In discussing permeability, we are describing one of the fundamental barrier functions of oral mucosa. Despite assumptions to the contrary, the oral mucosa is not a uniformly, highly permeable tissue like gut, but shows regional variation. The keratinized areas, such as gingiva and hard palate, are least permeable and nonkeratinized lining areas are most permeable. This variation appears to reflect differences in the types of lipid making up the intercellular permeability barrier in the superficial layers of the epithelium. Differences in permeability may be related to regional differences in the prevalence of certain mucosal diseases and can be utilized to advantage for local and systemic drug delivery.

The use of smokeless tobacco (chewing tobacco or snuff) results in contact between this material and the lining of the mouth over relatively long periods of time. As tobacco contains nicotine and a carcinogen, nitrosonornicotine (NNN) there is a likelihood of systemic absorption of both these compounds under these conditions. This study measured the penetration of nicotine and NNN across skin and various regions of oral mucosa. Specimens of porcine skin, keratinized gingiva and non-keratinized floor of mouth and cheek mucosa were placed in perfusion chambers and the flux across these tissues of isotopically labeled water, nicotine and NNN was determined; permeability constants were calculated for each compound and for each region and the values compared statistically. Skin showed a lower permeability than the oral regions to all compounds and floor of mouth was generally the most permeable site. Nicotine passed across oral mucosa almost as rapidly as water, the most permeable region being floor of mouth, whereas gingiva and buccal mucosa showed a similar, but lower, permeability. The non-keratinized oral regions were most permeable to NNN and this can be related to the known distribution of oral carcinomas, regions with the higher permeability being sites that show the greatest tendency to develop such lesions.

Fifty-two hamsters were divided into 6 groups and their cheek pouches treated with either 0.01% NNN, 0.01% NNN and 6% nicotine, 0.01% NNK, 0.01% NNK and 6% nicotine, 6% nicotine, or sesame oil. After painting each pouch 3 times per week for 13 months, the animals were killed and specimens from the cheek pouch and forestomach examined. Cheek pouch epithelium showed more frequent histologic changes, including hyperplasia, hyperkeratosis and, in one animal, moderate dysplasia, when nicotine was combined with NNN than after treatment with NNN (or nicotine) alone. There was a higher frequency of hyperplasia with hyperkeratosis in the forestomach when nicotine was combined with NNK than following NNK, or nicotine treatment alone, and squamous cell papillomas were evident in animals treated with both NNK and nicotine. These results suggest that in mucosal tissues nicotine may enhance the effect of weak carcinogens such as the nitrosamines.

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