WorldWideScience

Sample records for carcinogens

  1. Acrylamide carcinogenicity.

    Science.gov (United States)

    Klaunig, James E

    2008-08-13

    The induction of cancer by chemicals is a multiple-stage process. Acrylamide is carcinogenic to experimental mice and rats, causing tumors at multiple organ sites in both species when given in drinking water or by other means. In mice, acrylamide increased the incidence and multiplicity of lung tumors and skin tumors. In two bioassays in rats, acrylamide administered in drinking water consistently induced mesotheliomas of the testes, thyroid tumors, and mammary gland tumors. In addition, brain tumors appeared to be increased. In one of the rat bioassays, pituitary tumors, pheochromocytomas, uterine tumors, and pituitary tumors were noted. The conversion of acrylamide metabolically to the reactive, mutagenic, and genotoxic product, glycidamide, can occur in both rodent and humans. Glycidamide and frequently acrylamide have been positive for mutagenicity and DNA reactivity in a number of in vitro and in vivo assays. The effects of chronic exposure of glycidamide to rodents have not been reported. Epidemiologic studies of workers for possible health effects from exposures to acrylamide have not shown a consistent increase in cancer risk. Although an increase in the risk for pancreatic cancer (almost double) was seen in highly exposed workers, no exposure response relationship could be determined. The mode of action remains unclear for acrylamide-induced rodent carcinogenicity, but support for a genotoxic mechanism based on in vitro and in vivo DNA reactivity assays cannot be ruled out. In addition, the pattern of tumor formation in the rat following chronic exposure supports a genotoxic mode of action but also suggests a potential role of endocrine modification. PMID:18624430

  2. Rodent Carcinogenicity Dataset

    OpenAIRE

    Fjodorova, Natalja; Novič, Marjana

    2013-01-01

    The rodent carcinogenicity dataset was compiled from the Carcinogenic Potency Database (CPDBAS) and was applied for the classification of quantitative structure-activity relationship (QSAR) models for the prediction of carcinogenicity based on the counter-propagation artificial neural network (CP ANN) algorithm. The models were developed within EU-funded project CAESAR for regulatory use. The dataset contains the following information: common information about chemicals (ID, chemical name, an...

  3. Beryllium: genotoxicity and carcinogenicity

    International Nuclear Information System (INIS)

    Beryllium (Be) has physical-chemical properties, including low density and high tensile strength, which make it useful in the manufacture of products ranging from space shuttles to golf clubs. Despite its utility, a number of standard setting agencies have determined that beryllium is a carcinogen. Only a limited number of studies, however, have addressed the underlying mechanisms of the carcinogenicity and mutagenicity of beryllium. Importantly, mutation and chromosomal aberration assays have yielded somewhat contradictory results for beryllium compounds and whereas bacterial tests were largely negative, mammalian test systems showed evidence of beryllium-induced mutations, chromosomal aberrations, and cell transformation. Although inter-laboratory differences may play a role in the variability observed in genotoxicity assays, it is more likely that the different chemical forms of beryllium have a significant effect on mutagenicity and carcinogenicity. Because workers are predominantly exposed to airborne particles which are generated during the machining of beryllium metal, ceramics, or alloys, testing of the mechanisms of the mutagenic and carcinogenic activity of beryllium should be performed with relevant chemical forms of beryllium

  4. Carcinogenic risks of radiations

    International Nuclear Information System (INIS)

    Ionising radiations are known since the end of the 19th century. Early, after being discovered, they were applied in Medicine and the association with an increased number of different malignant tumors was proved. This paper presents a literature review concerning epidemiological proof of radiation induced cancer, molecular mechanisms and factors that increase or decrease the carcinogenic action of ionizing radiations

  5. Chemistry of carcinogenic metals.

    OpenAIRE

    Martell, A E

    1981-01-01

    The periodic distribution of known and suspected carcinogenic metal ions is described, and the chemical behavior of various types of metal ions is explained in terms of the general theory of hard and soft acids and bases. The chelate effect is elucidated, and the relatively high stability of metal chelates in very dilute solutions is discussed. The concepts employed for the chelate effect are extended to explain the high stabilities of macrocyclic and cryptate complexes. Procedures for the us...

  6. The carcinogenicity of chromium

    OpenAIRE

    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. Pres...

  7. Carcinogen risk assessment

    International Nuclear Information System (INIS)

    This article describes the methods by which risk factors for carcinogenic hazards are determined and the limitations inherent in the process. From statistical and epidemiological studies, the major identifiable factors related to cancer in the United States were determined to be cigarette smoking, diet, reproductive and sexual behavior, infections, ultraviolet and ionizing radiation, and alcohol consumption. The incidence of lung cancer due to air pollutants was estimated to be less than 2%. Research needs were discussed

  8. Food derived carcinogenic amnoimidazoazaarenes

    DEFF Research Database (Denmark)

    Frandsen, Henrik

    Carcinogenic aminoimidazoazaarenes are formed during cooking of meat and fish. Important factors for the formation of these compounds are meat type, cooking temperature and time. The compounds are genotoxic in bacterial and mammalian cells. In animal feeding studies the compounds tested so far were...... adducts with DNA. Adducts with 2-deoxyguanosine have been characterized for a number of aminoimidazoazaarenes. Adducts with DNA have also been found in animals after exposure to these compounds. In \\:iw major metabolic detoxification pathways are ring hydroxylation followed by conjugation and conjugation...... of the exocyclic amino group. Estimations of human cancer risk have indicated that ingestion of food containing aminoimidazoazaarenes are of importance....

  9. Arsenic Is A Genotoxic Carcinogen

    Science.gov (United States)

    Arsenic is a recognized human carcinogen; however, there is controversy over whether or not it should be considered a genotoxic carcinogen. Many possible modes of action have been proposed on how arsenic induces cancer, including inhibiting DNA repair, altering methylation patter...

  10. Oxidative Stress in the Carcinogenicity of Chemical Carcinogens

    Directory of Open Access Journals (Sweden)

    Hideki Wanibuchi

    2013-10-01

    Full Text Available This review highlights several in vivo studies utilizing non-genotoxic and genotoxic chemical carcinogens, and the mechanisms of their high and low dose carcinogenicities with respect to formation of oxidative stress. Here, we survey the examples and discuss possible mechanisms of hormetic effects with cytochrome P450 inducers, such as phenobarbital, a-benzene hexachloride and 1,1-bis(p-chlorophenyl-2,2,2-trichloroethane. Epigenetic processes differentially can be affected by agents that impinge on oxidative DNA damage, repair, apoptosis, cell proliferation, intracellular communication and cell signaling. Non-genotoxic carcinogens may target nuclear receptors and induce post-translational modifications at the protein level, thereby impacting on the stability or activity of key regulatory proteins, including oncoproteins and tumor suppressor proteins. We further discuss role of oxidative stress focusing on the low dose carcinogenicities of several genotoxic carcinogens such as a hepatocarcinogen contained in seared fish and meat, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, arsenic and its metabolites, and the kidney carcinogen potassium bromate.

  11. Oxidative Stress in the Carcinogenicity of Chemical Carcinogens

    Energy Technology Data Exchange (ETDEWEB)

    Kakehashi, Anna; Wei, Min [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-Ku, Osaka 545-8585 (Japan); Fukushima, Shoji [Japan Bioassay Research Center, Japan Industrial Safety and Health Association, 2445 Hirasawa, Hadano, Kanagawa 257-0015 (Japan); Wanibuchi, Hideki, E-mail: wani@med.osaka-cu.ac.jp [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-Ku, Osaka 545-8585 (Japan)

    2013-10-28

    This review highlights several in vivo studies utilizing non-genotoxic and genotoxic chemical carcinogens, and the mechanisms of their high and low dose carcinogenicities with respect to formation of oxidative stress. Here, we survey the examples and discuss possible mechanisms of hormetic effects with cytochrome P{sub 450} inducers, such as phenobarbital, α-benzene hexachloride and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane. Epigenetic processes differentially can be affected by agents that impinge on oxidative DNA damage, repair, apoptosis, cell proliferation, intracellular communication and cell signaling. Non-genotoxic carcinogens may target nuclear receptors and induce post-translational modifications at the protein level, thereby impacting on the stability or activity of key regulatory proteins, including oncoproteins and tumor suppressor proteins. We further discuss role of oxidative stress focusing on the low dose carcinogenicities of several genotoxic carcinogens such as a hepatocarcinogen contained in seared fish and meat, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, arsenic and its metabolites, and the kidney carcinogen potassium bromate.

  12. Oxidative Stress in the Carcinogenicity of Chemical Carcinogens

    International Nuclear Information System (INIS)

    This review highlights several in vivo studies utilizing non-genotoxic and genotoxic chemical carcinogens, and the mechanisms of their high and low dose carcinogenicities with respect to formation of oxidative stress. Here, we survey the examples and discuss possible mechanisms of hormetic effects with cytochrome P450 inducers, such as phenobarbital, α-benzene hexachloride and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane. Epigenetic processes differentially can be affected by agents that impinge on oxidative DNA damage, repair, apoptosis, cell proliferation, intracellular communication and cell signaling. Non-genotoxic carcinogens may target nuclear receptors and induce post-translational modifications at the protein level, thereby impacting on the stability or activity of key regulatory proteins, including oncoproteins and tumor suppressor proteins. We further discuss role of oxidative stress focusing on the low dose carcinogenicities of several genotoxic carcinogens such as a hepatocarcinogen contained in seared fish and meat, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, arsenic and its metabolites, and the kidney carcinogen potassium bromate

  13. EVALUATION OF THE POTENTIAL CARCINOGENICITY OF CYCLOPHOSPHAMIDE

    Science.gov (United States)

    Cyclophosphamide is a probable human carcinogen, classified as weight-of-evidence Group B1 under the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a).Evidence on potential carcinogenicity from animal studies is "Sufficient," and the evidence from human studies is "...

  14. Biomonitoring of exposure to chemical carcinogens

    Czech Academy of Sciences Publication Activity Database

    Šrám, Radim

    Poland : Institute of Nuclear Physics, 2002. s. -. [NATO advanced research workshop (Human monitoring for genetic effects). 23.06.2002-27.06.2002, Krakow - Poland] Institutional research plan: CEZ:AV0Z5039906 Keywords : carcinogens Subject RIV: FH - Neurology

  15. Mutagenic and carcinogenic properties of drinking water

    International Nuclear Information System (INIS)

    In this chapter results of oxidation treatments with chlorine, ozone, chlorine dioxide, and ultraviolet (UV), with respect to their effects on activity (Ames test) in drinking water supplies are reviewed. In addition, the authors present the preliminary results of a pilot plant study on the effects of chlorine and chlorine dioxide on mutagenicity. Furthermore, results of several carcinogenicity studies performed with organic drinking water concentrates are discussed in relation to the results of a Dutch carcinogenicity study with mutagenic drinking water concentrates

  16. The multitude and diversity of environmental carcinogens

    International Nuclear Information System (INIS)

    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

  17. The ISS Carcinogens Data Bank (BDC)

    International Nuclear Information System (INIS)

    The Data Bank on Carcinogens (Banca Dati Cancerogeni, BDC) is a factual data bank, available on the Istituto Superiore di Sanita web site, aimed at supporting the risk management decision making of central and local administrators. It can also represent a valuable tool for industry. The available information on carcinogenicity evaluations/classifications produced by European Union and by other institutions (IARC, USEPA, NTP, CCTN) is presented in a concise form accompanied by bibliographic references enabling the users to consult the original sources and, in some cases, to be directly connected to the relevant web site. The classifications carried out by each organization in accordance with its own criteria assign the examined agents to specific qualitative categories and do not include quantitative assessment. BDC intends to provide an easy tool for experts, researchers and risk managers dealing with carcinogenic agents

  18. Carcinogenic potential of various energy sources

    International Nuclear Information System (INIS)

    Evaluation of the health impacts of different sources of energy should include a comparison of the potential carcinogenic effects of the radioactive and chemical substances produced by various sources. In general, these potential health effects are too small to be measured directly and are therefore estimated by extrapolation, on the basis of a linear dose-response model, from measurable effects at high dose levels. Estimates of the carcinogenic potential of various energy sources available in North America are given in this paper. For most if not all of the energy sources for which data are currently available, it would appear that the known biological benefits in terms of life expectancy greatly outweigh all the potential harm due to carcinogenic (and genetic) effects on human beings, when expressed in the same terms, i.e. life expectancy. (author)

  19. Mechanisms of cellular transformation by carcinogenic agents

    International Nuclear Information System (INIS)

    This book contains 14 chapters. Some of the chapter titles are: DNA Modification by Chemical Carcinogens; Role of DNA Lesions and Repair in the Transformation of Human Cells; The Induction and Regulation of Radiogenic Transformation In Vitro: Cellular and Molecular Mechanisms; Cellular Transformation by Adenoviruses; and The fos Gene

  20. Biomonitoring human exposure to environmental carcinogenic chemicals

    DEFF Research Database (Denmark)

    Farmer, P.B.; Sepai, O.; Lawrence, R.;

    1996-01-01

    detecting carcinogen-induced damage to DNA and proteins, and subsequent biological effects. These methods were validated with the occupational exposures, which showed evidence of DNA and/or protein and/or chromosome damage in workers in a coke oven plant, garage workers exposed to diesel exhaust and workers...

  1. Mechanisms of cellular transformation by carcinogenic agents

    Energy Technology Data Exchange (ETDEWEB)

    Grunberger, D.; Goff, S.P.

    1987-01-01

    This book contains 14 chapters. Some of the chapter titles are: DNA Modification by Chemical Carcinogens; Role of DNA Lesions and Repair in the Transformation of Human Cells; The Induction and Regulation of Radiogenic Transformation In Vitro: Cellular and Molecular Mechanisms; Cellular Transformation by Adenoviruses; and The fos Gene.

  2. Carcinogenic effects of radiation-introduction

    International Nuclear Information System (INIS)

    The weight of experimental evidence reviewed indicates that UV damage to DNA, probably pyrimidine dimers, is the best molecular candidate for the initiating damage that leads to skin cancer. It is postulated that the carcinogenic action spectrum should be similar to the DNA action spectrum filtered through the upper layer of skin

  3. Carcinogens formed when Meat is Cooked

    Energy Technology Data Exchange (ETDEWEB)

    Felton, J S; Salmon, C P; Knize, M G

    2003-05-30

    Diet has been associated with varying cancer rates in human populations for many years, yet the causes of the observed variation in cancer patterns have not been adequately explained (Wynder et al. 1977). Along with the effect of diet on human cancer incidence is the strong evidence that mutations are the initiating events in the cancer process (Vogelstein et al. 1992). Foods, when heated, are a good source of genotoxic carcinogens that very likely are a cause for some of these events(Doll et al. 1981). These carcinogens fall into two chemical classes: heterocyclic aromatic amines (HAA) and polycyclic aromatic hydrocarbons (PAH). There is ample evidence that many of these compounds are complete carcinogens in rodents(El-Bayoumy et al. 1995; Ohgaki et al. 1991). Heterocyclic aromatic amines are among the most potent mutagenic substances ever tested in the Ames/Salmonella mutagenicity test (Wakabayashi et al. 1992). Both classes of carcinogen cause tumors in rodents at multiple sites, (El-Bayoumy et al. 1995; Ohgaki et al. 1991) many of which are common tumor sites in people on a Western diet. An HAA, PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), and a PAH, B[a]P (benzo[a]pyrene), of comparable carcinogenic potency caused mammary gland tumors in a feeding study in female rats (El-Bayoumy et al. 1995). In addition, PhIP has recently been shown to cause carcinomas in the prostate of the male rat (Shirai et al. 1997). Complementing the rodent cancer studies are numerous human case-control and prospective studies suggesting a relationship between overheated beef, chicken, and lamb, and cancer of the colon, breast, prostate, and stomach (Sinha et al. 1999; Ward et al. 1997; Zheng et al. 1998).

  4. Predictions for the outcome of rodent carcinogenicity bioassays: identification of trans-species carcinogens and noncarcinogens.

    OpenAIRE

    Tennant, R W; Spalding, J.

    1996-01-01

    Thirty chemicals or substances currently undergoing long-term carcinogenicity bioassays in rodents have been used in a project to further evaluate methods and information that may have the capability of predicting potential carcinogens. In our predictions the principal information used includes structural alerts and in vitro test results for Salmonella mutagenicity, relative subchronic toxicity, and the sites and types of pathology found in subchronic (90-day) studies. This group of chemicals...

  5. Multicomponent criteria for predicting carcinogenicity: dataset of 30 NTP chemicals.

    OpenAIRE

    Huff, J; Weisburger, E; Fung, V A

    1996-01-01

    This article is in response to the challenge issued to the scientific community by the National Toxicology Program to predict the carcinogenicity potential of 30 chemicals previously selected for long-term carcinogenicity testing. Utilizing the available toxicologic, genetic, and structural information on 30 chemicals previously selected for long-term carcinogenicity testing, we predict that 16 chemicals (53%) would induce some indication of carcinogenic activity in rodents; we further predic...

  6. EVALUATION OF THE POTENTIAL CARCINOGENICITY OF COKE OVEN EMISSIONS

    Science.gov (United States)

    Coke oven emissions are known human carcinogens, classified as weight-of-evidence Group A under the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a). vidence on potential carcinogenicity from animal studies is "Sufficient,". and the evidence rom human studies is "S...

  7. EVALUATION OF THE POTENTIAL CARCINOGENICITY OF TRYPAN BLUE

    Science.gov (United States)

    Trypan blue is a probable human carcinogen, classified as weight-of-evidence Group B2 under the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a). vidence on potential carcinogenicity from animal studies is "Sufficient," and the evidence from human studies is "No Da...

  8. Current and emerging challenges in toxicopathology: Carcinogenic threshold of phenobarbital and proof of arsenic carcinogenicity using rat medium-term bioassays for carcinogens

    International Nuclear Information System (INIS)

    For the last 25 years, Prof. Nobuyuki Ito and his laboratory have focused on the development of liver medium-term bioassay system for detection of carcinogens in F344 rats utilizing glutathione S-transferase placental form (GST-P)-positive foci as an end point marker. In this presentation, the outline and samples of medium-term bioassay systems were described. Furthermore, our data demonstrated the presence of a threshold for the non-genotoxic carcinogen, phenobarbital (PB), and the lack of linearity in the low-dose area of the dose-response curve, providing evidence for hormesis. In addition, the establishment and applications of multiorgan carcinogenicity bioassay (DMBDD model), used for the examination of the carcinogenicity of genotoxic and non-genotoxic chemicals, are discussed. Dimethylarsinic acid, one of organic arsenics, was found to be carcinogenic in rat bladder using DMBDD model and carcinogenicity test

  9. The multitude and diversity of environmental carcinogens.

    OpenAIRE

    Belpomme, Dominique; Irigaray, Philippe; Hardell, Lennart; Clapp, Richard; Montagnier, Luc; Epstein, Slava; Sasco, Annie

    2007-01-01

    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 Inter...

  10. RADON AND CARCINOGENIC RISK IN MOSCOW

    Directory of Open Access Journals (Sweden)

    S. M. Golovanev

    2015-01-01

    Full Text Available Objective: comparative evaluation of carcinogenic risk inMoscowfrom radon in indoor and atmospheric pollutants.Materials and methods: the lung cancer incidence in Moscow; radiation-hygienic passport of the territory; .U.S. EPA estimated average age at all and radon induced deaths, years of life lost; Report of UNSCEAR 2006 and WHO handbook on indoor radon, 2009. Trend analysis of incidence; evaluation of the excess relative risk; assessment of ratio radon-induced population risk and published values оf total population carcinogenic risk from chemical carcinogens.Results: it is shown that the 304 cases of lung cancer per year (1. 85 10-3 on average from 2006 to 2011 (21280diseases for 70 years in addition to background level induced by radon; the differences in average trends of all lungcancer incidence in the districts can exceed 25%.Conclusion. The potential of risk reduction by measures of mitigation radon concentration exceeds 5 times the cost efficiency to reduce emissions from vehicles and can reduce cancer incidence, on average 236 cases per year; population risk 16520 cases over 70 years or save not less than 2832 person-years of life per year. The annual effect of reducing losses from not-survival of 12 years as a result of radon-induced lung cancer deaths exceeds 14160000 dollars. The evaluating of the carcinogenic risk from radon in accordance with the definition of population risk increases the predictive evaluation of the effectiveness of preventive measures more than twice.

  11. Carcinogenic risk of hot-particle exposures

    International Nuclear Information System (INIS)

    It has been suggested that spatially non-uniform radiation exposures, such as those from small radioactive particles ('hot particles'), may be very much more carcinogenic than when the same amount of energy is deposited uniformly throughout a tissue volume. This review provides a brief summary of in vivo and in vitro experimental findings, and human epidemiology data, which can be used to evaluate the veracity of this suggestion. Overall, this supports the contrary view and indicates that average dose, as advocated by the ICRP, is likely to provide a reasonable estimate of carcinogenic risk (within a factor of ∼ ±3). There are few human data with which to address this issue. The limited data on lung cancer mortality following occupational inhalation of plutonium aerosols, and the incidence of liver cancer and leukaemia due to thorotrast administration for clinical diagnosis, do not appear to support a significant enhancement factor. Very few animal studies, including mainly lung and skin exposures, provide any indication of a hot-particle enhancement for carcinogenicity. Some recent in vitro malignant transformation experiments provide evidence for an enhanced cell transformation for hot-particle exposures but, properly interpreted, the effect is modest. Few studies extend below absorbed doses of ∼ 0.1 Gy. (review)

  12. Metabolism, genotoxicity, and carcinogenicity of comfrey.

    Science.gov (United States)

    Mei, Nan; Guo, Lei; Fu, Peter P; Fuscoe, James C; Luan, Yang; Chen, Tao

    2010-10-01

    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

  13. Impact and compliance: OSHA Carcinogen Policy

    Energy Technology Data Exchange (ETDEWEB)

    Meyer, A.F. Jr.; Crowder, C.; Wisniewski, S.; Russell, T.; Senn, K.

    1980-06-26

    This document provides an examination of various aspects of the Occupational Safety and Health Administration (OSHA)Carcinogen Policy. To satisfy the dimensions of the Policy's broad, general nature, a two-fold approach was taken. Throughout, the focus is on the possible effects of the Policy's implementation, but this is first approached as it generally will effect research and compliance activities across broad industry sectors, while specific impacts on DOE are addressed separately. To overview and integrate these approaches, and to provide a quick reference for further information, an outline of information is presented. General or industry-wide applications are addressed both in the Summary and Overview of the Policy (Chapters I and II) and in the discussion of the Model Standard (Chapter V). Also included is a copy of the Policy itself in the General Industry Standards and interpretations Change 10. Sections specifically addressed to the major concerns of DOE and its contractors are a discussion of implications for action regarding the synthetic fuels program, a comparison of the OSHA Model Regulations and the FE OSH Manual Standards for Carcinogens, and finally, a list of known carcinogens in coal gasification/liquefaction. Together, these elements illustrate the broad scope of the policy's impact, which economic and other constraining consequences begin to become visible. Measures to minimize these consequences are a common underlying theme to each of the sections.

  14. Carcinogenic potential of hydrotreated petroleum aromatic extracts.

    Science.gov (United States)

    Doak, S M; Hend, R W; van der Wiel, A; Hunt, P F

    1985-06-01

    Five experimental petroleum extracts were produced from luboil distillates derived from Middle East paraffinic crude by solvent extraction and severe hydrotreatment. The polycyclic aromatic content (PCA) of the extracts was determined by dimethyl sulphoxide extraction and ranged from 3.7-9.2% w/w. The five extracts were evaluated for their potential to induce cutaneous and systemic neoplasia in female mice derived from Carworth Farm No 1 strain (CF1). The test substances were applied undiluted (0.2 ml per application) to the shorn dorsal skin twice weekly for up to 78 weeks, with 48 mice in each treatment group and 96 in the untreated control group; two further groups, each of 48 mice, were similarly treated either with a non-hydrotreated commercial aromatic extract (PCA content, 19.7% w/v) or with a low dose of benzo(a)pyrene (12.5 micrograms/ml acetone). The mice were housed individually in polypropylene cages in specified pathogen free conditions. The incidence of cutaneous and systemic tumours was determined from histological analysis of haematoxylin and eosin stained tissue sections. The results were correlated with the PCA content of the extracts and compared with those from female mice exposed to a non-hydrotreated commercial aromatic extract. Four of the hydrotreated extracts were carcinogenic for murine skin; the two products with the lower PCA contents were less carcinogenic than the products with the higher PCA contents and all were less carcinogenic than the commercial extract. One extract with the lowest PCA content was non-carcinogenic. Thus refining by severe hydrotreatment was an effective method of reducing the carcinogenic potential of petroleum aromatic extracts. Although other physicochemical properties may influence the biological activity of oil products, the PCA content determined by dimethyl sulphoxide extraction may be a useful indicator of the potential of oil products to induce cutaneous tumours in experimental animals. There was no

  15. Carcinogen-induced damage to DNA

    International Nuclear Information System (INIS)

    Human cells respond to carcinogen-induced damage in their DNA in at least two ways. The first response, excision repair, proceeds by at least three variations, depending on the nature of the damage. Nucleotide excision results in relatively large repair patches but few free DNA breaks, since the endonuclease step is limiting. Apurinic repair is characterized by the appearance of numerous breaks in the DNA and by short repair patches. The pathways behave as though they function independently. Lymphoic cells derived from a xeroderma pigmentosum complementation group C patient are deficient in their ability to perform nucleotide excision and also to excise 6 methoxyguanine adducts, but they are apurinic repair competent. Organisms may bypass damage in their DNA. Lymphoblastoid cells, including those derived from xeroderma pigmentosum treated with 3H-anti-BPDE, can replicate their DNA at low doses of carcinogen. Unexcised 3H is found in the light or parental strand of the resulting hybrid DNA when replication occurs in medium with BrdUrd. This observation indicates a bypass reaction occurring by a mechanism involving branch migration at DNA growing points. Branch migration in DNA preparations have been observed, but the evidence is that most occurs in BrdUrd-containing DNA during cell lysis. The measurement of the bifilarly substituted DNA resulting from branch migration is a convenient method of estimating the proportion of new synthesis remaining in the vicinity of the DNA growing point. Treatment with carcinogens or caffeine results in accumulation of DNA growing points accompanied by the synthesis of shortened pieces of daughter DNA

  16. RADON AND CARCINOGENIC RISK IN MOSCOW

    OpenAIRE

    S. M. Golovanev

    2015-01-01

    Objective: comparative evaluation of carcinogenic risk inMoscowfrom radon in indoor and atmospheric pollutants.Materials and methods: the lung cancer incidence in Moscow; radiation-hygienic passport of the territory; .U.S. EPA estimated average age at all and radon induced deaths, years of life lost; Report of UNSCEAR 2006 and WHO handbook on indoor radon, 2009. Trend analysis of incidence; evaluation of the excess relative risk; assessment of ratio radon-induced population risk and published...

  17. Indoor air-assessment: Indoor concentrations of environmental carcinogens

    International Nuclear Information System (INIS)

    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, 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

  18. Trace elements and carcinogenicity: a subject in review

    OpenAIRE

    Mulware, Stephen Juma

    2012-01-01

    Cancer is known to be a multi-step process, which involves different stages including initiation, promotion, progression and metastasis. Chemical carcinogens including most trace elements can change any of these processes to induce their carcinogenic effects. Various studies confirm that cancer arises from the accumulation of irreversible DNA damage, which results from multiple mutations in critical genes in the body organ. Chemical carcinogens most often directly or after xenobiotic metaboli...

  19. A review of mechanisms of acrylamide carcinogenicity.

    Science.gov (United States)

    Besaratinia, Ahmad; Pfeifer, Gerd P

    2007-03-01

    The fact that acrylamide, a proven rodent carcinogen, is present in significant quantities (up to several mg/kg of foodstuff) in a wide range of commonly consumed human foods is alarming. Attempts to determine a possible involvement of dietary acrylamide in human cancers have not been conclusive, however. To resolve the carcinogenicity of acrylamide to humans, the as yet unknown mechanism of action of acrylamide needs to be unraveled. The present review is a synopsis of research on the known and hypothetical modes of action of acrylamide of relevance for carcinogenesis. Both genotoxic and non-genotoxic modes of action of acrylamide are discussed with special emphasis on DNA adduct-targeted mutagenesis. Mechanistic data are presented from various experimental systems including in vitro experiments and in vivo rodent and human studies with special focus on mouse models. Human exposure data, including estimates of daily intake of dietary acrylamide in different populations and the corresponding cancer risk assessments are provided. The significant gaps in knowledge, which currently preclude a more definitive evaluation of human cancer risk due to exposure to dietary acrylamide, are highlighted. Future directions for research on acrylamide and cancer are outlined, and potential challenges are underscored. PMID:17234719

  20. Estimation of carcinogenicity using molecular fragments tree.

    Science.gov (United States)

    Wang, Yong; Lu, Jing; Wang, Fei; Shen, Qiancheng; Zheng, Mingyue; Luo, Xiaomin; Zhu, Weiliang; Jiang, Hualiang; Chen, Kaixian

    2012-08-27

    Carcinogenicity is an important toxicological endpoint that poses high concern to drug discovery. In this study, we developed a method to extract structural alerts (SAs) and modulating factors of carcinogens on the basis of statistical analyses. First, the Gaston algorithm, a frequent subgraph mining method, was used to detect substructures that occurred at least six times. Then, a molecular fragments tree was built and pruned to select high-quality SAs. The p-value of the parent node in the tree and that of its children nodes were compared, and the nodes that had a higher statistical significance in binomial tests were retained. Finally, modulating factors that suppressed the toxic effects of SAs were extracted by three self-defining rules. The accuracy of the 77 SAs plus four SA/modulating factor pairs model for the training set, and the test set was 0.70 and 0.65, respectively. Our model has higher predictive ability than Benigni's model, especially in the test set. The results highlight that this method is preferable in terms of prediction accuracy, and the selected SAs are useful for prediction as well as interpretation. Moreover, our method is convenient to users in that it can extract SAs from a database using an automated and unbiased manner that does not rely on a priori knowledge of mechanism of action. PMID:22834690

  1. Carcinogenicity/tumour promotion by NDL PCB

    Energy Technology Data Exchange (ETDEWEB)

    Schrenk, D. [Kaiserslautern Univ. (Germany). Food Chemistry and Environmental Toxicology

    2004-09-15

    Polychlorinated biphenyls (PCBs) belong to the group of persistent environmental pollutants exhibiting neurotoxic, teratogenic and tumour-promoting effects in experimental animal models. PCB congeners can be divided into 'dioxinlike' and 'non-dioxinlike' congeners on the basis of their ability to act as aryl hydrocarbon receptor (AhR) agonists. Like the most toxic dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 'dioxinlike' PCBs bind to the AhR and show characteristic effects on the expression of AhR-regulated genes including the induction of cytochrome P450 (CYP) 1A1. On the other hand, 'non-dioxinlike' PCB congeners have a lower or no binding affinity to the AhR, but exhibit a 'phenobarbital-type' induction of CYP 2B1/2 activity. A carcinogenic potential of PCBs has been demonstrated with technical mixtures such as Aroclors or Clophens. In these studies the liver and the thyroid gland were found to be the principal target organs of PCB-mediated carcinogenesis in rodents. No studies have been published, however, on the carcinogenicity of individual congeners. In two-stage initiation-promotion protocols in rats, both technical mixtures and individual 'dioxinlike' and 'non-dioxinlike' congeners were reported to act as liver tumour promoters.

  2. Hepatic metabolism of carcinogenic β-asarone.

    Science.gov (United States)

    Cartus, Alexander T; Stegmüller, Simone; Simson, Nadine; Wahl, Andrea; Neef, Sylvia; Kelm, Harald; Schrenk, Dieter

    2015-09-21

    β-Asarone (1) belongs to the group of naturally occurring phenylpropenes like eugenol or anethole. Compound 1 is found in several plants, e.g., Acorus calamus or Asarum europaeum. Compound 1-containing plant materials and essential oils thereof are used to flavor foods and alcoholic beverages and as ingredients of many drugs in traditional phytomedicines. Although 1 has been claimed to have several positive pharmacological effects, it was found to be genotoxic and carcinogenic in rodents (liver and small intestine). The mechanism of action of carcinogenic allylic phenylpropenes consists of the metabolic activation via cytochrome P450 enzymes and sulfotransferases. In vivo experiments suggested that this pathway does not play a major role in the carcinogenicity of the propenylic compound 1 as is the case for other propenylic compounds, e.g., anethole. Since the metabolic pathways of 1 have not been investigated and its carcinogenic mode of action is unknown, we investigated the metabolism of 1 in liver microsomes of rats, bovines, porcines, and humans using (1)H NMR, HPLC-DAD, and LC-ESI-MS/MS techniques. We synthesized the majority of identified metabolites which were used as reference compounds for the quantification and final verification of metabolites. Microsomal epoxidation of the side chain of 1 presumably yielded (Z)-asarone-1',2'-epoxide (8a) which instantly was hydrolyzed to the corresponding erythro- and threo-configurated diols (9b, 9a) and the ketone 2,4,5-trimethoxyphenylacetone (13). This was the main metabolic pathway in the metabolism of 1 in all investigated liver microsomes. Hydroxylation of the side chain of 1 led to the formation of three alcohols at total yields of less than 30%: 1'-hydroxyasarone (2), (E)- and (Z)-3'-hydroxyasarone (4 and 6), with 6 being the mainly formed alcohol and 2 being detectable only in liver microsomes of Aroclor 1254-pretreated rats. Small amounts of 4 and 6 were further oxidized to the corresponding carbonyl

  3. Is nitrous oxide a genotoxic carcinogen?

    Science.gov (United States)

    O'Donovan, Michael R; Hammond, Timothy G

    2015-07-01

    Nitrous oxide (N2O) has been widely used as a dental and surgical anaesthetic for over 150 years. However, results from a recent study suggested that increased DNA damage was seen in lymphocytes from surgical patients and this led to its continued clinical use to be questioned. The data can be challenged on technical grounds and must be considered with other studies in order to assess any possible risk. There are other studies indicating that N2O has weak genotoxicity in man, but these are confused by exposure of the populations to other anaesthetic gases including isoflurane and sevoflurane, both of which have also been reported to increase DNA damage. It should be noted that the suggested genotoxic mechanisms are all indirect, including folate deficiency, oxidative stress and homocysteine toxicity. Further, results from in vitro studies indicate that N2O has no direct DNA reactivity as negative results were obtained in a bacterial mutation (Ames) test and an assay for mutation at the hprt locus in Chinese hamster lung cells. Although not performed to definitive study designs, no evidence of carcinogenicity was seen in two long-term tests in mice and another in rats. Although there is some evidence that N2O is weakly genotoxic in humans, this appears to be similar to that reported for isoflurane and sevoflurane and all the postulated mechanisms have clear thresholds with no evidence of direct DNA reactivity. Because any potential genotoxic mechanism would have a threshold, it seems reasonable to conclude that neither occasional high exposure to patients as an anaesthetic nor low-level exposure to staff within published recommended exposure limits presents any significant carcinogenic risk. PMID:25852088

  4. Chemical mechanisms of the interaction between radiation and chemical carcinogens

    International Nuclear Information System (INIS)

    There is evidence to suggest that ionizing radiation and chemical carcinogens can act synergistically to produce deleterious biological effects. In addition, many carcinogens undergo metabolic activation in vivo. This activation, initiated by biochemical redox reactions, can be simulated chemically, electrochemically, photochemically and radiation chemically. The principal reactive species formed by the action of ionizing radiation on aqueous solutions of macromolecules and mammalian cells, are hydroxyl radicals and superoxide anions. Pulse and steady-state radiolysis studies of model chemical systems have established that these species can 'activate' chemical carcinogens by a radical oxidation process, and that the resulting activated carcinogens can subsequently react with nucleophilic sites on DNA and other potential target macromolecules. Rate constants for some of the fast reactions involved in the radiation activation of carcinogens and in the subsequent carcinogen-DNA interactions have been determined, together with the yields of radiation-induced covalent DNA-carcinogen binding. A redox models for radiation-induced chemical carcinogenesis is proposed which describes a possible mechanism of action involving free radical species generated in the aqueous cellular milieu, which diffuse to and react with carcinogens located within the micro-environment of the cell. Preliminary experiments suggest that protection against radiation and chemical carcinogenesis can be achieved by radical scavenging or by competitive free radical inhibition

  5. Carcinogens in the Workplace: A Scientific, Political and Social Problem

    OpenAIRE

    Atherley, Gordon; Whiting, Robert

    1982-01-01

    Investigation, assessment, and management of carcinogenic risks are not only scientific but also political responsibilities. In Canada, this becomes cumbersome, since local, provincial and federal policies are involved. The process also involves workers and management. This article outlines Canadian legislative experience, the principles involved, the methods of risk assessment, and the classification of carcinogens in the workplace.

  6. Workshop on problem areas associated with developing carcinogen guidelines

    Energy Technology Data Exchange (ETDEWEB)

    1984-06-01

    A workshop was conducted to discuss problem areas associated with developing carcinogen guidelines. Session topics included (1) definition of a carcinogen for regulatory purposes; (2) potency; (3) risk assessment; (4) uncertainties; (5) de minimis quantity; and (6) legal and regulatory issues. Separate abstracts have been prepared for individual papers. (ACR)

  7. Environmental carcinogenic agents and cancer prevention. Risk assessment and management

    International Nuclear Information System (INIS)

    Many agents in our environment have been established as being carcinogenic, and in most cases, the carcinogenic properties of these agents were identified because of high-dose occupational or accidental exposure. Risk characterization, taking into account the dose-response relationship, and exposure assessment are essential for risk assessment and subsequent cancer prevention. Based on scientific risk assessment, risk management should be conducted practically by considering the economic, social, political, and other technical issues and by balancing the risks and benefits. Asbestos and environmental tobacco smoke are typical examples of established carcinogenic agents in the general environment, contributing to low-dose exposure. Further epidemiological studies are required to investigate the carcinogenicity of low-dose exposure to known carcinogenic agents such as arsenic and cadmium through dietary intake, radiation via medical and natural exposure, and air pollution due to diesel exhaust. In contrast, occupational chemical exposure to 1,2-dichloropropane and/or dichloromethane, whose carcinogenicity had not been established, was suggested to cause cholangiocarcinoma among workers involved in offset color proof-printing only after a rare situation of high-dose exposure was unveiled. Continuous monitoring of unusual cancer occurrences in target populations such as workers in occupational and regional settings as well as exposure reduction to suspected carcinogenic agents to levels as low as reasonably achievable is essential for reducing the risk of cancer due to environmental carcinogens. (author)

  8. Researchers exploring faster alternatives to 2-year test for carcinogenicity.

    OpenAIRE

    Schmidt, Charlie

    2006-01-01

    KEYWORDS - CLASSIFICATION: Animals;Animals,Laboratory;biomarkers of exposure & effect: validation;Carcinogenicity Tests;Carcinogens;Female;metabolism;methods;Male;Mice;Pharmaceutical Preparations;Predictive Value of Tests;Prognosis;Rats;standards;Species Specificity;trends;Time Factors;Tumor Markers,Biological;United States;United States Environmental Protection Agency;United States Food and Drug Administration.

  9. 29 CFR 1926.1103 - 13 carcinogens (4-Nitrobiphenyl, etc.).

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 8 2010-07-01 2010-07-01 false 13 carcinogens (4-Nitrobiphenyl, etc.). 1926.1103 Section 1926.1103 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... § 1926.1103 13 carcinogens (4-Nitrobiphenyl, etc.). Note: The requirements applicable to...

  10. 29 CFR 1915.1003 - 13 carcinogens (4-Nitrobiphenyl, etc.).

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false 13 carcinogens (4-Nitrobiphenyl, etc.). 1915.1003 Section 1915.1003 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... Hazardous Substances § 1915.1003 13 carcinogens (4-Nitrobiphenyl, etc.). Note: The requirements...

  11. 29 CFR 1910.1003 - 13 Carcinogens (4-Nitrobiphenyl, etc.).

    Science.gov (United States)

    2010-07-01

    ... employees, designated representatives, and the Assistant Secretary in accordance with 29 CFR 1910.1020 (a... 29 Labor 6 2010-07-01 2010-07-01 false 13 Carcinogens (4-Nitrobiphenyl, etc.). 1910.1003 Section... Substances § 1910.1003 13 Carcinogens (4-Nitrobiphenyl, etc.). (a) Scope and application. (1) This...

  12. Comparison of rat olfactory mucosal responses to carcinogenic and non-carcinogenic chloracetanilides

    OpenAIRE

    Genter, M.B.; Warner, B.M.; Medvedovic, M.; Sartor, M.A.

    2009-01-01

    Alachlor and butachlor are chloracetanilide herbicides that induce olfactory tumors in rats, whereas propachlor does not. The mechanism by which alachlor induces tumors is distinct from many other nasal carcinogens, in that alachlor induces a gradual de-differentiation of the olfactory mucosa (OM) to a more respiratory-like epithelium, in contrast to other agents that induce cytotoxicity, followed by an aberrant regenerative response. We studied biochemical and genomic effects of these compou...

  13. Lymphocyte reactivity of workers exposed to carcinogenic and non-carcinogenic chemicals.

    OpenAIRE

    Kumar, S.; Taylor, G; Hurst, W; Wilson, P.; Costello, C B

    1981-01-01

    Immunological studies have shown an increased lymphocyte reactivity in patients with early stage bladder cancer and individuals with pre-stage T1 exposed to bladder carcinogens (2-naphthylamine and industrial 1-naphthylamine containing 4-8% 2-naphthylamine) before 1952-that is, those at high risk of developing bladder cancer. Because of the close chemical similarity of Tobias acid (2-naphthylamine-1 sulphonic acid) to 2-naphthylamine, the lymphocytotoxicity of workers exposed to this chemical...

  14. An estimation of the carcinogenic risk associated with the intake of multiple relevant carcinogens found in meat and charcuterie products.

    Science.gov (United States)

    Hernández, Ángel Rodríguez; Boada, Luis D; Almeida-González, Maira; Mendoza, Zenaida; Ruiz-Suárez, Norberto; Valeron, Pilar F; Camacho, María; Zumbado, Manuel; Henríquez-Hernández, Luis A; Luzardo, Octavio P

    2015-05-01

    Numerous epidemiological studies have demonstrated a link between excessive meat consumption and the incidence of various cancers, especially colorectal cancer, and it has been suggested that environmental carcinogens present in meat might be related to the increased risk of cancer associated with this food. However, there are no studies evaluating the carcinogenic potential of meat in relation to its content of carcinogens. Our purpose was to emphasize the relevance of environmental carcinogens existing in meat as a determinant of the association between cancer and meat consumption. Because within Europe, Spain shows high consumption of meat and charcuterie, we performed this study focusing on Spanish population. Based on the preferences of consumers we acquired 100 samples of meat and charcuterie that reflect the variety available in the European market. We quantified in these samples the concentration of 33 chemicals with calculated carcinogenic potential (PAHs, organochlorine pesticides, and dioxin-like PCBs). The carcinogenic risk of these contaminants was assessed for each food using a risk ratio based on the current consumption of meat and charcuterie and the maximum tolerable intake of these foods depending on the level of contamination by the carcinogens they contain. Our results indicate that the current consumption of beef, pork, lamb, chicken, and "chorizo", represents a relevant carcinogenic risk for consumers (carcinogenic risk quotient between 1.33 and 13.98). In order to reduce carcinogenic risk, the study population should halve the monthly consumption of these foods, and also not to surpass the number of 5 servings of beef/pork/chicken (considered together). PMID:25659303

  15. Metabolic activation of chemical carcinogens to reactive electrophiles

    International Nuclear Information System (INIS)

    Ionizing radiations and ultraviolet light constitute the principal known physical carcinogens. Likewise, a great variety and large number of chemicals and over 50 DNA and RNA viruses comprise the known chemical and viral carcinogens. These three categories of carcinogenic agents include the great majority of extrinsic agents known to induce cancer in mammals. Man is clearly susceptible to the action of physical and chemical carcinogens and, indeed, was the first species in which the activities of some of these agents were demonstated. It seems certain that viral carcinogenic information is involved in the etiology of at least some human tumors, but ethical and methodological problems have made it difficult to obtain unequivocal data. Given the long availability of experimental carcinogens of these three classes, there is surprisingly little known of their interrelationships in the production of cancer in experimental animals. The objective of this brief review is to present some salient aspects of experimental chemical carcinogenesis and an analysis of how some of these features relate to the mechanisms of action of radiation carcinogens

  16. Identification and monitoring of non-radiological carcinogens

    International Nuclear Information System (INIS)

    This study examines the feasibility of identifying and monitoring occupational exposures to non-radiological carcinogens in the workplace at Canadian nuclear establishments (Whiteshell Laboratories, Pickering Nuclear Generating Station, Cameco Limited and Canadian General Electric Company Limited). Recent epidemiological studies recommended that potential confounding factors of a non-radiological nature be identified and analyzed, particularly non-radiological carcinogens that may be present in the workplace at nuclear facilities. The feasibility of identifying and measuring occupational exposures to non-radiological carcinogens in Canadian nuclear facilities is examined. Also, the report describes the problem of chemical carcinogens and the mechanisms involved in chemical carcinogenesis; the epidemiology related to the problem, followed by a description of the analytical aspects of detection, monitoring and analysis of carcinogens, as well as a discussion on the regulatory aspects and the regulations in place; and the findings, recommendations and concluding remarks of this study. Several problem areas became apparent as the study proceeded. For example, the classification of a chemical as a human carcinogen is a difficult problem, as is its adequate monitoring and analysis. This situation reflects, in turn, the regulatory aspects in the workplace. A list of chemical carcinogens used industrially at the four Canadian nuclear facilities has been identified. The list includes arsenic, asbestos, benzene, cadmium, beryllium, nickel, polychlorinated biphenyls, lead and trichloroethylene. Several recommendations are made in relation to the need for practical and efficient monitoring methods for chemical carcinogens, the definition of radiation and chemical dose equivalencies, and the classification of human chemical carcinogens, as well as their disposal. (author). 122 refs., 8 tabs., 6 figs

  17. Biologic markers in risk assessment for environmental carcinogens

    Energy Technology Data Exchange (ETDEWEB)

    Perera, F.; Mayer, J.; Santella, R.M.; Brenner, D.; Jeffrey, A.; Latriano, L.; Smith, S.; Warburton, D.; Young, T.L.; Tsai, W.Y.; Brandt-Rauf, P. (Columbia Univ. School of Public Health, New York, NY (United States)); Hemminki, K. (Finnish School of Occupational Health, Helsinki (Finland))

    1991-01-01

    The potential of biologic markers to provide more timely and precise risk assessments for environmental carcinogens is viewed against the current state-of-the-art in biological monitoring/molecular epidemiology. Biologic markers such as carcinogen-DNA adducts and oncogene activation are currently considered valid qualitative indicators of potential risk, but for most chemical exposures research is needed to establish their validity as quantitative predictors of cancer risk. Biologic markers have, however, already provided valuable insights into the magnitude of interindividual variation in response to carcinogenic exposures, with major implications for risk assessment.

  18. Biologic markers in risk assessment for environmental carcinogens

    International Nuclear Information System (INIS)

    The potential of biologic markers to provide more timely and precise risk assessments for environmental carcinogens is viewed against the current state-of-the-art in biological monitoring/molecular epidemiology. Biologic markers such as carcinogen-DNA adducts and oncogene activation are currently considered valid qualitative indicators of potential risk, but for most chemical exposures research is needed to establish their validity as quantitative predictors of cancer risk. Biologic markers have, however, already provided valuable insights into the magnitude of interindividual variation in response to carcinogenic exposures, with major implications for risk assessment

  19. Trichloroethylene: Mechanistic, Epidemiologic and Other Supporting Evidence of Carcinogenic Hazard

    OpenAIRE

    Rusyn, Ivan; Chiu, Weihsueh A.; Lawrence H. Lash; Kromhout, Hans; Hansen, Johnni; Guyton, Kathryn Z.

    2013-01-01

    The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence formin...

  20. Critical analysis of carcinogenicity study outcomes. Relationship with pharmacological properties.

    Science.gov (United States)

    van der Laan, Jan Willem; Kasper, Peter; Silva Lima, Beatriz; Jones, David R; Pasanen, Markku

    2016-08-01

    Predicting the outcome of life-time carcinogenicity studies in rats based on chronic (6-month) toxicity studies in this species is possible in some instances. This should reduce the number of such studies and hence have a significant impact on the total number of animals used in safety assessment of new medicines. From a regulatory perspective, this should be sufficient to grant a waiver for a carcinogenicity study in those cases where there is confidence in the outcome of the prediction. Pharmacological properties are a frequent key factor for the carcinogenic mode of action of some pharmaceuticals, but data-analysis on a large dataset has never been formally conducted. We have conducted an analysis of a dataset based on the perspective of the pharmacology of 255 compounds from industrial and regulatory sources. It is proposed that a pharmacological, class-specific, model may consist of an overall causal relationship between the pharmacological class and the histopathology findings in rats after 6 months treatment, leading to carcinogenicity outcome after 2 years. Knowledge of the intended drug target and pathway pharmacology should enhance the prediction of either positive or negative outcomes of rat carcinogenicity studies. The goal of this analysis is to review the pharmacological properties of compounds together with the histopathology findings from the chronic toxicity study in rodents in order to introduce an integrated approach to estimate the risk of human carcinogenicity of pharmaceuticals. This approach would allow scientists to define conditions under which 2-year rat carcinogenicity studies will or will not add value to such an assessment. We have demonstrated the possibility of a regulatory waiver for a carcinogenicity study in rats, as currently discussed in the International Council for Harmonization (ICH) - formerly known as the International Conference on Harmonization (ICH), by applying the proposed prediction approach in a number of case studies

  1. Biologic markers in risk assessment for environmental carcinogens

    OpenAIRE

    Perera, F.; Mayer, J.; Santella, R. M.; Brenner, D; Jeffrey, A.; Latriano, L; Smith, S.; Warburton, D; Young, T. L.; Tsai, W. Y.; Hemminki, K; Brandt-Rauf, P

    1991-01-01

    The potential of biologic markers to provide more timely and precise risk assessments for environmental carcinogens is viewed against the current state-of-the-art in biological monitoring/molecular epidemiology. Biologic markers such as carcinogen-DNA adducts and oncogene activation are currently considered valid qualitative indicators of potential risk, but for most chemical exposures research is needed to establish their validity as quantitative predictors of cancer risk. Biologic markers h...

  2. Carcinogenicity evaluations and ongoing studies: the IARC databases.

    OpenAIRE

    Vainio, H.; Coleman, M.; Wilbourn, J

    1991-01-01

    Many thousands of chemicals are produced industrially and many more occur naturally. Information on the toxicology of these chemicals is often minimal or absent. The International Agency for Research on Cancer (IARC) has published evaluations of the carcinogenic risk to humans of over 700 chemicals, groups of chemicals, and complex mixtures as a regular series of monographs. A database has been created containing summaries of all the relevant epidemiological, animal carcinogenicity, and other...

  3. Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard.

    Science.gov (United States)

    Rusyn, Ivan; Chiu, Weihsueh A; Lash, Lawrence H; Kromhout, Hans; Hansen, Johnni; Guyton, Kathryn Z

    2014-01-01

    The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. The strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE. PMID:23973663

  4. Induction of active melanocytes in mouse skin by carcinogens: a new method for detection of skin carcinogens.

    Science.gov (United States)

    Iwata, K; Inui, N; Takeuchi, T

    1981-01-01

    Application of potent skin carcinogens, such as 7,12-dimethylbenz[a]anthracene, 3-methylcholanthrene, benzo[a]pyrene and 4-nitroquinoline-1-oxide, induced numerous dihydroxyphenylalanine (dopa)-positive cells in the interfollicular epidermis of C57BL/6 mice in a dose- and time-dependent fashion. Chrysene, a weak skin carcinogen, and croton oil, a tumor promoter, also induced 3--4 times more dopa-positive cells than acetone. Liver carcinogens, such as 3'-methyl-4-dimethylaminoazobenzene and N-2-acetylaminofluorene, and non-carcinogenic aromatic hydrocarbons, such as anthracene, fluoranthene, fluorene and pyrene, did not induce increase in these cells. These results indicate that increase in the number of dopa-positive cells after application of chemicals is well correlated with the abilities of these compounds to induce skin carcinogenesis and suppress sebaceous glands. PMID:7273337

  5. Two azole fungicides (carcinogenic triadimefon and non-carcinogenic myclobutanil) exhibit different hepatic cytochrome P450 activities in medaka fish

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Chun-Hung [Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan (China); Chou, Pei-Hsin [Department of Environmental Engineering, National Cheng-Kung University, Tainan, Taiwan (China); Chen, Pei-Jen, E-mail: chenpj@ntu.edu.tw [Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan (China)

    2014-07-30

    Highlights: • We assess ecotoxicological impact of azole fungicides in the aquatic environment. • Carcinogenic and non-carcinogenic azoles show different CYP activities in medaka. • We compare azole-induced CYP expression and carcinogenesis between fish and rodents. • Liver CYP-enzyme induction is a key event in conazole-induced tumorigenesis. • We suggest toxicity evaluation methods for azole fungicides using medaka fish. - Abstract: Conazoles are a class of imidazole- or triazole-containing drugs commonly used as fungicides in agriculture and medicine. The broad application of azole drugs has led to the contamination of surface aquifers receiving the effluent of municipal or hospital wastewater or agricultural runoff. Several triazoles are rodent carcinogens; azole pollution is a concern to environmental safety and human health. However, the carcinogenic mechanisms associated with cytochrome P450 enzymes (CYPs) of conazoles remain unclear. We exposed adult medaka fish (Oryzias latipes) to continuous aqueous solutions of carcinogenic triadimefon and non-carcinogenic myclobutanil for 7 to 20 days at sub-lethal or environmentally relevant concentrations and assessed hepatic CYP activity and gene expression associated with CYP-mediated toxicity. Both triadimefon and myclobutanil induced hepatic CYP3A activity, but only triadimefon enhanced CYP1A activity. The gene expression of cyp3a38, cyp3a40, pregnane x receptor (pxr), cyp26b, retinoid acid receptor γ1 (rarγ1) and p53 was higher with triadimefon than myclobutanil. As well, yeast-based reporter gene assay revealed that 4 tested conazoles were weak agonists of aryl hydrocarbon receptor (AhR). We reveal differential CYP gene expression with carcinogenic and non-carcinogenic conazoles in a lower vertebrate, medaka fish. Liver CYP-enzyme induction may be a key event in conazole-induced tumorigenesis. This information is essential to evaluate the potential threat of conazoles to human health and fish

  6. Two azole fungicides (carcinogenic triadimefon and non-carcinogenic myclobutanil) exhibit different hepatic cytochrome P450 activities in medaka fish

    International Nuclear Information System (INIS)

    Highlights: • We assess ecotoxicological impact of azole fungicides in the aquatic environment. • Carcinogenic and non-carcinogenic azoles show different CYP activities in medaka. • We compare azole-induced CYP expression and carcinogenesis between fish and rodents. • Liver CYP-enzyme induction is a key event in conazole-induced tumorigenesis. • We suggest toxicity evaluation methods for azole fungicides using medaka fish. - Abstract: Conazoles are a class of imidazole- or triazole-containing drugs commonly used as fungicides in agriculture and medicine. The broad application of azole drugs has led to the contamination of surface aquifers receiving the effluent of municipal or hospital wastewater or agricultural runoff. Several triazoles are rodent carcinogens; azole pollution is a concern to environmental safety and human health. However, the carcinogenic mechanisms associated with cytochrome P450 enzymes (CYPs) of conazoles remain unclear. We exposed adult medaka fish (Oryzias latipes) to continuous aqueous solutions of carcinogenic triadimefon and non-carcinogenic myclobutanil for 7 to 20 days at sub-lethal or environmentally relevant concentrations and assessed hepatic CYP activity and gene expression associated with CYP-mediated toxicity. Both triadimefon and myclobutanil induced hepatic CYP3A activity, but only triadimefon enhanced CYP1A activity. The gene expression of cyp3a38, cyp3a40, pregnane x receptor (pxr), cyp26b, retinoid acid receptor γ1 (rarγ1) and p53 was higher with triadimefon than myclobutanil. As well, yeast-based reporter gene assay revealed that 4 tested conazoles were weak agonists of aryl hydrocarbon receptor (AhR). We reveal differential CYP gene expression with carcinogenic and non-carcinogenic conazoles in a lower vertebrate, medaka fish. Liver CYP-enzyme induction may be a key event in conazole-induced tumorigenesis. This information is essential to evaluate the potential threat of conazoles to human health and fish

  7. Two azole fungicides (carcinogenic triadimefon and non-carcinogenic myclobutanil) exhibit different hepatic cytochrome P450 activities in medaka fish.

    Science.gov (United States)

    Lin, Chun-Hung; Chou, Pei-Hsin; Chen, Pei-Jen

    2014-07-30

    Conazoles are a class of imidazole- or triazole-containing drugs commonly used as fungicides in agriculture and medicine. The broad application of azole drugs has led to the contamination of surface aquifers receiving the effluent of municipal or hospital wastewater or agricultural runoff. Several triazoles are rodent carcinogens; azole pollution is a concern to environmental safety and human health. However, the carcinogenic mechanisms associated with cytochrome P450 enzymes (CYPs) of conazoles remain unclear. We exposed adult medaka fish (Oryzias latipes) to continuous aqueous solutions of carcinogenic triadimefon and non-carcinogenic myclobutanil for 7 to 20 days at sub-lethal or environmentally relevant concentrations and assessed hepatic CYP activity and gene expression associated with CYP-mediated toxicity. Both triadimefon and myclobutanil induced hepatic CYP3A activity, but only triadimefon enhanced CYP1A activity. The gene expression of cyp3a38, cyp3a40, pregnane x receptor (pxr), cyp26b, retinoid acid receptor γ1 (rarγ1) and p53 was higher with triadimefon than myclobutanil. As well, yeast-based reporter gene assay revealed that 4 tested conazoles were weak agonists of aryl hydrocarbon receptor (AhR). We reveal differential CYP gene expression with carcinogenic and non-carcinogenic conazoles in a lower vertebrate, medaka fish. Liver CYP-enzyme induction may be a key event in conazole-induced tumorigenesis. This information is essential to evaluate the potential threat of conazoles to human health and fish populations in the aquatic environment. PMID:24962053

  8. Food Additives of Public Concern for their Carcinogenicity

    Directory of Open Access Journals (Sweden)

    Fatih Gultekin

    2015-08-01

    Full Text Available No-Observed-Adverse Effect Level (NOAEL of food additives has been long determined on the basis of toxicological studies. Acceptable Daily Intake (ADI levels of food additives for human are derived from these NOAEL, and their legal limits are then established for the food products, intentionally added with food additives. However, recent studies demonstrated that consumption of some processed food containing certain food additives might have increased the risk of cancer in human although the legal limits of these additives in processed foods are well respected by the manufacturers. Possible reasons for increased carcinogenicity risk in processed foods containing these additives can be due to various factors: -interaction of additives with some food ingredients, -food processing may change the chemical formula of food additive to a formula to be acting similarly as carcinogenic compound, -a negative synergistic effects when combined with other additives, -improper storage conditions, and -unknown carcinogenic by-products occurring during the food processing. Due to the above mentioned factors we recommend that an additive, intentionally added to the food during processing must be traced officially for its carcinogenicity. In this review, we overviewed all of the food additives authorized in European Union. Therefore, the traceability issues of processed foods containing certain food additives, which have a negligible probability of carcinogenicity in legal limits, must be reinforced in the perspective of public health concerns.

  9. Understanding arsenic carcinogenicity by the use of animal models

    International Nuclear Information System (INIS)

    Although numerous epidemiological studies have indicated that human arsenic exposure is associated with increased incidences of bladder, liver, skin, and lung cancers, limited attempts have been made to understand mechanisms of carcinogenicity using animal models. Dimethylarsinic acid (DMA), an organic arsenic compound, is a major metabolite of ingested inorganic arsenics in mammals. Recent in vitro studies have proven DMA to be a potent clastogenic agent, capable of inducing DNA damage including double strand breaks and cross-link formation. In our attempts to clarify DMA carcinogenicity, we have recently shown carcinogenic effects of DMA and its related metabolites using various experimental protocols in rats and mice: (1) a multi-organ promotion bioassay in rats; (2) a two-stage promotion bioassay by DMA of rat urinary bladder and liver carcinogenesis; (3) a 2-year carcinogenicity test of DMA in rats; (4) studies on the effects of DMA on lung carcinogenesis in rats; (5) promotion of skin carcinogenesis by DMA in keratin (K6)/ornithine decarboxylase (ODC) transgenic mice; (6) carcinogenicity of DMA in p53(+/-) knockout and Mmh/8-OXOG-DNA glycolase (OGG1) mutant mice; (7) promoting effects of DMA and related organic arsenicals in rat liver; (8) promoting effects of DMA and related organic arsenicals in a rat multi-organ carcinogenesis test; and (9) 2-year carcinogenicity tests of monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO) in rats. The results revealed that the adverse effects of arsenic occurred either by promoting and initiating carcinogenesis. These data, as covered in the present review, suggest that several mechanisms may be involved in arsenic carcinogenesis

  10. Current issues in carcinogenic effect of low-dose radiation

    International Nuclear Information System (INIS)

    A review of publications dealing with study of radiation sources and biological evaluation of increasing doses of people irradiation under occupational and usual living conditions is presented. The existing natural and artifial irradiation sources are considered. It is noted that all types of ionizing radiations are characterized by high carcinogenic efficiency and can induce benign and malignant tumors practically in all organs. Statistically reliable data in experimental and epidemiological investigations were recorded under the effect of large and mean doses. Minor radiation doses not responsible for visible functional and morphological changes in early periods can cause pathological changes in delayed periods. The data on carcinogenic effect of relatively small radiation doses are available

  11. Environmental carcinogens in human target tissues in culture: Progress report

    International Nuclear Information System (INIS)

    We have accumulated more experimental evidences that demonstrated the comparative approaches with human cells will allow us to predict human risk with good accuracy following exposure to toxic chemicals. We also synthesized several carcinogenic DNA adducts, i.e., the major benzo[a]pyrene DNA adduct, 06-methyldeoxyguanosine, 7-methyl- deoxyguanosine and 2-methyl-deoxyguanosine to be used as standards for quantitating DNA adduct formation in carcinogen exposed cells. A simple synthetic method was developed for preparation of the major B[a]p DNA adduct with yields better than those reported. The main accomplishments related to the originally stated objectives are summarized. 8 refs., 2 figs., 1 tab

  12. A call to expand regulation to all carcinogenic fibrous minerals

    Science.gov (United States)

    Baumann, F.; Steele, I.; Ambrosi, J.; Carbone, M.

    2013-05-01

    The regulatory term "asbestos" groups only the six fibrous minerals that were commercially used among approximately 400. The carcinogenicity of these six regulated minerals has been largely demonstrated and is related to fiber structure, fiber length/diameter ratio, and bio-persistence. From a public perception, the generic term "asbestos" refers to the fibrous minerals that cause asbestosis, mesothelioma and other cancers. However, other non-regulated fibrous minerals are potentially as dangerous as the regulatory asbestos because they share similar physical and chemical properties, epidemiological studies have demonstrated their relationship with asbestos-related diseases, and both in vitro and in vivo experiments have established the toxicity of these minerals. For example, the non-regulated asbestiform winchite and richterite minerals that contaminated the vermiculite mined from Libby, Montana, (USA) were associated with mesothelioma, lung cancer and asbestosis observed among the area's residents and miners. Many other examples of non-regulated carcinogenic fibrous minerals include, but are not limited to, antigorite, arfvedsonite, balangeroite, carlosturanite, erionite, fluoro-edenite, hornblende, mordenite, palygorskite, and sepiolite. To propose a regulatory definition that would provide protection from all carcinogenic fibers, we have conducted an interdisciplinary literature review to compare the characteristics of "asbestos" and of non-regulated mineral fibers that relate to carcinogenicity. We specifically studied two non-regulated fibrous minerals that are associated with asbestos-related diseases: the serpentine antigorite and the zeolite erionite. Both examples underscore the problem of regulation based on commercial, rather than scientific principles: 1) the occurrence of fibrous antigorite in materials used to pave roads has been correlated with high mesothelioma rates in New Caledonia. Antigorite was also the cause of asbestosis in Poland, and in

  13. 18. Adduct detection in human monitoring for carcinogen exposure

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@Determination of the covalently bound products (adducts) of carcinogens with DNA or proteins may be used for the monitoring of exposure to these compounds. Protein adducts are generally stable and are not enzymatically repaired, and the use of these for cxposure monitoring is normally carried out with globin or albumin, because

  14. Chronic toxicity and carcinogenicity study of erythritol in rats

    NARCIS (Netherlands)

    Lina, B.A.R.; Bos-Kuijpers, M.H.M.; Til, H.P.; Bär, A.

    1996-01-01

    The potential toxicity and carcinogenicity of erythritol, a low-calorie sugar substitute, were examined in Wistar Crl:(WI) WU BR rats. Groups of 50 rats of each sex consumed diets with 0, 2, 5, or 10% erythritol, or 10% mannitol, for a period of 104-107 weeks. To each of these main groups, two satel

  15. IARC Monographs: 40 Years of Evaluating Carcinogenic Hazards to Humans

    NARCIS (Netherlands)

    Pearce, Neil E; Blair, Aaron; Vineis, Paolo; Ahrens, Wolfgang; Andersen, Aage; Anto, Josep M; Armstrong, Bruce K; Baccarelli, Andrea A; Beland, Frederick A; Berrington, Amy; Bertazzi, Pier A; Birnbaum, Linda S; Brownson, Ross C; Bucher, John R; Cantor, Kenneth P; Cardis, Elisabeth; Cherrie, John W; Christiani, David C; Cocco, Pierluigi; Coggon, David; Comba, Pietro; Demers, Paul A; Dement, John M; Douwes, Jeroen; Eisen, Ellen A; Engel, Lawrence S; Fenske, Richard A; Fleming, Lora E; Fletcher, Tony; Fontham, Elizabeth; Forastiere, Francesco; Frentzel-Beyme, Rainer; Fritschi, Lin; Gerin, Michel; Goldberg, Marcel; Grandjean, Philippe; Grimsrud, Tom K; Gustavsson, Per; Haines, Andy; Hartge, Patricia; Hansen, Johnni; Hauptmann, Michael; Heederik, Dick; Hemminki, Kari; Hemon, Denis; Hertz-Picciotto, Irva; Hoppin, Jane A; Huff, James; Jarvholm, Bengt; Kang, Daehee; Karagas, Margaret R; Kjaerheim, Kristina; Kjuus, Helge; Kogevinas, Manolis; Kriebel, David; Kristensen, Petter; Kromhout, Hans; Laden, Francine; Lebailly, Pierre; LeMasters, Grace; Lubin, Jay H; Lynch, Charles F; Lynge, Elsebeth; 't Mannetje, Andrea; McMichael, Anthony J; McLaughlin, John R; Marrett, Loraine; Martuzzi, Marco; Merchant, James A; Merler, Enzo; Merletti, Franco; Miller, Anthony; Mirer, Franklin E; Monson, Richard; Nordby, Karl-Kristian; Olshan, Andrew F; Parent, Marie-Elise; Perera, Frederica P; Perry, Melissa J; Pesatori, Angela C; Pirastu, Roberta; Porta, Miquel; Pukkala, Eero; Rice, Carol; Richardson, David B; Ritter, Leonard; Ritz, Beate; Ronckers, Cecile M; Rushton, Lesley; Rusiecki, Jennifer A; Rusyn, Ivan; Samet, Jonathan M; Sandler, Dale P; de Sanjose, Silvia; Schernhammer, Eva; Seniori Constantini, Adele; Seixas, Noah; Shy, Carl; Siemiatycki, Jack; Silvermann, Debra T; Simonato, Lorenzo; Smith, Allan H; Smith, Martyn T; Spinelli, John J; Spitz, Margaret R; Stallones, Lorann; Stayner, Leslie T; Steenland, Kyle; Stenzel, Mark; Stewart, Bernard W; Stewart, Patricia A; Symanski, Elaine; Terracini, Benedetto; Tolbert, Paige E; Vainio, Harri; Vena, John; Vermeulen, Roel; Victora, Cesar G; Ward, Elizabeth M; Weinberg, Clarice R; Weisenburger, Dennis; Wesseling, Catharina; Weiderpass, Elisabete; Zahm, Shelia H

    2015-01-01

    BACKGROUND: Recently the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also the approach used to perform these evaluations. Some critics have claimed that IARC Working Groups' fa

  16. Modern Electrochemical Methods for Monitoring of Chemical Carcinogens

    OpenAIRE

    Zima, J; Moreira, J.; J. Barek

    2005-01-01

    This contribution is based on our presentation at the 1st International Symposium on Sensor Science, Paris, 16-20 June 2003. It presents recent results regarding the electrochemical determination of submicromolar and nanomolar concentrations of various carcinogenic substances (nitrated polycyclic aromatic hydrocarbons, heterocyclic compounds, azo compounds, aromatic amino compounds, etc.) using both traditional (classical dropping mercury electrode, static mercury drop electrode, hanging merc...

  17. DETECTION OF CARCINOGENICITY BASED ON MUTAGENICITY IN ARABIDOPSIS

    Science.gov (United States)

    Thirty-seven synthetic chemicals plus two mycotoxins were tested for mutagenicity in an Arabidopsis embryo system. The results of this test, prokaryotic repair tests, bacterial mutation assays, eukaryotic cell systems, and in vivo tests were compared to the carcinogenicity classi...

  18. Non—Genotoxic Carcinogens.Approaches to Their Rish Assessment

    Institute of Scientific and Technical Information of China (English)

    J.A.CASTRO; M.I.DiazGomez; 等

    1993-01-01

    Epidemiological studies support the idea that most human cancers are related to chemicals present in the human environment.In turn,chemicals are believed to cause cancer via either genotoxic or non-genotoxic mechanisms.There were described in literature several simple rapid and inexpensive short term ests to reasonably predict the genotoxic nature of chemicals but in contrast,there is no reliable test or battery of tests available to predict the carcinogenicity of non-genotoxic compounds and this poses a major problem to their rish assessment.In addition,there are conflictive opinions about rish assessment needs for both classes of carcinogens.Some workers elieve that for non-genotoxic carcinogens,thresholds for exposure can be drawn while others do not.In this review,the reasons behind both of these opinions and the present hypotheses about the mechanism of action of non-genotoxic carcinogens are described and analyzed in relation to future needs.

  19. Flavonoids and alkenylbenzenes: mechanisms of mutagenic action and carcinogenic risk

    NARCIS (Netherlands)

    Rietjens, I.M.C.M.; Boersma, M.G.; Woude, van der H.; Jeurissen, S.M.F.; Schutte, M.E.; Alink, G.M.

    2005-01-01

    The present review focuses on the mechanisms of mutagenic action and the carcinogenic risk of two categories of botanical ingredients, namely the flavonoids with quercetin as an important bioactive representative, and the alkenylbenzenes, namely safrole, methyleugenol and estragole. For quercetin a

  20. Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard

    NARCIS (Netherlands)

    Rusyn, Ivan; Chiu, Weihsueh A.; Lash, Lawrence H.; Kromhout, Hans; Hansen, Johnni; Guyton, Kathryn Z.

    2014-01-01

    The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studie

  1. COMPLEMENTARITY OF GENOTOXIC AND NONGENOTOXIC PREDICTORS OF RODENT CARCINOGENICITY

    Science.gov (United States)

    Twenty-one chemicals known to be carcinogenic in rodent bioassays were selected for study. he chemicals were administered by gavage in two dose levels to female Sprague-Dawley rats. he effects of these 21 chemicals on four biochemical assays (hepatic DNA damage by alkaline elutio...

  2. Risk assessment of DNA-reactive carcinogens in food

    International Nuclear Information System (INIS)

    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 B1 (AFB1), a limit of 20 ppb or ∼30 μg/day has been set and is considered a tolerable daily intake (TDI). Since AFB1 is considered a potent carcinogen, doses of 32P-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

  3. Carcinogenicity of the insulation wools: reassessment of the IARC evaluation.

    Science.gov (United States)

    Brown, R C; Davis, J M; Douglas, D; Gruber, U F; Hoskins, J A; Ilgren, E B; Johnson, N F; Rossiter, C E; Wagner, J C

    1991-08-01

    In assessing the health evidence concerning man-made mineral fibers, the chemical composition, surface activity, durability, and size of fibers have to be taken into account. Special-purpose fine glass fibers need to be separated from the insulation wools (glass, rock, and slag wool). The epidemiological evidence is sufficient to conclude that there has been no mesothelioma risk to workers producing or using glass wool, rock wool, or slag wool. The epidemiological studies have been large and powerful, and they show no evidence of a cause-effect relationship between lung cancer and exposure to glass wool, rock wool, or slag wool fibers. There is some evidence of a small cancer hazard attached to the manufacturing process in slag wool plants 20 to 50 years ago, when asbestos was used in some products and other carcinogenic substances were present. However, this hazard is not associated with any index of exposure to slag wool itself. Animal inhalation studies of ordinary insulation wools also show that there is no evidence of hazard associated with exposure to these relatively coarse, soluble fibers. The evidence of carcinogenicity is limited to experiments with special-purpose fine durable glass fibers or experimental fibers, and only when these fibers are injected directly into the pleural or peritoneal cavity. Multiple chronic inhalation studies of these same special-purpose fine glass fibers have not produced evidence of carcinogenicity. It is suggested that the present IARC evaluation of the carcinogenic risk of insulation wools should be revised to Category 3: not classifiable as to carcinogenicity to humans. PMID:1947241

  4. Biostatistical issues in the design and analysis of animal carcinogenicity experiments.

    OpenAIRE

    Portier, C.J.

