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PubMed1984

Monitoring endogenous nitrosamine formation in man.

Results from animal experiments and studies in human subjects indicated that the amount of nitrosoproline (NPRO) excreted in the 24-h urine, following ingestion of precursors, is an index for the rate of endogenous nitrosation; this method was found to be sensitive, reproducible and could be satisfactorily applied to human subjects in clinical and field studies. N-Nitrosothiazolidine 4-carboxylic acid (NTCA) and its 2-methyl derivative (NMTCA) were also identified in the urine of human subjects. As the respective amino precursors (thiazolidine 4-carboxylic acids) can be formed by reaction of formaldehyde or acetaldehyde with cysteine, measurement of NTCA and NMTCA in urine may provide a further index for endogenous nitrosation in the human body and may also allow monitoring of exposure of human subjects to aldehydes, nitrate and nitrite. The yield of nitroso compounds formed endogenously in the human body was shown to be linked to the intake of precursors, but several inhibitors and catalysts, either as pure substances or occurring in complex mixtures, were shown to modify the nitrosation reaction in vivo. In particular, ingestion of ascorbic acid after nitrate-rich meals was efficient in lowering human exposure to endogenously formed N-nitroso compounds. A dose-response relationship was established for the formation of NPRO in rats in vivo, after concurrent administration of various concentrations of the precursors, L-proline and sodium nitrite. The logarithm of the amount of NPRO formed was found to be proportional to the logarithm of the product of the proline dose and the square of the nitrite dose. On the basis of these results, a kinetic model was formulated allowing the estimation of the daily precursor dose quantity, ([amine][nitrite]2), required to give 50% tumour incidence in rats after two years of feeding. The potential application of this model, for the estimation of carcinogenic risk from endogenously formed N-nitrosamines in humans, is discussed. Our results demonstrate unequivocally the endogenous formation of N-nitroso compounds in the human body, the significance of which in human carcinogenesis remains to be established.

Animals↗
PubMed1990

Spin trapping of inorganic radicals.

The use of nitrose compounds and nitrones as spin traps for the detection of short-lived inorganic radicals is discussed. To a certain degree nitrones and nitroso compounds are complementary. While nitroso compounds are superior with respect to spin trapping metal-centred radicals, nitrones form more persistent spin adducts with most small inorganic radicals. Erroneous results may be obtained when hydrolysis and redox reactions involving the spin adducts are ignored. Spin trapping of pseudohalide radicals (.N3, .CN, .SCN) are discussed in more detail.

Chemical Phenomena↗
PubMed1986

Evaluation of the nitrosamine hypothesis of gastric carcinogenesis in precancerous conditions.

A 24 hour gastric aspiration study was carried out on nine Polya gastrectomy, eight pernicious anaemia, and nine matched control subjects. Intragastric pH, bacteria, nitrite, and N-nitroso compounds were assessed half hourly whilst ambulant and hourly when in bed. Both total and nitrate reducing bacterial counts were positively related to pH (chi 2 = 279.3; p less than 0.001), as was nitrite concentration (F = 19.1; p less than 0.0001). By contrast, total (F = 40.6; p less than 0.0001) and stable (F = 257.4; p less than 0.0001) N-nitroso compound concentrations were negatively related to pH. Clear differences in these gastric juice factors were not apparent between matched control and either pernicious anaemia, or Polya gastrectomy because the Polya gastrectomy and matched control groups were heterogeneous for gastric acidity. Thus, although eight of eight pernicious anaemia subjects were hypoacidic (defined as intragastric pH greater than 4 for greater than 50% of both daytime and night time periods), only five of nine Polya gastrectomy and two of nine matched control subjects were hypoacidic. When subjects were rearranged into hypoacidic (n = 15) and acidic (n = 11) groups, bacterial counts (p less than 0.01) and nitrite concentrations (p less than 0.01) were higher, whereas N-nitroso compounds tended to be lower (NS) in the hypoacidic group. These data suggest that, although hypoacidity predisposes to bacterial overgrowth and nitrite generation, it does not enhance nitrosation. Instead, this is maximal at low pH, suggesting chemical rather than bacterial nitrosation, contrary to the nitrosamine hypothesis of gastric carcinogenesis.

Aged↗
PubMed1983

Cytochrome P-455 nm complex formation in the metabolism of phenylalkylamines. VII. Enzyme interactions with synthetic 2-nitroso-1-phenylalkanes.

