Sample records for quantitative structure carcinogenicity

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

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

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

    2008-09-01

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

  2. Qualitative and quantitative approaches in the dose-response assessment of genotoxic carcinogens.

    PubMed

    Fukushima, Shoji; Gi, Min; Kakehashi, Anna; Wanibuchi, Hideki; Matsumoto, Michiharu

    2016-05-01

    Qualitative and quantitative approaches are important issues in field of carcinogenic risk assessment of the genotoxic carcinogens. Herein, we provide quantitative data on low-dose hepatocarcinogenicity studies for three genotoxic hepatocarcinogens: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and N-nitrosodiethylamine (DEN). Hepatocarcinogenicity was examined by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, which are the preneoplastic lesions in rat hepatocarcinogenesis and the endpoint carcinogenic marker in the rat liver medium-term carcinogenicity bioassay. We also examined DNA damage and gene mutations which occurred through the initiation stage of carcinogenesis. For the establishment of points of departure (PoD) from which the cancer-related risk can be estimated, we analyzed the above events by quantitative no-observed-effect level and benchmark dose approaches. MeIQx at low doses induced formation of DNA-MeIQx adducts; somewhat higher doses caused elevation of 8-hydroxy-2'-deoxyquanosine levels; at still higher doses gene mutations occurred; and the highest dose induced formation of GST-P positive foci. These data indicate that early genotoxic events in the pathway to carcinogenesis showed the expected trend of lower PoDs for earlier events in the carcinogenic process. Similarly, only the highest dose of IQ caused an increase in the number of GST-P positive foci in the liver, while IQ-DNA adduct formation was observed with low doses. Moreover, treatment with DEN at low doses had no effect on development of GST-P positive foci in the liver. These data on PoDs for the markers contribute to understand whether genotoxic carcinogens have a threshold for their carcinogenicity. The most appropriate approach to use in low dose-response assessment must be approved on the basis of scientific judgment. © The Author 2015. Published by Oxford University Press on behalf of

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

    PubMed

    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.

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

    PubMed Central

    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. PMID:27625608

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

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

    Purdy, R.

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

  6. Novel Uses of In Vitro Data to Develop Quantitative Biological Activity Relationship Models for in Vivo Carcinogenicity Prediction.

    PubMed

    Pradeep, Prachi; Povinelli, Richard J; Merrill, Stephen J; Bozdag, Serdar; Sem, Daniel S

    2015-04-01

    The availability of large in vitro datasets enables better insight into the mode of action of chemicals and better identification of potential mechanism(s) of toxicity. Several studies have shown that not all in vitro assays can contribute as equal predictors of in vivo carcinogenicity for development of hybrid Quantitative Structure Activity Relationship (QSAR) models. We propose two novel approaches for the use of mechanistically relevant in vitro assay data in the identification of relevant biological descriptors and development of Quantitative Biological Activity Relationship (QBAR) models for carcinogenicity prediction. We demonstrate that in vitro assay data can be used to develop QBAR models for in vivo carcinogenicity prediction via two case studies corroborated with firm scientific rationale. The case studies demonstrate the similarities between QBAR and QSAR modeling in: (i) the selection of relevant descriptors to be used in the machine learning algorithm, and (ii) the development of a computational model that maps chemical or biological descriptors to a toxic endpoint. The results of both the case studies show: (i) improved accuracy and sensitivity which is especially desirable under regulatory requirements, and (ii) overall adherence with the OECD/REACH guidelines. Such mechanism based models can be used along with QSAR models for prediction of mechanistically complex toxic endpoints. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. SYN-JEM: A Quantitative Job-Exposure Matrix for Five Lung Carcinogens.

    PubMed

    Peters, Susan; Vermeulen, Roel; Portengen, Lützen; Olsson, Ann; Kendzia, Benjamin; Vincent, Raymond; Savary, Barbara; Lavoué, Jérôme; Cavallo, Domenico; Cattaneo, Andrea; Mirabelli, Dario; Plato, Nils; Fevotte, Joelle; Pesch, Beate; Brüning, Thomas; Straif, Kurt; Kromhout, Hans

    2016-08-01

    The use of measurement data in occupational exposure assessment allows more quantitative analyses of possible exposure-response relations. We describe a quantitative exposure assessment approach for five lung carcinogens (i.e. asbestos, chromium-VI, nickel, polycyclic aromatic hydrocarbons (by its proxy benzo(a)pyrene (BaP)) and respirable crystalline silica). A quantitative job-exposure matrix (JEM) was developed based on statistical modeling of large quantities of personal measurements. Empirical linear models were developed using personal occupational exposure measurements (n = 102306) from Europe and Canada, as well as auxiliary information like job (industry), year of sampling, region, an a priori exposure rating of each job (none, low, and high exposed), sampling and analytical methods, and sampling duration. The model outcomes were used to create a JEM with a quantitative estimate of the level of exposure by job, year, and region. Decreasing time trends were observed for all agents between the 1970s and 2009, ranging from -1.2% per year for personal BaP and nickel exposures to -10.7% for asbestos (in the time period before an asbestos ban was implemented). Regional differences in exposure concentrations (adjusted for measured jobs, years of measurement, and sampling method and duration) varied by agent, ranging from a factor 3.3 for chromium-VI up to a factor 10.5 for asbestos. We estimated time-, job-, and region-specific exposure levels for four (asbestos, chromium-VI, nickel, and RCS) out of five considered lung carcinogens. Through statistical modeling of large amounts of personal occupational exposure measurement data we were able to derive a quantitative JEM to be used in community-based studies. © The Author 2016. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

  8. Development of Quantitative Structure-Activity Relationship (QSAR) Models to Predict the Carcinogenic Potency of Chemicals

    EPA Science Inventory

    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 either: (1) identify alternative toxicity measures (shorter duration) that may be used as...

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

    PubMed

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

    2015-09-01

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

  10. Risk assessment of carcinogens in food.

    PubMed

    Barlow, Susan; Schlatter, Josef

    2010-03-01

    Approaches for the risk assessment of carcinogens in food have evolved as scientific knowledge has advanced. Early methods allowed little more than hazard identification and an indication of carcinogenic potency. Evaluation of the modes of action of carcinogens and their broad division into genotoxic and epigenetic (non-genotoxic, non-DNA reactive) carcinogens have played an increasing role in determining the approach followed and provide possibilities for more detailed risk characterisation, including provision of quantitative estimates of risk. Reliance on experimental animal data for the majority of risk assessments and the fact that human exposures to dietary carcinogens are often orders of magnitude below doses used in experimental studies has provided a fertile ground for discussion and diverging views on the most appropriate way to offer risk assessment advice. Approaches used by national and international bodies differ, with some offering numerical estimates of potential risks to human health, while others express considerable reservations about the validity of quantitative approaches requiring extrapolation of dose-response data below the observed range and instead offer qualitative advice. Recognising that qualitative advice alone does not provide risk managers with information on which to prioritise the need for risk management actions, a "margin of exposure" approach for substances that are both genotoxic and carcinogenic has been developed, which is now being used by the World Health Organization and the European Food Safety Authority. This review describes the evolution of risk assessment advice on carcinogens and discusses examples of ways in which carcinogens in food have been assessed in Europe.

