UDC 614.7:615.277.4:546.226’173

P. A. Bogovskii, K. Wettig

Hygienic Aspects of the Study of Carcinogenic N-Nitroso Compounds

Institute of Experimental and Clinical Medicine, Ministry of Health of the Estonian SSR, Tallinn; Berlin-Buch Branch, Research Institute of Hygiene and Microbiology, Bad Elster, GDR

The environment plays a leading role in the development of malignant tumors, posing a number of challenges for public health specialists.

This review considers the occurrence of N-nitroso compounds (NOCs) in the environment and their formation in the body from precursors.

NOCs are among the most potent environmental carcinogens. More than 300 NOCs have been tested in animal experiments, and over 85% were found to be carcinogenic. The International Agency for Research on Cancer has recommended [37] that NOCs be regarded as practical carcinogenic hazards to humans. The carcinogenic properties of NOCs have been demonstrated in 40 animal species [4, 71]. Although NOCs also have toxic, mutagenic, teratogenic, and embryotoxic properties, we agree with R. Preussmann [60] that the carcinogenic effect of these compounds is decisive in their assessment.

The total human exposure to NOCs can be presented schematically, following R. Preussmann [60].

1. Exogenous exposure to NOCs. Tobacco and tobacco smoke, studied in detail with respect to their NOC content by D. Hoffmann and coauthors [36], are the principal nonoccupational source of NOCs for humans. The concentration of nitrates in tobacco has been found to be the primary determinant of NOC content in tobacco smoke. When the nitrate content of cigarette tobacco is experimentally increased from 0.52% to 3.05%, the contents of tar, nicotine, benzo(a)pyrene (BP), and catechol decrease statistically significantly, but the contents of nitrogen oxides, NOCs, and especially tobacco-specific NOCs (TSNOCs) also increase significantly. At the same time, despite the reduction in BP content, the carcinogenic effect of nitrate-enriched cigarettes increases [7]. Both the alkaloid content of tobacco [48] and the agricultural conditions under which it is grown [9] are of great importance for NOC concentrations in tobacco smoke. It has been shown [36] that the concentration of volatile NOCs in tobacco smoke released into the environment is considerably higher than in mainstream smoke, pointing to the importance of passive smoking. TSNOCs are formed by nitrosation of tobacco alkaloids (nornicotine, anabasine, and others) during cigarette manufacture or smoking. The content of TSNOCs and other NOCs, which are virtually the only carcinogens in chewing tobacco and snuff, correlates with the increased incidence of oral tumors in people who chew tobacco. This is regarded as the principal direct evidence of the carcinogenic effect of NOCs in humans. The high content of nitrosatable amines and nitrogen oxides in tobacco smoke is considered an additional factor in the endogenous formation of NOCs. A person smoking 20 cigarettes a day takes in 16–86 µg of NOCs. A comparison of chewing tobacco varieties from six countries [14] showed that their volatile NOC content was relatively low (less than 100 µg/kg), but the nonvolatile NOC content exceeded 1,000 µg/kg in all varieties except the Uzbek variety. TSNOC content ranged from 5,900 to 240,000 µg/kg, two orders of magnitude higher than the NOC concentrations in all food products studied to date.

Food products. For a long time, beer was the principal source of NOCs.

Changes in brewing technology made it possible to reduce its NOC content sharply [69]. The content of nonvolatile NOCs in beer has not yet been adequately studied. Some evidence suggests that nonvolatile NOCs may form during fermentation.

Changes in bacon production technology in the United States reduced its N-nitrosopyrrolidine content from 20–1,000 µg/kg in 1971–1972 to 5–15 µg/kg in 1977 [33].

Data on the intake of nitrosodimethylamine (NDMA) from various foods are presented in Table 1 [75].

The NDMA content of certain foods in other countries is presented in Table 2. It should be emphasized that some food samples had high NOC contents, depending on the production technology used. NOC content in foods may also vary sharply depending on whether prepared dishes or “market basket” samples are studied. In the latter case, analytical values were an order of magnitude lower [68], probably owing not only to the formation of NDMA during food preparation. International comparisons are also hampered by the use of different analytical methods that have not been validated through interlaboratory studies of identical samples.

Cosmetics. As an emulsifier in various cosmetic preparations (creams, lotions

Scheme of human exposure to N-nitroso compounds (NCs)

• Total exposure
• Exogenous exposure
  • Lifestyle: tobacco and tobacco smoke, food, cosmetics, chemical products, household chemicals, indoor air, medications
  • Occupation: rubber, leather, chemical and mining industries; production of pesticides and detergents; fish-processing plants
• Endogenous exposure
  • Intake of precursors: nitrites, nitrogen oxides, nitrosatable amines and amides
  • Formation of precursors: nitrite from nitrate (saliva, gastric juice); nitrate through oxidation of ammonium compounds, hydroxylamine and amino acids

…and others), diethanolamine and triethanolamine are frequently used. NC formation in these products is caused by the use of contaminated amines [76], reactions with nitrites or nitrogen oxides, and the simultaneous use of bactericides containing nitro groups. Nitrosodiethanolamine (NDELA) is readily absorbed through the skin [24], but total human exposure to this substance is difficult to estimate. It is noteworthy that nitrogen oxides adsorbed onto soot produce NDELA more readily than nitrites do [52].

