N-Nitrosonornicotine

Toxicity

It has been classified as a Group 1 carcinogen. Although no adequate studies of the relationship between exposure to NNN and human cancer have been reported, there is sufficient evidence that NNN causes cancer in experimental animals.

Sources

NNN is found in a variety of tobacco products including smokeless tobacco like chewing tobacco and snuff, cigarettes, and cigars. It is present in smoke from cigars and cigarettes, in the saliva of people who chew betel quid with tobacco, and in the saliva of oral-snuff and e-cigarette users. NNN is produced by the nitrosation of nornicotine during the curing, aging, processing, and smoking of tobacco. Roughly half of the NNN originates in the unburnt tobacco, with the remainder being formed during burning.

NNN can be produced in the acidic environment of the stomach in users of oral nicotine replacement therapies, due to the combination of dietary/endogenous nitrates, and nornicotine (either present as a minor metabolite of nicotine, or as an impurity in the product).

Mechanism of action

NNN is metabolized by cytochrome P450, which adds a hydroxy group to either the 2' or 5' carbon on the 5-membered ring. 2'-hydroxylation appears more prevalent in humans, while 5'-hydroxylation is more prevalent in non-primate animals. Upon hydroxylation, the 5-membered ring opens up, allowing the compound to bind to the base of one of the nucleotides.

Synthesis

The nitrosonium group forms from nitrous acid (HNO2) under acidic conditions present in the tobacco curing process. It can also be formed in the stomach when stomach acid reacts with nitrite ions that are typically used as a salt to preserve red meats and inhibit bacterial growth. Nitrous acid becomes protonated on its hydroxy group to form nitrosooxonium. This compound then splits off to form nitrosonium and water.

Symptoms

Symptoms of NNN are similar to those of nicotine poisoning and include irritation at the point of absorption (for example, the gums when dipping tobacco is used), nausea and vomiting, sleep disturbances, headache, and chest pain. The substance is also a known carcinogen, meaning that any exposure to the substance can lead to cancer and is proven to cause esophageal and nasal cancer in animals. There is no known "safe" levels of NNN ingestion in humans due to its carcinogenic activity. However, in mice, the median lethal dose (LD50) is 1g/kg.

In cigarette smoke, NNN has been found in levels between 2.2 and 6.6 parts per million (ppm). The FDA has put limits of nitrosamines in other consumable products (such as cured meats) at levels below 10 parts per billion (ppb).

References

FORCETOC

References

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