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Stephen S Hecht - One of the best experts on this subject based on the ideXlab platform.
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thirdhand tobacco smoke a tobacco specific lung Carcinogen on surfaces in smokers homes
Nicotine & Tobacco Research, 2014Co-Authors: Janet L Thomas, Stephen S Hecht, Xianghua Luo, Xun Ming, Jasjit S Ahluwalia, Steven G CarmellaAbstract:INTRODUCTION Thirdhand tobacco smoke consists of substances remaining on the surfaces or in the dust of areas where people have smoked. While previous studies have demonstrated the presence of nicotine and various other constituents of tobacco smoke on surfaces in smokers' homes, none has investigated the presence of tobacco-specific Carcinogens. METHODS We used liquid chromatography-tandem mass spectrometry to analyze surface dust samples from both the homes of smokers and nonsmokers for the powerful tobacco-specific lung Carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). RESULTS We positively identified NNK on surfaces in 33 of 37 smokers' homes (700±788 pg/100cm(2) [range, not detected-3,500 pg/100cm(2)]), but only in 3 of 19 nonsmokers' homes (235±176 pg/100cm(2) in the homes where NNK was detected [range, not detected-435 pg/100cm(2)]). The differences in occurrence and levels of NNK in the homes of smokers and nonsmokers were significant (p < .0001). CONCLUSIONS The powerful tobacco-specific lung Carcinogen NNK is present on surfaces in most homes occupied by smokers. Potential renters or buyers of apartments or homes should be notified if previous residents were smokers in order to avoid unnecessary exposure of their families to a potent lung Carcinogen.
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lung Carcinogenesis by tobacco smoke
International Journal of Cancer, 2012Co-Authors: Stephen S HechtAbstract:Cigarette smoke is a complex mixture of chemicals including multiple genotoxic lung Carcinogens. The classic mechanisms of Carcinogen metabolic activation to DNA adducts, leading to miscoding and mutations in critical growth control genes, applies to this mixture but some aspects are difficult to establish because of the complexity of the exposure. This article discusses certain features of this mechanism including the role of nicotine and its receptors; lung Carcinogens, co-Carcinogens and related substances in cigarette smoke; structurally characterized DNA adducts in the lungs of smokers; the mutational consequences of DNA adduct formation in smokers' lungs; and biomarkers of nicotine and Carcinogen uptake as related to lung cancer. While there are still uncertainties which may never be fully resolved, the general mechanisms by which cigarette smoking causes lung cancer are well understood and provide insights relevant to prevention of lung cancer, the number one cancer killer in the world, causing 1.37 million deaths per year.
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Carcinogen derived biomarkers applications in studies of human exposure to secondhand tobacco smoke
Tobacco Control, 2004Co-Authors: Stephen S HechtAbstract:Objective: To review the literature on Carcinogen derived biomarkers of exposure to secondhand tobacco smoke (SHS). These biomarkers are specifically related to known Carcinogens in tobacco smoke and include urinary metabolites, DNA adducts, and blood protein adducts. Method: Published reviews and the current literature were searched for relevant articles. Results: The most consistently elevated biomarker in people exposed to SHS was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Gluc), urinary metabolites of the tobacco specific lung Carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The tobacco specificity of this biomarker as well as its clear relation to an established lung Carcinogen are particularly appropriate for its application in studies of SHS exposure. Conclusion: The results of the available Carcinogen derived biomarker studies provide biochemical data which support the conclusion, based on epidemiologic investigations, that SHS causes lung cancer in non-smokers.
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tobacco Carcinogens their biomarkers and tobacco induced cancer
Nature Reviews Cancer, 2003Co-Authors: Stephen S HechtAbstract:The devastating link between tobacco products and human cancers results from a powerful alliance of two factors — nicotine and Carcinogens. Without either one of these, tobacco would be just another commodity, instead of being the single greatest cause of death due to preventable cancer. Nicotine is addictive and toxic, but it is not Carcinogenic. This addiction, however, causes people to use tobacco products continually, and these products contain many Carcinogens. What are the mechanisms by which this deadly combination leads to 30% of cancer-related deaths in developed countries, and how can Carcinogen biomarkers help to reveal these mechanisms?
