N‐Nitroso Compounds

Abstract

N ‐Nitroso compounds, which include nitrosamines and nitrosamides, have been known for more than 100 years, but nothing was known of their toxicological properties until 1937, when Freund described a laboratory poisoning by nitrosodimethylamine (NDMA). Then Barnes and Magee in 1954 (also following an accidental exposure of humans to NDMA being used as a solvent) described a thorough toxicological examination of the compound in several species, in which liver and/or lung injury caused death. This culminated in a chronic toxicity test in rats, which resulted in a high incidence of animals with liver tumors within a year. The finding that a member of a large class of water‐soluble compounds was carcinogenic aroused considerable interest and an investigation began into the relationship between the chemical structure of N ‐nitroso compounds and their carcinogenic properties, initially by Druckrey et al. (mainly in rats), followed by other chemists and pathologists. The objective was to obtain clues to the mechanism(s) of carcinogenesis by these compounds, but other issues arose. One of the most interesting was the widespread nature of nitrosamine carcinogenesis that affected all species examined, although tumors of the same type were not induced in all species. Indeed, as the number of N ‐nitroso compounds tested increased (more than 300 have been examined), it became apparent that virtually every type of human tumor was reproduced in some animal with some N ‐nitroso compound. The N ‐nitroso compounds varied widely in toxic and carcinogenic potency, but not in parallel, although the most acutely toxic compounds tended to be the most potent carcinogens. Many quite potent carcinogens, however, showed relatively low toxicity, and vice versa. For many years, the carcinogenic N ‐nitroso compounds were considered an interesting curiosity, but in the 1960s it was found that some batches of fish meal that had been treated with sodium nitrite for preservation caused toxic liver injury in sheep. The cause of the injury was traced to nitrosodimethylamine that had formed in the fish meal. This was a surprise because nitrosamines, it was thought, formed by interaction of secondary amines with nitrite in acid solution, not at neutral pH. It has since become obvious that tertiary amines, as well as secondary amines, interact with nitrite under certain conditions (above pH 4) to form nitrosamines. Further investigations revealed that many commonly used drugs and medicines that are tertiary amines are also easily nitrosated to form N ‐nitroso compounds, thereby presenting a risk of human exposure to these carcinogens. These old studies point out that human exposure to N ‐nitroso compounds can occur from eating nitrite‐preserved food (meat or fish) containing N ‐nitroso compounds. While deaths have occurred from acute exposure to N ‐nitroso compounds such as NDMA, epidemiological studies mostly in the 1980s and 1990s have linked childhood brain cancers with high consumption of cured meats either by their pregnant mothers or by the child. These observations are supported by animal models for several N ‐nitroso compounds documenting the induction of nervous system tumors through transplacental action of exposed pregnant animals. Since the first report of nitrosamines (NDMA) in tobacco smoke in 1974, there has been considerable research into this topic, mainly by the group of Hoffmann and Hecht. Apart from the volatile nitrosamines, nitrosopyrrolidine, NDMA, methylnitrosoethylamine (MNEA), and nitrosodiethylamine (NDEA), a number of so‐called tobacco‐specific nitrosamines were discovered: nitrosonornicotine (NNN) and 4‐methylnitrosamino‐1‐(3‐pyridyl)‐1‐butanone (abbreviated to NNK), which is a potent carcinogen that causes liver and lung tumors in rats and hamsters and is one of the most abundant carcinogens in tobacco and tobacco smoke. NNK is also a prominent ingredient in chewing tobacco or snuff (as much as 8 ppm), one of the few carcinogens in these products (nitrosonornicotine is another, but much weaker) that certainly contributes to the carcinogenic risk to users, who not infrequently develop oral cancers. In 2007, the International Agency for Cancer Research reviewed the evidence associated with several tobacco‐specific nitrosamines and concluded the both NNN and NNK are human carcinogens (Group 1). Other sources of exposure of humans to N ‐nitroso compounds include the air in and near factories in which nitrosamines are made or used (usually NDMA), such as those that produce or use the rocket fuel 1,1‐dimethylhydrazine, and factories in which pesticides are made, which are often stored or sold as dimethylamine salts, and which nitrogen oxides can convert to the volatile NDMA. An important source of nitrosamines is the rubber and tire industry. Nitrosamines have also been found in leather tanning establishments (mainly NDMA). Perhaps the largest industrial exposure to nitrosamines is from metalworking fluids (including cutting oils) in which concentrations of nitrosodiethanolamine (NDELA) as high as 3% have been reported, although usually less. The NDELA arises from triethanolamine (containing diethanolamine), used as an emulsifier, that combines with sodium nitrite used as a corrosion inhibitor. A combination of an alkanolamine, an aldehyde, and a nitrite, as may be present in a metalworking fluid, can also give rise to cyclic nitrosamines containing oxygen, such as a nitrosooxazolidine, that are potent carcinogens. The Consumer Products Commission and the Federal Drug Administration have reported that nitrosamines have been found in pacifiers and baby bottle nipples and can migrate into saliva. NDMA is receiving significant attention over the past decade because it can be present in drinking water as a by‐product of water chlorination from treatment plants that use chloramines for disinfection. It can also be found in ground water at levels as high as 10 ppm as NDMA is formed by the reaction of commonly occurring primary, secondary, or tertiary amines with nitrates.

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