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A 90-day study of sub-chronic oral toxicity of 20 nm positively charged zinc oxide nanoparticles in Sprague Dawley rats.

Park HS, Kim SJ, Lee TJ, Kim GY, Meang E, Hong JS, Kim SH, Koh SB, Hong SG, Sun YS, Kang JS, Kim YR, Kim MK, Jeong J, Lee JK, Son WC, Park JH - Int J Nanomedicine (2014)

Bottom Line: The total red blood cell count was increased, and hematocrit, albumin, mean cell volume, mean cell hemoglobin, and mean cell hemoglobin concentration were decreased significantly compared with control in both 500 mg/kg groups.Total protein and albumin levels were decreased significantly in both sexes in the 250 and 500 mg/kg groups.The significant toxic change was observed to be below 125 mg/kg, so the no-observed-adverse-effect level was not determined, but the lowest-observed-adverse-effect level was considered to be 125 mg/kg in both sexes and the target organs were found to be the pancreas, eye, and stomach.

View Article: PubMed Central - PubMed

Affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.

ABSTRACT

Purpose: The study reported here was conducted to determine the systemic oral toxicity and to find the no-observed-adverse-effect level of 20 nm positively charged zinc oxide (ZnO(SM20(+))) nanoparticles in Sprague Dawley rats for 90 days.

Methods: For the 90-day toxicity study, the high dose was set as 500 mg per kg of body weight (mg/kg) and the middle and low dose were set to 250 mg/kg and 125 mg/kg, respectively. The rats were held for a 14-day recovery period after the last administration, to observe for the persistence or reduction of any toxic effects. A distributional study was also carried out for the systemic distribution of ZnO(SM20(+)) NPs.

Results: No rats died during the test period. There were no significant clinical changes due to the test article during the experimental period in functional assessment, body weight, food and water consumption, ophthalmological testing, urine analysis, necropsy findings, or organ weights, but salivation was observed immediately after administration in both sexes. The total red blood cell count was increased, and hematocrit, albumin, mean cell volume, mean cell hemoglobin, and mean cell hemoglobin concentration were decreased significantly compared with control in both 500 mg/kg groups. Total protein and albumin levels were decreased significantly in both sexes in the 250 and 500 mg/kg groups. Histopathological studies revealed acinar cell apoptosis in the pancreas, inflammation and edema in stomach mucosa, and retinal atrophy of the eye in the 500 mg/kg group.

Conclusion: There were significant parameter changes in terms of anemia in the hematological and blood chemical analyses in the 250 and 500 mg/kg groups. The significant toxic change was observed to be below 125 mg/kg, so the no-observed-adverse-effect level was not determined, but the lowest-observed-adverse-effect level was considered to be 125 mg/kg in both sexes and the target organs were found to be the pancreas, eye, and stomach.

No MeSH data available.


Related in: MedlinePlus

Histopathological findings of glandular stomach.Notes: (A) Normal glandular stomach of a male Sprague Dawley (SD) rat in 0 mg/kg zinc oxide (ZnO). Note the normal submucosa (NS) in the glandular stomach. (B) Submucosal inflammatory cell infiltration (SI) in glandular stomach of a male SD rat administered 500 mg/kg ZnO by gavage for 90 days. (C) Normal glandular stomach of a male SD rat administered 0 mg/kg ZnO by gavage for 90 days. Note the normal parietal cell distribution (arrows) in the glandular stomach. (D) Mucous cell hyperplasia (arrows) – stained blue – in the glandular stomach of a male SD rat administered 500 mg/kg ZnO by gavage for 90 days. Scale bar: 100 mm; A and B, hematoxylin and eosin staining; C and D, Alcian Blue staining.
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f4-ijn-9-093: Histopathological findings of glandular stomach.Notes: (A) Normal glandular stomach of a male Sprague Dawley (SD) rat in 0 mg/kg zinc oxide (ZnO). Note the normal submucosa (NS) in the glandular stomach. (B) Submucosal inflammatory cell infiltration (SI) in glandular stomach of a male SD rat administered 500 mg/kg ZnO by gavage for 90 days. (C) Normal glandular stomach of a male SD rat administered 0 mg/kg ZnO by gavage for 90 days. Note the normal parietal cell distribution (arrows) in the glandular stomach. (D) Mucous cell hyperplasia (arrows) – stained blue – in the glandular stomach of a male SD rat administered 500 mg/kg ZnO by gavage for 90 days. Scale bar: 100 mm; A and B, hematoxylin and eosin staining; C and D, Alcian Blue staining.

Mentions: Acinar cell apoptosis and chronic inflammation of the pancreas in all groups were observed. Two cases of retinal atrophy were found in both the male recovery and 500 mg/kg groups, while an additional three cases were also identified in the female recovery group (Figure 2). In all treatment groups, various gastric lesions of different grades were observed. Therefore, we examined these lesions, classifying them as non-glandular stomach and glandular stomach lesions. In all males and females in all groups, squamous cell hyperplasia, squamous cell vacuolation, and subepithelial inflammatory cell infiltration in non-glandular stomach and submucosal inflammatory cells infiltration, superficial epithelial degeneration/regeneration, intracytoplasmic hyaline droplet, mucous cell hyperplasia, and eosinophilic chief cells in glandular stomach were observed (Figures 3 and 4). The lesions observed in the pancreas and stomach disappeared in the recovery group, and we considered that most lesions recovered due to the interruption of test-article administration. Also in the 500mg/kg male and female recovery group, eye retinal atrophy was of the same grade of lesion as those in main study (Table 10).


