Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes

Abstract

BackgroundEngineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m3, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation.ResultsTwenty-three percent of the filtered air controls, 26.5% of the MWCNT-exposed, and 51.9% of the MCA-exposed mice, had lung bronchiolo-alveolar adenomas and lung adenocarcinomas. The average number of tumors per mouse was 0.25, 0.81 and 0.38 respectively. By contrast, 90.5% of the mice which received MCA followed by MWCNT had bronchiolo-alveolar adenomas and adenocarcinomas with an average of 2.9 tumors per mouse 17months after exposure. Indeed, 62% of the mice exposed to MCA followed by MWCNT had bronchiolo-alveolar adenocarcinomas compared to 13% of the mice that received filtered air, 22% of the MCA-exposed, or 14% of the MWCNT-exposed. Mice with early morbidity resulting in euthanasia had the highest rate of metastatic disease. Three mice exposed to both MCA and MWCNT that were euthanized early had lung adenocarcinoma with evidence of metastasis (5.5%). Five mice (9%) exposed to MCA and MWCNT and 1 (1.6%) exposed to MCA developed serosal tumors morphologically consistent with sarcomatous mesotheliomas, whereas mice administered MWCNT or air alone did not develop similar neoplasms.ConclusionsThese data demonstrate that some MWCNT exposures promote the growth and neoplastic progression of initiated lung cells in B6C3F1 mice. In this study, the mouse MWCNT lung burden of 31.2 μg/mouse approximates feasible human occupational exposures. Therefore, the results of this study indicate that caution should be used to limit human exposures to MWCNT.

Repeated exposure to carbon nanotube-based aerosols does not affect the functional properties of a 3D human epithelial airway model

“…Sargent et al (2014) have performed an inhalation study with mice and exposed them with 5 mg/m 3 MWCNTs for 5 h per day, 5 d a week for 15 d and calculated a total deposited material concentration in the lungs to 0.06 mg/cm 2 mimicking a two week human occupational exposure scenario. Another study has modelled the alveolar mass retention of a full working lifetime exposure to 1 mg/m 3 aerosol concentration of CNT is ranging from 12.4 to 46.5 mg/cm 2 (Gangwal et al, 2011).…”

Perturbation of physiological systems by nanoparticles

“…Although whether MWCNTs alone cause cancer in mice was not suggested, in one recent study, MWCNTs were found to be a potent promoter of carcinogenicity. 388 In that study, 7 days after treatment with methylcholanthrene, a known carcinogen, inhalation of MWCNTs in B6C3F1 mice by an occupational exposure dose (5 mg m À3 , 5 hours per day, 5 days per week) dramatically increased both the incidence of carcinogenicity in mice and the number of tumors per animal. Three days after a single intratracheal administration of 0.5 or 2 mg MWCNT (11 nm in diameter and 700 nm in length) to Wistar rats, micronuclei can be detected in lung epithelial cells.…”

Carbon nanotubes – Characteristic of the substance, biological effects and occupational exposure levels

“…Szczególny rodzaj wielościennych nanorurek węglowych MWCNT-7 (o średnicy ok. 50 nm) wywoływał międzybłoniaki otrzewnej u samic i samców szczura po 1-krotnym podaniu dootrzewnowym [47], po podaniu domosznowym [49] oraz u samców myszy p53± w 2 badaniach (podanie dootrzewnowe) [50]. Stwierdzono ponadto, że MWCNT-7 inhalacyjnie mogą być czynnikiem ułatwiającym promocję raków i gruczolaków pęcherzykowo-oskrzelikowych u samców myszy [54]. Jednocześnie nie ma informacji na temat rakotwórczego działania CNT u ludzi [55].…”