Carcinogenicity of multi-walled carbon nanotubes: challenging issue on hazard assessment

Abstract

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.

Keywords: Inhalation exposure; Lung burden; Lung carcinogenicity; MWCNT; Mesothelioma; Multi-walled carbon nanotube.

Fig. 1.

Aerosol generation and inhalation exposure system. MWNT-7 aerosol is generated by the cyclone sieve method and sent to the inhalation chamber.

Fig. 2.

MWNT-7 concentrations in the inhalation chambers throughout the 104 week experimental period. MWNT-7 aerosols were constantly generated for each concentration group during the exposure period (6 h/day, 5 days/week, 104 weeks).

Fig. 3.

Scanning electron microscope (SEM) images of MWNT-7 fibers. a: MWNT-7 fibers at a concentration of 0.2 mg/m³ in the inhalation chamber. MWNT-7 fibers were well dispersed. b: MWNT-7 fibers after digestion of an alveolar macrophage. MWNT-7 fibers form a cocoon-like mass. c: A representative MWNT-7 fiber in the pleural lavage fluid. The MWNT-7 fiber is single, long, and straight. d: A representative MWNT-7 fiber in the peritoneal cavity. The MWNT-7 fiber is single, long, and straight.

Fig. 4.

Lung burden measurement method of MWNT-7. A defining feature of the method is the use of a hybrid marker, benzo[ghi]perylene, for coupling and adsorption onto the MWNT-7 fiber.

Fig. 5.

Summarized results of lung burden measured in male and female of rats exposed to 3 concentrations at week 2, week 13, and week 104 of inhalation exposure studies. Concentrations: 0.2, 1, and 5 mg/m³ in 2-week and 13-week studies, and 0.02, 0.2, and 2 mg/m³ in 2-year study.

Fig. 6.

Comparison of the area under the lung burden curves in the MWNT-7 carcinogenicity study of rats by inhalation exposure and MWCNT-N carcinogenicity study of rats by intratracheal administration. The shapes of the areas under the lung burden curves are clearly different.

Fig. 7.

Relationship between qualitative events and quantitative doses in MeIQx hepatocarcinogenesis in rats.