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Smokeless tobacco consumption, which is widespread throughout the world, leads to oral submucous fibrosis (OSMF), which is a long-lasting and devastating condition of the oral cavity with the potential for malignancy. In this review, we mainly focus on the consumption of smokeless tobacco, such as paan and gutkha , and the role of these substances in the induction of OSMF and ultimately oral cancer. The list of articles to be examined was established using citation discovery tools provided by PubMed, Scopus, and Google Scholar. The continuous chewing of paan and swallowing of gutkha trigger progressive fibrosis in submucosal tissue. Generally, OSMF occurs due to multiple risk factors, especially smokeless tobacco and its components, such as betel quid, areca nuts, and slaked lime, which are used in paan and gutkha . The incidence of oral cancer is higher in women than in men in South Asian countries. Human oral epithelium cells experience carcinogenic and genotoxic effects from the slaked lime present in the betel quid, with or without areca nut. Products such as 3-(methylnitrosamino)-proprionitrile, nitrosamines, and nicotine initiate the production of reactive oxygen species in smokeless tobacco, eventually leading to fibroblast, DNA, and RNA damage with carcinogenic effects in the mouth of tobacco consumers. The metabolic activation of nitrosamine in tobacco by cytochrome P450 enzymes may lead to the formation of N-nitrosonornicotine, a major carcinogen, and micronuclei, which are an indicator of genotoxicity. These effects lead to further DNA damage and, eventually, oral cancer.

Earlier studies have investigated the tumor suppressor gene p53 as a co-factor in the development of oral squamous cell carcinoma (OSCC). Our previous studies have indicated that chronic use of Sudanese snuff (toombak) and the presence of human papilloma virus (HPV) may be involved in the high prevalence of OSCC in Sudan. This study investigated the prevalence of p53 codon 72 polymorphism in brush biopsies obtained from a Sudanese population. A total of 174 individuals were included in the study; chronic toombak users (n=152) and non-users (n=22). DNA was extracted from all the samples and genotyped for the codon 72 polymorphism by polymerase chain reaction/restriction fragment length polymorphism. The Arg/Pro genotype was found in 53% of the 174 study participants, compared to 21% found with Arg/Arg and 26% found with Pro/Pro. Stratifying by toombak use, 28 (18%), 45 (29%) and 79 (52%) of the 152 samples from toombak users had Arg/Arg, Pro/Pro and Arg/Pro respectively, compared to 9 (41%), 0 (0%) and 13 (59%) found in the 22 samples from non users. The differences between the samples from toombak users and non users in Arg/Arg and Pro/Pro codon 72 polymorphism and HPV infection were statistically significant (p<0.05). Our study indicated that a high prevalence of the genotype Arg/Pro at the p53 codon 72 may contribute to susceptibility to OSCC, especially in combination with the use of carcinogenic tobacco-specific nitrosamine (TSNA)-rich toombak. Our observations warrant an in-depth study for understanding the role of p53 polymorphism in human oral cancers.

Objectives: Telomeres are critical to maintain the integrity of the chromosomes, and telomere abnormalities are important features of carcinogenesis. Telomere length differs among individuals due to genetic and environmental factors. Aiming to examine the relationship between DNA-damaging agents and average telomere length in peripheral blood, we conducted a cross-sectional study among 157 workers working in the rubber industry in Sweden., Methods: N-nitrosamines were measured in air by personal sampling on Thermosorb/N tubes and analyzed by liquid chromatography tandem mass spectrometry (LC/MS/MS) for 60 individuals. Based on a similar working situation, the exposure was estimated for all workers. Polycyclic aromatic hydrocarbons (PAH) were measured as the metabolite 1-hydroxypyrene (1-HP) in urine by LC. Carbon disulphide (CS2) was measured as the metabolite 2-thiothiazolidine-4-carboxylic acid (TTCA) in urine by LC/MS/MS. Toluidines (orto-, meta-, and para-) were measured in urine by gas chromatography (GC)/MS. The average telomere length in peripheral blood was determined by quantitative polymerase chain reaction (PCR)., Results: There was a reduction in telomere length with increasing exposure to N-nitrosamines in air [measured (N=60) N-nitrosamines β-coefficient= -10, (95% confidence interval [95% CI] -17- -1.9) P=0.016; estimated (N=157) N-nitrosamines β-coefficient = -5.3, (95% CI -9.5- -0.97) P=0.016]. Also, there were negative associations between para-toluidine [β-coefficient= -0.031 (95% CI -0.055- -0.0063) P=0.014], as well as age β-coefficient= -0.005 (95% CI -0.007- -0.002) P=0.001] and telomere length. There were no strong associations between other exposures and telomere length nor did smoking modify the effect., Conclusion: N-nitrosamines exposure may lead to telomere shortening.