  11. Risk assessment of carcinogens in food

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

    Barlow, Susan, E-mail: suebarlow@mistral.co.u; Schlatter, Josef; Federal Office of Public Health, Consumer Protection Directorate, Stauffacherstrasse 101, CH-8004 Zuerich

    2010-03-01

    Approaches for the risk assessment of carcinogens in food have evolved as scientific knowledge has advanced. Early methods allowed little more than hazard identification and an indication of carcinogenic potency. Evaluation of the modes of action of carcinogens and their broad division into genotoxic and epigenetic (non-genotoxic, non-DNA reactive) carcinogens have played an increasing role in determining the approach followed and provide possibilities for more detailed risk characterisation, including provision of quantitative estimates of risk. Reliance on experimental animal data for the majority of risk assessments and the fact that human exposures to dietary carcinogens are often orders of magnitudemore » below doses used in experimental studies has provided a fertile ground for discussion and diverging views on the most appropriate way to offer risk assessment advice. Approaches used by national and international bodies differ, with some offering numerical estimates of potential risks to human health, while others express considerable reservations about the validity of quantitative approaches requiring extrapolation of dose-response data below the observed range and instead offer qualitative advice. Recognising that qualitative advice alone does not provide risk managers with information on which to prioritise the need for risk management actions, a 'margin of exposure' approach for substances that are both genotoxic and carcinogenic has been developed, which is now being used by the World Health Organization and the European Food Safety Authority. This review describes the evolution of risk assessment advice on carcinogens and discusses examples of ways in which carcinogens in food have been assessed in Europe.« less

  12. STRUCTURE-ACTIVITY RELATIONSHIPS (SARS) AMONG MUTAGENS AND CARCINOGENS: A REVIEW

    EPA Science Inventory

    The review is an introduction to methods for evaluating structure-activity relationships (SARs), and, in particular, to those methods that have been applied to study mutagenicity and carcinogenicity. A brief history and some background material on the earliest attempts to correla...

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2012-10-01

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

  15. Development of an exposure measurement database on five lung carcinogens (ExpoSYN) for quantitative retrospective occupational exposure assessment.

    PubMed

    Peters, Susan; Vermeulen, Roel; Olsson, Ann; Van Gelder, Rainer; Kendzia, Benjamin; Vincent, Raymond; Savary, Barbara; Williams, Nick; Woldbæk, Torill; Lavoué, Jérôme; Cavallo, Domenico; Cattaneo, Andrea; Mirabelli, Dario; Plato, Nils; Dahmann, Dirk; Fevotte, Joelle; Pesch, Beate; Brüning, Thomas; Straif, Kurt; Kromhout, Hans

    2012-01-01

    SYNERGY is a large pooled analysis of case-control studies on the joint effects of occupational carcinogens and smoking in the development of lung cancer. A quantitative job-exposure matrix (JEM) will be developed to assign exposures to five major lung carcinogens [asbestos, chromium, nickel, polycyclic aromatic hydrocarbons (PAH), and respirable crystalline silica (RCS)]. We assembled an exposure database, called ExpoSYN, to enable such a quantitative exposure assessment. Existing exposure databases were identified and European and Canadian research institutes were approached to identify pertinent exposure measurement data. Results of individual air measurements were entered anonymized according to a standardized protocol. The ExpoSYN database currently includes 356 551 measurements from 19 countries. In total, 140 666 personal and 215 885 stationary data points were available. Measurements were distributed over the five agents as follows: RCS (42%), asbestos (20%), chromium (16%), nickel (15%), and PAH (7%). The measurement data cover the time period from 1951 to present. However, only a small portion of measurements (1.4%) were performed prior to 1975. The major contributing countries for personal measurements were Germany (32%), UK (22%), France (14%), and Norway and Canada (both 11%). ExpoSYN is a unique occupational exposure database with measurements from 18 European countries and Canada covering a time period of >50 years. This database will be used to develop a country-, job-, and time period-specific quantitative JEM. This JEM will enable data-driven quantitative exposure assessment in a multinational pooled analysis of community-based lung cancer case-control studies.

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

    PubMed

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

    2011-09-01

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

  17. Interrelationships among carcinogenicity, mutagenicity, acute toxicity, and chemical structure in a genotoxicity data base

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

    Benigni, R.; Andreoli, C.; Giuliani, A.

    1989-01-01

    The interrelationships among carcinogenicity, mutagenicity, acute toxicity (LD50), and a number of molecular descriptors were studied by computerized data analysis methods on the data base generated by the International Program for the Evaluation of Short-Term Test for Carcinogens (IPESTTC). With the use of statistical regression methods, three main associations were evidenced: (1) the well-known correlation between carcinogenicity and mutagenicity; (2) a correlation between mutagenicity and toxicity (LD50 ip in mice); and (3) a correlation between toxicity and a recently introduced estimator of the free energy of binding of the molecules to biological receptors. As expected on the basis of themore » large variety of chemical classes represented in the IPESTTC data base, no simple relationship between mutagenicity or carcinogenicity and chemical descriptors was found. To overcome this problem, a new pattern recognition method (REPAD), developed by us for structure-activity studies of noncongeneric chemicals, has been used. This allowed us to highlight a significant difference between the whole patterns of relationships among chemicophysical variables in the two groups to active (mutagenicity and/or carcinogenic) and inactive chemicals. This approach generated a classification rule able to correctly assign about 80% of carcinogens or mutagens.« less

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

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

    King, R.D.; Srinivasan, A.

    1996-10-01

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

  19. Approaches to the risk assessment of genotoxic carcinogens in food: a critical appraisal.

    PubMed

    O'Brien, J; Renwick, A G; Constable, A; Dybing, E; Müller, D J G; Schlatter, J; Slob, W; Tueting, W; van Benthem, J; Williams, G M; Wolfreys, A

    2006-10-01

    The present paper examines the particular difficulties presented by low levels of food-borne DNA-reactive genotoxic carcinogens, some of which may be difficult to eliminate completely from the diet, and proposes a structured approach for the evaluation of such compounds. While the ALARA approach is widely applicable to all substances in food that are both carcinogenic and genotoxic, it does not take carcinogenic potency into account and, therefore, does not permit prioritisation based on potential risk or concern. In the absence of carcinogenicity dose-response data, an assessment based on comparison with an appropriate threshold of toxicological concern may be possible. When carcinogenicity data from animal bioassays are available, a useful analysis is achieved by the calculation of margins of exposure (MOEs), which can be used to compare animal potency data with human exposure scenarios. Two reference points on the dose-response relationship that can be used for MOE calculation were examined; the T25 value, which is derived from linear extrapolation, and the BMDL10, which is derived from mathematical modelling of the dose-response data. The above approaches were applied to selected food-borne genotoxic carcinogens. The proposed approach is applicable to all substances in food that are DNA-reactive genotoxic carcinogens and enables the formulation of appropriate semi-quantitative advice to risk managers.

