Sub-chronic toxicity study in rats orally exposed to nanostructured silica

Abstract

BackgroundSynthetic Amorphous Silica (SAS) is commonly used in food and drugs. Recently, a consumer intake of silica from food was estimated at 9.4 mg/kg bw/day, of which 1.8 mg/kg bw/day was estimated to be in the nano-size range. Food products containing SAS have been shown to contain silica in the nanometer size range (i.e. 5 – 200 nm) up to 43% of the total silica content. Concerns have been raised about the possible adverse effects of chronic exposure to nanostructured silica.MethodsRats were orally exposed to 100, 1000 or 2500 mg/kg bw/day of SAS, or to 100, 500 or 1000 mg/kg bw/day of NM-202 (a representative nanostructured silica for OECD testing) for 28 days, or to the highest dose of SAS or NM-202 for 84 days.ResultsSAS and NM-202 were extensively characterized as pristine materials, but also in the feed matrix and gut content of the animals, and after in vitro digestion. The latter indicated that the intestinal content of the mid/high-dose groups had stronger gel-like properties than the low-dose groups, implying low gelation and high bioaccessibility of silica in the human intestine at realistic consumer exposure levels. Exposure to SAS or NM-202 did not result in clearly elevated tissue silica levels after 28-days of exposure. However, after 84-days of exposure to SAS, but not to NM-202, silica accumulated in the spleen. Biochemical and immunological markers in blood and isolated cells did not indicate toxicity, but histopathological analysis, showed an increased incidence of liver fibrosis after 84-days of exposure, which only reached significance in the NM-202 treated animals. This observation was accompanied by a moderate, but significant increase in the expression of fibrosis-related genes in liver samples.ConclusionsAlthough only few adverse effects were observed, additional studies are warranted to further evaluate the biological relevance of observed fibrosis in liver and possible accumulation of silica in the spleen in the NM-202 and SAS exposed animals respectively. In these studies, dose-effect relations should be studied at lower dosages, more representative of the current exposure of consumers, since only the highest dosages were used for the present 84-day exposure study.

Risk assessment of titanium dioxide nanoparticles via oral exposure, including toxicokinetic considerations

“…When focusing on the liver, the calculated liver concentrations at the effect level differ by a factor seven between the NCI study and the study of Wang et al (2013). This difference in internal concentration may well be explained by animal variation, a lower absorption at the very high doses up to 2500 mg/kg bw/d in the NCI study, as seen for silica (van der Zande et al, 2014), or a smaller fraction of NPs in the tested titanium white in the NCI study. Peters et al (2014) found a range of 0.012-0.31% NPs (by weight) in seven different brands of E 171 and for the NCI study the highest measured fraction of 0.31% was assumed as a worst-case scenario.…”

“…It is unknown whether the doses used in the toxicity studies, which are all much higher than human intakes (4250-fold) and are given as a daily bolus dose in most studies instead of consumption and thus gradual uptake during the day, are absorbed differently than the amounts ingested by humans. SiO 2 NPs have been reported to gelate at higher doses in the gut (van der Zande et al, 2014), resulting in lower oral absorption at a high dose than at lower doses. We are not aware of studies indicating whether TiO 2 NPs can gelate as well in the gut, although it is common knowledge that NP aggregation increases with concentration.…”

Histologic investigation of cytotoxicity of nanocomposite particles used for direct restorations in dentistry in rat models

“…Известны многочисленные исследования, доказываю-щие цитотоксическое действие наночастиц оксида кремния при их ингаляции на произ-водстве [4,5]. Помимо дыхательных путей, наночастицы могут попадать в организм и через желудочно-кишечный тракт [6,7].…”

Statistical modelling of variability and uncertainty in risk assessment of nanoparticles

“…This means that we are only interested in the median particle size. Considering various studies, we assumed a median particle size of 100 nm (Peters et al, 2012;van der Zande et al, 2014 Hazard is expressed as the Individual Benchmark Dose (IBMD), which is the dose at which an individual human experiences a predefined response to a substance (higher IBMD means lower hazard). Starting from a B M D ani mal obtained from a dose-response modelling of data from an animal study, the IBMD is calculated using the formula…”

“…This choice was based on studies (Peters et al, 2012;van der Zande et al, 2014) in which particle sizes were measured. Due to the limitations of the instrumentation and the difficulty in measuring single particles in a large agglomeration such as found in food products, a perfect estimate for the median particle size was not possible.…”