    1994-01-01

    Two-year animal carcinogenicity experiments are used to evaluate the potential carcinogenicity from exposure to chemicals. The choice of exposure levels, the allocation of animals to doses, the length of exposure, and the choice of interim sacrifice times all affect the power of statistical tests for carcinogenic effects and the variance of interpolated estimates of carcinogenic risk. In this paper, one aspect of this problems is considered: the ability of tumor incidence data to provide info...

  5. Multiple mechanisms for the carcinogenic effects of asbestos and other mineral fibers.

    OpenAIRE

    Barrett, J C; Lamb, P W; Wiseman, R. W.

    1989-01-01

    Asbestos and other mineral fibers are carcinogenic to humans and animals but differ from many carcinogens in that they do not induce gene mutations. An understanding of these interesting human carcinogens, therefore, is an important problem in cancer research. Asbestos and other fibers induce predominantly two types of cancers: mesotheliomas and bronchogenic carcinomas. Fiber size is an important factor in the carcinogenic activity of these substances as has been shown for mesothelioma induct...

  6. In vivo Comet assay on isolated kidney cells to distinguish genotoxic carcinogens from epigenetic carcinogens or cytotoxic compounds.

    Science.gov (United States)

    Nesslany, Fabrice; Zennouche, Nadia; Simar-Meintières, Sophie; Talahari, Ismaïl; Nkili-Mboui, Esther-Nadège; Marzin, Daniel

    2007-06-15

    The objective of this study was to determine the ability of the alkaline in vivo Comet assay (pH>13) to distinguish genotoxic carcinogens from epigenetic carcinogens when performed on freshly isolated kidney cells and to determine the possible interference of cytotoxicity by assessing DNA damage induced by renal genotoxic, epigenetic or toxic compounds after enzymatic isolation of kidney cells from OFA Sprague-Dawley male rats. The ability of the Comet assay to distinguish (1) genotoxicity versus cytotoxicity and (2) genotoxic versus non-genotoxic (epigenetic) carcinogens, was thus investigated by studying five known genotoxic renal carcinogens acting through diverse mechanisms of action, i.e. streptozotocin, aristolochic acids, 2-nitroanisole, potassium bromate and cisplatin, two rodent renal epigenetic carcinogens: d-limonene and ciclosporine and two nephrotoxic compounds: streptomycin and indomethacin. Animals were treated once with the test compound by the appropriate route of administration and genotoxic effects were measured at the two sampling times of 3-6 and 22-26h after treatment. Regarding the tissue processing, the limited background level of DNA migration observed in the negative control groups throughout all experiments demonstrated that the enzymatic isolation method implemented in the current study is appropriate. On the other hand, streptozotocin, 20mg/kg, used as positive reference control concurrently to each assay, caused a clear increase in the mean Olive Tail Moment median value, which allows validating the current methodology. Under these experimental conditions, the in vivo rodent Comet assay demonstrated good sensitivity and good specificity: all the five renal genotoxic carcinogens were clearly detected in at least one expression period either directly or indirectly, as in the case of cisplatin: for this cross-linking agent, the significant decrease in DNA migration observed under standard electrophoresis conditions was clearly amplified

  7. [Update on benzene: from industrial toxicant to environmental carcinogen].

    Science.gov (United States)

    Manno, Maurizio

    2013-01-01

    Benzene, an industrial chemical myelotoxic at high doses in workers, is now an almost ubiquitous pollutant. It is also a no-threshold genotoxic carcinogen causing acute leukemia and other lymphoaematological tumours. Although its mechanism of action has not been fully clarified, benzene toxicity and carcinogenicity depend on metabolic activation. Polymorphism of activating and detoxifying enzymes (CYP, GST, NQO1) may be critical, therefore, in modulating individual susceptibility to benzene. Further uncertainty factors in assessing low level benzene exposure are the limited sensitivity and specificity of most exposure biomarkers, the frequent coexposure to other volatile organic chemicals (VOC), and the presence of non occupational sources of exposure, such as cigarette smoke and veicular traffic. The aim of this presentation is to introduce the main current critical issues in the risk assessment and the biological monitoring of occupational exposure to benzene at low doses. PMID:24303704

  8. Mammalian cell transformation: Mechanisms of carcinogenesis and assays for carcinogens

    International Nuclear Information System (INIS)

    This book contains nine sections, each consisting of several papers. The section titles are: Molecular Changes in Cell Transformation; Differentiation, Growth Control, and Cell Transformation; Mutagenesis and Cell Transformation; Tumor Promotion and Cell Transformation; Mechanisms of Transformation of Human Fibroblasts; Mechanisms of Transformation of Epithelial Cells; Mechanisms of C3H 10T12 Cell Transformation; Mechanisms of Radiation-Induced Cell Transformation; and Use of Cell Transformation Assays for Carcinogen Testing

  9. The role of pancreatic islets in experimental pancreatic carcinogenicity.

    OpenAIRE

    ISHIKAWA, O; Ohigashi, H.; Imaoka, S.; Nakai, I.; Mitsuo, M.; Weide, L. van der; Pour, P. M.

    1995-01-01

    Our previous studies have suggested that the presence of intact islets is essential for the induction of pancreatic exocrine tumors in the Syrian hamster model. To validate this, we investigated the effect of the carcinogen, N-nitrosobis(2-oxo-propyl)amine (BOP) in hamsters, in which homologous isolated intact islets were transplanted into the submandibular gland (SMG). Freshly isolated pure islets from hamster donors were transplanted into the left SMG of 20 female host hamsters. Ten of thes...

  10. Cannabis and tobacco smoke are not equally carcinogenic

    OpenAIRE

    Melamede Robert

    2005-01-01

    Abstract More people are using the cannabis plant as modern basic and clinical science reaffirms and extends its medicinal uses. Concomitantly, concern and opposition to smoked medicine has occurred, in part due to the known carcinogenic consequences of smoking tobacco. Are these reactions justified? While chemically very similar, there are fundamental differences in the pharmacological properties between cannabis and tobacco smoke. Cannabis smoke contains cannabinoids whereas tobacco smoke c...

  11. Gene discovery for the carcinogenic human liver fluke, Opisthorchis viverrini

    OpenAIRE

    Gasser Robin B; Smout Michael J; Sripa Manop; Sripa Banchob; Mulvenna Jason; Pinlaor Porntip; Laha Thewarach; Brindley Paul J; Loukas Alex

    2007-01-01

    Abstract Background Cholangiocarcinoma (CCA) – cancer of the bile ducts – is associated with chronic infection with the liver fluke, Opisthorchis viverrini. Despite being the only eukaryote that is designated as a 'class I carcinogen' by the International Agency for Research on Cancer, little is known about its genome. Results Approximately 5,000 randomly selected cDNAs from the adult stage of O. viverrini were characterized and accounted for 1,932 contigs, representing ~14% of the entire tra...

  12. Cellular-signaling pathways unveil the carcinogenic potential of chemicals.

    Science.gov (United States)

    Hendriks, Giel; van de Water, Bob; Schoonen, Willem; Vrieling, Harry

    2013-06-01

    Most of the current in vitro carcinogenicity assays assess the potential carcinogenic properties of chemicals through the detection of inflicted DNA damage or subsequent chromosome damage and gene mutations. Unfortunately, these assays generally do not provide mechanistic insight into the reactive properties of a chemical. Upon chemical-induced damage of biomolecules, molecular sensors will activate general and damage-specific cellular response pathways that provide protection against the (geno)toxic and potential carcinogenic properties of chemicals. These cellular defense mechanisms include activation of cell-cycle checkpoints, DNA repair systems and induction of apoptosis or necrosis. Visualization of activated cellular-signaling pathways forms a powerful means to readily detect the genotoxic potential of chemical compounds and simultaneously gain insight into their reactive properties. Over the past years, various in vitro reporter assays have been developed that monitor activation of general and more specific cellular-signaling pathways, including the GreenScreen HC and ToxTracker assays. In this review we provide a perspective on how we can exploit activation of cellular signaling pathways to shed light on the mode of action of the chemical exposure and to develop sophisticated mechanism-based in vitro assays for cancer risk assessment. PMID:23339022

  13. Workplace carcinogen and pesticide exposures in Costa Rica.

    Science.gov (United States)

    Partanen, Timo; Chaves, Jorge; Wesseling, Catharina; Chaverri, Fabio; Monge, Patricia; Ruepert, Clemens; Aragón, Aurora; Kogevinas, Manolis; Hogstedt, Christer; Kauppinen, Timo

    2003-01-01

    The CAREX data system converts national workforce volumes and proportions of workers exposed to workplace carcinogens into numbers of exposed in 55 industrial categories. CAREX was adapted for Costa Rica for 27 carcinogens and seven groups of pesticides. Widespread workplace carcinogens in the 1.3 million workforce of Costa Rica are solar radiation (333,000 workers), diesel engine exhaust (278,000), environmental tobacco smoke (71,000), hexavalent chromium compounds (55,000), benzene (52,000), wood dust (32,000), silica dust (27,000), lead and inorganic lead compounds (19,000), and polycyclic aromatic compounds (17,000). The most ubiquitous pesticides were paraquat and diquat (175,000), mancozeb, maneb, and zineb (49,000), chlorothalonil (38,000), benomyl (19,000), and chlorophenoxy herbicides (11,000). Among women, formaldehyde, radon, and methylene chloride overrode pesticides, chromium, wood dust, and silica dust in numbers of exposed. High-risk sectors included agriculture, construction, personal and household services, land and water transport and allied services, pottery and similar industries, woodworks, mining, forestry and logging, fishing, manufacturing of electrical machinery, and bar and restaurant personnel. PMID:12848237

  14. Potential co-carcinogens in the uranium mine environment

    International Nuclear Information System (INIS)

    Studies of increased incidence of lung cancer in uranium miners have focussed on the relationship between lung cancer and miners' exposure to radon daughters and smoking. However, epidemiologic analyses of uranium miner populations also include the effects of exposure to external gamma rays, long-lived alpha emitters and other non-radioactive workplace contaminants. The diversity and variability of miner exposures to potentially carcinogenic substances and combinations of substances, and the natural difficulties involved in the study of lung cancer in human populations, make the assessment of the relative effects of causative agents difficult if not impossible. Moreover, concentrations of most of the substances have rarely been measured in mine environments, and data on human response to these substances is sparse. Nonetheless, research on the potential effects of such substances is required to understand the potential hazards in the mining environment. This paper examines the potential carcinogenic and co-carcinogenic effects of agents other than ionizing radiation, which may currently be present in uranium mine atmospheres

  15. Artificial sweeteners--do they bear a carcinogenic risk?

    Science.gov (United States)

    Weihrauch, M R; Diehl, V

    2004-10-01

    Artificial sweeteners are added to a wide variety of food, drinks, drugs and hygiene products. Since their introduction, the mass media have reported about potential cancer risks, which has contributed to undermine the public's sense of security. It can be assumed that every citizen of Western countries uses artificial sweeteners, knowingly or not. A cancer-inducing activity of one of these substances would mean a health risk to an entire population. We performed several PubMed searches of the National Library of Medicine for articles in English about artificial sweeteners. These articles included 'first generation' sweeteners such as saccharin, cyclamate and aspartame, as well as 'new generation' sweeteners such as acesulfame-K, sucralose, alitame and neotame. Epidemiological studies in humans did not find the bladder cancer-inducing effects of saccharin and cyclamate that had been reported from animal studies in rats. Despite some rather unscientific assumptions, there is no evidence that aspartame is carcinogenic. Case-control studies showed an elevated relative risk of 1.3 for heavy artificial sweetener use (no specific substances specified) of >1.7 g/day. For new generation sweeteners, it is too early to establish any epidemiological evidence about possible carcinogenic risks. As many artificial sweeteners are combined in today's products, the carcinogenic risk of a single substance is difficult to assess. However, according to the current literature, the possible risk of artificial sweeteners to induce cancer seems to be negligible. PMID:15367404

  16. Evaluation of carcinogenic potential of the herbicide glyphosate, drawing on tumor incidence data from fourteen chronic/carcinogenicity rodent studies.

    Science.gov (United States)

    Greim, Helmut; Saltmiras, David; Mostert, Volker; Strupp, Christian

    2015-03-01

    Abstract Glyphosate, an herbicidal derivative of the amino acid glycine, was introduced to agriculture in the 1970s. Glyphosate targets and blocks a plant metabolic pathway not found in animals, the shikimate pathway, required for the synthesis of aromatic amino acids in plants. After almost forty years of commercial use, and multiple regulatory approvals including toxicology evaluations, literature reviews, and numerous human health risk assessments, the clear and consistent conclusions are that glyphosate is of low toxicological concern, and no concerns exist with respect to glyphosate use and cancer in humans. This manuscript discusses the basis for these conclusions. Most toxicological studies informing regulatory evaluations are of commercial interest and are proprietary in nature. Given the widespread attention to this molecule, the authors gained access to carcinogenicity data submitted to regulatory agencies and present overviews of each study, followed by a weight of evidence evaluation of tumor incidence data. Fourteen carcinogenicity studies (nine rat and five mouse) are evaluated for their individual reliability, and select neoplasms are identified for further evaluation across the data base. The original tumor incidence data from study reports are presented in the online data supplement. There was no evidence of a carcinogenic effect related to glyphosate treatment. The lack of a plausible mechanism, along with published epidemiology studies, which fail to demonstrate clear, statistically significant, unbiased and non-confounded associations between glyphosate and cancer of any single etiology, and a compelling weight of evidence, support the conclusion that glyphosate does not present concern with respect to carcinogenic potential in humans. PMID:25716480

  17. Carcinogenic and Non-Carcinogenic Assessment of Phthalates Exposure Through Consumption of Bottled Water During the Storage Time

    OpenAIRE

    M Zare Jeddi; Rastkari, N.; R Ahmadkhaniha; M Alimohammadi; M. Yunesian

    2015-01-01

    Background and Objectives: Bottles for packaging drinking water represent one of the most popular uses of plastic and polymer additives. Recently, public concerns related to possibility of exposure to chemicals through the consumption of polyethylene terephthalate bottled water has caused great concern to consumers. Phthalate esters, as a class of these compounds, are often classified as endocrine disruptors and one of them is a possible carcinogen for human. The aim of this study was to dete...

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

    Science.gov (United States)

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

    2016-04-01

    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. PMID:26986491

  19. Effect of Radiation on the Functions of Carcinogenic Viruses

    International Nuclear Information System (INIS)

    When carcinogenic viruses are irradiated under suitable experimental conditions with ultra-violet rays or ionizing radiation, the various viral functions can be dissociated and virions defective in certain functions can be obtained. These defects are real mutations; they are passed on to subsequent generations provided the virions affected remain capable of reproduction. It has been possible to obtain various types of mutant, e.g. hyper producers of virions, non-productive transformers, non-transforming producers. The production of these mutants opens up certain experimental possibilities with regard to the transformation mechanism and the possible consequences of irradiation in vivo. Attention will be devoted in particular to the increased oncogenic capability in vivo which is sometimes observed in pre-irradiated viruses, and also to the consequences of this effect in the radiotherapy of certain malignant infections. These studies are also of interest for analysing the structure of the viral genome and throwing light on that fraction of the genome which is responsible for the transforming capacity. In the case of small viruses with a single DNA molecule (polyoma, SV-40) it has been possible to measure the fraction of the molecule responsible for the transforming capacity. In the case of the Rous virus the experiments suggest that the viral RNA is made up of sub-units capable of independent replication, the transforming capacity being possessed by only one of these sub-units. The induced defect may reveal the presence of transforming capacity in a virus considered as non- oncogenic because the transformed cells are usually eliminated by the infective process. In this way irradiation could render carcinogenic a virus which is not carcinogenic under normal conditions. The paper covers work done at the various viral radiobiology laboratories of the Radium Institute during the last two years. (author)

  20. Results of screening NCI/NTP nongenotoxic carcinogens and genotoxic noncarcinogens with the ke test

    International Nuclear Information System (INIS)

    The interdependence of the electrophilic and carcinogenic properties of chemicals that was demonstrated two decades ago rekindled interest in the somatic mutation theory of carcinogenesis. Interest in this theory grew with the development of a reverse-mutation bacterial assay in the laboratory of B.N. Ames that permitted the mutagenic properties of the chemicals to be determined quickly and yielded results which indicated that ''carcinogens are mutagens.'' Subsequent validation studies of this bioassay, the Salmonella typhimurium/microsome or ''Ames test,'' by Ames' group and others provided additional support for the correlation between mutagenicity and carcinogenicity which led to the worldwide deployment of the Ames test in thousands of laboratories and to the development of more than 100 other short-term tests that continue to be used to identify potential carcinogens via various end-points of genotoxicity. This document discusses electrophilicity, mutagenicity, and carcinogenicity relationships as well as carcinogen-screening of chemicals. 28 refs., 4 tabs

  1. Prostaglandin hydroperoxidase-catalyzed activation of certain N-substituted aryl renal and bladder carcinogens

    OpenAIRE

    Zenser, T V; Cohen, S M; Mattammal, M. B.; Wise, R. W.; Rapp, N. S.; Davis, B B

    1983-01-01

    Certain carcinogens are thought to induce renal and bladder cancer following metabolic activation. We propose a model system for this activation and provide supporting experimental evidence. This model proposes that renal and bladder carcinogens' entry into the urinary tract is facilitated, that carcinogens are activated by the prostaglandin hydroperoxidase activity of prostaglandin endoperoxide synthetase (PES), and that activation results in covalent binding to nucleic acids which can initi...

  2. Discrimination of Carcinogens by Hepatic Transcript Profiling in Rats Following 28-day Administration

    Directory of Open Access Journals (Sweden)

    Hiroshi Matsumoto

    2009-11-01

    Full Text Available This study aimed at discriminating carcinogens on the basis of hepatic transcript profiling in the rats administrated with a variety of carcinogens and non-carcinogens. We conducted 28-day toxicity tests in male F344 rats with 47 carcinogens and 26 non- carcinogens, and then investigated periodically the hepatic gene expression profiles using custom microarrays. By hierarchical cluster analysis based on significantly altered genes, carcinogens were clustered into three major groups (Group 1 to 3. The formation of these groups was not affected by the gene sets used as well as the administration period, indicating that the grouping of carcinogens was universal independent of the conditions of both statistical analysis and toxicity testing. Seventeen carcinogens belonging to Group 1 were composed of mainly rat hepatocarcinogens, most of them being mutagenic ones. Group 2 was formed by three subgroups, which were composed of 23 carcinogens exhibiting distinct properties in terms of genotoxicity and target tissues, namely nonmutagenic hepatocarcinogens, and mutagenic and nonmutagenic carcinogens both of which are targeted to other tissues. Group 3 contained 6 carcinogens including 4 estrogenic substances, implying the group of estrogenic carcinogens. Gene network analyses revealed that the significantly altered genes in Group 1 included Bax, Tnfrsf6, Btg2, Mgmt and Abcb1b, suggesting that p53-mediated signaling pathway involved in early pathologic alterations associated with preceding mutagenic carcinogenesis. Thus, the common transcriptional signatures for each group might reflect the early molecular events of carcinogenesis and hence would enable us to identify the biomarker genes, and then to develop a new assay for carcinogenesis prediction.

  3. Predicting carcinogenicity of organic compounds based on CPDB.

    Science.gov (United States)

    Wu, Xiuchao; Zhang, Qingzhu; Wang, Hui; Hu, Jingtian

    2015-11-01

    Cancer is a major killer of human health and predictions for the carcinogenicity of chemicals are of great importance. In this article, predictive models for the carcinogenicity of organic compounds using QSAR methods for rats and mice were developed based on the data from CPDB. The models was developed based on the data of specific target site liver and classified according to sex of rats and mice. Meanwhile, models were also classified according to whether there is a ring in the molecular structure in order to reduce the diversity of molecular structure. Therefore, eight local models were developed in the final. Taking into account the complexity of carcinogenesis and in order to obtain as much information, DRAGON descriptors were selected as the variables used to develop models. Fitting ability, robustness and predictive power of the models were assessed according to the OECD principles. The external predictive coefficients for validation sets of each model were in the range of 0.711-0.906, and for the whole data in each model were all greater than 0.8, which represents that all models have good predictivity. In order to study the mechanism of carcinogenesis, standardized regression coefficients were calculated for all predictor variables. In addition, the effect of animal sex on carcinogenesis was compared and a trend that female showed stronger tolerance for cancerogen than male in both species was appeared. PMID:26070146

  4. Ochratoxin A carcinogenicity involves a complex network of epigenetic mechanisms.

    Science.gov (United States)

    Marin-Kuan, Maricel; Cavin, Christophe; Delatour, Thierry; Schilter, Benoît

    2008-08-01

    Ochratoxin A (OTA) is a mycotoxin occurring in a wide range of food products. Because of the limitation of human epidemiological data, the safety significance of OTA in food has to rely on animal data, with renal toxicity and carcinogenicity being considered the pivotal effects. The elucidation of the mechanism of action would improve the use of experimental animal data for risk assessment. Direct genotoxicity versus epigenetic mechanisms appears to be a key question. In the present review, the increasingly documented epigenetic cellular effects of OTA and their potential toxicological relevance are discussed. The information available suggests that OTA is unlikely to act through a single, well-defined mechanism of action. Instead, it is proposed that a network of interacting epigenetic mechanisms, including protein synthesis inhibition, oxidative stress and the activation of specific cell signalling pathways, is responsible for OTA carcinogenicity. From a risk assessment perspective, it has to be noted that the mechanisms proposed above depend mainly upon gene expression and enzyme activation, and are, therefore, likely to be thresholded. PMID:18649906

  5. Carcinogenic effects ofcircadian disruption:an epigenetic viewpoint

    Institute of Scientific and Technical Information of China (English)

    Abbas Salavaty

    2015-01-01

    Circadian rhythms refer to the endogenous rhythms that are generated to synchronize physiology and behavior with 24-h environmental cues. These rhythms are regulated by both external cues and molecular clock mechanisms in almost all cells. Disruption of circadian rhythms, which is called circadian disruption, affects many biological processes within the body and results in different long-term diseases, including cancer. Circadian regulatory pathways result in rhythmic epigenetic modiifcations and the formation of circadian epigenomes. Aberrant epigenetic modiifcations, such as hypermethylation, due to circadian disruption may be involved in the transformation of normal cells into cancer cells. Several studies have indicated an epigenetic basis for the carcinogenic effects of circadian disruption. In this review, I ifrst discuss some of the circadian genes and regulatory proteins. Then, I summarize the current evidence related to the epigenetic modiifcations that result in circadian disruption. In addition, I explain the carcinogenic effects of circadian disruption and highlight its potential role in different human cancers using an epigenetic view-point. Finally, the importance of chronotherapy in cancer treatment is highlighted.

  6. Review of genotoxicity and rat carcinogenicity investigations with astaxanthin.

    Science.gov (United States)

    Edwards, James A; Bellion, Phillip; Beilstein, Paul; Rümbeli, Robert; Schierle, Joseph

    2016-03-01

    Synthetic astaxanthin has been extensively tested for safety. Genotoxicity studies including Ames and in vitro Micronucleus Tests show absence of genotoxic potential. Although a long-term mouse study showed no carcinogenicity potential, the rat carcinogenicity study with dietary dosages of 0 (control), 0 (placebo beadlet), 40, 200 and 1000 mg astaxanthin/kg bw/day showed an increased incidence of benign, hepatocellular adenoma in females only, at 200 mg/kg bw/day and above. There was no clear evidence of toxicity during the in-life phase. Discoloration of feces was observed and a reduction in body weight gain in all groups receiving beadlets, probably reflecting a nutritional influence. Blood sampling confirmed systemic exposure and some minor clinical chemistry differences in females at 200 and 1000 mg/kg bw/day. There was no effect on adjusted liver weight. Histopathological examination showed hepatic changes indicative of slight hepatotoxicity and hepatocyte regeneration in females at 200 and 1000 mg/kg bw/day, in addition to the adenoma. Taking into account this pathological background in the female rat, and a wide variety of other supporting information, it is concluded that the hepatocellular adenoma in female rats was secondary to hepatotoxicity and regeneration, and is most probably a species-specific phenomenon of doubtful human relevance. PMID:26713891

  7. Carcinogen specific dosimetry model for passive smokers of various ages

    International Nuclear Information System (INIS)

    Studies indicate that being exposed to second hand smoke increases the chance of developing lung cancer. Understanding the deposition of carcinogenic particles present in second hand smoke is necessary to understand the development of specific histologic type cancers. In this study, a deposition model is presented for subjects of various ages exposed to sidestream smoke. The model included particle dynamics of coagulation, hygroscopic growth, charge and cloud behavior. Concentrations were varied from the maximum measured indoor concentrations (106 particles/cm3) to what would be expected from wisps of smoke (108 particles/cm3). Model results agreed well with experimental data taken from human subject deposition measurements (four studies). The model results were used to determine the dose intensity (dose per unit airway surface area) of Benzo[a]pyrene (BaP) in the respiratory tract for subjects of various ages. Model predictions for BaP surface concentration on the airway walls paralleled incident rates of tumors by location in the upper tracheobronchial region. Mass deposition efficiency was found to be larger for younger subjects, consistent with diffusion being the predominant mechanism for this particle size range. However, the actual dose intensity of BaP was found to be smaller for children than adults. This occurred due to the predominant effect of the smaller initial inhaled mass for children resulting from smaller tidal volumes. The resulting model is a useful tool to predict carcinogen specific particle deposition

  8. Systems biology perspectives on the carcinogenic potential of radiation

    International Nuclear Information System (INIS)

    This review focuses on recent experimental and modeling studies that attempt to define the physiological context in which high linear energy transfer (LET) radiation increases epithelial cancer risk and the efficiency with which it does so. Radiation carcinogenesis is a two-compartment problem: ionizing radiation can alter genomic sequence as a result of damage due to targeted effects (TE) from the interaction of energy and DNA; it can also alter phenotype and multicellular interactions that contribute to cancer by poorly understood non-targeted effects (NTE). Rather than being secondary to DNA damage and mutations that can initiate cancer, radiation NTE create the critical context in which to promote cancer. Systems biology modeling using comprehensive experimental data that integrates different levels of biological organization and time-scales is a means of identifying the key processes underlying the carcinogenic potential of high-LET radiation. We hypothesize that inflammation is a key process, and thus cancer susceptibility will depend on specific genetic predisposition to the type and duration of this response. Systems genetics using novel mouse models can be used to identify such determinants of susceptibility to cancer in radiation sensitive tissues following high-LET radiation. Improved understanding of radiation carcinogenesis achieved by defining the relative contribution of NTE carcinogenic effects and identifying the genetic determinants of the high-LET cancer susceptibility will help reduce uncertainties in radiation risk assessment

  9. Formaldehyde in dentistry: a review of mutagenic and carcinogenic potential

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, B.B.; Chestner, S.B.

    1981-09-01

    For many years there has been controversy over the value of antimicrobial drugs for intracanal dressings in endodontics. Formocresol, a formaldehyde compound, has evolved as the preferred drug for routine endodontic procedures, as well as pediatric endodontics. The increase in the use of formaldehyde has been complicated by the introduction of paraformaldehyde pastes for filling root canals. Neither of these formulas has ever been standardized. The doses are arbitrary, and the common dose of formocresol has been shown to be many times greater than the minimum dose needed for effect. The efficacy of paraformaldehyde pastes is questionable and remains clouded by inconclusive evidence, conflicting research, inadequate terminology, and a lack of convincing statistical evidence. The clinical use and delivery of formocresol and paraformaldehyde pastes remain arbitrary and unscientific. Formaldehyde has a known toxic mutagenic and carcinogenic potential. Many investigations have been conducted to measure the risk of exposure to formaldehyde; it is clear that formaldehyde poses a carcinogenic risk in humans. There is a need to reevaluate the rationale underlying the use of formaldehyde in dentistry particularly in light of its deleterious effects.

  10. Neoplastic transformation of human diploid fibroblast cells by chemical carcinogens

    Science.gov (United States)

    Kakunaga, Takeo

    1978-01-01

    Cultured fibroblast cells derived from a skin biopsy sample taken from normal human adult were exposed to a potent carcinogen, 4-nitroquinoline 1-oxide. Alterations of cell growth pattern such as higher density and piling up of cells were noticed in some fractions of cultures that were successively subcultured after nitroquinoline oxide treatment. Morphologically altered cells retained this growth pattern and became established lines of transformed cells without showing the limited life-span characteristic of normal cells in culture. The transformed cells showed a higher saturation density and the ability to grow in soft agar, properties that are usually correlated with neoplastic transformation of cells in culture. Selection of preexisting transformed human cells as a mechanism of this observed transformation seemed unlikely because clones of these normal cells could also be used to assess the transforming effect of nitroquinoline oxide. Preliminary results suggest that numerous cell divisions were required for the development of the transformation after nitroquinoline oxide treatment of these human cells. When the transformed cell lines were injected subcutaneously into nude (athymic) mice, solid tumors were produced at the site of inoculation. Treatment with N-methyl-N′-nitro-N-nitrosoguanidine also induced cell transformation, in a manner similar to treatment with nitroquinoline oxide. However, transformation was not induced with (i) 4-aminoquinoline 1-oxide (a noncarcinogenic derivative of 4-nitroquinoline 1-oxide), (ii) 3-methylcholanthrene (a carcinogen that cannot be metabolically activated by the target cells employed), or (iii) the solvent dimethyl sulfoxide. Images PMID:418410

  11. Predicting carcinogenicity of diverse chemicals using probabilistic neural network modeling approaches

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Kunwar P., E-mail: kpsingh_52@yahoo.com [Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research, New Delhi (India); Environmental Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box 80, Mahatma Gandhi Marg, Lucknow 226 001 (India); Gupta, Shikha; Rai, Premanjali [Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research, New Delhi (India); Environmental Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box 80, Mahatma Gandhi Marg, Lucknow 226 001 (India)

    2013-10-15

    Robust global models capable of discriminating positive and non-positive carcinogens; and predicting carcinogenic potency of chemicals in rodents were developed. The dataset of 834 structurally diverse chemicals extracted from Carcinogenic Potency Database (CPDB) was used which contained 466 positive and 368 non-positive carcinogens. Twelve non-quantum mechanical molecular descriptors were derived. Structural diversity of the chemicals and nonlinearity in the data were evaluated using Tanimoto similarity index and Brock–Dechert–Scheinkman statistics. Probabilistic neural network (PNN) and generalized regression neural network (GRNN) models were constructed for classification and function optimization problems using the carcinogenicity end point in rat. Validation of the models was performed using the internal and external procedures employing a wide series of statistical checks. PNN constructed using five descriptors rendered classification accuracy of 92.09% in complete rat data. The PNN model rendered classification accuracies of 91.77%, 80.70% and 92.08% in mouse, hamster and pesticide data, respectively. The GRNN constructed with nine descriptors yielded correlation coefficient of 0.896 between the measured and predicted carcinogenic potency with mean squared error (MSE) of 0.44 in complete rat data. The rat carcinogenicity model (GRNN) applied to the mouse and hamster data yielded correlation coefficient and MSE of 0.758, 0.71 and 0.760, 0.46, respectively. The results suggest for wide applicability of the inter-species models in predicting carcinogenic potency of chemicals. Both the PNN and GRNN (inter-species) models constructed here can be useful tools in predicting the carcinogenicity of new chemicals for regulatory purposes. - Graphical abstract: Figure (a) shows classification accuracies (positive and non-positive carcinogens) in rat, mouse, hamster, and pesticide data yielded by optimal PNN model. Figure (b) shows generalization and predictive

  12. Molecular basis of carcinogenicity of tungsten alloy particles

    International Nuclear Information System (INIS)

    The tungsten alloy of 91% tungsten, 6% nickel and 3% cobalt (WNC 91–6–3) induces rhabdomyosarcoma when implanted into a rat thigh muscle. To investigate whether this effect is species-specific human HSkMc primary muscle cells were exposed to WNC 91–6–3 particles and responses were compared with those from a rat skeletal muscle cell line (L6-C11). Toxicity was assessed by the adenylate kinase assay and microscopy, DNA damage by the Comet assay. Caspase 3 enzyme activity was measured and oligonucleotide microarrays were used for transcriptional profiling. WNC 91–6–3 particles caused toxicity in cells adjacent to the particles and also increased DNA strand breaks. Inhibition of caspase 3 by WNC 91–6–3 occurred in rat but not in human cells. In both rat and human cells, the transcriptional response to WNC 91–6–3 showed repression of transcripts encoding muscle-specific proteins with induction of glycolysis, hypoxia, stress responses and transcripts associated with DNA damage and cell death. In human cells, genes encoding metallothioneins were also induced, together with genes related to angiogenesis, dysregulation of apoptosis and proliferation consistent with pre-neoplastic changes. An alloy containing iron, WNF 97–2–1, which is non-carcinogenic in vivo in rats, did not show these transcriptional changes in vitro in either species while the corresponding cobalt-containing alloy, WNC 97–2–1 elicited similar responses to WNC 91–6–3. Tungsten alloys containing both nickel and cobalt therefore have the potential to be carcinogenic in man and in vitro assays coupled with transcriptomics can be used to identify alloys, which may lead to tumour formation, by dysregulation of biochemical processes. - Highlights: • Use of transcriptomics to identify likely carcinogenic tungsten alloys in vitro • Cobalt containing alloys cause oxidative stress, DNA-damage and perturb apoptosis. • Presence of cobalt causes changes in gene expression

  13. Molecular biomarkers of oxidative stress associated with bromate carcinogenicity

    International Nuclear Information System (INIS)

    Potassium bromate (KBrO3) is a chemical oxidizing agent found in drinking water as a disinfection byproduct of surface water ozonation. Chronic exposures to KBrO3 cause renal cell tumors in rats, hamsters and mice and thyroid and testicular mesothelial tumors in rats. Experimental evidence indicates that bromate mediates toxicological effects via the induction of oxidative stress. To investigate the contribution of oxidative stress in KBrO3-induced cancer, male F344 rats were administered KBrO3 in their drinking water at multiple concentrations for 2-100 weeks. Gene expression analyses were performed on kidney, thyroid and mesothelial cell RNA. Families of mRNA transcripts differentially expressed with respect to bromate treatment included multiple cancer, cell death, ion transport and oxidative stress genes. Multiple glutathione metabolism genes were up-regulated in kidney following carcinogenic (400 mg/L) but not non-carcinogenic (20 mg/L) bromate exposures. 8-Oxodeoxyguanosine glycosylase (Ogg1) mRNA was up-regulated in response to bromate treatment in kidney but not thyroid. A dramatic decrease in global gene expression changes was observed following 1 mg/L compared to 20 mg/L bromate exposures. In a separate study oxygen-18 (18O) labeled KBrO3 was administered to male rats by oral gavage and tissues were analyzed for 18O deposition. Tissue enrichment of 18O was observed at 5 and 24 h post-KBr18O3 exposure with the highest enrichment occurring in the liver followed by the kidney, thyroid and testes. The kidney dose response observed was biphasic showing similar statistical increases in 18O deposition between 0.25 and 50 mg/L (equivalent dose) KBr18O3 followed by a much greater increase above 50 mg/L. These results suggest that carcinogenic doses of potassium bromate require attainment of a threshold at which oxidation of tissues occurs and that gene expression profiles may be predictive of these physiological changes in renal homeostasis

  14. Molecular basis of carcinogenicity of tungsten alloy particles

    Energy Technology Data Exchange (ETDEWEB)

    Harris, Robert M.; Williams, Tim D.; Waring, Rosemary H.; Hodges, Nikolas J., E-mail: n.hodges@bham.ac.uk

    2015-03-15

    The tungsten alloy of 91% tungsten, 6% nickel and 3% cobalt (WNC 91–6–3) induces rhabdomyosarcoma when implanted into a rat thigh muscle. To investigate whether this effect is species-specific human HSkMc primary muscle cells were exposed to WNC 91–6–3 particles and responses were compared with those from a rat skeletal muscle cell line (L6-C11). Toxicity was assessed by the adenylate kinase assay and microscopy, DNA damage by the Comet assay. Caspase 3 enzyme activity was measured and oligonucleotide microarrays were used for transcriptional profiling. WNC 91–6–3 particles caused toxicity in cells adjacent to the particles and also increased DNA strand breaks. Inhibition of caspase 3 by WNC 91–6–3 occurred in rat but not in human cells. In both rat and human cells, the transcriptional response to WNC 91–6–3 showed repression of transcripts encoding muscle-specific proteins with induction of glycolysis, hypoxia, stress responses and transcripts associated with DNA damage and cell death. In human cells, genes encoding metallothioneins were also induced, together with genes related to angiogenesis, dysregulation of apoptosis and proliferation consistent with pre-neoplastic changes. An alloy containing iron, WNF 97–2–1, which is non-carcinogenic in vivo in rats, did not show these transcriptional changes in vitro in either species while the corresponding cobalt-containing alloy, WNC 97–2–1 elicited similar responses to WNC 91–6–3. Tungsten alloys containing both nickel and cobalt therefore have the potential to be carcinogenic in man and in vitro assays coupled with transcriptomics can be used to identify alloys, which may lead to tumour formation, by dysregulation of biochemical processes. - Highlights: • Use of transcriptomics to identify likely carcinogenic tungsten alloys in vitro • Cobalt containing alloys cause oxidative stress, DNA-damage and perturb apoptosis. • Presence of cobalt causes changes in gene expression

  15. IARC Monographs: 40 Years of Evaluating Carcinogenic Hazards to Humans

    Science.gov (United States)

    Blair, Aaron; Vineis, Paolo; Ahrens, Wolfgang; Andersen, Aage; Anto, Josep M.; Armstrong, Bruce K.; Baccarelli, Andrea A.; Beland, Frederick A.; Berrington, Amy; Bertazzi, Pier Alberto; Birnbaum, Linda S.; Brownson, Ross C.; Bucher, John R.; Cantor, Kenneth P.; Cardis, Elisabeth; Cherrie, John W.; Christiani, David C.; Cocco, Pierluigi; Coggon, David; Comba, Pietro; Demers, Paul A.; Dement, John M.; Douwes, Jeroen; Eisen, Ellen A.; Engel, Lawrence S.; Fenske, Richard A.; Fleming, Lora E.; Fletcher, Tony; Fontham, Elizabeth; Forastiere, Francesco; Frentzel-Beyme, Rainer; Fritschi, Lin; Gerin, Michel; Goldberg, Marcel; Grandjean, Philippe; Grimsrud, Tom K.; Gustavsson, Per; Haines, Andy; Hartge, Patricia; Hansen, Johnni; Hauptmann, Michael; Heederik, Dick; Hemminki, Kari; Hemon, Denis; Hertz-Picciotto, Irva; Hoppin, Jane A.; Huff, James; Jarvholm, Bengt; Kang, Daehee; Karagas, Margaret R.; Kjaerheim, Kristina; Kjuus, Helge; Kogevinas, Manolis; Kriebel, David; Kristensen, Petter; Kromhout, Hans; Laden, Francine; Lebailly, Pierre; LeMasters, Grace; Lubin, Jay H.; Lynch, Charles F.; Lynge, Elsebeth; ‘t Mannetje, Andrea; McMichael, Anthony J.; McLaughlin, John R.; Marrett, Loraine; Martuzzi, Marco; Merchant, James A.; Merler, Enzo; Merletti, Franco; Miller, Anthony; Mirer, Franklin E.; Monson, Richard; Nordby, Karl-Cristian; Olshan, Andrew F.; Parent, Marie-Elise; Perera, Frederica P.; Perry, Melissa J.; Pesatori, Angela Cecilia; Pirastu, Roberta; Porta, Miquel; Pukkala, Eero; Rice, Carol; Richardson, David B.; Ritter, Leonard; Ritz, Beate; Ronckers, Cecile M.; Rushton, Lesley; Rusiecki, Jennifer A.; Rusyn, Ivan; Samet, Jonathan M.; Sandler, Dale P.; de Sanjose, Silvia; Schernhammer, Eva; Costantini, Adele Seniori; Seixas, Noah; Shy, Carl; Siemiatycki, Jack; Silverman, Debra T.; Simonato, Lorenzo; Smith, Allan H.; Smith, Martyn T.; Spinelli, John J.; Spitz, Margaret R.; Stallones, Lorann; Stayner, Leslie T.; Steenland, Kyle; Stenzel, Mark; Stewart, Bernard W.; Stewart, Patricia A.; Symanski, Elaine; Terracini, Benedetto; Tolbert, Paige E.; Vainio, Harri; Vena, John; Vermeulen, Roel; Victora, Cesar G.; Ward, Elizabeth M.; Weinberg, Clarice R.; Weisenburger, Dennis; Wesseling, Catharina; Weiderpass, Elisabete; Zahm, Shelia Hoar

    2015-01-01

    Background: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans. Objectives: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed. Discussion: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed. Conclusions: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public’s health. Citation: Pearce N, Blair A, Vineis P, Ahrens W, Andersen A, Anto JM, Armstrong BK, Baccarelli AA, Beland FA, Berrington A, Bertazzi PA, Birnbaum LS, Brownson RC, Bucher JR, Cantor KP

  16. Screening tests for determination of cytotoxic agent, mutagens and carcinogens

    Energy Technology Data Exchange (ETDEWEB)

    Spiegelberg, T.; Koerdel, W.; Goertz, T.; Thriemer, A.

    1983-01-01

    It is supposed that chemical substances are the primary factors responsible for the development of tumors and genetic damages. From this results the urgend demand to examine at least the frequently applied and suspicious substances on possibly health-affecting effects. The performance of these examinations with experimental animals requires a lot of time and financial support and has increasingly been criticised in public with regard to protection of animals. Experience gained in the U.S.A. revealed that the carcinogenicity test of one single substance performed with animal experiments takes approximately 3 years and costs about 300,000 Dollars. Therefore the application of cell cultures for such examinations and tests has been postulated and discussed for several years. Cell cultures require only little space and generally the observed effects develop after only a short time. Objectification and statistical assessment (due to high cell amounts per test) can be performed without any problems.

  17. Occurrence of the carcinogenic compound ptaquiloside in the soil environment

    DEFF Research Database (Denmark)

    Rasmussen, Lars Holm; Kroghsbo, Stine; Frisvad, Jens Christian;

    2003-01-01

    Bracken (Pteridium aquilinum (L.) Kuhn) is a common fern found on all continents except Antarctica. It is under suspicion of causing cancer among people who utilizes it as food. The main carcinogenic compound is thought to be the water-soluble compound ptaquiloside. Ptaquiloside-uptake may occur....... The ptaquiloside-content in the standing biomass, which could be transferred to the soil by the end of the growing season, ranged between 10 and 260 mgm2, with nine sites having ptaquiloside loads over 100 mgm2. The carbon-content in the O-horizon, the precipitation, the amount of Bracken-litter, the...... turnover rate and the size of Bracken-stands determined the ptaquiloside-content in the soil materials while the content in fronds was found to be a function of the frond-height and the light-exposure in the ecosystem....

  18. The Weight of Evidence Does Not Support the Listing of Styrene as "Reasonably Anticipated to be a Human Carcinogen" in NTP's Twelfth Report on Carcinogens.

    Science.gov (United States)

    Rhomberg, Lorenz R; Goodman, Julie E; Prueitt, Robyn L

    2013-01-01

    Styrene was listed as "reasonably anticipated to be a human carcinogen" in the twelfth edition of the National Toxicology Program's Report on Carcinogens based on what we contend are erroneous findings of limited evidence of carcinogenicity in humans, sufficient evidence of carcinogenicity in experimental animals, and supporting mechanistic data. The epidemiology studies show no consistent increased incidence of, or mortality from, any type of cancer. In animal studies, increased incidence rates of mostly benign tumors have been observed only in certain strains of one species (mice) and at one tissue site (lung). The lack of concordance of tumor incidence and tumor type among animals (even within the same species) and humans indicates that there has been no particular cancer consistently observed among all available studies. The only plausible mechanism for styrene-induced carcinogenesis-a non-genotoxic mode of action that is specific to the mouse lung-is not relevant to humans. As a whole, the evidence does not support the characterization of styrene as "reasonably anticipated to be a human carcinogen," and styrene should not be listed in the Report on Carcinogens. PMID:23335843

  19. A carcinogenicity study of sucralose in the CD-1 mouse.

    Science.gov (United States)

    Mann, S W; Yuschak, M M; Amyes, S J; Aughton, P; Finn, J P

    2000-01-01

    The potential carcinogenicity of sucralose was evaluated by feeding groups of 52 male and 52 female CD-1 mice a diet containing sucralose at 0.3% (3000 ppm), 1.0% (10,000 ppm) or 3.0% (30,000 ppm) for 104 weeks. A group of 72 male and 72 female mice received diet without sucralose and served as controls. Week 1 achieved doses ranging from 543 to 5870mg/kg body weight/day in the low-dose males and high-dose females, respectively. Sucralose had no adverse effect on survival. No significant changes attributable to sucralose were found in the clinical condition or behaviour of the mice. Organ weights and the gross appearance of tissues were unaffected by treatment. The mean erythrocyte counts of females receiving the highest dietary concentration were slightly, but statistically significantly, lower than those of the controls after 104 weeks of treatment. Group mean body weight gain at the highest dietary concentration of sucralose was significantly less than that of the control in mice of both sexes. Food consumption, after correction for sucralose content, was lower for female mice, but not statistically significant. Water consumption for male mice receiving the highest dietary concentration was approximately 9% higher than that of the controls. There were statistically significant increases in the incidence of several non-neoplastic findings, but these were not considered to be related to sucralose administration. Treatment with sucralose did not increase the incidence of any tumour or influence the types of tumours observed. It was concluded that sucralose is not carcinogenic in CD-1 mice. The body weight gain and erythrocyte observations at the 3.0% dietary level were of limited biological significance as they were not accompanied by any histopathologic finding and had no impact on survival. The remaining dose levels were judged to have no effects. PMID:10882820

  20. The carcinogenicity of dietary acrylamide intake: A comparative discussion of epidemiological and experimental animal research

    NARCIS (Netherlands)

    Hogervorst, J.G.F.; Baars, B.-J.; Schouten, L.J.; Konings, E.J.M.; Goldbohm, R.A.; Brandt, P.A. van den

    2010-01-01

    Since 2002, it is known that the probable human carcinogen acrylamide is present in commonly consumed carbohydrate-rich foods, such as French fries and potato chips. In this review, the authors discuss the body of evidence on acrylamide carcinogenicity from both epidemiological and rodent studies, i

  1. Study of isotopic tracing related with mechanism of cancer caused by carcinogenic substance

    International Nuclear Information System (INIS)

    In order to understand the mechanism of cancer caused by carcinogenic substance, a project using 41Ca as tracer and accelerator mass spectrometry (AMS) as measurement method to investigate the origin of the increased Ca2+ when the cells are exposed to carcinogenic substances is being undertaken. Several results as bellow have been obtained

  2. Carcinogenic potential of some pesticides in a medium-term multi-organ bioassay in rats.

    Science.gov (United States)

    Hasegawa, R; Cabral, R; Hoshiya, T; Hakoi, K; Ogiso, T; Boonyaphiphat, P; Shirai, T; Ito, N

    1993-05-28

    The carcinogenic potential of 5 pesticides was analyzed using a medium-term multi-organ bioassay for carcinogenicity. Male F344 rats were initially treated with 3 known carcinogens (diethylnitrosamine, N-methyl-N-nitrosourea and N-bis(2-hydroxypropyl)nitrosamine) during a period of 4 weeks to induce neoplastic changes in a variety of organs, and then given one of 5 pesticides in the diet for a further 16 weeks. Neoplastic and pre-neoplastic lesions were found in the thyroid, kidney and urinary bladder with propineb, in the forestomach, kidney and thyroid with captan and folpet. The number of glutathione S-transferase placental-form-positive liver-cell foci was significantly increased in the captan- and phosmet-treated groups. Based on these findings, captan and propineb can be considered as carcinogens and carcinogenicity is suspected for folpet and phosmet. These results are in concordance with reported long-term carcinogenicity for captan, folpet and propineb. Daminozide was considered not to be carcinogenic. Thus, the present assay of 20 weeks' duration is useful for the prediction of potential carcinogens. PMID:8509224

  3. Micro-total envelope system with silicon nanowire separator for safe carcinogenic chemistry

    Science.gov (United States)

    Singh, Ajay K.; Ko, Dong-Hyeon; Vishwakarma, Niraj K.; Jang, Seungwook; Min, Kyoung-Ik; Kim, Dong-Pyo

    2016-01-01

    Exploration and expansion of the chemistries involving toxic or carcinogenic reagents are severely limited by the health hazards their presence poses. Here, we present a micro-total envelope system (μ-TES) and an automated total process for the generation of the carcinogenic reagent, its purification and its utilization for a desired synthesis that is totally enveloped from being exposed to the carcinogen. A unique microseparator is developed on the basis of SiNWs structure to replace the usual exposure-prone distillation in separating the generated reagent. Chloromethyl methyl ether chemistry is explored as a carcinogenic model in demonstrating the efficiency of the μ-TES that is fully automated so that feeding the ingredients for the generation is all it takes to produce the desired product. Syntheses taking days can be accomplished safely in minutes with excellent yields, which bodes well for elevating the carcinogenic chemistry to new unexplored dimensions. PMID:26916423

  4. The in vivo rodent test systems for assessment of carcinogenic potential

    DEFF Research Database (Denmark)

    van der Laan, Jan-Willem; Spindler, Per

    2002-01-01

    mouse models, the RasH2 and Tg.AC transgenic mouse models, and the neonatal mouse model. The "ICH Guideline S1B on Testing for Carcinogenicity of Pharmaceuticals" advocates that carcinogenicity testing of pharmaceuticals, when needed, might be carried out choosing one 2-year rodent carcinogenicity study...... (rat) plus one other study that supplements the 2-year study and providing additional information that is not readily available from the 2-year study: either (1) a short- or medium-term in vivo rodent test system or (2) a 2-year carcinogenicity study in a second rodent species (mouse). Another topic of...... end of 2001. The use of the short- and medium-term rodent test systems were not considered appropriate for the assessment of carcinogenic potential of biotechnology-derived medicinal products....

  5. Micro-total envelope system with silicon nanowire separator for safe carcinogenic chemistry.

    Science.gov (United States)

    Singh, Ajay K; Ko, Dong-Hyeon; Vishwakarma, Niraj K; Jang, Seungwook; Min, Kyoung-Ik; Kim, Dong-Pyo

    2016-01-01

    Exploration and expansion of the chemistries involving toxic or carcinogenic reagents are severely limited by the health hazards their presence poses. Here, we present a micro-total envelope system (μ-TES) and an automated total process for the generation of the carcinogenic reagent, its purification and its utilization for a desired synthesis that is totally enveloped from being exposed to the carcinogen. A unique microseparator is developed on the basis of SiNWs structure to replace the usual exposure-prone distillation in separating the generated reagent. Chloromethyl methyl ether chemistry is explored as a carcinogenic model in demonstrating the efficiency of the μ-TES that is fully automated so that feeding the ingredients for the generation is all it takes to produce the desired product. Syntheses taking days can be accomplished safely in minutes with excellent yields, which bodes well for elevating the carcinogenic chemistry to new unexplored dimensions. PMID:26916423

  6. Enhanced replication of UV-damaged Simian virus 40 DNA in carcinogen-treated mammalian cells

    International Nuclear Information System (INIS)

    The replication of UV-damaged Simian virus 40 (SV40) in carcinogen-treated monkey cells has been studied to elucidate the mechanism of carcinogen-enhanced reactivation. Carcinogen enhanced reactivation is the observed increase in UV-irradiated virus survival in host cells treated with low doses of carcinogen compared to UV-irradiated virus survival in untreated hosts. Carcinogen treatment of monkey kidney cells with either N-acetoxy-2-acetylaminofluorene (AAAF) or UV radiation leads to an enhanced capacity to replicate UV-damaged virus during the first round of infection. To further define the mechanism leading to enhanced replication, a detailed biochemical analysis of replication intermediates in carcinogen-treated cells was performed. Several conclusions can be drawn. First enhanced replication can be observed in the first four rounds of replication after UV irradiation of viral templates. The second major finding is that the relaxed circular intermediate model proposed for the replication of UV-damaged templates in untreated cells appears valid for replication of UV-damaged templates in carcinogen-treated cells. Possible mechanisms and the supporting evidence are discussed and future experiments outlined

  7. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline

    Directory of Open Access Journals (Sweden)

    Buonaguro Franco M

    2009-06-01

    Full Text Available Abstract Virtually all cases of cervical cancer are caused by persistent infections with a restricted set of human papillomaviruses (HPV. Some HPV types, like HPV16 and HPV18, are clear and powerful carcinogens. However, the categorization of the most weakly carcinogenic HPV types is extremely challenging. The decisions are important for screening test and vaccine development. This article describes for open discussion an approach recently taken by a World Health Organization International Agency for Research on Cancer (IARC Monographs Working Group to re-assess the carcinogenicity of different HPV types.

  8. Childhood cancer: Overview of incidence trends and environmental carcinogens

    Energy Technology Data Exchange (ETDEWEB)

    Zahm, S.H.; Devesa, S.S. [National Cancer Inst., Rockville, MD (United States)

    1995-09-01

    An estimated 8000 children 0 to 14 years of age are diagnosed annually with cancer in the United States. Leukemia and brain tumors are the most common childhood malignancies, accounting for 30 and 20% of newly diagnosed cases, respectively. From 1975 to 1978 to 1987 to 1990, cancer among white children increased slightly from 12.8 to 14.1/100,000. Increases are suggested for leukemia, gliomas, and, to a much lesser extent, Wilms` tumor. There are a few well-established environmental causes of childhood cancer such as radiation, chemotherapeutic agents, and diethylstilbestrol. Many other agents such as electromagnetic fields, pesticides, and some parental occupational exposures are suspected of playing roles, but the evidence is not conclusive at this time. Some childhood exposures such as secondhand cigarette smoke may contribute to cancers that develop many years after childhood. For some exposures such as radiation and pesticides data suggest that children may be more susceptible to the carcinogenic effects than similarly exposed adults. 143 refs., 1 fig., 3 tabs.

  9. Urban air carcinogens and their effects on health

    Energy Technology Data Exchange (ETDEWEB)

    Lechner, J.F.

    1994-11-01

    Airborne carcinogens may be relevant especially in metropolitan regions with extreme smog as a primary cause of lung cancer. Lung cancer is most common in urban environs and the incidence directly correlates with the size of the city. In addition, several, but not all formal epidemiological studies also suggest a positive correlation between lung cancer incidence and the intensity of air pollution exposure. There is further support for a role of air pollution; as of 1993, 4.4% of all of the bronchogenic adenocarcinoma cancer cases among Mexicans living in industrialized cities are under 40 years of age. It is plausible that chronic inhalation of automobile combustion products, factory emissions, and/or radon is at least partially responsible for the higher incidence of lung cancer exemplified by the never-smoking urban residents. The exceptionally high incidence of lung cancer cases among never-smokers living in highly industrialized Mexican cities offers a unique opportunity to use molecular epidemiology to test whether chronic inhalation of atmospheric pollutants increases the risk for this disease. Overall, the analysis of the genetic alterations in two cancer genes, and possibly the hprt locus should give new insight as to whether the urban never-smokers developed their cancers because of exposure to environmental pollutants.

  10. [Urban air pollution by carcinogenic N-nitrosamines].

    Science.gov (United States)

    Khesina, A Ia; Krivosheeva, L V; Sokol'skaia, N N; Koliadich, M N

    1996-01-01

    Moscow is used as an example to discuss the problem of urban atmospheric pollution by carcinogenic N-nitrosamines. An analytical method is proposed, which is based on the use of a Russian gas chromatograph compatible with a chemiluminescence detector, that is a TEA thermal energy analyzer (USA) having some modifications to reduce the time of analysis and loss during sample pretreatment. The minimal detected concentration is 3 ng/m3 for 2-hour sampling. The method identifies and quantifies 7 volatile N-nitrosamines: N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine, N-nitrosodibutylamine, N-nitrosodipropylamine, N-nitrosopiperidine, N-nitrosopyrrolidine, N-nitrosomorpholine. The pollution of the Moscow air was evaluated in the center of Moscow (30-60 ng/m3 for NDMA), in the industrial emission area (as high as several hundred ng/m3, and in the heavy traffic area (100 ng/m3 or more). It is proposed to study the working area for rubber and tire industries, to establish nitrosamine tolerances for these industries and maximum allowable discharge concentrations in the urban air and to monitor these parameters. PMID:8672956

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

    Science.gov (United States)

    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.

  12. Determination of potentially carcinogenic compounds in food : trace analysis of vinylchloride, vinylidenechloride, acrylonitrile, epichlorohydrin and diethylpyrocarbonate

    NARCIS (Netherlands)

    Lierop, van J.B.H.

    1979-01-01

    Toxicological evidence shows that some monomers present in packaging materials may be carcinogenic. These monomers, notably vinylchloride, vinylidenechloride, acrylonitrile and epichlorohydrin, may migrate from the packaging material into the food. Therefore, severe limits are set to the contents of

  13. AI AND SAR APPROACHES FOR PREDICTING CHEMICAL CARCINOGENICITY: SURVEY AND STATUS REPORT

    Science.gov (United States)

    A wide variety of artificial intelligence (AI) and structure-activity relationship (SAR approaches have been applied to tackling the general problem of predicting rodent chemical carcinogenicity. Given the diversity of chemical structures and mechanisms relative to this endpoin...

  14. An investigation of carcinogenic agents at the Mississippi Sandhill Crane National Wildlife Refuge

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This report summarizes a study with the following results: 1. Three of the metals reported as carcinogens, arsenic, chromium, and nickel, were found within the...

  15. 78 FR 15020 - Report on Carcinogens Webinar on Pentachlorophenol; Notice of Public Webinar and Registration...

    Science.gov (United States)

    2013-03-08

    ... HUMAN SERVICES National Institutes of Health Report on Carcinogens Webinar on Pentachlorophenol; Notice of Public Webinar and Registration Information SUMMARY: The National Toxicology Program (NTP) announces a public webinar, ``Human cancer studies on exposure to pentachlorophenol (PCP):...

  16. Carcinogenicity prediction of noncongeneric chemicals by augmented top priority fragment classification.

    Science.gov (United States)

    Casalegno, Mosè; Sello, Guido

    2016-04-01

    Carcinogenicity prediction is an important process that can be performed to cut down experimental costs and save animal lives. The current reliability of the results is however disputed. Here, a blind exercise in carcinogenicity category assessment is performed using augmented top priority fragment classification. The procedure analyses the applicability domain of the dataset, allocates in clusters the compounds using a leading molecular fragment, and a similarity measure. The exercise is applied to three compound datasets derived from the Lois Gold Carcinogenic Database. The results, showing good agreement with experimental data, are compared with published ones. A final discussion on our viewpoint on the possibilities that the carcinogenicity modelling of chemical compounds offers is presented. PMID:26878128

  17. A review of biosensing techniques for detection of trace carcinogen contamination in food products.

    Science.gov (United States)

    Li, Zhanming; Yu, Yue; Li, Zhiliang; Wu, Tao

    2015-04-01

    Carcinogen contaminations in the food chain, for example heavy metal ions, pesticides, acrylamide, and mycotoxins, have caused serious health problems. A major objective of food-safety research is the identification and prevention of exposure to these carcinogens, because of their impossible-to-reverse tumorigenic effects. However, carcinogen detection is difficult because of their trace-level presence in food. Thus, reliable and accurate separation and determination methods are essential to protect food safety and human health. This paper summarizes the state of the art in separation and determination methods for analyzing carcinogen contamination, especially the advances in biosensing methods. Furthermore, the application of promising technology including nanomaterials, imprinted polymers, and microdevices is detailed. Challenges and perspectives are also discussed. PMID:25694149

  18. 78 FR 57868 - Nominations to the Report on Carcinogens; Request for Information

    Science.gov (United States)

    2013-09-20

    ... RoC. 20 Substances Nominated to the RoC* Aloe vera whole leaf extract (Aloe barbadensis Miller) 2..., ongoing, or planned studies related to evaluating carcinogenicity; (3) scientific issues important...

  19. Occupational toxicants. Critical data evaluation for MAK values and classification of carcinogens. Vol. 4

    International Nuclear Information System (INIS)

    33 occupational toxicants are reviewed. Data are presented according to toxic effects in animals and man, mode of action, carcinogenicity, genotoxicity, reproductive and development toxicity, and MAK value. (MG)

  20. Biomarkers for assessing potential carcinogenic effects of chronic arsenic exposure in Inner Mongolia, CHINA

    Science.gov (United States)

    Arsenic is ubiquitous in the environment. Chronic arsenic exposure via drinking water has been associated. with carcinogenic, cardiovascular, neurological and diabetic effects in humans and has been of great public health concern worldwide. In 2001, U.S. Environmental Protection ...

  1. An Analysis of the Role of Tobacco-Specific Nitrosamines in the Carcinogenicity of Tobacco Smoke

    OpenAIRE

    Brown, Buddy G.; Borschke, August J.; Doolittle, David J.

    2003-01-01

    Cigarette smoke is a complex mixture consisting of more than 4500 chemicals, including several tobacco-specific nitrosamines (TSNA). TSNA typically form in tobacco during the post-harvest period, with some fraction being transferred into mainstream smoke when a cigarette is burned during use. The most studied of the TSNA is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK has been shown to be carcinogenic in laboratory animals. Studies examining the carcinogenicity of NNK frequently ...

  2. Perturbation of Mitosis through Inhibition of Histone Acetyltransferases: The Key to Ochratoxin A Toxicity and Carcinogenicity?

    OpenAIRE

    Czakai, Kristin; Müller, Katja; Mosesso, Pasquale; Pepe, Gaetano; Schulze, Markus; Gohla, Antje; Patnaik, Debasis; Dekant, Wolfgang; Higgins, Jonathan M.G.; Mally, Angela

    2011-01-01

    Ochratoxin A (OTA) is one of the most potent rodent renal carcinogens studied to date. Although controversial results regarding OTA genotoxicity have been published, it is now widely accepted that OTA is not a mutagenic, DNA-reactive carcinogen. Instead, increasing evidence from both in vivo and in vitro studies suggests that OTA may promote genomic instability and tumorigenesis through interference with cell division. The aim of the present study was to provide further support for disruption...

  3. Recent developments in the multistage modeling of cohort data for carcinogenic risk assessment.

    OpenAIRE

    Mazumdar, S; Redmond, C K; Costantino, J P; Patwardhan, R N; Zhou, S. Y.

    1991-01-01

    The modeling of cohort data based on the Armitage-Doll multistage model of the carcinogenic process has gained popular acceptance as a methodology for quantitative risk assessment for estimating the dose-related relationships between different occupational and environmental carcinogenic exposures and cancer mortality. The multistage model can be used for extrapolation to low doses relevant for setting environmental standards and also provides information regarding whether more than one stage ...

  4. Carcinogenic effects of the combined action of /sup 241/Am and. gamma. -radiation

    Energy Technology Data Exchange (ETDEWEB)

    Filippova, L.G.; Buldakov, L.A.; Nifatov, A.P. (Institut Biofiziki, Moscow (USSR))

    In experiments on Wistar rats a study was made of the carcinogenic effects of the combined exposure to /sup 241/Am administered intrapertioneally (6.7 to 229.4 kBq/kg body weight) and external ..gamma..-radiation (/sup 137/Cs, 175 cGy). The occurrence of osteosarcoma, leucosis, skin and mammary tumors increased in the exposed animals. The combined irradiation produced an additive carcinogenic effect.

  5. A review of the genotoxic and carcinogenic effects of aspartame: does it safe or not?

    OpenAIRE

    Yılmaz, Serkan; Uçar, Aslı

    2014-01-01

    The objective of this article is to review genotoxicologic and carcinogenic profile of the artificial sweetener aspartame. Aspartame is a synthetic dipeptide, nearly 180–200 times sweeter than sucrose. It is the most widely used artificial sweetener especially in carbonated and powdered soft drinks, beverages, drugs and hygiene products. There is a discussion ongoing for many years whether aspartame posses genotoxic and carcinogenic risk for humans. This question led to many studies to specif...

  6. In vivo transgenic bioassays and assessment of the carcinogenic potential of pharmaceuticals.

    OpenAIRE

    Contrera, J F; DeGeorge, J J

    1998-01-01

    There is general agreement in the scientific community on the need to improve carcinogenicity testing and the assessment of human carcinogenic risk and to incorporate more information on mechanisms and modes of action into the risk assessment process. Advances in molecular biology have identified a growing number of genes such as protooncogenes and tumor-suppressor genes that are highly conserved across species and are associated with a wide variety of human and animal cancers. In vivo transg...

  7. Carcinogenic effects of the combined action of 241Am and γ-radiation

    International Nuclear Information System (INIS)

    In experiments on Wistar rats a study was made of the carcinogenic effects of the combined exposure to 241Am administered intrapertioneally (6.7 to 229.4 kBq/kg body weight) and external γ-radiation (137Cs, 175 cGy). The occurrence of osteosarcoma, leucosis, skin and mammary tumors increased in the exposed animals. The combined irradiation prodUced an additive carcinogenic effect

  8. Analysis of carcinogenicity testing for regulatory purposes in the European Union

    OpenAIRE

    MADIA FEDERICA; Worth, Andrew; Corvi, Raffaella

    2016-01-01

    The approaches for evaluating the carcinogenic potential of substances, including whether carcinogenicity studies should be conducted, differ substantially across sectors. Despite variations in testing schemes, the two-year bioassay study in rodents represents the standard element across all sectors. The validity of the two-year bioassay though has been questioned in the last decade. Uncertainty is associated with the extrapolation of data from rodents to humans. Furthermore, these stud...

  9. Carcinogens in Israeli milk: a study in regulatory failure.

    Science.gov (United States)

    Westin, J B

    1993-01-01

    The potential danger to humans of exposure to chemicals shown to be carcinogenic in animals has become increasingly clear in the last 20 years. A gap still exists, however, between the appreciation of the risk by scientists and the willingness of public health authorities to reduce it. Three pesticides, shown repeatedly to produce over a dozen different types of cancer in rats and mice, were discovered in inordinately high concentrations in Israeli milk and dairy products. The three pesticides--alpha-BHC, gamma-BHC (lindane), and DDT--had been shown to be present for ten years or more at mean concentrations up to 100 times those found in U.S. dairy products--with resultant concentrations in breast milk being possibly 800 times greater than those in the United States--yet neither the Ministry of Health nor the Israel Cancer Association made any apparent moves either to warn the public or to rectify the situation. A small consumer organization, Consumer Shield, brought the issue into the open. Through public pressure, court action, and the threat of further legal redress--and despite repeated attacks in the media by the milk producers, the Ministry, and the Cancer Association--Consumer Shield forced the authorities to outlaw the use of alpha-BHC and lindane (DDT no longer being in general use). The ban resulted in a precipitous drop in the concentrations of these substances in Israeli milk. Recent epidemiological and laboratory findings suggest that the dramatic drop in breast cancer mortality rates subsequent to the pesticide ban could be a direct result of that ban. PMID:8375952

  10. Gene discovery for the carcinogenic human liver fluke, Opisthorchis viverrini

    Directory of Open Access Journals (Sweden)

    Gasser Robin B

    2007-06-01

    Full Text Available Abstract Background Cholangiocarcinoma (CCA – cancer of the bile ducts – is associated with chronic infection with the liver fluke, Opisthorchis viverrini. Despite being the only eukaryote that is designated as a 'class I carcinogen' by the International Agency for Research on Cancer, little is known about its genome. Results Approximately 5,000 randomly selected cDNAs from the adult stage of O. viverrini were characterized and accounted for 1,932 contigs, representing ~14% of the entire transcriptome, and, presently, the largest sequence dataset for any species of liver fluke. Twenty percent of contigs were assigned GO classifications. Abundantly represented protein families included those involved in physiological functions that are essential to parasitism, such as anaerobic respiration, reproduction, detoxification, surface maintenance and feeding. GO assignments were well conserved in relation to other parasitic flukes, however, some categories were over-represented in O. viverrini, such as structural and motor proteins. An assessment of evolutionary relationships showed that O. viverrini was more similar to other parasitic (Clonorchis sinensis and Schistosoma japonicum than to free-living (Schmidtea mediterranea flatworms, and 105 sequences had close homologues in both parasitic species but not in S. mediterranea. A total of 164 O. viverrini contigs contained ORFs with signal sequences, many of which were platyhelminth-specific. Examples of convergent evolution between host and parasite secreted/membrane proteins were identified as were homologues of vaccine antigens from other helminths. Finally, ORFs representing secreted proteins with known roles in tumorigenesis were identified, and these might play roles in the pathogenesis of O. viverrini-induced CCA. Conclusion This gene discovery effort for O. viverrini should expedite molecular studies of cholangiocarcinogenesis and accelerate research focused on developing new interventions

  11. Carcinogenicity assessments of biotechnology-derived pharmaceuticals: a review of approved molecules and best practice recommendations.

    Science.gov (United States)

    Vahle, John L; Finch, Gregory L; Heidel, Shawn M; Hovland, David N; Ivens, Inge; Parker, Suezanne; Ponce, Rafael A; Sachs, Clifford; Steigerwalt, Ronald; Short, Brian; Todd, Marque D

    2010-06-01

    An important safety consideration for developing new therapeutics is assessing the potential that the therapy will increase the risk of cancer. For biotherapeutics, traditional two-year rodent bioassays are often not scientifically applicable or feasible. This paper is a collaborative effort of industry toxicologists to review past and current practice regarding carcinogenicity assessments of biotherapeutics and to provide recommendations. Publicly available information on eighty marketed protein biotherapeutics was reviewed. In this review, no assessments related to carcinogenicity or tumor growth promotion were identified for fifty-one of the eighty molecules. For the twenty-nine biotherapeutics in which assessments related to carcinogenicity were identified, various experimental approaches were employed. This review also discusses several key principles to aid in the assessment of carcinogenic potential, including (1) careful consideration of mechanism of action to identify theoretical risks, (2) careful investigation of existing data for indications of proliferative or immunosuppressive potential, and (3) characterization of any proliferative or immunosuppressive signals detected. Traditional two-year carcinogenicity assays should not be considered as the default method for assessing the carcinogenicity potential of biotherapeutics. If experimentation is considered warranted, it should be hypothesis driven and may include a variety of experimental models. Ultimately, it is important that preclinical data provide useful guidance in product labeling. PMID:20472697

  12. Effect of DNA type on response of DNA biosensor for carcinogens

    Science.gov (United States)

    Sani, Nor Diyana bt. Md.; Heng, Lee Yook; Surif, Salmijah; Lazim, Azwani Mat

    2013-11-01

    Carcinogens are cancer causing chemicals that can bind to DNA and cause damage to the DNA. These chemicals are available everywhere including in water, air, soil and food. Therefore, a sensor that can detect the presence of these chemicals will be a very useful tool. Since carcinogens bind to DNA, DNA can be used as the biological element in a biosensor. This study has utilized different types of DNA in a biosensor for carcinogen detection. The DNAs include double stranded calf thymus DNA, single stranded calf thymus DNA and guanine rich single stranded DNA. The modified SPE was exposed to a carcinogen followed by interaction with methylene blue which acts as the electroactive indicator. The SPE was then analysed using differential pulse voltammetry (DPV). Optimization studies were conducted for MB concentration and accumulation time, DNA concentration, as well as effect of buffer concentration, buffer pH and ionic strength. The performance of the biosensor was tested on a group 1 carcinogen, formaldehyde. The results indicated that the usage of guanine rich single stranded DNA also gives higher response as carcinogens prefer to bind with guanine compared to other bases.