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

    EPA Science Inventory

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-09-01

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

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

    PubMed Central

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

    1977-01-01

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

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

    PubMed Central

    Bartsch, H; Tomatis, L

    1983-01-01

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

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

    PubMed Central

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

    2008-01-01

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

  6. Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

    PubMed Central

    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 efforts, an in-depth, mechanism-based structure-activity relationship analysis, supplemented by extensive literature search for genotoxicity and other data, was conducted for ranking the carcinogenic potential of DBPs that met the following criteria: a) detected in actual drinking water samples, b) have insufficient cancer bioassay data for risk assessment, and c) have structural features/alerts or short-term predictive assays indicative of carcinogenic potential. A semiquantitative concern rating scale of low, marginal, low-moderate, moderate, high-moderate, and high was used along with delineation of scientific rationale. Of the 209 DBPs analyzed, 20 were of priority concern with a moderate or high-moderate rating. Of these, four were structural analogs of MX and five were haloalkanes that presumably will be controlled by existing and future THM regulations. The other eleven DBPs, which included halonitriles (6), haloketones (2), haloaldehyde (1), halonitroalkane (1), and dialdehyde (1), are suitable priority candidates for future carcinogenicity testing and/or mechanistic studies. PMID:11834465

  7. Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis.

    PubMed

    García-Nieto, Pablo E; Schwartz, Erin K; King, Devin A; Paulsen, Jonas; Collas, Philippe; Herrera, Rafael E; Morrison, Ashby J

    2017-10-02

    The development of many sporadic cancers is directly initiated by carcinogen exposure. Carcinogens induce malignancies by creating DNA lesions (i.e., adducts) that can result in mutations if left unrepaired. Despite this knowledge, there has been remarkably little investigation into the regulation of susceptibility to acquire DNA lesions. In this study, we present the first quantitative human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation, the ubiquitous carcinogen in sunlight that causes skin cancer. Remarkably, the pattern of carcinogen susceptibility across the genome of primary cells significantly reflects mutation frequency in malignant melanoma. Surprisingly, DNase-accessible euchromatin is protected from UV, while lamina-associated heterochromatin at the nuclear periphery is vulnerable. Many cancer driver genes have an intrinsic increase in carcinogen susceptibility, including the BRAF oncogene that has the highest mutation frequency in melanoma. These findings provide a genome-wide snapshot of DNA injuries at the earliest stage of carcinogenesis. Furthermore, they identify carcinogen susceptibility as an origin of genome instability that is regulated by nuclear architecture and mirrors mutagenesis in cancer. © 2017 The Authors.

  8. Listing Occupational Carcinogens

    PubMed Central

    Siemiatycki, Jack; Richardson, Lesley; Straif, Kurt; Latreille, Benoit; Lakhani, Ramzan; Campbell, Sally; Rousseau, Marie-Claude; Boffetta, Paolo

    2004-01-01

    The occupational environment has been a most fruitful one for investigating the etiology of human cancer. Many recognized human carcinogens are occupational carcinogens. There is a large volume of epidemiologic and experimental data concerning cancer risks in different work environments. It is important to synthesize this information for both scientific and public health purposes. Various organizations and individuals have published lists of occupational carcinogens. However, such lists have been limited by unclear criteria for which recognized carcinogens should be considered occupational carcinogens, and by inconsistent and incomplete information on the occupations and industries in which the carcinogenic substances may be found and on their target sites of cancer. Based largely on the evaluations published by the International Agency for Research on Cancer, and augmented with additional information, the present article represents an attempt to summarize, in tabular form, current knowledge on occupational carcinogens, the occupations and industries in which they are found, and their target organs. We have considered 28 agents as definite occupational carcinogens, 27 agents as probable occupational carcinogens, and 113 agents as possible occupational carcinogens. These tables should be useful for regulatory or preventive purposes and for scientific purposes in research priority setting and in understanding carcinogenesis. PMID:15531427

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

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

    Valerio, Luis G.; Arvidson, Kirk B.; Chanderbhan, Ronald F.

    2007-07-01

    Consistent with the U.S. Food and Drug Administration (FDA) Critical Path Initiative, predictive toxicology software programs employing quantitative structure-activity relationship (QSAR) models are currently under evaluation for regulatory risk assessment and scientific decision support for highly sensitive endpoints such as carcinogenicity, mutagenicity and reproductive toxicity. At the FDA's Center for Food Safety and Applied Nutrition's Office of Food Additive Safety and the Center for Drug Evaluation and Research's Informatics and Computational Safety Analysis Staff (ICSAS), the use of computational SAR tools for both qualitative and quantitative risk assessment applications are being developed and evaluated. One tool of current interest ismore » MDL-QSAR predictive discriminant analysis modeling of rodent carcinogenicity, which has been previously evaluated for pharmaceutical applications by the FDA ICSAS. The study described in this paper aims to evaluate the utility of this software to estimate the carcinogenic potential of small, organic, naturally occurring chemicals found in the human diet. In addition, a group of 19 known synthetic dietary constituents that were positive in rodent carcinogenicity studies served as a control group. In the test group of naturally occurring chemicals, 101 were found to be suitable for predictive modeling using this software's discriminant analysis modeling approach. Predictions performed on these compounds were compared to published experimental evidence of each compound's carcinogenic potential. Experimental evidence included relevant toxicological studies such as rodent cancer bioassays, rodent anti-carcinogenicity studies, genotoxic studies, and the presence of chemical structural alerts. Statistical indices of predictive performance were calculated to assess the utility of the predictive modeling method. Results revealed good predictive performance using this software's rodent carcinogenicity module of over 1200

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

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

    Singh, Kunwar P., E-mail: kpsingh_52@yahoo.com; Environmental Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box 80, Mahatma Gandhi Marg, Lucknow 226 001; Gupta, Shikha

    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 wasmore » 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

  11. Chemistry of mutagens and carcinogens in broiled food.

    PubMed Central

    Nishimura, S

    1986-01-01

    From a chemical point of view, the following subjects are important areas in studies on mutagens and carcinogens in broiled foods. In addition to heterocyclic amines which need microsomal activation, the structural elucidation of more labile direct-acting mutagens is necessary. It is known that there are still various unknown minor mutagens in broiled foods. Although the structural characterization of such compounds is more difficult, it is important since they might be hazardous in spite of their low mutagenicity. A more feasible and easier method for quantitative analysis of mutagens, in addition to HPLC and GC/MS methods presently employed, must be developed. The mechanism of formation of mutagens by broiling of food should be studied. An effective chemical method to prevent formation of mutagens or to destroy them, once formed, should be developed. PMID:3757944

  12. Identifying occupational carcinogens: an update from the IARC Monographs.

    PubMed

    Loomis, Dana; Guha, Neela; Hall, Amy L; Straif, Kurt

    2018-05-16

    The recognition of occupational carcinogens is important for primary prevention, compensation and surveillance of exposed workers, as well as identifying causes of cancer in the general population. This study updates previously published lists of known occupational carcinogens while providing additional information on cancer type, exposure scenarios and routes, and discussing trends in the identification of carcinogens over time. Data were extracted from International Agency for Research on Cancer (IARC) Monographs covering the years 1971-2017, using specific criteria to ensure occupational relevance and provide high confidence in the causality of observed exposure-disease associations. Selected agents were substances, mixtures or types of radiation classified in IARC Group 1 with 'sufficient evidence of carcinogenicity' in humans from studies of exposed workers and evidence of occupational exposure documented in the pertinent monograph. The number of known occupational carcinogens has increased over time: 47 agents were identified as known occupational carcinogens in 2017 compared with 28 in 2004. These estimates are conservative and likely underestimate the number of carcinogenic agents present in workplaces. Exposure to these agents causes a wide range of cancers; cancers of the lung and other respiratory sites, followed by skin, account for the largest proportion. The dominant routes of exposure are inhalation and dermal contact. Important progress has been made in identifying occupational carcinogens; nevertheless, there is an ongoing need for research on the causes of work-related cancer. Most workplace exposures have not been evaluated for their carcinogenic potential due to inadequate epidemiologic evidence and a paucity of quantitative exposure data. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  13. Method for converting asbestos to non-carcinogenic compounds

    DOEpatents

    Selby, Thomas W.

