BackgroundMulti-walled carbon nanotubes (MWCNTs) constitute one of the most promising types of nanomaterials in industry today. With their increasing use, the potential toxicity and carcinogenicity of MWCNT needs to be evaluated in bioassay studies using rodents. Since humans are mainly exposed to MWCNT by inhalation, we performed a 104-week carcinogenicity study using whole-body inhalation exposure chambers with a fibrous straight type of MWCNT at concentrations of 0, 0.02, 0.2, and 2 mg/m3 using male and female F344 rats.ResultsLung carcinomas, mainly bronchiolo-alveolar carcinoma, and combined carcinomas and adenomas were significantly increased in males exposed to 0.2 and 2 mg/m3 MWNT-7 and in females exposed to 2 mg/m3 MWNT-7 compared to the clean air control group. However, no development of pleural mesothelioma was observed. Concentration-dependent toxic effects in the lung such as epithelial hyperplasia, granulomatous change, localized fibrosis, and alteration in BALF parameters were found in MWNT-7 treatment groups of both sexes. There were no MWNT-7-specific macroscopic findings in the other organs, including the pleura and peritoneum. Absolute and relative lung weights were significantly elevated in male rats exposed to 0.2 and 2 mg/m3 MWNT-7 and in all exposed female groups. The lung burdens of MWNT-7 were clearly increased in a concentration-dependent as well as a duration-dependent manner.ConclusionThere is clear evidence that MWNT-7 is carcinogenic to the lungs of male and female F344 rats, however no plural mesothelioma was observed.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-016-0164-2) contains supplementary material, which is available to authorized users.

Cancer development due to fiber-like straight type of multi-walled carbon nanotubes (MWCNTs) has raised concerns for human safety because of its shape similar to asbestos. To set concentrations of MWCNT for a rat carcinogenicity study, we conducted a 13-week whole body inhalation study. F344 male and female rats, 6-week-old at the commencement of the study, were exposed by whole-body inhalation to MWCNT at concentrations of 0, 0.2, 1 and 5 mg/m(3) with a generation and exposure system utilizing the cyclone sieve method. Measured concentrations in the exposure chambers were 0.20 ± 0.02, 1.01 ± 0.11 and 5.02 ± 0.25 mg/m(3) for 13 weeks. The MMAD (GSD) of MWCNT were 1.4-1.6 μm (2.3-3.0), and mean width and length were 94.1-98.0 nm and 5.53-6.19 μm, respectively, for each target concentration. Lung weights were increased 1.2-fold with 1 mg/m(3) and 1.3-fold with 5 mg/m(3) in both sexes compared to the controls. In the bronchoalveolar lavage fluid (BALF) analyses, inflammatory parameters were increased concentration-dependently in both sexes from 0.2 mg/m(3). Granulomatous changes in the lung were induced at 1 and 5 mg/m(3) in females and even at 0.2 mg/m(3) in males. Focal fibrosis of the alveolar wall was observed in both sexes at 1 mg/m(3) or higher. Inflammatory infiltration in the visceral pleural and subpleural areas was induced only at 5 mg/m(3). In conclusion, we determined 0.2 mg/m(3) as the low-observed-adverse-effect level (LOAEL) for respiratory tract toxicity in the present inhalation exposure study of rats.

Objectives: This report reviews the carcinogenicity of multi-walled carbon nanotubes (MWCNTs) in experimental animals, concentrating on MWNT-7, a straight fibrous MWCNT. Methods: MWCNTs were administered to mice and rats by intraperitoneal injection, intrascrotal injection, subcutaneous injection, intratracheal instillation and inhalation. Results: Intraperitoneal injection of MWNT-7 induced peritoneal mesothelioma in mice and rats. Intrascrotal injection induced peritoneal mesothelioma in rats. Intratracheal instillation of MWCNT-N (another straight fibrous MWCNT) induced both lung carcinoma and pleural mesothelioma in rats. In the whole body inhalation studies, in mice MWNT-7 promoted methylcholanthrene-initiated lung carcinogenesis. In rats, inhalation of MWNT-7 induced lung carcinoma and lung burdens of MWNT-7 increased with increasing concentration of airborne MWNT-7 and increasing duration of exposure. Conclusions: Straight, fibrous MWCNTs exerted carcinogenicity in experimental animals. Phagocytosis of MWCNT fibers by macrophages was very likely to be a principle factor in MWCNT lung carcinogenesis. Using no-observed-adverse-effect level-based approach, we calculated that the occupational exposure limit (OEL) of MWNT-7 for cancer protection is 0.15 μg/m3 for a human worker. Further studies on the effects of the shape and size of MWCNT fibers and mode of action on the carcinogenicity are required.

Two‐year Study of Carcinogenicity and Chronic Toxicity of Biphenyl in Rats: Yumi Umeda, et al. Japan Bioassay Research Center, Japan Industrial Safety and Health Association— Carcinogenicity and chronic toxicity of biphenyl were examined in 50 male and 50 female F344 rats exposed to 0, 500, 1,500 or 4,500 ppm biphenyl in the diet for 105 weeks. Bladder tumors were found in the 4,500 ppm males, as evidenced by significantly increased incidence of carcinoma (24/50) and papilloma (10/50) of the transitional cells as well as one rarely observed case both of carcinoma and papilloma of the squamous cells. The survival rate of the 4500 ppm males significantly decreased, due to the bladder tumors and the hematuria accompanied by bladder calculi. The bladder calculi were found in 43 males in the 4,500 ppm group, but in only 8 females. Urinary pH significantly increased in the males, and occult blood was observed both in males and females in the 4,500 ppm group. The pre‐neoplastic lesions were hyperplasia of transitional epithelium (simple, nodular and papillary hyperplasia) in the bladder of the 4,500 ppm males. Incidences of calculus formation and transitional cell hyperplasia in the renal pelvis also significantly increased in the 4,500 ppm males and females. On the other hand, the incidences of the transitional cell hyperplasia and the calculus formation in the bladder and the renal pelvis were far lower in females than in males, and no bladder tumors were observed in the females. Causative factors of the bladder tumors and their male predominance were discussed with reference to the findings reported in the literature and the previous study of biphenyl metabolism.

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