[Synthesis of a new nitrosamine, N-1'-methylacetonyl-N-3-methylbutyl nitrosamine].
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Nitrosamines↗
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A novel pathway of nitrosamine metabolism in liver microsomes: denitrosation of nitrosamines by cytochrome P-450.
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Animals↗
Analysis of volatile N-nitrosamines in meat products using oxidation of N-nitrosamines to N-nitramines and electron-capture detection of N-nitramines.
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Amines↗
Salivary levels of N-nitrosamines and some metabolites after IP injection of N-nitrosamines in rats.
The carcinogens N-nitrosodimethylamine (DMN) and N-nitrosodiethylamine (DEN) were detected in rat saliva by gas liquid chromatography or HPLC after their ip injections. Salivary levels were equal to or greater than blood levels. A fairly linear dose response in salivary levels was observed in the range of 1-50 mg/kg. Salivary levels of DMN and DEN decreased between 0.5 and 1.0 hr after administration with the decrease becoming more prominent at lower doses. Formaldehyde and bicarbonate, metabolites of DMN, were also detected in rat saliva.
Animals↗
Effect of antibiotics on enterocystoplasty urinary nitrosamine levels.
OBJECTIVES: To evaluate the microbiologic characteristics of enterocystoplasty urine and assess the influence of bacteria type and effect of prophylactic and therapeutic antibiotic administration on the urinary nitrosamine levels of patients with enterocystoplasty. Nitrosamines have been implicated in the development of cancer in patients with an enterocystoplasty. Urinary tract infection (UTI) is associated with elevated nitrosamine levels. METHODS: Urine samples were collected to determine the urinary nitrosamine levels and for microscopy, culture, and sensitivity from 42 patients with an enterocystoplasty and 6 normal controls. A subgroup of 5 enterocystoplasty patients with proven UTI was also evaluated by measuring the urinary nitrosamine levels before and after a therapeutic course of antibiotics. RESULTS: Of the 42 cystoplasty patients, 22 had a proven UTI; none of the controls had one. Sixteen of the cystoplasty patients were taking prophylactic antibiotics and had mean N-nitrosamine levels equivalent to the control levels. The mean nitrosamine levels were highest in patients with a UTI (1.9 micromol/L). Escherichia coli was the most common infecting organism (11 patients) and resulted in the highest mean nitrosamine levels (2.1 micromol/L). The nitrosamine levels fell with UTI treatment to within the control range. CONCLUSIONS: UTI occurs in 51% of enterocystoplasty patients and is associated with elevated mean urinary nitrosamine levels. E. coli is the infecting organism in 50% of cases. Antibiotic prophylaxis reduces the nitrosamine levels to those of the controls. UTI treatment results in a rapid reduction of elevated nitrosamine levels to control levels.
Adolescent↗
Approaches to cancer prevention based on an understanding of N-nitrosamine carcinogenesis.
Understanding carcinogenesis is critical for development of rational approaches to cancer prevention. This paper uses N-nitrosamine carcinogenesis as an example. N-Nitrosamines are a large group of potent carcinogens. Approximately 300 different N-nitrosamines are carcinogenic. At least 30 animal species are responsive to their effects. There is little doubt that humans exposed to sufficient amounts of N-nitrosamines would also be susceptible to their carcinogenic effects. Human exposure to preformed N-nitrosamines occurs through the diet, in certain occupational settings, and through the use of tobacco products, cosmetics, pharmaceutical products, and agricultural chemicals. Diminishing human exposure to these carcinogens is one approach to prevention of cancer, and this has been accomplished in many instances, although exposure to N-nitrosamines in tobacco products is still unacceptably high. Human exposure to N-nitrosamines also occurs by nitrosation of amines in the body, via their acid or bacterial catalyzed reaction with nitrite, or by reaction with products of nitric oxide generated during inflammation or infection. A second approach toward prevention of N-nitrosamine carcinogenesis is inhibition of this endogenous N-nitrosamine formation. Substantial reductions have been achieved with ascorbic acid and other nitrite scavengers. N-Nitrosamines undergo a simple cytochrome P450-mediated metabolic activation step, which is critical for their carcinogenicity. The third approach involves the use of chemopreventive agents that block this step, or other steps in the carcinogenic process. A large number of potent chemopreventive agents against nitrosamine carcinogenesis have been identified. Chemoprevention of lung cancer induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is discussed as an example of this approach.