    1996-01-01

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

  14. Carcinogenicity and Mutagenicity Data: New Initiatives to ...

    EPA Pesticide Factsheets

    Currents models for prediction of chemical carcinogenicity and mutagenicity rely upon a relatively small number of publicly available data resources, where the data being modeled are highly summarized and aggregated representations of the actual experimental results. A number of new initiatives are underway to improve access to existing public carcinogenicity and mutagenicity data for use in modeling, as well as to encourage new approaches to the use of data in modeling. Rodent bioassay results from the NIEHS National Toxicology Program (NTP) and the Berkeley Carcinogenic Potency Database (CPDB) have provided the largest public data resources for building carcinogenicity prediction models to date. However, relatively few and limited representations of these data have actually informed existing models. Initiatives, such as EPA's DSSTox Database Network, offer elaborated and quality reviewed presentations of the CPDB and expanded data linkages and coverage of chemical space for carcinogenicity and mutagenicity. In particular the latest published DSSTox CPDBAS structure-data file includes a number of species-specific and summary activity fields, including a species-specific normalized score for carcinogenic potency (TD50) and various weighted summary activities. These data are being incorporated into PubChem to provide broad

  15. Predictive Models for Carcinogenicity and Mutagenicity ...

    EPA Pesticide Factsheets

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

  16. Method for converting asbestos to non-carcinogenic compounds

    DOEpatents

    Selby, T.W.

    1996-08-06

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

  17. Deriving a Mutation Index of Carcinogenicity Using Protein Structure and Protein Interfaces

    PubMed Central

    Hakas, Jarle; Pearl, Frances; Zvelebil, Marketa

    2014-01-01

    With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/. PMID:24454733

  18. Carcinogenic compounds in alcoholic beverages: an update.

    PubMed

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

    2016-10-01

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

  19. Unscheduled DNA synthesis in human bronchial epithelium treated with various chemical carcinogens in vitro

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

    Ishikawa, T.; Ide, F.; Kodama, K.

    1984-07-01

    A system was developed in which organ culture of human bronchial epithelium was used in combination with autoradiography for quantitative measurement of unscheduled DNA synthesis (UDS) in bronchial epithelial cells. Human bronchi obtained at surgery were cut into small sections and treated with various carcinogens plus (methyl-/sup 3/H)thymidine in short-term organ culture. Significant numbers of silver grains, indicating UDS, were detected on the nuclei of epithelial cells of human bronchi treated with carcinogens, and the numbers were proportional to the concentrations of carcinogens. In this system seven representative carcinogens induced UDS. Four active metabolites of benzo(a)pyrene, and benz(a)anthracene also weremore » found to induce very active UDS in human bronchial epithelium. These findings suggest that human bronchial epithelial cells can repair different types of DNA modification induced by chemical carcinogens.« less

  20. Structure alerts for carcinogenicity, and the Salmonella assay system: a novel insight through the chemical relational databases technology.

    PubMed

    Benigni, Romualdo; Bossa, Cecilia

    2008-01-01

    In the past decades, chemical carcinogenicity has been the object of mechanistic studies that have been translated into valuable experimental (e.g., the Salmonella assays system) and theoretical (e.g., compilations of structure alerts for chemical carcinogenicity) models. These findings remain the basis of the science and regulation of mutagens and carcinogens. Recent advances in the organization and treatment of large databases consisting of both biological and chemical information nowadays allows for a much easier and more refined view of data. This paper reviews recent analyses on the predictive performance of various lists of structure alerts, including a new compilation of alerts that combines previous work in an optimized form for computer implementation. The revised compilation is part of the Toxtree 1.50 software (freely available from the European Chemicals Bureau website). The use of structural alerts for the chemical biological profiling of a large database of Salmonella mutagenicity results is also reported. Together with being a repository of the science on the chemical biological interactions at the basis of chemical carcinogenicity, the SAs have a crucial role in practical applications for risk assessment, for: (a) description of sets of chemicals; (b) preliminary hazard characterization; (c) formation of categories for e.g., regulatory purposes; (d) generation of subsets of congeneric chemicals to be analyzed subsequently with QSAR methods; (e) priority setting. An important aspect of SAs as predictive toxicity tools is that they derive directly from mechanistic knowledge. The crucial role of mechanistic knowledge in the process of applying (Q)SAR considerations to risk assessment should be strongly emphasized. Mechanistic knowledge provides a ground for interaction and dialogue between model developers, toxicologists and regulators, and permits the integration of the (Q)SAR results into a wider regulatory framework, where different types of

  1. Diesel Exhaust and Lung Cancer-Aftermath of Becoming an IARC Group 1 Carcinogen.

    PubMed

    Silverman, Debra T

    2018-06-01

    The International Agency for Research on Cancer reclassified diesel exhaust from Group 2A (probably carcinogenic to humans) to Group 1 (carcinogenic to humans) in 2012. Since then, reevaluation and reanalysis of 2 major studies (Diesel Exhaust in Miners Study and Trucking Industry Particle Study) that were influential to the International Agency for Research on Cancer evaluation have replicated the original findings and demonstrated the suitability of these epidemiologic data for the quantitative risk assessment needed to set safe exposure limits in occupational and outdoor ambient environments. The challenge now is to protect the workers and general populations in urban areas from the carcinogenicity of diesel exhaust.

