Nitrosodimethylamine Research Articles

Dosimetry of O6-methylguanine in rat DNA after low-dose, chronic exposure to N-nitrosodimethylamine (NDMA). Implications for the mechanism of NDMA hepatocarcinogenesis.

Groups of female Wistar Furth/NCr rats, aged 6 weeks or 7 months at the start of the experiment, were administered drinking water containing N-nitrosodimethylamine (NDMA) for up to 28 days at concentrations in the range 0.2-2.64 p.p.m., resulting in daily intakes in the range 28-372 micrograms/kg/day at age 10 weeks. The levels of the premutagenic DNA adduct O6-methylguanine (O6-meG) in liver and blood leukocyte DNA were measured at different times during this exposure as well as on the days immediately following cessation of exposure. The adduct was found to accumulate rapidly in both tissues, reaching within 2-7 days steady states in the range 0.08-0.45 mumol/molG, similar in young and adult animals. Accumulation of O6-meG in blood leukocytes was approximately 30% lower than in the liver. Following cessation of NDMA treatment, adducts were lost rapidly from the DNA of both tissues, with an apparent t1/2 of approximately 19-23 h for the liver and 30-35 h for blood leukocytes. No change in liver O6-alkylguanine-DNA alkyltransferase (AGT) took place throughout this treatment. The steady-state adduct levels were approximately linearly related to NDMA dose-rate, except that a clear break (corresponding to a 2.6-fold lower slope) was observed at dose rates > 0.4 p.p.m. (approximately 56 micrograms/kg/day). This dose-response relationship is in contrast to the sharp increase in the liver tumour induction in rats chronically treated with similar concentrations of NDMA reported by Peto et al. (Cancer Res., 51, 6415-6451) and suggests that accumulation of O6-meG cannot by itself account for the hepatocarcinogenic efficacy of NDMA in the rat. Following i.g. administration of single doses of NDMA in a range approximately corresponding to the daily intake during the above mentioned chronic exposure study (25, 50 or 100 micrograms/kg), repair of O6-meG followed sharply biphasic kinetics in both liver and blood leukocytes. In the liver, an initial rapid phase (t1/2 approximately 1.5-1.7 h) was followed by much slower repair (t1/2 approximately 20.7-24.9 h) despite the absence of any change in AGT. Extrapolation of the two segments of the repair kinetics plots back to 0 time suggests that approximately 52-61% of the adducts originally formed in the liver and 33-35% of those formed in blood leukocytes belonged to the rapidly repaired category.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of Ceramics Radiation on Nitrosodimethylamine Production

The effects of ceramics radiation on nitrosation of dimethylamine with nitrite in citrate buffer of pH 3.4 was studied using a ceramics plate and a ceramics heater. The rate constant of nitrosodimethylamine (NDMA) production under the irradiation conditions decreased by 81% from the non-irradiated reaction, and that of nitrite degradation increased 1.5-fold. The activation energy for NDMA production and nitrite degradation after 4 h of irradiation decreased by 53 and 73% of the non-irradiated reactions, respectively. It was estimated that the hydration effects of the ceramics radiation were concerned in the repression of NDMA production and the acceleration of nitrite degradation.

Examination of alpha-carbonyl derivatives of nitrosodimethylamine and ethylnitrosomethylamine as putative proximate carcinogens.

