Healthy mind--healthy body.
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Attitude to Health↗
Biomedical subjects
D Hoffmann
Publications and source records attributed to D Hoffmann.
Biochemical epidemiology of cervical neoplasia: measuring cigarette smoke constituents in the cervix.
In preparation for an epidemiological investigation of cigarette smoking and cervical neoplasia, we studied methods of measuring cervical exposure to tobacco smoke. The measurement of cotinine in cervical flushes by radioimmunoassay proved to be highly accurate in distinguishing smokers from nonsmokers, achieving 100% sensitivity and 97% specificity. In most subjects, quantitative levels of cervical cotinine and nicotine mirrored recent smoking intensity. Some of the apparent exceptions may have resulted from metabolic/secretory traits of the subjects. If so, the biochemical measurement of smoke constituents in the cervix might prove more valuable for epidemiological studies of cervical neoplasia than data on current smoking behavior collected by interview.
Adolescent↗
3-(Methylnitrosamino)propionitrile: occurrence in saliva of betel quid chewers, carcinogenicity, and DNA methylation in F344 rats.
3-(Methylnitrosamino)propionitrile (MNPN), a potent carcinogen in F344 rats, was detected for the first time in the saliva of betel quid chewers at levels ranging from 0.5 to 11.4 micrograms/liter. The tumorigenic properties of MNPN and its potential to methylate DNA in F344 rats were evaluated. Groups of 21 male and 21 female rats were given 60 s.c. injections over a 20-week period (total doses 0.055 and 0.23 mmol per rat). The experiment was terminated after 106 weeks. MNPN at the higher dose induced 18 (86%) malignant tumors of the nasal cavity in male and 15 (71%) in female rats. The lower dose induced nine (43%) liver tumors. Groups of four or five male F344 rats were treated with a single s.c. or i.v. injection of MNPN (0.4 mmol/kg). MNPN was also administered to rats by swabbing the oral cavity (2.21 mmol/kg). The levels of 7-methylguanine and O6-methylguanine, formed 0.5-36 h after treatment, were measured in the liver, nasal mucosa, esophagus, and oral issues. The highest levels of methylated guanines were detected in the nasal cavity independent of the route of administration. The results of this study demonstrate that MNPN is present in the saliva of betel quid chewers and is a potent carcinogen in F344 rats.
Adult↗
Mandibular osteodystrophy fibrosa in Indonesian goats fed Leucaena.
Four Indonesian goats fed Leucaena leucocephala with a calcium to phosphorus ratio in excess of 6:1 for 472 days developed mandibular osteodystrophy fibrosa to varying degrees ranging from severe to slight. The animals appeared to grow normally but the animal with the most severe clinical symptoms lost weight for 35 days prior to the termination of the experiment. The other three animals either maintained or gained weight during this period. A balance study performed part way through the experiment revealed that the animal which subsequently lost weight was probably not storing calcium or phosphorus whereas the other animals had a positive calcium balance and were probably storing small amounts of phosphorus. Histological examination of tissues taken after a post-mortem revealed that the kidney, parathyroid and thyroid glands and long bones were normal.
Animal Feed↗
Tobacco-specific N-nitrosamines in dry snuff.
Case-control studies have shown that the oral use of dry snuff has an aetiological association with cancer of the oral cavity. This communication reports high concentrations of the powerful carcinogen N'-nitrosonornicotine (9.37-55.3 micrograms/g), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (1.98-14.4 micrograms/g) and of N'-nitrosoanatabine (18.8-40.2 micrograms/g) and N'-nitrosoanabasine (0.66-1.17 microgram/g) in three popular brands of dry snuff available in the USA.
Alkaloids↗
A critical look at N-nitrosamines in environmental tobacco smoke.
The amounts of cigarette smoke carcinogens released into the environment as sidestream smoke (SS) constituents are generally twice as high as the levels of the carcinogens that are inhaled as mainstream smoke (MS). However, certain carcinogens in undiluted SS, such as nitrosamines, exceed MS levels up to 50 times. Regardless of the fact that SS is usually substantially diluted before being inhaled, its constituents can be determined in environmental tobacco smoke (ETS) by modern analytical methods and levels of exposure of involuntary smokers can be assessed by the use of specific markers. Currently, the uptake of ETS by nonsmokers is determined by measuring nicotine and its metabolite cotinine in saliva, serum and/or urine. In on-going studies, we are now exploring the determination of the two highly carcinogenic nicotine-derived nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), respectively of their metabolites, in physiological fluids of smokers and nonsmokers.
Animals↗
Uptake of sidestream smoke by Syrian golden hamsters.