  13. A comprehensive review of the carcinogenic and anticarcinogenic potential of capsaicin.

    Science.gov (United States)

    Bley, Keith; Boorman, Gary; Mohammad, Bashir; McKenzie, Donald; Babbar, Sunita

    2012-08-01

    Human exposure to capsaicin, the most abundant pungent chili pepper component, is ubiquitous. Evaluation of capsaicin's carcinogenic potential has produced variable results in in vitro and in vivo genotoxicity and carcinogenicity assays. The capsaicin tested in older studies was often from pepper plant extracts and included other capsaicinoids and diverse impurities. Recent studies utilizing high-purity capsaicin and standardized protocols provide evidence that the genotoxic and carcinogenic potential of capsaicin is quite low and that the purity of capsaicin is important. Several small epidemiological studies suggest a link between capsaicin consumption and stomach or gall bladder cancer, but contamination of capsaicin-containing foods with known carcinogens renders their interpretation problematic. The postulated ability of capsaicin metabolites to damage DNA and promote carcinogenesis remains unsupported. Anticancer activities of capsaicin have been widely reported, as it inhibits the activity of carcinogens and induces apoptosis in numerous cancer cell lines in vitro and explanted into rodents. Diverse mechanisms have been postulated for capsaicin's anticancer properties. One hypothesis is that inhibition of cytochrome P450 enzymes-particularly CYP2E1-retards carcinogen activation but is contradicted by the low potency of capsaicin for CYP inhibition. The potential for dietary capsaicin to act as a chemopreventative is now widely postulated. PMID:22563012

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

    OpenAIRE

    Purdy, R.

    1996-01-01

    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, ...

  15. Evaluation of human health risks posed by carcinogenic and non-carcinogenic multiple contaminants associated with consumption of fish from Taihu Lake, China.

    Science.gov (United States)

    Yu, Yingxin; Wang, Xinxin; Yang, Dan; Lei, Bingli; Zhang, Xiaolan; Zhang, Xinyu

    2014-07-01

    The present study estimated the human daily intake and uptake of organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs), and toxic trace elements [mercury (Hg), chromium (Cr), cadmium (Cd), and arsenic (As)] due to consumption of fish from Taihu Lake, China, and the associated potential health risks posed by these contaminants. The health risks posed by the contaminants were assessed using a risk quotient of the fish consumption rate to the maximum allowable fish consumption rate considering the contaminants for carcinogenic and non-carcinogenic effect endpoints. The results showed that fish consumption would not pose non-cancer risks. However, some species would cause a cancer risk. Relative risks of the contaminants were calculated to investigate the contaminant which posed the highest risk to humans. As a result, in view of the contaminants for carcinogenic effects, As was the contaminant which posed the highest risk to humans. However, when non-carcinogenic effects of the contaminants were considered, Hg posed the highest risk. The risk caused by PBDEs was negligible. The results demonstrated that traditional contaminants, such as As, Hg, DDTs (dichlorodiphenyltrichloroethane and its metabolites), and PCBs, require more attention in Taihu Lake than the other target contaminants. PMID:24727049

  16. Comparison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver

    International Nuclear Information System (INIS)

    Application of recently developed gene expression techniques using microarrays in toxicological studies (toxicogenomics) facilitate the interpretation of a toxic compound's mode of action and may also allow the prediction of selected toxic effects based on gene expression changes. In order to test this hypothesis, we investigated whether carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate characteristic sets of genes in a short term in vivo study and whether these deregulated genes represent defined biological pathways. Male Wistar rats were dosed with the four nongenotoxic hepatocarcinogens methapyrilene (MPy, 60 mg/kg/day), diethylstilbestrol (DES, 10 mg/kg/day), Wy-14643 (Wy, 60 mg/kg/day), and piperonylbutoxide (PBO, 1200 mg/kg/day). After 1, 3, 7, and 14 days, the livers were taken for histopathological evaluation and for analysis of the gene expression profiles on Affymetrix RGU34A arrays. The expression profile of the four nongenotoxic carcinogens were compared to the profiles of the four genotoxic carcinogens 2-nitrofluorene (2-NF), dimethylnitrosamine (DMN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and aflatoxin B1 (AB1) from a similar study reported previously. By using statistical and clustering tools characteristically deregulated genes were extracted and functionally classified. Distinct cellular pathways were affected by the nongenotoxic carcinogens compared to the genotoxic carcinogens which at least partly correlated with the two-stage model of carcinogenesis. Characteristic to genotoxic carcinogens were a DNA damage response and the activation of proliferative and survival signaling. Nongenotoxic carcinogens showed responses to oxidative DNA or protein damage, as well as cell cycle progression and signs of regeneration. Many of the gene alterations found with the nongenotoxic carcinogens imply compound-specific mechanisms. Although neither a single gene nor a single pathway will be sufficient to

  17. Comparison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver

    Energy Technology Data Exchange (ETDEWEB)

    Ellinger-Ziegelbauer, Heidrun [Bayer Healthcare AG, Department of Molecular and Genetic Toxicology, Aprather Weg 18a, 42096 Wuppertal (Germany)]. E-mail: heidrun.ellinger-ziegelbauer@bayerhealthcare.com; Stuart, Barry [Bayer Crop Science, Department of Toxicology, Stilwell, KS (United States); Wahle, Brad [Bayer Crop Science, Department of Toxicology, Stilwell, KS (United States); Bomann, Werner [Bayer Crop Science, Department of Toxicology, Stilwell, KS (United States); Ahr, Hans Juergen [Bayer Healthcare AG, Department of Molecular and Genetic Toxicology, Aprather Weg 18a, 42096 Wuppertal (Germany)

    2005-08-04

    Application of recently developed gene expression techniques using microarrays in toxicological studies (toxicogenomics) facilitate the interpretation of a toxic compound's mode of action and may also allow the prediction of selected toxic effects based on gene expression changes. In order to test this hypothesis, we investigated whether carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate characteristic sets of genes in a short term in vivo study and whether these deregulated genes represent defined biological pathways. Male Wistar rats were dosed with the four nongenotoxic hepatocarcinogens methapyrilene (MPy, 60 mg/kg/day), diethylstilbestrol (DES, 10 mg/kg/day), Wy-14643 (Wy, 60 mg/kg/day), and piperonylbutoxide (PBO, 1200 mg/kg/day). After 1, 3, 7, and 14 days, the livers were taken for histopathological evaluation and for analysis of the gene expression profiles on Affymetrix RG{sub U}34A arrays. The expression profile of the four nongenotoxic carcinogens were compared to the profiles of the four genotoxic carcinogens 2-nitrofluorene (2-NF), dimethylnitrosamine (DMN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and aflatoxin B1 (AB1) from a similar study reported previously. By using statistical and clustering tools characteristically deregulated genes were extracted and functionally classified. Distinct cellular pathways were affected by the nongenotoxic carcinogens compared to the genotoxic carcinogens which at least partly correlated with the two-stage model of carcinogenesis. Characteristic to genotoxic carcinogens were a DNA damage response and the activation of proliferative and survival signaling. Nongenotoxic carcinogens showed responses to oxidative DNA or protein damage, as well as cell cycle progression and signs of regeneration. Many of the gene alterations found with the nongenotoxic carcinogens imply compound-specific mechanisms. Although neither a single gene nor a single pathway will be

  18. Use of the modified Ames test as an indicator of the carcinogenicity of residual aromatic extracts

    Energy Technology Data Exchange (ETDEWEB)

    Boogaard, P.; Hedelin, A.; Riley, A.; Rushton, E.; Vaissiere, M.; Minsavage, G.; Rohde, A.; Dalbey, W.

    2013-01-15

    Existing data demonstrate that residual aromatic extracts (RAEs) can be either carcinogenic or non-carcinogenic. CONCAWE had previously concluded that 'Although limited data available indicate that some RAEs are weakly carcinogenic, it is not possible to provide a general recommendation. Classify on a case-by-case basis' (CONCAWE 2005). Therefore CONCAWE's Health/Toxicology Subgroup (H/TSG) has developed a proposal for the use of the modified Ames test as a short-term predictive screening tool for decisions on the classification of RAEs for carcinogenicity. The relationship between RAE chemistry and carcinogenic potential is not as well understood as it is for some other categories of substances, e.g. Other Lubricant Base Oils (OLBO). However, a correlation has been found between the results of the skin carcinogenicity bioassay and the mutagenicity index (MI) obtained from the modified Ames test. Data supporting this correlation are summarised in this report. The H/TSG confirmed that the modified Ames test can be used as a predictive screening tool and that a cut-off value can be established to make a distinction between carcinogenic and non-carcinogenic products. RAEs with a MI > 0.4 demonstrated carcinogenic potential upon dermal application to mouse skin with chronic exposure. RAEs with a MI > 0.4 did not demonstrate a carcinogenic potential. To justify the use of the modified Ames test with RAEs, additional analysis of the repeatability of the test with RAEs was required. With this objective, CONCAWE sponsored a round robin study with different samples of RAEs from member companies, at three different laboratories. The repeatability demonstrated in the round robin study with RAEs support the proposed use of the modified Ames test. As part of the tools available for use by member companies, the H/TSG proposed a standard operating procedure (SOP) (included as an Appendix to this report) on the conduct of the modified Ames test with RAEs. The H

  19. Development of quantitative structure-activity relationship (QSAR) models to predict the carcinogenic potency of chemicals

    International Nuclear Information System (INIS)

    Determining the carcinogenicity and carcinogenic potency of new chemicals is both a labor-intensive and time-consuming process. In order to expedite the screening process, there is a need to identify alternative toxicity measures that may be used as surrogates for carcinogenic potency. Alternative toxicity measures for carcinogenic potency currently being used in the literature include lethal dose (dose that kills 50% of a study population [LD50]), lowest-observed-adverse-effect-level (LOAEL) and maximum tolerated dose (MTD). The purpose of this study was to investigate the correlation between tumor dose (TD50) and three alternative toxicity measures as an estimator of carcinogenic potency. A second aim of this study was to develop a Classification and Regression Tree (CART) between TD50 and estimated/experimental predictor variables to predict the carcinogenic potency of new chemicals. Rat TD50s of 590 structurally diverse chemicals were obtained from the Cancer Potency Database, and the three alternative toxicity measures considered in this study were estimated using TOPKAT, a toxicity estimation software. Though poor correlations were obtained between carcinogenic potency and the three alternative toxicity (both experimental and TOPKAT) measures for the CPDB chemicals, a CART developed using experimental data with no missing values as predictor variables provided reasonable estimates of TD50 for nine chemicals that were part of an external validation set. However, if experimental values for the three alternative measures, mutagenicity and logP are not available in the literature, then either the CART developed using missing experimental values or estimated values may be used for making a prediction

  20. Detection of genotoxic and non-genotoxic carcinogens in Xpc−/−p53+/− mice

    International Nuclear Information System (INIS)

    An accurate assessment of the carcinogenic potential of chemicals and pharmaceutical drugs is essential to protect humans and the environment. Therefore, substances are extensively tested before they are marketed to the public. Currently, the rodent two-year bioassay is still routinely used to assess the carcinogenic potential of substances. However, over time it has become clear that this assay yields false positive results and also has several economic and ethical drawbacks including the use of large numbers of animals, the long duration, and the high cost. The need for a suitable alternative assay is therefore high. Previously, we have proposed the Xpa*p53 mouse model as a very suitable alternative to the two-year bioassay. We now show that the Xpc*p53 mouse model preserves all the beneficial traits of the Xpa*p53 model for sub-chronic carcinogen identification and can identify both genotoxic and non-genotoxic carcinogens. Moreover, Xpc*p53 mice appear to be more responsive than Xpa*p53 mice towards several genotoxic and non-genotoxic carcinogens. Furthermore, Xpc*p53 mice are far less sensitive than Xpa*p53 mice for the toxic activity of DNA damaging agents and as such clearly respond in a similar way as wild type mice do. These advantageous traits of the Xpc*p53 model make it a better alternative for in vivo carcinogen testing than Xpa*p53. This pilot study suggests that Xpc*p53 mice are suited for routine sub-chronic testing of both genotoxic and non-genotoxic carcinogens and as such represent a suitable alternative to possibly replace the murine life time cancer bioassay. Highlights: ► The Xpc*p53 mouse model is able to identify genotoxic and non-genotoxic carcinogens. ► Time, animals and cost can be significantly reduced compared to the 2-year bioassay. ► Xpc*p53 mice are more advantageous for carcinogen identification than Xpa*p53 mice. ► Xpc*p53 mice exhibit a wild type response upon exposure to genotoxicants.

  1. Opportunities for an alternative integrating testing strategy for carcinogen hazard assessment?

    Science.gov (United States)

    Doktorova, Tatyana Y; Pauwels, Marleen; Vinken, Mathieu; Vanhaecke, Tamara; Rogiers, Vera

    2012-02-01

    The 2-year rodent carcinogenicity bioassay evolved more than 40 years ago, and although it is complex, long lasting, expensive, and animal consuming, it is still the only generally accepted test for assessing the carcinogenicity of chemicals. Over time, different alternative approaches have been developed with the final goal to replace the bioassay. Unfortunately, at present, none of these strategies alone provides sufficient assurance of accurate prediction. In this review paper, we discuss the major advantages and pitfalls of the existing alternative methodologies to the carcinogenicity bioassay. Finally, based on the available scientific data in the public domain, we propose what we would like to call a "feasible integrated testing strategy" which incorporates some promising alternatives, providing at the same time information on the mechanism of action and the toxic nature of the compounds tested. It is, however, clear that the adoption of whatever "new" testing scheme should be considered with caution and its effectiveness should be experimentally demonstrated in advance by addressing a reasonable number of chemical carcinogens and non-carcinogens from a variety of structural and functional classes. PMID:22141324

  2. Partial lipectomy reduces dimethylhydrazine-induced carcinogenic initiation in the colon of rats

    International Nuclear Information System (INIS)

    This study investigated whether visceral adipose tissue directly modulates the development of preneoplastic lesions in the colon of carcinogen-treated rats. Wistar rats (n = 64) were randomly assigned to 8 experimental groups in two experiments. In one experiment, 32 rats were exposed or not to either carcinogen treatment (dimethylhydrazine, DMH; 125 mg/kg) or high-fat diet (standard chow enriched with 14% lard) or both for 56 days. In a second experiment, 32 rats were exposed to a carcinogen or they underwent partial lipectomy or both for 30 days (partial lipectomy groups underwent ablation of mesenteric and parametrial fat pads, whereas sham groups did not; all rats were fed with standard chow). Colon was collected for histopathological analysis. After 56 experimental days a high-fat diet increased carcinogenic mutations in the colonic epithelia. Partial lipectomy reduced weight gain in carcinogen-exposed rats and decreased the de novo formation of mesenteric and parametrial fat pads. Partial lipectomy significantly inhibited the mutational process after 30 days: there were fewer colonic preneoplastic lesions and less proliferation, apoptosis, and inflammation. These data suggest that visceral adipose tissue promotes colon carcinogenesis and enhances the establishment and expansion of genetically mutated cells in colonic epithelia

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

    International Nuclear Information System (INIS)

    Prevention of environmentally induced cancers is a major health problem of which solutions depend on the rapid and accurate screening of potential chemical hazards. Lately, theoretical approaches such as the one proposed here - Quantitative Structure-Activity Relationship (QSAR) - are increasingly used for assessing the risks of environmental chemicals, since they can markedly reduce costs, avoid animal testing, and speed up policy decisions. This paper reports a QSAR study based on the Topological Substructural Molecular Design (TOPS-MODE) approach, aiming at predicting the rodent carcinogenicity of a set of nitroso-compounds selected from the Carcinogenic Potency Data Base (CPDB). The set comprises nitrosoureas (14 chemicals), N-nitrosamines (18 chemicals) C-nitroso-compounds (1 chemical), nitrosourethane (1 chemical) and nitrosoguanidine (1 chemical), which have been bioassayed in male rat using gavage as the route of administration. Here we are especially concerned in gathering the role of both parameters on the carcinogenic activity of this family of compounds. First, the regression model was derived, upon removal of one identified nitrosamine outlier, and was able to account for more than 84% of the variance in the experimental activity. Second, the TOPS-MODE approach afforded the bond contributions - expressed as fragment contributions to the carcinogenic activity - that can be interpreted and provide tools for better understanding the mechanisms of carcinogenesis. Finally, and most importantly, we demonstrate the potentialities of this approach towards the recognition of structural alerts for carcinogenicity predictions

  4. Is peroxisome proliferation an obligatory precursor step in the carcinogenicity of di(2-ethylhexyl)phthalate (DEHP)?

    OpenAIRE

    Melnick, R L

    2001-01-01

    Di(2-ethylhexyl)phthalate (DEHP), a peroxisome proliferator, has been listed by the International Agency for Research on Cancer (IARC) and by the National Toxicology Program as a possible or reasonably anticipated human carcinogen because it induces dose-related increases in liver tumors in both sexes of rats and mice. Recently, the suggestion has been advanced that DEHP should be considered unlikely to be a human carcinogen because it is claimed that the carcinogenic effects of this agent in...

  5. Production of thymine glycols in DNA by radiation and chemical carcinogens as detected by a monoclonal antibody.

    OpenAIRE

    Leadon, S A

    1987-01-01

    In order to understand the role in carcinogenesis of damage indirectly induced by chemical carcinogens, it is important to identify the primary DNA lesions. We have measured the formation and repair of one type of DNA modification, 5,6-dihydroxydihydrothymine (thymine glycol), following exposure of cultured human cells to the carcinogens N-hydroxy-2-naphthylamine or benzo(a)pyrene. The efficiency of production of thymine glycols in DNA by these carcinogens was compared to that by ionizing rad...

  6. Modulation of carcinogen bioavailability by immunisation with benzo[a]pyrene-conjugate vaccines.

    Science.gov (United States)

    Grova, Nathalie; Prodhomme, Emmanuel J F; Schellenberger, Mario T; Farinelle, Sophie; Muller, Claude P

    2009-06-24

    Benzo[a]pyrene (B[a]P) conjugate vaccines based on ovalbumin, tetanus toxoid and diphtheria toxoid (DT) as carrier proteins were developed to investigate the effect of specific antibodies on the bioavailability of this ubiquitous carcinogen and its metabolites. After metabolic activation of this prototype carcinogen, B[a]P forms DNA adducts which initiate chemical carcinogenesis. B[a]P-DT conjugate induced the most robust immune response. The antibodies reacted not only with B[a]P but also with the proximate carcinogen 7,8-diol-B[a]P. Antibodies modulated the bioavailability of B[a]P and its metabolic activation in a dose-dependent manner by sequestration in the blood. Our results showed that this immune prophylactic strategy influences the pharmacokinetic of B[a]P and further studies to investigate their effects on chemical carcinogenesis are warranted. PMID:19406187

  7. Factors modifying sensitivity to carcinogens and the problem of threshold in carcinogenesis

    International Nuclear Information System (INIS)

    Maximum allowable concentrations of chemical carcinogens and dose rates of ionizing radiation have been under extensive study both experimentally and epidemiologically. The problem of the carcinogenic hazards of low-level radiation is a very difficult one: in epidemiological studies it is hard to take into account the many factors (e.g. diseases, diet, genetic peculiarities) that may affect sensitivity to radiation; in experimental studies it is hard to extrapolate with accuracy from one species to another or from the individual threshold to that of the whole population. Age, enzyme activity, sex, and DNA repair capability also modify sensitivity to radiation; when factors such as these are better understood it is expected that epidemiological studies will give a solution that allows estimation of the carcinogenic risk from low-level radiation and hence establishment of a threshold dose. (author)

  8. A review of the genotoxic and carcinogenic effects of aspartame: does it safe or not?

    Science.gov (United States)

    Yılmaz, Serkan; Uçar, Aslı

    2014-12-01

    The objective of this article is to review genotoxicologic and carcinogenic profile of the artificial sweetener aspartame. Aspartame is a synthetic dipeptide, nearly 180-200 times sweeter than sucrose. It is the most widely used artificial sweetener especially in carbonated and powdered soft drinks, beverages, drugs and hygiene products. There is a discussion ongoing for many years whether aspartame posses genotoxic and carcinogenic risk for humans. This question led to many studies to specify the adverse effects of aspartame. Therefore, we aimed to review the oldest to latest works published in major indices to gather information within this article. With respect to published data, genotoxicity and carcinogenicity of aspartame is still confusing. So, consumers should be aware of the potential side effects of aspartame before they consume it. PMID:24510317

  9. Cell-mediated mutagenesis and cell transformation of mammalian cells by chemical carcinogens

    International Nuclear Information System (INIS)

    We have developed a cell-mediated mutagenesis assay in which cells with the appropriate markers for mutagenesis are co-cultivated with either lethally irradiated rodent embryonic cells that can metabolize carcinogenic hydrocarbons or with primary rat liver cells that can metabolize chemicals carcinogenic to the liver. During co-cultivation, the reactive metabolites of the procarcinogen appear to be transmitted to the mutable cells and induce mutations in them. Assays of this type make it possible to demonstrate a relationship between carcinogenic potency of the chemicals and their ability to induce mutations in mammalian cells. In addition, by simultaneously comparing the frequencies of transformation and mutation induced in normal diploid hamster cells by benzo(a)pyrene (BP) and one of its metabolites, it is possible to estimate the genetic target size for cell transformation in vitro

  10. Carcinogenicity of consumption of red and processed meat: What about environmental contaminants?

    Science.gov (United States)

    Domingo, José L; Nadal, Martí

    2016-02-01

    In October 26, 2015, the International Agency for Research on Cancer (IARC) issued a press release informing of the recent evaluation of the carcinogenicity of red and processed meat consumption. The consumption of red meat and processed meat was classified as "probably carcinogenic to humans", and as "carcinogenic to humans", respectively. The substances responsible of this potential carcinogenicity would be generated during meat processing, such as curing and smoking, or when meat is heated at high temperatures (N-nitroso-compounds, polycyclic aromatic hydrocarbons and heterocyclic aromatic amines). However, in its assessments, the IARC did not make any reference to the role that may pose some carcinogenic environmental pollutants, which are already present in raw or unprocessed meat. The potential role of a number of environmental chemical contaminants (toxic trace elements, polycyclic aromatic hydrocarbons, polychlorinated dibenzo-p-dioxins and dibenzofurans, polychlorinated biphenyls, polybrominated diphenyl ethers, polychlorinated diphenyl ethers, polychlorinated naphthalenes and perfluoroalkyl substances) on the carcinogenicity of consumption of meat and meat products is discussed in this paper. A case-study, Catalonia (Spain), is specifically assessed, while the influence of cooking on the concentrations of environmental pollutants is also reviewed. It is concluded that although certain cooking processes could modify the levels of chemical contaminants in food, the influence of cooking on the pollutant concentrations depends not only on the particular cooking process, but even more on their original contents in each specific food item. As most of these environmental pollutants are organic, cooking procedures that release or remove fat from the meat should tend to reduce the total concentrations of these contaminants in the cooked meat. PMID:26656511

  11. Chemical carcinogenic and mutagenic agents in the workplace, Poland, 2008–2010

    Directory of Open Access Journals (Sweden)

    Katarzyna Konieczko

    2013-04-01

    Full Text Available Background: The aim of this paper is to present a concise but comprehensive information on the occurrence of carcinogenic or mutagenic agents in Polish enterprises and the number of workers exposed to those agents reported to the central register by employers. Objectives and responsibilities of the register, as well as the range and methods of data gathering are discussed. Material and Methods: Data concerning carcinogenic or mutagenic chemical substances and technological processes reported to central register in 2008-2010 were analyzed. Results: In 2008-2010 more than 300 carcinogenic or mutagenic chemical substances were reported to the register. Approximately 2500 plants reported above 150 000 per-person-exposures annually. Among all technological processes regarded as occupational carcinogens, hardwood dusts exposure (about 660 companies; 11 000-13 000 exposed workers each year and exposure to polycyclic aromatic hydrocarbons (PAHs present in coal products (117-125 plantsl 3000 exposed per year were reported. Conclusions: The most widespread carcinogenic/mutagenic substances were: benzene, chromium(VI compounds: potassium dichromate and chromate, chromium(VI trioxide and other chromium compounds, ethylene oxide, asbestos, benzo[a]pyrene and gasoline. The highest number of men was exposed to particular PAHs and benzene , and the majority of women was exposed to benzene, potassium dichromate and chromate, acrylamide, ethylene oxide and gasoline. The lack of clear-cut definitione of occupational exposure to carcinogen creates a problem faced by employers in defining the accurate number of exposed workers. Med Pr 2013;64(2:181–192

  12. Embryonic turkey liver: activities of biotransformation enzymes and activation of DNA-reactive carcinogens

    Energy Technology Data Exchange (ETDEWEB)

    Perrone, Carmen E.; Duan, Jian Dong; Jeffrey, Alan M.; Williams, Gary M. [New York Medical College, Department of Pathology, Valhalla (United States); Ahr, Hans-Juergen; Schmidt, Ulrich [Bayer AG, Institute of Toxicology, Wuppertal (Germany); Enzmann, Harald H. [Federal Institute for Drugs and Medical Devices, Bonn (Germany)

    2004-10-01

    Avian embryos are a potential alternative model for chemical toxicity and carcinogenicity research. Because the toxic and carcinogenic effects of some chemicals depend on bioactivation, activities of biotransformation enzymes and formation of DNA adducts in embryonic turkey liver were examined. Biochemical analyses of 22-day in ovoturkey liver post-mitochondrial fractions revealed activities of the biotransformation enzymes 7-ethoxycoumarin de-ethylase (ECOD), 7-ethoxyresorufin de-ethylase (EROD), aldrin epoxidase (ALD), epoxide hydrolase (EH), glutathione S-transferase (GST), and UDP-glucuronyltransferase (GLUT). Following the administration of phenobarbital (24 mg/egg) on day 21, enzyme activities of ECOD, EROD, ALD, EH and GLUT, but not of GST, were increased by two-fold or higher levels by day 22. In contrast, acute administration of 3-methylcholanthrene (5 mg/egg) induced only ECOD and EROD activities. Bioactivation of structurally diverse pro-carcinogens was also examined using {sup 32}P-postlabeling for DNA adducts. In ovoexposure of turkey embryos on day 20 of gestation to 2-acetylaminofluorene (AAF), 4,4'-methylenebis(2-chloroaniline) (MOCA), benzo[a]pyrene (BaP), and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) resulted in the formation of DNA adducts in livers collected by day 21. Some of the DNA adducts had {sup 32}P-postlabeling chromatographic migration patterns similar to DNA adducts found in livers from Fischer F344 rats exposed to the same pro-carcinogens. We conclude that 21-day embryonic turkey liver is capable of chemical biotransformation and activation of genotoxic carcinogens to form DNA adducts. Thus, turkey embryos could be utilized to investigate potential chemical toxicity and carcinogenicity. (orig.)

  13. Carcinogen-induced DNA repair in nucleotide-permeable Escherichia coli cells. Induction of DNA repair by the carcinogens methyl and ethyl nitrosourea and methyl methanesulfonate.

    Science.gov (United States)

    Thielmann, H W; Vosberg, H P; Reygers, U

    1975-08-15

    Ether-permeabilized (nucleotide-permeable) cells of Escherichia coli show excision repair of their DNA after having been exposed to the carcinogens N-methyl-N-nitrosourea (MeNOUr), N-ethyl-N-nitrosourea (EtNOUr) and methyl methanesulfonate (MeSO2OMe) which are known to bind covalently to DNA. Defect mutations in genes uvrA, uvrB, uvrC, recA, recB, recC and rep did not inhibit this excision repair. Enzymic activities involved in this repair were identified by measuring size reduction of DNA, DNA degradation to acid-soluble nucleotides and repair polymerization. 1. In permeabilized cells methyl and ethyl nitrosourea induced endonucleolytic cleavage of endogenous DNA, as determined by size reduction of denatured DNA in neutral and alkaline sucrose gradients. An enzymic activity from E. coli K-12 cell extracts was purified (greater than 2000-fold) and was found to cleave preferentially methyl-nitrosourea-treated DNA and to convert the methylated supercoiled DNA duplex (RFI) of phage phiX 174 into the nicked circular form. 2. Degradation of alkylated cellular DNA to acid solubility was diminished in a mutant lacking the 5' leads to 3' exonucleolytic activity of DNA polymerase I but was not affected in a mutant which lacked the DNA polymerizing but retained the 5' leads 3' exonucleolytic activity of DNA polymerase I. 3. An easily measurable effect is carcinogen-induced repair polymerization, making it suitable for detection of covalent binding of carcinogens and potentially carcinogenic compounds. PMID:170107

  14. Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides.

    OpenAIRE

    Kawanishi, Shosuke; Oikawa, Shinji; Inoue, Sumiko; Nishino, Kohsuke

    2002-01-01

    The U.S. National Toxicology Program has shown clear evidence of carcinogenicity of nickel subsulfide (Ni(3)S(2)) and some evidence of carcinogenicity of NiO (green) in rats. In the present study, DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. In cultured HeLa cells, Ni(3)S(2) induced a significant increase in 8-hydroxydeoxyguanosine (8-OH-dG) formation, whereas NiO (black), NiO (green), and NiS...

  15. Chemoprevention with Acetylsalicylic Acid, Vitamin D and Calcium Reduces Risk of Carcinogen-induced Lung Tumors

    DEFF Research Database (Denmark)

    Pommergaard, Hans-Christian; Burcharth, Jakob; Rosenberg, J; Raskov, Hans

    2013-01-01

    Background/Aim: Research has shown that chemoprevention may be effective against the development of lung cancer. The purpose of the present study was to evaluate the effect of oral chemoprevention in a mouse model of tobacco carcinogen-induced lung tumor.......Background/Aim: Research has shown that chemoprevention may be effective against the development of lung cancer. The purpose of the present study was to evaluate the effect of oral chemoprevention in a mouse model of tobacco carcinogen-induced lung tumor....

  16. Analysis of mutagenic and carcinogenic risks: nitrates, nitrites, N-Nitroso compounds. Comparison with radioactive risks

    International Nuclear Information System (INIS)

    This report comes within the scope of the general studies on mutagenic and carcinogenic agents other than ionizing radiations. Through feeding, way of life and working activities, man is exposed to genotoxic risks of N-nitroso compounds (NNC). In spite of differences in the molecular modes of action, there exists some analogy between the effects of radiation exposures and those of NNC: DNA is the target in either instance. Unlike radiations, NNC are alkylating agents. The whole activation process of carcinogens arises from mechanisms leading to DNA repair

  17. The Cigarette Smoke Carcinogen Benzo[a]pyrene Enhances Human Papillomavirus Synthesis▿

    OpenAIRE

    Alam, Samina; Conway, Michael J; Chen, Horng-Shen; Meyers, Craig

    2007-01-01

    Epidemiological studies suggest that cigarette smoke carcinogens are cofactors which synergize with human papillomavirus (HPV) to increase the risk of cervical cancer progression. Benzo[a]pyrene (BaP), a major carcinogen in cigarette smoke, is detected in the cervical mucus and may interact with HPV. Exposure of cervical cells to high concentrations of BaP resulted in a 10-fold increase in HPV type 31 (HPV31) viral titers, whereas treatment with low concentrations of BaP resulted in an increa...

  18. Tobacco Carcinogen NNK Transporter MRP2 Regulates CFTR Function in Lung Epithelia: Implications for Lung Cancer

    OpenAIRE

    Li, Chunying; Schuetz, John D.; Naren, Anjaparavanda P.

    2010-01-01

    Lung cancer is the leading cause of cancer death in the United States. About 85% of all lung cancers are linked to tobacco smoke, in which more than 50 lung carcinogens have been identified and one of the most abundant is 4-(methylnitrosamino)-1-(3-pyridyl)- 1-butanone (NNK). The human lung epithelium constitutes the first line of defense against tobacco specific carcinogens, in which apically-localized receptors, transporters, and ion channels in the airway may play a critical role in this n...

  19. DIRECT-ACTING, DNA-DAMAGING AS (III)-METHYLATED SPECIES: IMPLICATIONS FOR A CARCINOGENIC MECHANISM OF ACTION OF ARSENICALS

    Science.gov (United States)

    Direct-acting, DNA-damaging As (III)-methylated species: implications for a carcinogenic . mechanism of action of arsenicals Inorganic arsenic (iAs, arsenite and arsenate) has been thought to act as a carcinogen without reacting directly with DNA; neither iAs nor the As(...

  20. 75 FR 79320 - Animal Drugs, Feeds, and Related Products; Regulation of Carcinogenic Compounds in Food-Producing...

    Science.gov (United States)

    2010-12-20

    ... human diet that represents no significant increase in the risk of cancer to people. The concentration... defined, adequately addresses concentrations of residues of carcinogenic concern in the total human diet... secondarily as corresponding to the concentration of residue of carcinogenic concern in the total human...

  1. Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans.

    Science.gov (United States)

    Pfohl-Leszkowicz, Annie; Manderville, Richard A

    2007-01-01

    Ochratoxin A (OTA) is a ubiquitous mycotoxin produced by fungi of improperly stored food products. OTA is nephrotoxic and is suspected of being the main etiological agent responsible for human Balkan endemic nephropathy (BEN) and associated urinary tract tumours. Striking similarities between OTA-induced porcine nephropathy in pigs and BEN in humans are observed. International Agency for Research on Cancer (IARC) has classified OTA as a possible human carcinogen (group 2B). Currently, the mode of carcinogenic action by OTA is unknown. OTA is genotoxic following oxidative metabolism. This activity is thought to play a central role in OTA-mediated carcinogenesis and may be divided into direct (covalent DNA adduction) and indirect (oxidative DNA damage) mechanisms of action. Evidence for a direct mode of genotoxicity has been derived from the sensitive 32P-postlabelling assay. OTA facilitates guanine-specific DNA adducts in vitro and in rat and pig kidney orally dosed, one adduct comigrates with a synthetic carbon (C)-bonded C8-dG OTA adduct standard. In this paper, our current understanding of OTA toxicity and carcinogenicity are reviewed. The available evidence suggests that OTA is a genotoxic carcinogen by induction of oxidative DNA lesions coupled with direct DNA adducts via quinone formation. This mechanism of action should be used to establish acceptable intake levels of OTA from human food sources. PMID:17195275

  2. Environmental exposure to carcinogenic polycyclic aromatic hydrocarbons – the interpretation of cytogenetic analysis by FISH

    Czech Academy of Sciences Publication Activity Database

    Šrám, Radim; Beskid, Olena; Rössnerová, Andrea; Rössner st., Pavel; Lněničková, Zdena; Milcová, Alena; Solansky, I.; Binková, Blanka

    2007-01-01

    Roč. 172, - (2007), s. 12-20. ISSN 0378-4274 R&D Projects: GA MŽP SL/5/160/05 Institutional research plan: CEZ:AV0Z50390512 Keywords : environmental pollution * carcinogenic polycyclic aromatic hydrocarbons * cytogenetic analysis Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 2.826, year: 2007

  3. 29 CFR 1990.131 - Priority lists for regulating potential occupational carcinogens.

    Science.gov (United States)

    2010-07-01

    ... review or be the basis for any legal action. The Secretary may regulate a potential occupational... 29 Labor 9 2010-07-01 2010-07-01 false Priority lists for regulating potential occupational... POTENTIAL OCCUPATIONAL CARCINOGENS Priority Setting § 1990.131 Priority lists for regulating...

  4. Carcinogens, Teratogens and Mutagens: Their Impact on Occupational Health, Particularly for Women in Veterinary Medicine.

    Science.gov (United States)

    Milligan, J. E.; And Others

    1983-01-01

    Pregnant women, especially those working in veterinary medicine, face occupational health/disease risks from mutagens, teratogens, and carcinogens. These hazards can be placed into three categories: physical, chemical, and biological. Each of these hazards is discussed with examples. (Author/JN)

  5. AN EVALUATION OF THE HUMAN CARCINOGENIC POTENTIAL OF ETHYLENE GLYCOL BUTYL ETHER: INTERIM FINAL POSITION PAPER

    Science.gov (United States)

    In order to determine the merit of a petition to remove ethylene glycol ether (EGBE) from the Agency's Hazardous Air Pollutant (HAP) list, EPA has developed an interim final position paper, An Evaluation of the Human Carcinogenic Potential of Ethylene Glycol Butyl Ether, t...

  6. Evaluation of an information campaign about working safely with carcinogenic substances

    NARCIS (Netherlands)

    Moonen, I.P.P.; Rijt, G.A.J. van der; Koppen, K.F.C.J. van; Gulden, J.W.J. van der

    1995-01-01

    An information campaign, organised in the Netherlands to foster safer working conditions for those who find themselves exposed to carcinogenic substances, has been evaluated. Posters, leaflets, and booklets had been distributed to those who are liable to run a risk while at work, managers as well as

  7. Human bronchus-mediated mutagenesis of mammalian cells by carcinogenic polycyclic aromatic hydrocarbon

    DEFF Research Database (Denmark)

    1978-01-01

    was found in Chinese hamster V-79 cells when they were cocultivated with bronchial explants in the presence of BzaP. The proximate carcinogenic form of BzaP, the 7,8-diol [(+/-)-r7,t8-dihyroxy-7,8-dihydrobenzo[a]pyrene], was 5-fold more potent as a promutagen than the parent compound. Neither BzaP nor...

  8. Rapid screening of potential human bladder carcinogens: genotoxicity in meiosis repair deficient Drosophila melanogaster.

    Science.gov (United States)

    Lamm, L M; Reichert, D F; Lamm, D L

    1989-11-01

    To find a quick screen of potential bladder carcinogens, a genotoxicity test in Drosophila melanogaster stocks containing DNA repair mutations was evaluated. Meiosis repair deficient male Drosophila melanogaster mei-9, mei-41, and the double mutant mei-9-41 were allowed to mate with attached -x females on media containing the test agent. Genotoxic agents produce DNA damage which accumulates and can be lethal in mei males, whereas the attached -x females are able to repair the damage and survive. Thus, the sex ratio of the progeny is a measure of genotoxicity which can be correlated with mutagenicity and carcinogenicity. In this study, tea, coffee, and saccharin were not genotoxic (p greater than 0.3). Dose dependent toxicity was observed in bracken fern (p less than 0.001). The known mutagen and bladder carcinogen, cyclophosphamide, was highly genotoxic (p less than .001). Drosophila genotoxicity not only permits rapid screening of mutagens, but may also have advantages over other systems in the screening of potential bladder carcinogens. PMID:2509735

  9. 40 CFR 799.9430 - TSCA combined chronic toxicity/carcinogenicity.

    Science.gov (United States)

    2010-07-01

    ... Good Laboratory Practice Standards at 40 CFR part 792, subpart J, the following specific information.... The study must be conducted in compliance with 40 CFR Part 792—Good Laborary Practice Standards. (h...) Page, N.P. Chronic Toxicity and Carcinogenicity Guidelines. Journal of Environmental Pathology...

  10. Repair of DNA treated with lambda-irradiation and chemical carcinogens. Progress report, 1984-1985

    International Nuclear Information System (INIS)

    Research progress is reported in the following areas: (1) DNA repair in HeLa cells; (2) a search for human transposable elements; (3) the effect of radiation and carcinogens on the activation of LTR sequences; and (4) studies on oncogenes of central nervous system tumors

  11. Environmental Carcinogen Releases and Lung Cancer Mortality in Rural-Urban Areas of the United States

    Science.gov (United States)

    Luo, Juhua; Hendryx, Michael

    2011-01-01

    Purpose: Environmental hazards are unevenly distributed across communities and populations; however, little is known about the distribution of environmental carcinogenic pollutants and lung cancer risk across populations defined by race, sex, and rural-urban setting. Methods: We used the Toxics Release Inventory (TRI) database to conduct an…

  12. Carcinogen-induced DNA repair in nucleotide-permeable Escherichia coli cells

    International Nuclear Information System (INIS)

    Upon exposure to the carcinogens N-acetoxy-N-2-acetylaminofluorene and 7-bromomethyl-benz[a]anthracene, which bind covalently to DNA, ether-permeabilized (nucleotide-permeable) Escherichia coli wild-type cells responded with DNA excision repair. This repair was missing in mutants carrying defects in genes uvrA, uvrB and uvrC, whereas it was present in uvrD and several rec mutants. Enzymic activities involved were identified by measuring repair polymerization and size reduction of denatured DNA. An easily measurable effect in E. coli wild-type cells was carcinogen-induced repair polymerization. When initiated by N-acetoxy-N-2-acetylaminofluorene or 7-bromomethyl-benz[a]anthracene, it depended upton an ATP-requiring step; CTP, GTP or UTP did not substitute for ATP. DNA repair synthesis was inhibited by p-chloromercuribenzoate and quinacrine. In uvrA, uvrB and uvrC mutants no carcinogen-stimulated DNA synthesis could be detected, indicating that steps involved in pyrimidine dimer excision are also involved in chemorepair. In recA, recB and recC mutant cells, repair synthesis was stimulated by the carcinogens to a normal extent. This evidence excludes the ATP-dependent recB,C deoxyribonuclease and recA gene products as playing an important role in carcinogen-induced excision repair. polA1 cells showed drastically reduced levels of repair polymerization, indicating that DNA polymerase I is the main polymerizing enzyme. As determined by DNA size reduction in alkaline sucrose gradients, the arylalkylating carcinogens caused endonucleolytic cleavage of endogenous DNA in wild-type cells. This incision step was most effectively performed in the presence of ATP; UTP, CTP and GTP were only slightly effective. Incision was inhibited by p-chloromercuribenzoate and quinacrine. When exposed to the arylalkylating carcinogens, uvrA, uvrB and uvrC mutant cells did not perform the incision step in the presence of ATP, suggesting the involvement of the respective gene products in the

  13. Ochratoxin A induces rat renal carcinogenicity with limited induction of oxidative stress responses

    International Nuclear Information System (INIS)

    Ochratoxin A (OTA) has displayed nephrotoxicity and renal carcinogenicity in mammals, however, no clear mechanisms have been identified detailing the relationship between oxidative stress and these toxicities. This study was performed to clarify the relationship between oxidative stress and the renal carcinogenicity induced by OTA. Rats were treated with 70 or 210 μg/kg b.w. OTA for 4 or 13 weeks. In the rats administrated with OTA for 13 weeks, the kidney was damaged seriously. Cytoplasmic vacuolization was observed in the outer stripe of the outer medulla. Karyomegaly was prominent in the tubular epithelium. Kidney injury molecule-1 (Kim-1) was detected in the outer stripe of the outer medulla in both low- and high-dose groups. OTA increased the mRNA levels of clusterin in rat kidneys. Interestingly, OTA did not significantly alter the oxidative stress level in rat liver and kidney. Yet, some indications related to proliferation and carcinogenicity were observed. A dose-related increase in proliferating cell nuclear antigen (PCNA) was observed at 4 weeks in both liver and kidney, but at 13 weeks, only in the kidney. OTA down-regulated reactive oxygen species (ROS) and up-regulated vimentin and lipocalin 2 in rat kidney at 13 weeks. The p53 gene was decreased in both liver and kidney at 13 weeks. These results suggest that OTA caused apparent kidney damage within 13 weeks but exerted limited effect on oxidative stress parameters. It implies that cell proliferation is the proposed mode of action for OTA-induced renal carcinogenicity. - Highlights: • We studied OTA toxicities in both the rat liver and kidney for 13 weeks. • OTA exerts limited effects on oxidative stress in the rat liver and kidney. • OTA induced renal carcinogenicity resulting from cell proliferation

  14. Radiation equivalency: A conceptual relationship for indexing the carcinogenic properties of radiation and environmental pollutants

    International Nuclear Information System (INIS)

    A Tier-Two type of bioassay complimentary to the National Cancer Institute whole-animal protocol has been proposed based upon relating the antitumor cell-mediated immune responses induced by the test substance to those immune effects induced by a localized exposure to X-rays, a concept which termed the substance's Radiation Equivalency. The conceptual principle for the Radiation Equivalency entails the hypothesis that a mutagenic/carcinogenic insult results in the development of transformed ''foreign-like'' cells which then initiate their specific recognition by the host's immune system. This immune sensitization can then be quantitated by measuring the increased injury and killing of cultured tumor cells by the now so-called educated peripheral blood lymphoid-cells obtained from the exposed animals. The authors proposed that all carcinogenic agents will interact with their particular organoismal components in a constant fashion to induce such antitumor immune responses, thus permitting the experimental results to be interpreted according to the Law of Mass Action. The findings have been accordingly described in terms of Michaelis-Menton kinetics with specific experimental comparisons in the rate presented between the colon carcinogen, 1,2-dimethylhydrazine (DMH), and the X-irradiation effects upon the localized hypoxic small bowel to obtain a Radiation Equivalency value for the chemical. Similar measurements have also been utilized for the analysis of mutagens/carcinogens present in the urine obtained from DMH-exposed rats such to arrive at its Radiation Equivalency. Previous findings have been summarized together, all of which suggest that the Radiation Equivalency concept may readily serve as a method for indexing the carcinogenic properties of various environmental pollutants

  15. Ochratoxin A induces rat renal carcinogenicity with limited induction of oxidative stress responses

    Energy Technology Data Exchange (ETDEWEB)

    Qi, Xiaozhe; Yu, Tao; Zhu, Liye; Gao, Jing [College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083 (China); He, Xiaoyun; Huang, Kunlun; Luo, Yunbo [College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083 (China); The Supervision, Inspection and Testing Center of Genetically Modified Organisms, Ministry of Agriculture, Beijing 100083 (China); Xu, Wentao, E-mail: xuwentao@cau.edu.cn [College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083 (China); The Supervision, Inspection and Testing Center of Genetically Modified Organisms, Ministry of Agriculture, Beijing 100083 (China)

    2014-11-01

    Ochratoxin A (OTA) has displayed nephrotoxicity and renal carcinogenicity in mammals, however, no clear mechanisms have been identified detailing the relationship between oxidative stress and these toxicities. This study was performed to clarify the relationship between oxidative stress and the renal carcinogenicity induced by OTA. Rats were treated with 70 or 210 μg/kg b.w. OTA for 4 or 13 weeks. In the rats administrated with OTA for 13 weeks, the kidney was damaged seriously. Cytoplasmic vacuolization was observed in the outer stripe of the outer medulla. Karyomegaly was prominent in the tubular epithelium. Kidney injury molecule-1 (Kim-1) was detected in the outer stripe of the outer medulla in both low- and high-dose groups. OTA increased the mRNA levels of clusterin in rat kidneys. Interestingly, OTA did not significantly alter the oxidative stress level in rat liver and kidney. Yet, some indications related to proliferation and carcinogenicity were observed. A dose-related increase in proliferating cell nuclear antigen (PCNA) was observed at 4 weeks in both liver and kidney, but at 13 weeks, only in the kidney. OTA down-regulated reactive oxygen species (ROS) and up-regulated vimentin and lipocalin 2 in rat kidney at 13 weeks. The p53 gene was decreased in both liver and kidney at 13 weeks. These results suggest that OTA caused apparent kidney damage within 13 weeks but exerted limited effect on oxidative stress parameters. It implies that cell proliferation is the proposed mode of action for OTA-induced renal carcinogenicity. - Highlights: • We studied OTA toxicities in both the rat liver and kidney for 13 weeks. • OTA exerts limited effects on oxidative stress in the rat liver and kidney. • OTA induced renal carcinogenicity resulting from cell proliferation.

  16. Effect of chemical mutagens and carcinogens on gene expression profiles in human TK6 cells.

    Directory of Open Access Journals (Sweden)

    Lode Godderis

    Full Text Available Characterization of toxicogenomic signatures of carcinogen exposure holds significant promise for mechanistic and predictive toxicology. In vitro transcriptomic studies allow the comparison of the response to chemicals with diverse mode of actions under controlled experimental conditions. We conducted an in vitro study in TK6 cells to characterize gene expression signatures of exposure to 15 genotoxic carcinogens frequently used in European industries. We also examined the dose-responsive changes in gene expression, and perturbation of biochemical pathways in response to these carcinogens. TK6 cells were exposed at 3 dose levels for 24 h with and without S9 human metabolic mix. Since S9 had an impact on gene expression (885 genes, we analyzed the gene expression data from cells cultures incubated with S9 and without S9 independently. The ribosome pathway was affected by all chemical-dose combinations. However in general, no similar gene expression was observed among carcinogens. Further, pathways, i.e. cell cycle, DNA repair mechanisms, RNA degradation, that were common within sets of chemical-dose combination were suggested by clustergram. Linear trends in dose-response of gene expression were observed for Trichloroethylene, Benz[a]anthracene, Epichlorohydrin, Benzene, and Hydroquinone. The significantly altered genes were involved in the regulation of (anti- apoptosis, maintenance of cell survival, tumor necrosis factor-related pathways and immune response, in agreement with several other studies. Similarly in S9+ cultures, Benz[a]pyrene, Styrene and Trichloroethylene each modified over 1000 genes at high concentrations. Our findings expand our understanding of the transcriptomic response to genotoxic carcinogens, revealing the alteration of diverse sets of genes and pathways involved in cellular homeostasis and cell cycle control.

  17. Prediction of rodent carcinogenicity using the DEREK system for 30 chemicals currently being tested by the National Toxicology Program. The DEREK Collaborative Group.

    OpenAIRE

    Marchant, C A

    1996-01-01

    DEREK is a knowledge-based expert system for the qualitative prediction of toxicity. The DEREK system has been used to predict the carcinogenicity in rodents of the 30 chemicals in the second National Toxicology Program (NTP) carcinogenicity prediction exercise. Seven of the chemicals were predicted to be carcinogens. For 23 chemicals, there was no evidence in the DEREK knowledge base to suggest carcinogenic activity. Supplementary data from a variety of sources have been evaluated by human e...

  18. Homeostatic response under carcinogen withdrawal, heme oxygenase 1 expression and cell cycle association

    Directory of Open Access Journals (Sweden)

    Batlle Alcira

    2006-12-01

    Full Text Available Abstract Background Chronic injury deregulates cellular homeostasis and induces a number of alterations leading to disruption of cellular processes such as cell cycle checkpoints and apoptosis, driving to carcinogenesis. The stress protein heme oxygenase-1 (HO-1 catalyzes heme degradation producing biliverdin, iron and CO. Induction of HO-1 has been suggested to be essential for a controlled cell growth. The aim of this work was to analyze the in vivo homeostatic response (HR triggered by the withdrawal of a potent carcinogen, p-dimethylaminoazobenzene (DAB, after preneoplastic lesions were observed. We analyzed HO-1 cellular localization and the expression of HO-1, Bcl-2 and cell cycle related proteins under these conditions comparing them to hepatocellular carcinoma (HC. Methods The intoxication protocol was designed based on previous studies demonstrating that preneoplastic lesions were evident after 89 days of chemical carcinogen administration. Male CF1 mice (n = 18 were used. HR group received DAB (0.5 % w/w in the diet for 78 days followed by 11 days of carcinogen deprivation. The HC group received the carcinogen and control animals the standard diet during 89 days. The expression of cell cycle related proteins, of Bcl-2 and of HO-1 were analyzed by western blot. The cellular localization and expression of HO-1 were detected by immnunohistochemistry. Results Increased expression of cyclin E/CDK2 was observed in HR, thus implicating cyclin E/CDK2 in the liver regenerative process. p21cip1/waf1 and Bcl-2 induction in HC was restituted to basal levels in HR. A similar response profile was found for HO-1 expression levels, showing a lower oxidative status in the carcinogen-deprived liver. The immunohistochemical studies revealed the presence of macrophages surrounding foci of necrosis and nodular lesions in HR indicative of an inflammatory response. Furthermore, regenerative cells displayed changes in type, size and intensity of HO-1

  19. Homeostatic response under carcinogen withdrawal, heme oxygenase 1 expression and cell cycle association

    International Nuclear Information System (INIS)

    Chronic injury deregulates cellular homeostasis and induces a number of alterations leading to disruption of cellular processes such as cell cycle checkpoints and apoptosis, driving to carcinogenesis. The stress protein heme oxygenase-1 (HO-1) catalyzes heme degradation producing biliverdin, iron and CO. Induction of HO-1 has been suggested to be essential for a controlled cell growth. The aim of this work was to analyze the in vivo homeostatic response (HR) triggered by the withdrawal of a potent carcinogen, p-dimethylaminoazobenzene (DAB), after preneoplastic lesions were observed. We analyzed HO-1 cellular localization and the expression of HO-1, Bcl-2 and cell cycle related proteins under these conditions comparing them to hepatocellular carcinoma (HC). The intoxication protocol was designed based on previous studies demonstrating that preneoplastic lesions were evident after 89 days of chemical carcinogen administration. Male CF1 mice (n = 18) were used. HR group received DAB (0.5 % w/w) in the diet for 78 days followed by 11 days of carcinogen deprivation. The HC group received the carcinogen and control animals the standard diet during 89 days. The expression of cell cycle related proteins, of Bcl-2 and of HO-1 were analyzed by western blot. The cellular localization and expression of HO-1 were detected by immnunohistochemistry. Increased expression of cyclin E/CDK2 was observed in HR, thus implicating cyclin E/CDK2 in the liver regenerative process. p21cip1/waf1 and Bcl-2 induction in HC was restituted to basal levels in HR. A similar response profile was found for HO-1 expression levels, showing a lower oxidative status in the carcinogen-deprived liver. The immunohistochemical studies revealed the presence of macrophages surrounding foci of necrosis and nodular lesions in HR indicative of an inflammatory response. Furthermore, regenerative cells displayed changes in type, size and intensity of HO-1 immunostaining. These results demonstrate that the

  20. [Carcinogenic risk of polycyclic aromatic hydrocarbons: classification and interpretation of the monitoring].

    Science.gov (United States)

    Catalani, Simona; Fostinelli, Jacopo; Apostoli, Pietro

    2014-01-01

    The polycyclic aromatic hydrocarbons (PAHs) are widespread contaminants characterized by various chemical, physical and toxic properties. The characterization of occupational and environmental exposures and the use of suitable measurements protocols are very significant because their presence in mixtures and environmental persistency. In the past few years, the knowledge concerning carcinogenicity of PAHs have been reviewed, the mechanisms involved are the interaction of PAH's metabolites with DNA and oxidative damages. The main requirement for research concerns lack of knowledge on reference values and occupational exposure's assessment in particular PAHs sampling methods that can lead to combined measurements of vapor and aerosol mixtures. Aims of this study are to describe a possible occupational sources of PAHs providing also an update of mechanism involved in their carcinogenicity and risk calculation as is done in the TEF approach. The classifications provided by International Agencies and Institutions and the limit values adopted have been reviewed and taken into account. PMID:25369710

  1. Gravity-flow alkaline elution: a method to rapidly detect carcinogen-induced DNA strand breaks

    International Nuclear Information System (INIS)

    A rapid, sensitive and reliable gravity-flow alkaline elution assay was developed to detect DNA strand breaks in cultured Madin-Darby bovine kidney epithelial cells. Elution was completed within 2 h without the use of pumps. The system was validated by exposing the cells to X-irradiation (25-1500 R) which resulted in a significant dose dependent response (p less than 0.05) with excellent correlation (r-0.93). The assay reliably detected the DNA damage of seven genotoxic carcinogens. In general, the measured DNA damage was dose dependent and significantly different from control values for all genotoxic carcinogens tested. Six non-genotoxic compounds were tested and showed no detectable DNA damage

  2. Fibrogenic and carcinogenic characteristics of asbestos occurring in Mohmand Agency, northern Pakistan

    International Nuclear Information System (INIS)

    This study has been carried out to identify the fibrogenic and carcinogenic characteristics including the type, physical dimension, and the fiber dose over time-weighted averages (TWA) of asbestos fibers mined, milled and used in Mohamand Agency. Fifteen representative rock and air samples of respirable particulates matter (0.45-10 micro m) collected from various mines and milling units were analyzed using X-Ray Diffraction (XRD). Polarized light Microscope (PLM) and Scanning Electron Microscope (SEM). The types of asbestos were classified as chrysotile, tremolite and anthophyllite. The concentration of asbestos fibers identified in respirable particulates (PM/sub 10. 7. 5. 3. 2. and 8 um long and indicate that the type of asbestos fibers released during mining and milling in Mohamand Agency is potentially carcinogenic. (author)

  3. The role of biomethylation in toxicity and carcinogenicity of arsenic: a research update.

    OpenAIRE

    Stýblo, Miroslav; Drobná, Zuzana; Jaspers, Ilona; Lin, Shan; Thomas, David J.

    2002-01-01

    Recent research of the metabolism and biological effects of arsenic has profoundly changed our understanding of the role of metabolism in modulation of toxicity and carcinogenicity of this metalloid. Historically, the enzymatic conversion of inorganic arsenic to mono- and dimethylated species has been considered a major mechanism for detoxification of inorganic arsenic. However, compelling experimental evidence obtained from several laboratories suggests that biomethylation, particularly the ...

  4. Oxidative damage by carcinogenic polycyclic aromatic hydrocarbons and organic extracts from urban air particulate matter

    Czech Academy of Sciences Publication Activity Database

    Hanzalová, Kateřina; Rössner ml., Pavel; Šrám, Radim

    2010-01-01

    Roč. 696, č. 2 (2010), s. 114-121. ISSN 1383-5718 R&D Projects: GA MŠk 2B08005; GA MŽP(CZ) SP/1B3/8/08 Institutional research plan: CEZ:AV0Z50390512 Keywords : carcinogenic polycyclic aromatic hydrocarbons * oxidative damage in vitro * extractable organic matter Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 2.938, year: 2010

  5. Evaluation of toxicogenomics approaches for assessing the risk of nongenotoxic carcinogenicity in rat liver.

    Directory of Open Access Journals (Sweden)

    Johannes Eichner

    Full Text Available The current gold-standard method for cancer safety assessment of drugs is a rodent two-year bioassay, which is associated with significant costs and requires testing a high number of animals over lifetime. Due to the absence of a comprehensive set of short-term assays predicting carcinogenicity, new approaches are currently being evaluated. One promising approach is toxicogenomics, which by virtue of genome-wide molecular profiling after compound treatment can lead to an increased mechanistic understanding, and potentially allow for the prediction of a carcinogenic potential via mathematical modeling. The latter typically involves the extraction of informative genes from omics datasets, which can be used to construct generalizable models allowing for the early classification of compounds with unknown carcinogenic potential. Here we formally describe and compare two novel methodologies for the reproducible extraction of characteristic mRNA signatures, which were employed to capture specific gene expression changes observed for nongenotoxic carcinogens. While the first method integrates multiple gene rankings, generated by diverse algorithms applied to data from different subsamplings of the training compounds, the second approach employs a statistical ratio for the identification of informative genes. Both methods were evaluated on a dataset obtained from the toxicogenomics database TG-GATEs to predict the outcome of a two-year bioassay based on profiles from 14-day treatments. Additionally, we applied our methods to datasets from previous studies and showed that the derived prediction models are on average more accurate than those built from the original signatures. The selected genes were mostly related to p53 signaling and to specific changes in anabolic processes or energy metabolism, which are typically observed in tumor cells. Among the genes most frequently incorporated into prediction models were Phlda3, Cdkn1a, Akr7a3, Ccng1 and Abcb4.

  6. Carcinogen-specific mutations in preferred Ras-Raf pathway oncogenes directed by strand bias.

    Science.gov (United States)

    Keller, Ross R; Gestl, Shelley A; Lu, Amy Q; Hoke, Alicia; Feith, David J; Gunther, Edward J

    2016-08-01

    Carcinogen exposures inscribe mutation patterns on cancer genomes and sometimes bias the acquisition of driver mutations toward preferred oncogenes, potentially dictating sensitivity to targeted agents. Whether and how carcinogen-specific mutation patterns direct activation of preferred oncogenes remains poorly understood. Here, mouse models of breast cancer were exploited to uncover a mechanistic link between strand-biased mutagenesis and oncogene preference. When chemical carcinogens were employed during Wnt1-initiated mammary tumorigenesis, exposure to either 7,12-dimethylbenz(a)anthracene (DMBA) or N-ethyl-N-nitrosourea (ENU) dramatically accelerated tumor onset. Mammary tumors that followed DMBA exposure nearly always activated the Ras pathway via somatic Hras(CAA61CTA) mutations. Surprisingly, mammary tumors that followed ENU exposure typically lacked Hras mutations, and instead activated the Ras pathway downstream via Braf(GTG636GAG) mutations. Hras(CAA61CTA) mutations involve an A-to-T change on the sense strand, whereas Braf(GTG636GAG) mutations involve an inverse T-to-A change, suggesting that strand-biased mutagenesis may determine oncogene preference. To examine this possibility further, we turned to an alternative Wnt-driven tumor model in which carcinogen exposures augment a latent mammary tumor predisposition in Apc(min) mice. DMBA and ENU each accelerated mammary tumor onset in Apc(min) mice by introducing somatic, "second-hit" Apc mutations. Consistent with our strand bias model, DMBA and ENU generated strikingly distinct Apc mutation patterns, including stringently strand-inverse mutation signatures at A:T sites. Crucially, these contrasting signatures precisely match those proposed to confer bias toward Hras(CAA61CTA) versus Braf(GTG636GAG) mutations in the original tumor sets. Our findings highlight a novel mechanism whereby exposure history acts through strand-biased mutagenesis to specify activation of preferred oncogenes. PMID:27207659

  7. Biomarkers of carcinogen exposure and cancer risk in a coke plant.

    OpenAIRE

    Assennato, G; Ferri, G M; Tockman, M S; Poirier, M C; Schoket, B; Porro, A.; Corrado, V.; Strickland, P T

    1993-01-01

    To evaluate the association between an indicator of carcinogen exposure (peripheral blood leukocyte DNA adducts of polycyclic aromatic hydrocarbons) and an early indicator of neoplastic transformation (sputum epithelial cell membrane antigens binding by monoclonal antibodies against small cell lung cancer and against nonsmall cell lung cancer), a survey of 350 coke-oven workers and 100 unexposed workers was planned. This paper reports a pilot investigation on a subgroup of 23 coke-oven worker...

  8. Evaluation of the potential carcinogenic action of radiocalcium internal irradiation in Swiss albino mice

    International Nuclear Information System (INIS)

    The carcinogenic action of 45Ca on inducing hepatocelluar carcinoma (HCC) in Swiss albino mice has been statistically evaluated. HCC proved to be radiation-induced and not due to spontaneous origin. Also, the higher incidence of male hepatocarcinogenesis due to internal irradiation has been found to be significant. The precise possible mechanism regarding the higher male susceptibility to liver cancer has been discussed in the light of available literature. (author)

  9. STAT3 as a chemoprevention target in carcinogen-induced head and neck squamous cell carcinoma.

    OpenAIRE

    Peyser, ND; Wang, L.; Zeng, Y.; Acquafondata, M.; Freilino, ML; Li, H.; M. Sen; Gooding, WE; Satake, M; Wang, Z.; Johnson; Grandis, JR

    2016-01-01

    Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal disease due in large part to a high rate of second primary tumor (SPT) formation. The 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis provides a robust system in which to study chemopreventive agents in the context of chemically-induced HNSCC tumors. Signal transducer and activator of transcription 3 (STAT3) is a potent oncogene that is hyperactivated by tyrosine phosphorylation early in HNSCC carcinogenes...

  10. Nicotine: Carcinogenicity and Effects on Response to Cancer Treatment – A Review

    OpenAIRE

    Sanner, Tore; Tom K Grimsrud

    2015-01-01

    Tobacco use is considered the single most important man-made cause of cancer that can be avoided. The evidence that nicotine is involved in cancer development is reviewed and discussed in this paper. Both tobacco smoke and tobacco products for oral use contain a number of carcinogenic substances, such as polycyclic hydrocarbons and tobacco-specific N-nitrosamines (TSNA), which undoubtedly contribute to tobacco related cancer. Recent studies have shown that nicotine can affect several importan...

  11. Clinical and biochemical studies support smokeless tobacco’s carcinogenic potential in the human oral cavity

    OpenAIRE

    Mallery, Susan R.; Tong, Meng; Michaels, Gregory C.; Kiyani, Amber R.; Hecht, Stephen S

    2013-01-01

    In 2007, International Agency for Cancer Research presented compelling evidence that linked smokeless tobacco use to the development of human oral cancer. While these findings imply vigorous local carcinogen metabolism, little is known regarding levels and distribution of Phase I, II and drug egress enzymes in human oral mucosa. In the study presented here, we integrated clinical data, imaging and histopathologic analyses of an oral squamous cell carcinoma that arose at the site of smokeless ...

  12. Repair of DNA treated with γ-irradiation and chemical carcinogens. Progress report, 1980-1983

    International Nuclear Information System (INIS)

    We have studied in vitro DNA repair with the isolation and characterization of DNA glycosylases active in the removable of 3-methyladenine and the problem of repair of DNA in chromatin. The second area of focus has been on transposable elements and carcinogen action. The work on DNA adducts with β-propiolactone was done to define potential new substrates useful in a search for new glycosylases

  13. Carcinogens induce reversion of the mouse pink-eyed unstable mutation

    OpenAIRE

    Schiestl, Robert H.; Aubrecht, Jiri; Khogali, Fathia; Carls, Nicholas

    1997-01-01

    Deletions and other genome rearrangements are associated with carcinogenesis and inheritable diseases. The pink-eyed unstable (pun) mutation in the mouse is caused by duplication of a 70-kb internal fragment of the p gene. Spontaneous reversion events in homozygous pun/pun mice occur through deletion of a duplicated sequence. Reversion events in premelanocytes in the mouse embryo detected as black spots on the gray fur of the offspring were inducible by the carcinogen x-rays, ethyl methanesul...

  14. Urban air pollution by carcinogenic and genotoxic polyaromatic hydrocarbons in the former USSR.

    OpenAIRE

    Khesina AYa,

    1994-01-01

    The content of major carcinogenic and genotoxic polyaromatic hydrocarbons (PAH) in urban air, vehicle, and industrial emissions is assessed. A sensitive, specific, and selective method for PAH and nitro-PAH quantitation was developed on the basis of low-temperature luminescence-spectra of frozen polycrystalline solutions. Polyarene contents in urban air and urban industrial emissions, as well as vehicle exhausts, are compared to the Russian Ministry of Health standard of maximal permissible c...

  15. Studies on the Mutagenicity and Teratogenicity of Kuianchun and Its Potential Carcinogenicity Prediction

    Institute of Scientific and Technical Information of China (English)

    LIANG Jian-ping; ZHANG Li; CAO Sui-zhong; ZHOU Li-xia; ZHOU Xue-hui; LIU Zong-ping; WEI Chun-mei; MIAO Xiao-lin; WEI Zeng-quan

    2002-01-01

    Kuianchun is a newly synthesized antibacterial and growth-promoting drug. This paper selected a battery of three short-term tests, including Ames test, micronucleus test and sperm abnormality test, to detect the mutagenicity of Kuianchun. The carcinogenicity prediction and battery selection method (CPBS method) was used to determine the probability of carcinogenicity of Kuianchun based upon the results of shortterm tests mentioned above. In addition, traditional teratogenic test was selected to study teratogenicity of Kuianchun. In Ames test, Kuianchun showed mutagenic for Salmonella typhimurium strains TA98 and TA100 in the absence and presence of microsomal metabolic activation system (S9-mix). However, the mutagenicity was reduced by the addition of S9-mix. In micronucleus test, Kuianchun was administered intra-peritoneally to male mouse 30 hours and 6 hours before they were killed respectively. The result indicated that there was no significant difference on the number of micronucleated polychromatic erythrocytes (PCEs) in the mouse bone marrow induced by Kuianchun compared with the negative contrast (50% DMSO) (P > 0.05). In sperm abnormality test, Kuianchun was administered through a gastric incubation to male mouse as a suspension in 2% Tween-80. The dosage levels were 450, 750, 1000 and 1500mg/kg per day for 5 days. The result indicated that the percentage of abnormal sperms induced by Kuianchun was not significant compared with the negative contrast (P>0.05). In traditional teratogenic test, Kuianchun was given orally to pregnant mouse at 1/30,1/20 and 1/15 LDs0 during 6 - 15days of pregnancy period (the LD50 = 9000mg/kg). No toxicity was found either on mother and embryo in mouse, and teratogenic effects were also not observed at all tested dosages. The probability of carcinogenicity of Kuianchun is 23.8 % (θ = 0.238). The result demonstrated that Kuianchun is a non-carcinogen.

  16. Mechanism-Based Classification of PAH Mixtures to Predict Carcinogenic Potential.

    Science.gov (United States)

    Tilton, Susan C; Siddens, Lisbeth K; Krueger, Sharon K; Larkin, Andrew J; Löhr, Christiane V; Williams, David E; Baird, William M; Waters, Katrina M

    2015-07-01

    We have previously shown that relative potency factors and DNA adduct measurements are inadequate for predicting carcinogenicity of certain polycyclic aromatic hydrocarbons (PAHs) and PAH mixtures, particularly those that function through alternate pathways or exhibit greater promotional activity compared to benzo[a]pyrene (BaP). Therefore, we developed a pathway-based approach for classification of tumor outcome after dermal exposure to PAH/mixtures. FVB/N mice were exposed to dibenzo[def,p]chrysene (DBC), BaP, or environmental PAH mixtures (Mix 1-3) following a 2-stage initiation/promotion skin tumor protocol. Resulting tumor incidence could be categorized by carcinogenic potency as DBC > BaP = Mix2 = Mix3 > Mix1 = Control, based on statistical significance. Gene expression profiles measured in skin of mice collected 12 h post-initiation were compared with tumor outcome for identification of short-term bioactivity profiles. A Bayesian integration model was utilized to identify biological pathways predictive of PAH carcinogenic potential during initiation. Integration of probability matrices from four enriched pathways (P < .05) for DNA damage, apoptosis, response to chemical stimulus, and interferon gamma signaling resulted in the highest classification accuracy with leave-one-out cross validation. This pathway-driven approach was successfully utilized to distinguish early regulatory events during initiation prognostic for tumor outcome and provides proof-of-concept for using short-term initiation studies to classify carcinogenic potential of environmental PAH mixtures. These data further provide a 'source-to-outcome' model that could be used to predict PAH interactions during tumorigenesis and provide an example of how mode-of-action-based risk assessment could be employed for environmental PAH mixtures. PMID:25908611

  17. Quantitative assessment of exposure and risk for three carcinogenics in long-standing pollution sites

    International Nuclear Information System (INIS)

    The project attempts a quantitative assessment of risks for three carcinogenics that are common in sites of long-standing pollution. Benzo(a)pyrene stands for the group of polycyclic aromatic hydrocarbons, cadmium for heavy metals, and benzene for volatile aromatic compounds. The report discusses the general fundamentals of exposure and risk assessment. The exposure model is described in detail and applied to the three test substances. (orig./MG)

  18. Gene–environment interactions between DNA repair polymorphisms and exposure to the carcinogen vinyl chloride

    OpenAIRE

    Li, Yongliang; Marion, Marie-Jeanne; Zipprich, Jennifer; Santella, Regina M.; Freyer, Greg; Brandt-Rauf, Paul W.

    2009-01-01

    We have recently suggested that polymorphisms in metabolism and repair pathways may play a role in modulating the effects of exposure to the carcinogen vinyl chloride in the production of biomarkers of its mutagenic damage. The aim of the present study was to extend these observations by examining gene–environment interactions between several common polymorphisms in the DNA repair genes XRCC1 and ERCC2/XPD and vinyl chloride exposure on the production of vinyl chloride-induced biomarkers of m...

  19. Carcinogenicity tests of N-nitroso derivatives of two drugs, phenmetrazine and methylphenidate

    Energy Technology Data Exchange (ETDEWEB)

    Lijinsky, W.; Taylor, H.W.

    1976-01-01

    Two commonly used drugs that are derivatives of cyclic secondary amines, phenmetrazine and methylphenidate, were converted to their N-nitroso derivatives by reaction with nitrite in acid solution, and the products were tested by chronic administration to rats in doses comparable with those used to test the unsubstituted parent nitrosamines. No tumors were seen that could be attributed to these nitrosamines, and it is concluded that, under these conditions, neither compound is carcinogenic.

  20. Biomarkers of exposure to carcinogenic PAHs and their relationship with environmental factors

    Czech Academy of Sciences Publication Activity Database

    Taioli, E.; Šrám, Radim; Binková, Blanka; Kalina, I.; Popov, T. A.; Garte, S.; Farmer, P. B.

    2007-01-01

    Roč. 620, - (2007), s. 16-21. ISSN 0027-5107 Grant ostatní: EU(GB) 2000-00091 Institutional research plan: CEZ:AV0Z50390512 Source of funding: R - rámcový projekt EK Keywords : DNA adducts * air pollution * carcinogenic PAHs Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 4.159, year: 2007

  1. On use of the multistage dose-response model for assessing laboratory animal carcinogenicity

    OpenAIRE

    Nitcheva, Daniella; Piegorsch, Walter W.; West, R. Webster

    2007-01-01

    We explore how well a statistical multistage model describes dose-response patterns in laboratory animal carcinogenicity experiments from a large database of quantal response data. The data are collected from the U.S. EPA’s publicly available IRIS data warehouse and examined statistically to determine how often higher-order values in the multistage predictor yield significant improvements in explanatory power over lower-order values. Our results suggest that the addition of a second-order par...

  2. Bioavailability and potential carcinogenicity of polycyclic aromatic hydrocarbons from wood combustion particulate matter in vitro.