Metabolites produced by enzymic oxidation are believed to be responsible for the mutagenicity and carcinogenicity of N-nitrosamines. Although alpha-hydroxy compounds are often considered, a related and more stable oxidation product, the alpha-carbonyl compound, was studied here. The alpha-carbonyl derivatives of nitrosodimethylamine (NDMA) and ethylnitrosomethylamine (oxidized at either the methyl or the ethyl group) were synthesized. The derivatives were methylnitrosoformamide (MNFA), ethylnitrosoformamide (ENFA) and methylnitrosoacetamide (MNAA). These compounds were then studied as potential toxic, mutagenic and carcinogenic intermediates. All three compounds were very potent directly acting mutagens to Salmonella typhimurium TA1535. Mutational Fingerprints in Escherichia coli of MNFA and ENFA (but not MNAA) matched those produced by SN1-type methylating and ethylating compounds respectively. The latter results indicate that the two alkylnitrosoformamides could be intermediates in the mutagenicity of the parent nitrosamines. In animal studies the putative metabolite MNFA was more acutely toxic than NDMA in F344 rats. In chronic experiments with MNFA in F344 rats and Syrian golden hamsters, tumors of the forestomach were induced by oral administration in most animals (except female hamsters) within 8 months. The properties of these oxidized derivatives of N-nitrosamines are consistent with expectations for proximate carcinogenic intermediates.

Studies on etiological factors of nasopharyngeal carcinoma.

A case-control study of nasopharyngeal carcinoma (NPC) was performed in Guangzhou, southern China in 1987 to 1989. We investigated 205 cases and an equal number of matched controls. Epstein-Barr virus (EBV) infection with positive IgA against viral capsid antigen (VCA-IgA) was shown to be the most important predictor in NPC. Consumption of salted fish was also strongly associated with NPC but not to the same extent as EBV. In order to investigate the possible carcinogenic effect of salted fish, Sprague-Dawley rats were given a diet containing salted fish for 2 years. Three rats with nasal and 3 with nasopharyngeal tumors were found in the experimental groups of 122 rats but none in the control group. Nitrosodimethylamine (NDMA) was found in kidney and liver but not in urine in the rats fed with salted fish. In a non-tumorigenic human keratinocyte line, RHEK-1, transfection of EBV latent membrane protein (EBV-LMP, originated from NPC cell line) induced alterations of morphology and immunophenotype. The LMP expressing sublines showed higher proliferative capacity and lower differentiation in vitro and some of the sublines produced tumors in SCID mice. When cultured in media containing salted fish extract in vitro parental RHEK-1 cells died after 12 weeks. In contrast, LMP expressing sublines survived indicating that exposure to some chemical compounds in salted fish and expression of EBV-gene may be of importance for the transformation of epithelial cells and thus for the pathogenesis of NPC.

BENZODIAZEPINE METABOLISM IN ETHANOL-TREATED MALE RATS: USE OF PAIR-FED AND AGE-MATCHED CONTROLS

The effects of chronic moderate (15%) ethanol consumption and ageing on rat hepatic cytochrome P450 monooxygenase activities were examined using diazepam, nordazepam, d-benzphetamine, erythromycin, ethylmorphine and nitrosodimethylamine (NDMA) as substrates. In addition, the effects of moderate ethanol alone on the oxidation of metoprolol, morphine and temazepam were examined. Cytochrome P450 specific content increased significantly only in the 6-week ethanol-treated rats, and no changes in percentage liver to body weights were apparent in any of the ethanol-treated animals compared with pair-fed controls. Only cytochrome P450IIIA enzyme activities displayed age-related decreases, these being identified in the pair-fed animals. C3-hydroxylation of diazepam and nordazepam (36% of controls) and N-demethylation of erythromycin and ethylmorphine (58% and 64% of controls) were decreased in 6-week ethanol-treated animals, these effects being less pronounced in the 12, 24 and 48-week ethanol-treated groups. The decrease seen for diazepam and d-benzphetamine N-demethylation caused by ethanol consumption was approximately 80% of control groups for the duration of the treatment. NDMA and morphine N-demethylations were increased to 120% of control activities and metoprolol alpha-hydroxylase was increased to 140% of control activities at 6 weeks, whilst metoprolol O-demethylase activity remained unaltered. NDMA N-demethylase activity showed a two-fold induction at 24 and 48 weeks of ethanol treatment, compared with corresponding pair-fed control groups. These results support previous findings from this laboratory showing that the same or similar P450IIIA family isozymes are involved in the C3-hydroxylation of diazepam and nordazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