  2. Integration of QSAR and SAR methods for the mechanistic interpretation of predictive models for carcinogenicity

    PubMed Central

    Fjodorova, Natalja; Novič, Marjana

    2012-01-01

    The knowledge-based Toxtree expert system (SAR approach) was integrated with the statistically based counter propagation artificial neural network (CP ANN) model (QSAR approach) to contribute to a better mechanistic understanding of a carcinogenicity model for non-congeneric chemicals using Dragon descriptors and carcinogenic potency for rats as a response. The transparency of the CP ANN algorithm was demonstrated using intrinsic mapping technique specifically Kohonen maps. Chemical structures were represented by Dragon descriptors that express the structural and electronic features of molecules such as their shape and electronic surrounding related to reactivity of molecules. It was illustrated how the descriptors are correlated with particular structural alerts (SAs) for carcinogenicity with recognized mechanistic link to carcinogenic activity. Moreover, the Kohonen mapping technique enables one to examine the separation of carcinogens and non-carcinogens (for rats) within a family of chemicals with a particular SA for carcinogenicity. The mechanistic interpretation of models is important for the evaluation of safety of chemicals. PMID:24688639

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

    PubMed

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

    2016-04-02

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

  4. Is There a Safe Level of Exposure to a Carcinogen?

    ERIC Educational Resources Information Center

    Hrudey, Steve E.; Krewski, Daniel

    1995-01-01

    Presents an approach to estimating the "safe" levels of low-dose exposure to carcinogens that involves working upward from the smallest conceivable chronic dose instead of extrapolating downward from high exposures. Discusses expert and public opinion and other issues related to quantitative cancer risk assessment. (LZ)

  5. A carcinogenic potency database of the standardized results of animal bioassays

    PubMed Central

    Gold, Lois Swirsky; Sawyer, Charles B.; Magaw, Renae; Backman, Georganne M.; De Veciana, Margarita; Levinson, Robert; Hooper, N. Kim; Havender, William R.; Bernstein, Leslie; Peto, Richard; Pike, Malcolm C.; Ames, Bruce N.

    1984-01-01

    The preceding paper described our numerical index of carcinogenic potency, the TD50 and the statistical procedures adopted for estimating it from experimental data. This paper presents the Carcinogenic Potency Database, which includes results of about 3000 long-term, chronic experiments of 770 test compounds. Part II is a discussion of the sources of our data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Part III is a guide to the plot of results presented in Part IV. A number of appendices are provided to facilitate use of the database. The plot includes information about chronic cancer tests in mammals, such as dose and other aspects of experimental protocol, histopathology and tumor incidence, TD50 and its statistical significance, dose response, author's opinion and literature reference. The plot readily permits comparisons of carcinogenic potency and many other aspects of cancer tests; it also provides quantitative information about negative tests. The range of carcinogenic potency is over 10 million-fold. PMID:6525996

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

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

    Fukushima, Shoji; Morimura, Keiichirou; Wanibuchi, Hideki

    2005-09-01

    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 themore » 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.« less

  7. AutoQSAR: an automated machine learning tool for best-practice quantitative structure-activity relationship modeling.

    PubMed

    Dixon, Steven L; Duan, Jianxin; Smith, Ethan; Von Bargen, Christopher D; Sherman, Woody; Repasky, Matthew P

    2016-10-01

    We introduce AutoQSAR, an automated machine-learning application to build, validate and deploy quantitative structure-activity relationship (QSAR) models. The process of descriptor generation, feature selection and the creation of a large number of QSAR models has been automated into a single workflow within AutoQSAR. The models are built using a variety of machine-learning methods, and each model is scored using a novel approach. Effectiveness of the method is demonstrated through comparison with literature QSAR models using identical datasets for six end points: protein-ligand binding affinity, solubility, blood-brain barrier permeability, carcinogenicity, mutagenicity and bioaccumulation in fish. AutoQSAR demonstrates similar or better predictive performance as compared with published results for four of the six endpoints while requiring minimal human time and expertise.

  8. Monitoring carcinogen actions on DNA by 32P-postlabeling.

    PubMed

    Randerath, K; Randerath, E

    1990-01-01

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

  9. A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens

    PubMed Central

    Hernández, Lya G.; van Benthem, Jan; Johnson, George E.

    2013-01-01

    Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption is that clastogens and aneugens have linear and non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biological mechanisms are linked with dose-response evaluations. For aneugens, the MOA has been well characterised as disruptors of mitotic machinery where chromosome loss via micronuclei (MN) formation is an accepted endpoint used in risk assessment. In this study we performed the cytokinesis-block micronucleus assay and immunofluorescence mitotic machinery visualisation in human lymphoblastoid (AHH-1) and Chinese Hamster fibroblast (V79) cell lines after treatment with the aneugen 17-β-oestradiol (E2). Results were compared to previously published data on bisphenol-A (BPA) and Rotenone data. Two concentration-response approaches (the threshold-[Td] and benchmark-dose [BMD] approaches) were applied to derive a point of departure (POD) for in vitro MN induction. BMDs were also derived from the most sensitive carcinogenic endpoint. Ranking comparisons of the PODs from the in vitro MN and the carcinogenicity studies demonstrated a link between these two endpoints for BPA, E2 and Rotenone. This analysis was extended to include 5 additional aneugens, 5 clastogens and 3 mutagens and further concentration and dose-response correlations were observed between PODs from the in vitro MN and carcinogenicity. This approach is promising and may be further extended to other genotoxic carcinogens, where MOA and quantitative information from the in vitro MN studies could be used in a quantitative manner to further inform cancer risk assessment. PMID:23675539

  10. Identifying and regulating carcinogens. Background paper

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

    Not Available

    1987-11-01

    Contents include: Introduction and summary; policies for testing, assessing, and regulating carcinogens; federal agency assessment and regulation of carcinogens; the national toxicology program; agency responses to the annual report on carcinogens and NCI/NTP test results; statutory authority for regulating carcinogens; chemicals listed in annual report on carcinogens and NCI/NTP test results.

  11. [Carcinogenic effects of diesel emission: an epidemiological review].

    PubMed

    Szadkowska-Stańczyk, I; Ruszkowska, J

    2000-01-01

    The results of recent epidemiological studies and meta-analysis relating to carcinogenic effects of diesel emissions in exposed populations were reviewed. Statistical, but still not causal association between risk of lung cancer and occupational exposure to diesel emissions was found in a great number of studies under review. Long-term exposure to diesel exhausts (> 20 years) increases by 30-40% lung cancer risk in workers of the transport industry: truck drivers, diesel engine mechanics, locomotive engineers and brakesmen. The results are inconsistent among heavy equipment operators, bus drivers and miners. Relative risk of lung cancer among workers occupationally exposed to diesel emission may be comparable with that of environmental tobacco smoke. Further research is also needed in the area of carcinogenic mechanisms, and biomarkers of exposure should be developed and validated before reliable quantitative estimates of risk of harmful effects to the human health in occupational setting are made.

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

    PubMed

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

    1995-01-01

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

  13. A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens.

    PubMed

    Felter, Susan P; Conolly, Rory B; Bercu, Joel P; Bolger, P Michael; Boobis, Alan R; Bos, Peter M J; Carthew, Philip; Doerrer, Nancy G; Goodman, Jay I; Harrouk, Wafa A; Kirkland, David J; Lau, Serrine S; Llewellyn, G Craig; Preston, R Julian; Schoeny, Rita; Schnatter, A Robert; Tritscher, Angelika; van Velsen, Frans; Williams, Gary M

    2011-07-01

    Quantitative methods for estimation of cancer risk have been developed for daily, lifetime human exposures. There are a variety of studies or methodologies available to address less-than-lifetime exposures. However, a common framework for evaluating risk from less-than-lifetime exposures (including short-term and/or intermittent exposures) does not exist, which could result in inconsistencies in risk assessment practice. To address this risk assessment need, a committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute conducted a multisector workshop in late 2009 to discuss available literature, different methodologies, and a proposed framework. The proposed framework provides a decision tree and guidance for cancer risk assessments for less-than-lifetime exposures based on current knowledge of mode of action and dose-response. Available data from rodent studies and epidemiological studies involving less-than-lifetime exposures are considered, in addition to statistical approaches described in the literature for evaluating the impact of changing the dose rate and exposure duration for exposure to carcinogens. The decision tree also provides for scenarios in which an assumption of potential carcinogenicity is appropriate (e.g., based on structural alerts or genotoxicity data), but bioassay or other data are lacking from which a chemical-specific cancer potency can be determined. This paper presents an overview of the rationale for the workshop, reviews historical background, describes the proposed framework for assessing less-than-lifetime exposures to potential human carcinogens, and suggests next steps.