Cytochrome P-455 nm complex formation in rat liver microsomes was investigated with 2-nitroso-1-phenylpropane, the nitroso compound related to amphetamine, and six homologues comprising different alpha-alkyl substituents. The C-nitroso compounds were synthesized and obtained as trans nitroso dimers, the only form in which they are available in pure solid state. Their physical and chemical properties were investigated and their decomposition in ethanol solutions was correlated with the complexing efficacies of these solutions. Dissociation of the nitroso dimers to monomers constitutes an equilibrium which is displaced in favour of the dimer but with the monomers ultimately undergoing tautomerization to oximes. Based on these kinetics a mathematical model was produced, which by computer simulations gave simultaneously the dimer (Mo2), monomer (Mo) and oxime (Ox) concentrations of the substrate solutions used in the complex formation studies. The results show that the formation of cytochrome P-455 nm complexes is directly related to the numerically predicted concentrations of the nitroso monomers, but is very slow or absent when the dimer or oxime concentrations are at their highest. Substrate solutions derived from nitroso dimers with larger alpha-alkyl substituents (3-4 carbons) were devoid of complexing activities because of low solubility and very slow chemical kinetics.

Animals↗
PubMed1985

In vivo formation and persistence of modified nucleosides resulting from alkylating agents.

Alkylating agents are ubiquitous in the human environment and are continuously synthesized in vivo. Although many classes exist, interest has been focused on the N-nitroso compounds, since many are mutagens for bacteria, phage, and cells, and carcinogens for mammals. In contrast to aromatic amines and polyaromatic hydrocarbons which can react at carbons, simple alkylating agents react with nitrogens and oxygens: 13 sites are possible, including the internucleotide phosphodiester. However, only the N-nitroso compounds react extensively with oxygens. In vivo, most possible derivatives have been found after administration of methyl and ethyl nitroso compounds. The ethylating agents are more reactive toward oxygens than are the methylating agents and are more carcinogenic in terms of total alkylation. This is true regardless of whether or not the compounds require metabolic activation. It has been hypothesized that the level and persistence of specific derivatives in a "target" cell correlates with oncogenesis. However, no single derivative can be solely responsible for this complex process, since correlations cannot be made for even a single carcinogen acting on various species or cell types. Some derivatives are chemically unstable, and the glycosyl bond is broken (3- and 7-alkylpurines), leaving apurinic sites which may be mutagenic. These, as well as most adducts, are recognized by different enzymatic activities which remove/repair at various rates and efficiencies depending on the number of alkyl derivatives, as well as enzyme content in the cell and recognition of the enzyme. Evaluation of human exposure requires early and sensitive methods to detect the initial damage and the extent of repair of each of the many promutagenic adducts.

Alkylating Agents↗
PubMed1987

N-nitrosamine formation in urinary-tract infections.

Urine samples from 31 patients with urinary-tract infections and from 31 controls were analysed for volatile nitrosamines, N-nitrosamino acids, total N-nitroso compounds as a group, and nitrite/nitrate. The concentration of N-nitrosodimethylamine was significantly elevated in urines infected with Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae. The levels of nitrite, N-nitrosoproline and total N-nitroso compounds, when expressed as the amount per mol creatinine, were also significantly increased in patients with bacteriuria. Several bacterial strains were capable of catalysing nitrosation of morpholine at neutral pH. These results suggest that N-nitroso compounds can be formed in vivo in the infected bladder, which could explain the association between urinary-tract infections and increased risk for bladder cancer.

Adolescent↗
PubMed1991

Helicobacter pylori and progressive gastric pathology that predisposes to gastric cancer.

Evidence is presented suggesting that infection by Helicobacter pylori triggers and continuously contributes to the pathophysiology of progressive gastric changes that can ultimately lead to gastric cancer. In Peru, especially in population groups of low socioeconomic status, infection by H. pylori begins earlier in life and is more prevalent and persistent than in developed countries. The infection produces a destructive lesion of the mucinous surface epithelium which probably enables other aggressive luminal factors to cause further mucosal damage. As a consequence, active chronic gastritis appears. The gastritis is of the superficial type at the beginning but may progressively change to atrophic. Chronic atrophic gastritis is found more frequently and at a younger age in dyspeptic patients with low socioeconomic status--that is, in patients having higher prevalence of persistent infection by H. pylori since earlier in life. When chronic atrophic gastritis becomes severe and extensive, hypochlorhydria ensues. Hypochlorhydria favors the appearance of bacterial overgrowth, nitrites, and N-nitroso compounds in the gastric lumen. N-nitroso compounds, because of their mutagenic-carcinogenic properties, probably induce gastric premalignant lesions like intestinal metaplasia and dysplasia of the gastric mucosa. Oral bismuth therapy apparently reverses H. pylori-associated gastric dysplasia. It is proposed that future programs designed for the control of gastric cancer would be incomplete if they do not include further evaluation of the many effects of infection by H. pylori on the gastric mucosa and of cost-effective methods to eradicate the infection.