実験動物用市販固形飼料中のニトロソジメチルアミン

To know the conditions of contamination by the chemicals in the experimental animal diets, the contents of nitrosodimethylamine (NDMA) were analyzed in the diets for mice and rats. The raw materials of the diets were also analyzed. In addition, NDMA levels were determined in the diets which were stored long or heated in the autoclaves. The averages of NDMA in these diets were less than 10 ppb. In the raw materials, alfalfa contained a higher levels of NDMA. There was no clear tendency of increase or decrease in NDMA levels, when the diets were stored for six months at room temperature (23-25 degrees C) or at low temperature (7-10 degrees C). Heating the diets at 121 degrees C, no remarkable changes were observed in NDMA levels. It seems that little adverse influences on the conduct of the animal experiments would be anticipated by the NDMA in the commercial diets.

Role of ras protooncogene activation in the formation of spontaneous and nitrosamine-induced lung tumors in the resistant C3H mouse

The role of ras activation in the formation of spontaneous and chemically induced tumors was evaluated in the C3H mouse, a strain that has a low incidence of spontaneous lung tumors. Lung tumors were induced in C3H mice by treatment with 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 50 mg/kg, or nitrosodimethylamine (NDMA), 3 mg/kg for 7 weeks (3 times/week, i.p.). Eleven tumors from each treatment group were evaluated for activated ras genes by direct sequencing and oligonucleotide hybridization to slot blots of amplified DNA from these tumors. An activated K-ras gene was detected in 100% of NDMA- and NNK-induced lung tumors, and the activating mutation detected in all samples was a GC to AT transition (GGT to GAT) in codon 12. In contrast, only 40% of the seven spontaneous lung tumors analyzed contained an activated K-ras gene and the mutations identified were not localized to either a specific base or codon. Both NNK and NDMA can be activated via alpha-hydroxylation to methylating agents. The GC to AT mutation observed in codon 12 in the nitrosamine-induced tumors is consistent with the formation of an O6-methylguanine (O6MG) adduct. Similar concentrations (13-15 pmoles/mumol deoxyguanosine) of this promutagenic adduct were detected in lungs during treatment with either NNK or NDMA. Thus, both these nitrosamines appear to activate the K-ras gene in lung through a direct genotoxic mechanism involving the formation of the O6MG adduct. The frequency of K-ras activation was similar in chemically induced lung tumors from the sensitive A/J strain and the C3H mouse, indicating that susceptibility for neoplasia in these stains is not related to the ability to activate this gene. Although tumors were induced in lung from 100% of C3H mice following chronic carcinogen exposure, both the size and the multiplicity was significantly less, while latency was longer than that observed in the A/J mouse. These differences could not be attributed to an altered propensity for DNA damage, but rather suggest that genetic loci which regulate clonal expansion and growth of initiated cells play a major role in the susceptibility of pulmonary neoplasia.

Role of DNA methylation in the activation of proto-oncogenes and the induction of pulmonary neoplasia by nitrosamines

The relationships between DNA methylation and repair induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to the activation of proto-oncogenes and the induction of pulmonary neoplasia by this carcinogen is described. The formation of the O 6-methylguanine (O 6MG) adduct following metabolic activation of NNK appears to be a major factor in the induction of lung tumors in both rats and mice and in the activation of the K- ras oncogene in lung tumors from A/J mouse. The potent carcinogenicity of NNK in the rat lung correlated strongly with cell specificity for formation and persistence of the O 6MG adduct in the Clara cells. This conclusion was supported by studies with nitrosodimethylamine (NDMA), a weak carcinogen in the rodent lung. Treatment with NDMA was not associated with any pulmonary cell specificity for DNA methylation. The high affinity for activation of NNK compared to NDMA was ascribed to a difference in cytochrome P-450 isozymes involved in the activation of these two nitrosamines. In the A/J mouse, the induction of pulmonary tumorigenesis involved direct genotoxic activation of the K- ras proto-oncogene as a result of the base mispairing produced by formation of the O 6MG adduct. In contrast, the induction of pulmonary tumors in the rat by NNK does not appear to involve the ras pathway. It is apparent that different molecular mechanisms are involved in the development of pulmonary tumors by NNK in the mouse and rat. The studies described in this paper illustrate the utility of performing dose-response experiments and the quantitation of DNA methylation and repair in not only target tissues but also target cell types. The fundamental knowledge gained from unraveling the mechanism of carcinogenesis by NNK could lead ultimately to the identification of factors important in the development of human lung cancer.

