Organ accumulation and carcinogenicity of highly dispersed multi-walled carbon nanotubes administered intravenously in transgenic rasH2 mice

Abstract

Purpose

Multiwalled carbon nanotubes (MWCNTs) have been known to enter the circulatory system via the lungs from inhalation exposure; however, its carcinogenicity and subsequent accumulation in other organs have not been adequately reported in the literature. Moreover, the safety of MWCNTs as a biomaterial has remained a matter of debate, particularly when the material enters the circulatory system. To address these problems, we used carcinogenic rasH2 transgenic mice to intravenously administer highly dispersed MWCNTs and to evaluate their carcinogenicity and accumulation in the organs.

Methods

Two types of MWCNTs (thin- and thick-MWCNTs) were intravenously administered at a high dose (approximately 0.7 mg per kg body weight) and low dose (approximately 0.07 mg per kg body weight).

Results

MWCNTs showed pancreatic accumulation in 3.2% of mice administered with MWCNTs, but there was no accumulation in other organs. In addition, there was no significant difference in the incidence of tumor among the four MWCNTs-administered groups compared to the vehicle group without MWCNTs administration. Blood tests revealed elevated levels in mean red blood cell volume and mean red blood cell hemoglobin level for the MWCNTs-administered group, in addition to an increase in eotaxin.

Conclusion

The present study demonstrated that the use of current technology to sufficiently disperse MWCNTs resulted in minimal organ accumulation with no evidence of carcinogenicity.

Keywords:

• multiwalled carbon nanotubes
• rasH2 transgenic mouse
• carcinogenicity
• organ accumulation
• dispersion

Supplementary materials

Figure S1 Method of intravenous administration of rasH2 mice. After sufficient sedation with inhaled anesthesia, a skin incision of approximately 5 mm was performed on the right cervical skin of rasH2 mouse to identify the sternocephalic muscle, which was displaced to the median side. The right external jugular vein between the sternocephalic and cleidbrachial muscle was verified, and tension was applied with traction to the sternocephalic muscle towards the cranial side. Under this condition, 50 μl of solution was injected with a 32G syringe while being cautious to minimize leakages. The figure shows the intravenous administration of thin-MWCNTs (high-dose).Abbreviation: MWCNTs, multiwalled carbon nanotubes

Table S1 Histopathological findings in rasH2 mice treated with vehicle and MNU by jugular vein administration

Acknowledgments

We thank Kiyokazu Kametani (Research Center for Human and Environmental Sciences, Shinshu University) for his technical assistance in TEM analysis, Kayo Suzuki (Research Center for Human and Environmental Sciences, Shinshu University), Misako Yamada (Research Center for Human and Environmental Sciences, Shinshu University) for their technical assistance in the preparation of tissue sections. We would like to thank Sho Sugita (OrthoTranslations) for English language editing. This work was supported in part by the Japan Agency for Medical Research and Development (study numbers: 15hk0102021h0001, 16hk0102021h0002, and 17hk0102021h0003). 

Disclosure

Naoto Saito reports grants from the Japan Agency for Medical Research and Development, during the conduct of the study. The authors report no other conflicts of interest in this work.