Age Factors↗
PubMed1986

Effect of ring substituents on the transketolase-catalyzed conversion of nitroso aromatics to hydroxamic acids.

Transketolase catalyzed the conversion of eight different aromatic C-nitroso compounds into the corresponding N-glycolyl derived hydroxamic acids. Three of the nitroso compounds were also found to be converted in part to the arylhydroxylamines by a reductive process. A correlation was found for the rates of production of these metabolites with the electronegativities of substituent groups that were present on the aromatic ring. The rates of reaction of these substituted nitroso substrates with transketolase and D-fructose-6-phosphate were found to decrease in the order 4-NO2 much greater than 4-CF3 greater than 3-CF3, unsubstituted greater than 4-Cl greater than 4-CH3, 4-phenyl greater than 4-OC2H5. N,N-Dimethyl-p-nitrosoaniline was not metabolized by transketolase under the conditions employed for the other substrates. Those substrates possessing the strong electron-withdrawing groups 4-NO2, 4-CF3 and 3-CF3 were the only substrates that were found to undergo enzymatic reduction to the hydroxylamines as a competing process. A mechanism was proposed that involves a redox reaction between the nitroso substrate and the enzymatic intermediate "active glycolaldehyde" at the active-site of transketolase.

Animals↗
PubMed1997

Dietary and other lifestyle factors of women with brain gliomas in Los Angeles County (California, USA)

A population-based interview study in Los Angeles County (California, USA) of 94 women with intracranial gliomas and 94 individually matched neighborhood controls investigated the relationship to various sources of exposure to N-nitroso compounds and their precursors and to vitamins which inhibit the endogenous formation of these compounds. The study offers some support for the hypothesis that dietary sources of nitroso exposure relate to risk. Risk increased with increasing consumption of cured meats, most notably of bacon (odds ratio [OR] for the third tertile of intake = 6.6, 95 percent confidence interval [CI] = 1.9-22.5, P trend < 0.001). Risk was reduced with increasing intake of vegetables such as bell peppers (OR for third tertile = 0.2, CI = 0.1-0.7, P trend < 0.01). In addition, use of vitamin supplements appeared protective, and there was some suggestion that eating cured meats in combination with foods which inhibit endogenous nitrosation mitigates risk. Other potential sources of nitroso exposure such as smoking, cosmetics, and drinking water did not relate to risk. Despite the limitations of data on usual adult diet, it appears that dietary sources of nitroso compounds may be important in the development of gliomas.

Adult↗
PubMed1983

Gastric juice nitrite and bacteria in gastroduodenal disease and resected stomach.

The N-nitroso-compounds and the bacteriological contamination of gastric juice could represent a risk factor for cancer of the stomach when the mucosal barrier is altered. In the unresected stomach and gastric stump, the hypo-achlorhydria and bilopancreatic reflux permit the development of bacterial flora and the production of N-nitroso-compounds in the presence of nitrite. A survey was performed on 71 patients: 15 normal controls, 31 with gastroduodenal disease (9 gastrites, 10 gastric ulcers, 10 duodenal ulcers, 7 neoplasias), 20 patients with gastric resection (8 BI, 12 BII), using an endoscopic-histopathologic control and a chemical-bacteriological analysis of the gastric juice. We studied the gastric juice for the following parameters: pH, concentration of nitrite, identification of bacterial type, count and nitrate-reductase activity. An inverse relationship was found between the concentration of nitrite and the hydrogen ion concentration. In the alkaline gastric juice, we identified aerobic bacteria with nitrate-reductase activity and anaerobic bacteria. The latter has the ability to transform biliary salts into carcinogenic and cocarcinogenic compounds and to catalyze the nitrosations. The chemicobacteriological characteristics of the gastric juice from gastric ulcers (Johnson type I), atrophic gastrites, and resected stomachs lead one to think that there is a risk of carcinogenesis brought about by the N-nitroso-compounds.