  14. Rodent carcinogens: Setting priorities

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

    Gold, L.S.; Slone, T.H.; Stern, B.R.

    1992-10-09

    The human diet contains an enormous background of natural chemicals, such as plant pesticides and the products of cooking, that have not been a focus of carcinogenicity testing. A broadened perspective that includes these natural chemicals is necessary. A comparison of possible hazards for 80 daily exposures to rodent carcinogens from a variety of sources is presented, using an index (HERP) that relates human exposure to carcinogenic potency in rodents. A similar ordering would be expected with the use of standard risk assessment methodology for the same human exposure values. Results indicate that, when viewed against the large background ofmore » naturally occurring carcinogens in typical portions of common foods, the residues of synthetic pesticides or environmental pollutants rank low. A similar result is obtained in a separate comparison of 32 average daily exposures to natural pesticides and synthetic pesticides residues in the diet. Although the findings do not indicate that these natural dietary carcinogens are important in human cancer, they cast doubt on the relative importance for human cancer of low-dose exposures to synthetic chemicals.« less

  15. Carcinogens in the Schools

    ERIC Educational Resources Information Center

    Block, J. Bradford

    1976-01-01

    Reports the presence and use of known carcinogens in Kentucky colleges, junior colleges, and high schools. Includes a listing of known carcinogens and the synonym names under which each may be labeled. (SL)

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

    PubMed

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

    1994-01-02

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

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

    PubMed

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

    2016-02-26

    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.

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

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

    Zielinski, J.M.; Krewski, D.

    1992-12-31

    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 describedmore » and illustrated, using data on lung-cancer mortality among Colorado uranium miners exposed to both radon and tobacco smoke.« less

  19. Foetal exposure to food and environmental carcinogens in human beings.

    PubMed

    Myöhänen, Kirsi; Vähäkangas, Kirsi

    2012-02-01

    Exposure to many different chemicals during pregnancy through maternal circulation is possible. Transplacental transfer of xenobiotics can be demonstrated using human placental perfusion. Also, placental perfusion can give information about the placental kinetics as well as metabolism and accumulation in the placenta because it retains the tissue structure and function. Although human placental perfusion has been used extensively to study the transplacental transfer of drugs, the information on food and environmental carcinogens is much more limited. This review deals with the foetal exposure to food and environmental carcinogens in human beings. In particular, human transplacental transfer of the food carcinogens such as acrylamide, glycidamide and nitrosodimethylamine are in focus. Because these carcinogens are genotoxic, the functional capacity of human placenta to induce DNA adduct formation or metabolize these above mentioned CYP2E1 substrates is of interest in this context. © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.

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

    PubMed

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

    2013-09-01

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

  1. Carcinogen Control in the Chemical Laboratory.

    ERIC Educational Resources Information Center

    Johnson, James S.

    1981-01-01

    Presents general and specific guidelines for handling carcinogens. Additional topics include: definition of potential occupational carcinogens; classification of carcinogens; inventory requirements; signs and labels for materials and laboratories; decontamination and disposal procedures; medical surveillance for employees working with controlled…

  2. Low-Dose Carcinogenicity Studies

    EPA Science Inventory

    One of the major deficiencies of cancer risk assessments is the lack of low-dose carcinogenicity data. Most assessments require extrapolation from high to low doses, which is subject to various uncertainties. Only 4 low-dose carcinogenicity studies and 5 low-dose biomarker/pre-n...

  3. Toxicity and carcinogenicity of potassium bromate--a new renal carcinogen

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

    Kurokawa, Y.; Maekawa, A.; Takahashi, M.

    Potassium bromate (KBrO3) is an oxidizing agent that has been used as a food additive, mainly in the bread-making process. Although adverse effects are not evident in animals fed bread-based diets made from flour treated with KBrO3, the agent is carcinogenic in rats and nephrotoxic in both man and experimental animals when given orally. It has been demonstrated that KBrO3 induces renal cell tumors, mesotheliomas of the peritoneum, and follicular cell tumors of the thyroid. In addition, experiments aimed at elucidating the mode of carcinogenic action have revealed that KBrO3 is a complete carcinogen, possessing both initiating and promoting activitiesmore » for rat renal tumorigenesis. However, the potential seems to be weak in mice and hamsters. In contrast to its weak mutagenic activity in microbial assays, KBrO3 showed relatively strong potential inducing chromosome aberrations both in vitro and in vivo. Glutathione and cysteine degrade KBrO3 in vitro; in turn, the KBrO3 has inhibitory effects on inducing lipid peroxidation in the rat kidney. Active oxygen radicals generated from KBrO3 were implicated in its toxic and carcinogenic effects, especially because KBrO3 produced 8-hydroxydeoxyguanosine in the rat kidney. A wide range of data from applications of various analytical methods are now available for risk assessment purposes.111 references.« less

  4. [Application of quantum-chemical methods to prediction of the carcinogenicity of chemical substances].

    PubMed

    Zholdikova, Z I; Kharchevnikova, N V

    2006-01-01

    A version of logical-combinatorial JSM type intelligent system was used to predict the presence and the degree of a carcinogenic effect. This version was based on combined description of chemical substances including both structural and numeric parameters. The new version allows for the fact that the toxicity and danger caused by chemical substances often depend on their biological activation in the organism. The authors substantiate classifying chemicals according to their carcinogenic activity, and illustrate the use of the system to predict the carcinogenicity of polycyclic aromatic hydrocarbons using a model of bioactivation via the formation of diolepoxides, and the carcinogenicity of halogenated alkanes using a model of bioactivation via oxidative dehalogenation. The paper defined the boundary level of an energetic parameter, the exceeding of which correlated with the inhibition of halogenated alkanes's metabolism and the absence of carcinogenic activity.

  5. The carcinogenicity of chromium

    PubMed Central

    Norseth, Tor

    1981-01-01

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

  6. Evaluating Pesticides for Carcinogenic Potential

    EPA Pesticide Factsheets

    EPA reviews pesticides for potential carcinogenicity. Learn about EPA's guidelines for evaluating a chemical's potential carcinogenicity and updates to EPA's guidelines to reflect increased understanding of ways chemicals may cause cancer.

  7. [Hygienic assessment of carcinogenic and noncarcinogenic risks of oral intake of drinking water chemical agents].

    PubMed

    Ignat'eva, L P; Pogorelova, I G; Potapova, M O

    2006-01-01

    Based on the quantitative and qualitative determination of drinking water pollution by a large number of substances of varying toxicity and hazard, the authors calculated a possible risks of their adverse impact on the body by the development of carcinogenic and noncarcinogenic effects.

