Ninety-Day Inhalation Study in Rats, Using Aged and Diluted Sidestream Smoke from a Reference Cigarette: DNA Adducts and Alveolar Macrophage Cytogenetics

To study the genotoxic effects of subchronic exposure to environmentaltobacco smoke, Sprague-Dawley rats were exposed to 0, 0.1, 1.0,and 10 mg total particulate matter (TPM)/m³ of aged and dilutedsidestream smoke (ADSS) from 1R4F reference cigarettes 6 hrper day, 5 days a week for 13 weeks. DNA from lung, heart, larynx,bladder, and liver was tested for adduct formation by the ³²P-postlabelingassay after 28 (except bladder) and 90 days of exposure and90 days after cessation of exposure. In addition, alveolar macrophagesfrom animals exposed for 28 or 90 days were examined for chromosomalaberrations. Exposure-related DNA adducts were not observedin any tissue in any of the animals exposed to 0.1 or 1.0 mgTPM/m³. However, increased levels of DNA adducts with diagonalradioactive zones were observed in lung, heart, and larynx DNAof animals exposed to the highest concentration of ADSS (10mg TPM/m³). Adduct analyses with varying amounts of DNA fromlungs of mid-and high-exposure animals clearly indicate thatthe dose-response for DNA adduct formation is nonlinear. Theadduct levels were highest after 90 days of exposure and weresignificantly reduced in all target tissues 90 days after cessationof exposure. Chromosomal aberrations in alveolar macrophageswere not elevated in any group after 28 or 90 days of exposure.These results indicate a no-observed-effect-level (NOEL) ofat least 1.0 mg/m³ for DNA adduct formation in lung, heart,and larynx, and a NOEL of at least 10 mg/m³ for the inductionof chromosome aberrations in alveolar macrophages, under theconditions of this study.