Dietary N-nitroso compounds, endogenous nitrosation, and the risk of esophageal and gastric cancer subtypes in the Netherlands Cohort Study.

PubMed

Keszei, András P; Goldbohm, R Alexandra; Schouten, Leo J; Jakszyn, Paula; van den Brandt, Piet A

2013-01-01

Dietary N-nitroso compounds and endogenous nitrosation are important carcinogenic factors, but human evidence of their role is scarce for esophageal cancer and inconsistent for gastric cancer. We studied the relation between risks of esophageal and gastric cancer subtypes and dietary intake of N-nitrosodimethylamine, heme iron, nitrite, and nitrate in the Netherlands Cohort Study. A total of 120,852 men and women aged 55-69 y were recruited in 1986, and diet, based on a 150-item food-frequency questionnaire, and other risk factors were assessed. The cohort was followed for 16.3 y, and 110 esophageal squamous cell carcinoma (ESCC), 151 esophageal adenocarcinoma, 166 gastric cardia adenocarcinoma, and 497 gastric noncardia adenocarcinoma (GNCA) cases were analyzed along with 4032 subcohort members in a case-cohort analysis. Positive associations were observed between N-nitrosodimethylamine intake and ESCC risk (HR for 0.1-μg/d increase in intake: 1.15; 95% CI: 1.05, 1.25; P-trend = 0.01 based on tertiles of intake) and GNCA risk (1.06; 95% CI: 1.01, 1.10; P-trend = 0.09) in men. ESCC risk was associated with nitrite intake (HR for 0.1-mg/d increase: 1.19; 95% CI: 1.05, 1.36; P-trend = 0.06) and heme-iron intake (HR for 1-mg/d increase: 1.83; 95% CI: 0.98, 3.39; P-trend = 0.03). Among women, exposure levels were lower, and we found no convincing positive associations. These results suggest that N-nitroso compounds may influence the risk of ESCC in men, but there are no clear associations for other esophageal and gastric subtypes.

Ingested Nitrate, Disinfection By-products, and Kidney Cancer Risk in Older Women.

PubMed

Jones, Rena R; Weyer, Peter J; DellaValle, Curt T; Robien, Kim; Cantor, Kenneth P; Krasner, Stuart; Beane Freeman, Laura E; Ward, Mary H

2017-09-01

N-nitroso compounds formed endogenously after nitrate/nitrite ingestion are animal renal carcinogens. Previous epidemiologic studies of drinking water nitrate did not evaluate other potentially toxic water contaminants, including the suspected renal carcinogen chloroform. In a cohort of postmenopausal women in Iowa (1986-2010), we used historical measurements to estimate long-term average concentrations of nitrate-nitrogen (NO3-N) and disinfection by-products (DBP) in public water supplies. For NO3-N and the regulated DBP (total trihalomethanes [THM] and the sum of five haloacetic acids [HAA5]), we estimated the number of years of exposure above one-half the current maximum contaminant level (>½-MCL NO3-N; >5 mg/L). Dietary intakes were assessed via food frequency questionnaire. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox models, and evaluated interactions with factors influencing N-nitroso compound formation. We identified 125 incident kidney cancers among 15,577 women reporting using water from public supplies >10 years. In multivariable models, risk was higher in the 95th percentile of average NO3-N (HRp95vsQ1 = 2.3; CI: 1.2, 4.3; Ptrend = 0.33) and for any years of exposure >½-MCL; adjustment for total THM did not materially change these associations. There were no independent relationships with total THM, individual THMs chloroform and bromodichloromethane, or with haloacetic acids. Dietary analyses yielded associations with high nitrite intake from processed meats but not nitrate or nitrite overall. We found no interactions. Relatively high nitrate levels in public water supplies were associated with increased risk of renal cancer. Our results also suggest that nitrite from processed meat is a renal cancer risk factor.

Mechanisms Linking Colorectal Cancer to the Consumption of (Processed) Red Meat: A Review.

PubMed

Demeyer, Daniel; Mertens, Birgit; De Smet, Stefaan; Ulens, Michèle

2016-12-09

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world. The vast majority of CRC cases have been linked to environmental causes rather than to heritable genetic changes. Over the last decades, epidemiological evidence linking the consumption of red and, more convincingly, of processed red meat to CRC has accumulated. In parallel, hypotheses on carcinogenic mechanisms underlying an association between CRC and the intake of red and processed red meat have been proposed and investigated in biological studies. The hypotheses that have received most attention until now include (1) the presence of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, two groups of compounds recognized as carcinogenic, (2) the enhancing effect of (nitrosyl)heme on the formation of carcinogenic N-nitroso compounds and lipid peroxidation. However, none of these hypotheses completely explains the link between red and processed red meat intake and the CRC risk. Consequently, scientists have proposed additional mechanisms or refined their hypotheses. This review first briefly summarizes the development of CRC followed by an in-depth overview and critical discussion of the different potential carcinogenic mechanisms underlying the increased CRC risk associated with the consumption of red and processed red meat.

Methylation of ribonucleic acid by the carcinogens dimethyl sulphate, N-methyl-N-nitrosourea and N-methyl-N′-nitro-N-nitrosoguanidine. Comparisons of chemical analyses at the nucleoside and base levels

PubMed Central

Lawley, P. D.; Shah, S. A.

1972-01-01

1. The following methods for hydrolysis of methyl-14C-labelled RNA, and for chromatographic isolation and determination of the products, were investigated: enzymic digestion to nucleosides at pH6 or 8; alkaline hydrolysis and conversion into nucleosides; hydrolysis by acid to pyrimidine nucleotides and purine bases, or completely to bases; chromatography on Dowex 50 (NH4+ form) at pH6 or 8.9, or on Dowex 50 (H+ form), or on Sephadex G-10. 2. The suitability of the various methods for determination of methylation products was assessed. The principal product, 7-methylguanosine, was unstable under the conditions used for determinations of nucleosides. 3- and 7-Methyladenine and 3- and 7-methylguanine are best determined as bases; 1-methyladenine and 3-methylcytosine can be isolated as either nucleosides or bases; O6-methylguanine is unstable under the acid hydrolysis conditions used and can be determined as the nucleoside; 3-methyluracil was detected, but may be derived from methylation of the ionized form of uracil. 3. Differences between the patterns of methylation of RNA and homopolyribonucleotides by the N-methyl-N-nitroso compounds and dimethyl sulphate were found: the nitroso compounds were able to methylate O-6 of guanine, were relatively more reactive at N-7 of adenine and probably at N-3 of guanine, but less reactive at N-1 of adenine, N-3 of cytosine and probably at N-3 of uridine. They probably reacted more with the ribose–phosphate chain, but no products from this were identified. 4. The possible influences of these differences on biological action of the methylating agents is discussed. Nitroso compounds may differ principally in their ability to induce miscoding in the Watson–Crick sense by reaction at O-6 of guanine. Both types of agent may induce miscoding to a lesser extent through methylation at N-3 of guanine; both can methylate N atoms, presumably preventing Watson–Crick hydrogen-bonding. N-Methyl-N-nitrosourea can degrade RNA, possibly through phosphotriester formation, but this mechanism is not proven. PMID:4673570

A critical overview on the biological and molecular features of red and processed meat in colorectal carcinogenesis.

PubMed

Jeyakumar, Arunan; Dissabandara, Lakal; Gopalan, Vinod

2017-04-01

A recent investigation by the World Health Organisation (WHO) has found that the consumption of processed meat and potentially red meat promotes carcinogenesis and can increase the risk of colorectal cancer. This literature review aims to summarise both the red and processed meat molecules associated with colorectal carcinogenesis and investigate their relationship with the pathogenic process of colorectal cancer. Literature relating to the carcinogenic effect of red and processed meat molecules was critically reviewed. There are multiple molecules present in red and processed meat with a potential carcinogenic effect on colorectal tissues. Processed meat is more carcinogenic compared to red meat because of the abundance of potent nitrosyl-heme molecules that form N-nitroso compounds. Studies have also noted that other molecules such as polycyclic aromatic hydrocarbons and heterocyclic amines have potential mechanisms for the initiation of colorectal cancer pathogenesis. The non-human sugar molecule N-glycolylneuraminic acid may account for the carcinogenic effects of pork despite its heme content being comparable to that of chicken. Red meat products, especially those that have been processed, have a wide variety of carcinogenic molecules known to increase the risk of colorectal cancer. Thus, the outcome of this review is consistent with the recent findings of WHO.

Dose-response studies and 'no-effect-levels' of N-nitroso compounds: some general aspects.

PubMed

Preussmann, R

1980-01-01

One major problem in the evaluation of potential carcinogenic food additives and contaminants is that of thresholds or, better, of 'no-adverse-effect-levels'. Arguments in favor of the postulated 'irreversibility' of carcinogenic effects are based on dose-response studies, single dose and multigeneration experiments as well as on the concept of somatic mutation as the first step in carcinogenesis with subsequent transmittance of induced defects during cell replication. The problem of extrapolation of results of animal experiments using high doses to low exposure and low incidences in man is not yet solved satisfactorily. Possible practical consequences include zero tolerance, acceptable thresholds at low risk and safety factors. Acceptable intakes should never be considered constants but should be changeable as soon as new facts in regard to the safety evaluation are available.

Transnitrosation of alicyclic N-nitrosamines containing a sulfur atom.

PubMed

Inami, Keiko; Kondo, Sonoe; Ono, Yuta; Saso, Chiharu; Mochizuki, Masataka

2013-12-15

Aromatic and aliphatic nitrosamines are known to transfer a nitrosonium ion to another amine. The transnitrosation of alicyclic N-nitroso compounds generates S-nitrosothiols, which are potential nitric oxide donors in vivo. In this study, certain alicyclic N-nitroso compounds based on non-mutagenic N-nitrosoproline or N-nitrosothioproline were synthesised, and the formation of S-nitrosoglutathione (GSNO) was quantified under acidic conditions. We then investigated the effect of a sulfur atom as the substituent and as a ring component on the GSNO formation. In the presence of thiourea under acidic conditions, GSNO was formed from N-nitrosoproline and glutathione, and an N-nitroso compound containing a sulfur atom and glutathione produced GSNO without thiourea. The quantity of GSNO derived from the reaction of the N-nitrosamines containing a sulfur atom and glutathione was higher than that from the N-nitrosoproline and glutathione plus thiourea. Among the analogues that contained a sulfur atom either in the ring or as a substituent, the thiazolidines produced a slightly higher quantity of GSNO than the analogue with a thioamide group. A compound containing sulfur atoms both in the ring and as a substituent exhibited the highest activity for GSNO formation among the alicyclic N-nitrosamines tested. The results indicate that the intramolecular sulfur atom plays an important role in the transnitrosation via alicyclic N-nitroso compounds to form GSNO. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Antimutagenic components in Glycyrrhiza against N-methyl-N-nitrosourea in the Ames assay.

PubMed

Inami, Keiko; Mine, Yusuke; Kojo, Yukiko; Tanaka, Satomi; Ishikawa, Satoko; Mochizuki, Masataka

2017-03-01

Antimutagenesis against N-nitroso compounds contribute to prevention of human cancer. We have found that Glycyrrhiza aspera ethanolic extract exhibits antimutagenic activity against N-methyl-N-nitrosourea (MNU) using the Ames assay with Salmonella typhimurium TA1535. In the present study, eight purified components from Glycyrrhiza, namely glabridin, glycyrrhetinic acid, glycyrrhizin, licochalcone A, licoricesaponin H2, licoricesaponin G2, liquiritigenin and liquiritin were evaluated for their antimutagenicity against MNU in the Ames assay with S. typhimurium TA1535. Glycyrrhetinic acid, glycyrrhizin, licoricesaponin G2, licoricesaponin H2 and liquiritin did not show the antimutagenicity against MNU in S. typhimurium TA1535. Glabridin, licochalcone A and liquiritigenin reduced revertant colonies derived from MNU in S. typhimurium TA1535 without showing cytotoxic effects, indicating that these compounds possess antimutagenic activity against MNU. The inhibitory activity of glabridin and licochalcone A was more effective than that of liquiritigenin. Thus, Glycyrrhiza contains antimutagenic components against DNA alkylating, direct-acting carcinogens.

Dietary N-nitroso compounds and risk of colorectal cancer: a case-control study in Newfoundland and Labrador and Ontario, Canada

PubMed Central

Zhu, Yun; Wang, Peizhong Peter; Zhao, Jing; Green, Roger; Sun, Zhuoyu; Roebothan, Barbara; Squires, Josh; Buehler, Sharon; Dicks, Elizabeth; Zhao, Jinhui; Cotterchio, Michelle; Campbell, Peter T.; Jain, Meera; Parfrey, Patrick S.; Mclaughlin, John R.

2015-01-01

Several N-nitroso compounds (NOC) have been shown to be carcinogenic in a variety of laboratory animals, but evidence of their carcinogenicity in humans is lacking. We aimed to examine the association between NOC intake and colorectal cancer (CRC) risk and possible effect modification by vitamins C and E and protein in a large case-control study carried out in Newfoundland and Labrador, and Ontario, Canada. A total of 1760 case patients with pathologically confirmed adenocarcinoma and 2481 population controls were asked to complete a self-administered FFQ to evaluate their dietary intakes 1 year before diagnosis (for cases) or interview (for controls). Adjusted OR and 95% CI were calculated across the quintiles of NOC (measured by N-nitrosodimethylamine (NDMA)) intake and relevant food items using unconditional logistic regression. NDMA intake was found to be associated with a higher risk of CRC (highest vs lowest quintiles, OR: 1.42; 95% CI: 1.03,1.96; p-trend=0.005), specifically for rectal carcinoma (OR: 1.61; 95% CI: 1.11,2.35; p-trend=0.01). CRC risk also increased with the consumption of NDMA-containing meats when the highest tertile was compared with the lowest tertile (OR: 1.47; 95% CI: 1.03,2.10; p-trend=0.20). There was evidence of effect modification between dietary vitamin E and NDMA. Individuals with high NDMA and low vitamin E intakes had a significantly increased risk than those with both low NDMA and vitamin E intakes (OR:3.01; 95% CI: 1.43,6.51; p-interaction=0.017). The present results support the hypothesis that NOC intake may be positively associated with CRC risk in humans. Vitamin E, which inhibits nitrosation, could modify the effect of NDMA on CRC risk. PMID:24160559

Quantitative structure carcinogenicity relationship for detecting structural alerts in nitroso-compounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Helguera, Aliuska Morales; Molecular Simulation and Drug Design, Chemical Bioactive Center, Central University of Las Villas, Santa Clara, 54830, Villa Clara; Department of Chemistry, Central University of Las Villas, Santa Clara, 54830, Villa Clara

2008-09-01

In this work, Quantitative Structure-Activity Relationship (QSAR) modelling was used as a tool for predicting the carcinogenic potency of a set of 39 nitroso-compounds, which have been bioassayed in male rats by using the oral route of administration. The optimum QSAR model provided evidence of good fit and performance of predicitivity from training set. It was able to account for about 84% of the variance in the experimental activity and exhibited high values of the determination coefficients of cross validations, leave one out and bootstrapping (q{sup 2}{sub LOO} = 78.53 and q{sup 2}{sub Boot} = 74.97). Such a model wasmore » based on spectral moments weighted with Gasteiger-Marsilli atomic charges, polarizability and hydrophobicity, as well as with Abraham indexes, specifically the summation solute hydrogen bond basicity and the combined dipolarity/polarizability. This is the first study to have explored the possibility of combining Abraham solute descriptors with spectral moments. A reasonable interpretation of these molecular descriptors from a toxicological point of view was achieved by means of taking into account bond contributions. The set of relationships so derived revealed the importance of the length of the alkyl chains for determining carcinogenic potential of the chemicals analysed, and were able to explain the difference between mono-substituted and di-substituted nitrosoureas as well as to discriminate between isomeric structures with hydroxyl-alkyl and alkyl substituents in different positions. Moreover, they allowed the recognition of structural alerts in classical structures of two potent nitrosamines, consistent with their biotransformation. These results indicate that this new approach has the potential for improving carcinogenicity predictions based on the identification of structural alerts.« less

[Effect of fruit and vegetable juices on the changes in the production of carcinogenic N-nitroso compounds in human gastric juice].

PubMed

Ilńitskiĭ, A P; Iurchenko, V A

1993-01-01

The study was made of the effect of apple, grapefruit, orange and beet juices on in vitro formation of N-nitrosodimethylamine (NDMA) from sodium nitrite and amidopirin in human gastric juice (GJ). Experimental samples of GJ from outpatients attending the outpatient department of the AMS Cancer Research Center were used. The patients had various forms of gastritis and gastric cancer. It was found that fruit and beet juices may inhibit or enhance NDMA formation depending on the GJ composition, pH in particular. In acid medium (pH-1.3-3.4) there was a trend to inhibition of NDMA synthesis, while in neutral and alkaline (pH = 7.4-8.5) medium NDMA synthesis is activated. Practical implications of the findings are discussed.

Impact of DNA repair on the dose-response of colorectal cancer formation induced by dietary carcinogens.

PubMed

Fahrer, Jörg; Kaina, Bernd

2017-08-01

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers, which is causally linked to dietary habits, notably the intake of processed and red meat. Processed and red meat contain dietary carcinogens, including heterocyclic aromatic amines (HCAs) and N-nitroso compounds (NOC). NOC are agents that induce various N-methylated DNA adducts and O 6 -methylguanine (O 6 -MeG), which are removed by base excision repair (BER) and O 6 -methylguanine-DNA methyltransferase (MGMT), respectively. HCAs such as the highly mutagenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) cause bulky DNA adducts, which are removed from DNA by nucleotide excision repair (NER). Both O 6 -MeG and HCA-induced DNA adducts are linked to the occurrence of KRAS and APC mutations in colorectal tumors of rodents and humans, thereby driving CRC initiation and progression. In this review, we focus on DNA repair pathways removing DNA lesions induced by NOC and HCA and assess their role in protecting against mutagenicity and carcinogenicity in the large intestine. We further discuss the impact of DNA repair on the dose-response relationship in colorectal carcinogenesis in view of recent studies, demonstrating the existence of 'no effect' point of departures (PoDs), i.e. thresholds for genotoxicity and carcinogenicity. The available data support the threshold concept for NOC with DNA repair being causally involved. Copyright © 2016 Elsevier Ltd. All rights reserved.

Experimental and Theoretical Investigation of Effects of Ethanol and Acetic Acid on Carcinogenic NDMA Formation in Simulated Gastric Fluid.

PubMed

Zhang, Ou; Zou, Xuan; Li, Qi-Hong; Sun, Zhi; Liu, Yong Dong; Zhong, Ru Gang

2016-07-07

N-nitrosodimethylamine (NDMA), as a representative of endogenously formed N-nitroso compounds (NOCs), has become the focus of considerable research interest due to its unusually high carcinogenicity. In this study, effects of ethanol and acetic acid on the formation of NDMA from dimethylamine (DMA) and nitrite in simulated gastric fluid (SGF) were investigated. Experimental results showed that ethanol in the concentrations of 1-8% (v/v) and acetic acid in the concentrations of 0.01-8% (v/v) exhibit inhibitory and promotion effects on the formation of NDMA, respectively. Moreover, they are both in a dose-dependent manner with the largest inhibition/promotion rate reaching ∼70%. Further experimental investigations indicate that ethanol and acetic acid are both able to scavenge nitrite in SGF. It implies that there are interactions of ethanol and acetic acid with nitrite or nitrite-related nitrosating agents rather than DMA. Theoretical calculations confirm the above experimental results and demonstrate that ethanol and acetic acid can both react with nitrite-related nitrosating agents to produce ethyl nitrite (EtONO) and acetyl nitrite (AcONO), respectively. Furthermore, the reactivities of ethyl nitrite, acetyl nitrite, and dinitrogen trioxide reacting with DMA were found in the order of AcONO > N2O3 ≫ EtONO. This is probably the main reason why there are completely different effects of ethanol and acetic acid on NDMA formation. On the basis of the above results, two requirements for a potential inhibitor of NOCs formation in SGF were provided. The results obtained in this study will be helpful in better understanding the inhibition/promotion mechanisms of compounds on NDMA formation in SGF and searching for protective substances to prevent carcinogenic NOCs formation.

Metabolism of 6-nitrochrysene by intestinal microflora

DOE Office of Scientific and Technical Information (OSTI.GOV)

Manning, B.W.; Campbell, W.L.; Franklin, W.

1988-01-01

Since bacterial nitroreduction may play a critical role in the activation of nitropolycyclic aromatic hydrocarbons, we have used batch and semicontinuous culture systems to determine the ability of intestinal microflora to metabolize the carcinogen 6-nitrochrysene (6-NC). 6-NC was metabolized by the intestinal microflora present in the semicontinuous culture system to 6-aminochrysene (6-AC), N-formyl-6-aminochrysene (6-FAC), and 6-nitrosochrysene (6-NOC). These metabolites were isolated and identified by high-performance liquid chromatography, mass spectrometry, and UV-visible spectrophotometry and compared with authentic compounds. Almost all of the 6-NC was metabolized after 10 days. Nitroreduction of 6-NC to 6-AC was rapid; the 6-AC concentration reached a maximummore » at 48 h. The ratio of the formation of 6-AC to 6-FAC to 6-NOC at 48 h was 93.4:6.3:0.3. Interestingly, compared with results in the semicontinuous culture system, the only metabolite detected in the batch studies was 6-AC. The rate of nitroreduction differed among human, rat, and mouse intestinal microflora, with human intestinal microflora metabolizing 6-NC to the greatest extent. Since 6-AC has been shown to be carcinogenic in mice and since nitroso derivatives of other nitropolycyclic aromatic hydrocarbons are biologically active, our results suggest that the intestinal microflora has the enzymatic capacity to generate genotoxic compounds and may play an important role in the carcinogenicity of 6-NC.« less

Repression by sustained-release. beta. -glucuronidase inhibitors of chemical carcinogen-mediated induction of a marker oncofetal protein in rodents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walaszek, Z.; Hanausek-Walaszek, M.; Webb, T.E.

1988-01-01

The degree of induction of an oncofetal protein marker in rodents by selected chemical carcinogens has been correlated with changes in carcinogenicity induced by dietary D-glucaro-1,4-lactone (GL) based anticarcinogens. These potent anticarcinogens may act to increase the clearance of carcinogens as glucuronides through the inhibition of ..beta..-glucuronidase. The sustained-release forms are particularly effective, 1.5 mmol/kg of GL maintaining serum ..beta..-glucuronidase activity at or below 50% for only 1 h, while an equivalent amount of calcium glucarate (CGT) maintained this level of inhibition for over 5 h. CGT or other sustained-release inhibitors, when fed to rodents during administration of carcinogens thatmore » undergo glucuronidation, caused a marked reduction in the induction of the marker protein. For those systems where other markers of carcinogenesis were also assessed, it was determined the inhibition of marker-protein induction was quantitatively similar to both the inhibition of binding of the carcinogen to DNA and the subsequent induction of tumors in target organs. The following carcinogens were administered intraperitoneally: benzo(a)pryene; 7,12-demethylbenz(a)anthracene; 3-methylcholanthrene; 2-acetylaminofluorene; 2-naphthylamine; N-nitroso-N,N-dibutylamine; aflatoxin B1; 1-nitropyrene.« less

Occupation and gastric cancer

PubMed Central

Raj, A; Mayberry, J; Podas, T

2003-01-01

Gastric cancer is a cause of significant morbidity and mortality. There are several risk factors, with occupation emerging as one of these. There is considerable evidence that occupations in coal and tin mining, metal processing, particularly steel and iron, and rubber manufacturing industries lead to an increased risk of gastric cancer. Other "dusty" occupations—for example, wood processing, or work in high temperature environments have also been implicated but the evidence is not strong. The mechanism of pathogenesis of gastric cancer is unclear and the identification of causative agents can be difficult. Dust is thought to be a contributor to the pathological process, but well known carcinogens such as N-nitroso compounds have been detected in some environments. Further research on responsible agents is necessary and screening for detection of precursor gastric cancer lesions at the workplace merits consideration. PMID:12782770

Reduction of aromatic and heterocyclic aromatic N-hydroxylamines by human cytochrome P450 2S1.

PubMed

Wang, Kai; Guengerich, F Peter

2013-06-17

Many aromatic amines and heterocyclic aromatic amines (HAAs) are known carcinogens for animals, and there is also strong evidence of some in human cancer. The activation of these compounds, including some arylamine drugs, involves N-hydroxylation, usually by cytochrome P450 enzymes (P450) in Family 1 (1A2, 1A1, and 1B1). We previously demonstrated that the bioactivation product of the anticancer agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203), an N-hydroxylamine, can be reduced by P450 2S1 to its amine precursor under anaerobic conditions and, to a lesser extent, under aerobic conditions [Wang, K., and Guengerich, F. P. (2012) Chem. Res. Toxicol. 25, 1740-1751]. In the study presented here, we tested the hypothesis that P450 2S1 is involved in the reductive biotransformation of known carcinogenic aromatic amines and HAAs. The N-hydroxylamines of 4-aminobiphenyl (4-ABP), 2-naphthylamine (2-NA), and 2-aminofluorene (2-AF) were synthesized and found to be reduced by P450 2S1 under both anaerobic and aerobic conditions. The formation of amines due to P450 2S1 reduction also occurred under aerobic conditions but was less apparent because the competitive disproportionation reactions (of the N-hydroxylamines) also yielded amines. Further, some nitroso and nitro derivatives of the arylamines could also be reduced by P450 2S1. None of the amines tested were oxidized by P450 2S1. These results suggest that P450 2S1 may be involved in the reductive detoxication of several of the activated products of carcinogenic aromatic amines and HAAs.

Reduction of Aromatic and Heterocyclic Aromatic N-Hydroxylamines by Human Cytochrome P450 2S1

PubMed Central

Wang, Kai; Guengerich, F. Peter

2013-01-01

Many aromatic amines and heterocyclic aromatic amines (HAAs) are known carcinogens for animals and there is also strong evidence for some in human cancer. The activation of these compounds, including some arylamine drugs, involves N-hydroxylation, usually by cytochrome P450 enzymes (P450) in Family 1 (1A2, 1A1, and 1B1). We previously demonstrated that the bioactivation product of the anti-cancer agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203), an N-hydroxylamine, can be reduced by P450 2S1 to its amine precursor under anaerobic conditions and, to a lesser extent, under aerobic conditions (Wang, K., and Guengerich, F. P. (2012) Chem. Res. Toxicol. 25, 1740–1751). In the present study, we tested the hypothesis that P450 2S1 is involved in the reductive biotransformation of known carcinogenic aromatic amines and HAAs. The N-hydroxylamines of 4-aminobiphenyl (4-ABP), 2-naphthylamine (2-NA), and 2-aminofluorene (2-AF) were synthesized and found to be reduced by P450 2S1 under both anaerobic and aerobic conditions. The formation of amines due to P450 2S1 reduction also occurred under aerobic conditions but was less apparent because the competitive disproportionation reactions (of the N-hydroxylamines) also yielded amines. Further, some nitroso and nitro derivatives of the arylamines could also be reduced by P450 2S1. None of the amines tested were oxidized by P450 2S1. These results suggest that P450 2S1 may be involved in the reductive detoxication of several of the activated products of carcinogenic aromatic amines and HAAs. PMID:23682735

N-O chemistry for antibiotics: discovery of N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds as selective antibacterial agents using nitroso Diels-Alder and ene chemistry.

PubMed

Wencewicz, Timothy A; Yang, Baiyuan; Rudloff, James R; Oliver, Allen G; Miller, Marvin J

2011-10-13

The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ∼100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring-opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium Micrococcus luteus ATCC 10240 (MIC(90) = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds.

N-O Chemistry for Antibiotics: Discovery of N-Alkyl-N-(pyridin-2-yl)hydroxylamine Scaffolds as Selective Antibacterial Agents Using Nitroso Diels-Alder and Ene Chemistry

PubMed Central

Wencewicz, Timothy A.; Yang, Baiyuan; Rudloff, James R.; Oliver, Allen G.; Miller, Marvin J.

2011-01-01

The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ~100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium Micrococcus luteus ATCC 10240 (MIC90 = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds. PMID:21859126

Dietary factors and the risk of glioma in adults: results of a case-control study in Melbourne, Australia.

PubMed

Giles, G G; McNeil, J J; Donnan, G; Webley, C; Staples, M P; Ireland, P D; Hurley, S F; Salzberg, M

1994-11-01

In a population-based case-control study of 416 incident gliomas in adults carried out in Melbourne, Australia, between 1987 and 1991, 409 age-sex-matched case-control pairs (243 male and 166 female) had adequate data available to examine associations between the dietary intake of N-nitroso compounds, N-nitroso precursors, other nutrients including N-nitroso inhibitors, and the risk of glioma. Dietary intakes were based on the reported frequency of consumption of 59 food items. Increased odds ratio (OR) were observed in males who consumed high levels of bacon, corned meats, apples, melons and oil. OR less than unity were observed in men consuming cabbage and cola drinks, and in women who consumed wholegrain bread, pasta, corned meat, bananas, cauliflower, brocoli, cola drinks and nuts. Generally, N-nitroso associations were greater in men and micronutrient associations were greater in women. Elevated OR in men, but not women, were associated with the intake of N-nitroso dimethylamine (NDMA), retinol and vitamin E. The intake of nitrate (largely of vegetable origin) was protective in women but not in men. When analyzed using multiple logistic regression, the association with NDMA intake in males was not modified by dietary micronutrient intakes. In females, beta carotene alone, though not directly associated with risk, modified the effect of NDMA. On balance, this study added only limited support to the N-nitroso hypothesis of glial carcinogenesis.

Maternal characteristics associated with the dietary intake of nitrates, nitrites, and nitrosamines in women of child-bearing age: a cross-sectional study

PubMed Central

2010-01-01

Background Multiple N-nitroso compounds have been observed in animal studies to be both mutagenic and teratogenic. Human exposure to N-nitroso compounds and their precursors, nitrates and nitrites, can occur through exogenous sources, such as diet, drinking water, occupation, or environmental exposures, and through endogenous exposures resulting from the formation of N-nitroso compounds in the body. Very little information is available on intake of nitrates, nitrites, and nitrosamines and factors related to increased consumption of these compounds. Methods Using survey and dietary intake information from control women (with deliveries of live births without major congenital malformations during 1997-2004) who participated in the National Birth Defects Prevention Study (NBDPS), we examined the relation between various maternal characteristics and intake of nitrates, nitrites, and nitrosamines from dietary sources. Estimated intake of these compounds was obtained from the Willet Food Frequency Questionnaire as adapted for the NBDPS. Multinomial logistic regression models were used to estimate odds ratios and 95% confidence intervals for the consumption of these compounds by self-reported race/ethnicity and other maternal characteristics. Results Median intake per day for nitrates, nitrites, total nitrites (nitrites + 5% nitrates), and nitrosamines was estimated at 40.48 mg, 1.53 mg, 3.69 mg, and 0.472 μg respectively. With the lowest quartile of intake as the referent category and controlling for daily caloric intake, factors predicting intake of these compounds included maternal race/ethnicity, education, body mass index, household income, area of residence, folate intake, and percent of daily calories from dietary fat. Non-Hispanic White participants were less likely to consume nitrates, nitrites, and total nitrites per day, but more likely to consume dietary nitrosamines than other participants that participated in the NBDPS. Primary food sources of these compounds also varied by maternal race/ethnicity. Conclusions Results of this study indicate that intake of nitrates, nitrites, and nitrosamines vary considerably by race/ethnicity, education, body mass index, and other characteristics. Further research is needed regarding how consumption of foods high in nitrosamines and N-nitroso precursors might relate to risk of adverse pregnancy outcomes and chronic diseases. PMID:20170520

Maternal characteristics associated with the dietary intake of nitrates, nitrites, and nitrosamines in women of child-bearing age: a cross-sectional study.

PubMed

Griesenbeck, John S; Brender, Jean D; Sharkey, Joseph R; Steck, Michelle D; Huber, John C; Rene, Antonio A; McDonald, Thomas J; Romitti, Paul A; Canfield, Mark A; Langlois, Peter H; Suarez, Lucina

2010-02-19

Multiple N-nitroso compounds have been observed in animal studies to be both mutagenic and teratogenic. Human exposure to N-nitroso compounds and their precursors, nitrates and nitrites, can occur through exogenous sources, such as diet, drinking water, occupation, or environmental exposures, and through endogenous exposures resulting from the formation of N-nitroso compounds in the body. Very little information is available on intake of nitrates, nitrites, and nitrosamines and factors related to increased consumption of these compounds. Using survey and dietary intake information from control women (with deliveries of live births without major congenital malformations during 1997-2004) who participated in the National Birth Defects Prevention Study (NBDPS), we examined the relation between various maternal characteristics and intake of nitrates, nitrites, and nitrosamines from dietary sources. Estimated intake of these compounds was obtained from the Willet Food Frequency Questionnaire as adapted for the NBDPS. Multinomial logistic regression models were used to estimate odds ratios and 95% confidence intervals for the consumption of these compounds by self-reported race/ethnicity and other maternal characteristics. Median intake per day for nitrates, nitrites, total nitrites (nitrites + 5% nitrates), and nitrosamines was estimated at 40.48 mg, 1.53 mg, 3.69 mg, and 0.472 microg respectively. With the lowest quartile of intake as the referent category and controlling for daily caloric intake, factors predicting intake of these compounds included maternal race/ethnicity, education, body mass index, household income, area of residence, folate intake, and percent of daily calories from dietary fat. Non-Hispanic White participants were less likely to consume nitrates, nitrites, and total nitrites per day, but more likely to consume dietary nitrosamines than other participants that participated in the NBDPS. Primary food sources of these compounds also varied by maternal race/ethnicity. Results of this study indicate that intake of nitrates, nitrites, and nitrosamines vary considerably by race/ethnicity, education, body mass index, and other characteristics. Further research is needed regarding how consumption of foods high in nitrosamines and N-nitroso precursors might relate to risk of adverse pregnancy outcomes and chronic diseases.

Biotransformation of nitroso aromatic compounds and 2-oxo acids to N-hydroxy-N-arylacylamides by thiamine-dependent enzymes in rat liver.

PubMed

Yoshioka, T; Uematsu, T

1998-07-01

The formation of N-hydroxy-N-arylacylamides from nitroso aromatic compounds and 2-oxo acids was investigated using rat liver subcellular fractions. Activities were found in both mitochondria and cytosol, except for activities for phenylpyruvate and glyoxylate; the former did not produce N-hydroxy-N-phenylphenylacetamide and the latter nonenzymatically produced N-hydroxy-N-phenylformamide with nitrosobenzene (NOB). The cytosolic activity of N-hydroxy-N-phenylglycolamide formation was indicated to be due to transketolase, which utilized hydroxypyruvate as a glycolic aldehyde donor to NOB. With mitochondria, 2-oxo acids (including hydroxypyruvate) served as substrates for the biotransformation of NOB to the corresponding N-hydroxy-N-phenylacylamides. The substrate preference was 2-oxobutyrate > pyruvate > 2-oxoisovalerate > 2-oxoisocaproate > 2-oxovalerate > 2-oxo-3-methylvalerate, judging from Vmax/half-saturating concentration for mitochondria values. The half-saturating concentrations for NOB were nearly constant. The mitochondrial activity was due to pyruvate dehydrogenase complex and branched-chain 2-oxo acid dehydrogenase complex (BCDHC). By using partially purified BCDHC, pyruvate and 2-oxobutyrate were found to be common substrates for both of the enzymes, and 2-oxoisovalerate was shown to be the most effective substrate for BCDHC. Analysis by the Taft equation indicated that the polar effects, rather than the steric effects, of the alkyl groups of 2-oxo acids are important for BCDHC-catalyzed formation of N-hydroxy-N-phenylacylamides. A positive Hammett constant obtained for the formation of N-hydroxy-N-arylisobutyramides indicates that an electron-withdrawing substituent makes the nitroso compounds susceptible to BCDHC-catalyzed biotransformation.

Importance of phenols structure on their activity as antinitrosating agents: A kinetic study

PubMed Central

Pessêgo, Márcia; Rosa da Costa, Ana M; Moreira, José A.

2011-01-01

Objective: Nitrosative deamination of DNA bases induced by reaction with reactive nitrogen species (RNS) has been pointed out as a probable cause of mutagenesis. (Poly)phenols, present in many food items from the Mediterranean diet, are believed to possess antinitrosating properties due to their RNS scavenging ability, which seems to be related to their structure. It has been suggested that phenolic compounds will react with the above-mentioned species more rapidly than most amino compounds, thus preventing direct nitrosation of the DNA bases and their transnitrosation from endogenous N-nitroso compounds, or most likely from the transient N-nitrosocompounds formed in vivo. Materials and Methods: In order to prove that assumption, a kinetic study of the nitroso group transfer from a N-methyl-N-nitrosobenzenesulfonamide (N-methyl-N-nitroso-4-methylbenzenesulfonamide, MeNMBS) to the DNA bases bearing an amine group and to a series of phenols was carried out. In the transnitrosation of phenols, the formation of nitrosophenol was monitored by Ultraviolet (UV) / Visible spectroscopy, and in the reactions of the DNA bases, the consumption of MeNMBS was followed by high performance liquid chromatography (HPLC). Results: The results obtained point to the transnitrosation of DNA bases being negligible, as well as that of phenols bearing electron-withdrawing groups. Phenols with methoxy substituents in positions 2, 4, and / or 6, although they seemed to react, did not afford the expected product. Phenols with electron-releasing substituents, unless these blocked the oxygen atom, reacted with our model compound at an appreciable rate. O-nitrosation of the phenolate ion followed by rearrangement of the C-nitrosophenol seemed to be involved. Conclusion: This study provided evidence that the above compounds might actually act as antinitrosating agents in vivo. PMID:21430963

Use of a modified N-nitrosoproline test to show intragastric nitrosation in patients at risk of gastric cancer.

PubMed Central

Houghton, P. W.; Leach, S.; Owen, R. W.; McC Mortensen, N. J.; Hill, M. J.; Williamson, R. C.

1989-01-01

Intragastric nitrosation has been implicated in the pathogenesis of gastric cancer and in precancerous conditions such as pernicious anaemia and the post-gastrectomy state. Intragastric nitrosation was assessed in at-risk patients by N-nitrosoproline (NPRO) excretion using both a conventional and a modified test. Twenty-four hour urinary excretion of NPRO was measured after oral administration of sodium nitrate (300 mg) and L-proline (500 mg) as an indirect indicator of intragastric nitrosation. In the conventional test no differences in intragastric nitrosation were found between at-risk patients and controls. In the modified test the loading dose of sodium nitrate was omitted and urinary NPRO levels were found to be significantly increased in Polya partial gastrectomy patients (P = 0.003) and post-vagotomy patients (P = 0.03) compared to controls. In pernicious anaemia patients NPRO levels were also higher than in controls but just failed to reach statistical significance. This study has confirmed that hypochlorhydria results in increased intragastric nitrosation, thus facilitating the formation of potentially carcinogenic N-nitroso compounds. PMID:2765371

In vitro assessment of anticytotoxic and antigenotoxic effects of CANOVA(®).

PubMed

do Nascimento, Henrique Fonseca Sousa; Cardoso, Plínio Cerqueira Dos Santos; Ribeiro, Helem Ferreira; Mota, Tatiane Cristina; Gomes, Lorena Monteiro; Khayat, André Salim; Guimarães, Adriana Costa; Amorim, Marucia Irena Medeiros; Burbano, Rommel Rodriguéz; Bahia, Marcelo de Oliveira

2016-08-01

CANOVA(®) (CA) is a homeopathic immunomodulator. It contains several homeopathic medicines prepares according to the Brazilian Pharmacopoeia. CA is indicated in clinical conditions in which the immune system is impaired and against tumors. N-methyl-N-nitrosourea (NMU) is an N-nitroso compound, with genotoxic/mutagenic properties. Although several studies have shown promising results in the use of CA, there are no studies reporting possible antigenotoxic effects. This study evaluated the in vitro antigenotoxic and anticytotoxic effects of CA in human lymphocytes exposed to NMU. Samples of human lymphocytes that were subjected to different concentrations of a mixture containing CA and NMU were used. The genotoxicity/antigenotoxicity of CA was evaluated by the comet assay, anticytotoxicity was assessed by quantification of apoptosis and necrosis using acridine orange/ethidium bromide. CA significantly reduced DNA damage induced by NMU and reduced significantly the frequency of NMU-induced apoptosis after 24 h of treatment. CA has an important cytoprotective effect significantly reducing the DNA damage and apoptosis induced by the carcinogen NMU. Copyright © 2016 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.

The Chemistry of Nitroxyl-Releasing Compounds

PubMed Central

DuMond, Jenna F.

2011-01-01

Abstract Nitroxyl (HNO) demonstrates a diverse and unique biological profile compared to nitric oxide, a redox-related compound. Although numerous studies support the use of HNO as a therapeutic agent, the inherent chemical reactivity of HNO requires the use of donor molecules. Two general chemical strategies currently exist for HNO generation from nitrogen-containing molecules: (i) the disproportionation of hydroxylamine derivatives containing good leaving groups attached to the nitrogen atom and (ii) the decomposition of nitroso compounds (X-N=O, where X represents a good leaving group). This review summarizes the synthesis and structure, the HNO-releasing mechanisms, kinetics and by-product formation, and alternative reactions of six major groups of HNO donors: Angeli's salt, Piloty's acid and its derivatives, cyanamide, diazenium diolate-derived compounds, acyl nitroso compounds, and acyloxy nitroso compounds. A large body of work exists defining these six groups of HNO donors and the overall chemistry of each donor requires consideration in light of its ability to produce HNO. The increasing interest in HNO biology and the potential of HNO-based therapeutics presents exciting opportunities to further develop HNO donors as both research tools and potential treatments. Antioxid. Redox Signal. 14, 1637–1648. PMID:21235345

Mammalian models of chemically induced primary malignancies exploitable for imaging-based preclinical theragnostic research

PubMed Central

Liu, Yewei; Yin, Ting; Feng, Yuanbo; Cona, Marlein Miranda; Huang, Gang; Liu, Jianjun; Song, Shaoli; Jiang, Yansheng; Xia, Qian; Swinnen, Johannes V.; Bormans, Guy; Himmelreich, Uwe; Oyen, Raymond

2015-01-01

Compared with transplanted tumor models or genetically engineered cancer models, chemically induced primary malignancies in experimental animals can mimic the clinical cancer progress from the early stage on. Cancer caused by chemical carcinogens generally develops through three phases namely initiation, promotion and progression. Based on different mechanisms, chemical carcinogens can be divided into genotoxic and non-genotoxic ones, or complete and incomplete ones, usually with an organ-specific property. Chemical carcinogens can be classified upon their origins such as environmental pollutants, cooked meat derived carcinogens, N-nitroso compounds, food additives, antineoplastic agents, naturally occurring substances and synthetic carcinogens, etc. Carcinogen-induced models of primary cancers can be used to evaluate the diagnostic/therapeutic effects of candidate drugs, investigate the biological influential factors, explore preventive measures for carcinogenicity, and better understand molecular mechanisms involved in tumor initiation, promotion and progression. Among commonly adopted cancer models, chemically induced primary malignancies in mammals have several advantages including the easy procedures, fruitful tumor generation and high analogy to clinical human primary cancers. However, in addition to the time-consuming process, the major drawback of chemical carcinogenesis for translational research is the difficulty in noninvasive tumor burden assessment in small animals. Like human cancers, tumors occur unpredictably also among animals in terms of timing, location and the number of lesions. Thanks to the availability of magnetic resonance imaging (MRI) with various advantages such as ionizing-free scanning, superb soft tissue contrast, multi-parametric information, and utility of diverse contrast agents, now a workable solution to this bottleneck problem is to apply MRI for noninvasive detection, diagnosis and therapeutic monitoring on those otherwise uncontrollable animal models with primary cancers. Moreover, it is foreseeable that the combined use of chemically induced primary cancer models and molecular imaging techniques may help to develop new anticancer diagnostics and therapeutics. PMID:26682141

Comparative DNA adduct formation and induction of colonic aberrant crypt foci in mice exposed to 2-amino-9H-pyrido[2,3-b]indole, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline and azoxymethane

PubMed Central

Kim, Sangyub; Guo, Jingshu; O’Sullivan, M. Gerald; Gallaher, Daniel D.; Turesky, Robert J.

2015-01-01

Considerable evidence suggests that environmental factors, including diet and cigarette smoke, are involved in the pathogenesis of colon cancer. Carcinogenic nitroso compounds (NOC), such as N-nitrosodimethylamine (NDMA), are present in tobacco and processed red meat, and NOC have been implicated in colon cancer. Azoxymethane (AOM), commonly used for experimental colon carcinogenesis, is an isomer of NDMA, and it produces the same DNA adducts as does NDMA. Heterocyclic aromatic amines (HAAs) formed during the combustion of tobacco and high-temperature cooking of meats are also associated with an elevated risk of colon cancer. The most abundant carcinogenic HAA formed in tobacco smoke is 2-amino-9H-pyrido[2,3-b]indole (AαC), whereas 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) is the most potent carcinogenic HAA formed during the cooking of meat and fish. However, the comparative tumor-initiating potential of AαC, MeIQ, and AOM is unknown. In this report, we evaluate the formation of DNA adducts as a measure of genotoxicity, and the induction of colonic aberrant crypt foci (ACF) and dysplastic ACF, as an early measure of carcinogenic potency of these compounds in the colon of male A/J mice. Both AαC and AOM induced a greater number of DNA adducts than MeIQ in the liver and colon. AOM induced a greater number of ACF and dysplastic ACF than either AαC or MeIQ. Conversely, based on adduct levels, MeIQ-DNA adducts were more potent than AαC- and AOM-DNA adducts at inducing ACF. Long-term feeding studies are required to relate levels of DNA adducts, induction of ACF, and colon cancer by these colon genotoxicants. PMID:26734915

Induction of colonic aberrant crypts in mice by feeding apparent N-nitroso compounds derived from hot dogs

PubMed Central

Davis, Michael E; Lisowyj, Michal P; Zhou, Lin; Wisecarver, James L; Gulizia, James M; Shostrom, Valerie K; Naud, Nathalie; Corpet, Denis E; Mirvish, Sidney S

2012-01-01

Nitrite-preserved meats (e.g., hot dogs) may help cause colon cancer because they contain N-nitroso compounds. We tested whether purified hot-dog-derived total apparent N-nitroso compounds (ANC) could induce colonic aberrant crypts, which are putative precursors of colon cancer. We purified ANC precursors in hot dogs and nitrosated them to produce ANC. In preliminary tests, CF1 mice received 1 or 3 i.p. injections of 5mg azoxymethane (AOM)/kg. In Experiments 1 and 2, female A/J mice received ANC in diet. In Experiment 1, ANC dose initially dropped sharply because the ANC precursors had mostly decomposed but, later in Experiment 1 and throughout Experiment 2, ANC remained at 85 nmol/g diet. Mice were killed after 8 (AOM tests) or 17–34 (ANC tests) wk. Median numbers of aberrant crypts in the distal 2 cm of the colon for 1 and 3 AOM injections, CF1 controls, ANC (Experiment 1), ANC (Experiment 2),and untreated A/J mice were 31, 74, 12, 20, 12, and 5–6, with P < 0.01 for both ANC tests. Experiment 2 showed somewhat increased numbers of colonic mucin-depleted foci in the ANC-treated group. We conclude that hot-dog-derived ANC induced significant numbers of aberrant crypts in the mouse colon. PMID:22293095

Meat, meat cooking methods and preservation, and risk for colorectal adenoma.

PubMed

Sinha, Rashmi; Peters, Ulrike; Cross, Amanda J; Kulldorff, Martin; Weissfeld, Joel L; Pinsky, Paul F; Rothman, Nathaniel; Hayes, Richard B

2005-09-01

Cooking meat at high temperatures produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). Processed meats contain N-nitroso compounds. Meat intake may increase cancer risk as HCAs, PAHs, and N-nitroso compounds are carcinogenic in animal models. We investigated meat, processed meat, HCAs, and the PAH benzo(a)pyrene and the risk of colorectal adenoma in 3,696 left-sided (descending and sigmoid colon and rectum) adenoma cases and 34,817 endoscopy-negative controls. Dietary intake was assessed using a 137-item food frequency questionnaire, with additional questions on meats and meat cooking practices. The questionnaire was linked to a previously developed database to determine exposure to HCAs and PAHs. Intake of red meat, with known doneness/cooking methods, was associated with an increased risk of adenoma in the descending and sigmoid colon [odds ratio (OR), 1.26; 95% confidence interval (95% CI), 1.05-1.50 comparing extreme quintiles of intake] but not rectal adenoma. Well-done red meat was associated with increased risk of colorectal adenoma (OR, 1.21; 95% CI, 1.06-1.37). Increased risks for adenoma of the descending colon and sigmoid colon were observed for the two HCAs: 2-amino-3,8-dimethylimidazo[4,5]quinoxaline and 2-amino-1-methyl-6-phenylimidazo[4,5]pyridine (OR, 1.18; 95% CI, 1.01-1.38 and OR, 1.17, 95% CI, 1.01-1.35, respectively) as well as benzo(a)pyrene (OR, 1.18; 95% CI, 1.02-1.35). Greater intake of bacon and sausage was associated with increased colorectal adenoma risk (OR, 1.14; 95% CI, 1.00-1.30); however, total intake of processed meat was not (OR, 1.04; 95% CI, 0.90-1.19). Our study of screening-detected colorectal adenomas shows that red meat and meat cooked at high temperatures are associated with an increased risk of colorectal adenoma.

The synergistic effect of chemical carcinogens enhances Epstein-Barr virus reactivation and tumor progression of nasopharyngeal carcinoma cells.

PubMed

Fang, Chih-Yeu; Huang, Sheng-Yen; Wu, Chung-Chun; Hsu, Hui-Yu; Chou, Sheng-Ping; Tsai, Ching-Hwa; Chang, Yao; Takada, Kenzo; Chen, Jen-Yang

2012-01-01

Seroepidemiological studies imply a correlation between Epstein-Barr virus (EBV) reactivation and the development of nasopharyngeal carcinoma (NPC). N-nitroso compounds, phorbols, and butyrates are chemicals found in food and herb samples collected from NPC high-risk areas. These chemicals have been reported to be risk factors contributing to the development of NPC, however, the underlying mechanism is not fully understood. We have demonstrated previously that low dose N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 0.1 µg/ml) had a synergistic effect with 12-O-tetradecanoylphorbol-13-acetate (TPA) and sodium butyrate (SB) in enhancing EBV reactivation and genome instability in NPC cells harboring EBV. Considering that residents in NPC high-risk areas may contact regularly with these chemical carcinogens, it is vital to elucidate the relation between chemicals and EBV and their contributions to the carcinogenesis of NPC. In this study, we constructed a cell culture model to show that genome instability, alterations of cancer hallmark gene expression, and tumorigenicity were increased after recurrent EBV reactivation in NPC cells following combined treatment of TPA/SB and MNNG. NPC cells latently infected with EBV, NA, and the corresponding EBV-negative cell, NPC-TW01, were periodically treated with MNNG, TPA/SB, or TPA/SB combined with MNNG. With chemically-induced recurrent reactivation of EBV, the degree of genome instability was significantly enhanced in NA cells treated with a combination of TPA/SB and MNNG than those treated individually. The Matrigel invasiveness, as well as the tumorigenicity in mouse, was also enhanced in NA cells after recurrent EBV reactivation. Expression profile analysis by microarray indicates that many carcinogenesis-related genes were altered after recurrent EBV reactivation, and several aberrations observed in cell lines correspond to alterations in NPC lesions. These results indicate that cooperation between chemical carcinogens can enhance the reactivation of EBV and, over recurrent reactivations, lead to alteration of cancer hallmark gene expression with resultant enhancement of tumorigenesis in NPC.

Microbiological Safety of Processed Meat Products Formulated with Low Nitrite Concentration: A Mini Review.

PubMed

Lee, Soomin; Lee, Heeyoung; Kim, Sejeong; Lee, Jeeyeon; Ha, Jimyeong; Choi, Yukyung; Oh, Hyemin; Choi, Kyoung-Hee; Yoon, Yohan

2018-03-13

Nitrite plays a major role in inhibiting the growth of foodborne pathogens, including Clostridium botulinum that causes botulism, a life-threatening disease. Nitrite serves as a color-fixing agent in processed meat products. However, N-nitroso compounds can be produced from nitrite. They are considered as carcinogens. Thus, consumers desire processed meat products that contain lower concentrations (below conventional concentrations of products) of nitrite or no nitrite at all, although the portion of nitrite intake by processed meat consumption in total nitrite intake is very low. However, lower nitrite levels might expose consumers to risk of botulism poisoning due to C. botulinum or illness caused by other foodborne pathogens. Hence, lower nitrite concentrations in combination with other factors such as low pH, high NaCl level, and others have been recommended to decrease the risk of food poisoning. In addition, natural compounds that can inhibit bacterial growth and function as color-fixing agents have been developed to replace nitrite in processed meat products. However, their antibotulinal effects have not been fully clarified. Therefore, to have processed meat products with lower nitrite concentrations, low pH, high NaCl concentration, and others should also be applied together. Before using natural compounds as replacement of nitrite, their antibotulinal activities should be examined.

40 CFR 721.9957 - N-Nitroso-N-methylurethane.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false N-Nitroso-N-methylurethane. 721.9957... Substances § 721.9957 N-Nitroso-N-methylurethane. (a) Chemical substance and significant new use subject to reporting. (1) The chemical substance N-nitroso-N-methylurethane (CAS No. 615-53-2) is subject to reporting...

40 CFR 721.9957 - N-Nitroso-N-methylurethane.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false N-Nitroso-N-methylurethane. 721.9957... Substances § 721.9957 N-Nitroso-N-methylurethane. (a) Chemical substance and significant new use subject to reporting. (1) The chemical substance N-nitroso-N-methylurethane (CAS No. 615-53-2) is subject to reporting...

N-Nitroso compounds and cancer incidence: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study.

PubMed

Loh, Yet Hua; Jakszyn, Paula; Luben, Robert N; Mulligan, Angela A; Mitrou, Panagiota N; Khaw, Kay-Tee

2011-05-01

Humans are exposed to preformed N-nitroso compounds (NOCs) and endogenous NOCs. Several NOCs are potential human carcinogens, including N-nitrosodimethylamine (NDMA), but evidence from population studies is inconsistent. We examined the relation between dietary NOCs (NDMA), the endogenous NOC index, and dietary nitrite and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, United Kingdom, study. This was a prospective study of 23,363 men and women, aged 40-79 y, who were recruited in 1993-1997 and followed up to 2008. The baseline diet was assessed with food-frequency questionnaires. There were 3268 incident cancers after a mean follow-up of 11.4 y. Dietary NDMA intake was significantly associated with increased cancer risk in men and women [hazard ratio (HR): 1.14; 95% CI: 1.03, 1.27; P for trend = 0.03] and in men (HR: 1.24; 95% CI: 1.07, 1.44; P for trend = 0.005) when the highest quartile was compared with the lowest quartile in age- and sex-adjusted analyses but not in multivariate analyses (HR: 1.10; 95% CI: 0.97, 1.24; HR for men: 1.18; 95% CI: 1.00, 1.40; P for trend ≥ 0.05). When continuously analyzed, NDMA was associated with increased risk of gastrointestinal cancers (HR: 1.13; 95% CI: 1.00, 1.28), specifically of rectal cancer (HR: 1.46; 95% CI: 1.16, 1.84) per 1-SD increase after adjustment for age, sex, body mass index, cigarette smoking status, alcohol intake, energy intake, physical activity, education, and menopausal status (in women). The endogenous NOC index and dietary nitrite were not significantly associated with cancer risk. There was a significant interaction between plasma vitamin C concentrations and dietary NDMA intake on cancer incidence (P for interaction < 0.00001). Dietary NOC (NDMA) was associated with a higher gastrointestinal cancer incidence, specifically of rectal cancer. Plasma vitamin C may modify the relation between NDMA exposure and cancer risk.

Kinetic and analytic investigations on the formation of N-nitroso-N-methyl-N-cyclohexylamine from bromhexine and nitrite.

PubMed

Schmid, J; Daneck, K; Koss, F W; Eisenbrand, G; Schlemmer, K H

1988-09-01

Bromhexine (N-methyl-N-cyclohexyl-(2-amino-3,5-dibromobenzyl)-ammoniumhydr ochloride) forms N-nitroso-N-methyl-N-cyclohexylamine (NMCA) under the conditions of the WHO Nitrosation Assay Procedure (NAP-test). The formation kinetics of this compound was investigated. The formation of NMCA depends on the square of the nitrite concentration. The reaction has a narrow pH-optimum at pH 3. The reaction is quick: After 1 h about 70% of the maximum amount of NMCA is formed. To study this reaction kinetics sensitive assays with a detection limit up to 0.5 ng/ml NMCA were developed. The stability of the components of the system, especially that of NMCA and nitrite, were further studied. The latter is rather instable under conditions found in an acidic stomach.

The Synergistic Effect of Chemical Carcinogens Enhances Epstein-Barr Virus Reactivation and Tumor Progression of Nasopharyngeal Carcinoma Cells

PubMed Central

Fang, Chih-Yeu; Huang, Sheng-Yen; Wu, Chung-Chun; Hsu, Hui-Yu; Chou, Sheng-Ping; Tsai, Ching-Hwa; Chang, Yao; Takada, Kenzo; Chen, Jen-Yang

2012-01-01

Seroepidemiological studies imply a correlation between Epstein-Barr virus (EBV) reactivation and the development of nasopharyngeal carcinoma (NPC). N-nitroso compounds, phorbols, and butyrates are chemicals found in food and herb samples collected from NPC high-risk areas. These chemicals have been reported to be risk factors contributing to the development of NPC, however, the underlying mechanism is not fully understood. We have demonstrated previously that low dose N-methyl-N’-nitro-N-nitrosoguanidine (MNNG, 0.1 µg/ml) had a synergistic effect with 12-O-tetradecanoylphorbol-13-acetate (TPA) and sodium butyrate (SB) in enhancing EBV reactivation and genome instability in NPC cells harboring EBV. Considering that residents in NPC high-risk areas may contact regularly with these chemical carcinogens, it is vital to elucidate the relation between chemicals and EBV and their contributions to the carcinogenesis of NPC. In this study, we constructed a cell culture model to show that genome instability, alterations of cancer hallmark gene expression, and tumorigenicity were increased after recurrent EBV reactivation in NPC cells following combined treatment of TPA/SB and MNNG. NPC cells latently infected with EBV, NA, and the corresponding EBV-negative cell, NPC-TW01, were periodically treated with MNNG, TPA/SB, or TPA/SB combined with MNNG. With chemically-induced recurrent reactivation of EBV, the degree of genome instability was significantly enhanced in NA cells treated with a combination of TPA/SB and MNNG than those treated individually. The Matrigel invasiveness, as well as the tumorigenicity in mouse, was also enhanced in NA cells after recurrent EBV reactivation. Expression profile analysis by microarray indicates that many carcinogenesis-related genes were altered after recurrent EBV reactivation, and several aberrations observed in cell lines correspond to alterations in NPC lesions. These results indicate that cooperation between chemical carcinogens can enhance the reactivation of EBV and, over recurrent reactivations, lead to alteration of cancer hallmark gene expression with resultant enhancement of tumorigenesis in NPC. PMID:23024765

Nitrate and nitrite in the diet: how to assess their benefit and risk for human health.

PubMed

Habermeyer, Michael; Roth, Angelika; Guth, Sabine; Diel, Patrick; Engel, Karl-Heinz; Epe, Bernd; Fürst, Peter; Heinz, Volker; Humpf, Hans-Ulrich; Joost, Hans-Georg; Knorr, Dietrich; de Kok, Theo; Kulling, Sabine; Lampen, Alfonso; Marko, Doris; Rechkemmer, Gerhard; Rietjens, Ivonne; Stadler, Richard H; Vieths, Stefan; Vogel, Rudi; Steinberg, Pablo; Eisenbrand, Gerhard

2015-01-01

Nitrate is a natural constituent of the human diet and an approved food additive. It can be partially converted to nitrogen monoxide, which induces vasodilation and thereby decreases blood pressure. This effect is associated with a reduced risk regarding cardiovascular disease, myocardial infarction, and stroke. Moreover, dietary nitrate has been associated with beneficial effects in patients with gastric ulcer, renal failure, or metabolic syndrome. Recent studies indicate that such beneficial health effects due to dietary nitrate may be achievable at intake levels resulting from the daily consumption of nitrate-rich vegetables. N-nitroso compounds are endogenously formed in humans. However, their relevance for human health has not been adequately explored up to now. Nitrate and nitrite are per se not carcinogenic, but under conditions that result in endogenous nitrosation, it cannot be excluded that ingested nitrate and nitrite may lead to an increased cancer risk and may probably be carcinogenic to humans. In this review, the known beneficial and detrimental health effects related to dietary nitrate/nitrite intake are described and the identified gaps in knowledge as well as the research needs required to perform a reliable benefit/risk assessment in terms of long-term human health consequences due to dietary nitrate/nitrite intake are presented. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

An aziridinium ion intermediate in the nitrosation of a hexetidine model.

PubMed

Loeppky, R N; Bae, J Y

1994-01-01

The nitrosation chemistry of 1,3,5-trimethyl-5-aminohexahydropyrimidine (2) has been investigated as a model for the behavior of the antimicrobial agent hexetidine (1) under similar conditions. The reaction of 2 with sodium nitrite in glacial acetic acid gives 4-methyl-4-[(methylnitrosamino)methyl]-3-nitroso-1,3-oxazolidine (4) as the major nitrosamine. This compound arises from a molecular rearrangement which proceeds through the diazotization of the primary amino group followed by intramolecular displacement of nitrogen to generate an aziridinium ion. The N-nitrosooxazolidine 4 forms from the nitrosation of an imidazolidine produced from the aziridinium ring hydrolytic opening. The N-nitrosooxazolidine 4, an isomer, 5-methyl-5-[(methylnitrosamino)methyl]-3-nitroso-1,3-oxazolidine (14), which is not formed in the nitrosation of 2, and an analog 4-methyl-4-[[(2-ethylhexyl)nitrosamino]methyl]-3-nitroso-1,3-oxazolidine (22) have been independently synthesized. The N-nitrosooxazolidine 22 which would be formed from hexetidine is not present in its nitrosation mixture, suggesting the absence of reactive aziridinium ions in that case. The dissimilar nitrosation chemistry of 2 and 1 are discussed.

Nitrate and drinking water from private wells: will there be an epidemic of cancers of the digestive tract, urinary bladder and thyroid?

PubMed

Njeze, G E; Dilibe, U; Ilo, C

2014-01-01

To estimate the nitrate levels in private wells located in different parts of Enugu and discuss the future health implications following chronic ingestion of well water. The map of Enugu was used to divide the city into many 25 units, using grid lines 1 cm apart. Cluster sampling method was used to collect samples. These samples were sent to two laboratories for estimation of nitrate levels. The people drawing water from the different wells were interviewed to determine what they used the water for. The subjects who were interviewed said they ingested the water. The nitrate levels found in these wells (median value of 31 mg/L) were significantly higher than the internationally accepted levels of nitrate in water for ingestion, (P < 0.0001). High nitrate levels drinking water is dangerous to health and can cause methemoglobinemia in children. It may also increase cancer risk in adults because nitrate is endogenously reduced to nitrite and subsequent nitrosation reactions give rise to N-nitroso compounds (NOCs), which are highly carcinogenic and can act systemically.

New sulfenamide accelerators derived from 'safe' amines for the rubber and tyre industry.

PubMed

Wacker, C D; Spiegelhalder, B; Preussmann, R

1991-01-01

A reduction of the high exposures to N-nitrosamines in the rubber and tyre industry is possible using the concept of 'safe' amines, in which vulcanization accelerators contain amine moieties that are both difficult to nitrosate and, on nitrosation, yield noncarcinogenic N-nitroso compounds. The toxicological and technological properties of more than 50 benzothiazole sulfenamides derived from 'safe' amines have been evaluated. Some of the new compounds show excellent vulcanization properties and seem suitable as replacements for traditional accelerators in this class of compounds.

Nitrite and nitroso compounds can serve as specific catalase inhibitors.

PubMed

Titov, Vladimir Yu; Osipov, Anatoly N

2017-03-01

We present evidence that nitrite and nitrosothiols, nitrosoamines and non-heme dinitrosyl iron complexes can reversibly inhibit catalase with equal effectiveness. Catalase activity was evaluated by the permanganatometric and calorimetric assays. This inhibition is not the result of chemical transformations of these compounds to a single inhibitor, as well as it is not the result of NO release from these substances (as NO traps have no effect on the extent of inhibition). It was found that chloride and bromide in concentration above 80 mM and thiocyanate in concentration above 20 μM enhance catalase inhibition by nitrite and the nitroso compounds more than 100 times. The inhibition degree in this case is comparable with that induced by azide. We propose that the direct catalase inhibitor is a positively charged NO-group. This group acquires a positive charge in the active center of enzyme by interaction of nitrite or nitroso compounds with some enzyme groups. Halides and thiocyanate protect the NO + group from hydration and thus increase its inhibition effect. It is probable that a comparatively low chloride concentration in many cells is the main factor to protect catalase from inhibition by nitrite and nitroso compounds.

Maternal diet and risk of astrocytic glioma in children: a report from the Childrens Cancer Group (United States and Canada)

PubMed

Bunin, G R; Kuijten, R R; Boesel, C P; Buckley, J D; Meadows, A T

1994-03-01

N-nitroso compounds and their precursors, nitrites and nitrates, have been hypothesized as risk factors, and vitamins C and E, which inhibit N-nitroso formation, as protective factors for brain tumors. A case-control study of maternal diet during pregnancy and risk of astrocytoma, the most common childhood brain tumor, was conducted by the Childrens Cancer Group. The study included 155 cases under age six at diagnosis and the same number of matched controls selected by random-digit dialing. A trend was observed for consumption of cured meats, which contain preformed nitrosamines (a class of N-nitroso compounds) and their precursors (adjusted odds ratio [OR] for highest quartile of intake relative to lowest = 1.7, P trend = 0.10). However, no strong trends were observed for nitrosamine (OR = 0.8, P = 0.60); nitrite (OR = 1.3, P = 0.54); nitrate (OR = 0.7, P = 0.43); vitamin C (OR = 0.7, P = 0.37); or vitamin E (OR = 0.7, P = 0.48). Iron supplements were associated with a significant decrease in risk (OR = 0.5, 95 percent confidence interval = 0.3-0.8). The effect of several dietary factors differed by income level, making interpretation of the results difficult. Future research should investigate the effect of dietary components not assessed in this study, as these may explain the disparate effects by income level. The results of this study provide limited support for the nitrosamine hypothesis.

Dietary intake of polyphenols, nitrate and nitrite and gastric cancer risk in Mexico City

PubMed Central

Hernández-Ramírez, Raúl U.; Galván-Portillo, Marcia V.; Ward, Mary H.; Agudo, Antonio; González, Carlos A.; Oñate-Ocaña, Luis F.; Herrera-Goepfert, Roberto; Palma-Coca, Oswaldo; López-Carrillo, Lizbeth

2009-01-01

N-Nitroso compounds (NOC) are potent animal carcinogens and potential human carcinogens. The primary source of exposure for most individuals may be endogenous formation, a process that can be inhibited by dietary polyphenols. To estimate the risk of gastric cancer (GC) in relation to the individual and combined consumption of polyphenols and NOC precursors (nitrate and nitrite), a population-based case–control study was carried out in Mexico City from 2004 to 2005 including 257 histologically confirmed GC cases and 478 controls. Intake of polyphenols, nitrate and nitrite were estimated using a food frequency questionnaire. High intakes of cinnamic acids, secoisolariciresinol and coumestrol were associated with an ~50% reduction in GC risk. A high intake of total nitrite as well as nitrate and nitrite from animal sources doubled the GC risk. Odds ratios around 2-fold were observed among individuals with both low intake of cinnamic acids, secoisolariciresinol or coumestrol and high intake of animal-derived nitrate or nitrite, compared to high intake of the polyphenols and low animal nitrate or nitrite intake, respectively. Results were similar for both the intestinal and diffuse types of GC. Our results show, for the first time, a protective effect for GC because of higher intake of cinnamic acids, secoisolariciresinol and coumestrol, and suggest that these polyphenols reduce GC risk through inhibition of endogenous nitrosation. The main sources of these polyphenols were pears, mangos and beans for cinnamic acids; beans, carrots and squash for secoisolariciresinol and legumes for coumestrol. PMID:19449378

Effects of Lactofermented Beetroot Juice Alone or with N-nitroso-N-methylurea on Selected Metabolic Parameters, Composition of the Microbiota Adhering to the Gut Epithelium and Antioxidant Status of Rats.

PubMed

Klewicka, Elżbieta; Zduńczyk, Zenon; Juśkiewicz, Jerzy; Klewicki, Robert

2015-07-16

An objective of this work was to assess the biological activity of beetroot juice (Chrobry variety, Beta vulgaris L. ssp. vulgaris), which was lactofermented by probiotic bacteria Lactobacillus brevis 0944 and Lactobacillus paracasei 0920. The oxidative status of blood serum, kidneys, and liver of rats consuming the fermented beetroot juice were determined. The experimental rats were divided into four groups on diet type: Basal diet, basal diet supplemented with fermented beetroot juice, basal diet and N-nitroso-N-methylurea treatment, and basal diet supplemented with fermented beetroot juice and N-nitroso-N-methylurea treatment. Mutagen N-nitroso-N-methylurea, which was added to diet in order to induce aberrant oxidative and biochemical processes and disadvantageous changes in the count and metabolic activity of the gut epithelium microbiota. The nutritional in vivo study showed that supplementing the diet of the rats with the lactofermented beetroot juice reduced the level of ammonia by 17% in the group treated with N-nitroso-N-methylurea. Furthermore, the positive modulation of the gut microflora and its metabolic activity was observed in groups of rats fed with the diet supplemented with the fermented beetroot juice. A concomitant decrease in the b-glucuronidase activity was a consequence of the gut epithelium microbiota modulation. The antioxidant capacity of blood serum aqueous fraction was increased by about 69% in the group of rats treated N-nitroso-N-methylurea mixed with the fermented beetroot juice and N-nitroso-N-methylurea versus to the N-nitroso-N-methylurea treatment, whereas the antioxidant parameters of the blood serum lipid fraction, kidneys, and liver remained unchanged.

Ionic Fluorine Chemistry.

DTIC Science & Technology

SOLID ROCKET OXIDIZERS, *LIQUID ROCKET OXIDIZERS, CHLORATES, FLUORIDES, ACETONES, CHLORINE COMPOUNDS, NITROSO COMPOUNDS, *HALOGEN COMPOUNDS, ADDITION REACTIONS, CESIUM COMPOUNDS, CHLORIDES, COMPLEX COMPOUNDS

Heme-Induced Biomarkers Associated with Red Meat Promotion of colon Cancer Are Not Modulated by the Intake of Nitrite

PubMed Central

Chenni, Fatima Z; Taché, Sylviane; Naud, Nathalie; Guéraud, Françoise; Hobbs, Ditte A; Kunhle, Gunter G C; Pierre, Fabrice H; Corpet, Denis E

2013-01-01

Red and processed meat consumption is associated with the risk of colorectal cancer. Three hypotheses are proposed to explain this association, via heme/alcenal, heterocyclic amines or N-nitroso compounds. Rats have often been used to study these hypotheses, but the lack of enterosalivary cycle of nitrate in rats casts doubt on the relevance of this animal model to predict nitroso- and heme-associated human colon carcinogenesis. The present study was thus designed to clarify whether a nitrite intake that mimics the enterosalivary cycle can modulate heme-induced nitrosation and fat peroxidation. This study shows that, in contrast with the starting hypothesis, salivary nitrite did not change the effect of hemoglobin on biochemical markers linked to colon carcinogenesis, notably lipid peroxidation and cytotoxic activity in the colon of rat. However, ingested sodium nitrite increased fecal nitroso-compounds level, but their fecal concentration and their nature (iron-nitrosyl) would not be associated with an increased risk of cancer. The rat model could thus be relevant to study the effect of red meat on colon carcinogenesis in spite of the lack of nitrite recycling in rat’s saliva. PMID:23441609

Resistance of Salmonella typhimurium TA 1535 to O6-guanine methylation and mutagenesis induced by low doses of N-methyl-N'-nitro-N-nitrosoguanidine: an apparent constitutive repair activity.

PubMed

Guttenplan, J B; Milstein, S

1982-01-01

Salmonella tester strains which are reverted by base-pair substitution mutagens are relatively insensitive to the mutagenic effects of N-methyl-N-nitroso compounds. One reason for this insensitivity is the ability of these strains to withstand low doses of these compounds before they become sensitive to their mutagenic effects. In this report it is shown that mutagenesis induced by treatment of Salmonella typhimurium TA 1535 with N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) in buffer is biphasic with a low sensitivity range at low doses where little mutagenesis occurs, followed by a high sensitivity range whose onset begins after an apparent threshold dose has been exceeded. levels of O6-methylguanine (O6-MeG) in the DNA extracted from the bacteria follow a similar dose-response curve suggesting a dependency of mutagenesis on O6-MeG. In contrast, levels of 7-methylguanine (7-MeG) in the DNA increase linearly with dose. O6-MeG was undetectable at the lowest dose of MNNG whereas 7-MeG was readily detectable. Although such resistance to O6-alkylation has been demonstrated in MNNG- pretreated (adapted) E. coli, it has not been reported in unpretreated cells. Then isolated DNA was treated with MNNG a linear dose-response in the generation of O6-MeG was observed. The lack of O6-MeG in DNA isolated from MNNG treated cells after low doses is attributed to a saturable, constitutive repair activity in the bacteria. An attempt to observe the removal of O6-MeG from the bacteria after exposure to a short challenge dose of N-nitroso-N-methylurea (NMU) followed by a subsequent incubation in buffer was unsuccessful, probably because all the repair occurred within the time necessary to treat and lyse the cells.

Expression of Neuronal and Inducible Nitric Oxide Synthase Isoforms and Generation of Protein Nitrotyrosine in Rat Brain Following Hypobaric Hypoxia

DTIC Science & Technology

2001-06-01

Promoci6n General del Conocimiento , Ministerio de Educaci6n y Cultura. We thank Mr. E. Sfnchez and directors and staff of the Hospital del Aire and CIMA... based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364: 626-632. Lowenstein, C.J

Specific and total N-nitrosamines formation potentials of nitrogenous micropollutants during chloramination.

PubMed

Piazzoli, Andrea; Breider, Florian; Aquillon, Caroline Gachet; Antonelli, Manuela; von Gunten, Urs

2018-05-15

N-nitrosamines are a group of potent human carcinogens that can be formed during oxidative treatment of drinking water and wastewater. Many tertiary and quaternary amines present in consumer products (e.g., pharmaceuticals, personal care and household products) are known to be N-nitrosodimethylamine (NDMA) precursors during chloramination, but the formation of other N-nitrosamines has been rarely studied. This study investigates the specific and total N-nitrosamine (TONO) formation potential (FP) of various precursors from nitrogen-containing micropollutants (chlorhexidine, metformin, benzalkonium chloride and cetyltrimethylammonium chloride) and tertiary and quaternary model amines (trimethyl amine, N,N-dimethylbutyl amine, N,N-dimethylbenzyl amine and tetramethyl ammonium). All the studied nitrogenous micropollutants displayed quantifiable TONO FP, with molar yields in the range 0.04-11.92%. However, the observed TONO pools constituted mostly of uncharacterized species, not included in US-EPA 8270 N-nitrosamines standard mix. Only the quaternary ammonium compound benzalkonium chloride showed quantifiable NDMA FP (0.56% molar yield), however, explaining only a minor fraction of the observed TONO FP. The studied model amines showed molar NDMA yields from 0.10% (trimethyl amine) to 5.05% (N,N-dimethylbenzyl amine), very similar to the molar TONO yields. The comparison of the FPs of micropollutants and model compounds showed that the presence of electron donating functional groups (such as a benzyl group) in tertiary and quaternary amine precursors leads to a higher formation of NDMA and uncharacterized N-nitrosamines, respectively. LC-qTOF screening of a list of proposed N-nitrosamine structures has enabled to identify a novel N-nitrosamine (N-nitroso-N-methyldodecylamine) from the chloramination of benzalkonium chloride. This finding supports the hypothesis that different functional groups in quaternary amines can act as leaving groups during chloramination and form differing N-nitrosamine structures at significant yield. Molar TONO yields determined for micropollutants were finally validated under experimental conditions closer to real water matrices, confirming their representativeness also for lower concentration ranges. Copyright © 2018 Elsevier Ltd. All rights reserved.

Volatile nitrosamines in foods and beverages: preliminary survey of the Italian market

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gavinelli, M.; Fanelli, R.; Bonfanti, M.

The question whether humans suffer from cancer as a result of exposure to N-nitroso compounds has not been yet answered. Food is one of the sources of human exposure to these compounds, and during the past decade considerable attention has in fact been paid to the identification and quantitative determination of N-nitroso compounds in food, volatile N-nitrosamines being those studied most extensively. Many studies have been made in different countries to establish the degree of contamination of foodstuffs typical for each country and to identify the efforts needed to remove or at least reduce their presence in the environment. Somore » far, there are only a few reports of nitrosamines in Italian cheese and beers, but no extensive studies have been made in Italy. The authors present here a preliminary survey on volatile nitrosamine content in foods and beverages on the Italian market, including canned beef, pork, poultry, cured meat, milk products, domestic Italian canned wines and beers. A recently developed methods used for measuring nitrosamines in solid food matrices by simultaneous distillation-extraction followed by high resolution gas chromatography-thermal energy analysis (HRGC-TEA). Liquid food matrices and beverages were screened for nitrosamine content after column extraction and HRGC-TEA.« less

Antimutagens as cancer chemopreventive agents in the diet.

PubMed

Ferguson, L R

1994-05-01

It has been suggested that the use of antimutagens and anticarcinogens in everyday life will be the most effective procedure for preventing human cancer and genetic disease. There are several ways in which mutagenesis can be reduced or prevented. Chemicals which act to interfere with DNA repair or with mutagen metabolism can be effective antimutagens: however such compounds may also increase the probability of mutations by different chemicals or at different sites. In contrast, mutagen scavengers may be less prone to increase mutations by other chemicals. Selected examples illustrate that antimutagenic effects are often specific to certain classes of mutagen and/or certain test systems. Thus, if antimutagens are to have any impact on human disease, it is essential that they are specifically directed against the most common mutagens in daily life. On our current understanding, these are quite diverse in nature, so that combinations of antimutagens will probably be necessary. Two groups of mutagen scavengers (porphyrins and some types of dietary fibre) show some selectivity for large planar and hydrophobic types of carcinogen, which appear to be common in a normal Western diet. Increasing consumption of vitamins C and E, either through increased consumption of fruit and vegetables or through dietary supplementation might reduce formation of N-nitroso compounds, another common class of mutagens. Similarly, carotenoids and related compounds, already present at high quantities in some fruits and vegetables, have excellent antioxidant properties and should be able to counteract effects of endogenous metabolism and other events which generate oxidising species and free radicals. Still other types of antimutagen might be necessary to act against smaller non-planar carcinogens, but there is some question as to the importance of this type of carcinogen in a normal Western diet. It may be necessary to adjust the selection of antimutagens for different population groups, or as our understanding of mutagens in the diet develops further. Current assays for cancer chemoprevention in animals are unlikely to detect some important types of antimutagens, such as mutagen scavengers. A structured testing strategy is suggested, progressing from in vitro to in vivo antimutagenicity tests against a selected range of mutagens. Optimal use of antimutagens might be as a dietary supplement, additional to practical advice on increasing consumption of fruit and vegetables.

Role of oral nitrate in the nitrosation of ( UC)proline by conventional microflora and germ-free rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mallett, A.K.; Rowland, I.R.; Walters, D.G.

