title: Comparative toxicity and biodistribution assessments in rats following subchronic oral exposure to copper nanoparticles and microparticles.
abstract: Copper nanoparticles (Cu NPs) have great potential in electronics and biomedical fields because of their efficient thermodynamic and anti-microbial properties. However, their potential toxic effects and kinetic data following repeated exposure are still unclear.
  
  
  
  We evaluated the physicochemical properties of Cu NPs (25 nm) and copper microparticles (Cu MPs, 14-25 μm). Comparative in vivo toxicity of Cu NPs and Cu MPs was evaluated by conducting a 28-day repeated oral dose study at equivalent dose levels of 0, 100, 200, and 400 mg/kg/day (vehicle, 1 % hydroxypropyl methylcellulose). We determined Cu levels in the blood, tissues, urine, and feces by using inductively coupled plasma mass spectrometry.
  
  
  
  The solubility of Cu NPs and Cu MPs was 84.5 and 17.2 %, respectively, in an acidic milieu; however, they scarcely dissolved in vehicle or intestinal milieus. The specific surface area of Cu NPs and Cu MPs was determined to be 14.7 and 0.16 m2/g, respectively. Cu NPs exhibited a dose-dependent increase of Cu content in the blood and tested organs, with particularly high levels of Cu in the liver, kidney, and spleen. Only for liver and kidney increased Cu levels were found in Cu MPs-treated rats. Cu NPs caused a dose-related increase in Cu levels in urine, whereas Cu MPs did not affect the urine Cu levels. Extremely high levels of Cu were detected in the feces of Cu MPs-treated rats, whereas much lower levels were detected in the feces of Cu NPs-treated rats. A comparative in vivo toxicity study showed that Cu NPs caused damages to red blood cells, thymus, spleen, liver, and kidney at ≥200 mg/kg/days, but Cu MPs did not cause any adverse effects even at the highest dose.
  
  
  
  Overall, the in vivo repeated dose toxicity study of Cu NPs and Cu MPs demonstrated that large surface area and high solubility in physiological milieus could directly influence the toxicological responses and biodistribution of Cu particles when administered orally. Under these experimental conditions, the no-observed-adverse-effect levels of Cu NPs and Cu MPs were determined to be 100 and ≥400 mg/kg/day, respectively.
authors: College of Veterinary Medicine BK21 Plus Project Team, Chonnam National University, Gwangju, 61186, Republic of Korea.|Natural Product Research Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup, 56212, Republic of Korea.
authors: In-Chul
authors: IC
authors: Lee
authors: College of Veterinary Medicine BK21 Plus Project Team, Chonnam National University, Gwangju, 61186, Republic of Korea.
authors: Je-Won
authors: JW
authors: Ko
authors: College of Veterinary Medicine BK21 Plus Project Team, Chonnam National University, Gwangju, 61186, Republic of Korea.
authors: Sung-Hyeuk
authors: SH
authors: Park
authors: College of Veterinary Medicine BK21 Plus Project Team, Chonnam National University, Gwangju, 61186, Republic of Korea.
authors: Na-Rae
authors: NR
authors: Shin
authors: College of Veterinary Medicine BK21 Plus Project Team, Chonnam National University, Gwangju, 61186, Republic of Korea.
authors: In-Sik
authors: IS
authors: Shin
authors: College of Veterinary Medicine BK21 Plus Project Team, Chonnam National University, Gwangju, 61186, Republic of Korea.
authors: Changjong
authors: C
authors: Moon
authors: Gyeongnam Department of Environment & Toxicology, Korea Institute of Toxicology, Gyeongnam, 52834, Republic of Korea.
authors: Je-Hein
authors: JH
authors: Kim
authors: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, ChungBuk, 28116, Republic of Korea. hckim@kribb.re.kr.
authors: Hyoung-Chin
authors: HC
authors: Kim
authors: College of Veterinary Medicine BK21 Plus Project Team, Chonnam National University, Gwangju, 61186, Republic of Korea. toxkim@jnu.ac.kr.
authors: Jong-Choon
authors: JC
authors: Kim
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003300:Copper / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008297:Male; D053768:Metal Nanoparticles / Q000633:toxicity*; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D059550:Toxicity Tests, Subchronic
chemical_list: D003300:Copper
keywords: Biodistribution; Comparative toxicity; Copper microparticles; Copper nanoparticles