Background: Previous epidemiologic studies found inconsistent results for the association between red meat intake, nitrosamines [NDMA: N-nitrosodimethylamine, and ENOC (endogenous nitroso compounds)], and the risk of bladder cancer. We investigated the association between red meat consumption, dietary nitrosamines, and heme iron and the risk of bladder cancer among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)., Methods: Data on food consumption and complete follow-up for cancer occurrence were available for a total of 481,419 participants, recruited in 10 European countries. Estimates of HRs were obtained by proportional hazard models, stratified by age at recruitment, gender, and study center and adjusted for total energy intake, smoking status, lifetime intensity of smoking, duration of smoking, educational level, and BMI., Results: After a mean follow-up of 8.7 years, 1,001 participants were diagnosed with bladder cancer. We found no overall association between intake of red meat (log2 HR: 1.06; 95% CI: 0.99-1.13), nitrosamines (log2 HR: 1.09; 95% CI: 0.92-1.30 and HR: 0.98; 95% CI: 0.92-1.05 for ENOC and NDMA, respectively) or heme iron (log2 HR: 1.05; 95 CI: 0.99-1.12) and bladder cancer risk. The associations did not vary by sex, high- versus low-risk bladder cancers, smoking status, or occupation (high vs. low risk)., Conclusions: Our findings do not support an effect of red meat intake, nitrosamines (endogenous or exogenous), or heme iron intake on bladder cancer risk., (©2011 AACR.)

Objectives: The aim of this study was twofold: (i) to evaluate the air levels of N-nitrosamines in the Swedish rubber industry and (ii) to estimate the risk of symptoms and changed levels of immunologic markers in relation to these levels., Methods: Using adsorption tubes, we collected samples of N-nitrosamines in the breathing zone of 96 rubber workers and analyzed them with liquid chromatography tandem mass spectrometry. Of these 96 workers, 66 were included in a medical examination and blood analysis together with an additional 106 rubber workers and 118 unexposed subjects. Medical and occupational histories were obtained in structured interviews, symptoms were recorded and immunologic markers analyzed in blood., Results: The sum of N-nitrosamines ranged from less than the limit of detection to 36 microg/m (3)and differed with the vulcanization (ie, curing process) method used. Workers vulcanizing with a salt bath had the highest levels (median 4.2 microg/m (3)). Compared to the unexposed subjects, the rubber workers had an increased risk of nosebleeds, eye and throat symptoms, hoarseness, cough, nausea, headache, and changed levels of eosinophils and total immunoglobulin G (IgG). However, we found no clear exposure-response relationship with the symptoms or the immunologic markers studied., Conclusions: High levels of N-nitrosamines were found and must be lowered considerably in order to decrease the risk of cancer. There is a need for an occupational exposure limit for N-nitrosamines in Sweden. The lack of exposure-response relationships with the subacute symptoms examined in this study may be due to a healthy-worker selection or to the possibility that the symptoms are caused by an exposure not co-varying with N-nitrosamines.

Nitrosamines mediate their mutagenic effects by causing DNA damage, oxidative stress, lipid peroxidation, and pro-inflammatory cytokine activation, which lead to increased cellular degeneration and death. However, the very same pathophysiological processes comprise the "unbuilding" blocks of aging and insulin-resistance diseases including, neurodegeneration, diabetes mellitus (DM), and non-alcoholic steatohepatitis (NASH). Previous studies demonstrated that experimental exposure to streptozotocin, a nitrosamine-related compound, causes NASH, and diabetes mellitus Types 1, 2 and 3 (Alzheimer (AD)-type neurodegeneration). Herein, we review evidence that the upwardly spiraling trends in mortality rates due to DM, AD, and Parkinson's disease typify exposure rather than genetic-based disease models, and parallel the progressive increases in human exposure to nitrates, nitrites, and nitrosamines via processed/preserved foods. We propose that such chronic exposures have critical roles in the pathogenesis of our insulin resistance disease pandemic. Potential solutions include: 1) eliminating the use of nitrites in food; 2) reducing nitrate levels in fertilizer and water used to irrigate crops; and 3) employing safe and effective measures to detoxify food and water prior to human consumption. Future research efforts should focus on refining our ability to detect and monitor human exposures to nitrosamines and assess early evidence of nitrosamine-mediated tissue injury and insulin resistance.