Animals↗
Toxicological evaluation of nitrosamines in condoms.
Volatile N-nitrosamines have been found in rubber products including gloves, balloons, toys, baby bottle teats, soothers, and condoms. N-Nitrosamines are potent carcinogens, and therefore, European legislation has limited the release of N-nitrosamines and N-nitrosatable compounds in teats and soothers to 0.01-0.1 mg/kg rubber, respectively. Previously, endogenous nitrosamine formation in the vagina has been suggested as a cause of cervical cancer. It was speculated that exogenous N-nitrosamines and N-nitrosatable compounds from condoms may also lead to genital cancer. Therefore, we reviewed the literature and calculated the risk for the induction of tumors by nitrosamines from condoms. In vitro Biaudet et al. (1997) found up to 88 ng nitrosatable compounds migrating from condoms to cervical mucous within 24 hrs. During sexual intercourse about 0.6 ng may migrate in the female genital mucous membranes because of the short contact to the condom, e.g. 10 min. Comparable amounts of nitrosamines may also migrate in the penile skin. Estimating 1500 contacts to condoms during lifetime (50 condoms/year for 30 years) this may result in the adsorption of up to 0.9 microgram nitrosamines in total. Animal studies in Syrian hamsters showed the induction of local and/or systemic tumors, in particular liver tumors, after topical application of nitrosamines to the skin or mucous membrane at a total dose of about 1 g. This dose exceeds the dose to be expected from contact with condoms by more than 1 million. Also, epidemiological studies do not support a role for condoms in the induction of cancer. The incidence of cervical cancer and liver tumors is high in developing countries, where condoms are seldom used. In addition, humans are regularly exposed to nitrosamines from food and tobacco smoke at a dose which is 1,000 to 10,000 fold higher than expected from condom use. In summary, the risk for the induction of tumors from nitrosamines in condoms is very low.
Animals↗
Factors causing variation in urinary N-nitrosamine levels in enterocystoplasties.
OBJECTIVE: To establish the presence or absence of any diurnal or long-term variation in N-nitrosamine levels (which might be important in the development of cancer in enterocystoplasties) in enterocystoplasty urine, and to assess other factors that might alter enterocystoplasty N-nitrosamine levels. Patients, subjects and methods Thirty-six patients with enterocystoplasties and six normal controls were assessed. Urine samples were collected every 4 h over a 24-h period and N-nitrosamine levels determined using a modification of the Pignatelli METHOD: An additional urine sample was assessed by microscopy, culture and sensitivity. In a subgroup of 16 patients with an enterocystoplasty, the urinary N-nitrosamine levels were re-measured at 3-monthly intervals. RESULTS: No diurnal or long-term variation in urinary N-nitrosamine levels was identified. The mean N-nitrosamine levels were significantly higher in the cystoplasty group than in the controls (1.7 vs 1.0 micromol/L; P = 0.008). Mean N-nitrosamine levels were also significantly higher in enterocystoplasty patients with sterile pyuria than in those with no pyuria (P = 0.01). Those taking prophylactic antibiotics had significantly lower mean N-nitrosamine levels than those not doing so (P = 0.05). Individuals with infected urine and those needing to intermittently catheterize had higher N-nitrosamine levels than their counterparts, but this difference was not significant. Conclusion There were no diurnal or long-term variations in urinary N-nitrosamine levels. Levels were consistently higher in patients with inflamed or infected cystoplasties, those using intermittent self-catheterization and those not taking antibiotic prophylaxis.
