Fullerene and fullerene whisker are not carcinogenic to the lungs and pleura in rat long-term study after 2-week intra-tracheal intrapulmonary administration

Our plain-English summary of Fullerene and fullerene whisker are not carcinogenic to the lungs and pleura in rat long-term study after 2-week intra-tracheal intrapulmonary administration, by A.N. Sheema, A. Naiki-Ito, A. Kakehashi, et al (Archives of Toxicology, 2024).

The study

• Authors: A.N. Sheema, A. Naiki-Ito, A. Kakehashi, O.H.M. Ahmed, D.B. Alexander, W.T. Alexander, T. Numano, H. Kato, Y. Goto, H. Takase, A. Hirose, T. Wakahara, K. Miyazawa, S. Takahashi, H. Tsuda
• Journal: Archives of Toxicology
• Published: 2024;98(12):4143-4158
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Fullerene whiskers (FLW)s are thin rod-like structures composed of C60 and C70 fullerene (FL). The shape of FLWs suggests potential toxic effects including carcinogenicity to the lung and pleura, similar to effects elicited by asbestos and multi-walled carbon nanotubes (MWCNT)s. However, no long-term carcinogenic studies of FL or FLW have been conducted. In the present study we investigated the pulmonary and pleural carcinogenicity of FL and FLW. Twelve-week-old male F344 rats were administered 0.25 or 0.5 mg FL, FLW, MWCNT-7, and MWCNT-N by intra-tracheal intra-pulmonary spraying (TIPS). Acute lung lesions and carcinogenicity were analyzed at 1 and 104 weeks after 8 doses/15 days TIPS administration. At week 1, FLW, MWCNT-7, and MWCNT-N significantly increased alveolar macrophage infiltration. Expression of Ccl2 and Ccl3, reactive oxygen species production, and cell proliferation were significantly increased by administration of MWCNT-7 and MWCNT-N but not FL or FLW. At week 104, the incidence of bronchiolo-alveolar adenoma plus adenocarcinoma was significantly increased in the MWCNT-7 and MWCNT-N groups, and the incidence of mesothelioma was significantly increased in the MWCNT-7 group. No significant induction of pulmonary or pleural tumorigenesis was observed in the FL or FLW groups. The number of 8-OHdG-positive cells in the alveolar epithelium was significantly increased in the MWCNT-7 and MWCNT-N groups but not in the FL or FLW groups. FL and FLW did not exert pulmonary or pleural carcinogenicity in our study. In addition, oxidative DNA damage was implicated in MWCNT-induced lung carcinogenesis, suggesting that it may be a useful initial marker of carcinogenicity.

© 2024. The Author(s).

In plain English

This animal experiment tested two carbon nanomaterials in rats: fullerene (FL) and fiber-shaped fullerene whiskers (FLW). Asbestos itself was not tested. The authors used 224 male F344 rats. Groups were sprayed into the lungs with FL, FLW, or one of two multi-walled carbon nanotubes (MWCNT-7, MWCNT-N), which the authors used as positive controls and called proven carcinogens. Treated rats received 8 doses over 15 days, totalling 0.25 or 0.5 mg. Control rats got no treatment or the vehicle alone. Lungs and pleura were examined 1 week and 104 weeks later. At 1 week, FLW caused a milder increase in lung inflammation than the nanotubes, and FL caused none. Neither significantly raised lung reactive oxygen species. At 104 weeks, no mesothelioma or lung adenocarcinoma occurred in FL or FLW groups. Lung hyperplasia or adenoma appeared in 1 to 2 animals in these groups and in control groups. The nanotubes significantly increased lung tumors, and MWCNT-7 at 0.5 mg produced mesothelioma in 4 of 17 rats. The authors concluded that FL and FLW were not carcinogenic to the lung. They found no early markers of pleural carcinogenicity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Two-year animal experiment (rats), with substances sprayed into the lungs through the trachea (TIPS method)
• Who was studied: 224 male F344 rats, divided into 10 body weight-matched groups. Five rats from the no-treatment, vehicle and high-dose groups were killed at 1 week; the rest were followed to 104 weeks. Housed at Nagoya City University, Japan.
• Exposure: C60 fullerene (FL) and fullerene whiskers (FLW) at 0.25 or 0.5 mg per rat in total. Positive controls were MWCNT-7 and MWCNT-N at the same doses. Control groups received no treatment or the vehicle (saline with 0.5% poloxamer-188). Material was sprayed into the lungs every other day for 15 days, 8 doses in all.
• Main results:
  • At week 1, FLW caused a milder version of the increase in alveolar macrophages and neutrophils seen with the two MWCNTs. FL caused no changes.
  • At week 1, reactive oxygen species in the lung rose significantly with MWCNT-7 and MWCNT-N. There was no significant change with FL or FLW.
  • At week 104, no lung adenocarcinoma and no mesothelioma were found in any FL or FLW group. Lung adenoma occurred in 1 of 17 rats in each of the FL 0.25 mg and FLW 0.25 mg groups, and also in 1 of 17 untreated rats. The authors did not attribute these lesions to FL or FLW.
  • Combined lung adenoma plus adenocarcinoma was significantly increased, at 4 of 17 rats (24%) in each of the MWCNT-7 0.25 mg, MWCNT-7 0.5 mg and MWCNT-N 0.25 mg groups.
  • Mesothelioma occurred only in MWCNT-treated groups. It was significantly increased only in the MWCNT-7 0.5 mg group, at 4 of 17 rats (24%) combined. One rat in that group died of pleural mesothelioma at 80 weeks.
  • At 104 weeks, about 1% of the FLW dose (1.4% and 1.7%) and 0.1% of the FL dose remained in the lungs. For the MWCNTs, 18.0 to 57.0% remained.
  • At week 104, oxidative DNA damage (8-OHdG) in lung cells was significantly raised in the MWCNT groups but not in the FL or FLW groups.
• The authors' conclusion: The authors concluded that FL and FLW were not carcinogenic to the lung in this study, and that no carcinogenic changes occurred in the lung or pleura after this exposure.
• Limitations the authors state:
  • The week-1 measurements found no early indicators of carcinogenicity to the pleural mesothelium, even in the MWCNT groups. The authors left this as an issue for future studies.
  • The authors used spraying into the airway as an alternative to inhalation exposure, which they described as ideal but extremely difficult and costly to conduct.
  • Electron microscopy showed very little FLW inside lung macrophages. The authors attributed this to fullerene dissolving during xylene tissue processing.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Carcinogenic, Pleura, Alveolar Macrophage, Reactive Oxygen Species (ROS), Adenocarcinoma, Mesothelioma, Tumorigenesis, 8-OHdG.

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