Carcinogenic Polynuclear Aromatic Hydrocarbons Research Articles

THE CHANGING CIGARETTE, 1950-1995

Nicotine is recognized to be the major inducer of tobacco dependence. The smoking of cigarettes as an advantageous delivery system for nicotine, accelerates and aggravates cardiovascular disease, and is causally associated with increased risks for chronic obstructive lung disease, cancer of the lung and of the upper aerodigestive system, and cancer of the pancreas, renal pelvis, and urinary bladder. It is also associated with cancer of the liver, cancer of the uterine cervix, cancer of the nasal cavity, and myeloid leukemia. In 1950, the first large-scale epidemiological studies documented that cigarette smoking induces lung cancer and described a dose-response relationship between number of cigarettes smoked and the risk for developing lung cancer. In the following decades these observations were not only confirmed by several hundreds of prospective and case-control studies but the plausibility of this causal association was also supported by bioassays and by the identification of carcinogens in cigarette smoke. Whole smoke induces lung tumors in mice and tumors in the upper respiratory tract of hamsters. The particulate matter of the smoke elicits benign and malignant tumors on the skin of mice and rabbits, sarcoma in the connective tissue of rats, and carcinoma in the lungs of rats upon intratracheal instillation. More than 50 carcinogens have been identified, including the following classes of compounds: polynuclear aromatic hydrocarbons (PAH), aromatic amines, and Nnitrosamines. Among the latter, the tobacco-specific N-nitrosamines (TSNA) have been shown to be of special significance. Since 1950, the makeup of cigarettes and the composition of cigarette smoke have gradually changed. In the United States, the sales-weighted average "tar" and nicotine yields have declined from a high of 38 mg "tar" and 2.7 mg nicotine in 1954 to 12 mg and 0.95 mg in 1992, respectively. In the United Kingdom, the decline was from about 32 mg "tar" and 2.2 mg nicotine to less than 12 mg "tar" and 1.0 mg nicotine per cigarette. During the same time, other smoke constituents changed correspondingly. These reductions of smoke yields were primarily achieved by the introduction of filter tips, with and without perforation, selection of tobacco types and varieties, utilization of highly porous cigarette paper, and incorporation into the tobacco blend of reconstituted tobacco, opened and cut ribs, and "expanded tobacco." In most countries where tobacco blends with air-cured (burley) tobacco are used, the nitrate content of the cigarette tobacco increased. In the United States nitrate levels in cigarette tobacco rose from 0.3-0.5% to 0.6-1.35%, thereby enhancing the combustion of the tobacco. More complete combustion decreases the carcinogenic PAH, yet the increased generation of nitrogen oxides enhances the formation of the carcinogenic N-nitrosamines, especially the TSNA in the smoke. However, all analytical measures of the smoke components have been established on the basis of standardized machine smoking conditions, such as those introduced by the Federal Trade Commission, that call for 1 puff to be taken once a minute over a 2-s period with a volume of 35 ml. These smoking parameters may have simulated the way in which people used to smoke the high-yield cigarettes; however, they no longer reflect the parameters applicable to contemporary smokers, and especially not those applicable to the smoking of low- and ultra-low-yield filter cigarettes. Recent smoking assays have demonstrated that most smokers of cigarettes with low nicotine yield take between 2 and 4 puffs per minute with volumes up to 55 ml to satisfy their demands for nicotine. The overview also discusses further needs for reducing the toxicity and carcinogenicity of cigarette smoke. From a public health perspective, nicotine in the smoke needs to be lowered to a level at which there is no induction of dependence on tobacco.