Adolescent↗
N-nitrosamines: bacterial mutagenesis and in vitro metabolism.
Many nitrosamines are potent mutagens. The rate-limiting step in their in vitro metabolism to mutagens is usually a single enzymatic reaction catalyzed by one or more of the many cytochrome P-450-dependent mixed-function oxidases present in the microsomal cell fraction. Current evidence indicates that this reaction activates nitrosamines to alpha-hydroxynitrosamines, which have half-lives on the order of seconds. This product decomposes to an aldehyde and a much shorter-lived ultimate metabolite which is probably an alkyl diazonium ion or an alkyl carbocation. This may react with DNA leading to premutagenic adducts. Such adducts represent a very small fraction of the ultimate mutagen, with the rest reacting with water to yield the corresponding alcohol. Evidence for this pathway includes (1) the observation of deuterium isotope effects in metabolism and mutagenesis, (2) products (aldehydes, alcohols, and N2) consistent with this pathway, (3) studies on metabolism of nitrosamines using purified cytochrome P-450, (4) formation of DNA adducts such as O6-alkylguanines which are consistent with those expected from the ultimate mutagen, (5) expected products and genotoxic effects of other sources of activated nitrosamines, e.g., alpha-acetoxynitrosamines, alkanediazotates and related compounds. Hydroxylation of nitrosamines at other positions also occurs in vitro (usually to a lesser extent), but these products are generally stable and must be further metabolized to exert mutagenic effects (with the exception of N-nitrosoalkyl(formylmethyl)amines, which are direct-acting mutagens). Because only low percentages of nitrosamines are metabolized in vitro, the contribution to mutagenesis by secondary metabolism is small. In this respect, in vitro metabolism can differ significantly from in vivo metabolism. Bacterial mutagenesis by nitrosamines has most often been studied in Salmonella typhimurium and to a lesser extent E. coli. Mutagenesis by nitrosamines generally requires a source of microsomes (a 9000 X g supernatant fraction is often used), and NADPH. Liver fractions from Aroclor-1254- or PB-induced rodents have been most frequently employed but liver fractions from untreated animals, and homogenates of other organs (lung, kidney, nasal mucosa, and pancreas) have also been utilized. Liver homogenates from humans are generally similar to those from untreated rats in metabolizing nitrosamines to mutagens but large interindividual variations are observed. Mutagenesis is often most effective using a liquid preincubation, a slightly acidic incubation mixture and hamster liver fractions.(ABSTRACT TRUNCATED AT 400 WORDS)
Alkylation↗
Estimation of volatile N-nitrosamines in rubber nipples for babies' bottles.
A method is described for the estimation of volatile N-nitrosamines in the rubber nipples of babies' bottles. In a study of rubber nipples from one manufacturer, N-nitrosodimethylamine, N-nitrosodiethylamine and N-nitrosopiperidine were determined by gas chromatography, using a thermal energy analyser, and their presence was confirmed by mass spectrometry with average levels of individual nitrosamines ranging from 22 to 281 ppb. When the nipples were sterilized in a conventional sterilizer together with milk or infant formula the three nitrosamines migrated into the milk or formula. Storing a bottle of milk with a rubber nipple inverted in it for 2 hr at room temperature or overnight in a refrigerator after sterilization resulted in an 8-13% average increase in the nitrosamine levels migrating into the milk. On repeated sterilization of a single nipple, the quantities of nitrosamines migrating into milk from rubber nipples declined steadily, but after seven sterilizations, nitrosamines were still readily detectable in the milk. Nitrosamine levels were higher in rubber nipples after sterilization, indicating the presence of nitrosamine precursors in the nipples. No nitrosamines were found in raw, uncured rubber. Chemical accelerators and stabilizers added during the vulcanization process are the source of the amine precursors in rubber nipples.
Bottle Feeding↗
Metabolic nitrite formation from N-nitrosamines: are there other pathways than reductive denitrosation by cytochrome P-450?
