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

Hark-Soo Park,¹ Sung-Sup Shin,¹ Eun Ho Meang,¹ Jeong-sup Hong,¹ Jong-Il Park,¹ Su-Hyon Kim,¹ Sang-Bum Koh,¹ Seung-Young Lee,¹ Dong-Hyouk Jang,¹ Jong-Yun Lee,¹ Yle-Shik Sun,¹ Jin Seok Kang,² Yu-Ri Kim,³ Meyoung-Kon Kim,³ Jayoung Jeong,⁴ Jong-Kwon Lee,⁴ Woo-Chan Son,⁵ Jae-Hak Park<sup>6

1</sup>General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea; ²Department of Biomedical Laboratory Science, Namseoul University, Cheonan, Korea; ³Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, Korea; ⁴National Institute of Food and Drug Safety Evaluation, Seoul, Korea; ⁵Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; ⁶Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea

Purpose: 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.
Conclusion: 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.

Keywords: negative charge, oral toxicity study, rat, ZnO

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