knockout mice allows one to delete gene functions (Arbeit and Hirose, 1999). At present these tools are better suited for mechanistic studies than for screening purposes, but in the future, genetically altered animals may become the standards for testing for specific types of toxicity, just as genetically altered Salmonella bacteria have become standards for testing the mutagenic potential of xenobiotics.

DNA microarray chips, which consist of an array of thousands of specific cDNA sequences or genes on a chip, allow one to detect and quantitate messenger RNAs that are the transcription products of the specific cDNA samples on the surface of the chips. Thus, if one knows the specific genes that are upregulated in association with the onset of a disease process, one could theoretically use the microarray technique to detect some of the earliest indicators that a disease process has begun (Nuwaysir et al., 1999). This type of tool should be invaluable in developing rapid screens for early indicators of developing disease in exposed animals (or for clinical purposes in humans) in contrast to the long time frame required to detect indicators of established disease in laboratory animals. The field is developing rapidly, and some microarrays designed to detect squamous cell carcinomas of the lung have already been reported (Wang et al., 2000). Future research will be required to determine which genes are upregulated at different times during the progression of specific diseases so that microchip arrays can be designed as accurate and specific preclinical indicators of developing disease.

SMOKELESS TOBACCO TOXICITY

Smokeless tobacco products, traditionally, are differentiated into snuff and chewing tobacco; are not combusted but exert their effects by direct mucosal contact and consequent entry of toxicants into the bloodstream. Snuff is typically a finely ground tobacco product that is used orally or nasally. Snuff is manufactured in a variety of forms including moist, dry, and fine cut (Connolly et al., 1986). The oral tobacco form that is chewed or simply kept in the mouth is generally known as chewing tobacco. Chewing tobacco is also produced in different forms including plug, loose-leaf, and twist varieties (Connolly et al., 1986). (See Chapter 4 for a more in-depth description of smokeless tobacco products and use statistics.)

Smokeless tobacco products are composed primarily of fire or air-cured dark tobacco (Wahlberg and Ringberger, 1999). The tobacco then undergoes an extended aging process that involves heating or fermentation depending on the product. During production, various additives are used for the desired flavor and aroma. The chemical composition of smokeless tobacco products varies due to differences in tobacco composition



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