No abstract

In rats, incidences of hepatocellular adenomas and carcinomas significantly increased in the 400 and 800 ppm-exposed groups and in the 800 ppm-exposed group, respectively. The hepatocellular adenoma did not increase significantly in the 400 ppmexposed female rats, but its incidence exceeded a range of historical control data in the Japan Bioassay Research Center (JBRC). In mice, incidences of hepatocellular adenomas and carcinomas significantly increased in all the DMF-exposed groups. Incidence of hepatoblastomas significantly increased in the 200 and 400 ppm-exposed male mice, and 4 cases of hepatoblastomas in the 400 ppm-exposed female mice and the 800 ppm-exposed male mice exceeded the range of historical control data of the JBRC. Incidences of altered cell foci increased in the liver of exposed rats and mice in an exposure concentration-related manner, and those foci were causally related to the hepatocellular tumors. Liver weights increased in both rats and mice exposed to DMF at 200 ppm and above. Increased levels of γ-GTP, ALT, AST and total bilirubin in exposed rats of both sexes and AST and ALT in exposed mice of both sexes were noted. It was concluded that 2-yr inhalation exposure to DMF increased incidences of hepatocellular adenomas and carcinomas in rats and incidences of hepatocellular adenomas, carcinomas and hepatoblastomas in mice, and that hepatocarcinogenicity of DMF was more Received Feb 26, 2004; Accepted Sep 1, 2004 Correspondence to: H. Senoh, Japan Bioassay Research Center, Japan Industrial Safety and Health Association, 2445 Hirasawa, Hadano, Kanagawa 257-0015, Japan (e-mail: h-seno@jisha.or.jp) potent in mice than in rats.

Toxicity due to 2-and 13-wk Inhalation E x p o s u r e s o f R a t s a n d M i c e t o N , NDimethylformamide: Hideki SENOH, et al. Japan Bioassay Research Center, Japan Industrial Safety and Health Association-In order to better characterize the toxicity of N,N-dimethylformamide (DMF) and to provide its basic toxicity data for risk assessment of workers exposed to DMF, F344 rats and BDF 1 mice of both sexes were exposed by inhalation (6 h/d × 5 d/wk) to 100, 200, 400, 800 or 1,600 ppm DMF for 2 wk, and 50, 100, 200, 400 or 800 ppm DMF for 13 wk. Three male and 7 female rats died during the 2-wk exposure to 1,600 ppm DMF, but no death of the exposed rats or mice occurred under any other exposure conditions. Massive, focal and single cell necroses were observed in the liver of DMF-exposed rats and mice. The massive necrosis associated with the centrilobular fibrosis occurred at the highest exposure concentration. The single cell necrosis was associated with fragmentation of the nucleoli as well as an increased mitotic figure. The 13-wk exposures of rats and mice to DMF were characterized by increases in the relative liver weight and the incidence of the centrilobular hepatocellular hypertrophy as well as increased serum levels of AST, ALT, LDH, total cholesterol and phospholipid. Lower confidence limits of the benchmark dose yielding the response with a 10% extra risk (BMDL 10 ) were determined for the relative liver weight and the incidence of hepatocellular hypertrophy of the 13-wk exposed animals. The BMDL 10 resulted in 1 ppm for the increased relative liver weight of male rats and mice and 17 ppm for the hepatocellular hypertrophy of male mice. (J Occup Health 2003; 45: 365-375)

Subchronic oral toxicity of 1,4-dioxane was examined by administering 1,4-dioxane in drinking water at 6 different concentrations of 0 (control), 640, 1,600, 4,000, 10,000 or 25,000 ppm (wt/wt) to F344 rats and BDF(1)mice of both sexes for 13 weeks. Food and water consumption and terminal body weight were decreased dose-dependently in rats and mice. A dose-dependent increase in the relative weights of kidney and lung was noted in rats and mice, while the relative liver weight was increased only in rats. Increases in plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and a decrease in plasma glucose were noted primarily in the rats and mice dosed 25,000 ppm. Histopathological examination revealed that 1,4-dioxane affected the upper and lower respiratory tracts, liver, kidneys and brain in rats, while only the former two organs were affected in mice. Nuclear enlargement occurred in the respiratory, olfactory, tracheal and bronchial epithelia of the 1,4-dioxane-dosed rats and mice. The 1,4-dioxane-induced hepatic lesions were characterized by centrilobular swelling and necrosis in rats and mice and by glutathione S-transferase placental form (GST-P)-positive altered hepatocellular foci in rats, which are known as preneoplastic lesions. A no-observed-adverse-effect-level (NOAEL) was determined at 640 ppm for both rats and mice, since the nuclear enlargement in the nasal respiratory epithelium and the centrilobular swelling of hepatocytes in rats and the nuclear enlargement in the bronchial epithelium in mice were observed at 1,600 ppm. The NOAEL value corresponded to the estimated 1,4-dioxane intake of 52 mg/kg/day in rats and 170 mg/kg/day in mice.

Systemic inflammation would likely occur in rats (or other hosts) exposed to MWCNT via inhalation due to increases in the expression of inflammatory cytokines in splenic macrophages. Moreover, decreases in IL-2 expression in T-lymphocytes may be critical to the potential reductions in anti-tumor responses in MWCNT-exposed hosts.