  8. Toxicity and carcinogenicity of potassium bromate--a new renal carcinogen.

    PubMed Central

    Kurokawa, Y; Maekawa, A; Takahashi, M; Hayashi, Y

    1990-01-01

    Potassium bromate (KBrO3) is an oxidizing agent that has been used as a food additive, mainly in the bread-making process. Although adverse effects are not evident in animals fed bread-based diets made from flour treated with KBrO3, the agent is carcinogenic in rats and nephrotoxic in both man and experimental animals when given orally. It has been demonstrated that KBrO3 induces renal cell tumors, mesotheliomas of the peritoneum, and follicular cell tumors of the thyroid. In addition, experiments aimed at elucidating the mode of carcinogenic action have revealed that KBrO3 is a complete carcinogen, possessing both initiating and promoting activities for rat renal tumorigenesis. However, the potential seems to be weak in mice and hamsters. In contrast to its weak mutagenic activity in microbial assays, KBrO3 showed relatively strong potential inducing chromosome aberrations both in vitro and in vivo. Glutathione and cysteine degrade KBrO3 in vitro; in turn, the KBrO3 has inhibitory effects on inducing lipid peroxidation in the rat kidney. Active oxygen radicals generated from KBrO3 were implicated in its toxic and carcinogenic effects, especially because KBrO3 produced 8-hydroxydeoxyguanosine in the rat kidney. A wide range of data from applications of various analytical methods are now available for risk assessment purposes. Images FIGURE 1. FIGURE 2. FIGURE 5. FIGURE 6. FIGURE 7. FIGURE 8. FIGURE 9. FIGURE 10. FIGURE 11. FIGURE 12. PMID:2269236

  9. 29 CFR 1990.112 - Classification of potential carcinogens.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 9 2012-07-01 2012-07-01 false Classification of potential carcinogens. 1990.112 Section... CARCINOGENS The Osha Cancer Policy § 1990.112 Classification of potential carcinogens. The following criteria for identification, classification and regulation of potential occupational carcinogens will be...

  10. 29 CFR 1990.112 - Classification of potential carcinogens.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 9 2013-07-01 2013-07-01 false Classification of potential carcinogens. 1990.112 Section... CARCINOGENS The Osha Cancer Policy § 1990.112 Classification of potential carcinogens. The following criteria for identification, classification and regulation of potential occupational carcinogens will be...

  11. 29 CFR 1990.112 - Classification of potential carcinogens.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 9 2014-07-01 2014-07-01 false Classification of potential carcinogens. 1990.112 Section... CARCINOGENS The Osha Cancer Policy § 1990.112 Classification of potential carcinogens. The following criteria for identification, classification and regulation of potential occupational carcinogens will be...

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

    PubMed

    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. Copyright © 2016 The Authors. Published by

  13. Arsenic Is A Genotoxic Carcinogen

    EPA Science Inventory

    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...

  14. PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC

    EPA Science Inventory

    PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC.

    Arsenic is a human carcinogen in skin, lung, liver, urinary bladder and kidney. In contrast,
    there is no accepted experimental animal model of inorganic arsenic carcinogenesis.
    Proposed mechanisms/modes of action for a...

  15. Consequences of synergy between environmental carcinogens

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

    Berenbaum, M.C.

    1985-12-01

    As it is generally impossible to determine dose-response relationships for carcinogens at the low concentrations in which they occur in the environment, risk-benefit considerations are by consensus based on the linear, no-threshold model, on the assumption that this represents the worst case. However, this assumption does not take into account the possibility of synergistic interactions between carcinogens. It is shown here that, as a result of such interactions, the dose-response curve for added risk due to any individual carcinogen will generally be steeper at lower doses than at higher doses, and consequently the risk at low environmental levels will bemore » higher than would be expected from a linear response. Moreover, this excess risk at low doses is shown to increase as the general level of environmental carcinogens rises and, independently of this effect, it may also increase with the number of carcinogens present.« less

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

    PubMed

    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). Copyright © 2015 Elsevier B.V. All rights reserved.

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

    EPA Science Inventory

    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...

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

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

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

    1988-01-01

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

  19. In vitro cell transformation assays for an integrated, alternative assessment of carcinogenicity: a data-based analysis.

    PubMed

    Benigni, Romualdo; Bossa, Cecilia; Tcheremenskaia, Olga

    2013-01-01

    The study of the chemical carcinogenesis mechanisms and the design of efficient prevention strategies and measures are of crucial importance to protect human health. The long-term carcinogenesis bioassays have played a central role in protecting human health, but for ethical and practical reasons their use is dramatically diminishing, and the genotoxicity short-term tests have taken the pivotal role in the pre-screening of carcinogenicity. However, there is evidence that this strategy is not sensitive enough to detect all genotoxic carcinogens and it cannot detect nongenotoxic carcinogens. In a previous article, we have shown that an integrated strategy consisting of the in vitro Ames and Syrian Hamster Embryo cells transformation assays, combined with structure-activity relationships, is a valid alternative to the present pre-screening strategies. Here, we expand the previous investigation by (i) including results of cell transformation assays on inorganics, together with an additional assay (Bhas 42), and (ii) considering new structural alerts for nongenotoxic carcinogenicity. We also present a new analysis on global relationships between toxicological endpoints. The new results confirm that the previously proposed integrated, alternative strategy is an efficient tool to identify both genotoxic and nongenotoxic carcinogens, with an estimated 90-95% sensitivity.

  20. [Carcinogenic effect of metals].

    PubMed

    Desurmont, M

    1983-09-01

    Some metals are essential oligo-elements for man. However, if the body load of these same metal derivatives becomes excessive they may be responsible for deleterious effects, particularly cytotoxic ones. Metals are divided into four categories: potent carcinogens; presumptive carcinogens with a documented cocarcinogenic effect; ascertained cocarcinogens; metals with no demonstrated carcinogenic or cocarcinogenic effect. The most common tumors induced by metals are those of the lung. Arsenic induces cancer of the lung and skin, beryllium may induce lung cancer, the effects of cobalt are dubious, cadmium can induce cancer of the lung and, above all, prostate, the role of iron is uncertain, hexavalent chrome may induce cancer of the lung and nasal fossae, nickel is responsible for cancer of lung and nasal fossae. Our understanding of metal carcinogenesis is clearly insufficient and more experimental research and epidemiologic studies addressing this subject are needed.

  1. [Risk assessment of carcinogenic and non-carcinogenic effects in the use of food].

    PubMed

    Frolova, O A; Karpova, M V

    2012-01-01

    Application of methodology for assessing the risk of diseases associated with consumption of contaminated foods, is aimed at predicting possible changes in the future and helps to create a framework for the prevention of negative effects on public health. The purpose of the study is assessment of health risks formed under the influence of chemical contaminants that pollute the food. Exponential average daily dose of receipt of chemicals in the body, non-carcinogenic and carcinogenic risks were calculated.