Spectrochemical Behavior of Carcinogenic Polynuclear Aromatic Hydrocarbons in Biological Systems. Part I: Steady-State Fluorometry of BaP and BeP in Living Cells

The rates of interactions of polycyclic aromatic hydrocarbons (PAHs) with biological cells studied with fluorescence appear to be different for cells from different origins. The monomer emission of benzo[ a]pyrene (BaP) is enhanced as in liposomes, but more significantly in normal liver cells than in liver cancer cells or kidney cells, and that enhancement is proportional to the amount of cells added. When PAHs are allowed to interact with cells for a certain period of time, metabolism appears to occur. The excimer emission is seen to dissipate continuously as reactions proceed, whereas the monomer emission increases, passes through a maximum, then starts to decrease when excimer emission becomes exhausted. The time plot of the BaP excimer emission in semilogarithmic coordinates indicates that the decrease or the mass transfer of microcrystalline BaP to the cell membrane is a first-order process. Metabolism has been investigated by monitoring the monomer emission. Liver cells have higher monomer emission than the kidney cells in the early stages of interaction, indicating that these cell membranes are more amenable to PAH absorption. Effects of vitamin K3 and radiation have also been investigated.

Synergistic activity of polynuclear aromatic hydrocarbon mixtures as aryl hydrocarbon (Ah) receptor agonists

The relative potencies of benzo[ a]pyrene and a complex mixture of polynuclear aromatic hydrocarbons (PAHs) produced as by-products of manufactured gas plant (MGP) residues as inducers of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity were determined in the B6C3F1 mouse. The ED 50 values for the induction response were 78 and 65 mg/kg for benzo[ a]pyrene and the MGP-PAH mixture, respectively. Analysis of the MGP-PAH mixture indicated that benzo[ a]pyrene and other compounds containing four or more rings and which are known to induce EROD activity were only present as trace components of this mixture. A comparison of the EROD induction potencies of benzo[ a]pyrene and the MGP-PAH mixture showed that the mixture was approximately 706 times more potent than expected based on its benzo[ a]pyrene content (0.17%). This induced P-450 activity could significantly increase the metabolism of the carcinogenic PAHs and thereby modulate the overall carcinogenicity of the mixture. The apparent synergistic activity of the MGP-PAH mixture was further investigated by comparing the activities of this mixture and benzo[ a]pyrene for several other aryl hydrocarbon (Ah) receptor-mediated responses including (i) induction of hepatic CYP1A1 mRNA levels, (ii) transformation of the rat cytosolic Ah receptor to a complex which binds to a dioxin responsive element, (iii) induction of EROD activity and (iv) antiestrogenicity in MCF-7 human breast cancer cells, and (v) inhibition of the splenic plaque-forming cell (PFC) response to both T cell-dependent and independent antigens in B6C3F1 mice. For the EROD and CYP1A1 mRNA induction and cytosolic transformation activities and immunosuppressive effects, the MGP-PAH mixture was approximately 100–900 times more potent as an Ah receptor agonist than expected based on its benzo[ a]pyrene content. The synergistic activity was lower (19-fold) for the antiestrogenic response in MCF-7 cells. The reason for the synergistic effects of the MGP-PAH mixture were not due to contamination of the mixture by 2,3,7,8-tetrachlorodibenzo- p-dioxin and related compounds and the results suggest that the enhanced potency of the mixture is due to unknown interactions between the individual PAHs present in the mixture.

ChemInform Abstract: Stereoelectronic Effects in the Deprotonation of Arylalkyl Radical Cations: meso‐Ethylanthracenes.

AbstractOxidations of the title compounds (III) and (IV) are performed to study further the "ethyl" effect, that is, the abolition of carcinogenic activity when certain otherwise carcinogenic polynuclear aromatic hydrocarbons are substituted at the meso position by an ethyl group.