Indoor air. K. Brunnemann and D. Hoffmann [15] found 0.01–0.13 µg/L of NDMA in smoke-filled rooms, corresponding to exposure of 5–200 µg/h. NCs are sometimes found in the air of kitchens [72] and new passenger cars [64].

Ambient air apparently can contain NCs only in the immediate vicinity of certain industrial facilities. The hygienic significance of amines and nitrogen oxides in ambient air for tumor formation was assessed by V. V. Benemansky and M. E. Leshchenko [2]. Concentrations of dimethylamine and nitrogen oxides exceeding the maximum permissible concentration tenfold double the incidence of tumors induced by NDMA. According to Kneip et al. [43], the total NC concentration in dust samples averaged 140 pmol/m³ in New York and 43 pmol/m³ in rural areas. Yanysheva et al. [6] measured concentrations ranging from 0 to 0.116 µg/m³ in the Ukrainian SSR. Data on NC concentrations in the air at various industrial sites are given in Table 3 [27].

Household chemicals. Dishwashing detergents often contain laurylamine oxides, in which N-nitrosomethyldodecylamine is frequently detected at concentrations of 112–661 µg/kg and N-nitrosomethyltetradecylamine at 45–151 µg/kg [51]. NCs have been found in baby pacifiers at concentrations of 1–280 µg/kg [32, 53, 61]. Recently, the situation has improved as a result of reductions in the amounts of amine-containing accelerators and polymerization stabilizers added. In Canada, for example, concentrations exceeding 30 µg/kg have recently been found in only 7 of 42 rubber samples; 26 samples tested negative [73].

Occupational factors. Among sources of increased risk, the rubber and tire industries have been studied most thoroughly [60]. Atmospheric nitrogen oxides and amine-containing accelerators and stabilizers give rise primarily to the highly carcinogenic N-nitrosodiphenylamine. Daily exposure ranges from 15 to 150 µg of NCs. The elevated mortality from stomach cancer among coal miners is attributed [81] to nitrosation of compounds contained in swallowed coal dust. Although attempts have recently been made to assess the risk of exposure to coolants used in the metalworking industry by biomonitoring, one can agree with R. Preussmann [60] that workplaces involving a risk of contact with NCs are not only far from fully studied but have not even all been identified.

Table 1

Mean daily dietary intake of NDMA (ng) in women and men in the Federal Republic of Germany

Table 2

NDMA content in selected foods from various countries

2. Endogenous exposure to nitroso compounds

The hypothesis that nitroso compounds (NCs) can be formed endogenously from precursors (nitrite and amines) was first advanced by H. Druckrey et al. [23]. Experimental confirmation was obtained by J. Sander and G. Bürkle [66], who induced malignant tumors of the liver and esophagus in rats by feeding them mixtures of morpholine or N-methylbenzylamine with nitrite. The formation of NCs in the human stomach was first demonstrated by J. Sander and F. Seif [67]. However, NCs, and especially NDMA, are rapidly metabolized, making them difficult to identify. Only recently was NDMA detected in urine at concentrations ranging from 0.5 to 10 µg/L following its administration together with ethanol [77]. This variation evidently depends on the nitrite content of saliva. Without ethanol, the rapid metabolism of the NDMA formed makes it difficult to detect in biological fluids. It would be incorrect, however, to conclude that low concentrations of NDMA in the body indicate a low rate of its formation from precursors. Also relevant to health-risk assessment is the fact that, in experimental tumor induction, reducing the dose not only lowers carcinogenic activity but also changes the organ tropism of the carcinogen [47]. Moreover, an important finding of experimental oncology is that repeated administration of a carcinogenic substance is more effective than a single administration [11, 38] of the same total dose.

For a long time, it remained unclear how to measure the extent of endogenous nitrosation in humans. A method was proposed [54, 57], also suitable for epidemiological studies, involving oral administration of the nitrosatable amino acid proline and sodium nitrite as the nitrosating agent, followed by quantitative determination of the nitrosoproline formed in urine and feces. Clear correlations were obtained, unlike in the study of saliva, between the amounts of precursors administered and the nitroso amino acid formed. Subsequently [56], the following relationship was established:

\[ [\mathrm{NPRO}]=a[\mathrm{proline}]^{b}[\mathrm{nitrite}]^{2b} \]

or

\[ \log[\mathrm{NPRO}]=\log a+b\log\{[\mathrm{proline}][\mathrm{nitrite}]^{2}\}, \]

where \(\log a=-1.394\), \(b=0.439\).

Using kinetic data on the nitrosation of other amines, this formula can be used to obtain values for their endogenous nitrosation.