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human urinary Carcinogen metabolites biomarkers for investigating tobacco and cancer
Carcinogenesis, 2002Co-Authors: Stephen S HechtAbstract:Measurement of human urinary Carcinogen metabolites is a practical approach for obtaining important information about tobacco and cancer. This review presents currently available methods and evaluates their utility. Carcinogens and their metabolites and related compounds that have been quantified in the urine of smokers or non-smokers exposed to environmental tobacco smoke (ETS) include trans,trans-muconic acid (tt-MA) and S-phenylmercapturic acid (metabolites of benzene), 1- and 2-naphthol, hydroxyphenanthrenes and phenanthrene dihydrodiols, 1-hydroxypyrene (1-HOP), metabolites of benzo[a]pyrene, aromatic amines and heterocyclic aromatic amines, N-nitrosoproline, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (NNAL and NNAL-Gluc), 8-oxodeoxyguanosine, thioethers, mercapturic acids, and alkyladenines. Nitrosamines and their metabolites have also been quantified in the urine of smokeless tobacco users. The utility of these assays to provide information about Carcinogen dose, delineation of exposed vs. non-exposed individuals, and Carcinogen metabolism in humans is discussed. NNAL and NNAL-Gluc are exceptionally useful biomarkers because they are derived from a Carcinogen- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- that is specific to tobacco products. The NNAL assay has high sensitivity and specificity, which are particularly important for studies on ETS exposure. Other useful assays that have been widely applied involve quantitation of 1-HOP and tt-MA. Urinary Carcinogen metabolite biomarkers will be critical components of future studies on tobacco and human cancer, particularly with respect to new tobacco products and strategies for harm reduction, the role of metabolic polymorphisms in cancer, and further evaluation of human Carcinogen exposure from ETS.
Daniel R. Dietrich - One of the best experts on this subject based on the ideXlab platform.
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Time-matched analysis of DNA adduct formation and early gene expression as predictive tool for renal Carcinogenesis in methylazoxymethanol acetate treated Eker rats
Archives of toxicology, 2017Co-Authors: Valentina Klaus, Heinke Bastek, Katja Damme, Leonard B. Collins, Roland Frötschl, Norbert Benda, Dominik Lutter, Heidrun Ellinger-ziegelbauer, James A. Swenberg, Daniel R. DietrichAbstract:Genotoxic Carcinogens pose great hazard to human health. Uncertainty of current risk assessment strategies and long latency periods between first Carcinogen exposure and diagnosis of tumors have raised interest in predictive biomarkers. Initial DNA adduct formation is a necessary step for genotoxin induced Carcinogenesis. However, as DNA adducts not always translate into tumorigenesis, their predictive value is limited. Here we hypothesize that the combined analysis of pro-mutagenic DNA adducts along with time-matched gene expression changes could serve as a superior prediction tool for genotoxic Carcinogenesis. Eker rats, heterozygous for the tuberous sclerosis (Tsc2) tumor suppressor gene and thus highly susceptible towards genotoxic renal Carcinogens, were continuously treated with the DNA alkylating Carcinogen methylazoxymethanol acetate (MAMAc). Two weeks of MAMAc treatment resulted in a time-dependent increase of O6-methylguanine and N7-methylguanine adducts in the kidney cortex, which was however not reflected by significant expression changes of cyto-protective genes involved in DNA repair, cell cycle arrest or apoptosis. Instead, we found a transcriptional regulation of genes involved in the tumor-related MAPK, FoxO and TGF-beta pathways. Continuous MAMAc treatment for up to 6 months resulted in a mild but significant increase of cancerous lesions. In summary, the combined analysis of DNA adducts and early gene expression changes could serve as a suitable predictive tool for genotoxicant-induced Carcinogenesis.
Karam Elbayoumy - One of the best experts on this subject based on the ideXlab platform.
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ploidy differences between hormone and chemical Carcinogen induced rat mammary neoplasms comparison to invasive human ductal breast cancer
Molecular Carcinogenesis, 2002Co-Authors: Dan Papa, Karam Elbayoumy, Marilyn Davis, John S Weroha, Marcelo C Aldaz, Jodi Ballenger, Ossama TawfikAbstract:To ascertain differences between solely hormone– and chemical Carcinogen–induced murine mammary gland tumors (MGTs), a direct comparison of their ploidy status was assessed. Nuclear image cytometry (NIC) was used to evaluate ploidy in ductal carcinoma in situ (DCIS) and MGTs induced solely by 17β-estradiol (E2) in female A-strain Copenhagen Irish hooded gene rats (ACI) and E2 plus testosterone propionate in male Noble rats. These results were compared to ploidy data from primary MGTs induced by two synthetic Carcinogens, 7,12-dimethylbenz[a]antracene and nitrosomethylurea in female Brown Lewis Norway rats and an environmental Carcinogen, 6-nitrochrysene, in female Sprague-Dawley rats. Both DCIS and primary MGTs induced solely by hormones were highly aneuploid (> 84%), whereas MGTs induced by either synthetic or environmental Carcinogens were primarily diploid (> 85%). Examination of 76 metaphase plates obtained from eight individual E2-induced ACI female rat MGTs revealed the following consistent chromosome alterations: gains in chromosomes 7, 11, 12, 13, 19, and 20 and loss of chromosome 12. On Southern blot analysis, six of nine ACI female rat primary E2-induced MGTs (66%) exhibited amplified copy numbers (range: 3.4–6.9 copies) of the c-myc gene. Fluorescence in situ hybridization (FISH) analysis of these MGTs revealed specific fluorescent hybridization signals for c-myc (7q33) on all three homologs of a trisomy in chromosome 7. NIC analysis of 140 successive nonfamilial sporadic invasive human ductal breast cancers (BCs) showed an aneuploid frequency of 61%, while 31 DCISs revealed a 71% aneuploid frequency. These results clearly demonstrate that the female ACI rat E2-induced MGTs more closely resemble invasive human DCIS and ductal BC in two pertinent aspects: they are highly aneuploid compared with chemical Carcinogen–induced MGTs and exhibit a high frequency of c-myc amplification. © 2002 Wiley-Liss, Inc.