Comparative carcinogenicity of the PAHs as a basis for acceptable exposure levels (AELs) in drinking water

The carcinogenicity of various polynuclear aromatic hydrocarbons (PAHs) has generally been demonstrated by their ability to act as complete carcinogens in the development of cancers in rodent skin tests. In order to develop proposed acceptable concentration levels for various PAHs in drinking water, we reviewed the studies that formed the basis for determining that these specific PAHs were carcinogenic in animals. We found that the relative potency of these PAHs varied over a range of many orders of magnitude. For example, the carcinogenic strength of benz aanthracene (BaA) is found to be about 1/2000th that of benzo apyrene (BaP). We have used the calculated carcinogenic potency of the various PAHs relative to that of BaP as a means for proposing specific acceptable concentration levels in drinking water for each of the specific PAHs. BaP is the only carcinogenic PAH for which EPA has published an acceptable concentration level based on carcinogenicity. Based on the level EPA set for BaP (0.028 μg/liter), this methodology has provided for the specific PAHs a determination of proposed acceptable concentration levels quantitatively based on the same data that were used to qualitatively determine them to be animal carcinogens. We have proposed acceptable concentration levels for the variinogenic PAHs in drinking water that range from 0.03 μg/liter for BaP to 6.5 μg/liter for BaA. We recommend that acceptable concentration levels for the various PAHs be based on their relative carcinogenic potencies rather than the EPA method of using the potency of only one specific PAH, BaP, to serve as the exposure level determinant for all PAHs. We further suggest that this methodology may be applicable to other classes of carcinogenic compounds. We have also found useful for the determination of acceptable concentration levels for the noncarcinogenic PAHs an analogous methodology based on the relative toxicities of the noncarcinogenic PAHs.

Gas chromatographic-mass spectrometric analysis of creosotes extracted from wooden sleepers installed in playgrounds.

In order to evaluate their hygienic risk, wood samples from sleepers (railroad cross ties) impregnated with coal tar creosote were taken from playgrounds and investigated for hazardous compounds. The samples were extracted with ether, and acid-base-neutral separations were made on the creosote extracts. Water-soluble compounds were also isolated. All the fractions were investigated by capillary gas chromatography-mass spectrometry. Besides phenols in the acidic fractions and N-heterocyclic polynuclear aromatic hydrocarbons (PAH) in the basic fractions, high amounts of neutral PAH and also, in several samples high levels of carcinogenic and cocarcinogenic PAH were determined.

Characterization and temperature dependence of PAH emissions from a simulated rubber combustion operation.

The operation investigated uses two induction furnaces for removal of rubber from tracked-vehicle treads. A laboratory-scale simulation of the field operation was employed to generate emissions at 399 degrees C (750 degrees F) and 677 degrees C (1250 degrees F), and emission samples were collected using glass fiber filters and Tenax as the sampling media. Sampling and analytical methods were developed and evaluated with 10 representative polynuclear aromatic hydrocarbons (PAH). High-pressure liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC/MS) were used to characterize emissions. The PAH were profiled as subsets and graphically displayed as micrograms (micrograms) of emissions per kilogram of rubber and as percentages of total emissions. In each subset, relative amounts of PAH were found to be related to combustion temperatures. Identical coal tar pitch volatiles (CTPV) exposures to emissions generated at the two temperatures studied would result in a 178-fold difference in exposure to carcinogenic PAH.

Liquid Chromatographic Determination of Trace Residues of Polynuclear Aromatic Hydrocarbons in Smoked Foods

A liquid chromatographic (LC) method was developed and applied to the determination of polynuclear aromatic hydrocarbons (PAHs) in a variety of smoked, market basket commodities. The PAHs are extracted with 1,1,2-trichloro-1,2,2-trifluoroethane (Freon 113) from alcoholic KOH digests of the commodities. The extracts are purified by column chromatography through a deactivated silica gel/alumina column and by liquid-liquid partitioning between dimethyl sulfoxide and cyclohexane before separation of the PAHs by LC. Both fluorescence and UV detectors are used to monitor the LC column effluent to detect nanogram quantities of PAHs. Trace levels of carcinogenic and non-carcinogenic PAHs were found in all samples analyzed, although generally at less than 1 ppb levels.

