title: Sub-chronic toxicity study in rats orally exposed to nanostructured silica.
abstract: BACKGROUND
  Synthetic 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.
  
  
  METHODS
  Rats 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.
  
  
  RESULTS
  SAS 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.
  
  
  CONCLUSIONS
  Although 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.
authors: RIKILT - Wageningen University & Research Centre, 6700 AE Wageningen, The Netherlands. Meike.vanderzande@wur.nl.
authors: Meike
authors: M
authors: van der Zande
authors: Rob J
authors: RJ
authors: Vandebriel
authors: Maria J
authors: MJ
authors: Groot
authors: Evelien
authors: E
authors: Kramer
authors: Zahira E
authors: ZE
authors: Herrera Rivera
authors: Kirsten
authors: K
authors: Rasmussen
authors: Jan S
authors: JS
authors: Ossenkoppele
authors: Peter
authors: P
authors: Tromp
authors: Eric R
authors: ER
authors: Gremmer
authors: Ruud J B
authors: RJ
authors: Peters
authors: Peter J
authors: PJ
authors: Hendriksen
authors: Hans J P
authors: HJ
authors: Marvin
authors: Ron L A P
authors: RL
authors: Hoogenboom
authors: Ad A C M
authors: AA
authors: Peijnenburg
authors: Hans
authors: H
authors: Bouwmeester
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004548:Elasticity; D019570:Inhalation Exposure; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008297:Male; D013058:Mass Spectrometry; D049329:Nanostructures / Q000633:toxicity*; D010316:Particle Size; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012822:Silicon Dioxide / Q000493:pharmacokinetics / Q000633:toxicity*; D013055:Spectrophotometry, Infrared; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D014018:Tissue Distribution; D059467:Transcriptome / Q000187:drug effects; D014783:Viscosity
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D012822:Silicon Dioxide