    Science.gov (United States)

    Gauggel-Lewandowski, Susanne; Heussner, Alexandra H; Steinberg, Pablo; Pieterse, Bart; van der Burg, Bart; Dietrich, Daniel R

    2013-11-25

    Due to increasing energy demand and limited fossil fuels, renewable energy sources have gained in importance. Particulate matter (PM) in general, but also PM from the combustion of wood is known to exert adverse health effects in human. These are often related to specific toxic compounds adsorbed to the PM surface, such as polycyclic aromatic hydrocarbons (PAH), of which some are known human carcinogens. This study focused on the bioavailability of PAHs and on the tumor initiation potential of wood combustion PM, using the PAH CALUX® reporter gene assay and the BALB/c 3T3 cell transformation assay, respectively. For this, both cell assays were exposed to PM and their respective organic extracts from varying degrees of combustion. The PAH CALUX® experiments demonstrated a concentration-response relationship matching the PAHs detected in the samples. Contrary to expectations, PM samples from complete (CC) and incomplete combustion (IC) provided for a stronger and weaker response, respectively, suggesting that PAH were more readily bioavailable in PM from CC. These findings were corroborated via PAH spiking experiments indicating that IC PM contains organic components that strongly adsorb PAH thereby reducing their bioavailability. The results obtained with organic extracts in the cell transformation assay presented the highest potential for carcinogenicity in samples with high PAH contents, albeit PM from CC also demonstrated a carcinogenic potential. In conclusion, the in vitro assays employed emphasize that CC produces PM with low PAH content however with a general higher bioavailability and thus with a nearly similar carcinogenic potential than IC PM. PMID:23796820

  3. Zizyphus Spina-Christi Extract Protects Against Aflatoxin B1-Intitiated Hepatic Carcinogenicity

    OpenAIRE

    Abdel-Wahhab, Mosaad A; Omara, Enayat A.; Abdel-Galil, Mona M; Hassan, Nabila S.; Nada, Somaia A; Saeed, Ataa; ElSayed, Magdy M

    2007-01-01

    Aflatoxins (AF), a group of closely related, extremely toxic mycotoxins, produced by Aspergillus flavus and A. parasiticus can occur as natural contaminants of foods and feeds. Aflatoxins have been shown to be hepatotoxic, carcinogenic, mutagenic, and teratogenic to different animal species. Zizyphus spina-christi L. extract was investigated for its antifungal and antimicrobial activities. The aim of the present work was to evaluate the antioxidant activity of the methanol extract of Z. spina...

  4. A one-electron oxidation of carcinogenic nonaminoazo dye Sudan I by horseradish peroxidase

    Czech Academy of Sciences Publication Activity Database

    Semanská, M.; Dračínský, Martin; Martínek, V.; Hudeček, J.; Hodek, P.; Frei, E.; Stiborová, M.

    2008-01-01

    Roč. 29, č. 5 (2008), s. 712-716. ISSN 0172-780X Grant ostatní: GA MŠk(CZ) 1M0505; GA ČR(CZ) GA203/06/0329 Institutional research plan: CEZ:AV0Z40550506 Keywords : carcinogen * Sudan I * peroxidase * NMR spectroscopy * mechanism of oxidation Subject RIV: CC - Organic Chemistry Impact factor: 1.359, year: 2008 http://node.nel.edu

  5. The role of the Akt/mTOR pathway in tobacco-carcinogen induced lung tumorigenesis

    OpenAIRE

    Memmott, Regan M.; Dennis, Phillip A.

    2009-01-01

    Lung cancer is the leading cause of cancer-related death in the United States, and 85–90% of lung cancer cases are associated with tobacco use. Tobacco components promote lung tumorigenesis through genotoxic effects, as well as through biochemical modulation of signaling pathways such as the Akt/mTOR pathway that regulate cell proliferation and survival. This review will describe cell surface receptors and other upstream components required for tobacco-carcinogen induced activation of Akt and...

  6. A Comparative Survey on Parameters Influencing on Hexavalent Chromium Measurement as an Occupational Carcinogen

    OpenAIRE

    A. Tirgar; F. Golbabaie; S.J. Shahtaheri; K. Nori; J. Hamedi; Ganjali, M.R.

    2008-01-01

    Introduction & Objective: Hexavalent chromium, Cr+6, is a very harmful pollutant and a relatively unstable compound that is present in many industries. It is a known human respiratory carcinogen and occupational exposure to this chemical is associated with different health hazards. The purpose of this study was to evaluate the effects of four parameters including: type of sampling head, sampling height from the surface of electroplating solution, sampling duration, and sample storage duration...

  7. Studies on the biological effects of internal exposure of alpha emitters. Carcinogenicity test of plutonium

    International Nuclear Information System (INIS)

    Outlines of carcinogenicity tests in animals given with injected or inhaled plutonium (Pu) were described. Insoluble 239PuO2 particles were nasally inhaled in rats maintained for life. The dose response relationship between incidence of their lung tumor and absorbed radiation dose in the lung revealed that>1 Gy dose increased the incidence of malignant lung tumors, which differed from findings in the U.S. probably due to the difference between particle sizes. Further, a carcinogenic mechanism specific for alpha-ray was suggested based on tumor-related gene analysis. After soluble 239Pu (citrate salt) was injected in mice, significant reduction of lifetime and early tumor- or non-tumor-death were observed when the bone dose exceeded 3 Gy. Tumors were mostly osteosarcoma, lymphoma and other soft tissue solid cancers and were different from those induced by gamma-ray, X-ray and neutron irradiation. Studies on the strain difference, on the carcinogenic mechanism and alpha-ray induced mutation and transformation are in progress, which may lead to elucidation of the biological effects of internal exposure of alpha-emitters. (K.H.)

  8. An update on direct genotoxicity as a molecular mechanism of ochratoxin a carcinogenicity.

    Science.gov (United States)

    Pfohl-Leszkowicz, Annie; Manderville, Richard A

    2012-02-20

    Ochratoxin A (OTA) is a naturally occurring chlorophenolic fungal toxin that contaminates a wide range of food products and poses a cancer threat to humans. The mechanism of action (MOA) for OTA renal carcinogenicity is a controversial issue. In 2005, direct genotoxicity (covalent DNA adduct formation) was proposed as a MOA for OTA-mediated carcinogenicity [ Manderville , R. A. ( 2005 ) Chem. Res. Toxicol. 18 , 1091 - 1097 ]. At that time, inconsistent results had been published on OTA genotoxicity/mutagenicity, and conclusive evidence for OTA-mediated DNA adduction had been lacking. In this update, published data from the past 6-7 years are presented that provide new hypotheses for the MOA of OTA-mediated carcinogenicity. While direct genotoxicity remains a controversial issue for OTA, new findings from the Umemura and Nohmi laboratories provide definitive results for the mutagenicity of OTA in the target tissue (outer medulla) of male rat kidney that rules out oxidative DNA damage. These findings, coupled with our own efforts that provide new structural evidence for DNA adduction by OTA, has strengthened the argument for involvement of direct genotoxicity in OTA-mediated renal carcinogenesis. This MOA should be taken into consideration for OTA human risk assessment. PMID:22054007

  9. Inhibitory effect of diet related sulphydryl compounds on the formation of carcinogenic nitrosamines.

    Science.gov (United States)

    Shenoy, N R; Choughuley, A S

    1992-08-31

    N-Nitroso compounds (NOCs) are known to be strong carcinogens in various animals including primates (Preussman and Stewart, (1984) N-Nitroso Compounds). Human exposure to these compounds can be by ingestion or inhalation of preformed NOCs or by endogenous nitrosation from naturally occurring precursors (Bartsch and Montesano, Carcinogenesis, 5 (1984) 1381-1393; Tannebaum (1979) Naturally Occuring Carcinogens, Mutagens and Modulators of Carcinogenesis; Shephard et al., Food Chem. Toxicol., 25 (1987) 91-108). Several factors present in the diet can modify levels of endogenously formed nitrosamines by acting as catalysts or inhibitors. Compounds in the human diet that alter nitrosamine formation would thus play an important role in carcinogenesis study. Earlier researchers have reported the nitrite scavenging nature of sulphydryl compounds (Williams, Chem. Soc. Rev., 15 (1983) 171-196). We therefore studied the modifying effect of sulphydryl compounds viz., cysteine (CE), cystine (CI), glutathione (GU), cysteamine (CEA), cystamine (CEI), cysteic acid (CIA) and thioglycolic acid (TGA) on the nitrosation of model amines viz., pyrrolidine (PYR), piperidine (NPIP) and morpholine (NMOR). Many of these compounds are present in the food we consume. The present work also describes the inhibitory effect of onion and garlic juices on the nitrosation reactions. Both onion and garlic are known to contain sulphur compounds (Block, Sci. Am., 252 (1985) 114-119). Most of these compounds behave as antinitrosating agents and their inhibitory activity towards formation of carcinogenic nitrosamines, under different conditions is described. PMID:1516037

  10. Carcinogenic effects of MGP-7 and B(a)P on the Hamster Cheek Pouch

    Energy Technology Data Exchange (ETDEWEB)

    Brandon, J.L.; Conti, C.J.; Goldstein, L.S.; DiGiovanni, J.; Gimenez-Conti, I.B. [University of Texas MD Anderson Cancer Center, Smithville, TX (United States). Dept. of Carcinogenesis

    2009-10-15

    This study was performed to examine the carcinogenic effects of benzo(a)pyrene (B(a)P) and manufactured gas plant (MGP) residues on the hamster cheek pouch (HCP). Syrian hamsters were treated topically with a suspension of 2%, 10%, or 20% B(a)P or 50% or 100% MGP-7 (a mixture of residues from 7 MGP sites) in mineral oil for eight (short-term study) and sixteen, twenty, twenty-eight, and thirty-two weeks (long-term study). The short-term study showed that B(a)P induced p53 protein accumulation, indicative of genotoxic damage, as well as increased cell proliferation, hyperplasia, and inflammation, which is usually associated with promotional activity. In contrast, the MGP-7 presented only marginal p53 accumulation and induction of BrdU incorporation. In the long-term experiments, animals treated with 2% and 10% of B(a)P continued to show p53 protein accumulation as well as hyperplasia and increased cell proliferation and inflammation. By thirty weeks, all the animals treated with B(a)P had a 100% incidence of squamous cell carcinoma (SCC). Animals treated with 50% and 100% MGP-7 showed only weak hyperplasia and a low proliferation rate and accumulation of p53 protein through thirty-two weeks. Benzo(a)pyrene was highly carcinogenic when used at adequate doses. Manufactured gas plant residue, however, was not carcinogenic in this model.

  11. Synthesis, structural characterization and anti-carcinogenic activity of new cyclotriphosphazenes containing dioxybiphenyl and chalcone groups

    Science.gov (United States)

    Görgülü, Ahmet Orhan; Koran, Kenan; Özen, Furkan; Tekin, Suat; Sandal, Süleyman

    2015-05-01

    2,2-Dichloro-4,4,6,6-bis[spiro(2‧,2″-dioxy-1‧,1″-biphenylyl]cyclotriphosphazene (2) was synthesized from hexachlorocyclotriphosphazene (HCCP) and 2,2‧-dihydroxybiphenyl. The mixed substituent chalcone/dioxybiphenyl cyclophosphazenes (2a-h) were obtained from the reactions of (2) with hydroxy chalcone compounds in K2CO3/acetone system. The chalcone-cyclophosphazene compounds were characterized by elemental analysis, FT-IR, 1H, 13C, 31P NMR techniques. In vitro anti-carcinogenic activities of all compounds were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Anti-carcinogenic activity of the compounds (2a-h) against androgen-dependent (LNCaP) and independent (PC-3) human prostate cancer cell lines were investigated. Our results indicate that the chalcone-phosphazene compounds (2a-h) have anti-carcinogenic activity on PC-3 and LNCaP cell lines (p < 0.05). The effective dose of the compounds was determined as 100 μM.

  12. Chronic Dermal Toxicity of Epoxy Resins I. Skin Carcinogenic Potency and General Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Holland, J.M.

    2001-01-16

    Epoxy resins are a diverse class of chemicals that differ in structure, physical properties, and, presumably, biological activity. The purpose of these experiments was to compare the chronic dermal toxicity and carcinogenicity of selected commercial epoxy resins and to determine the potential for positive synergistic carcinogenic interactions between different resins. This work is an extension and continuation of a Department of Energy sponsored program to evaluate epoxy resins for potential occupational health risks. The materials examined were chosen on the basis of their interest to the U.S. government. They are representative of the manufacturer's production at the time, and therefore the data are completely valid only for the specific production period. Results of the experimental exposures will be reported in two parts. This report describes the test materials, their chemical and physical characteristics and the experimental design. General (systemic) toxicity will be evaluated and the skin carcinogenicity of the materials compared. A subsequent report will provide morphological descriptions of skin and significant internal pathology induced by the various treatments.

  13. Human hair follicles, a convenient tissue for genetic studies on carcinogen metabolism

    International Nuclear Information System (INIS)

    Basal levels of benzo(a)pyrene metabolism were measured in hair follicles of seven monozygotic twins, eight dizygotic twins and ten pairs of unrelated individuals. Organic soluble metabolites were separated by thin-layer chromatography, visualised by autoradiography and quantified by scanning of the films. Activity was expressed as pmol 7,8- and 9,10-dihydrodiol metabolites of benzo(a)pyrene per μg DNA per hour. Intra-twin differences in benzo(a)pyrene metabolism for monozygotic twins were smaller than for dizygotic twins and intra-pair differences for dizygotic twins were smaller than for pairs of unrelated individuals. The results clearly suggest that individual differences in benzo(a)pyrene metabolism in hair follicles are partly genetically determined. Thus, hair follicles my be used for investigations on the suggested relations between genetic predisposition to carcinogen-induced cancer and individual differences in carcinogen metabolism. The relevance of these findings to research into the induction of neoplasms by carcinogens in epithelial tissues is discussed. (author)

  14. 78 FR 68849 - Draft Current Intelligence Bulletin “Update of NIOSH Carcinogen Classification and Target Risk...

    Science.gov (United States)

    2013-11-15

    .... Place: Surface Transportation Board Hearing Room, Patriots Plaza One, 395 E Street SW., 1st Floor, Room... sufficient evidence from animal data'' meet the criteria for GHS Carcinogen Category 1B. Chemicals...

  15. Application of the two-stage clonal expansion model in characterizing the joint effect of exposure to two carcinogens

    International Nuclear Information System (INIS)

    In this paper, we describe application of the two-stage clonal expansion model to characterize the joint effect of exposure to two carcinogens. This biologically based model of carcinogenesis provides a useful framework for the quantitative description of carcinogenic risks and for defining agents that act as initiators, promoters, and completers. Depending on the mechanism of action, the agent-specific relative risk following exposure to two carcinogens can be additive, multiplicative, or supramultiplicative, with supra-additive relative risk indicating a synergistic effect between the two agents. Maximum-likelihood methods for fitting the two-stage clonal expansion model with intermittent exposure to two carcinogens are described and illustrated, using data on lung-cancer mortality among Colorado uranium miners exposed to both radon and tobacco smoke

  16. NANOSTRUCTURED POROUS SILICON AND LUMINESCENT POLYSILOLES AS CHEMICAL SENSORS FOR CARCINOGENIC CHROMIUM(VI) AND ARSENIC(V)

    Science.gov (United States)

    The chief goal is to develop new selective solid state sensors for carcinogenic and toxic chromium(VI) and arsenic(V) in water based on redox quenching of the luminescence from nanostructured porous silicon and polysiloles.

  17. The International Agency for Research on Cancer (IARC) evaluation of the carcinogenicity of outdoor air pollution: focus on China

    OpenAIRE

    Dana Loomis; Wei Huang; Guosheng Chen

    2014-01-01

    The International Agency for Research on Cancer (IARC) has classified outdoor air pollution and the particulate matter (PM) in outdoor air pollution as carcinogenic to humans, as based on sufficient evidence of carcinogenicity in humans and experimental animals and strong support by mechanistic studies. The data with important contributions to the evaluation are reviewed, highlighting the data with particular relevance to China, and implications of the evaluation with respect to China are dis...

  18. Prediction of rodent carcinogenicity of further 30 chemicals bioassayed by the U.S. National Toxicology Program.

    OpenAIRE

    Benigni, R; Andreoli, C; Zito, R

    1996-01-01

    Recently the U.S. National Toxicology Program (NTP) sponsored a comparative exercise in which different prediction approaches (both biologically and chemically based) were challenged for their predictive abilities of rodent carcinogenicity of a common set of chemicals. The exercise enjoyed remarkable scientific success and stimulated NTP to sponsor a second challenging round of tests, inviting participants to present predictions relative to the rodent carcinogenicity of a further 30 chemicals...

  19. Red meat intake, doneness, polymorphisms in genes that encode carcinogen-metabolizing enzymes and colorectal cancer risk

    OpenAIRE

    Cotterchio, Michelle; Boucher, Beatrice A.; Manno, Michael; Gallinger, Steven; Okey, Allan B; Harper, Patricia A.

    2008-01-01

    Colorectal cancer literature regarding the interaction between polymorphisms in carcinogen-metabolizing enzymes and red meat intake/doneness is inconsistent. A case-control study was conducted to evaluate the interaction between red meat consumption, doneness and polymorphisms in carcinogen-metabolizing enzymes. Colorectal cancer cases diagnosed 1997-2000, aged 20-74 years, were identified through the population-based Ontario Cancer Registry and recruited by the Ontario Family Colorectal Canc...

  20. Liver fatty acid-binding protein: specific mediator of the mitogenesis induced by two classes of carcinogenic peroxisome proliferators.

    OpenAIRE

    S H Khan; Sorof, S

    1994-01-01

    Peroxisome proliferators (PP) are a diverse group of chemicals that induce dramatic increases in peroxisomes in rodent hepatocytes, followed by hypertrophy, hepatomegaly, alterations in lipid metabolism, mitogenesis, and finally hepatocarcinomas. Termed nongenotoxic carcinogens, they do not interact with DNA, are not mutagenic in bacterial assays, and fail to elicit many of the phenotypes associated with classic genotoxic carcinogens. We report here that the mitogenesis induced by the major P...

  1. The metabolic N-oxidation of carcinogenic arylamines in relation to nitrogen charge density and oxidation potential.

    OpenAIRE

    Kadlubar, F F; Fu, P P; Jung, H.; Shaikh, A U; Beland, F A

    1990-01-01

    The N-oxidation of carcinogenic arylamines to form N-hydroxy arylamines has long been regarded as a necessary metabolic step for conversion to proximate carcinogenic derivatives. In contrast, arylamine ring-oxidation has been generally considered to be an important detoxification mechanism. Both enzymatic reactions are carried out in the liver and usually involve the cytochrome P-450 monooxygenases. Studies on the metabolic oxidation of certain arylamines have indicated that the relative char...

  2. [Mechanisms of action for metallic elements and their species classified carcinogen R 45 and R 49 by EU].

    Science.gov (United States)

    Apostoli, P; Catalani, S

    2008-01-01

    In this paper we will deal with mechanism of carcinogenic action of metallic elements and their species (arsenic, beryllium, cadmium, cobalt, chromium, nickel) identified by EU as carcinogen R 45 or R 49. The carcinogenic effect depended on the ability of to penetrate the cell and interacted with the target sites, therefore the state of oxidation, charging, the solubility, type of binding, stereochemistry and the ability to interact with other xenobiotics were crucial. The carcinogenic metallic elements classified R45 or R49 are essentially weak mutagen and do not form adducts with the DNA as initial step of their carcinogenicity In spite of the wide range of metallic elements physicochemical properties, some common general mechanisms of carcinogenesis emerge:from the induction of oxidative stress, to inhibition of DNA repair, from activation of mitogenic signalling, to epigenetic modification of gene expression. However, each species lead to specific molecular interactions and were subject to different bioavailability. It has been also strongly supported the hypothesis that the metallic elements may act as a co-carcinogen with other organic compounds, for example with PAH. PMID:19344091

  3. Temporal aspects of tumorigenic response to individual and mixed carcinogens. Progress report, October 1, 1978-September 30, 1979

    International Nuclear Information System (INIS)

    The research proposed here is designed to obtain a better understanding of the temporal kinetics of tumor induction when one or more carcinogens are present simultaneously or sequentially for prolonged periods of time. Studies done to date under this contract have shown that carcinogenesis in mouse skin by polycyclic aromatic hydrocarbon carcinogens is consistent with the induction of dependent and autonomous cell transformations by the carcinogen followed by the conversion of autonomous tumor cells into malignancies at a rate which is determined by the level of carcinogen exposure. Dependent cell transformations remain latent in the skin unless expressed by a promoting agent. Dependent neoplasia appears to follow one-hit kinetics while malignancy is a multihit endpoint. Dose-related and time-related aspects of tumor induction are separable in the initiation-promotion system of mouse skin which along with rat skin and hamster lung is being used as a model for testing hypotheses. Results to date provide the basis for a new interpretation of the linear non-threshold extrapolation model. The broad aim of the study is to provide a basis or rationale for estimating risks associated with prolonged exposures to carcinogens found in the environment and to predict how different tissues and species respond to the carcinogens, promoters, and cocarcinogens

  4. Detection of strand breaks in phiX 174 RFI and PM2 DNA reacted with ultimate and proximate carcinogens.

    Science.gov (United States)

    Thielmann, H W

    1977-10-01

    Supercoiled DNA duplexes of phages phiX 174 and PM2 were treated in aqueous solution at neutral pH with ultimate and proximate carcinogens. Subsequently, the carcinogen-treated phage DNAs were subjected to velocity sedimentation in neutral and alkaline sucrose to quantitative introduction of single strand breaks. Reaction of phage DNA with the ultimate carcinogens N-methyl-N-nitrosourea (MeNOUr), N-ethyl-N-nitrosourea (EtNOUr), 7-bromomethyl-benza[a]-anthracene, N-acetoxy-2-acetylaminofluorene [(Ac)2ONFln] and K-region oxides for short periods followed by sedimentation in neutral sucrose gradients led to very few breaks. Incubation with the proximate carcinogens N-hydroxy-2-acetylaminofluorene, 2-acetylaminofluorene, 7-methyl-, and 7,12-dimethyl-benza[a]anthracene did not result in breaks. However, when the phage DNAs were reacted with the ultimate carcinogens under the same conditions but subsequently alkali-denatured and sedimented in alkaline sucrose gradients, single strand breaks were readily introduced. Incubation with the proximate carcinogens followed by alkali denaturation and sedimentation in alkaline sucrose showed that only 7,12-dimethyl-benz[a]anthracene and, to a minor extent, 7-methyl-benz[]anthracene caused alkali-inducible breaks. The ability of N-methyl-N'-nitro-N-nitrosoguanidine to effect breakdown of superhelical phage DNA in alkali was found enhanced in the presence of N-acetyl-cysteine. PMID:145749

  5. Results of screening NCI/NTP nongenotoxic carcinogens and genotoxic noncarcinogens with the k sub e test

    Energy Technology Data Exchange (ETDEWEB)

    Mendelsohn, M.L. (ed.); Bakale, G.; McCreary, R.D.

    1989-01-01

    The interdependence of the electrophilic and carcinogenic properties of chemicals that was demonstrated two decades ago rekindled interest in the somatic mutation theory of carcinogenesis. Interest in this theory grew with the development of a reverse-mutation bacterial assay in the laboratory of B.N. Ames that permitted the mutagenic properties of the chemicals to be determined quickly and yielded results which indicated that carcinogens are mutagens.'' Subsequent validation studies of this bioassay, the Salmonella typhimurium/microsome or Ames test,'' by Ames' group and others provided additional support for the correlation between mutagenicity and carcinogenicity which led to the worldwide deployment of the Ames test in thousands of laboratories and to the development of more than 100 other short-term tests that continue to be used to identify potential carcinogens via various end-points of genotoxicity. This document discusses electrophilicity, mutagenicity, and carcinogenicity relationships as well as carcinogen-screening of chemicals. 28 refs., 4 tabs.

  6. Production of thymine glycols in DNA by radiation and chemical carcinogens as detected by a monoclonal antibody.

    Science.gov (United States)

    Leadon, S A

    1987-06-01

    In order to understand the role in carcinogenesis of damage indirectly induced by chemical carcinogens, it is important to identify the primary DNA lesions. We have measured the formation and repair of one type of DNA modification, 5,6-dihydroxydihydrothymine (thymine glycol), following exposure of cultured human cells to the carcinogens N-hydroxy-2-naphthylamine or benzo(a)pyrene. The efficiency of production of thymine glycols in DNA by these carcinogens was compared to that by ionizing radiation and ultraviolet light. Thymine glycols were detected using a monoclonal antibody against this product in a sensitive immunoassay. We found that thymine glycols were produced in DNA in a dose dependent manner after exposure to the carcinogens and that their production was reduced if either catalase or superoxide dismutase or both were present at the time of treatment. The efficiency of thymine glycol production following exposure to the chemical carcinogens was greater than that following equi-toxic doses of radiation. Thymine glycols were efficiently removed from the DNA of human cells following treatment with either the chemical carcinogens, ionizing radiation or ultraviolet light. PMID:3477281

  7. Combining QSAR Modeling and Text-Mining Techniques to Link Chemical Structures and Carcinogenic Modes of Action

    Science.gov (United States)

    Papamokos, George; Silins, Ilona

    2016-01-01

    There is an increasing need for new reliable non-animal based methods to predict and test toxicity of chemicals. Quantitative structure-activity relationship (QSAR), a computer-based method linking chemical structures with biological activities, is used in predictive toxicology. In this study, we tested the approach to combine QSAR data with literature profiles of carcinogenic modes of action automatically generated by a text-mining tool. The aim was to generate data patterns to identify associations between chemical structures and biological mechanisms related to carcinogenesis. Using these two methods, individually and combined, we evaluated 96 rat carcinogens of the hematopoietic system, liver, lung, and skin. We found that skin and lung rat carcinogens were mainly mutagenic, while the group of carcinogens affecting the hematopoietic system and the liver also included a large proportion of non-mutagens. The automatic literature analysis showed that mutagenicity was a frequently reported endpoint in the literature of these carcinogens, however, less common endpoints such as immunosuppression and hormonal receptor-mediated effects were also found in connection with some of the carcinogens, results of potential importance for certain target organs. The combined approach, using QSAR and text-mining techniques, could be useful for identifying more detailed information on biological mechanisms and the relation with chemical structures. The method can be particularly useful in increasing the understanding of structure and activity relationships for non-mutagens.

  8. Prediction of rodent carcinogenic potential of naturally occurring chemicals in the human diet using high-throughput QSAR predictive modeling

    International Nuclear Information System (INIS)

    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 is 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

  9. Metabolic dephenylation of the rubber antioxidant N-phenyl-2-naphthylamine to carcinogenic 2-naphthylamine in rats.

    Science.gov (United States)

    Weiss, Tobias; Bolt, Hermann M; Schlüter, Gerhard; Koslitz, Stephan; Taeger, Dirk; Welge, Peter; Brüning, Thomas

    2013-07-01

    N-Phenyl-2-naphthylamine (P2NA) was widely used as oxidation inhibitor, particularly in rubber manufacturing. Technical-grade P2NA was contaminated with carcinogenic 2-naphthylamine (2NA), and bladder cancer risk in exposed workers was attributed to this impurity. Investigations in humans and mammalian species revealed that small amounts of 2NA are excreted into urine after exposure to P2NA. However, since 2NA per se is not carcinogenic and main downstream metabolites of 2NA have not been found in urine so far, it remained uncertain if 2NA derived from P2NA dephenylation is further activated to carcinogenic downstream metabolites. An experimental animal study was therefore designed to indicate if, and if yes to which extent, 2NA from P2NA dephenylation is accessible to the metabolic pathway that is held responsible for the carcinogenicity of 2NA. Groups of 5 male and female CD rats were dosed with P2NA (2-550 mg/kg b.w.) and 2NA (0.075-75 mg/kg b.w.); 2NA-haemoglobin adducts and urinary 2NA excretion were determined applying GC-MS/MS. 2NA haemoglobin adducts originated dose-dependently after 2NA and P2NA dosing. To induce identical adduct concentrations, an approximately 100-200-fold higher dose of P2NA was necessary compared to 2NA. Since haemoglobin adducts are formed by the same pathway (N-hydroxylation) as the ultimate carcinogens from 2NA, the comparison of adduct concentrations after 2NA and P2NA dosage permits a quantitative estimate of the carcinogenicity of P2NA. The results show that 2NA derived from dephenylation of P2NA enters the carcinogenic downstream pathway of 2NA in rats. Hence, the bladder cancer risk after human exposures to P2NA must be re-evaluated. PMID:23423714

  10. The function and significance of SELENBP1 downregulation in human bronchial epithelial carcinogenic process.

    Directory of Open Access Journals (Sweden)

    Gu-Qing Zeng

    Full Text Available BACKGROUND: Our quantitative proteomic study showed that selenium-binding protein 1 (SELENBP1 was progressively decreased in human bronchial epithelial carcinogenic process. However, there is little information on expression and function of SELENBP1 during human lung squamous cell cancer (LSCC carcinogenesis. METHODS: iTRAQ-tagging combined with 2D LC-MS/MS analysis was used to identify differentially expressed proteins in the human bronchial epithelial carcinogenic process. SELENBP1, member of selenoproteins family and progressively downregulated in this process, was selected to further study. Both Western blotting and immunohistochemistry were performed to detect SELENBP1 expression in independent sets of tissues of bronchial epithelial carcinogenesis, and ability of SELENBP1 for discriminating NBE (normal bronchial epithelium from preneoplastic lesions from invasive LSCC was evaluated. The effects of SELENBP1 downregulation on the susceptibility of benzo(apyrene (B[a]P-induced human bronchial epithelial cell transformation were determined. RESULTS: 102 differentially expressed proteins were identified by quantitative proteomics, and SELENBP1 was found and confirmed being progressively decreased in the human bronchial epithelial carcinogenic process. The sensitivity and specificity of SELENBP1 were 80% and 79% in discriminating NBE from preneoplastic lesions, 79% and 82% in discriminating NBE from invasive LSCC, and 77% and 71% in discriminating preneoplastic lesions from invasive LSCC, respectively. Furthermore, knockdown of SELENBP1 in immortalized human bronchial epithelial cell line 16HBE cells significantly increased the efficiency of B[a]P-induced cell transformation. CONCLUSIONS: The present data shows for the first time that decreased SELENBP1 is an early event in LSCC, increases B[a]P-induced human bronchial epithelial cell transformation, and might serve as a novel potential biomarker for early detection of LSCC.

  11. Carcinogenic potential of soils contaminated with polycyclic aromatic hydrocarbons (PAHs) in Xiamen metropolis, China.

    Science.gov (United States)

    Cai, Chao; Zhang, Youchi; Reid, Brian J; Nunes, Luis M

    2012-12-01

    Xiamen is one of China's most rapidly developing metropolises. The objectives of the present study were: (1) to establish the levels and spatial distribution of polycyclic aromatic hydrocarbons (PAHs) in soil across the Xiamen metropolis, (2) to evaluate the extent to which PAH concentrations were elevated in the high urbanization area (HUA) of the island and how these compared with those in the low urbanization area (LUA) of the mainland, and (3) to evaluate the PAH hazard based upon their Carcinogenic Potential (CP), defined as toxicity equivalence of ∑PAHs. Twenty two alternative relative carcinogenic potency schemes were used and compared. Results demonstrated PAH concentrations to be greatly elevated across the entire metropolis. Significantly, the most enriched compounds represented the greatest concern with respect to carcinogenicity. The CP of more than 25% of the industrial samples from the island surpassed the Canadian guidance threshold value (600 μg kg⁻¹) for an excess lifetime cancer risk (ELCR) of 1 in 10⁻⁶. While soil samples from the remaining land uses on the island were all below this threshold, PAH levels in soil were nonetheless elevated (enrichment factors of between 4.1 ± 1.9 and 16.3 ± 12.4 in the HUA, and between 1.3 ± 0.7 and 10.8 ± 4.4 in the LUA). Results relating to agricultural locations on the island indicated 75% of the samples in HUA and 28% of the samples in LUA to be above the USEPA guidance value for BaP (15 μg kg⁻¹). Given the exceptionally high population density on the island there is a need for further research to evaluate multiple pathway PAH exposure risks. PMID:23092998

  12. Inhibition of DNA synthesis by chemical carcinogens in cultures of initiated and normal proliferating rat hepatocytes

    International Nuclear Information System (INIS)

    Rat hepatocytes in primary culture can be stimulated to replicate under the influence of rat serum and sparse plating conditions. Higher replication rates are induced by serum from two-thirds partially hepatectomized rats. The effects of carcinogens and noncarcinogens on the ability of hepatocytes to synthesize DNA were examined by measuring the incorporation of [3H]thymidine by liquid scintillation counting and autoradiography. Hepatocyte DNA synthesis was not decreased by ethanol or dimethyl sulfoxide at concentrations less than 0.5%. No effect was observed when 0.1 mM ketamine, Nembutal, hypoxanthine, sucrose, ascorbic acid, or benzo(e)pyrene was added to cultures of replicating hepatocytes. Estrogen, testosterone, tryptophan, and vitamin E inhibited DNA synthesis by approximately 50% at 0.1 mM, a concentration at which toxicity was noticeable. Several carcinogens requiring metabolic activation as well as the direct-acting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine interfered with DNA synthesis. Aflatoxin B1 inhibited DNA synthesis by 50% (ID50) at concentrations between 1 X 10(-8) and 1 X 10(-7) M. The ID50 for 2-acetylaminofluorene was between 1 X 10(-7) and 1 X 10(-6) M. Benzo(a)pyrene and 3'-methyl-4-dimethylaminoazobenzene inhibited DNA synthesis 50% between 1 X 10(-5) and 1 X 10(-4) M. Diethylnitrosamine and dimethylnitrosamine (ID50 between 1 X 10(-4) and 5 X 10(-4) M) and 1- and 2-naphthylamine (ID50 between 1 X 10(-5) and 5 X 10(-4) M) caused inhibition of DNA synthesis at concentrations which overlapped with concentrations that caused measurable toxicity

  13. Evaluation of tests using DNA repair-deficient bacteria for predicting genotoxicity and carcinogenicity

    Energy Technology Data Exchange (ETDEWEB)

    Leifer, Z.; Kada, T.; Mandel, M.; Zeiger, E.; Stafford, R.; Rosenkranz, H.S.

    1981-01-01

    The detection of DNA-damaging agents by repair-deficient bacterial assays is based on the differential inhibition of growth of repair-proficient and repair-deficient bacterial pairs. The various methodologies used are described and recommendations are made for their improved use. In a survey of the literature through April 1979, 91 of 276 papers evaluated contained usable data, resulting in an analysis of 611 compounds that had been assayed in 1 or more of 55 pairs of repair-proficient and repair-deficient strains. The results indicate that a liquid suspension assay is more sensitive than a spot (diffusion) test. There was a 78% correspondence between results obtained with E. coli polA and Bacillus subtilis (H17/M45, 17A/45T) rec assay and between E. coli polA and Proteus mirabilis. In a comparison of test results with carcinogenicity data, 44 of 71 (62%) carcinogenic compounds assayed by the polA system were positive, 10 (14%) were negative, and 17 (24%) gave No Test or doubtful results. The results were analyzed with respect to chemical classes. E. coli polA detected the highest percentage of hydroxylamines and alkyl epoxides. The B. subtilis rec assay detected the highest percentage of nitrosamines and sulfur and nitrogen oxides. It is concluded that some of these test systems are effective tools for the detection of DNA-damaging and potentially carcinogenic compounds, especially if the assay is done in liquid suspension and if more than 1 pair of tester strains is used. Advantages and disadvantages of the assay are discussed and suggestions are made for improvements in the system.

  14. Differences in gene expression profiles in the liver between carcinogenic and non-carcinogenic isomers of compounds given to rats in a 28-day repeat-dose toxicity study.

    Science.gov (United States)

    Nakayama, Koji; Kawano, Yukiko; Kawakami, Yuuki; Moriwaki, Norichika; Sekijima, Masaru; Otsuka, Masanori; Yakabe, Yoshikuni; Miyaura, Hideki; Saito, Koichi; Sumida, Kayo; Shirai, Tomoyuki

    2006-12-15

    Some compounds have structural isomers of which one is apparently carcinogenic, and the other not. Because of the similarity of their chemical structures, comparisons of their effects can allow gene expression elicited in response to the basic skeletons of the isomers to be disregarded. We compared the gene expression profiles of male Fischer 344 rats administered by daily oral gavage up to 28 days using an in-house oligo microarray. 2-Acetylaminofluorene (2-AAF), 2,4-diaminotoluene (2,4-DAT), 2-nitropropane (2-NP), and 2-nitro-p-phenylenediamine (2-NpP) are hepatocarcinogenic. However, their isomers, 4-acetylaminofluorene (4-AAF), 2,6-diaminotoluene (2,6-DAT), 1-nitropropane (1-NP), and 4-nitro-o-phenylenediamine (4-NoP), are non-hepatocarcinogenic. Because of the limited carcinogenicity of 2-NpP, we attempted to perform two-parametric comparison analyses with (1) a set of 4 isomers: 2-AAF, 2,4-DAT, 2-NP, and 2-NpP as "carcinogenic", and 4-AAF, 2,6-DAT, 1-NP, and 4-NoP as "non-carcinogenic"; and (2) a set of 3 isomers: 2-AAF, 2,4-DAT, and 2-NP, as "carcinogenic", and 4-AAF, 2,6-DAT, and 1-NP as "non-carcinogenic". After ratio filtering and Welch's approximate t-test analysis, 54 and 28 genes were selected from comparisons between the sets of 3 and 4 isomers, respectively, for day 28 data. Using hierarchical clustering analysis with the 54 or 28 genes, 2-AAF, 2,4-DAT, and 2-NP clustered into a "carcinogenic" branch. 2-NpP was in the same cluster as 4-NoP and 4-AAF. This clustering corresponded to the previous finding that 2-NpP is not carcinogenic in male Fischer 344 rats, which indicates that comparing the differences in gene expression elicited by different isomers is an effective method of developing a prediction system for carcinogenicity. PMID:17070881

  15. Mechanisms of immunosuppression induced in mice by orthoaminoazotoluene and its non-carcinogenic analogue

    International Nuclear Information System (INIS)

    Single injections of ortho-aminoazotoluene (OAT) or aminoazobenzene (AB) decrease the immune response of DD mice to the strain-nonspecific Krebs-2 tumor. The immunosuppressive action of AB is due to its toxicity for lymphoid cells, whereas the OAT effect is mediated by adrenal glands. After OAT injection, 2-oxycorticosteroids level is elevated although their production by adrenal glands is not increased. The accumulation of glucocorticoids in blood after OAT injection is assumed to be the result of a decreased hormone utilization because of the blockade of receptor proteins or metabolizing enzymes in liver cells by a carcinogen

  16. The Carcinogenic Agent Azoxymethane (AOM) Enhances Early Inflammation-induced Colon Crypt Pathology

    DEFF Research Database (Denmark)

    Venning, Freja Albjerg; Claesson, Mogens Helweg; Kissow, Hannelouise

    2013-01-01

    Severe combined immunodeficiency (SCID) mice transplanted with CD4+ T cells depleted of CD25+ regulatory T cells develop colitis within 2-3 weeks after the T cell transfer. In the present study we studied the effect of the carcinogen azoxymethane (AOM) on the colon crypt pathology of normal SCID...... mice and SCID mice with transfer colitis. AOM by itself did result in neither weight loss nor inflammation although treatment affected crypt widths and numbers. Although AOM together with T cell transfer did not increase the level of gut inflammation including COX-2 expression, AOM increased crypt...

  17. A theoretical concept of low level/low LET radiation carcinogenic risk (LLCR) projection

    Energy Technology Data Exchange (ETDEWEB)

    Filyushkin, I.V. [Laboratory of Theoretical Radiobiology, Moscow (Russian Federation)

    1992-06-01

    Carcinogenic risk to humans resulting from low level/low LET radiation exposure (LLLCR) has not been observed directly because epidemiological observations have not yet provided statistically significant data on risk values. However, these values are of great interest for radiation health science and radiation protection practice under both normal conditions and emergency situations. This report presents a theoretical contribution to the validation of dose and dose rate efficiency factors (DDREF) transforming cocinogenic risk coefficients from those revealed in A-bomb survivors to factors appropriate for the projection of the risk resulting from very low levels of low LET radiation.

  18. Formation and Human Risk of Carcinogenic Heterocyclic Amines Formed from Natural Precursors in Meat

    Energy Technology Data Exchange (ETDEWEB)

    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.

  19. Reproductive and carcinogenic health risks to hospital personnel from chemical exposure--a literature review.

    Science.gov (United States)

    Babich, H

    1985-01-01

    Hospital personnel, both those involved directly (surgeons, anesthesiologists, operating room nurses) and indirectly (pharmacists, laboratory technicians) with promoting the well-being of patients, and those involved in maintaining the proper functioning of the hospital (housekeeping personnel, painters, machinists), may be exposed to chemicals that are potential reproductive and carcinogenic hazards. Waste anesthetic gases, sterilants, such as ethylene oxide and formaldehyde, antineoplastic drugs, methylmethacrylate, asbestos, and various organic reagents and solvents may induce genetic damage, cancer, congenital malformation, still-birth, and spontaneous abortion. PMID:10274220

  20. A theoretical concept of low level/low LET radiation carcinogenic risk (LLCR) projection

    International Nuclear Information System (INIS)

    Carcinogenic risk to humans resulting from low level/low LET radiation exposure (LLLCR) has not been observed directly because epidemiological observations have not yet provided statistically significant data on risk values. However, these values are of great interest for radiation health science and radiation protection practice under both normal conditions and emergency situations. This report presents a theoretical contribution to the validation of dose and dose rate efficiency factors (DDREF) transforming cocinogenic risk coefficients from those revealed in A-bomb survivors to factors appropriate for the projection of the risk resulting from very low levels of low LET radiation

  1. Sorption, degradation and mobility of ptaquiloside, a carcinogenic Bracken (Pteridium sp.) constituent, in the soil environment

    DEFF Research Database (Denmark)

    Rasmussen, Lars Holm; Lauren, Denis; Hansen, Hans Christian Bruun

    2005-01-01

    Ptaquiloside (PTA) is a carcinogenic norsesquiterpene glucoside produced by Bracken in amounts up to at least 13 500 mg m2. The toxin is transferred from Bracken to the underlying soil from where it may leach to surface and groundwaters impairing the quality of drinking water. The objectives of the...... present study were to characterize the solubility, degradation and retention of PTA in soils in order to evaluate the risk for groundwater contamination. PTA was isolated from Bracken. The logarithmic octanol–water and ethyl acetate–water partitioning coefficients for PTA were 0.63 and 0.88, respectively...

  2. Occurrence of the carcinogenic Bracken constituent ptaquiloside in fronds, topsoils and organic soil layers in Denmark

    DEFF Research Database (Denmark)

    Rasmussen, L.H.; Kroghsbo, S.; Frisvad, Jens Christian;

    2003-01-01

    Bracken (Pteridium aquilinum (L.) Kuhn) is a common fern found on all continents except Antarctica. It is under suspicion of causing cancer among people who utilizes it as food. The main carcinogenic compound is thought to be the water-soluble compound ptaquiloside. Ptaquiloside-uptake may occur...... Bracken-litter, the turnover rate and the size of Bracken-stands determined the ptaquiloside-content in the soil materials while the content in fronds was found to be a function of the frond-height and the light-exposure in the ecosystem....

  3. Trichinella spiralis: Mere Co-Existence or Carcinogenic Parasite For Oral Squamous Cell Carcinoma?

    Science.gov (United States)

    Shirazi, Nadia; Bist, Sampan Singh; Ahmad, Sohaib; Harsh, Meena

    2015-10-01

    Trichinella spiralis is a parasite which is usually seen in pork-eaters. Most of the trichinosis infections cause little or no symptoms. We report a rare case of a middle aged North Indian male who presented with a painless ulcer in right buccal mucosa which was biopsied and reported as squamous cell carcinoma. Wide local excision was done subsequently which showed encysted larvae of Trichinella spiralis in the deeper skeletal muscle bundles. This article supports the carcinogenic potential of trichinosis and suggests timely work-up and treatment of the parasite. PMID:26557527

  4. Preferential binding of growth inhibitory prostaglandins by the target protein of a carcinogen.

    OpenAIRE

    S H Khan; Sorof, S

    1990-01-01

    Liver fatty acid binding protein (L-FABP) is the principal target protein of the hepatic carcinogen N-(2-fluorenyl)acetamide (2-acetylaminofluorene) in rat liver. In addition, the cyclopentenone prostaglandins (PG), PGA, PGJ2, and delta 12-PGJ2, inhibit the growth of many cell types in vitro. This report describes the preferential binding of the growth inhibitory prostaglandins by L-FABP and the reversible inhibition of thymidine incorporation into DNA by PGA2 and delta 12-PGJ2 in primary cul...

  5. Plasma proteins as early biomarkers of exposure to carcinogenic aromatic amines.

    Science.gov (United States)

    Miller, M J; Parmelee, D C; Benjamin, T; Sechi, S; Dooley, K L; Kadlubar, F F

    1994-12-01

    Two-dimensional gel electrophoresis (2DG) has been used to study the changes induced in dog plasma polypeptides by the known urinary bladder carcinogens, 4-aminobiphenyl (4-ABP) and 2-naphthylamine (2-NA). Treatment with 3-aminobiphenyl (3-ABP) and 1-naphthylamine (1-NA), both considered to be non-carcinogenic, were used as controls. The purpose of this study was: (1) to determine whether or not changes that occurred in the plasma protein patterns were specific to 4-ABP and/or other related carcinogenic arylamines; (2) to measure the time course in the changes of the major polypeptides during dosing and their resynthesis during a recovery period; and (3) to determine, by microsequencing, the biochemical identity of the affected proteins. The results indicate that only the most potent carcinogen, 4-ABP, had the effect of suppressing the expression of some proteins, while the other aromatic amines caused no discernible change in the 2DG patterns during a 12-week dosing period. The 4-ABP caused dramatic suppression of two sets of proteins. One set of three spots had an apparent molecular weight of 32.5 kDa, and a pI of 5.8-6.0. The major component in this group was identified as the beta-chain of haptoglobin. Expression of this protein decreased markedly during the first 2 weeks of treatment and recovered slowly after dosing stopped. Since haptoglobin functions to bind with free hemoglobin and facilitates its elimination from the blood stream, these results can be rationalized as a consequence of 4-ABP binding to hemoglobin in the erythrocyte, resulting in cell death and hemolysis. The 4-ABP modified hemoglobin then binds to haptoglobin and this tertiary complex is purged from the blood stream, resulting in the disappearance of free haptoglobin. A second set of spots (mol. wt., 65 kDa; pI, 6.5-6.6) disappeared much faster than the haptoglobin, and recovered more quickly. The major protein is about one-fifth the intensity of haptoglobin and appeared to be N

  6. Bacterial Metabolism in Humans of the Carcinogen IQ to the Direct Acting Mutagen Hydroxy-IQ

    OpenAIRE

    Van Tassell, R L; Carman, R. J.; Kingston, D. G. I.; Wilkins, T D

    2011-01-01

    7-hydroxy-IQ is the major product of the bacterial metabolism of IQ, a potent dietary carcinogen. Yet, unlike IQ, hydroxy-IQ is directly active in the salmonella/microsomal mutagenicity assay. Two subjects consumed a meal of fried meats containing IQ but no detectable hydroxy-IQ. Hydroxy-IQ was isolated from the subjects’ faeces collected within 30 h following the fried meat meal; it was absent from the subjects’ faeces before and after the meal. This is the first evidence that hy...

  7. Voltammetric Determination of Carcinogenic Air Pollutant 2-Nitrofluorene Using Polished Silver Solid Amalgam Composite Electrode

    Czech Academy of Sciences Publication Activity Database

    Vyskočil, V.; Krejčová, Z.; Daňhel, A.; Navrátil, Tomáš; Barek, J.

    Ústí nad Labem : Best Servis, 2009 - (Barek, J.; Navrátil, T.), s. 123-126 ISBN 978-80-254-3997-5. [Moderní elektrochemické metody /29./. Jet řichovice (CZ), 25.05.2009-29.05.2009] R&D Projects: GA MŠk(CZ) LC06035; GA ČR GA203/07/1195; GA AV ČR IAA400400806 Institutional research plan: CEZ:AV0Z40400503 Keywords : voltammetry * nitrocompounds * detection * carcinogens Subject RIV: CG - Electrochemistry

  8. Detection of genotoxic and non-genotoxic carcinogens in Xpc{sup −/−}p53{sup +/−} mice

    Energy Technology Data Exchange (ETDEWEB)

    Melis, Joost P.M. [Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven (Netherlands); Leiden University Medical Center, Department of Toxicogenetics, Leiden (Netherlands); Speksnijder, Ewoud N. [Leiden University Medical Center, Department of Toxicogenetics, Leiden (Netherlands); Kuiper, Raoul V. [Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven (Netherlands); Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht (Netherlands); Salvatori, Daniela C.F. [Leiden University Medical Center, Central Animal Facility, Leiden (Netherlands); Schaap, Mirjam M. [Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven (Netherlands); Leiden University Medical Center, Department of Toxicogenetics, Leiden (Netherlands); Maas, Saskia [Leiden University Medical Center, Central Animal Facility, Leiden (Netherlands); Robinson, Joke; Verhoef, Aart; Benthem, Jan van; Luijten, Mirjam [Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven (Netherlands); Steeg, Harry van, E-mail: Harry.van.Steeg@rivm.nl [Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven (Netherlands); Leiden University Medical Center, Department of Toxicogenetics, Leiden (Netherlands)

    2013-01-15

    An accurate assessment of the carcinogenic potential of chemicals and pharmaceutical drugs is essential to protect humans and the environment. Therefore, substances are extensively tested before they are marketed to the public. Currently, the rodent two-year bioassay is still routinely used to assess the carcinogenic potential of substances. However, over time it has become clear that this assay yields false positive results and also has several economic and ethical drawbacks including the use of large numbers of animals, the long duration, and the high cost. The need for a suitable alternative assay is therefore high. Previously, we have proposed the Xpa*p53 mouse model as a very suitable alternative to the two-year bioassay. We now show that the Xpc*p53 mouse model preserves all the beneficial traits of the Xpa*p53 model for sub-chronic carcinogen identification and can identify both genotoxic and non-genotoxic carcinogens. Moreover, Xpc*p53 mice appear to be more responsive than Xpa*p53 mice towards several genotoxic and non-genotoxic carcinogens. Furthermore, Xpc*p53 mice are far less sensitive than Xpa*p53 mice for the toxic activity of DNA damaging agents and as such clearly respond in a similar way as wild type mice do. These advantageous traits of the Xpc*p53 model make it a better alternative for in vivo carcinogen testing than Xpa*p53. This pilot study suggests that Xpc*p53 mice are suited for routine sub-chronic testing of both genotoxic and non-genotoxic carcinogens and as such represent a suitable alternative to possibly replace the murine life time cancer bioassay. Highlights: ► The Xpc*p53 mouse model is able to identify genotoxic and non-genotoxic carcinogens. ► Time, animals and cost can be significantly reduced compared to the 2-year bioassay. ► Xpc*p53 mice are more advantageous for carcinogen identification than Xpa*p53 mice. ► Xpc*p53 mice exhibit a wild type response upon exposure to genotoxicants.

  9. The Weight of Evidence Does Not Support the Listing of Styrene as “Reasonably Anticipated to be a Human Carcinogen” in NTP's Twelfth Report on Carcinogens

    OpenAIRE

    Rhomberg, Lorenz R.; Goodman, Julie E.; Prueitt, Robyn L.

    2013-01-01

    Styrene was listed as “reasonably anticipated to be a human carcinogen” in the twelfth edition of the National Toxicology Program's Report on Carcinogens based on what we contend are erroneous findings of limited evidence of carcinogenicity in humans, sufficient evidence of carcinogenicity in experimental animals, and supporting mechanistic data. The epidemiology studies show no consistent increased incidence of, or mortality from, any type of cancer. In animal studies, increased incidence ra...

  10. Genotoxicity, carcinogenicity, and mode of action of the fried food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ).

    OpenAIRE

    Weisburger, J H; Barnes, W S; Lovelette, C A; Tong, C; Tanaka, T; Williams, G.M.

    1986-01-01

    Because mutagens typified by 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) observed in cooked foods are widely consumed, detailed studies of their biochemical and biological properties including carcinogenicity are most important. IQ induces unscheduled DNA synthesis in liver cells, which when taken together with its powerful mutagenicity in the Salmonella typhimurium test system, predicts carcinogenicity. In female Sprague-Dawley rats, IQ did exhibit potent carcinogenicity for the mammary gla...

  11. Vanadium carcinogenic, immunotoxic and neurotoxic effects: a review of in vitro studies.

    Science.gov (United States)

    Zwolak, Iwona

    2014-01-01

    Deleterious health effects induced by inorganic vanadium compounds are linked with carcinogenic, immunotoxic and neurotoxic insults. The goal of this review is to provide a summary of mammalian cell culture studies (from the 1990s to most recent) looking into the mode of the above-mentioned adverse actions of vanadium. Regarding the carcinogenicity potential, the key cell-based studies have evidenced the ability of vanadium to induce genotoxic lesions, cell morphological transformation and anti-apoptotic effects in a certain type of cells. Two contradictory effects of vanadium on the immune functions of cells have been observed in cell culture studies. The first effect involves reduction of cell immune responses such as vanadium-dependent inhibition of cytokine-inducible functions, which may underlie the mechanism of vanadium-induced immunosuppression. The second one involves stimulation of immune activity, for example, a vanadium-mediated increase in cytokine production, which may contribute to vanadium-related inflammation. So far, an in vitro evaluation of vanadium neurotoxicity has only been reported in few articles. These papers indicate probable cytotoxic mechanisms resulting from exposure of neurons and glial cells to vanadium. In summary, this literature review collects in vitro reports on adverse vanadium effects and thus provides vanadium researchers with a single, concise source of data. PMID:24147425

  12. The carcinogenic risks of low-LET and high-LET ionizing radiations

    International Nuclear Information System (INIS)

    This report presents a discussion on risk from ionizing radiations to human populations. Important new information on human beings has come mainly from further follow-up of existing epidemiological studies, notably the Japanese atomic bomb survivors and the ankylosing spondylitis patients; from new epidemiological surveys, such as the patients treated for cancer of the uterine cervix; and from combined surveys, including workers exposed in underground mines. Since the numerous and complex differences among the different study populations introduce factors that influence the risk estimates derived in ways that are not completely understood, it is not clear how to combine the different risk estimates obtained. These factors involve complex biological and physical variables distributed over time. Because such carcinogenic effects occur too infrequently to be demonstrated at low doses, the risks of low-dose radiation can be estimated only by interpolation from observations at high doses on the basis of theoretical concepts, mathematical models and available empirical evidence, primarily the epidemiological surveys of large populations exposed to ionizing radiation. In spite of a considerable amount of research, only recently has there has been efforts to apply the extensive laboratory data in animals to define the dose-incidence relationship in the low dose region. There simply are insufficient data in the epidemiological studies of large human populations to estimate risk coefficients directly from exposure to low doses. The risk estimates for the carcinogenic effects of radiation have been, in the past, somewhat low and reassessment of the numerical values is now necessary

  13. Increased formation of carcinogenic PAH metabolites in fish promoted by nitrite

    International Nuclear Information System (INIS)

    Nitrite (NO2-), a highly reactive chemical species, accumulates in coastal waters as a result of pollution with nitrogenous waste and/or an imbalance in the bacterial processes of nitrification and denitrification. The present study probed the impact of nitrite (NO2-) on the metabolism of polycyclic aromatic hydrocarbons (PAHs) in fish. In a laboratory experiment, exposure of euryhaline fish, Oreochromis mossambicus to industrial effluents containing PAHs in the presence of NO2- enhanced the cytochrome P450-dependent biotransformation activity determined as 7-ethoxyresorufin-O-deethylase (EROD), by nearly 36% compared to the value observed in the absence of NO2- (50.2 ± 6.74 pmol resorufin min-1 g-1 liver). Fixed wavelength fluorescence measurements in bile revealed maximum enhancement to have occurred in the metabolites of benzo[a]pyrene, a carcinogenic PAH. Lasting, sublethal physiological deterioration was apparent in fish exposed simultaneously to an oil refinery effluent and NO2-, from the unremittingly decreasing liver somatic index, even after the withdrawal of the contaminants. - Nitrite increased formation of carcinogenic PAH metabolites in fish

  14. Impact of environmental exposures on the mutagenicity/carcinogenicity of heterocyclic amines

    International Nuclear Information System (INIS)

    Carcinogenic heterocyclic amines are produced from overcooked foods and are highly mutagenic in most short-term test systems. One of the most abundant of these amines, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), induces breast, colon and prostate tumors in rats. Human dietary epidemiology studies suggest a strong correlation between either meat consumption or well-done muscle meat consumption and cancers of the colon, breast, stomach, lung and esophagus. For over 20 years our laboratory has helped define the human exposure to these dietary carcinogens. In this report we describe how various environmental exposures may modulate the risk from exposure to heterocyclic amines, especially PhIP. To assess the impact of foods on PhIP metabolism in humans, we developed an LC/MS/MS method to analyze the four major PhIP urinary metabolites following the consumption of a single portion of grilled chicken. Adding broccoli to the volunteers' diet altered the kinetics of PhIP metabolism. At the cellular level we have found that PhIP itself stimulates a significant estrogenic response in MCF-7 cells, but even more interestingly, co-incubation of the cells with herbal teas appear to enhance the response. Numerous environmental chemicals found in food or the atmosphere can impact the exposure, metabolism, and cell proliferation response of heterocyclic amines

  15. Preferential binding of growth inhibitory prostaglandins by the target protein of a carcinogen

    Energy Technology Data Exchange (ETDEWEB)

    Khan, S.H.; Sorof, S. (Fox Chase Cancer Center, Philadelphia, PA (United States))

    1990-12-01

    Liver fatty acid binding protein (L-FABP) is the principal target protein of the hepatic carcinogen N-(2-fluorenyl)acetamide (2-acetylaminofluorene) in rat liver. In addition, the cyclopentenone prostaglandins (PG), PGA, PGJ{sub 2}, and {Delta}{sup 12}-PGJ{sub 2}, inhibit the growth of many cell types in vitro. This report describes the preferential binding of the growth inhibitory prostaglandins by L-FABP and the reversible inhibition of thymidine incorporation into DNA by PGA{sub 2} and {Delta}{sup 12}-PGJ{sub 2} in primary cultures of purified rat hepatocytes. As a model ligand, ({sup 3}H)PGA{sub 1} bound to L-FABP specifically, reversibly, rapidly, and with high affinity. Its dissociation constants were 134 nM (high affinity) and 3.6 {mu}M (low affinity). The high-affinity finding of ({sup 3}H)PGA{sup 1} correlated with their growth inhibitory activities reported previously and here. The in vitro actions of L-FABP are compatible with those of a specific and dissociable carrier of growth inhibitory prostaglandins in rat hepatocytes and suggest that the carcinogen may usurp the cellular machinery of the growth inhibitory prostaglandins.

  16. Protein adducts of the prostate carcinogen PhIP in children

    Energy Technology Data Exchange (ETDEWEB)

    Lawrence Livermore National Laboratory

    2004-02-20

    Prostate cancer is the second leading cause of cancer death in men in the United States. few epidemiology studies have indicated that exposure to PhIP, a rodent prostate carcinogen formed in meat during cooking, may be an important risk factor for prostate cancer in humans. Therefore, a highly sensitive biomarker assay is urgently needed to clarify the role of PhIP in prostate cancer. The goal of this project is to develop an assay that can be used to more accurately quantify human exposure to PhIP and potential prostate cancer risk. Our hypothesis is that an Accelerator Mass Spectrometry-based method can be developed to measure protein adducts of PhIP in the blood of humans. This will provide a measure of the internal dose, as well as the capacity for carcinogen bioactivation to a form that can initiate the cancer process. Towards this goal, we have characterized an adduct formed by PhIP in vitro with the amino acid cysteine. This adduct should provide a biomarker of dietary PhIP exposure and potential prostate cancer risk that could be used to identify individuals for prevention and for monitoring the effect chemoprevention strategies.

  17. Formation of carcinogenic 4(5)-methylimidazole in caramel model systems: a role of sulphite.

    Science.gov (United States)

    Lee, Kwang-Geun; Jang, Haewon; Shibamoto, Takayuki

    2013-02-15

    Aqueous caramel model systems consisted the D-glucose/NH(3)/sulphite were heated at 100°C for 2 h and amounts of carcinogenic 4(5)-methylimidazole (4-MI) formed were determined. The amount formed ranged from 7.0 to 155.0 ppm. A system with 0.1 M sulphite yielded the greatest amount of 4-MI, which was 54% more than that yielded from a system without sulphite. When the amount of sulphite increased over 0.1 M, the amount of 4-MI reduced. The greatest reduction was achieved with 0.2 M sulphite by 68% compared to 0 M sulphite, suggesting that sulphite plays an important role in the formation of carcinogenic 4-MI in caramel colour. Also, a system with 0.1 M sulphite yielded the most intense caramel colour but the other levels of sulphite did not change the colour intensity significantly. Sulphite contributed slightly to the level of flavour chemicals evaluated using pyrazine formation. The results suggest that sulphite addition at appropriate amount reduces 4-MI formation in caramel colour without sacrificing flavour and colour formation. PMID:23194510

  18. Impact of Environmental Exposures on the Mutagenicity/Carcinogenicity of Heterocyclic Amines

    Energy Technology Data Exchange (ETDEWEB)

    Felton, J S; Knize, M G; Bennett, L M; Malfatti, M A; Colvin, M E; Kulp, K S

    2003-12-19

    Carcinogenic heterocyclic amines are produced from overcooked foods and are highly mutagenic in most short-term test systems. One of the most abundant of these amines, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), induces breast, colon and prostate tumors in rats. Human dietary epidemiology studies suggest a strong correlation between either meat consumption or well-done muscle meat consumption and cancers of the colon, breast, stomach, lung and esophagus. For over 20 years our laboratory has helped define the human exposure to these dietary carcinogens. In this report we describe how various environmental exposures may modulate the risk from exposure to heterocyclic amines, especially PhIP. To assess the impact of foods on PhIP metabolism in humans, we developed an LC/MS/MS method to analyze the four major PhIP urinary metabolites following the consumption of a single portion of grilled chicken. Adding broccoli to the volunteers' diet altered the kinetics of PhIP metabolism. At the cellular level we have found that PhIP itself stimulates a significant estrogenic response in MCF-7 cells, but even more interestingly, co-incubation of the cells with herbal teas appear to enhance the response. Numerous environmental chemicals found in food or the atmosphere can impact the exposure, metabolism, and cell proliferation response of heterocyclic amines.

  19. The OSIRIS Weight of Evidence approach: ITS mutagenicity and ITS carcinogenicity.

    Science.gov (United States)

    Buist, Harrie; Aldenberg, Tom; Batke, Monika; Escher, Sylvia; Klein Entink, Rinke; Kühne, Ralph; Marquart, Hans; Pauné, Eduard; Rorije, Emiel; Schüürmann, Gerrit; Kroese, Dinant

    2013-11-01

    Risk assessment of chemicals usually implies data evaluation of in vivo tests in rodents to conclude on their hazards. The FP7 European project OSIRIS has developed integrated testing strategies (ITS) for relevant toxicological endpoints to avoid unnecessary animal testing and thus to reduce time and costs. This paper describes the implementation of ITS mutagenicity and carcinogenicity in the public OSIRIS webtool. The data requirements of REACH formed the basis for these ITS. The main goal was to implement procedures to reach a conclusion on the adequacy and validity of available data. For the mutagenicity ITS a quantitative Weight of Evidence approach based on Bayesian statistics was developed and implemented. The approach allows an overall quality assessment of all available data for the five types of mutagenicity data requirements: in vitro bacterial mutagenicity, in vitro and in vivo chromosome aberration, in vitro and in vivo mammalian mutagenicity. For the carcinogenicity ITS a tool was developed to evaluate the quality of studies not conforming (entirely) to guidelines. In a tiered approach three quality aspects are assessed: documentation (reliability), study design (adequacy) and scope of examination (validity). The quality assessment is based on expert and data driven quantitative Weight of Evidence. PMID:23357514

  20. Animal carcinogenicity studies on radiofrequency fields related to mobile phones and base stations

    International Nuclear Information System (INIS)

    Since a report in 1997 on an increased lymphoma incidence in mice chronically exposed to a mobile phone radiofrequency signal, none of the subsequent long-term studies in rodents have confirmed these results. On the other hand, several of the follow-up co- and carcinogenicity studies are still underway or are presently being initiated. Most of the published long-term studies used 1 exposure level only and suffer from a poor dosimetry which does not consider the animal's growth. Additional points of criticism are a limited, in some cases, questionable histopathology and inadequate group sizes. Overall, if dealing with new chemicals or drugs, these studies would not be acceptable for registration with the responsible authorities. The major critical points are taken into consideration within the European co- and carcinogenicity projects (CEMFEC and PERFORM-A), which are in their final stages and in the US long-term studies in mice and rats which are about to be initiated. Nevertheless, the WHO evaluation for health risk assessment of long-term telephone use and base station exposure will start in late 2005

  1. Preferential binding of growth inhibitory prostaglandins by the target protein of a carcinogen

    International Nuclear Information System (INIS)

    Liver fatty acid binding protein (L-FABP) is the principal target protein of the hepatic carcinogen N-(2-fluorenyl)acetamide (2-acetylaminofluorene) in rat liver. In addition, the cyclopentenone prostaglandins (PG), PGA, PGJ2, and Δ12-PGJ2, inhibit the growth of many cell types in vitro. This report describes the preferential binding of the growth inhibitory prostaglandins by L-FABP and the reversible inhibition of thymidine incorporation into DNA by PGA2 and Δ12-PGJ2 in primary cultures of purified rat hepatocytes. As a model ligand, [3H]PGA1 bound to L-FABP specifically, reversibly, rapidly, and with high affinity. Its dissociation constants were 134 nM (high affinity) and 3.6 μM (low affinity). The high-affinity finding of [3H]PGA1 correlated with their growth inhibitory activities reported previously and here. The in vitro actions of L-FABP are compatible with those of a specific and dissociable carrier of growth inhibitory prostaglandins in rat hepatocytes and suggest that the carcinogen may usurp the cellular machinery of the growth inhibitory prostaglandins

  2. Biodegradation of the metallic carcinogen hexavalent chromium Cr(VI by an indigenously isolated bacterial strain

    Directory of Open Access Journals (Sweden)

    Das Alok

    2010-01-01

    Full Text Available Background : Hexavalent chromium [Cr(VI], a potential mutagen and carcinogen, is regularly introduced into the environment through diverse anthropogenic activities, including electroplating, leather tanning, and pigment manufacturing. Human exposure to this toxic metal ion not only causes potential human health hazards but also affects other life forms. The World Health Organization, the International Agency for Research on Cancer, and the Environmental Protection Agency have determined that Cr(VI compounds are known human carcinogens. The Sukinda valley in Jajpur District, Orissa, is known for its deposit of chromite ore, producing nearly 98% of the chromite ore in India and one of the prime open cast chromite ore mines in the world (CES, Orissa Newsletter. Materials and Methods: Our investigation involved microbial remediation of Cr(VI without producing any byproduct. Bacterial cultures tolerating high concentrations of Cr were isolated from the soil sample collected from the chromite-contaminated sites of Sukinda, and their bioaccumulation properties were investigated. Strains capable of growing at 250 mg/L Cr(VI were considered as Cr resistant. Results: The experimental investigation showed the maximum specific Cr uptake at pH 7 and temperature 30oC. At about 50 mg/L initial Cr(VI concentrations, uptake of the selected potential strain exceeded 98% within 12 h of incubation. The bacterial isolate was identified by 16S rRNA sequencing as Brevebacterium casei. Conclusion: Results indicated promising approach for microbial remediation of effluents containing elevated levels of Cr(VI.

  3. Non-carcinogenic health risks of heavy metal in mudfish from Laguna Lake

    Directory of Open Access Journals (Sweden)

    Victorio B. Molina

    2012-06-01

    Full Text Available This paper examines the potential risks to human health associated with exposure to heavy metal that have bioaccumulated in Mudfish (Ophicephalus striatus from Laguna Lake. Fish samples were collected in eight sampling stations in three major areas of the lake during the dry and wet seasons. Dry season samples were collected from May to June 2010 and wet season samples, from September to November 2010. Coordinates of sampling site locations were recorded using Global Positioning System (GPS and plotted in Geographic Information System (GIS digital maps. Heavy metal analyses for cadmium (Cd, lead (Pb, mercury (Hg, arsenic (As, and chromium (Cr were conducted using Atomic Absorption Spectrophotometer (AAS and a Mercury Analyzer (Mercur-Duo. Estimates of health risks associated with mudfish consumption were summarized according to non-carcinogenic effects. Non-carcinogenic Hazard Quotient (NHQ values of five heavy metal showed that lead is the most urgent pollutant of concern in terms of adverse health effects from risks associated with mudfish consumption from all sampling locations in the lake. From the point of view of human health protection and disease prevention, mudfish from Laguna Lake is not fit for long-term human consumption primarily due to lead and mercury contamination.

  4. Evaluation of genome damage in subjects occupationally exposed to possible carcinogens.

    Science.gov (United States)

    Zeljezic, Davor; Mladinic, Marin; Kopjar, Nevenka; Radulovic, Azra Hursidic

    2016-09-01

    In occupational exposures, populations are simultaneously exposed to a mixture of chemicals. We aimed to evaluate DNA damage due to possible carcinogen exposure (phenylhydrazine, ethylene oxide, dichloromethane, and 1,2-dichloroethane) in lymphocytes of pharmaceutical industry workers from the same production line. Population comprised 16 subjects (9 females and 7 males) who were exposed to multiple chemicals for 8 months. Genome damage was assessed using alkaline comet assay, micronucleus assay, and comet assay coupled with fluorescent in situ hybridization (comet-FISH). After 8 months of exposure, the issue of irregular use of all available personal protective equipment (PPE) came into light. To decrease the risk of exposure, strict use of PPE was enforced. After 8 months of strict PPE use, micronuclei frequency and comet assay parameters in lymphocytes of pharmaceutical workers significantly decreased compared with prior period of irregular PPE use. Comet-FISH results indicated a significant shift in distribution of signals for the TP 53 gene toward a more frequent occurrence in the comet tail. Prolonged exposure to possible carcinogens may hinder DNA repair mechanisms and affect structural integrity of TP 53 Two indicators of loss of TP 53 gene integrity have risen, namely, TP 53 fragmentation rate in lymphocytes with persistently elevated primary damage and incidence of TP 53 deletions in undamaged lymphocytes. PMID:25653038

  5. Antiproliferative effects of fluoxetine on colon cancer cells and in a colonic carcinogen mouse model.

    Directory of Open Access Journals (Sweden)

    Vinicius Kannen

    Full Text Available The antidepressant fluoxetine has been under discussion because of its potential influence on cancer risk. It was found to inhibit the development of carcinogen-induced preneoplastic lesions in colon tissue, but the mechanisms of action are not well understood. Therefore, we investigated anti-proliferative effects, and used HT29 colon tumor cells in vitro, as well as C57BL/6 mice exposed to intra-rectal treatment with the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG as models. Fluoxetine increased the percentage of HT29 cells in the G(0/G(1 phase of cell-cycle, and the expression of p27 protein. This was not related to an induction of apoptosis, reactive oxygen species or DNA damage. In vivo, fluoxetine reduced the development of MNNG-induced dysplasia and vascularization-related dysplasia in colon tissue, which was analyzed by histopathological techniques. An anti-proliferative potential of fluoxetine was observed in epithelial and stromal areas. It was accompanied by a reduction of VEGF expression and of the number of cells with angiogenic potential, such as CD133, CD34, and CD31-positive cell clusters. Taken together, our findings suggest that fluoxetine treatment targets steps of early colon carcinogenesis. This confirms its protective potential, explaining at least partially the lower colon cancer risk under antidepressant therapy.