A 90-day study of sub-chronic oral toxicity of 20 nm positively charged zinc oxide nanoparticles in Sprague Dawley rats.

Park HS, Kim SJ, Lee TJ, Kim GY, Meang E, Hong JS, Kim SH, Koh SB, Hong SG, Sun YS, Kang JS, Kim YR, Kim MK, Jeong J, Lee JK, Son WC, Park JH - Int J Nanomedicine (2014)

Histopathological findings of glandular stomach.Notes: (A) Normal glandular stomach of a male Sprague Dawley (SD) rat in 0 mg/kg zinc oxide (ZnO). Note the normal submucosa (NS) in the glandular stomach. (B) Submucosal inflammatory cell infiltration (SI) in glandular stomach of a male SD rat administered 500 mg/kg ZnO by gavage for 90 days. (C) Normal glandular stomach of a male SD rat administered 0 mg/kg ZnO by gavage for 90 days. Note the normal parietal cell distribution (arrows) in the glandular stomach. (D) Mucous cell hyperplasia (arrows) – stained blue – in the glandular stomach of a male SD rat administered 500 mg/kg ZnO by gavage for 90 days. Scale bar: 100 mm; A and B, hematoxylin and eosin staining; C and D, Alcian Blue staining.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4279754&req=5

f4-ijn-9-093: Histopathological findings of glandular stomach.Notes: (A) Normal glandular stomach of a male Sprague Dawley (SD) rat in 0 mg/kg zinc oxide (ZnO). Note the normal submucosa (NS) in the glandular stomach. (B) Submucosal inflammatory cell infiltration (SI) in glandular stomach of a male SD rat administered 500 mg/kg ZnO by gavage for 90 days. (C) Normal glandular stomach of a male SD rat administered 0 mg/kg ZnO by gavage for 90 days. Note the normal parietal cell distribution (arrows) in the glandular stomach. (D) Mucous cell hyperplasia (arrows) – stained blue – in the glandular stomach of a male SD rat administered 500 mg/kg ZnO by gavage for 90 days. Scale bar: 100 mm; A and B, hematoxylin and eosin staining; C and D, Alcian Blue staining.
Mentions: Acinar cell apoptosis and chronic inflammation of the pancreas in all groups were observed. Two cases of retinal atrophy were found in both the male recovery and 500 mg/kg groups, while an additional three cases were also identified in the female recovery group (Figure 2). In all treatment groups, various gastric lesions of different grades were observed. Therefore, we examined these lesions, classifying them as non-glandular stomach and glandular stomach lesions. In all males and females in all groups, squamous cell hyperplasia, squamous cell vacuolation, and subepithelial inflammatory cell infiltration in non-glandular stomach and submucosal inflammatory cells infiltration, superficial epithelial degeneration/regeneration, intracytoplasmic hyaline droplet, mucous cell hyperplasia, and eosinophilic chief cells in glandular stomach were observed (Figures 3 and 4). The lesions observed in the pancreas and stomach disappeared in the recovery group, and we considered that most lesions recovered due to the interruption of test-article administration. Also in the 500mg/kg male and female recovery group, eye retinal atrophy was of the same grade of lesion as those in main study (Table 10).

Bottom Line: The total red blood cell count was increased, and hematocrit, albumin, mean cell volume, mean cell hemoglobin, and mean cell hemoglobin concentration were decreased significantly compared with control in both 500 mg/kg groups.Total protein and albumin levels were decreased significantly in both sexes in the 250 and 500 mg/kg groups.The significant toxic change was observed to be below 125 mg/kg, so the no-observed-adverse-effect level was not determined, but the lowest-observed-adverse-effect level was considered to be 125 mg/kg in both sexes and the target organs were found to be the pancreas, eye, and stomach.

View Article: PubMed Central - PubMed

Affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.

ABSTRACT

Purpose: The study reported here was conducted to determine the systemic oral toxicity and to find the no-observed-adverse-effect level of 20 nm positively charged zinc oxide (ZnO(SM20(+))) nanoparticles in Sprague Dawley rats for 90 days.

Methods: For the 90-day toxicity study, the high dose was set as 500 mg per kg of body weight (mg/kg) and the middle and low dose were set to 250 mg/kg and 125 mg/kg, respectively. The rats were held for a 14-day recovery period after the last administration, to observe for the persistence or reduction of any toxic effects. A distributional study was also carried out for the systemic distribution of ZnO(SM20(+)) NPs.

Results: No rats died during the test period. There were no significant clinical changes due to the test article during the experimental period in functional assessment, body weight, food and water consumption, ophthalmological testing, urine analysis, necropsy findings, or organ weights, but salivation was observed immediately after administration in both sexes. The total red blood cell count was increased, and hematocrit, albumin, mean cell volume, mean cell hemoglobin, and mean cell hemoglobin concentration were decreased significantly compared with control in both 500 mg/kg groups. Total protein and albumin levels were decreased significantly in both sexes in the 250 and 500 mg/kg groups. Histopathological studies revealed acinar cell apoptosis in the pancreas, inflammation and edema in stomach mucosa, and retinal atrophy of the eye in the 500 mg/kg group.

Conclusion: There were significant parameter changes in terms of anemia in the hematological and blood chemical analyses in the 250 and 500 mg/kg groups. The significant toxic change was observed to be below 125 mg/kg, so the no-observed-adverse-effect level was not determined, but the lowest-observed-adverse-effect level was considered to be 125 mg/kg in both sexes and the target organs were found to be the pancreas, eye, and stomach.

No MeSH data available.


Related in: MedlinePlus