1985-11-01

The urinary excretion of N-nitroso-L-(U- UC)proline by conventional microflora and germ free rats was used to assess the role of the gut bacteria and oral nitrate in the endogenous formation of N-nitroso compounds. The formation of nitrosoproline was qualitatively similar in conventional and germfree rats suggesting no involvement of the intestinal flora in this reaction. Furthermore, nitrosamino acid production was similar following the administration of nitrate and (U- UC)proline or (U- UC)proline alone, demonstrating no involvement of exogenous nitrate under the conditions of the experiment. Dietary contamination with nitrate/nitrite was negligible. The results are consistent with the suggestion that nitrate/nitritemore » reserves in the body are important in the formation of nitrosoproline in vivo.« less

Urinary Excretion of N-Nitroso Compounds in Rats Fed Sodium Nitrite and/or Hot Dogs

PubMed Central

2015-01-01

Nitrite-treated meat is a reported risk factor for colon cancer. Mice that ingested sodium nitrite (NaNO2) or hot dogs (a nitrite-treated product) showed increased fecal excretion of apparent N-nitroso compounds (ANC). Here, we investigated for the first time whether rats excrete increased amounts of ANC in their urine after they are fed NaNO2 and/or hot dogs. Rats were treated for 7 days with NaNO2 in drinking water or were fed hot dogs. Their 24 h urine samples were analyzed for ANC by thermal energy analysis on days 1–4 after nitrite or hot dog treatment was stopped. For two rats fed 480 mg NaNO2/L drinking water, mean urinary ANC excretion on days 1–4 was 30, 5.2, 2.5, and 0.8 nmol/day, respectively. For two to eight rats/dose given varied NaNO2 doses, mean urinary ANC output on day 1 increased from 0.9 (for no nitrite) to 37 (for 1000 mg NaNO2/L drinking water) nmol ANC/day. Urine samples of four rats fed 40–60% hot dogs contained 12–13 nmol ANC on day 1. Linear regression analysis showed highly significant correlations between urinary ANC excretion on day 1 after stopping treatment and varied (a) NaNO2 level in drinking water for rats fed semipurified or commercials diet and (b) hot dog levels in the diet. Some correlations remained significant up to 4 days after nitrite treatment was stopped. Urinary output of ANC precursors (compounds that yield ANC after mild nitrosation) for rats fed semipurified or commercial diet was 11–17 or 23–48 μmol/day, respectively. Nitrosothiols and iron nitrosyls were not detected in urinary ANC and ANCP. Excretion of urinary ANC was about 60% of fecal ANC excretion for 1 to 2 days after NaNO2 was fed. Administered NaNO2 was not excreted unchanged in rat urine. We conclude that urinary ANC excretion in humans could usefully be surveyed to indicate exposure to N-nitroso compounds. PMID:25183213

Selection of an in vitro carcinogenicity test for derivatives of the carcinogen hexamethylphosphoramide.

PubMed Central

Ashby, J.; Styles, J. A.; Anderson, D.

1977-01-01

The demonstration that hexamethylphosphoramide (HMPA) possesses potent carcinogenic properties has raised doubts about the safety of exposure to other phosphoric amides. In order to define a suitable short-term test with which to evaluate such analogues, the response of the Salmonella typhimurium mutation assay of Ames and cell transformation assay of Styles to HMPA and 3 selected analogues has been studied. These analogues were the related leukaemogen phosphoramide, the putative non-carcinogen, phosphoric trianilide and N.N'N''-trimethylphosphorothioic triamide, a compound of unknown and hitherto unpredictable properties. While both tests found the trianilide negative, the Ames test failed to detect phosphoramide as positive and gave an erratic and predominantly negative response to HMPA. In contrast, the transformation assay found both phosphoramide and HMPA positive. This test response profile indicates that the transformation assay is the preferred test with which to evaluate analogues of HMPA for potential carcinogenicity. Some structural requirements for potential carcinogenicity within this class of compounds are tentatively deduced. PMID:337998

Direct asymmetric N-specific reaction of nitrosobenzene with aldehydes catalyzed by a chiral primary amine-based organocatalyst.

PubMed

Qin, Long; Li, Lei; Yi, Lei; Da, Chao-Shan; Zhou, Yi-Feng

2011-08-01

Nitroso compounds have two reactive nitrogen and oxygen atoms. It is interesting and important to perform a nitrogen or oxygen selective reaction with interesting substrates. These atom specific reactions are crucial to specifically synthesis of specific compounds. An enantioselective N-specific reaction of nitrosobenzene with unmodified aldehydes was successfully achieved catalyzed first by a variety of primary amine-based organocatalysts with higher yield and enantioselectivity. The bulkier substituted groups of the organocatalyst and two hydrogen bonds from the organocatalyst and the oxygen atom of nitrosobenzene make the reaction preferentially N-specific and predominantly afford R products. Copyright © 2011 Wiley-Liss, Inc.

A diazonium ion cascade from the nitrosation of tolazoline, an imidazoline-containing drug.

PubMed

Loeppky, Richard N; Shi, Jianzheng; Barnes, Charles L; Geddam, Sailaja

2008-02-01

Tolazoline (1-benzylimidazoline), a representative imidazoline-containing drug, reacts readily with nitrite in acetic acid to produce a complex product mixture. Fourteen compounds have been identified as products of this transformation when an 8-fold excess of HNO2 is used. The products, which include N-nitrosoamides, esters, alcohols, and phenylacetic acid, are rationalized as arising from a cascade of reactive diazonium ions. N-Nitrosotolazoline can be isolated from the nitrosation reaction in good yield when the mixture is extracted with CH2Cl2 as the transformation progresses. It nitrosates much more rapidly (50x) than tolazoline to give, among other products, the oxime [1-( N-nitroso-2-imidazolinyl)benzylidene]hydroxylamine, which can also be produced in good yield from the reaction of tolazoline with isopropyl nitrite. At low substrate and nitrite concentrations, the main reaction products are N-nitrosotolazoline, its decomposition product N-2-hydroxyethylphenylacetamide, the above-mentioned oxime, phenyl acetic acid, and 2-hydroxyethyl phenylacetate. The tolazoline nitrosation rate in three buffer systems has been determined at pH 3.4 and 37 degrees C ( kobs = 6.25 x 10 (-5) s (-1) in 0.5 M acetate buffer with a 10 * [NO2(-)] = 250 mM). Because N-nitrosotolazoline exhibits the chemical properties of a direct-acting mutagen and carcinogen, we have used the rate data to estimate its level of formation at nitrite concentrations <3 mM. Cursory examination of the nitrosation chemistry of oxymetazoline, a related drug, is primarily focused at its electron-rich aromatic ring.

N-Nitroso-N-methylethylamine

Integrated Risk Information System (IRIS)

N - Nitroso - N - methylethylamine ; CASRN 10595 - 95 - 6 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments

Nitrate and Perchlorate Destruction and Potable Water Production Using Membrane Biofilm Reduction

DTIC Science & Technology

2014-01-01

NDMA N-nitrosodimethylamine NDPA N-nitroso-di-n-propylamine ng/L nanograms per liter NO2- nitrite NO3- nitrate NTU nephelometric turbidity units...Nitrosamines including N-nitrosodiethylamine (NDEA), N- nitrosodimethylamine ( NDMA ), and N-nitroso-di-n-propylamine (NDPA) were below their

N-Nitroso-di-n-butylamine

Integrated Risk Information System (IRIS)

N - Nitroso - di - n - butylamine ; CASRN 924 - 16 - 3 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for

Effect of DNA-injuring agents on B. stearothermophilus. Report 1. High resistance of B. stearothermophilus to N-nitroso-N-methylurea, ultraviolet and gamma radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gainullina, S.M.; Gumanova, A.V.; Vinogradova, N.A.

1978-01-01

The effects of DNA-attacking agents on thermophilic microorganisms were investigated. Bacillus stearothermophilus were treated with N-nitroso-N-methylurea, ultraviolet radiation or gamma radiation. Survival curves were plotted.

Review of the association between meat consumption and risk of colorectal cancer.

PubMed

Kim, Eunjung; Coelho, Desire; Blachier, François

2013-12-01

The incidence of colorectal cancer (CRC) is rapidly increasing in developing countries, especially among populations that are adopting Western-style diets. Several, but not all, epidemiological and experimental studies suggest that a high intake of meat, especially red and processed meat, is associated with increased CRC risk. Potential reasons for the association between high red and processed meat intake and CRC risk include the content of the meat (e.g. protein, heme) and compounds generated by the cooking process (e.g. N-nitroso compounds, heterocyclic amines). These factors can affect the large intestine mucosa with genotoxicity and metabolic disturbances. Increased bacterial fermentation (putrefaction) of undigested protein and production of bacterial metabolites derived from amino acids may affect colon epithelial homeostasis and renewal. This correlates with the fact that most colonic cancers are detected in the distal colon and rectum where protein fermentation actively occurs. However, there are still large controversies on the relationship between red meat consumption and CRC risk. Therefore, the purpose of this review is to enhance the current understanding on the association between high red and processed meat intakes with CRC risk. A principal focus of this review will be to discuss the meat-related components, such as proteins in the meat, heme, N-nitroso compounds, and heterocyclic amines, and the effects they have upon the large intestine mucosa and the intestinal gut microbiota. © 2013 Elsevier Inc. All rights reserved.

Dietary intake of nitrate relative to antioxidant vitamin in relation to breast cancer risk: a case-control study.

PubMed

Yang, Yoon Jung; Hwang, Se Hee; Kim, Hyun Ja; Nam, Seok-Jin; Kong, Gu; Kim, Mi Kyung

2010-01-01

Nitrate is a precursor in the endogenous formation of N-nitroso compounds, which are potent animal carcinogens, whereas antioxidant vitamins have been suggested to protect against carcinogenesis. Interestingly, nitrate and antioxidant vitamins stem from the same dietary sources. We investigated whether the intake of nitrate relative to antioxidant vitamins is associated with the risk of breast cancer. A total of 362 breast cancer cases were matched to the 362 controls by age and menopausal status. Dietary intake was assessed using a quantitative food frequency questionnaire with 121 food items by trained interviewers. The nitrate to antioxidant vitamin consumption ratio was then calculated. Conditional logistic regression analysis was used to obtain odds ratios (ORs) and corresponding 95% confidence intervals (CI). Mean intakes of nitrate for cases and controls were 421 mg/day and 424 mg/day, respectively. Intakes of nitrate, nitrate/beta-carotene, nitrate/vitamin C, and nitrate/vitamin E were not associated with breast cancer risk. However, higher breast cancer risk was observed with higher intake of nitrate/folate (OR = 2.03, 95% CI = 1.16-3.54, P for trend = 0.052). Our results suggest that lowering the ratio of nitrate to folate intake may be effective in reducing breast cancer risk.

Modeling groundwater nitrate concentrations in private wells in Iowa

USGS Publications Warehouse

Wheeler, David C.; Nolan, Bernard T.; Flory, Abigail R.; DellaValle, Curt T.; Ward, Mary H.

2015-01-01

Contamination of drinking water by nitrate is a growing problem in many agricultural areas of the country. Ingested nitrate can lead to the endogenous formation of N-nitroso compounds, potent carcinogens. We developed a predictive model for nitrate concentrations in private wells in Iowa. Using 34,084 measurements of nitrate in private wells, we trained and tested random forest models to predict log nitrate levels by systematically assessing the predictive performance of 179 variables in 36 thematic groups (well depth, distance to sinkholes, location, land use, soil characteristics, nitrogen inputs, meteorology, and other factors). The final model contained 66 variables in 17 groups. Some of the most important variables were well depth, slope length within 1 km of the well, year of sample, and distance to nearest animal feeding operation. The correlation between observed and estimated nitrate concentrations was excellent in the training set (r-square = 0.77) and was acceptable in the testing set (r-square = 0.38). The random forest model had substantially better predictive performance than a traditional linear regression model or a regression tree. Our model will be used to investigate the association between nitrate levels in drinking water and cancer risk in the Iowa participants of the Agricultural Health Study cohort.

Modeling groundwater nitrate concentrations in private wells in Iowa.

PubMed

Wheeler, David C; Nolan, Bernard T; Flory, Abigail R; DellaValle, Curt T; Ward, Mary H

2015-12-01

Contamination of drinking water by nitrate is a growing problem in many agricultural areas of the country. Ingested nitrate can lead to the endogenous formation of N-nitroso compounds, potent carcinogens. We developed a predictive model for nitrate concentrations in private wells in Iowa. Using 34,084 measurements of nitrate in private wells, we trained and tested random forest models to predict log nitrate levels by systematically assessing the predictive performance of 179 variables in 36 thematic groups (well depth, distance to sinkholes, location, land use, soil characteristics, nitrogen inputs, meteorology, and other factors). The final model contained 66 variables in 17 groups. Some of the most important variables were well depth, slope length within 1 km of the well, year of sample, and distance to nearest animal feeding operation. The correlation between observed and estimated nitrate concentrations was excellent in the training set (r-square=0.77) and was acceptable in the testing set (r-square=0.38). The random forest model had substantially better predictive performance than a traditional linear regression model or a regression tree. Our model will be used to investigate the association between nitrate levels in drinking water and cancer risk in the Iowa participants of the Agricultural Health Study cohort. Copyright © 2015 Elsevier B.V. All rights reserved.

Grignard reagent-mediated conversion of an acyl nitroso-anthracene cycloadduct to a nitrone.

PubMed

Chen, Weibin; Day, Cynthia S; King, S Bruce

2006-11-24

An intramolecular hetero-Diels-Alder cycloadduct of an acyl nitroso compound and a 9,10-dimethyl anthracene derivative was prepared as a potential nitroxyl (HNO) donor. This compound did not release HNO under any of the conditions tested. Treatment of this cycloadduct with excess MeMgCl resulted in the formation of a nitrone, whose structure was confirmed by X-ray crystallography. A mechanism where MeMgCl acts as a nucleophile, strong base, and Lewis acid possibly explains the formation of this product.

Grignard Reagent-Mediated Conversion of an Acyl Nitroso-Anthracene Cycloadduct to a Nitrone

PubMed Central

Chen, Weibin; Day, Cynthia S.

2012-01-01

An intramolecular hetero-Diels-Alder cycloadduct of an acyl nitroso compound and a 9, 10-dimethyl anthracene derivative was prepared as a potential nitroxyl (HNO) donor. This compound did not release HNO under any of the conditions tested. Treatment of this cycloadduct with excess MeMgCl resulted in the formation of a nitrone, whose structure was confirmed by X-ray crystallography. A mechanism where MeMgCl acts as a nucleophile, strong base and Lewis acid possibly explains the formation of this product. PMID:17109552

New Nitration Concepts

DTIC Science & Technology

1987-09-01

CIECLASSiPCAflON DOWNGRAAING SCHEDULE d is trib ut ion unlimited N/A _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 4 PERFORM!NG ORGANIZATION REPORT NUMBER(S) s. moio OGNZTON...substitute nitroso for silicon by reaction of the silylated compound with nitrosonium fluoroborate but time and funding did not permit completion of...acetylenes, 10.8,9 The synthesis is achieved by treating a bis-substituted trialkylsilyl- acetylene with a nitronium ion 3ource (i.e., nitronium tetrafluoro

The relaxation induced by S-nitroso-glutathione and S-nitroso-N-acetylcysteine in rat aorta is not related to nitric oxide production.

PubMed

Ceron, P I; Cremonez, D C; Bendhack, L M; Tedesco, A C

2001-08-01

S-nitroso-glutathione (GSNO) and S-nitroso-N-acetylcysteine (NACysNO) are nitrosothiols that release nitric oxide (NO) and mimic the effects of endogenous NO. This study investigated the relaxation induced by GSNO and NACysNO in rat aorta and the relation between relaxation and NO formation. Both compounds at concentrations from 10(-9) M to 10(-4) M relaxed the rat aorta in a concentration-dependent manner. However, NO production depended on the concentration of nitrosothiols present and was detected only above 100 microM GSNO or NACysNO. To determine whether K+ channels are involved in the relaxation induced by nitrosothiols, the contractions were induced with KCl at concentrations of 30, 60, or 90 mM. The concentration-effect curves for the relaxation induced by nitrosothiols were shifted to the right for all the K+ concentrations compared with aortas precontracted with phenylephrine. These results indicate the participation of K+ channels in the relaxation induced by GSNO and NACysNO. A selective inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, significantly inhibited the relaxation induced by the nitrosothiols. The relaxation induced by GSNO and NACysNO was inhibited by the K+ channel blockers glibenclamide, selective K(ATP) channels, and apamin, selective for low-conductance Ca2+-activated K+ channels in rat aorta, but was not inhibited by charybdotoxin, a potent and selective Ca2+-activated K+ channel blocker, or by 4-aminopyridine, a voltage-gated K+ channel blocker. These results indicate that relaxation induced by GSNO and NACysNO is partially due to activation of K(ATP) channels and partially due to activation of low-conductance Ca2+-activated K+ channels. However, the ability of the nitrosothiol compounds to overcome the inhibitory effect of high extracellular K+ concentrations suggests another mechanism of relaxation contributing to the nitrosothiol response. The most intriguing finding is that relaxation is not related to the NO produced in rat aorta.

Effect of nitroso complexes of some transition metals on the activity of soluble guanylate cyclase.

PubMed

Severina, I S; Bussygina, O G; Grigorjev, N B

1992-03-01

Effects of nitroso complexes of some transition metals (Fe, Co, Cr), differing in the character of NO oxidation on the activity of human and rat platelet guanylate cyclase were studied. 3 types of nitroso complexes were used: (1) NO group carries a positive charge--a nitrosonium cation (Na2[FeNO + (CN)5]-nitroprusside); (2) NO is neutral--(K3[CrNO(CN)5 and [CoNO(NH3)5]SO4) and (3) NO is coordinated as anion NO- (K3[CoNO-(CN)5]. It is shown that the highest stimulatory effect is produced by sodium nitroprusside, whose activating action is due to the interaction of its NO group with the guanylate cyclase heme. Nitroso complexes (Co and Cr) the NO group of which is neutral stimulated guanylate cyclase activity insignificantly and this activation was not guanylate cyclase heme directed. Nitroso complex (Co) with NO coordinated as anion NO(-)--is a guanylate cyclase inhibitor. In contrast to nitroprusside, the nitroso complexes used (Co and Cr) have no hypotensive effect. It was concluded that the essential requirement for the realization of the hypotensive effect of transition metals' nitroso complexes is the ability of these compounds to activate soluble guanylate cyclase solely by the heme-dependent mechanism.

Sensitive determination of RDX, nitroso-RDX metabolites, and other munitions in ground water by solid-phase extraction and isotope dilution liquid chromatography-atmospheric pressure electro-spray [correction of chemical] ionization mass spectrometry.

PubMed

Cassada, D A; Monson, S J; Snow, D D; Spalding, R F

1999-06-04

Recent improvements in the LC-MS interface have increased the sensitivity and selectivity of this instrument in the analysis of polar and thermally-labile aqueous constituents. Determination of RDX, nitroso-RDX metabolites, and other munitions was enhanced using LC-MS with solid-phase extraction, 15N3-RDX internal standard, and electrospray ionization (ESI) in negative ion mode. ESI produced a five-fold increase in detector response over atmospheric pressure chemical ionization (APCI) for the nitramine compounds, while the more energetic APCI produced more than twenty times the ESI response for nitroaromatics. Method detection limits in ESI for nitramines varied from 0.03 microgram l-1 for MNX to 0.05 microgram l-1 for RDX.

Compounds formed by treatment of corn (Zea mays) with nitrous acid.

PubMed

Archer, M C; Hansen, T J; Tannenbaum, S R

1980-01-01

Nitrohexane has been identified as a major product formed following treatment of corn (Zea mays) with nitrous acid. Preliminary evidence suggests that another compound isolated from the nitrosated corn is an unsaturated nitrolic acid. As an aid to the analysis of N-nitro compounds, we have characterized the response of a chemiluminescence detector (Thermal Energy Analyzer) as a function of pyrolysis chamber temperature for several nitrosamines and for an aliphatic C-nitroso compound, an aromatic C-nitro compound, a nitramine and an alkyl nitrite. The response-temperature profiles are valuable in distinguishing among the various compounds and in optimizing the sensitivity of the detector for use in chromatography. Other tests, including photolysis and stability toward nitrite-scavenging reagents, further aid in distinguishing among the various compounds.

A mechanism-mediated model for carcinogenicity: Model content and prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 25 organic chemicals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Purdy, R.

A hierarchical model consisting of quantitative structure-activity relationships based mainly on chemical reactivity was developed to predict the carcinogenicity of organic chemicals to rodents. The model is comprised of quantitative structure-activity relationships, QSARs based on hypothesized mechanisms of action, metabolism, and partitioning. Predictors included octanol/water partition coefficient, molecular size, atomic partial charge, bond angle strain, atomic acceptor delocalizibility, atomic radical superdelocalizibility, the lowest unoccupied molecular orbital (LUMO) energy of hypothesized intermediate nitrenium ion of primary aromatic amines, difference in charge of ionized and unionized carbon-chlorine bonds, substituent size and pattern on polynuclear aromatic hydrocarbons, the distance between lone electron pairsmore » over a rigid structure, and the presence of functionalities such as nitroso and hydrazine. The model correctly classified 96% of the carcinogens in the training set of 306 chemicals, and 90% of the carcinogens in the test set of 301 chemicals. The test set by chance contained 84% of the positive thiocontaining chemicals. A QSAR for these chemicals was developed. This posttest set modified model correctly predicted 94% of the carcinogens in the test set. This model was used to predict the carcinogenicity of the 25 organic chemicals the U.S. National Toxicology Program was testing at the writing of this article. 12 refs., 3 tabs.« less

The enhancing effect of ethanol on the mutagenic activation of N-nitrosomethylbenzylamine by cytochrome P450 2A in the rat oesophagus.

PubMed

Tatematsu, Kenjiro; Koide, Akihiro; Morimura, Keiichirou; Fukushima, Shoji; Mori, Yukio

2013-03-01

Alcohol consumption is frequently associated with various cancers and the enhancement of the metabolic activation of carcinogens has been proposed as a mechanism underlying this relationship. The ethanol-induced enhancement of N-nitrosodiethylamine (DEN)-mediated carcinogenesis can be attributed to an increase in hepatic activity. However, the mechanism of elevation of N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis remains unclear. To elucidate the mechanism underlying the role of ethanol in the enhancement of NMBA-induced oesophageal carcinogenesis, we evaluated the hepatic and extrahepatic levels of the cytochrome P450 (CYP) and mutagenic activation of environmental carcinogens by immunoblot analyses and Ames preincubation test, respectively, in F344 rats treated with ethanol. Five weeks of treatment with 10% ethanol added to the drinking water or two intragastric treatments with 50% ethanol, both resulted in elevated levels of CYP2E1 (1.5- to 2.3-fold) and mutagenic activities of DEN, N-nitrosodimethylamine and N-nitrosopyrrolidine in the presence of rat liver S9 (1.5- to 2.4-fold). This was not the case with CYP1A1/2, CYP2A1/2, CYP2B1/2 or CYP3A2, nor with the activities of 2-amino-3-methylimidazo[4,5-f]quinoline, 3-amino-1-methyl-5H-pyrido[4,3-b]indole, aflatoxin B(1) or other N-nitroso compounds (NOCs), including NMBA. Ethanol-induced elevations of CYP2A and CYP2E1 were observed in the oesophagus (up to 1.7- and 2.3-fold) and kidney (up to 1.5- and 1.8-fold), but not in the lung or colon. In oesophagus and kidney, the mutagenic activities of NMBA and four NOCs were markedly increased (1.3- to 2.4-fold) in treated rats. The application of several CYP inhibitors revealed that CYP2A were likely to contribute to the enhancing effect of ethanol on NMBA activation in the rat oesophagus and kidney, but that CYP2E1 failed to do so. These results showed that the enhancing effect of ethanol on NMBA-induced oesophageal carcinogenesis could be attributed to an increase in the metabolic activation of NMBA by oesophageal CYP2A during the initiation phase, and that this occurred independently of CYP2E1.

Nitrosamine-induced carcinogenesis. The alkylation of N-7 of guanine of nucleic acids of the rat by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate

PubMed Central

Swann, P. F.; Magee, P. N.

1971-01-01

1. The extent of ethylation of N-7 of guanine in the nucleic acids of rat tissue in vivo by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate was measured. 2. All compounds produced measurable amounts of 7-ethyl-guanine. 3. A single dose of diethylnitrosamine or N-ethyl-N-nitrosourea produced tumours of the kidney in the rat. Three doses of ethyl methanesulphonate produced kidney tumours, but a single dose did not. 4. A single dose of diethylnitrosamine produced twice as much ethylation of N-7 of guanine in DNA of kidney as did N-ethyl-N-nitrosourea. A single dose of both compounds induced kidney tumours, although of a different histological type. 5. A single dose of ethyl methanesulphonate produced ten times as much ethylation of N-7 of guanine in kidney DNA as did N-ethyl-N-nitrosourea without producing tumours. 6. The relevance of these findings to the hypothesis that alkylation of a cellular component is the mechanism of induction of tumours by nitroso compounds is discussed. PMID:5145908

A Theoretical Study of the Mechanism of the Alkylation of Guanine by N- Nitroso Compounds.

DTIC Science & Technology

1992-01-01

Later, Loveless isolated an 0 6 - methylated product from treatment with MNU and was the first to suggest a relevance of O6 alkylation 11 to the...replication. The ultimate metabolite involved in the alkylation reaction has generally been thought to be an alkyldiazonium ion or, its decomposition... Methylation of Formamide by the Methyldiazonium Ion .................... 60 Table 3.10: Intrinsic Barriers for Degenerate SN 2 Reactions .......... 66 Table

Theoretical study of some nitrososulfamide compounds with antitumor activity.

PubMed

Djameleddine, Khatmi; Soumeya, Seridi; Fatiha, Madi

2004-09-30

The lowest-energy conformations of four 2-chloroethylnitrososulfamides were determined using the MM+ molecular mechanics method as implemented in Hyperchem 6.0. Some of the calculated structural parameters, angles and bonds lengths were compared with the crystal structure data of N-nitroso-N-(2-chloroethyl)-N'-sulfamoyl- proline. Using MM+, AM1 and PM3 the anti conformation was predicted to be more stable than the syn conformation in each of these compounds. With these methods we found that the relative energy of the transition state (TS) was considerably higher, but with the ab initio method using RHF with minimal basic function STO-3G we found that the syn conformation is predicted to be slightly more stable. The determination of some atomic charges of a selection of atoms on the syn, anti and TS structures of the various compounds provided some details about the nature of the transition state.

Interaction of nitrate and folate on the risk of breast cancer among postmenopausal women

PubMed Central

Inoue-Choi, Maki; Ward, Mary H.; Cerhan, James R.; Weyer, Peter J.; Anderson, Kristin E.; Robien, Kim

2012-01-01

Ingested nitrate can be endogenously reduced to nitrite, which may form N-nitroso compounds, known potent carcinogens. However, some studies have reported no or inverse associations between dietary nitrate intake and cancer risk. These associations may be confounded by a protective effect of folate, which plays a vital role in DNA repair. We evaluated the interaction of dietary and water nitrate intake with total folate intake on breast cancer risk in the Iowa Women’s Health Study. Dietary intake was assessed at study baseline. Nitrate intake from public water was assessed using a historical database on Iowa municipal water supplies. After baseline exclusions, 34,388 postmenopausal women and 2,875 incident breast cancers were included. Overall, neither dietary nor water nitrate was associated with breast cancer risk. Among those with folate intake ≥400 μg/d, breast cancer risk was significantly increased in public water users with the highest nitrate quintile (HR=1.40, 95%CI=1.05–1.87) and private well users (HR=1.38, 95%CI=1.05–1.82) compared to public water users with the lowest nitrate quintile; in contrast, there was no association among those with lower folate intake. Our findings do not support a previous report of increased risk of breast cancer among individuals with high dietary nitrate but low folate intake. PMID:22642949

Interaction of nitrate and folate on the risk of breast cancer among postmenopausal women.

PubMed

Inoue-Choi, Maki; Ward, Mary H; Cerhan, James R; Weyer, Peter J; Anderson, Kristin E; Robien, Kim

2012-01-01

Ingested nitrate can be endogenously reduced to nitrite, which may form N-nitroso compounds, known potent carcinogens. However, some studies have reported no or inverse associations between dietary nitrate intake and cancer risk. These associations may be confounded by a protective effect of folate, which plays a vital role in DNA repair. We evaluated the interaction of dietary and water nitrate intake with total folate intake on breast cancer risk in the Iowa Women's Health Study. Dietary intake was assessed at study baseline. Nitrate intake from public water was assessed using a historical database on Iowa municipal water supplies. After baseline exclusions, 34,388 postmenopausal women and 2,875 incident breast cancers were included. Overall, neither dietary nor water nitrate was associated with breast cancer risk. Among those with folate intake ≥400 μg/day, breast cancer risk was significantly increased in public water users with the highest nitrate quintile (HR = 1.40, 95% CI = 1.05-1.87) and private well users (HR = 1.38, 95% CI = 1.05-1.82) compared to public water users with the lowest nitrate quintile; in contrast, there was no association among those with lower folate intake. Our findings do not support a previous report of increased risk of breast cancer among individuals with high dietary nitrate but low folate intake.

Cured meat, vegetables, and bean-curd foods in relation to childhood acute leukemia risk: a population based case-control study.

PubMed

Liu, Chen-Yu; Hsu, Yi-Hsiang; Wu, Ming-Tsang; Pan, Pi-Chen; Ho, Chi-Kung; Su, Li; Xu, Xin; Li, Yi; Christiani, David C

2009-01-13

Consumption of cured/smoked meat and fish leads to the formation of carcinogenic N-nitroso compounds in the acidic stomach. This study investigated whether consumed cured/smoked meat and fish, the major dietary resource for exposure to nitrites and nitrosamines, is associated with childhood acute leukemia. A population-based case-control study of Han Chinese between 2 and 20 years old was conducted in southern Taiwan. 145 acute leukemia cases and 370 age- and sex-matched controls were recruited between 1997 and 2005. Dietary data were obtained from a questionnaire. Multiple logistic regression models were used in data analyses. Consumption of cured/smoked meat and fish more than once a week was associated with an increased risk of acute leukemia (OR = 1.74; 95% CI: 1.15-2.64). Conversely, higher intake of vegetables (OR = 0.55; 95% CI: 0.37-0.83) and bean-curd (OR = 0.55; 95% CI: 0.34-0.89) was associated with a reduced risk. No statistically significant association was observed between leukemia risk and the consumption of pickled vegetables, fruits, and tea. Dietary exposure to cured/smoked meat and fish may be associated with leukemia risk through their contents of nitrites and nitrosamines among children and adolescents, and intake of vegetables and soy-bean curd may be protective.

Handling and Use of Fluorine and Fluorine - Oxygen Mixtures in Rocket Systems,

DTIC Science & Technology

1967-01-01

with nitroso rubber, which could normally be expected to burn when exposed to the flow of liquid fluorine. The materials tested included (1) Nitroso...the system free of contamination. Most common metals of construction are compatible for use in a fluorine environment. Metals can burn with fluorine...conditions of contact), fluorinated compounds in their highest state of oxidation, and a few fluorinated polymers. Even these polymers may burn in fluorine

A new comprehensive technique of catheterisation, blood sampling, sample preparation and sample analysis by means of high-pressure liquid chromatography for pharmacokinetic studies with estradiol-linked nitrosoureas and their metabolites.

PubMed

Betsch, B; Berger, M R; Spiegelhalder, B

1990-09-01

Estradiol-linked nitrosoureas are offering new perspectives in the antineoplastic chemotherapy of estradiol-receptor positive mammary carcinomas. In such a molecule estradiol has the function of a carrier which brings about a specific accumulation of the anticancer drug in estradiol-receptor containing tumor cells. However, there is only little knowledge about the pharmacokinetic behavior of this new group of anticancer agents. For that reason a new comprehensive technique of catheterisation, blood sampling, sample preparation and sample analysis with high-pressure liquid chromatography (HPLC) for preclinical pharmacokinetic studies with estradiol-linked nitrosoureas and their metabolites has been developed. N-(2-Chloroethyl)-N-nitroso-carbamoyl-L-alanine-estradiol-17-ester (CNC-alanine-estradiol-17-ester) and N-(2-chloroethyl)-N-nitroso-carbamoyl-L-alanine (CNC-alanine) were used as test compounds. The drugs were tested in female Sprague-Dawley rats with chemically induced mammary carcinomas. The laboratory animals were supplied with two catheters prior to the pharmacokinetic experiments. The blood samples were drawn from the vena cava catheter after the drug had been applied through a vena jugularis catheter. The compounds were extracted from plasma with C18 silicagel reversed phase cartridges. The clean-up technique delivered clear samples only slightly contaminated with the biological matrix. The recovery from plasma was 75 +/- 5% for the hormone-linked CNC-alanine-estradiol-17-ester and 70 +/- 5% for the unlinked CNC-alanine. The analysis was carried out by means of HPLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Environmental contaminants as etiologic factors for diabetes.

PubMed Central

Longnecker, M P; Daniels, J L

2001-01-01

For both type 1 and type 2 diabetes mellitus, the rates have been increasing in the United States and elsewhere; rates vary widely by country, and genetic factors account for less than half of new cases. These observations suggest environmental factors cause both type 1 and type 2 diabetes. Occupational exposures have been associated with increased risk of diabetes. In addition, recent data suggest that toxic substances in the environment, other than infectious agents or exposures that stimulate an immune response, are associated with the occurrence of these diseases. We reviewed the epidemiologic data that addressed whether environmental contaminants might cause type 1 or type 2 diabetes. For type 1 diabetes, higher intake of nitrates, nitrites, and N-nitroso compounds, as well as higher serum levels of polychlorinated biphenyls have been associated with increased risk. Overall, however, the data were limited or inconsistent. With respect to type 2 diabetes, data on arsenic and 2,3,7,8-tetrachlorodibenzo-p-dioxin relative to risk were suggestive of a direct association but were inconclusive. The occupational data suggested that more data on exposure to N-nitroso compounds, arsenic, dioxins, talc, and straight oil machining fluids in relation to diabetes would be useful. Although environmental factors other than contaminants may account for the majority of type 1 and type 2 diabetes, the etiologic role of several contaminants and occupational exposures deserves further study. PMID:11744505

Process for making surfactant capped metal oxide nanocrystals, and products produced by the process

DOEpatents

Alivisatos, A. Paul; Rockenberger, Joerg

2006-01-10

Disclosed is a process for making surfactant capped nanocrystals of metal oxides which are dispersable in organic solvents. The process comprises decomposing a metal cupferron complex of the formula M^XCup_X, wherein M is a metal, and Cup is a N-substituted N-Nitroso hydroxylamine, in the presence of a coordinating surfactant, the reaction being conducted at a temperature ranging from about 150 to about 400.degree. C., for a period of time sufficient to complete the reaction. Also disclosed are compounds made by the process.

Nitrate and nitrite ingestion and risk of ovarian cancer among postmenopausal women in Iowa

PubMed Central

Inoue-Choi, Maki; Jones, Rena R.; Anderson, Kristin E.; Cantor, Kenneth P.; Cerhan, James R.; Krasner, Stuart; Robien, Kim; Weyer, Peter J.; Ward, Mary H.

2014-01-01

Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds (NOC), potential human carcinogens. We evaluated the association of nitrate and nitrite ingestion with postmenopausal ovarian cancer risk in the Iowa Women’s Health Study. Among 28,555 postmenopausal women, we identified 315 incident epithelial ovarian cancers from 1986 to 2010. Dietary nitrate and nitrite intakes were assessed at baseline using food frequency questionnaire data. Drinking water source at home was obtained in a 1989 follow-up survey. Nitrate-nitrogen (NO3-N) and total trihalomethane (TTHM) levels for Iowa public water utilities were linked to residences and average levels were computed based on each woman’s duration at the residence. We computed multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards regression. We tested interactions of nitrate with TTHMs and dietary factors known to influence NOC formation. Ovarian cancer risk was 2.03 times higher (CI=1.22–3.38, ptrend=0.003) in the highest quartile (≥2.98 mg/L) compared with the lowest quartile (≤0.47 mg/L; reference) of NO3-N in public water, regardless of TTHM levels. Risk among private well users was also elevated (HR=1.53, CI=0.93–2.54) compared with the same reference group. Associations were stronger when vitamin C intake was

Dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women’s Health Study

PubMed Central

DellaValle, Curt T.; Xiao, Qian; Yang, Gong; Shu, Xiao Ou; Aschebrook-Kilfoy, Briseis; Zheng, Wei; Li, Hong Lan; Ji, Bu-Tian; Rothman, Nathaniel; Chow, Wong-Ho; Gao, Yu-Tang; Ward, Mary H.

2014-01-01

Nitrate and nitrite are precursors of endogenously formed N-nitroso compounds (NOC), known animal carcinogens. Nitrosation reactions forming NOCs can be inhibited by vitamin C and other antioxidants. We prospectively investigated the association between dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women’s Health Study, a cohort of 73,118 women ages 40 to 70 residing in Shanghai. We evaluated effect modification by factors that affect endogenous formation of NOCs: vitamin C (at or above/below median) and red meat intake (at or above/below median). Nitrate, nitrite and other dietary intakes were estimated from a 77-item food frequency questionnaire administered at baseline. Over a mean of 11 years of follow-up, we identified 619 colorectal cancer cases (n=383, colon; n=236, rectum). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression. Overall, nitrate intake was not associated with colorectal cancer risk (HR = 1.08; 95% CI: 0.73–1.59). However, among women with vitamin C intake below the median (83.9 mg/day) and hence higher potential exposure to NOCs, risk of colorectal cancer increased with increasing quintiles of nitrate intake (highest vs. lowest quintile HR = 2.45; 95% CI: 1.15–5.18; p-trend = 0.02). There was no association among women with higher vitamin C intake. We found no association between nitrite intake and risk of colorectal cancer overall or by intake level of vitamin C. Our findings suggest that high dietary nitrate intake among subgroups expected to have higher exposure to endogenously-formed NOCs increases risk of colorectal cancer. PMID:24242755

S-Nitroso-N-acetyl-L-cysteine ethyl ester (SNACET) and N-acetyl-L-cysteine ethyl ester (NACET)-Cysteine-based drug candidates with unique pharmacological profiles for oral use as NO, H2S and GSH suppliers and as antioxidants: Results and overview.

PubMed

Tsikas, Dimitrios; Schwedhelm, Kathrin S; Surdacki, Andrzej; Giustarini, Daniela; Rossi, Ranieri; Kukoc-Modun, Lea; Kedia, George; Ückert, Stefan

2018-02-01

S -Nitrosothiols or thionitrites with the general formula RSNO are formally composed of the nitrosyl cation (NO + ) and a thiolate (RS - ), the base of the corresponding acids RSH. The smallest S -nitrosothiol is HSNO and derives from hydrogen sulfide (HSH, H 2 S). The most common physiological S -nitrosothiols are derived from the amino acid L-cysteine (CysSH). Thus, the simplest S -nitrosothiol is S -nitroso-L-cysteine (CysSNO). CysSNO is a spontaneous potent donor of nitric oxide (NO) which activates soluble guanylyl cyclase to form cyclic guanosine monophosphate (cGMP). This activation is associated with multiple biological actions that include relaxation of smooth muscle cells and inhibition of platelet aggregation. Like NO, CysSNO is a short-lived species and occurs physiologically at concentrations around 1 nM in human blood. CysSNO can be formed from CysSH and higher oxides of NO including nitrous acid (HONO) and its anhydride (N 2 O 3 ). The most characteristic feature of RSNO is the S-transnitrosation reaction by which the NO + group is reversibly transferred to another thiolate. By this way numerous RSNO can be formed such as the low-molecular-mass S -nitroso- N -acetyl-L-cysteine (SNAC) and S -nitroso-glutathione (GSNO), and the high-molecular-mass S -nitrosol-L-cysteine hemoglobin (HbCysSNO) present in erythrocytes and S -nitrosol-L-cysteine albumin (AlbCysSNO) present in plasma at concentrations of the order of 200 nM. All above mentioned RSNO exert NO-related biological activity, but they must be administered intravenously. This important drawback can be overcome by lipophilic charge-free RSNO. Thus, we prepared the ethyl ester of SNAC, the S -nitroso- N -acetyl-L-cysteine ethyl ester (SNACET), from synthetic N -acetyl-L-cysteine ethyl ester (NACET). Both NACET and SNACET have improved pharmacological features over N -acetyl-L-cysteine (NAC) and S -nitroso- N -acetyl-L-cysteine (SNAC), respectively, including higher oral bioavailability. SNACET exerts NO-related activities which can be utilized in the urogenital tract and in the cardiovascular system. NACET, with high oral bioavailability, is a strong antioxidant and abundant precursor of GSH, unlike its free acid N -acetyl-L-cysteine (NAC). Here, we review the chemical and pharmacological properties of SNACET and NACET as well as their analytical chemistry. We also report new results from the ingestion of S -[ 15 N]nitroso- N -acetyl-L-cysteine ethyl ester (S 15 NACET) demonstrating the favorable pharmacological profile of SNACET.

Efficiency of PBN to Trap 3-CAR in B6C3F1 Mouse Liver Slices: An EPR Study.

DTIC Science & Technology

1995-09-01

be identified by electron paramagnetic resonance (EPR) using the spin trap N-tert-butyl-a phenyl nitrone (PBN). To quantitate the radicals detected...phenyl nitrone TCE trichloroethylene Vll INTRODUCTION Understanding free radical reactions is important to the military. The main objective of this...short lived radical with a spin trap’, usually a nitrone or nitroso compound yielding a longer lived nitroxide spin adduct which can be detected by

Red meat and poultry intake, polymorphisms in the nucleotide excision repair and mismatch repair pathways and colorectal cancer risk

PubMed Central

Joshi, Amit D.; Corral, Román; Siegmund, Kimberly D.; Haile, Robert W.; Le Marchand, Loïc; Martínez, Maria Elena; Ahnen, Dennis J.; Sandler, Robert S.; Lance, Peter; Stern, Mariana C.

2009-01-01

Diets high in red meat have been consistently associated with colorectal cancer (CRC) risk and may result in exposure to carcinogens that cause DNA damage [i.e polycyclic aromatic hydrocarbons, heterocyclic amines (HCAs) and N-nitroso compounds]. Using a family-based study, we investigated whether polymorphisms in the nucleotide excision repair (NER) (ERCC1 3′ untranslated region (UTR) G/T, XPD Asp312Asn and Lys751Gln, XPC intron 11 C/A, XPA 5′ UTR C/T, XPF Arg415Gln and XPG Asp1104His) and mismatch repair (MLH1 Ile219Val and MSH2 Gly322Asp) pathways modified the association with red meat and poultry intake. We tested for gene–environment interactions using case-only analyses (n = 577) and compared the results using case-unaffected sibling comparisons (n = 307 sibships). Increased risk of CRC was observed for intake of more than or equal to three servings per week of red meat [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.3–2.5)] or high-temperature cooked red meat (OR = 1.6, 95% CI = 1.1–2.2). Intake of red meat heavily brown on the outside or inside increased CRC risk only among subjects who carried the XPD codon 751 Lys/Lys genotype (case-only interaction P = 0.006 and P = 0.001, respectively, for doneness outside or inside) or the XPD codon 312 Asp/Asp genotype (case-only interaction P = 0.090 and P < 0.001, respectively). These interactions were stronger for rectal cancer cases (heterogeneity test P = 0.002 for XPD Asp312Asn and P = 0.03 for XPD Lys751Gln) and remained statistically significant after accounting for multiple testing. Case-unaffected sibling analyses were generally supportive of the case-only results. These findings highlight the possible contribution of diets high in red meat to the formation of lesions that elicit the NER pathway, such as carcinogen-induced bulky adducts. PMID:19029193

NITRATE IN LEAFY GREEN VEGETABLES AND ESTIMATED INTAKE.

PubMed

Brkić, Danijel; Bošnir, Jasna; Bevardi, Martina; Bošković, Andrea Gross; Miloš, Sanja; Lasić, Dario; Krivohlavek, Adela; Racz, Aleksandar; Ćuić, Ana Mojsović; Trstenjak, Natalija Uršulin

2017-01-01

Vegetarian diets are rich in vegetables. Green leafy vegetables are foods that contain considerable amounts of nitrate, which can have both positive and negative effects on the human body. Their potential carcinogenicity and toxicity have been proven, particularly after the reduction of nitrate to nitrite itself or just serving as a reactant with amines and/or amides in the formation of N-nitroso compounds -N-nitrosamines and other nitrogen compounds which may have high levels of nitrate. The aim of this study was to determine whether there is a significant difference, considering the location and seasonal sampling period, in the level of nitrate in certain types of green vegetables, all in order to be able to assess their intake, and possible impact on human health, especially knowing that exposure to nitrate can be potentially higher for vegetarian population group. For this purpose, the sampling of 200 different leafy green vegetables was conducted, all of which could be found in free sale in the Republic of Croatia. The sampling was conducted during two seasonal periods - the spring and autumn period. In the springtime, lettuce (sem), spinach (pinacho), kale (kale), chard (mangel) and cabbage (brassica) were sampled, and in autumn lettuce, spinach, kale, chard and arugula. Samples were analyzed using high performance liquid chromatography (HPLC) with UV detection. The results from the spring sampling phase were in the range of 603 mg/kg for cabbage - 972 mg/kg for chard, and for autumn phase of 1.024 mg/kg for chard to 4.354 mg/kg for the arugula. The results showed that there were significant differences (p <0.05) for most of the samples analyzed, considering the sampling locations and time period. The results indicate that the analyzed vegetables contain significant amounts of nitrate in their composition, which represents relatively significant, but still acceptable intake into the human body.

NITRATE IN LEAFY GREEN VEGETABLES AND ESTIMATED INTAKE

PubMed Central

Brkić, Danijel; Bošnir, Jasna; Bevardi, Martina; Bošković, Andrea Gross; Miloš, Sanja; Lasić, Dario; Krivohlavek, Adela; Racz, Aleksandar; Ćuić, Ana Mojsović; Trstenjak, Natalija Uršulin

2017-01-01

Background: Vegetarian diets are rich in vegetables. Green leafy vegetables are foods that contain considerable amounts of nitrate, which can have both positive and negative effects on the human body. Their potential carcinogenicity and toxicity have been proven, particularly after the reduction of nitrate to nitrite itself or just serving as a reactant with amines and/or amides in the formation of N-nitroso compounds -N-nitrosamines and other nitrogen compounds which may have high levels of nitrate. The aim of this study was to determine whether there is a significant difference, considering the location and seasonal sampling period, in the level of nitrate in certain types of green vegetables, all in order to be able to assess their intake, and possible impact on human health, especially knowing that exposure to nitrate can be potentially higher for vegetarian population group. Materials and Methods: For this purpose, the sampling of 200 different leafy green vegetables was conducted, all of which could be found in free sale in the Republic of Croatia. The sampling was conducted during two seasonal periods - the spring and autumn period. In the springtime, lettuce (sem), spinach (pinacho), kale (kale), chard (mangel) and cabbage (brassica) were sampled, and in autumn lettuce, spinach, kale, chard and arugula. Samples were analyzed using high performance liquid chromatography (HPLC) with UV detection. Results: The results from the spring sampling phase were in the range of 603 mg/kg for cabbage - 972 mg/kg for chard, and for autumn phase of 1.024 mg/kg for chard to 4.354 mg/kg for the arugula. The results showed that there were significant differences (p <0.05) for most of the samples analyzed, considering the sampling locations and time period. Conclusion: The results indicate that the analyzed vegetables contain significant amounts of nitrate in their composition, which represents relatively significant, but still acceptable intake into the human body. PMID:28480414

The World Cancer Research Fund report 2007: A challenge for the meat processing industry.

PubMed

Demeyer, Daniël; Honikel, Karl; De Smet, Stefaan

2008-12-01

One of the 10 universal guidelines for healthy nutrition in a report of the World Cancer Research Fund released at the end of 2007 is to "limit intake of red meat and avoid processed meat", as a result of the "convincing evidence" for an association with an increased risk of colorectal cancer development. In the present paper, the scientific evidence for the association between processed meats intake and colorectal cancer development is explored and the most probable hypothesis on the mechanism underlying this relationship formulated. It seems that the present state of knowledge is not well understood but relates to a combination of haem iron, oxidative stress, formation of N-nitroso compounds and related residues in the digestive tract as the causal factors. Although criticisms of the inaccurate definition of processed meats and the insufficient accounting for the large variability in composition of meat products have been expressed, it is clear that the report urges proper action by the meat and nutrition research community and the meat industry. Research items that in our view should be addressed are discussed. They include: (1) evaluating the health risks associated with processed meats intake within the context of the supply of beneficial nutrients and other nutrition associated health risks; (2) definition of the role of nitrites and nitrates in meat processing; (3) investigating the role of red and processed meats on the endogenous formation of N-nitroso compounds in the digestive tract; and (4) developing improved processed meats using new ingredients.

40 CFR Appendix V to Part 266 - Risk Specific Doses (10−5)

Code of Federal Regulations, 2013 CFR

2013-07-01

...-cyclohexane 58-89-9 3.8E−04 2.6E−02 Hexachlorocyclo-hexane, Technical 5.1E−04 2.0E−02 Hexachlorodibenzo-p....2E−02 Nickel Subsulfide 12035-72-2 4.8E−04 2.1E−02 2-Nitropropane 79-46-9 2.7E−02 3.7E−04 N-Nitroso-n-butylamine 924-16-3 1.6E−03 6.3E−03 N-Nitroso-n-methylurea 684-93-5 8.6E−02 1.2E−04 N-Nitrosodiethylamine 55...

40 CFR Appendix V to Part 266 - Risk Specific Doses (10−5)

Code of Federal Regulations, 2010 CFR

2010-07-01

...-cyclohexane 58-89-9 3.8E−04 2.6E−02 Hexachlorocyclo-hexane, Technical 5.1E−04 2.0E−02 Hexachlorodibenzo-p....2E−02 Nickel Subsulfide 12035-72-2 4.8E−04 2.1E−02 2-Nitropropane 79-46-9 2.7E−02 3.7E−04 N-Nitroso-n-butylamine 924-16-3 1.6E−03 6.3E−03 N-Nitroso-n-methylurea 684-93-5 8.6E−02 1.2E−04 N-Nitrosodiethylamine 55...

40 CFR Appendix V to Part 266 - Risk Specific Doses (10−5)

Code of Federal Regulations, 2014 CFR

2014-07-01

...-cyclohexane 58-89-9 3.8E−04 2.6E−02 Hexachlorocyclo-hexane, Technical 5.1E−04 2.0E−02 Hexachlorodibenzo-p....2E−02 Nickel Subsulfide 12035-72-2 4.8E−04 2.1E−02 2-Nitropropane 79-46-9 2.7E−02 3.7E−04 N-Nitroso-n-butylamine 924-16-3 1.6E−03 6.3E−03 N-Nitroso-n-methylurea 684-93-5 8.6E−02 1.2E−04 N-Nitrosodiethylamine 55...

40 CFR Appendix V to Part 266 - Risk Specific Doses (10−5)

Code of Federal Regulations, 2012 CFR

2012-07-01

...-cyclohexane 58-89-9 3.8E−04 2.6E−02 Hexachlorocyclo-hexane, Technical 5.1E−04 2.0E−02 Hexachlorodibenzo-p....2E−02 Nickel Subsulfide 12035-72-2 4.8E−04 2.1E−02 2-Nitropropane 79-46-9 2.7E−02 3.7E−04 N-Nitroso-n-butylamine 924-16-3 1.6E−03 6.3E−03 N-Nitroso-n-methylurea 684-93-5 8.6E−02 1.2E−04 N-Nitrosodiethylamine 55...

40 CFR Appendix V to Part 266 - Risk Specific Doses (10−5)

Code of Federal Regulations, 2011 CFR

2011-07-01

...-cyclohexane 58-89-9 3.8E−04 2.6E−02 Hexachlorocyclo-hexane, Technical 5.1E−04 2.0E−02 Hexachlorodibenzo-p....2E−02 Nickel Subsulfide 12035-72-2 4.8E−04 2.1E−02 2-Nitropropane 79-46-9 2.7E−02 3.7E−04 N-Nitroso-n-butylamine 924-16-3 1.6E−03 6.3E−03 N-Nitroso-n-methylurea 684-93-5 8.6E−02 1.2E−04 N-Nitrosodiethylamine 55...

Comet assay in reconstructed 3D human epidermal skin models--investigation of intra- and inter-laboratory reproducibility with coded chemicals.

PubMed

Reus, Astrid A; Reisinger, Kerstin; Downs, Thomas R; Carr, Gregory J; Zeller, Andreas; Corvi, Raffaella; Krul, Cyrille A M; Pfuhler, Stefan

2013-11-01

Reconstructed 3D human epidermal skin models are being used increasingly for safety testing of chemicals. Based on EpiDerm™ tissues, an assay was developed in which the tissues were topically exposed to test chemicals for 3h followed by cell isolation and assessment of DNA damage using the comet assay. Inter-laboratory reproducibility of the 3D skin comet assay was initially demonstrated using two model genotoxic carcinogens, methyl methane sulfonate (MMS) and 4-nitroquinoline-n-oxide, and the results showed good concordance among three different laboratories and with in vivo data. In Phase 2 of the project, intra- and inter-laboratory reproducibility was investigated with five coded compounds with different genotoxicity liability tested at three different laboratories. For the genotoxic carcinogens MMS and N-ethyl-N-nitrosourea, all laboratories reported a dose-related and statistically significant increase (P < 0.05) in DNA damage in every experiment. For the genotoxic carcinogen, 2,4-diaminotoluene, the overall result from all laboratories showed a smaller, but significant genotoxic response (P < 0.05). For cyclohexanone (CHN) (non-genotoxic in vitro and in vivo, and non-carcinogenic), an increase compared to the solvent control acetone was observed only in one laboratory. However, the response was not dose related and CHN was judged negative overall, as was p-nitrophenol (p-NP) (genotoxic in vitro but not in vivo and non-carcinogenic), which was the only compound showing clear cytotoxic effects. For p-NP, significant DNA damage generally occurred only at doses that were substantially cytotoxic (>30% cell loss), and the overall response was comparable in all laboratories despite some differences in doses tested. The results of the collaborative study for the coded compounds were generally reproducible among the laboratories involved and intra-laboratory reproducibility was also good. These data indicate that the comet assay in EpiDerm™ skin models is a promising model for the safety assessment of compounds with a dermal route of exposure.

Comet assay in reconstructed 3D human epidermal skin models—investigation of intra- and inter-laboratory reproducibility with coded chemicals

PubMed Central

Pfuhler, Stefan

2013-01-01

Reconstructed 3D human epidermal skin models are being used increasingly for safety testing of chemicals. Based on EpiDerm™ tissues, an assay was developed in which the tissues were topically exposed to test chemicals for 3h followed by cell isolation and assessment of DNA damage using the comet assay. Inter-laboratory reproducibility of the 3D skin comet assay was initially demonstrated using two model genotoxic carcinogens, methyl methane sulfonate (MMS) and 4-nitroquinoline-n-oxide, and the results showed good concordance among three different laboratories and with in vivo data. In Phase 2 of the project, intra- and inter-laboratory reproducibility was investigated with five coded compounds with different genotoxicity liability tested at three different laboratories. For the genotoxic carcinogens MMS and N-ethyl-N-nitrosourea, all laboratories reported a dose-related and statistically significant increase (P < 0.05) in DNA damage in every experiment. For the genotoxic carcinogen, 2,4-diaminotoluene, the overall result from all laboratories showed a smaller, but significant genotoxic response (P < 0.05). For cyclohexanone (CHN) (non-genotoxic in vitro and in vivo, and non-carcinogenic), an increase compared to the solvent control acetone was observed only in one laboratory. However, the response was not dose related and CHN was judged negative overall, as was p-nitrophenol (p-NP) (genotoxic in vitro but not in vivo and non-carcinogenic), which was the only compound showing clear cytotoxic effects. For p-NP, significant DNA damage generally occurred only at doses that were substantially cytotoxic (>30% cell loss), and the overall response was comparable in all laboratories despite some differences in doses tested. The results of the collaborative study for the coded compounds were generally reproducible among the laboratories involved and intra-laboratory reproducibility was also good. These data indicate that the comet assay in EpiDerm™ skin models is a promising model for the safety assessment of compounds with a dermal route of exposure. PMID:24150594

Toxic and carcinogenic agents in dry and moist snuff.

PubMed

Hoffmann, D; Adams, J D; Lisk, D; Fisenne, I; Brunnemann, K D

1987-12-01

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.

Final report on the safety assessment of Lecithin and Hydrogenated Lecithin.

PubMed

Fiume, Z

2001-01-01

Lecithin is a naturally occurring mixture of the diglycerides of stearic, palmitic, and oleic acids, linked to the choline ester of phosphoric acid, commonly called phosphatidylcholine. Hydrogenated Lecithin is the product of controlled hydrogenation of Lecithin. Bilayers of these phospholipids in water may form liposomes, a spherical structure in which the acyl chains are inside and not exposed to the aqueous phase. Lecithin and Hydrogenated Lecithin are used in a large number of cosmetic formulations as skin conditioning agents-miscellaneous and as surfactant-emulsifying agents. Hydrogenated Lecithin is also used as a suspending agent-nonsurfactant. Historical data on concentration of use of Lecithin reveals that 0.1% to 1.0% is the concentration range most frequently seen, with concentrations up to 50% reported for two moisturizing products. A solution of 65% Lecithin is currently reported to be used at concentrations up to 3% in cosmetics. Nonocclusive application of Lecithin-containing liposomes to murine skin resulted in 30% penetration to the subdermis. In piglet skin, the same application resulted in 99% accumulating in the stratum corneum. In general, liposomes are considered effective in capturing other compounds inside their spherical structure and delivering any such captured compound through the skin barrier. As a result, caution should be exhibited in formulating cosmetic products that contain these ingredients in combination with other ingredients whose safety is based on their lack of absorption or where dermal absorption is a concern. Lecithin is virtually nontoxic in acute oral studies, short-term oral studies, and subchronic dermal studies in animals. Lecithin is not a reproductive toxicant, nor is it mutagenic in several assays. In an oral carcinogenicity study, brain neoplasms were found in mice exposed to Lecithin. In a subcutaneous carcinogenicity study, no neoplasms were found in mice and rats exposed to Lecithin. Adverse reactions to Lecithin in a metered-dose inhaler have been reported. Lecithin and Hydrogenated Lecithin were generally nonirritating and nonsensitizing in animal and human skin. Based on the available data, Lecithin and Hydrogenated Lecithin are safe as used in rinse-off cosmetic products; they may be safely used in leave-on products at concentrations up to 15%, the highest concentration tested in clinical irritation and sensitization studies; but the safety of use could not be substantiated in cosmetic products likely to be inhaled. Because of the possibility of formation of nitrosamines, these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed.

Evaluation of a rat tracheal epithelial cell culture assay system to identify respiratory carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Steele, V.E.; Arnold, J.T.; Arnold, J.V.

1989-01-01

To evaluate a short-term epithelial cell assay system to detect respiratory carcinogens, primary cultures of rat tracheal epithelial cells were exposed to a series of 17 compounds and scored for morphologically transformed cell colonies 28 days later. The test compounds included known carcinogens and noncarcinogens in volatile or liquid form. Tracheal epithelial cells were isolate from F344 rats, plated onto collagen-coated dishes, and exposed to the test compounds on day 1 for 24 hours. At day 30 the cultures were fixed, stained, and scored for colonies having a density greater than 1,300 cells/mm{sup 2}. With standardized protocols, such colonies aremore » very infrequent in media and solvent control cultures. Concentration levels for each chemical were chosen over a range from nontoxic to toxic levels. Highly positive compounds in this assay included benzo(a)pyrene, benzo(l)aceanthrylene, 3-methylcholanthrene, and formaldehyde. Compounds which were negative in this assay included pyrene, benzo(e)pyrene, and 4-nitroquinoline-N-oxide. Examining the concordance of in vitro results with whole animal carcinogenesis studies revealed an accuracy of 88% with one false-positive and one false-negative compound. The results of these studies indicate that the rat tracheal epithelial cell assay may be useful in identifying potential respiratory carcinogens in our environment.« less

Inter-laboratory comparison of turkey in ovo carcinogenicity assessment (IOCA) of hepatocarcinogens.

PubMed

Enzmann, H; Brunnemann, K; Iatropoulos, M; Shpyleva, S; Lukyanova, N; Todor, I; Moore, M; Spicher, K; Chekhun, V; Tsuda, H; Williams, G

2013-09-01

In three independent laboratories carcinogens (diethylnitrosamine, DEN, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK) and non-carcinogens (N-nitrosoproline, nicotine) were evaluated in turkey eggs for in ovo carcinogenicity assessment (IOCA). Compounds were injected into aseptic fertilized eggs. After incubation for 24 days, foci of altered hepatocytes (FAH), some with a pseudoglandular structure and/or signs of compression of the surrounding tissue were observed in the fetal liver. All laboratories were able to distinguish unequivocally the hepatocarcinogen-exposed groups from those exposed to non-carcinogens or the vehicle controls, based on the pre-specified evaluation parameters: tumor-like lesions, pseudoglandular areas and FAH. In addition to focal changes, only the carcinogens induced hepatocellular karyomegaly. Lower doses of the carcinogens, which did not induce FAH, were sufficient to induce hepatocellular karyomegaly. After exposure to 4 mg DEN, gall bladder agenesis was observed in all fetuses. The IOCA may be a valuable tool for early investigative studies on carcinogenicity and since it does not use rodents may complement chronic rat or mouse bioassays. Test substances that are positive in both rodents and fertilized turkey eggs are most probably trans-species carcinogens with particular significance for humans. The good concordance observed among the three laboratories demonstrates that the IOCA is a reliable and robust method. Copyright © 2012 Elsevier GmbH. All rights reserved.

Structure-based thresholds of toxicological concern-guidance for application to substances present at low levels in the diet

DOE Office of Scientific and Technical Information (OSTI.GOV)

Renwick, A.G.

Health-based guidance values, such as the ADI, use chemical-specific data to determine the highest intake that would be without significant adverse health effects. A threshold of toxicological concern (TTC) is a level of intake predicted to be without adverse effects based on the toxicity of structurally related compounds. The main advantage of the use of TTCs is that the risk of low exposures can be evaluated without the need for chemical-specific animal toxicity data. TTCs have been used for many years for screening the safety of packaging migrants by the FDA in the USA, and of flavoring substances, by themore » JECFA. A recent reassessment of the use of TTCs, organized by ILSI Europe, has developed a decision tree which allows a systematic approach to the evaluation of low levels of diverse chemicals in food. The decision tree incorporates a series of increasing TTC values into a step-wise approach. Potentially genotoxic carcinogens are considered first, based on the presence of known structural alerts. Aflatoxin-like, azoxy- and nitroso-compounds are removed from consideration because they are the most potent, and a practical TTC could not be established. Other compounds with structural alerts for genotoxicity are allocated a TTC of 0.15 {mu}g/person per day. Compounds without structural alerts for genotoxicity are evaluated based on chemical structure and intake using a series of TTC values derived by the application of a 100-fold uncertainty factor to the 5th percentile of the distribution of NOAELs from chronic studies on compounds sharing similar structural characteristics.« less

Foci of aberrant crypts in the colons of mice and rats exposed to carcinogens associated with foods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tudek, B.; Bird, R.P.; Bruce, W.R.

1989-03-01

Aberrant crypt foci can be identified in the colons of rodents treated 3 wk earlier with azoxymethane, a known colon carcinogen. These crypts can easily be visualized in the unsectioned methylene blue-stained colons under light microscopy, where they are distinguished by their increased size, more prominent epithelial cells, and pericryptal space. They occur as single aberrant crypts or as two, three, or four aberrant crypts in a cluster. We compared the reported ability of carcinogens associated with the human diet to induce colon cancer with the measured rate of induction of aberrant crypts in female CF1 mice and Sprague-Dawley rats.more » The carcinogens used were 1,2-dimethylhydrazine, methyl nitrosourea, N-nitrosodimethylamine, benzo(a)pyrene, aflatoxin B1, 2-amino-6-methyldipyrido(1,2-alpha:3',2'-d)imidazole, 2-amino-3-methylimidazo(4,5-P)quinoline, 2-amino-3,4-dimethylimidazo(4,5-P)quinoline, and 3-amino-1-methyl-5H-pyrido(4,3-b)indole. Graded doses of these compounds were given to the animals by gavage twice with a 4-day interval, and the animals were terminated 3 wk later. All colon carcinogens induced aberrant crypts in a dose-related fashion. N-Nitrosodimethylamine and 3-amino-1-methyl-5H-pyrido(4,3-b)indole, carcinogenic compounds that do not induce colon cancer, did not induce them. The ability of the studied compounds to induce aberrant crypts was species specific; e.g., aflatoxin B1 and 2-amino-3,4-dimethylimidazo(4,5-P)quinoline induce about 20 times more in rats than mice. This relationship was consistent with their reported ability to induce colon cancer in these species. Results of the present study support the use of the aberrant crypt assays to screen colon-specific carcinogens and to study the process of colon carcinogenesis.« less

In vivo metabolism of fumonisin B1 to N-acylated ceramide-like compounds

USDA-ARS?s Scientific Manuscript database

Fumonisins are toxic and carcinogenic mycotoxins found in corn-based foods. Fumonisin B1 (FB1) metabolism to ceramide-like cytotoxic N-acylated FB1 (NAFB1) compounds has been shown in vitro, but in vivo metabolism has not been reported. Therefore, male Sprague-Dawley rats (2/group) were given 5 da...

Further analysis of Ames-negative rodent carcinogens that are only genotoxic in mammalian cells in vitro at concentrations exceeding 1 mM, including retesting of compounds of concern.

PubMed

Kirkland, David; Fowler, Paul

2010-11-01

In the analysis by Parry et al. [Parry, J. M., Parry, E., Phrakonkham, P. and Corvi, R. (2010) Analysis of published data for top concentration considerations in mammalian cell genotoxicity testing. Mutagenesis, 25, 531-538], 24 rodent carcinogens that were negative in the Ames test were identified that were only positive in mammalian cell tests at concentrations between 1 and 10 mM. These carcinogens can be subdivided into four groups as follows: (1) probable non-genotoxic (non-mutagenic) carcinogens, tumour promoters or negative for genotoxicity in vivo (n=10); (2) questionable carcinogens (n=4); (3) carcinogens with a probable genotoxic mode of action (n=5); (4) compounds where carcinogenicity or in vivo genotoxicity is unknown or unclear (n=5). It is not expected that in vitro mammalian cell tests should give positive results with Group 1 chemicals. Within Groups 2-4, five chemicals were considered a low priority because they could be detected using modified conditions because genotoxicity was associated with precipitate or pH shifts or because non-standard metabolism was required. The remaining nine chemicals were therefore considered most critical in terms of detection of genotoxic activity in mammalian cells. Daminozide was also included because it may have given positive responses between 1 and 10 mM. Many of the reported studies could have given positive results only at >1 mM because 'old' protocols were followed. These 10 chemicals have therefore been retested using modern protocols. Some were negative even up to 10 mM. Others were positive at concentrations <1 mM. Only methylolacrylamide was positive at a concentration >1 mM (2 mM = 202 μg/ml). Low-molecular weight substances may therefore require concentrations >1 mM, but further work is needed. Based on this analysis, it is concluded that the 10 mM upper limit in mammalian cell tests can be lowered without any loss of sensitivity in detecting genotoxic rodent carcinogens. A new limit of 1 mM or 500 μg/ml, whichever is the higher, is proposed.

The Evaporation and Degradation of N-Nitroso Dimethyl Amine in Aqueous Solutions.

DTIC Science & Technology

The fate of N-Nitroso Dimethyl Amine ( NDMA ) in aqueous solutions and in a 25 percent caustic waste stream which is produced in the manufacture of...degradation of NDMA in an open lagoon. It was found that for basic solutions, the removal was primarily evaporation, whereas, evaporation is low for...that nitrite severely inhibits the photolysis of NDMA in acid and neutral pHs, and an increase in ionic strength slightly increases the evaporation rate

Green Alternatives to Nitrates and Nitrites in Meat-based Products-A Review.

PubMed

Gassara, Fatma; Kouassi, Anne Patricia; Brar, Satinder Kaur; Belkacemi, Khaled

2016-10-02

Several food additives are added in food for their preservation to maintain the freshness of food (antioxidants) or to slow down or stop the growth of microorganisms (preservative agents). Nitrites and nitrates are used as preservative agents in meat. Nitrites give a smoked taste, a pinkish color in the meat and protect the consumers against the risk of bacterial deterioration. Their addition is however very limited as, in high dose, it can have risks on human health and the environment. Nitrites may also combine with secondary or tertiary amines to form N-nitroso derivatives. Certain N-nitroso compounds have been shown to produce cancers in a wide range of laboratory animals. Thus, alternatives of nitrates and nitrites are the object of numerous research studies. Alternatives, such as the addition of vitamins, fruits, chemicals products, natural products containing nitrite or spices, which have similar properties of nitrites, are in evaluation. In fact, spices are considered to have several organoleptic and anti-microbial properties which would be interesting to study. Several spices and combinations of spices are being progressively evaluated. This review discusses the sources of nitrites and nitrates, their use as additives in food products, their physicochemical properties, their negatives effects and the use of alternatives of nitrites and nitrates in preserving meat products.

Indoor air-assessment: Indoor concentrations of environmental carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gold, K.W.; Naugle, D.F.; Berry, M.A.

1991-01-01

In the report, indoor concentration data are presented for the following general categories of air pollutants: radon-222, environmental tobacco smoke (ETS), asbestos, gas phase organic compounds, formaldehyde, polycyclic aromatic hydrocarbons (PAH), pesticides, and inorganic compounds. These pollutants are either known or suspect carcinogens (i.e., radon-222, asbestos) or more complex mixtures or classes of compounds which contain known or suspect carcinogens. Concentration data for individual carcinogenic compounds in complex mixtures are usually far from complete. The data presented for complex mixtures often include compounds which are not carcinogenic or for which data are insufficient to evaluate carcinogenicity. Their inclusion is justified,more » however, by the possibility that further work may show them to be carcinogens, cocarcinogens, initiators or promotors, or that they may be employed as markers (e.g., nicotine, acrolein) for the estimation of exposure to complex mixtures.« less

Synthesis, SAR and biological evaluation of a novel series of 1-(2-chloroethyl)-1-nitroso-3-(2-(3-oxobenzoelenazol-2(3H)-yl)ethyl) urea: Organoselenium compounds for cancer therapy.

PubMed

Ye, S; Zheng, X; Hu, T; Zeng, H

2016-06-30

Thioredoxin reductase 1 (TrxR1) is an important potential anticancer drug target and closely related to both carcinogenesis and cancer progression. Ethaselen (BBSKE), a novel organoselenium compound inhibiting TrxR1 with selective antitumor effect, while its symmetrical structure results in poor solubility. Carmustine (BCNU), a DNA cross-link agent and also a deactivator of TrxR, is with high toxicity and low selectivity which limit its clinical application to some extents. Herein, a novel compound, 1-(2-chloroethyl)-1-nitroso-3-(2-(3-oxobenzoelenazol-2(3H)-yl)ethyl)urea(4a-1), which was designed through the combination of Ethaselen and Carmustine, showed good solubility, good tagetability, low toxicity and excellent antitumor activity by synergism. Using the structure of 4a-1 as a key active scaffold, a series of novel 1-(2-chloroethyl)-1-nitroso-3-(2-(3-oxobenzoelenazol-2(3H)-yl)ethyl)urea was designed, synthesized and evaluated to explore the structure-activity relationships (SARs) of these inhibitors and to improve their antitumor activities. Notably, 1-(2-chloroethyl)-3-(2-(6-fluoro-3-oxobenzoselenazol-2(3H)-yl)ethyl)-1-nitrosourea(4b-1) was found to exhibit more potent antitumor activities comparable to 4a-1 against all the four cancer cell lines, including Mia PaCa-2, PANC-1, RKO, LoVo. These results have highlighted compound 4b-1 as a new potential lead candidate for future development of novel potent broad-spectrum antitumor agents. In addition, a SAR model was established to conduct further structural modification.

Dual function catalysts. Dehydrogenation and asymmetric intramolecular Diels-Alder cycloaddition of N-hydroxy formate esters and hydroxamic acids: evidence for a ruthenium-acylnitroso intermediate.

PubMed

Chow, Chun P; Shea, Kenneth J

2005-03-23

The chiral ruthenium salen complex, 13b, functions as an efficient catalyst for the sequential oxidation and asymmetric Diels-Alder cycloaddition of hydroxamic acids and N-hydroxy formate esters. This result provides evidence for the formation of a ruthenium-nitroso formate (acyl nitroso) intermediate. The Diels-Alder precursors are prepared from simple building blocks, and the cycloadducts, bridged oxazinolactams, can serve as useful intermediates in organic synthesis.

Epithelial ovarian cancer and exposure to dietary nitrate and nitrite in the NIH-AARP Diet and Health Study.

PubMed

Aschebrook-Kilfoy, Briseis; Ward, Mary H; Gierach, Gretchen L; Schatzkin, Arthur; Hollenbeck, Albert R; Sinha, Rashmi; Cross, Amanda J

2012-01-01

Ovarian cancer is a leading cause of cancer death among women in the United States and it has the highest mortality rate of all gynecologic cancers. Internationally, there is a five-fold variation in incidence and mortality of ovarian cancer, which suggests a role for environmental factors, including diet. Nitrate and nitrite are found in various food items and they are precursors of N-nitroso compounds, which are known carcinogens in animal models. We evaluated dietary nitrate and nitrite intake and epithelial ovarian cancer in the National Institutes of Health (NIH)-AARP Diet and Health Study, including 151 316 women aged 50-71 years at the time of the baseline questionnaire in 1995-1996. The nitrate and nitrite intake was assessed using a 124-item validated food frequency questionnaire. Through 31 December 2006, 709 incident epithelial ovarian cancer cases with complete dietary information were identified. Using Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs), women in the highest intake quintile of dietary nitrate had a 31% increased risk (95% CI: 1.01-1.68) of epithelial ovarian cancer, compared with those in the lowest intake quintile. Although there was no association for total dietary nitrite, those in the highest intake category of animal sources of nitrite had a 34% increased risk (95% CI: 1.05-1.69) of ovarian cancer. There were no clear differences in risk by histologic subtype of ovarian cancer. Our findings suggest that a role of dietary nitrate and nitrite in ovarian cancer risk should be followed in other large cohort studies.

Nitrate in drinking water and colorectal cancer risk: A nationwide population-based cohort study.

PubMed

Schullehner, Jörg; Hansen, Birgitte; Thygesen, Malene; Pedersen, Carsten B; Sigsgaard, Torben

2018-07-01

Nitrate in drinking water may increase risk of colorectal cancer due to endogenous transformation into carcinogenic N-nitroso compounds. Epidemiological studies are few and often challenged by their limited ability of estimating long-term exposure on a detailed individual level. We exploited population-based health register data, linked in time and space with longitudinal drinking water quality data, on an individual level to study the association between long-term drinking water nitrate exposure and colorectal cancer (CRC) risk. Individual nitrate exposure was calculated for 2.7 million adults based on drinking water quality analyses at public waterworks and private wells between 1978 and 2011. For the main analyses, 1.7 million individuals with highest exposure assessment quality were included. Follow-up started at age 35. We identified 5,944 incident CRC cases during 23 million person-years at risk. We used Cox proportional hazards models to estimate hazard ratios (HRs) of nitrate exposure on the risk of CRC, colon and rectal cancer. Persons exposed to the highest level of drinking water nitrate had an HR of 1.16 (95% CI: 1.08-1.25) for CRC compared with persons exposed to the lowest level. We found statistically significant increased risks at drinking water levels above 3.87 mg/L, well below the current drinking water standard of 50 mg/L. Our results add to the existing evidence suggesting increased CRC risk at drinking water nitrate concentrations below the current drinking water standard. A discussion on the adequacy of the drinking water standard in regards to chronic effects is warranted. © 2018 UICC.

Genomic phenotyping by barcode sequencing broadly distinguishes between alkylating agents, oxidizing agents, and non-genotoxic agents, and reveals a role for aromatic amino acids in cellular recovery after quinone exposure.

PubMed

Svensson, J Peter; Quirós Pesudo, Laia; McRee, Siobhan K; Adeleye, Yeyejide; Carmichael, Paul; Samson, Leona D

2013-01-01

Toxicity screening of compounds provides a means to identify compounds harmful for human health and the environment. Here, we further develop the technique of genomic phenotyping to improve throughput while maintaining specificity. We exposed cells to eight different compounds that rely on different modes of action: four genotoxic alkylating (methyl methanesulfonate (MMS), N-Methyl-N-nitrosourea (MNU), N,N'-bis(2-chloroethyl)-N-nitroso-urea (BCNU), N-ethylnitrosourea (ENU)), two oxidizing (2-methylnaphthalene-1,4-dione (menadione, MEN), benzene-1,4-diol (hydroquinone, HYQ)), and two non-genotoxic (methyl carbamate (MC) and dimethyl sulfoxide (DMSO)) compounds. A library of S. cerevisiae 4,852 deletion strains, each identifiable by a unique genetic 'barcode', were grown in competition; at different time points the ratio between the strains was assessed by quantitative high throughput 'barcode' sequencing. The method was validated by comparison to previous genomic phenotyping studies and 90% of the strains identified as MMS-sensitive here were also identified as MMS-sensitive in a much lower throughput solid agar screen. The data provide profiles of proteins and pathways needed for recovery after both genotoxic and non-genotoxic compounds. In addition, a novel role for aromatic amino acids in the recovery after treatment with oxidizing agents was suggested. The role of aromatic acids was further validated; the quinone subgroup of oxidizing agents were extremely toxic in cells where tryptophan biosynthesis was compromised.

Toxico-Cheminformatics and QSPR Modeling of the Carcinogenic Potency Database

EPA Science Inventory

Report on the development of a tiered, confirmatory scheme for prediction of chemical carcinogenicity based on QSAR studies of compounds with available mutagenic and carcinogenic data. For 693 such compounds from the Carcinogenic Potency Database characterized molecular topologic...

Carcinogenic compounds in alcoholic beverages: an update.

PubMed

Pflaum, Tabea; Hausler, Thomas; Baumung, Claudia; Ackermann, Svenja; Kuballa, Thomas; Rehm, Jürgen; Lachenmeier, Dirk W

2016-10-01

The consumption of alcoholic beverages has been classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC) since 1988. More recently, in 2010, ethanol as the major constituent of alcoholic beverages and its metabolite acetaldehyde were also classified as carcinogenic to humans. Alcoholic beverages as multi-component mixtures may additionally contain further known or suspected human carcinogens as constituent or contaminant. This review will discuss the occurrence and toxicology of eighteen carcinogenic compounds (acetaldehyde, acrylamide, aflatoxins, arsenic, benzene, cadmium, ethanol, ethyl carbamate, formaldehyde, furan, glyphosate, lead, 3-MCPD, 4-methylimidazole, N-nitrosodimethylamine, pulegone, ochratoxin A, safrole) occurring in alcoholic beverages as identified based on monograph reviews by the IARC. For most of the compounds of alcoholic beverages, quantitative risk assessment provided evidence for only a very low risk (such as margins of exposure above 10,000). The highest risk was found for ethanol, which may reach exposures in ranges known to increase the cancer risk even at moderate drinking (margin of exposure around 1). Other constituents that could pose a risk to the drinker were inorganic lead, arsenic, acetaldehyde, cadmium and ethyl carbamate, for most of which mitigation by good manufacturing practices is possible. Nevertheless, due to the major effect of ethanol, the cancer burden due to alcohol consumption can only be reduced by reducing alcohol consumption in general or by lowering the alcoholic strength of beverages.

Nitrate and nitrite ingestion and risk of ovarian cancer among postmenopausal women in Iowa.

PubMed

Inoue-Choi, Maki; Jones, Rena R; Anderson, Kristin E; Cantor, Kenneth P; Cerhan, James R; Krasner, Stuart; Robien, Kim; Weyer, Peter J; Ward, Mary H

2015-07-01

Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds (NOC), potential human carcinogens. We evaluated the association of nitrate and nitrite ingestion with postmenopausal ovarian cancer risk in the Iowa Women's Health Study. Among 28,555 postmenopausal women, we identified 315 incident epithelial ovarian cancers from 1986 to 2010. Dietary nitrate and nitrite intakes were assessed at baseline using food frequency questionnaire data. Drinking water source at home was obtained in a 1989 follow-up survey. Nitrate-nitrogen (NO3 -N) and total trihalomethane (TTHM) levels for Iowa public water utilities were linked to residences and average levels were computed based on each woman's duration at the residence. We computed multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards regression. We tested interactions of nitrate with TTHMs and dietary factors known to influence NOC formation. Ovarian cancer risk was 2.03 times higher (CI = 1.22-3.38, ptrend  = 0.003) in the highest quartile (≥2.98 mg/L) compared with the lowest quartile (≤0.47 mg/L; reference) of NO3 -N in public water, regardless of TTHM levels. Risk among private well users was also elevated (HR = 1.53, CI = 0.93-2.54) compared with the same reference group. Associations were stronger when vitamin C intake was

The influence of human neutrophils on N-nitrosodimethylamine (NDMA) synthesis.

