Author(s)

Nathan M. Holt^1*, Ryan A. Black¹, Qiwei Liang¹, Saul Shiffman²

¹Regulatory Science, Juul Labs, Inc., Washington, DC, USA.
²Pinney Associates, Inc., Pittsburgh, USA.

Cigarette smoking is a leading cause of premature mortality, attributable to chronic exposure to toxic compounds in cigarette smoke, including tobacco-specific nitrosamines, which are known carcinogens. This research aims to assess the association between NNAL, a metabolite of the tobacco-specific nitrosamine NNK, and mortality. Data from 14,766 U.S. adults aged 21 - 79 in the National Health and Nutrition Examination Survey (2007-2014) included smoking status and urinary NNAL concentration at the time of examination. These data were linked to participants’ subsequent mortality status as recorded in the public-use Linked Mortality File (through 2015). Cox proportional hazards regression models assessed the relative risk of all-cause, cancer, cardiovascular disease (CVD), and other-causes mortality for increasing levels of natural log (creatinine-adjusted NNAL). In the whole sample, a unit increase in log (NNAL) is associated with a 20% higher risk of all-cause (HR = 1.20; 95% CI: 1.16 - 1.24), cancer (HR = 1.20; 95% CI: 1.14 - 1.26), CVD (HR = 1.21; 95% CI: 1.12 - 1.31) and other-causes (HR = 1.20; 95% CI: 1.15 - 1.25) mortality. Among current smokers, a unit increase in log (NNAL) is associated with 44% higher cancer mortality risk (HR = 1.44; 95% CI: 1.08 - 1.92) and a 96% higher CVD mortality risk (HR = 1.96; 95% CI: 1.20 - 3.20). Risks of all-cause and other-causes mortality, but neither cancer nor CVD mortality, were positively associated with NNAL among never and former smokers. Inferences are limited by the observational nature of the data, and by the focus on a single biomarker of tobacco-related exposure. The findings suggest that urinary NNAL concentration is acting as a proxy for exposure to the toxicants in cigarette smoke rather than as a biomarker of disease-specific mortality risk.

NHANES, NNAL, Mortality, Smoking, Cigarettes

Holt, N. , Black, R. , Liang, Q. and Shiffman, S. (2023) Association between NNAL and Mortality in U.S. Adults, NHANES 2007-2014 with 2015 Mortality Follow-Up. Open Journal of Preventive Medicine, 13, 239-255. doi: 10.4236/ojpm.2023.138016.