Rat pancreatitis produced by 13‐week administration of zinc oxide nanoparticles: biopersistence of nanoparticles and possible solutions

Abstract

Zinc oxide (ZnO) nanoparticles (NPs) are used in diverse applications ranging from paints and cosmetics to biomedicine and food. Although micron-sized ZnO is a traditional food supplement, ZnO NPs are an unknown public health risk because of their unique physicochemical properties. Herein, we studied the 13-week subchronic toxicity of ZnO NPs administered via the oral route according to Organization for Economic Cooperation and Development (OECD) test guideline 408. Well-dispersed ZnO NPs were administered to Sprague-Dawley (SD) rats (11/sex/group) at doses of 67.1, 134.2, 268.4 or 536.8 mg kg(-1) per body weight over a 13-week period. The mean body weight gain in males given 536.8 mg kg(-1) ZnO NPs was significantly lower than that of control male rats, whereas no significant differences were observed between the other treatment groups and the controls. Male and female rats dosed at 536.8 mg kg(-1) ZnO NPs had significant changes in anemia-related hematologic parameters. Mild to moderate pancreatitis also developed in both sexes dosed at 536.8 mg kg(-1) , whereas no histological changes were observed in the other treatment groups. To evaluate the mechanism of toxicity, we performed a bio-persistence study and evaluated the effects of the ZnO NPs on cell proliferation. The treatment of a human gastric adenocarcinoma cell line with ZnO NPs resulted in a significant inhibition of cellular proliferation. The anti-proliferative effect of ZnO NPs or Zn(2+) was effectively blocked by treatment with chelators. These results indicate that the bio-persistence of ZnO NPs after ingestion is key to their toxicity; the no-observed-adverse effect level (NOAEL) of ZnO NPs was found to be 268.4 mg kg(-1) per day for both sexes.

Biokinetics of zinc oxide nanoparticles: toxicokinetics, biological fates, and protein interaction

“…This suggests that the highest dose administered remained in the blood circulation 24 hours after final gavage. The no observed adverse-effect level of ZnO nanoparticles was 268.4 mg/kg for both male and female rats, 27 which seems to be closely correlated to persistence at 536.8 mg/kg in the body. Similar observations were found in a repeated dose 90-day oral TK study of 20 nm ZnO nanoparticles suspended in citrate/HEPES in rats;…”

“…21 The conclusion was drawn that the absorption of zinc ions from ZnO nanoparticles under acidic gastric conditions contributes to their oral toxicity -pancreatitis. 27 Paek et al recently demonstrated a contradicting report of partial dissolution (13%-14%) of 20 and 70 nm ZnO nanoparticles capped with citrate/HEPES or l-serine/HEPES in simulated gastric fluid. 26 When absorbed plasma levels and tissue-distribution concentration of ZnO nanoparticles or ZnCl 2 were calculated based on soluble …”

A 90-day study of subchronic oral toxicity of 20 nm, negatively charged zinc oxide nanoparticles in Sprague Dawley rats

“…A previous 90-day toxicity study of ZnO NPs reported that the manufactured NPs induced lesions attributable to pancreatitis. 23 Similarly, another study showed that the 14-day oral administration of 20 nm ZnO NPs in mice induced mild infiltration of inflammatory cells in the liver and pancreas, with severe stomach mucosal damage. 24 In addition, the oral administration of 20 nm ZnO NPs and ZnO microparticles in SD rats provoked histological lesions in the liver, pancreas, heart, and stomach.…”

Toxicity of 100 nm zinc oxide nanoparticles: a report of 90-day repeated oral administration in Sprague Dawley rats

“…Similarly, 13-week oral administration of 40 nm ZnO NPs in SD rats induced significant changes in anemia-related parameters such as Hb levels, Ht levels, MCV, and MCH. 21 Overdosing of metallic zinc…”