Relationship between the formation of promutagenic adducts and the activation of the K-ras protooncogene in lung tumors from A/J mice treated with nitrosamines : Belinsky SA, Devereux TR, Maronpot RR, Stoner GD, Anderson MW. Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709. Cancer Res 1989;49:5305-11

Lung and liver tumors were induced in female A/J mice after treatment for 7 weeks (3 times/week, i.p.) with either 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (50 mg/kg) or nitrosodimethylamine (NDMA) (3 mg/kg). Both compounds can be activated via alpha-hydroxylation to methylating agents, while NNK may also undergo hydroxylation at the N-methyl carbon to form a pyridyloxobutylated adduct. The purpose of these studies was to identify and characterize the activated oncogenes present in tumors induced by NDMA and NNK. Following transfection of high molecular weight DNA onto NIH/3T3 mouse fibroblasts, transforming genes were detected in 90% of both NNK- (10 of 11) and NDMA- (9 of 10) induced lung tumors. In contrast, transformation of NIH/3T3 fibroblasts was observed only in 40% (2 of 5) and 13% (1 of 8) of the liver tumors from NNK- and NDMA-treated mice, respectively. Southern blot analysis indicated that the transforming gene present in all lung tumors was an activated K-ras oncogene. Both rearranged bands and amplified signals were detected in the transfectants. The one transformant from the NDMA-induced liver tumor contained an activated K-ras gene. In contrast, the two liver transformants from NNK-induced tumors did not contain an activated ras or raf gene. Hybridization with oligonucleotide probes that were centered around either codon 12 or 61 of the K-ras gene were utilized to localize the mutations. Activation of this gene appeared to occur largely via a mutation in codon 12 (15 of 20 transformants) and was observed with a similar frequency in pulmonary tumors induced by either compound. The remaining mutations were found in codon 61. The specific mutation within these two codons was determined by amplifying the exon containing the base change, followed by direct sequencing. With one exception the mutation observed in codon 12 was a GC to AT transition (GGT to GAT). One transformant contained a GC to TA transversion. The activating mutation detected in codon 61 was always an AT to GC transition of the middle A (CAA to CGA). The GC to AT mutation observed in codon 12 is consistent with the formation of the O6-methylguanine adduct. Similar concentrations (23 to 32 pmol/mumol deoxyguanosine) of this promutagenic adduct were detected in lungs during treatment with either NNK or NDMA.(ABSTRACT TRUNCATED AT 400 WORDS)

Tissue specific regulation of renal n-nitrosodimethylamine-demethylase activity by testosterone in BALB/c mice

Nitrosodimethylamine (NDMA), like several other nitrosamines, is activated by the enzymes—mixed-function oxidases—present in the tissue microsomal fractions, producing mutagenic and carcinogenic effects. Previous studies in BALB/c mice have shown an age, sex and androgenic regulation of NDMA-induced mutagenicity. The present study was designed to test the correlation between renal NDMA-demethylase activity and previously published reports on NDMA-induced mutagenicity. Renal and hepatic NDMA-demethylases were determined from the microsomal fractions by quantitating formaldehyde. Renal NDMA-demethylase showed the presence of two isozymes, I and II, with K m values of 0.6 ± 0.2 and 20.2 ± 6.8 mM respectively. Isozyme I was detected in adult males and first appeared at the onset of puberty; it was absent in adult females and in immature mice. Renal isozyme II was detected in both males and females and was independent of age. Testosterone treatment of adult females resulted in the appearance of renal isozyme I. Castration of adult males caused a dramatic decrease in activity, whereas testesterone administration to such castrates increased activity, of renal isozyme I. Hepatic NDMA-demethylase activities were independent of age, sex or testosterone treatment. In conclusion, these results show an age, sex and tissue specific regulation of renal NDMA activity. Renal and hepatic NDMA-demethylase activities correlated positively with earlier studies on NDMA-induced mutagenesis and carcinogenesis.

