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A survey of 21 beers produced in Spain during 1994 was conducted to assess contamination with volatile N-nitrosamines. N-Nitrosodimethylamine (NDMA), the only volatile N-nitrosamine detected, was found in 52% of Spanish beers at or above the detection level (0.05 microgram/kg). The mean NDMA level for all samples was 0.11 microgram/kg, and the range was from not detected to 0.55 microgram/kg. No differences in the NDMA content were observed between the different beer types. Individual daily intake of NDMA may reach up to 0.021 microgram/person/day for Spanish people.

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A total of 194 beers (148 US and 46 Canadian) were analysed for volatile N-nitrosamines. The sampling was designed to include different types of beers brewed from malts at all commercial-scale malt houses by the major beer manufacturers in both countries. N-Nitrosodimethylamine (NDMA), the only volatile N-nitrosamine detected, was found in 56% of the beers (detection level, 0.05 microgram/kg), at a mean level of 0.074 microgram/kg. The results indicate that NMDA levels in present-day US and Canadian beers are approximately 1-5% of what they were a decade ago.

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The value of chemopreventive agents for reducing human response to mycotoxins and N-nitrosamines remains uncertain, especially since many such agents also can act as tumour promoters. Indole-3-carbinol (I3C) from cruciferous vegetables can inhibit DNA adduction and hepatocarcinogenesis induced by aflatoxin B1 (AFB1) or N-nitroso-diethylamine in trout if given before and with the carcinogen but promotes carcinogenesis when given after initiation. Similar results have been obtained with I3C and AFB1 in rats. In detailed studies using 10,000 trout, inhibition of AFB1 carcinogenesis was found to be saturable at high doses of I3C, approximately proportional to dose of I3C through the range of human intake and, within this range, quantitatively predicted by I3C-mediated reduction of AFB1-DNA adduction in liver. In a second study, post-initiation promotion of AFB1 carcinogenesis was approximately proportional to I3C dose, increased with duration of exposure, decreased with delayed onset of exposure, and reduced but still significant when I3C was given on alternate months or weeks or twice per week only. Hence, promotion by this common component of cruciferous vegetables required prolonged exposure but not necessarily on a daily basis.

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The nitrosation of gramine, a tertiary amine alkaloid present in barley malt, was carried out by reaction with sodium nitrite in buffered acetic acid (pH 3.4) for 1 hr at room temperature. Following the previous isolation and identification of the major nitrosation products (Ahmad et al. Fd Chem. Toxic. 1985, 23, 841), two minor products were isolated by HPLC and identified as indolin-3-one oxime and indole-3-aldehyde. Identification was based on mass spectrometry. The results give strong support to the hypothesis that gramine does not undergo nitrosation by nitrosative dealkylation.

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An approach to the synthesis of N1-nitroso-3-nitromethylindole, a nitrosation product of the alkaloid gramine, is described. The method involves a few reaction steps starting from indole-3-carbinol.

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The nitrosation of gramine, a tertiary amine alkaloid present in barley malt, was carried out by reaction with sodium nitrite in buffered acetic acid (pH 3.4) for 1 hr at room temperature. Two major non-volatile products of the nitrosation reaction were isolated by preparative HPLC and characterized as indole-3-carboxylic acid and N1-nitroso-3-nitromethylindole. This interpretation was supported by spectral data. The nature of these products indicated that gramine did not undergo nitrosation by the expected mechanism of nitrosative dealkylation. A mechanism is offered to explain the labile nature of the dimethylamino group found in gramine.

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The two tertiary amine alkaloids, hordenine and gramine, which are biosynthesized in malt during germination, were subjected to nitrosation under conditions typical for the study of tertiary amine nitrosation. At 65 degrees C in dilute aqueous acid (pH 4.4 or pH 6.4), nitrosation of both amines resulted in formation of N-nitrosodimethylamine (NDMA). At 24 degrees C in dilute acid (pH 3.4), the initial rate of NDMA formation from gramine was nearly equal to the initial rate of NDMA formation from dimethylamine. At the same temperature, the ratio of initial rates of formation of NDMA from gramine and trimethylamine was 6250:1. At 23 degrees C, the ratio of initial rates of formation of NDMA from gramine and hordenine was 5200:1. The rapid reaction of gramine with nitrous acid and the nature of the gramine nitrosation reaction products both indicated that gramine did not undergo nitrosation by the expected mechanism of nitrosative dealkylation. A new mechanism if proposed to explain the labile nature of the dimethylamino group of gramine and to account for the fact that NDMA is the only N-nitrosamine formed during the nitrosation of gramine.

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Nitrosamines are formed by reaction of secondary or tertiary amines with a nitrosating agent. In foods, the nitrosating agent is usually nitrous anhydride, formed from nitrite in acidic, aqueous solution. Food constituents and the physical make-up of the food can effect nitrosamine formation. Ascorbic acid and sulfur dioxide are used to inhibit nitrosamine formation in foods. Nitrosodimethylamine has been shown to be formed in certain foods as a result of the direct-fire drying process. In this case, oxides of nitrogen in the drying air nitrosate amines in the food being dried. The volatile nitrosamine which occurs most commonly in food is nitrosodimethylamine, and nitrosopyrrolidine occurs to a lesser extent. Due to limitations in analytical methodology, very little information is available on the levels of nonvolatile nitrosamines and other N-nitroso compounds in foods. Foods which have been shown to contain volatile nitrosamines include cured meats, primarily cooked bacon; beer; some cheeses; nonfat dry milk; and sometimes fish. It should be emphasized that not all samples analyzed contain detectable amounts of nitrosamines. When present, the volatile nitrosamines usually occur in the lower microgram/kg range. Estimates by several investigators suggest that the average daily intake of volatile nitrosamines from foods is approximately 1 microgram/person.