  6. Human gastric cancer, Helicobacter pylori and bracken carcinogens: A connecting hypothesis.

    Science.gov (United States)

    Oliveros-Bastidas, Alberto; Calcagno-Pissarelli, María Pía; Naya, Marlene; Ávila-Núñez, Jorge Luis; Alonso-Amelot, Miguel E

    2016-03-01

    Long term infection of Helicobacter pylori (Hp) virulent strains is a key factor in the genesis of human gastric cancer, and so are certain dietary proinflammatory and genotoxic compounds. Carcinogenic bracken fern (Pteridium spp.) is one of these. Toxins from this plant are consumed as bracken culinary preparations, through milk and meat of bracken-exposed livestock, and drain waters from bracken swards. Bracken toxin ptaquiloside (PtQ), a suspected human carcinogen, elicits complex responses in animals leading to death. PtQ and Hp might cooperate in gastric pathologies. This paper presents an hypothesis on PtQ-Hp association leading to the enhancement of carcinogenesis in the human gastric environment that might explain the high gastric cancer incidence and death rates among Hp-infected people living in bracken zones at two levels: (1) The macroscopic scale comprising the flow of PtQ in the human diet. (2) the microscopic scale encompassing (A) gastric luminal medium; (B) gastric mucus structure and mucin degradation elicited by Hp; (C) bacterial pH gradient modification of the gastric mucosa that favors PtQ survival and its penetration into epithelial tissue; (D) combined PtQ/Hp effects on gastric immune and inflammatory responses; (E) PtQ-Hp complementary activity at selected cell signaling cascades and genome disturbance. PMID:26632203

  7. Ferns and lycopods--a potential treasury of anticancer agents but also a carcinogenic hazard.

    Science.gov (United States)

    Tomšík, Pavel

    2014-06-01

    Many species of seedless vascular plants-ferns and lycopods-have been used as food and folk medicine since ancient times. Some of them have become the focus of intensive research concerning their anticancer properties. Studies on the anticancer effect of crude extracts are being increasingly replaced by bioactivity-guided fractionation, as well as detailed assessment of the mechanism of action. Numerous compounds-especially flavonoids such as amentoflavone and protoapigenone, and also simpler phenolic compounds, steroids, alkaloids and terpenoids-were isolated and found to be cytotoxic, particularly pro-apoptotic, or to induce cell cycle arrest in cancer cell lines in vitro. In in vivo experiments, some fern-derived compounds inhibited tumour growth with little toxicity. On the other hand, many ferns-not only the well-known Bracken (Pteridium)-may pose a significant hazard to human health due to the fact that they contain carcinogenic sesquiterpenoids and their analogues. The objective of this review is to summarise the recent state of research on the anticancer properties of ferns and lycopods, with a focus on their characteristic bioactive constituents. The carcinogenic hazard posed by ferns is also mentioned. PMID:24123573

  8. Enhancement of DNA repair capacity of mammalian cells by carcinogen treatment

    International Nuclear Information System (INIS)

    To determine whether DNA excision repair is enhanced in mammalian cells in response to DNA damage, as it is in bacteria as part of the SOS response, we used an expression vector-host cell reactivation assay to measure cellular DNA repair capacity. When UV-damaged chloramphenicol acetyltransferase (CAT) vector DNA was introduced into monkey cells (CV-1), the level of CAT activity was inversely related to the UV fluence due to inhibition of CAT gene expression by UV photoproducts. When CV-1 cells were treated with either UV radiation or mitomycin C, 24-48 h before transfection, CAT expression from the UV-irradiated plasmid was increased. This increase also occurred in a line of normal human cells, but not in repair-deficient human xeroderma pigmentosum cells. We confirmed that this increase in CAT expression was due to repair, and not to production of damage-free templates by recombination; the frequency of generation of supF+ recombinants after transfection with UV-irradiated pZ189 vectors carrying different point mutations in the supF gene did not significantly increase in carcinogen-treated CV-1 cells. From these results we conclude that carcinogen treatment enhances the excision-repair capacity of normal mammalian cells

  9. Exposure and Metabolic Activation Biomarkers of Carcinogenic Tobacco-Specific Nitrosamines.

    Science.gov (United States)

    Hecht, Stephen S; Stepanov, Irina; Carmella, Steven G

    2016-01-19

    Lung cancer is the leading cause of cancer death in the world, and cigarette smoking is its main cause. Oral cavity cancer is another debilitating and often fatal cancer closely linked to tobacco product use. While great strides have been made in decreasing tobacco use in the United States and some other countries, there are still an estimated 1 billion men and 250 million women in the world who are cigarette smokers and there are hundreds of millions of smokeless tobacco users, all at risk for cancer. Worldwide, lung cancer kills about three people per minute. This Account focuses on metabolites and biomarkers of two powerful tobacco-specific nitrosamine carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), considered to be among the main causes of lung cancer and oral cavity cancer in people who use tobacco products. Three properties of NNK and NNN are critical for successful biomarker studies: they are present in all tobacco products, they are tobacco-specific and are not found in any other product, and they are strong carcinogens. NNK and NNN are converted in humans to urinary metabolites that can be quantified by mass spectrometry as biomarkers of exposure to these carcinogens. They are also metabolized to diazonium ions and related electrophiles that react with DNA to form addition products that can be detected and quantified by mass spectrometry. These urinary metabolites and DNA addition products can serve as biomarkers of exposure and metabolic activation, respectively. The biomarkers of exposure, in particular the urinary NNK metabolites 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, have been extensively applied to document tobacco-specific lung carcinogen uptake in smokers and nonsmokers exposed to secondhand tobacco smoke. Highly sensitive mass spectrometric methods have been developed for quantitative analysis of these NNK metabolites as well as metabolites of NNN in human urine

  10. Experience from a long-term carcinogenicity study with intraperitoneal injection of biosoluble synthetic mineral fibers.

    Science.gov (United States)

    Grimm, Hans G; Bernstein, David M; Attia, Mahmoud; Richard, Jacques; De Reydellet, Aymon

    2002-08-01

    The carcinogenic potential in the intraperitoneal cavity of three newly developed biosoluble insulation glass wool fibers (M, P, and V) and one newly developed biosoluble insulation stone wool fiber (O) was investigated and compared to that of a previously developed soluble glass fiber (B). The in vitro dissolution coefficient of the three glass wool fibers ranged from 450 to 1037 ng/cm(2) x h and was 523 ng/cm(2) x h for the stone wool fiber. The in vitro dissolution coefficient of the B fiber was 580 ng/cm(2) x h. Groups of female Wistar rats (strain Crl: Wi BR) were exposed by repeated injections to doses of 0.5, 2, and 5 x 10(9) WHO fibers, which corresponds to between 41 mg to 724 mg fiber injected. In addition, 2 groups of crocidolite were used as positive controls at doses of 0.1 x 10(9) and 1 x 10(9) WHO fibers (0.5 and 5 mg). The in vitro dissolution coefficient of crocidolite is estimated to be approximately 1 ng/cm(2) x h. The protocol of the study and the size distribution of the test samples conformed to the European Commission Protocol EUR 18748 EN, and the study was executed under Good Laboratory Practice conditions. Two of the new insulation wools, fibers M and 0, showed no statistically significant tumorigenic response even at the very high dose of 5 x 10(9) WHO fibers injected. Fibers P and V showed a small tumorigenic response in the ip cavity similar in magnitude to the B fiber, which has been declared in the German fiber regulations as a noncarcinogenic fiber. The response to the soluble insulation fibers was notably different from that of the known carcinogen crocidolite, which produced 53% tumors at a comparatively low dose of 0.1 x 10(9) WHO fibers. The incidence of mesothelioma was found to be highly correlated to the incidence of intra-abdominal nodules and masses at different sites. The incidence of abdominal nodules and masses was highly correlated to the number of animals with ascites. The incidence of chronic peritonitis with fibrotic

  11. 2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice.

    Science.gov (United States)

    Moore, Robert W; Fritz, Wayne A; Schneider, Andrew J; Lin, Tien-Min; Branam, Amanda M; Safe, Stephen; Peterson, Richard E

    2016-08-15

    It is well established that the prototypical aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can both cause and protect against carcinogenesis in non-transgenic rodents. But because these animals almost never develop prostate cancer with old age or after carcinogen exposure, whether AHR activation can affect cancer of the prostate remained unknown. We used animals designed to develop this disease, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, to investigate the potential role of AHR signaling in prostate cancer development. We previously reported that AHR itself has prostate tumor suppressive functions in TRAMP mice; i.e., TRAMP mice in which Ahr was knocked out developed neuroendocrine prostate carcinomas (NEPC) with much greater frequency than did those with both Ahr alleles. In the present study we investigated effects of AHR activation by three different xenobiotics. In utero and lactational TCDD exposure significantly increased NEPC tumor incidence in TRAMP males, while chronic TCDD treatment in adulthood had the opposite effect, a significant reduction in NEPC incidence. Chronic treatment of adult TRAMP mice with the low-toxicity selective AHR modulators indole-3-carbinol or 3,3'-diindolylmethane did not significantly protect against these tumors. Thus, we demonstrate, for the first time, that ligand-dependent activation of the AHR can alter prostate cancer incidence. The nature of the responses depended on the timing of AHR activation and ligand structures. PMID:27151233

  12. Carcinogenicity of trace elements with reference to evaluations made by the International Agency for Research on Cancer.

    Science.gov (United States)

    Boffetta, P

    1993-01-01

    The monograph program of the International Agency for Research of on Cancer has evaluated many trace elements for their carcinogenicity to humans. Five groups of compounds were considered human carcinogens: arsenic and arsenic compounds, beryllium and beryllium compounds, cadmium and cadmium compounds, hexavalent chromium compounds, and nickel compounds. Antimony trioxide, cobalt and cobalt compounds, lead and inorganic lead compounds, methylmercury compounds, and metallic nickel were considered possibly carcinogenic to humans. Antimony trisulfide, trivalent chromium compounds, metallic chromium, ferric oxide, organolead compounds, metallic mercury, inorganic mercury compounds, selenium and selenium compounds, and titanium dioxide were not classifiable. Trace elements studied to a limited extent include copper, manganese, tin, vanadium, and zinc. Among the problems are the lack of relevant data, the definition of active species, the extrapolation of the results of experimental studies to humans, the methodological problems of epidemiologic studies, and the possible anticarcinogenic activity of some trace elements. PMID:8159977

  13. Effects of combined exposure of F344 rats to inhaled 239PuO2 and a chemical carcinogen (NNK)

    International Nuclear Information System (INIS)

    Workers in nuclear weapons facilitates have a significant potential for exposure to chemical carcinogens and to radiation from external sources or from internally deposited radionuclides such as 239Pu. Although the carcinogenic effects of inhaled 239Pu and many chemicals have been studied individually, very little information is available on their combined effects. One chemical carcinogen that workers could be exposed to, via tobacco smoke, is the tobacco-specific nitrosamine 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a product of the curing of tobacco and pyrolysis of nicotine in tobacco. NNK causes lung tumors in rats, regardless of the route of administration and to a lesser extent tumors in the liver, nasal passages, and pancreas. The purpose of this study is to characterize the effects of combined exposure of rats to NNK and internally deposited plutonium, as well as to these agents alone

  14. Comparison of in vivo genotoxic and carcinogenic potency to augment mode of action analysis: Case study with hexavalent chromium.

    Science.gov (United States)

    Thompson, Chad M; Bichteler, Anne; Rager, Julia E; Suh, Mina; Proctor, Deborah M; Haws, Laurie C; Harris, Mark A

    2016-04-01

    Recent analyses-highlighted by the International Workshops on Genotoxicity Testing Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment-have identified a correlation between (log) estimates of a carcinogen's in vivo genotoxic potency and in vivo carcinogenic potency in typical laboratory animal models, even when the underlying data have not been matched for tissue, species, or strain. Such a correlation could have important implications for risk assessment, including informing the mode of action (MOA) of specific carcinogens. When in vivo genotoxic potency is weak relative to carcinogenic potency, MOAs other than genotoxicity (e.g., endocrine disruption or regenerative hyperplasia) may be operational. Herein, we review recent in vivo genotoxicity and carcinogenicity data for hexavalent chromium (Cr(VI)), following oral ingestion, in relevant tissues and species in the context of the aforementioned correlation. Potency estimates were generated using benchmark doses, or no-observable-adverse-effect-levels when data were not amenable to dose-response modeling. While the ratio between log values for carcinogenic and genotoxic potency was ≥1 for many compounds, the ratios for several Cr(VI) datasets (including in target tissue) were less than unity. In fact, the ratios for Cr(VI) clustered closely with ratios for chloroform and diethanolamine, two chemicals posited to have non-genotoxic MOAs. These findings suggest that genotoxicity may not play a major role in the cancers observed in rodents following exposure to high concentrations of Cr(VI) in drinking water-a finding consistent with recent MOA and adverse outcome pathway (AOP) analyses concerning Cr(VI). This semi-quantitative analysis, therefore, may be useful to augment traditional MOA and AOP analyses. More case examples will be needed to further explore the general applicability and validity of this approach for human health risk assessment. PMID:27085472

  15. Low Doses of the Carcinogen Furan Alter Cell Cycle and Apoptosis Gene Expression in Rat Liver Independent of DNA Methylation

    OpenAIRE

    Tao CHEN; Mally, Angela; Ozden, Sibel; Chipman, J. Kevin

    2010-01-01

    Background Evidence of potent rodent carcinogenicity via an unclear mechanism suggests that furan in various foods [leading to an intake of up to 3.5 μg/kg body weight (bw)/day] may present a potential risk to human health. Objectives We tested the hypothesis that altered expression of genes related to cell cycle control, apoptosis, and DNA damage may contribute to the carcinogenicity of furan in rodents. In addition, we investigated the reversibility of such changes and the potential role of...

  16. Repair of DNA treated with γ-irradiation and chemical carcinogens. Final report, June 1, 1981-May 31, 1984

    International Nuclear Information System (INIS)

    Work done in the past three years has been on DNA repair, on genetic transposition and on the effect of carcinogens on alu sequence transcription. DNA repair work was completed on β-propiolactone DNA adducts, on procaryotic and eucaryotic enzymes capable of removal of 3-methyladenine from DNA, and on in vitro repair of neucleosomal core particle DNA and chromatin DNA. Attempts were made to isolate a human transposable element through the isolation of double stranded RNA and probing of a human library. Experiments were also done to determine whether carcinogens altered the expression of alu sequences in human DNA

  17. Evaluation of the E mu-pim-1 transgenic mouse model for short-term carcinogenicity testing

    DEFF Research Database (Denmark)

    van Kreijl, C. F.; van Oordt, C. W. V.; Kroese, E. D.; Sørensen, Ilona Kryspin; Breuer, M. L.; Storer, R. D.

    1998-01-01

    present article, the results from 2 recent short-term assays (with mitomycin C and x-rays) are briefly presented, together with a review of all 11 performed bioassays and their corresponding histopathologic and molecular data. The overall results allow the first evaluation of the E mu-pim-1 mouse model...... with regard to its usefulness in short-term carcinogenicity testing. It has been shown that the model is primarily suitable as a sensitive short-term assay for genotoxic carcinogens that not only induce (at least) gene mutations and/or large deletions and rearrangements but that also sufficiently...

  18. Radiobiology in clinical radiation therapy - Part IV: Long term risks - Carcinogenic, hereditary, and teratogenetic effects

    International Nuclear Information System (INIS)

    The long-term risks induced by radiation are of much concern to patients and clinicians alike. As an example, perceived radiation risks are frequently cited in a woman's decision to choose a radical mastectomy over lumpectomy + radiation. In consequence, the actual radiation risks are often considerably overstated, or unreasonably downplayed. In this lecture we will discuss just what is known about the long term risks following radiotherapy, both from the human experience and from the laboratory. We will discuss risks both to the patient and to radiotherapy personnel. A good deal is known about the carcinogenic effects of high and low doses of radiation, in large part thanks to the careful study of the survivors of the atomic bombing in Japan, as well as studies of individuals exposed to medical x rays. It is possible to make an estimate, which is probably good to within a factor of, perhaps, three to five, of the cancer risks faced by a patient of a particular age and sex who is going to undergo a particular radiotherapeutic regimen. It is also possible to make an estimate of the risks faced by radiotherapy and nursing staff exposed to low doses. Brachytherapy related risk estimates are likely to be somewhat more uncertain, due to the poorly known sparing effects of the low dose rates used; for the radiotherapy personnel in brachytherapy, because of the doses which can be received, the risks can be quite significant. A recent complication in external-beam radiotherapy is the advent of high-energy linacs, which can produce a significant fast neutron dose which, dose for dose, may be ten to fifty times more carcinogenic than gamma rays. Data relating to the risks of hereditary effects of radiation come almost entirely from laboratory experiments in animals. Studies involving several million mice form the basis of most of our current understanding of hereditary effects. The results of these studies indicate that radiation is a relatively inefficient mutagen. The

  19. Radiobiology in clinical radiation therapy: Long term risks - Carcinogenic, hereditary, and teratogenetic effects

    International Nuclear Information System (INIS)

    The long-term risks induced by radiation are of much concern to patients and clinicians alike. As an example, perceived radiation risks are frequently cited in a woman's decision to choose a radical mastectomy over lumpectomy + radiation. In consequence, the actual radiation risks are often considerably overstated, or unreasonably downplayed. In this lecture we will discuss just what is known about the long term risks following radiotherapy, both from the human experience and from the laboratory. We will discuss risks both to the patient and to radiotherapy personnel. A good deal is known about the carcinogenic effects of high and low doses of radiation, in large part thanks to the careful study of the survivors of the atomic bombing in Japan, as well as studies of individuals exposed to medical x rays. It is possible to make an estimate, which is probably good to within a factor of, perhaps, three to five, of the cancer risks faced by a patient of a particular age and sex who is going to undergo a particular radiotherapeutic regimen. It is also possible to make an estimate of the risks faced by radiotherapy and nursing staff exposed to low doses. Brachytherapy related risk estimates are likely to be somewhat more uncertain, due to the poorly known sparing effects of the low dose rates used; for the radiotherapy personnel in brachytherapy, because of the doses which can be received, the risks can be quite significant. A recent complication in external-beam radiotherapy is the advent of high-energy linacs, which can produce a significant fast neutron dose which, dose for dose, may be ten to fifty times more carcinogenic than gamma rays. Data relating to the risks of hereditary effects of radiation come almost entirely from laboratory experiments in animals. Studies involving several million mice form the basis of most of our current understanding of hereditary effects. The results of these studies indicate that radiation is a relatively inefficient mutagen. The

  20. Prevention of cancer and the dose-effect relationship: the carcinogenic effects of ionizing radiations

    International Nuclear Information System (INIS)

    Cancer prevention has to be based on robust biological and epidemiological data, therefore its reappraisal becomes mandatory in view of recent progress in the understanding of carcinogenesis. The first phase of the carcinogenic process, that of initiation, is generally associated with mutation; however the role of extrinsic mutagens is less critical than was thought two decades ago. During intracellular oxygen metabolism, reactive oxygen species (R.O.S.) are made which are potent mutagens. Defense mechanisms against these intrinsic mutagens include scavenger and enzymatic systems which destroy them (catalase, superoxide dismutase). When the radiation dose is low, DNA repair is very effective as well as the elimination of cells with unrepaired or bad repaired DNA. Therefore a small increase in the number of R.O.S., such as that caused by a small dose of radiation has most probably no significant effect on the risk of DNA damage. These conclusions are consistent with the concept of a practical threshold. The second phase, that of promotion, appears to be the key one. During the promotion phase, initiated cells must acquire new properties (immortalization, release of angiogenic factors, resistance to hypoxia, etc.) in order to become pre-cancerous. This evolution is due to the accumulation in the genome of 6 to 10 new alteration defects. In the clone of initiated cells, the occurrence in one cell of a mutation or an epigenetic event gives birth to a sub clone. There is a Darwinian type competition between the sub clones and those with the more rapid growth because dominant (the acceleration of the growth rate can be due to shorter cell cycles or to an alleviation of cell proliferation exerted by the neighboring cells or the microenvironment). In the dominant sub clones new genomic events provoke the appearance of new sub clones growing more rapidly and having greater autonomy. The process is very slow because the specific genetic events that favour this evolution

  1. New methods for toxicokinetic studies on chemicals carcinogens by means of analysis of DNA damage

    International Nuclear Information System (INIS)

    For investigating the potential carcinogenic properties of chemicals or for elucidating their mechanisms of activities, it is as important to determine their DNA damaging effects as it is to determine their mutagenicity. In the following, three methods will be presented which may be utilized to detect chemically induced DNA damage. These are the classical DNA filter elution procedure (AE), the in situ nick translation (NT), and the single cell microgel-electrophoresis (MGE) assay. Latter two methods have the advantage that they will allow genotoxic effects to be determined in many organs of the experimental animals, since only minute quantities of tissue are needed. Therefore it is possible to efficiently obtain data pertaining to the toxicokinetics of the test chemical which may be used for purposes of risk assessment. (orig.)

  2. Prepubertal exposure to cow's milk reduces susceptibility to carcinogen-induced mammary tumorigenesis in rats

    DEFF Research Database (Denmark)

    Nielsen, Tina Skau; Khan, Galam; Davis, Jennifer;

    2011-01-01

    Cow's milk contains high levels of estrogens, progesterone and insulin-like growth factor 1 (IGF-1), all of which are associated with breast cancer. We investigated whether prepubertal milk exposure affects mammary gland development and carcinogenesis in rats. Sprague-Dawley rats were given either...... whole milk or tap water to drink from postnatal day (PND) 14 to PND 35, and thereafter normal tap water. Mammary tumorigenesis was induced by administering 7,12-dimethylbenz[a]anthracene on PND 50. Milk exposure increased circulating E2 levels on PND 25 by 10-fold (p < 0.001) and accelerated vaginal...... opening, which marks puberty onset, by 2.5 days (p < 0.001). However, rats exposed to milk before puberty exhibited reduced carcinogen-induced mammary carcinogenesis; that is, their tumor latency was longer (p < 0.03) and incidence was lower (p < 0.05) than in the controls. On PND 25 and 50, mammary...

  3. Role of DNA lesions and DNA repair in mutagenesis by carcinogens in diploid human fibroblasts

    International Nuclear Information System (INIS)

    The authors investigated the cytotoxicity, mutagenicity, and transforming activity of carcinogens and radiation in diploid human fibroblasts, using cells which differ in their DNA repair capacity. The results indicate that cell killing and induction of mutations are correlated with the number of specific lesions remaining unrepaired in the cells at a particular time posttreatment. DNA excision repair acts to eliminate potentially cytotoxic and mutagenic (and transforming) damage from DNA before these can be converted into permanent cellular effects. Normal human fibroblasts were derived from skin biopsies or circumcision material. Skin fibroblasts from xeroderma pigmentosum (XP) patients provided cells deficient in nucleotide excision repair of pyrimidine dimers or DNA adducts formed by bulky ring structures. Cytotoxicity was determined from loss of ability to form a colony. The genetic marker used was resistance to 6-thioguanine (TG). Transformation was measured by determining the frequency of anchorage-independent cells

  4. Evolutionary constraints over microsatellite abundance in larger mammals as a potential mechanism against carcinogenic burden.

    Science.gov (United States)

    Park, Jung Youn; An, Yong-Rock; An, Chul-Min; Kang, Jung-Ha; Kim, Eun Mi; Kim, Heebal; Cho, Seoae; Kim, Jaemin

    2016-01-01

    Larger organisms tend to live longer, have more potentially carcinogenic cells, and undergo more cell divisions. While one might intuitively expect cancer incidence to scale with body size, this assertion does not hold over the range of different mammals. Explaining this lack of correlation, so-called 'Peto's paradox' can likely increase our understanding of how cancer defense mechanisms are shaped by natural selection. Here, we study the occurrence of microsatellite in mammal genomes and observe that animals with expanded body size restrain the number of microsatellite. To take into account of higher mutation rate in the microsatellite region compared to that of genome, limiting the abundance of somatic mutations might explain how larger organisms could overcome the burden of cancer. These observations may serve as the basis to better understand how evolution has modeled protective mechanisms against cancer development. PMID:27125812

  5. Land management of bracken needs to account for bracken carcinogens - a case study from Britain

    DEFF Research Database (Denmark)

    Rasmussen, Lars Holm; Donnelly, Eric; Strobel, Bjarne W.;

    2015-01-01

    Bracken ferns are some of the most widespread ferns in the World causing immense problems for land managers, foresters and rangers. Bracken is suspected of causing cancer in Humans due to its content of the carcinogen ptaquiloside. Ingestion of bracken, or food and drinking water contaminated with...... ptaquiloside may be the cause. The aim of this study was to monitor the content of ptaquiloside in 20 bracken stands from Britain to obtain a better understanding of the ptaquiloside dynamics and to evaluate the environmental implications of using different cutting regimes in bracken management. The...... in bracken stands at any given time is difficult to predict and did not show any correlations with edaphic growth factors. The content of ptaquiloside turned out to be higher in fronds emerging after cutting compared to uncut fronds. Environmental risk assessment and bracken management must therefore...

  6. Chlorophyll catalyse the photo-transformation of carcinogenic benzo[a]pyrene in water

    Science.gov (United States)

    Luo, Lijuan; Lai, Xueying; Chen, Baowei; Lin, Li; Fang, Ling; Tam, Nora F. Y.; Luan, Tiangang

    2015-08-01

    Algal blooms cause great damage to water quality and aquaculture. However, this study showed that dead algal cells and chlorophyll could accelerate the photo-transformation of benzo[a]pyrene (BaP), a ubiquitous and persistent pollutant with potently mutagenic and carcinogenic toxicities, under visible light irradiation. Chlorophyll was found to be the major active substance in dead algal cells, and generated a high level of singlet oxygen to catalyse the photo-transformation of BaP. According to various BaP metabolites formed, the degradation mechanism was proposed as that chlorophyll in dead algal cells photo-oxidized BaP to quinones via photocatalytic generation of singlet oxygen. The results provided a good insight into the role of chlorophyll in the photo-transformation of organic contaminants and could be a possible remediation strategy of organic pollutants in natural environment.

  7. Matrix of occupational exposures to carcinogenic agents and pesticides in Costa Rica

    International Nuclear Information System (INIS)

    The European data system CAREX converts national numbers of workers in 55 sectors and estimated proportions of workers exposed to carcinogenic agents into numbers of workers exposed to each agent. CAREX is applied and modified in Costa Rica (TICAREX) for the first time outside Europe. 27 carcinogenic agents and 7 groups of pesticides were included. Numbers of exposed were estimated separately for men and women. The most frequent agents in the 1.3 million labor force of Costa Rica were solar radiation (333,000 workers); diesel engine emissions (278,000); paraquat and diquat (175,000); environmental tobacco smoke (71,000); chromium (VI) compounds (55,000); benzene (52,000); mancozeb, maneb and zineb (49,000); chlorothalonil (38,000); wood dust (32,000); silica dust (27,000); benomyl (19,000); lead and its inorganic compounds (19,000); tetrachloroethylene (18,000); and polycyclic aromatic hydrocarbons (17,000). Owing to the different occupational distribution between the genders, formaldehyde, radon and methylene chloride were more frequent than pesticides, chromium (VI), wood dust, and silica dust in women. Agriculture, construction, personal and domestic services, land and water transport and allied services, pottery and similar industries, manufacture of wood products, mining, forestry, fishing, manufacture of electric products, and bars and restaurants were sectors with frequent exposures. Substantial reduction of occupational and environmental exposures to these agents would improve considerably public and occupational health. Reduction of occupational exposures is usually also followed by improvement of environmental quality. Monitoring of exposures and health of workers and the general public is essential in the control of environmental contamination and human exposures. This report presents details of the exposures matrix, which is the basis of TICAREX. (author)

  8. Carcinogenicity of deuterium-labeled 1,2-dimethylhydrazine in mice

    International Nuclear Information System (INIS)

    To study the effect of deuterium substitution on the carcinogenicity of 1,2-dimethylhydrazine (DMH) in mice, two comparisons were made between DMH and its fully methyl-deuterated analogue, [2H6]DMH. In a lifetime study with the CBA strain, groups of 19-30 animals of each sex were dosed s.c. weekly with 8 mg/kg of either DMH or [2H6]DMH for 8, 16, or 32 weeks. In the second study, female CF-1 mice were given DMH or [2H6]DMH in 10 weekly s.c. doses of 12 mg/kg each (13.2 mg/kg for [2H6]DMH) and examined for colon tumors 36 weeks after the first dose. Deuteration significantly decreased tumor incidence in the colon of males (P less than 0.01) and the anal tissue of both sexes (P less than 0.05) but increased that of hepatomas and lung tumors in males (P less than 0.01). Substrate deuteration did not significantly affect overall incidence of any other tumor type, however, including hemangioendotheliomas and kidney tumors in both sexes, as well as colon, uterine, ovarian, liver, and lung tumors in females. The results indicate that C--H bond breakage is kinetically important in the activation of DMH to its ultimately carcinogenic form in organs such as the male colon (relative risk in DMH-versus [2H6]DMH-treated animals approximately equal to 6), and that inhibition of this process by substrate deuteration allows a diversionary mechanism having a smaller isotope effect to become relatively more extensive. The qualitatively different effect in other organs (e.g., kidney, relative risk approximately equal to 1) supports recent suggestions that the net mechanism of activation can differ from one target tissue to another, possibly by striking a different balance between parallel metabolic pathways

  9. Toxicogenomic approaches for understanding molecular mechanisms of heavy metal mutagenicity and carcinogenicity.

    Science.gov (United States)

    Koedrith, Preeyaporn; Kim, Hyelim; Weon, Jong-Il; Seo, Young Rok

    2013-08-01

    Heavy metals that are harmful to humans include arsenic, cadmium, chromium, lead, mercury, and nickel. Some metals or their related compounds may even cause cancer. However, the mechanism underlying heavy metal-induced cancer remains unclear. Increasing data show a link between heavy metal exposure and aberrant changes in both genetic and epigenetic factors via non-targeted multiple toxicogenomic technologies of the transcriptome, proteome, metabolome, and epigenome. These modifications due to heavy metal exposure might provide a better understanding of environmental disorders. Such informative changes following heavy metal exposure might also be useful for screening of biomarker-monitored exposure to environmental pollutants and/or predicting the risk of disease. We summarize advances in high-throughput toxicogenomic-based technologies and studies related to exposure to individual heavy metal and/or mixtures and propose the underlying mechanism of action and toxicant signatures. Integrative multi-level expression analysis of the toxicity of heavy metals via system toxicology-based methodologies combined with statistical and computational tools might clarify the biological pathways involved in carcinogenic processes. Although standard in vitro and in vivo endpoint testing of mutagenicity and carcinogenicity are considered a complementary approach linked to disease, we also suggest that further evaluation of prominent biomarkers reflecting effects, responses, and disease susceptibility might be diagnostic. Furthermore, we discuss challenges in toxicogenomic applications for toxicological studies of metal mixtures and epidemiological research. Taken together, this review presents toxicogenomic data that will be useful for improvement of the knowledge of carcinogenesis and the development of better strategies for health risk assessment. PMID:23540489

  10. Biomonitoring of complex occupational exposures to carcinogens: The case of sewage workers in Paris

    International Nuclear Information System (INIS)

    Sewage workers provide an essential service in the protection of public and environmental health. However, they are exposed to varied mixtures of chemicals; some are known or suspected to be genotoxics or carcinogens. Thus, trying to relate adverse outcomes to single toxicant is inappropriate. We aim to investigate if sewage workers are at increased carcinogenic risk as evaluated by biomarkers of exposure and early biological effects. This cross sectional study will compare exposed sewage workers to non-exposed office workers. Both are voluntaries from Paris municipality, males, aged (20–60) years, non-smokers since at least six months, with no history of chronic or recent illness, and have similar socioeconomic status. After at least 3 days of consecutive work, blood sample and a 24-hour urine will be collected. A caffeine test will be performed, by administering coffee and collecting urines three hours after. Subjects will fill in self-administered questionnaires; one covering the professional and lifestyle habits while the a second one is alimentary. The blood sample will be used to assess DNA adducts in peripheral lymphocytes. The 24-hour urine to assess urinary 8-oxo-7, 8-dihydro-2'-deoxy-Guanosine (8-oxo-dG), and the in vitro genotoxicity tests (comet and micronucleus) using HeLa S3 or HepG2 cells. In parallel, occupational air sampling will be conducted for some Polycyclic Aromatic Hydrocarbons and Volatile Organic Compounds. A weekly sampling chronology at the offices of occupational medicine in Paris city during the regular medical visits will be followed. This protocol has been accepted by the French Est III Ethical Comitee with the number 2007-A00685-48. Biomarkers of exposure and of early biological effects may help overcome the limitations of environmental exposure assessment in very complex occupational or environmental settings

  11. Carcinogenicity study of ammonia-process caramel in F344 rats.

    Science.gov (United States)

    Maekawa, A; Ogiu, T; Matsuoka, C; Onodera, H; Furuta, K; Tanigawa, H; Hayashi, Y; Odashima, S

    1983-06-01

    The carcinogenicity of ammonia-process caramel, a food colouring, was examined in F344 rats. Caramel was dissolved in distilled water at levels of 0, 1 and 4% and groups of 50 male and 50 female rats were given 20-25 ml of one of these solutions/rat/day as their drinking water for 2 yr. There were no significant differences between the total incidences of tumours or mean survival times of control and experimental groups. A variety of tumours developed in all groups including the control group, and no dose-related effects were found either in the incidence or induction time of tumours in the various organs and tissues except in the pituitary gland of males, in which the incidence of tumours in males given 4% caramel solution was significantly higher than that in controls. Pituitary tumours are among the most common spontaneous tumours in ageing rats of this strain and have a variable incidence. In addition, almost all pituitary tumours detected in males given the 4% solution were microscopic tumours, and there was no significant difference between controls and treated groups in the incidence of hyperplasia or pre-neoplastic lesions in the pituitary gland. These results indicate that the significantly higher incidence of pituitary tumours in males given the 4% caramel solution was not related to caramel administration, but could be explained by the variability of the incidence of spontaneous pituitary tumours. Thus it is concluded that under these experimental conditions ammonia-process caramel was not carcinogenic in F344 rats. PMID:6683219

  12. Detection and impact on cancer causation of persons exhibiting abnormal susceptibility to carcinogenic agents

    International Nuclear Information System (INIS)

    The so-called 'late biological effects', like cancer and genetic consequences and cytotoxic effects (cell killing, at higher doses), were once thought to be an inevitable consequence of a given level of exposure, whether to background radiation, to chemicals in our biosphere, or form spontaneous damage, the 'wear and tear' of living. The measurement of exposure, which results in living organisms in the formation of a related amount of DNA damage, became a surrogate for the end-effects that constitute risk. This may not be entirely appropriate. The concept of 'equal exposure -- equal risk' assumes a homogeneous response of individuals. However, there are subgroups within the human population of persons whose cultured cells exhibit abnormal sensitivity to specific carcinogenic agents and who may be at increased risk of cancer induced by these of similar agents. Modern molecular biology has shown that the majority of the damage in DNA is repaired by enzymatic DNA repair processes that restitute or ameliorate the lesions and restore normal DNA structure and function. In this view, it is not the initial damage that is of consequence but rather the residual damage left after the repair processes have acted. Since the vast majority of the initial DNA damage undergoes repair normally, variation in the efficiency of these processes in different persons may affect the actual risk of exposure. The human side of the cancer causation formula, that is, considerable importance. To understand how human DNA repair processes function, our laboratories at Chalk River have studied 'mutant' human cell strains in tissue culture. Generally, these DNA repair-defective cell strains are derived from individual donors with heritable disorders that are associated with carcinogen-hypersensitivity and cancer-proneness. Such studies, together with related epidemiological research, have highlighted the importance of this new 'human' factor in carcinogenesis

  13. The carcinogenic risks of low-LET and high-LET ionizing radiations

    International Nuclear Information System (INIS)

    New information is available concerning the carcinogenic effects of radiation and the implications for risk assessment and risk management. This information comes from further follow-up of the epidemiological studies of the Japanese atomic bomb survivors, patients irradiated medically for cancer and allied conditions, and workers exposed in various occupations. In the Japanese atomic bomb survivors the carcinogenic risks are estimated to be somewhat higher than previously, due to the reassessment of the atomic-bomb dosimetry, further follow-up with increase in the number of excess cancer deaths, particularly in survivors irradiated early in life, and changes in the methods of analysis to compute the age-specific risks of cancer. Because of the characteristics of the atomic bomb survivor series as regards sample size, age and sex distribution, duration for follow-up, person-years at risk, and type of dosimetry, the mortality experience of the atomic bomb survivors was selected by the UNSCEAR Committee and the BEIR V Committee as the more appropriate basis for projecting risk estimates for the general population. In the atomic bomb survivors, the dose-effect relationship for overall cancer mortality other than leukemia is consistent with linearity below 3 Gy, while the dose-effect relationship for leukemia, excluding chronic lymphatic leukemia, conforms best to a linear-quadratic function. The shape of the dose-incidence curve at low doses still remains uncertain, and the data do not rule out the possible existence of a threshold for an neoplasm. The excess relative risk of mortality from all cancers combined is estimated to be 1.39 per Gy (shielded kerma), which corresponds to an absolute risk of 10.0 excess cancer deaths per 10,000 PYGy; the relative risks is 1.41 at 1 Gy (organ-absorbed dose), and an absolute risk of 13.07 excess cancer deaths per 10,000 PYGy. 19 refs

  14. SEROLOGICAL ALTERATIONS IN CARCINOGEN-EXPOSED TELEOSTS: PROCEDURES FOR PREPARATION AND ANALYSIS OF SAMPLES FROM SMALL FISH

    Science.gov (United States)

    To study the effects of environmental carcinogens on the immune system of Cyprinodon variegatus, the authors had to miniaturize or modify standard immunological procedures due to the small size of the fish. Modifications in standard bleeding procedures allowed collection of suffi...

  15. Human cytochrome P450 enzymes of importance for the bioactivation of methyleugenol to the proximate carcinogen 1′-hydroxymethyleugenol

    NARCIS (Netherlands)

    Jeurissen, S.M.F.; Bogaards, J.J.P.; Boersma, M.G.; Horst, J.P.F. ter; Awad, H.M.; Fiamegos, Y.C.; Beek, T.A. van; Alink, G.M.; Sudhölter, E.J.R.; Cnubben, N.H.P.; Rietjens, I.M.C.M.

    2006-01-01

    In vitro studies were performed to elucidate the human cytochrome P450 enzymes involved in the bioactivation of methyleugenol to its proximate carcinogen 1′-hydroxymethyleugenol. Incubations with Supersomes, expressing individual P450 enzymes to a high level, revealed that P450 1A2, 2A6, 2C9, 2C19,

  16. Effects of combined exposure of F344 rats to inhaled Plutonium-239 dioxide and a chemical carcinogen (NNK)

    Energy Technology Data Exchange (ETDEWEB)

    Lundgren, D.L.; Carlton, W.W. [Purdue Univ., Lafayette, IN (United States); Griffith, W.C. [and others

    1995-12-01

    Workers in nuclear weapons facilities have a significant potential for exposure to chemical carcinogens and to radiation from external sources or from internally deposited radionuclides such as {sup 239}Pu. Although the carcinogenic effects of inhaled {sup 239}Pu and many chemicals have been studied individually, very little information is available on their combined effects. One chemical carcinogen that workers could be exposed to via tobacco smoke is the tobacco-specific nitrosamine 4-(N-methyl-n-nitrosamino)-1-(3-pyridyl)-1(3-pyridyl)-1-butanone (NNK), a product of tobacco curing and the pyrolysis of nicotine in tobacco. NNK causes lung tumors in rats, regardless of the route of administration and to a lesser extent liver, nasal, and pancreatic tumors. From the results presented, it can be concluded that exposure to a chemical carcinogen (NNK) in combination with {alpha}-particle radiation from inhaled {sup 239}PuO{sub 2} acts in, at best, an additive manner in inducing lung cancer in rats.

  17. Studies on carcinogenicity or anticarcinogenicity of isonicotinic acid hydrazide and caffeine by nine-week assay system

    International Nuclear Information System (INIS)

    According to many surveys, cancer is one of the major causes of death in most developed countries and the incidence of cancer appears to be on the increase. Therefore, many studies on detection of carcinogenic or anticarcinogenic agents need urgently. The purpose of this investigation is evaluation the carcinogenic or anticarcinogenic effect of INH and caffeine, which were interpreted as showing either the presence or the absence of a carcinogenic or anticarcinogenic effect, using nine-week assay system. The non-inbred NIH(GP) newborn mice were injected subcutaneously with NIH(400,425, 450 or 480 μg/ head) or caffeine (75 or 100 μg/head) for evaluation of carcinogenicity. Caffeine (1 or 2 mg/ml of drinking water) was administered orally to the mice, which were injected subcutaneously with BP(500μg/head) at new-born, during 6 weeks after weaning for evaluation of anticarcinogenicity. Each group was killed at 9 weeks after the start of exanination. All major organs were examined grossly and histopathologically. Decreased lung adenoma incidence was observed statistically significant in mice fed with caffeine 1 mg(18.8%) or 2 mg(5.1%) per ml of drinking water compared to BP control group (41.3%). However, there was no statistical difference in the incidence of lung and other site tumor between the INH group and the normal control group or between caffeine injection group and normal control group. This result will be contribute to the prevention of cancer from the viewpoint of identifying carcinogenic or anticarcinogenic agents from the environment. (Author)

  18. Human health risk due to consumption of vegetables contaminated with carcinogenic polycyclic aromatic hydrocarbons

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Sardar [Chinese Academy of Sciences, Xiamen (China). Inst. of Urban Environment; Peshawar Univ. (Pakistan). Dept. of Environmental Science; Cao, Qing [Chinese Academy of Sciences, Beijing (China). Research Center for Eco-Environemntal Sciences

    2012-02-15

    Polycyclic aromatic hydrocarbons (PAH) are persistent, toxic, and carcinogenic contaminants present in soil ecosystem globally. These pollutants are gradually accumulating in wastewater-irrigated soils and lead to the contamination of vegetables. Food chain contamination with PAH is considered as one of the major pathways for human exposure. This study was aimed to investigate the concentrations of PAH in soils and vegetables collected from wastewater-irrigated fields from metropolitan areas of Beijing, China. Origin of PAH, daily intake, and health risks of PAH through consumption of contaminated vegetables were studied. Soil samples were collected from the upper horizon (0-20 cm) of both wastewater-irrigated and reference sites and sieved (<2 mm mesh) and then followed by freeze-drying at -50 C and 123 {+-} 2 Pa. Standing vegetables were also collected from the same sites used for soil sampling and divided into roots and shoots, thoroughly washed with deionized water, and freeze-dried. PAH were extracted using the Soxhlet method with 200 mL DCM for 24 h, and the extracts were cleaned with silica adsorption chromatography prepared with silica gel, alumina, and capped with anhydrous sodium. The final concentrated extracts (soil and vegetable) were analyzed using gas chromatography-mass spectrometry (Agilent 6890). Bioaccumulation factors, daily intake of PAH, and carcinogenicity of PAH were calculated by different statistical equations. Results indicate that the soils and grown vegetables were contaminated with all possible carcinogenic PAH (declared by USEPA 2002) except indeno[1,2,3-c,d]pyrene. The highest concentration (242.9 {mu}g kg{sup -1}) was found for benzo(k)fluoranthene (BkF), while lowest (79.12 {mu}g kg{sup -1}) for benzo[a]pyrene (BaP). The emission sources of PAH were both pyrogenic and petrogenic in nature. However, the total concentrations of PAH were lower than the permissible limits set by different countries like Canada, Denmark and Germany

  19. A combined chronic toxicity/carcinogenicity study of sucralose in Sprague-Dawley rats.

    Science.gov (United States)

    Mann, S W; Yuschak, M M; Amyes, S J; Aughton, P; Finn, J P

    2000-01-01

    The chronic toxicity and potential carcinogenicity of sucralose was evaluated by exposing Sprague-Dawley rats to dietary concentrations of this low-calorie sweetener both in utero and for up to 104 weeks following parturition. The rats assigned to the toxicity phase of this investigation were administered diets containing either 0% (control), 0.3% (3000 ppm), 1.0% (10,000 ppm) or 3.0% (30,000 ppm) sucralose. Each treatment group comprised 30 male and 30 female rats, of which 15 males and 15 females were sacrificed after 52 weeks of treatment. The surviving rats were killed following 78 weeks of sucralose administration. In the carcinogenicity phase of this investigation, groups of 50 male and 50 female rats were administered dietary sucralose at concentrations of 0% (control 1), 0% (control 2), 0.3%, 1.0% or 3.0% for 104 weeks. Evaluation of the data obtained from the two phases of this study showed that sucralose was not carcinogenic. Sucralose did not adversely affect the survival or clinical condition of the rats, and there were no toxicologically significant findings. Group mean body weight gain and food consumption were significantly decreased in a dose-dependent manner in sucralose-treated rats throughout the treatment period as compared to the controls. The primary effect of sucralose on food consumption, and secondarily on body weight gain, was established in later studies to be due to the fact that diets containing high concentrations of sucralose are unpalatable to rats. These subsequent studies established that the reduction of body weight gain seen in previous rat studies using sucralose in the diet at concentrations of 1% and below resulted from reduced food intake as a direct consequence of the unpalatable nature of sucralose. Similarly, at concentrations of 3% in the diet, it was shown that approximately 95% of the effect on body weight gain could be attributed to the reduction in food intake due to the reduced palatability of the diet, the remainder

  20. Fire fighting trainers' exposure to carcinogenic agents in smoke diving simulators.

    Science.gov (United States)

    Laitinen, Juha; Mäkelä, Mauri; Mikkola, Jouni; Huttu, Ismo

    2010-01-15

    It is well known that fire fighters are potentially exposed to various carcinogenic agents at a fire scene. An almost unheeded issue, however, is fire fighters' exposure to carcinogenic agents in smoke diving simulators. Biomonitoring (urinary muconic acid, 1-naphthol and 1-pyrenol), dermal (polycyclic aromatic hydrocarbons) and occupational hygiene measurements (cyanides, hydrogen cyanide, polycyclic aromatic hydrocarbons, volatile organic compounds and formaldehyde) were used to determine how the burning material, the type of simulator and protective clothing used affect fire fighting trainers' exposure. The highest excretion of 1-pyrenol (sampled 6h after end of exposure, in average 4.3-9.2nmol/L) and emissions of benzene (1.0-2.5mg/m(3)) and hydrogen cyanide (0.2-0.9mg/m(3)) were measured during the burning of conifer plywood and chipboard, and the lowest when pure pine and spruce wood (1.5nmol/L, 0.6mg/m(3), and 0.05mg/m(3)) was burned. However the safest burning material seemed to be propane (1.0nmol/L, 0.2mg/m(3), and not measured). The type of simulator used affected trainers' exposure very clearly. The highest dermal whole body exposures to polycyclic aromatic hydrocarbons were measured in the fire house simulator (in average 1200ng/cm(2)). Clearly lower exposure levels were measured in container training sessions (760ng/cm(2)), where the average dermal exposure level was 35% lower than in the fire house. The exposure levels (30ng/cm(2)) in the gas simulator in turn, were only 4% of the levels in container training sessions. The amount of polycyclic aromatic hydrocarbons decreased by 80% on trainers' hands when they used under gloves (in average 8.7ng/cm(2)) compared to those (48.4ng/cm(2)) who did not. There was not difference in protection efficiency against polycyclic aromatic hydrocarbons between tested fire suits (Brage and Bristol). PMID:19576276

  1. An assessment of the carcinogenic potential of ezetimibe using nonclinical data in a weight-of-evidence approach

    International Nuclear Information System (INIS)

    Ezetimibe blocks intestinal absorption of sterols via interaction with the Neimann-Pick C1-Like 1 (NPC1L1) transporter and is approved for use in the treatment of primary hyperlipidemia (heterozygous familial and non-familial), homozygous familial hypercholesterolemia, and homozygous sitosterolemia. A recently completed randomized clinical trial [simvastatin and ezetimibe in aortic stenosis (SEAS)] testing the effectiveness of VytorinTM (a combination of simvastatin and ezetimibe) in patients with aortic stenosis reported an unexpected safety finding: an increase in overall cancer incidence and cancer-associated mortality (all types) in the treated groups relative to the placebo control. A subsequent meta-analysis utilizing a much larger database from two ongoing clinical trials indicated that the observed findings in the SEAS trial were likely due to chance and not a true drug-induced effect. Nonetheless, it has been suggested by various commentators on the SEAS trial that ezetimibe may be carcinogenic. The extensive nonclinical database for ezetimibe was used to test the hypothesis that ezetimibe may be a direct or indirect carcinogen. Using two different in silico approaches, ezetimibe showed no structural alerts for genetic toxicity or carcinogenicity. Ezetimibe was not genotoxic in two reverse mutation assays, one in vitro clastogenicity assay, and two mouse micronucleus assays. No evidence of proliferative lesions was observed in three species in studies of 1-12 months in duration. Ezetimibe was not carcinogenic in standard 2-year bioassays in mice and rats. Additionally, in these 2-year bioassays, no drug-related non-neoplastic lesions were noted. The absence of drug-induced non-neoplastic or proliferative lesions in these studies indicates that ezetimibe treatment was not associated with findings characteristic of carcinogens (i.e., DNA reactivity or cell proliferation) Administration of pharmacologic doses of ezetimibe to mice did not alter hepatic

  2. Renal deterioration caused by carcinogens as a consequence of free radical mediated tissue damage: a review of the protective action of melatonin.

    Science.gov (United States)

    Gultekin, Fatih; Hicyilmaz, Hicran

    2007-10-01

    This brief review summarizes some of the publications that document the preventive role of melatonin in kidney damage caused by carcinogens such as 2-nitropropane, arsenic, carbon tetrachloride, nitrilotriacetic acid and potassium bromate. Numerous chemicals generate excessive free radicals that eventually induce renal worsening. Melatonin partially or totally prevents free radical mediated tissue damages induced by many carcinogens. Protective actions of melatonin against the harmful effects of carcinogens are believed to stem from its direct free radical scavenging and indirect antioxidant activities. Dietary or pharmacologically given melatonin may attenuate the oxidative stress, thereby mitigating the subsequent renal damage. PMID:17823789

  3. Renal deterioration caused by carcinogens as a consequence of free radical mediated tissue damage: a review of the protective action of melatonin

    Energy Technology Data Exchange (ETDEWEB)

    Gultekin, Fatih; Hicyilmaz, Hicran [Suleyman Demirel University, School of Medicine, Department of Biochemistry, Isparta (Turkey)

    2007-10-15

    This brief review summarizes some of the publications that document the preventive role of melatonin in kidney damage caused by carcinogens such as 2-nitropropane, arsenic, carbon tetrachloride, nitrilotriacetic acid and potassium bromate. Numerous chemicals generate excessive free radicals that eventually induce renal worsening. Melatonin partially or totally prevents free radical mediated tissue damages induced by many carcinogens. Protective actions of melatonin against the harmful effects of carcinogens are believed to stem from its direct free radical scavenging and indirect antioxidant activities. Dietary or pharmacologically given melatonin may attenuate the oxidative stress, thereby mitigating the subsequent renal damage. (orig.)

  4. The potential carcinogenic risk of tanning beds: clinical guidelines and patient safety advice

    International Nuclear Information System (INIS)

    In 2009, the WHO listed ultraviolet (UV) radiation as a group 1 carcinogen. In spite of this, each year, millions of people tan indoor in Western countries. The aim of this review is to summarize evidence of tanning bed carcinogenesis and to present guidelines for use of tanning beds and patient safety advice. A narrative review of the literature was conducted based on both PubMed and Medline searches and on literature review of the retrieved papers. Use of indoor tanning beds represents a significant and avoidable risk factor for the development of both melanoma and nonmelanoma skin cancers. Frequent tanners are more often adolescent females. Tanning beds have additional potential adverse effects such as burns, solar skin damage, infection, and possibly also addictive behavior. The effort in preventing UV light-induced carcinogenesis should currently be aimed at developing new strategies for public health information. Tanning beds are one preventable source of UV radiation. In the majority of people solar UV radiation continues to be the major factor and therefore anti-tanning campaigns must always include sunbathers

  5. What advice to give when ELF is classified as a possible human carcinogen

    International Nuclear Information System (INIS)

    In 1996, the World Health Organization (WHO) established the International Electromagnetic Fields (EMF) Project to address the health issues associated with exposure to EMF. This Project is intended to provide independent scientific assessment of health effects from exposure to EMF (0-300 GHz); identify gaps in knowledge requiring further research in order to improve health risk assessments; encourage focused, high quality research; and conduct formal WHO/IARC/ICNIRP health risk assessments after key research has been completed. The International EMF Project is currently reviewing research results and conducting risk assessments of exposure to static and extremely low frequency (ELF) electric and magnetic fields. WHO will be conducting an evaluation of all health effects from ELF field exposure during 2002-3. This paper summarizes what is known about ELF exposure on childhood leukaemia, what the IARC classification means and how some national authorities have responded. In addition, WHO recommendations are given to provide guidance to national authorities wanting to protect their populations against EMF exposure. Whenever electricity is conducted through transmission lines, distribution lines or is used in appliances, both electric and magnetic fields exist close to the lines or appliances. The power frequency used is 50 or 60 Hz. Use of electric power has become part of everyday life. However, questions have been raised as to whether these and other ELF fields are carcinogenic or can produce any other effects on health

  6. Cell kinetics in mouse lung following administration of carcinogens and butylated hydroxytoluene

    International Nuclear Information System (INIS)

    A series of experiments is described which was designed to test the hypothesis that, in mouse lung, enhancement of tumor development could occur independently of overall alveolar cell hyperplasia. Male A/J mice were given 1000 mg/kg of urethane or 10 mg/kg of 3-methylcholanthrene (MCA). Alveolar cells were labeled through continuous infusion of [3H]thymidine for 6 weeks after administration of the carcinogen. Urethane produced a significant hyperplasia of the type II alveolar cell population, whereas MCA had no such effect. Five repeated injections of 300 mg/kg of butylated hydroxytoluene (BHT), a procedure known to enhance lung tumor development, produced cell hyperplasia only during the first 2 weeks; later the mice became resistant to the action of BHT. In animals treated with piperonyl butoxide prior to BHT, cell proliferation was abolished. BHT still had a small but significant enhancing effect on tumor development. However, this effect was dwarfed by the observation that piperonyl butoxide alone greatly inhibited tumor development. The data do not allow exclusion of alveolar cell hyperplasia as a mechanism in BHT-mediated enhancement of mouse lung tumor development. 19 references, 4 figures, 3 tables

  7. Magnetic polyethyleneimine (PEI) microcapsules as retrievable traps for carcinogen electrophiles formed in the gastrointestinal tract

    International Nuclear Information System (INIS)

    Semi-permeable magnetic microcapsules containing polyethyleneimine (PEI) have been developed as retrievable carcinogen traps. In vitro, the soluble core PEI and membrane both bound reactive substances of limited aqueous stability, such as from [14C]N-methyl-N-nitrosourea ([14C]NMU), and aqueous stable dyes of molecular weight up to 1000. The core/membrane location ratio of binding was dependent upon membrane characteristics of the microcapsule batch used. Microcapsules administered intragastrically to rats bound up to 0.006% of [14C]dimethylhydrazine ([14C]DMH) and 1.4% of [14C]NMU administered i.p. or intrarectally, respectively. Time-dependency of [14C]DMH binding was consistent with labelling of microcapsules within the small intestine. There were no detectable metabolites from [14C]DMH trapped within the colon, whereas binding of [14C]NMU indicated that microcapsules could bind transient species present within the colon in competition with the faecal bulk. These results indicate that this approach could be used to detect highly unstable and possibly genotoxic substances in situ, hitherto unknown, formed within the intestinal lumen. (author). 20 refs

  8. Review of short-term screening tests for mutagens, toxigens, and carcinogens

    Energy Technology Data Exchange (ETDEWEB)

    Carney, H.J.; Hass, B.S.

    1979-07-01

    In order to test the thousands of man-made chemicals in the environment for carcinogenic and genetic hazards, a multitude of short-term screening tests has been developed to complement long-term mammalian bioassays and epidemiological studies. These tests cover a broad spectrum of organisms, and include the use of naked and viral nucleic acids, bacteria, fungi, higher plants, insects in vitro mammalian cell cultures (cell transformation, cell-mediated mutagenesis, DNA repair, and chromosome aberration tests) and live mammals. Assay end points include effects on nucleic acids, DNA repair synthesis, point or gene mutation, structural and numerical chromosome aberrations, cytological alterations, and in vitro cell transformation. The present review describes and compares these assays. In addition, it discusses their historical development, the problems and limitations associated with their use, and their implementation in comprehensive testing programs. It is intended to provide overview and specific information to the laboratory that is in the process of establishing genetic toxicological systems. (The literature is reviewed to January 1978.)

  9. Carcinogenic polycyclic aromatic hydrocarbons in umbilical cord blood of human neonates from Guiyu, China

    International Nuclear Information System (INIS)

    Unregulated electronic-waste recycling results in serious environmental pollution of polycyclic aromatic hydrocarbons (PAHs) in Guiyu, China. We evaluated the body burden of seven carcinogenic PAHs and potential health risks for neonates. Umbilical cord blood (UCB) samples were collected from Guiyu (n = 103), and the control area of Chaonan (n = 80), China. PAHs in UCB were determined by gas chromatography/mass spectrometry. The median ∑ 7c-PAH concentration was 108.05 ppb in UCB samples from Guiyu, vs. 79.36 ppb in samples from Chaonan. Residence in Guiyu and longer cooking time of food during the gestation period were significant factors contributing to the ∑ 7c-PAH level. Benzo[a]anthracene (BaA), chrysene (Chr), and benzo[a]pyrene (BaP) were found to correlate with reduced neonatal height and gestational age. Infants experiencing adverse birth outcomes, on the whole, displayed higher BaA, Chr, and BaP levels compared to those with normal outcomes. We conclude that maternal PAH exposure results in fetal accumulation of toxic PAHs, and that such prenatal exposure correlates with adverse effects on neonatal health.

  10. Carcinogenic polycyclic aromatic hydrocarbons in umbilical cord blood of human neonates from Guiyu, China

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Yongyong; Huo, Xia [Analytic Cytology Laboratory and the Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, Shantou (China); Wu, Kusheng [Analytic Cytology Laboratory and the Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, Shantou (China); Department of Preventive Medicine, Shantou University Medical College, Shantou (China); Liu, Junxiao; Zhang, Yuling [Analytic Cytology Laboratory and the Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, Shantou (China); Xu, Xijin, E-mail: xuxj@stu.edu.cn [Analytic Cytology Laboratory and the Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, Shantou (China); Department of Cell Biology and Genetics, Shantou University Medical College, Shantou (China)

    2012-06-15

    Unregulated electronic-waste recycling results in serious environmental pollution of polycyclic aromatic hydrocarbons (PAHs) in Guiyu, China. We evaluated the body burden of seven carcinogenic PAHs and potential health risks for neonates. Umbilical cord blood (UCB) samples were collected from Guiyu (n = 103), and the control area of Chaonan (n = 80), China. PAHs in UCB were determined by gas chromatography/mass spectrometry. The median N-Ary-Summation 7c-PAH concentration was 108.05 ppb in UCB samples from Guiyu, vs. 79.36 ppb in samples from Chaonan. Residence in Guiyu and longer cooking time of food during the gestation period were significant factors contributing to the N-Ary-Summation 7c-PAH level. Benzo[a]anthracene (BaA), chrysene (Chr), and benzo[a]pyrene (BaP) were found to correlate with reduced neonatal height and gestational age. Infants experiencing adverse birth outcomes, on the whole, displayed higher BaA, Chr, and BaP levels compared to those with normal outcomes. We conclude that maternal PAH exposure results in fetal accumulation of toxic PAHs, and that such prenatal exposure correlates with adverse effects on neonatal health.

  11. Estimation of the dermal carcinogenic activity of petroleum fractions using a modified Ames assay.

    Science.gov (United States)

    Blackburn, G R; Deitch, R A; Schreiner, C A; Mehlman, M A; Mackerer, C R

    1984-10-01

    The Ames Salmonella/microsomal activation mutagenesis assay has been adapted to improve sensitivity to complex hydrocarbon mixtures produced by the refining of petroleum. Extraction of oil samples with dimethyl sulfoxide produces aqueous-compatible solutions that more easily interact with the tester bacteria. These extracts, therefore, produce higher revertant values than do equivalent volumes of oil delivered neat or dissolved in organic solvent. Parallel increases in the liver microsomal S-9 concentration further improve the sensitivity of the assay, allowing detection of mutagenicity in otherwise inactive samples. The effect of increased microsomal fraction from rodent liver is apparently attributable to the higher levels of activating enzymes rather than to the concomitant increase in the overall hydrophobicity of the test system. The modified assay has been used to rank thirteen petroleum-derived oils and a corn oil control for relative mutagenic activity. This ranking closely correlates (r = 0.97) with potency rankings of the same samples previously determined from dermal carcinogenicity bioassays. PMID:6401126

  12. Carcinogenic Parasite Secretes Growth Factor That Accelerates Wound Healing and Potentially Promotes Neoplasia.

    Science.gov (United States)

    Smout, Michael J; Sotillo, Javier; Laha, Thewarach; Papatpremsiri, Atiroch; Rinaldi, Gabriel; Pimenta, Rafael N; Chan, Lai Yue; Johnson, Michael S; Turnbull, Lynne; Whitchurch, Cynthia B; Giacomin, Paul R; Moran, Corey S; Golledge, Jonathan; Daly, Norelle; Sripa, Banchob; Mulvenna, Jason P; Brindley, Paul J; Loukas, Alex

    2015-10-01

    Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). Injury from feeding activities of this parasite within the human biliary tree causes extensive lesions, wounds that undergo protracted cycles of healing, and re-injury over years of chronic infection. We show that O. viverrini secreted proteins accelerated wound resolution in human cholangiocytes, an outcome that was compromised following silencing of expression of the fluke-derived gene encoding the granulin-like growth factor, Ov-GRN-1. Recombinant Ov-GRN-1 induced angiogenesis and accelerated mouse wound healing. Ov-GRN-1 was internalized by human cholangiocytes and induced gene and protein expression changes associated with wound healing and cancer pathways. Given the notable but seemingly paradoxical properties of liver fluke granulin in promoting not only wound healing but also a carcinogenic microenvironment, Ov-GRN-1 likely holds marked potential as a therapeutic wound-healing agent and as a vaccine against an infection-induced cancer of major public health significance in the developing world. PMID:26485648

  13. House-heating emissions of carcinogenic substances. A problem of the new lander in Germany

    International Nuclear Information System (INIS)

    Intensive studies and analyses have been done to set up an air pollution management plan for an area of 752 km2 in the south of Saxony-Anhalt (182 000 inhabitants), the first one in the New Lander of Germany. The results show a higher level of harmful compounds in the ambient air in densly-populated areas, especially caused by exhaust gases from brown-coal (lignite) fired residential stoves. The combustion of indigenous lignite-briquettes with a high content of sulphur causes classical inorganic emissions, such as carbon monoxide (CO), sulphur dioxide (SO2), particulate matter and nitrogen oxides (NOx) as well as organic compounds, such as benzene, toluene, xylene (BTX), polycyclic aromatic hydrocarbons (PAH) and polychlorinated dioxins and furans (PCDD/F). The last-named are of special importance because of the carcinogenic effects. An inventory of house-heating facilities, set up on the basis of energy consumption for heating purposes in buildings, shows the still very high part of brown coal combustion (58 %) in the investigated area and in the New Lander of Germany. In the western part of Germany this percentage amounts only to 10 %. (orig.)

  14. Electrophoretic mobility of PM2 DNA treated with ultimate chemical carcinogens or with ultraviolet light

    International Nuclear Information System (INIS)

    Superhelical DNA of the Pseudomonas phage PM2 was irradiated with UV-light or reacted with covalently binding carcinogens, such as 7-bromomethyl-benz[a]anthracene, (Ac)2ONFln, K-region epoxides, and alkylating agents. Migration velocity of the DNA products was determined using agarose gel electrophoresis. In gels of more than 1.3%-1.9% agarose, modified PM2 DNA exhibited a dose-(concentration-)dependent decrease of migration velocity. This phenomenon is probably due to a decrease in superhelix density which caused the compact DNA coil to assume eventually an open-circular conformation. Comparison of the extent of DNA modification with the decrease of migration velocity revealed that the superhelical structure sensitively reflected the chemical DNA alterations. DNA species exhibiting in 1.6% agarose gels, a migration velocity of up to 30% of that of control DNA showed an increase of velocity in 0.4% agarose. Therefore, in 1.3%-1.9% agarose gels, the decrease of superhelix density is accompanied by an increase of the frictional coefficient, whereas in 0.4%-0.9% agarose gels the same decrease of superhelix density apparently led to a higher degree of flexibility of the macromolecule and/or exposure of additional electric charges. (orig.)

  15. Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism.

    Science.gov (United States)

    Redwan, Elrashdy M; Linjawi, Moustafa H; Uversky, Vladimir N

    2016-01-01

    Therapeutic insulin, in its native and biosynthetic forms as well as several currently available insulin analogues, continues to be the protein of most interest to researchers. From the time of its discovery to the development of modern insulin analogues, this important therapeutic protein has passed through several stages and product generations. Beside the well-known link between diabetes and cancer risk, the currently used therapeutic insulin analogues raised serious concerns due to their potential roles in cancer initiation and/or progression. It is possible that structural variations in some of the insulin analogues are responsible for the appearance of new oncogenic species with high binding affinity to the insulin-like growth factor 1 (IGF1) receptor. The question we are trying to answer in this work is: are there any specific features of the distribution of intrinsic disorder propensity within the amino acid sequences of insulin analogues that may provide an explanation for the carcinogenicity of the altered insulin protein? PMID:26983499

  16. Expression of a fms-related oncogene in carcinogen-induced neoplastic epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Walker, C.; Nettesheim, P.; Barrett, J.C.; Gilmer, T.M.

    1987-04-01

    Following carcinogen exposure in vitro, normal rat tracheal epithelial cells are transformed in a multistage process in which the cultured cells become immortal and ultimately, neoplastic. Five cell lines derived from tumors produced by neoplastically transformed rat tracheal epithelial cells were examined for the expression of 11 cellular oncogenes previously implicated in pulmonary or epithelial carcinogenesis. RNA homologous to fms was expressed at a level 5-19 times higher than normal tracheal epithelial cells in three of five of the tumor-derived lines. All three lines expressing high levels of fms-related RNA gave rise to invasive tumors of epithelial origin when injected into nude mice. Increased expression of the fms-related mRNA was not due to gene amplification, and no gene rearrangement was detected by Southern analyses. RNA blot analysis using a 3' v-fms probe detected a 9.5-kilobase message in the three tumor-derived lines, whereas both normal rat aveolar macrophages and the human choriocarcinoma line BeWo expressed a fms transcript of approx. = 4 kilobases. The authors conclude from these data that the gene expressed as a 9.5-kilobase transcript in these neoplastic epithelial cells is a member of a fms-related gene family but may be distinct from the gene that encodes the macrophage colony-stimulating factor (CSF-1) receptor.

  17. Clinical and biochemical studies support smokeless tobacco's carcinogenic potential in the human oral cavity.

    Science.gov (United States)

    Mallery, Susan R; Tong, Meng; Michaels, Gregory C; Kiyani, Amber R; Hecht, Stephen S

    2014-01-01

    In 2007, the International Agency for Research on Cancer presented compelling evidence that linked smokeless tobacco use to the development of human oral cancer. Although these findings imply vigorous local carcinogen metabolism, little is known about levels and distribution of phase I, II, and III (drug egress) enzymes in human oral mucosa. In this study here, we integrated clinical data, and imaging and histopathologic analyses of an oral squamous cell carcinoma that arose at the site of smokeless tobacco quid placement in a patient. Immunoblot and immunohistochemical (IHC) analyses were used to identify tumor and normal human oral mucosal smokeless tobacco-associated metabolic activation and detoxification enzymes. Human oral epithelium contains every known phase I enzyme associated with nitrosamine oxidative bioactivation with approximately 2-fold interdonor differences in protein levels. Previous studies have confirmed approximately 3.5-fold interdonor variations in intraepithelial phase II enzymes. Unlike the superficially located enzymes in nonreplicating esophageal surface epithelium, IHC studies confirmed that oral mucosal nitrosamine metabolizing enzymes reside in the basilar and suprabasilar region, which notably is the site of ongoing keratinocyte DNA replication. Clearly, variations in product composition, nitrosamine metabolism, and exposure duration will modulate clinical outcomes. The data presented here form a coherent picture consistent with the abundant experimental data that link tobacco-specific nitrosamines to human oral cancer. PMID:24265177

  18. Renal cell carcinomas of chronic kidney disease patients harbor the mutational signature of carcinogenic aristolochic acid.

    Science.gov (United States)

    Jelaković, Bojan; Castells, Xavier; Tomić, Karla; Ardin, Maude; Karanović, Sandra; Zavadil, Jiri

    2015-06-15

    Aristolochic acid (AA) is a potent dietary cytotoxin and carcinogen, and an established etiological agent underlying severe human nephropathies and associated upper urinary tract urothelial cancers, collectively designated aristolochic acid nephropathy (AAN). Its genome-wide mutational signature, marked by predominant A:T > T:A transversions occurring in the 5'-CpApG-3' trinucleotide context and enriched on the nontranscribed gene strand, has been identified in human upper urinary tract urothelial carcinomas from East Asian patients and in experimental systems. Here we report a whole-exome sequencing screen performed on DNA from formalin-fixed, paraffin-embedded renal cell carcinomas (RCC) arising in chronic renal disease patients from a Balkan endemic nephropathy (EN) region. In the EN regions, the disease results from the consumption of bread made from wheat contaminated by seeds of Aristolochia clematitis, an AA-containing plant. In five of eight (62.5%) tested RCC tumor specimens, we observed the characteristic global mutational signature consistent with the mutagenic effects of AA. This signature was absent in the control RCC samples obtained from patients from a nonendemic, metropolitan region. By identifying a new tumor type associated with the AA-driven genome-wide mutagenic process in the context of renal disease, our results suggest new epidemiological and public health implications for the RCC incidence worldwide, particularly for the high-risk regions with unregulated use of AA-containing traditional herbal medicines. PMID:25403517

  19. Immunological detection and quantification of DNA components structurally modified by alkylating carcinogens, mutagens and chemotherapeutic agents

    International Nuclear Information System (INIS)

    The detection and quantification of defined reaction products of chemical mutagens and carcinogens (and of many cancer chemotherapeutic agents) with DNA require highly sensitive analytical techniques. The exceptional capability of immunoglobulins to recognize subtle alterations of molecular structure (especially when monoclonal antibodies are used to maximize specificity), outstanding sensitivity of immunoanalysis by high-affinity antibodies, and the fact that radioactively-labelled agents are not required suggest the utility of a radioimmunoassay to recognize and quantitate alkylated DNA products. We have recently developed a set of high-affinity monoclonal antibodies (secreted by mouse x mouse as well as by rat x rat hybridomas; antibody affinity constants, 109 to > 1010 lmol) specifically directed against several DNA alkylation products with possible relevance in relation to both mutagenesis and malignant transformation of mammalian cells. These alkylation products include 06-N-butyldeoxyguanosine, and 04-ethyldeoxythymidine. When used in a radioimmunassay, an antibody specific for 06-ethyldeoxyguanosine, for example, will detect this product at an 06-ethyldeoxyguanosine/deoxyguanosine molar ratio of approx. 3 x 10-7 in a hydrolysate of 100 ug of DNA. The limit of detection can be lowered further if the respective alkyldeoxynucleosides are separated by HPLC from the DNA hydrolysate prior to the RIA. The anti-alkyldeoxynucleoside monoclonal antibodies can also be used to visualize, by immunostaining and fluorescence microscopy combined with electronic image intensification, specific alkylation products in the nuclear DNA of individual cells, and to localize structurally modified bases in double-stranded DNA molecules by transmission electron microscopy

  20. The toxic effects of flame retardants: a gene expression study in elucidating their carcinogenicity

    Science.gov (United States)

    Vagula, Mary; Al-Dhumani, Ali; Al-Dhumani, Sajaad; Mastro, Alexandra

    2013-05-01

    Polybrominated Diphenyl Ethers (PBDEs) are flame retardants widely used in many commercial products, including building materials, electronics, furnishings, motor vehicles, airplanes, plastics, polyurethane foams, and textiles. Although the specific toxic action of these chemicals is not clear, it is reported that they can cause serious damage to the nervous, reproductive, and endocrine systems. These chemicals are branded as "probable carcinogens" by Environmental Protection Agency (EPA). Therefore, this study is taken up to investigate the expression of genes namely, TP-53, RAD1, CRADD, and ATM, which are involved in apoptosis, DNA repair and cell cycle regulation. For this study human umbilical vein endothelial cells (HUVEC) are exposed to 5 μM of BDE-85 (a penta-BDE) and BDE-209 (deca-BDE). The results of this report reveal significant alteration in all the genes under investigation in BDE-85 and BDE-209 exposed cells. The BDE-85 induced responses are significantly more than BDE-209. These results emphasize the congener specific action of PBDEs on the expression of genes relevant to DNA repair and cell division of HUVEC cells.

