Carcinogenicity and Chronic Toxicity after Inhalation Exposure of Rats and Mice to N,N‐Dimethylformamide

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.

Orthopedic bioactive implants: Hydrogel enrichment of macroporous titanium for the delivery of mesenchymal stem cells and strontium

“…Hydrophilicity of CMC was increased by introducing amidic groups in the polymer backbone. To avoid the use of dimethylformamide, a very toxic reagent [41][42][43] used for the organic synthesis of CMCA, 37 a water-based synthesis was developed. FT-IR spectra [ Fig.…”

Carcinogenicity and Chronic Toxicity of 1,4-Dichloro-2-nitrobenzene in Rats and Mice by Two Years Feeding

“…Mouse hepatoblastomas occurred in aged animals, unlike human hepatoblastoma, which primarily occurred in children under 3 yr of age 26,27) . Treatment of strains of mice with chemicals such as Nnitrosodiethylamine 28,29) and N,N-dimethylformamide 30) has been reported to increase the incidence of rare hepatoblastomas. The present results can be taken to indicate that while DCNB produced clear evidence of hepatocarcinogenicity for two different species of rats and mice and different sexes of mice, the carcinogenic activity of DCNB was more potent in mice than in rats.…”

Enhanced proliferative response of hepatocytes to combined inhalation and oral exposures to N,N-dimethylformamide in male rats

“…Medical case reports, epidemiological studies and experimental toxicology studies on health or toxic effects of DMF revealed that DMF primarily affects the liver in humans Wang et al, 1991;Redlich et al, 1990;Fiorito et al, 1997;Nomiyama et al, 2001) and in experimental animals (Lundberg et al, 1981;Craig et al, 1984;Kennedy Jr. et al, 1986;Wang et al, 1999;Chieli et al, 1995;Lynch et al, 2003;Senoh et al, 2003;Malley et al, 1994;Senoh et al, 2004). The International Agency for Research on Cancer (IARC, 1999) made an carcinogenicity to humans (Group 3).…”

“…Malley et al (1994) reported no evidence of carcinogenicity after 2-year inhawas adopted for the IARC's evidence (1999) suggesting lack of carcinogenicity of DMF in experimental animals. More recently, however, Senoh et al (2004) demonstrated that 2-year inhalation exposure to DMF produces hepatocellular adenomas and carcinomas in rats and mice and hepatoblastomas in mice. Since results from a broad range of in vitro and in vivo genotoxicity assays have been reported to be consistently negative for DMF (IARC, 1999), it is suggested a nongenotoxic-cytotoxic-proliferative mode of action may operate in DMF-induced hapatocarcinogenesis.…”

“…Indeed, it has been recognized that 13-week inhalation exposure of rats and mice to DMF vapor induces such related lesions as necrosis, fragmented or enlarged nuclei and increased mitotic et al, 2003;Senoh et al, 2003). It is important to understand whether exposure of a general population to low levels of ubiquitously present DMF through both inhalation and ingestion may cause any subtle but untoward outcome on the liver, since the toxic effects have been evidenced in the experimental animals exposed to far high levels of DMF through single-route exposure of either inhalation or ingestion (Lundberg et al, 1981;Craig et al, 1984;Kennedy Jr. et al, 1986;Wang et al, 1999;Chieli et al, 1995;Lynch et al, 2003;Senoh et al, 2003;Malley et al, 1994;Senoh et al, 2004). Thus the present study was designed to examine hepatotoxicity induced by combined inhalation and oral exposures of male rats to DMF in comparison with those by single-route exposure through either inhalation or ingestion.…”