Tobacco products contain thousands of chemicals, with some of the most harmful being tobacco-specific nitrosamines (TSNAs). These compounds are a health concern for users of any tobacco product. Understanding what TSNAs are, how they form in tobacco, and their effects on the body is important for recognizing the risks of tobacco use.
The Chemical Makeup of TSNAs
Nitrosamines are a broad class of chemical compounds. The “tobacco-specific” designation means this subgroup is found almost exclusively in tobacco and products with nicotine derived from tobacco. Their structures originate from natural alkaloids in the tobacco plant, such as nicotine, which form TSNAs during a reaction called nitrosation.
The most studied TSNAs are N’-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Both are derived directly from nicotine and a related alkaloid. While other TSNAs like N’-nitrosoanatabine (NAT) are present, NNN and NNK are considered the most toxic and are listed by the FDA as harmful constituents due to their links to cancer.
How TSNAs Are Formed
TSNAs are not found in significant amounts in fresh tobacco leaves but form during the curing, aging, and processing stages. The methods used to prepare tobacco influence the final concentration of these compounds. One pathway for formation occurs during the curing of tobacco leaves. Air-curing, used for burley tobacco, is particularly conducive to TSNA formation as bacteria on the leaf convert nitrates into nitrites, which then react with tobacco alkaloids. Higher temperatures and humidity associated with some curing methods can accelerate this process.
A second pathway is combustion. When a cigarette or cigar is lit, high temperatures generate additional TSNAs not present in the unburnt tobacco. It is estimated that between 30% and 50% of the NNN and NNK in mainstream cigarette smoke is transferred from the tobacco, with the remainder created during smoking.
TSNA Levels in Various Tobacco Products
The concentration of TSNAs varies significantly across different types of tobacco products, largely due to differences in how the tobacco is cured and processed. This variation means the level of risk can differ depending on the product a person uses.
Smokeless tobacco products, such as dipping tobacco and snuff, often contain some of the highest levels of TSNAs. For example, some moist snuff products have high concentrations of NNN and NNK, contributing to the strong association between smokeless tobacco and cancers of the mouth and esophagus.
Cigarettes and cigars contain TSNAs in the unburnt tobacco, and combustion generates more. Studies of commercial cigarettes have found that NNN and N’-nitrosoanatabine (NAT) are the most abundant TSNAs in the tobacco filler, and filter ventilation can influence the amount delivered in the smoke.
In contrast, e-cigarettes and vaping products have much lower levels of TSNAs. The nicotine used in e-liquids is often pharmaceutical-grade or synthetic, containing only trace amounts. However, some studies have detected low levels of NNN and NNK in certain e-liquids and in the aerosol produced by vaping devices.
Health Consequences of TSNA Exposure
TSNAs are a primary contributor to the health risks of tobacco use. The International Agency for Research on Cancer (IARC) classifies both NNN and NNK as Group 1 carcinogens, meaning there is sufficient evidence that they cause cancer in humans. This classification places them in the same category as asbestos and plutonium.
TSNAs work by damaging human DNA. After being absorbed into the body, they are metabolically activated into substances that can bind to a person’s genetic material. This binding process creates DNA adducts, which are flaws in the DNA sequence. If the body’s repair mechanisms fail to correct these flaws, they can lead to permanent mutations in genes that control cell growth and cause cancer.
This DNA-damaging mechanism links TSNA exposure to several types of cancer. Research shows that NNN is a cause of esophageal cancer, while NNK is linked to cancers of the lung, pancreas, liver, and nasal cavity. When used together, NNN and NNK cause oral tumors, which aligns with the risks seen in users of smokeless tobacco.