Whereas the impact of tobacco specific nitrosamines in smokers is obscured by the presence of numerous other carcinogens and promoters, for smokeless tobacco virtually all the carcinogenic potential is associated with 4-(nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). In some countries exposure to smokeless tobacco with extremely high nitrosamine concentrations have been found to induce cancers in the head-neck region, whereas three recent large epidemiological studies failed to detect any such risk with respect to Swedish low-nitrosamine snuff. This review deals with quantitative aspects of DNA adduct formation from NNN and NNK in relation to the background levels ubiquitously found in healthy humans without known exposures to either tobacco or alkylating agents. The lack of significant increases of pro-mutagenic O6-methylations and DNA pyridyloxobutylations seen in smokers, as well as the negative outcome of the Swedish epidemiological studies, can be expected on basis of extrapolation of the dose response relationships found in rodents to actual exposures to NNK and NNN in Swedish snuff or from smoking. Sweden has the lowest prevalence of male smokers and smoking related diseases in the Western World, which has been ascribed to the fact that more than 20% of the grown up male population uses snuff. Smokeless tobacco represents an inexpensive and effective alternative to nicotine delivering products like nicotine patch, spray or gum. Considering that all other tobacco products are freely marketed, the ban on low-nitrosamine snuff in all countries in EU except Sweden is difficult to defend on either medical or ethical grounds.

Limited data are available on the carcinogenicity of smokeless tobacco products in organs other than the mouth. Snus is a smokeless tobacco product widely used in Norway. We studied 10,136 Norwegian men enrolled since 1966 in a prospective cohort study, 31.7% of whom were exposed to snus. The relative risk of pancreatic cancer for snus use was 1.67 (95% confidence interval [CI] = 1.12, 2.50); that of oral and pharyngeal cancer was 1.10 (95% CI = 0.50, 2.41), that of esophageal cancer was 1.40 (95% CI = 0.61, 3.24), and that of stomach cancer was 1.11 (95% CI = 0.83, 1.48). The relative risks of cancers of the lung (either all histological types or adenocarcinoma), urinary bladder and kidney were not increased among snus users. The increase in the relative risk of pancreatic cancer was similar in former and current snus users and was restricted to current tobacco smokers. Our study suggests that smokeless tobacco products may be carcinogenic on the pancreas. Tobacco-specific N-nitrosamines are plausible candidates for the carcinogenicity of smokeless tobacco products in the pancreas.

This paper will provide wastewater treatment utility professionals with a comprehensive synthesis of information pertinent to N-nitrosodimethylamine (NDMA) so that plant operators can make informed and cost-effective decisions regarding appropriate management techniques. A suspect disinfection byproduct, NDMA is a potential carcinogen and is presently under scrutiny from the U.S. Environmental Protection Agency because it poses a threat to groundwaters from reclaimed wastewaters. Recognizing that the current state of knowledge pertaining to the occurrence and treatment of NDMA from wastewater treatment is in its infancy, the information presented in this paper is timely and will help utility professionals develop confidence toward controlling NDMA during wastewater treatment. Given the increased probability of the formation of NDMA using current wastewater treatment technologies and also in the complex matrices of the wastewaters subjected to UV treatment, the investigation of occurrence pathways and means of suppression of NDMA formation before and after treatment needs to be investigated. This paper also summarizes strategies to minimize exposure such as modifying treatment or instituting waste and agricultural management practices that minimize inorganic and organic nitrogen discharges to wastewaters.

The modern cigarette is unnecessarily dangerous. Despite being lower in tar yield, and consequently in squamo-carcinogenic polyaromatic hydrocarbons such as benzo[a]pyrene, the nitrosamine yields are often higher than they need to be. Also, reductions in tar levels have not led to the consequential reductions in mortality that were anticipated several decades ago. The modern cigarette is also smoother, easier to smoke and to learn how to smoke, highly addictive and facilitates compensatory smoking. Compensatory smoking leads to excess inhalation of carcinogens and toxins in the hunt for nicotine. Its labelling is misleading in that supposedly low-yielding cigarettes may, due to compensation occurring as a result of cigarette design, lead to inhalation of much higher amounts of nicotine, carcinogens and toxins than the smoker is led to expect. Regulation of the product is needed to provide the persistent smoker with a cigarette lower in risk, accurately labelled, providing a relatively consistent and known dose of nicotine, and less likely to facilitate compensatory smoking. This will not produce a safe cigarette but should result in a reduction in harm if seriously implemented.