An inhalation bioassay with Syrian golden hamsters is being conducted to evaluate the toxic and carcinogenic potential of cigarette sidestream smoke (SS) relative to mainstream smoke (MS). A Hamburg II smoking machine is used to deliver MS by nose-only exposure to hamsters and a modification allows for the simultaneous collection of SS for whole-body delivery to a different rack of animals. The tolerated dose of SS was determined by varying the air/smoke dilutions drawn through the animal restrainers. Preliminary data indicated that 20% carboxyhemoglobin (COHb) could be obtained in SS-exposed animals without fatality. Optimum exposure levels were determined. Monthly measurements of COHb, nicotine and cotinine indicate that the SS-exposed animals are absorbing slightly higher amounts of these smoke constituents than the MS-exposed hamsters. Tumor incidence and carcinogenicity data are being collected through complete necropsy and histology protocols and uptake data continue to be collected. These studies should help elucidate the carcinogenic potential of SS which has been suggested from its composition and from recent epidemiological data of cancer incidence in non-smokers.
Animals↗
Effect of snuff and nicotine on DNA methylation by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
In this study we assayed the effects of snuff and nicotine on the DNA methylation by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a powerful tobacco-specific N-nitrosamine. Male F344 rats were pretreated for 2 weeks with either a solution of a snuff extract or 0.002% nicotine in the drinking water. Subsequently, the rats were given a single dose of NNK and the effects of snuff and nicotine on the methylation of guanine by NNK in the DNA of target organs of this carcinogenic nitrosamine were determined. Formation of 7-methylguanine in the liver, nasal mucosae and oral cavity and of O6-methylguanine in the liver and oral cavity was much lower in the rats pretreated with snuff extract than in those not pretreated. On the other hand, pretreatment of the rats with nicotine had no significant effect on the methylation of DNA by NNK nor on the elimination constants of NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridly)-1-butanol.
Animals↗
Identification and analysis of a new tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol.
A new tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL) was isolated from snuff tobacco. Structural characterization of this N-nitrosamine was confirmed by mass spectral analysis. Five popular US brands of moist snuff and three popular US brands of dry snuff tobacco were analyzed for moisture, nicotine and tobacco-specific N-nitrosamines. The moisture content varied from 20 to 53% in moist snuff and from 4.7 to 5.6% in dry snuff. The nicotine levels in these samples varied from 0.6 to 3.2%. The newly identified iso-NNAL was present in concentrations ranging from 0.07 to 2.5 p.p.m. whereas other tobacco-specific N-nitrosamines, N-nitrosonornicotine, N-nitrosoanatabine, N-nitrosoanabasine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone were found to range from 0.1 to 178 p.p.m. Iso-NNAL was not detected in mainstream and sidestream smoke of cigarettes. Iso-NNAL is genotoxic in primary rat hepatocytes; its tumorigenic properties are currently being tested in mice and rats.
Carcinogens↗
Toxic and carcinogenic agents in undiluted mainstream smoke and sidestream smoke of different types of cigarettes.
The mainstream and sidestream smoke of four types of popular US cigarettes were analyzed for toxic and carcinogenic agents. The cigarettes included one without a filter tip, and one filter cigarette each with medium, low and ultra-low smoke yields. The analyses clearly demonstrated that 12 toxic agents determined in this study were significantly reduced in the mainstream smoke of filter cigarettes, as compared with smoke yields from the nonfilter cigarette. In the case of the ultra-low yield cigarette, mainstream smoke emissions were reduced by about 90%. In contrast to this finding, the emissions of the same toxic and carcinogenic components into sidestream smoke of the filter cigarettes were not greatly reduced. Sidestream smoke is the major contributor to environmental tobacco smoke, to which both smokers and non-smokers are exposed. Although the exposure of the smoker to mainstream smoke components is decreased due to proportionally greater consumption of low and ultra-low yield cigarettes, and lower rates of consumption of cigarettes with high smoke yields, the carcinogenic potential of indoor pollutants originating from tobacco products is not diminished.
Ammonia↗
Pathology of the accessory sex glands of rams infected with Brucella ovis.
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Animals↗
Selenium in mainstream and sidestream smoke of cigarettes containing fly ash-grown tobacco.
The quantities of selenium, tar and nicotine present in mainstream (MS) and sidestream (SS) smoke of machine-smoked cigarettes was studied. The cigarettes were prepared from tobacco purposely cultured on fly ash-amended soil so as to increase its selenium concentration. Selenium concentration was found to be the same in the gaseous phase of both MS and SS smoke, but its concentration was significantly higher (p less than 0.05) in the particulate matter of the MS smoke. Tar was higher in MS smoke and nicotine in SS smoke. Factors affecting selenium concentrations in tobacco and its possible environmental significance are discussed.
Carbon↗
Effectiveness of cigarette filter tips for reducing cadmium in relation to other mainstream smoke constituents.
The effectiveness of filter tips for reducing cadmium, tar, nicotine, carbon monoxide and carbon dioxide in cigarettes was studied. The cigarettes were made from tobacco grown on municipal sewage sludge-amended soil and were therefore high in cadmium. When machine-smoked, filter tips did not result in a significant reduction of cadmium deposited on Cambridge filters. This may indicate that a considerable fraction of cadmium is present in the vapor phase of the smoke and therefore not reduced to the same extent as the tar by certain filters. Nicotine and carbon monoxide were reduced to a lesser extent than tar. This indicates that the filter tip has influenced the combustion of the tobacco column during smoking.
