Inhalation of tetranitromethane causes nasal passage irritation and pulmonary carcinogenesis in rodents

Implications for risk assessment of suggested nongenotoxic mechanisms of chemical carcinogenesis.

“…However, this transient response was not sufficient to account for the promoting effect of phenobarbital because prolonged exposure (> 100 days) was required to promote 2-acetylaminofluorene-initiated liver lesions (23).The long-term inhalation studies of tetranitromethane are also instructive with respect to the role of regenerative hyperplasia in chemical carcinogenicity. Tetranitromethane, which is mutagenic in Salmonella and induces chromosomal aberrations and sister chromatid exchanges in CHO cells, produced high incidences of benign and malignant lung neoplasms in both sexes of rats and mice at exposure concentrations ranging from 0.5 to 5 ppm (24). These exposures also produced high incidences of hyperplasia of the respiratory epithelium in rats and mice without inducing tumors of the nasal cavity in either species.…”

Determination of 3-Nitrotyrosine by High-Pressure Liquid Chromatography with a Dual-Mode Electrochemical Detector

“…Using a reverse-phase HPLC system with the EC detector connected in series with a photodiode array detector for the determination of tyrosine simultaneously with 3-nitrotyrosine, we are able to detect femtomole levels of 3-nitrotyrosine. As a biological application, we describe its use for determining the levels of tyrosine nitration in blood plasma and selected tissues of rats treated with tetranitromethane, a lung carcinogen and a tyrosine-nitrating agent (27,28).…”

Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

“…For this reason, "cell proliferation is not necessarily a tumor promoter or cocarcinogen" (Melnick et al, 1996;Ward et al, 1993) and regenerative hyperplasia is not always associated with increased tumor risk. Nevertheless, it has long been well recognized that sustained cell proliferation may contribute to tumor development caused by chronic chemical exposures that are both genotoxic and cytotoxic (Schulte-Hermann et al, 1983;Ward et al, 1993;IARC, 2003)-i.e., that values of F h > 1 can and do occur-as illustrated by the effectiveness of initiation-promotion protocols, and by DMOA carcinogens, including tissuespecific or contact irritants that can also damage DNA, such as formaldehyde (Conolly et al, 2004), ethyl acrylate (Ghanayem et al, 1986;Ciaccio et al, 1998), vinyl acetate (Hengstler et al, 2003), tetranitromethane (TNM) (Bucher et al, 1991;Murata et al, 1996) and, as proposed here, naphthalene.…”