Dataset Information

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.

SUBMITTER: van der Zande M

PROVIDER: S-EPMC3922429 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Publications

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

van der Zande Meike M Vandebriel Rob J RJ Groot Maria J MJ Kramer Evelien E Herrera Rivera Zahira E ZE Rasmussen Kirsten K Ossenkoppele Jan S JS Tromp Peter P Gremmer Eric R ER Peters Ruud J B RJ Hendriksen Peter J PJ Marvin Hans J P HJ Hoogenboom Ron L A P RL Peijnenburg Ad A C M AA Bouwmeester Hans H

Particle and fibre toxicology 20140207

<h4>Background</h4>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.<h4>Met ...[more]

PMID: 24507464

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Project description:Occupational exposure to crystalline silica results in serious health effects, most notably, silicosis and cancer. A proper understanding of the mechanism(s) underlying the initiation and progression of silica-induced pulmonary toxicity is critical for the intervention and/or prevention of the adverse health effects associated with crystalline silica exposure. Rats were exposed to crystalline silica by inhalation at a concentration of 15 mg/m3, 6 hours/day, 5 days/week for 3, 6 or 12 weeks. At the end of each exposure time point, toxicity and global gene expression changes were determined in the lungs. In general, silica exposure resulted in pulmonary toxicity that was dependent on the duration of silica exposure. A significant and silica exposure time-dependent increase in lactate dehydrogenase activity and accumulation of alveolar macrophages and infiltrating neutrophils in the bronchoalveolar lavage fluid suggested crystalline silica-induced pulmonary toxicity in the rats. Histological changes indicative of pulmonary toxicity were detectable only in the lungs of rats that were exposed to silica for 6- or 12-weeks. Minimal, sub-acute pulmonary inflammation consisting mainly of macrophage accumulation and infiltration of neutrophils was seen in 2 out of 8 rats in the 6-week silica exposure group. Chronic active inflammation, type II pneumocyte hyperplasia, and fibrosis were detected following 12-weeks of silica exposure in all rat lungs. In addition, crystalline silica was visible in the lungs of the rats belonging to the 12-week exposure group. A significant increase in the number of neutrophils seen in the blood indicated silica-induced systemic inflammation in the rats. Microarray analysis of the global gene expression profiles of the rat lungs detected significant differential expression (FDR p <0.05 and fold change >1.5) of 38, 77 and 99 genes in the rats exposed to silica for 3-, 6- and 12-weeks, respectively, compared to the time-matched controls. Bioinformatics analysis of the differentially expressed genes identified significant enrichment of functions, networks and pathways related to inflammation, cancer, oxidative stress, fibrosis and tissue remodeling in the lungs of the silica exposed rats. Collectively, the results of our study provided insights into the molecular mechanisms underlying pulmonary toxicity following sub-chronic exposure to silica in rats.

Project description:The effect, if any, of age on the pulmonary toxicity induced by Min-U-Sil 5 crystalline silica exposure was investigated in rats. As part of the study, the changes in global gene expression profiles in the blood and lungs of the animals were determined. To conduct these studies, to determine if age influences the pulmonary response to crystalline silica exposure, two different age groups of healthy, male F344 rats were used. In this study the old age group of rats (12 months old at the time of exposure) was exposed to either air or crystalline silica (Min-U-Sil 5) (15 mg/m3, 6 hours/day, 5 days) by whole body inhalation. The old age group of rats simulates a group of workers who would be 45 to 50 years old. At two crystalline silica post-exposure time periods (1-day and 6-months) animals were euthanized and pulmonary inflammatory, cytotoxic, and oxidant responses were determined. Analysis of bronchoalveolar lavage parameters of toxicity such as oxidant generation and inflammation revealed significant changes in pulmonary toxicity in the crystalline silica exposed rats compared with the time-matched, air exposed control rats. The blood gene expression profiles showed only minimal changes, at both the time points, in the crystalline silica exposed rats compared with the controls. Specifically, no genes were significantly differentially expressed (fold change >1.5 and FDR p<0.05) in the one-day post-exposure group and only 6 genes were significantly differentially expressed in the 6-month post-exposure group. However, the lung gene expression profiles showed substantial changes in the crystalline silica exposed animals at both one-day and 6-month post-exposure. Specifically, there were a total of 325 genes significantly differentially expressed (fold change >1.5 and FDR p<0.05) at the one-day post-exposure group and 3348 genes significantly differentially expressed at the 6-month post-exposure. The data obtained from the present study demonstrated that crystalline silica inhalation exposure, under the conditions employed in the present study, resulted in significant changes in lung toxicity parameters and lung gene expression profile in the rats at both 1-day and 6-month post-exposure.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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