NDMA

Nitroisodimethylamine (NDMA) is a rocket fuel. It is toxic in drinking water in parts per trillion When the space shuttle Columbia burned up on reentry in 2003, NASA warned people not to touch pieces of debris because of this fuel. The widespread contamination from this chemical is just now being realized. 

---

Toxicity. Many /V-nitrosamines are toxic to animals and cells in culture (4,6—8,88). /V-Nitrosodimethy1amine [62-75-9] (NDMA) is known to be acutely toxic to the Hver in humans, and exposure can result in death (89). Liver damage, diffuse bleeding, edema, and inflammation are toxic effects observed in humans as a result of acute and subacute exposure to NDMA. These effects closely resemble those observed in animals dosed with NDMA (89,90). 

Preparation ndMa.nufa.cture. Monoorganotin haHdes are the basic raw materials for all other triorganotin compounds and are generally prepared by Kocheshkov redistribution from the tetraorganotin, eg, tetrabutyltin or the higher organotin haHdes ... 

Amine in BPO-amine system DMT HDMA DMA NDMA DMAB... 

Diacyl peroxide] = [amine] = 1.0 x 10 mol/L,45 C HDMA p-hydroxymethyl-A/,A/-dimethylaniline NDMA p-nitro-A/,A/-dimethylani-line DMAB p-dimethylaminobenzaldehyde. 

Our result, therefore, suggests that the methylating agent formed from NOPPA is similar in reactivitjr to that formed from NDMA, and would support the hypothesis of Kruger (13) that NMPA may be the methylating agent formed from NOPPA. 

To prevent this contamination, there were several approaches which this mechanistic information suggested. But the one which the manufacturers proposed ( ) was to stop using nitrite to control corrosion of the container. Most dimethylamine phenoxyalkanoic acid products now contain non-detectable NDMA (18). 

Figure 4, Postulated pathway by which 2,4-D became contaminated with NDMA, as suggested by Ross et al, (2),...

For several reasons, this was not surprising. First of all, most of the data on the disposition of nitrosamlnes In plant parts relies on the use of compounds such as NDMA, which, by analogy to Its behavior In animals (24). might be expected to have a short biological half-life In plants It could be especially difficult to detect such compounds when the analyses are performed several weeks after applying the precursors to the plants. In addition, one might expect to find relatively little nitrosatlon of dimethylamlne In a plant, as such relatively basic amines are... 

Only a few studies have been undertaken on the role of bacteria in nitrosation at neutral pH in the Intestinal tract itself. Hashimoto al. (9 ) demonstrated that by changing the equilibrium between different species of microorganisms in the gut, (by administration of antibiotics and inoculation with nitrate-reducing strains) dimethylnitrosamine (NDMA) accumulated in the stomach and cecum of rats fed dlmethylamine (DMA) and nitrate. The authors describe only one experimental group, however, and the mechanism of NDMA formation is not clear. 

In order to define the conditions of the growing cultures, buffered medium (VL) inoculated with E, coli ATCC 11775 and supplemented with nitrate, glucose and DMA was incubated at 37 C, and pH, nitrite concentration, nitrate concentration, cell growth and nitrosamine formation were followed (Fig. 1). Within 2 hrs, >90% of the nitrate is converted to nitrite (some of the nitrite is further reduced) and over 8 hrs the pH drops from 7.3 to 6.0. This would indicate that in experiments carried out for 20 hrs or more the control medium should be adjusted to pH 6.0 to 6.5 and nitrite should be added rather than nitrate. Such a control medium (VL) was supplemented with nitrite and DMA and NDMA formation was followed (Fig. 2). It can be seen that even without the addition of cells the rate of nitrosation is 4 fold greater than... 

Figure L pH, nitrite, nitrate, and NDMA concentration as a function of cell growth in VL medium, E. coli ATCC 11775 was inoculated into sealed tubes containing VL medium (described in the legend to Table 1) supplemented with 0,2% glucose, 0.05% dimethylamine, and 0,08% sodium nitrate. The tubes were incubated at 37°C and cell growth was followed with spectronic 20 (Bausch Lomb) at 660 nm. Nitrite and nitrate were measured as described in ( ) and NDMA detection as described in the legend to Table I,...

Figure 2, Accumulation of NDMA in VL medium at pH 6A, The pH of VL medium was adjusted to 6,4 with HCl and NDMA formation was followed at 37°C, Nitrite concentration in the medium was 0,2% and dimethylamine 0.05%, Theoretical curve was calculated according to Fan and Tannenbaum (15),...

NaN02 pM NDMA theoretical pM NDMA actual pM ac tual/theoret ical... 

VL medium, pH 6 4, with or without cells was incubated in sealed tubes for 10 hrs at 37 C NDMA was determined by gas chromatography with the Thermal Energy Analyzer as a detector (Thermo Electron Corp, Waltham, MA). The identity of NDMA was confirmed by 6C mass spectrometry. 