PubMed

Jabłoński, Jakub; Jabłońska, Ewa; Iwanowska, Jolanta; Marcińczyk, Magda; Moniuszko-Jakoniuk, Janina

2006-01-01

N-nitrozodimethyloamine (NDMA) is a carcinogenic compound that can be formed in vivo. NDMA is synthesized from precursors-amines and nitrosating agents. Nitrosating agents are formed through the reaction of oxide, reactive oxygen species and nitric oxide (NO). Human neutrophils (PMN) are an important source of the most reactive oxygen species as well as of the nitric oxide. The increase in oxygen metabolism of PMN can lead to the increase nitrosating agent and nitroso-forms. Inflammatory process is associated with locally decreased pH that may favor nitrosation reaction. In the present study, we estimated the NDMA synthesis by LPS-stimulated PMN in the presence of the iNOS inhibitor--N-nitro-L-arginine methyl ester (L-NAME). In the nitrosation reaction dimethylamine (DMA) was used as substrat. The viability of the cells was measured by cytometric method. NDMA concentrations the culture media was measured by GCMS method. NO production was estimated by Griess's method. Expression of iNOS was determined by western blotting. Results obtained showed that DMA nitrosation is most effective in pH between 3-4.5. Nonstimulated PMN produced lower concentrations of NO than LPS-stimulated cells (1.27 microg/cm3 and 1.57 microg/cm3, respectively). In the culture of nonstimulated PMN supplemented with DMA, there was NDMA (mean--0.99 ng/cm3). In the culture of LPS-stimulated PMN in the presence of DMA, the concentration of NDMA was higher than in the culture of nonstimulated PMN (median--1.45 ng/cm3). In the supernatants of cells incubated without DMA and with DMA, LPS and L-NAME, no NDMA was detected. These results indicate that PMN can be one of sources of nitrosating agents and can play a role in endogenous NDMA synthesis. Stimulation of PMN can lead to the increase of NDMA concentration following the increase of NO production. Different pathological conditions associated with PMN activation as well as the decreased pH may favor endogenous NDMA synthesis.

Induction of mammary tumors in rat by intraperitoneal injection of NMU: histopathology and estral cycle influence.

PubMed

Rivera, E S; Andrade, N; Martin, G; Melito, G; Cricco, G; Mohamad, N; Davio, C; Caro, R; Bergoc, R M

1994-11-11

In order to obtain an experimental model we induced mammary tumors in female Sprague-Dawley rats. The carcinogen N-nitroso-N-methylurea (NMU) was injected intraperitoneally (i.p.) at doses of 50 mg/kg body weight when animals were 50, 80 and 110 days old. Tumor sizes were measured with a caliper and their growth parameters and histopathological properties were tested. For 100 rats, 88.4% of developed lesions were ductal carcinomas, histologically classified as 52.8% cribiform variety, 30.6% solid carcinoma. Metastases in liver, spleen and lung were present. Other primary tumors were detected with low incidence. The influence of the rat estrous cycle during the first exposure to intraperitoneal NMU injection was studied. The latency period in estrus, proestrus and diestrus was 82 +/- 15, 77 +/- 18 and 79 +/- 18 days, respectively. Tumor incidence was significantly higher in estrus (95.2%) than proestrus (71.4%) or diestrus (77.4), (P < 0.01). Mean number or tumors per animal was similar among the three groups (4.4 +/- 3.2, 3.8 +/- 3.6, 3.2 +/- 1.8). The procedure described appears to be the simplest method for inducing experimental mammary tumors in rats.

Genomic Phenotyping by Barcode Sequencing Broadly Distinguishes between Alkylating Agents, Oxidizing Agents, and Non-Genotoxic Agents, and Reveals a Role for Aromatic Amino Acids in Cellular Recovery after Quinone Exposure

PubMed Central

Svensson, J. Peter; Quirós Pesudo, Laia; McRee, Siobhan K.; Adeleye, Yeyejide; Carmichael, Paul; Samson, Leona D.

2013-01-01

Toxicity screening of compounds provides a means to identify compounds harmful for human health and the environment. Here, we further develop the technique of genomic phenotyping to improve throughput while maintaining specificity. We exposed cells to eight different compounds that rely on different modes of action: four genotoxic alkylating (methyl methanesulfonate (MMS), N-Methyl-N-nitrosourea (MNU), N,N′-bis(2-chloroethyl)-N-nitroso-urea (BCNU), N-ethylnitrosourea (ENU)), two oxidizing (2-methylnaphthalene-1,4-dione (menadione, MEN), benzene-1,4-diol (hydroquinone, HYQ)), and two non-genotoxic (methyl carbamate (MC) and dimethyl sulfoxide (DMSO)) compounds. A library of S. cerevisiae 4,852 deletion strains, each identifiable by a unique genetic ‘barcode’, were grown in competition; at different time points the ratio between the strains was assessed by quantitative high throughput ‘barcode’ sequencing. The method was validated by comparison to previous genomic phenotyping studies and 90% of the strains identified as MMS-sensitive here were also identified as MMS-sensitive in a much lower throughput solid agar screen. The data provide profiles of proteins and pathways needed for recovery after both genotoxic and non-genotoxic compounds. In addition, a novel role for aromatic amino acids in the recovery after treatment with oxidizing agents was suggested. The role of aromatic acids was further validated; the quinone subgroup of oxidizing agents were extremely toxic in cells where tryptophan biosynthesis was compromised. PMID:24040048

Method for converting asbestos to non-carcinogenic compounds

DOEpatents

Selby, Thomas W.

1996-01-01

Hazardous and carcinogenic asbestos waste characterized by a crystalline fibrous structure is transformed into non-carcinogenic, relatively nonhazardous, and non-crystalline solid compounds and gaseous compounds which have commercial utilization. The asbestos waste is so transformed by the complete fluorination of the crystalline fibrous silicate mineral defining the asbestos.

Method for converting asbestos to non-carcinogenic compounds

DOEpatents

Selby, T.W.

1996-08-06

Hazardous and carcinogenic asbestos waste characterized by a crystalline fibrous structure is transformed into non-carcinogenic, relatively nonhazardous, and non-crystalline solid compounds and gaseous compounds which have commercial utilization. The asbestos waste is so transformed by the complete fluorination of the crystalline fibrous silicate mineral defining the asbestos. 7 figs.

Highly sensitive sites for guanine-O6 ethylation in rat brain DNA exposed to N-ethyl-N-nitrosourea in vivo.

PubMed Central

Nehls, P; Rajewsky, M F; Spiess, E; Werner, D

1984-01-01

Brain chromosomal DNA isolated from fetal BDIX-rats 1 h after i.v. administration of the ethylating N-nitroso carcinogen N-ethyl-N-nitrosourea (75 micrograms/g body weight), statistically contained one molecule of O6-ethyl-2'-deoxyguanosine (O6-EtdGuo) per 81 micron of DNA, as determined in enzymatic DNA hydrolysates by competitive radio-immunoassay using a high-affinity anti-(O6-EtdGuo) monoclonal antibody (ER-6). After fragmentation of the DNA by the restriction enzyme AluI (average fragment length, Lav = 0.28 micron = 970 bp; length range, Lr = 1.87-0.02 micron = 6540 - 60 bp), a small (approximately 2%) fraction of DNA enriched in specific polypeptides tightly associated with DNA was separated from the bulk DNA by a glass fiber binding technique. As analyzed by immune electron microscopy, approximately 1% of the DNA molecules in this fraction contained clusters of 2-10 (O6-EtdGuo)-antibody binding sites (ABS). On the cluster-bearing fragments (Lav, 0.85 micron +/- 0.50 micron S.D.; corresponding to 2970 +/- 1760 bp) the average ABS-ABS interspace distance was 110 nm (= 390 bp; range approximately 9-600 nm), indicating a highly non-random distribution of O6-EtdGuo in target cell DNA. Images Fig. 2. PMID:6370677

Retention behavior of long chain quaternary ammonium homologues and related nitroso-alkymethylamines

USGS Publications Warehouse

Abidi, S.L.

1985-01-01

Several chromatographic methods have been utilized to study the retentionbehavior of a homologous series of n-alkylbenzyldimethylammonium chlorides (ABDAC) and the corresponding nitroso-n-alkylmethylamines (NAMA). Linear correlation of the logarithmic capacity factor (k') with the number of carbons in the alkyl chain provides useful information on both gas chromatographic (GC) and high-performance liquid chromatographich (HPLC) retention parameters of unknown components. Under all conditions empolyed, GC methodology has proved effective in achieving complete resolution of the homologous mixture of NMA despite its obvious inadequacy in the separation of E-Z configurational isomers. Conversely, normal-phase HPLC on silica demonstrates that the selectivity (a) value for an E-Z pair is much higher than that for an adjacent homologous pair. In the reversed-phase HPLC study, three different silica-based column systems were examined under various mobile phase conditions. The extent of variation in k' was found to be a function of the organic modifier, counter-ion concentration, eluent pH, nature of counter-ion, and the polarity and type of stationary phase. The k'—[NaClO4] profiles showed similar trends between the ABDAC and the NAMA series, supporting the dipolar electronic structures of the latter compounds. Mobile phase and stationary phase effects on component separation are described. The methodology presented establishes the utility of HPLC separation techniques as versatile analytical tools for practical application.

Cloning and Characterization of a Hybridoma Secreting a 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-Specific Monoclonal Antibody and Recombinant F(ab)

PubMed Central

Wanczyk, Heather; Barker, Tolga; Rood, Debra; Zapata, Daniel I.; Howell, Amy R.; Richardson, Stewart K.; Zinckgraf, John; Marusov, Gregory P.; Lynes, Michael A.; Silbart, Lawrence K.

2013-01-01

Smokeless tobacco products have been associated with increased risks of oro-pharyngeal cancers, due in part to the presence of tobacco-specific nitrosamines (TSNAs) such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These potent carcinogens are formed during tobacco curing and as a result of direct nitrosation reactions that occur in the oral cavity. In the current work we describe the isolation and characterization of a hybridoma secreting a high-affinity, NNK-specific monoclonal antibody. A structurally-related benzoyl derivative was synthesized to facilitate coupling to NNK-carrier proteins, which were characterized for the presence of the N-nitroso group using the Griess reaction, and used to immunize BALB/c mice. Splenocytes from mice bearing NNK-specific antibodies were used to create hybridomas. Out of four, one was selected for subcloning and characterization. Approximately 99% of the monoclonal antibodies from this clone were competitively displaced from plate-bound NNKB conjugates in the presence of free NNK. The affinity of the monoclonal antibody to the NNKB conjugates was Kd = 2.93 nM as determined by surface plasmon resonance. Free nicotine was a poor competitor for the NNKB binding site. The heavy and light chain antibody F(ab) fragments were cloned, sequenced and inserted in tandem into an expression vector, with an FMDV Furin 2A cleavage site between them. Expression in HEK 293 cells revealed a functional F(ab) with similar binding features to that of the parent hybridoma. This study lays the groundwork for synthesizing transgenic tobacco that expresses carcinogen-sequestration properties, thereby rendering it less harmful to consumers. PMID:23518474

Nitroxide stable radicals interacting as Lewis bases in hydrogen bonds: A search in the Cambridge structural data base for intermolecular contacts

NASA Astrophysics Data System (ADS)

Alkorta, Ibon; Elguero, José; Elguero, Eric

2017-11-01

1125 X-ray structures of nitroxide free radicals presenting intermolecular hydrogen bonds have been reported in the Cambridge Structural Database. We will report in this paper a qualitative and quantitative analysis of these bonds. The observation in some plots of an excluded region was statistically analyzed using convex hull and kernel smooting methodologies. A theoretical study at the MP2 level with different basis has been carried out indicating that the nitronyl nitroxide radicals (five electrons) lie just in between nitroso compounds (four electrons) and amine N-oxides (six electrons) as far as hydrogen-bond basicity is concerned.

Biomimetic trapping cocktail to screen reactive metabolites: use of an amino acid and DNA motif mixture as light/heavy isotope pairs differing in mass shift.

PubMed

Hosaka, Shuto; Honda, Takuto; Lee, Seon Hwa; Oe, Tomoyuki

2018-06-01

Candidate drugs that can be metabolically transformed into reactive electrophilic products, such as epoxides, quinones, and nitroso compounds, are of special concern because subsequent covalent binding to bio-macromolecules can cause adverse drug reactions, such as allergic reactions, hepatotoxicity, and genotoxicity. Several strategies have been reported for screening reactive metabolites, such as a covalent binding assay with radioisotope-labeled drugs and a trapping method followed by LC-MS/MS analyses. Of these, a trapping method using glutathione is the most common, especially at the early stage of drug development. However, the cysteine of glutathione is not the only nucleophilic site in vivo; lysine, histidine, arginine, and DNA bases are also nucleophilic. Indeed, the glutathione trapping method tends to overlook several types of reactive metabolites, such as aldehydes, acylglucuronides, and nitroso compounds. Here, we introduce an alternate way for screening reactive metabolites as follows: A mixture of the light and heavy isotopes of simplified amino acid motifs and a DNA motif is used as a biomimetic trapping cocktail. This mixture consists of [ 2 H 0 ]/[ 2 H 3 ]-1-methylguanidine (arginine motif, Δ 3 Da), [ 2 H 0 ]/[ 2 H 4 ]-2-mercaptoethanol (cysteine motif, Δ 4 Da), [ 2 H 0 ]/[ 2 H 5 ]-4-methylimidazole (histidine motif, Δ 5 Da), [ 2 H 0 ]/[ 2 H 9 ]-n-butylamine (lysine motif, Δ 9 Da), and [ 13 C 0 , 15 N 0 ]/[ 13 C 1 , 15 N 2 ]-2'-deoxyguanosine (DNA motif, Δ 3 Da). Mass tag triggered data-dependent acquisition is used to find the characteristic doublet peaks, followed by specific identification of the light isotope peak using MS/MS. Forty-two model drugs were examined using an in vitro microsome experiment to validate the strategy. Graphical abstract Biomimetic trapping cocktail to screen reactive metabolites.

The 2:1 salt-type adduct formed between 6-amino-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione and piperidine: sheets containing 20 independent hydrogen bonds.

PubMed

Orozco, Fabián; Insuasty, Braulio; Cobo, Justo; Glidewell, Christopher

2009-05-01

The title compound, piperidinium 6-amino-3-methyl-5-nitroso-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ide 6-amino-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione, C(5)H(12)N(+).C(5)H(5)N(4)O(3)(-).C(5)H(6)N(4)O(3), (I), crystallizes with Z' = 2 in the space group P1. There is an intramolecular N-H...O hydrogen bond in each pyrimidine unit and within the selected asymmetric unit the six independent components are linked by 11 hydrogen bonds, seven of the N-H...O type and four of the N-H...N type. These six-component aggregates are linked into sheets by five further hydrogen bonds, three of the N-H...O type and one each of the N-H...N and C-H...O types.

Nitric oxide donors, sodium nitroprusside and S-nitroso-N-acetylpencillamine, stimulate myoblast proliferation in vitro

NASA Technical Reports Server (NTRS)

Ulibarri, J. A.; Mozdziak, P. E.; Schultz, E.; Cook, C.; Best, T. M.

1999-01-01

Nitric oxide (NO) is an inter- and intracellular messenger involved in a variety of physiologic and pathophysiologic conditions. The effect of two NO donors, sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) and their effect on myoblast proliferation was examined. Both donors stimulated an increase in myoblast cell number over a range (1-10 microM) of donor concentrations. However, 50 microM SNAP inhibited myoblast proliferation. Cell numbers from cultures treated with degraded 10 microM SNAP were equivalent to the control. Therefore, it appears NO can stimulate as well as inhibit myoblast proliferation.

Molecular mechanisms of transformation of C3H/10T1/2 C1 8 mouse embryo cells and diploid human fibroblasts by carcinogenic metal compounds.

PubMed Central

Landolph, J R

1994-01-01

Carcinogenic arsenic, nickel, and chromium compounds induced morphological and neoplastic transformation but no mutation to ouabain resistance in 10T1/2 mouse embryo cells; lead chromate also did not induce mutation to ouabain or 6-thioguanine resistance in Chinese hamster ovary cells. The mechanism of metal-induced morphological transformation was likely not due to the specific base substitution mutations measured in ouabain resistance mutation assays, and for lead chromate, likely not due to this type of base substitution mutation or to frameshift mutations. Preliminary data indicate increases in steady-state levels of c-myc RNA in arsenic-, nickel-, and chromium-transformed cell lines. We also showed that carcinogenic nickel, chromium, and arsenic compounds and N-methyl-N-nitro-N-nitrosoguanidine (MNNG) induced stable anchorage independence (Al) in diploid human fibroblasts (DHF) but no focus formation or immortality. Nickel subsulfide and lead chromate induced Al but not mutation to 6-thioguanine resistance. The mechanism of induction of Al by metal salts in DHF was likely not by the type of base substitution or frameshift mutations measured in these assays. MNNG induced Al, mutation to 6-thioguanine resistance, and mutation to ouabain resistance, and might induce Al by base substitution or frameshift mutations. Dexamethasone, aspirin, and salicylic acid inhibited nickel subsulfide, MNNG, and 12-O-tetrade-canoylphorbol-13-acetate (TPA)-induced Al in DHF, suggesting that arachidonic acid metabolism and oxygen radical generation play a role in induction of Al. We propose that nickel compounds stimulate arachidonic acid metabolism, consequent oxygen radical generation, and oxygen radical attack upon DNA.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1. PMID:7843085

[Mammary gland tumor induction in rats by N-nitroso-N-methylurea and N-methyl-N1-nitro-N-nitrosoguanidine].

PubMed

Eliseev, V V; Vlasov, N N

1980-01-01

Cancer of the mammary gland was induced in female non-inbred rats under the local effect of N-nitroso-N-methylurea (NMU) and N-methyl-N-nitro-N-nitrosoguanidine (MNNG). During 10 weeks 2.5 mg of the substance in 0.2 ml of saline was injected in the region of the third mammary gland once a week. Under NMU exposure a primary tumor arose 3 months following the initiation of the experiment, the average latent period being 5.8 months, the incidence rate--76.7%. All tumors of this series were adenocarcinomas, in 5 cases there were noted sites of fibroadenomatosis with malignification along the tumor node margins. MNNG produced a primary tumor at the 7th month of the experiment, an average latent period--8.3 months, the incidence rate--56.7%. Tumors were mostly adenocarcinomas.

Testing chemical carcinogenicity by using a transcriptomics HepaRG-based model?

PubMed Central

Doktorova, T. Y.; Yildirimman, Reha; Ceelen, Liesbeth; Vilardell, Mireia; Vanhaecke, Tamara; Vinken, Mathieu; Ates, Gamze; Heymans, Anja; Gmuender, Hans; Bort, Roque; Corvi, Raffaella; Phrakonkham, Pascal; Li, Ruoya; Mouchet, Nicolas; Chesne, Christophe; van Delft, Joost; Kleinjans, Jos; Castell, Jose; Herwig, Ralf; Rogiers, Vera

2014-01-01

The EU FP6 project carcinoGENOMICS explored the combination of toxicogenomics and in vitro cell culture models for identifying organotypical genotoxic- and non-genotoxic carcinogen-specific gene signatures. Here the performance of its gene classifier, derived from exposure of metabolically competent human HepaRG cells to prototypical non-carcinogens (10 compounds) and hepatocarcinogens (20 compounds), is reported. Analysis of the data at the gene and the pathway level by using independent biostatistical approaches showed a distinct separation of genotoxic from non-genotoxic hepatocarcinogens and non-carcinogens (up to 88 % correct prediction). The most characteristic pathway responding to genotoxic exposure was DNA damage. Interlaboratory reproducibility was assessed by blindly testing of three compounds, from the set of 30 compounds, by three independent laboratories. Subsequent classification of these compounds resulted in correct prediction of the genotoxicants. As expected, results on the non-genotoxic carcinogens and the non-carcinogens were less predictive. In conclusion, the combination of transcriptomics with the HepaRG in vitro cell model provides a potential weight of evidence approach for the evaluation of the genotoxic potential of chemical substances. PMID:26417288

O-nitroso aldol synthesis: Catalytic enantioselective route to α-aminooxy carbonyl compounds via enamine intermediate

PubMed Central

Momiyama, Norie; Torii, Hiromi; Saito, Susumu; Yamamoto, Hisashi

2004-01-01

The approach using pyrrolidine enamine as substrate has been studied for this synthesis, and an important catalyst structural feature has been developed. After survey of pyrrolidine-based Brønsted acid catalyst, tetrazole catalyst (3f) was found to be optimal in synthesis of aminooxy carbonyl compounds in high yields, with complete enantioselectivity not only for aldehydes but also for ketones. PMID:15067138

Respiratory carcinogenicity assessment of soluble nickel compounds.

PubMed Central

Oller, Adriana R

2002-01-01

The many chemical forms of nickel differ in physicochemical properties and biological effects. Health assessments for each main category of nickel species are needed. The carcinogenicity assessment of water-soluble nickel compounds has proven particularly difficult. Epidemiologic evidence indicates an association between inhalation exposures to nickel refinery dust containing soluble nickel compounds and increased risk of respiratory cancers. However, the nature of this association is unclear because of limitations of the exposure data, inconsistent results across cohorts, and the presence of mixed exposures to water-insoluble nickel compounds and other confounders that are known or suspected carcinogens. Moreover, well-conducted animal inhalation studies, where exposures were solely to soluble nickel, failed to demonstrate a carcinogenic potential. Similar negative results were seen in animal oral studies. A model exists that relates respiratory carcinogenic potential to the bioavailability of nickel ion at nuclear sites within respiratory target cells. This model helps reconcile human, animal, and mechanistic data for soluble nickel compounds. For inhalation exposures, the predicted lack of bioavailability of nickel ion at target sites suggests that water-soluble nickel compounds, by themselves, will not be complete human carcinogens. However, if inhaled at concentrations high enough to induce chronic lung inflammation, these compounds may enhance carcinogenic risks associated with inhalation exposure to other substances. Overall, the weight of evidence indicates that inhalation exposure to soluble nickel alone will not cause cancer; moreover, if exposures are kept below levels that cause chronic respiratory toxicity, any possible tumor-enhancing effects (particularly in smokers) would be avoided. PMID:12426143

Identification of potential fish carcinogens in sediment from Hamilton Harbour, Ontario, Canada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Balch, G.C.; Metcalfe, C.D.; Huestis, S.Y.

1995-01-01

A carcinogenicity- and mutagenicity-directed fractionation approach was used to identify the carcinogenic compounds in contaminated sediments that are putatively responsible for the high prevalence of tumors in bottom-dwelling fish from Hamilton Harbour, Ontario. Mutagenic activity was detected with Ames tester strains (TA98, TA100) in relatively nonpolar fractions of sediment extract containing PAHs and nitrogen-containing aromatic compounds (NCACs). These fractions were also carcinogenic in an in vivo carcinogenicity bioassay with rainbow trout (Oncorhynchus mykiss). When a more polar extract fraction was tested for mutagenicity and carcinogenicity, weak mutagenic activity was detected with an O-acetyltransferase-enriched Ames tester strain (YG1024), and weak carcinogenicmore » activity was detected in the rainbow trout assay. These data indicate that PAHs in contaminated Hamilton Harbour sediments are potent fish carcinogens, but it is also evident that other organic compounds in the sediment, such as NCACs and nitroarenes, may contribute to carcinogenicity.« less

Epithelial ovarian cancer and exposure to dietary nitrate and nitrite in the NIH-AARP Diet and Health Study

PubMed Central

Aschebrook-Kilfoy, Briseis; Ward, Mary H.; Gierach, Gretchen L.; Schatzkin, Arthur; Hollenbeck, Albert R.; Sinha, Rashmi; Cross, Amanda J.

2012-01-01

Ovarian cancer is a leading cause of cancer death among women in the United States and it has the highest mortality rate of all gynecologic cancers. Internationally, there is a five-fold variation in incidence and mortality of ovarian cancer, which suggests a role for environmental factors, including diet. Nitrate and nitrite are found in various food items and they are precursors of N-nitroso compounds, which are known carcinogens in animal models. We evaluated dietary nitrate and nitrite intake and epithelial ovarian cancer in the National Institutes of Health (NIH)-AARP Diet and Health Study, including 151 316 women aged 50–71 years at the time of the baseline questionnaire in 1995–1996. The nitrate and nitrite intake was assessed using a 124-item validated food frequency questionnaire. Through 31 December 2006, 709 incident epithelial ovarian cancer cases with complete dietary information were identified. Using Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs), women in the highest intake quintile of dietary nitrate had a 31% increased risk (95% CI: 1.01–1.68) of epithelial ovarian cancer, compared with those in the lowest intake quintile. Although there was no association for total dietary nitrite, those in the highest intake category of animal sources of nitrite had a 34% increased risk (95% CI: 1.05–1.69) of ovarian cancer. There were no clear differences in risk by histologic subtype of ovarian cancer. Our findings suggest that a role of dietary nitrate and nitrite in ovarian cancer risk should be followed in other large cohort studies. PMID:21934624

Nitrate Intake Does Not Influence Bladder Cancer Risk: The Netherlands Cohort Study

PubMed Central

Zeegers, Maurice P.; Selen, Roel F.M.; Kleinjans, Jos C.S.; Goldbohm, R. Alexandra; van den Brandt, Piet A.

2006-01-01

Objectives N-nitroso compounds, endogenously formed from nitrate-derived nitrite, are suspected to be important bladder carcinogens. However, the association between nitrate exposure from food or drinking water and bladder cancer has not been substantially investigated in epidemiologic studies. Methods We evaluated the associations between nitrate exposure and bladder cancer in the Netherlands Cohort Study, conducted among 120,852 men and women, 55–69 years of age at entry. Information on nitrate from diet was collected via a food frequency questionnaire in 1986 and a database on nitrate content of foods. Individual nitrate exposures from beverages prepared with tap water were calculated by linking the postal code of individual residence at baseline to water company data. After 9.3 years of follow-up and after excluding subjects with incomplete or inconsistent dietary data, 889 cases and 4,441 subcohort members were available for multivariate analyses. We calculated incidence rate ratios (RR) and corresponding 95% confidence intervals (CIs) using Cox regression analyses. We also evaluated possible effect modification of dietary intake of vitamins C and E (low/high) and cigarette smoking (never/ever). Results The multivariate RRs for nitrate exposure from food, drinking water, and estimated total nitrate exposure were 1.06 (95% CI, 0.81–1.31), 1.06 (95% CI, 0.82–1.37), and 1.09 (95% CI, 0.84–1.42), respectively, comparing the highest to the lowest quintiles of intake. Dietary intake of vitamins C and E (low/high) and cigarette smoking (never/ever) had no significant impact on these results. Conclusion Although the association between nitrate exposure and bladder cancer risk is biologically plausible, our results in this study do not support an association between nitrate exposure and bladder cancer risk. PMID:17035137

Dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women's Health Study.

PubMed

Dellavalle, Curt T; Xiao, Qian; Yang, Gong; Shu, Xiao-Ou; Aschebrook-Kilfoy, Briseis; Zheng, Wei; Lan Li, Hong; Ji, Bu-Tian; Rothman, Nathaniel; Chow, Wong-Ho; Gao, Yu-Tang; Ward, Mary H

2014-06-15

Nitrate and nitrite are precursors of endogenously formed N-nitroso compounds (NOC), known animal carcinogens. Nitrosation reactions forming NOCs can be inhibited by vitamin C and other antioxidants. We prospectively investigated the association between dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women's Health Study, a cohort of 73,118 women ages 40-70 residing in Shanghai. We evaluated effect modification by factors that affect endogenous formation of NOCs: vitamin C (at or above/below median) and red meat intake (at or above/below median). Nitrate, nitrite and other dietary intakes were estimated from a 77-item food frequency questionnaire administered at baseline. Over a mean of 11 years of follow-up, we identified 619 colorectal cancer cases (n = 383, colon; n = 236, rectum). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression. Overall, nitrate intake was not associated with colorectal cancer risk (HR = 1.08; 95% CI: 0.73-1.59). However, among women with vitamin C intake below the median (83.9 mg day(-1) ) and hence higher potential exposure to NOCs, risk of colorectal cancer increased with increasing quintiles of nitrate intake (highest vs. lowest quintile HR = 2.45; 95% CI: 1.15-5.18; p trend = 0.02). There was no association among women with higher vitamin C intake. We found no association between nitrite intake and risk of colorectal cancer overall or by intake level of vitamin C. Our findings suggest that high dietary nitrate intake among subgroups expected to have higher exposure to endogenously formed NOCs increases risk of colorectal cancer. © 2013 UICC.

Colorectal cancer risk and nitrate exposure through drinking water and diet.

PubMed

Espejo-Herrera, Nadia; Gràcia-Lavedan, Esther; Boldo, Elena; Aragonés, Nuria; Pérez-Gómez, Beatriz; Pollán, Marina; Molina, Antonio J; Fernández, Tania; Martín, Vicente; La Vecchia, Carlo; Bosetti, Cristina; Tavani, Alessandra; Polesel, Jerry; Serraino, Diego; Gómez Acebo, Inés; Altzibar, Jone M; Ardanaz, Eva; Burgui, Rosana; Pisa, Federica; Fernández-Tardón, Guillermo; Tardón, Adonina; Peiró, Rosana; Navarro, Carmen; Castaño-Vinyals, Gemma; Moreno, Victor; Righi, Elena; Aggazzotti, Gabriella; Basagaña, Xavier; Nieuwenhuijsen, Mark; Kogevinas, Manolis; Villanueva, Cristina M

2016-07-15

Ingested nitrate leads to the endogenous synthesis of N-nitroso compounds (NOCs), animal carcinogens with limited human evidence. We aimed to evaluate the risk of colorectal cancer (CRC) associated with nitrate exposure in drinking water and diet. A case-control study in Spain and Italy during 2008-2013 was conducted. Hospital-based incident cases and population-based (Spain) or hospital-based (Italy) controls were interviewed on residential history, water consumption since age 18, and dietary information. Long-term waterborne ingested nitrate was derived from routine monitoring records, linked to subjects' residential histories and water consumption habits. Dietary nitrate intake was estimated from food frequency questionnaires and published food composition databases. Odd ratios (OR) were calculated using mixed models with area as random effect, adjusted for CRC risk factors and other covariables. Generalized additive models (GAMs) were used to analyze exposure-response relationships. Interaction with endogenous nitrosation factors and other covariables was also evaluated. In total 1,869 cases and 3,530 controls were analyzed. Average waterborne ingested nitrate ranged from 3.4 to 19.7 mg/day, among areas. OR (95% CIs) of CRC was 1.49 (1.24, 1.78) for >10 versus ≤5 mg/day, overall. Associations were larger among men versus women, and among subjects with high red meat intake. GAMs showed increasing exposure-response relationship among men. Animal-derived dietary nitrate was associated with rectal, but not with colon cancer risk. In conclusion, a positive association between CRC risk and waterborne ingested nitrate is suggested, mainly among subgroups with other risk factors. Heterogeneous effects of nitrate from different sources (water, animal and vegetables) warrant further research. © 2016 UICC.

A computational method for the identification of new candidate carcinogenic and non-carcinogenic chemicals.

PubMed

Chen, Lei; Chu, Chen; Lu, Jing; Kong, Xiangyin; Huang, Tao; Cai, Yu-Dong

2015-09-01

Cancer is one of the leading causes of human death. Based on current knowledge, one of the causes of cancer is exposure to toxic chemical compounds, including radioactive compounds, dioxin, and arsenic. The identification of new carcinogenic chemicals may warn us of potential danger and help to identify new ways to prevent cancer. In this study, a computational method was proposed to identify potential carcinogenic chemicals, as well as non-carcinogenic chemicals. According to the current validated carcinogenic and non-carcinogenic chemicals from the CPDB (Carcinogenic Potency Database), the candidate chemicals were searched in a weighted chemical network constructed according to chemical-chemical interactions. Then, the obtained candidate chemicals were further selected by a randomization test and information on chemical interactions and structures. The analyses identified several candidate carcinogenic chemicals, while those candidates identified as non-carcinogenic were supported by a literature search. In addition, several candidate carcinogenic/non-carcinogenic chemicals exhibit structural dissimilarity with validated carcinogenic/non-carcinogenic chemicals.

Comparative risk assessment of carcinogens in alcoholic beverages using the margin of exposure approach.

PubMed

Lachenmeier, Dirk W; Przybylski, Maria C; Rehm, Jürgen

2012-09-15

Alcoholic beverages have been classified as carcinogenic to humans. As alcoholic beverages are multicomponent mixtures containing several carcinogenic compounds, a quantitative approach is necessary to compare the risks. Fifteen known and suspected human carcinogens (acetaldehyde, acrylamide, aflatoxins, arsenic, benzene, cadmium, ethanol, ethyl carbamate, formaldehyde, furan, lead, 4-methylimidazole, N-nitrosodimethylamine, ochratoxin A and safrole) occurring in alcoholic beverages were identified based on monograph reviews by the International Agency for Research on Cancer. The margin of exposure (MOE) approach was used for comparative risk assessment. MOE compares a toxicological threshold with the exposure. MOEs above 10,000 are judged as low priority for risk management action. MOEs were calculated for different drinking scenarios (low risk and heavy drinking) and different levels of contamination for four beverage groups (beer, wine, spirits and unrecorded alcohol). The lowest MOEs were found for ethanol (3.1 for low risk and 0.8 for heavy drinking). Inorganic lead and arsenic have average MOEs between 10 and 300, followed by acetaldehyde, cadmium and ethyl carbamate between 1,000 and 10,000. All other compounds had average MOEs above 10,000 independent of beverage type. Ethanol was identified as the most important carcinogen in alcoholic beverages, with clear dose response. Some other compounds (lead, arsenic, ethyl carbamate, acetaldehyde) may pose risks below thresholds normally tolerated for food contaminants, but from a cost-effectiveness point of view, the focus should be on reducing alcohol consumption in general rather than on mitigative measures for some contaminants that contribute only to a limited extent (if at all) to the total health risk. Copyright © 2012 UICC.

N-tert-butylmethanimine N-oxide is an efficient spin-trapping probe for EPR analysis of glutathione thiyl radical

PubMed Central

Scott, Melanie J.; Billiar, Timothy R.; Stoyanovsky, Detcho A.

2016-01-01

The electron spin resonance (EPR) spin-trapping technique allows detection of radical species with nanosecond half-lives. This technique is based on the high rates of addition of radicals to nitrones or nitroso compounds (spin traps; STs). The paramagnetic nitroxides (spin-adducts) formed as a result of reactions between STs and radical species are relatively stable compounds whose EPR spectra represent “structural fingerprints” of the parent radical species. Herein we report a novel protocol for the synthesis of N-tert-butylmethanimine N-oxide (EBN), which is the simplest nitrone containing an α-H and a tertiary α′-C atom. We present EPR spin-trapping proof that: (i) EBN is an efficient probe for the analysis of glutathione thiyl radical (GS•); (ii) β-cyclodextrins increase the kinetic stability of the spin-adduct EBN/•SG; and (iii) in aqueous solutions, EBN does not react with superoxide anion radical (O2−•) to form EBN/•OOH to any significant extent. The data presented complement previous studies within the context of synthetic accessibility to EBN and efficient spin-trapping analysis of GS•. PMID:27941944

[The chiral mutagens: cytogenetic effects on higher plants].

PubMed

Morgun, V V; Larchenko, E A; Kostianovskiĭ, R G; Keterinchuk, A M

2011-01-01

The paper covers investigation of cytogenetic activity of chiral mutagens and their specific effects on the plant cells chromosomes of soft winter wheat (Triticum aestivum L.). Comparative analysis of cytogenetic activity of chiral NEU: S(+)1-N-nitroso- 1-N-methyl-3-N-sec-buthylureas (S(+)NMsBU) and R(-)1-N-nitroso- 1N-methyl-3-Nsec-buthylureas (R(-)NMsBU) on winter wheat was performed. As it was shown by the frequency of chromosomal aberrations the S(+) stereoisomer was twice more active than R(-). In addition to typical anaphase aberrations (fragments, bridges, lagging chromosomes) the numerous mitosis pathologies were revealed - K-mitoses, hyperspiralization and despiralization of chromosomes, unequal allocation of chromosomes between the daughter nuclei, mass fragmentation, nondisjunction and chromosome adhesion, three-pole mitoses, etc. Neither of the mentioned pathologies was observed under the action of NEU and gamma-rays.

[Cytotoxicity of lysomustine and its isomers, and their potential use for selection of cells].

PubMed

Rozov, F N; Grinenko, T S; Levit, G L; Grishakov, A N; Beliavskiĭ, A V; Krasnov, V P

2011-01-01

N epsilon-Nitroso-N epsilon- [N'-(2-chloroethyl)carbamoyl]-L-lysine (I) and N epsilon- [N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-L-lysine (II), the isomers being the constituents of antitumor agent Lysomustine, were obtained by RFHPLC. The study of cytotoxicity of the above compounds against K562 cells showed that the lesions induced by isomer (II) produce a significant cytotoxic effect but can be efficiently repaired by the action of MGMT (O6-methylaguanine DNA methyltransferase). Under similar conditions, the lesions induced by isomer (I) produce substantially smaller effect but are weakly if at all repairable by MGMT. The effects of a clinically approved agent Lysomustine, which is the mixture of isomers (I) and (II), are similar to those of isomer (II). The results obtained point to a different chemical nature of DNA lesions induced by two Lysomustine isomers. Our data indicate that Lysomustine and its isomer (II) can be used for in vitro selection of cells expressing MGMT.

Explosive composition with group VIII metal nitroso halide getter

DOEpatents

Walker, Franklin E.; Wasley, Richard J.

1982-01-01

An improved explosive composition is disclosed and comprises a major portion of an explosive having a detonation velocity between about 1,500 and 10,000 meters per second and a minor amount of a getter additive comprising a non-explosive compound or mixture of non-explosive compounds capable of chemically reacting with free radicals or ions under shock initiation conditions of 2,000 calories/cm.sup.2 or less of energy fluence.

Explosive composition with group VIII metal nitroso halide getter

DOEpatents

Walker, F.E.; Wasley, R.J.

1982-06-22

An improved explosive composition is disclosed and comprises a major portion of an explosive having a detonation velocity between about 1,500 and 10,000 meters per second and a minor amount of a getter additive comprising a non-explosive compound or mixture of non-explosive compounds capable of chemically reacting with free radicals or ions under shock initiation conditions of 2,000 calories/cm[sup 2] or less of energy fluence.

The determination of N-nitrosodiethanolamine (NDELA) at trace levels in shampoos and skin creams by a simple, rapid colorimetric method.

PubMed

Telling, G M; Dunnett, P C

1981-10-01

Synopsis A technique is described for the rapid determination of N-nitrosodiethanolamine (NDELA) in shampoos, skin creams and similar products based on aqueous extraction, partition into ethyl acetate and colorimetric determination using the Eisenbrand-Preussman cleavage reaction. Recoveries of NDELA added at levels of 5-100 mug kg(-1) to a range of shampoo and cream types ranged from 90-101%. The limit of determination for the method is 2.5 mug kg(-1). Observations on the application of a thermal energy analyser linked to a gas chromatograph are also reported. Application of the technique to a survey of a wide range of shampoo and skin cream types showed that levels of total N-nitroso compounds were less than 30 mug kg(-1) in < 90% of samples and, in many cases, less than 2.5 mug kg-1.

Synthesis of Chiral 1,2-Oxazinanes and Isoxazolidines via Nitroso Aldol Reaction of Distal Dialdehydes.

PubMed

Ramakrishna, Isai; Ramaraju, Panduga; Baidya, Mahiuddin

2018-02-16

The first catalytic enantioselective nitroso aldol reaction of distal dialdehydes is reported. The reaction is catalyzed by simple l-proline at room temperature and subsequent reduction delivered biologically potent and synthetically versatile N-O bond containing five- and six-membered heterocycles, 1,2-oxazinanes, and isoxazolidines in high yields and excellent enantioselectivities (up to >99% ee). The method was further exploited to prepare chiral 3-hydroxypiperidines and -pyrrolidines that are otherwise difficult to access.

Evaluation of the in vivo genotoxic potential of three carcinogenic aromatic amines using the Big Blue{trademark} transgenic mouse mutation assay

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suter, W.; Ahiabor, R.; Blanco, B.

Three genotoxic mouse carcinogens, 4-chloro-o-phenylenediamine (4-C-o-PDA), 2-nitro-p-phenylenediamine (2-N-p-PDA), and 2,4-diaminotoluene (2,4-DAT), were tested in the Big Blue{trademark} transgenic mouse mutation assay. Each experiment consisted of a vehicle control group with ten Big Blue{trademark} C57BL/6 mice, five of either sex, and an equally sized group treated with a high dose of the test chemical. In addition, four animals were treated with the vehicle and six animals with the test compound for the measurement of bromodeoxyuridine (BrdU) incorporation to determine cellular proliferation. The doses used in the main study were 200 mg/kg/day for 4-C-o-PDA, 150 mg/kg/day for 2-N-p-PDA, and 80 mg/kg/day formore » 2,4-DAT. There was no increase in BrdU incorporation immediately after treatment with 4-C-o-PDA or with 2,4-DAT. However, 10 days after the last treatment with 2,4-DAT, a strong mitogenic effect was found with both techniques. 4-C-o-PDA, a liver carcinogen in both genders of mice, induced a small, statistically significant increase of the mutant frequencies in females, none in males. 2-N-p-PDA was found positive in males and was clearly negative in females. 2,4-DAT, a liver carcinogen in female mice, was positive in females and negative in males when the animals were killed 10 days after the last treatment. After an expression time of 28 days, 2,4-DAT induced a statistically significant increase in both sexes. The effect in females was marginally stronger than after 10 days` expression time and almost identical to the effect observed in makes under these test conditions. In conclusion, the experiments showed that the Big Blue{trademark} assay detects the genotoxicity of the three carcinogenic monocyclic aromatic amines tested. However, it seems that the sex specificity of the carcinogenic effects of these compounds is not reflected by the mutagenicity data in Big Blue{trademark} mice. 39 refs., 6 tabs.« less

Fluorescence-based recombination assay for sensitive and specific detection of genotoxic carcinogens in human cells.

PubMed

Ireno, Ivanildce C; Baumann, Cindy; Stöber, Regina; Hengstler, Jan G; Wiesmüller, Lisa

2014-05-01

In vitro genotoxicity tests are known to suffer from several shortcomings, mammalian cell-based assays, in particular, from low specificities. Following a novel concept of genotoxicity detection, we developed a fluorescence-based method in living human cells. The assay quantifies DNA recombination events triggered by DNA double-strand breaks and damage-induced replication fork stalling predicted to detect a broad spectrum of genotoxic modes of action. To maximize sensitivities, we engineered a DNA substrate encompassing a chemoresponsive element from the human genome. Using this substrate, we screened various human tumor and non-transformed cell types differing in the DNA damage response, which revealed that detection of genotoxic carcinogens was independent of the p53 status but abrogated by apoptosis. Cell types enabling robust and sensitive genotoxicity detection were selected for the generation of reporter clones with chromosomally integrated DNA recombination substrate. Reporter cell lines were scrutinized with 21 compounds, stratified into five sets according to the established categories for identification of carcinogenic compounds: genotoxic carcinogens ("true positives"), non-genotoxic carcinogens, compounds without genotoxic or carcinogenic effect ("true negatives") and non-carcinogenic compounds, which have been reported to induce chromosomal aberrations or mutations in mammalian cell-based assays ("false positives"). Our results document detection of genotoxic carcinogens in independent cell clones and at levels of cellular toxicities <60 % with a sensitivity of >85 %, specificity of ≥90 % and detection of false-positive compounds <17 %. Importantly, through testing cyclophosphamide in combination with primary hepatocyte cultures, we additionally provide proof-of-concept for the identification of carcinogens requiring metabolic activation using this novel assay system.

New clues on carcinogenicity-related substructures derived from mining two large datasets of chemical compounds.

PubMed

Golbamaki, Azadi; Benfenati, Emilio; Golbamaki, Nazanin; Manganaro, Alberto; Merdivan, Erinc; Roncaglioni, Alessandra; Gini, Giuseppina

2016-04-02

In this study, new molecular fragments associated with genotoxic and nongenotoxic carcinogens are introduced to estimate the carcinogenic potential of compounds. Two rule-based carcinogenesis models were developed with the aid of SARpy: model R (from rodents' experimental data) and model E (from human carcinogenicity data). Structural alert extraction method of SARpy uses a completely automated and unbiased manner with statistical significance. The carcinogenicity models developed in this study are collections of carcinogenic potential fragments that were extracted from two carcinogenicity databases: the ANTARES carcinogenicity dataset with information from bioassay on rats and the combination of ISSCAN and CGX datasets, which take into accounts human-based assessment. The performance of these two models was evaluated in terms of cross-validation and external validation using a 258 compound case study dataset. Combining R and H predictions and scoring a positive or negative result when both models are concordant on a prediction, increased accuracy to 72% and specificity to 79% on the external test set. The carcinogenic fragments present in the two models were compared and analyzed from the point of view of chemical class. The results of this study show that the developed rule sets will be a useful tool to identify some new structural alerts of carcinogenicity and provide effective information on the molecular structures of carcinogenic chemicals.

Solid-supported nitroso hetero Diels-Alder reactions. 1. Acylnitroso dienophiles: scope and limitations.

PubMed

Krchnák, Viktor; Moellmann, Ute; Dahse, Hans-Martin; Miller, Marvin J

2008-01-01

Polymer-supported acylnitroso dienophiles were prepared and used in hetero Diels-Alder (HDA) reactions with a variety of dienes. The transient acylnitroso dienophiles were prepared in situ from immobilized hydroxamates, which were attached to solid supports via several linkers each cleavable by different cleavage reagents, and served for the synthesis of both N-unsubstituted and N-derivatized HDA adducts. Model compounds were used to (i) optimize reaction conditions for solid-supported HDA reactions, (ii) evaluate the outcome of the reactions with various dienes, (iii) compare relative reactivities of dienes, and (iv) assess the stability of HDA adducts toward cleavage conditions typically used in solid-phase syntheses. Cleaved products were submitted to biological assays, and the results are reported. The accompanying paper, focused on complementary arylnitroso HDA reactions, includes a comparison of both HDA reactions.

The carcinogenicity of chromium

PubMed Central

Norseth, Tor

1981-01-01

The carcinogenicity of chromium compounds is reviewed with specific attention to the gaps in knowledge for risk estimation and research needs. The most important problems at present are whether trivalent chromium compounds cause cancer, and whether there is a difference in cancer causing effects between the soluble and the slightly soluble hexavalent compounds in the practical exposure situation. Dose estimates for risk estimation based on epidemiological investigations are also lacking. Present evidence indicates that the trivalent chromium compounds do not cause cancer although high concentrations in some in vitro systems have shown genetic toxicity. Hexavalent chromium compounds cause cancer in humans, in experimental animals and exert genetic toxicity in bacteria and in mammalian cells in vitro. Epidemiological evidence and animal experiments indicate that the slightly soluble hexavalent salts are the most potent carcinogens, but proper identification and characterization of exposure patterns in epidemiological work are lacking. Workers also tend to have mixed exposures. Soluble and slightly soluble salts are equally potent genotoxic agents in vitro. Further work for establishing dose estimates for risk evaluation in epidemiological work is important. In vitro systems should be applied for further identification of the mechanism of the carcinogenic effects, and animal experiments are urgent for comparison of the carcinogenic potency of the different hexavalent salts. Hexavalent chromium salts must be regarded as established carcinogens, and proper action should be taken in all industries with regard to such exposure. At present the carcinogenic risk to the general population caused by chromium compounds seems to be negligible, chromium in cigarettes, however, is an uncertainty in this respect. The amount of chromium and the type of chromium compounds inhaled from cigarettes is not known. PMID:7023928

Hemin potentiates nitric oxide-mediated nitrosation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to 2-nitrosoamino-3-methylimidazo[4,5-f]quinoline.

PubMed

Lakshmi, Vijaya M; Clapper, Margie L; Chang, Wen-Chi; Zenser, Terry V

2005-03-01

Heme has been reported to be an important contributor to endogenous N-nitrosation within the colon and to the enhanced incidence of colon cancer observed with increased intake of red meat. This study uses the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) as a target to evaluate hemin potentiation of nitric oxide (NO)-mediated nitrosation. Formation of 14C-2-nitrosoamino-3-methylimidazo[4,5-f]quinoline (N-NO-IQ) was monitored by HPLC following incubation of 10 microM IQ with the NO donor spermine NONOate (1.2 microM NO/min) at pH 7.4 in the presence or absence of hemin. N-NO-IQ formation due to autoxidation of NO was at the limit of detection (0.1 microM) and increased 22-fold in the presence of 10 microM hemin and an in situ system for generating H2O2 (glucose oxidase/glucose). A linear increase in N-NO-IQ formation was observed from 1 to 10 microM hemin. Significant nitrosamine formation occurred at fluxes of NO and H2O2 as low as 0.024 and 0.25 microM/min, respectively. Potentiation by hemin was not affected by a 400-fold excess flux of H2O2 over NO or a 4.8-fold excess flux of NO over H2O2. Reactive nitrogen species produced by hemin potentiation had a 46-fold greater affinity for IQ than those produced by autoxidation. Azide inhibited autoxidation, suggesting involvement of the nitrosonium ion, NO+. Hemin potentiation was inhibited by NADH, but not azide, suggesting oxidative nitrosylation with NO2* or a NO2*-like species. IQ and 2,3-diaminonaphthylene were much better targets for nitrosation than the secondary amine morpholine. Apc(min) mice with dextran sulfate sodium-induced colitis demonstrated increased levels of urinary nitrite and nitrate consistent with increased expression of iNOS and NO synthesis. As reported previously, identical conditions increased fecal N-nitroso compounds. Thus, hemin potentiation of NO-mediated nitrosation of heterocyclic amines provides a testable mechanism by which red meat consumption can generate N-nitroso compounds and initiate colon cancer under inflammatory conditions, such as colitis.

Local and systemic vasodilatory effects of low molecular weight S-nitrosothiols.

PubMed

Liu, Taiming; Schroeder, Hobe J; Wilson, Sean M; Terry, Michael H; Romero, Monica; Longo, Lawrence D; Power, Gordon G; Blood, Arlin B

2016-02-01

S-nitrosothiols (SNOs) such as S-nitroso-L-cysteine (L-cysNO) are endogenous compounds with potent vasodilatory activity. During circulation in the blood, the NO moiety can be exchanged among various thiol-containing compounds by S-transnitrosylation, resulting in SNOs with differing capacities to enter the cell (membrane permeability). To determine whether the vasodilating potency of SNOs is dependent upon membrane permeability, membrane-permeable L-cysNO and impermeable S-nitroso-D-cysteine (D-cysNO) and S-nitroso-glutathione (GSNO) were infused into one femoral artery of anesthetized adult sheep while measuring bilateral femoral and systemic vascular conductances. L-cysNO induced vasodilation in the infused hind limb, whereas D-cysNO and GSNO did not. L-cysNO also increased intracellular NO in isolated arterial smooth muscle cells, whereas GSNO did not. The infused SNOs remained predominantly in a low molecular weight form during first-passage through the hind limb vasculature, but were converted into high molecular weight SNOs upon systemic recirculation. At systemic concentrations of ~0.6 μmol/L, all three SNOs reduced mean arterial blood pressure by ~50%, with pronounced vasodilation in the mesenteric bed. Pharmacokinetics of L-cysNO and GSNO were measured in vitro and in vivo and correlated with their hemodynamic effects, membrane permeability, and S-transnitrosylation. These results suggest local vasodilation by SNOs in the hind limb requires membrane permeation, whereas systemic vasodilation does not. The systemic hemodynamic effects of SNOs occur after equilibration of the NO moiety amongst the plasma thiols via S-transnitrosylation. Copyright © 2015 Elsevier Inc. All rights reserved.

Synthesis of Difluoroaminoxy-, Difluoroamino- or Fluorodiazonium-Containing Materials.

DTIC Science & Technology

1987-01-30

the olefin. The cyclic nitroso compounds underwent thermal decomposition at 165 OC in Pyrex glass to form colorless nitro derivatives. 1,2...absence of glass , (perfluorocvcloaikvl)difluoroamines, e.g., (DNF2 , formed. All of the new compounds are stable at 25 "C and are hvdrolvticallv stable...extended periods in Pyrex glass at 25 OC. Strong vibrational bands in the Raman spectra at 7󈧶 cm r were assigned to v__ H. Carbonvl fluoride as a

Evaluation of advanced bladder technology

NASA Technical Reports Server (NTRS)

Christensen, M. V.; Pasternak, R. A.

1972-01-01

Research conducted during this period is reported. Studies presented include: (1) diffusion and permeation of CO2, O2, N2, and NO2 through polytetra fluoroethylene; (2) diffusion, permeation and solubility of simple gases (CO2, O2, N2, CH4, C2H6, C3H8, and C2H4) through a copolymer of hexafluoro propylene and tetrafluoro ethylene (FEP); (3) viscous flow and diffusion of gases throug small apertures; (4) diffusion and permeation of O2, N2, CO2, CH4, C2H6, and C3H8 through nitroso rubber; and (5) results of gas transport studies with carborane siloxane, nitroso rubber, silicone membrane, krytox coating on teflon, and FEP coated glass cloth. Publications generated under this program are listed.

Comparative Genotoxicity and Cytotoxicity of Four Hexavalent Chromium Compounds in Human Bronchial Cells

PubMed Central

Wise, Sandra S.; Holmes, Amie L.; Qin, Qin; Xie, Hong; Katsifis, Spiros P.; Thompson, W. Douglas; Wise, John Pierce

2010-01-01

Hexavalent chromium (Cr(VI)) compounds are well-established human lung carcinogens. Solubility plays an important role in their carcinogenicity with the particulate Cr(VI) compounds being the most carcinogenic. Epidemiology and animal studies suggest that zinc chromate is the most potent particulate Cr(VI) compound, however, there are few comparative data to support these observations. The purpose of this study was to compare the genotoxicity of zinc chromate with two other particulate Cr(VI) compounds, barium chromate and lead chromate, and one soluble Cr(VI) compound, sodium chromate. The clastogenic effects of barium chromate and zinc chromate were similar but lead chromate induced significantly less damage. The levels of DNA damage measured by gamma-H2A.X foci formation were similar for the three particulate chromium compounds. Corrected for chromium uptake differences, we found that zinc chromate and barium chromate were the most cytotoxic and lead chromate and sodium chromate were less cytotoxic. Zinc chromate was more clastogenic than all other chromium compounds and lead chromate was the least clastogenic. There was no significant difference between any of the compounds for the induction of DNA double strand breaks. All together, these data suggest that the difference in the carcinogenic potency of zinc chromate over the other chromium compounds is not due solely to a difference in chromium ion uptake and the zinc cation may in fact have an important role in its carcinogenicity. PMID:20000473

Preclinical studies of steroid-linked nitrosoureas in murine pancreatic adenocarcinoma PANO2.

PubMed

Papageorgiou, A; Lialiaris, Th; Stergiou, E; Stergiou, I; Tsigris, C; Kourti, A; Geromichalos, G; Stravoravdi, P; Trafalis, D; Athanassiou, A E; Pitsas, A; Camoutsis, Ch

2008-01-01

In earlier studies, this laboratory carried out research on the synthesis and anticancer evaluation of hybrid compounds, which combine two molecules in one such as homo-aza-steroidal esters (HASE) of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline. In this combination, steroidal hormones are employed as carriers for transporting the alkylating agents to specific targeted tissues. Aiming to continue our research, we used alkylating agents, as nitrosoureas, instead of nitrogen mustards. In this work the N-[N- (2-chloroethyl)-N-nitroso-carbomoyl]-L-alanine (CNC-ala) has been used and was bound to 7 newly synthesized modified steroidal esters (carrier molecule) of nitrosourea and the hybrid molecules were tested for antitumor activity against PANO2 murine pancreatic adenocarcinoma. PANO2 adenocarcinoma was used in this study. C57Bl mice were used for chemotherapy evaluation. The activity was assessed from the inhibition of tumor growth and the oncostatic parameter T/C %. The antitumor activity displayed by 7 hybrid steroidal esters of nitrosourea was quite interesting. It was able to discern 4 of 7 compounds that exhibited considerable antitumor activity, increasing the lifespan of the tumor-bearing mice by inhibiting the tumor growth. The comparative study of 7 newly synthesized hybrid steroidal esters of nitrosourea shows that the antitumor effects of compound 7, which has an enlarged (7 carbon atoms) A-lactamic ring and nitrosourea esterified at the position 17, which seems to be the most appropriate for the connection of a DNA cross-linking amino acid derivative is superior.

Detection of endogenous DNA adducts, O-carboxymethyl-2'-deoxyguanosine and 3-ethanesulfonic acid-2'-deoxycytidine, in the rat stomach after duodenal reflux.

PubMed

Terasaki, Masaru; Totsuka, Yukari; Nishimura, Koichi; Mukaisho, Ken-Ichi; Chen, Kuan-Hao; Hattori, Takanori; Takamura-Enya, Takeji; Sugimura, Takashi; Wakabayashi, Keiji

2008-09-01

The endogenous DNA adducts O(6)-carboxymethyl-deoxyguanosine (O(6)-CM-dG) and 3-ethanesulfonic acid-deoxycytidine (3-ESA-dC) are produced from N-nitroso bile acid conjugates, such as N-nitrosoglycocholic acid (NO-GCA) and N-nitrosotaurocholic acid (NO-TCA), respectively. Formation of these DNA adducts in vivo was here analyzed by 32P-postlabeling in the glandular stomach of rats subjected to duodenal content reflux surgery. In this model, all duodenal contents, including bile acid conjugates, flow back from the jejunum into the gastric corpus. The levels of O(6)-CM-dG found at 4 and 8 weeks after surgery were 40.9 +/- 9.4 and 56.3 +/- 3.2 per 10(8) nucleotides, respectively, whereas the sham operation groups had values of 5.8 +/- 2.3 and 5.9 +/- 0.5 per 10(8) nucleotides. Moreover, adduct spots corresponding to 3-ESA-dC were detected in both duodenal reflux and sham operation groups and levels in the duodenal reflux groups were around four-fold elevated at 11.2 +/- 1.0 and 8.9 +/- 1.0 per 10(8) nucleotides after 4 and 8 weeks, respectively. When the duodenal reflux animals were treated with a nitrite trapping agent, thiazolidine- 4-carboxylic acid (thioproline, TPRO), the levels of O(6)-CM-dG and 3-ESA-dC were reduced to the same levels as in the sham operation animals. These observations suggest that NO-TCA and NO-GCA are formed by nitrosation of glycocholic acid and taurocholic acid, respectively, and these nitroso compounds produce DNA adducts in the glandular stomach of rats subjected to duodenal content reflux surgery.

Control of NO concentration in solutions of nitrosothiol compounds by light.

PubMed

Zhelyaskov, V R; Gee, K R; Godwin, D W

1998-03-01

We studied the thermal and photolytic decomposition of two S-nitrosothiols, S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylpenicillamine (SNAP), in water or propanol solutions. A "concentration clamp" (relatively constant concentration of NO as a function of time) could be implemented in a closed volume by varying the pH, concentration of nitrovasodilator and intensity of the light source. Depending on the conditions, the light either stimulated NO release or sharply decreased NO concentration in the test solutions. Changes in the absorption spectra of GSNO solutions were monitored as a function of light exposure. Generation of superoxide as a product of a photolytic decomposition reaction of S-nitrosothiols and further oxidation of NO is the most likely mechanism for light suppression of NO concentration.

Foods and risk of bladder cancer: a case-control study in Uruguay.

PubMed

Balbi, J C; Larrinaga, M T; De Stefani, E; Mendilaharsu, M; Ronco, A L; Boffetta, P; Brennan, P

2001-10-01

A case-control study on 144 cases of transitional cell bladder carcinoma and 576 hospitalized controls was conducted in Montevideo, Uruguay. Barbecued meat, salted meat and fried eggs were associated with significant increased risks of bladder cancer (odds ratio (OR) for high intake of salted meat 4.04, 95% confidence interval (CI) 2.24-7.27). On the other hand, all fruits, cooked vegetables, potatoes and cheese were associated with inverse associations (OR for high consumption of potatoes 0.38, 95% CI 0.23-0.64). The associations with salted and barbecued meat suggest that the way of preserving or cooking meat play a role in bladder carcinogenesis. More precisely, N-nitroso compounds and heterocyclic amines could be involved in this process.

Induction of mutagenesis and transformation in BALB/c-3T3 clone A31-1 cells by diverse chemical carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lubet, R.A.; Kouri, R.E.; Curren, R.A.

1990-01-01

BALB/c-3T3 cells were employed to examine the genotoxic potential of a variety of known chemical carcinogens. BALB/c-3T3 cells displayed a dose-dependent transformation response to a variety of carcinogens (polycyclic hydrocarbons, methylating agents, ethylating agents, aflatoxin B{sub 1} (AFT{sub 1}), and 4-nitroquinoline-N-oxide (4-NQO)). When the ability of these compounds to induce mutagenesis to resistance to the cardiac glycoside ouabain (OUA{sup R}) was examined, the authors found the short chain alkylating agents to be particularly effective mutagens, causing biologic effects at doses below those necessary to induce a transformation response. In contrast, the polycyclic hydrocarbons which were potent transforming agents were weaker,more » albeit significant, mutagens for the OUA{sup R} locus in this system, while AFB{sub 1} was quite weak. Further studies were performed with 5-azacytidine (5-AZA) and the nongenotoxic carcinogen cinnamyl anthranilate (CIN). 5-AZA was a potent transforming agent, but failed to cause mutagenesis. CIN similarly caused in vitro transformation. When a series of eight structurally diverse compounds were examined in both the BALB/c-3T3 and C3H10T1/2 mouse fibroblast transformation systems, the BALB/c-3T3 system was shown to be sensitive to a wide variety of potential carcinogens, whereas the C3H10T1/2 system proved routinely sensitive only to the polycyclic hydrocarbons.« less

Investigating the different mechanisms of genotoxic and non-genotoxic carcinogens by a gene set analysis.

PubMed

Lee, Won Jun; Kim, Sang Cheol; Lee, Seul Ji; Lee, Jeongmi; Park, Jeong Hill; Yu, Kyung-Sang; Lim, Johan; Kwon, Sung Won

2014-01-01

Based on the process of carcinogenesis, carcinogens are classified as either genotoxic or non-genotoxic. In contrast to non-genotoxic carcinogens, many genotoxic carcinogens have been reported to cause tumor in carcinogenic bioassays in animals. Thus evaluating the genotoxicity potential of chemicals is important to discriminate genotoxic from non-genotoxic carcinogens for health care and pharmaceutical industry safety. Additionally, investigating the difference between the mechanisms of genotoxic and non-genotoxic carcinogens could provide the foundation for a mechanism-based classification for unknown compounds. In this study, we investigated the gene expression of HepG2 cells treated with genotoxic or non-genotoxic carcinogens and compared their mechanisms of action. To enhance our understanding of the differences in the mechanisms of genotoxic and non-genotoxic carcinogens, we implemented a gene set analysis using 12 compounds for the training set (12, 24, 48 h) and validated significant gene sets using 22 compounds for the test set (24, 48 h). For a direct biological translation, we conducted a gene set analysis using Globaltest and selected significant gene sets. To validate the results, training and test compounds were predicted by the significant gene sets using a prediction analysis for microarrays (PAM). Finally, we obtained 6 gene sets, including sets enriched for genes involved in the adherens junction, bladder cancer, p53 signaling pathway, pathways in cancer, peroxisome and RNA degradation. Among the 6 gene sets, the bladder cancer and p53 signaling pathway sets were significant at 12, 24 and 48 h. We also found that the DDB2, RRM2B and GADD45A, genes related to the repair and damage prevention of DNA, were consistently up-regulated for genotoxic carcinogens. Our results suggest that a gene set analysis could provide a robust tool in the investigation of the different mechanisms of genotoxic and non-genotoxic carcinogens and construct a more detailed understanding of the perturbation of significant pathways.

Investigating the Different Mechanisms of Genotoxic and Non-Genotoxic Carcinogens by a Gene Set Analysis

PubMed Central

Lee, Won Jun; Kim, Sang Cheol; Lee, Seul Ji; Lee, Jeongmi; Park, Jeong Hill; Yu, Kyung-Sang; Lim, Johan; Kwon, Sung Won

2014-01-01

Based on the process of carcinogenesis, carcinogens are classified as either genotoxic or non-genotoxic. In contrast to non-genotoxic carcinogens, many genotoxic carcinogens have been reported to cause tumor in carcinogenic bioassays in animals. Thus evaluating the genotoxicity potential of chemicals is important to discriminate genotoxic from non-genotoxic carcinogens for health care and pharmaceutical industry safety. Additionally, investigating the difference between the mechanisms of genotoxic and non-genotoxic carcinogens could provide the foundation for a mechanism-based classification for unknown compounds. In this study, we investigated the gene expression of HepG2 cells treated with genotoxic or non-genotoxic carcinogens and compared their mechanisms of action. To enhance our understanding of the differences in the mechanisms of genotoxic and non-genotoxic carcinogens, we implemented a gene set analysis using 12 compounds for the training set (12, 24, 48 h) and validated significant gene sets using 22 compounds for the test set (24, 48 h). For a direct biological translation, we conducted a gene set analysis using Globaltest and selected significant gene sets. To validate the results, training and test compounds were predicted by the significant gene sets using a prediction analysis for microarrays (PAM). Finally, we obtained 6 gene sets, including sets enriched for genes involved in the adherens junction, bladder cancer, p53 signaling pathway, pathways in cancer, peroxisome and RNA degradation. Among the 6 gene sets, the bladder cancer and p53 signaling pathway sets were significant at 12, 24 and 48 h. We also found that the DDB2, RRM2B and GADD45A, genes related to the repair and damage prevention of DNA, were consistently up-regulated for genotoxic carcinogens. Our results suggest that a gene set analysis could provide a robust tool in the investigation of the different mechanisms of genotoxic and non-genotoxic carcinogens and construct a more detailed understanding of the perturbation of significant pathways. PMID:24497971

Nitrite curing of chicken, pork, and beef inhibits oxidation but does not affect N-nitroso compound (NOC)-specific DNA adduct formation during in vitro digestion.

PubMed

Van Hecke, Thomas; Vanden Bussche, Julie; Vanhaecke, Lynn; Vossen, Els; Van Camp, John; De Smet, Stefaan

2014-02-26

Uncured and nitrite-cured chicken, pork, and beef were used as low, medium, and high sources of heme-Fe, respectively, and exposed to an in vitro digestion model simulating the mouth, stomach, duodenum, and colon. With increasing content of iron compounds, up to 25-fold higher concentrations of the toxic lipid oxidation products malondialdehyde, 4-hydroxy-2-nonenal, and other volatile aldehydes were formed during digestion, together with increased protein carbonyl compounds as measurement of protein oxidation. Nitrite curing of all meats lowered lipid and protein oxidation to the level of oxidation in uncured chicken. Strongly depending on the individual fecal inoculum, colonic digestion of beef resulted in significantly higher concentrations of the NOC-specific DNA adduct O(6)-carboxymethyl-guanine compared to chicken and pork, whereas nitrite curing had no significant effect. This study confirms previously reported evidence that heme-Fe is involved in the epidemiological association between red meat consumption and colorectal cancer, but questions the role of nitrite curing in this association.

The expression of xenobiotic-metabolizing enzymes in human prostate and in prostate epithelial cells (PECs) derived from primary cultures.

PubMed

Al-Buheissi, S Z; Cole, K J; Hewer, A; Kumar, V; Bryan, R L; Hudson, D L; Patel, H R; Nathan, S; Miller, R A; Phillips, D H

2006-06-01

Dietary heterocyclic amines (HCAs) are carcinogenic in rodent prostate requiring activation by enzymes such as cytochrome P450 (CYP) and N-acetyltransferase (NAT). We investigated by Western blotting and immunohistochemistry the expression of CYP1A1, CYP1A2, and NAT1 in human prostate and in prostate epithelial cells (PECs) derived from primary cultures and tested their ability to activate the dietary carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and its N-hydroxy metabolite (N-OH-IQ) to DNA-damaging moieties. Western blotting identified CYP1A1, CYP1A2, and NAT1. Immunohistochemistry localized NAT1 to the cytoplasm of PECs. Inter-individual variation was observed in the expression levels of CYP1A1, 1A2, and NAT1 (11, 75, and 35-fold, respectively). PECs expressed CYP1A1 and NAT1 but not CYP1A2. When incubated with IQ or N-OH-IQ, PECs formed DNA adducts indicating their ability to metabolically activate these compounds. Prostate cells possess the capacity to activate dietary carcinogens. PECs may provide a useful model system to study their role in prostate carcinogenesis.

Genomic Models of Short-Term Exposure Accurately Predict Long-Term Chemical Carcinogenicity and Identify Putative Mechanisms of Action

PubMed Central

Gusenleitner, Daniel; Auerbach, Scott S.; Melia, Tisha; Gómez, Harold F.; Sherr, David H.; Monti, Stefano

2014-01-01

Background Despite an overall decrease in incidence of and mortality from cancer, about 40% of Americans will be diagnosed with the disease in their lifetime, and around 20% will die of it. Current approaches to test carcinogenic chemicals adopt the 2-year rodent bioassay, which is costly and time-consuming. As a result, fewer than 2% of the chemicals on the market have actually been tested. However, evidence accumulated to date suggests that gene expression profiles from model organisms exposed to chemical compounds reflect underlying mechanisms of action, and that these toxicogenomic models could be used in the prediction of chemical carcinogenicity. Results In this study, we used a rat-based microarray dataset from the NTP DrugMatrix Database to test the ability of toxicogenomics to model carcinogenicity. We analyzed 1,221 gene-expression profiles obtained from rats treated with 127 well-characterized compounds, including genotoxic and non-genotoxic carcinogens. We built a classifier that predicts a chemical's carcinogenic potential with an AUC of 0.78, and validated it on an independent dataset from the Japanese Toxicogenomics Project consisting of 2,065 profiles from 72 compounds. Finally, we identified differentially expressed genes associated with chemical carcinogenesis, and developed novel data-driven approaches for the molecular characterization of the response to chemical stressors. Conclusion Here, we validate a toxicogenomic approach to predict carcinogenicity and provide strong evidence that, with a larger set of compounds, we should be able to improve the sensitivity and specificity of the predictions. We found that the prediction of carcinogenicity is tissue-dependent and that the results also confirm and expand upon previous studies implicating DNA damage, the peroxisome proliferator-activated receptor, the aryl hydrocarbon receptor, and regenerative pathology in the response to carcinogen exposure. PMID:25058030

Delayed myelosuppression with acute exposure to hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and environmental degradation product hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) in rats.

PubMed

Jaligama, Sridhar; Kale, Vijay M; Wilbanks, Mitchell S; Perkins, Edward J; Meyer, Sharon A

2013-02-01

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a widely used munitions compound, and hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), its N-nitroso product of anaerobic microbial nitroreduction, are contaminants of military sites. Previous studies have shown MNX to be the most acutely toxic among the nitroreduced degradation products of RDX and to cause mild anemia at high dose. The present study compares hematotoxicity with acute oral exposure to MNX with parent RDX. Both RDX and MNX caused a modest decrease in blood hemoglobin and ~50% loss of granulocytes (NOAELs=47 mg/kg) in female Sprague-Dawley rats observed 14 days post-exposure. We explored the possibility that blood cell loss observed after 14 days was delayed in onset because of toxicity to bone marrow (BM) progenitors. RDX and MNX decreased granulocyte/macrophage-colony forming cells (GM-CFCs) at 14, but not 7, days (NOAELs=24 mg/kg). The earliest observed time at which MNX decreased GM-CFCs was 10 days post-exposure. RDX and MNX likewise decreased BM burst-forming units-erythroid (BFU-Es) at 14, but not 7, days. Granulocyte-erythrocyte-monocyte-megakaryocyte (GEMM)-CFCs were unaffected by RDX and MNX at 7 days suggesting precursor depletion did not account for GM-CFC and BFU-E loss. MNX added to the culture media was without effect on GM-CFC formation indicating no direct inhibition. Flow cytometry showed no differential loss of BM multilineage progenitors (Thy1.1(+)) or erythroid (CD71(+)) precursors with MNX suggesting myeloid and erythroid lineages were comparably affected. Collectively, these data indicate that acute exposure to both RDX and MNX caused delayed suppression of myelo- and erythropoiesis with subsequent decrease of peripheral granulocytes and erythrocytes. Copyright © 2012 Elsevier Inc. All rights reserved.

Calcium and α-tocopherol suppress cured-meat promotion of chemically induced colon carcinogenesis in rats and reduce associated biomarkers in human volunteers123

PubMed Central

Martin, Océane CB; Santarelli, Raphaelle L; Taché, Sylviane; Naud, Nathalie; Guéraud, Françoise; Audebert, Marc; Dupuy, Jacques; Meunier, Nathalie; Attaix, Didier; Vendeuvre, Jean-Luc; Mirvish, Sidney S; Kuhnle, Gunter CG; Cano, Noel; Corpet, Denis E

2013-01-01

Background: Processed meat intake has been associated with increased colorectal cancer risk. We have shown that cured meat promotes carcinogen-induced preneoplastic lesions and increases specific biomarkers in the colon of rats. Objectives: We investigated whether cured meat modulates biomarkers of cancer risk in human volunteers and whether specific agents can suppress cured meat–induced preneoplastic lesions in rats and associated biomarkers in rats and humans. Design: Six additives (calcium carbonate, inulin, rutin, carnosol, α-tocopherol, and trisodium pyrophosphate) were added to cured meat given to groups of rats for 14 d, and fecal biomarkers were measured. On the basis of these results, calcium and tocopherol were kept for the following additional experiments: cured meat, with or without calcium or tocopherol, was given to dimethylhydrazine-initiated rats (47% meat diet for 100 d) and to human volunteers in a crossover study (180 g/d for 4 d). Rat colons were scored for mucin-depleted foci, putative precancer lesions. Biomarkers of nitrosation, lipoperoxidation, and cytotoxicity were measured in the urine and feces of rats and volunteers. Results: Cured meat increased nitroso compounds and lipoperoxidation in human stools (both P < 0.05). Calcium normalized both biomarkers in rats and human feces, whereas tocopherol only decreased nitro compounds in rats and lipoperoxidation in feces of volunteers (all P < 0.05). Last, calcium and tocopherol reduced the number of mucin-depleted foci per colon in rats compared with nonsupplemented cured meat (P = 0.01). Conclusion: Data suggest that the addition of calcium carbonate to the diet or α-tocopherol to cured meat may reduce colorectal cancer risk associated with cured-meat intake. This trial was registered at clinicaltrials.gov as NCT00994526. PMID:24025632

Chicken Fetal Liver DNA Damage and Adduct Formation by Activation-Dependent DNA-Reactive Carcinogens and Related Compounds of Several Structural Classes

PubMed Central

Williams, Gary M.; Duan, Jian-Dong; Brunnemann, Klaus D.; Iatropoulos, Michael J.; Vock, Esther; Deschl, Ulrich

2014-01-01

The chicken egg genotoxicity assay (CEGA), which utilizes the liver of an intact and aseptic embryo-fetal test organism, was evaluated using four activation-dependent DNA-reactive carcinogens and four structurally related less potent carcinogens or non-carcinogens. In the assay, three daily doses of test substances were administered to eggs containing 9–11-day-old fetuses and the fetal livers were assessed for two endpoints, DNA breaks using the alkaline single cell gel electrophoresis (comet) assay and DNA adducts using the 32P-nucleotide postlabeling (NPL) assay. The effects of four carcinogens of different structures requiring distinct pathways of bioactivation, i.e., 2-acetylaminofluorene (AAF), aflatoxin B1 (AFB1), benzo[a]pyrene (B[a]P), and diethylnitrosamine (DEN), were compared with structurally related non-carcinogens fluorene (FLU) and benzo[e]pyrene (B[e]P) or weak carcinogens, aflatoxin B2 (AFB2) and N-nitrosodiethanolamine (NDELA). The four carcinogens all produced DNA breaks at microgram or low milligram total doses, whereas less potent carcinogens and non-carcinogens yielded borderline or negative results, respectively, at higher doses. AAF and B[a]P produced DNA adducts, whereas none was found with the related comparators FLU or B[e]P, consistent with comet results. DEN and NDELA were also negative for adducts, as expected in the case of DEN for an alkylating agent in the standard NPL assay. Also, AFB1 and AFB2 were negative in NPL, as expected, due to the nature of ring opened aflatoxin adducts, which are resistant to enzymatic digestion. Thus, the CEGA, using comet and NPL, is capable of detection of the genotoxicity of diverse DNA-reactive carcinogens, while not yielding false positives for non-carcinogens. PMID:24973097

Kinetics and mechanism of S-nitrosothiol acid-catalyzed hydrolysis: sulfur activation promotes facile NO+ release.

PubMed

Moran, Ernesto E; Timerghazin, Qadir K; Kwong, Elizabeth; English, Ann M

2011-03-31

The denitrosation of three primary S-nitrosothiols (RSNO; S-nitrosocysteine, S-nitroso-N-acetylcysteine, and S-nitrosoglutathione) and two tertiary RSNOs (S-nitrosopenicillamine and S-nitroso-N-acetylpenicillamine) was investigated in 3.75 M H(2)SO(4) to probe the mechanism of acid-catalyzed RSNO hydrolysis and its dependence on RSNO structure. This reversible reaction was forced to proceed in the denitrosation direction by trapping the nitrosating agent with HN(3). The primary RSNOs exhibited hydrolysis k(obs) values of ∼2 × 10(-4) s(-1), and the tertiary RSNO k(obs) values were an order of magnitude higher. Product analysis by HPLC revealed that the parent thiols (RSHs) were formed in 90-100% yield on 79-99% RSNO denitrosation. Possible hydrolysis mechanisms were studied computationally at the CBS-QB3 level using S-nitrosomethanethiol (MeSNO) as a model RSNO. Consideration of RSNOs as a combination of conventional R-S-N═O, zwitterionic R-S(+)═N-O(-), and RS(-)/NO(+) ion-pair resonance structures was key in understanding the mechanistic details of acid-catalyzed hydrolysis. Protonation of the S-nitroso oxygen or nitrogen activates the sulfur and nucleophilic attack by H(2)O at this atom leads to the formation of the sulfoxide-protonated N-hydroxysulfinamide, MeS(+)(OH)NHOH, with barriers of 19 and 29 kcal/mol, respectively. Proton loss and reprotonation at the nitrogen lead to secondary hydrolysis that produces the sulfinic acid MeS(═O)OH and NH(2)OH. Notably, no low-energy RSNO hydrolysis pathway for HNO release was found in the computational analysis. Protonation of the S-nitroso sulfur gives rise to NO(+) release with a low activation barrier (ΔH(double dagger)(calc) ≈ 6 kcal/mol) and the formation of MeSH in agreement with experiment. The experimental k(obs) can be expressed as K(a)k(1), where K(a) is the acid dissociation constant for protonation of the S-nitroso sulfur and k(1) the pseudo-first-order hydrolysis rate constant. Given the low ΔH(double dagger)(calc) for denitrosation of the S-protonated isomer, the observed slow rates of acid-catalyzed RSNO hydrolysis must be controlled by the magnitude of K(a). The 10-fold higher K(a) calculated for Me(3)CS(H(+))NO (∼10(-15)) compared to MeS(H(+))NO (10(-16)) is consistent with the order of magnitude larger k(obs) reported here for the tertiary vs primary RSNOs.

Genotoxicity of a Low-Dose Nitrosamine Mixture as Drinking Water Disinfection Byproducts in NIH3T3 Cells.

PubMed

Wang, Hai-Yan; Qin, Ming; Dong, Lei; Lv, Jia-Ying; Wang, Xia

2017-01-01

N - nitrosamines (NAms), which can arise as byproducts of disinfection agents, are reportedly found in drinking water, and their potential carcinogenicity is a concern; however, little research exists regarding the genotoxicity or carcinogenicity of NAms exposure as a low-dose mixture. The three most common NAms components in China's drinking water are N -nitrosodimethylamine (NDMA), N -nitrosodiethylamine (NDEA) and N -nitrosomethylethylamine (NMEA). Thus, we measured the genotoxic and carcinogenic potential of these compounds and measured the cell cycle and gene expression. The data show that exposure to the NAms-mixture doubled the revertants in the TA98 and TA100 S. typhimurium strains and increased the DNA double-strand breaks and the micronuclear frequency in the NIH3T3 cells compared to a single exposure. After long-term NAms mixture exposure, a malignant transformation of NIH3T3 and a significantly increased G2/M distribution were observed. Furthermore, P53, CDK1, P38, CDC25A and CyclinB expressions were down-regulated in the NAms-mixture exposure group; however, P21 and GADD45A genes were up-regulated. Interestingly, the CHK1/CHK2 and CDC25A genes had two responses, depending on the NAms concentrations. Thus, we observed mutagenic, genotoxic and carcinogenic effects after a low-dose NAms-mixture exposure in drinking water, and DNA repair and apoptosis pathways may contribute to these adverse effects.

