G.Y. Saspugayeva

Eurasian National University named after L.N. Gumilev

NITROSODIMETHYLAMINE AND ITS CHARACTER

N-Nitrosodimethylamine, or NDMA, can occur in drinking-water through the degradation of dimethylhydrazine (a component of rocket fuel) as well as from several other industrial processes. It is also a contaminant of certain pesticides. NDMA has recently been identified as a disinfection by-product of chloramination (by the reaction of monochloramine with dimethylamine, a ubiquitous component of waters impacted by wastewater discharges) and, to

some extent, chlorination. NDMA can also be formed as a by-product of anion-exchange treatment of water. [1]

N-nitroso-dimethylamine (NDMA) is a potent hepatocarcinogen in all animal species tested. High oral doses lead to tumours of the kidney and nasal cavity, which is also the target after inhalation of NDMA . N-nitro-dimethylamine (NTDMA) is also carcinogenic, albeit at much higher concentrations than NDMA, and leads to tumours of the nasal cavity if administered by gavage. If the compound is given continuously in drinking water, liver and kidneys are additional targets. Both compounds are hydroxylated, NDMA to formaldehyde and the ultimate carcinogen methyldiazonium ion, and NTDMA is oxidized to HCHO and N-nitromethylamine. [2]

The latter compound, on further activation, probably reduction, leads to tumours of the spinal cord. NDMA is metabolized by CYP2E1, an enzyme that is inducible by ethanol, which stabilizes the protein, and by fasting, which increases CYP2E1 mRNA levels. Because NTDMA is structurally so similar to NDMA our working hypothesis is that both compounds are hydroxylated by the same enzyme. Since the product of NTDMA hydroxylation, N-nitromethylamine, is not an ultimate carcinogen and the tumour site is different for the two compounds, we postulated a reduction of NTDMA to NDMA as the first step in NTDMA activation to the ultimate carcinogen.

NDMA occurs in various foods and alcoholic beverages, and is also detected in cigarette smoke. NDMA has also been detected in California drinking water. This specific chemical has been extensively studied in experimental animals and is considered an animal carcinogen. Because of similarities in its metabolism to reactive intermediates in animals and humans, it is considered as a likely human carcinogen. NDMA has become more important in California because of its increasing detection in drinking water. It has been associated with the chloramine drinking water disinfection process, and has also been reported to be formed in the chlorination of wastewater used for aquifer recharge. [3]

N-nitrosodimethylamine, also commonly referred to as dimethylnitrosamine, is a yellow oily liquid at room temperature. The Chemical Abstracts Service Registry number for NDMA is 62-75-9; its molecular formula is C₂H₆N₂O.

The first task in identifying the probable risk associated with NDMA is to determine the level of exposure where adverse effects occur. The problem is that exposures may occur from multiple sources, i.e., food, water, air and environmental pollutants and produce varied responses in different individuals. Symptoms may also be delayed and not be evident for years. The synergistic nature of NDMA effects combined with other pollutants are also not known; currently, the U.S. Environmental Protection Agency (USEPA) is evaluating the reference concentration for NDMA where health effects are likely to occur-a vital piece of information for estimating risk.

Another important question to answer is how much exposure to NDMA is due to water relative to other sources? In other words, what NDMA sources are most important relative to the associated heath risks? Considering levels in milk may range from 90-to-100 ppt (up to 3,559 for nonfat dry milk), and there are 50-to-7,700 ppt in beer, 2,600-to-2,700 ppt in bacon, and as much as 5,350 ppt in salami-the levels found in water seem relatively insignificant. The important thing to remember about water, however, is the relative dose consumed compared to other foods. Salami may be eaten rarely but water tends to be ingested on a constant, daily basis. [4,5]

The amount of NDMA that results in health effects in humans is unknown; however, epidemiological studies have shown a clear connection between NDMA and cancer. A study in Finland showed people with a diet high in nitrosamine compounds (including NDMA) were more likely to develop colorectal cancer than others. The study followed 9,985 people for up to 24 years and found those consuming smoked and salted fish containing nitrosamines and other preservatives were nearly 2.6 times more at risk for cancer than individuals not consuming these foods.

The USEPA has classified NDMA as a "probable human carcinogen." The carcinogenic effect of NDMA has been classified as a medium hazard. The USEPA states that individuals are most likely to be exposed to NDMA in occupational settings such as in the rubber, tannery, fish processing, dye, and surfactant industries. Other exposures may be from cigarette smoke and contaminated air. Drinking water is listed as a potential exposure route but how prevalent this route is hasn't been determined.

References

2 Bartsch H, Spiegelhalder B. Environmental exposure to N-nitroso compounds (NNOC) and precursors: an over-view. Eur J Cancer Prev. 1996; 5 Suppl1: 11–7.

1. Havery, D.C. and T. Fazio, "Survey of baby bottle rubber nipples for volatile N-nitrosamines." Journal for the Association of Official Analytical Chemists, 1983. 66(6):p.1500-3.
2. Orange County Water District, "Background information on N-Nitrosodimethylamine (NDMA)." 2000, OCWD Online. www.ocwd.com/pages/ndma.htm
3. Desjardins, R., M. Fournier, F. Denizeau, and K. Krzystyniak, "Immunosuppression by chronic exposure to N-nitrosodimethylamine (NDMA) in mice." Journal of Toxicology and Environmental Health, 1992. 37(3): p. 351-61.

4. Scherf,H.R., Frei,E. and Wiessler,M. (1989) Carcinogenic properties of N-nitrodimethylamine and N-nitromethylamine in the rat. Carcinogenesis, 10, 1977–1981.

5. Litvinov, N.N., D. Parfenov Iu, V.M. Voronin, and V.S. Zhurkov, "Calculation of maximum allowable concentration of N- nitrosodimethylamine and N-nitrosodiethylamine based on chronic experiments in mice." Gigiena I Sanitarria, 1990(4): p. 33-6.