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chemoprevention of lung tumorigenesis induced by a mixture of benzo a pyrene and 4 methylnitrosamino 1 3 pyridyl 1 butanone by the organoselenium compound 1 4 phenylenebis methylene selenocyanate
Cancer Letters, 2000Co-Authors: Bogdan Prokopczyk, Jose Rosa, Shantu Amin, Dhimant Desai, Ock Soon Sohn, Emerich S. Fiala, Karam ElbayoumyAbstract:We evaluated the chemopreventive efficacy of the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) against the development of tumors of the lung and forestomach induced by a mixture of benzo(a)pyrene (B(a)P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), two of the major lung Carcinogens present in tobacco smoke. A/J mice (20 mice/group) were given intragastric doses of a mixture of B(a)P (3 μmol/mouse) and NNK (3 μmol/mouse) in cottonseed oil (0.1 ml) once a week for eight consecutive weeks. Mice were fed either AIN-76A control diet or control diet containing p-XSC (10 ppm selenium), either during or after Carcinogen administration. Dietary p-XSC significantly reduced lung tumor multiplicity, regardless of whether it was given during or after Carcinogen administration. p-XSC was also an effective inhibitor of tumor development in the forestomach. To provide some biochemical insights into the protective role of p-XSC, its effect on selected phase I and II enzyme activities involved in the metabolism of NNK and B(a)P was also examined in vivo in this animal model. Dietary p-XSC significantly inhibited the activities of the phase I enzymes, methoxyresorufin O-dealkylase (MROD) and N-nitrosodimethylamine N-demethylase (NDMAD), in mouse liver, but it had no effect on ethoxyresorufin O-dealkylase (EROD), pentoxyresorufin O-dealkylase (PROD), and erythromycin N-demethylase (ERYTD). Total glutathione S-transferase (GST) enzyme activity, as well as GST-π and GST-μ enzyme activities, were significantly induced by dietary p-XSC in both the lung and liver. Glutathione peroxidase (GPX) activity was also induced by p-XSC in mouse lung, but not in the liver. Dietary p-XSC had no effect on selenium-dependent glutathione peroxidase (GPXSe), GST-α, and UDP-glucuronosyl transferase (UDPGT) enzyme activities in either the lung or the liver. These studies suggest that the chemopreventive efficacy of p-XSC, when fed during Carcinogen administration, may be, in part, due to the inhibition of certain phase I enzymes involved in the metabolic activation of these Carcinogens, and the induction of specific phase II enzymes involved in their detoxification. The mechanisms that account for the effect of p-XSC when fed after Carcinogen administration remain to be determined.
Cheryl E Peters - One of the best experts on this subject based on the ideXlab platform.
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the current burden of cancer attributable to occupational exposures in canada
Preventive Medicine, 2019Co-Authors: Chaojie Song, Cheryl E Peters, Manisha Pahwa, Calvin Ge, Victoria H Arrandale, Christopher B McleodAbstract:Abstract Exposure to occupational Carcinogens is often overlooked as a contributor to the burden of cancer. To estimate the proportion of cancer cases attributable to occupational exposure in Canada in 2011, exposure prevalence and levels of 44 Carcinogens were informed by data from the Canadian Carcinogen exposure surveillance project (CAREX Canada). These were used with Canadian Census (between 1961 and 2011) and Labour Force Survey (annual surveys between 1976 and 2013) data to estimate the number of workers ever exposed to occupational Carcinogens. Risk estimates of the association between each Carcinogen and cancer site were selected mainly from published literature reviews. Population attributable risks were estimated using Levin's equation and applied to the 2011 cancer statistics from the Canadian Cancer Registry. It is estimated that 15.5 million Canadians alive in 2011 were exposed, during at least one year between 1961 and 2001, to at least one Carcinogen in the workplace. Overall, we estimated that in 2011, between 3.9% (95% CI: 3.1%–8.1%) and 4.2% (95% CI: 3.3%–8.7%) of all incident cases of cancer were due to occupational exposure, corresponding to lower and upper numbers of 7700–21,800 cases. Five of the cancer sites – mesothelioma, non-melanoma skin cancer, lung, female breast, and urinary bladder – account for a total of 7600 to 21,200 cancers attributable to occupational exposures such as solar radiation, asbestos, diesel engine exhaust, crystalline silica, and night shift work. Our study highlights cancer sites and occupational exposures that need recognition and efforts by all stakeholders to avoid preventable cancers in the future.