Adult↗
PubMed1994

Comparison of antioxidant properties of nifedipine and illuminated nifedipine with nitroso spin traps in low density lipoproteins and phosphatidylcholine liposomes.

Illumination nifedipine, a calcium channel blocker, gives a nitroso-compound, 2,6-dimethyl-4-(2-nitrosophenyl)-3,5-pyridine-dicarboxylic acid dimethyl ester (NTP), which has spin trapping properties. The antioxidant ability of NTP was tested in a model of lipid peroxidation in low density lipoproteins (LDL) and phosphatidylcholine liposomes, and was compared with parent nifedipine and with other nitroso spin traps such as 3,5-dibromo-4-nitrosobenzene-sulfonic acid (BNTB), nitrosobenzene (NTB) and 2-methyl-2-nitrosopropane (MNP). Nifedipine (20-200 mumol/l) did not inhibit lipid peroxidation either in LDL on in liposomes, whereas its photolytical product NTP was found to be very effective at the same concentrations. The average antioxidant potencies of the nitroso spin traps were similar in both models and decreased in the order: NTP > or = BNTB > NTB > or = MNP. As detected by EPR spectroscopy, the studied nitroso compounds formed stable nitroxide radicals in a pseudo-Diels-Alder reaction, as a result of their interaction with unsaturated bonds of lipids in LDL and liposomes. The relative concentrations of thus formed radicals were in the order: NTP >> BNTB >> NTB approximately MNP and were related to their antioxidant properties. Thus it seems that the ability of the nitroso-compounds to form nitroxide radicals with unsaturated lipids may play a role in the antioxidant effect of these compounds.

Antioxidants↗
PubMed2003

Gastric juice nitrite and vitamin C in patients with gastric cancer and atrophic gastritis: is low acidity solely responsible for cancer risk?

BACKGROUND: N-nitroso compounds are carcinogens formed from nitrite, a process that is inhibited by vitamin C in gastric juice. Helicobacter pylori infection has been reported to increase nitrite and decrease vitamin C in gastric juice. Therefore, susceptibility to gastric cancer in H. pylori-infected patients may be derived from increased N-nitroso compounds in gastric juice. However, most H. pylori-infected patients do not develop gastric cancer. OBJECTIVE: To investigate additional factors that may affect susceptibility to gastric cancer, we compared nitrite and vitamin C levels in gastric juice from H. pylori-infected patients with and without gastric cancer. METHODS: Serum and gastric juice were obtained from 95 patients undergoing diagnostic endoscopy, including those with normal findings, duodenal ulcer, gastric ulcer, atrophic gastritis and gastric cancer. Serum was analysed for H. pylori antibody, nitrate and nitrite, gastrin and pepsinogens; gastric juice was analysed for pH, nitrite and vitamin C. RESULTS: pH and nitrite levels were increased and vitamin C levels decreased in the gastric juice of patients with atrophic gastritis and gastric cancer compared with other patients. However, in patients with a similar gastric acidity (pH 5-8), nitrite concentrations in the gastric juice were significantly higher and vitamin C levels significantly lower in patients with gastric cancer than in those with atrophic gastritis. CONCLUSION: Although hypochlorhydria increases intraluminal nitrite and decreases intraluminal vitamin C, which increases the intraluminal formation of N-nitroso compounds, our results indicate that patients with gastric cancer may have additional factors that emphasize these changes.

Aged↗
PubMed1995

Suppressive effect of molybdenum on hepatotoxicity of N-nitrosodiethylamine in rats.

In order to elucidate the mechanism by which molybdenum prevents the carcinogenesis of N-nitroso compounds, the effects of Na2MoO4-pretreatment on N-nitrosodiethylamine (NDEA)-induced DNA strand breaks, fluctuation in cation contents and lipid peroxidation levels in rat liver were examined. Male Wistar rats weighing 170-190 g were pretreated with Na2MoO4 (1.24 mmol/kg body weight, i.p., once a day) for 3 d and on day 4, they were exposed to NDEA (50 mg/kg body weight, once, i.p.). Three days after exposure to NDEA, the nitroso compound caused DNA strand breaks and disrupted potassium (K) and calcium (Ca) metabolism in the liver but did not affect lipid peroxidation levels. Na2MoO4-pretreatment prevented both NDEA-induced DNA damage and disruption of the metabolism of those cations but rather enhanced lipid peroxidation. These results suggest that Mo prevented NDEA-induced DNA damage by preventing disruption of intracellular Ca metabolism while stimulating the metabolism of the nitroso compound via a nontoxic pathway.