To demonstrate whether there are any pathways of nitrite formation from N-nitrosamines other than reductive denitrosation by cytochrome P-450 we performed the following experiments. An esterified alpha-hydroxylated nitrosamine was incubated in a microsomal system to test if nitrite generation is coupled with or linked to the oxidative bioactivation pathway. Simultaneously, inhibitors of microsomal esterases were added to test if the intact molecule or a metabolite from the oxidative metabolism was responsible for nitrite formation. To check if the superoxide radical anion could be related to the mechanism of nitrite generation, nitrosamines were incubated with a xanthine oxidase/hypoxanthine system. To test if the OH radical was involved in nitrite formation, nitrosamines were incubated with an artificial hydroxy-radical generating system (xanthine oxidase/hypoxanthine system supplemented with Fe2+/EDTA). Measurable amounts of nitrite were detected after incubation of the esterified-hydroxylated N-nitrosamine when the hydrolysis by microsomal esterases was inhibited by diisopropylfluorophosphate or paraoxon and when the N-nitrosamines were incubated with the artificial hydroxy-radical generating system. Nitrite formation could not be detected in the O2(-)-generating system (xanthine oxidase/hypoxanthine) or when the esterified alpha-hydroxylated N-nitrosamine was incubated without inhibition of the microsomal esterases. These results demonstrate that besides reductive denitrosation by cytochrome P-450, nitrite generation from N-nitrosamines can also be caused by hydroxy-radicals. The importance of this possible pathway for the in vivo situation of nitrosamine metabolism is discussed.
Animals↗
N-nitrosamines: environmental occurrence, in vivo formation and metabolism.
A number of amines and quaternary ammonium salts can be nitrosated to N-nitrosamines under environmental conditions as well as in vivo. Of the N-nitrosamines which have been bioassayed to date, more than 250 are proven animal carcinogens. In the absence of data which document that N-nitrosamines can be carcinogenic to man, we concur with the International Agency for Research on Cancer that those nitrosamines that were proven carcinogens in at least 2 animal species "should be regarded for practical purposes as if they were carcinogenic to humans" (1). Such evaluation pertains also to N-nitrosodiethanolamine (NDELA), N-nitrosomorpholine (NMOR) and the tobacco-specific N-nitrosamines (TSNA). This presentation discusses the environmental occurrence, analysis, reduction, bioassay data for carcinogenicity and metabolism of these 3 types of nitrosamines. The data at hand make it prudent to encourage reduction of the occurrence of N-nitrosamines in the workplace, in the environment and in food, tobacco and other personal use products. Emphasis should also be placed on research efforts to inhibit the in vivo formation of N-nitrosamines and their metabolic activation to reactive carcinogenic species. The latter efforts require increased knowledge as to the activation of nitrosamines and their reaction with cellular macromolecules including DNA.
Animals↗
Formation and occurrence of nitrosamines in food.
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.
Animals↗
Mutagenicity of N-alkyl-N-(alpha-acetoxyalkyl) nitrosamines in V79 Chinese hamster cells in relation to alkylating activity.