Genotoxicity of a Low-Dose Nitrosamine Mixture as Drinking Water Disinfection Byproducts in NIH3T3 Cells

PubMed Central

Wang, Hai-yan; Qin, Ming; Dong, Lei; Lv, Jia-ying; Wang, Xia

2017-01-01

N-nitrosamines (NAms), which can arise as byproducts of disinfection agents, are reportedly found in drinking water, and their potential carcinogenicity is a concern; however, little research exists regarding the genotoxicity or carcinogenicity of NAms exposure as a low-dose mixture. The three most common NAms components in China's drinking water are N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and N-nitrosomethylethylamine (NMEA). Thus, we measured the genotoxic and carcinogenic potential of these compounds and measured the cell cycle and gene expression. The data show that exposure to the NAms-mixture doubled the revertants in the TA98 and TA100 S. typhimurium strains and increased the DNA double-strand breaks and the micronuclear frequency in the NIH3T3 cells compared to a single exposure. After long-term NAms mixture exposure, a malignant transformation of NIH3T3 and a significantly increased G2/M distribution were observed. Furthermore, P53, CDK1, P38, CDC25A and CyclinB expressions were down-regulated in the NAms-mixture exposure group; however, P21 and GADD45A genes were up-regulated. Interestingly, the CHK1/CHK2 and CDC25A genes had two responses, depending on the NAms concentrations. Thus, we observed mutagenic, genotoxic and carcinogenic effects after a low-dose NAms-mixture exposure in drinking water, and DNA repair and apoptosis pathways may contribute to these adverse effects. PMID:28924367

Synthesis and bacterial metabolism of cis- and trans-2-alkyl analogues of sodium cyclamate.

PubMed

Wiley, R A; Pearson, D A; Schmidt, V; Wesche, S B; Roxon, J J

1983-07-01

Sodium cyclamate is an effective artificial sweetner, which has been banned from the U.SD. market because of alleged carcinogenic properties. It appears that cyclohexylamine, liberated from cyclamate as a result of bacterial mtabolism, is the proximate carcinogen. In an effort to elucidate the extent to which analogues of cyclamate would enter into the bacterial metabolic pathway, as well as any stereochemical requirements which might exist, several 2-alkaly analogues of sodium cyclamate were prepared. It was found that trans-N-(2-methylcyclohexyl)sulfamate (trans-2a) and trans-N-(2-ethylcyclohexyl)sulfamate were hydrolyzed by freshly collected fecal suspensions from rats fed cyclamate, but not from control rats, at the same rate as cyclamate itself. trans-N-(2-Isopropylcyclohexyl)sulfamate (trans-2c) was not hydrolyzed at all. Surprisingly, two of the analogous cis compounds (cis-2a and cis-2c, respectively) were hydrolyzed by fecal suspensions from control, as well as from cyclamate-fed, rats. Moreover, cis-2a was hydrolyzed by incubating it in medium only. Thus, it is apparent that stereochemical influences on the chemical properties of these compounds are substantial. These results do not appear to point the way toward a safe, nonmetabolizable sweetening agent.

Synthesis, crystal structure determination, biological screening and docking studies of N1-substituted derivatives of 2,3-dihydroquinazolin-4(1H)-one as inhibitors of cholinesterases.

PubMed

Sultana, Nargis; Sarfraz, Muhammad; Tanoli, Saba Tahir; Akram, Muhammad Safwan; Sadiq, Abdul; Rashid, Umer; Tariq, Muhammad Ilyas

2017-06-01

Pursuing the strategy of developing potent AChE inhibitors, we attempted to carry out the N 1 -substitution of 2,3-dihydroquinazolin-4(1H)-one core. A set of 32 N-alkylated/benzylated quinazoline derivatives were synthesized, characterized and evaluated for their inhibition against cholinesterases. N-alkylation of the series of the compounds reported previously (N-unsubstituted) resulted in improved activity. All the compounds showed inhibition of both enzymes in the micromolar to submicromolar range. Structure activity relationship (SAR) of the 32 derivatives showed that N-benzylated compounds possess good activity than N-alkylated compounds. N-benzylated compounds 2ad and 2af were found very active with their IC 50 values toward AChE in submicromolar range (0.8µM and 0.6µM respectively). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. Computational predictions of ADMET studies reveal that all the compounds have good pharmacokinetic properties with no AMES toxicity and carcinogenicity. Moreover, all the compounds are predicted to be absorbed in human intestine and also have the ability to cross blood brain barrier. Overall, the synthesized compounds have established a structural foundation for the design of new inhibitors of cholinesterase. Copyright © 2017 Elsevier Inc. All rights reserved.

Binding effect of polychlorinated compounds and environmental carcinogens on rice bran fiber.

PubMed

Sera, Nobuyuki; Morita, Kunimasa; Nagasoe, Masami; Tokieda, Hisako; Kitaura, Taeko; Tokiwa, Hiroshi

2005-01-01

To accelerate the fecal excretion of polycyclic biphenyl (PCB), polychlorinated dibenzofurans (PCDFs), polychlorinated-p-dioxines (PCDDs) and various mutagens and carcinogens, their binding effect on rice bran fiber (RBF) was investigated for nine heterocyclic amines, six nitroarenes, 4-nitroquinoline-N-oxide, benzo[a]pyrene, furylfuramide, two kinds of flavonoid compounds and formaldehyde and ascorbic acid. PCBs, PCDFs and PCDDs suspended in nonane were incubated with RBF (10 mg/ml) at 37 degrees C and after centrifugation, unbound chemicals in the supernatant were analyzed by high-performance liquid chromatography (HPLC) and gas chromatography (GC). The binding effects on RBF were enhanced more than other dietary fibers (DFs), which were tested including corn, wheat bran, spinach, Hijiki (a kind of seaweed), sweet potatoes and burdock fibers. It was found that the binding effects were related to lignin contents. Binding of 3-amino-1(or 1,4)-dimethyl-5H-pyrido[4,3-b]indole (Trp-p-1 and Trp-p-2), food-derived carcinogens and 1-nitropyrene (1-NP), suspended in methanol, to RBF occurred within 10 min of incubation at 37 degrees C at pH 5-7, and decreased below pH 4; binding of food-derived carcinogens was pH dependent. The binding effects to RBF and pulp lignin were obtained at ratio of over 90%, while corn fiber and cellulose were at ratios of 4-30%. Polycyclic aromatic compounds were related to the number of rings, showing high binding effects to chemical structures with triple rings. Binding of 1-NP and PCB to RBF was not influenced in any aerobic and anaerobic bacterial cultures. It was also found that RBF was capable of binding even conjugates containing mutagens such as glucuronides and sulfates, as well as metabolites in urine. It was suggested, therefore, that mutagens and carcinogens were available for the fecal excretion of residual chemicals and their metabolites, and also for the fecal excretion of PCBs, PCDFs and related compound residues in patients of Yusho disease, who suffered food poisoning due to rice oil contaminated with PCB in Japan.

Determination of traces of cobalt in soils: A field method

USGS Publications Warehouse

Almond, H.

1953-01-01

The growing use of geochemical prospecting methods in the search for ore deposits has led to the development of a field method for the determination of cobalt in soils. The determination is based on the fact that cobalt reacts with 2-nitroso-1-naphthol to yield a pink compound that is soluble in carbon tetrachloride. The carbon tetrachloride extract is shaken with dilute cyanide to complex interfering elements and to remove excess reagent. The cobalt content is estimated by comparing the pink color in the carbon tetrachloride with a standard series prepared from standard solutions. The cobalt 2-nitroso-1-naphtholate system in carbon tetrachloride follows Beer's law. As little as 1 p.p.m. can be determined in a 0.1-gram sample. The method is simple and fast and requires only simple equipment. More than 40 samples can be analyzed per man-day with an accuracy within 30% or better.

Safety Assessment of Diethanolamine and Its Salts as Used in Cosmetics.

PubMed

Fiume, Monice M; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of diethanolamine and its salts as used in cosmetics. Diethanolamine functions as a pH adjuster; the 16 salts included in this rereview reportedly function as surfactants, emulsifying agents, viscosity increasing agents, hair or skin conditioning agents, foam boosters, or antistatic agents. The Panel reviewed available animal and clinical data, as well as information from previous CIR reports. Since data were not available for each individual ingredient, and since the salts dissociate freely in water, the Panel extrapolated from previous reports to support safety. The Panel concluded that diethanolamine and its salts are safe for use when formulated to be nonirritating. These ingredients should not be used in cosmetic products in which N-nitroso compounds can be formed.

Ingested Nitrate and Breast Cancer in the Spanish Multicase-Control Study on Cancer (MCC-Spain).

PubMed

Espejo-Herrera, Nadia; Gracia-Lavedan, Esther; Pollan, Marina; Aragonés, Nuria; Boldo, Elena; Perez-Gomez, Beatriz; Altzibar, Jone M; Amiano, Pilar; Zabala, Ana Jiménez; Ardanaz, Eva; Guevara, Marcela; Molina, Antonio J; Barrio, Juan Pablo; Gómez-Acebo, Ines; Tardón, Adonina; Peiró, Rosana; Chirlaque, Maria Dolores; Palau, Margarita; Muñoz, Montse; Font-Ribera, Laia; Castaño-Vinyals, Gemma; Kogevinas, Manolis; Villanueva, Cristina M

2016-07-01

Ingested nitrate leads to endogenous formation of N-nitroso compounds that are breast carcinogens in animals, but human evidence is limited. We evaluated ingested nitrate as a risk factor for breast cancer (BC) in a multicase-control study. Hospital-based incident BC cases and population-based controls were recruited in eight Spanish regions in 2008-2013; participants provided residential and water consumption from 18 years of age and information on known BC risk factors. Long-term nitrate levels (1940-2010) were estimated and linked with residential histories and water consumption to calculate waterborne ingested nitrate (milligrams/day). Dietary ingested nitrate (milligrams/day) was calculated using food frequency questionnaires and published dietary nitrate contents. Interactions with endogenous nitrosation factors and other variables were evaluated. A total of 1,245 cases and 1,520 controls were included in the statistical analysis. Among the study regions, average ± SD waterborne ingested nitrate ranged from 2.9 ± 1.9 to 13.5 ± 7.5 mg/day, and dietary ingested nitrate ranged from 88.5 ± 48.7 to 154 ± 87.8 mg/day. Waterborne ingested nitrate was not associated with BC overall, but among postmenopausal women, those with both high nitrate (> 6 vs. < 2.6 mg/day) and high red meat intake (≥ 20 vs. < 20 g/day) were more likely to be cases than women with low nitrate and low red meat intake (adjusted odds ratio = 1.64; 95% confidence interval: 1.08, 2.49; overall interaction p-value = 0.17). No association was found with dietary nitrate. Waterborne ingested nitrate was associated with BC only among postmenopausal women with high red meat consumption. Dietary nitrate was not associated with BC regardless of the animal or vegetable source or of menopausal status. Espejo-Herrera N, Gracia-Lavedan E, Pollan M, Aragonés N, Boldo E, Perez-Gomez B, Altzibar JM, Amiano P, Zabala AJ, Ardanaz E, Guevara M, Molina AJ, Barrio JP, Gómez-Acebo I, Tardón A, Peiró R, Chirlaque MD, Palau M, Muñoz M, Font-Ribera L, Castaño-Vinyals G, Kogevinas M, Villanueva CM. 2016. Ingested nitrate and breast cancer in the Spanish Multicase-Control Study on Cancer (MCC-Spain). Environ Health Perspect 124:1042-1049; http://dx.doi.org/10.1289/ehp.1510334.

QSAR Study for Carcinogenic Potency of Aromatic Amines Based on GEP and MLPs

PubMed Central

Song, Fucheng; Zhang, Anling; Liang, Hui; Cui, Lianhua; Li, Wenlian; Si, Hongzong; Duan, Yunbo; Zhai, Honglin

2016-01-01

A new analysis strategy was used to classify the carcinogenicity of aromatic amines. The physical-chemical parameters are closely related to the carcinogenicity of compounds. Quantitative structure activity relationship (QSAR) is a method of predicting the carcinogenicity of aromatic amine, which can reveal the relationship between carcinogenicity and physical-chemical parameters. This study accessed gene expression programming by APS software, the multilayer perceptrons by Weka software to predict the carcinogenicity of aromatic amines, respectively. All these methods relied on molecular descriptors calculated by CODESSA software and eight molecular descriptors were selected to build function equations. As a remarkable result, the accuracy of gene expression programming in training and test sets are 0.92 and 0.82, the accuracy of multilayer perceptrons in training and test sets are 0.84 and 0.74 respectively. The precision of the gene expression programming is obviously superior to multilayer perceptrons both in training set and test set. The QSAR application in the identification of carcinogenic compounds is a high efficiency method. PMID:27854309

Absence of mutagenicity effects of Psidium cattleyanum Sabine (Myrtaceae) extract on peripheral blood and bone marrow cells of mice.

PubMed

Costa, T D A; Vieira, S; Andrade, S F; Maistro, E L

2008-07-29

Cattley guava (Psidium cattleyanum Sabine) is a native fruit of Brazil that is popular both as a sweet food and for its reputed therapeutic properties. We examined whether it could damage DNA using the alkaline single-cell gel electrophoresis (comet assay) and the micronucleus test in leukocytes and in bone marrow cells of mice. P. cattleyanum leaf extract was tested at concentrations of 1000, 1500 and 2000 mg/kg. N-nitroso-N-ethylurea was used as a positive control. Peripheral blood leukocytes were collected 4 and 24 h after the treatments for the comet assay, and bone marrow cells were collected after 24 and 48 h for the micronucleus test. Unlike N-nitroso-N-ethylurea, P. cattleyanum extract failed to induce a significant increase in cell DNA damage, in micronucleated cell frequency, and in bone marrow toxicity. The lack of mutagenicity and cytotoxicity with high doses of this plant extract means that it can be safely used in traditional medicine.

Moesin Is a Biomarker for the Assessment of Genotoxic Carcinogens in Mouse Lymphoma

PubMed Central

Lee, Yoen Jung; Choi, In-Kwon; Sheen, Yhun Yhong; Park, Sue Nie; Kwon, Ho Jeong

2012-01-01

1,2-Dibromoethane and glycidol are well known genotoxic carcinogens, which have been widely used in industry. To identify a specific biomarker for these carcinogens in cells, the cellular proteome of L5178Y mouse lymphoma cells treated with these compounds was analyzed by 2-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry (MS). Of 50 protein spots showing a greater than 1.5-fold increase or decrease in intensity compared to control cells on a 2-D gel, we focused on the candidate biomarker moesin. Western analysis using monoclonal rabbit anti-moesin confirmed the identity of the protein and its increased level of expression upon exposure to the carcinogenic compounds. Moesin expression also increased in cells treated with six additional genotoxic carcinogens, verifying that moesin could serve as a biomarker to monitor phenotypic change upon exposure to genotoxic carcinogens in L5178Y mouse lymphoma cells. PMID:22358511

Moesin is a biomarker for the assessment of genotoxic carcinogens in mouse lymphoma.

PubMed

Lee, Yoen Jung; Choi, In-Kwon; Sheen, Yhun Yhong; Park, Sue Nie; Kwon, Ho Jeong

2012-02-01

1,2-Dibromoethane and glycidol are well known genotoxic carcinogens, which have been widely used in industry. To identify a specific biomarker for these carcinogens in cells, the cellular proteome of L5178Y mouse lymphoma cells treated with these compounds was analyzed by 2-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry (MS). Of 50 protein spots showing a greater than 1.5-fold increase or decrease in intensity compared to control cells on a 2-D gel, we focused on the candidate biomarker moesin. Western analysis using monoclonal rabbit anti-moesin confirmed the identity of the protein and its increased level of expression upon exposure to the carcinogenic compounds. Moesin expression also increased in cells treated with six additional genotoxic carcinogens, verifying that moesin could serve as a biomarker to monitor phenotypic change upon exposure to genotoxic carcinogens in L5178Y mouse lymphoma cells.

Destruction of carcinogenic and mutagenic N-nitrosamides in laboratory wastes.

PubMed

Lunn, G; Sansone, E B; Andrews, A W; Castegnaro, M; Malaveille, C; Michelon, J; Brouet, I; Keefer, L K

1984-01-01

The chemical degradation of five N-nitrosamides used widely for the experimental induction of cancer has been studied with the goal of identifying, and experimentally validating, reliable methods that can be recommended for the destruction of carcinogenic N-nitrosoureas and related compounds in laboratory wastes. Although data are not yet complete, preliminary evidence indicates that none of the five methods studied thus far is ideal for hazard-control purposes. Decomposition with 1 mol/L potassium hydroxide solution destroyed the N-nitrosamides, but generated diazoalkanes, which are carcinogenic, toxic and potentially explosive. Treatment with strong acid in the presence of sulfamic acid or iron filings completely decomposed all N-nitrosamides without forming diazoalkanes, but failed in the presence of solvents which were immiscible with water. Cleavage with hydrogen bromide in glacial acetic acid proceeded to a point of maximum degradation, following which gradual reformation of the N-nitrosamide was observed; this resynthesis could be avoided by carefully bubbling nitrogen through the reaction mixture, but degradation was slow or failed completely in the presence of hydroxylic solvents. Permanganate oxidation was effective in sulfuric acid solution, but was incomplete when an alcohol or dimethyl sulfoxide was present. Salmonella typhimurium tester strains TA1535, TA1530 and TA100, which detect base-pair substitutions in DNA, detected mutagenic degradation products in each of the destruction methods, with the exception of the hydrobromic acid/acetic acid procedure.

Partitioning studies of coal-tar constituents in a two-phase contaminated ground-water system

USGS Publications Warehouse

Rostad, C.E.; Pereira, W.E.; Hult, M.F.

1985-01-01

Organic compounds derived from coal-tar wastes in a contaminated aquifer in St. Louis Park, Minnesota, were identified, and their partition coefficients between the tar phase and aqueous phase were determined and compared with the corresponding n-octanol/water partition coefficients. Coal tar contains numerous polycyclic aromatic compounds, many of which are suspected carcinogens or mutagens. Groundwater contamination by these toxic compounds may pose an environmental health hazard in nearby public water-supply wells. Fluid samples from this aquifer developed two phases upon settling: an upper aqueous phase, and a lower oily-tar phase. After separating the phases, polycyclic aromatic compounds in each phase were isolated using complexation with N-methyl-2-pyrrolidone and identified by fused-silica capillary gas chromatography/mass spectrometry. Thirty-one of the polycyclic aromatic compounds were chosen for further study from four different classes: 12 polycyclic aromatic hydrocarbons, 10 nitrogen heterocycles, 5 sulfur heterocycles, and 4 oxygen heterocycles. Within each compound class, the tar/water partition coefficients of these compounds were reasonably comparable with the respective n-octanol/water partition coefficient.

Ring-rearrangement metathesis of nitroso Diels-Alder cycloadducts.

PubMed

Vincent, Guillaume; Kouklovsky, Cyrille

2011-03-01

Strained nitroso Diels-Alder bicyclo[2.2.1] or [2.2.2] adducts functionalized with alkene side chains of diverse length undergo a ring-rearrangement metathesis process with external alkenes and Grubbs II or Hoveyda-Grubbs II ruthenium catalysts, under microwave irradiation or classical heating, to deliver cis-fused bicycles of various ring sizes, which contain a N-O bond. These scaffolds are of synthetic relevance for the generation of molecular diversity and to the total synthesis of alkaloids. The observation of unexpected reactions, such as epimerization or one-carbon homologation of the alkene side chain, is also reported. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Role of cobalt, iron, lead, manganese, mercury, platinum, selenium, and titanium in carcinogenesis.

PubMed Central

Kazantzis, G

1981-01-01

The possible carcinogenicity of cobalt, iron, lead, manganese, mercury, platinum, selenium, and titanium is reviewed, taking into account epidemiological data, the results of animal experimental studies, data on mutagenic effects and on other in vitro test systems. Of the great variety of occupations where exposure to one of these metals may occur, only haematite mining has been clearly shown to involve an increased human cancer risk. While the possibility that haematite might in some way act as a carcinogen has to be taken into consideration it is more likely that other carcinogens are responsible. Certain platinum coordination complexes are used in cancer chemotherapy, are mutagenic, and likely to be carcinogenic. Cobalt, its oxide and sulfide, certain lead salts, one organomanganese, and one organotitanium compound have been shown to have a limited carcinogenic effect in experimental animal studies, and except for titanium appear to be mutagenic. Certain mercury compounds are mutagenic but none have been shown to be carcinogenic. The presently available data are inadequate to assess the possible carcinogenicity of selenium compounds, but a few observations suggest that selenium may suppress the effect of other carcinogens administered to experimental animals and may even be associated with lower cancer mortality rates in man. Epidemiological observations are essential for the assessment of a human cancer risk, but the difficulty in collecting past exposure data in occupational groups and the complexity of multiple occupational exposures with changes over time, limits the usefulness of retrospective epidemiological studies. PMID:7023929

Ingested nitrate and nitrite, disinfection by-products, and pancreatic cancer risk in postmenopausal women.

PubMed

Quist, Arbor J L; Inoue-Choi, Maki; Weyer, Peter J; Anderson, Kristin E; Cantor, Kenneth P; Krasner, Stuart; Freeman, Laura E Beane; Ward, Mary H; Jones, Rena R

2018-01-15

Nitrate and nitrite are precursors of N-nitroso compounds (NOC), probable human carcinogens that cause pancreatic tumors in animals. Disinfection by-products (DBP) exposures have also been linked with digestive system cancers, but few studies have evaluated relationships with pancreatic cancer. We investigated the association of pancreatic cancer with these drinking water contaminants and dietary nitrate/nitrite in a cohort of postmenopausal women in Iowa (1986-2011). We used historical monitoring and treatment data to estimate levels of long-term average nitrate and total trihalomethanes (TTHM; the sum of the most prevalent DBP class) and the duration exceeding one-half the maximum contaminant level (>½ MCL; 5 mg/L nitrate-nitrogen, 40 µg/L TTHM) among participants on public water supplies (PWS) >10 years. We estimated dietary nitrate and nitrite intakes using a food frequency questionnaire. We computed hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and evaluated nitrate interactions with smoking and vitamin C intake. We identified 313 cases among 34,242 women, including 152 with >10 years PWS use (N = 15,710). Multivariable models of average nitrate showed no association with pancreatic cancer (HR p95 vs . Q1  = 1.16, 95% CI: 0.51-2.64). Associations with average TTHM levels were also null (HR Q4 vs . Q1  = 0.70, 95% CI:0.42-1.18). We observed no trend with increasing years of exposure to either contaminant at levels >½ MCL. Positive associations were suggested in the highest dietary nitrite intake from processed meat (HR p95 vs . Q1  = 1.66, 95% CI 1.00-2.75;p trend  = 0.05). We found no interactions of nitrate with known modifiers of endogenous NOC formation. Our results suggest that nitrite intake from processed meat may be a risk factor for pancreatic cancer. 2017 UICC.

Development and calibration of a dietary nitrate and nitrite database in the NIH–AARP Diet and Health Study

PubMed Central

Inoue-Choi, Maki; Virk-Baker, Mandeep K; Aschebrook-Kilfoy, Briseis; Cross, Amanda J; Subar, Amy F; Thompson, Frances E; Sinha, Rashmi; Ward, Mary H

2016-01-01

Objective Nitrate and nitrite are probable human carcinogens when ingested under conditions that increase the formation of N-nitroso compounds. There have been limited efforts to develop US databases of dietary nitrate and nitrite for standard FFQ. Here we describe the development of a dietary nitrate and nitrite database and its calibration. Design We analysed data from a calibration study of 1942 members of the NIH–AARP (NIH–AARP, National Institutes of Health–AARP) Diet and Health Study who reported all foods and beverages consumed on the preceding day in two non-consecutive 24 h dietary recalls (24HR) and completed an FFQ. Based on a literature review, we developed a database of nitrate and nitrite contents for foods reported on these 24HR and for food category line items on the FFQ. We calculated daily nitrate and nitrite intakes for both instruments, and used a measurement error model to compute correlation coefficients and attenuation factors for the FFQ-based intake estimates using 24HR-based values as reference data. Results FFQ-based median nitrate intake was 68·9 and 74·1 mg/d, and nitrite intake was 1·3 and 1·0 mg/d, in men and women, respectively. These values were similar to 24HR-based intake estimates. Energy-adjusted correlation coefficients between FFQ- and 24HR-based values for men and women respectively were 0·59 and 0·57 for nitrate and 0·59 and 0·58 for nitrite; energy-adjusted attenuation factors were 0·59 and 0·57 for nitrate and 0·47 and 0·38 for nitrite. Conclusions The performance of the FFQ in assessing dietary nitrate and nitrite intakes is comparable to that for many other macro- and micronutrients. PMID:26626817

Toxicity prediction of compounds from turmeric (Curcuma longa L).

PubMed

Balaji, S; Chempakam, B

2010-10-01

Turmeric belongs to the ginger family Zingiberaceae. Currently, cheminformatics approaches are not employed in any of the spices to study the medicinal properties traditionally attributed to them. The aim of this study is to find the most efficacious molecule which does not have any toxic effects. In the present study, toxicity of 200 chemical compounds from turmeric were predicted (includes bacterial mutagenicity, rodent carcinogenicity and human hepatotoxicity). The study shows out of 200 compounds, 184 compounds were predicted as toxigenic, 136 compounds are mutagenic, 153 compounds are carcinogenic and 64 compounds are hepatotoxic. To cross validate our results, we have chosen the popular curcumin and found that curcumin and its derivatives may cause dose dependent hepatotoxicity. The results of these studies indicate that, in contrast to curcumin, few other compounds in turmeric which are non-mutagenic, non-carcinogenic, non-hepatotoxic, and do not have any side-effects. Hence, the cost-effective approach presented in this paper could be used to filter toxic compounds from the drug discovery lifecycle. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Emerging Issues in Genotoxicity and Carcinogenicity with Implications for Structure Activity Analyses

EPA Science Inventory

In silico systems for the prediction of the ability of chemicals to induce carcinogenicity in rodents have generally relied on knowledge of the structure and physical-chemical features of the compound, as well as the mutagenic and genotoxic features of the compound in various bio...

Influence of Selected Organic Micropollutants on Organisms

NASA Astrophysics Data System (ADS)

Włodarczyk-Makuła, Maria

2017-03-01

This article describes the toxicity of organic micropollutants on tested microorganisms. Itis a current issue because organic micropollutants are identified in all elements of environmental (surface water, ground water, soils) and in food products. The organic micropollutants include: polychlorinated dibenzodioxyns PCDD, polychlorinated dibenzofurans PCDF, polychlorinated biphenyls PCB, polycyclic aromatic hydrocarbons PAH, halogenated compounds and by-products of water treatment. Some organic compounds cause hazard for health and human life due to their estrogenic biological activity, carcinogenic, mutagenic or teratogenic activity. The influence on organisms indicators of these compounds based on literature data were presented. The level of TEQ (toxic equivalency) in response to organic chlorine derivatives (PCDDs, PCDF, PCBs) is usually determined by toxic equivalency factor (TEF). The International Agency for Research on Cancer classifies organic micropollutants as carcinogenic to humans (Group 1), possibly carcinogenic (Group 2A) or probably carcinogenic to humans (Group 2B).

Chromium oxidation state mapping in human cells

NASA Astrophysics Data System (ADS)

Ortega, R.; Fayard, B.; Salomé, M.; Devès, G.; Susini, J.

2003-03-01

The widespread use of chromium in industrial applications such as chemical production of pigments, refractory brick production, tanning, metallurgy, electroplating, and combustion of fuels has lead to human occupational exposure and to its increased introduction into the environment. Hexavalent chromium compounds are established carcinogens but their mechanism of cell transformation is not known. Up to now, no microanalytical technique was sensitive enough to allow the observation of chromium distribution, and oxidation state identification, within isolated cells at carcinogenic concentrations. In this experiment, we used successfully the ID-21 X-ray microscope to map Cr(VI) and total Cr distributions in cells exposed in vitro to soluble, and insoluble, Cr(VI) compounds. Exposure to soluble compounds, weak carcinogens, resulted in a homogeneous intracellular distribution of Cr, confirming by in situ measurement that Cr is present in the cell nucleus. Cr(VI) was never detected in cells which suggests a mechanism of rapid intracellular reducticn. On the other hand, exposure to insoluble compounds, strong carcinogens, also resulted in a homogeneous distribution of reduced forms of Cr in cells, and their nucleus. However, in this case, Cr(VI)-rich structures were observed into the cells suggesting that carcinogenicity is enhanced when oxidation reactions due to Cr(VI) chronic exposure are associated to Cr-DNA alterations.

CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO THE MALE F344/N RAT AND B6C3F1 MOUSE

EPA Science Inventory

Chlorine added to surface waters for the purposes of disinfection, reacts with humic material in the water to produce a variety of compounds collectively known as disinfection by-product (DBPs). The trihalomethanes (THM), the class of DBPs that occur at the highest concentrations...

[Exposure to metal compounds in occupational galvanic processes].

PubMed

Surgiewicz, Jolanta; Domański, Wojciech

2006-01-01

Occupational galvanic processes are provided in more than 600 small and medium enterprises in Poland. Workers who deal with galvanic coating are exposed to heavy metal compounds: tin, silver, copper and zinc. Some of them are carcinogenic, for example, hexavalent chromium compounds, nickel and cadmium compounds. Research covered several tens of workstations involved in chrome, nickel, zinc, tin, silver, copper and cadmium plating. Compounds of metals present in the air were determined: Cr, Ni, Cd, Sn, Ag--by atomic absorption spectrometry with electrothermal atomization (ET-AAS) and Zn--by atomic absorption spectrometry with flame atomization (F-AAS). The biggest metal concentrations--of silver and copper--were found at workstations of copper, brass, cadmium, nickel and chrome plating, conducted at the same time. Significant concentrations of copper were found at workstations of maintenance bathing and neutralizing of sewage. The concentrations of metals did not exceed Polish MAC values. MAC values were not exceeded for carcinogenic chromium(VI), nickel or cadmium, either. In galvanic processes there was no hazard related to single metals or their compounds, even carcinogenic ones. Combined exposure indicators for metals at each workstation did not exceed 1, either. However, if there are even small quantities of carcinogenic agents, health results should always be taken into consideration.

Unconventional oil and gas development and risk of childhood leukemia: Assessing the evidence.

PubMed

Elliott, Elise G; Trinh, Pauline; Ma, Xiaomei; Leaderer, Brian P; Ward, Mary H; Deziel, Nicole C

2017-01-15

The widespread distribution of unconventional oil and gas (UO&G) wells and other facilities in the United States potentially exposes millions of people to air and water pollutants, including known or suspected carcinogens. Childhood leukemia is a particular concern because of the disease severity, vulnerable population, and short disease latency. A comprehensive review of carcinogens and leukemogens associated with UO&G development is not available and could inform future exposure monitoring studies and human health assessments. The objective of this analysis was to assess the evidence of carcinogenicity of water contaminants and air pollutants related to UO&G development. We obtained a list of 1177 chemicals in hydraulic fracturing fluids and wastewater from the U.S. Environmental Protection Agency and constructed a list of 143 UO&G-related air pollutants through a review of scientific papers published through 2015 using PubMed and ProQuest databases. We assessed carcinogenicity and evidence of increased risk for leukemia/lymphoma of these chemicals using International Agency for Research on Cancer (IARC) monographs. The majority of compounds (>80%) were not evaluated by IARC and therefore could not be reviewed. Of the 111 potential water contaminants and 29 potential air pollutants evaluated by IARC (119 unique compounds), 49 water and 20 air pollutants were known, probable, or possible human carcinogens (55 unique compounds). A total of 17 water and 11 air pollutants (20 unique compounds) had evidence of increased risk for leukemia/lymphoma, including benzene, 1,3-butadiene, cadmium, diesel exhaust, and several polycyclic aromatic hydrocarbons. Though information on the carcinogenicity of compounds associated with UO&G development was limited, our assessment identified 20 known or suspected carcinogens that could be measured in future studies to advance exposure and risk assessments of cancer-causing agents. Our findings support the need for investigation into the relationship between UO&G development and risk of cancer in general and childhood leukemia in particular. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Prevention by thioethers of the hepatotoxicity and covalent binding to macromolecules of N-hydroxy-2-acetylaminofluorene and its sulfate ester in rat liver in vivo and in vitro.

PubMed

van den Goorbergh, J A; de Wit, H; Tijdens, R B; Mulder, G J; Meerman, J H

1987-02-01

In order to find potentially effective compounds that could prevent the covalent binding of the carcinogen N-hydroxy-2-acetylaminofluorene (N-OH-AAF) to rat liver macromolecules in vivo, the prevention of the covalent binding to RNA of the sulfate ester of the carcinogen N-OH-AAF by a series of thioethers was investigated in vitro. The most effective thioethers, which inhibited the covalent binding by 70% or more, were studied for their protection against acute hepatotoxicity of N-OH-AAF in the rat in vivo. Three of these thioethers, thiazolidine, methyl 4-(methylthio)benzoate, and 2-(methylthio)benzimidazole significantly decreased the hepatoxicity of N-OH-AAF, by 45, 71 and 83%, respectively. The effects of these thioethers on the covalent binding of N-OH-AAF to cellular macromolecules in vivo were also studied. Methyl 4-(methylthio)benzoate and 2-(methylthio)benzimidazole decreased the adduct formation of N-OH-AAF to DNA by 54 and 44%, respectively, but had no effect on protein adduct formation. Only 2-(methylthio)benzimidazole caused a slight decrease (23%) in the AAF-- protein adduct formation. 2-Acetylaminofluorene (AAF) and methyl 4-(methyl-sulfinyl)benzoate were the main products in the incubation of methyl 4-(methylthio)benzoate with AAF-N-sulfate in vitro. This suggests that the thioether attacks the nitrenium ion which is formed by spontaneous breakdown of AAF-N-sulfate; the formation of a sulfonium--AAF conjugate is postulated which decomposes into AAF and a sulfinyl compound.

Mechanism of Error-Free DNA Replication Past Lucidin-Derived DNA Damage by Human DNA Polymerase κ.

PubMed

Yockey, Oliver P; Jha, Vikash; Ghodke, Pratibha P; Xu, Tianzuo; Xu, Wenyan; Ling, Hong; Pradeepkumar, P I; Zhao, Linlin

2017-11-20

DNA damage impinges on genetic information flow and has significant implications in human disease and aging. Lucidin-3-O-primeveroside (LuP) is an anthraquinone derivative present in madder root, which has been used as a coloring agent and food additive. LuP can be metabolically converted to genotoxic compound lucidin, which subsequently forms lucidin-specific N 2 -2'-deoxyguanosine (N 2 -dG) and N 6 -2'-deoxyadenosine (N 6 -dA) DNA adducts. Lucidin is mutagenic and carcinogenic in rodents but has low carcinogenic risks in humans. To understand the molecular mechanism of low carcinogenicity of lucidin in humans, we performed DNA replication assays using site-specifically modified oligodeoxynucleotides containing a structural analogue (LdG) of lucidin-N 2 -dG DNA adduct and determined the crystal structures of DNA polymerase (pol) κ in complex with LdG-bearing DNA and an incoming nucleotide. We examined four human pols (pol η, pol ι, pol κ, and Rev1) in their efficiency and accuracy during DNA replication with LdG; these pols are key players in translesion DNA synthesis. Our results demonstrate that pol κ efficiently and accurately replicates past the LdG adduct, whereas DNA replication by pol η, pol ι is compromised to different extents. Rev1 retains its ability to incorporate dCTP opposite the lesion albeit with decreased efficiency. Two ternary crystal structures of pol κ illustrate that the LdG adduct is accommodated by pol κ at the enzyme active site during insertion and postlesion-extension steps. The unique open active site of pol κ allows the adducted DNA to adopt a standard B-form for accurate DNA replication. Collectively, these biochemical and structural data provide mechanistic insights into the low carcinogenic risk of lucidin in humans.

Cross-Platform Toxicogenomics for the Prediction of Non-Genotoxic Hepatocarcinogenesis in Rat

PubMed Central

Metzger, Ute; Templin, Markus F.; Plummer, Simon; Ellinger-Ziegelbauer, Heidrun; Zell, Andreas

2014-01-01

In the area of omics profiling in toxicology, i.e. toxicogenomics, characteristic molecular profiles have previously been incorporated into prediction models for early assessment of a carcinogenic potential and mechanism-based classification of compounds. Traditionally, the biomarker signatures used for model construction were derived from individual high-throughput techniques, such as microarrays designed for monitoring global mRNA expression. In this study, we built predictive models by integrating omics data across complementary microarray platforms and introduced new concepts for modeling of pathway alterations and molecular interactions between multiple biological layers. We trained and evaluated diverse machine learning-based models, differing in the incorporated features and learning algorithms on a cross-omics dataset encompassing mRNA, miRNA, and protein expression profiles obtained from rat liver samples treated with a heterogeneous set of substances. Most of these compounds could be unambiguously classified as genotoxic carcinogens, non-genotoxic carcinogens, or non-hepatocarcinogens based on evidence from published studies. Since mixed characteristics were reported for the compounds Cyproterone acetate, Thioacetamide, and Wy-14643, we reclassified these compounds as either genotoxic or non-genotoxic carcinogens based on their molecular profiles. Evaluating our toxicogenomics models in a repeated external cross-validation procedure, we demonstrated that the prediction accuracy of our models could be increased by joining the biomarker signatures across multiple biological layers and by adding complex features derived from cross-platform integration of the omics data. Furthermore, we found that adding these features resulted in a better separation of the compound classes and a more confident reclassification of the three undefined compounds as non-genotoxic carcinogens. PMID:24830643

Nitrate from Drinking Water and Diet and Bladder Cancer Among Postmenopausal Women in Iowa.

PubMed

Jones, Rena R; Weyer, Peter J; DellaValle, Curt T; Inoue-Choi, Maki; Anderson, Kristin E; Cantor, Kenneth P; Krasner, Stuart; Robien, Kim; Freeman, Laura E Beane; Silverman, Debra T; Ward, Mary H

2016-11-01

Nitrate is a drinking water contaminant arising from agricultural sources, and it is a precursor in the endogenous formation of N-nitroso compounds (NOC), which are possible bladder carcinogens. We investigated the ingestion of nitrate and nitrite from drinking water and diet and bladder cancer risk in women. We identified incident bladder cancers among a cohort of 34,708 postmenopausal women in Iowa (1986-2010). Dietary nitrate and nitrite intakes were estimated from a baseline food frequency questionnaire. Drinking water source and duration were assessed in a 1989 follow-up. For women using public water supplies (PWS) > 10 years (n = 15,577), we estimated average nitrate (NO3-N) and total trihalomethane (TTHM) levels and the number of years exceeding one-half the maximum contaminant level (NO3-N: 5 mg/L, TTHM: 40 μg/mL) from historical monitoring data. We computed hazard ratios (HRs) and 95% confidence intervals (CIs), and assessed nitrate interactions with TTHM and with modifiers of NOC formation (smoking, vitamin C). We identified 258 bladder cancer cases, including 130 among women > 10 years at their PWS. In multivariable-adjusted models, we observed nonsignificant associations among women in the highest versus lowest quartile of average drinking water nitrate concentration (HR = 1.48; 95% CI: 0.92, 2.40; ptrend = 0.11), and we found significant associations among those exposed ≥ 4 years to drinking water with > 5 mg/L NO3-N (HR = 1.62; 95% CI: 1.06, 2.47; ptrend = 0.03) compared with women having 0 years of comparable exposure. TTHM adjustment had little influence on associations, and we observed no modification by vitamin C intake. Relative to a common reference group of never smokers with the lowest nitrate exposures, associations were strongest for current smokers with the highest nitrate exposures (HR = 3.67; 95% CI: 1.43, 9.38 for average water NO3-N and HR = 3.48; 95% CI: 1.20, 10.06 and ≥ 4 years > 5 mg/L, respectively). Dietary nitrate and nitrite intakes were not associated with bladder cancer. Long-term ingestion of elevated nitrate in drinking water was associated with an increased risk of bladder cancer among postmenopausal women. Citation: Jones RR, Weyer PJ, DellaValle CT, Inoue-Choi M, Anderson KE, Cantor KP, Krasner S, Robien K, Beane Freeman LE, Silverman DT, Ward MH. 2016. Nitrate from drinking water and diet and bladder cancer among postmenopausal women in Iowa. Environ Health Perspect 124:1751-1758; http://dx.doi.org/10.1289/EHP191.

Small fish models for identifying carcinogens in the aqueous environment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hawkins, W.E.; Overstreet, R.M.; Walker, W.W.

1988-10-01

Contaminants in water and sediments can be carcinogenic to aquatic wildlife as well as humans. Identifying those carcinogens, however, is difficult because they often occur in low concentrations and exert their effects over a large part of the life span of affected organisms. Furthermore, the carcinogens are often components of complex mixtures. Recent studies suggest that laboratory-reared fish species might be well suited for testing water-associated and other carcinogens. Here, we review the principal carcinogen exposure methods that utilize small fish species or can be adapted to utilize small fish species to detect carcinogens in aqueous environments. Emphasis is placedmore » on methods for which the end-point is tumor induction. The methods discussed are dietary exposures, skin painting, embryo microinjection, early life stage (pulse) exposures, static water exposures, flow-through exposures, and controlled field exposures. Early life stage exposures seem to have the greatest utility with regard to carcinogen sensitivity, ease of administration, disposal of test compounds, and economy of materials and effort. For certain types of carcinogens, however, long-term flow-through exposures are probably required. In summary, small fish carcinogenesis models offer an array of methodologies that can be utilized in a variety of combinations depending on compounds tested, exposure parameters employed, and end point sought.« less

Chicken fetal liver DNA damage and adduct formation by activation-dependent DNA-reactive carcinogens and related compounds of several structural classes.

PubMed

Williams, Gary M; Duan, Jian-Dong; Brunnemann, Klaus D; Iatropoulos, Michael J; Vock, Esther; Deschl, Ulrich

2014-09-01

The chicken egg genotoxicity assay (CEGA), which utilizes the liver of an intact and aseptic embryo-fetal test organism, was evaluated using four activation-dependent DNA-reactive carcinogens and four structurally related less potent carcinogens or non-carcinogens. In the assay, three daily doses of test substances were administered to eggs containing 9-11-day-old fetuses and the fetal livers were assessed for two endpoints, DNA breaks using the alkaline single cell gel electrophoresis (comet) assay and DNA adducts using the (32)P-nucleotide postlabeling (NPL) assay. The effects of four carcinogens of different structures requiring distinct pathways of bioactivation, i.e., 2-acetylaminofluorene (AAF), aflatoxin B1 (AFB1), benzo[a]pyrene (B[a]P), and diethylnitrosamine (DEN), were compared with structurally related non-carcinogens fluorene (FLU) and benzo[e]pyrene (B[e]P) or weak carcinogens, aflatoxin B2 (AFB2) and N-nitrosodiethanolamine (NDELA). The four carcinogens all produced DNA breaks at microgram or low milligram total doses, whereas less potent carcinogens and non-carcinogens yielded borderline or negative results, respectively, at higher doses. AAF and B[a]P produced DNA adducts, whereas none was found with the related comparators FLU or B[e]P, consistent with comet results. DEN and NDELA were also negative for adducts, as expected in the case of DEN for an alkylating agent in the standard NPL assay. Also, AFB1 and AFB2 were negative in NPL, as expected, due to the nature of ring opened aflatoxin adducts, which are resistant to enzymatic digestion. Thus, the CEGA, using comet and NPL, is capable of detection of the genotoxicity of diverse DNA-reactive carcinogens, while not yielding false positives for non-carcinogens. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Activity of nitric oxide-generating compounds against encephalomyocarditis virus.

PubMed Central

Guillemard, E; Geniteau-Legendre, M; Kergot, R; Lemaire, G; Petit, J F; Labarre, C; Quero, A M

1996-01-01

Nitric oxide (NO) generated by two NO donors (sodium nitroprusside or S-nitroso-L-glutathione) was shown to exert a dose-dependent inhibition of encephalomyocarditis virus growth in L-929 cells. This activity was not due to the cytotoxic or direct virucidal effects of NO donors. L-929 cells were shown to produce NO endogenously, but this low level of production did not counter encephalomyocarditis virus replication. PMID:8849231

Leaching of nitroso rubber material removes uncured polymer

NASA Technical Reports Server (NTRS)

Bratfisch, W. A.; Gonzalez, R.

1972-01-01

New leaching process removes uncured polymer from nitroso rubber, elastomer used in presence of nitrogen tetroxide. Uncured portion is removed by controlled soaking of polymer slab in Freon TF. Leaching with Freon TF prevents nitroso rubber from adhering to adjoining surfaces and limiting its usefulness in either static or dynamic applications.

Addendum to the Principles And Practices Manual. Loading Rates and Impacts of Substrate Delivery for Enhanced Anaerobic Bioremediation

DTIC Science & Technology

2010-01-01

attenuation MSDS material safety data sheet NAVFAC ESC Naval Facilities Engineering Command/Engineering Services Center NDMA N-nitrosodimethylamine...compounds (ER-1607, ER-200425, and ER- 201028). N-nitrosodimethylamine ( NDMA ) is used with propellants and is a carcinogen and emerging groundwater...contaminant at a number of DoD and DOE facilities. NDMA may be amendable to enhanced in situ bioremediation (Szecsody et al., 2009; Hatzinger et al., 2008

Host-guest complex of N-(2-chloroethyl), N-nitroso, N‧, N‧ -dicyclohexylsulfamid with β-cyclodextrin: Fluorescence, QTAIM analysis and structure-chemical reactivity

NASA Astrophysics Data System (ADS)

Bensouilah, Nadjia; Fisli, Hassina; Bensouilah, Hamza; Zaater, Sihem; Abdaoui, Mohamed; Boutemeur-Kheddis, Baya

2017-10-01

In this work, the inclusion complex of DCY/CENS: N-(2-chloroethyl), N-nitroso, N‧, N‧-dicyclohexylsulfamid and β-cyclodextrin (β-CD) is investigated using the fluorescence spectroscopy, PM3, ONIOM2 and DFT methods. The experimental part reveals that DCY/CENS forms a 1:1 stoichiometric ratio inclusion complex with β-CD. The constant of stability is evaluated using the Benesi-Hildebrand equation. The results of the theoretical optimization showed that the lipophilic fraction of molecule (cyclohexyl group) is inside of β-CD. Accordingly, the Nitroso-Chloroethyl moiety is situated outside the cavity of the macromolecule host. The favorable structure of the optimized complex indicates the existence of weak intermolecular hydrogen bonds and the most important van der Waals (vdW) interactions which are studied on the basis of Natural Bonding Orbital (NBO) analysis. The NBO is employed to compute the electronic donor-acceptor exchanges between drug and β-CD. Furthermore, a detailed topological charge density analysis based on the quantum theory of atoms in molecules (QTAIM), has been accomplished on the most favorable complex using B3LYP/6-31G(d) method. The presence of stabilizing intermolecular hydrogen bonds and van der Waals interactions in the most favorable complex is predicted. Also, the energies of these interactions are estimated with Espinosa's formula. The findings of this investigation reveal that the correlation between the structural parameters and the electronic density is good. Finally, and based on DFT calculations, the reactivity of the interesting molecule in free state was studied and compared with that in the complexed state using chemical potential, global hardness, global softness, electronegativity, electrophilicity and local reactivity descriptors.

Human risk of diseases associated with red meat intake: Analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid.

PubMed

Alisson-Silva, Frederico; Kawanishi, Kunio; Varki, Ajit

2016-10-01

One of the most consistent epidemiological associations between diet and human disease risk is the impact of red meat consumption (beef, pork, and lamb, particularly in processed forms). While risk estimates vary, associations are reported with all-cause mortality, colorectal and other carcinomas, atherosclerotic cardiovascular disease, type II diabetes, and possibly other inflammatory processes. There are many proposed explanations for these associations, some long discussed in the literature. Attempts to explain the effects of red meat consumption have invoked various red meat-associated agents, including saturated fat, high salt intake, Trimethylamine-N-oxide (TMAO) generation by microbiota, and environmental pollutants contaminating red meat, none of which are specific for red meat. Even the frequently mentioned polycyclic aromatic carcinogens arising from high temperature cooking methods are not red meat specific, as these are also generated by grilling poultry or fish, as well as by other forms of cooking. The traditional explanations that appear to be more red meat specific invoke the impact of N-nitroso compounds, heme iron, and the potential of heme to catalyze endogenous nitrosation. However, heme can be denatured by cooking, high levels of plasma hemopexin will block its tissue delivery, and much higher amounts of heme likely originate from red blood cell breakdown in vivo. Therefore, red meat-derived heme could only contribute to colorectal carcinoma risk, via direct local effects. Also, none of these mechanisms explain the apparent human propensity i.e., other carnivores have not been reported at high risk for all these diseases. A more recently proposed hypothesis involves infectious agents in beef from specific dairy cattle as agents of colorectal cancer. We have also described another mechanistic explanation for the human propensity for risk of red-meat associated diseases that is consistent with most observations: metabolic incorporation of a non-human sialic acid N-glycolylneuraminic acid (Neu5Gc) into the tissues of red meat consumers and the subsequent interaction with inflammation-provoking antibodies against this "xenoautoantigen". Overall, we conclude that while multiple mechanisms are likely operative, many proposed theories to date are not specific for red meat, and that the viral and xenoautoantigen theories deserve further consideration. Importantly, there are potential non-toxic dietary antidotes, if the xenoautoantigen theory is indeed correct. Copyright © 2016 Elsevier Ltd. All rights reserved.

Human Risk of Diseases Associated with Red Meat Intake: Analysis of Current Theories and Proposed Role for Metabolic Incorporation of a Non-Human Sialic Acid

PubMed Central

Alisson-Silva, Frederico; Kawanishi, Kunio; Varki, Ajit

2016-01-01

One of the most consistent epidemiological associations between diet and human disease risk is the impact of red meat consumption (beef, pork, and lamb, particularly in processed forms). While risk estimates vary, associations are reported with all-cause mortality, colorectal and other carcinomas, atherosclerotic cardiovascular disease, type II diabetes, and possibly other inflammatory processes. There are many proposed explanations for these associations, some long discussed in the literature. Attempts to explain the effects of red meat consumption have invoked various red meat-associated agents, including saturated fat, high salt intake, Trimethylamine–N-oxide (TMAO) generation by microbiota, and environmental pollutants contaminating red meat, none of which are specific for red meat. Even the frequently mentioned polycyclic aromatic carcinogens arising from high temperature cooking methods are not red meat specific, as these are also generated by grilling poultry or fish, as well as by other forms of cooking. The traditional explanations that appear to be more red meat specific invoke the impact of N-nitroso compounds, heme iron, and the potential of heme to catalyze endogenous nitrosation. However, heme can be denatured by cooking, high levels of plasma hemopexin will block its tissue delivery, and much higher amounts of heme likely originate from red blood cell breakdown in vivo. Therefore, red meat-derived heme could only contribute to colorectal carcinoma risk, via direct local effects. Also, none of these mechanisms explain the apparent human propensity i.e., other carnivores have not been reported at high risk for all these diseases. A more recently proposed hypothesis involves infectious agents in beef from specific dairy cattle as agents of colorectal cancer. We have also described another mechanistic explanation for the human propensity for risk of red-meat associated diseases that is consistent with most observations: metabolic incorporation of a non-human sialic acid N-glycolylneuraminic acid (Neu5Gc) into the tissues of red meat consumers and the subsequent interaction with inflammation-provoking antibodies against this “xenoautoantigen”. Overall, we conclude that while multiple mechanisms are likely operative, many proposed theories to date are not specific for red meat, and that the viral and xenoautoantigen theories deserve further consideration. Importantly, there are potential non-toxic dietary antidotes, if the xenoautoantigen is indeed correct. PMID:27421909

Installation Restoration Program. Remedial Investigation Report. Site 1. Fire Training Area. Volk Field Air National Guard Base, Camp Douglas, WI. Volume 1

DTIC Science & Technology

1990-07-01

Nitroaniline 4-Nitroaniline N-Nitroso-di-n-butylamine N-Nitrosopiperidine Pentachlorobenzene Pentachloronitrobenzene Phenacetin 2- Picoline Pronarnide 1,2,4,5... chromium . Cu: Chemical symbol for copper. 3 DARCY’S LAW: An equation describing the flow of fluids in porous media based on the assumption that the flow

76 FR 8674 - Notice of a Public Meeting: Environmental Justice Considerations for Drinking Water Regulatory...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-15

... perchlorate and carcinogenic volatile organic compounds (VOCs). While the Agency is in the very preliminary stages of developing the regulatory efforts for perchlorate and carcinogenic VOCs, EPA plans to discuss..., Regulatory Determinations 3, perchlorate, and carcinogenic VOCs rulemaking efforts. Date and Location: The...

Seasonal and spatial variability of nitrosamines and their precursor sources at a large-scale urban drinking water system.

PubMed

Woods, Gwen C; Trenholm, Rebecca A; Hale, Bruce; Campbell, Zeke; Dickenson, Eric R V

2015-07-01

Nitrosamines are considered to pose greater health risks than currently regulated DBPs and are subsequently listed as a priority pollutant by the EPA, with potential for future regulation. Denver Water, as part of the EPA's Unregulated Contaminant Monitoring Rule 2 (UCMR2) monitoring campaign, found detectable levels of N-nitrosodimethylamine (NDMA) at all sites of maximum residency within the distribution system. To better understand the occurrence of nitrosamines and nitrosamine precursors, Denver Water undertook a comprehensive year-long monitoring campaign. Samples were taken every two weeks to monitor for NDMA in the distribution system, and quarterly sampling events further examined 9 nitrosamines and nitrosamine precursors throughout the treatment and distribution systems. NDMA levels within the distribution system were typically low (>1.3 to 7.2 ng/L) with a remote distribution site (frequently >200 h of residency) experiencing the highest concentrations found. Eight other nitrosamines (N-nitrosomethylethylamine, N-nitrosodiethylamine, N-nitroso-di-n-propylamine, N-nitroso-di-n-butylamine, N-nitroso-di-phenylamine, N-nitrosopyrrolidine, N-nitrosopiperidine, N-nitrosomorpholine) were also monitored but none of these 8, or precursors of these 8 [as estimated with formation potential (FP) tests], were detected anywhere in raw, partially-treated or distribution samples. Throughout the year, there was evidence that seasonality may impact NDMA formation, such that lower temperatures (~5-10°C) produced greater NDMA than during warmer months. The year of sampling further provided evidence that water quality and weather events may impact NDMA precursor loads. Precursor loading estimates demonstrated that NDMA precursors increased during treatment (potentially from cationic polymer coagulant aids). The precursor analysis also provided evidence that precursors may have increased further within the distribution system itself. This comprehensive study of a large-scale drinking water system provides insight into the variability of NDMA occurrence in a chloraminated system, which may be impacted by seasonality, water quality changes and/or the varied origins of NDMA precursors within a given system. Copyright © 2015 Elsevier B.V. All rights reserved.

Antiatherogenic effects of S-nitroso-N-acetylcysteine in hypercholesterolemic LDL receptor knockout mice.

PubMed

Krieger, M H; Santos, K F R; Shishido, S M; Wanschel, A C B A; Estrela, H F G; Santos, L; De Oliveira, M G; Franchini, K G; Spadari-Bratfisch, R C; Laurindo, F R M

2006-02-01

The pathophysiology of the NO/NO synthase system and dysfunctional changes in the endothelium in the early phases of the atherogenic process are incompletely understood. In this study, we investigated the effects of the nitrosothiol NO donor S-nitroso-N-acetylcysteine (SNAC) in the early prevention of plaque development in the hypercholesterolemic LDLr-/- mice as well as the changes in endothelium-dependent relaxation and NO synthase expression. LDLr-/- mice were fed a 1.25% cholesterol-enriched diet for 15 days. Plasma cholesterol/triglyceride levels increased and this increase was accompanied by the development of aortic root lesions. Aortic vasorelaxation to acetylcholine was increased, although endothelium-independent relaxation in response to sodium nitroprusside did not change, which suggest stimulated NO release enhanced. This dysfunction was associated with enhanced aortic superoxide production and with increased levels of constitutive NOS isoform expression, particularly neuronal NOS. SNAC (S-nitroso-N-acetylcysteine) administration (0.51 micromol/kg/day i.p. for 15 days) decreased the extent of the plaque by 55% in hypercholesterolemic mice, but had no effects on vasomotor changes. It did, however, lead to a decrease in constitutive NOS expression. The SNAC induced only minor changes in plasma lipid profile. The present study has shown that, in early stages of plaque development in LDLr-/- mice, specific changes in NO/NO synthase system develop, that are characterized by increased endothelium-dependent vasorelaxation and increased constitutive NOS expression. Since the development of plaque and the indicator of endothelial cell dysfunction were prevented by SNAC, such treatment may constitute a novel strategy for the halting of progression of early plaque.

Detection of in vitro S-Nitrosylated Compounds with Cavity Ring-Down Spectroscopy

NASA Astrophysics Data System (ADS)

Rad, Mary Lynn; Mezher, Monique Michele; Gaston, Benjamin M.; Lehmann, Kevin

2016-06-01

Nitric oxide has been of strong biological interest for nearly 40 years due to its role in cardiovascular and nervous signaling. It has been shown that S-nitrosocompounds are the main carrier molecule for nitric oxide in biological systems. These compounds are also of interest due to their relationship to several diseases including muscular dystrophy, stroke, myocardial infarction, Alzheimer's disease, Parkinson's disease, cystic fibrosis, asthma, and pulmonary arterial hypertension. Understanding the role of these S-nitrosocompounds in these diseases requires concentration studies in healthy and diseased tissues as well as metabolic studies using isotopically labeled S-nitroso precursors such at 15N-arginine. The current widely used techniques for these studies include chemiluminescence, which is blind to isotopic substitution, and mass spectrometry, which is known to artificially create and break S-NO bonds in the sample preparation stages. To this end we have designed and constructed a mid-IR cavity ring-down spectrometer for the detection of nitric oxide released from the target S-nitrosocompounds. Progress toward measuring S-NO groups in biological samples using the CRDS instrument will be presented.

Development of Improved Rubber Compounds for Use in Weapon Applications

DTIC Science & Technology

1974-08-01

temperature properties, oil resistance or resistance to aging were noted for the Japanese elastomers. Rubber For Use In Liquid Propellants Results of a...gun systems. However. EPDM . Hydrln. Butyl EPRVxton an3 Nitroso rubbers were indicated as likely choices. Vulc.nlzates based on the last three of... rubber already in use. An EPDM vulcanizate, Nordel 1070, could be used in liquid propeliant gun systans in which hydrazine is used as an oxidizer

Thermal reactivity of some nitro- and nitroso-compounds derived from 1,3,5,7-tetraazabicyclo[3.3.1]nonane at contamination by ammonium nitrate.

PubMed

Zeman, Svatopluk; Shu, Yuanjie; Friedl, Zdenek; Vágenknecht, Jirí

2005-05-20

Thermal reactivity of 3,7-dinitro-1,3,5,7-tetraazabicyclo[3.3.1]nonane (DPT), 3,7-dinitroso-1,3,5,7-tetraazabicyclo[3.3.1]nonane (DNPT), 1,3,5-trinitroso-1,3,5-triazinane (TMTA or R-salt), 1,3,5-trinitro-1,3,5-triazinane (hexogen or RDX), 1,5-diacetyl-3,7-dinitro-1,3,5,7-tetrazocane (DADN), alpha-modification of the 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (octogen or HMX) and of their mixtures with 2wt.% of ammonium nitrate (AN) has been examined by means of non-isothermal differential thermal analysis. The resulting data were analyzed according to the Kissinger method. The reactivity was expressed as the E(a)R(-1) slopes of the Kissinger relationship. A relatively high reactivity has been found with mixtures of DPT and DNPT with AN. Electronic charges q(N) at nitrogen atoms in molecules of the compounds studied were calculated by means of ab initio DFT B3LYP/6-31G** method. The relationships were confirmed between the slopes E(a)R(-1) and the q(N) values for the nitrogen atoms primarily undergoing reaction. On the basis of these relationships it is stated that the destabilizing effect of AN is due to acidolytic attack of nitric acid (resulting from dissociation of ammonium nitrate) at the nitrogen atoms with the most negative q(N) values in the molecules of the compounds studied.

New public QSAR model for carcinogenicity

PubMed Central

2010-01-01

Background One of the main goals of the new chemical regulation REACH (Registration, Evaluation and Authorization of Chemicals) is to fulfill the gaps in data concerned with properties of chemicals affecting the human health. (Q)SAR models are accepted as a suitable source of information. The EU funded CAESAR project aimed to develop models for prediction of 5 endpoints for regulatory purposes. Carcinogenicity is one of the endpoints under consideration. Results Models for prediction of carcinogenic potency according to specific requirements of Chemical regulation were developed. The dataset of 805 non-congeneric chemicals extracted from Carcinogenic Potency Database (CPDBAS) was used. Counter Propagation Artificial Neural Network (CP ANN) algorithm was implemented. In the article two alternative models for prediction carcinogenicity are described. The first model employed eight MDL descriptors (model A) and the second one twelve Dragon descriptors (model B). CAESAR's models have been assessed according to the OECD principles for the validation of QSAR. For the model validity we used a wide series of statistical checks. Models A and B yielded accuracy of training set (644 compounds) equal to 91% and 89% correspondingly; the accuracy of the test set (161 compounds) was 73% and 69%, while the specificity was 69% and 61%, respectively. Sensitivity in both cases was equal to 75%. The accuracy of the leave 20% out cross validation for the training set of models A and B was equal to 66% and 62% respectively. To verify if the models perform correctly on new compounds the external validation was carried out. The external test set was composed of 738 compounds. We obtained accuracy of external validation equal to 61.4% and 60.0%, sensitivity 64.0% and 61.8% and specificity equal to 58.9% and 58.4% respectively for models A and B. Conclusion Carcinogenicity is a particularly important endpoint and it is expected that QSAR models will not replace the human experts opinions and conventional methods. However, we believe that combination of several methods will provide useful support to the overall evaluation of carcinogenicity. In present paper models for classification of carcinogenic compounds using MDL and Dragon descriptors were developed. Models could be used to set priorities among chemicals for further testing. The models at the CAESAR site were implemented in java and are publicly accessible. PMID:20678182

S-Nitrosylation and the Development of Pulmonary Hypertension

DTIC Science & Technology

2008-02-01

endothelium . In the experiments performed, N -acetyl cysteine (NAC) is used as a tracer to 1) monitor SNO formation...antioxidant N - acetylcysteine (NAC) as a bait reactant to measure NO transfer reactions in blood and to study the vascular effects of these reactions in vivo...NAC was converted to S-nitroso- N - acetylcysteine (SNOAC), decreasing erythrocytic S-nitrosothiol content, both during whole- blood deoxygenation

Use of Cell Viability Assay Data Improves the Prediction Accuracy of Conventional Quantitative Structure–Activity Relationship Models of Animal Carcinogenicity

PubMed Central

Zhu, Hao; Rusyn, Ivan; Richard, Ann; Tropsha, Alexander

2008-01-01

Background To develop efficient approaches for rapid evaluation of chemical toxicity and human health risk of environmental compounds, the National Toxicology Program (NTP) in collaboration with the National Center for Chemical Genomics has initiated a project on high-throughput screening (HTS) of environmental chemicals. The first HTS results for a set of 1,408 compounds tested for their effects on cell viability in six different cell lines have recently become available via PubChem. Objectives We have explored these data in terms of their utility for predicting adverse health effects of the environmental agents. Methods and results Initially, the classification k nearest neighbor (kNN) quantitative structure–activity relationship (QSAR) modeling method was applied to the HTS data only, for a curated data set of 384 compounds. The resulting models had prediction accuracies for training, test (containing 275 compounds together), and external validation (109 compounds) sets as high as 89%, 71%, and 74%, respectively. We then asked if HTS results could be of value in predicting rodent carcinogenicity. We identified 383 compounds for which data were available from both the Berkeley Carcinogenic Potency Database and NTP–HTS studies. We found that compounds classified by HTS as “actives” in at least one cell line were likely to be rodent carcinogens (sensitivity 77%); however, HTS “inactives” were far less informative (specificity 46%). Using chemical descriptors only, kNN QSAR modeling resulted in 62.3% prediction accuracy for rodent carcinogenicity applied to this data set. Importantly, the prediction accuracy of the model was significantly improved (72.7%) when chemical descriptors were augmented by HTS data, which were regarded as biological descriptors. Conclusions Our studies suggest that combining NTP–HTS profiles with conventional chemical descriptors could considerably improve the predictive power of computational approaches in toxicology. PMID:18414635

Monitoring carcinogen actions on DNA by 32P-postlabeling.

PubMed

Randerath, K; Randerath, E

1990-01-01

Among several recently developed analytical methods, 32P-postlabeling analysis is a highly sensitive method for the detection and measurement of covalent carcinogen-DNA adducts and other DNA modifications. Since the method does not require radioactive carcinogens, it is suitable for DNA of humans exposed to environmental or occupational genotoxicants. The basic procedure entails the enzymatic incorporation of 32P-label into monomeric or dimeric hydrolysis products of DNA, followed by chromatographic mapping and autoradiography of the 32P-labeled digestion products and quantitation by scintillation spectrometry. Microgram amounts of DNA are analyzed; thus the assay is well suited for limited amounts of cells or tissue. Various versions of the assay afford different sensitivities of adduct detection. Under optimal conditions, one aromatic or bulky/hydrophobic adduct in 10(8)-10(10) nucleotides can be detected and measured (corresponding to 0.3-30 amol adduct/microgram DNA or 0.1-10 nmol adduct/mol DNA-P). The assay has been successfully applied to a variety of mutagenic (genotoxic) as well as non-mutagenic carcinogens. In humans, the 32P-postlabeling assay has been applied to DNA specimens from cigarette smokers, iron foundry workers, and coke oven workers. Estimation of total aromatic adduct levels in exposed individuals gave values of 1 adduct in 10(6)-10(8) DNA nucleotides. These values are similar to the total levels of persistent adducts in tissues of animals after exposure to initiating or carcinogenic doses of authentic aromatic genotoxicants. Among the non-mutagenic carcinogens investigated are estrogens, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), choline-devoid diet, carbon tetrachloride, and peroxisome proliferators. In addition, age-dependent DNA modifications (I-compounds) are being detected by 32P-postlabeling in animals that have not been knowingly exposed to mutagens/carcinogens. I-compound profiles and levels are dependent on species, tissue, sex, and diet. Reduced levels of I-compounds have been consistently noted in the target organ of carcinogen-exposed animals and in resulting neoplasms, suggesting that I-compound loss may play a role in carcinogenesis.

Evidence That the Capacity of Nongenotoxic Carcinogens to Induce Oxidative Stress Is Subject to Marked Variability

PubMed Central

Henderson, Colin J.; Cameron, Amy R.; Chatham, Lynsey; Stanley, Lesley A.; Wolf, Charles Roland

2015-01-01

Many drugs and environmental chemicals which are not directly mutagenic have the capacity to increase the incidence of tumors in the liver and other tissues. For this reason, such compounds are known as nongenotoxic carcinogens. The mechanisms underlying their effects remain unclear; however, their capacity to induce oxidative stress is considered to be a critical step in the carcinogenic process, although the evidence that this is actually the case remains equivocal and sparse. We have exploited a novel heme oxygenase-1 reporter mouse to evaluate the capacity of nongenotoxic carcinogens with different mechanisms of action to induce oxidative stress in the liver in vivo. When these compounds were administered at doses reported to cause liver tumors, marked differences in activation of the reporter were observed. 1,4-Dichlorobenzene and nafenopin were strong inducers of oxidative stress, whereas phenobarbital, piperonyl butoxide, cyproterone acetate, and WY14,643 were, at best, only very weak inducers. In the case of phenobarbital and thioacetamide, the number of LacZ-positive hepatocytes increased with time, and for the latter also with dose. The data obtained demonstrate that although some nongenotoxic carcinogens can induce oxidative stress, it is not a dominant feature of the response to these compounds. Therefore in contrast to the current models, these data suggest that oxidative stress is not a key determinant in the mechanism of nongenotoxic carcinogenesis but may contribute to the effects in a compound-specific manner. PMID:25690736

Cytotoxicity of nitric oxide in Fu5 rat hepatoma cells: evidence for co-operative action with hydrogen peroxide.

PubMed Central

Ioannidis, I; de Groot, H

1993-01-01

The NO-releasing compounds 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1), sodium nitroprusside (SNP) and S-nitroso-N-acetyl-DL-penicillamine (SNAP) mediated a rapid loss of viability of Fu5 rat hepatoma cells. SIN-1 in addition to NO also released the superoxide anion radical (O2-.). Its cytotoxicity, however, was not affected by superoxide dismutase. In contrast, the H2O2-converting enzyme catalase significantly, but not completely, diminished cell damage, indicating participation of H2O2 in the tumoricidal activity of SIN-1. Glucose oxidase (5 m-units/ml), producing similar amounts of H2O2 to 5 mM SIN-1, had no effect on cell viability. When 5 m-units/ml glucose oxidase was added to incubations with 5 mM SNP, which alone initiated cell injury of about 40%, cell damage was significantly increased up to 95%. Similar results were observed with 1 mM SNAP and 20 m-units/ml xanthine oxidase, which mediated cytotoxicity of about 90% when both compounds were added together, compared with 35% and 55% cell injury, respectively, induced by the single compounds. The results indicate that a co-operative action with H2O2 enhances the tumoricidal activity of NO in Fu5 cells. No evidence for an interplay of NO with O2-. in cytotoxicity, e.g. via the peroxynitrite anion (ONOO-), was found. PMID:8257422

The regulation of host cellular and gut microbial metabolism in the development and prevention of colorectal cancer.

PubMed

Zhou, Cheng-Bei; Fang, Jing-Yuan

2018-01-23

Metabolism regulation is crucial in colorectal cancer (CRC) and has emerged as a remarkable field currently. The cellular metabolism of glucose, amino acids and lipids in CRC are all reprogrammed. Each of them changes tumour microenvironment, modulates bacterial composition and activity, and eventually promotes CRC development. Metabolites such as short chain fatty acids, secondary bile acids, N-nitroso compounds, hydrogen sulphide, polyphenols and toxins like fragilysin, FadA, cytolethal distending toxin and colibactin play a dual role in CRC. The relationship of gut microbe-metabolite is essential in remodelling intestinal microbial ecology composition and metabolic activity. It regulates the metabolism of colonic epithelial cells and changes the tumour microenvironment in CRC. Microbial metabolism manipulation has been considered to be potentially preventive in CRC, but more large-scale clinical trials are required before their application in clinical practice in the near future.

Too much of a good thing? Nitrate from nitrogen fertilizers and cancer.

PubMed

Ward, Mary H

2009-01-01

Nitrate levels in water supplies have been increasing in many areas of the world; therefore, additional studies of populations with well-characterized exposures are urgently needed to further our understanding of cancer risk associated with nitrate ingestion. Future studies should assess exposure for individuals (e.g., case-control, cohort studies) in a time frame relevant to disease development, and evaluate factors affecting nitrosation. Estimating N-nitroso compounds formation via nitrate ingestion requires information on dietary and drinking water sources of nitrate, inhibitors of nitrosation (e.g., vitamin C), nitrosation precursors (e.g., red meat, nitrosatable drugs), and medical conditions that may increase nitrosation (e.g., inflammatory bowel disease). Studies should account for the potentially different effects of dietary and water sources of nitrate and should include the population using private wells for whom exposure levels are often higher than public supplies.

Safety Assessment of Ethanolamine and Ethanolamine Salts as Used in Cosmetics.

PubMed

Fiume, Monice M; Heldreth, Bart A; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

2015-09-01

The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) assessed the safety of ethanolamine and 12 salts of ethanolamine as used in cosmetics. Ethanolamine functions as a pH adjuster. The majority of the salts are reported to function as surfactants, and the others are reported to function as pH adjusters, hair fixatives, or preservatives. The Panel reviewed available animal and clinical data, as well as information from previous relevant CIR reports. Because data were not available for each individual ingredient and because the salts dissociate freely in water, the Panel extrapolated from those previous reports to support safety. The Panel concluded that these ingredients are safe in the present practices of use and concentrations (rinse-off products only) when formulated to be nonirritating, and these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed. © The Author(s) 2015.

Assessment of volatile organic compounds and particulate matter in a dental clinic and health risks to clinic personnel.

PubMed

Hong, Yu-Jue; Huang, Yen-Ching; Lee, I-Long; Chiang, Che-Ming; Lin, Chitsan; Jeng, Hueiwang Anna

2015-01-01

This study was conducted to assess (1) levels of volatile organic compounds (VOCs) and particulate matter (PM) in a dental clinic in southern Taiwan and (2) dental care personnel's health risks associated with due to chronic exposure to VOCs. An automatic, continuous sampling system and a multi-gas monitor were employed to quantify the air pollutants, along with environmental comfort factors, including temperature, CO2, and relative humidity at six sampling sites in the clinic over eight days. Specific VOC compounds were identified and their concentrations were quantified. Both non-carcinogenic and carcinogenic VOC compounds were assessed based on the US Environmental Protection Agency's Principles of Health Risk Assessment in terms of whether those indoor air pollutants increased health risks for the full-time dental care professionals at the clinic. Increased levels of VOCs were recorded during business hours and exceeded limits recommended by the Taiwan Environmental Protection Agency. A total of 68 VOC compounds were identified in the study area. Methylene methacrylate (2.8 ppm) and acetone (0.176 ppm) were the only two non-carcinogenic compounds that posed increased risks for human health, yielding hazard indexes of 16.4 and 4.1, respectively. None of the carcinogenic compounds increased cancer risk. All detected PM10 levels ranged from 20 to 150 μg/m(3), which met the Taiwan EPA and international limits. The average PM10 level during business hours was significantly higher than that during non-business hours (P = 0.04). Improved ventilation capacity in the air conditioning system was recommended to reduce VOCs and PM levels.

Global structure–activity relationship model for nonmutagenic carcinogens using virtual ligand-protein interactions as model descriptors

PubMed Central

Cunningham, Albert R.; Trent, John O.

2012-01-01

Structure–activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe the use of a traditional fragment-based SAR approach along with a new virtual ligand-protein interaction-based approach for modeling of nonmutagenic carcinogens. The ligand-based SAR models used descriptors derived from computationally calculated ligand-binding affinities for learning set agents to 5495 proteins. Two learning sets were developed. One set was from the Carcinogenic Potency Database, where chemicals tested for rat carcinogenesis along with Salmonella mutagenicity data were provided. The second was from Malacarne et al. who developed a learning set of nonalerting compounds based on rodent cancer bioassay data and Ashby’s structural alerts. When the rat cancer models were categorized based on mutagenicity, the traditional fragment model outperformed the ligand-based model. However, when the learning sets were composed solely of nonmutagenic or nonalerting carcinogens and noncarcinogens, the fragment model demonstrated a concordance of near 50%, whereas the ligand-based models demonstrated a concordance of 71% for nonmutagenic carcinogens and 74% for nonalerting carcinogens. Overall, these findings suggest that expert system analysis of virtual chemical protein interactions may be useful for developing predictive SAR models for nonmutagenic carcinogens. Moreover, a more practical approach for developing SAR models for carcinogenesis may include fragment-based models for chemicals testing positive for mutagenicity and ligand-based models for chemicals devoid of DNA reactivity. PMID:22678118

Global structure-activity relationship model for nonmutagenic carcinogens using virtual ligand-protein interactions as model descriptors.

PubMed

Cunningham, Albert R; Carrasquer, C Alex; Qamar, Shahid; Maguire, Jon M; Cunningham, Suzanne L; Trent, John O

2012-10-01

Structure-activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe the use of a traditional fragment-based SAR approach along with a new virtual ligand-protein interaction-based approach for modeling of nonmutagenic carcinogens. The ligand-based SAR models used descriptors derived from computationally calculated ligand-binding affinities for learning set agents to 5495 proteins. Two learning sets were developed. One set was from the Carcinogenic Potency Database, where chemicals tested for rat carcinogenesis along with Salmonella mutagenicity data were provided. The second was from Malacarne et al. who developed a learning set of nonalerting compounds based on rodent cancer bioassay data and Ashby's structural alerts. When the rat cancer models were categorized based on mutagenicity, the traditional fragment model outperformed the ligand-based model. However, when the learning sets were composed solely of nonmutagenic or nonalerting carcinogens and noncarcinogens, the fragment model demonstrated a concordance of near 50%, whereas the ligand-based models demonstrated a concordance of 71% for nonmutagenic carcinogens and 74% for nonalerting carcinogens. Overall, these findings suggest that expert system analysis of virtual chemical protein interactions may be useful for developing predictive SAR models for nonmutagenic carcinogens. Moreover, a more practical approach for developing SAR models for carcinogenesis may include fragment-based models for chemicals testing positive for mutagenicity and ligand-based models for chemicals devoid of DNA reactivity.

Mechanism of action of (2-haloethyl)nitrosoureas on DNA. Isolation and reactions of postulated 2-(alkylimino)-3-nitrosooxazolidine intermediates in the decomposition of 1,3-bis(2-chloroethyl)-, 1-(2-chloroethyl)-3-cyclohexyl-, and 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)-1-nitrosourea.

PubMed

Lown, J W; Chauhan, S M

1981-03-01

Three examples of the postulated but hitherto unisolated 2-(alkylimino)-3-nitrosooxazolidines (2) have been prepared containing cyclohexyl, trans-4-methylcyclohexyl, and 2-chloroethyl groups at the 2 position, respectively. These compounds correspond to intermediates previously postulated to be formed in the aqueous decomposition of the antitumor agents 1-(2-chloroethyl)-3-cyclohexyl- (CCNU), 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)- (MeCCNU), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), respectively, Compounds 2 decompose under physiological conditions to give a range of products similar to those formed from the corresponding (2-chloroethyl)nitrosoureas, including the hitherto unrecognized 2-hydroxyethl N-alkylcarbamates (9). Compounds 2a and 2b are converted with hydrochloric acid into CCNU and MeCCNU, respectively, suggesting that 2a and 2b may be reaction intermediates of decomposition. The corresponding 3-alkyl-1-nitroso-1-(2-hydroxyethyl)ureas (4) were characterized and, since they also decompose to give the same products as 2, may arise from the ring opening of 2. The intermediacy of compounds 4 can explain the formation of hydroxyethylated nucleosides isolated by other workers from the reaction of (2-chloroethyl)nitrosoureas on polynucleotides.

Reactivities of various mediators and laccases with kraft pulp and lignin model compounds.

PubMed

Bourbonnais, R; Paice, M G; Freiermuth, B; Bodie, E; Borneman, S

1997-12-01

Laccase-catalyzed oxygen delignification of kraft pulp offers some potential as a replacement for conventional chemical bleaching and has the advantage of requiring much lower pressure and temperature. However, chemical mediators are required for effective delignification by laccase, and their price is currently too high at the dosages required. To date, most studies have employed laccase from Trametes versicolor. We have found significant differences in reactivity between laccases from different fungi when they are tested for pulp delignification in the presence of the mediators 2,2(prm1)-azinobis(3-ethylbenzthiazoline-6-sulfonate) (ABTS) and 1-hydroxybenzotriazole (HBT). A more detailed study of T. versicolor laccase with ABTS and HBT showed that HBT gave the most extensive delignification over 2 h but deactivated the enzyme, and therefore a higher enzyme dosage was required. Other mediators, including 1-nitroso-2-naphthol-3,6-disulfonic acid, 4-hydroxy-3-nitroso-1-naphthalenesulfonic acid, promazine, chlorpromazine, and Remazol brilliant blue, were also tested for their ability to delignify kraft pulp. Studies with dimeric model compounds indicated that the mechanisms of oxidation by ABTS and HBT are different. In addition, oxygen uptake by laccase is much slower with HBT than with ABTS. It is proposed that the dication of ABTS and the 1-oxide radical of HBT, with redox potentials in the 0.8- to 0.9-V range, are required for pulp delignification.

Reactivities of Various Mediators and Laccases with Kraft Pulp and Lignin Model Compounds

PubMed Central

Bourbonnais, R.; Paice, M. G.; Freiermuth, B.; Bodie, E.; Borneman, S.