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The secondary amine barley malt alkaloids N-methyltyramine and N-methyl-3-aminomethylindole were synthesized, nitrosated in dilute acetic acid and the products characterized by mass spectrometry and NMR spectroscopy. The nitrosation products of N-methyltyramine were p-hydroxy-m-nitro-N-nitroso-N-methyl-2-phenylethylamine and p-hydroxy-N-nitroso-N-methyl-2-phenylethylamine. Upon nitrosation, N-methyl-3-aminomethylindole formed N-nitroso-N-methyl-3-aminomethylindole and the dinitrosated product N1-nitroso-N-nitroso-N-methyl-3-aminomethylindole.

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Dietary exposures have demonstrated rainbow trout to be the most sensitive experimental animal to the hepatocarcinogenicity of aflatoxin B1 (AFB1). More recently the development of an alternate exposure method has shown trout to be even more sensitive to AFB1. This method involves the single exposure of fertile rainbow trout eggs (embryos) to a 0.5 ppm aqueous solution of AFB1 for 30 minutes, rinsing the eggs in water, and allowing hatching, swim-up and the onset of feeding to proceed as usual. Resulting fish are fed a control diet for 1 year at which time approximately two-thirds of the population will have developed hepatocellular carcinoma of the liver. Variables, such as embryo age of greatest sensitivity, carcinogen concentration, and length of exposure, have been defined for AFB1 exposures. Sensitivity to AFB1 increased with increasing age of the embryo, the model system showed a dose-response to increasing carcinogen concentrations, and one-half hour exposures appeared to be optimum for AFB1. Experiments with other carcinogens have shown the embryo model system to be sensitive to the hepatocarcinogenicity of AFB1 metabolites (aflatoxicol, aflatoxin M1, and aflatoxin G1), sterigmatocystin, versicolorin A, dimethylnitrosamine, and N-methyl-N'-nitro-N-nitrosoguanidine. The latter compound also initiated nephroblastomas of the kidneys. The results demonstrate the potential for the trout embryo to be developed into a convenient, economical, and sensitive whole animal model system for experimental carcinogenesis.

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Microsomes and postmicrosomal supernatant were prepared from the esophagus and non-grandular stomach of rats. Using these fractions, we could not demonstrate in vitro metabolism of 2,6-dimethyldinitrosopiperazine (DMDNP), a potent esophageal and non-grandular stomach carcinogen in rats. The esophageal and non-grandular stomach fractions did metabolize N-nitrosopyrrolidine (NPYR) to a small extent, and liver microsomes and postmicrosomal supernatant metabolized both nitrosamines to a similar extent. Therefore, we advise caution in the interpretation of metabolic studies using 'target' and 'non-target' organs as indicative of activation of compounds to proximate carcinogens.

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Volatile N-nitrosamines were confirmed in foods at concentrations of less than 10 micrograms/kg by full scan low resolution mass spectrometry. Ground samples were vacuum-distilled from mineral oil and condensed in liquid nitrogen-cooled vapor traps. The thawed distillate was extracted, the extract was cleaned up and concentrated, and the N-nitrosamine content was determined by combined gas chromatograph-thermal energy analysis. Positive samples were further cleaned up, trapped from a gas chromatographic column, and purged into a gas chromatograph-mass spectrometer for qualitative confirmation by full scan low resolution mass spectrometry. This procedure was applied to foods spiked at 1 microgram/kg and to fried commercial bacons with volatile N-nitrosamine contents of 2 to 5 micrograms/kg.

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An analytical procedure has been outlined in which volatile N-nitrosamines in foods are isolated by vacuum distillation, cleaned up, identified and quantified by GC-TEA and qualitatively confirmed by GC-MS, coupled with a data system. Spectra are presented which demonstrate that this technique is capable of confirming NDMA and NPYR in a variety of foods at levels of 1 to 10 micrograms/kg. Unequivocal confirmation is based on three types of evidence: (1) the compound is TEA positive; (2) the compound has the correct retention time on a packed and on a capillary column; (3) the complete mass spectrum closely matches standard spectra. These procedures have been used to confirm the presence of trace levels of NDMA in domestic beer and in non-fat dry milk.

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5 nitrosamines formed from the nitrosation of spermidine were investigated for mutagenicity using various strains of Salmonella typhimurium in the presence and absence of S9 mix. Using the plate incorporation method, 3-butenyl-(2-propenyl)-N-nitrosamine, 3-hydroxybutyl (2-hydroxypropyl)-N-nitrosamine, 4-hyroxybutyl-(2-hydroxypropyl)-N-nitrosamine, 4 hydroxybutyl-(3-hydroxypropyl)-N-nitrosamine, and in the liquid test 3-hydroxybutyl-(3-hydroxypropyl)-N-nitrosamine were mutagenic in the absence of S9 mix.

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