Nitrosation indices can also be determined in humans using proline and nitrite, because: 1) nitrosoproline (NPRO) has neither carcinogenic nor mutagenic properties [50]; 2) after administration of (\(^{14}\mathrm{C}\)) NPRO to rats, neither the formation of \(^{14}\mathrm{CO}_{2}\) nor the alkylation of deoxyribonucleic acid is detected, whereas

Table 3

NC content in ambient air around selected industrial facilities

Table 4

Selected substances that catalyze NC formation

NPRO is excreted rapidly and completely [18, 22, 57]; 3) the NPRO content in the urine of rats given proline and nitrite fully reflects endogenous nitrosation [55].

This method was used in field epidemiological studies in China to investigate the causes of esophageal cancer. Preliminary findings indicate increased nitrosation of proline among residents of Linxian province, where the incidence of esophageal cancer is higher than in Fanxian province [48]. P. A. Bogovskii and coauthors [3] showed that measurement of NPRO in sweat has an advantage over measurement in urine, because the composition of sweat is closer to that of blood serum than is the composition of urine.

Another method for determining the level of endogenous nitrosation involves the use of $^{14}\mathrm{C}$-labeled aminopyrine and nitrite, followed by quantitative determination of $^{14}\mathrm{C}$-me$^{7}$guanine in urine [30].

Endogenous nitrosation is inhibited by a number of factors (vitamins C and E, cinnamic acid derivatives, thioproline). Other factors enhance nitrosation (Table 4).

The role of modifying factors of endogenous or exogenous origin in carcinogenesis deserves particular emphasis. It is now evident that vitamin C and thioproline as inhibitors, and thiocyanate and bacteria as catalysts, play a very important role in carcinogenesis.

Study of the role of bacteria is important not only because of their catalytic effect on the formation of N-nitroso compounds (NOCs), but also because of the microbial formation of NOC precursors. Microorganisms with nitrate reductase activity reduce nitrate to nitrite, while microbial decarboxylation of amino acids produces amines [10, 16, 34]. For example, the microflora of the oral cavity is strongly influenced by such factors as diet, smoking, medication use, dental condition, and so on, making it difficult to assess the carcinogenic hazards these factors pose to humans. Of particular importance is the bacterial flora in hypoacidic and anacidic stomachs, for example after a Billroth II operation, in which the concentration of NOCs is 20 times that in normal stomachs [70].

A number of investigators [26, 39, 79] have identified other possible pathways for endogenous NOC synthesis. In mice and rats, inhalation of nitrogen dioxide after administration of morpholine or aminopyrine was found to cause formation of the corresponding NOC in the body. Similar results were obtained both in whole animals and in isolated, ventilated and perfused lungs in the presence of nitrogen oxides and amines [59].

3. Risk assessment

To date, no epidemiological studies have been conducted that would permit determination of the degree of risk of cancer in humans due to exposure to NOCs. Extrapolation from animal experiments permits the carcinogenic risk to be estimated at $1/10^{6}$ for administration of NDMA at a dose of 5.84 ng per kg of body weight. If a person weighing 65 kg is assumed to receive an average of 50 ng of NOCs per day, the daily dose would be 7.7 ng/kg, corresponding to a risk of $1.32/10^{6}$ [19]. This estimate does not take endogenous NOC formation into account.

There is no doubt that assessing the risk of human cancer from endogenously formed NOCs is currently one of the most important tasks in cancer epidemiology. R. Doll and R. Peto [5] believe that there is still no conclusive evidence of the carcinogenic properties of the NOC precursors nitrite and nitrate. Accordingly, the detailed studies by R. Zaldivar and coauthors [84] on the relationship between the extent of nitrate-containing fertilizer use and mortality from stomach cancer in Chile may be regarded as indirect evidence of the role of NOCs. The same applies to studies of esophageal cancer incidence in Africa [20], China [49], Colombia [21], and southwestern Colombia [35]. The pronounced dependence of stomach cancer incidence on geographical region indicates the action of an exogenous factor [29]. However, there are no convincing epidemiological studies directly demonstrating a link between stomach cancer incidence and NOC consumption.

In S. Tannenbaum’s laboratory, a study of Colombian data revealed [83] that nitrosation of 4-chloro-6-methoxyindole yields a strongly mutagenic NOC. This indole derivative is present in fava beans, which are widely consumed in the high-risk area. When these beans were treated with nitrite under conditions simulating those in the stomach, a product was formed whose activity was comparable to that of the most potent known mutagens. Similar results were published simultaneously by Van der Hoeven [78]. We regard these findings as the first convincing evidence of a link between increased stomach cancer incidence and exposure to an endogenously formed NOC. In principle, human exposure to NOCs formed in the environment can be prevented, as in the case of tobacco smoke and, to some extent, occupational exposure; however, the quantitative contribution of endogenous NOC formation remains difficult to assess. G. Ellen and coauthors [25] estimate that the endogenous NDMA burden in humans is three times the exogenous burden. This is inconsistent with theoretical calculations [17] of NDMA burden, according to which the exogenous burden accounts for 94% and the endogenous burden for only 6%.

All the facts presented above indicate that both reducing the exogenous NOC burden (above all by limiting smoking) and taking every possible measure to reduce endogenous

…of the synthesis of N-nitroso compounds (including the use of anticarcinogens and inhibitors of nitrosation) will help reduce the risk of cancer in humans.

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Received 01.04.87.