Water soluble exogenous compounds are commonly excreted by the kidneys, but most of the exogenous substances are lipid soluble and have therefore first to be metabolized in the liver to water soluble compounds. Depending upon the nature of the chemical compound, the metabolism in the liver leads either to detoxification or toxification. Alcohol belongs to the most important substances which may cause severe liver injury. Alterations of the liver due to hydrocarbons as well as carcinogens, mycotoxins and thorium dioxide are relatively rare. Compounds such as analgesic and antiarrhythmic drugs, antibiotics, oral antidiabetic agents, antihypertensive and antirheumatic agents, chemotherapeutic drugs, hormones, laxatives, psychotropic drugs, thyreostatic and antineoplastic agents may also cause liver injury. For establishing the diagnosis, a detailed past history is required especially with respect to alcohol and drug consumption as well as regarding occupational exposure towards toxic compounds. Although the determination of liver enzyme activities in the serum may give some indication for liver cell injury, the histological examination of the liver by needle biopsy is required for the diagnosis. The therapy consists of the exclusion of the toxic compound and, if possible, of an increased elimination of the ingested toxins.

Alpha1-fetoprotein (AFP) was detected by serological, light and electron microscopic methods in various experimental models. These included (a) liver regeneration after partial hepatectomy or CCl4 intoxication (mouse and rat); (b) liver intoxication by high doses of N-nitrosomorpholine (NNM) and chemical induction of hepatomas (rat). AFP levels varied greatly according to the animal species and strains used. Low and high AFP-producing species and strains were distinguished. In liver regeneration after hepatectomy or CCl4 intoxication, cellular AFP was found in the cytoplasm of hepatocytes. In NNM-intoxicated livers, elevated AFP levels were associated with proliferation of canalicular epithelial cells in which AFP was localized. In early stages of hepatocarcinogenesis, significant AFP increase occurred after high-dose carcinogen feeding and AFP was also localized in proliferating canalicular epithelial cells. On low-dose NNM feeding, no cellular AFP was detected unless hepatomas had developed. At the stage of malignant conversion, distinct AFP staining and non-AFP staining hepatocellular carcinomas appeared in livers.

The epidemiology of nasopharyngeal cancer (NPC) has been compared with that of other pharyngeal cancers in Los Angeles County. Epstein-Barr virus (EBV) antibody titers were elevated in Caucasians with pharyngeal squamous cell carcinomas regardless of subsite. As expected, an excess of NPC cases was found among Chinese. The role of various etiologic factors in NPC including EBV, inhaled carcinogens, and salted fish was discussed.

During 1955--1974, forty cases of oesophageal cancer were diagnosed among indigenous Greenlanders. The annual incidence rates per 100,000, age adjusted to the "world" population, were 16.3 for males and 11.8 for females in 1955--1964. The corresponding rates in 1965--1974 were 15.9 for males and 6.7 for females with a male:feamle ratio of 2.4:1. These rates rank among the moderately high rates found in India, Puerto Rico and France and in the black population in the US. Age distribution, anatomical location and prognosis followed the normal pattern for oesophageal cancer disease. No particular occupational trend was apparent and there was no difference between towns and settlements. However, a statistically significant geographical gradient of frequency was found with higher rates in the southernmost 3 districts. The traditional Greenland diet may contain concentrations of precursors sufficient to create carcinogenic levels of nitrosamines. Further studies are needed in particular of environmental factors such as foodstuffs, homebrewed beer, drinking water and cigarette smoking. Attention should be focused on the special ecological conditions in southern Greenland.

An appraisal is made of these chemical carcinogens available in the human environment that have been implicated in the etiology of liver cancer. The possible role of mycotoxins is discussed in detail, in particular the association between the aflatoxins and liver cancer in Africa and the Far East.

Volatile nitrosamines were determined in alcoholic drinks during epidemiologic studies on the relationship between esophageal cancer incidence and alcohol consumption in Normandy, France. Nitrosodimethylamine (NDMA) was found commonly in most alcoholic drinks tested, with the exception of wine. The average level, about 2 micrograms/liter in beers, was higher than that for other drinks; the range was 0.2--8.6 micrograms/liter. Traces of nitrosodiethylamine (NDEA) were also detected in spirits and ciders. No significant increases in levels were found after nitrosation. Calculation of daily intake in the study region showed that the main intake of volatile nitrosamine is from NDMA in beer. The intake of NDEA through consumption of cider is about one-third that of NDMA from all sources.

