Showing papers by "Dietrich Hoffmann published in 1981"

Carcinogenic Tobacco-specific N-Nitrosamines in Snuff and in the Saliva of Snuff Dippers

Abstract: Human data indicate an increased risk for cancer of the oral cavity for snuff dippers. Popular snuff products from the United States, Germany, Sweden, and Denmark were analyzed for tobacco-specific N-nitrosamines (TSNA). These compounds are formed during tobacco processing from nicotine, nornicotine, and anatabine and represent the only known carcinogens in snuff. N'-Nitrosonornicotine, a moderately active carcinogen, ranged in dry snuff from 3.5 to 77 ppm; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a relatively strong carcinogen, ranged from 0.6 to 7.0 ppm; and N'-nitrosoanatabine, thus far not bioassayed, ranged from 0.8 to 44 ppm. The concentrations of TSNA in a given snuff product can vary widely, and aging in the open air can lead to an increase in TSNA. Analysis of the saliva of snuff dippers revealed that these nitrosamines are extracted from the tobacco plug during snuff dipping and that their concentrations in saliva can vary widely between users. Efforts should be made to reduce the TSNA in snuff by modifications of the production process and by wrapping individual snuff portions in airtight packets.

Comparative Carcinogenicity and Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and N′-Nitrosonornicotine in Syrian Golden Hamsters

Abstract: The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) were tested for carcinogenic activity in Syrian golden hamsters. In Assay A, 30 hamsters were each given 19 s.c. injections of 0.048 mmol of NNK or NNN. In Assay B, 20 hamsters each received 75 s.c. injections of 0.012 mmol of NNK or NNN. Among the NNK-treated hamsters in Assay A, three developed carcinomas of the nasal cavity, and 19 had adenomas and/or adenocarcinomas of the lung. In the NNN group, one hamster developed a lung adenoma, and five had tracheal papillomas. In Assay B, 11 of the NNK-treated hamsters developed carcinomas of the nasal cavity, 16 had lung adenomas and/or adenocarcinomas, and seven had tracheal papillomas; in the NNN group, we recorded only one hamster with a lung adenoma and one with a tracheal papilloma. These findings in the Syrian golden hamster confirm that NNK is a more powerful carcinogen than NNN, as was shown previously in assays with rats and mice. In metabolism studies, 96 to 98% of the radioactivity of the injected [1-14C]NNK was recovered in the urine, 4% was recovered in the feces, and less than 0.5% was recovered as exhaled 14CO2. The corresponding distribution for [2'-14C]NNN was 62 to 78% in urine, 10% in feces, and less than 0.5% in respiratory 14CO2. The levels of binding of [1-14C]NNK and [2'-14C]NNN to the trichloroacetic acid-insoluble fractions were highest in liver, lung, kidney, and adrenals. The urinary metabolites of NNK and NNN resulted from alpha-hydroxylation, from N-oxidation of NNN to N'-nitrosonornicotine-1-N-oxide, and from reduction of NNK to 4-(methylnitrosamino)-1-(3-pyridyl)butan-1-ol.

Assessment of the carcinogenic N-nitrosodiethanolamine in tobacco products and tobacco smoke

Abstract: A simple, reproducible gas chromatography-thermal energy analyzer (g.c.-TEA) method has been developed for the analysis of N-nitrosodiethanolamine (NDELA) in tobacco and tobacco smoke. The extract of tobacco or the trapped particulates of tobacco smoke are chromatographed on silica gel. The NDELA containing fractions are concentrated, silylated and analyzed with a modified g.c.-TEA system. (/sup 14/C)NDELA serves as internal standard for the quantitative analysis. Experimental cigarettes made from tobaccos which were treated with the sucker growth inhibitor maleic hydrazidediethanolamine (MH-DELA) contained 115--420 p.p.b. of NDELA and their smoke contained 20--290 ng/cigarette, whereas hand-suckered tobacco and its smoke were free of NDELA. The tobacco of US smoking products contained 115--420 p.p.b. of NDELA and the mainstream smoke from such products yielded 10--68 ng/cigar or cigarette. NDELA levels in chewing tobacco ranged from 220--280 p.p.b. and in two commercial snuff products were 3,200 and 6,800 p.p.b. Although the five analyzed MH-DELA preparations contained between 0.6--1.9 p.p.m. NDELA it is evident that the major portion of NDELA in tobacco is formed from the DELA residue during the tobacco processing. Based on bioassay data from various laboratories which have shown that NDELA is a relatively strong carcinogen and based on the results of this studymore » the use of MH-DELA for the cultivation of tobacco is questioned.« less

A Study of Tobacco Carcinogenesis. XX. Role of Catechol as a Major Cocarcinogen in the Weakly Acidic Fraction of Smoke Condensate

Abstract: The weakly acidic fraction of cigarette smoke condensate was fractionated by preparative high-pressure liquid chromatography into major subfractions I-IV. Major subfractions II and III were fractionated further into subfractions A-J. Subfractions A-J were tested for cocarcinogenicity on the skin of noninbred Ha:ICR Swiss albino mice by application with 0.003% benzo[a]pyrene. Subfractions A-C and F-J showed significant cocarcinogenic activity; subfractions A, F, and H were the most active. Catechol was a major component of subfraction A and was also detected in subfractions B-D and F. Major components of the other subfractions included hydroquinone (B), coniferyl alcohol (C and H), hydroxyphenyl alcohols (D), alkyl-2-hydroxy-2-cyclopenten-1-ones (C, D, and F), hydroxyacetophenones (F), phenolic cyano compounds (F), and fatty acids (F). The results demonstrate the importance of catechol as a cocarcinogen in the weakly acidic fraction of cigarette smoke condensate and indicate the presence of other cocarcinogens.