Cadmium↗
Significance of exposure to sidestream tobacco smoke.
The presence of toxins and carcinogens in ambient air polluted with tobacco smoke is largely due to the sidestream smoke emissions from the smouldering tobacco products. Levels of these toxins and carcinogens in sidestream smoke often exceed their concentrations in mainstream smoke. Dosimetry of tobacco-specific markers of exposure in physiologic fluids suggests that in regard to nicotine--which is the major tobacco alkaloid--exposure of humans to environmental tobacco smoke causes but a few percent of the nicotine levels reached as a result of active inhalation of cigarette mainstream smoke. Yet, this measurement of exposure is not universally applicable to all of the tobacco smoke pollutants in this complex matrix. Existing knowledge of the chemical composition of sidestream smoke and evidence of biological activity of sidestream smoke components suggests that this environmental pollutant has carcinogenic potential. Significance of exposure to environmental tobacco smoke must be evaluated on the basis of the severity of the pollution, the duration of exposure and personal variations in uptake.
Air Pollutants↗
Determination of aromatic amines in sidestream smoke by gas chromatography.
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Air Pollutants↗
Toxic and carcinogenic agents in dry and moist snuff.
The oral use of snuff is causatively associated with cancer of the oral cavity. Since most epidemiologic studies to date relate to the long-term use of dry snuff, which has dominated the U.S. smokeless tobacco market in the past, the concentrations of several toxic and carcinogenic agents in the three most popular dry snuff brands have been compared with those in the five most popular moist snuff brands sold in the United States. All eight samples were analyzed for nitrate, alkaloids, polyphenols, volatile carbonyl compounds, lead, cadmium, selenium, and the carcinogenic compounds benzo[a]pyrene (CAS: 50-32-8), polonium-210 (CAS: 13981-52-7), volatile N-nitrosamines (VNAs), N-nitrosodiethanolamine (CAS: 1116-54-7), and the tobacco-specific N-nitrosamines (TSNAs). Most of the snuff brands were rich in nitrate (greater than or equal to 1.5%), total polyphenols (greater than 2%), and in nicotine (greater than or equal to 1.5%), which is the habituating factor in tobacco use. Concentrations of the VNAs were significantly above the permissible limits set for some food products; the concentrations of the TSNAs in both snuff types exceeded the levels of nitrosamines in other consumer products by at least two to three orders of magnitude. The extremely high levels of the TSNAs in snuff have remained unchanged during the last decade and present the major carcinogenic risk factor for the oral use of snuff. Polonium-210 contributes further to the carcinogenic risk associated with snuff. The chemical-analytical data presented in this study do not indicate marked differences in the carcinogenic potential of moist snuff compared to dry snuff.
Acetone↗
A study of snuff carcinogenesis.
Dry snuff contains high levels of tobacco-specific N-nitrosamines (TSNA); their concentrations exceed by more than 100 times the quantities of nitrosamines found in any other consumer product. The concentrations of TSNA are similar in dry snuff and in the more popular moist snuff. In addition to the four TSNA identified earlier [N'-nitrosonornicotine (NNN), 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK), N'-nitrosoanatabine (NAT) and N'-nitrosoanabasine (NAB)], two new nitrosamines were detected in snuff, namely 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanol (NNAl; 0.07-0.15 ppm) and 4-(N-nitrosomethylamino)-4-(3-pyridyl)-1-butanol (iso-NNAl; 0.06-1.1 ppm). After oral swabbing with a mixture of NNN and NNK, rats developed tumours of the oral cavity and lung, showing that these TSNA are not only organ-specific carcinogens but can also induce local tumours. After swabbing an extract of snuff containing the same concentrations of NNN and NNK, significantly fewer tumours were induced in the oral cavity and lung, indicating inhibition of the tumorigenic activity of the TSNA by other snuff constituents.
Animals↗
The role of N-(nitrosomethylamino)propionitrile in betel-quid carcinogenesis.
N-(Nitrosomethylamino)propionitrile (NMAP) was isolated and identified in the saliva of betel-quid chewers in amounts ranging from 0.5 to 11.4 micrograms/l. Groups of 21 male and 21 female rats were given 60 subcutaneous injections of NMAP over a 20-week period (total doses, 0.055 and 0.23 mmol/rat). After 106 weeks, the higher dose had induced 18 (86%) malignant tumours of the nasal cavity in male and 15 (71%) in female rats. Nine (43%) liver tumours were observed among animals treated with the lower dose. Fischer 344 rats were treated with a single dose of NMAP (intravenously or subcutaneously, 0.4 mmol/kg; or by swabbing the oral cavity, 2.21 mmol/kg), and the levels of N7-methylguanine (7-meG) and O6-methylguanine (O6-meG) were measured in DNA isolated from oesophagus and nasal mucosa, which are target organs, and from liver which is not. Higher levels of O6-meG and 7-meG were detected in the nasal mucosa and lesser DNA methylation in the liver and oesophagus, independent of the mode of administration. This correlates with the results of the study of the tumorigenic properties of NMAP in rats.
Alkylation↗