Mutation to ouabain resistance and cytotoxicity were tested in V79 Chinese hamster cells after the cells had been treated for 2.5 hr with a series of N,N-dialkylnitrosamines (alkyl=methyl, ethyl, propyl, butyl or tert-butyl) monosubstituted at the alpha-carbon with an acetoxy group. The effects of the length of alkyl chain and the mode of substitution with the acetoxy group on the cytotoxicity and mutagenicity were examined. In the series of N-alkyl-N-(acetoxy-methyl) nitrosamines with an acetoxy group at the primary alpha-carbon, the methylating compound N-methyl-N-(acetoxymethyl) nitrosamine was the most cytotoxic and mutagenic, and the biological activities decreased in the order of ethyl, butyl and propyl homologs. N-tert-Butyl-N-(acetoxymethyl) nitrosamine was not mutagenic at the concentration tested. At equitoxic concentrations, N-ethyl-N-(acetoxymethyl) nitrosamine was found to be the most mutagenic. Of the two N-alkyl-N-(alpha-acetoxybutyl) nitrosamines having an acetoxy group at the secondary alpha-carbon, N-methyl-N-(alpha-acetoxybutyl) nitrosamine was more cytotoxic and mutagenic than N-butyl-N-(alpha acetoxybutyl) nitrosamine. A comparison of the corresponding N-alkyl-N-(acetoxymethyl) nitrosamines and N-alkyl-N-(alpha-acetoxybutyl) nitrosamines showed that the latter had stronger activities. A plot of the mutation frequency versus the ability of the alpha-acetoxy compounds to alkylate 4-(p-nitrobenzyl) pyridine was linear. This indicates that the chemical reactivity of the compounds plays an important role in inducing mutation in V79 Chinese hamster cells.
Alkylating Agents↗
Assessment of exposure to carcinogenic N-nitrosamines in the rubber industry.
Exposures to volatile nitrosamines were measured at 24 rubber manufacturing plants from 1992 to 1995. A total of 709 exposure measurements were taken in general areas or personal breathing zones to estimate exposure according to production types (seals, joints, tyres, gloves, etc.) and production steps, from mixing to storage. Five different nitrosamines were identified. N-Nitrosodimethylamine is the most frequently encountered nitrosamine and represents the most important fraction of the total nitrosamine concentration measured in a given sample. This fact is consistent with the use of rubber additives containing corresponding amine precursors. One hundred and forty-one of the 709 values exceeded the German target value (TRK) of 2.5 micrograms/m3 for all nitrosamines present from rubber vulcanisation, the only available standard for occupational nitrosamine exposures. The salt bath curing process generates particularly high nitrosamine levels, 90% of the 96 measurements being over the TRK, with many values exceeding 20 micrograms/m3. The reasons why the TRK is exceeded are generally well identified. To reduce nitrosamine emission levels it would be advisable to eliminate nitrogen oxide sources, principally by using a process other than salt bath curing, and to develop different rubber stocks that do not contain secondary aliphatic amine functional groups ("safe amines").
Adult↗
Effects of UV repair, error-prone repair and critical site of mutation on mutagenesis induced by N-nitrosamines.
Many N-nitrosamines have been assayed for mutagenic activity in bacteria but few have been systematically compared in a series of strains. In this study through the use of several Salmonella tester strains, we have examined the effects of Uvr repair, error-prone repair, and the critical site for mutation (GC or AT base pair) on the mutagenic activities of a diverse group of N-nitrosamines. We have employed the histidine autotrophs, TA1975 (uvrB+), TA1535 (uvrB-) and TA100 (uvrB-/pKM101) which are hisG46 strains, sensitive mainly to G-C base damage, and TA104 (uvrB-/pKM101), a hisG428 strain, which can be reverted at the hisG428 locus by damage to A-T base-pairs, or by suppression at G-C base pairs. The N-nitrosamines studied were, N-nitroso: dimethylamine, diethylamine, dipropylamine, dibutylamine, pyrrolidine, piperidine, morpholine, methylbenzylamine, bis-(2-hydroxypropyl)amine, bis-(2-oxopropyl)amine and 3,4-dichloropyrrolidine. For all of the nitrosamines larger than diethylnitrosamine (except for methylbenzylnitrosamine) mutagenesis was greatly enhanced (3-20 X) by the lack of uvrB activity, indicating that the DNA adducts produced by these nitrosamines can be classified as "bulky adducts". For most nitrosamines the plasmid, pKM101, enhanced mutagenesis in hisG46 strains, several fold, suggesting that error-prone DNA repair plays a role in mutagenesis by these compounds. All of the compounds tested were more mutagenic in TA100 than TA104 except diethylnitrosamine and methylbenzylnitrosamine which were more potent in TA104. Revertants induced by all of the nitrosamines in TA100 were due predominantly to damage at G-C base pairs. Revertants induced by all the nitrosamines except diethylnitrosamine and dibutylnitrosamine resulted mainly from damage to G-C base pairs in TA104.