1997-01-01

Laccase-catalyzed oxygen delignification of kraft pulp offers some potential as a replacement for conventional chemical bleaching and has the advantage of requiring much lower pressure and temperature. However, chemical mediators are required for effective delignification by laccase, and their price is currently too high at the dosages required. To date, most studies have employed laccase from Trametes versicolor. We have found significant differences in reactivity between laccases from different fungi when they are tested for pulp delignification in the presence of the mediators 2,2(prm1)-azinobis(3-ethylbenzthiazoline-6-sulfonate) (ABTS) and 1-hydroxybenzotriazole (HBT). A more detailed study of T. versicolor laccase with ABTS and HBT showed that HBT gave the most extensive delignification over 2 h but deactivated the enzyme, and therefore a higher enzyme dosage was required. Other mediators, including 1-nitroso-2-naphthol-3,6-disulfonic acid, 4-hydroxy-3-nitroso-1-naphthalenesulfonic acid, promazine, chlorpromazine, and Remazol brilliant blue, were also tested for their ability to delignify kraft pulp. Studies with dimeric model compounds indicated that the mechanisms of oxidation by ABTS and HBT are different. In addition, oxygen uptake by laccase is much slower with HBT than with ABTS. It is proposed that the dication of ABTS and the 1-oxide radical of HBT, with redox potentials in the 0.8- to 0.9-V range, are required for pulp delignification. PMID:16535747

Prediction of rodent carcinogenicity bioassays from molecular structure using inductive logic programming

DOE Office of Scientific and Technical Information (OSTI.GOV)

King, R.D.; Srinivasan, A.

1996-10-01

The machine learning program Progol was applied to the problem of forming the structure-activity relationship (SAR) for a set of compounds tested for carcinogenicity in rodent bioassays by the U.S. National Toxicology Program (NTP). Progol is the first inductive logic programming (ILP) algorithm to use a fully relational method for describing chemical structure in SARs, based on using atoms and their bond connectivities. Progol is well suited to forming SARs for carcinogenicity as it is designed to produce easily understandable rules (structural alerts) for sets of noncongeneric compounds. The Progol SAR method was tested by prediction of a set ofmore » compounds that have been widely predicted by other SAR methods (the compounds used in the NTP`s first round of carcinogenesis predictions). For these compounds no method (human or machine) was significantly more accurate than Progol. Progol was the most accurate method that did not use data from biological tests on rodents (however, the difference in accuracy is not significant). The Progol predictions were based solely on chemical structure and the results of tests for Salmonella mutagenicity. Using the full NTP database, the prediction accuracy of Progol was estimated to be 63% ({+-}3%) using 5-fold cross validation. A set of structural alerts for carcinogenesis was automatically generated and the chemical rationale for them investigated-these structural alerts are statistically independent of the Salmonella mutagenicity. Carcinogenicity is predicted for the compounds used in the NTP`s second round of carcinogenesis predictions. The results for prediction of carcinogenesis, taken together with the previous successful applications of predicting mutagenicity in nitroaromatic compounds, and inhibition of angiogenesis by suramin analogues, show that Progol has a role to play in understanding the SARs of cancer-related compounds. 29 refs., 2 figs., 4 tabs.« less

Predictive Models for Carcinogenicity and Mutagenicity ...

EPA Pesticide Factsheets

Mutagenicity and carcinogenicity are endpoints of major environmental and regulatory concern. These endpoints are also important targets for development of alternative methods for screening and prediction due to the large number of chemicals of potential concern and the tremendous cost (in time, money, animals) of rodent carcinogenicity bioassays. Both mutagenicity and carcinogenicity involve complex, cellular processes that are only partially understood. Advances in technologies and generation of new data will permit a much deeper understanding. In silico methods for predicting mutagenicity and rodent carcinogenicity based on chemical structural features, along with current mutagenicity and carcinogenicity data sets, have performed well for local prediction (i.e., within specific chemical classes), but are less successful for global prediction (i.e., for a broad range of chemicals). The predictivity of in silico methods can be improved by improving the quality of the data base and endpoints used for modelling. In particular, in vitro assays for clastogenicity need to be improved to reduce false positives (relative to rodent carcinogenicity) and to detect compounds that do not interact directly with DNA or have epigenetic activities. New assays emerging to complement or replace some of the standard assays include VitotoxTM, GreenScreenGC, and RadarScreen. The needs of industry and regulators to assess thousands of compounds necessitate the development of high-t

Nitrite fixation by humic substances: Nitrogen-15 nuclear magnetic resonance evidence for potential intermediates in chemodenitrification

USGS Publications Warehouse

Thorn, K.A.; Mikita, M.A.

2000-01-01

Studies have suggested that NO2/-, produced during nitrification and denitrification, can become incorporated into soil organic matter and, in one of the processes associated with chemodenitrification, react with organic matter to form trace N gases, including N2O. To gain an understanding of the nitrosation chemistry on a molecular level, soil and aquatic humic substances were reacted with 15N-labeled NaNO2, and analyzed by liquid phase 15N and 13C nuclear magnetic resonance (NMR). The International Humic Substances Society (IHSS) Pahokee peat and peat humic acid were also reacted with Na15NO2 and analyzed by solid-state 15N NMR. In Suwannee River, Armadale, and Laurentian fulvic acids, phenolic rings and activated methylene groups underwent nitrosation to form nitrosophenols (quinone monoximes) and ketoximes, respectively. The oximes underwent Beckmann rearrangements to 2??amides, and Beckmann fragmentations to nitriles. The nitriles in turn underwent hydrolysis to 1??amides. Peaks tentatively identified as imine, indophenol, or azoxybenzene nitrogens were clearly present in spectra of samples nitrosated at pH 6 but diminished at pH 3. The 15N NMR spectrum of the peat humic acid exhibited peaks corresponding with N-nitroso groups in addition to nitrosophenols, ketoximes, and secondary Beckmann reaction products. Formation of N-nitroso groups was more significant in the whole peat compared with the peat humic acid. Carbon-13 NMR analyses also indicated the occurrence of nitrosative demethoxylation in peat and soil humic acids. Reaction of 15N-NH3 fixated fulvic acid with unlabeled NO2/- resulted in nitrosative deamination of aminohydroquinone N, suggesting a previously unrecognized pathway for production of N2 gas in soils fertilized with NH3.Studies have suggested that NO2-, produced during nitrification and denitrification, can become incorporated into soil organic matter and, in one of the processes associated with chemodenitrification, react with organic matter to form trace N gases, including N2O. To gain an understanding of the nitrosation chemistry on a molecular level, soil and aquatic humic substances were reacted with 15N-labeled NaNO2, and analyzed by liquid phase 15N and 13C nuclear magnetic resonance (NMR). The International Humic Substances Society (IHSS) Pahokee peat and peat humic acid were also reacted with Na15NO2 and analyzed by solid-state 15N NMR. In Suwannee River, Armadale, and Laurentian fulvic acids, phenolic rings and activated methylene groups underwent nitrosation to form nitrosophenols (quinone monoximes) and ketoximes, respectively. The oximes underwent Beckmann rearrangements to 2?? amides, and Beckmann fragmentations to nitriles. The nitriles in turn underwent hydrolysis to 1?? amides. Peaks tentatively identified as imine, indophenol, or azoxybenzene nitrogens were dearly present in spectra of samples nitrosated at pH 6 but diminished at pH 3. The 15N NMR spectrum of the peat humic acid exhibited peaks corresponding with N-nitroso groups in addition to nitrosophenols, ketoximes, and secondary Beckmann reaction products. Formation of N-nitroso groups was more significant in the whole peat compared with the peat humic acid. Carbon-13 NMR analyses also indicated the occurrence of nitrosative demethoxylation in peat and soil humic acids. Reaction of 15N-NH3 fixated fulvic acids with unlabeled NO2- resulted in nitrosative deamination of aminohydroquinone N, suggesting a previously unrecognized pathway for production of N2 gas in soils fertilized with NH3.

Characterization of N-methyl-D-aspartate-evoked taurine release in the developing and adult mouse hippocampus.

PubMed

Saransaari, P; Oja, S S

2003-01-01

Taurine is an inhibitory amino acid acting as an osmoregulator and neuroromodulator in the brain, with neuroprotective properties. The ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) greatly potentiates taurine release from brain preparations in both normal and ischemic conditions, the effect being particularly marked in the developing hippocampus. We now characterized the regulation of NMDA-stimulated taurine release from hippocampal slices from adult (3-month-old) and developing (7-day-old) mouse using a superfusion system. The NMDA-stimulated taurine release was receptor-mediated in both adult and developing mouse hippocampus. In adults, only NO-generating compounds, sodium nitroprusside, S-nitroso-N-acetylpenicillamine and hydroxylamine reduced the release, as did also NO synthase inhibitors, 7-nitroindazole and nitroarginine, indicating that the release is mediated by the NO/cGMP pathway. On the other hand, the regulation of the NMDA-evoked taurine release proved to be somewhat complex in the immature hippocampus. It was not affected by the NOergic compounds, but enhanced by the protein kinase C activator 4 beta-phorbol 12-myristate 13-acetate and adenosine receptor A(1) agonists, N(6)-cyclohexyladenosine and R(-)N(6)-(2-phenylisopropyl)adenosine in a receptor-mediated manner. The activation of both ionotropic 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors and metabotropic glutamate group I receptors also enhanced the evoked release. The NMDA-receptor-stimulated taurine release could be a part of the neuroprotective properties of taurine, being important particularly under cell-damaging conditions in the developing hippocampus and hence preventing excitotoxicity.

N-nitrosations of basic amino acid residues in polypeptide.

PubMed

Kuo, Wu-Nan; Ivy, Dynisha; Guruvadoo, Luvina; White, Atavia; Graham, Latia

2004-09-01

Changes in the electrophoretic pattern were noted in the products of polypeptides of identical basic amino acids preincubated with reactive or degraded PN, suggesting the occurrence of N-nitrosation of the epsilon-amino group of lysine, the guanido group of arginine and the imidazole group of histidine. Additionally, increase in the N-nitroso immunoreactivity of preincubated histones H2A and H2B was detected by Western blot analysis.

Association of Metronidazole with Cancer: A Potential Risk Factor or Inconsistent Deductions?

PubMed

Adil, Muhammad; Iqbal, Waheed; Adnan, Fazal; Wazir, Shabnam; Khan, Imran; Khayam, Mohammad Umar; Kamal, Mohammad Amjad; Ahmad, Shafiq; Ahmad, Jawad; Khan, Ishaq N

2018-03-29

Metronidazole is a synthetic derivative of nitroimidazole that has been widely used for the treatment of several bacterial and protozoal parasitic infections including trichomoniasis, amoebiasis, giardiasis, liver abscess, acute ulcerative gingivitis, syphilis and tropical phagedena. In addition to its toxicity in the gastrointestinal tract and central/peripheral nervous system, metronidazole has been reported to cause mucosal imbalance by affecting the expression of mucin (Muc2 gene), which is responsible to form an insoluble mucous barrier that protects the gut lumen from microbial colonization. Since metronidazole is a nitro-group containing compound and used significantly for therapeutic purposes, scientists evaluated its carcinogenicity in different preclinical in-vitro and in-vivo studies. In addition to the preclinical in-vitro validation of DNA damage, metronidazole has been reported to induce cancer in the variety of animal models including lung cancer, malignant lymphomas, breast cancer, hepatocellular carcinoma, pituitary tumors, testicular neoplasms and uterine cancer. Several retrospective cohort studies have reported metronidazole as a potential risk factor for lung cancer (n = 771), cervical cancer (n = 2500), breast cancer (n = 2), cholangiocarcinoma (n = 1), and neuroblastoma (n = 28). So far, all the reported data have confirmed metronidazole carcinogenicity in animals; however, it is still controversial in humans. Based on previous observations, the oxidative metabolites from metronidazole metabolism are shown to have more carcinogenic effects than the parent drug itself. Since ~40% of drug metabolism is reliant on cytochromes, the inter-patient' differences in metronidazole metabolism potentially indicate the individual susceptibility to developing cancer. Due to these potent carcinogenic behaviors, use of metronidazole for animals treatment and its uses in animal food products are barred in the USA and European countries; however, its clinical use in human population is increasing. For this purpose, updated and improved research studies are required to explicate its mechanism/s involved in carcinogenesis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Ingested Nitrate and Breast Cancer in the Spanish Multicase-Control Study on Cancer (MCC-Spain)

PubMed Central

Espejo-Herrera, Nadia; Gracia-Lavedan, Esther; Pollan, Marina; Aragonés, Nuria; Boldo, Elena; Perez-Gomez, Beatriz; Altzibar, Jone M.; Amiano, Pilar; Zabala, Ana Jiménez; Ardanaz, Eva; Guevara, Marcela; Molina, Antonio J.; Barrio, Juan Pablo; Gómez-Acebo, Ines; Tardón, Adonina; Peiró, Rosana; Chirlaque, Maria Dolores; Palau, Margarita; Muñoz, Montse; Font-Ribera, Laia; Castaño-Vinyals, Gemma; Kogevinas, Manolis; Villanueva, Cristina M.

2016-01-01

Background: Ingested nitrate leads to endogenous formation of N-nitroso compounds that are breast carcinogens in animals, but human evidence is limited. Objective: We evaluated ingested nitrate as a risk factor for breast cancer (BC) in a multicase–control study. Methods: Hospital-based incident BC cases and population-based controls were recruited in eight Spanish regions in 2008–2013; participants provided residential and water consumption from 18 years of age and information on known BC risk factors. Long-term nitrate levels (1940–2010) were estimated and linked with residential histories and water consumption to calculate waterborne ingested nitrate (milligrams/day). Dietary ingested nitrate (milligrams/day) was calculated using food frequency questionnaires and published dietary nitrate contents. Interactions with endogenous nitrosation factors and other variables were evaluated. A total of 1,245 cases and 1,520 controls were included in the statistical analysis. Results: Among the study regions, average ± SD waterborne ingested nitrate ranged from 2.9 ± 1.9 to 13.5 ± 7.5 mg/day, and dietary ingested nitrate ranged from 88.5 ± 48.7 to 154 ± 87.8 mg/day. Waterborne ingested nitrate was not associated with BC overall, but among postmenopausal women, those with both high nitrate (> 6 vs. < 2.6 mg/day) and high red meat intake (≥ 20 vs. < 20 g/day) were more likely to be cases than women with low nitrate and low red meat intake (adjusted odds ratio = 1.64; 95% confidence interval: 1.08, 2.49; overall interaction p-value = 0.17). No association was found with dietary nitrate. Conclusions: Waterborne ingested nitrate was associated with BC only among postmenopausal women with high red meat consumption. Dietary nitrate was not associated with BC regardless of the animal or vegetable source or of menopausal status. Citation: Espejo-Herrera N, Gracia-Lavedan E, Pollan M, Aragonés N, Boldo E, Perez-Gomez B, Altzibar JM, Amiano P, Zabala AJ, Ardanaz E, Guevara M, Molina AJ, Barrio JP, Gómez-Acebo I, Tardón A, Peiró R, Chirlaque MD, Palau M, Muñoz M, Font-Ribera L, Castaño-Vinyals G, Kogevinas M, Villanueva CM. 2016. Ingested nitrate and breast cancer in the Spanish Multicase-Control Study on Cancer (MCC-Spain). Environ Health Perspect 124:1042–1049; http://dx.doi.org/10.1289/ehp.1510334 PMID:26942716

Phase I and phase II reductive metabolism simulation of nitro aromatic xenobiotics with electrochemistry coupled with high resolution mass spectrometry.

PubMed

Bussy, Ugo; Chung-Davidson, Yu-Wen; Li, Ke; Li, Weiming

2014-11-01

Electrochemistry combined with (liquid chromatography) high resolution mass spectrometry was used to simulate the general reductive metabolism of three biologically important nitro aromatic molecules: 3-trifluoromethyl-4-nitrophenol (TFM), niclosamide, and nilutamide. TFM is a pesticide used in the Laurential Great Lakes while niclosamide and nilutamide are used in cancer therapy. At first, a flow-through electrochemical cell was directly connected to a high resolution mass spectrometer to evaluate the ability of electrochemistry to produce the main reduction metabolites of nitro aromatic, nitroso, hydroxylamine, and amine functional groups. Electrochemical experiments were then carried out at a constant potential of -2.5 V before analysis of the reduction products by LC-HRMS, which confirmed the presence of the nitroso, hydroxylamine, and amine species as well as dimers. Dimer identification illustrates the reactivity of the nitroso species with amine and hydroxylamine species. To investigate xenobiotic metabolism, the reactivity of nitroso species to biomolecules was also examined. Binding of the nitroso metabolite to glutathione was demonstrated by the observation of adducts by LC-ESI(+)-HRMS and the characteristics of their MSMS fragmentation. In conclusion, electrochemistry produces the main reductive metabolites of nitro aromatics and supports the observation of nitroso reactivity through dimer or glutathione adduct formation.

Monocyclic aromatic amines as potential human carcinogens: old is new again

PubMed Central

Skipper, Paul L.; Kim, Min Young; Sun, H.-L. Patty; Wogan, Gerald N.; Tannenbaum, Steven R.

2010-01-01

Alkylanilines are a group of chemicals whose ubiquitous presence in the environment is a result of the multitude of sources from which they originate. Exposure assessments indicate that most individuals experience lifelong exposure to these compounds. Many alkylanilines have biological activity similar to that of the carcinogenic multi-ring aromatic amines. This review provides an overview of human exposure and biological effects. It also describes recent investigations into the biochemical mechanisms of action that lead to the assessment that they are most probably more complex than those of the more extensively investigated multi-ring aromatic amines. Not only is nitrenium ion chemistry implicated in DNA damage by alkylanilines but also reactions involving quinone imines and perhaps reactive oxygen species. Recent results described here indicate that alkylanilines can be potent genotoxins for cultured mammalian cells when activated by exogenous or endogenous phase I and phase II xenobiotic-metabolizing enzymes. The nature of specific DNA damage products responsible for mutagenicity remains to be identified but evidence to date supports mechanisms of activation through obligatory N-hydroxylation as well as subsequent conjugation by sulfation and/or acetylation. A fuller understanding of the mechanisms of alkylaniline genotoxicity is expected to provide important insights into the environmental and genetic origins of one or more human cancers and may reveal a substantial role for this group of compounds as potential human chemical carcinogens. PMID:19887514

Use of a standardized JaCVAM in vivo rat comet assay protocol to assess the genotoxicity of three coded test compounds; ampicillin trihydrate, 1,2-dimethylhydrazine dihydrochloride, and N-nitrosodimethylamine.

PubMed

McNamee, J P; Bellier, P V

2015-07-01

As part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline comet assay (comet assay), our laboratory examined ampicillin trihydrate (AMP), 1,2-dimethylhydrazine dihydrochloride (DMH), and N-nitrosodimethylamine (NDA) using a standard comet assay validation protocol (v14.2) developed by the JaCVAM validation management team (VMT). Coded samples were received by our laboratory along with basic MSDS information. Solubility analysis and range-finding experiments of the coded test compounds were conducted for dose selection. Animal dosing schedules, the comet assay processing and analysis, and statistical analysis were conducted in accordance with the standard protocol. Based upon our blinded evaluation, AMP was not found to exhibit evidence of genotoxicity in either the rat liver or stomach. However, both NDA and DMH were observed to cause a significant increase in % tail DNA in the rat liver at all dose levels tested. While acute hepatoxicity was observed for these compounds in the high dose group, in the investigators opinion there were a sufficient number of consistently damaged/measurable cells at the medium and low dose groups to judge these compounds as genotoxic. There was no evidence of genotoxicity from either NDA or DMH in the rat stomach. In conclusion, our laboratory observed increased DNA damage from two blinded test compounds in rat liver (later identified as genotoxic carcinogens), while no evidence of genotoxicity was observed for the third blinded test compound (later identified as a non-genotoxic, non-carcinogen). This data supports the use of a standardized protocol of the in vivo comet assay as a cost-effective alternative genotoxicity assay for regulatory testing purposes. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

Bioassay of Military Relevant Compounds for Carcinogenic Activity by the Strain A Mouse Lung Tumor Bioassay

DTIC Science & Technology

1985-01-01

enzymes resulted mainly in the formation of 2-amino-6-nitrotoluene and 2-(N-acetylami no)-6-nitrotoluene and minor amounts of 2,6-diaminotoluene. I.p...2,6-DNT to DNA of cultured hepatocytes from both A/N mice and Fischer-344 rats required prior metabolism of 2,6-DNT by the respective cecal enzymes . DNA...64 37. In Vitro Metabolism of [3- 3H]2,6-DNT by Cecal Enzymes from A/ Mice and Fischer-344 Rats ..... ............ 65 38. In Vivo Covalent

Quantitative comparison between in vivo DNA adduct formation from exposure to selected DNA-reactive carcinogens, natural background levels of DNA adduct formation and tumour incidence in rodent bioassays.

PubMed

Paini, Alicia; Scholz, Gabriele; Marin-Kuan, Maricel; Schilter, Benoît; O'Brien, John; van Bladeren, Peter J; Rietjens, Ivonne M C M

2011-09-01

This study aimed at quantitatively comparing the occurrence/formation of DNA adducts with the carcinogenicity induced by a selection of DNA-reactive genotoxic carcinogens. Contrary to previous efforts, we used a very uniform set of data, limited to in vivo rat liver studies in order to investigate whether a correlation can be obtained, using a benchmark dose (BMD) approach. Dose-response data on both carcinogenicity and in vivo DNA adduct formation were available for six compounds, i.e. 2-acetylaminofluorene, aflatoxin B1, methyleugenol, safrole, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and tamoxifen. BMD(10) values for liver carcinogenicity were calculated using the US Environmental Protection Agency BMD software. DNA adduct levels at this dose were extrapolated assuming linearity of the DNA adduct dose response. In addition, the levels of DNA adducts at the BMD(10) were compared to available data on endogenous background DNA damage in the target organ. Although for an individual carcinogen the tumour response increases when adduct levels increase, our results demonstrate that when comparing different carcinogens, no quantitative correlation exists between the level of DNA adduct formation and carcinogenicity. These data confirm that the quantity of DNA adducts formed by a DNA-reactive compound is not a carcinogenicity predictor but that other factors such as type of adduct and mutagenic potential may be equally relevant. Moreover, comparison to background DNA damage supports the notion that the mere occurrence of DNA adducts above or below the level of endogenous DNA damage is neither correlated to development of cancer. These data strongly emphasise the need to apply the mode of action framework to understand the contribution of other biological effect markers playing a role in carcinogenicity.

Evidence of carcinogenicity in humans of water-soluble nickel salts

PubMed Central

2010-01-01

Background Increased risks of nasal cancer and lung cancer in nickel refiners have been investigated scientifically and discussed since they were detected in the 1930s. Nickel compounds are considered to be the main cause of the cancer excess. Parts of the nickel producing industry and their consultants oppose the classification of water-soluble nickel salts as human carcinogens, and argue that the risk in exposed workers should be ascribed to other occupational exposures and smoking. Discussion Respiratory cancer risks in Welsh, Finnish, and Norwegian nickel refiners add to the evidence of carcinogenicity of water-soluble nickel. In Norwegian refiners, the first epidemiological study in 1973 identified high risks of lung cancer and nasal cancer among long-term electrolysis workers. Risk analyses based on exposure estimates developed in the 1980s supported the view that water-soluble nickel compounds were central in the development of cancer. Recently, new exposure estimates were worked out for the same cohort based on personal monitoring of total nickel and chemical determination of four forms of nickel. Additional data have been collected on life-time smoking habits, and on exposure to arsenic, asbestos, sulphuric acid mists, cobalt, and occupational lung carcinogens outside the refinery. After adjustment for these potential confounding exposures in case-control analyses, the risk pattern added to the evidence of an important role of water-soluble nickel compounds as causes of lung cancer. These Norwegian cancer studies rely on national Cancer Registry data, considered close to complete from 1953 onwards; and on National Population Register data continuously updated with mortality and emigration. Canadian mortality studies--perceived to offer the strongest support to the industry position not to recognise carcinogenicity of water-soluble nickel--appear to suffer from limitations in follow-up time, loss to follow-up, absence of risk analysis with individual exposure estimates, no confounder control, and a likely underestimation of cancer mortality. Conclusions Rejection to recognise water-soluble nickel as a human carcinogen seems to contradict material epidemiological evidence that demonstrates a strong association between water-soluble nickel compounds and risks of lung cancer and nasal cancer. Independent international scientific bodies have classified nickel compounds as carcinogenic to humans, inclusive of water-soluble nickel. PMID:20377901

Activated Metal Oxide Surfaces as Highly Basic and Reducing Environments.

DTIC Science & Technology

1987-05-21

were formed, as illustrated by [Mg iO] and 93 12[Mg9AI301 2] . Unique reaction properties were described. 2. Spin Traps Organic nitroso and nitrone ...J. V. Ortiz, R. Basu and Y. Ohrn, Chem. Phys. Lett. 103, 29 (1983). 39. K. J. Klabunde and A. Whetten, J. Am. Chem. Soc., 108, 6529 (1986). 40 . G. H...editor, Elsevier, in press. 40 . F. Mousa and K. J. Klabunde, "Base Condensation of Carbonyl Compounds on Thermally Activated Magnesium Oxide

Human health risk assessment of nitrosamines and nitramines for potential application in CO2 capture.

PubMed

Ravnum, S; Rundén-Pran, E; Fjellsbø, L M; Dusinska, M

2014-07-01

Emission and accumulation of carbon dioxide (CO2) in the atmosphere exert an environmental and climate change challenge. An attempt to deal with this challenge is made at Mongstad by application of amines for CO2 capture and storage (CO2 capture Mongstad (CCM) project). As part of the CO2 capture process, nitrosamines and nitramines may be emitted. Toxicological testing of nitrosamines and nitramines indicate a genotoxic potential of these substances. Here we present a risk characterization and assessment for five nitrosamines (N-Nitrosodi-methylamine (NDMA) N-Nitrosodi-ethylamine (NDEA), N-Nitroso-morpholine (NNM), N-Nitroso-piperidine (NPIP), and Dinitroso-piperazine (DNP)) and two nitramines (N-Methyl-nitramine (NTMA), Dimethyl-nitramine (NDTMA)), which are potentially emitted from the CO2 capture plant (CCP). Human health risk assessment of genotoxic non-threshold substances is a heavily debated topic, and no consensus methodology exists internationally. Extrapolation modeling from high-dose animal exposures to low-dose human exposures can be crucial for the final risk calculation. In the work presented here, different extrapolation models are discussed, and suggestions on applications are given. Then, preferred methods for calculating derived minimal effect level (DMEL) are presented with the selected nitrosamines and nitramines. Copyright © 2014 Elsevier Inc. All rights reserved.

Maximum workplace concentration values and carcinogenicity classification for mixtures.

PubMed Central

Bartsch, R; Forderkunz, S; Reuter, U; Sterzl-Eckert, H; Greim, H

1998-01-01

In Germany, the Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) generally sets maximum workplace concentration values (i.e., a proposed occupational exposure level [OEL]) for single substances, not for mixtures. For mixtures containing substances with a genotoxic and carcinogenic potential, the commission considered it scientifically inappropriate to establish a safe threshold. This approach is currently under discussion. Carcinogenic mixtures are categorized according to either the carcinogenicity of the mixture or the classification of the carcinogenic substances included. In regulating exposure to mixtures, an approach similar to that used by the American Conference of Governmental Hygienists is proposed: For components with the same target organ and mode of action or interfering metabolism, synergistic effects must be expected and the respective OELs must be lowered. However, if there is proof that the components act independently, the OELs of the individual compounds are not considered to be modified. In the view of the commission, calculating OELs for solvent mixtures according to their liquid phase composition is not justified, and the setting of scientifically based OELs for complex mixtures is not possible. PMID:9860883

ANALYSIS OF VAPORS FROM METHYLENE CHLORIDE EXTRACTS OF NUCLEAR GRADE HEPA FILTER FIBERGLASS SAMPLES

DOE Office of Scientific and Technical Information (OSTI.GOV)

FRYE JM; ANASTOS HL; GUTIERREZ FC

2012-06-07

While several organic compounds were detected in the vapor samples used in the reenactment of the preparation of mounts from the extracts of nuclear grade high-efficiency particulate air filter fiberglass samples, the most significant species present in the samples were methylene chloride, phenol, phenol-d6, and 2-fluorophenol. These species were all known to be present in the extracts, but were expected to have evaporated during the preparation of the mounts, as the mounts appeared to be dry before any vapor was collected. These species were present at the following percentages of their respective occupational exposure limits: methylene chloride, 2%; phenol, 0.4%;more » and phenol-d6, 0.6%. However, there is no established limit for 2-fluorophenol. Several other compounds were detected at low levels for which, as in the case of 2-fluorophenol, there are no established permissible exposure limits. These compounds include 2-chlorophenol; N-nitroso-1-propanamine; 2-fluoro-1,1{prime}-biphenyl; 1,2-dihydroacenaphthylene; 2,5-cyclohexadiene-1,4-dione,2,6-bis(1,1-dimethylethyl); trimethyl oxirane; n-propylpropanamine; 2-(Propylamino)ethanol; 4-methoxy-1-butene; 6-methyl-5-hepten-2-one; and 3,4-dimethylpyridine. Some of these were among those added as surrogates or spike standards as part ofthe Advanced Technologies and Laboratories International, Inc. preparation ofthe extract of the HEPA filter media and are indicated as such in the data tables in Section 2, Results; other compounds found were not previously known to be present. The main inorganic species detected (sulfate, sodium, and sulfur) are also consistent with species added in the preparation of the methylene chloride extract of the high-efficiency particulate air sample.« less

Computational study on nitronium and nitrosonium oxalate: potential oxidizers for solid rocket propulsion?

PubMed

Gökçinar, Elif; Klapötke, Thomas M; Kramer, Michael P

2010-08-26

The enthalpies of formation for solid ionic nitrosonium oxalate, [NO](2)[O(2)C-CO(2)], nitronium oxalate, [NO(2)](2)[O(2)C-CO(2)], as well as covalent bis(nitroso)oxalic acid, ON-O(2)C-CO(2)-NO, and oxalic acid dinitrate ester, O(2)N-O(2)C-CO(2)-NO(2), were calculated using the complete basis set (CBS-4M) method of Petersson and coworkers to obtain very accurate energies. For the nitrosonium species, the ionic form ([NO](2)[O(2)C-CO(2)]) was identified as the more stable isomer, whereas for the nitrosonium compound, the covalently bound dinitrate ester (O(2)N-O(2)C-CO(2)-NO(2)) was found to be more stable. The combustion parameters with respect to possible use as ingredients in solid rocket motors for both stable species were calculated using the EXPLO5 and the ICT code. The performance of an aluminized formulation with covalently bound dinitrate ester (O(2)N-O(2)C-CO(2)-NO(2)) was shown to be comparable to that of ammonium perchlorate/aluminum. This makes oxalic acid dinitrate ester a potentially interesting perchlorate-free and environmentally benign oxidizer for solid rocket propulsion.

Nitrate from Drinking Water and Diet and Bladder Cancer Among Postmenopausal Women in Iowa

PubMed Central

Jones, Rena R.; Weyer, Peter J.; DellaValle, Curt T.; Inoue-Choi, Maki; Anderson, Kristin E.; Cantor, Kenneth P.; Krasner, Stuart; Robien, Kim; Freeman, Laura E. Beane; Silverman, Debra T.; Ward, Mary H.

2016-01-01

Background: Nitrate is a drinking water contaminant arising from agricultural sources, and it is a precursor in the endogenous formation of N-nitroso compounds (NOC), which are possible bladder carcinogens. Objectives: We investigated the ingestion of nitrate and nitrite from drinking water and diet and bladder cancer risk in women. Methods: We identified incident bladder cancers among a cohort of 34,708 postmenopausal women in Iowa (1986–2010). Dietary nitrate and nitrite intakes were estimated from a baseline food frequency questionnaire. Drinking water source and duration were assessed in a 1989 follow-up. For women using public water supplies (PWS) > 10 years (n = 15,577), we estimated average nitrate (NO3-N) and total trihalomethane (TTHM) levels and the number of years exceeding one-half the maximum contaminant level (NO3-N: 5 mg/L, TTHM: 40 μg/mL) from historical monitoring data. We computed hazard ratios (HRs) and 95% confidence intervals (CIs), and assessed nitrate interactions with TTHM and with modifiers of NOC formation (smoking, vitamin C). Results: We identified 258 bladder cancer cases, including 130 among women > 10 years at their PWS. In multivariable-adjusted models, we observed nonsignificant associations among women in the highest versus lowest quartile of average drinking water nitrate concentration (HR = 1.48; 95% CI: 0.92, 2.40; ptrend = 0.11), and we found significant associations among those exposed ≥ 4 years to drinking water with > 5 mg/L NO3-N (HR = 1.62; 95% CI: 1.06, 2.47; ptrend = 0.03) compared with women having 0 years of comparable exposure. TTHM adjustment had little influence on associations, and we observed no modification by vitamin C intake. Relative to a common reference group of never smokers with the lowest nitrate exposures, associations were strongest for current smokers with the highest nitrate exposures (HR = 3.67; 95% CI: 1.43, 9.38 for average water NO3-N and HR = 3.48; 95% CI: 1.20, 10.06 and ≥ 4 years > 5 mg/L, respectively). Dietary nitrate and nitrite intakes were not associated with bladder cancer. Conclusions: Long-term ingestion of elevated nitrate in drinking water was associated with an increased risk of bladder cancer among postmenopausal women. Citation: Jones RR, Weyer PJ, DellaValle CT, Inoue-Choi M, Anderson KE, Cantor KP, Krasner S, Robien K, Beane Freeman LE, Silverman DT, Ward MH. 2016. Nitrate from drinking water and diet and bladder cancer among postmenopausal women in Iowa. Environ Health Perspect 124:1751–1758; http://dx.doi.org/10.1289/EHP191 PMID:27258851

Increased breath nitrous oxide after ingesting nitrate in patients with atrophic gastritis and partial gastrectomy.

PubMed

Mitsui, Takahiro; Kondo, Takaharu

2004-07-01

Toxic nitrite and N-nitroso compounds due to gastric bacterial growth are often detected in the stomach of patients with atrophic gastritis and partial gastrectomy. The aim of this study is to investigate whether breath N2O, a major metabolite of denitrification, detected after ingestion of nitrate is associated with atrophic gastritis and partial gastrectomy. Nine young, 16 normal older, nine atrophic gastritis and six partial gastrectomy subjects ingested 100 g lettuce, equal to 130 mg nitrate, and breath N2O was measured at 15-min intervals for 5 h. N2O was analyzed using an infrared-photoacoustic analyzer, and atrophic gastritis was diagnosed by pepsinogen test. The mean breath N2O concentrations were higher in the following order at all times: partial gastrectomy>atrophic gastritis>normal>young. The maximum N2O concentrations in the patients with partial gastrectomy and atrophic gastritis were 1655 +/- 296 and 1350 +/- 200 (mean +/- S.E.) ppb, respectively, which were higher than that of the normal subjects, 827 +/- 91 ppb (P < 0.05). The maximum N2O concentration in young people was 527 +/- 86 ppb, which was lower than that of the normal older people (P < 0.051). These higher N2O concentrations in gastric patients reflect bacterial growth in the stomach due to the reduction of gastric acid. Copyright 2004 Elsevier B.V.

A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds.

PubMed

Lipton, S A; Choi, Y B; Pan, Z H; Lei, S Z; Chen, H S; Sucher, N J; Loscalzo, J; Singel, D J; Stamler, J S

1993-08-12

Congeners of nitrogen monoxide (NO) are neuroprotective and neurodestructive. To address this apparent paradox, we considered the effects on neurons of compounds characterized by alternative redox states of NO: nitric oxide (NO.) and nitrosonium ion (NO+). Nitric oxide, generated from NO. donors or synthesized endogenously after NMDA (N-methyl-D-aspartate) receptor activation, can lead to neurotoxicity. Here, we report that NO.- mediated neurotoxicity is engendered, at least in part, by reaction with superoxide anion (O2.-), apparently leading to formation of peroxynitrite (ONOO-), and not by NO. alone. In contrast, the neuroprotective effects of NO result from downregulation of NMDA-receptor activity by reaction with thiol group(s) of the receptor's redox modulatory site. This reaction is not mediated by NO. itself, but occurs under conditions supporting S-nitrosylation of NMDA receptor thiol (reaction or transfer of NO+). Moreover, the redox versatility of NO allows for its interconversion from neuroprotective to neurotoxic species by a change in the ambient redox milieu. The details of this complex redox chemistry of NO may provide a mechanism for harnessing neuroprotective effects and avoiding neurotoxicity in the central nervous system.

PLASMID DNA DAMAGE CAUSED BY STIBINE AND TRIMETHYLSTIBINE

EPA Science Inventory

The in vitro genotoxicity of stibine and trimethylstibine

Abstract
Antimony is classified as `possibly carcinogenic to humans' and there is also sufficient evidence for antimony carcinogenicity in experimental animals. Stibine is a volatile inorganic antimony compound t...

Delayed myelosuppression with acute exposure to hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and environmental degradation product hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jaligama, Sridhar; Kale, Vijay M.; Wilbanks, Mitchell S.

2013-02-01

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a widely used munitions compound, and hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), its N-nitroso product of anaerobic microbial nitroreduction, are contaminants of military sites. Previous studies have shown MNX to be the most acutely toxic among the nitroreduced degradation products of RDX and to cause mild anemia at high dose. The present study compares hematotoxicity with acute oral exposure to MNX with parent RDX. Both RDX and MNX caused a modest decrease in blood hemoglobin and ∼ 50% loss of granulocytes (NOAELs = 47 mg/kg) in female Sprague–Dawley rats observed 14 days post-exposure. We explored the possibility that blood cell loss observedmore » after 14 days was delayed in onset because of toxicity to bone marrow (BM) progenitors. RDX and MNX decreased granulocyte/macrophage-colony forming cells (GM-CFCs) at 14, but not 7, days (NOAELs = 24 mg/kg). The earliest observed time at which MNX decreased GM-CFCs was 10 days post-exposure. RDX and MNX likewise decreased BM burst-forming units-erythroid (BFU-Es) at 14, but not 7, days. Granulocyte–erythrocyte–monocyte–megakaryocyte (GEMM)-CFCs were unaffected by RDX and MNX at 7 days suggesting precursor depletion did not account for GM-CFC and BFU-E loss. MNX added to the culture media was without effect on GM-CFC formation indicating no direct inhibition. Flow cytometry showed no differential loss of BM multilineage progenitors (Thy1.1{sup +}) or erythroid (CD71{sup +}) precursors with MNX suggesting myeloid and erythroid lineages were comparably affected. Collectively, these data indicate that acute exposure to both RDX and MNX caused delayed suppression of myelo- and erythropoiesis with subsequent decrease of peripheral granulocytes and erythrocytes. Highlights: ► Acute oral exposure to munitions RDX causes myelosuppression. ► Environmental degradation product MNX is comparable in effect. ► RDX and MNX are cytotoxic to both myeloid and erythroid progenitor cells. ► Myelosuppression is delayed in onset by > 7 days after single exposure.« less

Comparison between carcinogenicity and mutagenicity based on chemicals evaluated in the IARC monographs.

PubMed Central

Bartsch, H; Tomatis, L

1983-01-01

The qualitative relationship between carcinogenicity and mutagenicity (DNA-damaging activity), based on chemicals which are known to be or suspected of being carcinogenic to man and/or to experimental animals, is analyzed using 532 chemicals evaluated in Volumes 1-25 of the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. About 40 compounds (industrial processes) were found to be either definitely or probably carcinogenic to man, and 130 chemicals have been adequately tested in rodents and most of them also in various short-term assays. For a comparison between the carcinogenicity of a chemical and its behavior in short-term tests, systems were selected that have a value for predicting carcinogenicity. These were divided into mutagenicity in (A) the S. typhimurium/microsome assay, (B) other submammalian systems and (C) cultured mammalian cells; (D) chromosomal abnormalities in mammalian cells; (E) DNA damage and repair; (F) cell transformation (or altered growth properties) in vitro. The following conclusions can be drawn. In the absence of studies in man, long-term animal tests are still today the only ones capable of providing evidence of the carcinogenic effect of a chemical. The development and application of an appropriate combination of short-term tests (despite current limitations) can significantly contribute to the prediction/confirmation of the carcinogenic effects of chemicals in animals/man. Confidence in positive tests results is increased when they are confirmed in multiple short-term tests using nonrepetitive end points and different activation systems. Assays to detect carcinogens which do not act via electrophiles (promoters) need to be developed. The results of a given short-term test should be interpreted in the context of other toxicological data. Increasing demand for quantitative carcinogenicity data requires further examination of whether or not there is a quantitative relationship between the potency of a carcinogen in experimental animals/man, and its genotoxic activity in short-term tests. At present, such a relationship is not sufficiently established for it to be used for the prediction of the carcinogenic potency of new compounds. PMID:6337827

[An in vivo DNA adduct database for carcinogens: O6-alkylguanine, O4-alkylthymine and 8-hydroxyguanine].

PubMed

Morimoto, K; Kimura, M; Murata, T; Imai, Y; Ookami, N; Igarashi, T; Kanoh, N; Kaminuma, T; Hayashi, Y

1994-01-01

Many carcinogens react with DNA and form critical DNA adducts, such as O6-alkylguanine (O6-AG), O4-alkylthymine (O4-AT), and 8-hydroxyguanine (8-OHG). This study provides a database that can be used for molecular dosimetry of these DNA adducts. A literature survey on DNA binding in vivo was done by the Dialog search from the MEDLINE database. We propose a Critical Covalent Binding Index (CCBI) for the assessment of in vivo DNA binding level (expressed as micro mol chemical bound per mol G or T/mmol chemical administered per kg body weight). The number of records and compounds in parenthesis of O6-AG, O4-AT, and 8-OHG were 245(13), 54(4), 79(15), respectively. Since the CCBI values for N-nitrosamine in target organ were higher than for non-target organ, they may provide a useful index for estimation of target organ site and carcinogenic potency. As a case example, CCBI values for O4-AT from animal data were applied for diethylnitrosamine human exposure estimation by diethylnitrosamine.

A simplified approach to the determination of N-nitroso glyphosate in technical glyphosate using HPLC with post-derivatization and colorimetric detection.

PubMed

Kim, Manuela; Stripeikis, Jorge; Iñón, Fernando; Tudino, Mabel

2007-05-15

A simple and sensitive HPLC post-derivatization method with colorimetric detection has been developed for the determination of N-nitroso glyphosate in samples of technical glyphosate. Separation of the analyte was accomplished using an anionic exchange resin (2.50mmx4.00mm i.d., 15mum particle size, functional group: quaternary ammonium salt) with Na(2)SO(4) 0.0075M (pH 11.5) (flow rate: 1.0mLmin(-1)) as mobile phase. After separation, the eluate was derivatized with a colorimetric reagent containing sulfanilamide 0.3% (w/v), [N-(1-naphtil)ethilendiamine] 0.03% (w/v) and HCl 4.5M in a thermostatized bath at 95 degrees C. Detection was performed at 546nm. All stages of the analytical procedure were optimized taking into account the concept of analytical minimalism: less operation times and costs; lower sample, reagents and energy consumption and minimal waste. The limit of detection (k=3) calculated for 10 blank replicates was 0.04mgL(-1) (0.8mgkg(-1)) in the solid sample which is lower than the maximum tolerable accepted by the Food and Agriculture Organization of the United Nations.

Investigating the Mechanisms of Action and the Identification of Breast Carcinogens by Computational Analysis of Female Rodent Carcinogena

DTIC Science & Technology

2004-08-01

of Female Rodent Carcinogens PRINCIPAL INVESTIGATOR: Albert R. Cunningham, Ph.D. CONTRACTING ORGANIZATION : Louisiana State University, Baton Rouge... non -carcinogen) and molecular fragments as SAR descriptors. Therefore, this seemed a reasonable substitute SAR approach for MCASE. However, upon... target site summary (15) we developed a SAR learning set of 100 compounds shown to induce breast cancer in rat. The cat- SAR program develops SAR

Identification and Characterization of 2′-Deoxyadenosine Adducts formed by Isoprene Monoepoxides In Vitro

PubMed Central

Begemann, Petra; Boysen, Gunnar; Georgieva, Nadia I.; Sangaiah, Ramiah; Koshlap, Karl M.; Koc, Hasan; Zhang, Daping; Golding, Bernard T.; Gold, Avram; Swenberg, James A.

2011-01-01

Isoprene, the 2-methyl analog of 1,3-butadiene, is ubiquitous in the environment, with major contributions to total isoprene emissions stemming from natural processes despite the compound being a bulk industrial chemical. Additionally, isoprene is a combustion product and a major component in cigarette smoke. Isoprene has been classified as possibly carcinogenic to humans (group 2B) by IARC and as reasonably anticipated to be a human carcinogen by the National Toxicology Program. Isoprene, like butadiene, requires metabolic activation to reactive epoxides to exhibit its carcinogenic properties. The mode of action has been postulated to be that of a genotoxic carcinogen, with formation of promutagenic DNA adducts being essential for mutagenesis and carcinogenesis. In rodents, isoprene-induced tumors show unique point mutations (A→T transversions) in the K-ras protooncogene at codon 61. Therefore, we investigated adducts formed after reaction of 2′-deoxyadenosine (dAdo1) with the two monoepoxides of isoprene, 2-ethenyl-2-methyloxirane (IP-1,2-O) and propen-2-yloxirane (IP-3,4-O), under physiological conditions. The formation of N1–2′-deoxyinosine (N1-dIno) due to deamination of N1-dAdo adducts was of particular interest, since N1-dIno adducts are suspected to have high mutagenic potential based on in vitro experiments. Major stable adducts were identified by HPLC, UV-Spectrometry and LC-MS/MS and characterized by 1H and 1H,13C HSQC and NMR experiments. Adducts of IP-1,2-O that were fully identified are: R,S-C1-N6-dAdo, R-C2-N6-dAdo, and S-C2-N6-dAdo; adducts of IP-3,4-O are: S-C3-N6-dAdo, R-C3-N6-dAdo, R,S-C4-N6-dAdo, S-C4-N1-dIno, R-C4-N1-dIno, R-C3-N1-dIno, S-C3-N1-dIno, and C3-N7-Ade. Both monoepoxides formed adducts on the external and internal oxirane carbons. This is the first study to describe adducts of isoprene monoepoxides with dAdo. Characterization of adducts formed by isoprene monoepoxides with deoxynucleosides and subsequently with DNA represent the first step toward evaluating their potential for being converted into a mutation, or as biomarkers of isoprene metabolism and exposure. PMID:21548641

Oxidation of Methyl and Ethyl Nitrosamines by Cytochromes P450 2E1 and 2B1

PubMed Central

Chowdhury, Goutam; Calcutt, M. Wade; Nagy, Leslie D.; Guengerich, F. Peter

2012-01-01

Cytochrome P450 (P450) 2E1 is the major enzyme that oxidizes N-nitrosodimethylamine (N,N-dimethylnitrosamine, DMN), a carcinogen and also a representative of some nitrosamines formed endogenously. Oxidation of DMN by rat or human P450 2E1 to HCHO showed a high apparent intrinsic kinetic deuterium isotope effect (KIE), ≥ 8. The KIE was not attenuated in non-competitive intermolecular experiments with rat liver microsomes (DV 12.5, D(V/K) 10.9, nomenclature of Northrop, D.B. (1982) Methods Enzymol. 87, 607–625) but was with purified human P450 2E1 (DV 3.3, D(V/K) 3.7), indicating that C-H bond breaking is partially rate-limiting with human P450 2E1. With N-nitrosodiethylamine (N,N-diethylnitrosamine, DEN), the intrinsic KIE was slightly lower and was not expressed (e.g., D(V/K) 1.2) in non-competitive intermolecular experiments. The same general pattern of KIEs was also seen in the D(V/K) results with DMN and DEN for the minor products resulting from the denitrosation reactions (CH3NH2, CH3CH2NH2, and NO2−). Experiments with deuterated N-nitroso-N-methyl,N-ethylamine demonstrated that the lower KIEs associated for ethyl compared to methyl oxidation could be distinguished within a single molecule. P450 2E1 oxidized DMN and DEN to aldehydes and then to the carboxylic acids. No kinetic lags were observed in acid formation; pulse-chase experiments with carrier aldehydes showed only limited equilibration with P450 2E1-bound aldehydes, indicative of processive reactions, as reported for P450 2A6 (Chowdhury, G. et al. (2010) J. Biol. Chem. 285, 8031–8044). These same features (no lag phase for HCO2H formation, lack of equilibration in pulse-chase assays) were also seen with (rat) P450 2B1, which has lower catalytic efficiency for DMN oxidation and a larger active site. Thus, the processivity of dialkylnitrosamine oxidation appears to be shared by a number of P450s. PMID:23186213

Reducing the use of carcinogens: the Massachusetts experience.

PubMed

Jacobs, Molly M; Massey, Rachel I; Tenney, Heather; Harriman, Elizabeth

2014-01-01

Toxics use reduction (TUR) is one part of a comprehensive cancer prevention strategy. TUR emphasizes reducing the use of cancer-causing chemicals by improving manufacturing processes and identifying and adopting safer alternatives. This analysis draws on 20 years of data collected from industries reporting to the Massachusetts Toxics Use Reduction Act (TURA) program to assess trends in the use and release of chemicals associated with cancer. We used a master list of known and suspected carcinogens developed from authoritative sources and a list of carcinogens grouped by their association with 11 cancer sites to analyze trends in use and release of chemicals by industrial facilities reporting to the TURA program from 1990 to 2010. The trend analysis shows that reported use and releases of carcinogens by these Massachusetts companies have decreased dramatically over time. Reported use declined 32% from 1990 to 2010, and reported releases declined 93% from 1991 to 2010 (1991 is when additional industrial sectors, including electric utilities, were phased into the program). Particularly large reductions were achieved in the use of trichloroethylene, perchloroethylene and cadmium and cadmium compounds. The analysis of groups of chemicals associated with specific cancer sites shows similar trends. Important opportunities for further reductions in many carcinogens, including formaldehyde, hexavalent chromium, and a variety of halogenated compounds are identified. Continued work to minimize the use of carcinogens can help to reduce the burden of cancer in Massachusetts and elsewhere.

Relationship between organic precursors and N-nitrosodimethylamine (NDMA) formation in tropical water sources.

PubMed

Qi, Wang; Fang Yee, Lim; Jiangyong, Hu

2014-12-01

The presence of organic compounds in water sources is one of the concerns in water treatment. They are potential precursors of disinfection byproducts (DBPs) and thus induce health problems in humans. Among the emerging DBPs, carcinogenic compound N-nitrosodimethylamine (NDMA) has been receiving attention during the last decade. This study examined the characteristics of organic components in various water sources and investigated their relationships with NDMA formation. Experiments were carried out on selected water samples from both natural water and wastewater. Results showed similar NDMA formation kinetics for both water sources. However, more contribution of NDMA precursors was found to be from the wastewater due to its higher organic nitrogen content. NDMA formation potential (NDMAFP) of secondary effluent ranged from 264 to 530 ng/L. A correlation study between organic compound characteristics and NDMAFP indicated that the majority of NDMA precursors came from dissolved organic nitrogen (DON) compound with small molecular weight (smaller than 500 Da), with correlation R(2) = 0.898. Although secondary treatment removed more than 90% of NDMA precursors, the remaining precursors in secondary effluent would still pose a challenge for water quality.

Repellence Produced by Monoterpenes on Rhodnius prolixus (Hemiptera: Reduviidae) Decreases After Continuous Exposure to These Compounds

PubMed Central

Lutz, Alejandra; Sfara, Valeria; Alzogaray, Raúl Adolfo

2014-01-01

Abstract Botanical monoterpenes are secondary metabolites present in essential oils produced by plants. Some of them are insect repellents. The bloodsucking bug Rhodnius prolixus Ståhl (Hemiptera: Reduviidae) is one of the main vectors of Chagas disease in the north of South America and some countries in Central America. In this study, we studied the repellence produced by two monoterpenes, menthyl acetate and geraniol, on fifth instar nymphs of R. prolixus . In the absence of other stimuli, both menthyl acetate and geraniol produced a repellent effect from 740 μg/cm 2 and 74 μg/cm 2 , respectively. Pre-exposure to each monoterpene reduced the repellent activity produced by the same substance. Additionally, pre-exposure to one monoterpene decreased the behavioral response of the nymphs to the other one. The repellent effect of both monoterpenes also decreased when nymphs’ antennae were previously treated with the nitric oxide donor S-nitroso-N-acetyl-cysteine. PMID:25525113

DNA adductomics to study the genotoxic effects of red meat consumption with and without added animal fat in rats.

PubMed

Hemeryck, Lieselot Y; Van Hecke, Thomas; Vossen, Els; De Smet, Stefaan; Vanhaecke, Lynn

2017-09-01

Digestion of red and processed meat has been linked to the formation of genotoxic N-nitroso compounds (NOCs) and lipid peroxidation products (LPOs) in the gut. In this study, rats were fed a meat based diet to compare the possible genotoxic effects of red vs. white meat, and the interfering role of dietary fat. To this purpose, liver, duodenum and colon DNA adductomes were analyzed with UHPLC-HRMS. The results demonstrate that the consumed meat type alters the DNA adductome; the levels of 22 different DNA adduct types significantly increased upon the consumption of beef (compared to chicken) and/or lard supplemented beef or chicken. Furthermore, the chemical constitution of the retrieved DNA adducts hint at a direct link with an increase in NOCs and LPOs upon red (and processed) meat digestion, supporting the current hypotheses on the causal link between red and processed meat consumption and the development of colorectal cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical structure determines target organ carcinogenesis in rats

PubMed Central

Carrasquer, C. A.; Malik, N.; States, G.; Qamar, S.; Cunningham, S.L.; Cunningham, A.R.

2012-01-01

SAR models were developed for 12 rat tumour sites using data derived from the Carcinogenic Potency Database. Essentially, the models fall into two categories: Target Site Carcinogen – Non-Carcinogen (TSC-NC) and Target Site Carcinogen – Non-Target Site Carcinogen (TSC-NTSC). The TSC-NC models were composed of active chemicals that were carcinogenic to a specific target site and inactive ones that were whole animal non-carcinogens. On the other hand, the TSC-NTSC models used an inactive category also composed of carcinogens but to any/all other sites but the target site. Leave one out validations produced an overall average concordance value for all 12 models of 0.77 for the TSC-NC models and 0.73 for the TSC-NTSC models. Overall, these findings suggest that while the TSC-NC models are able to distinguish between carcinogens and non-carcinogens, the TSC-NTSC models are identifying structural attributes that associate carcinogens to specific tumour sites. Since the TSC-NTSC models are composed of active and inactive compounds that are genotoxic and non-genotoxic carcinogens, the TSC-NTSC models may be capable of deciphering non-genotoxic mechanisms of carcinogenesis. Together, models of this type may also prove useful in anticancer drug development since they essentially contain chemicals moieties that target specific tumour site. PMID:23066888

KIDNEY TOXICOGENOMICS OF CHRONIC POTASSIUM BROMATE EXPOSURE IN F344 MALE RAT

EPA Science Inventory

Potassium bromate (KBrO3), used in both the food and cosmetics industry, and a drinking water disinfection by-product, is a nephrotoxic compound and rodent carcinogen. To gain insight into the carcinogenic mechanism of action and provide possible biomarkers of KBrO3 exposure, the...

Development and calibration of a passive sampler for N-nitrosodimethylamine (NDMA) in water.

PubMed

Kaserzon, Sarit L; Kennedy, Karen; Hawker, Darryl W; Holling, Neil; Escher, Beate I; Booij, Kees; Mueller, Jochen F

2011-07-01

N-Nitrosamines such as N-nitrosodimethylamine (NDMA) are organic compounds of environmental concern in groundwater, wastewater and potable water due to their potent carcinogenicity in laboratory animal studies and probable human carcinogenicity. While passive sampling techniques have become a widely used tool for providing time-averaged estimates of trace pollutant concentration, for chemicals such as NDMA that have relatively high water solubility, the selection of a suitable sorbent is difficult. This work is a proof of principle study that investigated for the first time the use of coconut charcoal as a passive sampler sorbent. Apparent charcoal/water sorption coefficients for NDMA were >551 mL g(-1) at environmentally relevant aqueous concentrations of less than 1 μg L(-1). Under the experimental conditions employed, a sampling rate of 0.45 L d(-1) was determined and for an aqueous concentration of 1000 ng L(-1), it is predicted that the sampler remains in the linear uptake stage for approximately 4d, while equilibrium attainment would require about 26 d. The presence of humic acid, used as a surrogate for DOC, enhanced NDMA sorption on the coconut charcoal. Copyright © 2011 Elsevier Ltd. All rights reserved.

Induction of prophage lambda by chlorinated organics: Detection of some single-species/single-site carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeMarini, D.M.; Brooks, H.G.

1992-01-01

Twenty-eight chlorinated organic compounds were evaluated for their ability to induce DNA damage using the Microscreen prophage-induction assay in Escherichia coli. Comparison of the performance characteristics of the prophage-induction and Salmonella assays to rodent carcinogenicity assays showed that the prophage-induction assay had a somewhat higher specificity than did the Salmonella assay (70% vs. 50%); sensitivity, concordance, and positive and negative predictivity were similar for the two microbial assays. The Microscreen prophage-induction assay failed to detect eight carcinogens, perhaps due to toxicity or other unknown factors; five of these eight carcinogens were detected by the Salmonella assay. However, the prophage-induction assaymore » did detect six carcinogens that were not detected by the Salmonella assay, and five of these were single-species, single-site carcinogens, mostly mouse liver carcinogens. Some of these carcinogens, such as the chloroethanes, produce free radicals, which may be the basis for their carcinogenicity and ability to induce prophage. The prophage-induction (or other SOS) assay may be useful in identifying some genotoxic chlorinated carcinogens that induce DNA damage that do not revert the standard Salmonella tester strains.« less

Quality of Chemical Safety Information in Printing Industry.

PubMed

Tsai, Chung-Jung; Mao, I-Fang; Ting, Jo-Yu; Young, Chi-Hsien; Lin, Jhih-Sian; Li, Wei-Lun

2016-04-01

Employees in printing industries can be exposed to multiple solvents in their work environment. The objectives of this study were to investigate the critical components of chemical solvents by analyzing the components of the solvents and collecting the Safety data sheets (SDSs), and to evaluate the hazard communication implementation status in printing industries. About 152 printing-related industries were recruited by area-stratified random sampling and included 23 plate-making, 102 printing and 27 printing-assistance companies in Taiwan. We analyzed company questionnaires (n = 152), SDSs (n = 180), and solvents (n = 20) collected from this sample of printing-related companies. Analytical results indicated that benzene and ethylbenzene, which were carcinogen and possibly carcinogen, were detectable in the cleaning solvents, and the detection rate were 54.5% (concentrations: <0.011-0.035 wt%) and 63.6% (concentrations: <0.011-6.22 wt%), respectively; however, neither compound was disclosed in the SDS for the solvents. Several other undisclosed components, including methanol, isopropanol and n-butanol, were also identified in the printing inks, fountain solutions and dilution solvents. We noted that, of the companies we surveyed, only 57.2% had a hazard communication program, 61.8% had SDSs on file and 59.9% provided employee safety and health training. We note that hazard communication programs were missing or ineffective in almost half of the 152 printing industries surveyed. Current safety information of solvents components in printing industries was inadequate, and many hazardous compounds were undisclosed in the SDSs of the solvents or the labels of the containers. The implementation of hazard communications in printing industries was still not enough for protecting the employees' safety and health. © The Author 2015. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Quality of Chemical Safety Information in Printing Industry

PubMed Central

Tsai, Chung-Jung; Mao, I-Fang; Ting, Jo-Yu; Young, Chi-Hsien; Lin, Jhih-Sian; Li, Wei-Lun

2016-01-01

Objectives: Employees in printing industries can be exposed to multiple solvents in their work environment. The objectives of this study were to investigate the critical components of chemical solvents by analyzing the components of the solvents and collecting the Safety data sheets (SDSs), and to evaluate the hazard communication implementation status in printing industries. Method: About 152 printing-related industries were recruited by area-stratified random sampling and included 23 plate-making, 102 printing and 27 printing-assistance companies in Taiwan. We analyzed company questionnaires (n = 152), SDSs (n = 180), and solvents (n = 20) collected from this sample of printing-related companies. Results: Analytical results indicated that benzene and ethylbenzene, which were carcinogen and possibly carcinogen, were detectable in the cleaning solvents, and the detection rate were 54.5% (concentrations: <0.011–0.035 wt%) and 63.6% (concentrations: <0.011–6.22 wt%), respectively; however, neither compound was disclosed in the SDS for the solvents. Several other undisclosed components, including methanol, isopropanol and n-butanol, were also identified in the printing inks, fountain solutions and dilution solvents. We noted that, of the companies we surveyed, only 57.2% had a hazard communication program, 61.8% had SDSs on file and 59.9% provided employee safety and health training. We note that hazard communication programs were missing or ineffective in almost half of the 152 printing industries surveyed. Conclusions: Current safety information of solvents components in printing industries was inadequate, and many hazardous compounds were undisclosed in the SDSs of the solvents or the labels of the containers. The implementation of hazard communications in printing industries was still not enough for protecting the employees’ safety and health. PMID:26568584

Tobacco, Microbes, and Carcinogens: Correlation Between Tobacco Cure Conditions, Tobacco-Specific Nitrosamine Content, and Cured Leaf Microbial Community.

PubMed

Law, Audrey D; Fisher, Colin; Jack, Anne; Moe, Luke A

2016-07-01

Tobacco-specific nitrosamines are carcinogenic N-nitrosamine compounds present at very low levels in freshly harvested tobacco leaves that accumulate during leaf curing. Formation of N-nitrosamine compounds is associated with high nitrate levels in the leaf at harvest, and nitrate is presumed to be the source from which the N-nitrosation species originates. More specifically, nitrite is considered to be a direct precursor, and nitrite is linked with N-nitrosation in many environmental matrices where it occurs via microbial nitrate reduction. Here, we initiate work exploring the role of leaf microbial communities in formation of tobacco-specific nitrosamines. Leaves from burley tobacco line TN90H were air cured under various temperature and relative humidity levels, and 22 cured tobacco samples were analyzed for their microbial communities and leaf chemistry. Analysis of nitrate, nitrite, and total tobacco-specific nitrosamine levels revealed a strong positive correlation between the three variables, as well as a strong positive correlation with increasing relative humidity during cure conditions. 16S rRNA gene amplicon sequencing was used to assess microbial communities in each of the samples. In most samples, Proteobacteria predominated at the phylum level, accounting for >90 % of the OTUs. However, a distinct shift was noted among members of the high tobacco-specific nitrosamine group, with increases in Firmicutes and Actinobacteria. Several OTUs were identified that correlate strongly (positive and negative) with tobacco-specific nitrosamine content. Copy number of bacterial nitrate reductase genes, obtained using quantitative PCR, did not correlate strongly with tobacco-specific nitrosamine content. Incomplete denitrification is potentially implicated in tobacco-specific nitrosamine levels.

Potential carcinogenicity of homoisoflavanoids and flavonoids from Resina sanguinis draconis (Dracaena cinnabari Balf.).

PubMed

Vachálková, A; Novotný, L; Nejedlíková, M; Suchý, V

1995-01-01

Polarographic behavior of three homoisoflavanoids and four flavanoids isolated from the dragon's blood (Resina sanguinis draconis. Dracaena cinnabari Balf.), collected at Sokotra, was investigated in aprotic solution and an index of potential carcinogenicity tg alpha was determined. Generally, homoisoflavanoids and flavanoids were reduced in two two-electron steps, the first being reversible and the second one irreversible. The parameter tg alpha values indicated that the majority of these compounds possesses no or only marginal potential carcinogenic activity. However, it was demonstrated that some structural modifications in basic flavonoid structure lead to changed electrochemical properties and a substantial increase of derivative potential carcinogenicity.

Toxicological significance of azo dye metabolism by human intestinal microbiota

PubMed Central

Feng, Jinhui; Cerniglia, Carl E.; Chen, Huizhong

2018-01-01

Approximately 0.7 million tons of azo dyes are synthesized each year. Azo dyes are composed of one or more R1-N=N-R2 linkages. Studies have shown that both mammalian and microbial azoreductases cleave the azo bonds of the dyes to form compounds that are potentially genotoxic. The human gastrointestinal tract harbors a diverse microbiota comprised of at least several thousand species. Both water-soluble and water-insoluble azo dyes can be reduced by intestinal bacteria. Some of the metabolites produced by intestinal microbiota have been shown to be carcinogenic to humans although the parent azo dyes may not be classified as being carcinogenic. Azoreductase activity is commonly found in intestinal bacteria. Three types of azoreductases have been characterized in bacteria. They are flavin dependent NADH preferred azoreductase, flavin dependent NADPH preferred azoreductase, and flavin free NADPH preferred azoreductase. This review highlights how azo dyes are metabolized by intestinal bacteria, mechanisms of azo reduction, and the potential contribution in the carcinogenesis/mutagenesis of the reduction of the azo dyes by intestinal microbiota. PMID:22201895

Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin.

PubMed Central

Stamler, J S; Jaraki, O; Osborne, J; Simon, D I; Keaney, J; Vita, J; Singel, D; Valeri, C R; Loscalzo, J

1992-01-01

We have recently shown that nitric oxide or authentic endothelium-derived relaxing factor generated in a biologic system reacts in the presence of specific protein thiols to form S-nitrosoprotein derivatives that have endothelium-derived relaxing factor-like properties. The single free cysteine of serum albumin, Cys-34, is particularly reactive toward nitrogen oxides (most likely nitrosonium ion) under physiologic conditions, primarily because of its anomalously low pK; given its abundance in plasma, where it accounts for approximately 0.5 mM thiol, we hypothesized that this plasma protein serves as a reservoir for nitric oxide produced by the endothelial cell. To test this hypothesis, we developed a methodology, which involves UV photolytic cleavage of the S--NO bond before reaction with ozone for chemiluminescence detection, with which to measure free nitric oxide, S-nitrosothiols, and S-nitrosoproteins in biologic systems. We found that human plasma contains approximately 7 microM S-nitrosothiols, of which 96% are S-nitrosoproteins, 82% of which is accounted for by S-nitroso-serum albumin. By contrast, plasma levels of free nitric oxide are only in the 3-nM range. In rabbits, plasma S-nitrosothiols are present at approximately 1 microM; 60 min after administration of NG-monomethyl-L-arginine at 50 mg/ml, a selective and potent inhibitor of nitric oxide synthetases, S-nitrosothiols decreased by approximately 40% (greater than 95% of which were accounted for by S-nitrosoproteins, and approximately 80% of which was S-nitroso-serum albumin); this decrease was accompanied by a concomitant increase in mean arterial blood pressure of 22%. These data suggest that naturally produced nitric oxide circulates in plasma primarily complexed in S-nitrosothiol species, principal among which is S-nitroso-serum albumin. This abundant, relatively long-lived adduct likely serves as a reservoir with which plasma levels of highly reactive, short-lived free nitric oxide can be regulated for the maintenance of vascular tone. PMID:1502182

Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin.

PubMed

Stamler, J S; Jaraki, O; Osborne, J; Simon, D I; Keaney, J; Vita, J; Singel, D; Valeri, C R; Loscalzo, J

1992-08-15

We have recently shown that nitric oxide or authentic endothelium-derived relaxing factor generated in a biologic system reacts in the presence of specific protein thiols to form S-nitrosoprotein derivatives that have endothelium-derived relaxing factor-like properties. The single free cysteine of serum albumin, Cys-34, is particularly reactive toward nitrogen oxides (most likely nitrosonium ion) under physiologic conditions, primarily because of its anomalously low pK; given its abundance in plasma, where it accounts for approximately 0.5 mM thiol, we hypothesized that this plasma protein serves as a reservoir for nitric oxide produced by the endothelial cell. To test this hypothesis, we developed a methodology, which involves UV photolytic cleavage of the S--NO bond before reaction with ozone for chemiluminescence detection, with which to measure free nitric oxide, S-nitrosothiols, and S-nitrosoproteins in biologic systems. We found that human plasma contains approximately 7 microM S-nitrosothiols, of which 96% are S-nitrosoproteins, 82% of which is accounted for by S-nitroso-serum albumin. By contrast, plasma levels of free nitric oxide are only in the 3-nM range. In rabbits, plasma S-nitrosothiols are present at approximately 1 microM; 60 min after administration of NG-monomethyl-L-arginine at 50 mg/ml, a selective and potent inhibitor of nitric oxide synthetases, S-nitrosothiols decreased by approximately 40% (greater than 95% of which were accounted for by S-nitrosoproteins, and approximately 80% of which was S-nitroso-serum albumin); this decrease was accompanied by a concomitant increase in mean arterial blood pressure of 22%. These data suggest that naturally produced nitric oxide circulates in plasma primarily complexed in S-nitrosothiol species, principal among which is S-nitroso-serum albumin. This abundant, relatively long-lived adduct likely serves as a reservoir with which plasma levels of highly reactive, short-lived free nitric oxide can be regulated for the maintenance of vascular tone.

Dermal application of nitric oxide releasing acidified nitrite-containing liniments significantly reduces blood pressure in humans.

PubMed

Opländer, Christian; Volkmar, Christine M; Paunel-Görgülü, Adnana; Fritsch, Thomas; van Faassen, Ernst E; Mürtz, Manfred; Grieb, Gerrit; Bozkurt, Ahmet; Hemmrich, Karsten; Windolf, Joachim; Suschek, Christoph V

2012-02-15

Vascular ischemic diseases, hypertension, and other systemic hemodynamic and vascular disorders may be the result of impaired bioavailability of nitric oxide (NO). NO but also its active derivates like nitrite or nitroso compounds are important effector and signal molecules with vasodilating properties. Our previous findings point to a therapeutical potential of cutaneous administration of NO in the treatment of systemic hemodynamic disorders. Unfortunately, no reliable data are available on the mechanisms, kinetics and biological responses of dermal application of nitric oxide in humans in vivo. The aim of the study was to close this gap and to explore the therapeutical potential of dermal nitric oxide application. We characterized with human skin in vitro and in vivo the capacity of NO, applied in a NO-releasing acidified form of nitrite-containing liniments, to penetrate the epidermis and to influence local as well as systemic hemodynamic parameters. We found that dermal application of NO led to a very rapid and significant transepidermal translocation of NO into the underlying tissue. Depending on the size of treated skin area, this translocation manifests itself through a significant systemic increase of the NO derivates nitrite and nitroso compounds, respectively. In parallel, this translocation was accompanied by an increased systemic vasodilatation and blood flow as well as reduced blood pressure. We here give evidence that in humans dermal application of NO has a therapeutic potential for systemic hemodynamic disorders that might arise from local or systemic insufficient availability of NO or its bio-active NO derivates, respectively. Copyright © 2012 Elsevier Inc. All rights reserved.

Mutagens and carcinogens - Occurrence and role during chemical and biological evolution

NASA Technical Reports Server (NTRS)

Giner-Sorolla, A.; Oro, J.

1981-01-01

The roles of mutagenic and carcinogenic substances in early biologic evolution is examined, along with terrestrial and extraterrestrial sources of mutagens and carcinogens. UV solar radiation is noted to have served to stimulate prebiotic life while also causing harmful effects in plants and animals. Aromatic compounds have been found in meteorites, and comprise leukemogens, polycyclic hydrocarbons, and nitrasamine precursors. Other mutagenic sources are volcanoes, and the beginning of evolution with mutagenic substances is complicated by the appearance of malignancies due to the presence of carcinogens. The atmosphere of the Precambrian period contained both mutagens and early carcinogens and, combined with volcanic activity discharges, formed an atmospheric chemical background analogous to the background ionizing radiation. Carcinogenesis is concluded to be intrinsic to nature, having initiated evolution and, eventually, cancer cells.

Carcinogens Report Adds Seven Agents.

PubMed

2017-01-01

The National Toxicology Program has added seven new substances to its 14th Report on Carcinogens, bringing the total number in this congressionally mandated report to 248. The latest additions are the chemical trichloroethylene; cobalt metal and compounds that release cobalt ions in vivo; and five viruses, including HIV-1. ©2017 American Association for Cancer Research.

COMPARATIVE POTENCY METHOD FOR CANCER RISK ASSESSMENT: APPLICATION TO THE QUANTITATIVE ASSESSMENT OF THE CONTRIBUTION OF COMBUSTION EMISSIONS TO LUNG CANCER RISK

EPA Science Inventory

Combustion sources emit soot particles containing carcinogenic polycyclic organic compounds which are mutagenic in short-term genetic bioassays in microbial and mammalian cells and are tumorigenic in animals. Although soot is considered to be a human carcinogen, soots from differ...

77 FR 50591 - Animal Drugs, Feeds, and Related Products; Regulation of Carcinogenic Compounds in Food-Producing...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-22

... is calculated from tumor data of the cancer bioassays using a statistical extrapolation procedure... regulated as a carcinogen, FDA will analyze the data submitted using either a statistical extrapolation... million. * * * * * 0 3. In Sec. 500.84, revise paragraph (c) introductory text to read as follows: Sec...

Beryllium Metal II. A Review of the Available Toxicity Data

PubMed Central

Strupp, Christian

2011-01-01

Beryllium metal was classified in Europe collectively with beryllium compounds, e.g. soluble salts. Toxicological equivalence was assumed despite greatly differing physicochemical properties. Following introduction of the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation, beryllium metal was classified as individual substance and more investigational efforts to appropriately characterize beryllium metal as a specific substance apart from soluble beryllium compounds was required. A literature search on toxicity of beryllium metal was conducted, and the resulting literature compiled together with the results of a recently performed study package into a comprehensive data set. Testing performed under Organisation for Economic Co-Operation and Development guidelines and Good Laboratory Practice concluded that beryllium metal was neither a skin irritant, an eye irritant, a skin sensitizer nor evoked any clinical signs of acute oral toxicity; discrepancies between the current legal classification of beryllium metal in the European Union (EU) and the experimental results were identified. Furthermore, genotoxicity and carcinogenicity were discussed in the context of the literature data and the new experimental data. It was concluded that beryllium metal is unlikely to be a classical nonthreshold mutagen. Effects on DNA repair and morphological cell transformation were observed but need further investigation to evaluate their relevance in vivo. Animal carcinogenicity studies deliver evidence of carcinogenicity in the rat; however, lung overload may be a species-specific confounding factor in the existing studies, and studies in other species do not give convincing evidence of carcinogenicity. Epidemiology has been intensively discussed over the last years and has the problem that the studies base on the same US beryllium production population and do not distinguish between metal and soluble compounds. It is noted that the correlation between beryllium exposure and carcinogenicity, even including the soluble compounds, remains under discussion in the scientific community and active research is continuing. PMID:21196456

Evidence that the capacity of nongenotoxic carcinogens to induce oxidative stress is subject to marked variability.

PubMed

Henderson, Colin J; Cameron, Amy R; Chatham, Lynsey; Stanley, Lesley A; Wolf, Charles Roland

2015-05-01

Many drugs and environmental chemicals which are not directly mutagenic have the capacity to increase the incidence of tumors in the liver and other tissues. For this reason, such compounds are known as nongenotoxic carcinogens. The mechanisms underlying their effects remain unclear; however, their capacity to induce oxidative stress is considered to be a critical step in the carcinogenic process, although the evidence that this is actually the case remains equivocal and sparse. We have exploited a novel heme oxygenase-1 reporter mouse to evaluate the capacity of nongenotoxic carcinogens with different mechanisms of action to induce oxidative stress in the liver in vivo. When these compounds were administered at doses reported to cause liver tumors, marked differences in activation of the reporter were observed. 1,4-Dichlorobenzene and nafenopin were strong inducers of oxidative stress, whereas phenobarbital, piperonyl butoxide, cyproterone acetate, and WY14,643 were, at best, only very weak inducers. In the case of phenobarbital and thioacetamide, the number of LacZ-positive hepatocytes increased with time, and for the latter also with dose. The data obtained demonstrate that although some nongenotoxic carcinogens can induce oxidative stress, it is not a dominant feature of the response to these compounds. Therefore in contrast to the current models, these data suggest that oxidative stress is not a key determinant in the mechanism of nongenotoxic carcinogenesis but may contribute to the effects in a compound-specific manner. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.

Agaritine purified from Agaricus blazei Murrill exerts anti-tumor activity against leukemic cells.

PubMed

Endo, Masahiro; Beppu, Hidehiko; Akiyama, Hidehiko; Wakamatsu, Kazumasa; Ito, Shosuke; Kawamoto, Yasuko; Shimpo, Kan; Sumiya, Toshimitu; Koike, Takaaki; Matsui, Taei

2010-07-01

Mushrooms of the genus Agaricus are a common folk remedy against carcinoma. The active ingredients, polysaccharides and protein-polysaccharide complexes containing beta-glucan, have been isolated and shown to have indirect tumor-suppressing activity via an immunological activation. The diffusible fraction of a hot-water extract of Agaricus blazei Murrill (ABM) powder was fractionated by HPLC based on the anti-tumor activity against leukemic cells in vitro. The structure of the anti-tumor substance was determined by NMR and MS analyses. We purified a tumorcidal substance from the diffusible fraction of ABM and identified it as agaritine, beta-N-(gamma-l(+)-glutamyl)-4-(hydroxymethyl) phenylhydrazine, having a molecular mass of 267 Da. This compound inhibited the proliferation of leukemic cell lines such as U937, MOLT4, HL60 and K562 with IC(50) values of 2.7, 9.4, 13.0, and 16.0 microg/mL, respectively, but showed no significant effect on normal lymphatic cells at concentrations up to 40 microg/mL. Although agaritine has been suspected of having genotoxic or carcinogenic properties, agaritine did not activate the umu gene of Salmonella, which reacts to carcinogens. The results indicate that agaritine from ABM has direct anti-tumor activity against leukemic tumor cells in vitro. This is in contrast to the carcinogenic activity previously ascribed to this compound. Our results also show that this activity is distinct from that of beta-glucan, which indirectly suppresses proliferation of tumor cells. Copyright 2010 Elsevier B.V. All rights reserved.

Reaction kinetics and transformation of carbadox and structurally related compounds with aqueous chlorine.

PubMed

Shah, Amisha D; Kim, Jae-Hong; Huang, Ching-Hua

2006-12-01

The potential release of carbadox (CDX), a commonly used antibacterial agent in swine husbandry, into water systems is of a concern due to its carcinogenic and genotoxic effects. Until this study, the reactivity of carbadox (possessing quinoxaline N,N'-dioxide and hydrazone moieties) toward aqueous chlorine has yetto be investigated in depth. Chemical reactivity, reaction kinetics, and transformation pathways of carbadox and structurally related compounds with free chlorine under typical water treatment conditions were determined. This study found that only CDX and desoxycarbadox (DCDX), a main metabolite of CDX with no ring N-oxide groups, react rapidly with free chlorine while other structurally related compounds including olaquindox, quindoxin, quinoxaline N-oxide, quinoxaline, and quinoline N-oxide do not. The reaction kinetics of CDX and DCDX with chlorine are highly pH dependent (e.g., the apparent second-order rate constant, kapp, for CDX ranges from 51.8 to 3.15 x 10(4) M(-1)s(-1) at pH 4-11). The high reactivity of CDX and DCDX to chlorine involves deprotonation of their hydrazone N-H moieties where initial chlorine attack results in a reactive intermediate that is further attacked by nucleophiles in the matrix to yield non-chlorinated, hydroxylated, and larger molecular weight byproducts. All of the CDX's byproducts retain their biologically active N-oxide groups, suggesting that they may remain as active antibacterial agents.

Dose and Time Dependencies in Stress Pathway Responses during Chemical Exposure: Novel Insights from Gene Regulatory Networks.

PubMed

Souza, Terezinha M; Kleinjans, Jos C S; Jennen, Danyel G J

2017-01-01

Perturbation of biological networks is often observed during exposure to xenobiotics, and the identification of disturbed processes, their dynamic traits, and dose-response relationships are some of the current challenges for elucidating the mechanisms determining adverse outcomes. In this scenario, reverse engineering of gene regulatory networks (GRNs) from expression data may provide a system-level snapshot embedded within accurate molecular events. Here, we investigate the composition of GRNs inferred from groups of chemicals with two distinct outcomes, namely carcinogenicity [azathioprine (AZA) and cyclophosphamide (CYC)] and drug-induced liver injury (DILI; diclofenac, nitrofurantoin, and propylthiouracil), and a non-carcinogenic/non-DILI group (aspirin, diazepam, and omeprazole). For this, we analyzed publicly available exposed in vitro human data, taking into account dose and time dependencies. Dose-Time Network Identification (DTNI) was applied to gene sets from exposed primary human hepatocytes using four stress pathways, namely endoplasmic reticulum (ER), NF-κB, NRF2, and TP53. Inferred GRNs suggested case specificity, varying in interactions, starting nodes, and target genes across groups. DILI and carcinogenic compounds were shown to directly affect all pathway-based GRNs, while non-DILI/non-carcinogenic chemicals only affected NF-κB. NF-κB-based GRNs clearly illustrated group-specific disturbances, with the cancer-related casein kinase CSNK2A1 being a target gene only in the carcinogenic group, and opposite regulation of NF-κB subunits being observed in DILI and non-DILI/non-carcinogenic groups. Target genes in NRF2-based GRNs shared by DILI and carcinogenic compounds suggested markers of hepatotoxicity. Finally, we indicate several of these group-specific interactions as potentially novel. In summary, our reversed-engineered GRNs are capable of revealing dose dependent, chemical-specific mechanisms of action in stress-related biological networks.

