Nitrosamines and Cancer

Nitrosamines are a class of chemical compounds that were first described in the chemical literature over 100 years ago, but not until 1956 did they receive much attention. In that year two British scientists, John Barnes and Peter Magee, reported that dimethylnitrosamine produced liver tumors in rats. This discovery was made during a routine screening of chemicals that were being proposed for use as solvents in the dry cleaning industry.
Magee and Barnes' landmark discovery caused scientists around the world to investigate the carcinogenic properties of other nitrosamines and N-nitroso compounds. Approximately 300 of these compounds have been tested, and 90% of them have been found to be carcinogenic in a wide variety of experimental animals. Most nitrosamines are mutagens and a number are transplacental carcinogens. Most are organ specific. For instance, dimethylnitrosamine causes liver cancer in experimental animals, whereas some of the tobacco specific nitrosamines cause lung cancer. Since nitrosamines are metabolized the same in human and animal tissues, it seems highly likely that humans are susceptible to the carcinogenic properties of nitrosamines.
In the early 1970s, there were outbreaks of liver disorders, including cancer, in various farm animals in Norway. Intensive investigations revealed that all of the affected animals had consumed rations containing herring meal, which had been preserved by the addition of relatively large amounts of sodium nitrite. Further investigation showed that the herring meal contained dimethylnitrosamine, the same compound that Magee and Barnes had reported as a strong liver carcinogen nearly a decade earlier. Dimethylnitrosamine was formed in the fish meal as a result of a chemical reaction between dimethylamine, a commonly occurring amine in fish meal, and a nitrosating agent that formed from the sodium nitrite. This observation caused scientists to begin asking serious questions about the occurrence of nitrosamines. If dimethylnitrosamine could form from a commonly occurring amine and sodium nitrite in fish meal, could nitrosamines be formed in human foods? Amines occur commonly, and sodium nitrite is added to cured meats to prevent toxin production by Clostridium botulinum, the microorganism responsible for botulism. When these questions were raised in the late 1960s, they couldn't be answered because reliable analytical methods did not exist for detecting low levels of nitrosamines in foods. During the 1970s and 1980s, reliable analytical methods to determine nitrosamine levels in foods and beverages were developed and later applied to a variety of other consumer products, occupational settings, and body fluids (see table).
Nitrosamines occur commonly because their chemical precursors--amines and nitrosating agents--occur commonly, and the chemical reaction for nitrosamine formation is quite facile. Research on the prevention or reduction of nitrosamine formation has been productive, and most of the items shown in the table contain considerably lower amounts of nitrosamines than they did a few decades ago.
Cured meats can contain nitrosamines because meats contain amines, and sodium nitrite, a source of nitrosating agents, is added to cured meats as a preservative. Of all the cured meats, bacon has received the most attention. It almost always contains detectable levels of nitrosamines, principally nitrosopyrrolidine and, to a lesser extent, dimethylnitrosamine. The very high cooking temperatures used to fry bacon are conducive to nitrosamine formation. In the late 1970s, extensive attention was focused on the issue of nitrosamines in cured meats, and the removal of sodium nitrite as a food additive was considered. However, the prospect of sodium nitrite removal presented a formidable dilemma for the regulatory agencies. Removal of sodium nitrite would prevent nitrosamine formation, but it might also increase the risk of botulism poisoning. Sodium nitrite and sodium chloride together are particularly effective against Clostridium botulinum. The solution to the dilemma was to limit the addition of sodium nitrite to 120 parts per million (ppm), the lowest level found to be effective in controlling growth and toxin production by Clostridium botulinum.

Nitrosamines in Food, Body Fluids, and Occupational Exposure  Fried bacon Cured meats Beer  Nonfat dry milk  Tobacco products  Gastric juices  Rubber products  Rubber manufacturing  Metal industries  Pesticide production and use  Certain cosmetics  Certain chemical manufacturing

About 1970 it was discovered that ascorbic acid inhibits nitrosamine formation. Consequently, the addition of 550 ppm of ascorbic acid is now required in the manufacture of cured meat in the U.S. Actually, most cured meat manufacturers add erythorbic acid (an isomer of ascorbic acid) rather than ascorbic acid. Although erythorbic acid has reduced vitamin C activity, it is as effective as ascorbic acid in inhibiting nitrosamine formation and is also cheaper than vitamin C. Another antioxidant, alpha-tocopherol (vitamin E), is added to some cured meats to inhibit nitrosamine formation. As a result of these strategies, there are now significantly lower levels of nitrosamines in fried bacon and other cured meats than there were some years ago. Ascorbic acid, erythorbic acid, and alpha-tocopherol inhibit nitrosamine formation due to their oxidation-reduction properties. For example, when ascorbic acid is oxidized to dehydroascorbic acid, nitrous anhydride, a potent nitrosating agent formed from sodium nitrite, is reduced to nitric oxide, which is not a nitrosating agent. The discovery that ascorbic acid can inhibit nitrosamine formation was serendipitous. 
In the late 1960s researchers at the University of Nebraska Medical Center were studying nitrosamine formation from a drug called aminopyrine. Mysteriously, when they used a new batch of aminopyrine, no nitrosamines were formed. Further investigation revealed that the new batch of aminopyrine was formulated with ascorbic acid as a preservative, whereas the original batch that readily formed nitrosamines was not. Sometimes unexpected negative results can be very informative!
In 1980, several European scientists detected dimethylnitrosamine in beer. The nitrosamine was not formed during the brewing process--it was formed by direct-fire drying of barley malt, an ingredient used in making beer. By converting the process from direct-fire drying to indirect-fire drying, the nitrosating agents and the formation of dimethylnitrosamine were markedly reduced. Beer now contains only 2% of the amount of dimethylnitrosamine that was present 20 years ago. 
As indicated in the table, nitrosamines can form in the gastric juice of the human stomach. This is commonly referred to as endogenous nitrosation. Bacteria in the mouth chemically reduce nitrate, which is prevalent in many vegetables, to nitrite, which in turn can form nitrosating agents. Many foods contain amines that can react with nitrosating agents in the acidic stomach to form nitrosamines. While it has been demonstrated that ascorbic acid can reduce nitrosation in the stomach, more research will be required for a fuller understanding of endogenous nitrosation and its ramifications for health and disease.
Nitrosamines are carcinogenic in animals. What level of exposure to these carcinogens do humans have? A 1981 report from the National Academy of Sciences (NAS) estimated that the per capita exposure is about 1 microgram per day from foods and beverages, mainly from fried bacon and beer. Current exposure is probably closer to 0.1 microgram per day due to successful efforts over the past 20 years to reduce nitrosamine formation in foods and beverages. In contrast, the NAS report estimated an exposure of 17 micrograms per day from cigarette smoking, although the use of filters has somewhat lowered smokers' exposure. Recent reports indicate that industrial exposure, such as found in a rubber or chemical manufacturing plant, can be relatively high.
Do these types of exposure to nitrosamines cause human cancer? An enormous amount of indirect evidence indicates that nitrosamines are human carcinogens. For instance, tobacco-specific nitrosamines are one of the major groups of chemical carcinogens in tobacco products, and no doubt remains about the causal link between tobacco use and cancer. But it is difficult to evaluate the risk of cancer from daily exposure of 1 microgram from foods and beverages. The same difficulty applies to the risk assessment of the exposure to minute amounts of aflatoxin, polycyclic aromatic hydrocarbons, and heterocyclic amines in a variety of foods and beverages. Unfortunately, our current level of science is unable to answer these questions satisfactorily, but future scientific advances will undoubtedly provide better solutions.