Mono-, di- and trimethylamine in human gastric fluid: potential substrates for nitrosodimethylamine formation.

Nitrosodimethylamine (NDMA) is a potent carcinogen in a wide variety of animal species. In experimental animals, dimethylamine and nitrite, precursors of NDMA, are found in gastric fluid where the acidic conditions are suitable for formation of nitrosamines. In this study we measured the concentrations of mono-, di- and trimethylamine (MMA, DMA and TMA) in gastric fluid from humans, rats, dogs and ferrets, as well as in saliva, blood and urine from humans. Human gastric fluid contained 3.7 +/- 0.4 (SEM) nmol/ml MMA, 12.6 +/- 1.4 nmol/ml DMA and 2.0 +/- 0.4 nmol/ml TMA. MMA, DMA and TMA concentrations in human gastric fluid were similar to those present in human saliva and blood, but were much lower than those present in human urine. The concentrations of these amines in human gastric fluid were lower than those measured in gastric fluid from experimental animals. When we added sodium nitrite to human gastric fluid, NDMA was formed. We have shown that DMA is normally present in human gastric fluid, and that it can be nitrosated to form NDMA.

Rapid oxidative stress induced by [formula omitted]-nitrosamines

We have investigated the generation of prooxidant state shortly after administration of N -nitrosamines (NA) to rats. N -Nitrosodimethylamine (NDMA) was found to increase ethane exhalation (EE) rapidly in a dose-related manner. EE remained elevated for several days after single doses of NDMA. Similarly, lipid peroxidation (LP) in the liver (measured by four methods) increased rapidly showing a peak 20 min after NDMA dose. The increase of LP was preceded by a decrease in retinol concentration in the liver. N -Nitrosodiethanolamine, too, increased EE and LP in the liver, whereas N -nitrosomethylbenzylamine had no effect. Thus, hepatocarcinogenic NA induced LP in their target tissue, and the LP enhancing effects of NA were not related to their acute toxic effects.

Determination of volatile nitrosamines in cheese and cured meat products. Model study of a temperature- and pH-dependent artefact formation phenomenon in alkaline medium.

The present paper describes how the formation of artefactual nitrosodimethylamine (NDMA) may jeopardize attempts at determining volatile nitrosamines in cheese by the mineral oil technique (MOT) or the glycerol isolation technique (GIT). When such isolation techniques were performed at an initial pH of about 11 and a final temperature of 100 degrees C (compared to 70 degrees C), up to about 10 micrograms NDMA per kg was formed. In a meat product, which was examined for comparison, even more extensive artefact formation (up to 70 micrograms NDMA per kg) was found. The addition of 10 mg/kg morpholine, as a readily nitrosatable substrate, to this meat product resulted (under the most unfavourable conditions) in formation of 250 micrograms/kg artefactual nitrosomorpholine. Alkalization of samples before nitrosamine analysis is a widely practised method to prevent artefact formation and has been emphatically recommended by an international working group, convened by the International Agency for Research on Cancer (Lyon). The mechanism of this peculiar artefact formation, which is strongly temperature- and pH-dependent, is not as yet known. It may however involve transnitrosation by C-, S- or O-nitroso compounds, e.g. nitrosophenols, nitrosothiols, alkyl nitrites, sugar nitrite esters, or lipid-nitrite reaction products. Several parameters of initial pH, final temperature and use of inhibitors under which the phenomenon will or will not occur are discussed. The artefact formation described here occurs mostly at pH values which are common to laboratory situations, but which are rare as for as the preparation of food in the household is concerned. Therefore, the effect does not appear to imply a risk to the consumer's health.