Allylation of Nitrosobenzene with Pinacol Allylboronates. A Regioselective Complement to Peroxide Oxidation

PubMed Central

Kyne, Robert E.; Ryan, Michael C.; Kliman, Laura T.; Morken, James P.

2010-01-01

Addition of nitrosobenzene to pinacol allylboronates leads to oxidation of the organoboron with concomitant rearrangement of the substrate alkene. This reaction appears to proceed by allylboration of the nitroso group in analogy to carbonyl and imine allylation reactions. Remarkably, the N-O bond is cleaved during the reaction such that simple alcohols are the final reaction product. PMID:20687578

Study of Crystal Formation and Nitric Oxide (NO) Release Mechanism from S-Nitroso-N-acetylpenicillamine (SNAP)-Doped CarboSil Polymer Composites for Potential Antimicrobial Applications.

PubMed

Wo, Yaqi; Li, Zi; Colletta, Alessandro; Wu, Jianfeng; Xi, Chuanwu; Matzger, Adam J; Brisbois, Elizabeth J; Bartlett, Robert H; Meyerhoff, Mark E

2017-07-15

Stable and long-term nitric oxide (NO) releasing polymeric materials have many potential biomedical applications. Herein, we report the real-time observation of the crystallization process of the NO donor, S -nitroso- N -acetylpenicillamine (SNAP), within a thermoplastic silicone-polycarbonate-urethane biomedical polymer, CarboSil 20 80A. It is demonstrated that the NO release rate from this composite material is directly correlated with the surface area that the CarboSil polymer film is exposed to when in contact with aqueous solution. The decomposition of SNAP in solution (e.g. PBS, ethanol, THF, etc.) is a pseudo-first-order reaction proportional to the SNAP concentration. Further, catheters fabricated with this novel NO releasing composite material are shown to exhibit significant effects on preventing biofilm formation on catheter surface by Pseudomonas aeruginosa and Proteus mirabilis grown in CDC bioreactor over 14 days, with a 2 and 3 log-unit reduction in number of live bacteria on their surfaces, respectively. Therefore, the SNAP-CarboSil composite is a promising new material to develop antimicrobial catheters, as well as other biomedical devices.

Nitrosation of aryl and heteroaryltrifluoroborates with nitrosonium tetrafluoroborate.

PubMed

Molander, Gary A; Cavalcanti, Livia N

2012-05-04

Organotrifluoroborates have emerged as an alternative to toxic and air- and moisture-sensitive organometallic species for the synthesis of functionalized aryl and heteroaryl compounds. It has been shown that the trifluoroborate moiety can be easily converted into a variety of different substituents in a late synthetic stage. In this paper, we disclose a mild, selective, and convenient method for the ipso-nitrosation of organotrifluoroborates using nitrosonium tetrafluoroborate (NOBF(4)). Aryl- and heteroaryltrifluoroborates were converted into the corresponding nitroso products in good to excellent yields. This method proved to be tolerant of a broad range of functional groups.

NITROSATION OF ARYL AND HETEROARYLTRIFLUOROBORATES WITH NITROSONIUM TETRAFLUOROBORATE

PubMed Central

Cavalcanti, Livia N.

2012-01-01

Organotrifluoroborates have emerged as an alternative to toxic and air- and moisture sensitive organometallic species for the synthesis of functionalized aryl and heteroaryl compounds. It has been shown that the trifluoroborate moiety can be easily converted into a variety of different substituents in a late synthetic stage. In this paper we disclose a mild, selective, and convenient method for the ipso-nitrosation of organotrifluoroborates using nitrosonium tetrafluoroborate (NOBF4). Aryl- and heteroaryltrifluoroborates were converted into the corresponding nitroso products in good to excellent yields. This method proved to be tolerant of a broad range of functional groups. PMID:22524190

Application of the Margin of Exposure (MoE) Approach to Substances in Food that are Genotoxic and Carcinogenic Example: Benzo[a]pyrene and polycyclic aromatic hydrocarbons

EPA Science Inventory

This paper presents the work of an expert group established by the International Life Sciences Institute - European branch (ILSI Europe) to follow up the recommendations of an international conference on "Risk Assessment of Compounds that are both Genotoxic and Carcinogenic: New ...

Polynuclear aromatic hydrocarbons in forest fire smoke

Treesearch

Charles K. McMahon; Skevos N. Tsoukalas

1978-01-01

The occurrence of polynuclear aromatic hydrocarbons (PAH) in the combustion products of carbonaceous fuels is a well known phenomenon. Several PAW are known to be carcinogenic in animals. Benzo[a]pyrene (BaP) is the most well-known and studied compound of those classified by the National Academy of Science (NAS) as strongly carcinogenic. Ambient BaP concentrations...

75 FR 79320 - Animal Drugs, Feeds, and Related Products; Regulation of Carcinogenic Compounds in Food-Producing...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-20

... is calculated from tumor data of the cancer bioassays using a statistical extrapolation procedure... carcinogenic concern currently set forth in Sec. 500.84 utilizes a statistical extrapolation procedure that... procedures did not rely on a statistical extrapolation of the data to a 1 in 1 million risk of cancer to test...

O-Raffinose Crosslinking Substantially Ameliorates the Vasoconstrictive and Nitric-Oxide-Inactivating Effects of Unmodified Human Hemoglobin in the Rat

DTIC Science & Technology

1997-07-11

severity of the increase in MAP and SVR is accounted for by the profound depressant effect of Ao SFH on cardie output (Table III). We have not examined...1985. N- acetylcysteine potentiates inhibition of platelet aggregation by nitroglycerin. / Clin Invest 76:703-708. 34. Mendelsohn, M., S. O’Neill...D. George, and J. Loscalzo. 1990. Inhibition of fibrinogen binding to human platelets by S-nitroso-N- acetylcysteine . / Biol Chem 265:19028-19034. 27

The Red Blood Cell Transfusion Trigger: Has the Sin of Commission Now Become a Sin of Omission?.

DTIC Science & Technology

1997-05-01

disease. N . Engl. J. Med. 1995;333:251-253. 85. Ignarro LJ, Buga GM, Wood KS, et al. Endothelium -derived relaxing factor produced and released from...George D, Loscalzo J. Inhibition of fibrinogen binding to human platelets by S-nitroso- N - acetylcysteine . J. Biol. Chem. 1990;265:19028-19034. 28 92...attributable primarily to shear stress-induced nitric oxide release from the endothelium , it would seem logical that transfusing red blood cells to the 30

The Role of Rearranged Neu Genes in the Progression of Rat Mammary Tumors Induced by N-nitroso N’-methylurea.

DTIC Science & Technology

1997-08-01

anti-neu antibody response of DNA vaccine immunized mice again by indirectly flowcytometry assay, we confirm our previous finding. We also examine the... flowcytometry assay, I have confirmed my previous finding from Elisa assay. 5 I also examined the cellular immunity response of DNA immunized mice by CTL...immunized mice by indirectly flowcytometry assay. I also find mice immunized with neu DNA vaccine did not develop detectable cytotoxic T lymphocyte

Synergism of herpes simplex virus and tobacco-specific N'-nitrosamines in cell transformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, N.H.; Dokko, H.; Li, S.L.

1991-03-01

Previous studies indicate that herpes simplex virus (HSV) enhances the carcinogenic activity of smokeless tobacco and tobacco-related chemical carcinogens in animals. Since tobacco-specific N'-nitrosamines (TSNAs) such as N'-nitrosonornicotine (NNN) and 4-(N-methyl-N'-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are major chemical carcinogens of smokeless tobacco and are known to be responsible for the development of oral cancers in smokeless tobacco users, the combined effects of TSNAs and HSV in cell transformation were investigated. Exposure of cells to NNN or NNK followed by virus infection resulted in a significant enhancement of transformation frequency when compared with that observed with chemical carcinogens or virus alone. This study suggestsmore » that TSNAs and HSV can interact together and show synergism in cell transformation.« less

Biological Degradation of 2,4,6-Trinitrotoluene

PubMed Central

Esteve-Núñez, Abraham; Caballero, Antonio; Ramos, Juan L.

2001-01-01

Nitroaromatic compounds are xenobiotics that have found multiple applications in the synthesis of foams, pharmaceuticals, pesticides, and explosives. These compounds are toxic and recalcitrant and are degraded relatively slowly in the environment by microorganisms. 2,4,6-Trinitrotoluene (TNT) is the most widely used nitroaromatic compound. Certain strains of Pseudomonas and fungi can use TNT as a nitrogen source through the removal of nitrogen as nitrite from TNT under aerobic conditions and the further reduction of the released nitrite to ammonium, which is incorporated into carbon skeletons. Phanerochaete chrysosporium and other fungi mineralize TNT under ligninolytic conditions by converting it into reduced TNT intermediates, which are excreted to the external milieu, where they are substrates for ligninolytic enzymes. Most if not all aerobic microorganisms reduce TNT to the corresponding amino derivatives via the formation of nitroso and hydroxylamine intermediates. Condensation of the latter compounds yields highly recalcitrant azoxytetranitrotoluenes. Anaerobic microorganisms can also degrade TNT through different pathways. One pathway, found in Desulfovibrio and Clostridium, involves reduction of TNT to triaminotoluene; subsequent steps are still not known. Some Clostridium species may reduce TNT to hydroxylaminodinitrotoluenes, which are then further metabolized. Another pathway has been described in Pseudomonas sp. strain JLR11 and involves nitrite release and further reduction to ammonium, with almost 85% of the N-TNT incorporated as organic N in the cells. It was recently reported that in this strain TNT can serve as a final electron acceptor in respiratory chains and that the reduction of TNT is coupled to ATP synthesis. In this review we also discuss a number of biotechnological applications of bacteria and fungi, including slurry reactors, composting, and land farming, to remove TNT from polluted soils. These treatments have been designed to achieve mineralization or reduction of TNT and immobilization of its amino derivatives on humic material. These approaches are highly efficient in removing TNT, and increasing amounts of research into the potential usefulness of phytoremediation, rhizophytoremediation, and transgenic plants with bacterial genes for TNT removal are being done. PMID:11527999

[The implementation of polymerase chain reaction technique: the real time to reveal and differentiate the viruses of human papilloma of high carcinogenic risk].

PubMed

Andosova, L D; Kontorshchikova, K N; Blatova, O L; Kudel'kina, S Iu; Kuznetsova, I A; Belov, A V; Baĭkova, R A

2011-07-01

The polymerase chain reaction technique was applied in "real time" format to evaluate the occurrence rate and infection ratio of various genotypes of human papilloma of high carcinogenic risk in virus-positive women and contact persons. The examination sampling consisted of 738 women aged of 17-50 years. The examination results permitted to establish high percentage of infection of 546 patients (74%) by carcinogenic papilloma viruses. The analysis of detection rate of various genotypes of human papilloma of high carcinogenic risk established that the 56th and 16th types of high carcinogenic risk are revealed more often than others--in 33% and 15.4% correspondingly. In males, first place in occurrence rate is for those types of virus of human papilloma: the 56th n = 10 (33.3%), 16th n = 3 (10%), 45th n = 3 (10%), 51th n = 3 (10%). The rest of genotypes are detected in 3-7% cases.

Vanillin as a modulator agent in SMART test: inhibition in the steps that precede N-methyl-N-nitrosourea-, N-ethyl-N-nitrosourea-, ethylmethanesulphonate- and bleomycin-genotoxicity.

PubMed

Sinigaglia, Marialva; Lehmann, Maurício; Baumgardt, Paula; do Amaral, Viviane Souza; Dihl, Rafael Rodrigues; Reguly, Maria Luíza; de Andrade, Heloísa Helena Rodrigues

2006-09-05

Vanillin (VA), the world's major flavoring compound used in food industry and confectionery products - that has antimutagenic and anticarcinogenic activity against a variety of mutagenic/carcinogenic agents - was tested for the interval between the formation of premutational lesion and it is finalization as a DNA lesion. The overall findings using co-treatment protocols in SMART test suggest that VA can lead to a significant protection against the general genotoxicity of ethylmethanesulphonate (EMS), N-ethyl-N-nitrosourea (ENU), N-methyl-N-nitrosourea (MNU) and bleomycin sulphate (BLEO). Considering MNU, ENU and EMS the desmutagenic activity observed could result from VA-stimulation of detoxification, via induction of glutathione S-transferase. However, the protector effect related to BLEO could be attributed to its powerful scavenger ability, which has the potential to prevent oxidative damage induced by BLEO.

Approaches to cancer prevention based on an understanding of N-nitrosamine carcinogenesis.

PubMed

Hecht, S S

1997-11-01

Understanding carcinogenesis is critical for development of rational approaches to cancer prevention. This paper uses N-nitrosamine carcinogenesis as an example. N-Nitrosamines are a large group of potent carcinogens. Approximately 300 different N-nitrosamines are carcinogenic. At least 30 animal species are responsive to their effects. There is little doubt that humans exposed to sufficient amounts of N-nitrosamines would also be susceptible to their carcinogenic effects. Human exposure to preformed N-nitrosamines occurs through the diet, in certain occupational settings, and through the use of tobacco products, cosmetics, pharmaceutical products, and agricultural chemicals. Diminishing human exposure to these carcinogens is one approach to prevention of cancer, and this has been accomplished in many instances, although exposure to N-nitrosamines in tobacco products is still unacceptably high. Human exposure to N-nitrosamines also occurs by nitrosation of amines in the body, via their acid or bacterial catalyzed reaction with nitrite, or by reaction with products of nitric oxide generated during inflammation or infection. A second approach toward prevention of N-nitrosamine carcinogenesis is inhibition of this endogenous N-nitrosamine formation. Substantial reductions have been achieved with ascorbic acid and other nitrite scavengers. N-Nitrosamines undergo a simple cytochrome P450-mediated metabolic activation step, which is critical for their carcinogenicity. The third approach involves the use of chemopreventive agents that block this step, or other steps in the carcinogenic process. A large number of potent chemopreventive agents against nitrosamine carcinogenesis have been identified. Chemoprevention of lung cancer induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is discussed as an example of this approach.

Recent Research Progress on Garlic (大蒜 dà suàn) as a Potential Anticarcinogenic Agent Against Major Digestive Cancers

PubMed Central

Raghu, Rajasekaran; Lu, Kuan-Hung; Sheen, Lee-Yan

2012-01-01

Garlic (大蒜 dà suàn; the bulb of Allium sativum), bestowed with an array of organosulfur compounds finds its application in treating many ailments including cardiovascular problems, common cold, bacterial and fungal infections and cancer. Numerous epidemiological evidences document the beneficial effects of various bioactive organosulfur compounds of garlic against different types of cancer. Studies involving the animal and cell models indicate garlic bioactive compounds could be effective in treating all the stages of cancer. This review gives an update on the recent pre-clinical and clinical trials, carried out to evaluate the efficacy of various garlic bioactive compounds along with the mechanism of action pertaining to major digestive cancers including liver, gastric and colorectal cancers. The major anti-carcinogenic mechanisms are caspase dependent and/or independent induction of apoptosis, anti-proliferative, anti-metastasis, anti-oxidant and immunomodulative properties. Form the clinical trials an increase in the garlic consumption of 20 g/day reduced the risk of gastric and colorectal cancer. In summary, increased uptake of garlic in diet may prevent the incidence of digestive cancers. PMID:24716132

Carcinogenicity of 4-methoxyphenol and 4-methylcatechol in F344 rats.

PubMed

Asakawa, E; Hirose, M; Hagiwara, A; Takahashi, S; Ito, N

1994-01-02

The carcinogenic potentials of 4-methoxyphenol (4-MP) and 4-methylcatechol (4-MC), phenolic compounds which are structurally similar to the known forestomach carcinogen BHA and the glandular stomach carcinogen catechol respectively, and cause considerably enhanced cell proliferation and cytotoxicities in rat forestomach and/or glandular stomach epithelium, were examined in male and female F344 rats. Groups of 30 male and female animals were administered diets containing 2% 4-MP or 2% 4-MC for 104 weeks. Histopathological findings in the 4-MP case included atypical hyperplasias (male, 67%, female, 37%), papillomas (50%, 23%) and squamous-cell carcinomas (77%, 20%) in the forestomach. 4-MC induced forestomach papillomas (70%, 93%) and squamous-cell carcinomas (53%, 37%), also glandular stomach submucosal hyperplasias (90%, 93%), adenomas (100%, 100%) and adenocarcinomas (57%, 47%), with ulceration or erosion. The degree of differentiation of the squamous-cell carcinomas induced by 4-MP was less than with 4-MC. The present study demonstrated unequivocal forestomach carcinogenicity for 4-MP and forestomach and glandular stomach carcinogenicity for 4-MC, with cytotoxicity and cell proliferation both appearing as important factors for these non-genotoxic carcinogens.

Dissecting modes of action of non-genotoxic carcinogens in primary mouse hepatocytes.

PubMed

Schaap, Mirjam M; Zwart, Edwin P; Wackers, Paul F K; Huijskens, Ilse; van de Water, Bob; Breit, Timo M; van Steeg, Harry; Jonker, Martijs J; Luijten, Mirjam

2012-11-01

Under REACH, the European Community Regulation on chemicals, the testing strategy for carcinogenicity is based on in vitro and in vivo genotoxicity assays. Given that non-genotoxic carcinogens are negative for genotoxicity and chronic bioassays are no longer regularly performed, this class of carcinogens will go undetected. Therefore, test systems detecting non-genotoxic carcinogens, or even better their modes of action, are required. Here, we investigated whether gene expression profiling in primary hepatocytes can be used to distinguish different modes of action of non-genotoxic carcinogens. For this, primary mouse hepatocytes were exposed to 16 non-genotoxic carcinogens with diverse modes of action. Upon profiling, pathway analysis was performed to obtain insight into the biological relevance of the observed changes in gene expression. Subsequently, both a supervised and an unsupervised comparison approach were applied to recognize the modes of action at the transcriptomic level. These analyses resulted in the detection of three of eight compound classes, that is, peroxisome proliferators, metalloids and skin tumor promotors. In conclusion, gene expression profiles in primary hepatocytes, at least in rodent hepatocytes, appear to be useful to detect some, certainly not all, modes of action of non-genotoxic carcinogens.

[Glyphosate--a non-toxic pesticide?].

PubMed

Pieniazek, Danuta; Bukowska, Bozena; Duda, Wirgiliusz

2003-01-01

Glyphosate is currently the most commonly applied herbicide and its use is still growing. Nowadays, over 50 commercial preparations containing this compound are used, and these formulations are much more toxic than their active compound, glyphosate, owing to the presence of many surfactants and carrier compounds. Toxicological investigations provide evidence that glyphosate is an extremely "safe" herbicide for animals. This is why its use in agriculture is universal. In June 1991, the Environmental Protection Agency (EPA) categorized this compound into class E (according to EPA there are five categories of carcinogenicity), which means that it is probably not carcinogenic to humans. Unfortunately, the study carried out by Swedish oncologists in 2001 showed that glyphosate may induce cancer of the lymphatic system. The results of the Swedish study have changed our opinion about "safety" of this herbicide. Investigations concerning both its accumulation and toxic effect in animals and plants are now under way in many laboratories.

To the application of the emission Mössbauer and positron annihilation spectroscopies for detection of carcinogens

NASA Astrophysics Data System (ADS)

Bokov, A. V.; Byakov, V. M.; Kulikov, L. A.; Perfiliev, Yu. D.; Stepanov, S. V.

2017-11-01

Being the main cause of cancer, almost all chemical carcinogens are strong electrophiles, that is, they have a high affinity for the electron. We have shown that positron annihilation lifetime spectroscopy (PALS) is able to detect chemical carcinogens by their inhibition of positronium (Ps) formation in liquid media. Electrophilic carcinogens intercept thermalized track electrons, which are precursors of Ps, and as a result, when they are present Ps atom does not practically form. Available biophysical data seemingly indicate that frozen solutions model better an intracellular medium than the liquid ones. So it is reasonable to use emission Mössbauer spectroscopy (EMS) to detect chemical carcinogens, measuring the yield of 57Fe2+ions formed in reactions of Auger electrons and other secondary electrons they produced with 57Fe3+. These reactions are similar to the Ps formation process in the terminal part the positron track: e++ e- =>Ps. So EMS and PALS are complementary methods for detection of carcinogenic compounds.

Chemical Carcinogen (Hydrazine, Polynuclear Hydrocarbon and/or Synthetic Jet Fuel Components) Induced Carcinogenesis of Human Cells, In Vitro

DTIC Science & Technology

1981-08-01

Various levels of DNA repair synthesis in Xeroderma pigmenrosum cells exposed to the carcinogens N-hydroxy and N-acetoxy-2-acetylsminofluorene...Nature (New Biol.). 238 (1972) 9. 5 V.M Maher, N. Birch, J.R. Otto and J. McCormick, Cytotoxicity of carcinogenic aro- matic amides in normal and Xeroderma ... pigmentosum fibroblasts with different DNA repair capabilities, J. Nati. Cancer Inst., 54 (1975) 1287. 6 R.H. Heflich, R.M. Hazard, L. Lommnel, J.D

Volatile N-nitrosamines in meat products: Potential precursors, influence of processing, and mitigation strategies.

PubMed

De Mey, Eveline; De Maere, Hannelore; Paelinck, Hubert; Fraeye, Ilse

2017-09-02

Meat products can be contaminated with carcinogenic N-nitrosamines, which is ascribed to the reaction between a nitrosating agent, originating from nitrite or smoke, and a secondary amine, derived from protein and lipid degradation. Although in model systems it is demonstrated that many amine containing compounds can be converted to N-nitrosamines, the yield is dependent of reaction conditions (e.g., low pH and high temperature). In this article, the influence of the composition of the meat products (e.g., pH, a w , spices) and processing (e.g., ageing, ripening, fermentation, smoking, heat treatment and storage) on the presence and availability of the amine precursors and the N-nitrosamine formation mechanism is discussed. In addition, this article explores the current N-nitrosamine mitigation strategies in order to obtain healthier and more natural meat products.

Chronic Exposure to Zinc Chromate Induces Centrosome Amplification and Spindle Assembly Checkpoint Bypass in Human Lung Fibroblasts

PubMed Central

Holmes, Amie L.; Wise, Sandra S.; Pelsue, Stephen C.; Aboueissa, AbouEl-Makarim; Lingle, Wilma; Salisbury, Jeffery; Gallagher, Jamie; Wise, John Pierce

2010-01-01

Hexavalent chromium (Cr(VI)) compounds are known human lung carcinogens. Solubility plays an important role in its carcinogenicity with the particulate or insoluble form being the most potent. Of the particulate Cr(VI) compounds, zinc chromate appears to be the most potent carcinogen, however, very few studies have investigated its carcinogenic mechanism. In this study, we investigated the ability of chronic exposure to zinc chromate to induce numerical chromosome instability. We found no increase in aneuploidy after a 24 hour exposure to zinc chromate, but with more chronic exposures, zinc chromate induced concentration- and time-dependent increases in aneuploidy in the form of hypodiploidy, hyperdiploidy and tetraploidy. Zinc chromate also induced centrosome amplification in a concentration- and time-dependent manner in both interphase and mitotic cells after chronic exposure, producing cells with centriolar defects. Further, chronic exposure to zinc chromate induced concentration- and time-dependent increases in spindle assembly checkpoint bypass with increases in centromere spreading, premature centromere division and premature anaphase. Lastly, we found that chronic exposure to zinc chromate induced a G2 arrest. All together, these data indicate that zinc chromate can induce chromosome instability after prolonged exposures. PMID:20030412

Carcinogenicity bioassays of vinyl chloride monomer: a model of risk assessment on an experimental basis.

PubMed Central

Maltoni, C; Lefemine, G; Ciliberti, A; Cotti, G; Carretti, D

1981-01-01

Data are presented regarding the final results of the Bentivoglio (Bologna) project on long-term carcinogenicity bioassays of vinyl chloride (VC). The experimental project studied the effects of the monomer, administered by different routes, concentrations and schedules of treatment, to animals (near 7000) of different species, strains, sex and age. To our knowledge this is the largest experimental carcinogenicity study performed on a single compound by a single institution. The results indicate that VC is a multipotential carcinogen, affecting a variety of organs and tissues. In the experimental conditions studied, the neoplastic effects of the monomer were also detected at low doses. The experimental and biological factors greatly affect the neoplastic response to VC. Long-term carcinogenicity bioassays are, at present, a unique tool for the identification and quantification of environmental and occupational risks. Precise and highly standardized experimental procedures are needed to obtain data for risk assessment. PMID:6800782

Anaerobic bioremediation of RDX by ovine whole rumen fluid and pure culture isolates.

PubMed

Eaton, H L; Duringer, J M; Murty, L D; Craig, A M

2013-04-01

The ability of ruminal microbes to degrade the explosive compound hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in ovine whole rumen fluid (WRF) and as 24 bacterial isolates was examined under anaerobic conditions. Compound degradation was monitored by high-performance liquid chromatography analysis, followed by liquid chromatography-tandem mass spectrometry identification of metabolites. Organisms in WRF microcosms degraded 180 μM RDX within 4 h. Nitroso-intermediates hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX) were present as early as 0.25 h and were detected throughout the 24-h incubation period, representing one reductive pathway of ring cleavage. Following reduction to MNX, peaks consistent with m/z 193 and 174 were also produced, which were unstable and resulted in rapid ring cleavage to a common metabolite consistent with an m/z of 149. These represent two additional reductive pathways for RDX degradation in ovine WRF, which have not been previously reported. The 24 ruminal isolates degraded RDX with varying efficiencies (0-96 %) over 120 h. Of the most efficient degraders identified, Clostridium polysaccharolyticum and Desulfovibrio desulfuricans subsp. desulfuricans degraded RDX when medium was supplemented with both nitrogen and carbon, while Anaerovibrio lipolyticus, Prevotella ruminicola, and Streptococcus bovis IFO utilized RDX as a sole source of nitrogen. This study showed that organisms in whole rumen fluid, as well as several ruminal isolates, have the ability to degrade RDX in vitro and, for the first time, delineated the metabolic pathway for its biodegradation.

Carcinogenic N-Nitrosamines. Formation, Properties, and Analysis

NASA Astrophysics Data System (ADS)

Kostyukovskii, Ya L.; Melamed, D. B.

1988-04-01

Literature data on the formation of carcinogenic N-nitrosamines in the environment, their physicochemical properties, their action on the human organism, the methods for their microanalysis, and also their content in the atmosphere, water sources, soil, and industrial agricultural and food products are described systematically and surveyed. The principal features of this comparatively new class of powerful chemical carcinogens are indicated. The bibliography includes 284 references.

Evaluation of genotoxic activity of maleic hydrazide, ethyl methane sulfonate, and N-nitroso diethylamine in Tradescantia.

PubMed

Alvarez-Moya, C; Santerre-Lucas, A; Zúñiga-González, G; Torres-Bugarín, O; Padilla-Camberos, E; Feria-Velasco, A

2001-01-01

To assess the genotoxic activity of N-nitroso diethylamine (NDEA), maleic hydrazide (MH), and ethyl methane sulfonate (EMS) using two systems: the comet assay on nuclei from Tradescantia, and the pink mutation test on Tradescantia staminal hairs (clone 4430). Tradescantia cups was obtained from Laboratorio de Citogenética y Mutagénesis del Centro de Ciencias de la Atmósfera de la Universidad Nacional Autónoma de México and treated with: N-nitroso diethylamine (NDEA) at 1, 5, 10 mM, maleic hydrazide (MH) at 1, 5, 10 mM and ethyl methane sulfonate (EMS) at 15, 30 and 45 mM; and used in both pink mutation assay and comet assay using cellular nuclei from Tradescantia staminal hairs. The observation of staminal hair was realized along eight days (6-14) after treatment), flowers produced day 14 after treatment were utilized done according to Underbrink. In previous reports on plants, were comet assay was used, breaking cellular wall and separating by centrifugation gradient are necessary. Here, nuclei from staminal hairs were obtained by squashing the cells (is not necessary to utilize to break special procedure cellular wall), collected using a nylon mesh of 80 Mm and next the comet assay was applied. Student's T test was the statistical test used for analyzing the comet assay data. Both assays showed a great sensitivity to the studied mutagens. A relationship between the dose-pink event and the dose-tail length was evident. Even though the Tradescantia mutation assay is a sensitive test with MH and EMS, low doses of NDEA were not able to induce a significant increase in the pink event frequencies; however, the comet assay was able to detect the mutagenic effect of NDEA at the same dose. Thus, it is clear that the comet assay is highly sensitive to the lowest dose of chemical mutagens. The comet assay on nuclei from Tradescantia staminal hairs is a useful tool to monitor genotoxic agents; it is simple, highly sensitive, and faster than the pink mutation test.

Megakaryocyte expansion and macrophage infiltration in bone marrow of rats subchronically treated with MNX, N-nitroso environmental degradation product of munitions compound RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine).

PubMed

Ramasahayam, Sindhura; Jaligama, Sridhar; Atwa, Sahar M; Salley, Joshua T; Thongdy, Marissa; Blaylock, Benny L; Meyer, Sharon A

2017-08-01

Hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), environmental degradation product of munitions hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), causes seizures in rats with acute oral exposure like parent RDX. Our previous studies have additionally reported hematotoxicity with acute MNX exposure manifested as myelosuppression, anemia and splenic hemosiderosis. This study explored whether MNX administered subchronically continued to target bone marrow to elicit peripheral blood cytopenia. Female Sprague-Dawley rats were gavaged daily for 4 or 6 weeks with 47 mg kg -1  day -1 MNX (¼ LD 50 ) or vehicle (5% dimethyl sulfoxide in corn oil) and hematological and clinical chemistry parameters, spleen weights, spleen and bone marrow histopathology and immunohistochemistry with ED1 anti-CD68 macrophage marker were evaluated 24 h after the last dose. Unexpectedly, no decrease in blood erythroid parameters was seen with subchronic MNX and convulsions and tremors ceased after 2 weeks of treatment. Toxicological effects observed were MNX-induced increases in blood granulocyte and platelet counts and in bone marrow megakaryocyte and ED1 + -macrophage density. MNX was without effect on bone marrow cellularity and picrosirius red stained/collagen fiber deposition. Spleen weight increased modestly with extramedullary hematopoiesis evident, but hemosiderin and relative red and white pulp areas were unaffected. Collectively, this study demonstrated that erythroid effects characteristic of acute MNX exposure were not evident with subchronic exposure. However, megakaryocyte proliferation in bone marrow coincident with thrombocytosis after subchronic MNX exposure suggested continued hematotoxicity, but with a qualitatively different outcome. Granulocytosis and increased bone marrow macrophages implicated an inflammatory component in MNX hematotoxicity. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

21 CFR 500.84 - Conditions for approval of the sponsored compound.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Conditions for approval of the sponsored compound. 500.84 Section 500.84 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS GENERAL Regulation of Carcinogenic Compounds...

21 CFR 500.84 - Conditions for approval of the sponsored compound.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Conditions for approval of the sponsored compound. 500.84 Section 500.84 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS GENERAL Regulation of Carcinogenic Compounds...

21 CFR 500.84 - Conditions for approval of the sponsored compound.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Conditions for approval of the sponsored compound. 500.84 Section 500.84 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS GENERAL Regulation of Carcinogenic Compounds...

21 CFR 500.84 - Conditions for approval of the sponsored compound.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Conditions for approval of the sponsored compound. 500.84 Section 500.84 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS GENERAL Regulation of Carcinogenic Compounds...

21 CFR 500.84 - Conditions for approval of the sponsored compound.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Conditions for approval of the sponsored compound. 500.84 Section 500.84 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS GENERAL Regulation of Carcinogenic Compounds...

NDMA formation during chlorination and chloramination of aqueous diuron solutions.

PubMed

Chen, Wei-Hsiang; Young, Thomas M

2008-02-15

Formation of the potent carcinogen N-nitrosodimethylamine (NDMA) during chlorine disinfection of water containing secondary amines is now generally acknowledged. The phenylurea herbicide diuron is one of the most widely used herbicides in California, has been frequently detected in California's water sources with a transient nature of appearance, and has a structure that suggests it might be an NDMA precursor. This study sought to quantify the potential for NDMA formation from aqueous diuron solutions under varied chlorine and chloramine conditions. NDMA formation was consistently observed even in the absence of added ammonia, which has usually been the source of the nitroso-nitrogen during chloramination of other precursors. It appears that both nitrogen atoms in NDMA are donated by diuron during chlorination in the absence of added ammonia. For a given chlorine and diuron dose, NDMA formation increased in the order OCl- < NH2Cl < NHCl2, a result consistentwith previous NDMAformation studies. Significant quantities of NDMA (170 ng/L) were produced during dichloramination of diuron using a low dichloramine concentration and a diuron concentration at the upper end of typically detected concentrations in California (20 microg/L), suggesting a need for further investigation to accurately assess the human health risks posed by diuron with respect to NDMA formation potential. A reaction pathway is proposed to provide a possible explanation for NDMA formation from diuron during chlorination or chloramination. The findings in this study identify a specific potential precursor of NDMA formation, one that arises from nonpoint sources. This further highlights the difficulties associated with determining the environmental safety of chemicals and their associated byproducts.

Antagonistic interactions of an arsenic-containing mixture in a multiple organ carcinogenicity bioassay.

PubMed

Pott, W A; Benjamin, S A; Yang, R S

1998-11-27

Inorganic arsenic (As), 1,2-dichloroethane (DCE), vinyl chloride (VC) and trichloroethylene (TCE) are frequently identified as groundwater contaminants near hazardous waste disposal sites. While the carcinogenicity of each of these chemicals has been extensively studied individually, little information exists regarding their carcinogenic potential in combination. Therefore, we investigated the carcinogenic promoting potential of chemical mixtures containing arsenic, DCE, VC and TCE following multiple initiator administration in a multiple organ carcinogenicity bioassay (N. Ito, T. Shirai, S. Fukushima, Medium-term bioassay for carcinogens using multiorgan models, in: N. Ito, H. Sugano (Eds.), Modification of Tumor Development in Rodents, Prog. Exp. Tumor Res., 33, 41-57, Basel, Karger, 1991). Our results reveal a dose-responsive antagonistic effect of this four-chemical mixture on the development of preneoplastic hepatic lesions (altered hepatocellular foci and glutathione S-transferase pi positive foci) as well as bronchioalveolar hyperplasia and adenoma formation.

Enzymes and Inhibitors in Neonicotinoid Insecticide Metabolism

PubMed Central

Shi, Xueyan; Dick, Ryan A.; Ford, Kevin A.; Casida, John E.

2009-01-01

Neonicotinoid insecticide metabolism involves considerable substrate specificity and regioselectivity of the relevant CYP450, aldehyde oxidase, and phase II enzymes. Human CYP450 recombinant enzymes carry out the following conversions: CYP3A4, 2C19 and 2B6 for thiamethoxam (TMX) to clothianidin (CLO); 3A4, 2C19 and 2A6 for CLO to desmethyl-CLO; 2C19 for TMX to desmethyl-TMX. Human liver aldehyde oxidase reduces the nitro substituent of CLO to nitroso much more rapidly than that of TMX. Imidacloprid (IMI), CLO and several of their metabolites do not give detectable N-glucuronides but 5-hydroxy-IMI, 4,5-diol-IMI and 4-hydroxy-thiacloprid are converted to O-glucuronides in vitro with mouse liver microsomes and UDP-glucuronic acid or in vivo in mice. Mouse liver cytosol with S-adenosylmethionine converts desmethyl-CLO to CLO but not desmethyl-TMX to TMX. Two organophosphorus CYP450 inhibitors partially block IMI, thiacloprid and CLO metabolism in vivo in mice, elevating the brain and liver levels of the parent compounds while reducing amounts of the hydroxylated metabolites. PMID:19391582

Meat, dairy, and cancer.

PubMed

Abid, Zaynah; Cross, Amanda J; Sinha, Rashmi

2014-07-01

In 2007 the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) report judged that the evidence for an association between red and processed meat consumption and colorectal cancer was convincing. In addition, the effect of other animal products on cancer risk has been studied, and the WCRF/AICR report concluded that milk probably decreases the risk of colorectal cancer but diets high in calcium probably increase the risk of prostate cancer, whereas there was limited evidence for an association between milk and bladder cancer and insufficient evidence for other cancers. There are several potential mechanisms relating meat to cancer, including heterocyclic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, and heme iron. Although the evidence in favor of a link between red and processed meat and colorectal cancer is convincing, the relations with other cancers are unclear. In this review, we summarize cohort studies conducted by the National Cancer Institute on meat and dairy intake in relation to cancer since the 2007 WCRF/AICR report. We also report the findings of meta-analyses published since 2007. © 2014 American Society for Nutrition.

Development of a new analytical tool for assessing the mutagen 2-methyl-1,4-dinitro-pyrrole in meat products by LC-ESI-MS/MS.

PubMed

Molognoni, Luciano; Daguer, Heitor; de Sá Ploêncio, Leandro Antunes; Yotsuyanagi, Suzana Eri; da Silva Correa Lemos, Ana Lucia; Joussef, Antonio Carlos; De Dea Lindner, Juliano

2018-08-01

The use of sorbate and nitrite in meat processing may lead to the formation of 2-methyl-1,4-dinitro-pyrrole (DNMP), a mutagenic compound. This work was aimed at developing and validating an analytical method for the quantitation of DNMP by liquid chromatography-tandem mass spectrometry. Full validation was performed in accordance to Commission Decision 2002/657/EC and method applicability was checked in several samples of meat products. A simple procedure, with low temperature partitioning solid-liquid extraction, was developed. The nitrosation during the extraction was monitored by the N-nitroso-DL-pipecolic acid content. Chromatographic separation was achieved in 8 min with di-isopropyl-3-aminopropyl silane bound to hydroxylated silica as stationary phase. Samples of bacon and cooked sausage yielded the highest concentrations of DNMP (68 ± 3 and 50 ± 3 μg kg -1 , respectively). The developed method proved to be a reliable, selective, and sensitive tool for DNMP measurements in meat products. Copyright © 2018 Elsevier B.V. All rights reserved.

Repellence produced by monoterpenes on Rhodnius prolixus (Hemiptera: Reduviidae) decreases after continuous exposure to these compounds.

PubMed

Lutz, Alejandra; Sfara, Valeria; Alzogaray, Raúl Adolfo

2014-01-01

Botanical monoterpenes are secondary metabolites present in essential oils produced by plants. Some of them are insect repellents. The bloodsucking bug Rhodnius prolixus Ståhl (Hemiptera: Reduviidae) is one of the main vectors of Chagas disease in the north of South America and some countries in Central America. In this study, we studied the repellence produced by two monoterpenes, menthyl acetate and geraniol, on fifth instar nymphs of R. prolixus. In the absence of other stimuli, both menthyl acetate and geraniol produced a repellent effect from 740 μg/cm(2) and 74 μg/cm(2), respectively. Pre-exposure to each monoterpene reduced the repellent activity produced by the same substance. Additionally, pre-exposure to one monoterpene decreased the behavioral response of the nymphs to the other one. The repellent effect of both monoterpenes also decreased when nymphs' antennae were previously treated with the nitric oxide donor S-nitroso-N-acetyl-cysteine. © The Author 2014. Published by Oxford University Press on behalf of the Entomological Society of America.

Meat consumption, meat cooking and risk of lung cancer among Uruguayan men.

PubMed

De Stefani, Eduardo; Ronco, Alvaro L; Boffetta, Paolo; Deneo-Pellegrini, Hugo; Acosta, Gisele; Mendilaharsu, María

2010-01-01

A case-control study was conducted in Uruguay, including 876 male cases of lung cancer and 876 male hospitalized controls, frequency matched for age (ten-year intervals), residence and hospital. The following explanatory variables were included in the study: fried red meat, barbecued red meat, boiled red meat, and salted red meat. These items were log transformed and energy-adjusted by the residuals method. The following potential confounders were included into the models: age, residence, hospital, education, family history of lung cancer, body mass index, smoking index, alcohol drinking, mate consumption, total energy intake, non-meat fatty foods and total fruits. The main objective was to estimate the odds ratios associated with lung cancer risk. Whereas fried meat, barbecued meat, and salted meat were positively associated with risk (OR of the highest quartile of salted meat versus the lowest, 2.90, 95 % CI 1.99-4.25, p-value for trend<0.0001), boiled red meat was mainly protective. We conclude that salted meat was the main risk factor. The mechanisms could be related to the content of N-nitroso compounds in salted meat.

Meat, dairy, and cancer1234

PubMed Central

Abid, Zaynah; Cross, Amanda J; Sinha, Rashmi

2014-01-01

In 2007 the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) report judged that the evidence for an association between red and processed meat consumption and colorectal cancer was convincing. In addition, the effect of other animal products on cancer risk has been studied, and the WCRF/AICR report concluded that milk probably decreases the risk of colorectal cancer but diets high in calcium probably increase the risk of prostate cancer, whereas there was limited evidence for an association between milk and bladder cancer and insufficient evidence for other cancers. There are several potential mechanisms relating meat to cancer, including heterocyclic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, and heme iron. Although the evidence in favor of a link between red and processed meat and colorectal cancer is convincing, the relations with other cancers are unclear. In this review, we summarize cohort studies conducted by the National Cancer Institute on meat and dairy intake in relation to cancer since the 2007 WCRF/AICR report. We also report the findings of meta-analyses published since 2007. PMID:24847855

Retro iminonitroso Diels-Alder reactions: interconversion of nitroso cycloadducts

PubMed Central

Yang, Baiyuan; Lin, Weimin; Krchnak, Viktor; Miller, Marvin J.

2009-01-01

Retro iminonitroso Diels-Alder reactions were investigated in both solution and solid phase. In thermal or Cu(I)-mediated reactions, interconversion of various nitroso cycloadducts occurred in the presence of separate dienes. Up to 99% of conversion was observed. Use of chiral ligands in the Cu(I)-medicated reactions gave new cycloadducts enantioselectively. PMID:20161032

32P-postlabeling analysis of dibenz[a,j]acridine DNA adducts in mice: preliminary determination of initial genotoxic metabolites and their effect on biomarker levels.

PubMed

Roh, J; Schamer, M; Reilman, R; Xue, W; Warshawsky, D; Talaska, G

1993-01-01

N-Heterocyclic aromatics (NHA) are widely occurring environmental pollutants formed during the pyrolysis of nitrogen-containing organic chemicals. NHA are found in significant amounts in tobacco condensates, synthetic fuels, gasoline engine exhaust, and effluents from the heating of coal. Dibenz[a,j]acridine (DBA) is an example of NHA. The potency of many carcinogenic compounds is related, at least in part, to the efficiency of their biological activation. We undertook studies to determine which initial metabolites of DBA lead to the formation of high levels of carcinogen-DNA adducts in vivo. DBA and its metabolites, trans-DBA-1,2-dihydrodiol (DBA-1,2-DHD), trans-DBA-3,4-dihydrodiol (DBA-3,4-DHD), and trans-DBA-5,6-dihydrodiol (DBA-5,6-DHD), were applied to the skin of mice. DNA was isolated using enzyme-solvent extraction method. DNA was 32P-postlabeled under conditions of limiting [32P]ATP. In skin, DBA produced two distinct adducts. The same two adducts were seen when DBA-3,4-DHD was applied. In addition the total adduct level elicited by DBA-3,4-DHD was higher than that of parent compound. Two adducts were seen when DBA-5,6DHD was applied, but these were very different from adducts seen with DBA. These results suggested that activation of DBA to DNA-binding compounds in skin includes initial formation of DBA-3,4-DHD. The data support development of biomarkers for the exposure and effect of this compound, and also suggest that specific metabolic susceptibility markers might be able to predict populations at increased risk.

Halogenated volatile organic compounds from the use of chlorine-bleach-containing household products.

PubMed

Odabasi, Mustafa

2008-03-01

Sodium hypochlorite (NaOCl) and many organic chemicals contained in household cleaning products may react to generate halogenated volatile organic compounds (VOCs). Halogenated VOC emissions from eight different chlorine bleach containing household products (pure and diluted) were investigated by headspace experiments. Chloroform and carbon tetrachloride were the leading compounds along with several halogenated compounds in the headspace of chlorine bleach products. One of the most surprising results was the presence of carbon tetrachloride (a probable human carcinogen and a powerful greenhouse gas that was banned for household use by the U.S. Food and Drug Administration) in very high concentrations (up to 101 mg m(-3)). By mixing surfactants or soap with NaOCl, it was shown that the formation of carbon tetrachloride and several other halogenated VOCs is possible. In addition to quantitatively determined halogenated VOCs (n = 15), several nitrogen-containing (n = 4), chlorinated (n = 10), oxygenated compounds (n = 22), and hydrocarbons (n = 14) were identified in the headspace of bleach products. Among these, 1,1-dichlorobutane and 2-chloro-2-nitropropane were the most abundant chlorinated VOCs, whereas trichloronitromethane and hexachloroethane were the most frequently detected ones. Indoor air halogenated VOC concentrations resulting from the use of four selected household products were also measured before, during, and 30 min after bathroom, kitchen, and floor cleaning applications. Chloroform (2.9-24.6 microg m(-3)) and carbon tetrachloride (0.25-459 microg m(-3)) concentrations significantly increased during the use of bleach containing products. During/ before concentration ratios ranged between 8 and 52 (25 +/- 14, average +/- SD) for chloroform and 1-1170 (146 +/- 367, average +/- SD) for carbon tetrachloride, respectively. These results indicated that the bleach use can be important in terms of inhalation exposure to carbon tetrachloride, chloroform and several other halogenated VOCs.

Determination of eight nitrosamines in water at the ng L(-1) levels by liquid chromatography coupled to atmospheric pressure chemical ionization tandem mass spectrometry.

PubMed

Ripollés, Cristina; Pitarch, Elena; Sancho, Juan V; López, Francisco J; Hernández, Félix

2011-09-19

In this work, we have developed a sensitive method for detection and quantification of eight N-nitrosamines, N-nitrosodimethylamine (NDMA), N-nitrosomorpholine (NMor), N-nitrosomethylethylamine (NMEA), N-nitrosopirrolidine (NPyr), N-nitrosodiethylamine (NDEA), N-nitrosopiperidine (NPip), N-nitroso-n-dipropylamine (NDPA) and N-nitrosodi-n-butylamine (NDBA) in drinking water. The method is based on liquid chromatography coupled to tandem mass spectrometry, using atmospheric pressure chemical ionization (APCI) in positive mode with a triple quadrupole analyzer (QqQ). The simultaneous acquisition of two MS/MS transitions in selected reaction monitoring mode (SRM) for each compound, together with the evaluation of their relative intensity, allowed the simultaneous quantification and reliable identification in water at ppt levels. Empirical formula of the product ions selected was confirmed by UHPLC-(Q)TOF MS accurate mass measurements from reference standards. Prior to LC-MS/MS QqQ analysis, a preconcentration step by off-line SPE using coconut charcoal EPA 521 cartridges (by passing 500 mL of water sample) was necessary to improve the sensitivity and to meet regulation requirements. For accurate quantification, two isotope labelled nitrosamines (NDMA-d(6) and NDPA-d(14)) were added as surrogate internal standards to the samples. The optimized method was validated at two concentration levels (10 and 100 ng L(-1)) in drinking water samples, obtaining satisfactory recoveries (between 90 and 120%) and precision (RSD<20%). Limits of detection were found to be in the range of 1-8 ng L(-1). The described methodology has been applied to different types of water samples: chlorinated from drinking water and wastewater treatment plants (DWTP and WWTP, respectively), wastewaters subjected to ozonation and tap waters. Copyright © 2011 Elsevier B.V. All rights reserved.

Approaches to the risk assessment of genotoxic carcinogens in food: a critical appraisal.

PubMed

O'Brien, J; Renwick, A G; Constable, A; Dybing, E; Müller, D J G; Schlatter, J; Slob, W; Tueting, W; van Benthem, J; Williams, G M; Wolfreys, A

2006-10-01

The present paper examines the particular difficulties presented by low levels of food-borne DNA-reactive genotoxic carcinogens, some of which may be difficult to eliminate completely from the diet, and proposes a structured approach for the evaluation of such compounds. While the ALARA approach is widely applicable to all substances in food that are both carcinogenic and genotoxic, it does not take carcinogenic potency into account and, therefore, does not permit prioritisation based on potential risk or concern. In the absence of carcinogenicity dose-response data, an assessment based on comparison with an appropriate threshold of toxicological concern may be possible. When carcinogenicity data from animal bioassays are available, a useful analysis is achieved by the calculation of margins of exposure (MOEs), which can be used to compare animal potency data with human exposure scenarios. Two reference points on the dose-response relationship that can be used for MOE calculation were examined; the T25 value, which is derived from linear extrapolation, and the BMDL10, which is derived from mathematical modelling of the dose-response data. The above approaches were applied to selected food-borne genotoxic carcinogens. The proposed approach is applicable to all substances in food that are DNA-reactive genotoxic carcinogens and enables the formulation of appropriate semi-quantitative advice to risk managers.

Role of drosophila in chemical mutagenesis testing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nix, C.E.; Brewen, B.

1978-01-01

An important question facing our society is the impact of numerous chemical insults on the health of man and his environment. Faced with a staggering array of chemicals and enormous testing costs, only a few chemicals can be tested for possible carcinogenic effects. Recent results with the Salmonella/mammalian microsome mutagenesis bioassay system demonstrate a striking correlation between carcinogenicity and mutagenicity of many chemical compounds and offer the possibility that mutagenesis assay systems can provide a quick identification of potential carcinogens. Results from microbial assays can serve as a guideline for further mutagenesis testing as well as identify those compounds requiringmore » more extensive analysis in mammalian systems. Reliance on the results from a single mutagenic assay system is rather risky. It would be preferable to use a battery of tests (the tier approach) which would include the rapid microbial assays as well as mammalian systems. Also the use of Drosophila as a bridge between the microbial and mammalian assays has many desirable features which are discussed.« less

Risk of human health by particulate matter as a source of air pollution--comparison with tobacco smoking.

PubMed

Enomoto, Makoto; Tierney, William J; Nozaki, Kohsuke

2008-08-01

Increased air pollution, containing carcinogenic particulate matter smaller than 2.5 microm (PM(2.5)), has gained particular attention in recent years as a causative factor in the increased incidence of respiratory diseases, including lung cancer. Extensive carcinogenicity studies conducted recently under Good Laboratory Practice conditions by National Toxicology Program in the USA, Ramazzini Foundation in Italy or Contract Research Organizations on numerous chemical compounds have demonstrated the importance of considering dose levels, times and duration of exposure in the safety evaluation of carcinogenic as well as classical toxic agents. Data on exposure levels to chemical carcinogens that produce tumor development have contributed to the evaluation of human carcinogens from extrapolation of animal data. A popular held misconception is that the risk from smoking is the result of inhaling assorted particulate matter and by products from burning tobacco rather than the very low ng levels of carcinogens present in smoke. Consider the fact that a piece of toasted bread contains ng levels of the carcinogen urethane (ethyl carbamate). Yet, no one has considered toast to be a human carcinogen. Future human carcinogenic risk assessment should emphasize consideration of inhalation exposure to higher levels of benzo (a) pyrene and other possible carcinogens and particulate matter present in polluted air derived from automobile exhaust, pitch and coal tar on paved roads and asbestos, in addition to other environmental contaminant exposure via the food and drinking water.

A Systematic Review of Carcinogenic Outcomes and Potential Mechanisms from Exposure to 2,4-D and MCPA in the Environment

PubMed Central

von Stackelberg, Katherine

2013-01-01

Chlorophenoxy compounds, particularly 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxy)acetic acid (MCPA), are amongst the most widely used herbicides in the United States for both agricultural and residential applications. Epidemiologic studies suggest that exposure to 2,4-D and MCPA may be associated with increased risk non-Hodgkins lymphoma (NHL), Hodgkin's disease (HD), leukemia, and soft-tissue sarcoma (STS). Toxicological studies in rodents show no evidence of carcinogenicity, and regulatory agencies worldwide consider chlorophenoxies as not likely to be carcinogenic or unclassifiable as to carcinogenicity. This systematic review assembles the available data to evaluate epidemiologic, toxicological, pharmacokinetic, exposure, and biomonitoring studies with respect to key cellular events noted in disease etiology and how those relate to hypothesized modes of action for these constituents to determine the plausibility of an association between exposure to environmentally relevant concentrations of 2,4-D and MCPA and lymphohematopoietic cancers. The combined evidence does not support a genotoxic mode of action. Although plausible hypotheses for other carcinogenic modes of action exist, a comparison of biomonitoring data to oral equivalent doses calculated from bioassay data shows that environmental exposures are not sufficient to support a causal relationship. Genetic polymorphisms exist that are known to increase the risk of developing NHL. The potential interaction between these polymorphisms and exposures to chlorophenoxy compounds, particularly in occupational settings, is largely unknown. PMID:23533401

Gastritis, nitrosamines, and gastric cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stemmermann, G.N.; Mower, H.

1981-01-01

Gastritis is associated with peptic ulcer, gastroenterostomy, pernicious anemia, and exposure to nitrosamines. Once established, the process may be self-perpetuating, resulting in atrophy, metaplasia, dysplasia, and neoplasia. This can be explained by the process of endogenous nitrosation of amines in the inflamed gastric mucosa. Evidence is presented to support this hypothesis. Several drugs given parenterally have been identified as mutagenic nitroso compounds in homogenates of human and canine antral mucosa. Nitrite for this process is apparently derived from the inflamed mucosa. Different amines appear to be nitrosated at different places in the antrum, suggesting the presence of site-specific enzymes thatmore » control these reactions.« less

Identification of fipronil metabolites by time-of-flight mass spectrometry for application in a human exposure study

PubMed Central

McMahen, Rebecca L.; Strynar, Mark J.; Dagnino, Sonia; Herr, David W.; Moser, Virginia C.; Garantziotis, Stavros; Andersen, Erik M.; Freeborn, Danielle L.; McMillan, Larry; Lindstrom, Andrew B.

2016-01-01

Fipronil is a phenylpyrazole insecticide commonly used in residential and agricultural applications. To understand more about the potential risks for human exposure associated with fipronil, urine and serum from dosed Long Evans adult rats (5 and 10 mg/kg bw) were analyzed to identify metabolites as potential biomarkers for use in human biomonitoring studies. Urine from treated rats was found to contain seven unique metabolites, two of which had not been previously reported—M4 and M7 which were putatively identified as a nitroso compound and an imine, respectively. Fipronil sulfone was confirmed to be the primary metabolite in rat serum. The fipronil metabolites identified in the respective matrices were then evaluated in matched human urine (n = 84) and serum (n = 96) samples from volunteers with no known pesticide exposures. Although no fipronil or metabolites were detected in human urine, fipronil sulfone was present in the serum of approximately 25% of the individuals at concentrations ranging from 0.1 to 4 ng/mL. These results indicate that many fipronil metabolites are produced following exposures in rats and that fipronil sulfone is a useful biomarker in human serum. Furthermore, human exposure to fipronil may occur regularly and require more extensive characterization. PMID:25687022

Identification of fipronil metabolites by time-of-flight mass spectrometry for application in a human exposure study.

PubMed

McMahen, Rebecca L; Strynar, Mark J; Dagnino, Sonia; Herr, David W; Moser, Virginia C; Garantziotis, Stavros; Andersen, Erik M; Freeborn, Danielle L; McMillan, Larry; Lindstrom, Andrew B

2015-05-01

Fipronil is a phenylpyrazole insecticide commonly used in residential and agricultural applications. To understand more about the potential risks for human exposure associated with fipronil, urine and serum from dosed Long Evans adult rats (5 and 10mg/kg bw) were analyzed to identify metabolites as potential biomarkers for use in human biomonitoring studies. Urine from treated rats was found to contain seven unique metabolites, two of which had not been previously reported-M4 and M7 which were putatively identified as a nitroso compound and an imine, respectively. Fipronil sulfone was confirmed to be the primary metabolite in rat serum. The fipronil metabolites identified in the respective matrices were then evaluated in matched human urine (n=84) and serum (n=96) samples from volunteers with no known pesticide exposures. Although no fipronil or metabolites were detected in human urine, fipronil sulfone was present in the serum of approximately 25% of the individuals at concentrations ranging from 0.1 to 4ng/mL. These results indicate that many fipronil metabolites are produced following exposures in rats and that fipronil sulfone is a useful biomarker in human serum. Furthermore, human exposure to fipronil may occur regularly and require more extensive characterization. Published by Elsevier Ltd.

(Bio)transformation of 2,4-dinitroanisole (DNAN) in Soils

PubMed Central

Olivares, Christopher I.; Abrell, Leif; Khatiwada, Raju; Chorover, Jon; Sierra-Alvarez, Reyes; Field, Jim A.

2015-01-01

Recent studies have begun to assess the environmental fate and toxicity of 2,4-dinitroanisole (DNAN), an insensitive munition compound of interest to defense agencies. Aerobic and anaerobic DNAN biotransformation in soils was evaluated in this study. Under aerobic conditions, there was little evidence of transformation; most observed removal was attributed to adsorption and subsequent slow chemical reactions. Under anaerobic conditions, DNAN was reductively (bio)transformed and the rate of the transformation was positively correlated with soil organic carbon (OC) up to a threshold of 2.07% OC. H2 addition enhanced the nitroreduction rate compared to endogenous treatments lacking H2. Heat-killed treatments provided rates similar to the endogenous treatment, suggesting that abiotic factors play a role in DNAN reduction. Ten (bio)transformation products were detected by high-resolution mass spectrometry. The proposed transformation pathway involves reduction of DNAN to aromatic amines, with putative reactive nitroso-intermediates coupling with the amines to form azo dimers. Secondary reactions include N-alkyl substitution, O-demethylation (sometimes followed by dehydroxylation), and removal of an N-containing group. Globally, our results suggest that the main reaction DNAN undergoes in anaerobic soils is nitroreduction to 2-methoxy-5-nitroaniline (MENA) and 2,4-diaminoanisole (DAAN), followed by anaerobic coupling reactions yielding azo-dimers. The dimers were subsequently subject to further (bio)transformations. PMID:26551225

DNA adduct profiling of in vitro colonic meat digests to map red vs. white meat genotoxicity.

PubMed

Hemeryck, Lieselot Y; Rombouts, Caroline; De Paepe, Ellen; Vanhaecke, Lynn

2018-05-01

The consumption of red meat has been linked to an increased colorectal cancer (CRC) risk. One of the major hypotheses states that heme iron (present in red meat) stimulates the formation of genotoxic N-nitroso compounds (NOCs) and lipid peroxidation products (LPOs). By means of DNA adductomics, chemically induced DNA adduct formation can be mapped in relation to e.g. dietary exposures. In this study, this state-of-the-art methodology was used to investigate alkylation and (lipid per)oxidation induced DNA adduct formation in in vitro red vs. white meat digests. In doing so, 90 alkylation and (lipid per)oxidation induced DNA adduct types could be (tentatively) identified. Overall, 12 NOC- and/or LPO-related DNA adduct types, i.e. dimethyl-T (or ethyl-T), hydroxymethyl-T, tetramethyl-T, methylguanine (MeG), guanidinohydantoin, hydroxybutyl-C, hydroxymethylhydantoin, malondialdehyde-x3-C, O 6 -carboxymethylguanine, hydroxyethyl-T, carboxyethyl-T and 3,N 4 -etheno-C were singled out as potential heme-rich meat digestion markers. The retrieval of these DNA adduct markers is in support of the heme, NOC and LPO hypotheses, suggesting that DNA adduct formation may indeed contribute to red meat related CRC risk. Copyright © 2018 Elsevier Ltd. All rights reserved.

Nitrolysis of the CN Single Bond and Related Chemistry of Nitro and Nitroso Groups.

DTIC Science & Technology

1984-03-01

8217-dimethylpiperazine 2, triethylamine 1A, tri-a-butylamine 1i, N,N-dimethylbenzylamine 13, 1,4-diazabicyclo [2,2,2] octane 15, Eschenmoser’s salt, nitrosonium and...was not detected by either tlc or nmr; an authentic sample gave nmr (CF3CO2H): 63.40 (s). Nitrosolysis. To a slurry of nitrosonium tetrafluoroborate...with saturated salt solut- ion and then dried (MgSO4). Removal of the solvent left a yellow oil of benzylmethylnitrosamine 21 (1.20 g, 68%). The

Nitric oxide-releasing nanoparticles: synthesis, characterization, and cytotoxicity to tumorigenic cells

NASA Astrophysics Data System (ADS)

Pelegrino, Milena T.; Silva, Letícia C.; Watashi, Carolina M.; Haddad, Paula S.; Rodrigues, Tiago; Seabra, Amedea B.

2017-02-01

Nitric oxide (NO) is involved in several biological processes, including toxicity against tumor cells. The aim of this study was to synthesize, characterize, and evaluate the cytotoxicity of NO-releasing chitosan nanoparticles. A thiol-containing molecule, mercaptosuccinic acid (MSA), was encapsulated (encapsulation efficiency of 99%) in chitosan/sodium tripolyphosphate nanoparticles (CS NPs). The obtained nanoparticles showed an average hydrodynamic size of 108.40 ± 0.96 nm and polydispersity index of 0.26 ± 0.01. MSA-CS NPs were nitrosated leading to S-nitroso-MSA-CS NPs, which act as NO donor. The cytotoxicity of CS NPs, MSA-CS NPs, and S-nitroso-MSA-CS NPs were evaluated in several tumor cells, including human hepatocellular carcinoma (HepG2), mouse melanoma (B16F10), and human chronic myeloid leukemia (K562) cell lines and Lucena-1, a vincristine-resistant K562 cell line. Both CS NPs and MSA-CS NPs did not cause toxic effects in these cells, whereas S-nitroso-MSA-CS NPs caused potent cytotoxic effects in all the tested tumor cell lines. The half-maximal inhibitory concentration values of S-nitroso-MSA-CS NPs were 19.7, 10.5, 22.8, and 27.8 μg·mL-1 for HepG2, B16F10, K562, and Lucena-1 cells, respectively. In contrast, S-nitroso-MSA-CS NPs exhibited lower cytotoxic to non-tumorigenic melanocytes (Melan-A) when compared with melanoma B16F10. Therefore, the results highlight the potential use of NO-releasing CS NPs in antitumor chemotherapy.

Low-Dose Carcinogenicity Studies

EPA Science Inventory

One of the major deficiencies of cancer risk assessments is the lack of low-dose carcinogenicity data. Most assessments require extrapolation from high to low doses, which is subject to various uncertainties. Only 4 low-dose carcinogenicity studies and 5 low-dose biomarker/pre-n...

S-Nitroso-N-acetylpenicillamine (SNAP) Impregnated Silicone Foley Catheters: A Potential Biomaterial/Device To Prevent Catheter-Associated Urinary Tract Infections

PubMed Central

2016-01-01

Urinary Foley catheters are utilized for management of hospitalized patients and are associated with high rates of urinary tract infections (UTIs). Nitric oxide (NO) potently inhibits microbial biofilm formation, which is the primary cause of catheter associated UTIs (CAUTIs). Herein, commercial silicone Foley catheters are impregnated via a solvent swelling method with S-nitroso-N-acetyl-D-penicillamine (SNAP), a synthetic NO donor that exhibits long-term NO release and stability when incorporated into low water-uptake polymers. The proposed catheters generate NO surface-fluxes >0.7 × 10–10 mol min–1 cm–2 for over one month under physiological conditions, with minimal SNAP leaching. These biomedical devices are demonstrated to significantly decrease formation of biofilm on the surface of the catheter tubings over 3, 7, and 14 day periods by microbial species (Staphylococcus epidermidis and Proteus mirabilis) commonly causing CAUTIs. Toxicity assessment demonstrates that the SNAP-impregnated catheters are fully biocompatible, as extracts of the catheter tubings score 0 on a 3-point grading scale using an accepted mouse fibroblast cell-line toxicity model. Consequently, SNAP-impregnated silicone Foley catheters can likely provide an efficient strategy to greatly reduce the occurrence of nosocomial CAUTIs. PMID:26462294

Exocyclic Deoxyadenosine Adducts of 1,2,3,4-Diepoxybutane: Synthesis, Structural Elucidation, and Mechanistic Studies

PubMed Central

Seneviratne, Uthpala; Antsypovich, Sergey; Goggin, Melissa; Dorr, Danae Quirk; Guza, Rebecca; Moser, Adam; Thompson, Carrie; York, Darrin M.; Tretyakova, Natalia

2009-01-01

1,2,3,4-Diepoxybutane (DEB)1 is considered the ultimate carcinogenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant present in urban air. Although it preferentially modifies guanine within DNA, DEB induces a large number of A → T transversions, suggesting that it forms strongly mispairing lesions at adenine nucleobases. We now report the discovery of three potentially mispairing exocyclic adenine lesions of DEB: N6,N6-(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine (compound 2), 1,N6-(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2′-deoxyadenosine (compound 3), and 1,N6-(1-hydroxymethyl-2-hydroxypropan-1,3-diyl)-2′-deoxyadenosine (compound 4). The structures and stereochemistry of the novel DEB-dA adducts were determined by a combination of UV and NMR spectroscopy, tandem mass spectrometry, and independent synthesis. We found that synthetic N6-(2-hydroxy-3,4-epoxybut-1-yl)-2′-deoxyadenosine (compound 1) representing the product of N6-adenine alkylation by DEB spontaneously cyclizes to form 3 under aqueous conditions or 2 under anhydrous conditions in the presence of organic base. Compound 3 can be interconverted with 4 by a reversible unimolecular pericyclic reaction favoring 4 as a more thermodynamically stable product. Both 3 and 4 are present in double stranded DNA treated with DEB in vitro and in liver DNA of laboratory mice exposed to 1,3-butadiene by inhalation. We propose that in DNA under physiological conditions, DEB alkylates the N-1 position of adenine in DNA to form N1-(2-hydroxy-3,4-epoxybut-1-yl)-adenine adducts, which undergo an SN2-type intramolecular nucleophilic substitution and rearrangement to give 3 (minor) and 4 (major). Formation of exocyclic DEB-adenine lesions following exposure to 1,3-butadiene provides a possible mechanism of mutagenesis at the A:T base pairs. PMID:19883087

Carcinogenicity of antioxidants BHA, caffeic acid, sesamol, 4-methoxyphenol and catechol at low doses, either alone or in combination, and modulation of their effects in a rat medium-term multi-organ carcinogenesis model.

PubMed

Hirose, M; Takesada, Y; Tanaka, H; Tamano, S; Kato, T; Shirai, T

1998-01-01

The carcinogenicity of low dietary levels of the antioxidants butylated hydroxyanisole (BHA), caffeic acid, sesamol, 4-methoxyphenol (4-MP) and catechol, known to target the forestomach or glandular stomach, were examined alone or in combination in a 2-year long-term experiment and their modifying effects assessed in a medium-term multiorgan model. In the carcinogenicity study, groups of 30-31 male F344 rats were treated with 0.4% BHA, 0.4% caffeic acid, 0.4% sesamol, 0.4% 4-MP and 0.16% catechol either alone or in combination for up to 104 weeks and then killed. In the medium-term multi-organ model, groups of 10 to 15 male F344 rats were given diethylnitrosamine (DEN), N-methylnitrosourea (MNU), 1,2-dimethylhydrazine (DMH), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) for a total multiple initiation period of 4 weeks (DMBDD treatment). BHA, caffeic acid, sesamol and 4-MP, each at doses of 0.4% or 0.08%, and catechol at doses of 0.16% or 0.032% were administered in the diet either alone or in combination after completion of the initiation regimen. All surviving animals were killed at the end of week 28, and major organs were examined histopathologically. In the carcinogenicity study, slightly increased incidences of forestomach papillomas were found in the sesamol- (15.8%), caffeic acid- (14.8%), catechol- (3%) and 4-MP- (11.5%) treated groups as compared with basal diet (0%), and a significant increase was observed with the five antioxidants in combination (42.9%, P < 0.001). In a medium-term multiorgan carcinogenesis model, incidences of forestomach papillomas and/or carcinomas were increased in each high dose group, but additive or synergistic effects were not found in the combination group. In the low dose case, the incidence of forestomach papillomas was significantly increased only in the combination group. With regard to other organs, the incidence of colon tumors was significantly decreased only in the high dose combination group. The results indicate that even at low dose levels phenolic compounds can exert additive/synergistic effect on carcinogenesis.

A TWO-YEAR DOSE-RESPONSE STUDY OF LESION SEQUENCES DURING HEPATOCELLULAR CARCINOGENESIS IN THE MALE B6C3F1 MOUSE GIVEN THE DRINKING WATER CHEMICAL DICHLOROACETIC ACID

EPA Science Inventory

ABSTRACT

Dichloroacetic acid (DCA) is carcinogenic to the B6C3F 1 mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver, and the known concentrations of this compound in drinking water, reliable biologically-based models to reduce the uncertai...

Formation of 4-ethoxy-4'-nitrosodiphenylamine in the reaction of the phenacetin metabolite 4-nitrosophenetol with glutathione.

PubMed

Klehr, H; Eyer, P; Schäfer, W

1987-08-01

Phenacetin, a constituent of several analgesic and antipyretic formulations has been made responsible for a variety of toxic and carcinogenic actions. 4-Nitrosophenetol, the N-oxydation product of intermediate 4-phenetidine, forms methemoglobin and binds covalently to sulfhydryl groups of proteins and glutathione. In the reaction of 4-nitrosophenetol with glutathione and other thiols an intermediate so-called "semimercaptal" is formed from which N-(thiol-S-yl)-4-phenetidine S-oxide, N-(thiol-S-yl)-4-phenetidine and 4-phenetidine derive. Besides thiol adducts, a yellow compound is formed which was isolated as a pure crystalline product (elemental analysis) and identified by FAB-MS, EI-MS, 13C-, 1H-NMR, and UV-VIS spectroscopy as 4-ethoxy-4'-nitrosodiphenylamine. This nitrosoarene is formed by an unknown mechanism from 4-nitrosophenetol and 4-phenetidine under liberation of ethanol. In human erythrocytes this compound is easily reduced to 4-amino-4'-ethoxydiphenylamine (FAB-MS, EI-MS, 13C-NMR). During the reaction of 4-nitrosophenetol with red cells only traces of 4-ethoxy-4'-nitrosodiphenylamine were formed, whereas up to 10% appeared as the reduction product 4-amino-4'-ethoxydiphenylamine. This latter compound is unstable in red cells and is metabolized further to unidentified products.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Malfatti, M A; Felton, J S

A number of carcinogenic heterocyclic amines (PhIP, MeIQx, and DiMeIQx) are produced from the condensation of creatinine, hexoses and amino acids during the cooking of meat (1). There are many variables that impact the production and subsequent ingestion of these compounds in our diet. Temperature, type of meat product, cooking method, doneness, and other factors affect the quantity of these carcinogens consumed by humans. Estimates of ingestion of these carcinogens are 1-20 ng/kg body weight per day (2). Human case control studies that correlate meat consumption from well-done cooking practices with cancer incidence indicate excess tumors for breast, colon, stomach,more » esophagus, and possibly prostate (3-5).« less

Urinary carcinogenic 4-6 ring polycyclic aromatic hydrocarbons in coke oven workers and in subjects belonging to the general population: role of occupational and environmental exposure.

PubMed

Campo, Laura; Fustinoni, Silvia; Consonni, Dario; Pavanello, Sofia; Kapka, Lucyna; Siwinska, Ewa; Mielzyňska, Danuta; Bertazzi, PierAlberto

2014-03-01

A new solid phase microextraction-gas chromatography-mass spectrometry method (SPME-GC-MS) to detect urinary unmetabolized 3-, 6-ring polycyclic aromatic hydrocarbons (PAHs) was applied to coke oven workers and general population subjects with the aim to assess exposure to carcinogenic PAHs, to evaluate the role of occupational and environmental variables on PAHs levels, and to compare present results with those previously obtained with a less sensitive method. A total of 104 coke oven workers (CW) from Poland [recruited in 2000 (CW-2000; n=55) and 2006 (CW-2006; n=49)], and 45 control subjects from the same area, provided urine spot samples for measurement of 10 PAHs (from phenanthrene to benzo[g,h,i]perylene). The comparison between the two methods was performed only on CW-2000 subjects. Information regarding personal characteristics and job variables was collected by a questionnaire. The new method enables the quantification of 5-, 6-ring PAHs; precision and accuracy were in the 7.3-20.8% and 89.4-110% range, respectively; in CW-2000 samples results obtained with the new and the old method were highly correlated (Lin's concordance correlation coefficients: from 0.790 to 0.965); the mean difference between measured PAHS increased with the molecular weight of the analytes (from +5 to +27%). Urinary PAHs were above or equal to the quantification limit, depending on the compound, in 67-100% (min-max), 26-100% and 6-100% of samples from CW-2000, CW-2006 and controls, respectively. Chrysene and benz[a]anthracene were the most abundant carcinogenic PAHs with median levels of 43.4, 13.4, and 2.3 ng/L and 45.9, 14.9, and 0.7 ng/L in CW-2000, CW-2006, and controls, respectively, while benzo[a]pyrene levels were 6.5, 0.7 and <0.5 ng/L. The multiple linear regression model showed that the determinants of exposure were the use of wood and/or coke for house heating for controls, and job title or the plant for CW-2006. Urinary benzo[a]pyrene and other carcinogenic PAHs were, for the first time, quantified in urine samples from both occupationally and environmentally exposed subjects. These results show that urinary PAHs can discriminate exposure at different levels. Moreover, the simultaneous determination of several PAHs allows for the development of excretion profiles to assess exposure to specific compounds. Copyright © 2013 Elsevier GmbH. All rights reserved.

Carcinogenic nitrosamines in traditional beer as the cause of oesophageal squamous cell carcinoma in black South Africans.

PubMed

Pillay, Viness; Isaacson, Charles; Mothobi, Pride; Hale, Martin; Tomar, Lomas Kumar; Tyagi, Charu; Altini, Mario; Choonara, Yahya Essop; Kumar, Pradeep

2015-09-21

Before the 1930s, squamous cell carcinoma (SCC) of the oesophagus was almost unknown among black South Africans. From the 1930s the annual frequency rose. A dietary cause was sought, the staple diet of black people having changed from sorghum to maize (corn), with traditional beer being brewed from maize. Carcinogenic N-nitrosamines in traditional beer were suggested as a cause of SCC of the oesophagus, with Fusarium moniliforme, a corn saprophyte, thought to play a role. To confirm the presence of N-nitrosamines in traditional beer and demonstrate a mechanism for the oncogenesis of oesophageal carcinoma. Analysis by high-performance liquid chromatography was conducted for the identification of nitrosamines in traditional beer samples, and molecular docking studies were employed to predict the affinity between N-nitrosamines and the S100A2 protein. Carcinogenic N-nitrosamines were identified in all six samples of traditional beer examined (N=18 analyses), and docking studies confirmed a high affinity of the nitrosamine N-nitrosopyrrolidone with the S100A2 protein. This may result in the altered expression of the S100A2 protein, leading to tumour progression and prognosis. It is suggested that carcinogenic N-nitrosamines in traditional beer are a major factor in the causation of SCC of the oesophagus in black South Africans. N-nitrosamines have been shown to produce cancer experimentally, but there has not been conclusive epidemiological evidence that N-nitrosamines are carcinogenic to humans. This study is the first to demonstrate the potential link between N-nitrosamines and a human tumour.

Occupational exposure to rubber vulcanization products during repair of rubber conveyor belts in a brown coal mine.

PubMed

Gromiec, Jan P; Wesołowski, Wiktor; Brzeźnicki, Sławomir; Wróblewska-Jakubowska, Krystyna; Kucharska, Małgorzata

2002-12-01

Several hundred chemical compounds were found in workroom environments in the rubber industry, but most of the published exposure data relate to the production of tyres; information from the "non-tyre" sections are very limited, if any. This study was carried out to identify chemical substances and measure their air concentrations in the repair shop of a brown coal mine in which damaged rubber conveyor belts were repaired. GC-MS and HPLC analysis of stationary air samples resulted in identification of aliphatic and aromatic hydrocarbons to C12, PAHs, alcohols, phenols, ketones, heterocyclic nitrogen and sulfur compounds. Quantitative evaluation of occupational exposure included determination of organic compound vapours collected on charcoal (GC-MSD), polycyclic aromatic hydrocarbons (HPLC), N-nitrosoamines and other amines (GC-NPD) and DNPH derivatives of aldehydes (HPLC) in the breathing zone of workers representing all job titles. The concentrations of investigated compounds were very low. Carcinogenic substances: N-nitrosoamines, benzene, PAHs were not present in workroom air in concentrations exceeding limits of detection of the analytical methods being applied; concentrations of methylisobutylketone, tetrachloroethylene, naphtha, aromatic hydrocarbons, phthalates and aldehydes were much lower than the respective occupational exposure limit values. The results indicate much lower exposure than that reported in the production of tyres and other fabricated rubber products.

Genetic damage of organic matter in the Brazilian Amazon: a comparative study between intense and moderate biomass burning.

PubMed

de Oliveira Alves, Nilmara; de Souza Hacon, Sandra; de Oliveira Galvão, Marcos Felipe; Simões Peixotoc, Milena; Artaxo, Paulo; de Castro Vasconcellos, Pérola; de Medeiros, Silvia Regina Batistuzzo

2014-04-01

The biomass burning that occurs in the Amazon region has an adverse effect on environmental and human health. However, in this region, there are limited studies linking atmospheric pollution and genetic damage. We conducted a comparative study during intense and moderate biomass burning periods focusing on the genetic damage and physicochemical analyses of the particulate matter (PM). PM and black carbon (BC) were determined; organic compounds were identified and quantified using gas chromatography with flame ionization detection, the cyto-genotoxicity test was performed using two bioassays: cytokinesis-block micronucleus (CBMN) in A549 cells and Tradescantia pallida micronucleus (Trad-MCN) assay. The PM10 concentrations were lower than the World Health Organization air quality standard for 24h. The n-alkanes analyses indicate anthropogenic and biogenic influences during intense and moderate biomass burning periods, respectively. Retene was identified as the most abundant polycyclic aromatic hydrocarbon during both sampling periods. Carcinogenic and mutagenic compounds were identified. The genotoxic analysis through CBMN and Trad-MCN tests showed that the frequency MCN from the intense burning period is significantly higher compared to moderate burning period. This is the first study using human alveolar cells to show the genotoxic effects of organic PM from biomass burning samples collected in Amazon region. The genotoxicity of PM can be associated with the presence of several mutagenic and carcinogenic compounds, mainly benzo[a]pyrene. These findings have potential implications for the development of pollution abatement strategies and can minimize negative impact on health. Copyright © 2014 Elsevier Inc. All rights reserved.

Gender differences in the metabolism of 1,3-butadiene to butadiene diepoxide in Sprague-Dawley rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thornton-Manning, J.R.; Dahl, A.R.; Bechtold, W.E.

1995-12-01

1,3-Butadiene (BD), a gaseous compound used in the production of rubber, is a potent carcinogen in mice and a weak carcinogen in rats. The mechanism of BD-induced carcinogenicity is thought to involve genotoxic effects of its reactive epoxide metabolites butadiene monoepoxide (BDO) and butadiene diepoxide (BDO{sub 2}). Studies in our laboratory have shown that levels of the epoxides, particularly BDO{sub 2}, are greater in mice-the more sensitive species-than rats. While both epoxides are genotoxic in a number of assays, BDO{sub 2} is mutagenic in TK6 human lymphoblastoid cells at concentrations approximately 100-fold lower than BDO. Species differences in carcinogenicity ofmore » BD have posed a dilemma to investigators deciding which animal model is most appropriate for BD risk assessment.« less

Contributions of Human Enzymes in Carcinogen Metabolism

PubMed Central

Rendic, Slobodan; Guengerich, F. Peter

2012-01-01

Considerable support exists for roles of metabolism in modulating the carcinogenic properties of chemicals. In particular, many of these compounds are procarcinogens that require activation to electrophilic forms to exert genotoxic effects. We systematically analyzed the existing literature on metabolism of carcinogens by human enzymes, which has been developed largely in the past 25 years. The metabolism and especially bioactivation of carcinogens are dominated by cytochrome P450 enzymes (66% of bioactivations). Within this group, six P450s—1A1, 1A2, 1B1, 2A6, 2E1, and 3A4—accounted for 77% of the P450 activation reactions. The roles of these P450s can be compared with those estimated for drug metabolism and should be considered in issues involving enzyme induction, chemoprevention, molecular epidemiology, inter-individual variations, and risk assessment. PMID:22531028

Protective effect of hydroxychavicol, a phenolic component of betel leaf, against the tobacco-specific carcinogens.

