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Toxicological Sciences 68, 322-330 (2002)
Copyright © 2002 by the Society of Toxicology

CARCINOGENICITY

A Mouse Lung Tumor Model of Tobacco Smoke Carcinogenesis

Hanspeter Witschi*,1, Imelda Espiritu*, Stephanie T. Dance{dagger} and Mark Steven Miller{dagger}

* Center for Health and the Environment, University of California, Davis, One Shields Avenue, Davis, California 95616; and {dagger} Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

We examined the possibility of developing an animal model of tobacco smoke carcinogenesis. Male Balb/c and SWR mice were exposed for 5 months to tobacco smoke (6 h/day, 5 days/week; average concentration, 122 mg/m3 of total suspended particulates [TSP]) followed by a recovery period of 4 months in air. In both strains there was an increase in lung tumor multiplicities and incidence, although statistical significance was only observed with lung tumor multiplicity in the SWR mice. An analysis of 11 previous and independently conducted assays with strain A/J mice that followed the same protocol was performed. In each experiment, lung tumor multiplicities were significantly higher in tobacco smoke-exposed mice compared with air-exposed controls, and a good correlation between exposure (average tobacco smoke concentrations multiplied by length of exposure in months) and lung tumor multiplicities was found. In 7 experiments involving tobacco smoke concentrations greater than 100 mg/m3 of TSP, lung tumor incidences were 5 times higher than in control mice. Tobacco smoke-exposed mice had a smaller percentage of adenomas with carcinomatous foci or adenocarcinomas than air-exposed controls, and no differences between the two groups were found in an analysis of Ki-ras mutations. After 6 h of exposure to tobacco smoke, plasma cotinine levels in mice were comparable to those found in active human smokers. The lung tumor model might be suitable for future evaluation of chemopreventive agents or modified tobacco products.

Key Words: tobacco smoke; lung tumors; strain A/J mice; Balb/c mice; SWR mice; plasma cotinine; K-ras mutations; dose-response relationship; tobacco smoke inhalation.


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