title: A 90-day study of subchronic oral toxicity of 20 nm, negatively charged zinc oxide nanoparticles in Sprague Dawley rats.
abstract: OBJECTIVE
  The widespread use of nanoparticles (NPs) in industrial and biomedical applications has prompted growing concern regarding their potential toxicity and impact on human health. This study therefore investigated the subchronic, systemic oral toxicity and no-observed-adverse-effect level (NOAEL) of 20 nm, negatively charged zinc oxide (ZnO(SM20(-))) NPs in Sprague Dawley rats for 90 days.
  
  
  METHODS
  The high-dose NP level was set at 500 mg/kg of bodyweight, and the mid- and low-dose levels were set at 250 and 125 mg/kg, respectively. The rats were observed during a 14-day recovery period after the last NP administration for the persistence or reduction of any adverse effects. Toxicokinetic and distribution studies were also conducted to determine the systemic distribution of the NPs.
  
  
  RESULTS
  No rats died during the test period. However, ZnO(SM20(-)) NPs (500 mg/kg) induced changes in the levels of anemia-related factors, prompted acinar cell apoptosis and ductular hyperplasia, stimulated periductular lymphoid cell infiltration and excessive salivation, and increased the numbers of regenerative acinar cells in the pancreas. In addition, stomach lesions were seen at 125, 250, and 500 mg/kg, and retinal atrophy was observed at 250 and 500 mg/kg. The Zn concentration was dose-dependently increased in the liver, kidney, intestines, and plasma, but not in other organs investigated.
  
  
  CONCLUSIONS
  A ZnO(SM20(-)) NP NOAEL could not be established from the current results, but the lowest-observed-adverse-effect level was 125 mg/kg. Furthermore, the NPs were associated with a number of undesirable systemic actions. Thus, their use in humans must be approached with caution.
authors.affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.
authors.forename: Hark-Soo
authors.initials: HS
authors.lastname: Park
authors.affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.
authors.forename: Sung-Sup
authors.initials: SS
authors.lastname: Shin
authors.affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.
authors.forename: Eun Ho
authors.initials: EH
authors.lastname: Meang
authors.affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.
authors.forename: Jeong-sup
authors.initials: JS
authors.lastname: Hong
authors.affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Park
authors.affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.
authors.forename: Su-Hyon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.
authors.forename: Sang-Bum
authors.initials: SB
authors.lastname: Koh
authors.affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.
authors.forename: Seung-Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.
authors.forename: Dong-Hyouk
authors.initials: DH
authors.lastname: Jang
authors.affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.
authors.forename: Jong-Yun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea.
authors.forename: Yle-Shik
authors.initials: YS
authors.lastname: Sun
authors.affiliation: Department of Biomedical Laboratory Science, Namseoul University, Cheonan, Korea.
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, Korea.
authors.forename: Yu-Ri
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, Korea.
authors.forename: Meyoung-Kon
authors.initials: MK
authors.lastname: Kim
authors.affiliation: National Institute of Food and Drug Safety Evaluation, Seoul, Korea.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Jeong
authors.affiliation: National Institute of Food and Drug Safety Evaluation, Seoul, Korea.
authors.forename: Jong-Kwon
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors.forename: Woo-Chan
authors.initials: WC
authors.lastname: Son
authors.affiliation: Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
authors.forename: Jae-Hak
authors.initials: JH
authors.lastname: Park
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000838:Anions; D017209:Apoptosis / Q000187:drug effects; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D010179:Pancreas / Q000187:drug effects; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D059550:Toxicity Tests, Subchronic; D015034:Zinc Oxide / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D000838:Anions; D015034:Zinc Oxide
keywords: ZnO; negative charge; oral toxicity study; rat