  1. Cadmium accumulation in Panax notoginseng: levels, affecting factors and the non-carcinogenic health risk.

    Science.gov (United States)

    Zhu, Meilin; Jiang, Yang; Cui, Bin; Jiang, Yanxue; Cao, Hongbin; Zhang, Wensheng

    2016-04-01

    Cadmium (Cd) contamination has been reported to be a problem for the safe usage of Panax notoginseng (Sanchi); thus, it is necessary to elucidate the Cd accumulation in Sanchi and to assess its associated health risk. Samples were collected from major producing areas in Yunnan, China. The average concentration of Cd in Sanchi was 0.43 mg/kg, which exceeds the standard level for herbal medicine in China (0.3 mg/kg). A stepwise regression analysis showed that zinc and the pH were the related factors that most significantly impacted Cd in Sanchi roots. The hazard quotient values were estimated as 0.0010 (men) and 0.0012 (women) for consumers taking preparations and were 0.011 (men) and 0.013 (women) for consumers taking health products, implying that there is no non-carcinogenic hazard associated with Sanchi consumption. However, a Monte Carlo simulation showed that approximately 0.80 % of male and 1.02 % of female consumers via drug consumption and 36.28 % of male and 41.87 % of female consumers via health product consumption had an exposure exceeding the acceptable daily intake (ADI) of Cd from drugs (1 % of the total oral ADI as suggested by the World Health Organization). These people should control their oral Cd intake from both Sanchi consumption and diet as a whole. PMID:26070861

  2. Modelling the effect of exposure to environmetal carcinogens on incidence of cancers in populations

    International Nuclear Information System (INIS)

    Risk estimation is a complex problem with very important public health consequences. The models in general use for this purpose are simple models that describe some measure of risk as a mathematically simple function of exposure. The available data about environmental carcinogens, however, is rarely enough to allow the authors to test the validity of such models. A solution to this problem is to choose a model that agrees with the understanding of carcinogenesis and exposure effects. Here, exposure effects are modelled quantitative in the framework of a model for carcinogenesis at the cellular level proposed by Moolgavkar and Knudson (1981). The model postulates that a normal cell must undergo two changes before it becomes malignant. It also allows for growth of normal tissue, intermediate cell clones and malignant tumors. Derivations of hazards and relative risks based on various patterns (acute, chronic) and qualities (initiators, promoters) of exposure are shown. The use of such models for data analysis is illustrated on two sets of data: one on acute exposure to γ-rays in an animal carcinogensis experiment; the other on a chronic exposure to arsenic in a cohort of workers from a copper smelter. Results from the analysis are compared to those obtained with standard methods of risk estimation

  3. Estimation of the carcinogenic risk of radiotherapy of benign diseases from shoulder to heel

    International Nuclear Information System (INIS)

    Background and purpose: To estimate risk on fatal tumour induction in patients by radiotherapy of benign diseases at various body sites, including heterotopic ossification, omarthritis, gonarthrosis, heel spurs and hidradenitis suppurativa. Material and methods: The carcinogenic risk is estimated by applying the effective dose concept from the ICRP with the average risk factor of 10% per Sv for high dose and high dose rate. Although, the concept of effective dose for the present study has limitations, its use is considered acceptable for a fairly rough risk estimate. The organ doses are calculated using a Monte Carlo radiation transport code and anthropomorphic mathematical phantoms. Special risk modifying factors like patient's age at exposure and gender are taken into account. Results: For the treatment of heterotopic ossification, omarthritis, gonarthrosis, heel spurs and hidradenitis suppurativa the effective dose is in the range of 5-400 mSv. For an average-aged population, the estimated number of radiation-induced fatal tumours due to these treatments is assessed to be between 0.5 and 40 persons per 1000 patients treated. At higher ages the risks are reduced. Conclusions: The range of effective doses found for the various types of treatment at various body sites is large. There are several possibilities to optimise the treatment protocols resulting in reduced effective doses and related radiation risks

  4. Anti-carcinogenic and Anti-bacterial Properties of Selected Spices: Implications in Oral Health.

    Science.gov (United States)

    Ganjre, Anjali; Kathariya, Rahul; Bagul, Neeta; Pawar, Vivek

    2015-10-01

    "Let food be thy medicine and medicine be thy food", as said by the father of medicine, Hippocrates in 431 B.C. Nature has provided us with a variety of treatment modalities in the form of food. For the first 5,000 years of civilization, humans relied on herbs and foods for medicine. Only in the past 60 years have we forgotten our medicinal "roots" in favor of patented medicines. While pharmaceutical ingredients have their value, we should not overlook the well-documented, non-toxic and inexpensive healing properties of food. As an individual we consume food several times a day without a complete understanding of its innate qualities. As part of a daily diet, food plays a significant role in helping our bodies function at their best. There are hundreds of extremely nutritious foods, but the items in this article do more than providing healthy nutrients. Many of them consist of ingredients with hidden pharmaceutical qualities ranging from anti-inflammatory to anti-carcinogenic agent. They not only boost our innate immunity but also act as an adjunct to medicines for specific treatment. Prevention and management of symptoms can often be improved significantly through the foods we consume regularly. This paper overviews these beneficial traits of food ingredients, consumed on a daily basis, in various oral diseases. PMID:26566515

  5. Malignant transformation in vitro: criteria, biological markers, and application in environmental screening of carcinogens

    International Nuclear Information System (INIS)

    Biological markers which distinguish malignantly transformed fibroblasts from their normal counterpart include pleomorphic morphology, lowered requirement for nutritional factors, loss of density inhibition of growth, complex topography as discernible by scanning electron microscopy, loss in surface proteins, incomplete glycosylation of membrane glycolylipids and glycoproteins, increased production of specific proteases, decreased organization of the cytoskeleton, and acquisition of neoantigens. Several of these markers are not consistently found in transformed epithelial cells and therefore cannot serve to distinguish unequivocally neoplastic epithelial cells from the normal counterparts. The only criteria associated with the transformed nature of both fibroblasts and epithelial cells are the ability of the cells to proliferate in semisolid medium and to induce tumors in appropriate hosts. In vitro systems represent a powerful tool for screening the mutagenic/oncogenic potential of physical, chemical, and environmental agents. Fibroblasts rather than epithelial cells are preferred for this purpose at the present time because of the clear-cut phenotypic differences between the normal and the transformed cells. These systems have been useful in establishing that malignant transformation can be induced by doses as low as 1 rad of X rays or 0.1 rad of neutrons, and that fractionation at low dose levelsleads to enhanced transformation. They have been useful in identifying a large number of hazardous chemicals and in evaluating the relationship between the mutagenic and carcinogenic potential of radiation and chemicals

  6. Anti-carcinogenic and Anti-bacterial Properties of Selected Spices: Implications in Oral Health

    Science.gov (United States)

    Ganjre, Anjali; Bagul, Neeta; Pawar, Vivek

    2015-01-01

    "Let food be thy medicine and medicine be thy food", as said by the father of medicine, Hippocrates in 431 B.C. Nature has provided us with a variety of treatment modalities in the form of food. For the first 5,000 years of civilization, humans relied on herbs and foods for medicine. Only in the past 60 years have we forgotten our medicinal "roots" in favor of patented medicines. While pharmaceutical ingredients have their value, we should not overlook the well-documented, non-toxic and inexpensive healing properties of food. As an individual we consume food several times a day without a complete understanding of its innate qualities. As part of a daily diet, food plays a significant role in helping our bodies function at their best. There are hundreds of extremely nutritious foods, but the items in this article do more than providing healthy nutrients. Many of them consist of ingredients with hidden pharmaceutical qualities ranging from anti-inflammatory to anti-carcinogenic agent. They not only boost our innate immunity but also act as an adjunct to medicines for specific treatment. Prevention and management of symptoms can often be improved significantly through the foods we consume regularly. This paper overviews these beneficial traits of food ingredients, consumed on a daily basis, in various oral diseases. PMID:26566515

  7. Species and diet related resistance to chemical carcinogens: biochemical mechanisms of aflatoxin B1 detoxification

    International Nuclear Information System (INIS)

    To provide insight into the biochemical mechanisms mediating species and diet related resistance to chemical carcinogens, the biotransformation and covalent binding to DNA of the potent hepatocarcinogen aflatoxin B1(AFB) was investigated in resistant and susceptible species fed standard and butylated hydroxyanisole (BHA)-supplemented diets. The rat is sensitive to the hepatocarcinogenic effects of AFB, whereas the mouse, and rats fed BHA-supplemented diet, are resistant. To differentiate between enzyme induction and direct antioxidant effects, BHA was administered to rats for 9 days, or as a single dose 4-7 hrs prior to i.p. injection of 3H-AFB. Long-term treatment with BHA doubled the biliary excretion of the glutathione conjugate of AFB and the AFP1-glucuronide, and reduced the binding of AFB to hepatic DNA to 16% of control. Single-dose BHA treatment had no effect. To determine if glutathione S-transferase (GST) activity towards the AFB-epoxide mediates both treatment and species related resistance to AFB carcinogenesis, a method was developed to measure the rate of formation of the AFB-epoxide, and the rate of inactivation of the epoxide via GST. To demonstrate the importance of GST-mediated detoxification of the AFB-epoxide in the mouse in vivo, depletion of hepatic GSH was accomplished by administration of L-buthionine-S,R-sulfoximine and diethyl maleate, prior to administration of AFB. GSH depletion was associated with a 30-fold increase in AFB-DNA binding

  8. The commuters' exposure to volatile chemicals and carcinogenic risk in Mexico City

    Science.gov (United States)

    Shiohara, Naohide; Fernández-Bremauntz, Adrián A.; Blanco Jiménez, Salvador; Yanagisawa, Yukio

    The commuters' exposure levels to volatile organic compounds were investigated in the following public transport modes: private car, microbus, bus, and metro along three commuting routes in the Metropolitan Area of Mexico City. The target chemicals were benzene, toluene, ethylbenzene, m/ p-xylene, and formaldehyde. Integrated samples were taken while traveling during the morning rush hour (weekdays 7:00-9:00 a.m.) for six consecutive weeks in June and July, 2002. Scheffe test showed that the average concentrations of all chemicals inside cars and microbuses were statistically higher than in metro trains ( Pautomobiles were significantly higher than in metro trains and buses ( Pcar, bus, and metro ( Pcar and microbus passengers are exposed to higher levels of volatile organic compounds than bus and metro commuters. These findings are consistent with previous studies looking at exposure of commuters to carbon monoxide. The lifetime carcinogenic risk from commuting by car was 2.0×10 -5-3.1×10 -5, that by microbus was 3.1×10 -5-4.0×10 -5, that by bus was 2.0×10 -5-2.7×10 -5, and that by metro was 1.3×10 -5-1.7×10 -5 in Mexico City.

  9. The effectiveness of chemical carcinogens to induce atherosclerosis in the white carneau pigeon

    International Nuclear Information System (INIS)

    The frequency of atherosclerotic lesions of the abdominal aorta has been reported to increase significantly in chickens exposed to benzo(a)pyrene and 7,12-dimethylbenz(a,h)anthracene. The present studies were performed to determine in another experimental model frequently used in atherosclerotic studies (i.e. White Carneau Pigeons) whether these and other chemical carcinogens enhance atherosclerosis. The induction and enhancement of atherosclerotic lesions were observed in pigeons treated with 7,12-dimethylbenz(a,h)anthracene, benzo(a)pyrene and 3-methylcholanthrene. The number and size of plaques in the aorta were frequently greater in pigeons treated with the higher concentrations (i.e. 100 mg/kg) of these 3 polycyclic aromatic hydrocarbons. Benzo(e)pyrene and 2,4,6-trichlorophenol were ineffective in the induction or enhancement of atherosclerosis in the pigeons. The results of the present and previous studies suggest that the polycyclic aromatic hydrocarbons (excluding benzo(e)pyrene) may be the only potential atherogens in avian atherosclerosis. This relationship may be associated with how these hydrocarbons are transported in the plasma (i.e. by lipoproteins) as demonstrated by the present distribution studies (author)

  10. Neoplastic transformation of human breast epithelial cells by estrogens and chemical carcinogens.

    Science.gov (United States)

    Russo, Jose; Tahin, Quivo; Lareef, M Hasan; Hu, Yun-Fu; Russo, Irma H

    2002-01-01

    Sporadic breast cancer, the most common cancer diagnosed in American and Northern European women, is gradually increasing in incidence in most Western countries. Prevention would be the most efficient way of eradicating this disease. This goal, however, cannot be accomplished until the specific agent(s) or mechanisms that initiate the neoplastic process are identified. Experimental studies have demonstrated that mammary cancer is a hormone-dependent multistep process that can be induced by a variety of compounds and mechanisms, that is, hormones, chemicals, radiation, and viruses, in addition to or in combination with genetic factors. Although estrogens have been shown to play a central role in breast cancer development, their carcinogenicity on human breast epithelial cells (HBECs) has not yet been clearly demonstrated. Breast cancer initiates in the undifferentiated lobules type 1, which are composed of three cell types: highly proliferating cells that are estrogen-receptor negative (ER-), nonproliferating cells that are ER positive (ER+), and very few (17p13.2. The relevance of these findings is highlighted by the observation that E(2)- and B[a]P-induced genomic alterations in the same loci found in ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma of the breast. PMID:11921196

  11. Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. European Study Group on Cytogenetic Biomarkers and Health

    DEFF Research Database (Denmark)

    Bonassi, S; Hagmar, L; Strömberg, U; Montagud, A H; Tinnerberg, H; Forni, A; Heikkilä, P; Wanders, S; Wilhardt, P; Hansteen, I L; Knudsen, Lisbeth E.; Norppa, H

    2000-01-01

    played by exposure to carcinogens is still uncertain because of the requisite information concerning occupation and lifestyle was lacking. We evaluated in the present study whether CAs predicted cancer because they were the result of past exposure to carcinogens or because they were an intermediate end...... point in the pathway leading to disease. A nested case-control study was performed on 93 incident cancer cases and 62 deceased cancer cases coming from two prospective cohort studies performed in Nordic countries (Denmark, Finland, Norway, and Sweden) and Italy. For each case, four controls matched by...... compared to those with a low level in the Nordic cohort (odds ratio, 2.35; 95% confidence interval, 1.31-4.23) and in the Italian cohort (odds ratio, 2.66; 95% confidence interval, 1.26-5.62). These estimates were not affected by the inclusion of occupational exposure level and smoking habit in the...

  12. Understanding the gender disparity in bladder cancer risk: The impact of sex hormones and liver on bladder susceptibility to carcinogens

    OpenAIRE

    Zhang, Yuesheng

    2013-01-01

    It has long been known that bladder cancer (BC) incidence is approximately 4-fold higher in men than in women in the US, and a similar disparity also exists in other countries. The reason for this phenomenon is not known, which impedes progress in BC prevention. However, BC incidence is also significantly higher in male animals than in their female counterparts after treatment with aromatic amines, which are principal human bladder carcinogens. These animal studies and related studies in the ...

  13. Transplacental carcinogenicity of inorganic arsenic in the drinking water: induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice

    International Nuclear Information System (INIS)

    Arsenic is a known human carcinogen, but development of rodent models of inorganic arsenic carcinogenesis has been problematic. Since gestation is often a period of high sensitivity to chemical carcinogenesis, we performed a transplacental carcinogenicity study in mice using inorganic arsenic. Groups (n=10) of pregnant C3H mice were given drinking water containing sodium arsenite (NaAsO2) at 0 (control), 42.5, and 85 ppm arsenite ad libitum from day 8 to 18 of gestation. These doses were well tolerated and body weights of the dams during gestation and of the offspring subsequent to birth were not reduced. Dams were allowed to give birth, and offspring were weaned at 4 weeks and then put into separate gender-based groups (n=25) according to maternal exposure level. The offspring received no additional arsenic treatment. The study lasted 74 weeks in males and 90 weeks in females. A complete necropsy was performed on all mice and tissues were examined by light microscopy in a blind fashion. In male offspring, there was a marked increase in hepatocellular carcinoma incidence in a dose- related fashion (control, 12%; 42.5 ppm, 38%; 85 ppm, 61%) and in liver tumor multiplicity (tumors per liver; 5.6-fold over control at 85 ppm). In males, there was also a dose-related increase in adrenal tumor incidence and multiplicity. In female offspring, dose-related increases occurred in ovarian tumor incidence (control, 8%; 42.5 ppm, 26%; 85 ppm, 38%) and lung carcinoma incidence (control, 0%; 42.5 ppm, 4%; 85 ppm, 21%). Arsenic exposure also increased the incidence of proliferative lesions of the uterus and oviduct. These results demonstrate that oral inorganic arsenic exposure, as a single agent, can induce tumor formation in rodents and establishes inorganic arsenic as a complete transplacental carcinogen in mice. The development of this rodent model of inorganic arsenic carcinogenesis has important implications in defining the mechanism of action for this common environmental

  14. Vinyl carbamate epoxide, a major strong electrophilic, mutagenic and carcinogenic metabolite of vinyl carbamate and ethyl carbamate (urethane).

    Science.gov (United States)

    Park, K K; Liem, A; Stewart, B C; Miller, J A

    1993-03-01

    Vinyl carbamate epoxide (VCO) was found to possess strong electrophilic, mutagenic and carcinogenic activities. It reacted with water at 37 degrees C and pH 7.4 (phosphate buffer) to form glycolaldehyde and several related reducing compounds; none of these products were mutagenic for Salmonella typhimurium TA1535. Under these conditions VCO had a half-life (determined chemically and mutagenically) of approximately 10.5 min. This half-life was progressively lowered by increasing concentrations of chloride ion (liver, serum and isotonic levels). This ion reacted with VCO to form chloroacetaldehyde. VCO also reacted with other nucleophiles such as glutathione, DNA and its constituent guanine and adenine bases. The purine adducts formed by VCO in DNA in vitro and in vivo were released by weak acid treatment and consisted of 7-(2'-oxoethyl)guanine and N2,3-ethenoguanine as major products with 1,N6-ethenoadenine as a minor product. VCO was a strong direct mutagen in Salmonella typhimurium TA1535 and TA100 but was only weakly active in the TA98 mutant. VCO was a stronger initiator of carcinogenesis in the skin of CD-1 mice and in the liver of infant male B6C3F1 mice than its metabolic precursors vinyl carbamate (VC) and ethyl carbamate (EC). Unlike VC and EC, VCO was a strong complete carcinogen in the skin of CD-1 mice and induced papillomas and carcinomas following repetitive administration of sub-ulcerogenic doses. VCO also exhibited some carcinogenic activity in the lungs of mice and in the s.c. and mammary tissue of female Sprague-Dawley rats. These data and those from other recent studies support the conclusion that VCO is a major strong electrophilic, mutagenic and carcinogenic metabolite of EC and VC in the mouse. PMID:8453720

  15. Comparative carcinogenic potencies of particulates from diesel engine exhausts, coke oven emissions, roofing tar aerosols and cigarette smoke.

    OpenAIRE

    Albert, R E

    1983-01-01

    Mammalian cell mutagenesis, transformation and skin tumorigenesis assays show similar results in comparing the potencies of diesel, coke oven, roofing tar and cigarette smoke particulates. These assay results are reasonably consistent with the comparative carcinogenic potencies of coke oven and roofing tar emissions as determined by epidemiological studies. The bacterial mutagenesis assay tends to show disproportionately high potencies, particularly with diesel particulates. Results to date e...

  16. Review of carcinogenicity of asbestos and proposal of approval standards of an occupational cancer caused by asbestos in Korea

    OpenAIRE

    Im, Sanghyuk; Youn, Kan-woo; Shin, Donghee; Lee, Myeoung-jun; Choi, Sang-Jun

    2015-01-01

    Carcinogenicity of asbestos has been well established for decades and it has similar approval standards in most advanced countries based on a number of studies and international meetings. However, Korea has been lagging behind such international standards. In this study, we proposed the approval standards of an occupational cancer due to asbestos through intensive review on the Helsinki Criteria, post-Helsinki studies, job exposure matrix (JEM) based on the analysis of domestic reports and re...

  17. Ultrafine particles are not major carriers of carcinogenic PAHs and their genotoxicity in size-segregated aerosols

    Czech Academy of Sciences Publication Activity Database

    Topinka, Jan; Milcová, Alena; Schmuczerová, Jana; Kroužek, J.; Hovorka, J.

    2013-01-01

    Roč. 754, 1-2 (2013), s. 1-6. ISSN 1383-5718 R&D Projects: GA ČR(CZ) GAP503/11/0142; GA ČR(CZ) GBP503/12/G147 Grant ostatní: MZP(CZ) SP/1A3/149/08 Institutional support: RVO:68378041 Keywords : Air pollution * Ultrafine particles * Carcinogenic PAHs Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 2.481, year: 2013

  18. Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells

    OpenAIRE

    West, Kip A.; Brognard, John; Clark, Amy S.; Linnoila, Ilona R.; Yang, Xiaowei; Swain, Sandra M.; Harris, Curtis; Belinsky, Steven; Dennis, Phillip A.

    2003-01-01

    Tobacco-related diseases such as lung cancer cause over 4.2 million deaths annually, with approximately 400,000 deaths per year occurring in the US. Genotoxic effects of tobacco components have been described, but effects on signaling pathways in normal cells have not been described. Here, we show activation of the serine/threonine kinase Akt in nonimmortalized human airway epithelial cells in vitro by two components of cigarette smoke, nicotine and the tobacco-specific carcinogen 4-(methylni...

  19. Toxicity of smokeless tobacco in human oral epithelium with emphasis on carcinogen metabolism and regulation of programmed cell death

    OpenAIRE

    Vondracek, Martin

    2002-01-01

    The oral mucosa is globally a common site for cancer development. Primary risk factors include tobacco smoking and alcohol consumption whereas the contribution from usage of smokeless tobacco remains debated. The susceptibility of the human oral epithelium to carcinogens in tobacco likely depends on the presence of biotransformation enzymes, capable of metabolically activating or detoxifying these agents as well opposing influences from oxidative stress. Induction of program...

  20. Evaluation of carcinogenic modes of action for pesticides in fruit on the Swedish market using a text-mining tool

    OpenAIRE

    Ilona eSilins; Anna eKorhonen; Ulla eStenius

    2014-01-01

    Toxicity caused by chemical mixtures has emerged as a significant challenge for toxicologists and risk assessors. Information on individual chemicals’ modes of action is an important part of the hazard identification step. In this study, an automatic text mining-based tool was employed as a method to identify the carcinogenic modes of action of pesticides frequently found in fruit on the Swedish market. The current available scientific literature on the 26 most common pesticides found in appl...

  1. Evaluation of carcinogenic modes of action for pesticides in fruit on the Swedish market using a text-mining tool

    OpenAIRE

    Silins, Ilona; Korhonen, Anna; Stenius, Ulla

    2014-01-01

    Toxicity caused by chemical mixtures has emerged as a significant challenge for toxicologists and risk assessors. Information on individual chemicals' modes of action is an important part of the hazard identification step. In this study, an automatic text mining-based tool was employed as a method to identify the carcinogenic modes of action of pesticides frequently found in fruit on the Swedish market. The current available scientific literature on the 26 most common pesticides found in appl...

  2. Specific growth stimulation by linoleic acid in hepatoma cell lines transfected with the target protein of a liver carcinogen.

    OpenAIRE

    Keler, T; Barker, C. S.; Sorof, S

    1992-01-01

    The hepatic carcinogen N-2-fluorenylacetamide (2-acetylaminofluorene) was shown previously to interact specifically with its target protein, liver fatty acid binding protein (L-FABP), early during hepatocarcinogenesis in rats. In search of the significance of the interaction, rat L-FABP cDNA in the sense and antisense orientations was transfected into a subline of the rat hepatoma HTC cell line that did not express L-FABP. After the transfections, the basal doubling times of the cells were no...

  3. Population variability in biological adaptive responses to DNA damage and the shapes of carcinogen dose-response curves

    International Nuclear Information System (INIS)

    Carcinogen dose-response curves for both ionizing radiation and chemicals are typically assumed to be linear at environmentally relevant doses. This assumption is used to ensure protection of the public health in the absence of relevant dose-response data. A theoretical justification for the assumption has been provided by the argument that low dose linearity is expected when an exogenous agent adds to an ongoing endogenous process. Here, we use computational modeling to evaluate (1) how two biological adaptive processes, induction of DNA repair and cell cycle checkpoint control, may affect the shapes of dose-response curves for DNA-damaging carcinogens and (2) how the resulting dose-response behaviors may vary within a population. Each model incorporating an adaptive process was capable of generating not only monotonic dose-responses but also nonmonotonic (J-shaped) and threshold responses. Monte Carlo analysis suggested that all these dose-response behaviors could coexist within a population, as the spectrum of qualitative differences arose from quantitative changes in parameter values. While this analysis is largely theoretical, it suggests that (a) accurate prediction of the qualitative form of the dose-response requires a quantitative understanding of the mechanism (b) significant uncertainty is associated with human health risk prediction in the absence of such quantitative understanding and (c) a stronger experimental and regulatory focus on biological mechanisms and interindividual variability would allow flexibility in regulatory treatment of environmental carcinogens without compromising human health

  4. Different mechanisms of modulation of gap junction communication by non-genotoxic carcinogens in rat liver in vivo

    International Nuclear Information System (INIS)

    This is a comparative study of the mechanisms by which three different rodent non-genotoxic carcinogens modulate connexin-mediated gap junction intercellular communication in male rat liver in vivo. In the case of the peroxisome proliferating agent Wy-14,643, a non-hepatotoxic dose of 50 mg/kg led to a marked loss of inter-hepatocyte dye transfer associated with a loss of both Cx32 and Cx26 protein expression. In contrast, p,p'-dichlorodiphenyltrichloroethane (DDT) at a non-hepatotoxic dose (25 mg/kg) was not found to alter Cx32 or Cx26 expression or to produce a measurable Cx32 serine phosphorylation but did give a small, significant reduction of cell communication. Carbon tetrachloride (CCl4) did not affect cell communication (despite a small significant reduction of Cx32 content) at a non-hepatotoxic dose. Both loss of communication and Cx32 expression was observed only at a dose that caused hepatocyte toxicity as evidenced by increased serum alanine aminotransferase activity. Overall, the findings emphasise that loss of gap junctional communication in vivo can contribute to carcinogenesis by non-genotoxic carcinogens through different primary mechanism. In contrast to Wy-14,643 and DDT, the results with CCl4 are consistent with a requirement for hepatotoxicity in its carcinogenic action

  5. Source apportionment of the carcinogenic potential of polycyclic aromatic hydrocarbons (PAH) associated to airborne PM10 by a PMF model.

    Science.gov (United States)

    Callén, M S; Iturmendi, A; López, J M; Mastral, A M

    2014-02-01

    In order to perform a study of the carcinogenic potential of polycyclic aromatic hydrocarbons (PAH), benzo(a)pyrene equivalent (BaP-eq) concentration was calculated and modelled by a receptor model based on positive matrix factorization (PMF). Nineteen PAH associated to airborne PM10 of Zaragoza, Spain, were quantified during the sampling period 2001-2009 and used as potential variables by the PMF model. Afterwards, multiple linear regression analysis was used to quantify the potential sources of BaP-eq. Five sources were obtained as the optimal solution and vehicular emission was identified as the main carcinogenic source (35 %) followed by heavy-duty vehicles (28 %), light-oil combustion (18 %), natural gas (10 %) and coal combustion (9 %). Two of the most prevailing directions contributing to this carcinogenic character were the NE and N directions associated with a highway, industrial parks and a paper factory. The lifetime lung cancer risk exceeded the unit risk of 8.7 x 10(-5) per ng/m(3) BaP in both winter and autumn seasons and the most contributing source was the vehicular emission factor becoming an important issue in control strategies. PMID:24022101

  6. Do cage effects influence tumor incidence? An examination of laboratory animal carcinogenicity studies utilizing Fischer 344 rats.

    Science.gov (United States)

    Haseman, J K

    1988-08-01

    Approximately 125 carcinogenicity studies in Fischer 344 rats conducted by the National Toxicology Program (NTP) were examined to determine the frequency with which cage effects were associated with observed carcinogenic responses. All studies involving groups of 50 rats housed five per cage and showing evidence of chemically-related carcinogenicity were considered. For each of these experiments, two statistical analyses were carried out for each dosed and control group: (i) a test to determine whether or not the occurrence of tumors clustered within cages; and (ii) an evaluation to determine whether or not tumor incidences differed significantly between differing cage shelf levels. These analyses showed that the numbers of statistically significant (P less than 0.05 or P less than 0.01) effects were consistent with the number expected by chance alone. Thus, cage-related factors appeared to have little or no impact upon tumor incidence in these particular studies. Experimental design protocols now used by the NTP (which include random assignment of animals to cages; random assignment of columns of cages to dosed and control groups; and periodic rotation of cage location) further reduce the likelihood that factors associated with the housing of the animals could influence tumor incidence in current studies. PMID:3183292

  7. Amplification of SV40 and cellular genes in SV40 transformed Chinese hamster embryo cells treated with chemical carcinogens

    International Nuclear Information System (INIS)

    To study the effect of chemical carcinogens on the amplification of specific genes, we have constructed a model system, utilizing integrated SV40 as an example for an endogenous gene. Recently, we have shown that exposure of SV40 transformed Chinese hamster cells to a variety of carcinogens induced the amplification of the integrated SV40 genome. Functional T-antigen was necessary for the amplification phenomenon. The work presented in this manuscript shows that the functional origin of replication, which consists of the sequences at the origin of replication and an active T-antigen, is required for the amplification. Utilizing cloned SV40 inserts and the adjacent Chinese hamster sequences we were able to show that SV40 and the flanking cellular sequences were amplified. As the distance from the SV40 origin of replication increased, the extent of amplification was decreased. The amplified sequences are associated with both chromosomal and extrachromosomal sequences. Carcinogen-mediated amplification is not restricted to SV40 sequences and endogenous genes such as dehydrofolate reductase (dhfr), the histocompatibility gene (HLA) and c-ras/sup Ha/ gene are amplified. 26 references, 5 figures

  8. Characterisation of particulates and carcinogenic polycyclic aromatic hydrocarbons in wintertime wood-fired heating in residential areas

    Science.gov (United States)

    Bari, Md. Aynul; Baumbach, Guenter; Brodbeck, Johannes; Struschka, Michael; Kuch, Bertram; Dreher, Werner; Scheffknecht, Guenter

    2011-12-01

    Wood as a renewable and worldwide available fuel is used for residential heating in small-scale firings during winter. This wood combustion can cause very high emissions of inhalable particles resulting in short and long-term health effects. The target of this study was to characterise particulate matter, emissions of polycyclic aromatic hydrocarbons (PAHs) and their size distribution and to show that those emissions can be found in the ambient air of residential areas with wood-fired heating. Emission samples were collected from pellet stove and log wood boiler under different combustion conditions. Ambient PM 10 sampling was performed during two winter seasons at two rural residential areas near Stuttgart in Germany. Samples were extracted using toluene with ultrasonic bath and analysed by gas chromatography mass spectrometry (GC-MS). Twenty-one PAH compounds including nine carcinogenic ones were detected and quantified. It was found that emission concentrations of carcinogenic PAHs were higher during incomplete combustion compared to complete combustion. Significant amounts of ambient PAHs were found in the residential villages, where the contribution of carcinogenic PAHs was 44% of total PAHs in the ambient air during winter 2009. The morphology and elemental analysis of ambient particles were also investigated. The findings indicate a rising concern to reduce emissions from wood-fired heating during winter in residential areas and underline the importance of using good wood combustion technologies to improve the air quality.

  9. Enhancements of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism and carcinogenic risk via NNK/arsenic interaction

    International Nuclear Information System (INIS)

    Epidemiological studies indicated an enhancement of cigarette smoke-induced carcinogenicity, including hepatocellular carcinoma, by arsenic. We believe that arsenic will enhance the expression of hepatic CYP2A enzyme and NNK metabolism (a cigarette smoke component), thus its metabolites, and carcinogenic DNA adducts. Male ICR mice were exposed to NNK (0.5 mg/mouse) and sodium arsenite (0, 10, or 20 mg/kg) daily via gavaging for 10 days and their urine was collected at day 10 for NNK metabolite analysis. Liver samples were also obtained for CYP2A enzyme and DNA adducts evaluations. Both the cyp2a4/5 mRNA levels and the CYP2A enzyme activity were significantly elevated in arsenic-treated mice liver. Furthermore, urinary NNK metabolites in NNK/arsenic co-treated mice also increased compared to those treated with NNK alone. Concomitantly, DNA adducts (N7-methylguanine and O6-methylguanine) were significantly elevated in the livers of mice co-treated with NNK and arsenic. Our findings provide clear evidence that arsenic increased NNK metabolism by up-regulation of CYP2A expression and activity leading to an increased NNK metabolism and DNA adducts (N7-methylguanine and O6-methylguanine). These findings suggest that in the presence of arsenic, NNK could induce greater DNA adducts formation in hepatic tissues resulting in higher carcinogenic potential

  10. [MATline, a job-exposure matrix for the prevision of exposure to carcinogens: new functions and potential applications].

    Science.gov (United States)

    Falcone, Umberto; Gilardi, Luisella; Santoro, Silvano; Orengia, Manuela; Marighella, Massimo; Coffano, Maria Elena

    2013-01-01

    MATline, the job-exposure matrix for carcinogenic agents, is a data bank free accessible online. It provides data as classification and toxicological properties of carcinogenic agents, and a list of industrial processes with potential exposure to each carcinogen agent, and an up-to-date estimation of the number of activities and workers related to the industrial process on Regional basis. It also lists the target organs for which a causal relationship with the agent has been established. MATline was recently updated with the new classifications introduced by Regulation EC No. 1272/2008 (CLP). The Authorisation List or the Restriction of the Registration, Evaluation, Authorization of Chemicals (REACh) regulation specifically mark chemicals. The matrix is helpful for professionals in the public health sector to identify in advance the potential sources of exposure, and prioritise intervention plans; for occupational physicians to help identifying causes of occupational cancer cases; for health professionals in the private sector to address chemical risks; for company physicians to validate health surveillance plans; for trade unions to independently check formation contents provided to workers potentially exposed to such risks. PMID:23585435

  11. Potent Methyl Oxidation of 5-Methyl-2′-deoxycytidine by Halogenated Quinoid Carcinogens and Hydrogen Peroxide via a Metal-independent Mechanism

    OpenAIRE

    Shao, Jie; Huang, Chun-Hua; Kalyanaraman, Balaraman; Zhu, Ben-Zhan

    2013-01-01

    Halogenated quinones are a class of carcinogenic intermediates and newly identified chlorination disinfection byproducts in drinking water. We found recently that the highly reactive and biologically important hydroxyl radical (•OH) can be produced by halogenated quinones and H2O2 independent of transition metal ions. However, it is not clear whether these quinoid carcinogens and H2O2 can oxidize the nucleoside 5-methyl-2′-deoxycytidine (5mdC) to its methyl oxidation prod...

  12. Polycyclic aromatic hydrocarbon-DNA adducts in cervix of women infected with carcinogenic human papillomavirus types: An immunohistochemistry study

    Energy Technology Data Exchange (ETDEWEB)

    Pratt, M. Margaret [Carcinogen-DNA Interactions Section, LCBG, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD (United States)], E-mail: prattm@mail.nih.gov; Sirajuddin, Paul; Poirier, Miriam C. [Carcinogen-DNA Interactions Section, LCBG, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD (United States); Schiffman, Mark [Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD (United States); Glass, Andrew G.; Scott, David R.; Rush, Brenda B. [Northwest Kaiser Permanente, Portland, OR (United States); Olivero, Ofelia A. [Carcinogen-DNA Interactions Section, LCBG, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD (United States); Castle, Philip E. [Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD (United States)

    2007-11-01

    Among women infected with carcinogenic human papillomavirus (HPV), there is a two- to five-fold increased risk of cervical precancer and cancer in women who smoke compared to those who do not smoke. Because tobacco smoke contains carcinogenic polycyclic aromatic hydrocarbons (PAHs), it was of interest to examine human cervical tissue for PAH-DNA adduct formation. Here, we measured PAH-DNA adduct formation in cervical biopsies collected in follow-up among women who tested positive for carcinogenic HPV at baseline. A semi-quantitative immunohistochemistry (IHC) method using antiserum elicited against DNA modified with r7,t8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) was used to measure nuclear PAH-DNA adduct formation. Cultured human cervical keratinocytes exposed to 0, 0.153, or 0.331 {mu}M BPDE showed dose-dependent increases in r7,t8,t9-trihydroxy-c-10-(N{sup 2}deoxyguanosyl)-7,8,9, 10-tetrahydro-benzo[a]pyrene (BPdG) adducts. For BPdG adduct analysis, paraffin-embedded keratinocytes were stained by IHC with analysis of nuclear color intensity by Automated Cellular Imaging System (ACIS) and, in parallel cultures, extracted DNA was assayed by quantitative BPDE-DNA chemiluminescence immunoassay (CIA). For paraffin-embedded samples from carcinogenic HPV-infected women, normal-appearing cervical squamous epithelium suitable for scoring was found in samples from 75 of the 114 individuals, including 29 cases of cervical precancer or cancer and 46 controls. With a lower limit of detection of 20 adducts/10{sup 8} nucleotides, detectable PAH-DNA adduct values ranged from 25 to 191/10{sup 8} nucleotides, with a median of 75/10{sup 8} nucleotides. PAH-DNA adduct values above 150/10{sup 8} nucleotides were found in eight samples, and in three samples adducts were non-detectable. There was no correlation between PAH-DNA adduct formation and either smoking or case status. Therefore, PAH-DNA adduct formation as measured by this methodology did not appear

  13. Polycyclic aromatic hydrocarbon-DNA adducts in cervix of women infected with carcinogenic human papillomavirus types: An immunohistochemistry study

    International Nuclear Information System (INIS)

    Among women infected with carcinogenic human papillomavirus (HPV), there is a two- to five-fold increased risk of cervical precancer and cancer in women who smoke compared to those who do not smoke. Because tobacco smoke contains carcinogenic polycyclic aromatic hydrocarbons (PAHs), it was of interest to examine human cervical tissue for PAH-DNA adduct formation. Here, we measured PAH-DNA adduct formation in cervical biopsies collected in follow-up among women who tested positive for carcinogenic HPV at baseline. A semi-quantitative immunohistochemistry (IHC) method using antiserum elicited against DNA modified with r7,t8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) was used to measure nuclear PAH-DNA adduct formation. Cultured human cervical keratinocytes exposed to 0, 0.153, or 0.331 μM BPDE showed dose-dependent increases in r7,t8,t9-trihydroxy-c-10-(N2deoxyguanosyl)-7,8,9, 10-tetrahydro-benzo[a]pyrene (BPdG) adducts. For BPdG adduct analysis, paraffin-embedded keratinocytes were stained by IHC with analysis of nuclear color intensity by Automated Cellular Imaging System (ACIS) and, in parallel cultures, extracted DNA was assayed by quantitative BPDE-DNA chemiluminescence immunoassay (CIA). For paraffin-embedded samples from carcinogenic HPV-infected women, normal-appearing cervical squamous epithelium suitable for scoring was found in samples from 75 of the 114 individuals, including 29 cases of cervical precancer or cancer and 46 controls. With a lower limit of detection of 20 adducts/108 nucleotides, detectable PAH-DNA adduct values ranged from 25 to 191/108 nucleotides, with a median of 75/108 nucleotides. PAH-DNA adduct values above 150/108 nucleotides were found in eight samples, and in three samples adducts were non-detectable. There was no correlation between PAH-DNA adduct formation and either smoking or case status. Therefore, PAH-DNA adduct formation as measured by this methodology did not appear related to the increased risk of

  14. Assessment of the carcinogenic N-nitrosodiethanolamine in tobacco products and tobacco smoke

    International Nuclear Information System (INIS)

    A simple, reproducible gas chromatography-thermal energy analyzer (g.c.-TEA) method has been developed for the analysis of N-nitrosodiethanolamine (NDELA) in tobacco and tobacco smoke. The extract of tobacco or the trapped particulates of tobacco smoke are chromatographed on silica gel. The NDELA containing fractions are concentrated, silylated and analyzed with a modified g.c.-TEA system. [/sup 14/C]NDELA serves as internal standard for the quantitative analysis. Experimental cigarettes made from tobaccos which were treated with the sucker growth inhibitor maleic hydrazidediethanolamine (MH-DELA) contained 115--420 p.p.b. of NDELA and their smoke contained 20--290 ng/cigarette, whereas hand-suckered tobacco and its smoke were free of NDELA. The tobacco of US smoking products contained 115--420 p.p.b. of NDELA and the mainstream smoke from such products yielded 10--68 ng/cigar or cigarette. NDELA levels in chewing tobacco ranged from 220--280 p.p.b. and in two commercial snuff products were 3,200 and 6,800 p.p.b. Although the five analyzed MH-DELA preparations contained between 0.6--1.9 p.p.m. NDELA it is evident that the major portion of NDELA in tobacco is formed from the DELA residue during the tobacco processing. Based on bioassay data from various laboratories which have shown that NDELA is a relatively strong carcinogen and based on the results of this study the use of MH-DELA for the cultivation of tobacco is questioned

  15. Investigations into the mechanisms of aflatoxin B1 genotoxicity and carcinogenicity

    International Nuclear Information System (INIS)

    Aflatoxin B1 (AFB1) was used as a model carcinogen for investigations into the initiation, promotion and progression phases of chemically induced carcinogenesis. In initial experiments 3H-AFB1 was evaluated for its rate of tritium exchange in vitro and in vivo. Tritium exchange form 3H-AFB1 to water in vitro (pH 7.4, 37 degree C) and in-vivo from covalently bound AFB1 had a half-life of ∼1 week. The physical interaction of AFB1 with DNA was examined to further characterize the steps involved in initiation. Using Nuclear Magnetic Resonance spectroscopy it was established that AFB1 binds to the outside of the DNA double helix and does not intercalate between the base pairs in spite of its relatively planar structure. In contrast to results obtained from NMR experiments, AFB1 and AFM1 were found to be direct acting mutagens in the Ames test and strain sensitivity indicated the direct mutagenicity was a result of a frameshift mutation suggesting intercalation. To determine if a free radical mechanism was converting the parent compound to a mutagenic derivative, the effect of the free radical inhibitor, butylated hydroxytoluene (BHT), on the mutagenicity of AFB1 to Salmonella typhimurium TA98 was determined. DNA sequences believed responsible for reversion of different Salmonella typhimurium strains were compared to the direct mutagenicity of AFB1 in these strains and with the rules reported in the literature for the sequence specific covalent binding of AFB1. An alternative mechanism for the metabolic activation of AFB1 and AFM1 to genotoxic metabolites was investigated

  16. The relevance of radiation induced bystander effects for low dose radiation carcinogenic risk

    International Nuclear Information System (INIS)

    Full text: Where epidemiology studies lack the ability to prescribe radiation doses, customise sample sizes and replicate findings, radiobiology experiments provide greater flexibility to control experimental conditions. This control simplifies the process of answering questions concerning carcinogenic risk after low dose radiation exposures. However, the flexibility requires critical evaluation of radiobiology findings to ensure that the right questions are being asked, the experimental conditions are relevant to human exposure scenarios and that the data are cautiously interpreted in the context of the experimental model. In particular, low dose radiobiology phenomena such as adaptive responses, genomic instability and bystander effects need to be investigated thoroughly, with continual reference to the way these phenomena might occur in the real world. Low dose radiation induced bystander effects are of interest since their occurrence in vivo could complicate the shape of the radiation dose-response curve in the low dose range for a number of biological endpoints with subsequent effects on radiation-induced cancer risk. Conversely, radiation-induced abscopal effects implicate biological consequences of radiation exposure outside irradiated volumes, and complicate the notion of effective dose calculations. Achieving a consensus on the boundaries that distinguish the radiobiology phenomena of bystander and abscopal effects will aid progress towards understanding their relevance to in vivo radiation exposures. A proposed framework for discussing bystander effects and abscopal effects in their appropriate context will be outlined, with a discussion on the future investigation of radiation-induced bystander effects. Such frameworks can assist the integration of results from experimental radiobiology to risk evaluation and management practice. This research was funded by the Low Dose Radiation Research Program, BioI. and Environ. Research, US Dept. of Energy, Grant DE

  17. Roles of human sulfotransferases in genotoxicity of carcinogens using genetically engineered umu test strains.

    Science.gov (United States)

    Oda, Yoshimitsu; Zhang, Yu; Buchinger, Sebastian; Reifferscheid, Georg; Yang, Min

    2012-03-01

    Human sulfotransferase (SULT) 1A1, 1A2, and 1A3 cDNA genes were subcloned separately into the pTrc99A(KM) vector. The generated plasmids were introduced into the Salmonella typhimurium O-acetyltransferase-deficient strain NM6000 (TA1538/1,8-DNP/pSK1002), resulting in the new strains NM7001, NM7002, and NM7003. We compared the sensitivities of these three strains with the parental strain NM7000 against 51 chemicals including aromatic amines, nitroarenes, alkenylbenzenes, estrogens-like chemicals, and other compounds with and without S9 mix by making use of the umu test system that is based on the bacterial SOS induction. 2-Amino-6-methyl-dipyrido[1,2-α:3',2'-d]imidazole, 3-methoxy-4-aminoazobenzene, 3-nitrobenzanthrone, 5-nitroacenaphthene, and 3,9-dinitrofluoranthene caused high genotoxicity in the NM7001 strain. The genotoxic effects of 2-aminofluorene, 2-acetylaminofluorene, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 2-nitrofluorene, 1-nitropyrene, and 2-nitropropane were stronger in the NM7002 strain compared with the NM7001 and NM7003 strains. Among the tested benzylic and allylic compounds, 1-hydroxymethylpyrene was detected in the NM7001 strain with the highest sensitivity. Estragole and 1'-hydroxysafrole exhibited strong genotoxicity in the NM7003 strain. The estrogen-like chemicals such as bisphenol A, genistein, p,n-nonylphenol, and 4-hydroxytamoxifen were not detected as genotoxins in any strain used. Collectively, the present results suggest that the generated test strains are valuable tools in order to elucidate the role of SULT enzymes in the bioactivation of chemicals to environmental carcinogens. PMID:22072630

  18. Investigations into the mechanisms of aflatoxin B sub 1 genotoxicity and carcinogenicity

    Energy Technology Data Exchange (ETDEWEB)

    Olsen, H.E.

    1989-01-01

    Aflatoxin B{sub 1} (AFB{sub 1}) was used as a model carcinogen for investigations into the initiation, promotion and progression phases of chemically induced carcinogenesis. In initial experiments {sup 3}H-AFB{sub 1} was evaluated for its rate of tritium exchange in vitro and in vivo. Tritium exchange form {sup 3}H-AFB{sub 1} to water in vitro (pH 7.4, 37{degree}C) and in-vivo from covalently bound AFB{sub 1} had a half-life of {approx}1 week. The physical interaction of AFB{sub 1} with DNA was examined to further characterize the steps involved in initiation. Using Nuclear Magnetic Resonance spectroscopy it was established that AFB{sub 1} binds to the outside of the DNA double helix and does not intercalate between the base pairs in spite of its relatively planar structure. In contrast to results obtained from NMR experiments, AFB{sub 1} and AFM{sub 1} were found to be direct acting mutagens in the Ames test and strain sensitivity indicated the direct mutagenicity was a result of a frameshift mutation suggesting intercalation. To determine if a free radical mechanism was converting the parent compound to a mutagenic derivative, the effect of the free radical inhibitor, butylated hydroxytoluene (BHT), on the mutagenicity of AFB{sub 1} to Salmonella typhimurium TA98 was determined. DNA sequences believed responsible for reversion of different Salmonella typhimurium strains were compared to the direct mutagenicity of AFB{sub 1} in these strains and with the rules reported in the literature for the sequence specific covalent binding of AFB{sub 1}. An alternative mechanism for the metabolic activation of AFB{sub 1} and AFM{sub 1} to genotoxic metabolites was investigated.

  19. The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report

    International Nuclear Information System (INIS)

    Since tacrolimus ointment was approved by the U.S. Food and Drug Administration (FDA) as a promising treatment for atopic dermatitis, it has been approved in more than 30 additional countries, including numerous European Union member nations. Moreover, in the current clinical routine the use of this drug is no longer restricted to the approved indication, but has been extended to a wide variety of inflammatory skin diseases including some with the potential of malignant transformation. So far, the side-effects reported from the topical use of tacrolimus have been relatively minor (e.g. burning, pruritus, erythema). Recently, however, the FDA reviewed the safety of topical tacrolimus, which resulted in a warning that the use of calcineurin inhibitors may be associated with an increased risk of cancer. Oral lichen planus (OLP) was diagnosed in a 56-year-old women in February 1999. After several ineffective local and systemic therapeutic measures an off-label treatment of this recalcitrant condition using Tacrolimus 0.1% ointment was initiated in May 2002. After a few weeks of treatment most of the lesions ameliorated, with the exception of the plaques on the sides of the tongue. Nevertheless, the patient became free of symptoms which, however, reoccurred once tacrolimus was weaned, as a consequence treatment was maintained. In April 2005, the plaques on the left side of the tongue appeared increasingly compact and a biopsy specimen confirmed the suspected diagnosis of an oral squamous cell carcinoma. The suspected causal relationship between topical use of tacrolimus and the development of a squamous cell carcinoma prompted us to test the notion that the carcinogenicity of tacrolimus may go beyond mere immune suppression. To this end, tacrolimus has been shown to have an impact on cancer signalling pathways such as the MAPK and the p53 pathway. In the given case, we were able to demonstrate that these pathways had also been altered subsequent to tacrolimus therapy

  20. A Comparative Survey on Parameters Influencing on Hexavalent Chromium Measurement as an Occupational Carcinogen

    Directory of Open Access Journals (Sweden)

    A. Tirgar

    2008-07-01

    Full Text Available Introduction & Objective: Hexavalent chromium, Cr+6, is a very harmful pollutant and a relatively unstable compound that is present in many industries. It is a known human respiratory carcinogen and occupational exposure to this chemical is associated with different health hazards. The purpose of this study was to evaluate the effects of four parameters including: type of sampling head, sampling height from the surface of electroplating solution, sampling duration, and sample storage duration on Cr+6 mist monitoring.Materials & Methods: To evaluate the influence of the main parameters as an experimental study, the 24 factorial design was applied at constant electroplating condition. A chromium electroplating bath with the ability to produce homogenous mist was used to create Cr+6 mist in laboratory setting. The National Institute for Occupational Safety and Health (NIOSH method 7600 was used to determine the Cr+6 concentration. Results: The results of 48 Cr+6 mist samples showed that Cr+6 concentration was higher: (1 for sampling by closed-face filter cassettes than for sampling by open-face filter cassettes (P<0.001; (2 for samples collected at 35 cm above the electroplating solution surface than for samples collected at 50 cm (P <0.001; (3 for sampling duration of 30 minutes than for sampling duration of 180 minutes (P <0.001; and, (4 for samples extracted immediately after sampling than for samples with delayed extraction (24 hours after sampling (P <0.001. Conclusion: It is concluded that the accuracy of Cr+6 mist sampling in electroplating shops will be enhanced when: (1 a closed-face filter cassette is used to prevent liquid splash contamination; (2 the sampling height is suitable as determined by further research; (3 the sampling duration is short (approximately 30 minutes; and, (4 the extraction of the Cr+6 sample is performed as soon as the sampling is completed.

  1. Chemomodulation of carcinogen metabolising enzymes, antioxidant profiles and skin and forestomach papillomagenesis by Spirulina platensis.

    Science.gov (United States)

    Dasgupta, T; Banejee, S; Yadav, P K; Rao, A R

    2001-10-01

    Numerous reports have revealed an inverse association between consumption of some selective natural products and risk of developing cancer. In the present study the effect of 250 and 500 mg/kg body wt. of Spirulina was examined on drug metabolising phase I and phase II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation in the liver of 7-week-old Swiss albino mice. The implications of these biochemical alterations have been further evaluated adopting the protocol of benzo(a)pyrene induced forestomach and 7,12 dimethylbenz(a)anthracene (DMBA) initiated and croton oil promoted skin papillomagenesis. Our primary findings reveal the 'Monofunctional' nature of Spirulina as deduced from its potential to induce only the phase II enzyme activities associated mainly with carcinogen detoxification. The glutathione S-transferase and DT-diaphorase specific activities were induced in hepatic and all the extrahepatic organs examined (lung, kidney and forestomach) by Spirulina pretreatment (significance level being from p < 0.05 to p < 0.005) except for the low dose treatment in forestomach. With reference to antioxidant enzymes viz., superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and reduced glutathione were increased significantly by both the chosen doses of Spirulina from p < 0.01 to p < 0.005. Chemopreventive response was quantitated by the average number of papillomas per effective mouse (tumor burden) as well as percentage of tumor bearing animals. There was a significant inhibition of tumor burden as well as tumor incidence in both the tumor model systems studied. In the skin tumor studies tumor burden was reduced from 4.86 to 1.20 and 1.15 by the low and high dose treatment respectively. In stomach tumor studies tumor burden was 2.05 and 1.73 by the low and high doses of Spirulina treatment against 3.73 that of control. PMID:11768236

  2. Lung cancer incidence decreases with elevation: evidence for oxygen as an inhaled carcinogen

    Directory of Open Access Journals (Sweden)

    Kamen P. Simeonov

    2015-01-01

    Full Text Available The level of atmospheric oxygen, a driver of free radical damage and tumorigenesis, decreases sharply with rising elevation. To understand whether ambient oxygen plays a role in human carcinogenesis, we characterized age-adjusted cancer incidence (compiled by the National Cancer Institute from 2005 to 2009 across counties of the elevation-varying Western United States and compared trends displayed by respiratory cancer (lung and non-respiratory cancers (breast, colorectal, and prostate. To adjust for important demographic and cancer-risk factors, 8–12 covariates were considered for each cancer. We produced regression models that captured known risks. Models demonstrated that elevation is strongly, negatively associated with lung cancer incidence (p < 10−16, but not with the incidence of non-respiratory cancers. For every 1,000 m rise in elevation, lung cancer incidence decreased by 7.23 99% CI [5.18–9.29] cases per 100,000 individuals, equivalent to 12.7% of the mean incidence, 56.8. As a predictor of lung cancer incidence, elevation was second only to smoking prevalence in terms of significance and effect size. Furthermore, no evidence of ecological fallacy or of confounding arising from evaluated factors was detected: the lung cancer association was robust to varying regression models, county stratification, and population subgrouping; additionally seven environmental correlates of elevation, such as exposure to sunlight and fine particulate matter, could not capture the association. Overall, our findings suggest the presence of an inhaled carcinogen inherently and inversely tied to elevation, offering epidemiological support for oxygen-driven tumorigenesis. Finally, highlighting the need to consider elevation in studies of lung cancer, we demonstrated that previously reported inverse lung cancer associations with radon and UVB became insignificant after accounting for elevation.

  3. A simple procedure for estimating pseudo risk ratios from exposure to non-carcinogenic chemical mixtures.

    Science.gov (United States)

    Scinicariello, Franco; Portier, Christopher

    2016-03-01

    Non-cancer risk assessment traditionally assumes a threshold of effect, below which there is a negligible risk of an adverse effect. The Agency for Toxic Substances and Disease Registry derives health-based guidance values known as Minimal Risk Levels (MRLs) as estimates of the toxicity threshold for non-carcinogens. Although the definition of an MRL, as well as EPA reference dose values (RfD and RfC), is a level that corresponds to "negligible risk," they represent daily exposure doses or concentrations, not risks. We present a new approach to calculate the risk at exposure to specific doses for chemical mixtures, the assumption in this approach is to assign de minimis risk at the MRL. The assigned risk enables the estimation of parameters in an exponential model, providing a complete dose-response curve for each compound from the chosen point of departure to zero. We estimated parameters for 27 chemicals. The value of k, which determines the shape of the dose-response curve, was moderately insensitive to the choice of the risk at the MRL. The approach presented here allows for the calculation of a risk from a single substance or the combined risk from multiple chemical exposures in a community. The methodology is applicable from point of departure data derived from quantal data, such as data from benchmark dose analyses or from data that can be transformed into probabilities, such as lowest-observed-adverse-effect level. The individual risks are used to calculate risk ratios that can facilitate comparison and cost-benefit analyses of environmental contamination control strategies. PMID:25667015

  4. DNA repair in mammalian cells exposed to combinations of carcinogenic agents

    International Nuclear Information System (INIS)

    Cells defective in one or more aspects of repair are killed and often mutagenized more readily than normal cells by DNA damaging agents, and humans whose cells are deficient in repair are at an increased carcinogenic risk compared to normal individuals. The excision repair of uv induced pyrimidine dimers is a well studied system, but the details of the steps in this repair system are far from being understood in human cells. We know that there are a number of chemicals that mimic uv in that normal human cells repair DNA damage from both these agents and from uv by a long patch excision repair system, and that xeroderma pigmentosum cells defective in repair of uv are also defective in the repair of damage from these chemicals. The chemicals we have investigated are AAAF, 4-NQO, DMBA-epoxide, and ICR-170. We describe experiments, using several techniques, in which DNA excision repair is measured after treatment of various human cell strains with combinations of uv and these agents. If two agents have a common rate limiting step then, at doses high enough to saturate the repair system, one would expect the observed repair after a treatment with a combination of agents to be equal to that from one agent alone. Such is not the case for normal human or excision-deficient XP cells. In the former repair is additive and in the latter repair is usually appreciably less than that observed with either agent alone. Models that attempt to explain these surprising results involve complexes of enzymes and cofactors

  5. The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report

    Directory of Open Access Journals (Sweden)

    Vetter Claudia S

    2006-01-01

    Full Text Available Abstract Background Since tacrolimus ointment was approved by the U.S. Food and Drug Administration (FDA as a promising treatment for atopic dermatitis, it has been approved in more than 30 additional countries, including numerous European Union member nations. Moreover, in the current clinical routine the use of this drug is no longer restricted to the approved indication, but has been extended to a wide variety of inflammatory skin diseases including some with the potential of malignant transformation. So far, the side-effects reported from the topical use of tacrolimus have been relatively minor (e.g. burning, pruritus, erythema. Recently, however, the FDA reviewed the safety of topical tacrolimus, which resulted in a warning that the use of calcineurin inhibitors may be associated with an increased risk of cancer. Case presentation Oral lichen planus (OLP was diagnosed in a 56-year-old women in February 1999. After several ineffective local and systemic therapeutic measures an off-label treatment of this recalcitrant condition using Tacrolimus 0.1% ointment was initiated in May 2002. After a few weeks of treatment most of the lesions ameliorated, with the exception of the plaques on the sides of the tongue. Nevertheless, the patient became free of symptoms which, however, reoccurred once tacrolimus was weaned, as a consequence treatment was maintained. In April 2005, the plaques on the left side of the tongue appeared increasingly compact and a biopsy specimen confirmed the suspected diagnosis of an oral squamous cell carcinoma. Conclusion The suspected causal relationship between topical use of tacrolimus and the development of a squamous cell carcinoma prompted us to test the notion that the carcinogenicity of tacrolimus may go beyond mere immune suppression. To this end, tacrolimus has been shown to have an impact on cancer signalling pathways such as the MAPK and the p53 pathway. In the given case, we were able to demonstrate that these

  6. Comparative genomics and proteomics of Helicobacter mustelae, an ulcerogenic and carcinogenic gastric pathogen

    LENUS (Irish Health Repository)

    O'Toole, Paul W

    2010-03-10

    Abstract Background Helicobacter mustelae causes gastritis, ulcers and gastric cancer in ferrets and other mustelids. H. mustelae remains the only helicobacter other than H. pylori that causes gastric ulceration and cancer in its natural host. To improve understanding of H. mustelae pathogenesis, and the ulcerogenic and carcinogenic potential of helicobacters in general, we sequenced the H. mustelae genome, and identified 425 expressed proteins in the envelope and cytosolic proteome. Results The H. mustelae genome lacks orthologs of major H. pylori virulence factors including CagA, VacA, BabA, SabA and OipA. However, it encodes ten autotransporter surface proteins, seven of which were detected in the expressed proteome, and which, except for the Hsr protein, are of unknown function. There are 26 putative outer membrane proteins in H. mustelae, some of which are most similar to the Hof proteins of H. pylori. Although homologs of putative virulence determinants of H. pylori (NapA, plasminogen adhesin, collagenase) and Campylobacter jejuni (CiaB, Peb4a) are present in the H. mustelae genome, it also includes a distinct complement of virulence-related genes including a haemagglutinin\\/haemolysin protein, and a glycosyl transferase for producing blood group A\\/B on its lipopolysaccharide. The most highly expressed 264 proteins in the cytosolic proteome included many corresponding proteins from H. pylori, but the rank profile in H. mustelae was distinctive. Of 27 genes shown to be essential for H. pylori colonization of the gerbil, all but three had orthologs in H. mustelae, identifying a shared set of core proteins for gastric persistence. Conclusions The determination of the genome sequence and expressed proteome of the ulcerogenic species H mustelae provides a comparative model for H. pylori to investigate bacterial gastric carcinogenesis in mammals, and to suggest ways whereby cag minus H. pylori strains might cause ulceration and cancer. The genome sequence was

  7. Temporal aspects of tumorigenic response to individual and mixed carcinogens. Comprehensive progress report, June 1, 1975--May 31, 1978. [Mouse skin, rats, hamsters

    Energy Technology Data Exchange (ETDEWEB)

    Albert, R.E.; Burns, F.J.; Altshuler, B.

    1978-02-01

    The research proposed here is designed to obtain a better understanding of the temporal kinetics of tumor induction when one or more carcinogens are present simultaneously or sequentially for prolonged periods of time. Studies done to date under this contract have shown that carcinogenesis in mouse skin by polycyclic aromatic hydrocarbon carcinogens is consistent with the induction of dependent and autonomous cell transformations by the carcinogen followed by the conversion of autonomous tumor cells into malignancies at a rate which is determined by the level of carcinogen exposure. Dependent cell transformations remain latent in the skin unless expressed by a promoting agent. Dependent neoplasia appears to follow one-hit kinetics while malignancy is a multihit endpoint. Dose-related and time-related aspects of tumor induction are separable in the initiation-promotion system of mouse skin which along with rat skin and hamster lung is being used as a model for testing hypotheses. Results to date provide the basis for a new interpretation of the linear non-threshold extrapolation model. The broad aim of the study is to provide a basis or rationale for estimating risks associated with prolonged exposures to carcinogens found in the environment and to predict how different tissues and species respond to the same carcinogens.

  8. Joint action of a chemical carcinogen and a neoplastic virus to induce cancer in rabbits; results of exposing epidermal cells to a carcinogenic hydrocarbon at time of infection with the Shope papilloma virus.

    Science.gov (United States)

    ROGERS, S; ROUS, P

    1951-05-01

    Areas of rabbit skin previously rendered hyperplastic with turpentine were scarified, inoculated with the Shope papilloma virus, and covered with a dressing that contained 20-methylcholanthrene (MC) or 9:10-dimethyl-1:2-benzanthracene (9:10). The dressing was left on until healing had been well completed, a matter of 5 to 7 days. The papillomas which subsequently arose often appeared later, were fewer, and remained less vigorous than those due to the action of virus alone, but throughout several months they appeared to differ from these in no other ways. Then, more or less abruptly, the large majority became carcinomatous, frequently at several situations, whereas with few exceptions the control growths underwent no such alteration. The cancers were of the sorts ordinarily deriving, by secondary change, from epidermal cells infected with the virus. Collateral data have made plain that the hydrocarbons acted in their carcinogenic capacity to bring on the cancers. Indeed in control tests 9: 10 sometimes conferred latent neoplastic potentialities on uninoculated epidermis exposed to it while healing after scarification, a fact disclosed months later by painting these expanses with chloroform until hyperplasia occurred. Under the promoting influence of this agent papillomas formed which had the distinctive morphology of those induced by the chemical carcinogens. So strong and enduring were the effects of MC and 9:10 as to cause cancers to arise from many virus papillomas which were retrogressing after months of proliferation, that is to say under circumstances ordinarily unfavorable to malignant change. The facts justify the conclusion that the virus and the hydrocarbons acted jointly and in their carcinogenic capacities. PMID:14832395

  9. Concordance between Results of Medium-term Liver Carcinogenesis Bioassays and Long-term Findings for Carcinogenic 2-Nitropropane and Non-carcinogenic 1-Nitropropane in F344 Rats

    OpenAIRE

    Doi, Yuko; Tamano, Seiko; Kawabe, Mayumi; Sano,Masashi; Imai, Norio; Nakashima, Hironao; Furukawa, Fumio; Hagiwara, Akihiro; OTSUKA,MASANORI; Shirai, Tomoyuki

    2012-01-01

    This study was conducted to determine the concordance of results for a pair of structural isomers, 2-nitropropane (2-NP) and 1-nitropropane (1-NP), using the rat medium-term liver carcinogenesis bioassay (Ito test) and previously published long-term carcinogenicity tests. Male F344 rats were given a single intraperitoneal injection of DEN (200 mg/kg b.w.) to initiate hepatocarcinogenesis. After 2 weeks, they received per os 0, 0.8, 4 or 20 mg/kg/day of 2-NP or 1-NP six times a week and were s...

  10. [Notion of threshold in mutagenesis: implications for mutagenic and carcinogenic risk assessment].

    Science.gov (United States)

    Marzin, D

    2007-11-01

    account. A very important point to consider is to demonstrate that the mechanism with threshold was really thee only one involved in the mutagenic effect. The demonstration of such thresholds is of particular interest for human risk assessment in the case of mutagens and of genotoxic carcinogens. PMID:18079673

  11. A common carcinogen benzo[a]pyrene causes neuronal death in mouse via microglial activation.

    Directory of Open Access Journals (Sweden)

    Kallol Dutta

    Full Text Available BACKGROUND: Benzo[a]pyrene (B[a]P belongs to a class of polycyclic aromatic hydrocarbons that serve as micropollutants in the environment. B[a]P has been reported as a probable carcinogen in humans. Exposure to B[a]P can take place by ingestion of contaminated (especially grilled, roasted or smoked food or water, or inhalation of polluted air. There are reports available that also suggests neurotoxicity as a result of B[a]P exposure, but the exact mechanism of action is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Using neuroblastoma cell line and primary cortical neuron culture, we demonstrated that B[a]P has no direct neurotoxic effect. We utilized both in vivo and in vitro systems to demonstrate that B[a]P causes microglial activation. Using microglial cell line and primary microglial culture, we showed for the first time that B[a]P administration results in elevation of reactive oxygen species within the microglia thereby causing depression of antioxidant protein levels; enhanced expression of inducible nitric oxide synthase, that results in increased production of NO from the cells. Synthesis and secretion of proinflammatory cytokines were also elevated within the microglia, possibly via the p38MAP kinase pathway. All these factors contributed to bystander death of neurons, in vitro. When administered to animals, B[a]P was found to cause microglial activation and astrogliosis in the brain with subsequent increase in proinflammatory cytokine levels. CONCLUSIONS/SIGNIFICANCE: Contrary to earlier published reports we found that B[a]P has no direct neurotoxic activity. However, it kills neurons in a bystander mechanism by activating the immune cells of the brain viz the microglia. For the first time, we have provided conclusive evidence regarding the mechanism by which the micropollutant B[a]P may actually cause damage to the central nervous system. In today's perspective, where rising pollution levels globally are a matter of grave concern, our

  12. The carcinogenic risk of high dose total body irradiation in non-human primates

    International Nuclear Information System (INIS)

    High dose total body irradiation (TBI) in combination with chemotherapy, followed by rescue with bone marrow transplantation (BMT), is increasingly used for the treatment of haematological malignancies. With the increasing success of this treatment and its current introduction for treating refractory autoimmune diseases the risk of radiation carcinogenesis is of growing concern. Studies on turnout induction in non-human primates are of relevance in this context since the response of this species to radiation does not differ much from that in man. Since the early sixties, studies have been performed on acute effects in Rhesus monkeys and the protective action of bone marrow transplantation after irradiation with X-rays (average total body dose 6.8 Gy) and fission neutrons (average dose 3.4 Gy). Of those monkeys, which were irradiated and reconstituted with autologous bone marrow, 20 animals in the X-irradiated group and nine animals in the neutron group survived more than 3 years. A group of 21 non-irradiated Rhesus monkeys of a comparable age distribution served as controls. All animals were regularly screened for the occurrence of neoplasms. Complete necropsies were performed after natural death or euthanasia. At post-irradiation intervals of 4-21 years an appreciable number of tumours was observed. In the neutron irradiated group eight out of nine animals died with one or more malignant tumours. In the X-irradiated group this fraction was 10 out of 20. The tumours in the control group, in seven out of the 21 animals, appeared at much older a-e compared with those in the irradiated cohorts. The histogenesis of the tumours was diverse with a preponderance of renal carcinoma, sarcomas among which osteosarcormas, and malignant glomus tumours in the irradiated groups. When corrected for competing risks, the carcinogenic risk of TBI in the Rhesus monkeys is similar to that derived from the studies of the Japanese atomic bomb survivors. The increase of the risk by a

  13. A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID study of the species differences in the carcinogenicity of benzene derivatives chemicals.

    Science.gov (United States)

    Fratev, Filip; Benfenati, Emilio

    2008-09-01

    A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID methods was applied as a tool to study and predict the mechanism of action of 100 carcinogenic benzene derivatives. Two 3D-QSAR models were obtained: (i) model of mouse carcinogenicity on the basis of 100 chemicals (model 1) and (ii) model of the differences in mouse and rat carcinogenicity on the basis of 73 compounds (model 2). 3D-QSAR regression maps indicated the important differences in species carcinogenicity, and the molecular positions associated with them. In order to evaluate the role of P450 metabolic process in carcinogenicity, the following approaches were used. The 3D models of CYP2E1 for mouse and rat were built up. A docking study was applied and the important ligand-protein residues interactions and oxidation positions of the molecules were identified. A new approach for quantitative assessment of metabolism pathways was developed, which enabled us to describe the species differences in CYP2E1 metabolism, and how it can be related to differences in the carcinogenic potential for a subset of compounds. The binding energies of the important substituents (local-binding energy-LBE) were calculated, in order to quantitatively demonstrate the contribution of the substituents in metabolic processes. Furthermore, a computational procedure was used for determining energetically favourable binding sites (GRID examination) of the enzymes. The GRID procedure allowed the identification of some important differences, related to species metabolism in CYP2E1. Comparing GRID, 3D-QSAR maps and LBE results, a similarity was identified, indicating a relationship between P450 metabolic processes and the differences in the carcinogenicity. PMID:18495507

  14. 32P-Postlabeling test for covalent DNA binding of chemicals in vivo: Application to a variety of aromatic carcinogens and methylating agents

    International Nuclear Information System (INIS)

    Carcinogen--DNA adducts were detected and determined by 32P-postlabeling assay after exposure of mouse or rat tissues in vivo to a total of 28 compounds comprising 7 arylamines and derivatives, 3 azo compounds, 2 nitroaromatics, 12 polycyclic aromatic hydrocarbons, and 4 methylating agents. DNA was isolated from mouse skin, mouse liver, and rat liver after treatment with the individual carcinogens, then digested enzymatically to deoxyribonucleoside 3'-monophosphates, which were converted to 5'-32P-labeled deoxyribonucleoside 3',5'-bisphosphates by T4 polynucleotide kinase-catalyzed [32P]phosphate transfer from [gamma-32P]ATP. The nucleotides were resolved by anion-exchange t.l.c. on polyethyleneimine-cellulose and detected by autoradiography. The determination of low levels of DNA binding of the aromatic carcinogens entailed the removal of normal nucleotides prior to the resolution of adduct nucleotides. For this purpose, an alternative procedure employing reversed-phase t.l.c. was devised which offered advantages for the detection of quantitatively minor adducts. The procedures described enabled the detection of 1 aromatic DNA adduct in approximately 10(8) normal nucleotides, while the limit of detection of methylated adducts was 1 adduct in approximately 6 X 10(5) nucleotides. The results show that a great number of carcinogen-DNA adducts of diverse structure are substrates for 32P-labeling by polynucleotide kinase-catalyzed phosphorylation. Because covalent DNA adduct formation in vivo appears to be an essential property of the majority of chemical carcinogens, 32P-postlabeling analysis of carcinogen--DNA adducts in mammalian tissues may serve as a test for the screening of chemicals for potential carcinogenicity

  15. In vitro cytogenetic results supporting a DNA nonreactive mechanism for ochratoxin A, potentially relevant for its carcinogenicity.

