title: 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.
authors: Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, 110-799, Korea.
authors: Seung Hyeok
authors: SH
authors: Seok
authors: Wan-Seob
authors: WS
authors: Cho
authors: Jung Shin
authors: JS
authors: Park
authors: Yirang
authors: Y
authors: Na
authors: Ahram
authors: A
authors: Jang
authors: Hojoong
authors: H
authors: Kim
authors: Yujin
authors: Y
authors: Cho
authors: Taesung
authors: T
authors: Kim
authors: Ji-Ran
authors: JR
authors: You
authors: Sanghoon
authors: S
authors: Ko
authors: Byeong-Cheol
authors: BC
authors: Kang
authors: Jong Kwon
authors: JK
authors: Lee
authors: Jayoung
authors: J
authors: Jeong
authors: Jeong-Hwan
authors: JH
authors: Che
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D010195:Pancreatitis / Q000139:chemically induced* / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D059550:Toxicity Tests, Subchronic; D015034:Zinc Oxide / Q000737:chemistry / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D002614:Chelating Agents; D005029:Ethylenediamines; D004492:Edetic Acid; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; D015034:Zinc Oxide
keywords: OECD test guideline; anemia; bio-persistence; nanoparticles; oral toxicity; pancreatitis