certain types of zeolites, a class of aluminosilicates with well-described ion (cation)-exchange properties have been shown to release orthosilicic acid [1]. Overall, 191 unique zeolites have been described with over 40 naturally occurring zeolites identified. These are already widely employed in chemical and food industries, agriculture, and environmental technologies but could find much greater use as medicinal and/or nutritional agents. In fact, the biomedical applications of zeolites include, in part, modulation of enzyme kinetics, use in hemodialysis, prevention of diabetes, increased bone formation, function as an antidiarrheal and antibacterial agent and as vaccine and tumor adjuvants [1]. The numerous biological activities of some types of zeolites documented so far is thought to be due, in large part, to the orthosilicic acid-releasing property.

6 Summary and Future Directions

In conclusion, silicon, as silica and silicates, represents a very large family of molecules with potential health benefits but also with potential toxic effects depending on the form, water-solubility, route of exposure, and amount consumed. For example, inhaled particulate fibrous crystalline silica can be toxic and depends heavily on route of exposure and chemical form. Silica can also dissolve in water to form non-toxic bioavailable silicic acids and specifically orthosilicic acid. This form of absorbable silica found in foods and water sources, is readily absorbed, reaches key tissue and organ target sites of action, and is efficiently excreted. The lack of apparent toxicity of water-soluble forms that are consumed, as opposed to inhaled, and the ongoing debate regarding essentiality as a micronutrient have obscured the relative importance of chemical speciation and potential contributions of silica.

Even though water-soluble to some degree, there are limitations to absorption dictated largely by chemical instability, e.g., propensity to polymerize, and maximum allowable concentrations of water-soluble orthosilicic acids. However, there has been development of acid forms with markedly increased stability and, as a result, significant increased concentrations and bioavailability of silicon. Choline chloride-stabilized orthosilicic acid is a pharmaceutical formulation that is particularly promising but other forms exist including sodium or potassium silicates, and orthosilicic acid-releasing forms such as zeolites.

Further research on silicon is critically needed particularly focusing on the physiological roles of silicon and how this relates to human health, as well as the dependence on chemical speciation. Specifically, ample data exist to support a possible role of silicon in wound repair, atherosclerosis and hypertension, diabetes, several bone and connective tissue disorders, neurodegenerative diseases, e.g., Alzheimer’s and Parkinson‘s disease, and other conditions that occur particularly in the aging population. It is also important to further elucidate biochemical mechanisms of action of silicon-containing molecules, as silicic acids, and to extend testing more into whole body systems. Specifically, larger studies with humans are needed to explore the medicinal and nutritional potential of silicon.

DRI:

dietary reference intake

IARC:

International Agency for Research on Cancer

IFN-γ:

interferon-γ

IL:

interleukin

MCP-1:

monocyte chemoattractant protein-1

NF-κB:

nuclear factor B

NHANES:

National Health and Nutrition Examination Survey

NK cells:

natural killer cells

NTF:

tumor necrosis factor

OSA:

orthosilicic acid

RDA:

recommended dietary allowance

ROS:

reactive oxygen species

TUL:

tolerable upper limit