A simple, highly effective and economical method is developed for conversion of polyamines/putrescine, spermidine and spermine into their chlorhyndrates with a yield about 100%. The melting points of the preparations obtained and those available from "Serva" /FRG/ were identical; all the preparations were oxidized by diamine oxidase from rat liver tissue at the same rate. Tissues of transplanted hepatomas and malignant liver exhibited an absolute inability to oxidative deamination. The diamine oxidase activity in regenerating liver tissue was similar to the rate of deamination, estimated in liver tissue of sham-operated animals.

Diethylnitrosamine (NDEA) was administered subcutaneously to non-icteric and icteric Gunn rats. A single dose led predominantly to liver cell tumours. The average survival times and tumour latencies were not dose dependent, but a slightly raised tumour multiplicity was observed in icteric animals. The minimal effective dose was apparently less than 0.05 LD50 and more than 0.025 LD50. Chronic treatment in Gunn rats revealed dose response relationships for body weight development, average survival times and tumour latencies. The most common tumours found in the liver of both non-icteric and icteric animals were hepatocellular neoplasms followed by cholangiocellular tumours and haemangio-endotheliomas. Neoplastic growth was also found in the respiratory tract and upper digestive tract. The maximal effective carcinogenic dose for non-icteric and icteric rats was 0.1 LD50. The carcinogenic effect of NDEA in Gunn rats was only marginally influenced by the changes in the liver associated with icterus.

Gastrointestinal cancers, mainly oesophageal, gastric, pancreatic and large bowel cancer, account for about 40,000 deaths annually in England and Wales which is 32% of all cancer deaths. Nutritional factors have been implicated in the cause of each cancer and probably act by promoting the effect of carcinogenic substances taken in the diet or produced in the gut. Gastric cancer for example may be due to nitrosamine production in the stomach. This is enhanced by readily available sources of dietary nitrite and nitrate whilst the reaction is inhibited by vitamin C and low temperatures (2 degrees C). By contrast large bowel cancer can be related to high fat and meat intakes whilst a protective role for dietary fibre has been suggested. Dietary factors in the aetiology of oesophageal cancer differ from one high incidence area to another.

Both cooking and processing of food can produce toxic compounds in food, if the appropriate precursors are present. N-Nitrosamines, polycyclic aromatic hydrocarbons and phenolic compounds, lipid polymerisation products resulting from deep-fat frying, lipid oxidation products, Maillard-browning products and other products of protein reactions are discussed as well as their formation, concentration and control. The conclusion points out that contamination of human food is almost impossible to avoid and must be considered together with the beneficial effects of food processing on food safety, flavour, shelf-life and convenience.

The effect of administration of carbon tetrachloride and dimethylnitrosamine in vivo on hepatic microsomal function related to drug metabolism was measured. It was found that the capacity of isolated microsomes to demethylate dimethylaniline was diminished during the first hour after carbon tetrachloride poisoning and during the second hour after dimethylnitrosamine poisoning. Thereafter the microsomes from carbon tetrachloride-poisoned livers showed a continuous decline in activity so that at 24hr. there was little residual capacity to undertake demethylation. Microsomes from dimethylnitrosamine-poisoned animals were not different from controls at 24hr. During the first 3hr. there was a transient rise in the accumulation of the N-oxide intermediate in carbon tetrachloride-poisoned livers, with a subsequent fall to below control values. In dimethylnitrosamine poisoning there was a parallel decrease in N-oxide accumulation with decreased demethylation. In the latter part of the first 24hr. the ratio of N-oxide accumulation to demethylation was increased in both instances. At 2hr. after poisoning with either compound there was no evidence of altered NADPH(2)-dependent neotetrazolium reduction or lipid peroxidation. NADPH(2)-dependent azo-dye cleavage was decreased. There was no difference in microsomal cytochrome b(5) content, but there was a decrease in the amount of cytochrome P-450. This latter change was correlated with the decreased capacity for NADPH(2)-dependent oxidative demethylation. It is suggested that dimethylnitrosamine is associated with a defect in microsomal NADPH(2)-dependent electron transport at the level of cytochrome P-450. In addition to affecting cytochrome P-450, carbon tetrachloride is associated with a second severe block involving the release of formaldehyde from the N-oxide intermediate.