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Some tissues such as oral mucosa have not been thoroughly studied. Due to the small quantity and cartilaginous nature of oral cavity tissues, development of special prosection and DNA isolation methods was required to permit robust analysis of mutations in these tissues. Improved surgical methods permitted collection of adequate and reproducible quantities of tissue (\u223c45 mg gingiva\/buccal and \u223c30 mg gingiva\/palate). Optimized DNA isolation methods included use of liquid nitrogen pulverization, homogenization, nuclei pelleting, digestion, and phenol\/chloroform extraction, to yield sufficient quantities of DNA from these tissues. In preliminary optimization work, mutant frequency (MF) in tongue and gingiva was increased in rats exposed to the promutagen, benzo[a]pyrene, and the direct mutagen, <jats:italic>N<\/jats:italic>\u2010ethyl\u2010<jats:italic>N<\/jats:italic>\u2010nitrosourea. The oral cavity carcinogen, 4\u2010nitroquinoline\u20101\u2010oxide (4\u2010NQO; 10 ppm in drinking water; 28 days), was qualified as a positive control for mutagenesis in oral tissues since it caused significant increases in <jats:italic>cII<\/jats:italic> MFs in gingiva\/palate (50.2\u2010fold) and gingiva\/buccal tissues (21.3\u2010fold), but not in liver or bone marrow (0.9\u2010 and 1.4\u2010fold, respectively). These results are consistent with the observation that 4\u2010NQO primarily induces tumors in oral cavity. Results also demonstrate the utility of the BB rat mutation assay and optimized methods for investigation of oral cavity mutagenicity, and by extension, analysis of other small and cartilaginous tissues. Environ. Mol. 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