Only very high, unrealistic doses of silica nanoparticles cause inflammatory reactions and toxic effects in laboratory studies with rodents. Low doses of SiO₂ nanoparticles do not induce toxicity in studies with experimental animals.

Distribution and Effects in the Body

Nanoparticles of silicon dioxide (SiO₂) can be either amorphous or crystalline and both forms have different effects on cells . Consumer products contain the amorphous form. Synthesized particles are also mostly amorphous, whereas nanoscale crystalline SiO₂ is formed by grinding coarse quartz. In general, according to current knowledge (year 2020), nanoparticles of amorphous silica tend to be considered harmless . Crystalline SiO₂ nanoparticles, however, trigger significant effects, including DNA damage in cells . To study the distribution of silica particles (nano- or microscale) in the body is not possible after "normal" exposure via the lungs (inhalation) , the gastrointestinal tract (ingestion) or via the skin, since the overall amount of material which enters the body via these uptake routes is too small to be detected. Therefore, all studies on the distribution of silica in the body are performed by injection. For this purpose, the total dose is injected either directly into the bloodstream (intravenously = i.v.) or into the abdominal cavity (intraperitoneally = i.p.).

Direct administration into the organism via injection into the bloodstream A distribution of silica nanoparticles can only be reliably investigated if the entire dose is injected directly into the body. This was done in all studies cited in this section via injection into the blood vascular system (i.v.). Strict care must be taken that the amount of particles injected is not too large, as this can lead to the formation of blood clots (thrombosis) and thus directly to vascular occlusion with subsequent infarction and death of the animals. This observation was made when large amounts of silica were injected into rats to study the acute toxicity of SiO₂ . However, after repeated administration of smaller amounts of SiO₂, no adverse effects such as DNA damage were observed. When acute toxicity is investigated, contradictory results are found in the literature. While in one study the LD₅₀ for SiO₂ nanoparticles was 262 mg/kg in mice , in a more recent study with up to 300 mg/kg not a single mouse died . Distribution in the organism A number of studies have addressed the question of whether silica nanoparticles reach internal organs in the organism after being injected into the body of animals. These internal organs include the heart, liver, kidney, spleen, lungs, or brain. For this purpose, mice or rats were injected with up to several hundred milligrams of SiO₂ per kilogram of body weight, sometimes injected in repeated dose experiments . . The following key statements apply to the majority of the cited studies:

1. The injected nanoparticles accumulate mainly within the liver, followed by the spleen, lungs, and kidney. Thus, the nanoparticles behave like any other foreign substance, which enters the body.
2. Other organs such as the heart and brain are not affected, which also means that the blood-brain barrier is not crossed.
3. If the silicon dioxide is administered in high doses (> 100 mg/kg) or in repeated dose experiments, inflammatory processes and a slight fibrosis can be observed in the liver. However, this subsides rapidly after the treatment has been stopped.
4. No direct DNA damage was observed in animals even at high doses.
5. Concentrations below 50 mg/kg do not induce any effect in the animals, neither in the major organs, such as liver and spleen, nor in the vessels or other cells.

Placental barrier and the foetus One study addressed the distribution of silica nanoparticles in pregnant mice. In these experiments, it was observed that the particles (between 25 and 115 nm in size) could cross the placental barrier after injection into the pregnant females but did not cause clinical symptoms in either the female mice or the foetuses . Inhalation uptake and dose dependence In studies in which laboratory rats of different ages inhaled amorphous silica particles, it was shown that old rats responded more sensitively to identical treatment than young or adult animals. Effects on the lungs and heart could be observed . In a comparative study, two groups of rats inhaled crystalline micrometer-sized quartz particles or amorphous silica nanoparticles for three months. The inflammatory reactions in the lungs of the rats and other effects (e.g. genotoxicity) were analyzed in this study. The crystalline form (quartz) triggered significant inflammation by this treatment, which did not subside by the end of the experiment. The amorphous nanoscale SiO₂, on the other hand, triggered a short-lived inflammation at high doses, but this quickly subsided, and no further adverse effects occurred . These results are confirmed by further studies, which did not observe any statistically significant effects of (micro- or nanoscale) amorphous SiO₂ in animal experiments .. As in the in vitro studies, the dosage in vivo plays a decisive role. Treatment with very high doses leads to an overloading effect of the lung ("overload effect" ). Such high doses induce the development of fibrosis or trigger other damage such as inflammatory processes or oxidative stress . For silica particles, there is a clear distinction between crystalline SiO₂ (quartz), which can cause a known and well-studied lung disease, and amorphous SiO₂, which is used in many products and has very little to no toxicity.  

Uptake and Effects in Cells

Silicon dioxide has been the subject of toxicological studies in the laboratory for many decades. Depending on the cell type and crystal structure of the silicon dioxide, different reactions are triggered. Electron microscopy can be used to show the uptake and localization of silicon dioxide nanoparticles in cells.

Micrometer-sized crystalline silica particles (quartz) are known to enter the interior of cells. They are enclosed by membranes inside the cell and remain there .

As is true for many other nanomaterials, amorphous silica nanoparticles can be taken up by cells. They accumulate in cells in vesicles , which serve, among other things, to digest molecules in the cell. SiO₂ nanoparticles are not found in the nucleus and do not cause structural changes in cells. A large-scale comparison study with cell types of different target organs (e.g. respiratory tract, immune system, digestive tract) demonstrated that the effect of amorphous silica nanoparticles can also be cell-specific. While stem cells and some immune cells showed a reaction already at lower concentrations, the majority of the investigated cell cultures of the respiratory tract or other organs were very insensitive and reacted only at very high SiO₂ nanoparticle concentrations or not at all . These results are confirmed by other studies, all of which observed uptake of SiO2 nanoparticles, but the biological responses of treated cells occurred exclusively at high or very high concentrations . In realistic concentration ranges, i.e. relevant for humans, silica nanoparticles do not cause significant effects and are not toxic . Coculture systems often respond more sensitively to external influences because communication between the different cell types is possible, which is not the case in cultures with only one cell type. Thus, such coculture systems show stronger effects to SiO₂ treatment when compared with the effects of studies with only one cell type  . The low or non-existent toxicity of silicon dioxide is also interesting for medical applications. Thus, attempts are being made to use porous SiO₂ particles to introduce genes into the lungs of mice , or they are "loaded" with drugs and thus serve as a carrier to specifically combat diseases directly at the site of action .  

The liver is the most important detoxification organ in mammals and all foreign substances accumulate and are processed there. This is also true for injected SiO₂ nanoparticles and thus it is not surprising that they accumulate in the liver and lead to mild inflammation and fibrotic effects at high exposures. Internal tissue barriers are either not crossed at all (blood-brain barrier) or only in rare exceptions (placental barrier), as shown in experiments with pregnant mice. However, it must be taken into account that the placenta of mice have a completely different structure and are much more permeable than the placenta in humans.

Silicon dioxide nanoparticles are hardly absorbed into the body via the "normal" uptake routes (lungs and gastrointestinal tract) and not at all via the skin. Even if they are injected directly into the body, they have an effect only in very high concentrations, but usually also very low (inflammatory processes, DNA damage, etc.) and reversible. Thus, amorphous silica nanoparticles can be classified as non-toxic.