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Hypothesizing that their respective genetic backgrounds would confer an increased sensitivity to lung tumorigenesis, the plausibility of selected rodent models for the inhalation testing of mainstream tobacco smoke (MTS) was evaluated. Strain A/J and rasH2 transgenic (Tg) mice were exposed to MTS from Kentucky 1R4F research cigarettes using either a whole-body or nose-only exposure regimen. The whole-body regimen consisted of a 20-week exposure period [0.200 mg wet total particulate matter/liter (WTPM/l), 6 h/day, 5 days/week]; nose-only dosing proceeded for 28 weeks [0.040, 0.125, or 0.400 mg WTPM/l, 3 h/day, 5 days/week]. Both regimens included a 16-week recovery period. Gross and microscopic examinations of the lungs were used to evaluate tumor formation, with experimental results supporting the following conclusions: 1. Evaluation of MTS-induced tumorigenicity based on gross evaluation versus microscopic confirmation provides strikingly disparate results, indicating that serial sectioning is necessary for a definitive assessment of lung tumors. 2. While the dosing regimens employed do not allow for a definitive comparison, whole-body exposure appeared to be more effective for inducing statistical changes in tumor multiplicity and incidence compared to nose-only exposure. 3. Exposure-related stress, evidenced as reductions in both body weight gain and background tumor formation, represents a potential confounder during inhalation testing of MTS tumorigenicity, with additional investigation warranted to validate the specificity of exposure-related responses. 4. Comparative findings between A/J and rasH2 Tg mice suggest that the former may be overly sensitive to exposure-related stress, potentially influencing tumorigenic responses.

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Sprague-Dawley rats were exposed nose-only for 1 h/day on weekdays for 13 weeks to the smoke from test and reference cigarettes. The test cigarette was a new prototype: the tobacco is heated rather than burned. The University of Kentucky lR4F cigarette was used as a reference. The exposures used were around 25% higher than those used in earlier studies, and for the test cigarette the resulting blood carboxyhemoglobin concentrations approached those associated with death (62 + %). The smoke from the reference cigarette produced substantial reductions in breathing frequency, whereas the smoke from the test cigarette did not. The availability of nicotine from test and reference cigarettes was very similar. The histopathology seen (mucus-secreting cells; nasal, laryngeal, and bronchial hyperplasia and squamous metaplasia, pulmonary macrophages) indicated that most of the changes observed in the reference animals were absent in the test animals. When changes were seen in the test groups (primarily in the larynx), they were substantially reduced when compared with the reference groups and were completely reversible.The authors thank