The influence of methyl substitution on the mutagenicity of nitronaphthalenes and nitrobiphenyls

Abstract: A series of nitrobiphenyls, nitronaphthalenes, and their methyl-substituted derivatives were assayed for mutagenicity toward S. typhimurium TA98 and TA100. In assays conducted in the absence of rat liver S9 fraction, substitution of a methyl group ortho to the nitro group decreased mutagenicity (3-methyl-4-nitrobiphenyl, 2-methyl-1-nitronaphthalene, and 3-methyl-2-nitronaphthalene). The mutagenicity of 4-nitrobiphenyl was also inhibited by methyl substitution at the 2'-position (2'-methyl-4-nitrobiphenyl), and at both the 3- and 2'-positions (3,2'-dimethyl-4-nitrobiphenyl). In assays conducted in the presence of rat liver S9 fraction, inhibition of mutagenicity by methyl substitution was demonstrated for 2-methyl-1-nitronaphthalene, 3-methyl-2-nitronaphthalene and 3,2'-dimethyl-4-nitrobiphenyl. Thus, methyl substitution of nitrobiphenyls and nitronaphthalenes generally decreased mutagenicity, when assays were conducted in the absence of rat liver S9 fraction. However, in the presence of rat liver S9 fraction, the inhibitory effect of methyl substitution on mutagenicity was less pronounced. These results contrast to the usual enhancing effect of ortho-methyl substitution of the corresponding aromatic amines and their N-oxidized derivatives (hydroxylamines and C-nitroso compounds).

Reduction of Tumorigenicity and of Dihydrodiol Formation by Fluorine Substitution in the Angular Rings of Dibenzo(a,i)pyrene

Abstract: The tumor-initiating activities on mouse skin and in vitro metabolism of dibenzo( a,i )pyrene, 2-fluorodibenzo( a,i )pyrene, 3-fluorodibenzo( a,i )pyrene, and 2,10-difluorodibenzo( a,i )pyrene were compared. After an initiating dose of 500 µg, followed by promotion with tetradecanoylphorbol acetate, dibenzo( a,i )pyrene induced skin tumors in 85% of the mice and caused 5.8 skin tumors/mouse. The corresponding tumorigenic activities for the fluorinated compounds were: 2-fluorodibenzo( a,i )pyrene (85%; 1.7 tumors/mouse); 3-fluorodibenzo( a,i )pyrene (80%; 3.1 tumors/mouse); and 2,10-difluorodibenzo( a,i )pyrene (10%; 0.1 tumors/mouse). After an initiating dose of 100 µg, only dibenzo( a,i )pyrene showed significant tumor-initiating activity. 3,4-Dihydro-3,4-dihydroxydibenzo( a,i )pyrene was identified as a metabolite of dibenzo( a,i )pyrene formed by the 9000 × g supernatant from the livers of Aroclor 1254-pretreated rats. Another dihydrodiol was tentatively identified as 1,2-dihydro-1,2-dihydroxydibenzo( a,i )pyrene. The formation of these angular ring dihydrodiols was inhibited in the metabolism of 2-fluorodibenzo( a,i )pyrene and 3-fluorodibenzo( a,i )pyrene. Angular ring dihydrodiols were not detected in the metabolism of 2,10-difluorodibenzo( a,i )pyrene. These results suggest that an angular ring dihydrodiol, 3,4-dihydro-3,4-dihydroxydibenzo( a,i )pyrene, which can form a bay-region dihydrodiol epoxide, may be a proximate carcinogen of dibenzo( a,i )pyrene.

Mutagenicity of aminocarbazoles and nitrocarbazoles.

Abstract: The mutagenic activity of all 4 isomeric aminocarbazoles and 4 nitrocarbazoles was evaluated in Salmonella typhimurium tester strains TA98, TA100 and TA1535. All compounds were assayed both in the presence and absence of liver homogenate from Aroclor-treated rats. Among the aminocarbazoles, 2-aminocarbazole was found to be most active in both tester strains, although somewhat less active than 2-aminofluorene. 3-Aminocarbazole was the only other isomer that was mutagenic towards TA98 at the dose levels employed (5–200 μg). 4-Aminocarbazole was moderately active in TA100, and 1-aminocarbazole was inactive in both TA98 and TA100. Similar differences in mutagenic potency and specificity towards the tester strains were observed for the related series of nitrocarbazoles.

Mass Spectra of Tobacco Alkaloid - Derived Nitrosamines, their Metabolites, and Related Compounds

Abstract: Abstract The mass spectra of the tobacco alkaloid - derived nitrosamines NNN, NNK, NNA, NAB and NAtB and of known mammalian metabolites of NNN and NNK are presented. Mass spectra of synthetic derivatives related to these nitrosamines and their metabolites are also included. These spectra will be useful in studies on the occurrence and metabolism of the tobacco alkaloid - derived nitrosamines and in investigations of other compounds related to the tobacco alkaloids.