魚粉における揮発性ニトロサミンの存在および生成 ＩＩ 魚粉の製造条件と揮発性ニトロサミンの生成

Factors affecting the formation of volatile N-nitrosamines (VNA) in the preparation process of fish meals were examined. In the present sutdy, we prepared sardine meals in our laboratory, and test meal samples were exposed to gaseous NO2 in sealed flasks under different conditions. Results obtained are summarized as follows: 1. The amounts of VNA formed were found to be directly proportional to the NO2 con-centrations; in contrast, VNA levels were remarkably lowered by the increment of moisture con-tents ln the meal samples. Formation of nitrosodimethylamine (NDMA), nitrosopyrrolidine (NPYR) and nitrosothiazolidine (NTHZ) in the NO2-trcated samples increased upon raising the reaction temperature in a range from 80 to 140°C. However, when samples were heated at 150°C or above, the formation of NTHZ and NPYR lowered, particularly marked decrease was noted in NTHZ contents, whereas the amount of NDMA increased almost consistently 2. The VNA formation in NO2-treated samples were much influenced by the freshness or storage period of raw fish materials, viz., meals made from decomposed materials yielded fairly low levels of both NDMA and NTHZ, while NPYR contents increased. The amounts of NDMA and NPYR formed in the NO2-treated samples were proportional to the levels of trimethylam-inoxide and proline in the test meals, indicating that these compounds would be the principal precursors of respective VNA. 3. The VNA levels in the NO2-treated samples were found to decrease gradually during storage at 30°, 10°and even-10°C, and the higher the storage temperature, the decreasing rate was observed to be faster.

THE CHEMISTRY OF NITROSAMINE FORMATION: RELEVANCE TO MALTING AND BREWING

This paper reviews the chemistry of nitrosamine formation with special reference to malting and brewing. Whilst the main emphasis is on the formation of nitrosodimethylamine (NDMA), the chemistry is also related to the formation of other nitrosamines and certain other nitrocompounds. It seems likely that in malting and brewing the only important source of the nitroso group is the mixture of oxides of nitrogen (NOx) in the hot air in contact with malt during kilning. Under normal commercial conditions there appears to be little if any formation of nitrosamines at other stages of malting or brewing. It is suggested that much of the nitrosation is due to NOx which exists temporarily in the form of nitrogen trioxide (N2O3) and nitrogen tetroxide (N2O4) as it dissolves in water in the moist malt or in malt lipids. The dissolved NOx subsequently reaches equilibrium with nitrite and nitrate ions formed from it. The origin of the dimethylamine portion of the NDMA is still not clear. The most likely sources are free DMA, gramine and hordenine, all of which are produced in germinating barley. On balance it seems that hordenine is the most important source of NDMA in the malt at the end of kilning. The reasons for the low yield of nitrosamines from the precursors and NOx present during kilning are discussed and related to the formation of other nitroso- and nitro-compounds. The occurrence of competing reactions which reduce nitrosamine formation is also described.

Formation of O6-methylguanine in rat liver DNA by nitrosamines does not predict initiation of preneoplastic foci.

Nitrosodimethylamine (NDMA) at 26 mumol/kg, and nitrosomethylbenzylamine (NMBzA) at 33.5 mumol/kg were equally potent in producing 7-methylguanine and O6-methylguanine in rat liver DNA. These doses were used to compare the abilities of the two nitrosamines to initiate production of putative preneoplastic foci in rat liver. Whereas NMBzA resulted in no increase above the background level of foci (0.9 +/- 0.1 foci/cm2), NDMA produced 7.5 +/- 0.6 foci/cm2. Co-administration of NDMA and NMBzA produced no more foci than NDMA alone, even though the combined effect of the two nitrosamines on DNA methylation was additive. The results suggest that methylation of hepatic DNA by nitrosamines does not predict initiation of preneoplastic foci.