PubMed

Amonkar, A J; Padma, P R; Bhide, S V

1989-02-01

The phenolic compound, hydroxychavicol (HC), present in betel leaf, was synthesised and tested for its antimutagenic effect against the mutagenicity of the 2 tobacco-specific N-nitrosamines (TSNA), N'-nitrosonornicotine (NNN) and 4-(nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK), in 2 different test systems, viz. the Ames Salmonella/microsome assay and the micronucleus test using Swiss male mice. We are reporting the synthesis of HC of a high degree of purity. We observed that HC suppressed the mutagenic effects of NNN and NNK in both test systems used. These results indicate that HC may have a role to play in reducing the risk of oral cancer in betel quid with tobacco chewers.

Rapid communication: effects of tobacco processing on the quantity of benzo[a]pyrene in mainstream smoke.

PubMed

Martin, Lin Alicia; Byrd, Sherell K; Milofsky, Robert E

2003-07-25

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon produced during incomplete combustion of organic compounds and is one of the more carcinogenic PAHs detected in tobacco smoke. Addition of organic compounds during tobacco processing increases the likelihood of finding elevated concentrations of BaP in mainstream smoke when compared to smoke from unprocessed tobacco. To test this hypothesis, the tobacco from Marlboro "Red" (processed) cigarettes and nonprocessed Burley tobacco leaf cigarettes was combusted and the resulting combustion products were collected onto glass fiber filter pads. The quantity of BaP in the tobacco tar extracted from the pads was measured using reversed-phase liquid chromatography with fluorescence detection. The concentration of BaP in the processed tobacco smoke was significantly higher than in unprocessed tobacco smoke. These results suggest that compounds added during tobacco processing increase the concentrations of BaP and therefore the carcinogenic potential of cigarettes.

Nitrous Acid as an Oxidant in Acidic Media

DTIC Science & Technology

1979-09-25

nitroso oxidations were run in sulfuric acid. The Hammett acidity function is used as the abscissa because it conveniently represents the acidity region...oxidation. 13 Consistent with the general mechanism, equations (1)-(3), and in contrast to nitration, phenol nitrosation displays a primary kinetic...oxidized 1(III) + Alc - 104O + C-O (4) with the only route now removing HNO being NO+ + H - H + + 2N0 (5) Apparently while alcohol remains, equation (5

Epidemiological and experimental aspects of metal carcinogenesis: physicochemical properties, kinetics, and the active species.

PubMed Central

Magos, L

1991-01-01

The carcinogenic properties of selected metals and their compounds are reviewed to provide a useful reference for existing knowledge on relationships between physical and chemical forms, kinetics and carcinogenic potential and between epidemiology, bioassays, and short-term tests. Extensive consideration is given to arsenic, beryllium, cadmium, chromium, lead, and nickel. Other metals such as antimony, cobalt, copper, iron, manganese, selenium, and zinc are discussed briefly. PMID:1821370

Evidence for a possible role for nitric oxide in the modulation of heart activity in Achatina fulica and Helix aspersa.

PubMed

White, A R; Curtis, S A; Walker, R J

2004-02-01

The effects of nitric oxide (NO) donors, S-nitroso-N-acetylpenicillamine, S-nitroso-l-glutathione, sodium nitroprusside and sodium nitrite were investigated on the activity of the isolated hearts of Achatina fulica and Helix aspersa. NO donors inhibited heart activity in a concentration-dependent manner. The only exception was sodium nitroprusside, which excited H. aspersa heart. The inhibitory effects of these NO donors were reduced by the NO scavenger, methylene blue, the guanylyl cyclase inhibitor, 1H-(1,2,4) Oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), and potentiated by 8-Br-cGMP and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Acetylcholine also inhibited the heart activity, and this inhibition was reduced by methylene blue and ODQ. Positive NADPH-diaphorase staining was located in the outer pericardial layer of the heart of A. fulica. The present results provide evidence that NO may modulate the activity of gastropod hearts, and this modulation may modify the inhibitory action of acetylcholine on heart activity.

Second chronological supplement to the Carcinogenic Potency Database: standardized results of animal bioassays published through December 1984 and by the National Toxicology Program through May 1986.

PubMed Central

Gold, L S; Slone, T H; Backman, G M; Magaw, R; Da Costa, M; Lopipero, P; Blumenthal, M; Ames, B N

1987-01-01

This paper is the second chronological supplement to the Carcinogenic Potency Database, published earlier in this journal (1,2,4). We report here results of carcinogenesis bioassays published in the general literature between January 1983 and December 1984, and in Technical Reports of the National Cancer Institute/National Toxicology Program between January 1983 and May 1986. This supplement includes results of 525 long-term, chronic experiments of 199 test compounds, and reports the same information about each experiment in the same plot format as the earlier papers: e.g., the species and strain of test animal, the route and duration of compound administration, dose level and other aspects of experimental protocol, histopathology and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, author's opinion about carcinogenicity, and literature citation. We refer the reader to the 1984 publications for a description of the numerical index of carcinogenic potency (TD50), a guide to the plot of the database, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The three plots of the database are to be used together, since results of experiments published in earlier plots are not repeated. Taken together, the three plots include results for more than 3500 experiments on 975 chemicals. Appendix 14 is an index to all chemicals in the database and indicates which plot(s) each chemical appears in. PMID:3691431

AN ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA) FOR DETERMINING DIOXINS IN SEDIMENT AND SOIL SAMPLES

EPA Science Inventory

The dioxins comprise a family of compounds chemically referred to as polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). The most toxic of these compounds is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a known human carcinogen. Dioxins are formed ...

4-Aminobiphenyl Downregulation of NAT2 Acetylator Genotype–Dependent N- and O-acetylation of Aromatic and Heterocyclic Amine Carcinogens in Primary Mammary Epithelial Cell Cultures from Rapid and Slow Acetylator Rats

PubMed Central

Jefferson, Felicia A.; Xiao, Gong H.; Hein, David W.

2009-01-01

Aromatic and heterocyclic amine carcinogens present in the diet and in cigarette smoke induce breast tumors in rats. N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) enzymes have important roles in their metabolic activation and deactivation. Human epidemiological studies suggest that genetic polymorphisms in NAT1 and/or NAT2 modify breast cancer risk in women exposed to these carcinogens. p-Aminobenzoic acid (selective for rat NAT2) and sulfamethazine (SMZ; selective for rat NAT1) N-acetyltransferase catalytic activities were both expressed in primary cultures of rat mammary epithelial cells. PABA, 2-aminofluorene, and 4-aminobiphenyl N-acetyltransferase and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine and N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline O-acetyltransferase activities were two- to threefold higher in mammary epithelial cell cultures from rapid than slow acetylator rats. In contrast, SMZ (a rat NAT1-selective substrate) N-acetyltransferase activity did not differ between rapid and slow acetylators. Rat mammary cells cultured in the medium supplemented 24 h with 10μM ABP showed downregulation in the N-and O-acetylation of all substrates tested except for the NAT1-selective substrate SMZ. This downregulation was comparable in rapid and slow NAT2 acetylators. These studies clearly show NAT2 acetylator genotype–dependent N- and O-acetylation of aromatic and heterocyclic amine carcinogens in rat mammary epithelial cell cultures to be subject to downregulation by the arylamine carcinogen ABP. PMID:18842621

Combined exposure to X-irradiation followed by N-ethyl-N-nitrosourea treatment alters the frequency and spectrum of Ikaros point mutations in murine T-cell lymphoma.

PubMed

Kakinuma, Shizuko; Nishimura, Mayumi; Amasaki, Yoshiko; Takada, Mayumi; Yamauchi, Kazumi; Sudo, Satomi; Shang, Yi; Doi, Kazutaka; Yoshinaga, Shinji; Shimada, Yoshiya

2012-09-01

Ionizing radiation is a well-known carcinogen, but its potency may be influenced by other environmental carcinogens, which is of practical importance in the assessment of risk. Data are scarce, however, on the combined effect of radiation with other environmental carcinogens and the underlying mechanisms involved. We studied the mode and mechanism of the carcinogenic effect of radiation in combination with N-ethyl-N-nitrosourea (ENU) using doses approximately equal to the corresponding thresholds. B6C3F1 mice exposed to fractionated X-irradiation (Kaplan's method) followed by ENU developed T-cell lymphomas in a dose-dependent manner. Radiation doses above an apparent threshold acted synergistically with ENU to promote lymphoma development, whereas radiation doses below that threshold antagonized lymphoma development. Ikaros, which regulates the commitment and differentiation of lymphoid lineage cells, is a critical tumor suppressor gene frequently altered in both human and mouse lymphomas and shows distinct mutation spectra between X-ray- and ENU-induced lymphomas. In the synergistically induced lymphomas, we observed a low frequency of LOH and an inordinate increase of Ikaros base substitutions characteristic of ENU-induced point mutations, G:C to A:T at non-CpG, A:T to G:C, G:C to T:A and A:T to T:A. This suggests that radiation doses above an apparent threshold activate the ENU mutagenic pathway. This is the first report on the carcinogenic mechanism elicited by combined exposure to carcinogens below and above threshold doses based on the mutation spectrum of the causative gene. These findings constitute a basis for assessing human cancer risk following exposure to multiple carcinogens. Copyright © 2012 Elsevier B.V. All rights reserved.

Prediction of rodent carcinogenic potential of naturally occurring chemicals in the human diet using high-throughput QSAR predictive modeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valerio, Luis G.; Arvidson, Kirk B.; Chanderbhan, Ronald F.

2007-07-01

Consistent with the U.S. Food and Drug Administration (FDA) Critical Path Initiative, predictive toxicology software programs employing quantitative structure-activity relationship (QSAR) models are currently under evaluation for regulatory risk assessment and scientific decision support for highly sensitive endpoints such as carcinogenicity, mutagenicity and reproductive toxicity. At the FDA's Center for Food Safety and Applied Nutrition's Office of Food Additive Safety and the Center for Drug Evaluation and Research's Informatics and Computational Safety Analysis Staff (ICSAS), the use of computational SAR tools for both qualitative and quantitative risk assessment applications are being developed and evaluated. One tool of current interest ismore » MDL-QSAR predictive discriminant analysis modeling of rodent carcinogenicity, which has been previously evaluated for pharmaceutical applications by the FDA ICSAS. The study described in this paper aims to evaluate the utility of this software to estimate the carcinogenic potential of small, organic, naturally occurring chemicals found in the human diet. In addition, a group of 19 known synthetic dietary constituents that were positive in rodent carcinogenicity studies served as a control group. In the test group of naturally occurring chemicals, 101 were found to be suitable for predictive modeling using this software's discriminant analysis modeling approach. Predictions performed on these compounds were compared to published experimental evidence of each compound's carcinogenic potential. Experimental evidence included relevant toxicological studies such as rodent cancer bioassays, rodent anti-carcinogenicity studies, genotoxic studies, and the presence of chemical structural alerts. Statistical indices of predictive performance were calculated to assess the utility of the predictive modeling method. Results revealed good predictive performance using this software's rodent carcinogenicity module of over 1200 chemicals, comprised primarily of pharmaceutical, industrial and some natural products developed under an FDA-MDL cooperative research and development agreement (CRADA). The predictive performance for this group of dietary natural products and the control group was 97% sensitivity and 80% concordance. Specificity was marginal at 53%. This study finds that the in silico QSAR analysis employing this software's rodent carcinogenicity database is capable of identifying the rodent carcinogenic potential of naturally occurring organic molecules found in the human diet with a high degree of sensitivity. It is the first study to demonstrate successful QSAR predictive modeling of naturally occurring carcinogens found in the human diet using an external validation test. Further test validation of this software and expansion of the training data set for dietary chemicals will help to support the future use of such QSAR methods for screening and prioritizing the risk of dietary chemicals when actual animal data are inadequate, equivocal, or absent.« less

Studies on promoting action in skin carcinogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saffiotti, U.; Shubik, P.

1963-01-01

A number of substances were tested for carcinogenic promoting activity in Swiss mice by applying them twice weekly to the clipped dorsal skin, beginning 1 wk after a single application of 9,10-dimethyl-1, 2-benzanthracene (DMBA; 1 to 1.5% in mineral oil). Tests with silver nitrate (10% aqueous), iodoacetic acid (0.9% in acetone, fumaric acid (1% in acetone), ethylphenylpropiolate (5% in acetone), trihydroxymethylanthraquinone. (Emodin; 0.5% in acetone), oleic alcohol, monostearin (5% in acetone) and sorbitan monolaurate were essentially negative; when a single application of croton oil (5% in mineral oil) was interspersed between the carcinogen and silver nitrate, 6/20 mice developed 14more » benign tumors and 1 carcinoma. N-Dodecane showed moderate promoting activity (26 tumors, with 2 carcinomas, in 12/30 mice). Tests of several petroleum fractions showed high initial promoting activity (404 tumors, with 31 carcinomas, in 36/50 mice), but the activity disappeared on storage; while there was no carcinogenic activity in mice, in New Zealand albino rabbits the petroleum fractions alone produced considerable numbers of tumors. One application of DMBA, however, did increase tumor incidence and shorten the latent period. The hexane-eluted fraction of a methanolic extract of croton seeds (which had little vesicant activity), had all the promoting activity of the original croton oil; this could be demonstrated with uethan (20 mg/day ip for 5 days) as the initiator as well as with DMBA. In conclusion, the authors distinguish sharply between the promoting activity of compounds such as croton oil, which lead mostly to benign tumors (many of which regress spontaneously), and the additive effects of carcinogenic substances which may have a stimulatory effect on the second stage of carcinogenesis; for this additive carcinogenic effect, they suggest the term developing action. Other studies on croton oil are also reviewed.« less

Procarcinogens – Determination and Evaluation by Yeast-Based Biosensor Transformed with Plasmids Incorporating RAD54 Reporter Construct and Cytochrome P450 Genes

PubMed Central

Bui, Van Ngoc; Nguyen, Thi Thu Huyen; Mai, Chi Thanh; Bettarel, Yvan; Hoang, Thi Yen; Trinh, Thi Thuy Linh; Truong, Nam Hai; Chu, Hoang Ha; Nguyen, Vu Thanh Thanh; Nguyen, Huu Duc

2016-01-01

In Vietnam, a great number of toxic substances, including carcinogens and procarcinogens, from industrial and agricultural activities, food production, and healthcare services are daily released into the environment. In the present study, we report the development of novel yeast-based biosensor systems to determine both genotoxic carcinogens and procarcinogens by cotransformation with two plasmids. One plasmid is carrying human CPR and CYP (CYP3A4, CYP2B6, or CYP2D6) genes, while the other contains the RAD54-GFP reporter construct. The three resulting coexpression systems bearing both CPR-CYP and RAD54-GFP expression cassettes were designated as CYP3A4/CYP2B6/CYP2D6 + RAD54 systems, respectively and used to detect and evaluate the genotoxic potential of carcinogens and procarcinogens by selective activation and induction of both CPR-CYP and RAD54-GFP expression cassettes in response to DNA damage. Procarcinogens were shown to be predominantly, moderately or not bioactivated by one of the CYP enzymes and thus selectively detected by the specific coexpression system. Aflatoxin B1 and benzo(a)pyrene were predominantly detected by the CYP3A4 + RAD54 system, while N-nitrosodimethylamine only moderately activated the CYP2B6 + RAD54 reporter system and none of them was identified by the CYP2D6 + RAD54 system. In contrast, the genotoxic carcinogen, methyl methanesulfonate, was detected by all systems. Our yeast-reporter system can be performed in 384-well microplates to provide efficient genotoxicity testing to identify various carcinogenic compounds and reduce chemical consumption to about 53% as compared with existing 96-well genotoxicity bioassays. In association with a liquid handling robot, this platform enables rapid, cost-effective, and high-throughput screening of numerous analytes in a fully automated and continuous manner without the need for user interaction. PMID:28006013

Bioassay of complex mixtures derived from fossil fuels.

PubMed Central

Bingham, E; Barkley, W

1979-01-01

The conversion or processing of shale, coal, or petroleum involves elevated temperatures and altered pressures, and under these conditions polynuclear aromatic hydrocarbons are likely to form. Certain compounds of this type exhibit carcinogenic activity for a variety of organ sites in experimental animals and epidemiological evidence strongly implicates their role as carcinogens in man. It is then not unexpected that many liquid fractions derived from shale and coal are carcinogenic when subjected to bioassay. Benzo(a)pyrene, [B(a)P], is frequently considered to be an indicator substance. It is clear that when a small quantity of B(a)P is present in a fraction, the fraction will exhibit carcinogenic activity in a bioassay (mouse skin). However, it does not follow that the lack of detectable B(a)P insures that the fraction will be noncarcinogenic. Several fractions have been analyzed for their content of B(a)P and then subjected to bioassay. A method for testing complex mixtures for their carcinogenic potential is described. The carcinogenic potency of these fractions are compared to petroleum fractions. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. FIGURE 8. FIGURE 9. PMID:446446

An evaluation of risk estimation procedures for mixtures of carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, J.S.; Chen, J.J.

1999-12-01

The estimation of health risks from exposure to a mixture of chemical carcinogens is generally based on the combination of information from several available single compound studies. The current practice of directly summing the upper bound risk estimates of individual carcinogenic components as an upper bound on the total risk of a mixture is known to be generally too conservative. Gaylor and Chen (1996, Risk Analysis) proposed a simple procedure to compute an upper bound on the total risk using only the upper confidence limits and central risk estimates of individual carcinogens. The Gaylor-Chen procedure was derived based on anmore » underlying assumption of the normality for the distributions of individual risk estimates. IN this paper the authors evaluated the Gaylor-Chen approach in terms the coverages of the upper confidence limits on the true risks of individual carcinogens. In general, if the coverage probabilities for the individual carcinogens are all approximately equal to the nominal level, then the Gaylor-Chen approach should perform well. However, the Gaylor-Chen approach can be conservative or anti-conservative if some of all individual upper confidence limit estimates are conservative or anti-conservative.« less

Adsorption isotherm studies of chromium (VI) from aqueous solutions using sol-gel hydrotalcite-like compounds.

PubMed

Ramos-Ramírez, Esthela; Ortega, Norma L Gutiérrez; Soto, Cesar A Contreras; Gutiérrez, Maria T Olguín

2009-12-30

In under-developed countries, industries such as paint and pigment manufacturing, leather tanning, chrome plating and textile processing, usually discharge effluents containing Cr(VI) and Cr(III) into municipal sanitary sewers. It has been reported that Cr(VI) acts as a powerful epithelial irritant and as a human carcinogen. In the present work, hydrotalcite-like compounds with a Mg/Al ratio=2 were synthesized by the sol-gel method. The hydrotalcite-like compounds and their corresponding thermally treated products were characterized by powder X-ray diffraction, infrared spectroscopy and N(2) adsorption. The hydrotalcite-like compounds and the heated solids were used as adsorbents for Cr(VI) in aqueous solutions. Adsorption isotherm studies of Cr(VI) from aqueous solution are described. The adsorbent capacity was determined using the Langmuir, Freundlich and Dubinin-Radushkevich adsorption isotherm models. The Cr(VI) adsorption isotherm data fit best to the Langmuir isotherm model. The maximum Cr(VI) uptake by hydrotalcite and the heated solids was determined using the Langmuir equation and was found to range between 26 and 29 mg Cr(VI)/g adsorbent.

A simple and highly sensitive UPLC-ESI-MS/MS method for the simultaneous quantification of nicotine, cotinine, and the tobacco-specific carcinogens N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in serum samples.

PubMed

Loukotková, Lucie; VonTungeln, Linda S; Vanlandingham, Michelle; da Costa, Gonçalo Gamboa

2018-01-01

According to the World Health Organization, the consumption of tobacco products is the single largest cause of preventable deaths in the world, exceeding the total aggregated number of deaths caused by diseases such as AIDS, tuberculosis, and malaria. An important element in the evaluation of the health risks associated with the consumption of tobacco products is the assessment of the internal exposure to the tobacco constituents responsible for their addictive (e.g. nicotine) and carcinogenic (e.g. N-nitrosamines such as NNN and NNK) properties. However, the assessment of the serum levels of these compounds is often challenging from an analytical standpoint, in particular when limited sample volumes are available and low detection limits are required. Currently available analytical methods often rely on complex multi-step sample preparation procedures, which are prone to low analyte recoveries and ex-vivo contamination due to the ubiquitous nature of these compounds as background contaminants. In order to circumvent these problems, we report a facile and highly sensitive method for the simultaneous quantification of nicotine, cotinine, NNN, and NNK in serum samples. The method relies on a simple "one pot" liquid-liquid extraction procedure and isotope dilution ultra-high pressure (UPLC) hydrophilic interaction liquid chromatography (HILIC) coupled with tandem mass spectrometry. The method requires only 10μL of serum and presents a limit of quantification of 0.02nmol (3000pg/mL) nicotine, 0.6pmol (100pg/mL) cotinine, 0.05pmol NNK (10pg/mL), and 0.06pmol NNN (10pg/mL), making it appropriate for pharmacokinetic evaluations. Published by Elsevier B.V.

Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

PubMed Central

2009-01-01

CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism. PMID:19531241

Indoor air - assessment: Methods of analysis for environmental carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peterson, M.R.; Naugle, D.F.; Berry, M.A.

1990-06-01

The monograph describes, in a general way, published sampling procedures and analytical approaches for known and suspected carcinogens. The primary focus is upon carcinogens found in indoor air, although the methods described are applicable to other media or environments. In cases where there are no published methods for a particular pollutant in indoor air, methods developed for the workplace and for ambient air are included since they should be adaptable to indoor air. Known and suspected carcinogens have been grouped into six categories for the purposes of this and related work. The categories are radon, asbestos, organic compounds, inorganic species,more » particles, and non-ionizing radiation. Some methods of assessing exposure that are not specific to any particular pollutant category are covered in a separate section. The report is the fifth in a series of EPA/Environmental Criteria and Assessment Office Monographs.« less

CARCINOGEN METABOLISM GENES, RED MEAT AND POULTRY INTAKE, AND COLORECTAL CANCER RISK

PubMed Central

Wang, Jun; Joshi, Amit D.; Corral, Román; Siegmund, Kimberly D.; Le Marchand, Loïc; Martinez, Maria Elena; Haile, Robert W.; Ahnen, Dennis J.; Sandler, Robert S.; Lance, Peter; Stern, Mariana C.

2011-01-01

Diets high in red meat are established risk factors for colorectal cancer (CRC). Carcinogenic compounds generated during meat cooking have been implicated as causal agents. We conducted a family-based case-control study to investigate the association between polymorphisms in carcinogen metabolism genes (CYP1A2 -154A>C, CYP1B1 Leu432Val, CYP2E1 -1054C>T, GSTP1 Ile105Val, PTGS2 5UTR -765, EPHX1 Tyr113His, NAT2 Ile114Thr, NAT2 Arg197Gln and NAT2 Gly286Glu) and CRC risk. We tested for gene-environment interactions using case-only analyses (N = 577) and compared statistically significant results to those obtained using case-unaffected sibling comparisons (N = 307 sibships). Our results suggested that CYP1A2 -154A>C might modify the association between intake of red meat cooked using high temperature methods and well done on the inside and CRC risk (case-only interaction OR = 1.53; 95% CI = 1.19-1.97; p = 0.0008) and the association between intake of red meat heavily browned on the outside and rectal cancer risk (case-only interaction OR = 0.65; 95% CI = 0.48-0.86; p = 0.003). We also found that GSTP1 Ile105Val might modify the association between intake of poultry cooked with high temperature methods and CRC risk (p = 0.0035), a finding that was stronger among rectal cancer cases. Our results support a role for heterocyclic amines that form in red meat as a potential explanation for the observed association between diets high in red meat and CRC. Our findings also suggest a possible role for diets high in poultry cooked at high temperatures in CRC risk. PMID:21618522

Improved hemocompatibility of silicone rubber extracorporeal tubing via solvent swelling-impregnation of S-nitroso-N-acetylpenicillamine (SNAP) and evaluation in rabbit thrombogenicity model.

PubMed

Brisbois, Elizabeth J; Major, Terry C; Goudie, Marcus J; Bartlett, Robert H; Meyerhoff, Mark E; Handa, Hitesh

2016-06-01

Blood-contacting devices, including extracorporeal circulation (ECC) circuits, can suffer from complications due to platelet activation and thrombus formation. Development of nitric oxide (NO) releasing polymers is one method to improve hemocompatibility, taking advantage of the ability of low levels of NO to prevent platelet activation/adhesion. In this study a novel solvent swelling method is used to load the walls of silicone rubber tubing with the NO donor S-nitroso-N-acetylpenicillamine (SNAP). This SNAP-silicone rubber tubing exhibits an NO flux of ca. 1×10(-10)molcm(-2)min(-1), which mimics the range of NO release from the normal endothelium, which is stable for at least 4h. Images of the tubing before and after swelling, obtained via scanning electron microscopy, demonstrate that this swelling method has little effect on the surface properties of the tubing. The SNAP-loaded silicone rubber and silicone rubber control tubing are used to fabricate ECC circuits that are evaluated in a rabbit model of thrombogenicity. After 4h of blood flow, the SNAP-loaded silicone rubber circuits were able to preserve the blood platelet count at 64% of baseline (vs. 12% for silicone rubber control). A 67% reduction in the degree of thrombus formation within the thrombogenicity chamber was also observed. This study demonstrates the ability to improve the hemocompatibility of existing/commercial silicone rubber tubing via a simple solvent swelling-impregnation technique, which may also be applicable to other silicone-based blood-contacting devices. Localized nitric oxide (NO) release can be achieved from biomedical grade polymers doped with S-nitroso-N-acetylpenicillamine (SNAP). Despite the promising in vitro and in vivo biocompatibility results reported for these NO releasing polymers, many of these materials may face challenges in being translated to clinical applications, especially in the areas of polymer processing and manufacturing. In this study, we report a solvent swelling-impregnation technique to incorporate SNAP into extracorporeal circuit (ECC) tubing. These NO-releasing ECCs were able to attenuate the activation of platelets and maintain their functionality, while significantly reducing the extent of thrombus formation during 4h blood flow in the rabbit model of thrombogenicity. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Concentration-dependent inhibition of Escherichia coli O157:H7 and potentially carcinogenic heterocyclic amines in heated ground beef patties by apple,olive,and onion powders and clove bud oil

USDA-ARS?s Scientific Manuscript database

We determined the effects of plant compounds on Escherichia coli O157:H7 and two major carcinogenic heterocyclic amines (HCAs), 2-amino-3,8-dimethylamidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP) in grilled ground beef patties. Ground beef with added apple...

Carcinogenicity and mode of action evaluation for alpha-hexachlorocyclohexane: Implications for human health risk assessment.

PubMed

Bradley, Ann E; Shoenfelt, Joanna L; Durda, Judi L

2016-04-01

Alpha-hexachlorocyclohexane (alpha-HCH) is one of eight structural isomers that have been used worldwide as insecticides. Although no longer produced or used agriculturally in the United States, exposure to HCH isomers is of continuing concern due to legacy usage and persistence in the environment. The U.S. Environmental Protection Agency (EPA) classifies alpha-HCH as a probable human carcinogen and provides a slope factor of 6.3 (mg/kg-day)(-1) for the compound, based on hepatic nodules and hepatocellular carcinomas observed in male mice and derived using a default linear approach for modeling carcinogens. EPA's evaluation, last updated in 1993, does not consider more recently available guidance that allows for the incorporation of mode of action (MOA) for determining a compound's dose-response. Contrary to the linear approach assumed by EPA, the available data indicate that alpha-HCH exhibits carcinogenicity via an MOA that yields a nonlinear, threshold dose-response. In our analysis, we conducted an MOA evaluation and dose-response analysis for alpha-HCH-induced liver carcinogenesis. We concluded that alpha-HCH causes liver tumors in rats and mice through an MOA involving increased promotion of cell growth, or mitogenesis. Based on these findings, we developed a threshold, cancer-based, reference dose (RfD) for alpha-HCH. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Solid-Phase Extraction and High-Performance Liquid Chromatography Mass Spectrometry Analysis of Nitrosamines in Treated Drinking Water and Wastewater

EPA Science Inventory

N-Nitrosamines, including N-dimethylnitrosamine (NDMA), were identified as chlorination byproducts in drinking water in 1989. Nitrosamines are known rodent carcinogens and probable human carcinogens, so that they have been considered disinfection byproducts (DBPs) of public healt...

Role of renal metabolism and excretion in 5-nitrofuran-induced uroepithelial cancer in the rat.

PubMed Central

Spry, L A; Zenser, T V; Cohen, S M; Davis, B B

1985-01-01

5-Nitrofurans have been used in the study of chemical carcinogenesis. There is substantial evidence that N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) is deformylated to 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) in the process of FANFT-induced bladder cancer. Paradoxically, ANFT is less potent as a uroepithelial carcinogen than FANFT when fed to rats. Feeding aspirin with FANFT to rats decreases the incidence of bladder cancer. Isolated kidneys were perfused with 5-nitrofurans to determine renal clearances and whether aspirin acts to decrease urinary excretion of the carcinogen. In FANFT-perfused kidneys, FANFT was deformylated to ANFT and excreted (1.06 +/- 0.22 nmol/min) at a rate eightfold higher than excretion of FANFT. In kidneys perfused with equimolar ANFT, excretion of ANFT was 0.25 +/- 0.05 nmol/min, which suggests a coupling of renal deformylation of FANFT to excretion of ANFT in FANFT-perfused kidneys. Neither aspirin nor probenecid altered the urinary excretion or half-life of FANFT or ANFT. In rats fed 0.2% FANFT as part of their diet, coadministration of aspirin (0.5%) increased urinary excretion of ANFT during a 12-wk feeding study, which suggests decreased tissue binding or metabolism of ANFT. Kidney perfusion with acetylated ANFT (NFTA), a much less potent uroepithelial carcinogen, resulted in no ANFT excretion or accumulation, which indicates the specificity of renal deformylase. Renal deformylase activity was found in broken cell preparations of rat and human kidney. These data describe a unique renal metabolic/excretory coupling for these compounds that appears to explain the differential carcinogenic potential of the 5-nitrofurans tested. These results are consistent with the hypothesis that aspirin decreases activation of ANFT by inhibiting prostaglandin H synthase. PMID:4044826

Selective determination of semi-volatile thiophene compounds in water by molecularly imprinted polymer thin films with direct headspace gas chromatography sulfur chemiluminescence detection.

PubMed

Hijazi, Hassan Y; Bottaro, Christina S

2018-02-26

Water-compatible molecularly imprinted polymer (MIP) thin films are coupled with headspace gas chromatography sulfur chemiluminescence detection (HS-GC-SCD) to create a new approach for the determination of trace concentrations of thiophene compounds in water samples. Thiophene compounds are persistent, typically petrogenic, organic pollutants of concern due to their potential for biomagnification and bioaccumulation, mutagenicity, and carcinogenicity in terrestrial and aquatic fauna. Identification and quantitation in water, particularly following oil spills, is a priority. Following adsorption of the thiophenes to the MIPs, the MIP-bound analytes are analyzed directly by HS-GC-SCD, with minimal sample manipulation and virtually no organic solvent. Calibration curves of spiked seawater were linear from 5 μg L -1 to 100 μg L -1 and limits of detection (LOD) were in the range of 0.24-0.82 μg L -1 . Low matrix effects were observed in the analysis of thiophene compounds in seawater making the method suitable for use in fresh and saline waters without modification. Acceptable reproducibility was obtained for analysis of thiophene compounds from spiked seawater samples at RSDs ≤7.0% (n = 3).

Studies Update Vinyl Chloride Hazards.

ERIC Educational Resources Information Center

Rawls, Rebecca

1980-01-01

Extensive study affirms that vinyl chloride is a potent animal carcinogen. Epidemiological studies show elevated rates of human cancers in association with extended contact with the compound. (Author/RE)

[Definition of parameters of the condition of oxidizing stress in smooth muscle cells under influence of exogenous nitroso-glutatyon in vitro].

PubMed

Kapilevich, L V; Nosarev, A V; D'iakova, E Iu; Andrushkevich, V V; Nasedkina, A K; Nosareva, O L; Davlet'iarova, K V; Ogorodova, L M; Kovalev, I V; Baskakov, M B; Medvedev, M A

2007-08-01

Influence of exogenous nitroso-glutatyon on intensity of oxidizing processes in smooth muscles of colon and bronchial tubes in intact and atopic sensitised porpoises (guinea pigs) was studied. In sensitised porpoises, antioxidant protection has been initially reduced against the background of increased maintenance of products of oxidizing that reflects a picture of oxidizing damage and can be associated with an inflammatory process. In incubation with nitroso-glutatyon, a decrease in activities of syperoxiddismutase and catalase is marked and, in sensitised animals, this effect has been expressed to a lesser degree. Syperoxiddismutase and catalase are antioxidant for the enzymes participating in protection of cells from free-radical damage. A dose-dependence decrease in activity catalase and syperoxiddismutase is defined by a parity of the enzymes participating in disintegration of nitrosoglutatyon and the enzymes which have kept antioxidant activity.

Experimental verification, and domain definition, of structural alerts for protein binding: epoxides, lactones, nitroso, nitros, aldehydes and ketones.

PubMed

Nelms, M D; Cronin, M T D; Schultz, T W; Enoch, S J

2013-01-01

This study outlines how a combination of in chemico and Tetrahymena pyriformis data can be used to define the applicability domain of selected structural alerts within the profilers of the OECD QSAR Toolbox. Thirty-three chemicals were profiled using the OECD and OASIS profilers, enabling the applicability domain of six structural alerts to be defined, the alerts being: epoxides, lactones, nitrosos, nitros, aldehydes and ketones. Analysis of the experimental data showed the applicability domains for the epoxide, nitroso, aldehyde and ketone structural alerts to be well defined. In contrast, the data showed the applicability domains for the lactone and nitro structural alerts needed modifying. The accurate definition of the applicability domain for structural alerts within in silico profilers is important due to their use in the chemical category in predictive and regulatory toxicology. This study highlights the importance of utilizing multiple profilers in category formation.

Cancer in Experimental Animals Exposed to Arsenic and Arsenic Compounds

PubMed Central

Tokar, Erik J.; Benbrahim-Tallaa, Lamia; Ward, Jerold M.; Lunn, Ruth; Sams, Reeder L.; Waalkes, Michael P.

2011-01-01

Inorganic arsenic is a ubiquitous environmental contaminant that has long been considered a human carcinogen. Recent studies raise further concern about the metalloid as a major, naturally occurring carcinogen in the environment. However, during this same period it has proven difficult to provide experimental evidence of the carcinogenicity of inorganic arsenic in laboratory animals and, until recently, there was considered to be a lack of clear evidence for carcinogenicity of any arsenical in animals. More recent work with arsenical methylation metabolites and early life exposures to inorganic arsenic has now provided evidence of carcinogenicity in rodents. Given that tens of millions of people worldwide are exposed to potentially unhealthy levels of environmental arsenic, in vivo rodent models of arsenic carcinogenesis are a clear necessity for resolving critical issues, like mechanisms of action, target tissue specificity, and sensitive subpopulations, and in developing strategies to reduce cancers in exposed human populations. This work reviews the available rodent studies considered relevant to carcinogenic assessment of arsenicals, taking advantage of the most recent review by the International Agency for Research on Cancer (IARC) that has not yet appeared as a full monograph but has been summarized (IARC 2009). Many valid studies show that arsenic can interact with other carcinogens/agents to enhance oncogenesis, and help elucidate mechanisms, and these too are summarized in this review. Finally, this body of rodent work is discussed in light of its impact on mechanisms and in the context of the persistent argument that arsenic is not carcinogenic in animals. PMID:20812815

Risk assessment of DNA-reactive carcinogens in food.

PubMed

Jeffrey, A M; Williams, G M

2005-09-01

Risk assessment of DNA-reactive carcinogens in food requires knowledge of the extent of DNA damage in the target organ which results from the competition between DNA adduct formation and repair. Estimates of DNA adduct levels can be made by direct measurement or indirectly as a consequence of their presence, for example, by tumor formation in animal models or exposed populations epidemiologically. Food-borne DNA-reactive carcinogens are present from a variety of sources. They are generally not intrinsically DNA-reactive but require bioactivation to DNA-reactive metabolites a process which may be modulated by the compound itself or the presence of other xenobiotics. A single DNA reactant may form several distinct DNA adducts each undergoing different rates of repair. Some DNA reactants may be photochemically activated or produce reactive oxygen species and thus indirect oxidative DNA damage. The levels of DNA adducts arising from exposures influenced by variations in the doses, the frequency with which an individual is exposed, and rates of DNA repair for specific adducts. Each adduct has a characteristic efficiency with which it induces mutations. Based on experience with the well-studied DNA-reactive food carcinogen aflatoxin B(1) (AFB(1)), a limit of 20 ppb or approximately 30 microg/day has been set and is considered a tolerable daily intake (TDI). Since AFB(1) is considered a potent carcinogen, doses of <1.5 microg of unknown compounds are considered TDIs. Most DNA-reactants, including acrylamide, heterocyclic amines, and alpha,beta-unsaturated carbonyl are below this value. Above that value, measurement of actual DNA adducts levels in either experimental animals with a risk assessment, or, when this occurs, exposed humans are needed. A number of approaches to undertake this are described including immunological, mass spectrometric and (32)P-postlabeling or the use of surrogates such as hemoglobin adducts, together with approaches to evaluate the results. A discussion of approaches to estimating possible threshold effects for DNA-reactive carcinogens is made.

Risk assessment of DNA-reactive carcinogens in food

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeffrey, A.M.; Williams, G.M.

2005-09-01

Risk assessment of DNA-reactive carcinogens in food requires knowledge of the extent of DNA damage in the target organ which results from the competition between DNA adduct formation and repair. Estimates of DNA adduct levels can be made by direct measurement or indirectly as a consequence of their presence, for example, by tumor formation in animal models or exposed populations epidemiologically. Food-borne DNA-reactive carcinogens are present from a variety of sources. They are generally not intrinsically DNA-reactive but require bioactivation to DNA-reactive metabolites a process which may be modulated by the compound itself or the presence of other xenobiotics. Amore » single DNA reactant may form several distinct DNA adducts each undergoing different rates of repair. Some DNA reactants may be photochemically activated or produce reactive oxygen species and thus indirect oxidative DNA damage. The levels of DNA adducts arising from exposures influenced by variations in the doses, the frequency with which an individual is exposed, and rates of DNA repair for specific adducts. Each adduct has a characteristic efficiency with which it induces mutations. Based on experience with the well-studied DNA-reactive food carcinogen aflatoxin B{sub 1} (AFB{sub 1}), a limit of 20 ppb or {approx}30 {mu}g/day has been set and is considered a tolerable daily intake (TDI). Since AFB{sub 1} is considered a potent carcinogen, doses of <1.5 {mu}g of unknown compounds are considered TDIs. Most DNA-reactants, including acrylamide, heterocyclic amines, and {alpha},{beta}-unsaturated carbonyl are below this value. Above that value, measurement of actual DNA adducts levels in either experimental animals with a risk assessment, or, when this occurs, exposed humans are needed. A number of approaches to undertake this are described including immunological, mass spectrometric and {sup 32}P-postlabeling or the use of surrogates such as hemoglobin adducts, together with approaches to evaluate the results. A discussion of approaches to estimating possible threshold effects for DNA-reactive carcinogens is made.« less

Carcinogenicity of airborne combustion products observed in subcutaneous tissue and lungs of laboratory rodents.

PubMed Central

Pott, F; Stöber, W

1983-01-01

Most air pollution in West Germany is caused by combustion products. Particulate organic matter released by incomplete combustion is suspected to contribute to the "urban factor" of lung cancer frequency in urban-industrial centers. The carcinogenic potential of single components, groups of compounds and total source emissions of combustion processes was investigated in laboratory animals by subcutaneous injection, intratracheal instillation or inhalation. Tests by subcutaneous injection of condensates of automobile exhaust, extracts of coal furnace emissions and of airborne particles and different fractions of these extracts showed that the polycyclic aromatic hydrocarbons (PAH) with four to six benzene rings have the strongest experimental carcinogenicity. However, polar compounds (heterocyclic nitrogen-containing PAH, phenols, and others) also show remarkable carcinogenic potency. There were large differences between the dose-response relationships of several PAHs. In the subcutaneous tissue, benzo(a)pyrene and dibenz(a,h)anthracene are the most carcinogenic of the tested airborne PAHs. Furthermore, they can induce high tumor rates in the lung after subcutaneous injection in newborn mice and after intratracheal instillation of mice or hamsters. The tumor rate of benzo(a)pyrene did not further increase after simultaneous instillation of carbon black, but lead chloride may have a promoting effect. Far more than 100 PAHs are found in the urban atmosphere. However, because of the remarkable similarity of the PAH profiles in the examined samples, it may be sufficient to measure just a few stable PAHs in the urban air in order to facilitate an assessment of the carcinogenic potency of the PAH content in the atmosphere. To examine the carcinogenic or cocarcinogenic effects of gas and vapor emissions, studies with a two-phase model were carried out: phase 1 relates to the induction of a basic tumor rate in the lung by a well known carcinogen, while phase 2 is characterized by an inhalation of the substance under investigation. In an experiment with mice, the inhalation of a mixture of SO2 and NO2 seemed to increase the basic tumor rate induced by dibenz(a,h)anthracene. In a similar two-phase experiment conducted with hamsters, the inhalation of diesel exhaust (total exhaust as well as exhaust without particles) increased a basic tumor rate induced by diethyl nitrosamine. These experiments deserve confirmation before a detailed interpretation is attempted. PMID:6186480

Carcinogenicity of airborne combustion products observed in subcutaneous tissue and lungs of laboratory rodents.

PubMed

Pott, F; Stöber, W

1983-01-01

Most air pollution in West Germany is caused by combustion products. Particulate organic matter released by incomplete combustion is suspected to contribute to the "urban factor" of lung cancer frequency in urban-industrial centers. The carcinogenic potential of single components, groups of compounds and total source emissions of combustion processes was investigated in laboratory animals by subcutaneous injection, intratracheal instillation or inhalation. Tests by subcutaneous injection of condensates of automobile exhaust, extracts of coal furnace emissions and of airborne particles and different fractions of these extracts showed that the polycyclic aromatic hydrocarbons (PAH) with four to six benzene rings have the strongest experimental carcinogenicity. However, polar compounds (heterocyclic nitrogen-containing PAH, phenols, and others) also show remarkable carcinogenic potency. There were large differences between the dose-response relationships of several PAHs. In the subcutaneous tissue, benzo(a)pyrene and dibenz(a,h)anthracene are the most carcinogenic of the tested airborne PAHs. Furthermore, they can induce high tumor rates in the lung after subcutaneous injection in newborn mice and after intratracheal instillation of mice or hamsters. The tumor rate of benzo(a)pyrene did not further increase after simultaneous instillation of carbon black, but lead chloride may have a promoting effect. Far more than 100 PAHs are found in the urban atmosphere. However, because of the remarkable similarity of the PAH profiles in the examined samples, it may be sufficient to measure just a few stable PAHs in the urban air in order to facilitate an assessment of the carcinogenic potency of the PAH content in the atmosphere. To examine the carcinogenic or cocarcinogenic effects of gas and vapor emissions, studies with a two-phase model were carried out: phase 1 relates to the induction of a basic tumor rate in the lung by a well known carcinogen, while phase 2 is characterized by an inhalation of the substance under investigation. In an experiment with mice, the inhalation of a mixture of SO2 and NO2 seemed to increase the basic tumor rate induced by dibenz(a,h)anthracene. In a similar two-phase experiment conducted with hamsters, the inhalation of diesel exhaust (total exhaust as well as exhaust without particles) increased a basic tumor rate induced by diethyl nitrosamine. These experiments deserve confirmation before a detailed interpretation is attempted.

BINDING OF CARCINOGENS TO DNA AND COVALENT ADDUCTS DNA DAMAGE - PAH, AROMATIC AMINES, NITRO-AROMATIC COMPOUNDS, AND HALOGENATED COMPOUNDS

EPA Science Inventory

DNA adducts are the covalent addition products resulting from binding of reactive chemical species to DNA bases. The cancer initiating role of DNA adducts is well-established, and is clearly reflected in the high cancer incidence observed in individuals with deficiencies in any o...

Metallic elements in fossil fuel combustion products: amounts and form of emissions and evaluation of carcinogenicity and mutagenicity.

PubMed

Vouk, V B; Piver, W T

1983-01-01

Metallic elements contained in coal, oil and gasoline are mobilized by combustion processes and may be emitted into the atmosphere, mainly as components of submicron particles. The information about the amounts, composition and form of metal compounds is reviewed for some fuels and combustion processes. Since metal compounds are always contained in urban air pollutants, they have to be considered whenever an evaluation of biological impact of air pollutants is made. The value of currently used bioassays for the evaluation of the role of trace metal compounds, either as major biologically active components or as modifiers of biological effects of organic compounds is assessed. The whole animal bioassays for carcinogenicity do not seem to be an appropriate approach. They are costly, time-consuming and not easily amenable to the testing of complex mixtures. Some problems related to the application and interpretation of short-term bioassays are considered, and the usefulness of such bioassays for the evaluation of trace metal components contained in complex air pollution mixtures is examined.

Metallic elements in fossil fuel combustion products: amounts and form of emissions and evaluation of carcinogenicity and mutagenicity.

PubMed Central

Vouk, V B; Piver, W T

1983-01-01

Metallic elements contained in coal, oil and gasoline are mobilized by combustion processes and may be emitted into the atmosphere, mainly as components of submicron particles. The information about the amounts, composition and form of metal compounds is reviewed for some fuels and combustion processes. Since metal compounds are always contained in urban air pollutants, they have to be considered whenever an evaluation of biological impact of air pollutants is made. The value of currently used bioassays for the evaluation of the role of trace metal compounds, either as major biologically active components or as modifiers of biological effects of organic compounds is assessed. The whole animal bioassays for carcinogenicity do not seem to be an appropriate approach. They are costly, time-consuming and not easily amenable to the testing of complex mixtures. Some problems related to the application and interpretation of short-term bioassays are considered, and the usefulness of such bioassays for the evaluation of trace metal components contained in complex air pollution mixtures is examined. PMID:6337825

A carcinogenic potency database of the standardized results of animal bioassays

PubMed Central

Gold, Lois Swirsky; Sawyer, Charles B.; Magaw, Renae; Backman, Georganne M.; De Veciana, Margarita; Levinson, Robert; Hooper, N. Kim; Havender, William R.; Bernstein, Leslie; Peto, Richard; Pike, Malcolm C.; Ames, Bruce N.

1984-01-01

The preceding paper described our numerical index of carcinogenic potency, the TD50 and the statistical procedures adopted for estimating it from experimental data. This paper presents the Carcinogenic Potency Database, which includes results of about 3000 long-term, chronic experiments of 770 test compounds. Part II is a discussion of the sources of our data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Part III is a guide to the plot of results presented in Part IV. A number of appendices are provided to facilitate use of the database. The plot includes information about chronic cancer tests in mammals, such as dose and other aspects of experimental protocol, histopathology and tumor incidence, TD50 and its statistical significance, dose response, author's opinion and literature reference. The plot readily permits comparisons of carcinogenic potency and many other aspects of cancer tests; it also provides quantitative information about negative tests. The range of carcinogenic potency is over 10 million-fold. PMID:6525996

Interactions of the interferon system with cellular metabolism

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald

1986-01-01

The results of studies concerning the interaction of the interferon (Inf) system with the activities of carcinogens, tumor promoters, and cytochrome P-450 are presented. The results show that the addition of a tumor promoter (TPA or 4-O-methyl-TPA) to a tissue culture enhances virus-induced Inf-gamma production, suggesting a potential value of tumor promoters in the biosynthesis of commercial Inf. On the other hand, the carcinogens were reported to inhibit the induction of Inf-alpha/beta in cultured cells and in intact animals (with no effect on the administered or preformed Inf). The demonstration of a correlation between the carcinogenic potential of a compound and its inhibitive effect on Inf production suggests a possible use of the Inf production assay in the evaluation of the carcinogenicity of chemicals. In addition, it was shown that the induction of Inf-alpha/beta as well as the administration of this Inf depresses the levels of rat liver cytochrome P-450 which is responsible for binding lipophilic drugs, steroids, and carcinogens, thus increasing the toxicity of the respective chemical.

ANALYSIS OF 2,3,7,8-TCDD TUMOR PROMOTION ACTIVITY ...

EPA Pesticide Factsheets

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has a high estimated cancer potency in animals which has been reasoned to imply that TCDD might be carcinogenic to man. The animal cancer data show that TCDD can act in a solitary manner causing tumors without the participation of other known factors. owever, there exist animal cancer data indicating that TCDD can act as a tumor-promoting compound. This analysis examines which type of carcinogen and which mechanism best characterize TCDD cancer activity. It is suggested that TCDD acts by a hormonal mechanism to cause cancer in solitary manner, at low doses, in two species, and in a number of different organs, including rare sites. These observations in toto characterize TCDD as a complete carcinogen, which by definition encompasses both initiation and promotion carcinogenic activities. This analysis examines which type of carcinogen and which mechanism best characterize TCDD cancer activity. It is suggested that TCDD acts by a hormonal mechanism to cause cancer in solitary manner, at low doses, in two species, and in a number of different organs, including rare sites

Use of human peripheral blood lymphocytes to measure DNA binding capacity of chemical carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gupta, R.C.; Earley, K.; Sharma, S.

1988-05-01

Although animal models have been used successfully to study metabolic activation and binding of carcinogens to DNA, only limited studies have been done in human systems. To circumvent the problems associated with the inaccessibility of human tissues and a lack of sensitive methods to detect DNA damage, the authors have investigated the capability of human peripheral blood lymphocytes in vitro to metabolize carcinogens to their DNA binding species by a {sup 32}P-labeled adduct assay. Freshly isolated lymphocytes were exposed at 37{degree}C for 18 hr to 4-aminobiphenyl, 2-aminofluorene, 2-anthramine, 2-acetylaminophenanthrene, benzidine, 1-nitropyrene, 1,2-benzanthracene, triphenylene, 7,12-dimethylbenz(a)anthracene, or benzo(a)pyrene at 30 {mu}M each,more » compounds that are shown or suspected to be carcinogenic in experimental animals. The data indicate that all test carcinogens formed readily measurable levels of DNA adducts. Analysis of exposed DNAs by {sup 32}P-labeling after digestion and adduct enrichment showed exclusively or predominantly one major adduct for all test carcinogens, except for 2-anthramine, triphenylene, and 7,12-dimethylbenz(a)anthracene, which showed two or three adducts. From 12 lymphocyte specimens studied thus far, significant interindividual variations were observed. The lymphocyte system in combination with the {sup 32}P-adduct assay may prove to be an ultrasensitive means to determine interindividual variations in the ability to biotransform carcinogens.« less

Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations.

PubMed

Dolan, David G; Naumann, Bruce D; Sargent, Edward V; Maier, Andrew; Dourson, Michael

2005-10-01

A scientific rationale is provided for estimating acceptable daily intake values (ADIs) for compounds with limited or no toxicity information to support pharmaceutical manufacturing operations. These ADIs are based on application of the "thresholds of toxicological concern" (TTC) principle, in which levels of human exposure are estimated that pose no appreciable risk to human health. The same concept has been used by the US Food and Drug Administration (FDA) to establish "thresholds of regulation" for indirect food additives and adopted by the Joint FAO/WHO Expert Committee on Food Additives for flavoring substances. In practice, these values are used as a statement of safety and indicate when no actions need to be taken in a given exposure situation. Pharmaceutical manufacturing relies on ADIs for cleaning validation of process equipment and atypical extraneous matter investigations. To provide practical guidance for handling situations where relatively unstudied compounds with limited or no toxicity data are encountered, recommendations are provided on ADI values that correspond to three categories of compounds: (1) compounds that are likely to be carcinogenic, (2) compounds that are likely to be potent or highly toxic, and (3) compounds that are not likely to be potent, highly toxic or carcinogenic. Corresponding ADIs for these categories of materials are 1, 10, and 100 microg/day, respectively.

Nicotine, Carcinogen, and Toxin Exposure in Long-Term E-Cigarette and Nicotine Replacement Therapy Users: A Cross-sectional Study.

PubMed

Shahab, Lion; Goniewicz, Maciej L; Blount, Benjamin C; Brown, Jamie; McNeill, Ann; Alwis, K Udeni; Feng, June; Wang, Lanqing; West, Robert

2017-03-21

Given the rapid increase in the popularity of e-cigarettes and the paucity of associated longitudinal health-related data, the need to assess the potential risks of long-term use is essential. To compare exposure to nicotine, tobacco-related carcinogens, and toxins among smokers of combustible cigarettes only, former smokers with long-term e-cigarette use only, former smokers with long-term nicotine replacement therapy (NRT) use only, long-term dual users of both combustible cigarettes and e-cigarettes, and long-term users of both combustible cigarettes and NRT. Cross-sectional study. United Kingdom. The following 5 groups were purposively recruited: combustible cigarette-only users, former smokers with long-term (≥6 months) e-cigarette-only or NRT-only use, and long-term dual combustible cigarette-e-cigarette or combustible cigarette-NRT users (n = 36 to 37 per group; total n = 181). Sociodemographic and smoking characteristics were assessed. Participants provided urine and saliva samples and were analyzed for biomarkers of nicotine, tobacco-specific N-nitrosamines (TSNAs), and volatile organic compounds (VOCs). After confounders were controlled for, no clear between-group differences in salivary or urinary biomarkers of nicotine intake were found. The e-cigarette-only and NRT-only users had significantly lower metabolite levels for TSNAs (including the carcinogenic metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol [NNAL]) and VOCs (including metabolites of the toxins acrolein; acrylamide; acrylonitrile; 1,3-butadiene; and ethylene oxide) than combustible cigarette-only, dual combustible cigarette-e-cigarette, or dual combustible cigarette-NRT users. The e-cigarette-only users had significantly lower NNAL levels than all other groups. Combustible cigarette-only, dual combustible cigarette-NRT, and dual combustible cigarette-e-cigarette users had largely similar levels of TSNA and VOC metabolites. Cross-sectional design with self-selected sample. Former smokers with long-term e-cigarette-only or NRT-only use may obtain roughly similar levels of nicotine compared with smokers of combustible cigarettes only, but results varied. Long-term NRT-only and e-cigarette-only use, but not dual use of NRTs or e-cigarettes with combustible cigarettes, is associated with substantially reduced levels of measured carcinogens and toxins relative to smoking only combustible cigarettes. Cancer Research UK.

LC/QTOF-MS fragmentation of N-nitrosodimethylamine precursors in drinking water supplies is predictable and aids their identification.

PubMed

Hanigan, David; Ferrer, Imma; Thurman, E Michael; Herckes, Pierre; Westerhoff, Paul

2017-02-05

N-Nitrosodimethylamine (NDMA) is carcinogenic in rodents and occurs in chloraminated drinking water and wastewater effluents. NDMA forms via reactions between chloramines and mostly unidentified, N-containing organic matter. We developed a mass spectrometry technique to identify NDMA precursors by analyzing 25 model compounds with LC/QTOF-MS. We searched isolates of 11 drinking water sources and 1 wastewater using a custom MATLAB ® program and extracted ion chromatograms for two fragmentation patterns that were specific to the model compounds. Once a diagnostic fragment was discovered, we conducted MS/MS during a subsequent injection to confirm the precursor ion. Using non-target searches and two diagnostic fragmentation patterns, we discovered 158 potential NDMA precursors. Of these, 16 were identified using accurate mass combined with fragment and retention time matches of analytical standards when available. Five of these sixteen NDMA precursors were previously unidentified in the literature, three of which were metabolites of pharmaceuticals. Except methadone, the newly identified precursors all had NDMA molar yields of less than 5%, indicating that NDMA formation could be additive from multiple compounds, each with low yield. We demonstrate that the method is applicable to other disinfection by-product precursors by predicting and verifying the fragmentation patterns for one nitrosodiethylamine precursor. Copyright © 2016. Published by Elsevier B.V.

The fifth plot of the Carcinogenic Potency Database: results of animal bioassays published in the general literature through 1988 and by the National Toxicology Program through 1989.

PubMed Central

Gold, L S; Manley, N B; Slone, T H; Garfinkel, G B; Rohrbach, L; Ames, B N

1993-01-01

This paper is the fifth plot of the Carcinogenic Potency Database (CPDB) that first appeared in this journal in 1984 (1-5). We report here results of carcinogenesis bioassays published in the general literature between January 1987 and December 1988, and in technical reports of the National Toxicology Program between July 1987 and December 1989. This supplement includes results of 412 long-term, chronic experiments of 147 test compounds and reports the same information about each experiment in the same plot format as the earlier papers: the species and strain of test animal, the route and duration of compound administration, dose level and other aspects of experimental protocol, histopathology and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, author's opinion about carcinogenicity, and literature citation. We refer the reader to the 1984 publications (1,5,6) for a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The five plots of the database are to be used together, as results of individual experiments that were published earlier are not repeated. In all, the five plots include results of 4487 experiments on 1136 chemicals. Several analyses based on the CPDB that were published earlier are described briefly, and updated results based on all five plots are given for the following earlier analyses: the most potent TD50 value by species, reproducibility of bioassay results, positivity rates, and prediction between species.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8354183

Third chronological supplement to the carcinogenic potency database: standardized results of animal bioassays published through December 1986 and by the National Toxicology Program through June 1987.

PubMed Central

Gold, L S; Slone, T H; Backman, G M; Eisenberg, S; Da Costa, M; Wong, M; Manley, N B; Rohrbach, L; Ames, B N

1990-01-01

This paper is the third chronological supplement to the Carcinogenic Potency Database that first appeared in this journal in 1984. We report here results of carcinogenesis bioassays published in the general literature between January 1985 and December 1986, and in Technical Reports of the National Toxicology Program between June 1986 and June 1987. This supplement includes results of 337 long-term, chronic experiments of 121 compounds, and reports the same information about each experiment in the same plot format as the earlier papers, e.g., the species and strain of animal, the route and duration of compound administration, dose level, and other aspects of experimental protocol, histopathology, and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, opinion of the author about carcinogenicity, and literature citation. The reader needs to refer to the 1984 publication for a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The four plots of the database are to be used together as results published earlier are not repeated. In all, the four plots include results for approximately 4000 experiments on 1050 chemicals. Appendix 14 of this paper is an alphabetical index to all chemicals in the database and indicates which plot(s) each chemical appears in. A combined plot of all results from the four separate papers, that is ordered alphabetically by chemical, is available from the first author, in printed form or on computer tape or diskette. PMID:2351123

Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models.

PubMed

Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu; Yoshinari, Kouichi; Honda, Hiroshi

2017-03-01

Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

Exogenous and endogenous DNA modifications as monitored by 32P-postlabeling: relationships to cancer and aging.

PubMed

Randerath, K; Li, D; Nath, R; Randerath, E

1992-01-01

32P-postlabeling analysis, a highly sensitive method for the detection and measurement of covalent carcinogen-DNA adducts and other DNA modifications, does not require radioactive test substances and, therefore, can be applied to DNA of mammals, including humans exposed to low doses of environmental or occupational genotoxicants. The basic procedure entails the enzymatic incorporation of 32P-label into hydrolysis products of DNA, followed by chromatographic mapping and autoradiography of the 32P-labeled digestion products and quantitative scintillation spectrometry. Microgram amounts of DNA are analyzed: Thus the assay is suited for limited amounts of cells or tissues. Various versions of the assay afford different sensitivities of adduct detection. A single aromatic or bulky/hydrophobic adduct in 10(8)-10(10) nucleotides can be detected and measured (corresponding to 0.3-30 amol adduct/micrograms DNA or 0.1-10 nmol adduct/mol DNA-P). In animal models, the assay has been successfully applied to a variety of mutagenic (genotoxic) as well as nonmutagenic carcinogens. In humans, DNA specimens from cigarette smokers, iron foundry workers, and coke oven workers whose total aromatic adduct levels ranged from 1 adduct in 10(6)-10(8) DNA nucleotides have been examined by 32P-postlabeling. The assay also detects DNA modifications--Indigenous (I)-compounds--that increase with age in untreated animals. I-compound profiles and levels are highly species-, strain-, sex-, and tissue-specific, and also depend on diet composition. Caloric restriction, a highly efficient method for improving resistance to carcinogenesis and extending life span, increased rather than decreased I-compound levels in various tissues of male rats. Nonmutagenic hepatocarcinogens reduced levels of I-compounds in the target organ. Because of the specificity of this effect, reduction of I-compound levels appears to represent a novel biomarker for the action of nonmutagenic carcinogens. DNA from various hepatomas was found largely devoid of I-compounds. The results support a possible antineoplastic and antiaging role of these DNA modifications.

The chemistry of the S-nitrosoglutathione/glutathione system

PubMed Central

Singh, S. P.; Wishnok, J. S.; Keshive, M.; Deen, W. M.; Tannenbaum, S. R.

1996-01-01

S-Nitrosothiols have generated considerable interest due to their ability to act as nitric oxide (NO) donors and due to their possible involvement in bioregulatory systems—e.g., NO transfer reactions. Elucidation of the reaction pathways involved in the modification of the thiol group by S-nitrosothiols is important for understanding the role of S-nitroso compounds in vivo. The modification of glutathione (GSH) in the presence of S-nitrosoglutathione (GSNO) was examined as a model reaction. Incubation of GSNO (1 mM) with GSH at various concentrations (1–10 mM) in phosphate buffer (pH 7.4) yielded oxidized glutathione, nitrite, nitrous oxide, and ammonia as end products. The product yields were dependent on the concentrations of GSH and oxygen. Transient signals corresponding to GSH conjugates, which increased by one mass unit when the reaction was carried out with 15N-labeled GSNO, were identified by electrospray ionization mass spectrometry. When morpholine was present in the reaction system, N-nitrosomorpholine was formed. Increasing concentrations of either phosphate or GSH led to lower yields of N-nitrosomorpholine. The inhibitory effect of phosphate may be due to reaction with the nitrosating agent, nitrous anhydride (N2O3), formed by oxidation of NO. This supports the release of NO during the reaction of GSNO with GSH. The products noted above account quantitatively for virtually all of the GSNO nitrogen consumed during the reaction, and it is now possible to construct a complete set of pathways for the complex transformations arising from GSNO + GSH. PMID:8962068

[The role of glucosinolates in the prevention of cancer--mechanisms of actions].

PubMed

Kwiatkowska, Edyta; Bawa, Sa'eed

2007-01-01

Foods of plant origin, despite plenty of nutrients contain many non-nutrition compounds, which may prevent many diet-related non-communicable diseases, such as cancer. Plants produce thousands of phenolic compounds as secondary metabolites, such as nitrous compounds. Glucosinolates are responsible for the secretion of detoxifying enzymes that remove carcinogens for the organism. Furthermore, they activate proteins and II phase detoxifying enzymes. The compounds are very important that is why scientists are still investigating their beneficial note in cancer prevention and management.

Distribution and Fate of Energetics on DoD Test and Training Ranges: Interim Report 6

DTIC Science & Technology

2006-11-01

0.75 1,2,3,7,8-pentachlorodibenzofuran pg/g 2 6 0.34 0.73 0.54 1,2,4-trichlorobenzene μg/kg 1 353 2 2 2 1,2-dibromo-3- chloropropane μg/kg 0 5 ND ND...nitration products of TNT synthesis Hexahydro- 1 -nitroso-3,5-dinitro- 1,3,5-triazine MNX Mono nitroso derivative of RDX produced by microbial degradation...xvii 1 Introduction

Differential association for N-acetyltransferase 2 genotype and phenotype with bladder cancer risk in Chinese population.

PubMed

Quan, Lei; Chattopadhyay, Koushik; Nelson, Heather H; Chan, Kenneth K; Xiang, Yong-Bing; Zhang, Wei; Wang, Renwei; Gao, Yu-Tang; Yuan, Jian-Min

2016-06-28

N-acetyltransferase 2 (NAT2) is involved in both carcinogen detoxification through hepatic N-acetylation and carcinogen activation through local O-acetylation. NAT2 slow acetylation status is significantly associated with increased bladder cancer risk among European populations, but its association in Asian populations is inconclusive. NAT2 acetylation status was determined by both single nucleotide polymorphisms (SNPs) and caffeine metabolic ratio (CMR), in a population-based study of 494 bladder cancer patients and 507 control subjects in Shanghai, China. The CMR, a functional measure of hepatic N-acetylation, was significantly reduced in a dose-dependent manner among both cases and controls possessing the SNP-inferred NAT2 slow acetylation status (all P-values<5.0×10-10). The CMR-determined slow N-acetylation status (CMR<0.34) was significantly associated with a 50% increased risk of bladder cancer (odds ratio = 1.50, 95% confidence interval = 1.10-2.06) whereas the SNP-inferred slow acetylation statuses were significantly associated with an approximately 50% decreased risk of bladder cancer. The genotype-disease association was strengthened after the adjustment for CMR and was primarily observed among never smokers. The apparent differential associations for phenotypic and genetic measures of acetylation statuses with bladder cancer risk may reflect dual functions of NAT2 in bladder carcinogenesis because the former only measures the capacity of carcinogen detoxification pathway while the latter represents both carcinogen activation and detoxification pathways. Future studies are warranted to ascertain the specific role of N- and O-acetylation in bladder carcinogenesis, particularly in populations exposed to different types of bladder carcinogens.

Biodegradation of hexahydro-1,3,5-trinitro-1,3,5-triazine and its mononitroso derivative hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine by Klebsiella pneumoniae strain SCZ-1 isolated from an anaerobic sludge.

PubMed

Zhao, Jian-Shen; Halasz, Annamaria; Paquet, Louise; Beaulieu, Chantale; Hawari, Jalal

2002-11-01

In previous work, we found that an anaerobic sludge efficiently degraded hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), but the role of isolates in the degradation process was unknown. Recently, we isolated a facultatively anaerobic bacterium, identified as Klebsiella pneumoniae strain SCZ-1, using MIDI and the 16S rRNA method from this sludge and employed it to degrade RDX. Strain SCZ-1 degraded RDX to formaldehyde (HCHO), methanol (CH3OH) (12% of total C), carbon dioxide (CO(2)) (72% of total C), and nitrous oxide (N2O) (60% of total N) through intermediary formation of methylenedinitramine (O(2)NNHCH(2)NHNO(2)). Likewise, hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) was degraded to HCHO, CH3OH, and N2O (16.5%) with a removal rate (0.39 micromol. h(-1). g [dry weight] of cells(-1)) similar to that of RDX (0.41 micromol. h(-1). g [dry weight] of cells(-1)) (biomass, 0.91 g [dry weight] of cells. liter(-1)). These findings suggested the possible involvement of a common initial reaction, possibly denitration, followed by ring cleavage and decomposition in water. The trace amounts of MNX detected during RDX degradation and the trace amounts of hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine detected during MNX degradation suggested that another minor degradation pathway was also present that reduced -NO2 groups to the corresponding -NO groups.

The Enzymatic Release of O6-methylguanine and 3-methyladenine from DNA Reacted with the Carcinogen N-methyl-N-nitrosourea

PubMed Central

Kirtikar, D. M.; Goldthwait, D. A.

1974-01-01

Endonuclease II (deoxyribonucleate oligonucleotidohydrolase, EC 3.1.4.30) of Escherichia coli has been shown to break phosphodiester bonds in alkylated DNA and depurinated DNA. The hypothesis that depurination is a step in the mechanism of the reaction with alkylated DNA is supported by in vitro experiments with DNA reacted with N-methyl-N-nitrosourea. Endonuclease II releases O6-methylguanine and 3-methyladenine, but not 7-methylguanine, from DNA that has been methylated by the carcinogen N-methyl-N-nitrosourea. PMID:4600266

Veterinary antibiotics used in animal agriculture as NDMA precursors.

PubMed

Leavey-Roback, Shannon L; Krasner, Stuart W; Suffet, Irwin Mel H

2016-12-01

The formation of carcinogenic N-nitrosodimethylamine (NDMA) during chloramination at drinking water treatment plants has raised concerns as more plants have switched from chlorine to chloramine disinfection. In this study, a source of NDMA precursors that has yet to be investigated was examined. Veterinary antibiotics are used in large quantities at animal agricultural operations. They may contaminate drinking water sources and may not be removed during wastewater and drinking water treatment. Ten antibiotics used in animal agriculture were shown to produce NDMA or N-nitrosodiethylamine (NDEA) during chloramination. Molar conversions ranged from 0.04 to 4.9 percent, with antibiotics containing more than one dimethylamine (DMA) functional group forming significantly more NDMA. The highest formation for most of the compounds was seen near pH 8.4, in a range of pH 6 to 11 that was investigated. The effect of chlorine-to-ammonia ratio (Cl 2 /NH 3 ), temperature, and hold time varied for each chemical, suggesting that the effects of these parameters were compound-specific. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structure based virtual screening of the Ebola virus trimeric glycoprotein using consensus scoring.

PubMed

Onawole, Abdulmujeeb T; Kolapo, Temitope U; Sulaiman, Kazeem O; Adegoke, Rukayat O

2018-02-01

Ebola virus (EBOV) causes zoonotic viral infection with a potential risk of global spread and a highly fatal effect on humans. Till date, no drug has gotten market approval for the treatment of Ebola virus disease (EVD), and this perhaps allows the use of both experimental and computational approaches in the antiviral drug discovery process. The main target of potential vaccines that are recently undergoing clinical trials is trimeric glycoprotein (GP) of the EBOV and its exact crystal structure was used in this structure based virtual screening study, with the aid of consensus scoring to select three possible hit compounds from about 36 million compounds in MCULE's database. Amongst these three compounds, (5R)-5-[[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl]-N-[(4-methoxyphenyl)methyl]-4,5-dihydroisoxazole-3-carboxamide (SC-2, C 21 H 19 ClN 4 O 4 ) showed good features with respect to drug likeness, ligand efficiency metrics, solubility, absorption and distribution properties and non-carcinogenicity to emerge as the most promising compound that can be optimized to lead compound against the GP EBOV. The binding mode showed that SC-2 is well embedded within the trimeric chains of the GP EBOV with molecular interactions with some amino acids. The SC-2 hit compound, upon its optimization to lead, might be a good potential candidate with efficacy against the EBOV pathogen and subsequently receive necessary approval to be used as antiviral drug for the treatment of EVD. Copyright © 2017 Elsevier Ltd. All rights reserved.

CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO THE MALE F344/N RAT AND B6C3F, MOUSE

EPA Science Inventory

CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO THE MALE F344/N RAT AND B6C3F1 MOUSE.

Bromodichloromethane (BDCM) has been shown to produce kidney and large bowel tumors in both male and female F344/N rats, kidney tumors in male B6C3F 1 mice and ...

Sage Gene Expression Profiles Characterizing Cure

DTIC Science & Technology

2005-10-01

achieved in haematological malignancies. In addition, tumour cell lines showed a log-linear dose re- sponse when exposed to alkylating agents [26,27...direct carcinogen, N-methyl nitrosourea (NMU) and an indirect carcinogen, 7,12- dimethylbenzanthracene each depend upon the estrous cycle phase at the...a single dose of N-methyl-N- nitrosourea . Cancer Res 45: 3042–3047, 1995 8. Nagasawa H, Yanai R, Taniguchi H: Importance of mammary gland DNA synthesis

Production of carcinogenic acetaldehyde by Candida albicans from patients with potentially malignant oral mucosal disorders.

PubMed

Gainza-Cirauqui, M L; Nieminen, M T; Novak Frazer, L; Aguirre-Urizar, J M; Moragues, M D; Rautemaa, R

2013-03-01

Production of carcinogenic acetaldehyde by Candida has been suggested to contribute to epithelial dysplasia and oral carcinogenesis. Oral lichen planus (OLP), oral lichenoid lesion (OLL) and oral leukoplakia (OL) are potentially carcinogenic oral diseases where colonisation by Candida is common, but acetaldehyde production by Candida has not been studied. Acetaldehyde production in ethanol (11 mM), glucose (100 mM), ethanol-glucose (11 mM and 100 mM) or red wine (1200 mM ethanol) incubation by Candida albicans from patients with OLL (n = 6), OLP (n = 16), OL (n = 6) and controls (n = 6) was measured by gas chromatography. Participants completed a questionnaire regarding their smoking habits and alcohol consumption. All Candida albicans isolates produced potentially carcinogenic levels of acetaldehyde (>100 μM) in all incubations containing ethanol. The control group isolates produced the highest acetaldehyde levels. Isolates from smokers produced more acetaldehyde in all incubations than those from non-smokers. The difference was significant in ethanol-glucose incubation. Isolates from patients who were both smokers and drinkers produced the highest amounts when incubated in ethanol, ethanol-glucose and wine. Candida albicans isolated from potentially carcinogenic oral diseases can produce mutagenic amounts of acetaldehyde. Cigarette smoking and alcohol consumption may favour adaptational changes resulting in the upregulation of candidal acetaldehyde metabolism. © 2012 John Wiley & Sons A/S. All rights reserved.

Nitrolysis of the CN Single Bond and Related Chemistry of Nitro and Nitroso Groups.

DTIC Science & Technology

1988-03-01

oxime of be 4,5-diphenyl-l-triphenylmethoxy-l,23- triazole (11). It was benzoyl cyanide (Scheme 6), for which radical intermediates hydrolysed by...S-Pnitroxide (a radical scavenger) or benzoyl peroxide (a radical *PhC CCN)- NO2 Ag PhCON--CPh suc)I I source). A partial extension of the overall...two anomethylenenitronate anion. (Attempts to prepare the pathways for fragmentation of the ester (3) (C,.H,0 N.O,): one ketenimine (15) by a

Design of Classroom Intervention for Teaching Preschoolers to Identify and Avoid Inhaling Secondhand Tobacco Smoke

ERIC Educational Resources Information Center

Calabro, Karen S.; Le, Thuan A.; Marani, Salma K.; Tamí-Maury, Irene; Czerniak, Katarzyna; Khalil, Georges E.; Prokhorov, Alexander V.

2016-01-01

Secondhand smoke (SHS) is caused by burning tobacco products that emit up to 7000 chemicals and over 70 carcinogenic compounds. Thirdhand smoke (THS) is solid residue remaining on furniture and carpets, including suspended particles derived from a burned tobacco product. Exposure to these compounds occurs through inhalation, oral ingestion, or…

Pretreatment with the nitric oxide donor SNAP or nerve transection blocks humoral preconditioning by remote limb ischemia or intra-arterial adenosine.

PubMed

Steensrud, Tor; Li, Jing; Dai, Xiaojing; Manlhiot, Cedric; Kharbanda, Rajesh K; Tropak, Michael; Redington, Andrew

2010-11-01

We have previously shown that remote ischemic preconditioning (rIPC) by transient limb ischemia leads to the release of a circulating factor(s) that induces potent myocardial protection. Intra-arterial injection of adenosine into a limb also leads to cardioprotection, but the mechanism of its signal transduction is poorly understood. Eleven groups of rabbits received saline control or rIPC or adenosine administration with additional pretreatment with the nitric oxide (NO) synthase blocker N(G)-nitro-l-arginine methyl ester, the NO donor S-nitroso-N-acetylpenicillamine, its non-NO-donating derivative N-acetylpenicillamine, or femoral nerve section. Blood was then drawn from each animal, and the dialysate of the plasma was used to perfuse a naïve heart from an untreated donor. Infarct size was measured after 30 min of global ischemia and 120 min reperfusion. When compared with that of the control, mean infarct size was significantly smaller in groups treated with rIPC alone (P < 0.01) and intra-arterial adenosine (P < 0.01). Pretreatment with N(G)-nitro-l-arginine methyl ester or N-acetylpenicillamine did not affect the level of protection induced by rIPC (P = not significant, compared with rIPC alone) or intra-arterial adenosine (P = not significant, compared with intra-arterial adenosine alone), but prior femoral nerve transection or pretreatment with S-nitroso-N-acetylpenicillamine abolished the cardioprotective effect of intra-arterial adenosine and rIPC. Intra-arterial adenosine, like rIPC, releases a blood-borne cardioprotective factor(s) that is dependent on an intact femoral nerve and is inhibited by pretreatment with a NO donor. These results may be important when designing or assessing the results of clinical trials of adenosine or rIPC cardioprotection, where NO donors are used as part of therapy.

Agricultural pesticide use in California: pesticide prioritization, use densities, and population distributions for a childhood cancer study.

PubMed Central

Gunier, R B; Harnly, M E; Reynolds, P; Hertz, A; Von Behren, J

2001-01-01

Several studies have suggested an association between childhood cancer and pesticide exposure. California leads the nation in agricultural pesticide use. A mandatory reporting system for all agricultural pesticide use in the state provides information on the active ingredient, amount used, and location. We calculated pesticide use density to quantify agricultural pesticide use in California block groups for a childhood cancer study. Pesticides with similar toxicologic properties (probable carcinogens, possible carcinogens, genotoxic compounds, and developmental or reproductive toxicants) were grouped together for this analysis. To prioritize pesticides, we weighted pesticide use by the carcinogenic and exposure potential of each compound. The top-ranking individual pesticides were propargite, methyl bromide, and trifluralin. We used a geographic information system to calculate pesticide use density in pounds per square mile of total land area for all United States census-block groups in the state. Most block groups (77%) averaged less than 1 pound per square mile of use for 1991-1994 for pesticides classified as probable human carcinogens. However, at the high end of use density (> 90th percentile), there were 493 block groups with more than 569 pounds per square mile. Approximately 170,000 children under 15 years of age were living in these block groups in 1990. The distribution of agricultural pesticide use and number of potentially exposed children suggests that pesticide use density would be of value for a study of childhood cancer. PMID:11689348

Oxidative Stress Mechanisms Do Not Discriminate between Genotoxic and Nongenotoxic Liver Carcinogens.

PubMed

Deferme, Lize; Wolters, Jarno; Claessen, Sandra; Briedé, Jacco; Kleinjans, Jos

2015-08-17

It is widely accepted that in chemical carcinogenesis different modes-of-action exist, e.g., genotoxic (GTX) versus nongenotoxic (NGTX) carcinogenesis. In this context, it has been suggested that oxidative stress response pathways are typical for NGTX carcinogenesis. To evaluate this, we examined oxidative stress-related changes in gene expression, cell cycle distribution, and (oxidative) DNA damage in human hepatoma cells (HepG2) exposed to GTX-, NGTX-, and noncarcinogens, at multiple time points (4-8-24-48-72 h). Two GTX (azathriopine (AZA) and furan) and two NGTX (tetradecanoyl-phorbol-acetate, (TPA) and tetrachloroethylene (TCE)) carcinogens as well as two noncarcinogens (diazinon (DZN, d-mannitol (Dman)) were selected, while per class one compound was deemed to induce oxidative stress and the other not. Oxidative stressors AZA, TPA, and DZN induced a 10-fold higher number of gene expression changes over time compared to those of furan, TCE, or Dman treatment. Genes commonly expressed among AZA, TPA, and DZN were specifically involved in oxidative stress, DNA damage, and immune responses. However, differences in gene expression between GTX and NGTX carcinogens did not correlate to oxidative stress or DNA damage but could instead be assigned to compound-specific characteristics. This conclusion was underlined by results from functional readouts on ROS formation and (oxidative) DNA damage. Therefore, oxidative stress may represent the underlying cause for increased risk of liver toxicity and even carcinogenesis; however, it does not discriminate between GTX and NGTX carcinogens.

Capturing Labile Sulfenamide and Sulfinamide Serum Albumin Adducts of Carcinogenic Arylamines by Chemical Oxidation

PubMed Central

Peng, Lijuan; Turesky, Robert J.

2013-01-01

Aromatic amines and heterocyclic aromatic amines (HAAs) are a class of structurally related carcinogens that are formed during the combustion of tobacco or during the high temperature cooking of meats. These procarcinogens undergo metabolic activation by N-oxidation of the exocyclic amine group to produce N-hydroxylated metabolites, which are critical intermediates implicated in toxicity and DNA damage. The arylhydroxylamines and their oxidized arylnitroso derivatives can also react with cysteine (Cys) residues of glutathione or proteins to form, respectively, sulfenamide and sulfinamide adducts. However, sulfur-nitrogen linked adducted proteins are often difficult to detect because they are unstable and undergo hydrolysis during proteolytic digestion. Synthetic N-oxidized intermediates of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogenic HAA produced in cooked meats, and 4-aminobiphenyl, a carcinogenic aromatic amine present in tobacco smoke were reacted with human serum albumin (SA) and formed labile sulfenamide or sulfinamide adducts at the Cys34 residue. Oxidation of the carcinogen-modified SA with m-chloroperoxybenzoic acid (m-CPBA) produced the arylsulfonamide adducts, which were stable to heat and the chemical reduction conditions employed to denature SA. The sulfonamide adducts of PhIP and 4-ABP were identified, by liquid chromatography/mass spectrometry, in proteolytic digests of denatured SA. Thus, selective oxidation of arylamine-modified SA produces stable arylsulfonamide-SA adducts, which may serve as biomarkers of these tobacco and dietary carcinogens. PMID:23240913

Potential carcinogenic hazards of non-regulated disinfection by-products: haloquinones, halo-cyclopentene and cyclohexene derivatives, N-halamines, halonitriles, and heterocyclic amines.

