Exclusion of these subjects left 10 (50% of our participants) who demonstrated a decrease in total NNN similar to that inhibitor Sunitinib of total NNAL over the study period (see Figure 3C). This stratified analysis indicated that endogenous formation of NNN is more or less extensive in some patch users and is virtually nonexistent in others. The difference in the average rates of decrease of total NNN and total NNAL in the urine of some long-term patch users is consistent with the results of kinetic studies that show that nitrosation of nicotine produces more NNN than NNK (Hecht et al., 1978) and that nornicotine is nitrosated more readily than is nicotine (Mirvish et al., 1977), supporting endogenous NNN formation in patch users via nitrosation of nicotine or metabolically formed nornicotine.

Ascorbic acid is an effective inhibitor of endogenous nitrosation (Mirvish, 1986, 1994; Mirvish, Wallcave, Eagen, & Shubik, 1972), and we have demonstrated that it inhibits endogenous NNN formation in rats treated with nornicotine and sodium nitrite (Porubin et al., 2007). Therefore, a simple approach to block possible NNN formation in nicotine patch users could be supplementation with ascorbic acid. The absence of a control group in which subjects did not use any NRT product after they quit smoking is the major limitation of the present study. Factors other than endogenous formation, such as low rate of NNN clearance from the body and secondhand smoke exposure, also could contribute to the total NNN levels observed here.

However, the kinetics of NNN clearance from the body is unknown, and there are no published studies on total NNN levels in nonsmokers exposed to secondhand smoke. Comparison with a placebo patch group would allow us to address these issues. Also, users of other kinds of NRT products should be studied. In nicotine gum chewers and users of nicotine lozenges, for example, nicotine goes directly to the stomach, where conditions are highly favorable for nitrosation reactions (Mirvish, 1975; Shepard et al., 1987). In summary, the results of the present study demonstrate that endogenous formation of NNN may occur in some nicotine patch users. However, our findings should not call into question the use of nicotine patch as a smoking cessation product. NRT is an effective tool in the treatment of nicotine dependence.

AV-951 Smoking cessation and use of NRT products significantly decrease exposure to a wide range of carcinogens and toxicants present in cigarette smoke, and the levels of urinary total NNN and total NNAL during patch use were generally extremely low in our study. In the future, supplementation with ascorbic acid could be a simple approach to block possible endogenous NNN formation in nicotine patch users. Similar studies involving other types of NRT products should be conducted.