Potentiation of the hepatotoxicity of N-nitrosodimethylamine by fasting, diabetes, acetone, and isopropanol

Previous studies indicate that pretreatment with acetone or isopropanol, fasting, and streptozotocin-induced diabetes enhance hepatic microsomal nitrosodimethylamine (NDMA) demethylase in rats. This study demonstrates that these same treatments also potentiate the hepatotoxicity of NDMA as indicated by plasma glutamic pyruvate transaminase (GPT) levels and histologic data. Pretreatment with acetone or isopropanol (2.5 ml/kg) and 2 days of fasting caused a 2-fold potentiation of NDMA-induced plasma GPT elevation, whereas streptozotocin-induced diabetes caused a 4.6-fold potentiation. The centrilobular necrosis produced by NDMA was more severe after pretreatment with the inducers. NDMA treatment also decreased hepatic microsomal demethylase activity. These results lend support to the concept that a NDMA demethylase is responsible for the activation of NDMA in vivo to a toxic intermediate, and induction of this enzyme activity potentiates NDMA hepatotoxicity.

Carcinogenesis in rats by nitrosodimethylamine and other nitrosomethylalkylamines at low doses

Four nitrosomethylalkylamines were given to F344 rats in drinking water at concentrations of 0.22 mM or less. The total doses delivered to each animal were 0.5 and 0.2 mmol of nitrosodimethylamine (NDMA), 0.6 mmol of nitrosomethyl-2-oxopropylamine (NMOP) and nitrosomethyl-2-hydroxy-propylamine (NMHP) and 0.9 mmol of nitrosomethyl-2,3-dihydroxypropylamine (NMDHP). NDMA induced liver neoplasms in most of the animals, including 35% with hemangiosarcomas as well as hepatocellular tumors at the higher dose, but only hepatocellular tumors at the lower dose and the latter group of rats survived longer. NMOP induced a high incidence of esophageal tumors and NMHP induced a high incidence of both esophageal and nasal cavity tumors. NMDHP was the least potent of the 4 carcinogens, and induced lung tumors, neoplastic nodules in the liver, a few esophageal tumors and a few nasal cavity tumors, but after a long induction time.

Kinetics of oxidation of methylhydrazines in water. Factors controlling the formation of 1,1-dimethylnitrosamine

The kinetics of oxidation of methylhydrazine (MMH) and 1,1-dimethylhydrazine (UDMH) by dissolved oxygen in water has been measured at various acidities as a function of catalyst (cupric ion) concentration. In dilute solutions the oxidation occurs through a cupric ion catalyzed process as well as by an uncatalyzed step. The extent of formation of nitrosodimethylamine (NDMA) depends upon the initial UDMH concentration. In dilute solutions NDMA is not formed, but in more concentrated solutions, NDMA formation increases with increasing UDMH content, reaches a maximum at 60–80% UDMH (by volume) and then decreases. The NDMA yield appears to approximately parallel the viscosity of the medium, and it is speculated that the factors which control viscosity may also be responsible for governing NDMA formation.

Nitrosamine metabolism in kwashiorkor rats

The in vitro metabolism of nitrosodimethylamine (NDMA) was studied in liver tissue obtained from male weanling kwashiorkor wistar rats. The elimination of this compound and that of nitrosomorpholine (NMOR) from the blood, after a single intravenous dose, was also investigated. N-demethylase activity in liver microsomes of the test animals was not significantly different from that of the controls although the activity of this enzyme per gram wet liver tissue was considerably reduced in the model animals. On the other hand, the glutathione (GSH) content in liver cytosol of the kwashiorkor animals was much higher than that of the controls. The elimination of NDMA and NMOR from the blood of the experimental animals over 8 hr following i.v. administration of the carcinogens, showed that the clearance rate of each nitrosamine was significantly lower in the kwashiorkor rats.