PubMed

Bull, Richard J; Reckhow, David A; Li, Xingfang; Humpage, Andrew R; Joll, Cynthia; Hrudey, Steve E

2011-08-15

Drinking water disinfectants react with natural organic material (NOM) present in source waters used for drinking water to produce a wide variety of by-products. Several hundred disinfections by-products (DBPs) have been identified, but none have been identified with sufficient carcinogenic potency to account for the cancer risks projected from epidemiological studies. In a search for DBPs that might fill this risk gap, the present study projected reactions of chlorine and chloramine that could occur with substructures present in NOM to produce novel by-products. A review of toxicological data on related compounds, supplemented by use of a quantitative structure toxicity relationship (QSTR) program TOPKAT®) identified chemicals with a high probability of being chronically toxic and/or carcinogenic among 489 established and novel DBPs. Classes of DBPs that were specifically examined were haloquinones (HQs), related halo-cyclopentene and cyclohexene (HCP&H) derivatives, halonitriles (HNs), organic N-chloramines (NCls), haloacetamides (HAMs), and nitrosamines (NAs). A review of toxicological data available for quinones suggested that HQs and HCP&H derivatives appeared likely to be of health concern and were predicted to have chronic lowest observed adverse effect levels (LOAELs) in the low μg/kg day range. Several HQs were predicted to be carcinogenic. Some have now been identified in drinking water. The broader class of HNs was explored by considering current toxicological data on haloacetonitriles and extending this to halopropionitriles. 2,2-dichloropropionitrile has been identified in drinking water at low concentrations, as well as the more widely recognized haloacetonitriles. The occurrence of HAMs has been previously documented. The very limited toxicological data on HAMs suggests that this class would have toxicological potencies similar to the dihaloacetic acids. Organic N-halamines are also known to be produced in drinking water treatment and have biological properties of concern, but no member has ever been characterized toxicologically beyond bacterial or in vitro studies of genotoxicity. The documented formation of several nitrosamines from secondary amines from both natural and industrial sources prompted exploration of the formation of additional nitrosamines. N-diphenylnitrosamine was identified in drinking waters. Of more interest, however, was the formation of phenazine (and subsequently N-chorophenazine) in a competing reaction. These are the first heterocyclic amines that have been identified as chlorination by-products. Consideration of the amounts detected of members of these by-product classes and their probable toxicological potency suggest a prioritization for obtaining more detailed toxicological data of HQs>HCP&H derivatives>NCls>HNs. Based upon a ubiquitous occurrence and virtual lack of in vivo toxicological data, NCls are the most difficult group to assign a priority as potential carcinogenic risks. This analysis indicates that research on the general problem of DBPs requires a more systematic approach than has been pursued in the past. Utilization of predictive chemical tools to guide further research can help bring resolution to the DBP issue by identifying likely DBPs with high toxicological potency. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Genotoxic chemical carcinogens target inducible genes in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamilton, J.W.; McCaffrey, J.; Caron, R.M.

1994-12-31

Our laboratory is interested in whether carcinogen-induced DNA damage is distributed nonrandomly in the genome - that is, {open_quotes}targeted{close_quotes} to specific genes or gene regions in vivo. As an indirect measure of whether targeting occurs at the gene level, we have examined whether carcinogens differentially alter the expression of individual genes. We have compared the effects of model genotoxic carcinogens that principally induce either strand breaks, simple alkylations, bulky lesions, or DNA cross-links on the expression of several constitutive and inducible genes in a simple in vivo system, the chick embryo. Each agent was examined for its effects on genemore » expression over a 24 hour period corresponding to the period of maximal DNA damage and repair induced by each compound. The doses used in these studies represented the maximum doses that caused no overt toxicity over a 96 hour period but that induced significant levels of DNA damage. Our results demonstrate that inducible genes are targeted by chemical carcinogens. We hypothesize that such effects may be a result of DNA damage specifically altering DNA-protein interactions within the promoters of inducible genes.« less

Low-dose carcinogenicity of 2-amino-3-methylimidazo[4,5-f ]quinoline in rats: Evidence for the existence of no-effect levels and a mechanism involving p21(Cip / WAF1).

PubMed

Wei, Min; Wanibuchi, Hideki; Nakae, Dai; Tsuda, Hiroyuki; Takahashi, Satoru; Hirose, Masao; Totsuka, Yukari; Tatematsu, Masae; Fukushima, Shoji

2011-01-01

The carcinogenicity of the low amounts of genotoxic carcinogens present in food is of pressing concern. The purpose of the present study was to determine the carcinogenicity of low doses of the dietary genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and to investigate mechanisms by which IQ exerts its carcinogenic effects. A total of 1595 male F344 rats were divided into seven groups and administered with IQ at doses of 0, 0.001, 0.01, 0.1, 1, 10 and 100 p.p.m. in the diet for 16 weeks. We found that IQ doses of 1 p.p.m. and below did not induce preneoplastic lesions in either the liver or the colon, while IQ doses of 10 and 100 p.p.m. induced preneoplastic lesions in both of these organs. These results demonstrate the presence of no-effect levels of IQ for both liver and colon carcinogenicity in rats. The finding that p21(Cip/WAF1) was significantly induced in the liver at doses well below those required for IQ mediated carcinogenic effects suggests that induction of p21(Cip/WAF1) is one of the mechanisms responsible for the observed no-effect of low doses of IQ. Furthermore, IQ administration caused significant induction of CYP1A2 at doses of 0.01-10 p.p.m., but administration of 100 p.p.m. IQ induced CYP1A1 rather than CYP1A2. This result indicates the importance of dosage when interpreting data on the carcinogenicity and metabolic activation of IQ. Overall, our results suggest the existence of no-effect levels for the carcinogenicity of this genotoxic compound. © 2010 Japanese Cancer Association.

CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO MALE F344/N RATS AND B6C3F1 MICE

EPA Science Inventory

A life-time exposure study was conducted to assess the carcinogenicity of bromodichloromethane (BDCM) administered in the drinking water to male F344/N rats and B6C3F1 mice. Mouse: Target concentrations of BDCM (dissolved in deionized water containing 0.25% emulphor) were 0.05, ...

Genetic heterogeneity among slow acetylator N-acetyltransferase 2 phenotypes in cryopreserved human hepatocytes.

PubMed

Doll, Mark A; Hein, David W

2017-07-01

Genetic polymorphisms in human N-acetyltransferase 2 (NAT2) modify the metabolism of numerous drugs and carcinogens. These genetic polymorphisms modify both drug efficacy and toxicity and cancer risk associated with carcinogen exposure. Previous studies have suggested phenotypic heterogeneity among different NAT2 slow acetylator genotypes. NAT2 phenotype was investigated in vitro and in situ in samples of human hepatocytes obtained from various NAT2 slow and intermediate NAT2 acetylator genotypes. NAT2 gene dose response (NAT2*5B/*5B > NAT2*5B/*6A > NAT2*6A/*6A) was observed towards the N-acetylation of the NAT2-specific drug sulfamethazine by human hepatocytes both in vitro and in situ. N-acetylation of 4-aminobiphenyl, an arylamine carcinogen substrate for both N-acetyltransferase 1 and NAT2, showed the same trend both in vitro and in situ although the differences were not significant (p > 0.05). The N-acetylation of the N-acetyltransferase 1-specific substrate p-aminobenzoic acid did not follow this trend. In comparisons of NAT2 intermediate acetylator genotypes, differences in N-acetylation between NAT2*4/*5B and NAT2*4/*6B hepatocytes were not observed in vitro or in situ towards any of these substrates. These results further support phenotypic heterogeneity among NAT2 slow acetylator genotypes, consistent with differential risks of drug failure or toxicity and cancer associated with carcinogen exposure.

Comparison of carcinogen, carbon monoxide, and ultrafine particle emissions from narghile waterpipe and cigarette smoking: Sidestream smoke measurements and assessment of second-hand smoke emission factors

PubMed Central

Daher, Nancy; Saleh, Rawad; Jaroudi, Ezzat; Sheheitli, Hiba; Badr, Thérèse; Sepetdjian, Elizabeth; Al Rashidi, Mariam; Saliba, Najat; Shihadeh, Alan

2009-01-01

The lack of scientific evidence on the constituents, properties, and health effects of second-hand waterpipe smoke has fueled controversy over whether public smoking bans should include the waterpipe. The purpose of this study was to investigate and compare emissions of ultrafine particles (UFP, <100 nm), carcinogenic polyaromatic hydrocarbons (PAH), volatile aldehydes, and carbon monoxide (CO) for cigarettes and narghile (shisha, hookah) waterpipes. These smoke constituents are associated with a variety of cancers, and heart and pulmonary diseases, and span the volatility range found in tobacco smoke. Sidestream cigarette and waterpipe smoke was captured and aged in a 1 m3 Teflon-coated chamber operating at 1.5 air changes per hour (ACH). The chamber was characterized for particle mass and number surface deposition rates. UFP and CO concentrations were measured online using a fast particle spectrometer (TSI 3090 Engine Exhaust Particle Sizer), and an indoor air quality monitor. Particulate PAH and gaseous volatile aldehydes were captured on glass fiber filters and DNPH-coated SPE cartridges, respectively, and analyzed off-line using GC–MS and HPLC–MS. PAH compounds quantified were the 5- and 6-ring compounds of the EPA priority list. Measured aldehydes consisted of formaldehyde, acetaldehyde, acrolein, methacrolein, and propionaldehyde. We found that a single waterpipe use session emits in the sidestream smoke approximately four times the carcinogenic PAH, four times the volatile aldehydes, and 30 times the CO of a single cigarette. Accounting for exhaled mainstream smoke, and given a habitual smoker smoking rate of 2 cigarettes per hour, during a typical one-hour waterpipe use session a waterpipe smoker likely generates ambient carcinogens and toxicants equivalent to 2–10 cigarette smokers, depending on the compound in question. There is therefore good reason to include waterpipe tobacco smoking in public smoking bans. PMID:20161525

Comparison of carcinogen, carbon monoxide, and ultrafine particle emissions from narghile waterpipe and cigarette smoking: Sidestream smoke measurements and assessment of second-hand smoke emission factors

NASA Astrophysics Data System (ADS)

Daher, Nancy; Saleh, Rawad; Jaroudi, Ezzat; Sheheitli, Hiba; Badr, Thérèse; Sepetdjian, Elizabeth; Al Rashidi, Mariam; Saliba, Najat; Shihadeh, Alan

2010-01-01

The lack of scientific evidence on the constituents, properties, and health effects of second-hand waterpipe smoke has fueled controversy over whether public smoking bans should include the waterpipe. The purpose of this study was to investigate and compare emissions of ultrafine particles (UFP, <100 nm), carcinogenic polyaromatic hydrocarbons (PAH), volatile aldehydes, and carbon monoxide (CO) for cigarettes and narghile (shisha, hookah) waterpipes. These smoke constituents are associated with a variety of cancers, and heart and pulmonary diseases, and span the volatility range found in tobacco smoke. Sidestream cigarette and waterpipe smoke was captured and aged in a 1 m 3 Teflon-coated chamber operating at 1.5 air changes per hour (ACH). The chamber was characterized for particle mass and number surface deposition rates. UFP and CO concentrations were measured online using a fast particle spectrometer (TSI 3090 Engine Exhaust Particle Sizer), and an indoor air quality monitor. Particulate PAH and gaseous volatile aldehydes were captured on glass fiber filters and DNPH-coated SPE cartridges, respectively, and analyzed off-line using GC-MS and HPLC-MS. PAH compounds quantified were the 5- and 6-ring compounds of the EPA priority list. Measured aldehydes consisted of formaldehyde, acetaldehyde, acrolein, methacrolein, and propionaldehyde. We found that a single waterpipe use session emits in the sidestream smoke approximately four times the carcinogenic PAH, four times the volatile aldehydes, and 30 times the CO of a single cigarette. Accounting for exhaled mainstream smoke, and given a habitual smoker smoking rate of 2 cigarettes per hour, during a typical one-hour waterpipe use session a waterpipe smoker likely generates ambient carcinogens and toxicants equivalent to 2-10 cigarette smokers, depending on the compound in question. There is therefore good reason to include waterpipe tobacco smoking in public smoking bans.

Formation and Human Risk of Carcinogenic Heterocyclic Amines Formed from Natural Precursors in Meat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knize, M G; Felton, J S

2004-11-22

A group of heterocyclic amines that are mutagens and rodent carcinogens form when meat is cooked to medium and well-done states. The precursors of these compounds are natural meat components: creatinine, amino acids and sugars. Defined model systems of dry-heated precursors mimic the amounts and proportions of heterocyclic amines found in meat. Results from model systems and cooking experiments suggest ways to reduce their formation and, thus, to reduce human intake. Human cancer epidemiology studies related to consumption of well-done meat products are listed and compared.

Bioassay of 4'-(chloroacetyl)-acetanilide for possible carcinogenicity.

PubMed

1979-01-01

A bioassay for the possible carcinogenicity of 4'-(chloroacetyl)-acetanilide was conducted using Fischer 344 rats and B6C3F1 mice. 4'-(Chloroacetyl)-acetanilide was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of 4'-(chloroacetyl)-acetanilide were, respectively, 2,000 and 1,000 ppm for rats and 10,000 and 5,000 ppm for mice. The compound was administered for 87 weeks of a 102-week period in rats and for 90 weeks of a 105-week period in mice. Mice were killed at the end of the last week of compound administration, while rats were observed for 1 week after compound administration ceased. There were no significant positive associations between the concentration of 4'-(chloroacetyl)-acetanilide administered and mortality in rats or mice of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Dose-related mean body weight depression was observed for males and females of both species, indicating that the concentrations of 4'-(chloroacetyl)-acetanilide administered to the animals in this bioassay may have approximated the maximum tolerated concentrations. None of the statistical tests for any site in rats of either sex or in male mice indicated a significant positive association between compound administration and tumor incidence. Although there was a significant positive association between the concentration of the compound administered and the incidences of hepatocellular adenomas in female mice, the Fischer exact comparisons were not significant. Under the conditions of this bioassay, 4'-(chloroacetyl)-acetanilide was not carcinogenic when administered in the diet to Fischer 344 rats or B6C3F1 mice of either sex.

Antibacterial activity of nitric oxide releasing silver nanoparticles

NASA Astrophysics Data System (ADS)

Seabra, Amedea B.; Manosalva, Nixson; de Araujo Lima, Bruna; Pelegrino, Milena T.; Brocchi, Marcelo; Rubilar, Olga; Duran, Nelson

2017-06-01

Silver nanoparticles (AgNPs) are well known potent antimicrobial agents. Similarly, the free radical nitric oxide (NO) has important antibacterial activity, and due to its instability, the combination of NO and nanomaterials has been applied in several biomedical applications. The aim of this work was to synthesize, characterize and evaluate the antibacterial activity of a new NO-releasing AgNPs. Herein, AgNPs were synthesized by the reduction of silver ions (Ag+) by catechin, a natural polyphenol and potent antioxidant agent, derived from green tea extract. Catechin acts as a reducing agent and as a capping molecule on the surface of AgNPs, minimizing particle agglomeration. The as-synthesized nanoparticles were characterized by different techniques. The results showed the formation of AgNPs with average hydrodynamic size of 44 nm, polydispersity index of 0.21, and zeta potential of -35.9 mV. X-ray diffraction and Fourier transform infrared spectroscopy revealed the presence of the AgNP core and cathecin as capping agent. The low molecular weight mercaptosuccinic acid (MSA), which contain free thiol group, was added on the surface of catechin-AgNPs, leading to the formation of MSA-catechin-AgNPs (the NO precursor nanoparticle). Free thiol groups of MSA-catechin-AgNPs were nitrosated leading to the formation of S-nitroso-mercaptosuccinic acid (S-nitroso-MSA), the NO donor. The amount of 342 ± 16 µmol of NO was released per gram of S-nitroso-MSA-catechin-AgNPs. The antibacterial activities of catechin-AgNPs, MSA-catechin-AgNPs, and S-nitroso-MSA-catechin-AgNPs were evaluated towards different resistant bacterial strains. The results demonstrated an enhanced antibacterial activity of the NO-releasing AgNP. For instance, the minimal inhibitory concentration values for Pseudomonas aeruginosa (ATCC 27853) incubated with AgNPs-catechin, AgNPs-catechin-MSA, and AgNPs-catechin-S-nitroso-MSA were found to be 62, 125 and 3 µg/mL, respectively. While in the case of Klebsiella pneumoniae (ATCC 700603) the minimum bactericidal concentration values for treatments with AgNPs-catechin, AgNPs-catechin-MSA, and AgNPs-catechin-S-nitroso-MSA were found to be 1000, 500, and 125 µg/mL, respectively. The antibacterial actions of the NO-releasing nanoparticle were superior in comparison with the antibacterial effects of AgNPs, in most of the tested antibiotic resistant bacteria strains. These results highlight the promising uses of NO-releasing AgNPs against resistant bacteria in several biomedical applications.

Discovery of Specific Inhibitors for Intestinal E. coli   β-Glucuronidase through In Silico Virtual Screening

PubMed Central

Cheng, Ta-Chun; Cheng, Kai-Wen; Leu, Yu-Lin; Chuang, Chih-Hung; Huang, Chien-Chaio; Hsieh, Yuan-Chin; Chang, Long-Sen; Cheng, Tian-Lu

2015-01-01

Glucuronidation is a major metabolism process of detoxification for carcinogens, 4-(methylnitrosamino)-1-(3-pyridy)-1-butanone (NNK) and 1,2-dimethylhydrazine (DMH), of reactive oxygen species (ROS). However, intestinal E. coli    β-glucuronidase (eβG) has been considered pivotal to colorectal carcinogenesis. Specific inhibition of eβG may prevent reactivating the glucuronide-carcinogen and protect the intestine from ROS-mediated carcinogenesis. In order to develop specific eβG inhibitors, we found that 59 candidate compounds obtained from the initial virtual screening had high inhibition specificity against eβG but not human βG. In particular, we found that compounds 7145 and 4041 with naphthalenylidene-benzenesulfonamide (NYBS) are highly effective and selective to inhibit eβG activity. Compound 4041  (IC50 = 2.8 μM) shows a higher inhibiting ability than compound 7145  (IC50 = 31.6 μM) against eβG. Furthermore, the molecular docking analysis indicates that compound 4041 has two hydrophobic contacts to residues L361 and I363 in the bacterial loop, but 7145 has one contact to L361. Only compound 4041 can bind to key residue (E413) at active site of eβG via hydrogen-bonding interactions. These novel NYBS-based eβG specific inhibitors may provide as novel candidate compounds, which specifically inhibit eβG to reduce eβG-based carcinogenesis and intestinal injury. PMID:25839056

Discovery of specific inhibitors for intestinal E. coli  β-glucuronidase through in silico virtual screening.

PubMed

Cheng, Ta-Chun; Chuang, Kuo-Hsiang; Roffler, Steve R; Cheng, Kai-Wen; Leu, Yu-Lin; Chuang, Chih-Hung; Huang, Chien-Chaio; Kao, Chien-Han; Hsieh, Yuan-Chin; Chang, Long-Sen; Cheng, Tian-Lu; Chen, Chien-Shu

2015-01-01

Glucuronidation is a major metabolism process of detoxification for carcinogens, 4-(methylnitrosamino)-1-(3-pyridy)-1-butanone (NNK) and 1,2-dimethylhydrazine (DMH), of reactive oxygen species (ROS). However, intestinal E. coli   β-glucuronidase (eβG) has been considered pivotal to colorectal carcinogenesis. Specific inhibition of eβG may prevent reactivating the glucuronide-carcinogen and protect the intestine from ROS-mediated carcinogenesis. In order to develop specific eβG inhibitors, we found that 59 candidate compounds obtained from the initial virtual screening had high inhibition specificity against eβG but not human βG. In particular, we found that compounds 7145 and 4041 with naphthalenylidene-benzenesulfonamide (NYBS) are highly effective and selective to inhibit eβG activity. Compound 4041  (IC50 = 2.8 μM) shows a higher inhibiting ability than compound 7145  (IC50 = 31.6 μM) against eβG. Furthermore, the molecular docking analysis indicates that compound 4041 has two hydrophobic contacts to residues L361 and I363 in the bacterial loop, but 7145 has one contact to L361. Only compound 4041 can bind to key residue (E413) at active site of eβG via hydrogen-bonding interactions. These novel NYBS-based eβG specific inhibitors may provide as novel candidate compounds, which specifically inhibit eβG to reduce eβG-based carcinogenesis and intestinal injury.

The multitude and diversity of environmental carcinogens.

PubMed

Belpomme, D; Irigaray, P; Hardell, L; Clapp, R; Montagnier, L; Epstein, S; Sasco, A J

2007-11-01

We have recently proposed that lifestyle-related factors, screening and aging cannot fully account for the present overall growing incidence of cancer. In order to propose the concept that in addition to lifestyle related factors, exogenous environmental factors may play a more important role in carcinogenesis than it is expected, and may therefore account for the growing incidence of cancer, we overview herein environmental factors, rated as certainly or potentially carcinogenic by the International Agency for Research on Cancer (IARC). We thus analyze the carcinogenic effect of microorganisms (including viruses), radiations (including radioactivity, UV and pulsed electromagnetic fields) and xenochemicals. Chemicals related to environmental pollution appear to be of critical importance, since they can induce occupational cancers as well as other cancers. Of major concerns are: outdoor air pollution by carbon particles associated with polycyclic aromatic hydrocarbons; indoor air pollution by environmental tobacco smoke, formaldehyde and volatile organic compounds such as benzene and 1,3 butadiene, which may particularly affect children, and food pollution by food additives and by carcinogenic contaminants such as nitrates, pesticides, dioxins and other organochlorines. In addition, carcinogenic metals and metalloids, pharmaceutical medicines and cosmetics may be involved. Although the risk fraction attributable to environmental factors is still unknown, this long list of carcinogenic and especially mutagenic factors supports our working hypothesis according to which numerous cancers may in fact be caused by the recent modification of our environment.

An analysis of pharmaceutical experience with decades of rat carcinogenicity testing: support for a proposal to modify current regulatory guidelines.

PubMed

Sistare, Frank D; Morton, Daniel; Alden, Carl; Christensen, Joel; Keller, Douglas; Jonghe, Sandra De; Storer, Richard D; Reddy, M Vijayaraj; Kraynak, Andrew; Trela, Bruce; Bienvenu, Jean-Guy; Bjurström, Sivert; Bosmans, Vanessa; Brewster, David; Colman, Karyn; Dominick, Mark; Evans, John; Hailey, James R; Kinter, Lewis; Liu, Matt; Mahrt, Charles; Marien, Dirk; Myer, James; Perry, Richard; Potenta, Daniel; Roth, Arthur; Sherratt, Philip; Singer, Thomas; Slim, Rabih; Soper, Keith; Fransson-Steen, Ronny; Stoltz, James; Turner, Oliver; Turnquist, Susan; van Heerden, Marjolein; Woicke, Jochen; DeGeorge, Joseph J

2011-06-01

Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.

The multitude and diversity of environmental carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Belpomme, D.; Cancer Research Center, Association for Research and Treatments Against Cancer; Irigaray, P.

2007-11-15

We have recently proposed that lifestyle-related factors, screening and aging cannot fully account for the present overall growing incidence of cancer. In order to propose the concept that in addition to lifestyle related factors, exogenous environmental factors may play a more important role in carcinogenesis than it is expected, and may therefore account for the growing incidence of cancer, we overview herein environmental factors, rated as certainly or potentially carcinogenic by the International Agency for Research on Cancer (IARC). We thus analyze the carcinogenic effect of microorganisms (including viruses), radiations (including radioactivity, UV and pulsed electromagnetic fields) and xenochemicals. Chemicalsmore » related to environmental pollution appear to be of critical importance, since they can induce occupational cancers as well as other cancers. Of major concerns are: outdoor air pollution by carbon particles associated with polycyclic aromatic hydrocarbons; indoor air pollution by environmental tobacco smoke, formaldehyde and volatile organic compounds such as benzene and 1,3 butadiene, which may particularly affect children, and food pollution by food additives and by carcinogenic contaminants such as nitrates, pesticides, dioxins and other organochlorines. In addition, carcinogenic metals and metalloids, pharmaceutical medicines and cosmetics may be involved. Although the risk fraction attributable to environmental factors is still unknown, this long list of carcinogenic and especially mutagenic factors supports our working hypothesis according to which numerous cancers may in fact be caused by the recent modification of our environment.« less

Heterocyclic amines: Mutagens/carcinogens produced during cooking of meat and fish.

PubMed

Sugimura, Takashi; Wakabayashi, Keiji; Nakagama, Hitoshi; Nagao, Minako

2004-04-01

Research leading to the discovery of a series of mutagenic and carcinogenic heterocyclic amines (HCAs) was inspired by the idea that smoke produced during cooking of food, especially meat or fish, might be carcinogenic. More than ten kinds of HCAs, actually produced by cooking or heating of meat or fish, have now been isolated and their structures determined, most being previously unregistered compounds. They are highly mutagenic towards Salmonella typhimurium in the presence of S9 mix and are also mutagenic in vitro and in vivo toward mammalian cells. HCAs have now been chemically synthesized in quantity and subjected to long-term animal testing. When HCAs were fed in the diet, rodents developed cancers in many organs, including the colon, breast and prostate, and one HCA produced hepatomas in monkeys. The lesions exhibited alteration in genes including Apc, beta-catenin and Ha-ras, and these changes provide clues to the induction mechanisms. The HCAs are oxidized to hydroxyamino derivatives by cytochrome P450s, and further converted to ester forms by acetyltransferase and sulfotransferase. Eventually, they produce DNA adducts through the formation of N-C bonds at guanine bases. There are HCA-sensitive and resistant strains of rodents and a search for the responsible genes is now under way. While the content of HCAs in dishes consumed in ordinary life is low and not sufficient in itself to explain human cancer, the coexistence of many other mutagens/carcinogens of either autobiotic or xenobiotic type and the possibility that HCAs induce genomic instability and heightened sensitivity to tumor promoters suggest that avoidance of exposure to HCAs or reduction of HCAs' biological effects as far as possible are to be highly recommended. Usage of microwave ovens for cooking and supplementation of the diet, for example with soy-isoflavones, which have been found to suppress the occurrence of HCA-induced breast cancers, should be encouraged. Advice to the general public about how to reduce the carcinogenic load imposed by HCAs would be an important contribution to cancer prevention.

Role of N-acetyltransferase 2 acetylation polymorphism in 4, 4'-methylene bis (2-chloroaniline) biotransformation.

PubMed

Hein, David W; Zhang, Xiaoyan; Doll, Mark A

2018-02-01

Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) catalyze the acetylation of arylamine carcinogens. Single nucleotide polymorphisms in the NAT2 coding exon present in NAT2 haplotypes encode allozymes with reduced N-acetyltransferase activity towards the N-acetylation of arylamine carcinogens and the O-acetylation of their N-hydroxylated metabolites. NAT2 acetylator phenotype modifies urinary bladder cancer risk following exposures to arylamine carcinogens such as 4-aminobiphenyl. 4, 4'-methylene bis (2-chloroaniline) (MOCA) is a Group 1 carcinogen for which a role of the NAT2 acetylation polymorphism on cancer risk is unknown. We investigated the role of NAT2 and the genetic acetylation polymorphism on both MOCA N-acetylation and N-hydroxy-MOCA O-acetylation. MOCA N-acetylation exhibited a robust gene dose response in rabbit liver cytosol and in cryopreserved human hepatocytes derived from individuals of rapid, intermediate and slow acetylator NAT2 genotype. MOCA exhibited about 4-fold higher affinity for recombinant human NAT2 than NAT1. Recombinant human NAT2*4 (reference) and 15 variant recombinant human NAT2 allozymes catalyzed both the N-acetylation of MOCA and the O-acetylation of N-hydroxy-MOCA. Human NAT2 5, NAT2 6, NAT2 7 and NAT2 14 allozymes catalyzed MOCA N-acetylation and N-hydroxy-O-acetylation at rates much lower than the reference NAT2 4 allozyme. In conclusion, our results show that NAT2 acetylator genotype has an important role in MOCA metabolism and suggest that risk assessments related to MOCA exposures consider accounting for NAT2 acetylator phenotype in the analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

Curcumin Regulates Colon Cancer by Inhibiting P-Glycoprotein in In-situ Cancerous Colon Perfusion Rat Model.

PubMed

Neerati, Prasad; Sudhakar, Yakkanti A; Kanwar, Jagat R

2013-07-08

Studies on p-glycoprotein was carried out world vide with cell lines like Caco2, MDR1-LLC-PK1 and MDR1-MDCK in-vitro , but most of the results were failed to produce similar results in-vivo. In the present study curcumin inhibitory action on p-glycoprotein increased permeability of irinotecan, so in the colon cancer it would be beneficial if curcumin used as add on therapy. Intra-rectal administered of N-Nitroso N-methyl urea (2 mg/Kg) induced colon cancer. Single pass whole length of colon in-situ perfusion was carried out in rats with irinotecan to study the influence of p-glycoprotein modulators like verapamil and curcumin. The rats were divided in to 5 groups (n=6), Group I served as control perfused with 30 μg/ml of irinotecan, propronolol and phenol red. Group II was cancerous group, induced by N-methyl N-nitroso urea. Group III was perfused with irinotican in cancerous rats. Group IV, perfused with irinotican in presence of verapamil and group V was pre-treated with curcumin and then perfused with irinotican and was estimated by HPLC-UV to effective permeability coefficient. Our qRT-PCR and Western blot results confirmed that about 15-fold decreases in the expression of p-glycoprotein (P-gp) in curcumin treated colon cancer cells. Irinotecan was increased to 0.00066 cm/s and about 11-fold increase in verapamil-coperfused group, where curcumin pre-treated group irinotecan was increases 0.00006 cm/s to 0.00042 cm/s that is about 7-fold increase p-glycoprotein inhibitory activity by verapamil and curcumin found to be significantly enhanced the cancerous colon permeability of irinotecan. Any safe suitable p-glycoprotein inhibitors along with irinotecan will enhance the therapeutic benefit in the treatment of the colon cancer.

Reduction of Thrombosis and Bacterial Infection via Controlled Nitric Oxide (NO) Release from S-Nitroso-N-acetylpenicillamine (SNAP) Impregnated CarboSil Intravascular Catheters

PubMed Central

2017-01-01

Nitric oxide (NO) has many important physiological functions, including its ability to inhibit platelet activation and serve as potent antimicrobial agent. The multiple roles of NO in vivo have led to great interest in the development of biomaterials that can deliver NO for specific biomedical applications. Herein, we report a simple solvent impregnation technique to incorporate a nontoxic NO donor, S-nitroso-N-acetylpenicillamine (SNAP), into a more biocompatible biomedical grade polymer, CarboSil 20 80A. The resulting polymer-crystal composite material yields a very stable, long-term NO release biomaterial. The SNAP impregnation process is carefully characterized and optimized, and it is shown that SNAP crystal formation occurs in the bulk of the polymer after solvent evaporation. LC-MS results demonstrate that more than 70% of NO release from this new composite material originates from the SNAP embedded CarboSil phase, and not from the SNAP species leaching out into the soaking solution. Catheters prepared with CarboSil and then impregnated with 15 wt % SNAP provide a controlled NO release over a 14 d period at physiologically relevant fluxes and are shown to significantly reduce long-term (14 day) bacterial biofilm formation against Staphylococcus epidermidis and Pseudonomas aeruginosa in a CDC bioreactor model. After 7 h of catheter implantation in the jugular veins of rabbit, the SNAP CarboSil catheters exhibit a 96% reduction in thrombus area (0.03 ± 0.01 cm2/catheter) compared to the controls (0.84 ± 0.19 cm2/catheter) (n = 3). These results suggest that SNAP impregnated CarboSil can become an attractive new biomaterial for use in preparing intravascular catheters and other implanted medical devices. PMID:28317023

Performance evaluation of the UV/H2O2 process on selected nitrogenous organic compounds: reductions of organic contents vs. corresponding C-, N-DBPs formations.

PubMed

Chen, Huei-Wen; Chen, Chia-Yang; Wang, Gen-Shuh

2011-10-01

The presence of various organic contaminants in water sources is of concern due to their direct threats to human health and potential to react with disinfectants to form carcinogenic byproducts including trihalomethanes, haloacetic acids and nitrosamines in finished water. This study applied both medium-pressure and low-pressure ultraviolet light coupled with hydrogen peroxide (UV/H2O2) to evaluate its efficacy for degradation of selected nitrogenous organic compounds and corresponding disinfection byproduct (DBP) formation. Six organic compounds were chosen as target precursors based on their nitrogen contents and molecular structures. The results showed that higher oxidation capacity resulted in better reduction of organic matters and DBP formation potentials (DBPFPs). However, insufficient contact time and oxidant doses could lead to a rise of DBPFPs in the early stages of UV/H2O2 reactions. A greater percentage removal was achieved for organic carbon than organic nitrogen after UV/H2O2 treatment, especially for compounds with complicated structure such as diltiazem. During the UV/H2O2 treatment, the intermediate products include tertiary amine, dimethyl amine (DMA) or DMA-like structures, which are N-nitrosodimethylamine (NDMA) precursors after chlorination or chloramination. Furthermore, it was observed that using dissolved organic nitrogen and DMA to predict NDMAFP could lead to biased conclusions because of the complex nature of nitrogenous matters in aqueous environments. Copyright © 2011 Elsevier Ltd. All rights reserved.

Supplement to the Carcinogenic Potency Database (CPDB): results of animal bioassays published in the general literature in 1993 to 1994 and by the National Toxicology Program in 1995 to 1996.

PubMed Central

Gold, L S; Manley, N B; Slone, T H; Rohrbach, L

1999-01-01

The Carcinogenic Potency Database (CPDB) is a systematic and unifying analysis of results of chronic, long-term cancer tests. This paper presents a supplemental plot of the CPDB, including 513 experiments on 157 test compounds published in the general literature in 1993 and 1994 and in Technical Reports of the National Toxicology Program in 1995 and 1996. The plot standardizes the experimental results (whether positive or negative for carcinogenicity), including qualitative data on strain, sex, route of compound administration, target organ, histopathology, and author's opinion and reference to the published paper, as well as quantitative data on carcinogenic potency, statistical significance, tumor incidence, dose-response curve shape, length of experiment, duration of dosing, and dose rate. A numerical description of carcinogenic potency, the TD(subscript)50(/subscript), is estimated for each set of tumor incidence data reported. When added to the data published earlier, the CPDB now includes results of 5,620 experiments on 1,372 chemicals that have been reported in 1,250 published papers and 414 National Cancer Institute/National Toxicology Program Technical Reports. The plot presented here includes detailed analyses of 25 chemicals tested in monkeys for up to 32 years by the National Cancer Institute. Half the rodent carcinogens that were tested in monkeys were not carcinogenic, despite usually strong evidence of carcinogenicity in rodents and/or humans. Our analysis of possible explanatory factors indicates that this result is due in part to the fact that the monkey studies lacked power to detect an effect compared to standard rodent bioassays. Factors that contributed to the lack of power are the small number of animals on test; a stop-exposure protocol for model rodent carcinogens; in a few cases, toxic doses that resulted in stoppage of dosing or termination of the experiment; and in a few cases, low doses administered to monkeys or early termination of the experiment even though the doses were not toxic. Among chemicals carcinogenic in both monkeys and rodents, there is some support for target site concordance, but it is primarily restricted to liver tumors. Potency values are highly correlated between rodents and monkeys. The plot in this paper can be used in conjunction with the earlier results published in the CRC Handbook of Carcinogenic Potency and Genotoxicity Databases [Gold LS, Zeiger E, eds. Boca Raton FL:CRC Press, 1997] and with our web site (http://potency.berkeley.edu), which includes a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency (TD50), and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Two summary tables permit easy access to the literature of animal cancer tests by target organ and by chemical. For readers using the CPDB extensively, a combined plot on diskette or other format is available from the first author. It includes all results published earlier and in this paper, ordered alphabetically by chemical. A SAS database is also available. PMID:10421768

Current status of environmental, health, and safety issues of lithium ion electric vehicle batteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vimmerstedt, L.J.; Ring, S.; Hammel, C.J.

The lithium ion system considered in this report uses lithium intercalation compounds as both positive and negative electrodes and has an organic liquid electrolyte. Oxides of nickel, cobalt, and manganese are used in the positive electrode, and carbon is used in the negative electrode. This report presents health and safety issues, environmental issues, and shipping requirements for lithium ion electric vehicle (EV) batteries. A lithium-based electrochemical system can, in theory, achieve higher energy density than systems using other elements. The lithium ion system is less reactive and more reliable than present lithium metal systems and has possible performance advantages overmore » some lithium solid polymer electrolyte batteries. However, the possibility of electrolyte spills could be a disadvantage of a liquid electrolyte system compared to a solid electrolyte. The lithium ion system is a developing technology, so there is some uncertainty regarding which materials will be used in an EV-sized battery. This report reviews the materials presented in the open literature within the context of health and safety issues, considering intrinsic material hazards, mitigation of material hazards, and safety testing. Some possible lithium ion battery materials are toxic, carcinogenic, or could undergo chemical reactions that produce hazardous heat or gases. Toxic materials include lithium compounds, nickel compounds, arsenic compounds, and dimethoxyethane. Carcinogenic materials include nickel compounds, arsenic compounds, and (possibly) cobalt compounds, copper, and polypropylene. Lithiated negative electrode materials could be reactive. However, because information about the exact compounds that will be used in future batteries is proprietary, ongoing research will determine which specific hazards will apply.« less

Occurrence and environmental risk assessment of PAEs in Weihe River near Xi'an City, China.

PubMed

Guo, Xiaofeng; Wang, Lei; Wang, Xudong; Liu, Hanli

2013-01-01

The occurrence and distribution of phthalate acid esters (PAEs) in surface water of the Weihe River basin (eight mainstream sampling points and 15 tributary sampling points) in the Shaanxi section were investigated during the dry season, level period (spring), wet season and level period (autumn). The PAEs tested for were diethyl phthalate (DEP), di-n-butyl phthalate (DBP), dicyclohexyl phthalate (DCHP) and di-(2-ethylhexyl) phthalate (DEHP). The testing proceeded by millipore filtration, then solid phase extraction and then gas chromatography-mass spectrometry determination for all examined PAEs. The monitoring results indicated that, in terms of seasonal changes, concentration of the PAEs in the mainstream is: Dry season > Level period (spring) > Wet season ≈ Level period (autumn). An environmental risk assessment was then performed on PAE pollution levels of the Weihe River basin. This paper employed a risk assessment methodology to evaluate the potential adverse health effects of the individual PAE compounds according to their carcinogenicities. For DEP, DBP and DEHP, a low Risk Index (all of them were lower than the specified level of 1.0) reveals that small non-carcinogenic risks exist resulting from the presence of trace concentrations in the surface water of the Weihe River basin.

Identification of early target genes of aflatoxin B1 in human hepatocytes, inter-individual variability and comparison with other genotoxic compounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Josse, Rozenn; Dumont, Julie; Fautrel, Alain

Gene expression profiling has recently emerged as a promising approach to identify early target genes and discriminate genotoxic carcinogens from non-genotoxic carcinogens and non-carcinogens. However, early gene changes induced by genotoxic compounds in human liver remain largely unknown. Primary human hepatocytes and differentiated HepaRG cells were exposed to aflatoxin B1 (AFB1) that induces DNA damage following enzyme-mediated bioactivation. Gene expression profile changes induced by a 24 h exposure of these hepatocyte models to 0.05 and 0.25 μM AFB1 were analyzed by using oligonucleotide pangenomic microarrays. The main altered signaling pathway was the p53 pathway and related functions such as cellmore » cycle, apoptosis and DNA repair. Direct involvement of the p53 protein in response to AFB1 was verified by using siRNA directed against p53. Among the 83 well-annotated genes commonly modulated in two pools of three human hepatocyte populations and HepaRG cells, several genes were identified as altered by AFB1 for the first time. In addition, a subset of 10 AFB1-altered genes, selected upon basis of their function or tumor suppressor role, was tested in four human hepatocyte populations and in response to other chemicals. Although they exhibited large variable inter-donor fold-changes, several of these genes, particularly FHIT, BCAS3 and SMYD3, were found to be altered by various direct and other indirect genotoxic compounds and unaffected by non-genotoxic compounds. Overall, this comprehensive analysis of early gene expression changes induced by AFB1 in human hepatocytes identified a gene subset that included several genes representing potential biomarkers of genotoxic compounds. -- Highlights: ► Gene expression profile changes induced by aflatoxin B1 in human hepatocytes. ► AFB1 modulates various genes including tumor suppressor genes and proto-oncogenes. ► Important inter-individual variations in the response to AFB1. ► Some genes also altered by other genotoxic compounds requiring or not bioactivation.« less

Exposure to N-nitroso compounds in a population of high liver cancer regions in Thailand: volatile nitrosamine (VNA) levels in Thai food.

PubMed

Mitacek, E J; Brunnemann, K D; Suttajit, M; Martin, N; Limsila, T; Ohshima, H; Caplan, L S

1999-04-01

The recent case-control studies in Thailand indicate that a high incidence of liver cancer in Thailand has not been associated with common risk factors such as hepatitis B infection, aflatoxin intake and alcohol consumption. While the infestation by the liver fluke Opisthorchis viverrini (OV) accounted for the high risk in north-east Thailand, there was no such exposure in the other regions of the country where the incidence of liver cancer is also high. Case-control studies suggest that exposure to exogenous and possibly endogenous nitrosamines in food or tobacco in betel nut and cigarettes may play a role in the development of hepatocellular carcinoma (HCC), while OV infestation and chemical interaction of nitrosamines may also be aetiological factors in the development of cholangiocarcinoma (CCA). Over 1800 samples of fresh and preserved food were systematically collected and tested between 1988 and 1996. All the food items identified by anthropological studies to be consumed frequently in four major regions of Thailand were analysed for volatile nitrosamines using gas chromatography combined with a thermal energy analyser. Relatively high levels of N-nitrosodimethylamine (NDMA), N-nitrosopiperidine (NPIP) and N-nitrosopyrrolidine (NPYR) were detected in fermented fish ("Plasalid"). NDMA was also detected at levels ranging from trace amounts to 66.5 microg/kg in several salted and dried fish ("Larb-pla" and "Pla-siu"). NDMA and NPYR were frequently detected in several vegetables, particularly fermented beans ("Tau-chiau") at levels ranging between 1 and 95.1 microg/kg and 0-146 microg/kg, respectively. The possible role of nitrosamines in Thai food in the aetiology of liver cancer (HCC, CCA) is discussed.

Literature-based compound profiling: application to toxicogenomics.

PubMed

Frijters, Raoul; Verhoeven, Stefan; Alkema, Wynand; van Schaik, René; Polman, Jan

2007-11-01

To reduce continuously increasing costs in drug development, adverse effects of drugs need to be detected as early as possible in the process. In recent years, compound-induced gene expression profiling methodologies have been developed to assess compound toxicity, including Gene Ontology term and pathway over-representation analyses. The objective of this study was to introduce an additional approach, in which literature information is used for compound profiling to evaluate compound toxicity and mode of toxicity. Gene annotations were built by text mining in Medline abstracts for retrieval of co-publications between genes, pathology terms, biological processes and pathways. This literature information was used to generate compound-specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes after compound administration. To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with 11 hepatotoxicants. Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat aspecific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. A more detailed analysis of the keyword profiles of diethylhexylphthalate, dimethylnitrosamine and methapyrilene (MPy) showed that the differences in the keyword fingerprints of these three compounds are based upon known distinct modes of action. Visualization of MPy-linked keywords and MPy-induced genes in a literature network enabled us to construct a mode of toxicity proposal for MPy, which is in agreement with known effects of MPy in literature. Compound keyword fingerprinting based on information retrieved from literature is a powerful approach for compound profiling, allowing evaluation of compound toxicity and analysis of the mode of action.

21 CFR 500.92 - Implementation.

Code of Federal Regulations, 2010 CFR

2010-04-01

... cancer when ingested by man or animals, i.e., suspect carcinogens, §§ 500.80(b), 500.82, and 500.90 apply. (2) For those compounds that FDA determines have been shown to induce cancer when ingested by man or...

21 CFR 500.92 - Implementation.

Code of Federal Regulations, 2011 CFR

2011-04-01

... cancer when ingested by man or animals, i.e., suspect carcinogens, §§ 500.80(b), 500.82, and 500.90 apply. (2) For those compounds that FDA determines have been shown to induce cancer when ingested by man or...

21 CFR 500.92 - Implementation.

Code of Federal Regulations, 2014 CFR

2014-04-01

... cancer when ingested by man or animals, i.e., suspect carcinogens, §§ 500.80(b), 500.82, and 500.90 apply. (2) For those compounds that FDA determines have been shown to induce cancer when ingested by man or...

21 CFR 500.92 - Implementation.

Code of Federal Regulations, 2012 CFR

2012-04-01

... cancer when ingested by man or animals, i.e., suspect carcinogens, §§ 500.80(b), 500.82, and 500.90 apply. (2) For those compounds that FDA determines have been shown to induce cancer when ingested by man or...

21 CFR 500.92 - Implementation.

Code of Federal Regulations, 2013 CFR

2013-04-01

... cancer when ingested by man or animals, i.e., suspect carcinogens, §§ 500.80(b), 500.82, and 500.90 apply. (2) For those compounds that FDA determines have been shown to induce cancer when ingested by man or...

Cancer mortality among workers exposed to zinc chromate paints.

PubMed

Dalager, N A; Mason, T J; Fraumeni, J F; Hoover, R; Payne, W W

1980-01-01

To evaluate the carcinogenicity of chromium compounds among user industries, the proportionate mortality experience of spray painters exposed to zinc chromate primer paints and electroplaters exposed to chromic acid in the aircraft maintenance industry was examined. Compared to the mortality patterns of U.S. white males, no excess of cancer was found in the 48 deaths among electroplaters. Analysis of the 202 deaths among spray painters revealed a significant excess of cancer, primarily of the respiratory tract. The relative increase of respiratory cancer showed a positive gradient with the length of estimated exposure time, and was confined to painters whose interval from first employment to death was at least 20 years. The findings consistent with occupational exposure to chromium compounds, previously shown to be carcinogenic in manufacturing processes, but the effect of other paint constituents, tobacco smoking, or methodologic limitations could not be discounted.

Health Risk Assessment of Inhalation Exposure to Formaldehyde and Benzene in Newly Remodeled Buildings, Beijing

PubMed Central

Huang, Lihui; Mo, Jinhan; Sundell, Jan; Fan, Zhihua; Zhang, Yinping

2013-01-01

Objective To assess health risks associated with inhalation exposure to formaldehyde and benzene mainly emitted from building and decoration materials in newly remodeled indoor spaces in Beijing. Methods We tested the formaldehyde and benzene concentrations in indoor air of 410 dwellings and 451 offices remodeled within the past year, in which the occupants had health concerns about indoor air quality. To assess non-carcinogenic health risks, we compared the data to the health guidelines in China and USA, respectively. To assess carcinogenic health risks, we first modeled indoor personal exposure to formaldehyde and benzene using the concentration data, and then estimated the associated cancer risks by multiplying the indoor personal exposure by the Inhalation Unit Risk values (IURs) provided by the U.S. EPA Integrated Risk Information System (U.S. EPA IRIS) and the California Office of Environmental Health Hazard Assessment (OEHHA), respectively. Results (1) The indoor formaldehyde concentrations of 85% dwellings and 67% offices were above the acute Reference Exposure Level (REL) recommended by the OEHHA and the concentrations of all tested buildings were above the chronic REL recommended by the OEHHA; (2) The indoor benzene concentrations of 12% dwellings and 32% offices exceeded the reference concentration (RfC) recommended by the U.S. EPA IRIS; (3) The median cancer risks from indoor exposure to formaldehyde and benzene were 1,150 and 106 per million (based on U.S. EPA IRIS IURs), 531 and 394 per million (based on OEHHA IURs). Conclusions In the tested buildings, formaldehyde exposure may pose acute and chronic non-carcinogenic health risks to the occupants, whereas benzene exposure may pose chronic non-carcinogenic risks to the occupants. Exposure to both compounds is associated with significant carcinogenic risks. Improvement in ventilation, establishment of volatile organic compounds (VOCs) emission labeling systems for decorating and refurbishing materials are recommended to reduce indoor VOCs exposure. PMID:24244522

High Energy Materials. New Preparation Approaches to Nitro and Nitroso Derivatives.

DTIC Science & Technology

1981-06-01

hexane as the pyridazinofuroxan 2, a yellow solid, 67% mp 118-1190C (dec); satisfactory analysis for C, H and N; ir(KBr): 3460 (m), 3370 (m) and 1600 cm-l...la (tlc) left a clear yellow solution. The re- action mixture was concentrated at a temperature below 45°C until a crystalline solid 2 appeared...Dilution with ice-water brought further separation of the per- oxide 2a as a light yellow solid which was filtered and dried at room temperature, 7.2g(75

Biotransformation of N-Nitrosodimethylamine by Pseudomonas mendocina KR1▿

PubMed Central

Fournier, Diane; Hawari, Jalal; Streger, Sheryl H.; McClay, Kevin; Hatzinger, Paul B.

2006-01-01

N-Nitrosodimethylamine (NDMA) is a potent carcinogen and an emerging contaminant in groundwater and drinking water. The metabolism of NDMA in mammalian cells has been widely studied, but little information is available concerning the microbial transformation of this compound. The objective of this study was to elucidate the pathway(s) of NDMA biotransformation by Pseudomonas mendocina KR1, a strain that possesses toluene-4-monooxygenase (T4MO). P. mendocina KR1 was observed to initially oxidize NDMA to N-nitrodimethylamine (NTDMA), a novel metabolite. The use of 18O2 and H218O revealed that the oxygen added to NDMA to produce NTDMA was derived from atmospheric O2. Experiments performed with a pseudomonad expressing cloned T4MO confirmed that T4MO catalyzes this initial reaction. The NTDMA produced by P. mendocina KR1 did not accumulate, but rather it was metabolized further to produce N-nitromethylamine (88 to 94% recovery) and a trace amount of formaldehyde (HCHO). Small quantities of methanol (CH3OH) were also detected when the strain was incubated with NDMA but not during incubation with either NTDMA or HCHO. The formation of methanol is hypothesized to occur via a second, minor pathway mediated by an initial α-hydroxylation of the nitrosamine. Strain KR1 did not grow on NDMA or mineralize significant quantities of the compound to carbon dioxide, suggesting that the degradation process is cometabolic. PMID:16950909

Use of High Throughput Screening Data in IARC Monograph ...

EPA Pesticide Factsheets

Purpose: Evaluation of carcinogenic mechanisms serves a critical role in IARC monograph evaluations, and can lead to “upgrade” or “downgrade” of the carcinogenicity conclusions based on human and animal evidence alone. Three recent IARC monograph Working Groups (110, 112, and 113) pioneered analysis of high throughput in vitro screening data from the U.S. Environmental Protection Agency’s ToxCast program in evaluations of carcinogenic mechanisms. Methods: For monograph 110, ToxCast assay data across multiple nuclear receptors were used to test the hypothesis that PFOA acts exclusively through the PPAR family of receptors, with activity profiles compared to several prototypical nuclear receptor-activating compounds. For monographs 112 and 113, ToxCast assays were systematically evaluated and used as an additional data stream in the overall evaluation of the mechanistic evidence. Specifically, ToxCast assays were mapped to 10 “key characteristics of carcinogens” recently identified by an IARC expert group, and chemicals’ bioactivity profiles were evaluated both in absolute terms (number of relevant assays positive for bioactivity) and relative terms (ranking with respect to other compounds evaluated by IARC, using the ToxPi methodology). Results: PFOA activates multiple nuclear receptors in addition to the PPAR family in the ToxCast assays. ToxCast assays offered substantial coverage for 5 of the 10 “key characteristics,” with the greates

Selective Antiprotozoal Activity of Nitric Oxide-releasing Chitosan Nanoparticles Against Trypanosoma cruzi: Toxicity and Mechanisms of Action.

PubMed

Contreras Lancheros, Cesar Armando; Pelegrino, Milena Trevisan; Kian, Danielle; Tavares, Eliandro Reis; Hiraiwa, Priscila Mazzochi; Goldenberg, Samuel; Nakamura, Celso Vataru; Yamauchi, Lucy Megumi; Pinge-Filho, Phileno; Seabra, Amedea Barozzi; Yamada-Ogatta, Sueli Fumie

2018-01-01

Chagas' disease, caused by Trypanosoma cruzi, was described for the first time over a hundred years ago. Nonetheless, clinically available drugs still lack effective and selective properties. Nitric oxide (NO) produced by activated macrophages controls the progression of disease by killing the parasite. Here, chitosan nanoparticles (CS NPs) were synthesized and mercaptosuccinic acid (MSA), the NO donor precursor, was encapsulated into CS NPs, forming MSA-CS NPs, which had hydrodynamic size of 101.0±2.535 nm. Encapsulated MSA was nitrosated forming NO donor S-nitrosomercaptosuccinic acid-containing nanoparticles (S-nitroso-MSA-CS NPs). Kinetic data revealed a sustained release of NO from the nanoparticles. S-nitroso-MSA-CS NPs inhibited epimastigote proliferation and trypomastigote viability of T. cruzi, with IC50=75.0±6.5 µg·mL-1 and EC50=25.0±5.0 µg·mL-1, respectively. Treatment of peritoneal macrophages with nanoparticles decreased the number of T. cruzi-infected cells and the average number of intracellular replicative amastigotes per infected cells. Besides, the results have showed a selective behaviour of S-nitroso-MSA-CS NPs to parasites. Morphological and biochemical changes induced by these NO-releasing nanoparticles, such as cell shrinkage, cell cycle arrest, mitochondrial membrane depolarization and phosphatidylserine exposure on cell surface indicate that epimastigotes death is associated to the apoptotic pathway. S-nitroso-MSA-CS NPs are promising nanocarriers for the treatment of Chagas's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Health effects of exposure to diesel exhaust particles.

PubMed

McClellan, R O

1987-01-01

Diesel-powered vehicles emit substantially more particles than do gasoline-powered vehicles with contemporary emission control systems. The DEP are submicron in size and readily inhaled. Approximately one-fourth of the particle mass inhaled by people is deposited in the pulmonary region, some of which is retained with a half-life of several hundred days. In animal studies, exposure to high levels of DEP overwhelms the normal clearance mechanisms and results in lung burdens of DEP that exceed those predicted from observations at lower exposure concentrations. A variable amount of the mass of DEP is extractable with strong organic solvents. The extracted material contains more than a thousand individual compounds and is mutagenic in a number of bacterial and mammalian cell assays. Bioassay-directed chemical analysis of DEP had identified several hundred compounds. Many are PAHs, some of which are considered to have human carcinogenic potential. A number of nitrated compounds have been identified that account for a significant portion of the mutagenicity assayed in bacteria. The mutagenicity of the DEPE is generally reduced by addition of an S-9 cellular fraction or of serum proteins. Macrophages rapidly reduce the recoverable mutagenic activity associated with DEP. These findings support a hypothesis that detoxification of DEP-associated organics occurs rapidly in vivo. The association of benzo(a)pyrene and nitropyrene with DEP prolongs their retention in the lungs. This increased retention suggests the need to clarify the relative importance of competing mechanisms that detoxify particle-associated compounds and those that serve to enhance the retention of toxicologically important compounds. Some extracts of DEP evoke tumorigenic responses in skin-tumor bioassays, suggesting their carcinogenic potential in mammals. A number of large-scale studies have been conducted with laboratory rodents to evaluate the effects of chronic inhalation exposure to DE. An increased incidence of lung tumors, some of which were diagnosed as malignant, was observed in 5 studies with rats following exposure for 2 or more years to high levels of DE. Most of the lung tumors were observed after 2 years. Similar studies in Syrian hamsters have yielded negative results. Studies with mice have given mixed results. The results of some studies with laboratory animals exposed to DE and known carcinogens suggest that exposure to DE enhances the effect of the known carcinogens. The specific mechanisms of tumor induction in the DE-exposed rats are unknown. Hypotheses and experimental data have been advanced in support of both genetic and epigenetic mechanisms of action of the DE.(ABSTRACT TRUNCATED AT 400 WORDS)

On-line coupling of capillary isotachophoresis and zone electrophoresis for the assay of phenolic compounds in plant extracts.

PubMed

Urbánek, Marek; Pospísilová, Marie; Polásek, Miroslav

2002-04-01

The combination of capillary isotachophoresis (ITP) and capillary zone electrophoresis (CZE) in the column coupling configuration was optimized in a mode where the electrolyte for the CZE step is different from the leading and terminating ITP electrolytes. Two colored markers, picric acid and 1-nitroso-2-naphthol, were used for exact timing of the transfer of isotachophoretically stacked analyte zones into the CZE column and for the control of the residual amount of the leading and terminating ITP electrolytes entering the CZE capillary together with the analytes, thus controlling the duration of transient ITP migration in the CZE capillary and ensuring good separation of the analytes and reproducibility of the migration times (relative standard deviations 1%). ITP-CZE was applied to the simultaneous assay of several cinnamic acid derivatives and flavonoids in methanolic extracts of Sambucus flowers and Crataegus leaves and flowers. The preconcentrating and cleansing effect of the ITP step allowed injection of relatively large sample volumes (30 microL). The limits of detection were approximately 20-50 ng x mL(-1) and 100 ng x mL(-1) for the acids and flavonoids, respectively ( thick similar 200-times lower compared to conventional CE) with spectrophotometric detection at 254 nm. The ITP-CZE exhibited satisfactory linearity and precision when using CZE buffer of pseudo "pH" 9.0; 1-nitroso-2-naphthol was employed as the internal standard. The separation took approximately 35 min. The ITP-CZE results for rutin, hyperoside, and vitexin-2-O"-rhamnoside were in good accordance with those obtained previously by high-performance liquid chromatography.

Novel naïve Bayes classification models for predicting the chemical Ames mutagenicity.

PubMed

Zhang, Hui; Kang, Yan-Li; Zhu, Yuan-Yuan; Zhao, Kai-Xia; Liang, Jun-Yu; Ding, Lan; Zhang, Teng-Guo; Zhang, Ji

2017-06-01

Prediction of drug candidates for mutagenicity is a regulatory requirement since mutagenic compounds could pose a toxic risk to humans. The aim of this investigation was to develop a novel prediction model of mutagenicity by using a naïve Bayes classifier. The established model was validated by the internal 5-fold cross validation and external test sets. For comparison, the recursive partitioning classifier prediction model was also established and other various reported prediction models of mutagenicity were collected. Among these methods, the prediction performance of naïve Bayes classifier established here displayed very well and stable, which yielded average overall prediction accuracies for the internal 5-fold cross validation of the training set and external test set I set were 89.1±0.4% and 77.3±1.5%, respectively. The concordance of the external test set II with 446 marketed drugs was 90.9±0.3%. In addition, four simple molecular descriptors (e.g., Apol, No. of H donors, Num-Rings and Wiener) related to mutagenicity and five representative substructures of mutagens (e.g., aromatic nitro, hydroxyl amine, nitroso, aromatic amine and N-methyl-N-methylenemethanaminum) produced by ECFP_14 fingerprints were identified. We hope the established naïve Bayes prediction model can be applied to risk assessment processes; and the obtained important information of mutagenic chemicals can guide the design of chemical libraries for hit and lead optimization. Copyright © 2017 Elsevier B.V. All rights reserved.

The site of antiviral action of 3-nitrosobenzamide on the infectivity process of human immunodeficiency virus in human lymphocytes.

PubMed Central

Rice, W G; Schaeffer, C A; Graham, L; Bu, M; McDougal, J S; Orloff, S L; Villinger, F; Young, M; Oroszlan, S; Fesen, M R

1993-01-01

The C-nitroso compound 3-nitrosobenzamide, which has been shown to remove zinc from the retroviral-type zinc finger of p7NC nucleocapsid proteins, inhibits acute infection of human immunodeficiency virus type 1 in cultured human lymphocytes. The attachment of the virus to lymphocytes and the activities of critical viral enzymes, such as reverse transcriptase, protease, and integrase, are not affected by 3-nitrosobenzamide. However, the process of reverse transcription to form proviral DNA is effectively abolished by the drug, identifying the mode of action of 3-nitrosobenzamide as interrupting the role of p7NC in accurate proviral DNA synthesis during the infectious phase of the virus life cycle. Images Fig. 3 Fig. 4 PMID:7692451

Immunoaffinity purification of dietary heterocyclic amine carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vanderlaan, M.; Hwang, M.; Djanegara, T.

1993-03-01

Cooking meats produces a family of heterocyclic aromatic amines that are carcinogens in rodents and genotoxic in many short-term assays. Concern that these compounds may be human carcinogens has prompted us to develop immunochemical methods for quantifying these compounds in the human diet and for identifying the parent compounds and metabolites in urine and feces. Previously reported monoclonal antibodies to 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 6-phenyl-2-amino-1-methylimidazo[4,5-f]pyridine (PhIP) were used to purify by immunoaffinity these known mutagens and cross-reacting structural analogs from well-done cooked beef and urine samples. Materials recovered from the immunoaffinity columns were subsequently separated by HPLC to purify the knownmore » mutagens from cross-reacting chemicals that co-purify by immunoaffinity. Immunoaffinity chromatography was found to be a rapid means of quantifying individual known mutagens, with a minimum of precolumn sample clean-up required. In addition, this procedure has yielded several new mutagens present in cooked meats that are apparently structural analogs of PhIP. Immunoaffinity techniques were also used to purify metabolites from the urine of rats and humans exposed to MeIQx or PhIP. For MeIQx-exposed rats, the combination antibodies immunoconcentrated 75% of the total urinary radioactivity. Analysis of PhIP metabolites recovered from antibody columns is facilitated by the intrinsic fluorescence of PhIP and its metabolites, providing sufficient sensitivity to monitor individuals for the levels of PhIP excreted following consumption of typical western diets. 6 refs., 3 figs.« less

METABOLISM, GENOTOXICITY, AND CARCINOGENICITY OF COMFREY

PubMed Central

Mei, Nan; Guo, Lei; Fu, Peter P.; Fuscoe, James C.; Luan, Yang; Chen, Tao

2018-01-01

Comfrey has been consumed by humans as a vegetable and a tea and used as an herbal medicine for more than 2000 years. Comfrey, however, produces hepatotoxicity in livestock and humans and carcinogenicity in experimental animals. Comfrey contains as many as 14 pyrrolizidine alkaloids (PA), including 7-acetylintermedine, 7-acetyllycopsamine, echimidine, intermedine, lasiocarpine, lycopsamine, myoscorpine, symlandine, symphytine, and symviridine. The mechanisms underlying comfrey-induced genotoxicity and carcinogenicity are still not fully understood. The available evidence suggests that the active metabolites of PA in comfrey interact with DNA in liver endothelial cells and hepatocytes, resulting in DNA damage, mutation induction, and cancer development. Genotoxicities attributed to comfrey and riddelliine (a representative genotoxic PA and a proven rodent mutagen and carcinogen) are discussed in this review. Both of these compounds induced similar profiles of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and similar mutation spectra. Further, the two agents share common mechanisms of drug metabolism and carcinogenesis. Overall, comfrey is mutagenic in liver, and PA contained in comfrey appear to be responsible for comfrey-induced toxicity and tumor induction. PMID:21170807

Comparisons of carcinogenicities of nickel compounds in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sunderman, F.W. Jr.; Maenza, R.M.

This study demonstrates marked differences in the incidences of sarcomas in Fischer rats within 2 years after a single im injection of 4 insoluble nickel-containing powders amorphous nickel monosulfide (NiS), nickel subsulfide (..cap alpha..Ni/sub 3/S/sub 2/), partially converted nickel-iron sulfide matte, and metallic nickel. The powders (<2 ..mu..m median particle diameters) were administered in penicillin suspension, and each powder was tested at 2 dosages. Whereas ..cap alpha..Ni/sub 3/S/sub 2/ was highly carcinogenic, amorphous NiS did not induce any tumors. The carcinogenic potency of partially converted nickel-iron sulfide matte was less than ..cap alpha..Ni/sub 3/S/sub 2/ but greater than Ni powder.more » No sarcomas occurred at the injection site in two groups of control rats that received im injections of penicillin or Fe powder. The observed differences in carcinogenic potencies of ..cap alpha..Ni/sub 3/S/sub 2/ and amorphous NiS may provide an experimental approach to elucidate the molecular mechanisms of nickel carcinogenesis.« less

Rationale for Selection of Pesticides, Herbicides, and Related Compounds from the Hanford SST/DST Waste Considered for Analysis in Support of the Regulatory DQO (Privatization)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wiemers, K.D.; Daling, P.; Meier, K.

1999-01-04

Regulated pesticides, herbicides, miticides, and fungicides were evaluated for their potential past and current use at the Hanford Site. The starting list of these compounds is based on regulatory analyte input lists discussed in the Regulatory DQO. Twelve pesticide, herbicide, miticide, and fungicide compounds are identified for analysis in the Hanford SST and DST waste in support of the Regulatory DQO. The compounds considered for additional analyses are non-detected, considered stable in the tank waste matrix, and of higher toxicity/carcinogenicity.

Ecological Evaluation of Proposed Discharge of Dredged Material into Ocean Waters.

DTIC Science & Technology

1977-07-01

Methyl mercury Ref. 6 Oil and grease p. 229 - 5 5 Step 7.3 Petroleum hydrocarbons p. 226 Step 6.3 Phenol p. 241 Method SlO Method )I 78 p. 514 p. 4...and its compounds c. Cadmium and its compounds d. Petroleum hydrocarbons e. Known or suspected carcinogens, mutagens, or teratogens. 6 (This is a...its compounds 12 Cadmium and its compounds 12 6 0 Petroleum hydrocarbons : Aliphat ic 13 Aromatic 13 G8 0 0 * 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Table

Volatile Organic Compounds (VOCs)

MedlinePlus

... in the environment and their potential to cause human health effects EPA's Office of Drinking Water Regulations List ... to carbon monoxide. Carefully read the labels containing health hazard information and ... is a known human carcinogen. The main indoor sources of this chemical ...

Mutagenic activation reduces carcinogenic activity of ortho-aminoazotoluene for mouse liver.

PubMed

Ovchinnikova, L P; Bogdanova, L A; Kaledin, V I

2013-03-01

Pentachlorophenol (aromatic amine and azo stain metabolic stimulation inhibitor) reduced the hepatocarcinogenic activity of 4-aminoazobenzene and reduced that of ortho-aminoazotoluene in suckling mice. Both 4-aminoazobenzene and ortho-aminoazotoluene exhibited mutagenic activity in Ames' test in vitro on S. typhimurium TA 98 strain with activation with liver enzymes; this mutagenic activity was similarly suppressed by adding pentachlorophenol into activation medium. Induction of xenobiotic metabolism enzymes, stimulating the mutagenic activity of ortho-aminoazotoluene, suppressed its carcinogenic effect on mouse liver. Hence, ortho-aminotoluene (the initial compound), but not its mutagenic metabolites, was the direct active hepatocarcinogen for mice.

Carcinogenicity of 1-methyl-3(p-chlorophenyl)-1-nitrosourea and its 1-methyl trideuterated derivative in rats.

PubMed

Schreiber, D; Martin, J; Mendel, J

1986-01-01

The carcinogenic activity of 1-methyl-3(p-chlorophenyl)-1-nitrosourea (Cl-MPNU) and its 1-methyl trideuterated analog (Cl-MPNU-d3) was compared by intragastric administration to hooded rats of equimolar doses of both compounds. A 100% frequency of forestomach tumors was observed in both groups. However, the mean latency period of the animals treated with Cl-MPNU-d3 was significantly longer (P less than 0.01). The results suggest the occurrence of a deuterium isotope effect in nitrosoureas but not as distinct as in nitrosamines.

Health risk assessment of phthalate esters (PAEs) in drinking water sources of China.

PubMed

Wang, Wen-Long; Wu, Qian-Yuan; Wang, Chao; He, Tao; Hu, Hong-Ying

2015-03-01

Phthalate esters (PAEs) with endocrine disruption effects and carcinogenicity are widely detected in water environment. Occurrences of PAEs in source water and removal efficiencies of PAEs by drinking water treatment plants (DWTPs) in China were surveyed from publications in the last 10 years. Concentration of diethylhexyl phthalate (DEHP) in source water with median value of 1.3 μg/L was higher than that of dimethyl phthalate (DMP), diethyl phthalate (DEP), and di-n-butyl phthalate (DnBP). If the removal efficiencies of DEHP and DnBP reached 60 and 90 %, respectively, the calculated PAE concentration in drinking water can generally meet Standards for Drinking Water Quality in China. The health risks of PAEs, including non-carcinogenic and carcinogenic risks via the "water source-DWTP-oral ingestion/dermal permeation" pathway, were evaluated with Monte Carlo simulation and sensitivity analysis under certain removal efficiencies from 0 to 95 %. The carcinogenic risk of DEHP was lower than the upper acceptable carcinogenic risk level (10(-4)), while the probability of DEHP's carcinogenic risk between lower (10(-6)) and upper (10(-4)) acceptable carcinogenic risk level decreased from about 21.2 to 0.4 % through increasing DEHP removal efficiency from 0 to 95 %. The non-carcinogenic risk of DEHP was higher than that of DEP and DnBP. In all cases, the total non-carcinogenic risk of DEP, DnBP, and DEHP was lower than 1, indicating that there would be unlikely incremental non-carcinogenic risk to humans. Both carcinogenic risk and non-carcinogenic risk of PAEs in drinking water to female were a little higher than those to male.

CarcinoPred-EL: Novel models for predicting the carcinogenicity of chemicals using molecular fingerprints and ensemble learning methods.

PubMed

Zhang, Li; Ai, Haixin; Chen, Wen; Yin, Zimo; Hu, Huan; Zhu, Junfeng; Zhao, Jian; Zhao, Qi; Liu, Hongsheng

2017-05-18

Carcinogenicity refers to a highly toxic end point of certain chemicals, and has become an important issue in the drug development process. In this study, three novel ensemble classification models, namely Ensemble SVM, Ensemble RF, and Ensemble XGBoost, were developed to predict carcinogenicity of chemicals using seven types of molecular fingerprints and three machine learning methods based on a dataset containing 1003 diverse compounds with rat carcinogenicity. Among these three models, Ensemble XGBoost is found to be the best, giving an average accuracy of 70.1 ± 2.9%, sensitivity of 67.0 ± 5.0%, and specificity of 73.1 ± 4.4% in five-fold cross-validation and an accuracy of 70.0%, sensitivity of 65.2%, and specificity of 76.5% in external validation. In comparison with some recent methods, the ensemble models outperform some machine learning-based approaches and yield equal accuracy and higher specificity but lower sensitivity than rule-based expert systems. It is also found that the ensemble models could be further improved if more data were available. As an application, the ensemble models are employed to discover potential carcinogens in the DrugBank database. The results indicate that the proposed models are helpful in predicting the carcinogenicity of chemicals. A web server called CarcinoPred-EL has been built for these models ( http://ccsipb.lnu.edu.cn/toxicity/CarcinoPred-EL/ ).

MicroRNA Responses to the Genotoxic Carcinogens Aflatoxin B1 and Benzo[a]pyrene in Human HepaRG Cells.

PubMed

Marrone, April K; Tryndyak, Volodymyr; Beland, Frederick A; Pogribny, Igor P

2016-02-01

Recent advances in toxicogenomics present an opportunity to develop new in vitro testing methodologies to identify human carcinogens. We have investigated microRNA expression responses to the treatment of human liver HepaRG cells with the human genotoxic carcinogens aflatoxin B1 (AFB1) and benzo[a]pyrene (B[a]P), and the structurally similar compounds aflatoxin B2 (AFB2) and benzo[e]pyrene (B[e]P) that exhibit minimal carcinogenic potential. We demonstrate that treatment of HepaRG cells with AFB1 or B[a]P resulted in specific changes in the expression of miRNAs as compared with their non-carcinogenic analogues, particularly in a marked over-expression of miR-410. An additional novel finding is the dose- and time-dependent inhibition of miR-122 in AFB1-treated HepaRG cells. Mechanistically, the AFB1-induced down-regulation of miR-122 was attributed to inhibition of the HNF4A/miR-122 regulatory pathway. These results demonstrate that HepaRG cells can be used to investigate miRNA responses to xenobiotic exposure, and illustrate the existence of early non-genotoxic events, in addition to a well-established genotoxic mode of action changes, in the mechanism of AFB1 and B[a]P carcinogenicity. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

Context Matters: Contribution of Specific DNA Adducts to the Genotoxic Properties of the Tobacco-Specific Nitrosamine NNK.

PubMed

Peterson, Lisa A

2017-01-17

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen in laboratory animals. It is classified as a Group 1 human carcinogen by the International Agency for Cancer Research. NNK is bioactivated upon cytochrome P450 catalyzed hydroxylation of the carbon atoms adjacent to the nitrosamino group to both methylating and pyridyloxobutylating agents. Both pathways generate a spectrum of DNA damage that contributes to the overall mutagenic and toxic properties of this compound. NNK is also reduced to form 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is also carcinogenic. Like NNK, NNAL requires metabolic activation to DNA alkylating agents. Methyl hydroxylation of NNAL generates pyridylhydroxybutyl DNA adducts, and methylene hydroxylation leads to DNA methyl adducts. The consequence of this complex metabolism is that NNK generates a vast spectrum of DNA damage, any form of which can contribute to the overall carcinogenic properties of this potent pulmonary carcinogen. This Perspective reviews the chemistry and genotoxic properties of the collection of DNA adducts formed from NNK. In addition, it provides evidence that multiple adducts contribute to the overall carcinogenic properties of this chemical. The adduct that contributes to the genotoxic effects of NNK depends on the context, such as the relative amounts of each DNA alkylating pathway occurring in the model system, the levels and genetic variants of key repair enzymes, and the gene targeted for mutation.

Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats.

PubMed

McCormick, D L; Rao, K V; Dooley, L; Steele, V E; Lubet, R A; Kelloff, G J; Bosland, M C

1998-08-01

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar-Unilever rats.

Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

PubMed

Bercu, J P; Galloway, S M; Parris, P; Teasdale, A; Masuda-Herrera, M; Dobo, K; Heard, P; Kenyon, M; Nicolette, J; Vock, E; Ku, W; Harvey, J; White, A; Glowienke, S; Martin, E A; Custer, L; Jolly, R A; Thybaud, V

2018-04-01

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication. Copyright © 2018. Published by Elsevier Inc.

[Carcinogenic N-nitrosamines in the tire industry].

PubMed

Sokol?kaia, N N; Krivosheeva, L V; Khesing, A Ia; Piven, V A; Kavun, S M

1993-01-01

The level of volatile carcinogenic N-nitrosamines (NA) was studied in the air of various technological sites of tyre production. Reported total levels of NA in air exceeded MACs set in certain countries for the same enterprises. For example, German total MAC for 12 carcinogenic NA is 1 g/m3. N-nitrosomorpholine appeared to have the highest level (91 g/m3), probably, because its derivatives are used as raw material for technological process. Relative rate of volatile NA release from rubber samples containing 4-nitrosodiphenylamine (modifier) was studied. The parameter was reported to have no influence on NA outlet in conditions simulating technological process. NA was detected by means of gas chromatography with thermal energy detector TEA 502A provided by Thermo Electron Corporation, USA. The article necessitates regulation of NA in tyre production and better rubber mixtures to control the pollution of atmosphere.

Cancer risks in naval divers with multiple exposures to carcinogens.

PubMed Central

Richter, Elihu D; Friedman, Lee S; Tamir, Yuval; Berman, Tamar; Levy, Or; Westin, Jerome B; Peretz, Tamar

2003-01-01

We investigated risks for cancer and the case for a cause-effect relationship in five successive cohorts of naval commando divers (n = 682) with prolonged underwater exposures (skin, gastrointestinal tract, and airways) to many toxic compounds in the Kishon River, Israel's most polluted waterway, from 1948 to 1995. Releases of industrial, ship, and agricultural effluents in the river increased substantially, fish yields decreased, and toxic damage to marine organisms increased. Among the divers (16,343 person-years follow-up from 18 years of age to year 2000), the observed/expected ratio for all tumors was 2.29 (p<0.01). Risks increased in cohorts first diving after 1960 compared to risks in earlier cohorts, notably for hematolymphopoietic, central nervous system, gastrointestinal, and skin cancer; induction periods were often brief. The findings suggest that the increases in risk for cancer and short induction periods resulted from direct contact with and absorption of multiple toxic compounds. Early toxic effects in marine life predicted later risks for cancer in divers. PMID:12676624

Quantitative Proteomics Analysis of VEGF-Responsive Endothelial Protein S-Nitrosylation Using Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and LC-MS/MS1

PubMed Central

Zhang, Hong-Hai; Lechuga, Thomas J.; Chen, Yuezhou; Yang, Yingying; Huang, Lan; Chen, Dong-Bao

2016-01-01

Adduction of a nitric oxide moiety (NO•) to cysteine(s), termed S-nitrosylation (SNO), is a novel mechanism for NO to regulate protein function directly. However, the endothelial SNO-protein network that is affected by endogenous and exogenous NO is obscure. This study was designed to develop a quantitative proteomics approach using stable isotope labeling by amino acids in cell culture for comparing vascular endothelial growth factor (VEGFA)- and NO donor-responsive endothelial nitroso-proteomes. Primary placental endothelial cells were labeled with “light” (L-12C614N4-Arg and L-12C614N2-Lys) or “heavy” (L-13C615N4-Arg and L-13C615N2-Lys) amino acids. The light cells were treated with an NO donor nitrosoglutathione (GSNO, 1 mM) or VEGFA (10 ng/ml) for 30 min, while the heavy cells received vehicle as control. Equal amounts of cellular proteins from the light (GSNO or VEGFA treated) and heavy cells were mixed for labeling SNO-proteins by the biotin switch technique and then trypsin digested. Biotinylated SNO-peptides were purified for identifying SNO-proteins by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Ratios of light to heavy SNO-peptides were calculated for determining the changes of the VEGFA- and GSNO-responsive endothelial nitroso-proteomes. A total of 387 light/heavy pairs of SNO-peptides were identified, corresponding to 213 SNO-proteins that include 125 common and 27 VEGFA- and 61 GSNO-responsive SNO-proteins. The specific SNO-cysteine(s) in each SNO-protein were simultaneously identified. Pathway analysis revealed that SNO-proteins are involved in various endothelial functions, including proliferation, motility, metabolism, and protein synthesis. We collectively conclude that endogenous NO on VEGFA stimulation and exogenous NO from GSNO affect common and different SNO-protein networks, implicating SNO as a critical mechanism for VEGFA stimulation of angiogenesis. PMID:27075618

Survey on the micro-pollutants presence in surface water system of northern Serbia and environmental and health risk assessment.

PubMed

Škrbić, Biljana D; Kadokami, Kiwao; Antić, Igor

2018-06-07

This study demonstrates the occurrence of 940 organic micro-pollutants in surface water of four rivers, one irrigation canal system, and two lakes in Vojvodina Province, the northern part of Serbia, summing in total eighteen samples. The number of detected chemicals ranged from 22 to 84, with 127 micro-pollutants detected at least once, representing 13% of the studied substances. The targeted compounds include n-alkanes, sterols, polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides polychlorinated biphenyls, pesticides, pharmaceutical active compounds, industrial chemicals, plasticizers, etc. Among the analysed compounds, sterols were the most dominant with maximum quantified concentrations. The substances which were quantified with frequency over 50% were two PAHs (2-methylnaphthalene, benzo(ghi)perylene), five sterols (cholesterol, cholestanol, stigmasterol, fucosterol, beta-sitosterol), three pharmaceuticals and personal care products (L-menthol, diethyltoluamide, caffeine), and ten household chemicals (4-tert-octylphenol, dimethyl phthalate, methyl palmitate, phenylethyl alcohol, 1-nonanol, alpha-terpineol, 2-phenoxy-ethanol, methyl myristate, acetophenone, and 2-ethyl-1-hexanol). The list of priority substances under the European Union Directive 2013/39/EU includes 49 priority substances (PSs) out of which 34 were analysed. Among these, eleven PSs were quantified, and only two compounds (fluoranthene and benzo (a) pyrene) exceeded EU Environmental Quality Standards targeted values. The obtained results were compared with the previously published data that dealt with the same targeted number of micro-pollutants in sediment samples. This revealed connections between the same sampling locations. Environmental risk assessment showed the existence of potential ecological risk as 72% of the obtained values for the ecological hazard index (HI) at investigated locations were higher that the targeted value (HI > 1). Estimated values for hazard quotient (HQ) and hazard index (HI) for non-carcinogenic risk were lower than the targeted value, indicating no non-carcinogenic risk through dermal contact and non-intentional ingestion of water. Estimated values for cancer risk were all below 1 × 10 -6 , which is not considered to pose significant human health risk. Copyright © 2018. Published by Elsevier Inc.