Smoking mentholated cigarettes has been suggested to convey a greater cancer risk compared with smoking nonmentholated cigarettes. Two of the possible mechanisms by which mentholated cigarette smoking could increase risk are by increasing systemic exposure to tobacco smoke toxins and by affecting the metabolism of nicotine or tobacco smoke carcinogens. To examine these possibilities, we performed a crossover study in 14 healthy smokers, one-half of whom were African-Americans and one-half whites. Subjects were randomly assigned to smoke mentholated or nonmentholated cigarettes for 1 week, then to cross over to the other type of cigarettes for another week. Subjects were confined to a Clinical Research Center for 3 days of each week, during which time blood levels of nicotine and carbon monoxide were measured throughout the day and an intravenous infusion of deuterium-labeled nicotine and cotinine was administered to determine the rate and pathways of nicotine metabolism. The systemic intake of nicotine and carbon monoxide was, on average, not affected by mentholation of cigarettes. Mentholated cigarette smoking did significantly inhibit the metabolism of nicotine (clearance: 1289 versus 1431 ml/min, two sided, p ϭ 0.02). Inhibition of nicotine metabolism occurred both by slower oxidative metabolism to cotinine and by slower glucuronide conjugation. Our data do not support the hypothesis that mentholated cigarette smoking results in a greater absorption of tobacco smoke toxins. Our finding of impaired metabolism of nicotine while mentholated cigarette smoking suggests that mentholated cigarette smoking enhances systemic nicotine exposure.

The lower nicotine (and, therefore, tobacco smoke) intake per cigarette and the fewer cigarettes smoked per day, which may result, in part, from slower clearance of nicotine, may explain lower lung cancer rates in Chinese-Americans. Lower lung cancer rates among Latinos compared with whites, given their similar nicotine intake per cigarette, are probably due to smoking fewer cigarettes. The results with Chinese-Americans may have implications for dosing with nicotine medications to aid smoking cessation in Chinese- American smokers and perhaps in other Asian smokers.

Our study suggests that reduced-nicotine content cigarettes are reasonable candidates for trying to reduce the level of nicotine addiction in smokers. The flat nicotine dose-cardiovascular response curve is consistent with other studies demonstrating tolerance to the cardiovascular effects of nicotine.

Measurement of urine cotinine corrected for creatinine concentration appears to be the best predictor of plasma cotinine.