Animals↗
PubMed1993

Alcohol dehydrogenase-dependent reduction of 2-nitrosoflurene and rearrangement of N-hydroxy-2-aminofluorene.

Various C-nitroso compounds are intermediates of arylamine oxidation or nitroarene reduction. Reductive metabolism of C-nitroso compounds to their corresponding hydroxylamines is a necessary step in the activation of these compounds to mutagenic end points. In this study, 2-nitrosofluorene (2-NOF) has been investigated as an aldehyde substrate analogue for horse liver alcohol dehydrogenase (HLADH). The reaction products are assigned on the basis of their UV/visible spectra and coelution with authentic standards in reversed-phase HPLC. The direct product of 2-NOF reduction is N-hydroxy-2-aminofluorene (N-OH-2-AF), which undergoes further reduction to 2-aminofluorene (2-AF) and rearrangement to 1- and 3-hydroxy-2-aminofluorene (1- and 3-OH-2-AF). The formation of these products is potently inhibited by pyrazole indicating the involvement of active-site zinc ion in the role of a Lewis acid catalyst. It is suggested that the rearrangement reaction occurs via an inner-sphere N-OH 2AF-Zn2+...E-coenzyme complex following the elimination of the hydroxyl group from the N-OH-2-AF intermediate and the hydrolysis of the fluorenyl nitrenium-derived carbocations to yield the hydroxy 2-AF products. Herein ADH is identified as a C-nitroso-reducing enzyme which must be considered in the mutagenic sequelae of nitro and nitrosoarenes.

Alcohol Dehydrogenase↗
PubMed1986

Urinary excretion of N-nitrosamino acids and nitrate by inhabitants of high- and low-risk areas for esophageal cancer in Northern China: endogenous formation of nitrosoproline and its inhibition by vitamin C.

A total of 238 samples of 24-h urine were collected from inhabitants of high-risk (Lin-xian) and low-risk (Fan-xian) areas for esophageal cancer in northern China, according to three protocols: (a) from undosed subjects; (b) from subjects who had ingested 100 mg L-proline three times a day 1 h after each meal; and (c) from subjects in Lin-xian who had ingested 100 mg ascorbic acid together with 100 mg L-proline three times a day 1 h after each meal. As an index of individual exposure to N-nitroso compounds or their precursors, ingested in food and/or formed endogenously, the levels of four urinary N-nitrosamino acids and nitrate were determined. The amounts of N-nitrosoproline, N-nitrosothiazolidine 4-carboxylic acid, N-nitrososarcosine, and nitrate excreted in the 24-h urine of undosed subjects in Lin-xian were significantly higher than those in Fan-xian, indicating a higher exposure of the inhabitants in the high-risk area to N-nitroso compounds and their precursors. Ingestion of L-proline resulted in a marked increase in urinary N-nitrosoproline levels in inhabitants from both areas, suggesting that endogenous nitrosation may occur to a larger extent when appropriate amine precursors are ingested in foods. Intake of moderate doses of ascorbic acid by high-risk subjects effectively reduced the urinary levels of N-nitrosamino acids to those found in undosed subjects in the low-risk area. If N-nitroso compounds formed in vivo are among the causative factors for esophageal cancer in this area of northern China, ascorbic acid appears to be effective in lowering the body burden of these carcinogenic compounds, thus offering a rational basis for long-term intervention studies in this area.

Adult↗
PubMed2000

Novel functions of human alpha(1)-protease inhibitor after S-nitrosylation: inhibition of cysteine protease and antibacterial activity.

alpha(1)-Protease inhibitor (alpha(1)PI), the most abundant serine protease inhibitor found in human plasma (at 30-60 microM), is a glycoprotein (53 kDa) having a single cysteine residue at position 232 (Cys(232)). We have found that Cys(232) of human alpha(1)PI was readily S-nitrosylated by nitric oxide (NO) without affecting inhibitory activity to trypsin or elastase. S-nitrosylated alpha(1)PI (S-NO-alpha(1)PI) not only retained inhibitory activity against these serine proteases, but also gained thiol protease inhibitory activity against a Streptococcus pyogenes protease; the parental alpha(1)PI did not have this activity. Furthermore, S-NO-alpha(1)PI exhibited bacteriostatic activity against Salmonella typhimurium at concentrations of 0.1-10 microM, which were 20- to 3000-fold stronger than those of the other NO-generating compounds or S-nitroso compounds such as S-nitrosoalbumin and S-nitrosoglutathione. NO appears to be transferred into the bacterial cells from S-NO-alpha(1)PI via transnitrosylation, as evidenced by electron spin resonance spectroscopy with an NO spin trap. Thus, we conclude that S-NO-alpha(1)PI may be generated from the reaction between alpha(1)PI and NO under inflammatory conditions, in which production of both is known to increase. As a result, new functions, i.e., antibacterial and thiol protease inhibitory activities of alpha(1)PI, were generated.