Specificity of Interaction between Carcinogenic Polynuclear Aromatic Hydrocarbons and Nuclear Proteins: Widespread Occurrence of a Restricted Pattern of Histone Binding in Intact Cells

The first steps in the induction of malignancy by chemical carcinogens involve covalent interactions with cellular macromolecules. For the widespread environmental contaminant benzo[a] pyrene (B[a]P), metabolic activation by cellular enzymes produces a number of potentially reactive metabolites. The end products of one metabolic pathway, 7,8-dihydroxy-9,10-oxy-7,8,9,10 tetrahydro-B[a]P (BPDE), are responsible for essentially all DNA adduct formation in animal cells treated with B[a]P, and a particular stereoisomer, designated (+)-anti-BPDE is thought to be the ultimate carcinogenic derivative of B[a]P. It has been shown that in hamster embryo cell nuclei treated with (+)-anti-BPDE, two of the histones of nucleosomal core, H3 and H2A are covalently modified, while the remaining core histones—H4 and H2B—are essentially unmodified. All four purified core histones, however, serve as the targets for (+)-anti-BPDE in vitro .

Human bronchus-mediated mutagenesis of mammalian cells by carcinogenic polynuclear aromatic hydrocarbons.

Cultured human bronchial explants activated benzo[alpha]pyrene (BzaP) into electrophilic metabolites that bind to DNA in bronchial epithelial cells. Promutagenic and mutagenic metabolites of BzaP were also released into the culture medium. An increase in mutation frequency for ouabain resistance was found in Chinese hamster V-79 cells when they were cocultivated with bronchial explants in the presence of BzaP. The proximate carcinogenic form of BzaP, the 7,8-diol [(+/-)-r7,t8-dihyroxy-7,8-dihydrobenzo[a]pyrene], was 5-fold more potent as a promutagen than the parent compound. Neither BzaP nor the 7,8-diol increased the mutation frequency in V-79 cells when they were cultured without bronchial explants. The mutation frequency was directly related to the binding levels of BzaP to bronchial DNA and the concentratin of either BzaP or the 7,8-diol in the medium.

Identification of polynuclear aromatic hydrocarbons in cigarette smoke and their importance as tumorigens.

Fraction F20, which in other studies was the most tumorigenic neutral fraction of cigarette smoke condensate (CSC), was separated by gel filtration chromatography into refined subfractions for identification of the polynuclear aromatic hydrocarbons (PAH) and for bioassay on mouse skin. Several hundred PAH were positively identified. Subfraction F55. containing most of the carcinogenic PAH as well as numerous unidentified components, was almost as tumorigenic to 7,12-dimethylbenze[a]anthracene (DMBA)-pretreated female outbred CD-1 mice as was F20. When F55 was separated into two parts, the first containing unidentified material (F55A) and the second containing the PAH (F55B), neither was significantly tumorigenic. F55B, combined with two other active fractions from the neutral and the acidic portions of CSC, exhibited a synergistic tumorigenic effect on DMBA-pretreated mice. The results supported the concept that the PAH in cigarette smoke must interact with other components in order to exert a tumorigenic effect.

Gas chromatography/mass spectrometric and nuclear magnetic resonance spectrometric studies of carcinogenic polynuclear aromatic hydrocarbons in tobacco and marijuana smoke condensates.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTGas chromatography/mass spectrometric and nuclear magnetic resonance spectrometric studies of carcinogenic polynuclear aromatic hydrocarbons in tobacco and marijuana smoke condensatesM. L. Lee, Milos. Novotny, and K. D. BartleCite this: Anal. Chem. 1976, 48, 2, 405–416Publication Date (Print):February 1, 1976Publication History Published online1 May 2002Published inissue 1 February 1976https://doi.org/10.1021/ac60366a048RIGHTS & PERMISSIONSArticle Views1033Altmetric-Citations169LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (818 KB) Get e-Alerts Get e-Alerts