    Science.gov (United States)

    Mosesso, Pasquale; Cinelli, Serena; Piñero, Joaquin; Bellacima, Raffaela; Pepe, Gaetano

    2008-06-01

    Ochratoxin A (OTA) is a widespread mycotoxin of cereals and many agricultural products and causes high incidences of renal tumors in rodents. Although its carcinogenic properties have been known since the eighties, the precise mechanism of action is still relatively undefined. At present, increasing evidence suggests that OTA does not act with a direct genotoxic mechanism, opposed to other previous evidence where the formation of DNA adducts by 32P-postlabeling was observed. The genotoxic activity of OTA assessed in a variety of in vitro and in vivo studies was very low if genotoxic at all. In this study, we clearly show that OTA does not bear any clastogenic or aneugenic activity based on the absence of the induction of chromosome aberrations, sister chromatid exchanges, and micronuclei in human lymphocytes and V79 cells in vitro in both the absence and the presence of S9 metabolism. Alternatively, cytogenetic analyses evidenced significant increases in endoreduplicated cells and highly condensed metaphases with separated chromatids. This implies that OTA or its possible metabolites do not covalently bind DNA through the formation of adducts since structural chromosome aberrations are a very sensitive end points to detect chemical carcinogens with electrophilic substituents. Alternatively, induction of endoreduplication and chromatid separation provides strong evidence for a DNA nonreactive mechanism of OTA carcinogenicity involving the disruption of mitosis by interfering with key regulators of chromosome separation and progression of mitosis. This causes a temporary arrest of mitoses and premature exit from it (mitotic slippage) to generate endoreduplication and polyploidy accompanied by increased risk of aneuploidy and subsequent tumor formation. PMID:18500787

  16. Leisure time activities related to carcinogen exposure and lung cancer risk in never smokers. A case-control study

    Energy Technology Data Exchange (ETDEWEB)

    Ruano-Ravina, Alberto, E-mail: alberto.ruano@usc.es [Department of Preventive Medicine and Public Health, University of Santiago de Compostela, Santiago de Compostela (Spain); CIBER de Epidemiología y Salud Pública CIBERESP, Barcelona (Spain); García-Lavandeira, José Antonio [Department of Preventive Medicine and Public Health, University of Santiago de Compostela, Santiago de Compostela (Spain); Department of Preventive Medicine, A Coruña University Hospital Complex, Coruña (Spain); Torres-Durán, María [Department of Preventive Medicine and Public Health, University of Santiago de Compostela, Santiago de Compostela (Spain); Service of Neumology, University Hospital Complex of Vigo, Vigo (Spain); Prini-Guadalupe, Luciana [Department of Preventive Medicine and Public Health, University of Santiago de Compostela, Santiago de Compostela (Spain); Parente-Lamelas, Isaura [Service of Neumology, Ourense Hospital Complex, Ourense (Spain); Leiro-Fernández, Virginia [Service of Neumology, University Hospital Complex of Vigo, Vigo (Spain); Montero-Martínez, Carmen [Service of Neumology, University Hospital Complex of A Coruña, Coruña (Spain); González-Barcala, Francisco Javier; Golpe-Gómez, Antonio [Service of Neumology, Santiago de Compostela University Clinic Hospital, Santiago de Compostela (Spain); Martínez, Cristina [National Institute of Silicosis, University Hospital of Asturias, Oviedo, Asturias (Spain); Castro-Añón, Olalla [Service of Neumology, Hospital Lucus Augusti, Lugo (Spain); Mejuto-Martí, María José [Service of Neumology, Hospital Arquitecto Marcide, Ferrol (Spain); and others

    2014-07-15

    We aim to assess the relationship between leisure time activities related to exposure to carcinogenic substances and lung cancer risk in a hospital-based case-control study performed in never smokers. We included never smoking cases with anatomopathologically confirmed lung cancer and never smoking controls undergoing trivial surgery, at 8 Spanish hospitals. The study was conducted between January 2011 and June 2013. Participants were older than 30 and had no previous neoplasms. All were personally interviewed focusing on lifestyle, environmental tobacco smoke exposure, occupational history and leisure time activities (including duration of such activities). Results were analyzed through logistic regression and adjusted also by residential radon and education level. We included 513 never smokers, 191 cases and 322 controls. The OR for those performing the studied leisure time activities was 1.43 (95%CI 0.78–2.61). When we restricted the analysis to those performing do-it-yourself activities for more than 10 years the OR was 2.21 (95%CI 0.93–5.27). Environmental tobacco smoke exposure did not modify this association. The effect for the different lung cancer histological types was very close to significance for adenocarcinoma but only when these activities were performed for more than 10 years. We encourage health professionals to recommend protective measures for those individuals while performing these hobbies to reduce the risk of lung cancer. - Highlights: • Some leisure time activities are associated with the exposure to carcinogenic substances. • These activities are model-making, painting (artistic or not), furniture refinishing or wood working. • Few studies have assessed lung cancer risk due to these hobbies and none in never-smokers. • Leisure activities related to exposure to carcinogenic substances present higher lung cancer risk. • The risk is higher when these activities are performed for more than 10 years.

  17. The International Agency for Research on Cancer (IARC) evaluation of the carcinogenicity of outdoor air pollution:focus on China

    Institute of Scientific and Technical Information of China (English)

    Dana Loomis; Wei Huang; Guosheng Chen

    2014-01-01

    The International Agency for Research on Cancer (IARC) has classified outdoor air pol ution and the particulate matter (PM) in outdoor air pol ution as carcinogenic to humans, as based on sufficient evidence of carcinogenicity in humans and experimental animals and strong support by mechanistic studies. The data with important contributions to the evaluation are reviewed, highlighting the data with particular relevance to China, and implications of the evaluation with respect to China are discussed. The air pol ution levels in Chinese cities are among the highest observed in the world today and frequently exceed health-based national and international guidelines. Data from high-quality epidemiologic studies in Asia, Europe, and North America consistently show positive associations between lung cancer and PM exposure and other indicators of air pol ution, which persist after adjustment for important lung cancer risk factors, such as tobacco smoking. Epidemiologic data from China are limited but nevertheless indicate an increased risk of lung cancer associated with several air pol utants. Excess cancer risk is also observed in experimental animals exposed to pol uted outdoor air or extracted PM. The exposure of several species to outdoor air pollution is associated with markers of genetic damage that have been linked to increased cancer risk in humans. Numerous studies from China, especially genetic biomarker studies in exposed populations, support that the polluted air in China is genotoxic and carcinogenic to humans. The evaluation by IARC indicates both the need for further research into the cancer risks associated with exposure to air pol ution in China and the urgent need to act to reduce exposure to the population.

  18. Use of short-term test systems for the prediction of the hazard represented by potential chemical carcinogens

    International Nuclear Information System (INIS)

    It has been hypothesized that results from short-term bioassays will ultimately provide information that will be useful for human health hazard assessment. Historically, the validity of the short-term tests has been assessed using the framework of the epidemiologic/medical screens. In this context, the results of the carcinogen (long-term) bioassay is generally used as the standard. However, this approach is widely recognized as being biased and, because it employs qualitative data, cannot be used to assist in isolating those compounds which may represent a more significant toxicologic hazard than others. In contrast, the goal of this research is to address the problem of evaluating the utility of the short-term tests for hazard assessment using an alternative method of investigation. Chemicals were selected mostly from the list of carcinogens published by the International Agency for Research on Carcinogens (IARC); a few other chemicals commonly recognized as hazardous were included. Tumorigenicity and mutagenicity data on 52 chemicals were obtained from the Registry of Toxic Effects of Chemical Substances (RTECS) and were analyzed using a relative potency approach. The data were evaluated in a format which allowed for a comparison of the ranking of the mutagenic relative potencies of the compounds (as estimated using short-term data) vs. the ranking of the tumorigenic relative potencies (as estimated from the chronic bioassays). Although this was a preliminary investigation, it offers evidence that the short-term tests systems may be of utility in ranking the hazards represented by chemicals which may contribute to increased carcinogenesis in humans as a result of occupational or environmental exposures. 177 refs., 8 tabs

  19. Environmental carcinogenic polycyclic aromatic hydrocarbons in soil from Himalayas, India: Implications for spatial distribution, sources apportionment and risk assessment.

    Science.gov (United States)

    Devi, Ningombam Linthoingambi; Yadav, Ishwar Chandra; Shihua, Qi; Dan, Yang; Zhang, Gan; Raha, Priyankar

    2016-02-01

    The Indian Himalayan Region (IHR) is one of the important mountain ecosystems among the global mountain system which support wide variety of flora, fauna, human communities and cultural diversities. Surface soil samples (n = 69) collected from IHR were analysed for 16 priority polycyclic aromatic hydrocarbons (PAH) listed by USEPA. The ∑16PAH concentration in surface soil ranged from 15.3 to 4762 ngg(-1) (mean 458 ngg(-1)). The sum total of low molecular weight PAH (∑LMW-PAHs) (mean 74.0 ngg(-1)) were relatively lower than the high molecular weight PAH (∑HMW-PAHs) (mean 384 ngg(-1)). The concentration of eight carcinogenic PAHs (BaA, CHR, BbF, BkF, BaP, DahA, IcdP, BghiP) were detected high in mountain soil from IHR and ranged from 0.73 to 2729 ngg(-1) (mean 272 ngg(-1)). Based on spatial distribution map, high concentration of HMW- and LMW-PAHs were detected at GS1 site in Guwahati (615 and 4071 ngg(-1)), and lowest concentration of HMW-PAHs were found at IS6 in Itanagar (5.80 ngg(-1)) and LMW-PAHs at DS2 (17.3 ngg(-1)) in Dibrugarh. Total organic carbon (TOC) in mountain soil was poorly connected with ∑PAHs (r(2) = 0.072) and Car-PAHs (r(2) = 0.048), suggesting the little role of TOC in adsorption of PAHs. Isomeric ratio of PAHs showed the source of PAH contamination in IHR is mixed of petrogenic and pyrogenic origin and was affirmed by PAHs composition profile. These source apportionment results were further confirmed by principal component analysis (PCA). Eco-toxicological analysis showed the calculated TEQ for most carcinogenic PAH were 2-4 times more than the Dutch allowed limit, while TEQ of BaP was 25 times high, suggesting increasing trend of carcinogenicity of surface soil. PMID:26386774

  20. The International Agency for Research on Cancer (IARC evaluation of the carcinogenicity of outdoor air pollution: focus on China

    Directory of Open Access Journals (Sweden)

    Dana Loomis

    2014-04-01

    Full Text Available The International Agency for Research on Cancer (IARC has classified outdoor air pollution and the particulate matter (PM in outdoor air pollution as carcinogenic to humans, as based on sufficient evidence of carcinogenicity in humans and experimental animals and strong support by mechanistic studies. The data with important contributions to the evaluation are reviewed, highlighting the data with particular relevance to China, and implications of the evaluation with respect to China are discussed. The air pollution levels in Chinese cities are among the highest observed in the world today and frequently exceed health-based national and international guidelines. Data from high-quality epidemiologic studies in Asia, Europe, and North America consistently show positive associations between lung cancer and PM exposure and other indicators of air pollution, which persist after adjustment for important lung cancer risk factors, such as tobacco smoking. Epidemiologic data from China are limited but nevertheless indicate an increased risk of lung cancer associated with several air pollutants. Excess cancer risk is also observed in experimental animals exposed to polluted outdoor air or extracted PM. The exposure of several species to outdoor air pollution is associated with markers of genetic damage that have been linked to increased cancer risk in humans. Numerous studies from China, especially genetic biomarker studies in exposed populations, support that the polluted air in China is genotoxic and carcinogenic to humans. The evaluation by IARC indicates both the need for further research into the cancer risks associated with exposure to air pollution in China and the urgent need to act to reduce exposure to the population

  1. Use of short-term test systems for the prediction of the hazard represented by potential chemical carcinogens

    Energy Technology Data Exchange (ETDEWEB)

    Glass, L.R.; Jones, T.D.; Easterly, C.E.; Walsh, P.J.

    1990-10-01

    It has been hypothesized that results from short-term bioassays will ultimately provide information that will be useful for human health hazard assessment. Historically, the validity of the short-term tests has been assessed using the framework of the epidemiologic/medical screens. In this context, the results of the carcinogen (long-term) bioassay is generally used as the standard. However, this approach is widely recognized as being biased and, because it employs qualitative data, cannot be used to assist in isolating those compounds which may represent a more significant toxicologic hazard than others. In contrast, the goal of this research is to address the problem of evaluating the utility of the short-term tests for hazard assessment using an alternative method of investigation. Chemicals were selected mostly from the list of carcinogens published by the International Agency for Research on Carcinogens (IARC); a few other chemicals commonly recognized as hazardous were included. Tumorigenicity and mutagenicity data on 52 chemicals were obtained from the Registry of Toxic Effects of Chemical Substances (RTECS) and were analyzed using a relative potency approach. The data were evaluated in a format which allowed for a comparison of the ranking of the mutagenic relative potencies of the compounds (as estimated using short-term data) vs. the ranking of the tumorigenic relative potencies (as estimated from the chronic bioassays). Although this was a preliminary investigation, it offers evidence that the short-term tests systems may be of utility in ranking the hazards represented by chemicals which may contribute to increased carcinogenesis in humans as a result of occupational or environmental exposures. 177 refs., 8 tabs.

  2. Activation of the aryl hydrocarbon receptor by carcinogenic aromatic amines and modulatory effects of their N-acetylated metabolites.

    Science.gov (United States)

    Juricek, Ludmila; Bui, Linh-Chi; Busi, Florent; Pierre, Stéphane; Guyot, Erwan; Lamouri, Aazdine; Dupret, Jean-Marie; Barouki, Robert; Coumoul, Xavier; Rodrigues-Lima, Fernando

    2015-12-01

    Aromatic amines (AAs) are an important class of chemicals which account for 12 % of known carcinogens. The biological effects of AAs depend mainly on their biotransformation into reactive metabolites or into N-acetylated metabolites which are generally considered as less toxic. Although the activation of the aryl hydrocarbon receptor (AhR) pathway by certain carcinogenic AAs has been reported, the effects of their N-acetylated metabolites on the AhR have not been addressed. Here, we investigated whether carcinogenic AAs and their N-acetylated metabolites may activate/modulate the AhR pathway in the absence and/or the presence of a bona fide AhR ligand (benzo[a]pyrene/B(a)P]. In agreement with previous studies, we found that certain AAs activated the AhR in human liver and lung cells as assessed by an increase in cytochrome P450 1A1 (CYP1A1) expression and activity. Altogether, we report for the first time that these properties can be modulated by the N-acetylation status of the AA. Whereas 2-naphthylamine significantly activated the AhR and induced CYP1A1 expression, its N-acetylated metabolite was less efficient. In contrast, the N-acetylated metabolite of 2-aminofluorene was able to significantly activate AhR, whereas the parent AA, 2-aminofluorene, did not. In the presence of B(a)P, activation of AhR or antagonist effects were observed depending on the AA or its N-acetylated metabolite. Activation and/or modulation of the AhR pathway by AAs and their N-acetylated metabolites may represent a novel mechanism contributing to the toxicological effects of AAs. More broadly, our data suggest biological interactions between AAs and other classes of xenobiotics through the AhR pathway. PMID:25224404

  3. Leisure time activities related to carcinogen exposure and lung cancer risk in never smokers. A case-control study

    International Nuclear Information System (INIS)

    We aim to assess the relationship between leisure time activities related to exposure to carcinogenic substances and lung cancer risk in a hospital-based case-control study performed in never smokers. We included never smoking cases with anatomopathologically confirmed lung cancer and never smoking controls undergoing trivial surgery, at 8 Spanish hospitals. The study was conducted between January 2011 and June 2013. Participants were older than 30 and had no previous neoplasms. All were personally interviewed focusing on lifestyle, environmental tobacco smoke exposure, occupational history and leisure time activities (including duration of such activities). Results were analyzed through logistic regression and adjusted also by residential radon and education level. We included 513 never smokers, 191 cases and 322 controls. The OR for those performing the studied leisure time activities was 1.43 (95%CI 0.78–2.61). When we restricted the analysis to those performing do-it-yourself activities for more than 10 years the OR was 2.21 (95%CI 0.93–5.27). Environmental tobacco smoke exposure did not modify this association. The effect for the different lung cancer histological types was very close to significance for adenocarcinoma but only when these activities were performed for more than 10 years. We encourage health professionals to recommend protective measures for those individuals while performing these hobbies to reduce the risk of lung cancer. - Highlights: • Some leisure time activities are associated with the exposure to carcinogenic substances. • These activities are model-making, painting (artistic or not), furniture refinishing or wood working. • Few studies have assessed lung cancer risk due to these hobbies and none in never-smokers. • Leisure activities related to exposure to carcinogenic substances present higher lung cancer risk. • The risk is higher when these activities are performed for more than 10 years

  4. The synthesis of ( sup 3 H)-indole-3-carbinol, a natural anti-carcinogen from cruciferous vegetables

    Energy Technology Data Exchange (ETDEWEB)

    Dashwood, R.H.; Uyetake, Lyle; Fong, A.T.; Hendricks, J.D.; Bailey, G.S. (Oregon State Univ., Corvallis, OR (USA). Dept. of Food Science and Technology)

    1989-08-01

    Indole-3-carbinol is a natural anti-carcinogen found as a glucosinolate in cruciferous vegetables such as cabbage, cauliflower and broccoli. A complete understanding of the mechanisms of anti-carcinogenesis by this dietary inhibitor requires improved insight into the disposition and metabolic fate of indole-3-carbinol in vivo. Such metabolic studies have been hampered by the lack of a commercial source of radiolabelled compound. This provided the main impetus for the work reported here, the synthesis of 5-({sup 3}H)-indole-3-carbinol from 5-bromoindole. (author).

  5. The dose-effect relationship and the estimation of carcinogen effects of low dose of ionizing radiation

    International Nuclear Information System (INIS)

    The carcinogen risks of an exposure to ionizing radiation have been evaluated by numerous epidemiological studies between 0.2 and 5 Sv. But the field of doses that concerns the human health is generally under a decade of mSv. The epidemiological studies do not detect any effect for doses under 100 mSv, either there is not or the statistical power of inquiries is not sufficient to detect them. Progress in radiobiology has shown that a cell is not passively affected by the accumulation of lesions induced by ionizing radiation. It react through at least three mechanisms: first, by fighting against reactive oxygen species (R.O.S.) generated by ionizing radiation and by oxidative stress, secondly, by eliminating injured cells (mutated or instable), through two mechanisms: apoptosis which can be initiated by doses as low as a few mSv, thus eliminating cells with genomes that have been damaged or mis-repaired, death of cells during mitosis when lesions have not been repaired, thirdly by stimulating or activating DNA repair systems following slightly higher doses of about ten mSv. About radio-carcinogenesis, with regard to tissue, the mechanisms which govern embryogenesis and direct tissue repair after injury appear to play also an important role in the control of cell proliferation. This is particularly important when a transformed cell is surrounded by normal cells. These mechanisms could explain the lower efficacy of heterogeneous irradiation as well as the absence of a carcinogenic effect in humans or experimental animals contaminated by small quantities of alpha emitter radionuclides. The latter data suggest the existence of a threshold. Immuno-surveillance systems are able to eliminate clones of transformed cells as is shown by tumor cell transplants. These data show that it is not justified to use linear no-threshold relationship to assess the carcinogenic risk of low doses from observations made for doses from .2 to 5 Sv since for the same dose increment the

  6. Exposure Assessment Suggests Exposure to Lung Cancer Carcinogens in a Painter Working in an Automobile Bumper Shop

    OpenAIRE

    KIM, Boowook; Yoon, Jin-Ha; Choi, Byung-Soon; Shin, Yong Chul

    2013-01-01

    A 46-year-old man who had worked as a bumper spray painter in an automobile body shop for 15 years developed lung cancer. The patient was a nonsmoker with no family history of lung cancer. To determine whether the cancer was related to his work environment, we assessed the level of exposure to carcinogens during spray painting, sanding, and heat treatment. The results showed that spray painting with yellow paint increased the concentration of hexavalent chromium in the air to as much as 118.3...

  7. Analysis at the sequence level of mutations induced by the ultimate carcinogen N-acetoxy-N-2-acetylaminofluorene

    OpenAIRE

    Fuchs, Robert P. P.; Schwartz, Nicole; Daune, Michel P.

    1983-01-01

    The covalent binding of an ultimate carcinogen to the DNA bases or phosphate groups creates a premutational lesion that in vivo is processed by the repair, replication and recombination enzymes, and eventually may be converted into a mutation. Being interested in the way that an initial premutational event is converted into a stable heritable mutation, we have sequenced stable mutations in a gene that has formed covalent adducts in vitro with N-acetoxy-N-2-acetylaminofluorene (N-AcO-AAF, a mo...

  8. Evaluation of the E mu-pim-1 transgenic mouse model for short-term carcinogenicity testing

    DEFF Research Database (Denmark)

    van Kreijl, C. F.; van Oordt, C. W. V.; Kroese, E. D.; Sørensen, Ilona Kryspin; Breuer, M. L.; Storer, R. D.

    1998-01-01

    The value of the chronic rodent carcinogenicity assay in adequately predicting cancer risk in humans has become a matter of debate over the past few years. Therefore, more rapid and accurate alternative tests are urgently needed. Transgenic mouse models, those harboring genetic changes that are...... relevant to the multistage cancer process, may provide such alternative tests. Transgenic E mu-pim-1 mice, developed by Berns and coworkers in 1989, contain the pim-1 oncogene, which is expressed at elevated levels in their lymphoid compartments. As a result, these mice are predisposed to the development...

  9. The synthesis of [3H]-indole-3-carbinol, a natural anti-carcinogen from cruciferous vegetables

    International Nuclear Information System (INIS)

    Indole-3-carbinol is a natural anti-carcinogen found as a glucosinolate in cruciferous vegetables such as cabbage, cauliflower and broccoli. A complete understanding of the mechanisms of anti-carcinogenesis by this dietary inhibitor requires improved insight into the disposition and metabolic fate of indole-3-carbinol in vivo. Such metabolic studies have been hampered by the lack of a commercial source of radiolabelled compound. This provided the main impetus for the work reported here, the synthesis of 5-[3H]-indole-3-carbinol from 5-bromoindole. (author)

  10. (S)-N′-Nitrosonornicotine, a constituent of smokeless tobacco, is a powerful oral cavity carcinogen in rats

    OpenAIRE

    Balbo, Silvia; James-Yi, Sandra; Johnson, Charles S.; O’Sullivan, Michael G.; Stepanov, Irina; Wang, Mingyao; Bandyopadhyay, Dipankar; Kassie, Fekadu; Carmella, Steven; Upadhyaya, Pramod; Hecht, Stephen S

    2013-01-01

    Currently, smokeless tobacco products are being proposed as an alternative mode of tobacco use associated with less harm. All of these products contain the tobacco-specific carcinogen N′-nitrosonornicotine (NNN). The major form of NNN in tobacco products is (S)-NNN, shown in this study to induce a total of 89 benign and malignant oral cavity tumors in a group of 20 male F-344 rats treated chronically with 14 p.p.m. in the drinking water. The opposite enantiomer (R)-NNN was weakly active, but ...

  11. Carcinogenic effect of sequential artificial sunlight and UV-A irradiation in hairless mice. Consequences for solarium 'therapy'

    International Nuclear Information System (INIS)

    The carcinogenic effect of artificial UV sunlight followed by UV-A irradiation in human solaria doses has been studied with the use of the hairless mouse as an animal model. Artificial sunlight exposure alone induced only a moderate skin tumor incidence (animals with at least one tumor) of 0.15 after one year, and UV-A irradiation alone induced no tumor formation. However, the combination of artificial sunlight exposure and subsequent UV-A irradiation significantly increased the tumor incidence to 0.72. We conclude that, in humans, tanning with UV-A for cosmetic purposes may not be an innocuous procedure

  12. Carcinogenic effect of sequential artificial sunlight and UV-A irradiation in hairless mice. Consequences for solarium 'therapy'.

    Science.gov (United States)

    Staberg, B; Wulf, H C; Poulsen, T; Klemp, P; Brodthagen, H

    1983-08-01

    The carcinogenic effect of artificial UV sunlight followed by UV-A irradiation in human solaria doses has been studied with the use of the hairless mouse as an animal model. Artificial sunlight exposure alone induced only a moderate skin tumor incidence (animals with at least one tumor) of 0.15 after one year, and UV-A irradiation alone induced no tumor formation. However, the combination of artificial sunlight exposure and subsequent UV-A irradiation significantly increased the tumor incidence to 0.72. We conclude that, in humans, tanning with UV-A for cosmetic purposes may not be an innocuous procedure. PMID:6870317

  13. Biomonitoring the Cooked Meat Carcinogen 2-Amino-1-methy-6-phenylimidazo[4,5-b]pyridine in Canine Fur

    OpenAIRE

    Gu, Dan; Neuman, Zachary L.; Modiano, Jaime F; Turesky, Robert J.

    2012-01-01

    2-Amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP) is a heterocyclic aromatic amine (HAA) that is formed during the cooking of meat, poultry, and fish. PhIP is a rodent carcinogen and thought to contribute to several diet-related cancers in humans. PhIP is present in the hair of human omnivores but not in the hair of vegetarians. We have now identified PhIP in the fur of fourteen out of sixteen healthy dogs consuming different brands of commercial pet food. The levels of PhIP in canine f...

  14. MicroRNA Responses to the Genotoxic Carcinogens Aflatoxin B1 and Benzo[a]pyrene in Human HepaRG Cells.

    Science.gov (United States)

    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. PMID:26609139

  15. Treatment with topical khellin in combination with ultraviolet A or solar-simulated radiation is carcinogenic to lightly pigmented hairless mice.

    Science.gov (United States)

    Bech-Thomsen, N; Wulf, H C

    1996-01-01

    Khellin is used together with either UVA irradiation or sun exposure in the treatment of vitiligo. The purpose of this study was to investigate the carcinogenic effect of topically applied khellin together with UVA or solar simulated radiation (SSR) in lightly pigmented C3H/Tif mice. For comparison purposes a 0.1% 8-methoxypsoralen (8-MOP) cream was also tested in combination with SSR. Fifty microliters of a 5% khellin cream, a 0.1% 8-MOP cream, or a cream without active substances were spread uniformly on the back of the mice 30 minutes before UVA or SSR irradiation. All mice were irradiated 3 times a week until age or skin tumor development necessitated killing. Treatment with topical khellin and UVA irradiation was carcinogenic to lightly pigmented hairless mice, time to 50% of the mice had developed one tumor (t50) was 507 days. This indicates that the combination of topical khellin and UVA radiation, formerly expected to be rather innocuous, is carcinogenic to mice. Also the combination of khellin and SSR (t50 = 268 days) enhanced skin tumor development significantly compared with control cream and SSR (t50 = 330 days), P < 0.05. In addition, the combination of khellin and SSR was found to have the same carcinogenic effect as treatment with 0.1% 8-MOP and SSR (t50 = 262 days). This study shows that topically applied khellin increases the carcinogenic effect of both UVA and sunlight. PMID:8738715

  16. Carcinogenic risk assessment and management of ionising radiation, asbestos and nickel: a comparative approach

    International Nuclear Information System (INIS)

    assessment of individual exposures and their measurements are difficult to achieve. In this context, the ALARA approach refers mainly to the adoption of good practices. In this study, a quantitative comparison of risks in the various sectors is less important than a qualitative comparison of the risk-assessment and management approaches. It is felt that identifying similarities and differences is an objective in its own right in that it provides a basis on which to challenge, where necessary, some commonly-held beliefs regarding the advances that some sectors are assumed to have over others. The collected data reveal some significant similarities in the principles on which the assessment and management of risks of low-level exposure are based. At the same time, the procedures which are actually used in practice, despite being based on relatively distinct 'instruments', ultimately produce results that are not dissimilar and that in general reflect the shared concern to devise reasonable' solutions with regard to the prevention of carcinogenic risks. (author)

  17. Molecular mechanism of metal-independent decomposition of organic hydroperoxides by halogenated quinoid carcinogens and the potential biological implications.

    Science.gov (United States)

    Huang, Chun-Hua; Ren, Fu-Rong; Shan, Guo-Qiang; Qin, Hao; Mao, Li; Zhu, Ben-Zhan

    2015-05-18

    Halogenated quinones (XQ) are a class of carcinogenic intermediates and newly identified chlorination disinfection byproducts in drinking water. Organic hydroperoxides (ROOH) can be produced both by free radical reactions and enzymatic oxidation of polyunsaturated fatty acids. ROOH have been shown to decompose to alkoxyl radicals via catalysis by transition metal ions, which may initiate lipid peroxidation or transform further to the reactive aldehydes. However, it is not clear whether XQ react with ROOH in a similar manner to generate alkoxyl radicals metal-independently. By complementary applications of ESR spin-trapping, HPLC/high resolution mass spectrometric and other analytical methods, we found that 2,5-dichloro-1,4-benzoquinone (DCBQ) could significantly enhance the decomposition of a model ROOH tert-butylhydroperoxide, resulting in the formation of t-butoxyl radicals independent of transition metals. On the basis of the above findings, we detected and identified, for the first time, an unprecedented C-centered quinone ketoxy radical. Then, we extended our study to the more physiologically relevant endogenous ROOH 13-hydroperoxy-9,11-octadecadienoic acid and found that DCBQ could also markedly enhance its decomposition to generate the reactive lipid alkyl radicals and the genotoxic 4-hydroxy-2-nonenal (HNE). Similar results were observed with other XQ. In summary, these findings demonstrated that XQ can facilitate ROOH decomposition to produce reactive alkoxyl, quinone ketoxy, lipid alkyl radicals, and genotoxic HNE via a novel metal-independent mechanism, which may explain partly their potential genotoxicity and carcinogenicity. PMID:25789984

  18. Butylated Hydroxyanisole Blocks the Occurrence of Tumor Associated Macrophages in Tobacco Smoke Carcinogen-Induced Lung Tumorigenesis

    International Nuclear Information System (INIS)

    Tumor-associated macrophages (TAMs) promote tumorigenesis because of their proangiogenic and immune-suppressive functions. Here, we report that butylated hydroxyanisole (BHA) blocks occurrence of tumor associated macrophages (TAMs) in tobacco smoke carcinogen-induced lung tumorigenesis. Continuous administration of butylated hydroxyanisole (BHA), a ROS inhibitor, before or after NNK treatment significantly blocked tumor development, although less effectively when BHA is administered after NNK treatment. Strikingly, BHA abolished the occurrence of F4/80+ macrophages with similar efficiency no matter whether it was administered before or after NNK treatment. Detection of cells from bronchioalveolar lavage fluid (BALF) confirmed that BHA markedly inhibited the accumulation of macrophages while slightly reducing the number of lymphocytes that were induced by NNK. Immunohistological staining showed that BHA specifically abolished the occurrence of CD206+ TAMs when it was administered before or after NNK treatment. Western blot analysis of TAMs markers, arginase I and Ym-1, showed that BHA blocked NNK-induced TAMs accumulation. Our study clearly demonstrated that inhibiting the occurrence of TAMs by BHA contributes to the inhibition of tobacco smoke carcinogen-induced tumorigenesis, suggesting ROS inhibitors may serve as a therapeutic target for treating smoke-induced lung cancer

  19. Butylated Hydroxyanisole Blocks the Occurrence of Tumor Associated Macrophages in Tobacco Smoke Carcinogen-Induced Lung Tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yan; Choksi, Swati; Liu, Zheng-Gang, E-mail: zgliu@helix.nih.gov [Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2013-12-04

    Tumor-associated macrophages (TAMs) promote tumorigenesis because of their proangiogenic and immune-suppressive functions. Here, we report that butylated hydroxyanisole (BHA) blocks occurrence of tumor associated macrophages (TAMs) in tobacco smoke carcinogen-induced lung tumorigenesis. Continuous administration of butylated hydroxyanisole (BHA), a ROS inhibitor, before or after NNK treatment significantly blocked tumor development, although less effectively when BHA is administered after NNK treatment. Strikingly, BHA abolished the occurrence of F4/80{sup +} macrophages with similar efficiency no matter whether it was administered before or after NNK treatment. Detection of cells from bronchioalveolar lavage fluid (BALF) confirmed that BHA markedly inhibited the accumulation of macrophages while slightly reducing the number of lymphocytes that were induced by NNK. Immunohistological staining showed that BHA specifically abolished the occurrence of CD206{sup +} TAMs when it was administered before or after NNK treatment. Western blot analysis of TAMs markers, arginase I and Ym-1, showed that BHA blocked NNK-induced TAMs accumulation. Our study clearly demonstrated that inhibiting the occurrence of TAMs by BHA contributes to the inhibition of tobacco smoke carcinogen-induced tumorigenesis, suggesting ROS inhibitors may serve as a therapeutic target for treating smoke-induced lung cancer.

  20. Determination of some carcinogenic PAHs with toxic equivalency factor along roadside soil within a fast developing northern city of India

    Indian Academy of Sciences (India)

    Vaneet Kumar; N C Kothiyal; Saruchi; R Mehra; A Parkash; R R Sinha; S K Tayagi; R Gaba

    2014-04-01

    The objective of the present study was to ascertain contamination levels, distribution behaviour and PAHs exposure during summer, winter and autumn during 2011–2012 in one of the developing cities of northern India. Average PAHs concentration was found to be 18.17, 4.04 and 16.38 g g−1, whereas, concentration of 16 individual PAHs was found to vary between 0.02 and 200.23, 0.008 and 28.4 g g−1, and 0.01 and 252.55 g g−1 during summer, winter and autumn seasons, respectively. The average concentration of low and high carcinogenic PAHs during summer, winter and autumn was found to be 5.1 and 31.29, 2.1 and 6.4, 4.74 and 35.08 g g−1 at most intercepts. The average ratio of low to high carcinogenic PAHs was found to be 1:6, 1:3, 1:7.6 during summer, winter and autumn, respectively. Five ringed PAHs were found in higher concentration in all seasons. Dib(ah)A and B(a)P were the two individual PAHs found in highest concentration during summer, winter and autumn seasons. Two tailed T-test was applied for authenticity of the results. Toxic equivalency factor of B(a)P and Dib(ah)A was maximum as compared to other PAHs. The study could be of great significance for the planners while considering environmental remedial measures.

  1. Formation and persistence of DNA adducts from the carcinogen N-hydroxy-2-acetylaminofluorene in rat mammary gland in vivo

    International Nuclear Information System (INIS)

    The rat mammary carcinogen, N-hydroxy-2-acetylaminofluorene (N-hydroxy-2-AAF), has been proposed to be metabolically activated by mammary cytosolic N,O-acetyltransferase to a DNA binding species. To test this hypothesis, adult female Sprague-Dawley derived CD rats were treated, i.p., with 4.0 mg/kg [ring-3H]N-hydroxy-2-AAF. After 4 h, 1, 3, 14, and 28 days, the animals were killed, the mammary epithelium DNA was isolated and the carcinogen-deoxyribonucleoside adducts present were analyzed by high pressure liquid chromatography. At each time, only one adduct was detected and it was chromatographically identical to N-(deoxyguanosin-8-yl)-2-aminofluorene. The level of the adduct was maximal at 4 h (1.5 adducts/10(6) nucleotides) and then decreased, following first order kinetics with a t1/2 of 14.2 days. The detection of a single non-acetylated aminofluorene adduct is consistent with N,O-acyltransferase being involved in the metabolic activation of N-hydroxy-2-AAF in the rat mammary gland

  2. The potential effect of patulin on mice bearing melanoma cells: an anti-tumour or carcinogenic effect?

    Science.gov (United States)

    Boussabbeh, Manel; Ben Salem, Intidhar; Rjiba-Touati, Karima; Bouyahya, Chedy; Neffati, Fadwa; Najjar, Mohamed Fadhel; Bacha, Hassen; Abid-Essefi, Salwa

    2016-05-01

    Mycotoxins are bioactive compounds that are noxious to human. Their effects on oncogenesis have been satisfactorily elucidated, and some of mycotoxins have been classified as carcinogenic to humans. Nevertheless, patulin (PAT) is considered by the International Agency of Research on Cancer as 'not carcinogenic to humans'. The present study was designed to understand the effect of this mycotoxin on melanoma cells (B16F10) by measuring cell proliferation and assessing the anti-tumour effect in vivo in Balb/c mice. Our results revealed that intraperitoneally administration of PAT for 20 days significantly induces tumour regression in B16F10 cell-implanted mice. This effect was evidenced by the activation of apoptosis which is supported by the increase in p53 and Bax expressions, the downregulation of the protein levels of Bcl2, and the increase in caspase-3 activity. Moreover, systemic toxicity analysis demonstrated that there is no potential toxicity following PAT treatment unlike untreated melanoma mice which suffer from anaemia, inflammation and liver dysfunction. Remarkably, this is the first published report demonstrating the therapeutic efficacy of PAT in vivo models. PMID:26619846

  3. Butylated Hydroxyanisole Blocks the Occurrence of Tumor Associated Macrophages in Tobacco Smoke Carcinogen-Induced Lung Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Yan Zhang

    2013-12-01

    Full Text Available Tumor-associated macrophages (TAMs promote tumorigenesis because of their proangiogenic and immune-suppressive functions. Here, we report that butylated hydroxyanisole (BHA blocks occurrence of tumor associated macrophages (TAMs in tobacco smoke carcinogen-induced lung tumorigenesis. Continuous administration of butylated hydroxyanisole (BHA, a ROS inhibitor, before or after NNK treatment significantly blocked tumor development, although less effectively when BHA is administered after NNK treatment. Strikingly, BHA abolished the occurrence of F4/80+ macrophages with similar efficiency no matter whether it was administered before or after NNK treatment. Detection of cells from bronchioalveolar lavage fluid (BALF confirmed that BHA markedly inhibited the accumulation of macrophages while slightly reducing the number of lymphocytes that were induced by NNK. Immunohistological staining showed that BHA specifically abolished the occurrence of CD206+ TAMs when it was administered before or after NNK treatment. Western blot analysis of TAMs markers, arginase I and Ym-1, showed that BHA blocked NNK-induced TAMs accumulation. Our study clearly demonstrated that inhibiting the occurrence of TAMs by BHA contributes to the inhibition of tobacco smoke carcinogen-induced tumorigenesis, suggesting ROS inhibitors may serve as a therapeutic target for treating smoke-induced lung cancer.

  4. Major carcinogenic pathways identified by gene expression analysis of peritoneal mesotheliomas following chemical treatment in F344 rats

    International Nuclear Information System (INIS)

    This study was performed to characterize the gene expression profile and to identify the major carcinogenic pathways involved in rat peritoneal mesothelioma (RPM) formation following treatment of Fischer 344 rats with o-nitrotoluene (o-NT) or bromochloracetic acid (BCA). Oligo arrays, with over 20,000 target genes, were used to evaluate o-NT- and BCA-induced RPMs, when compared to a non-transformed mesothelial cell line (Fred-PE). Analysis using Ingenuity Pathway Analysis software revealed 169 cancer-related genes that were categorized into binding activity, growth and proliferation, cell cycle progression, apoptosis, and invasion and metastasis. The microarray data were validated by positive correlation with quantitative real-time RT-PCR on 16 selected genes including igf1, tgfb3 and nov. Important carcinogenic pathways involved in RPM formation included insulin-like growth factor 1 (IGF-1), p38 MAPkinase, Wnt/β-catenin and integrin signaling pathways. This study demonstrated that mesotheliomas in rats exposed to o-NT- and BCA were similar to mesotheliomas in humans, at least at the cellular and molecular level

  5. Structure, function and carcinogenicity of metabolites of methylated and non-methylated polycyclic aromatic hydrocarbons: a comprehensive review.

    Science.gov (United States)

    Flesher, James W; Lehner, Andreas F

    2016-03-01

    The Unified Theory of PAH Carcinogenicity accommodates the activities of methylated and non-methylated polycyclic aromatic hydrocarbons (PAHs) and states that substitution of methyl groups on meso-methyl substituted PAHs with hydroxy, acetoxy, chloride, bromide or sulfuric acid ester groups imparts potent cancer producing properties. It incorporates specific predictions from past researchers on the mechanism of carcinogenesis by methyl-substituted hydrocarbons, including (1) requirement for metabolism to an ArCH2X type structure where X is a good leaving group and (2) biological substitution of a meso-methyl group at the most reactive center in non-methylated hydrocarbons. The Theory incorporates strong inferences of Fieser: (1) The mechanism of carcinogenesis involves a specific metabolic substitution of a hydrocarbon at its most reactive center and (2) Metabolic elimination of a carcinogen is a detoxifying process competitive with that of carcinogenesis and occurring by a different mechanism. According to this outlook, chemical or biochemical substitution of a methyl group at the reactive meso-position of non-methylated hydrocarbons is the first step in the mechanism of carcinogenesis for most, if not all, PAHs and the most potent metabolites of PAHs are to be found among the meso methyl-substituted hydrocarbons. Some PAHs and their known or potential metabolites and closely related compounds have been tested in rats for production of sarcomas at the site of subcutaneous injection and the results strongly support the specific predictions of the Unified Theory. PMID:26894797

  6. Carcinogen-DNA interaction study by base sequence footprinting. Final report, July 1, 1983-June 30, 1986

    International Nuclear Information System (INIS)

    Our previous studies on acetylaminofluorene (AAF) modified DNA demonstrated three kinds of structural changes in DNA of defined base sequence. For example, adduct formation by N-Aco-AAF was found at each guanine. We studied the interaction of IgG specific for AAF guanosine in an in vitro system using AAF modified phi X-174 rf DNA. We had expected to find protection against DNAase I digestion. Instead, when the DNA was immunobound to an inert matrix via the IgG, DNAase I digestion was enhanced 20 fold without changing the base sequence pattern of digestion. DNAase I hypersensitive sites are a necessary but not a sufficient condition for transcription. Moreover, some hypersensitive sites are stably propagated, independent of the continued presence of the inducer. Stability of these hypersensitive sites in the absence of their inducer suggests that they can be propagated. It appeared likely that distortion of DNA by a carcinogen adduct such as AAF, and the interaction of this modified DNA with a specific protein such as IgG or cellular proteins might inappropriately enhance the transcription of specific genes. That hypothesis will be tested; surprisingly, little is known about the early action of carcinogens on expression of specific genes. 34 refs., 2 figs., 1 tab

  7. Activation of the germ-cell potential of human bone marrow-derived cells by a chemical carcinogen

    Science.gov (United States)

    Liu, Chunfang; Ma, Zhan; Xu, Songtao; Hou, Jun; Hu, Yao; Yu, Yinglu; Liu, Ruilai; Chen, Zhihong; Lu, Yuan

    2014-01-01

    Embryonic/germ cell traits are common in malignant tumors and are thought to be involved in malignant tumor behaviors. The reasons why tumors show strong embryonic/germline traits (displaced germ cells or gametogenic programming reactivation) are controversial. Here, we show that a chemical carcinogen, 3-methyl-cholanthrene (3-MCA), can trigger the germ-cell potential of human bone marrow-derived cells (hBMDCs). 3-MCA promoted the generation of germ cell-like cells from induced hBMDCs that had undergone malignant transformation, whereas similar results were not observed in the parallel hBMDC culture at the same time point. The malignant transformed hBMDCs spontaneously and more efficiently generated into germ cell-like cells even at the single-cell level. The germ cell-like cells from induced hBMDCs were similar to natural germ cells in many aspects, including morphology, gene expression, proliferation, migration, further development, and teratocarcinoma formation. Therefore, our results demonstrate that a chemical carcinogen can reactivate the germline phenotypes of human somatic tissue-derived cells, which might provide a novel idea to tumor biology and therapy. PMID:24998261

  8. Alkylation of deoxyribonucleic acid by carcinogens dimethyl sulphate, ethyl methanesulphonate, N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea

    International Nuclear Information System (INIS)

    The ethyl phosphotriester of thymidylyl(3'-5')thymidine, dTp((Et) dT, was identified as a product from the reaction of DNA with N-ethyl-N-nitrosourea. Enzymic degradation to yield alkyl phosphotriesters from DNA alkylated by this carcinogen, and by N-methyl-N-nitrosourea, dimethyl sulphate and ethyl methanesulphonate was studied quantitatively, and the relative yields of the triesters dTp(Alk)dT were determined. The relative reactivity of the phosphodiester group dTpdT to each of the four carcinogens was thus obtained, and compared with that of DNA overall, or with that of the N-7 atom of guanine in DNA. The results are related to steric factors, and the electrophilic character of each carcinogen. (author)

  9. Evaluation of the Xpa-deficient transgenic mouse model for short-term carcinogenicity testing: 9-month studies with haloperidol, reserpine, phenacetin, and D-mannitol.

    Science.gov (United States)

    Lina, Ben A R; Woutersen, Ruud A; Bruijntjes, Joost P; van Benthem, Jan; van den Berg, Jolanda A H; Monbaliu, Johan; Thoolen, Bob J J M; Beems, Rudolf B; van Kreijl, Coen F

    2004-01-01

    As part of the international evaluation program coordinated by ILSI/HESI, the potential of DNA repair deficient Xpa-/- mice and the double knockout Xpa-/-.p53+/- mice for short term carcinogenicity assays was evaluated. For comparison also wild-type C57BL/6 mice (WT) were included in these studies. Four test compounds were administered to groups of 15 male and 15 female Xpa-/- mice, Xpa-/-.p53+/- mice and WT mice for 39 weeks. The model compounds investigated were haloperidol, reserpine (nongenotoxic rodent carcinogens, putative human noncarcinogens), phenacetin (genotoxic rodent carcinogen, suspected human carcinogen), and D-mannitol (noncarcinogen in rodents and humans). The test compounds were administered as admixture to rodent diet at levels up to 25 mg/kg diet for haloperidol, 7.5 mg/kg diet for reserpine, 0.75% for phenacetin, and 10% for D-mannitol. These levels included the maximum tolerable dose (MTD). Survival was not affected with any of the test compounds. Haloperidol, reserpine and D-mannitol were negative in the carcinogenicity assay with Xpa-/- and Xpa-/-.p53+/- mice, showing low and comparable tumor incidences in controls and high-dose animals. The results obtained with phenacetin may be designated equivocal in Xpa-/-.p53+/- mice, based on the occurrence of a single rare tumor in the target organ (kidney) accompanied by a low incidence of hyperplastic renal lesions and a high incidence of karyomegaly. These results are in agreement with the currently known carcinogenic potential of the 4 test compounds in humans. PMID:15200157

  10. Carcinogen-Specific Gene Expression Profiles in Short-term Treated Eker and Wild-type Rats Indicative of Pathways Involved in Renal Tumorigenesis

    OpenAIRE

    Stemmer, Kerstin; Ellinger-Ziegelbauer, Heidrun; Ahr, Hans-Jürgen; Dietrich, Daniel R

    2007-01-01

    Eker rats heterozygous for a dominant germline mutation in the tuberous sclerosis 2 (Tsc2) tumor suppressor gene were used as a model to study renal carcinogenesis. Eker and corresponding wild-type rats were exposed to genotoxic aristolochic acid (AA) or non-genotoxic ochratoxin A (OTA) to elucidate early carcinogen-specific gene expression changes and to test whether Eker rats are more sensitive to carcinogen-induced changes in gene expression. Male Eker and wild-type rats were gavaged daily...

  11. Alternative Toxicity Testing: Analyses on Skin Sensitization, ToxCast Phases I and II, and Carcinogenicity Provide Indications on How to Model Mechanisms Linked to Adverse Outcome Pathways.

    Science.gov (United States)

    Benigni, Romualdo; Battistelli, Chiara Laura; Bossa, Cecilia; Giuliani, Alessandro; Tcheremenskaia, Olga

    2015-01-01

    This article studies alternative toxicological approaches, with new (skin sensitization, ToxCast) and previous (carcinogenicity) analyses. Quantitative modeling of rate-limiting steps in skin sensitization and carcinogenicity predicts the majority of toxicants. Similarly, successful (Quantitative) Structure-Activity Relationships models exploit the quantification of only one, or few rate-limiting steps. High-throughput assays within ToxCast point to promising associations with endocrine disruption, whereas markers for pathways intermediate events have limited correlation with most endpoints. Since the pathways may be very different (often not simple linear chains of events), quantitative analysis is necessary to identify the type of mechanism and build the appropriate model. PMID:26398111

  12. Lung Carcinogenic Bioassay of CuO and TiO2 Nanoparticles with Intratracheal Instillation Using F344 Male Rats

    OpenAIRE

    YOKOHIRA, MASANAO; Hashimoto, Nozomi; YAMAKAWA, KEIKO; Suzuki, Satoshi; Saoo, Kousuke; KUNO, TOSHIYA; Imaida, Katsumi

    2009-01-01

    Toxicity assessment of nanoparticles, now widespread in our environment, is an important issue. We have focused attention on the carcinogenic potential of copper oxide (CuO) and titanium dioxide (TiO2). In experiment 1, a sequential pilot study, the effectiveness of a carcinogenic bioassay featuring intraperitoneal injection (i.p.) of 20 mg 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) or 0.1% N-bis(2-hydroxypropyl)nitrosamine (DHPN) in drinking water for 2 weeks was examined. Based on...

  13. Toxicity and carcinogenicity studies of Caramel Colour IV in F344 rats and B6C3F1 mice.

    Science.gov (United States)

    MacKenzie, K M; Boysen, B G; Field, W E; Petsel, S R; Chappel, C I; Emerson, J L; Stanley, J

    1992-05-01

    Caramel Colour IV, a type of caramel colour used in the manufacture of cola soft drinks, was evaluated for subchronic and chronic toxicity in rats, and carcinogenicity in Fischer-344 (F344) rats and B6C3F1 mice. In each of the studies, Caramel Colour IV was mixed with demineralized water and the solutions given to the animals ad lib. in the drinking fluid. The concentrations of Caramel Colour IV in the drinking fluid were adjusted periodically to achieve the desired caramel colour intake per kg body weight. In the range-finding studies, groups of 30 rats/sex were given Caramel Colour IV at levels of 0, 15, 20, 25 or 30 g/kg for 13 wk, and groups of 10 male rats were given levels of 0, 2.5, 5, 10 or 15 g/kg for 6 wk followed, for some dose groups, by a 2-wk withdrawal period, and then re-initiation of dosing for another 2 wk. In the rat chronic toxicity study, levels of Caramel Colour IV of 0, 2.5, 5, 7.5 or 10 g/kg were given to groups of 25 rats/sex for 12 months. The test groups in the rat and mouse carcinogenicity studies were composed of 50 animals/sex and each species was given the caramel colour at levels of 0, 0, 2.5, 5 or 10 g/kg for 24 months. In each of the studies, treated animals tended to have dose-related lower water consumption than controls. This was attributed to poor palatability of the drinking fluid, and was generally associated with decreased food consumption and body weights. Rats given caramel colour often had soft or liquid malodorous faeces although there were no treatment-related ante-mortem observations in mice. Blood biochemical changes in the rat (i.e. reduced blood urea nitrogen, alkaline phosphatase and total serum protein) appeared to be related to dietary influences and were not considered toxicologically significant. There were no treatment-related alterations in haematological variables or treatment-related differences in survival or in the incidence of benign or malignant tumours among treated and control groups and no

  14. Exposure assessment suggests exposure to lung cancer carcinogens in a painter working in an automobile bumper shop.

    Science.gov (United States)

    Kim, Boowook; Yoon, Jin-Ha; Choi, Byung-Soon; Shin, Yong Chul

    2013-12-01

    A 46-year-old man who had worked as a bumper spray painter in an automobile body shop for 15 years developed lung cancer. The patient was a nonsmoker with no family history of lung cancer. To determine whether the cancer was related to his work environment, we assessed the level of exposure to carcinogens during spray painting, sanding, and heat treatment. The results showed that spray painting with yellow paint increased the concentration of hexavalent chromium in the air to as much as 118.33 μg/m(3). Analysis of the paint bulk materials showed that hexavalent chromium was mostly found in the form of lead chromate. Interestingly, strontium chromate was also detected, and the concentration of strontium chromate increased in line with the brightness of the yellow color. Some paints contained about 1% crystalline silica in the form of quartz. PMID:24422178

  15. Analysis of carcinogenic activity of some pesticides in a medium-term liver bioassay in the rat.

    Science.gov (United States)

    Hakoi, K; Cabral, R; Hoshiya, T; Hasegawa, R; Shirai, T; Ito, N

    1992-01-01

    Eight pesticides were tested in a medium-term bioassay based upon the induction of preneoplastic lesions in the liver. Rats were initially given diethylnitrosamine intraperitoneally at a dose of 200 mg/kg body weight and 2 weeks later were treated with the pesticides for 6 weeks and then killed; all rats had a partial hepatectomy at week 3. Hepatocarcinogenic potential was assessed by comparing the number and area of glutathione S-transferase placental form positive foci in the liver with those of controls given diethylnitrosamine (DEN) alone. Positive results were seen with p,p-DDT and Triadimefon. Permethrin (mixture of 39% cis form and 61% trans form) showed borderline results. Permethrin (25/75), Deltamethrin, Cypermethrin (52/48), while Trimorphamide and Propineb gave negative results. Our findings provide experimental evidence to indicate that compounds active in this assay have a potential for liver carcinogenicity in rodents. PMID:1363965

  16. Ejection of toxic and carcinogenic substances along with the exhaust gasses of gas turbine engines and ways of reducing them

    Energy Technology Data Exchange (ETDEWEB)

    Varshavskiy, I.L.; Kanilo, P.M.; Khesina, A.Y.; Ryabeka, V.P.; Smirnov, G.A.

    1981-01-01

    Studies of the amount of carcinogenic substances in exhaust gasses of piston aviation engines showed that the concentration of Benzene (A) tyrene in exhaust gasses is found at a level of 0.5-5 micrograms/m/sup 3/. It increases with an increase of a load, rotation frequency and angle of advance of fuel injection. The maximum concentration of Benzene(A)tyrene is observed in transitional states related to acceleration of the airplane. Measures to reduce the ejection of NO (injection of water into the combustion chamber, the use of water and fuel emulsions, recirculation of the treated gasses into the combustion chamber) relates to an increase of Benzene(a)tyrene ejections. Tests were carried out on an experimental test bed using the gas turbine aviation engine type AI-9 to determine the amount of waste gasses that are carcinogenic and toxic. The Benzene(a)tyrene concentration in waste gasses of piston engines (0.8 micrograms/m/sup 3/) with an increase of the total coefficient of excess air in a combustion chamber increases by a factor of 2 to 4. Enriching the fuel-air mixture with hydrogen in a combustion chamber of a gas turbine engine by adding hydrogen to the primary zone of the combustion chamber simultaneously reduces the concentration of waste gasses, Benzene(a)tyrene and CO. For the AI-25 gas turbine engine the addition of hydrogen in the amount of 5% mass of fuel reduces the ejection of CO by a factor of 2, and that of Benzene(a)tyrene by a factor of 7.

  17. Inhalation and dermal exposure to atmospheric polycyclic aromatic hydrocarbons and associated carcinogenic risks in a relatively small city.

    Science.gov (United States)

    Gungormus, Elif; Tuncel, Semra; Hakan Tecer, Lokman; Sofuoglu, Sait C

    2014-10-01

    The aim of this study was to conduct a carcinogenic risk assessment for exposure to polycyclic aromatic hydrocarbons (PAHs) via routes of inhalation and dermal contact. Concentrations of 19 PAH species were determined during a heating period at a site in the city of Balikesir, Turkey. Two questionnaires were administered to a sample of inhabitants to determine time-activity budgets and demographic information. The assessment was conducted for each participant and Balikesir population by deterministic and probabilistic approaches, respectively. Monte Carlo simulation was implemented to determine the population exposure-risk probability distributions. The estimates were based on benzo[a]pyrene equivalent (BaPeq) total PAH concentrations calculated using toxic equivalency factors. The mean and median BaPeq concentrations of gaseous and particulate phases were 3.25 and 1.34, and 38.5 and 34.0ng/m(3), respectively. Carcinogenic risk for inhalation exposure route was estimated by using two different slope factor values (3.9 and 304.5(mg/kg-day)(-1)), recommended by two different organizations, resulting in two (order(s) of magnitude apart) population risk ranges: 1.32×10(-7)-2.23×10(-4), and 1.61×10(-5)-7.95×10(-3), respectively. The population risks associated with dermal exposure were lower compared to those of inhalation, ranging from 6.58×10(-9) to 2.57×10(-6). The proportion of the population with risks higher than the general acceptable level (1.0×10(-6)) was estimated as >99 percent, for inhalation, and as 28 percent for dermal exposure route. PMID:25046852

  18. The history, genotoxicity, and carcinogenicity of carbon-based fuels and their emissions. Part 2: solid fuels.

    Science.gov (United States)

    Claxton, Larry D

    2014-01-01

    The combustion of solid fuels (like wood, animal dung, and coal) usually involves elevated temperatures and altered pressures and genotoxicants (e.g., PAHs) are likely to form. These substances are carcinogenic in experimental animals, and epidemiological studies implicate these fuels (especially their emissions) as carcinogens in man. Globally, ∼50% of all households and ∼90% of all rural households use solid fuels for cooking or heating and these fuels often are burnt in simple stoves with very incomplete combustion. Exposed women and children often exhibit low birth weight, increased infant and perinatal mortality, head and neck cancer, and lung cancer although few studies have measured exposure directly. Today, households that cannot meet the expense of fuels like kerosene, liquefied petroleum gas, and electricity resort to collecting wood, agricultural residue, and animal dung to use as household fuels. In the more developed countries, solid fuels are often used for electric power generation providing more than half of the electricity generated in the United States. The world's coal reserves, which equal approximately one exagram, equal ∼1 trillion barrels of crude oil (comparable to all the world's known oil reserves) and could last for 600 years. Studies show that the PAHs that are identified in solid fuel emissions react with NO2 to form direct-acting mutagens. In summary, many of the measured genotoxicants found in both the indoor and electricity-generating combustors are the same; therefore, the severity of the health effects vary with exposure and with the health status of the exposed population. PMID:25475420

  19. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

    Science.gov (United States)

    Goodson, William H.; Lowe, Leroy; Carpenter, David O.; Gilbertson, Michael; Manaf Ali, Abdul; Lopez de Cerain Salsamendi, Adela; Lasfar, Ahmed; Carnero, Amancio; Azqueta, Amaya; Amedei, Amedeo; Charles, Amelia K.; Collins, Andrew R.; Ward, Andrew; Salzberg, Anna C.; Colacci, Anna Maria; Olsen, Ann-Karin; Berg, Arthur; Barclay, Barry J.; Zhou, Binhua P.; Blanco-Aparicio, Carmen; Baglole, Carolyn J.; Dong, Chenfang; Mondello, Chiara; Hsu, Chia-Wen; Naus, Christian C.; Yedjou, Clement; Curran, Colleen S.; Laird, Dale W.; Koch, Daniel C.; Carlin, Danielle J.; Felsher, Dean W.; Roy, Debasish; Brown, Dustin G.; Ratovitski, Edward; Ryan, Elizabeth P.; Corsini, Emanuela; Rojas, Emilio; Moon, Eun-Yi; Laconi, Ezio; Marongiu, Fabio; Al-Mulla, Fahd; Chiaradonna, Ferdinando; Darroudi, Firouz; Martin, Francis L.; Van Schooten, Frederik J.; Goldberg, Gary S.; Wagemaker, Gerard; Nangami, Gladys N.; Calaf, Gloria M.; Williams, Graeme P.; Wolf, Gregory T.; Koppen, Gudrun; Brunborg, Gunnar; Lyerly, H. Kim; Krishnan, Harini; Ab Hamid, Hasiah; Yasaei, Hemad; Sone, Hideko; Kondoh, Hiroshi; Salem, Hosni K.; Hsu, Hsue-Yin; Park, Hyun Ho; Koturbash, Igor; Miousse, Isabelle R.; Scovassi, A.Ivana; Klaunig, James E.; Vondráček, Jan; Raju, Jayadev; Roman, Jesse; Wise, John Pierce; Whitfield, Jonathan R.; Woodrick, Jordan; Christopher, Joseph A.; Ochieng, Josiah; Martinez-Leal, Juan Fernando; Weisz, Judith; Kravchenko, Julia; Sun, Jun; Prudhomme, Kalan R.; Narayanan, Kannan Badri; Cohen-Solal, Karine A.; Moorwood, Kim; Gonzalez, Laetitia; Soucek, Laura; Jian, Le; D’Abronzo, Leandro S.; Lin, Liang-Tzung; Li, Lin; Gulliver, Linda; McCawley, Lisa J.; Memeo, Lorenzo; Vermeulen, Louis; Leyns, Luc; Zhang, Luoping; Valverde, Mahara; Khatami, Mahin; Romano, Maria Fiammetta; Chapellier, Marion; Williams, Marc A.; Wade, Mark; Manjili, Masoud H.; Lleonart, Matilde E.; Xia, Menghang; Gonzalez Guzman, Michael J.; Karamouzis, Michalis V.; Kirsch-Volders, Micheline; Vaccari, Monica; Kuemmerle, Nancy B.; Singh, Neetu; Cruickshanks, Nichola; Kleinstreuer, Nicole; van Larebeke, Nik; Ahmed, Nuzhat; Ogunkua, Olugbemiga; Krishnakumar, P.K.; Vadgama, Pankaj; Marignani, Paola A.; Ghosh, Paramita M.; Ostrosky-Wegman, Patricia; Thompson, Patricia A.; Dent, Paul; Heneberg, Petr; Darbre, Philippa; Leung, Po Sing; Nangia-Makker, Pratima; Cheng, Qiang (Shawn); Robey, R.Brooks; Al-Temaimi, Rabeah; Roy, Rabindra; Andrade-Vieira, Rafaela; Sinha, Ranjeet K.; Mehta, Rekha; Vento, Renza; Di Fiore, Riccardo; Ponce-Cusi, Richard; Dornetshuber-Fleiss, Rita; Nahta, Rita; Castellino, Robert C.; Palorini, Roberta; Hamid, Roslida A.; Langie, Sabine A.S.; Eltom, Sakina E.; Brooks, Samira A.; Ryeom, Sandra; Wise, Sandra S.; Bay, Sarah N.; Harris, Shelley A.; Papagerakis, Silvana; Romano, Simona; Pavanello, Sofia; Eriksson, Staffan; Forte, Stefano; Casey, Stephanie C.; Luanpitpong, Sudjit; Lee, Tae-Jin; Otsuki, Takemi; Chen, Tao; Massfelder, Thierry; Sanderson, Thomas; Guarnieri, Tiziana; Hultman, Tove; Dormoy, Valérian; Odero-Marah, Valerie; Sabbisetti, Venkata; Maguer-Satta, Veronique; Rathmell, W.Kimryn; Engström, Wilhelm; Decker, William K.; Bisson, William H.; Rojanasakul, Yon; Luqmani, Yunus; Chen, Zhenbang; Hu, Zhiwei

    2015-01-01

    Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. PMID:26106142

  20. Determination of genetic toxicity and potential carcinogenicity in vitro--challenges post the Seventh Amendment to the European Cosmetics Directive.

    Science.gov (United States)

    Tweats, D J; Scott, A D; Westmoreland, C; Carmichael, P L

    2007-01-01

    Genetic toxicology and its role in the detection of carcinogens is currently undergoing a period of reappraisal. There is an increasing interest in developing alternatives to animal testing and the three R's of reduction, refinement and replacement are the basis for EU and national animal protection laws the Seventh Amendment to the EU Cosmetics Directive will ban the marketing of cosmetic/personal care products that contain ingredients that have been tested in animal models. Thus in vivo tests such as the bone marrow micronucleus test, which has a key role in current testing strategies for genotoxicity, will not be available for this class of products. The attrition rate for new, valuable and safe chemicals tested in an in vitro-only testing battery, using the in vitro tests currently established for genotoxicity screening, will greatly increase once this legislation is in place. In addition there has been an explosion of knowledge concerning the cellular and molecular events leading to carcinogenesis. This knowledge has not yet been fully factored into screening chemicals for properties that are not directly linked to mutation induction. Thus there is a pressing need for new, more accurate approaches to determine genotoxicity and carcinogenicity. However, a considerable challenge is presented for these new approaches to be universally accepted and new tests sufficiently validated by March 2009 when the animal testing and marketing bans associated with the Seventh Amendment are due to come into force. This commentary brings together ideas and approaches from several international workshops and meetings to consider these issues. PMID:17142828

  1. Carcinogenicity of individual and a mixture of dioxin-like compounds in female Harlan Sprague Dawley rats

    Energy Technology Data Exchange (ETDEWEB)

    Walker, N.; Nyska, A. [National Institute of Environmental Health Sciences, Research Triangle Park, NC (United States); Crockett, P. [Constella Group, Research Triangle Park, NC (US)] (and others)

    2004-09-15

    The human health risk posed by exposure to persistent organochlorine pollutants (POPs), including polychlorinated-dioxins (PCDDs), -furans (PCDFs) and - biphenyls (PCBs), present in the food and the environment is one of widespread concern throughout the industrialized world. The dioxin Toxic Equivalency Factor (TEF) approach is currently the most feasible interim approach for assessing and managing the risk posed by exposure to mixtures of these compounds and has been formally adopted by regulatory bodies in many countries, the International Programme on Chemical Safety and the World Health Organization. The TEF methodology is a relative potency scheme that estimates the total exposure and biological effects of a mixture of chemicals based on a common mechanism of action involving an initial binding of the compound to the Aryl hydrocarbon receptor (AhR). An implicit assumption of the TEF methodology is that the combined risk of effects of the different congeners is dose additive. Therefore, the total dioxin toxic equivalents (TEQs) of a mixture of PCDDs, PCDFs, and PCBs may be estimated by the summation of the mass of each compound in the mixture after adjustment for its potency relative to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While dose additivity is supported for certain mixtures for some biological endpoints in some experimental models, this has never been evaluated for cancer risk. Here we present a summary of four chronic rodent bioassay conducted by the National Toxicology Program (US Department of Health and Human Services) that evaluated the carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3.3',4,4',5- pentachlorobiphenyl (PCB126) and 2,3,4,7,8 pentachlorodibenzofuran (PeCDF) and a mixture of these three dioxin-like compounds in female Harlan Sprague Dawley rats. Data from these studies will be used to test the hypothesis of dose-additivity of carcinogenicity by a defined mixture of dioxin-like compounds.

  2. Assessment of possible carcinogenicity of oxyfluorfen to humans using mode of action analysis of rodent liver effects.

    Science.gov (United States)

    Stagg, Nicola J; LeBaron, Matthew J; Eisenbrandt, David L; Gollapudi, B Bhaskar; Klaunig, James E

    2012-08-01

    Oxyfluorfen is a herbicide that is not genotoxic and produces liver toxicity in rodents, following repeated administration at high dose levels. Lifetime rodent feeding studies reported in 1977 with low-purity oxyfluorfen (85%) showed no increase in any tumor type in rats (800 ppm, high dose) and only a marginally increased incidence of hepatocellular tumors in male CD-1 mice at the highest dose (200 ppm). To evaluate the potential carcinogenicity of the currently registered oxyfluorfen (> 98% purity), we conducted a series of short-term liver mode of action (MOA) toxicology studies in male CD-1 mice administered dietary doses of 0, 40, 200, 800, and 1600 ppm for durations of 3, 7, 10, or 28 days. MOA endpoints examined included liver weight, histopathology, cell proliferation, nuclear receptor-mediated gene expression, and other peroxisome proliferator-specific endpoints and their reversibility. Minimal liver effects were observed in mice administered doses at or below 200 ppm for up to 28 days. Increased liver weight, single-cell necrosis, cell proliferation, and peroxisomal acyl-CoA oxidase (ACO) were observed at 800 ppm after 28 days, but there was no increase in peroxisomes. Expression of Cyp2b10 and Cyp4a10 transcripts, markers of constitutive androstane receptor and peroxisome proliferator activated receptor α nuclear receptor activation, respectively, were increased at 800 and 1600 ppm after 3 or 10 days. Collectively, these data along with the negative genotoxicity demonstrate that oxyfluorfen (> 98% purity) has the potential to induce mouse liver tumors through a nongenotoxic, mitogenic MOA with a clear threshold and is not predicted to be carcinogenic in humans at relevant exposure levels. PMID:22539621

  3. Review of carcinogenicity of asbestos and proposal of approval standards of an occupational cancer caused by asbestos in Korea.

    Science.gov (United States)

    Im, Sanghyuk; Youn, Kan-Woo; Shin, Donghee; Lee, Myeoung-Jun; Choi, Sang-Jun

    2015-01-01

    Carcinogenicity of asbestos has been well established for decades and it has similar approval standards in most advanced countries based on a number of studies and international meetings. However, Korea has been lagging behind such international standards. In this study, we proposed the approval standards of an occupational cancer due to asbestos through intensive review on the Helsinki Criteria, post-Helsinki studies, job exposure matrix (JEM) based on the analysis of domestic reports and recognized occupational lung cancer cases in Korea. The main contents of proposed approval standards are as follows; ① In recognizing an asbestos-induced lung cancer, diagnosis of asbestosis should be based on CT. In addition, initial findings of asbestosis on CT should be considered. ② High Exposure industries and occupations to asbestos should be also taken into account in Korea ③ An expert's determination is warranted in case of a worker who has been concurrently exposed to other carcinogens, even if the asbestos exposure duration is less than 10 years. ④ Determination of a larynx cancer due to asbestos exposure has the same approval standards with an asbestos-induced lung cancer. However, for an ovarian cancer, an expert's judgment is necessary even if asbestosis, pleural plaque or pleural thickening and high concentration asbestos exposure are confirmed. ⑤ Cigarette smoking status or the extent should not affect determination of an occupational cancer caused by asbestos as smoking and asbestos have a synergistic effect in causing a lung cancer and they are involved in carcinogenesis in a complicated manner. PMID:26719804

  4. Risk Assessment of Non-Carcinogenic Heavy Metals (Barium, Cadmium, and Lead in Hair Color in Markets of Tehran

    Directory of Open Access Journals (Sweden)

    F Khalili

    2016-06-01

    Full Text Available Background and Objectives: Chemical hair color are one of the most widely used cosmetics. The presence of heavy metals in these products can affect the health of consumers. Unlike other cosmetics, no study has been conducted on the heavy metal levels in the synthetic chemical hair colors. This study determined the concentration of heavy metals in these products and the risk assessment of non-carcinogenic effects by these elements were calculated. Material and Method: 32 samples of chemical hair color from eight brands (3 local and 5 imported ones and four most used colors were collected from the markets in Tehran. The concentration of cadmium, lead, and barium was determined using ICP-MS. The information required to assess exposure risk was gathered through  a questionnaire distributed among citizens of Tehran. The assessment of exposure was conducted using Mont Carlo method and  non-carcinogenic risk was determined using the index of Hazard Quotient. . Results: Barium concentration measured was 0.86 mg/kg and concentrations of Cadmium and Lead were 0.45 and 185.34 µg/kg respectively. Among the elements, Pb with Hazard Quotient equals to 7.46×10-4 had the most risk and cadmium with Hazard Quotient equals to 3.57×10-5 had the lowest risk. Moreover, the Iranian brand and blond had the highest risk among the samples. Conclusion: Based on the index of Hazard Quotient, heavy metals in the studied samples had no risk for consumers of these products.

  5. Squamous cell carcinoma in association with dental implants: an assessment of previously hypothesized carcinogenic mechanisms and a case report.

    Science.gov (United States)

    Bhatavadekar, Neel B

    2012-12-01

    Although dental implants have seen tremendous clinical success over the past few decades, there are some worrying reports in literature describing squamous cell carcinoma (SCC) in close association with dental implants. This article also provides a critical assessment of the published literature relating to the presence of carcinoma in association with dental implants, analyzing the previously published and hypothesized carcinogenic responses to an implant, to try and come to a conclusion regarding the plausibility and clinical risk for cancer formation in association with dental implants. An unusual case of an SCC noted in close proximity to a dental implant is also presented. A systematic search was conducted using Medline (PubMed), Cochrane Database, and Google Scholar with the search terms "cancer," "squamous cell carcinoma," "dental implant," "SCC," "peri-implantitis," "oral cancer," and "implantology" and using multiple combinations using Boolean operators "or" and "and." The search was not limited to dental literature; orthopedic and biomedical literature was also included. The results were then hand screened to pick out the relevant articles. In total, 14 previous published reports were found, where 24 dental implants were reported to be associated with SCC. Not all the reported patients had a history of cancer, but contributory factors such as smoking were found. An analysis of the biological plausibility of previously proposed carcinogenic mechanisms, such as corrosion, metallic ion release, and particulate debris, did not support the etiologic role for dental implants in cancer development, and the standardized incidence ratio was found to be extremely low (0.00017). Peri-implantitis should be assessed cautiously in patients receiving implants who have a previous history of cancer. Dental implants are a safe treatment modality based on the published data, and any change in surgical protocol is not mandated. PMID:21574824

  6. Determination of some carcinogenic PAHs with toxic equivalency factor along roadside soil within a fast developing northern city of India

    Science.gov (United States)

    Kumar, A. Vaneet; Kothiyal, N. C.; Kumari, Saruchi; Mehra, R.; Parkash, A.; Sinha, R. R.; Tayagi, S. K.; Gaba, R.

    2014-04-01

    The objective of the present study was to ascertain contamination levels, distribution behaviour and PAHs exposure during summer, winter and autumn during 2011-2012 in one of the developing cities of northern India. Average PAHs concentration was found to be 18.17, 4.04 and 16.38 μg g -1, whereas, concentration of 16 individual PAHs was found to vary between 0.02 and 200.23, 0.008 and 28.4 μg g -1, and 0.01 and 252.55 μg g -1 during summer, winter and autumn seasons, respectively. The average concentration of low and high carcinogenic PAHs during summer, winter and autumn was found to be 5.1 and 31.29, 2.1 and 6.4, 4.74 and 35.08 μg g -1 at most intercepts. The average ratio of low to high carcinogenic PAHs was found to be 1:6, 1:3, 1:7.6 during summer, winter and autumn, respectively. Five ringed PAHs were found in higher concentration in all seasons. Dib(ah)A and B(a)P were the two individual PAHs found in highest concentration during summer, winter and autumn seasons. Two tailed T-test was applied for authenticity of the results. Toxic equivalency factor of B(a)P and Dib(ah)A was maximum as compared to other PAHs. The study could be of great significance for the planners while considering environmental remedial measures.

  7. The use of one- and two- photon induced fluorescence spectroscopy for the optical characterization of carcinogenic aflatoxins

    Science.gov (United States)

    Smeesters, L.; Meulebroeck, W.; Raeymaekers, S.; Thienpont, H.

