Urine Metabolites for Estimating Daily Intake of Nicotine From Cigarette Smoking

Accurate measurement of nicotine exposure from cigarette smoke is important in studying disease risk and level of dependence. Urine total nicotine equivalents, the molar sum of nicotine and six metabolites (NE7), accounts for more than 90% of a nicotine dose and is independent of individual metabolic differences. However, measuring NE7 is technically difficult and costly. We compared NE7, the gold standard of nicotine intake, with different combinations of fewer urinary nicotine metabolites. We also examined the impact of individual differences in nicotine metabolic rate, sex, and race on strength of association with NE7.

Urine samples from 796 daily smokers, who participated across five clinical studies, were assayed for nicotine and/or metabolites. Associations with NE7 were assessed by regression and Bland-Altman analyses.

Overall, the molar sum of urine [cotinine + 3'-hydroxycotinine (3HC)] (NE2) and [nicotine + 
cotinine + 3HC] (NE3) were strongly correlated with NE7 (r = .97 and .99, respectively). However, in slow metabolizers NE2 was less predictive of NE7, whereas NE3 was equally robust. Urine total cotinine was also strongly correlated with NE7 (r = .87).

Urine NE3 is a robust biomarker of daily nicotine intake, independently of individual metabolic differences, whereas NE2 is less accurate in slow metabolizers. Our findings inform the selection of more rigorous and cost-effective measures to assess nicotine exposure in tobacco research studies.

The molar sum of urine total nicotine, cotinine and 3HC (NE3) is a robust biomarker of daily nicotine intake, independently of individual metabolic differences, and performs as well as measuring seven nicotine metabolites (NE7). The sum of cotinine and 3HC (NE2) is less accurate in slow metabolizers. Our findings inform the selection of more rigorous and cost-effective measures to assess nicotine exposure in tobacco research studies.