Chemical Carcinogenesis and Experimental Models Using Human Tissues

The majority of human cancer is caused by environmental agents including chemical carcinogens. These chemical carcinogens are both naturally-occurring compounds and products of an industrialized society. Most of the environmental chemical carcinogens require enzymatic activation into electrophilic metabolites which readily react with cellular macromolecules leading, in some cases, to malignant transformation of target epithelial cells. Model systems for studying carcinogenesis in human target tissues are being developed to link investigations using experimental animals with human cancer. Metabolism of chemical carcinogens is being studied in human tissues maintained in these model systems. For example, a marked variation among individuals in their capacity to metabolize carcinogenic polynuclear aromatic hydrocarbons has been observed. This inter-individual variation may, in part, be due to genetic factors. Model systems using human tissues should be useful in several areas of cancer research including: 1) identifying environmental carcinogens, their metabolic pathways and host factors determining susceptibility; and 2) testing new methods of prophylatic intervention in populations at high risk of developing cancer.

Experimental bladder carcinogenesis--using cigarette smoke condensate in the rat bladder.

AbstractThe human and experimental evidence with carcinogenic polynuclear aromatic hydrocarbons and other active products in the genesis of bladder cancer nevertheless demonstrates the urgent need for an epidemiologic analysis of worker groups occupationally exposed to such chemicals. Sections of the general population may also inhale or ingest such chemicals with cigarette smoking or the drinking water polluted with industrial effluents. The present studies noted bladder tumor induction after cigarette smoke condensate exposure. However, the incidence was not great and suggests that time of exposure and other as yet unidentified tumor promoting co‐factors were not present.

Chemical Studies on Tobacco Smoke. XIII. Inhibition of the Pyrosyntheses of Several Selective Smoke Constituents

AbstractEarlier studies demonstrated that polynuclear aromatic hydrocarbons (PAH) are selectively reduced in the smoke of alkali nitrate rich tobaccos. We hypothesized, therefore, that in the burning cone of a tobacco product, the non-volatilized organic compounds are partially pyrolyzed to C,H-radicals that may combine with each other and form, among others, the thermodynamically favoured PAH. Since we have in the burning cone of nitrate rich tobaccos an excess of thermically activated nitrogen oxides, we assumed that these may react as scavengers for C,H-radicals and, with it, partially inhibit the PAH pyrosynthesis. The present study was designed to challenge our working hypothesis. For the experiments we employed cigarettes to which we had added various amounts of KNO3 (0, 2.5, 5.0, 7.0 and 8.0 %). As expected, the yields of nitromethane, nitroethane, and nitrobenzene in the smoke increased with the increased of nitrate in the tobacco and the yields of phenanthrene, benz[a]anthracene, and benz[a]pyrene decreased. The concentration of naphthalene was only to a minor degree reduced with the increase of nitrates in the tobacco. One explanation for this observation could be that naphthalenes are primarily formed from specific tobacco terpenes, as suggested in the literature. As was expected, the smoke yields of N-unsubstituted and N-alkylated indoles was relatively little affected by the increase in the nitrate content, since these agents are predominantly formed from tryptophan. It was our objective to contribute to the understanding of the pyrosynthesis of carcinogenic PAH and the selective reduction of PAH in the smoke of nitrate rich tobacco. With the increase of our knowledge in this area we may also find an explanation for the reduced tumorigenicity of condensates from nitrate rich tobaccos

Polynuclear aza compounds in automative exhaust.

cancer. Wynder cites evidence that cigarette smoking plays the major role in the etiology of lung cancer. Hueper gives evidence that cigarette smoking is only one of many factors including air pollution which play a significant role in causing lung cancer. Be­ cause of this difference of opinion in the scientific community, it is felt that a more thorough study of the composition of the human environment in terms of carcinogens (and compounds of similar structure) should give some leads for more thorough biochemical, biological, and statistical studies of the cancer problem. The presence of carcinogenic polynuclear aromatic hydrocarbons in the atmospheres of American cities 3 ,4 is of particular interest to all people concerned with environmental health. Examination of extracts of airborne particulates from eight large American cities showed that all contained carcinogenic