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carex canada an enhanced model for assessing occupational Carcinogen exposure
Occupational and Environmental Medicine, 2015Co-Authors: Cheryl E Peters, Amy L Hall, Hugh W Davies, Paul A DemersAbstract:Objectives To estimate the numbers of workers exposed to known and suspected occupational Carcinogens in Canada, building on the methods of Carcinogen EXposure (CAREX) projects in the European Union (EU). Methods CAREX Canada consists of estimates of the prevalence and level of exposure to occupational Carcinogens. CAREX Canada includes occupational agents evaluated by the International Agency for Research on Cancer as known, probable or possible human Carcinogens that were present and feasible to assess in Canadian workplaces. A Canadian Workplace Exposure Database was established to identify the potential for exposure in particular industries and occupations, and to create exposure level estimates among priority agents, where possible. CAREX EU data were reviewed for relevance to the Canadian context and the proportion of workers likely to be exposed by industry and occupation in Canada was assigned using expert assessment and agreement by a minimum of two occupational hygienists. These proportions were used to generate prevalence estimates by linkage with the Census of Population for 2006, and these estimates are available by industry, occupation, sex and province. Results CAREX Canada estimated the number of workers exposed to 44 known, probable and suspected Carcinogens. Estimates of levels of exposure were further developed for 18 priority agents. Common exposures included night shift work (1.9 million exposed), solar ultraviolet radiation exposure (1.5 million exposed) and diesel engine exhaust (781 000 exposed). Conclusions A substantial proportion of Canadian workers are exposed to known and suspected Carcinogens at work.
David H Phillips - One of the best experts on this subject based on the ideXlab platform.
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the role of cytochrome p450 enzymes in Carcinogen activation and detoxication an in vivo in vitro paradox
Carcinogenesis, 2018Co-Authors: Lindsay Reed, Volker M. Arlt, David H PhillipsAbstract:Many chemical Carcinogens require metabolic activation via xenobiotic-metabolizing enzymes in order to exert their genotoxic effects. Evidence from numerous in-vitro studies, utilizing reconstituted systems, microsomal fractions and cultured cells, implicates cytochrome P450 enzymes as being the predominant enzymes responsible for the metabolic activation of many proCarcinogens. With the development of targeted gene disruption methodologies, knockout mouse models have been generated that allow investigation of the in-vivo roles of P450 enzymes in the metabolic activation of Carcinogens. This review covers studies in which five proCarcinogens representing different chemical classes, benzo[a]pyrene, 4-aminobiphenyl (4-ABP), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 2-amino-9H-pyrido[2,3-b]indole and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, have been administered to different P450 knockout mouse models. Paradoxically, while in-vitro studies using subcellular fractions enriched with P450 enzymes and their cofactors have been widely used to determine the pathways of activation of Carcinogens, there is evidence from the in-vivo studies of cases where these same enzyme systems appear to have a more predominant role in Carcinogen detoxication rather than activation.
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smoking related dna and protein adducts in human tissues
Carcinogenesis, 2002Co-Authors: David H PhillipsAbstract:Tobacco smoking causes not only lung cancer but also cancer of the oral and nasal cavities, oesophagus, larynx, pharynx, pancreas, liver, kidney, stomach, urinary tract and cervix. Tobacco smoke contains many Carcinogens that exert their biological effects through interaction of reactive intermediates with DNA to form DNA adducts. The same electrophilic species also react with cellular proteins. The effects of smoking are evident by the detection of elevated levels of Carcinogen-DNA adducts in many human tissues and of Carcinogen-protein adducts in blood. Components of tobacco smoke also induce oxidative DNA damage. Systemic exposure to tobacco-derived Carcinogens is demonstrated by the observation of elevated levels of DNA adducts in tissues not directly exposed to tobacco smoke. For many of these tissues there is epidemiological evidence, varying from comprehensive to preliminary, that smoking is a causative factor in cancer of that site. The effects of passive smoking, which also causes lung cancer in non-smokers, is also evident in elevated levels of protein adducts in exposed non-smokers so exposed, relative to non-exposed non-smokers. This paper reviews the literature on smoking-related DNA and protein adducts in human tissues and shows how such studies have provided mechanistic insight into the epidemiological associations between smoking and cancer.