    2014-09-01

    Carcinogenic and toxic contaminants in food and feed products are nowadays mostly detected by destructive, time-consuming chemical analyses, like HPLC and LC-MS/MS methods. However, as a consequence of the severe and growing regulations on food products by the European Union, there arose an increased demand for the ultra-fast, high-sensitive and non-destructive detection of contaminants in food and feed products. Therefore, we have investigated fluorescence spectroscopy for the characterization of carcinogenic aflatoxins. With the use of a tunable titanium-sapphire laser in combination with second and third harmonic wavelength generation, both one- and two-photon induced fluorescence excitation wavelengths could be generated using the same setup. We characterized and compared the one- and two-photon induced fluorescence spectra of pure aflatoxin powder, after excitation with 365nm and 730nm respectively. Moreover, we investigated the absolute fluorescence intensity as function of the excitation power density. Afterwards, we applied our characterization setup to the detection of aflatoxins in maize grains. The fluorescence spectra of both healthy and contaminated maize samples were experimentally characterized. In addition to the fluorescence spectrum of the pure aflatoxin, we observed an unwanted influence of the intrinsic fluorescence of the maize. Depending on the excitation wavelength, a varying contrast between the fluorescence spectra of the healthy and contaminated samples was obtained. After a comparison of the measured fluorescence signals, a detection criterion for the optical identification of the contaminated maize samples could be defined. As a result, this illustrates the use of fluorescence spectroscopy as a valuable tool for the non-destructive, real-time and high-sensitive detection of aflatoxins in maize.

  8. Antioxidant Activity and Anti carcinogenic Properties of Combination Extract of Soursop (Annona Muricata Linn) and Pearl Grass (Hedyotis Corymbosa (L.) Lam.)

    International Nuclear Information System (INIS)

    Soursop (Annona muricata) has numerous traditional medicinal uses in South American and the Caribbean, and it has become a popular nutritional medicinal supplement. In the other hand, pearl grass (Hedyotis corymbosa (L.) Lam.) has long been used traditionally as an anti-inflammatory. In this study, soursop and pearl grass combined to obtain extracts that have anticancer effects and anti-inflammatory effects, as most patients with cancer, particularly advanced breast cancer often experience inflammation. Two types of combination of extracts made by different solvents ie ethanol extract combination (CSEPE) and water extract combination (CSWPW) have been used. The anti carcinogenic properties of both extracts have been studied by using MTT assay. The anti oxidative activity of the extracts which could contribute to their cytotoxic properties was also studied by using DPPH assay. The results showed that the combination extract of ethanolic extract of soursop and pearl grass (CSEPE) has potential anti carcinogenic properties and the properties was decreased during the increment of incubation time but increased with the increasement of doses. However, the combination extract of water extract of soursop and pearl grass (CSWPW) did not displayed the potential anti carcinogenic properties. The anti carcinogenic properties of CSEPE could be due to their high antioxidant activities. (author)

  9. Advancing the 3Rs in regulatory toxicology - Carcinogenicity testing: Scope for harmonisation and advancing the 3Rs in regulated sectors of the European Union.

    Science.gov (United States)

    Annys, Erwin; Billington, Richard; Clayton, Rick; Bremm, Klaus-Dieter; Graziano, Michael; McKelvie, Jo; Ragan, Ian; Schwarz, Michael; van der Laan, Jan Willem; Wood, Charles; Öberg, Mattias; Wester, Piet; Woodward, Kevin N

    2014-07-01

    Different government agencies operating in the European Union regulate different types of chemical products but all require testing for carcinogenicity to support applications for product marketing and commercialisation. A conference was held in Brussels in 2013 where representatives of the pharmaceutical, animal health, chemical and plant protection industries, together with representatives of regulatory agencies, universities and other stakeholders, met under the auspices of The European Partnership for Alternative Approaches to Animal Testing (EPAA) to discuss the varying requirements for carcinogenicity testing, and how these studies might be refined to improve hazard evaluation and risk assessment while implementing principles of the 3Rs (replacement, refinement and reduction in animal studies). While there are some similarities, the regulatory approaches in pharmaceutical, animal health, chemical and plant protection sectors have varying degrees of flexibility in requirements for carcinogenicity testing, to an extent reflecting concerns over the magnitude and duration of human exposure, either directly as in therapeutic exposure to pharmaceuticals, or indirectly through the ingestion of residues of veterinary drugs or plant protection chemicals. The article discusses these differences and other considerations for modified carcinogenicity testing paradigms on the basis of scientific and 3Rs approaches. PMID:24768934

  10. Study of the mechanism of carcinogenesis by carcinogens which are negative in the Ames test. Progress report, April 1-September 1, 1979

    Energy Technology Data Exchange (ETDEWEB)

    None

    1979-01-01

    Carcinogens ethionine, thioacetamide, and actinomycin D, all of which are negative in the Ames test and all of which raise the progesterone level in the chicken, were tested to determine their physiological role in carcinogenesis. The optimization of the carcinogenesis model also included evaluation of the chicken as the biological indicator of physiological changes relative to the above compounds. (PCS)

  11. Organic mutagens and drinking water in the Netherlands : a study on mutagenicity of organic constituents in drinking water in The Netherlands and their possible carcinogenic effects

    NARCIS (Netherlands)

    Kool, H.J.

    1983-01-01

    Several mutagenic and carcinogenic organic compounds have been detected in Dutch surface waters and in drinking water prepared from these surface waters. Although the levels of these compounds in drinking- and surface water are relatively low, in general below μg per litre, it appeared that organic

  12. Morphological transformation and effect on gap junction intercellular communication in Syrian hamster embryo cells as screening tests for carcinogens devoid of mutagenic activity.

    Science.gov (United States)

    Rivedal, E; Mikalsen, S O; Sanner, T

    2000-04-01

    A large fraction of chemicals observed to cause cancer in experimental animals is devoid of mutagenic activity. It is therefore of importance to develop methods that can be used to detect and study environmental carcinogenic agents that do not interact directly with DNA. Previous studies have indicated that induction of in vitro cell transformation and inhibition of gap junction intercellular communication are endpoints that could be useful for the detection of non-genotoxic carcinogens. In the present work, 13 compounds [chlordane, Arochlor 1260, di(2-ethylhexyl)phthalate, 1,1,1-trichloro-2, 2-bis(4-chlorophenyl)ethane, limonene, sodium fluoride, ethionine, o-anisidine, benzoyl peroxide, o-vanadate, phenobarbital, 12-O-tetradecanoylphorbol 13-acetate and clofibrate] have been tested for their ability to induce morphological transformation and affect intercellular communication in Syrian hamster embryo cells. The substances were selected on the basis of being proven or suspected non-genotoxic carcinogens, and thus difficult to detect in short-term tests. The data show that nine of the 13 compounds induced morphological transformation, and seven of the 13 inhibited intercellular communication in hamster embryo cells. Taken together, 12 of the 13 substances either induced transformation or caused inhibition of communication. The data suggest that the combined use of morphological transformation and gap junction intercellular communication in Syrian hamster embryo cells may be beneficial when screening for non-genotoxic carcinogens. PMID:10793297

  13. Finding transcriptomics biomarkers for in vivo identification of (non-)genotoxic carcinogens using wild-type and Xpa/p53 mutant mouse models

    NARCIS (Netherlands)

    M.J. Jonker; O. Bruning; M. van Iterson; M.M. Schaap; T.V. van der Hoeven; H. Vrieling; R.B. Beems; A. de Vries; H. van Steeg; T.M. Breit; M. Luijten

    2009-01-01

    The carcinogenic potential of chemicals and pharmaceuticals is traditionally tested in the chronic, 2 year rodent bioassay. This assay is not only time consuming, expensive and often with a limited sensitivity and specificity but it also causes major distress to the experimental animals. A major imp

  14. Determination of site selectivity of different carcinogens for preferential mutational hot spots in oligonucleotide fragments by ion-pair reversed-phase nano liquid chromatography tandem mass spectrometry.

    Science.gov (United States)

    Sharma, Vaneet K; Xiong, Wennan; Glick, James; Vouros, Paul

    2014-01-01

    Ion-pair reversed-phase nano liquid chromatography coupled with nanospray ion trap mass spectrometry was used to investigate site selectivity of the known carcinogens N-acetoxy-2-acetylaminofluorene, N-hydroxy-4-aminobiphenyl and (+/-)-anti-benzo[a]pyrene diol epoxide with the synthetic double-strand 14-mer long oligonucleotide fragment of the p53 gene containing two mutational hot-spot codons (5'-P-ACC155 CGC156 GTC157 CGC158 GC/5'-GCG CGG ACG CGG GT). The investigation was performed using a monolithic polystyrene divinylbenzene capillary column and triethylammonium bicarbonate as an ion-pair reagent. The exact location of the carcinogen on the modified oligonucleotide backbone was determined using characteristic collision-induced dissociation fragmentation patterns obtained under negative-ion mode ionization. In all these cases, the adducted, isomeric oligonucleotides formed were chromatographically resolved and structural identification was performed without any prior deoxyribonucleic acid cleavage or hydrolysis. The knowledge of the site specificity of a carcinogen, especially at purported mutational hot spots, is of paramount importance (1) in establishing the identity of biomarkers for an early risk assessment of the formed DNA adducts, (2) developing repair mechanisms for the formed carcinogen adducted DNA, and (3) understanding the nature of the covalent bond formed and mapping the frequency of the adduction process. PMID:24881456

  15. How well can in vitro data predict in vivo effects of chemicals? Rodent carcinogenicity as a case study.

    Science.gov (United States)

    Anthony Tony Cox, Louis; Popken, Douglas A; Kaplan, A Michael; Plunkett, Laura M; Becker, Richard A

    2016-06-01

    A recent research article by the National Center for Computational Toxicology (NCCT) (Kleinstreuer et al., 2013), indicated that high throughput screening (HTS) data from assays linked to hallmarks and presumed pathways of carcinogenesis could be used to predict classification of pesticides as either (a) possible, probable or likely rodent carcinogens; or (b) not likely carcinogens or evidence of non-carcinogenicity. Using independently developed software to validate the computational results, we replicated the majority of the results reported. We also found that the prediction model correlating cancer pathway bioactivity scores with in vivo carcinogenic effects in rodents was not robust. A change of classification of a single chemical in the test set was capable of changing the overall study conclusion about the statistical significance of the correlation. Furthermore, in the subset of pesticide compounds used in model validation, the accuracy of prediction was no better than chance for about three quarters of the chemicals (those with fewer than 7 positive outcomes in HTS assays representing the 11 histopathological endpoints used in model development), suggesting that the prediction model was not adequate to predict cancer hazard for most of these chemicals. Although the utility of the model for humans is also unclear because a number of the rodent responses modeled (e.g., mouse liver tumors, rat thyroid tumors, rat testicular tumors, etc.) are not considered biologically relevant to human responses, the data examined imply the need for further research with HTS assays and improved models, which might help to predict classifications of in vivo carcinogenic responses in rodents for the pesticide considered, and thus reduce the need for testing in laboratory animals. PMID:26879462

  16. [To-day exposure to occupational carcinogens and their effects. The experience of the rubber industry, iron metallurgy, asphalt work and aviculture].

    Science.gov (United States)

    Barbieri, Pietro Gino

    2009-01-01

    While the progressive improvement of hygiene situations in the workplaces has taken to a reduction of chemical carcinogens exposure, in recent years in Italy the number of compensated occupational cancer resulting from carcinogens exposures of distant decades, has been increasing. Nevertheless, several experiences suggest that the proportion of occupational cancers unrecognised and not notified, as required by law, still remains important. This contribution concerns some experiences, performed between 2004-2008 by the Local Occupational Health Service (SPSAL) located in a highly industrialised province, on the working sector of rubber, iron and steel industry, the asphalt working and the poultry stock-breeders. This work concerns the following issues: - the evaluation of carcinogens exposure; - technical preventive measures and personal protection; - the level of workers' information and formation and the registration of exposed workers; - the characterization of work-related cancer. The results of the 5 years of activity allow us to underline that, in the most of 49 plants involved in the study, the carcinogens exposure evaluation and the prevention and protection measures were lacking. Information of workers was largely deficient and the registration of exposed workers was absent. A major attention to detect and to evaluate the work-related cancer has allowed us to recognize 50 new cases in the iron-steel industries and 21 new cases in a rubber industry. Although this experience concerns only few occupational fields, it provides the basis to call for a greater commitment of SPSAL addressed to companies and general practitioners to both, the promotion and surveillance of the correct procedures of carcinogens exposure evaluation and his prevention, and the active detection of occupational cancer, still missing. PMID:20124649

  17. The carcinogenic action of crystalline silica: a review of the evidence supporting secondary inflammation-driven genotoxicity as a principal mechanism.

    Science.gov (United States)

    Borm, Paul J A; Tran, Lang; Donaldson, Ken

    2011-10-01

    In 1987 the International Agency for Research on Cancer (IARC) classified crystalline silica (CS) as a probable carcinogen and in 1997 reclassified it as a Group 1 carcinogen, i.e., that there was sufficient evidence for carcinogenicity in experimental animals and sufficient evidence for carcinogenicity in humans. The Working Group noted that "carcinogenicity in humans was not detected in all industrial circumstances studied, carcinogenicity may be dependent on inherent characteristics of the crystalline silica or on external factors affecting its biological activity or distribution of its polymorphs." This unusual statement that the physicochemical form of the CS influences its carcinogenicity is well understood at the toxicological level and arises as a consequence of the fact that CS activity depends on the reactivity of the CS surface, which can be blocked by a number of agents. We reviewed the literature on CS genotoxicity that has been published since the 1997 monograph, with special reference to the mechanism of CS genotoxicity. The mechanism of CS genotoxicity can be primary, a result of direct interaction of CS with target cells, or indirect, as a consequence of inflammation elicited by quartz, where the inflammatory cell-derived oxidants cause the genotoxicity. The review revealed a number of papers supporting the hypothesis that the CS genotoxic and inflammatory hazard is a variable one. In an attempt to attain a quantitative basis for the potential mechanism, we carried out analysis of published data and noted a 5-fold greater dose required to reach a threshold for genotoxic effects than for proinflammatory effects in the same cell line in vitro. When we related the calculated threshold dose at the proximal alveolar region for inflammation in a published study with the threshold dose for genotoxicity in vitro, we noted that a 60-120-fold greater dose was required for direct genotoxic effects in vitro. These data strongly suggests that inflammation is

  18. Change of carcinogenic chrysotile fibers in the asbestos cement (eternit) to harmless waste by artificial carbonatization: Petrological and technological results

    International Nuclear Information System (INIS)

    Highlights: ► Carcinogenic chrysotile fibers in asbestos cement (eternit) are liquidated. ► Thermally modified eternit grist (at 650 °C, 1 h) reacts with CO2 + water. ► Carbonates hydromagnesite and magnesite are the newly formed products of artificial carbonatization. ► Neutralizing of extreme pH values (around 12) at large eternit dumps. ► An alternative methodology for permanent liquidation of a part of CO2 emissions. -- Abstract: Asbestos cement materials, mainly the eternit roof ceiling, being widely applied in the past, represent a serious environmental load. The solar radiation, rain and frost cause the deliberation of cement from the eternit roofing and consequently the wind contaminates the surrounding area by the asbestos (chrysotile) fibers. In combination with other carcinogens (e.g. smoking), or at reduced immunity of a man, they may cause serious respiratory diseases and lung cancer. The article presents the procedure and experimental results of artificial carbonatization, applied in the asbestos cement (eternit). The wet crushed and pulverized asbestos cement was thermally modified at 650 °C and then the chrysotile fibers easily and completely reacted with the mixture of CO2 and water, producing new Mg-rich carbonates – hydromagnesite and magnesite: 2Mg3Si2O5(OH)3thermallymodifiedchrysotile+5CO2+nH2O→Mg5(CO3)4(OH)2⋅4H2Ohydromagnesite+MgCO3magnesite+4SiO2 · nH2Oin amorphousphase;n=3÷9 Applying this methodology, the asbestos-bearing waste can be stabilized and environmentally friendly permanently deposited. Finding a way of neutralizing of extreme pH values (around 12) at large eternit dumps represents also an asset of presented research. Simultaneously, the artificial carbonatization of chrysotile asbestos, applying CO2, offers an alternative way for permanent liquidation of a part of industrial CO2 emissions, contributing to multiple benefit of this methodology

  19. Change of carcinogenic chrysotile fibers in the asbestos cement (eternit) to harmless waste by artificial carbonatization: Petrological and technological results

    Energy Technology Data Exchange (ETDEWEB)

    Radvanec, Martin; Tuček, Ľubomír; Derco, Ján; Čechovská, Katarína [State Geological Institute of Dionýz Štúr, Mlynská dolina 1, SK-817 04 Bratislava (Slovakia); Németh, Zoltán, E-mail: zoltan.nemeth@geology.sk [State Geological Institute of Dionýz Štúr, Mlynská dolina 1, SK-817 04 Bratislava (Slovakia)

    2013-05-15

    Highlights: ► Carcinogenic chrysotile fibers in asbestos cement (eternit) are liquidated. ► Thermally modified eternit grist (at 650 °C, 1 h) reacts with CO{sub 2} + water. ► Carbonates hydromagnesite and magnesite are the newly formed products of artificial carbonatization. ► Neutralizing of extreme pH values (around 12) at large eternit dumps. ► An alternative methodology for permanent liquidation of a part of CO{sub 2} emissions. -- Abstract: Asbestos cement materials, mainly the eternit roof ceiling, being widely applied in the past, represent a serious environmental load. The solar radiation, rain and frost cause the deliberation of cement from the eternit roofing and consequently the wind contaminates the surrounding area by the asbestos (chrysotile) fibers. In combination with other carcinogens (e.g. smoking), or at reduced immunity of a man, they may cause serious respiratory diseases and lung cancer. The article presents the procedure and experimental results of artificial carbonatization, applied in the asbestos cement (eternit). The wet crushed and pulverized asbestos cement was thermally modified at 650 °C and then the chrysotile fibers easily and completely reacted with the mixture of CO{sub 2} and water, producing new Mg-rich carbonates – hydromagnesite and magnesite: 2Mg{sub 3}Si{sub 2}O{sub 5}(OH){sub 3thermally} {sub modified} {sub chrysotile}+5CO{sub 2}+nH{sub 2}O→Mg{sub 5}(CO{sub 3}){sub 4}(OH){sub 2}⋅4H{sub 2}O{sub hydromagnesite}+MgCO{sub 3magnesite}+4SiO{sub 2} · nH{sub 2}O{sub in} a{sub morphous} {sub phase};n=3÷9 Applying this methodology, the asbestos-bearing waste can be stabilized and environmentally friendly permanently deposited. Finding a way of neutralizing of extreme pH values (around 12) at large eternit dumps represents also an asset of presented research. Simultaneously, the artificial carbonatization of chrysotile asbestos, applying CO{sub 2}, offers an alternative way for permanent liquidation of a part of

  20. Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan

    Energy Technology Data Exchange (ETDEWEB)

    Jackson, Anna Francina, E-mail: Francina.Jackson@hc-sc.gc.ca [Environmental Health Science and Research Bureau, Health Canada, Ottawa K1A 0K9 (Canada); Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa K1S 5B6 (Canada); Williams, Andrew, E-mail: Andrew.Williams@hc-sc.gc.ca [Environmental Health Science and Research Bureau, Health Canada, Ottawa K1A 0K9 (Canada); Recio, Leslie, E-mail: lrecio@ils-inc.com [ILS, Inc., P.O. Box 13501, Research Triangle Park, NC 27709 (United States); Waters, Michael D., E-mail: mwaters@ils-inc.com [ILS, Inc., P.O. Box 13501, Research Triangle Park, NC 27709 (United States); Lambert, Iain B., E-mail: Iain.Lambert@carleton.ca [Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa K1S 5B6 (Canada); Yauk, Carole L., E-mail: Carole.Yauk@hc-sc.gc.ca [Environmental Health Science and Research Bureau, Health Canada, Ottawa K1A 0K9 (Canada)

    2014-01-01

    Furan is a chemical hepatocarcinogen in mice and rats. Its previously postulated cancer mode of action (MOA) is chronic cytotoxicity followed by sustained regenerative proliferation; however, its molecular basis is unknown. To this end, we conducted toxicogenomic analysis of B3C6F1 mouse livers following three week exposures to non-carcinogenic (0, 1, 2 mg/kg bw) or carcinogenic (4 and 8 mg/kg bw) doses of furan. We saw enrichment for pathways responsible for cytotoxicity: stress-activated protein kinase (SAPK) and death receptor (DR5 and TNF-alpha) signaling, and proliferation: extracellular signal-regulated kinases (ERKs) and TNF-alpha. We also noted the involvement of NF-kappaB and c-Jun in response to furan, which are genes that are known to be required for liver regeneration. Furan metabolism by CYP2E1 produces cis-2-butene-1,4-dial (BDA), which is required for ensuing cytotoxicity and oxidative stress. NRF2 is a master regulator of gene expression during oxidative stress and we suggest that chronic NFR2 activity and chronic inflammation may represent critical transition events between the adaptive (regeneration) and adverse (cancer) outcomes. Another objective of this study was to demonstrate the applicability of toxicogenomics data in quantitative risk assessment. We modeled benchmark doses for our transcriptional data and previously published cancer data, and observed consistency between the two. Margin of exposure values for both transcriptional and cancer endpoints were also similar. In conclusion, using furan as a case study we have demonstrated the value of toxicogenomics data in elucidating dose-dependent MOA transitions and in quantitative risk assessment. - Highlights: • Global gene expression changes in furan-exposed mouse livers were analyzed. • A molecular mode of action for furan-induced hepatocarcinogenesis is proposed. • Key pathways include NRF2, SAPK, ERK and death receptor signaling. • Important roles for TNF-alpha, c-Jun, and NF

  1. Carcinogenicity of the environmental pollutants cyclopenteno-(cd)pyrene and cyclopentano(cd)pyrene in mouse skin

    Energy Technology Data Exchange (ETDEWEB)

    Cavalieri, E.; Rogan, E.; Toth, B.; Munhall, A.

    1981-01-01

    Cyclopenteno(cd)pyrene (CPEP) is a widespread environmental pollutant. This hydrocarbon and its 3,4-dihydro derivative, cyclopentano(cd)pyrene (CPAP), were tested on skin in a two-stage initiation-promotion experiment in CD-1 mice and by repeated application in Swiss mice. The biological effect of CPEP and CPAP was compared to that of benzo(a)-pyrene (BP). Nine-week-old female CD-1 mice in groups of 30 were treated every other day over a 20-day period at mini-dose levels of 0.18, 0.06 and 0.02 mumol of CPEP or CPAP in acetone. One group was treated with BP at the low mini-dose level. Initiation was followed by twice weekly application of tetradecanoyl phorbol acetate for 40 weeks. In the second experiments, nine-week-old female Swiss mice in groups of 30 were treated at dose levels of 1.8, 0.6 and 0.2 mumol CPEP or CPAP in acetone twice weekly for 30 weeks. One group was treated with BP at the low dose. CPAP was virtually inactive in both studies. In the initiation-promotion experiment CPEP was inactive at the low dose level, whereas BP exhibited significant tumorigenicity. At the medium and high doses CPEP showed weak, but statistically insignificant, tumorigenic activity. Repeated application of CPEP at the high, medium and low doses resulted in tumor incidences of 23, 37 and 57%, respectively. This reverse dose-response may be due to the relatively high cytotoxicity of CPEP, BP, which was compared to CPEP at the low dose, elicited tumors in 100% of the mice. Most of the CPEP-induced neoplasms were malignant and some metastasized to lungs and lymph nodes. The inactivity of CPAP suggests the carcinogenicity of CPEP is probably due to formation of the ultimate metabolite CPEP 3,4-oxide. In view of the abundance of CPEP in environmental and occupational pollutants, its moderately potent carcinogenicity may represent a potential health hazard.

  2. [Failure conditions of glass filament yarns: a contribution to the valuation of carcinogenic potentials of fiber fragments].

    Science.gov (United States)

    Oser, M; Ramseyer, C; Mayer, J; Wintermantel, E

    1998-09-01

    Failure of glass filament yarns results in the formation of many fragments. Through inhalation, these particles can intrude into the human body. If the fragments are sufficiently bioresistant and have a fiber dust geometry, according to the MAK-values (6), i.e. if they are longer than 5 microns and thinner than 3 microns and show an aspect ratio greater than 3, they have a carcinogenic potential. Since the glass filaments show a diameter greater than 3 microns, no fiber dust particles will be formed if transversal fiber failure occurs without crack-branching. In the present study the geometric distribution of fragments after failure of glass filament yarns under combined stress was investigated in order to estimate the carcinogenic potential of the fragments. The knot tension test was shown to be a suitable method for this investigation. A defined fraction of the total amount of fragments were analysed with scanning electron microscopy (SEM) by measuring their length and diameter. To investigate whether the analysed particles are fragments of the glass filament yarns, chemical analysis was performed with energy dispersive X-ray analysis (EDX). Morphologically, two different fragment types were observed: a) Fragments with their entire filament cross-section which were formed by transversal fiber fraction. b) Smaller fragments which were formed through crack-branching. These smaller fragments were observed to adhere on the bigger fragments due to high surface forces. During each knot tension test, 5-60 fragments per filament were formed. However, the fraction of fiber dust particles was very low and showed a maximum of 1.5%. Only in one of the four tested yarn types (high temperature yarn HT 75) the formation of fiber dust particles was observed. The other yarns showed fragments with dimensions close to fiber dust geometry. Therefore, it cannot be excluded that some fragments with fiber dust geometry may have been formed during mechanical testing. Fragment

  3. Swedish review strengthens grounds for concluding that radiation from cellular and cordless phones is a probable human carcinogen.

    Science.gov (United States)

    Davis, Devra Lee; Kesari, Santosh; Soskolne, Colin L; Miller, Anthony B; Stein, Yael

    2013-04-01

    With 5.9 billion reported users, mobile phones constitute a new, ubiquitous and rapidly growing exposure worldwide. Mobile phones are two-way microwave radios that also emit low levels of electromagnetic radiation. Inconsistent results have been published on potential risks of brain tumors tied with mobile phone use as a result of important methodological differences in study design and statistical power. Some studies have examined mobile phone users for periods of time that are too short to detect an increased risk of brain cancer, while others have misclassified exposures by placing those with exposures to microwave radiation from cordless phones in the control group, or failing to attribute such exposures in the cases. In 2011, the World Health Organization, International Agency for Research on Cancer (IARC) advised that electromagnetic radiation from mobile phone and other wireless devices constitutes a "possible human carcinogen," 2B. Recent analyses not considered in the IARC review that take into account these methodological shortcomings from a number of authors find that brain tumor risk is significantly elevated for those who have used mobile phones for at least a decade. Studies carried out in Sweden indicate that those who begin using either cordless or mobile phones regularly before age 20 have greater than a fourfold increased risk of ipsilateral glioma. Given that treatment for a single case of brain cancer can cost between $100,000 for radiation therapy alone and up to $1 million depending on drug costs, resources to address this illness are already in short supply and not universally available in either developing or developed countries. Significant additional shortages in oncology services are expected at the current growth of cancer. No other environmental carcinogen has produced evidence of an increased risk in just one decade. Empirical data have shown a difference in the dielectric properties of tissues as a function of age, mostly due to the

  4. Concordance between Results of Medium-term Liver Carcinogenesis Bioassays and Long-term Findings for Carcinogenic 2-Nitropropane and Non-carcinogenic1-Nitropropane in F344 Rats.

    Science.gov (United States)

    Doi, Yuko; Tamano, Seiko; Kawabe, Mayumi; Sano, Masashi; Imai, Norio; Nakashima, Hironao; Furukawa, Fumio; Hagiwara, Akihiro; Otsuka, Masanori; Shirai, Tomoyuki

    2011-12-01

    This study was conducted to determine the concordance of results for a pair of structural isomers, 2-nitropropane (2-NP) and 1-nitropropane (1-NP), using the rat medium-term liver carcinogenesis bioassay (Ito test) and previously published long-term carcinogenicity tests. Male F344 rats were given a single intraperitoneal injection of DEN (200 mg/kg b.w.) to initiate hepatocarcinogenesis. After 2 weeks, they received per os 0, 0.8, 4 or 20 mg/kg/day of 2-NP or 1-NP six times a week and were subjected to two-thirds partial hepatectomy at week 3. Non-initiated groups receiving 0 or 20 mg/kg/day were also included. The animals were sacrificed for quantitative analysis of GST-P-positive foci at week 8. With the highest dose of 2-NP, significantly increased numbers and areas of GST-P-positive foci were demonstrated as compared with the respective control but were not noted with 1-NP. In the non-DEN-initiated groups, many small GST-P-positive foci of less than 0.2 mm in diameter were also induced in the rats treated with 2-NP at 20 mg/kg/day but were lacking with 1-NP. These results strongly support that 2-NP is a complete hepatocarcinogen with a potent initiation activity, whereas 1-NP is not. PMID:22319232

  5. A Review of the Evidence that Ochratoxin A Is an Nrf2 Inhibitor: Implications for Nephrotoxicity and Renal Carcinogenicity

    Directory of Open Access Journals (Sweden)

    Alice Limonciel

    2014-01-01

    Full Text Available Several studies have demonstrated that ochratoxin A (OTA inhibits the nuclear factor, erythroid 2-like 2 (Nrf2 oxidative stress response pathway. At the cellular level this would attenuate (i glutathione synthesis; (ii recycling of oxidised glutathione; (iii activity of oxidoreductases; and (iv phase II metabolism inducibility. The effects combined would render the cell and tissue more vulnerable to oxidative stress. Indeed, Nrf2 knock out animals exhibit increased susceptibility to various types of chemical-induced injury. Several studies have shown that OTA exposure can inhibit Nrf2 responses. Such an action would initially lead to increased susceptibility to both physiological and chemical-induced cell stress. However, chronic exposure to OTA may also act as a selective pressure for somatic mutations in Nrf2 or its inhibitor Keap-1, leading to constitutive Nrf2 activation. Nrf2 overexpression confers a survival advantage and is often associated with cancer cell survival. Here we review the evidence for OTA’s role as an Nrf2 inhibitor and discuss the implications of this mechanism in nephrotoxicity and carcinogenicity.

  6. A review of the evidence that ochratoxin A is an Nrf2 inhibitor: implications for nephrotoxicity and renal carcinogenicity.

    Science.gov (United States)

    Limonciel, Alice; Jennings, Paul

    2014-01-01

    Several studies have demonstrated that ochratoxin A (OTA) inhibits the nuclear factor, erythroid 2-like 2 (Nrf2) oxidative stress response pathway. At the cellular level this would attenuate (i) glutathione synthesis; (ii) recycling of oxidised glutathione; (iii) activity of oxidoreductases; and (iv) phase II metabolism inducibility. The effects combined would render the cell and tissue more vulnerable to oxidative stress. Indeed, Nrf2 knock out animals exhibit increased susceptibility to various types of chemical-induced injury. Several studies have shown that OTA exposure can inhibit Nrf2 responses. Such an action would initially lead to increased susceptibility to both physiological and chemical-induced cell stress. However, chronic exposure to OTA may also act as a selective pressure for somatic mutations in Nrf2 or its inhibitor Keap-1, leading to constitutive Nrf2 activation. Nrf2 overexpression confers a survival advantage and is often associated with cancer cell survival. Here we review the evidence for OTA's role as an Nrf2 inhibitor and discuss the implications of this mechanism in nephrotoxicity and carcinogenicity. PMID:24448208

  7. Re-evaluation of the kidney tumors and renal histopathology occurring in a 2-year rat carcinogenicity bioassay of quercetin.

    Science.gov (United States)

    Hard, Gordon C; Seely, John Curtis; Betz, Laura J; Hayashi, Shim-Mo

    2007-04-01

    Renal histopathology in the most recent 2-year carcinogenicity bioassay of quercetin, in Fischer 344 rats, was re-evaluated in an attempt to determine a mode of action underlying a small increase in renal tubule tumors reported in the males (). The re-evaluation confirmed the reported increase in renal tumors in mid- and high-dose males, including a single carcinoma in a high-dose male, as well as an exacerbation of spontaneous, chronic progressive nephropathy (CPN) in male rats only. The re-evaluation also showed that there were no cellular alterations in the kidney indicative of chemical toxicity at 6 months, 15 months, or 2 years. The evidence linked the occurrence of the predominant basophilic adenomas and foci of atypical tubule hyperplasia (ATH) with the exacerbation of CPN to advanced grades of severity, supporting a mode of action involving quercetin interaction with CPN. This mode of action represents a secondary mechanism for renal tumor development, with no relevance for extrapolation to humans. In addition, the single carcinoma present in the high-dose males, along with 4 other lesions ranging from ATH to adenoma in male and female groups, were considered to have a unique phenotype associated previously with neoplasms of spontaneous and familial origin. PMID:17156907

  8. Acrylamide, an in vivo thyroid carcinogenic agent, induces DNA damage in rat thyroid cell lines and primary cultures.

    Science.gov (United States)

    Chico Galdo, V; Massart, C; Jin, L; Vanvooren, V; Caillet-Fauquet, P; Andry, G; Lothaire, P; Dequanter, D; Friedman, M; Van Sande, J

    2006-09-26

    Chronic treatment of rats with acrylamide induces various tumors among which thyroid tumors are the most frequent. The aim of the present study was to develop an in vitro model of acrylamide action on thyroid cells to allow the investigation of the mechanism of this tumorigenic action. The first part of the study considered as targets, characteristics of thyroid metabolism, which could explain the thyroid specificity of acrylamide action: the cAMP mitogenic effect and the important H2O2 generation by thyroid cells. However, acrylamide did not modulate H2O2 or cAMP generation in the thyroid cell models studied. No effect on thyroid cell proliferation was observed in the rat thyroid cell line FRTL5. On the other hand, as shown by the comet assay, acrylamide induced DNA damage, as the positive control H2O2 in the PC Cl3 and FRTL5 rat thyroid cell lines, as well as in thyroid cell primary cultures. The absence of effect of acrylamide on H2AX histone phosphorylation suggests that this effect does not reflect the induction of DNA double strand breaks. DNA damage leads to the generation of mutations. It is proposed that such mutations could play a role in the carcinogenic effect of acrylamide. The mechanism of this effect can now be studied in this in vitro model. PMID:16859826

  9. Effect of acetylator genotype on the levels of carcinogen-DNA adducts in inbred hamsters treated with 2-aminofluorene

    International Nuclear Information System (INIS)

    A genetic polymorphism in N-acetyltransferase has been described previously in humans and in animal models that is known to affect an individual's susceptibility to certain drug toxicities and diseases including bladder cancer. In hamsters, the polymorphism is known to regulate the conversion of carcinogenic 2-aminofluorene to its amide and of N-hydroxy-2-aminofluorene to a reactive electrophile that forms a covalently-bound adduct with DNA; an event thought to initiate the tumorigenic process. A single dose of 2-aminofluorene (60 mg/kg body wt., i.p) was administered to homozygous rapid- (rr) and homozygous slow-acetylator (ss) hamsters, and the levels of aminofluorene-DNA adducts in bladder and liver were evaluated by a 32P-postlabeling assay. Only a non-acetylated aminofluorene-DNA adduct was detected in the DNA samples. In this study, no differences were detected between the levels of hepatic 2-aminofluorene-DNA adducts in males or females or between the rr or ss hamsters. In contrast, the levels of 2-amino-fluorene-adducts in bladder DNA were 5-fold higher in the male rr than in the ss hamsters, and were 2-fold higher in the male rr than in the female rr animals

  10. 槟榔致癌物质与口腔癌%Areca nut-related carcinogens and oral cancer

    Institute of Scientific and Technical Information of China (English)

    黄龙; 翦新春

    2014-01-01

    Areca nut is a recently confirmed classⅠcarcinogen. The areca nut chewing habit is a primary environmental risk factor for the development of oral cancer due to cytotoxicity, genotoxicity, mutagenicity, and carcinogenicity of arecoline(ARC), areca-containing tannins, areca-specific nitrosamine(ASNA), and reactive oxygen species(ROS) produced during areca nut chewing. ARC is capable of inducing apoptosis of oral fibroblasts, keratinocytes, and human umbilical vein endothelial cells. The results of different types of short-term screening tests differ, so the genotoxicity and mutagenicity of areca-containing tannins remain controversial. Tannin-containing polyphenolic fraction is a primary carcinogenic ingredient. 3-Methyl-nitrosamino propionaldehyde can induce DNA strand breakage and DNA-protein cross-linkage for human buccal keratinocytes. 3-Methyl-nitrosamino propionitrile is a potent carcinogen that can induce nasal, esophageal, and tongue tumors in laboratory animals. ROS produced during areca nut chewing can promote tumorigenesis by inducing DNA oxidative damage and activating oncogenes. A newly found proteoglycan in the 3.0×104 to 10.0× 104 relative molecular mass fraction of areca nut extract induces oxidative stress and modulates a signaling cascade that upregulates hypoxia, inducing factor-1α expression in oral cancer cells, which eventually leads to autophagy. Autophagy can help cancer cells survive ARC-induced apoptosis and promote the development of oral cancer. Areca nut extract can enhance tongue cancer cell-induced platelet aggregation by generating ROS, thus promoting tongue cancer metastasis.%槟榔为一级致癌物,咀嚼槟榔引起口腔癌缘于槟榔中的槟榔碱(ARC)、槟榔鞣质、槟榔特异性亚硝胺(ASNA)和活性氧(ROS)等具有细胞毒性、遗传毒性、致突变性和致癌性。ARC可诱导口腔成纤维细胞、角质形成细胞和人脐静脉内皮细胞程序性死亡。槟榔鞣质有否遗传毒性

  11. AKT1E17K Is Oncogenic in Mouse Lung and Cooperates with Chemical Carcinogens in Inducing Lung Cancer

    Science.gov (United States)

    Malanga, Donatella; Belmonte, Stefania; Colelli, Fabiana; Scarfò, Marzia; De Marco, Carmela; Oliveira, Duarte Mendes; Mirante, Teresa; Camastra, Caterina; Gagliardi, Monica; Rizzuto, Antonia; Mignogna, Chiara; Paciello, Orlando; Papparella, Serenella; Fagman, Henrik; Viglietto, Giuseppe

    2016-01-01

    The hotspot AKT1E17K mutation in the pleckstrin homology domain of AKT1 occurs in approximately 0.6–2% of human lung cancers. Recently, we have demonstrated that AKT1E17K transforms immortalized human bronchial cells. Here by use of a transgenic Cre-inducible murine strain in the wild type Rosa26 (R26) locus (R26-AKT1E17K mice) we demonstrate that AKT1E17K is a bona-fide oncogene and plays a role in the development of lung cancer in vivo. In fact, we report that mutant AKT1E17K induces bronchial and/or bronchiolar hyperplastic lesions in murine lung epithelium, which progress to frank carcinoma at very low frequency, and accelerates tumor formation induced by chemical carcinogens. In conclusion, AKT1E17K induces hyperplasia of mouse lung epithelium in vivo and cooperates with urethane to induce the fully malignant phenotype. PMID:26859676

  12. Direct spectral analysis and determination of high content of carcinogenic bromine in bread using UV pulsed laser induced breakdown spectroscopy.

    Science.gov (United States)

    Mehder, A O; Gondal, Mohammed A; Dastageer, Mohamed A; Habibullah, Yusuf B; Iqbal, Mohammed A; Oloore, Luqman E; Gondal, Bilal

    2016-06-01

    Laser induced breakdown spectroscopy (LIBS) was applied for the detection of carcinogenic elements like bromine in four representative brands of loaf bread samples and the measured bromine concentrations were 352, 157, 451, and 311 ppm, using Br I (827.2 nm) atomic transition line as the finger print atomic transition. Our LIBS system is equipped with a pulsed laser of wavelength 266 nm with energy 25 mJ pulse(-1), 8 ns pulse duration, 20 Hz repetition rate, and a gated ICCD camera. The LIBS system was calibrated with the standards of known concentrations in the sample (bread) matrix and such plot is linear in 20-500 ppm range. The capability of our system in terms of limit of detection and relative accuracy with respect to the standard inductively coupled plasma mass spectrometry (ICPMS) technique was evaluated and these values were 5.09 ppm and 0.01-0.05, respectively, which ensures the applicability of our system for Br trace level detection, and LIBS results are in excellent agreement with that of ICPMS results. PMID:26950676

  13. Study of the combined action of inhaled plutonium oxide and two chemical carcinogens present in the environment

    International Nuclear Information System (INIS)

    The modifications of risk attributable to two carcinogens present in the environment - benzopyrene (BP) and dimethylnitrosamine (DMNA) - following inhalation of plutonium oxide have been studied in rats. BP (2x5 mg) was given intratracheally in association with Fe2O3, 2 and 3 weeks after inhalation of PuO2. DMNA (2 or 20 ppm) was added to the animals' drinking water. The results show, for BP, a strong synergistic effect which manifests itself in a substantial reduction of lifetime in animals that have inhaled a small quantity of PuO2 (17 nCi), and in a greater incidence of tumours and enhanced tumour invasiveness whatever the dose of PuO2 inhaled. Inhalation of PuO2 associated with regular ingestion of DMNA multiplies the metastases of liver cancers in the lung. Addition of BP or DMNA modifies the histological profile of radiation-induced tumours. The synergistic effects are no longer observed when the pollutant concentrations used produce subacute intoxication. (author)

  14. Biomonitoring the cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in canine fur.

    Science.gov (United States)

    Gu, Dan; Neuman, Zachary L; Modiano, Jaime F; Turesky, Robert J

    2012-09-12

    2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic aromatic amine (HAA) that is formed during the cooking of meat, poultry, and fish. PhIP is a rodent carcinogen and is thought to contribute to several diet-related cancers in humans. PhIP is present in the hair of human omnivores but not in the hair of vegetarians. We have now identified PhIP in the fur of 14 out of 16 healthy dogs consuming different brands of commercial pet food. The levels of PhIP in canine fur varied by over 85-fold and were comparable to the levels of PhIP present in human hair. However, high density fur containing PhIP covers a very high proportion of the body surface area of dogs, whereas high density terminal hair primarily covers the scalp and pubis body surface area of humans. These findings signify that the exposure and bioavailability of PhIP are high in canines. A potential role for PhIP in the etiology of canine cancer should be considered. PMID:22906298

  15. Cea-Expo: A facility exposure matrix to assess passed exposure to chemical carcinogens and radionuclides of nuclear workers

    International Nuclear Information System (INIS)

    A 'Facility-Exposure Matrix' (FEM) is proposed to assess exposure to chemical carcinogens and radionuclides in a cohort of nuclear workers. Exposures are to be attributed in the following way: a worker reports to an administrative unit and/or is monitored for exposure to ionising radiation in a specific workplace. These units are connected with a list of facilities for which exposure is assessed through a group of experts. The entire process of the FEM applied in one of the nuclear centres included in the study shows that the FEM is feasible: exposure durations as well as groups of correlated exposures are presented but have to be considered as possible rather than positive exposures. Considering the number of facilities to assess (330), ways to simplify the method are proposed: (i) the list of exposures will be restricted to 18 chemical products retained from an extensive bibliography study; (ii) for each of the following classes of facilities: nuclear reactors, fuel fabrication, high-activity laboratories and radiation chemistry, accelerators and irradiators, waste treatment, biology, reprocessing, fusion, occupational exposure will be deduced from the information already gathered by the initial method. Besides taking into account confusion factors in the low doses epidemiological study of nuclear workers, the matrix should help in the assessment of internal contamination and chemical exposures in the nuclear industry. (author)

  16. GST-π EXPRESSION IN TRANSFORMED CELLS BY TRANSFECTING OF DNA ISOLATED FROM HUMAN FETAL LUNG TISSUES TREATED WITH CARCINOGENS

    Institute of Scientific and Technical Information of China (English)

    Yao Denggao; Hu Guogang; Luo Xianmao; Zhu Ming

    1998-01-01

    Objective: To investigate the relationship between the GSTs, GST-π expression and initiation of lung carcinogenesis. Methods: The Rat-1 cells were transformed by carcinogens (DEN, MNU and CSC) treated fetal lung DNA for 24 h. Results: The GSTs activities toward 1-chloro-2, 4-dinitro-benzene (CDNB) in transformed cells were significantly higher than in the solvent control cells (P<0.05). GST-π content and GST-π mRNA expression level of transformed cells were also higher than those of control cells which were performed by ELISA and Northern blotting method respectively. The results indicated that the higher GSTS activities of transformed cells were due to the increase of GST-π content and the GST-π mRNA overexpressing may be responsible for the increase of GST-π protein level of the transformed cells. Conclusion: The changes of GSTs and GST-π may be considered as the one of the biomarkers of the initiation of human lung carcinogenesis.

  17. Transcriptionally active and inactive genes are similarly modified by chemical carcinogens or X-ray in normal human fibroblasts

    International Nuclear Information System (INIS)

    Chemical carcinogens and ionizing radiation induce DNA modifications and strand breaks in cells. This damage is reported to be affected by chromatin proteins or chromatin of a higher structure order. To compare the sensitivity of transcriptionally active and inactive genes on chromatin toward DNA-damaging agents, we treated normal human fibroblasts (WI-38) cells with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), X-ray, 4-hydroxyaminoquinoline 1-oxide or N-acetoxy-2-acetylaminofluorene, and high molecular weight DNA was isolated. After digestion with EcoRI to completion, the DNA was electrophoresed on an alkaline agarose gel, blotted on a nitrocellulose filter and hybridized with a transcriptionally active gene probe (human type I(α2) procollagen gene) or an inactive gene probe (human β-globin gene). The results show that both genes are similarly modified by these agents. Repair of DNA damage caused by MNNG also occurred similarly in collagen and β-globin genes after removal of MNNG. (Auth.)

  18. Synergism of diethylstilbestrol and other carcinogens in concurrent development of hepatic, mammary, and pituitary tumors in castrated male rats

    International Nuclear Information System (INIS)

    Castrated male WF rats, given implants of pellets containing 5.0 mg diethylstilbestrol (DES), were given N-butyl-N-nitrosourea (NBU) in small amounts, which alone produced no mammary tumors in intact female rats. Treatment resulted in the high yield of hepatic tumors (HT), mammary tumors (MT), and pituitary tumors (PT) concurrently in each rat. If animals were further tested with prolactin, the development of HT and MT was accelerated, whereas that of PT was suppressed. None of the intact or castrated rats receiving NBU and/or prolactin developed tumors in any tissues if DES treatment was omitted. Exposure of male rats, preconditioned similarly to NBU treatment, to 200 rads of 14.1-MeV fast-neutron radiation also elicited HT, MT, and PT with an efficiency comparable to that of NBU-treated rats. These findings indicate that DES played an essential role in the whole carcinogenic process in each tissue and that castrated male rats, if conditioned properly with estrogens, are useful for the study of the carcinogenesis mechanism in these tissues

  19. Role of prolactin in induction of mammary tumors in rats with low dose radiations or of a chemical carcinogen

    International Nuclear Information System (INIS)

    Synergy of prolactin with x-ray, fast neutron, N-nitrosobutylurea (NBU), in an induction of mammary tumors was discussed, and the following results were obtained. Conversion of mammary epithelium to malignant tumors was induced in rats which were exposed to x-ray of a dose estimated to be below carcinogenic dose or which were given chemical substances. Cells converted to malignant tumors by carcinogenetic treatment survived for a fairly long term without proliferation, responded to proper stimulations, and formed macroscopical tumors. The effect of prolactin was showed at maximum under the presence of normal function of the ovary. RBE of 14.1 MeV fast neutron in an induction of mammary tumor in rats was about 1.3 - 1.5 times of 180 kVp x-ray. From the above-mentioned results, the author would like to point out and emphasize that at present, radiation used frequently for diagnosis and therapy although in small dose incurs the danger of inducing tumors under the specific circumstances where the host lives, and especially that easy treatments for atomic bomb survivors would bring double misfortunes to them in future. (Ueda, J.)

  20. Carcinogenic 4(5)-methylimidazole found in beverages, sauces, and caramel colors: chemical properties, analysis, and biological activities.

    Science.gov (United States)

    Hengel, Matt; Shibamoto, Takayuki

    2013-01-30

    Since the National Toxicology Program (NTP) identified 4(5)-methylimidazole [4(5)-MI] as a cancer causing chemical in 2007 and the State of California added it to the Proposition 65 list of compounds as a carcinogen on January 7, 2011, many researchers and regulatory agencies have become focused on the presence of 4(5)-MI in foods and beverages. 4(5)-MI has been known to form in the Maillard reaction system consisting of a sugar and ammonia-a typical caramel-color preparation method for beverages. 4(5)-MI is identified in various beverages and sauces, which are colored with caramel, as well as in caramel color itself. Analysis of 4(5)-MI is extremely difficult due to its high water solubility, but the analytical method for 4(5)-MI has progressed from conventional paper chromatography, gas chromatography, and gas chromatography-mass spectrometry to the most advanced high-performance liquid chromatography-mass spectrometry. Various studies indicate that caramel colors and carbonated beverages contain 4(5)-MI in levels ranging from 0 to around 1000 ppm and from 0 to about 500 ppm, respectively. Reports of the toxicity of 4(5)-MI at relatively high levels suggest that it may cause some adverse effects on human consumers. PMID:23294412

  1. Comparative effect of irradiation and metabolization of some chemical pollutants in animals based upon mutagenic/carcinogenic activity

    International Nuclear Information System (INIS)

    Polycyclic aromatic hydrocarbons have long been implicated as mutagens and carcinogens. The compounds selected for this study, 3,4-benzo(a)pyrene (BP) and 3-methylcholanterene (MC), were considered the most representative substances of this chemical group. Of the tested metabolites of the first, only 1,2 and 9-hydroxy-BP and diasteromers diolepoxi (7,8,9,10-cis and trans) proved mutagens. BP and MC in mammalian cells produced DNA lesions in the form of single-strand breaks and inhibition of semiconservative synthesis. They did not inhibit rejoining of DNA single-strand breaks induced by ionizing radiation. BP and MC are both mutagens only after metabolic activation, as shown in host-mediated assay and by in-vitro test. In order to establish an equivalence, the effect of three chemicals were investigated: an alkylating agent, BP and MC, the latter requiring metabolic activation. Under the given experimental conditions, 1 rad appeared as equivalent to 55 ng of IOB-82 (a cytostatic), 115 ng of BP and 178 ng of MC. This concept could prove of great importance for evaluating the risks arising from chemical and physical pollutants in man's environment

  2. P-glycoprotein in adriamycin-resistant cells functions as an efflux pump for benzopyrene, a chemical carcinogen

    Energy Technology Data Exchange (ETDEWEB)

    Chao Yeh, G.; Poore, C.M.; Lopaczynska, J.; Phang, J.M. (NCI-FCRDC, Frederick, MD (United States))

    1991-03-15

    The physiological function of multidrug resistant gene (MDR 1) coded P-glycoprotein 170 (P-gp) in normal tissues remains unknown. The authors propose that P-gp functions as an efflux pump in normal tissues for benzopyrene and other xenobiotic substances. To examine their hypothesis the authors used a series of MDR human breast cancer MCF-7 cells with increasing degrees of drug resistance, expression of MDR and levels of P-gp. First, they found the IC{sub 50} for benzopyrene is linearly correlated with the levels of P-gp at different stages of adriamycin resistant MCF-7 cells. Using P-gp ({sup 3}H)azidopine labeling as a measurement of P-gp they found benzopyrene competes for labeling of P-gp. Finally, they directly measured cellular efflux of benzopyrene with adherent cell laser cytometry and found that resistant cells expressing high levels of P-gp showed rapid efflux of benzopyrene. By contrast, drug sensitive wild type cells with undetectable P-gp showed negligible efflux. They conclude that P-gp can function as an efflux pump for benzopyrene and suggest that P-gp may be a cellular mechanism for resistance to carcinogens.

  3. Meat intake, cooking methods, dietary carcinogens, and colorectal cancer risk: findings from the Colorectal Cancer Family Registry

    International Nuclear Information System (INIS)

    Diets high in red meat and processed meats are established colorectal cancer (CRC) risk factors. However, it is still not well understood what explains this association. We conducted comprehensive analyses of CRC risk and red meat and poultry intakes, taking into account cooking methods, level of doneness, estimated intakes of heterocyclic amines (HCAs) that accumulate during meat cooking, tumor location, and tumor mismatch repair proficiency (MMR) status. We analyzed food frequency and portion size data including a meat cooking module for 3364 CRC cases, 1806 unaffected siblings, 136 unaffected spouses, and 1620 unaffected population-based controls, recruited into the CRC Family Registry. Odds ratios (OR) and 95% confidence intervals (CI) for nutrient density variables were estimated using generalized estimating equations. We found no evidence of an association between total nonprocessed red meat or total processed meat and CRC risk. Our main finding was a positive association with CRC for pan-fried beefsteak (Ptrend < 0.001), which was stronger among MMR deficient cases (heterogeneity P = 0.059). Other worth noting associations, of borderline statistical significance after multiple testing correction, were a positive association between diets high in oven-broiled short ribs or spareribs and CRC risk (Ptrend = 0.002), which was also stronger among MMR-deficient cases, and an inverse association with grilled hamburgers (Ptrend = 0.002). Our results support the role of specific meat types and cooking practices as possible sources of human carcinogens relevant for CRC risk

  4. Quantitative determination of hydroxy polycylic aromatic hydrocarbons as a biomarker of exposure to carcinogenic polycyclic aromatic hydrocarbons.

    Science.gov (United States)

    Woudneh, Million B; Benskin, Jonathan P; Grace, Richard; Hamilton, M Coreen; Magee, Brian H; Hoeger, Glenn C; Forsberg, Norman D; Cosgrove, John R

    2016-07-01

    A high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS) method was developed for quantitative analysis of hydroxy polycyclic aromatic hydrocarbons (OH-PAHs). Four hydroxy metabolites of known and suspected carcinogenic PAHs (benzo[a]pyrene (B[a]P), benz[a]anthracene (B[a]A), and chrysene (CRY)) were selected as suitable biomarkers of PAH exposure and associated risks to human health. The analytical method included enzymatic deconjugation, liquid - liquid extraction, followed by derivatization with methyl-N-(trimethylsilyl) trifluoroacetamide and instrumental analysis. Photo-induced oxidation of target analytes - which has plagued previously published methods - was controlled by a combination of minimizing exposure to light, employing an antioxidant (2-mercaptoethanol) and utilizing a nitrogen atmosphere. Stability investigations also indicated that conjugated forms of the analytes are more stable than the non-conjugated forms. Accuracy and precision of the method were 77.4-101% (<4.9% RSD) in synthetic urine and 92.3-117% (<15% RSD) in human urine, respectively. Method detection limits, determined using eight replicates of low-level spiked human urine, ranged from 13 to 24pg/mL. The method was successfully applied for analysis of a pooled human urine sample and 78 mouse urine samples collected from mice fed with PAH-contaminated diets. In mouse urine, greater than 94% of each analyte was present in its conjugated form. PMID:27266337

  5. Exposure to Crystal Violet, Its Toxic, Genotoxic and Carcinogenic Effects on Environment and Its Degradation and Detoxification for Environmental Safety.

    Science.gov (United States)

    Mani, Sujata; Bharagava, Ram Naresh

    2016-01-01

    Crystal Violet (CV), a triphenylmethane dye, has been extensively used in human and veterinary medicine as a biological stain, as a textile dye in textile processing industries and also used to provide a deep violet color to paints and printing ink. CV is also used as a mutagenic and bacteriostatic agent in medical solutions and antimicrobial agent to prevent the fungal growth in poultry feed. Inspite of its many uses, CV has been reported as a recalcitrant dye molecule that persists in environment for a long period and pose toxic effects in environment. It acts as a mitotic poison, potent carcinogen and a potent clastogene promoting tumor growth in some species of fish. Thus, CV is regarded as a biohazard substance. Although, there are several physico-chemical methods such as adsorption, coagulation and ion-pair extraction reported for the removal of CV, but these methods are insufficient for the complete removal of CV from industrial wastewaters and also produce large quantity of sludge containing secondary pollutants. However, biological methods are regarded as cost-effective and eco-friendly for the treatment of industrial wastewaters, but these methods also have certain limitations. Therefore, there is an urgent need to develop such eco-friendly and cost-effective biological treatment methods, which can effectively remove the dye from industrial wastewaters for the safety of environment, as well as human and animal health. PMID:26613989

  6. Assessment of Carcinogenicity of di(2-ethylhexyl) phthalate in a short-term assay using Xpa(-/-) and Xpa(-/-)/p53(+/-) mice

    DEFF Research Database (Denmark)

    Mortensen, Alicja; Bertram, Margareta; Aarup, V.; Sørensen, Ilona Kryspin

    2002-01-01

    between the models. The only liver tumors in all models were adenomas in males with no statistically significantly increased incidence. For p-cresidine, the survival was decreased (p <0.05) only in transgenic models. Statistically significantly increased incidences of nonneoplastic lesions were recorded...... in the liver, urinary bladder, and nasal cavity in all models, and in kidneys in transgenic models. The only tumors with statistically significantly increased incidence were liver adenomas in transgenic models (XPA:1 vs 7; `XPA/p53': 0 vs 12; WT: 0 vs 5, p = 0.053) and urinary bladder carcinomas in...... XPA/p53 model (0 vs 7). The negative carcinogenic response to DEHP and the positive response to p-cresidine support the expected sensitivity to genotoxic carcinogens in these transgenic models....

  7. Ptaquiloside, the major carcinogen of bracken fern, in the pooled raw milk of healthy sheep and goats: an underestimated, global concern of food safety.

    Science.gov (United States)

    Virgilio, Antonella; Sinisi, Annamaria; Russo, Valeria; Gerardo, Salvatore; Santoro, Adriano; Galeone, Aldo; Taglialatela-Scafati, Orazio; Roperto, Franco

    2015-05-20

    Bracken fern (Pteridium aquilinum) is a worldwide plant containing toxic substances, which represent an important chemical hazard for animals, including humans. Ptaquiloside, 1, a norsesquiterpenoid glucoside, is the major carcinogen of bracken detected in the food chain, particularly in the milk from farm animals. To date, ptaquiloside has been shown in the milk of cows feeding on a diet containing bracken fern. This is the first study that shows the systematic detection of ptaquiloside, 1, and reports its direct quantitation in pooled raw milk of healthy sheep and goats grazing on bracken. Ptaquiloside, 1, was detected by a sensitive method based on the chemical conversion of ptaquiloside, 1, into bromopterosine, 4, following gas chromatography-mass spectrometry (GC-MS) analysis. The presence of ptaquiloside, 1, possibly carcinogenic to humans, in the milk of healthy animals is an unknown potential health risk, thus representing a harmful and potential global concern of food safety. PMID:25932502

  8. QSAR screening of 70,983 REACH substances for genotoxic carcinogenicity, mutagenicity and developmental toxicity in the ChemScreen project

    DEFF Research Database (Denmark)

    Wedebye, Eva Bay; Dybdahl, Marianne; Nikolov, Nikolai Georgiev;

    2015-01-01

    The ChemScreen project aimed to develop a screening system for reproductive toxicity based on alternative methods. QSARs can, if adequate, contribute to the evaluation of chemical substances under REACH and may in some cases be applied instead of experimental testing to fill data gaps for...... were used to reach overall predictions of substances with potential effects with the following result: 6.5% genotoxic carcinogens, 16.3% mutagens, 11.5% developmental toxicants. These results are similar to findings in earlier QSAR and experimental studies of chemical inventories, and illustrate how...... QSAR predictions may be used to identify potential genotoxic carcinogens, mutagens and developmental toxicants by high-throughput virtual screening....

  9. Molecular interaction analysis of cigarette smoke carcinogens NNK and NNAL with enzymes involved in DNA repair pathways: An in silico approach

    OpenAIRE

    Jamal, Qazi Mohd Sajid; Lohani, Mohtashim; Siddiqui, Mohd. Haris; Haneef, Mohd; Gupta, Shailendra Kumar; Wadhwa, Gulshan

    2012-01-01

    DNA damage occurs almost all the times in cells, but is repaired also continuously. Occurrence of all these mutations and their accumulation in one cell which finally becomes tumorigenic/carcinogenic appears possible if the DNA repair mechanism is hampered. We hypothesize that alterations in DNA repair pathways, either all or at least at one i.e. genetic, translational or posttranslational level, becomes quite imperative for the initiation and progression of Cancer. Therefore, we investigated...

  10. Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

    OpenAIRE

    Woo, Yin-Tak; Lai, David; McLain, Jennifer L; Manibusan, Mary Ko; Dellarco, Vicki

    2002-01-01

    Disinfection by-products (DBPs) are formed when disinfectants such as chlorine, chloramine, and ozone react with organic and inorganic matter in water. The observations that some DBPs such as trihalomethanes (THMs), di-/trichloroacetic acids, and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) are carcinogenic in animal studies have raised public concern over the possible adverse health effects of DBPs. To date, several hundred DBPs have been identified. To prioritize research effor...

  11. A Low-Cost Wheat Bran Medium for Biodegradation of the Benzidine-Based Carcinogenic Dye Trypan Blue Using a Microbial Consortium

    OpenAIRE

    Harshad Lade; Avinash Kadam; Diby Paul; Sanjay Govindwar

    2015-01-01

    Environmental release of benzidine-based dyes is a matter of health concern. Here, a microbial consortium was enriched from textile dye contaminated soils and investigated for biodegradation of the carcinogenic benzidine-based dye Trypan Blue using wheat bran (WB) as growth medium. The PCR-DGGE analysis of enriched microbial consortium revealed the presence of 15 different bacteria. Decolorization studies suggested that the microbial consortium has high metabolic activity towards Trypan Blue ...

  12. Inter‑laboratory study of human in vitro toxicogenomics‑based tests as alternative methods for evaluating chemical carcinogenicity: a bioinformatics perspective

    OpenAIRE

    Herwig, Ralf; GMUENDER Hans; Corvi, Raffaella; Bloch, K; CASTELL Jose; Ceelen, Liesbeth; Chesne, Christopher; DOKTOROVA Tatyana; Jennen, Danyel G.J.; Jennings, Paul; Limonciel, Alice; LOCK Edward; Mcmorrow, Tara; PHRAKONKHAM Pascal; Radford, R

    2015-01-01

    The assessment of the carcinogenic potential of chemicals with alternative, human-based in vitro systems has become a major goal of toxicogenomics. The central read-out of these assays is the transcriptome and the induced expression changes upon chemical exposure. While many studies exist that describe the transcriptomic responses of such systems, reports on robustness and reproducibility when testing the systems independently in different laboratories are uncommon. Furthermore, there is limi...

  13. Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

    OpenAIRE

    Koeberle, Andreas; Northoff, Hinnak; Werz, Oliver

    2009-01-01

    Abstract Garcinol (camboginol) from the fruit rind of Guttiferae species shows anti-carcinogenic and anti-inflammatory properties, but the underlying molecular mechanisms are unclear. Here we show that garcinol potently interferes with 5-lipoxygenase (EC 7.13.11.34) and microsomal prostaglandin (PG)E2 synthase (mPGES)-1 (EC 5.3.99.3), enzymes that play pivotal roles in inflammation and tumorigenesis. In cell-free assays, garcinol inhibited the activity of purified 5-lipoxygenase an...

  14. Tobacco carcinogen induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation.

    Science.gov (United States)

    Aizawa, Koichi; Liu, Chun; Tang, Sanyuan; Veeramachaneni, Sudipta; Hu, Kang-Quan; Smith, Donald E; Wang, Xiang-Dong

    2016-09-01

    Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non-alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carcinoma (HCC). In the present study, we investigated whether the tobacco carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lesions in both lungs and livers of ferrets with or without lycopene intervention. Male ferrets (6 groups, n = 8-10) were treated either with NNK (50 mg/kg BW, i.p., once a month for four consecutive months) or saline with or without dietary lycopene supplementation (2.2 and 6.6 mg/kg BW/day, respectively) for 26 weeks. Results demonstrate that NNK exposure results in higher incidences of lung tumors, HCC and steatohepatitis (which is characterized by severe inflammatory cell infiltration with concurrent fat accumulation in liver, hepatocellular ballooning degeneration and increased NF-κB expression), as well as elevations in bilirubin and AST levels in ferrets. Lycopene supplementation at two doses prevented NNK-induced expressions of α7 nicotinic acetylcholine receptor in the lung and NF-κB and CYP2E1 in the liver and attenuated the NNK-induced mortality and pathological lesions in both the lungs and livers of ferrets. The present study provided strong experimental evidence that the tobacco carcinogen NNK can induce both HCC and steatohepatitis in the ferrets and can be a useful model for studying tobacco carcinogen-associated NAFLD and liver cancer. Furthermore, lycopene could provide potential benefits against smoke carcinogen-induced pulmonary and hepatic injury. PMID:27116542

  15. Administration of a vaccine composed of dendritic cells pulsed with premalignant oral lesion lysate to mice bearing carcinogen-induced premalignant oral lesions stimulates a protective immune response

    OpenAIRE

    De Costa, Anna-Maria A.; Justis, Danielle N.; Schuyler, Corinne A.; M. Rita I. Young

    2012-01-01

    The use of dendritic cell (DC) vaccines as treatment for malignancy is complicated by immune evasion tactics often employed by carcinomas such as head and neck squamous cell carcinoma (HNSCC). The present study aims to determine if an immune response can be elicited by administering a DC vaccine during the premalignant stages of HNSCC, prior to development of immune escape. Mice treated with the carcinogen 4-nitroquinoline 1-oxide (4NQO) in drinking water develop premalignant oral lesions tha...

  16. [Mutagenic activation and carcinogenicity of aminoazo dyes of ortho-aminoazotoluene and 3'-methyl-4-dimethylaminoazobenzene in experiments on suckling mice].

    Science.gov (United States)

    Kaledin, V I; Il'nitskaia, S I; Ovchinnikova, L P; Popova, N A; Bogdanova, L A; Morozkova, T S

    2014-01-01

    It is found that after administration of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB,) which was hepatocarcinogenic to rats, in suckling mice, the number of neoplastic lesions in the liver of mice was 3 times higher than after analogous administration of equimolar dose of ortho-aminoazotoluene (OAT)). However, in the Ames test (TA-98 strain of Salmonella typhimurium) with activation by hepatic enzymes (S-9 fraction) of both intact and Aroclor-1254-induced mice and rats OAT contributed by an order of magnitude to revertant colonies compared to 3'-Me-DAB. In vivo inhibition of sulfotransferase activity, the enzyme which catalyzes the final stage of the mutagenic activation of aminoazo dyes, had no effect on carcinogenicity of 3'-Me-DAB but more than 4 times elevated that of OAT. It was concluded that the mechanism of carcinogenic action of aminoazo dyes studied is not genotoxic and that the carcinogenic potential of OAT is lost in the process of mutagenic activation. PMID:25715596

  17. Novel adducts from the reaction of 1-chloro-3-buten-2-one with 2'-deoxyguanosine. Structural characterization and potential as tools to investigate 1,3-butadiene carcinogenicity.

    Science.gov (United States)

    Zheng, Jin; Li, Yan; Yu, Ying-Xin; An, Jing; Zhang, Xin-Yu; Elfarra, Adnan A

    2015-01-25

    1-Chloro-3-buten-2-one (CBO) is a potential reactive metabolite of 1,3-butadiene (BD), a carcinogenic air pollutant. To develop tools that may help investigate the role of CBO in BD carcinogenicity and to develop biomarkers that can be used to assess BD exposure, the reaction of CBO with 2'-deoxyguanosine (dG) under in vitro physiological conditions (pH 7.4, 37°C) was investigated and the products (designated as CG-1, CG-2, CG-3, CG-4, CG-5, and CG-6 based on their retention times on HPLC) were characterized by MS and NMR spectroscopy. The structures of CG-1, CG-2, CG-3, and CG-4 were 1,N2-(3-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2'-deoxyguanosine, N7-(4-chloro-3-oxobutyl)-2'-deoxyguanosine, N7,8-(3-hydroxy-3-chloromethylpropan-1,3-diyl)guanine and N2-(4-chloro-3-oxobutyl)-2'-deoxyguanosine, respectively. CG-5 and CG-6, a pair of diastereomers, were characterized as 1,N2-(3-hydroxy-3-chloromethylpropan-1,3-diyl)-2'-deoxyguanosine. CG-1 was stable under in vitro physiological conditions, whereas CG-2, CG-3, CG-4, and CG-5/6 were unstable and exhibited the half-lives at mechanism of BD carcinogenicity and could also be used to develop biomarkers for BD exposure. PMID:25500269

  18. Carcinogen-specific gene expression profiles in short-term treated Eker and wild-type rats indicative of pathways involved in renal tumorigenesis.

    Science.gov (United States)

    Stemmer, Kerstin; Ellinger-Ziegelbauer, Heidrun; Ahr, Hans-Juergen; Dietrich, Daniel R

    2007-05-01

    Eker rats heterozygous for a dominant germline mutation in the tuberous sclerosis 2 (Tsc2) tumor suppressor gene were used as a model to study renal carcinogenesis. Eker and corresponding wild-type rats were exposed to genotoxic aristolochic acid (AA) or non-genotoxic ochratoxin A (OTA) to elucidate early carcinogen-specific gene expression changes and to test whether Eker rats are more sensitive to carcinogen-induced changes in gene expression. Male Eker and wild-type rats were gavaged daily with AA (10 mg/kg body weight) or OTA (210 microg/kg body weight). After 1, 3, 7, and 14 days of exposure, renal histopathology, tubular cell proliferation, and Affymetrix gene expression profiles from renal cortex/outer medulla were analyzed. AA-treated Eker and wild-type rats were qualitatively comparable in all variables assessed, suggesting a Tsc2-independent mechanism of action. OTA treatment resulted in slightly increased cortical pathology and significantly elevated cell proliferation in both strains, although Eker rats were more sensitive. Deregulated genes involved in the phosphatidylinositol 3-kinase-AKT-Tsc2-mammalian target of rapamycin signaling, among other important genes prominent in tumorigenesis, in conjunction with the enhanced cell proliferation and presence of preneoplastic lesions suggested involvement of Tsc2 in OTA-mediated toxicity and carcinogenicity, especially as deregulation of genes involved in this pathway was more prominent in the Tsc2 mutant Eker rat. PMID:17483316

  19. Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches

    Directory of Open Access Journals (Sweden)

    Marie Stiborová

    2014-06-01

    Full Text Available This review summarizes the results found in studies investigating the enzymatic activation of two genotoxic nitro-aromatics, an environmental pollutant and carcinogen 3-nitrobenzanthrone (3-NBA and a natural plant nephrotoxin and carcinogen aristolochic acid I (AAI, to reactive species forming covalent DNA adducts. Experimental and theoretical approaches determined the reasons why human NAD(PH:quinone oxidoreductase (NQO1 and cytochromes P450 (CYP 1A1 and 1A2 have the potential to reductively activate both nitro-aromatics. The results also contributed to the elucidation of the molecular mechanisms of these reactions. The contribution of conjugation enzymes such as N,O-acetyltransferases (NATs and sulfotransferases (SULTs to the activation of 3-NBA and AAI was also examined. The results indicated differences in the abilities of 3-NBA and AAI metabolites to be further activated by these conjugation enzymes. The formation of DNA adducts generated by both carcinogens during their reductive activation by the NOQ1 and CYP1A1/2 enzymes was investigated with pure enzymes, enzymes present in subcellular cytosolic and microsomal fractions, selective inhibitors, and animal models (including knock-out and humanized animals. For the theoretical approaches, flexible in silico docking methods as well as ab initio calculations were employed. The results summarized in this review demonstrate that a combination of experimental and theoretical approaches is a useful tool to study the enzyme-mediated reaction mechanisms of 3-NBA and AAI reduction.

  20. Bulky carcinogen-DNA adducts and exposure to environmental and occupational sources of polycyclic aromatic hydrocarbons. Influence of susceptibility genotypes on adduct level

    Energy Technology Data Exchange (ETDEWEB)

    Sabro Nielsen, P.

    1996-12-31

    PAH exposure, whether it is of occupational or environmental origin, is thought to result in an elevated risk of cancer especially in the lungs. DNA damage is considered an important step in the carcinogenic effect of PAH. Hence, methods that elucidate the steps in the carcinogenic process are important to understand the action of PAH. It may prove useful in the exposure assessment and in combination with classical epidemiological methods give better basis for risk estimation. The objective in this thesis was to evaluate the feasibility of the {sup 32}P-postlabeling method to detect carcinogen-DNA adducts for assessing exposure to DNA damaging compounds in different occupationally and environmentally exposed groups. The studies included groups, that have an elevated cancer risk due to occupational exposure to PAH. Exposure levels were supposed to be relatively low according to reports on occupational and environmental air quality programs. Another aim was to evaluate the influence of polymorphisms in metabolizing enzyme genes on DNA adduct levels. A third objective was to establish some kind of baseline DNA adduct level for individuals with supposed low exposure, and compare it to the more exposed groups. A fourth aim in these studies was to examine if biomarkers of genotoxic exposure could be useful in epidemiological studies to identify groups at risk and thereby contribute with better exposure estimates in the study of PAH related cancer risk. (EG).