Dosimetry for lung tumorigenesis induced by urethane, 4-(<i>N</i>-methyl-<i>N</i>-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and benzo[a]pyrene (B[a]P) in A/JJmsSlc mice

Abstract

Some chemicals are known to be lung carcinogens in rodents. While many studies using two-stage models have administered medium or high doses to mice, few have tested lower doses. The dose dependence of urethane, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and benzo[a]pyrene (B[a]P), three well-known lung carcinogens at high doses, has not been sufficiently reported in lower dose ranges. Our study evaluated the tumorigenicity of urethane, NNK, and B[a]P at 26 weeks after a single intraperitoneal administration of each compound within medium to low dose in male and/or female A/JJmsSlc (A/J) mice. Dose-dependent tumorigenesis was demonstrated histopathologically for the three compounds. These results suggested that the tumorigenicity of these chemicals is dose dependent in A/J mice, even at lower doses than previously reported.

Acrolein Increases the Pulmonary Tumorigenic Activity of the Tobacco-Specific Nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

“…dose of NNK generates a reproducibly quantifiable number of lung tumors 16 weeks postinjection. ,− Furthermore, the doses generate sufficient DNA damage to result in tumor initiation following a single dose. This model provides a predictable dose response between the levels of NNK-derived O 6 -methylguanine pulmonary DNA adducts and lung tumors, allowing us to assess the impact of an exposure on the formation and repair of this mutagenic adduct. , The rationale for performing these studies in female mice comes from the literature where most tumor bioassays with NNK are performed in female A/J mice ,− because female mice are more sensitive to the tumorigenic properties of NNK …”

“…24,25 The rationale for performing these studies in female mice comes from the literature where most tumor bioassays with NNK are performed in female A/J mice 10,38−41 because female mice are more sensitive to the tumorigenic properties of NNK. 42 Justification for Exposure Doses. The animals were exposed to 0, 2.5, or 7.5 μmol of NNK (i.p.…”