Base Sequence↗
Inhibition of repairable DNA-damage in Escherichia coli K-12 cells recovered from various organs of nitrosamine-treated mice by vitamin A, phenethylisothiocyanate, oleic acid and triolein.
The influence of various dietary constituents--phenethylisothiocyanate (PEITC), oleic acid (OA), triolein (TO), and vitamin A (ROL)--on the genotoxic activity of nitrosamines (NDMA, NDELA, NPYR) was investigated. For this purpose differential DNA repair assays with Escherichia coli K-12 strains were performed in vitro and in vivo with mice. Under in vitro conditions (liquid holding), all compounds reduced nitrosamine induced DNA-damage in the indicator bacteria in the dose range 1-10 micrograms/ml, the ranking order of efficiency being PEITC greater than OA greater than ROL greater than or equal to TO. In animal-mediated assays, acute oral treatment with PEITC (17-150 mg/kg), 2 h before nitrosamine administration, resulted in a marked decrease of nitrosamine genotoxicity in liver, kidneys, lungs and in the blood. Also in other organs (spleen, testes) an increase in differential survival (which serves as a measure for repairable DNA damage) occurred. With ROL only a comparatively moderate antigenotoxic effect was obtained at a high dose level (250 mg/kg) under identical experimental conditions. OA (2000 mg/kg) and TO (16,000 mg/kg) were completely inactive. Upon repeated treatment (consecutive oral administration of the putative antigenotoxins over 4 days, a final treatment 24 h before nitrosamine administration) PEITC (150 mg/kg/day), ROL (80 mg/kg/day) and OA (2000 mg/kg/day) had no influence on the genotoxic effects of the nitrosamines. Repeated treatment with TO (4000-16,000 mg/kg/day) resulted in a moderate dose-dependent reduction of NDMA-induced DNA-damage in the indicator bacteria, whereas in combination with NPYR only a marginal effect was observed. Biochemical experiments indicated that the antigenotoxic effects of PEITC seen under in vivo conditions were due to inhibition of alpha-hydroxylation of the nitrosamines, whereas ROL and TO appeared not to interfere strongly with this metabolic activation step. Our results indicate that in vitro assays do only partly reflect the antigenotoxic properties of the different food constituents in vivo and that animal-mediated DNA repair assays with E. coli strains are an appropriate approach to study the effects of modifiers of nitrosamine genotoxicity in the living animal.
Animals↗
Occupational nitrosamine exposure. 1. Rubber and tyre industry.
To determine the role of N-nitrosamines in the known increased cancer risk of rubber workers, air concentrations of such carcinogens were measured by area sampling or personal monitoring in 19 factories. N-Nitrosodimethylamine (NDMA) and N-nitrosomorpholine (NMOR) were found regularly, the air concentrations varying between 0.1 and 380 micrograms/m3 personal monitoring. The mean concentration was usually in the range of 1-10 micrograms/m3. Several other nitrosamines could be detected in certain production branches. In retail shops and storage rooms of tyres NDMA and NMOR were found. Most rubber chemicals based on amines are contaminated with N-nitrosamines, but this contamination cannot explain the air concentrations of nitrosamines found. The occurrence of nitrosamines mainly depends upon their formation during production of rubber and rubber products from used vulcanisation accelerators based on amines and the presence of nitrosating agents, such as diphenylnitrosamine (retarder A) and of nitrous gases, in products or production areas. Elimination of one or both precursors for nitrosamine formation resulted in significant reduction of airial contamination of nitrosamines. The results are discussed in regard to the mechanisms of nitrosamine formation during rubber production, as basis for future epidemiological studies and their potential for exposure prevention.
Air Pollutants↗