These results led us to reexamine the published work on nitrosation in the presence of bacteria (Table II) In two of the studies (, 10) the amount of NDMA formed is actually less than the amount that can be predicted from theoretical consideration of the uncatalyzed chemical reaction alone (15) In another study (12), the yield of NDMA is again slightly lower than the predicted chemical yield at the final pH (6 0) of the growing culture The work by Kunisaki and Hayashl (13), on the other hand, does indicate that resting cells of E. coli B catalyze... 

Summary of some published studies on the formation of dlmethylnltrosamlne (NDMA) In the... 

Other studies on the involvement of microorganisms with N-nitrosation have either been insufficiently controlled or have been only incompletely reported. Radomski ( ) found NDMA... 

The mechanism of NPYR formation has been studied by Coleman (37) and Bharucha et al. ( ). Coleman (37) reported that the requirement for a high temperature, the inhibitory effects of water and antioxidants, and the catalytic effect of a lipid hydroperoxide are consistent with the involvement of a free radical in the formation of NPYR. Similarly, Bharucha et al. (29) suggested that, since both NPYR and NDMA increase substantially towards the end of the frying process, N-nitros-amine formation during frying of bacon occurs essentially, if not entirely, in the fat phase after the bulk of the water is removed and therefore by a radical rather than an ionic mechanism. These authors speculated that, during the frying of... 

The inhibition of formation of NPYR and NDMA in fried bacon by the use of cure-solubilized a-tocopherol (500 mg/kg) has been demonstrated by Fiddler et al. (50). Walters et al. (53) also reported reduced levels of N-nitrosamines in the vapors during the frying of bacon in fat containing a-tocopherol. It has also been shown that a-tocopherol is dispersed quite effectively during frying of bacon slices therefore, application to bacon may be made by spray or dip to overcome the problem of water insolubility (51). Controlled addition of this antioxidant may be an effective and practical way of reducing the concentration of N-nitrosamines in cooked... 

N-Nitrosamines in Cured Meats Other Than Bacon. The presence of N-nitrosamines in cured meats other than bacon has been the subject of several recent surveys (19,58,59). In general, the majority of the positive samples contained extremely low levels of N-nitrosamine, usually less than I yg/kg (19,58). This low level could, in part, be attributed to the discontinuation of the use of nitrite-spice premixes in the mid-l970 s (l 9). In the Holland study (59), the predominant N-nitrosamines detected were NDMA and N-nitrosomorpholine (NMOR) and, generally, values of 4 yg/kg were obtained for each N-nitrosamine. More correctly, these are presumptive N-nitrsoamine levels since mass spectral confirmation of their identities was not achieved. 

Commercially available nonfat dried milk and dried buttermilk have also been shown to contain small but detectable levels of NDMA (, , ). It has been suggested that N-nitrosamine formation is possible in foods that are dried in a direct-fired dryer (65). In such a dryer, the products of combustion come into direct contact with the food being dried, and N-nitrosamine formation is probably due to the reaction between secondary and/or tertiary amines in the food and the oxides of nitrogen that are produced during fuel combusion (65). 

It has been shown in these studies that the principal, and probably only significant source of NDMA, is malt which had been dried by direct-fired drying (21, 73). It is well known that malts kilned by indirect firing have either low or non-detectable levels of NDMA (74). Consequently, changes in malting procedures have been implemented in both the U.S. and Canada which have resulted in marked reductions in N-nitrosamine levels in both malts and beer (70,74). For example, sulfur dioxide or products of sulfur combustion are now used routinely by all maltsters in the U.S. to minimize N-nitrosamine formation (70). The Canadian malting industry, on the other hand, has... 

Research on the formation of NDMA in beer has centered on three possible sources of amine precursors (74). N-Nitros-amine formation from amines such as hordenine, famine and methyltyramine which are formed endogenously in the germination of barley has been discussed elsewhere in this symposium (75). The Brewers Association of Canada (74) investigated the... 

Decomposition studies confirmed that N-nitrosamides are much less stable than volatile N-nitrosamines such as NPYR and NDMA (79). Thermal studies utilizing heating conditions commonly encountered in the cooking of bacon and pork roasts indicated that N nitrosomethylpropionamide (NOMP) was degraded to the extent of 74-97% compared to 3-14% for NPYR and NDMA (Table V). It was tentatively concluded that the major... 

Results of a systematic study ( ) of food from the German market indicate the average daily intake for male persons amounts to l.l yg for NDMA and 0.1-0.15 yg for NPYR. Approximately 64% of this total daily intake for NDMA is found in beer, while another 10% comes from cured meat products. It is also important to note that food is not only the only source of N-nitrosamine or N-nitrosatable amines to which we are... 

---