Nornicotine in Smokeless Tobacco as a Precursor for Carcinogen Exposure

Our goal in this study is to investigate the extent of endogenous nitrosation of nornicotine in smokeless tobacco users as a function of nornicotine content in smokeless products. This study will lead to an understanding of the endogenous formation of NNN from nornicotine in humans, and will also investigate the effect of the reduction of nornicotine content in smokeless tobacco on the extent of endogenous NNN formation. The knowledge gained in this study will lead to the development of recommendations for the regulation, or potentially elimination, of nornicotine in smokeless tobacco products in order to minimize exposure to NNN in the users of these products.

Study Overview

• Status: Active, not recruiting
• Conditions: Smokeless Tobacco
• Intervention / Treatment: Drug: Herbal Snuff (Smokeless Tobacco)

• Study Type: Interventional
• Enrollment (Estimated): 55
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55411
      • Masonic Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Male or female adult smokeless tobacco users 18-65 years of age, using at least 3 tins of product per week for 6 months;
• Used the same brand for >80% of their smokeless tobacco use over the course of at least 6 months, and used this brand exclusively for at least two weeks prior to the eligibility screening;
• Not smoking or using any other nicotine or tobacco product in the past 2 weeks (expired CO < 6 ppm);
• Participants are in good physical health (no unstable medical condition) and good general oral health as determined by the licensed medical professional;
• Participants are in stable, good mental health (e.g. not currently, within the past 6 months, experiencing unstable or untreated psychiatric diagnosis, including substance abuse) as determined by the licensed medical professional;
• Participants who are not taking any medications that affect relevant metabolic enzymes;
• Women who are not pregnant or nursing or planning to become pregnant;
• Participants have provided written informed consent to participate in the study.

Exclusion Criteria:

• Significant immune system disorders, respiratory diseases, kidney or liver diseases or any other medical disorders that may affect biomarker data as determined by the licensed medical professional;
• Vital signs out of range as determined by the licensed medical professional (participants failing for vital signs will be allowed to re-screen once):
• Evident poor oral health (significant gum recession, dental caries, tooth loss) as determined by the general oral health status check;
• Excessive drinking (e.g., 5 or more drinks daily) or problems with drinking or drugs (e.g., self-report of binge drinking alcohol or treatment for drug or alcohol abuse within last 3 months); to be assessed by PI or licensed medical professional;
• Regular smoking or tobacco use (e.g., greater than once a week) other than oral smokeless tobacco products;
• Currently (within the past 2 weeks) using nicotine replacement or other tobacco cessation products (to minimize confounding effects of another product);

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1 (N=15); 160 µg/g herbal snuff, median level found in commercial moist snuff	Drug: Herbal Snuff (Smokeless Tobacco); 4 levels of [D4]nornicotine in herbal snuff
Experimental: Group 2 (N=15); 70 µg/g herbal snuff, lowest level found in commercial moist snuff (rounded)	Drug: Herbal Snuff (Smokeless Tobacco); 4 levels of [D4]nornicotine in herbal snuff
Experimental: Group 3 (N=15); 3.5 µg/g herbal snuff, 5% of the lowest level found in commercial moist snuff	Drug: Herbal Snuff (Smokeless Tobacco); 4 levels of [D4]nornicotine in herbal snuff
Active Comparator: Group 4(N=10); 0 µg/g herbal snuff, control group will use unmodified herbal snuff	Drug: Herbal Snuff (Smokeless Tobacco); 4 levels of [D4]nornicotine in herbal snuff

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To investigate endogenous formation of NNN in smokeless tobacco users.	Presence of urinary [pyridine-D4]NNN ([D4]NNN)	2 Weeks
To investigate endogenous formation of NNN in smokeless tobacco users.	Level of urinary [pyridine-D4]NNN ([D4]NNN) present	2 Weeks

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Irina Stepanov, PhD, University of Minnesota, Division of Environmental Health Sciences

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2021
• Primary Completion (Actual): August 1, 2025
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: June 24, 2019
• First Submitted That Met QC Criteria: June 24, 2019
• First Posted (Actual): June 26, 2019

Study Record Updates

• Last Update Posted (Actual): November 26, 2025
• Last Update Submitted That Met QC Criteria: November 21, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavior; Tobacco Use; Manufactured Materials; Technology, Industry, and Agriculture; Smoking Devices; Tobacco Products; Tobacco, Smokeless
• Other Study ID Numbers: 2019NTLS123 (University of Minnesota Masonic Cancer Center); SPH-2019-23251 (Other Identifier: University of Minnesota)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No