Animals↗
PubMed1996

Maternal consumption of cured meats and vitamins in relation to pediatric brain tumors.

Brain tumors are the leading cause of death from childhood cancer, yet the causes of most of these tumors remain obscure. Few chemicals are effective in causing brain tumors experimentally after systemic administration of low doses; a notable exception is one group of N-nitroso compounds, the nitrosamides (in particular the nitrosoureas). Feeding pregnant animals nitrosamide precursors (e.g., sodium nitrite and an alkylamide such as ethylurea) causes a high incidence of nervous system tumors in offspring. This population-based epidemiological study was designed to test the hypothesis that maternal consumption during pregnancy of meats cured with sodium nitrite increases the risk of brain tumors among offspring. The intake of vitamins C and E blocks endogenous formation of nitroso compounds and was expected to be protective. Mothers of 540 children under age 20 with a primary brain tumor diagnosed during 1984-1991 and 801 control children in the same 19 counties on the U.S. West Coast were interviewed. Risk increased with increasing frequency of eating processed meats [odds ratio (OR) = 2.1 for eating at least twice a day compared to not eating; 95% confidence interval (CI) = 1.3-3.2; P = 0.003). Risk also increased with increasing average daily grams of cured meats or mg of nitrite from cured meats (P for each <0.005) but not with nitrate from vegetables. Daily use of prenatal vitamins throughout the pregnancy decreased risk (OR = 0.54; CI = 0.39-0.75). Risk among mothers who consumed above the median level of nitrite from cured meat was greater if vitamins were not taken (OR = 2.4; CI = 1.4-3.6) than if they were (OR = 1.3). These effects were evident for each of three major histological types and across social classes, age groups, and geographic areas. This largest study to date of maternal diet and childhood brain tumors suggests that exposure during gestation to endogenously formed nitroso compounds may be associated with tumor occurrence. Laboratory exploration is needed to: (a) define dietary sources of exposure to alkylamides; (b) investigate the reactivity of nitrite in high concentration such as around bits of cured meats in the stomach after ingestion compared to nitrite in dilute solution; and (c) confirm that simultaneous ingestion of alkylamides and cured meats leads to the endogenous formation of nitrosamides.

Adolescent↗
PubMed1993

Lack of effect of carcinogen treatment on development of tumors arising spontaneously in Fischer 344 rats.

The incidence of a set of neoplasms arising "spontaneously" in Fischer 344 (F344) rats was determined in control and carcinogen-treated animals. Data were obtained from approximately 9000 rats (4000 males and 5000 females) used to study the carcinogenicity of a variety of alkylating compounds, including N-nitroso compounds, azoxyalkanes, and triazenes. In these experiments treated rats and controls were allowed to die naturally and were necropsied, and the tissues were examined histopathologically. The spontaneous neoplasms of interest were mononuclear cell leukemia and neoplasms of the anterior pituitary, adrenal medulla, pancreas, thyroid gland, mammary gland, and testis. These tumors were generally absent from control animals that (rarely) died before 70 wk of age. Although many carcinogen-treated rats died early with treatment-related tumors, a substantial number (1700 males and 2300 females) survived as long as controls. The incidence of spontaneous neoplasms was determined among controls and chemically treated rats at 10-wk intervals from 0 to 140 wk. The incidence of spontaneous tumors was not higher and was frequently statistically lower among treated rats than the corresponding incidence in controls, with the exception of leukemia in female rats. The same result was obtained with the subset of carcinogens not requiring metabolic activation (mostly alkylnitrosoureas). These data indicate that in this rat tumor model system, the alkylating carcinogens, while capable collectively of tumor induction at more than 20 sites, did not accelerate the development of any of the six spontaneously arising solid tumors. This suggests that these spontaneous tumors might arise by a mechanism that is unresponsive to the actions of the alkylating carcinogens.

Animals↗