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.

No abstract

Two-and 13-week Inhalation Toxicities of Indium-tin Oxide and Indium Oxide in Rats: Kasuke NagaNo, et al. Japan Bioassay Research Center, Japan Industrial Safety and Health AssociationObjectives: Two-and 13-week inhalation toxicities of indium-tin oxide (ITO) and indium oxide (IO) were characterized for risk assessments of workers exposed to ITO. Methods: F344 rats of both sexes were exposed by inhalation to ITO or IO aerosol for 6 h/day, 5 day/wk for 2 wk at 0, 0.1, 1, 10 or 100 mg/m 3 or 13 wk at 0, 0.1or 1 mg/m 3 . An aerosol generator and inhalation exposure system was constructed. Results: Blood and lung contents of indium were elevated in a dose-related manner in the ITO-and IO-exposed rats. ITO and IO particles were deposited in the lung, mediastinal lymph node and nasal-associated lymphoid tissue. Exposures to ITO and IO induced alveolar proteinosis, infiltrations of alveolar macrophages and inflammatory cells and alveolar epithelial hyperplasia in addition to increased lung weight. ITO affected the lung more severely than IO did. Fibrosis of alveolar wall developed and some of these lesions worsened at the end of the 26-week post-exposure period. Conclusions: Persistent pulmonary lesions including alveolar proteinosis and macrophage infiltration occurred after 2-and 13-week inhalation exposures of rats to ITO and IO. Fibrosis of alveolar wall developed later. These lesions occurred after ITO exposure at the same concentration as the current occupational exposure limit in the USA and at blood indium levels below the biological exposure index in Japan for indium. (J Occup Health 2011; 53: 51-63)

To evaluate pulmonary toxicity of multi-walled carbon nanotubes (MWCNTs), F344 rats of both sexes were exposed by inhalation to 0.2, 1 or 5 mg/m3 MWCNT aerosol for 6 h/day, 5 days/week for 2 weeks using a whole-body exposure system. At the end of the 2-week exposure period, one-half of the rats were necropsied, and at the end of an additional 4-week postexposure period, the remaining rats were necropsied. MWCNTs were deposited in the lungs of all MWCNT-exposed groups and mostly remained in the lungs throughout the 4-week postexposure period. Granulomatous changes in the lung were found in the rats exposed to 5 mg/m3 MWCNTs, and these changes were slightly aggravated at the end of the 4-week postexposure period. In the bronchoalveolar lavage fluid (BALF), the numbers of neutrophils, percentages of bi- and multinucleated alveolar macrophages, levels of ALP activity and concentrations of total protein and albumin were elevated in the rats exposed to 1 and 5 mg/m3 MWCNTs. At the end of the 4-week postexposure period, the values of the BALF parameters tended to remain elevated. In addition, goblet cell hyperplasias in the nasal cavity and nasopharynx were observed in the rats exposed to 1 and 5 mg/m3 MWCNTs, but these lesions had largely regressed by the end of the postexposure period. Based on the histopathological and inflammatory changes, the no-observed-adverse-effect level (NOAEL) for inhalation of MWCNTs for 2 weeks was 0.2 mg/m3.

Thirteen-week Inhalation Toxicity of pDichlorobenzene in Mice and Rats: Shigetoshi AISO, et al. Japan Bioassay Research Center, Japan Industrial Safety and Health AssociationSubchronic inhalation toxicity of p-dichlorobenzene (p-DCB) was examined by exposing BDF 1 mice and F344 rats of both sexes (6 h/d and 5 d/wk) to inhalation of 25, 55, 120, 270 or 600 ppm (v/v) p-DCB vapor for 13 wk. The exposure to p-DCB vapor retarded the growth rate in the male mice, and induced hepatotoxicity in the mice and rats of both sexes and renal and hematological toxicity in the male rats. Hepatotoxicity was characterized by increased liver weight, hepatocellular hypertrophy, and increased serum levels of total cholesterol. Liver necrosis and increased serum levels of AST and ALT were observed in the exposed mice, whereas these changes, which indicate hepatocellular death, did not occur in any of the exposed rats. p-DCB-induced renal lesions occurred only in the male rats. Hyaline droplets were observed in the proximal tubular epithelial cells, and were stained positively with anti-α 2υ -globulin, suggesting excessive accumulation of α 2υ -globulin in the epithelial cells. Granular casts were formed in the tubular lumen, resulting from the necrotic desquamation of the renal tubular epithelium. Papillary mineralization in the renal pelvis and increased serum levels of BUN and creatinine were noted. These renal changes indicated α 2υ -globulin nephropathy. Decreases in red blood cell counts, hemoglobin concentration, hematocrit and mean corpuscular volume and increased spleen weight occurred in the exposed male rats. The NOAEL was 120 ppm for the hepatic endpoint in mice and for the renal endpoint in rats. The maximum tolerated dose for a 2-yr bioassay inhalation study of rodent carcinogenicity was estimated to be 300 ppm, based Received Nov 24, 2004: Accepted Feb 23, 2005 Correspondence to: S. Aiso, Japan Bioassay Research Center, 2445 Hirasawa, Hadano, Kanagawa 257-0015, Japan (e-mail: s-aiso@jisha.or.jp) on the present results. (J Occup Health 2005; 47: 249-260)