  2. High- to low-dose extrapolation: critical determinants involved in the dose response of carcinogenic substances.

    PubMed

    Swenberg, J A; Richardson, F C; Boucheron, J A; Deal, F H; Belinsky, S A; Charbonneau, M; Short, B G

    1987-12-01

    Recent investigations on mechanism of carcinogenesis have demonstrated important quantitative relationships between the induction of neoplasia, the molecular dose of promutagenic DNA adducts and their efficiency for causing base-pair mismatch, and the extent of cell proliferation in target organ. These factors are involved in the multistage process of carcinogenesis, including initiation, promotion, and progression. The molecular dose of DNA adducts can exhibit supralinear, linear, or sublinear relationships to external dose due to differences in absorption, biotransformation, and DNA repair at high versus low doses. In contrast, increased cell proliferation is a common phenomena that is associated with exposures to relatively high doses of toxic chemicals. As such, it enhances the carcinogenic response at high doses, but has little effect at low doses. Since data on cell proliferation can be obtained for any exposure scenario and molecular dosimetry studies are beginning to emerge on selected chemical carcinogens, methods are needed so that these critical factors can be utilized in extrapolation from high to low doses and across species. The use of such information may provide a scientific basis for quantitative risk assessment.

  3. 29 CFR 1990.121 - Candidate list of potential occupational carcinogens.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 9 2013-07-01 2013-07-01 false Candidate list of potential occupational carcinogens. 1990... OCCUPATIONAL CARCINOGENS Priority Setting § 1990.121 Candidate list of potential occupational carcinogens. (a... Potential Carcinogens or Category II Potential Carcinogens. For the purposes of this paragraph, “available...

  4. 29 CFR 1990.121 - Candidate list of potential occupational carcinogens.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 9 2012-07-01 2012-07-01 false Candidate list of potential occupational carcinogens. 1990... OCCUPATIONAL CARCINOGENS Priority Setting § 1990.121 Candidate list of potential occupational carcinogens. (a... Potential Carcinogens or Category II Potential Carcinogens. For the purposes of this paragraph, “available...

  5. 29 CFR 1990.121 - Candidate list of potential occupational carcinogens.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 9 2014-07-01 2014-07-01 false Candidate list of potential occupational carcinogens. 1990... OCCUPATIONAL CARCINOGENS Priority Setting § 1990.121 Candidate list of potential occupational carcinogens. (a... Potential Carcinogens or Category II Potential Carcinogens. For the purposes of this paragraph, “available...

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

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

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

    1991-01-01

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

  7. PUBLIC SOURCES OF MUTAGENICITY AND CARCINOGENICITY DATA: USE IN STRUCTURE-ACTIVITY RELATIONSHIP MODELS

    EPA Science Inventory

    No Abstract - first paragraph of INTRODUCTION

    Publicly supported compilations of mutagenicity and carcinogenicity data are available
    for a significant number and variety of environmental and industrial chemicals and, to a lesser
    extent, pharmaceutical chemicals. T...

  8. MOUSE LIVER TUMOR DATA: ASSESSMENT OF CARCINOGENIC ACTIVITY

    EPA Science Inventory

    A significant number of chemicals have been shown to be carcinogenic in mouse liver while lacking carcinogenic activity in other organs or tissues of mice or rats. The review focus on the reasons for the unique susceptibility of the mouse liver to these carcinogens, and the exten...

  9. A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens.

    PubMed

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

    2015-12-01

    Alternative methods to detect non-genotoxic carcinogens are urgently needed, as this class of carcinogens goes undetected in the current testing strategy for carcinogenicity under REACH. A complicating factor is that non-genotoxic carcinogens act through several distinctive modes of action, which makes prediction of their carcinogenic property difficult. We have recently demonstrated that gene expression profiling in primary mouse hepatocytes is a useful approach to categorize non-genotoxic carcinogens according to their modes of action. In the current study, we improved the methods used for analysis and added mouse embryonic stem cells as a second in vitro test system, because of their features complementary to hepatocytes. Our approach involved an unsupervised analysis based on the 30 most significantly up- and down-regulated genes per chemical. Mouse embryonic stem cells and primary mouse hepatocytes were exposed to a selected set of chemicals and subsequently subjected to gene expression profiling. We focused on non-genotoxic carcinogens, but also included genotoxic carcinogens and non-carcinogens to test the robustness of this approach. Application of the optimized comparison approach resulted in improved categorization of non-genotoxic carcinogens. Mouse embryonic stem cells were a useful addition, especially for genotoxic substances, but also for detection of non-genotoxic carcinogens that went undetected by primary hepatocytes. The approach presented here is an important step forward to categorize chemicals, especially those that are carcinogenic.

  10. Proposed Guidelines for Carcinogen Risk Assessment

    EPA Science Inventory

    The Proposed Guidelines for Carcinogen Risk Assessment were published in the Federal Register on April 23, 1996 (Federal Register: 17960-18011) for a 120-day public review and comment period. The Proposed Guidelines are a revision of EPA's 1986 Guidelines for Carcinogen Risk Ass...

  11. AGE-RELATED DIFFERENCES IN SUSCEPTIBILITY TO CARCINOGENESIS II, APPROACHES FOR APPLICATION AND UNCERTAINTY ANALYSES FOR INDIVIDUAL GENETICALLY ACTING CARCINOGENS

    EPA Science Inventory

    An earlier paper (Hattis et al., 2003) developed a quantitative likelihood-based statistical analysis of the differences in apparent sensitivity of rodents to mutagenic carcinogens across three life stages (fetal, birth-weaning, and weaning-60 days) relative to exposures in adult...

  12. Genetic toxicology of putative nongenotoxic carcinogens

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

    Jackson, M.A.; Stack, H.F.; Waters, M.D.

    1993-01-01

    The report examines a group of putative nongenotoxic carcinogens that have been cited in the published literature. Using short-term test data from the US Environmental Protection Agency/International Agency for Research on Cancer genetic activity profile (EPA/IARC GAP) database, these agents are classified on the basis of their mutagenicity emphasizing three genetic endpoints: gene mutation, chromosomal aberration and aneuploidy. On the basis of results of short-term tests for these effects, criteria was defined for evidence of mutagenicity (and nonmutagenicity) these criteria were applied in classifying the group of putative nongenotoxic carcinogens. The results from this evaluation based on the EPA/IARC GAPmore » database are presented along with a summary of the short-term test data for each chemical and the relevant carcinogenicity results from the NTP, Gene-Tox and IARC databases. The data clearly demonstrate that many of the putative nongenotoxic carcinogens that have been adequately tested in short-term bioassays induce gene or chromosomal mutations or aneuploidy.« less

  13. Occupational exposure to carcinogens: Benzene, pesticides and fibers

    PubMed Central

    Falzone, Luca; Marconi, Andrea; Loreto, Carla; Franco, Sabrina; Spandidos, Demetrios A.; Libra, Massimo

    2016-01-01

    It is well known that the occupational exposure to contaminants and carcinogens leads to the development of cancer in exposed workers. In the 18th century, Percivall Pott was the first to hypothesize that chronic exposure to dust in the London chimney sweeps was associated with an increased risk of developing cancer. Subsequently a growing body of evidence indicated that other physical factors were also responsible for oncogenic mutations. Over the past decades, many carcinogens have been found in the occupational environment and their presence is often associated with an increased incidence of cancer. Occupational exposure involves several factors and the association between carcinogens, occupational exposure and cancer is still unclear. Only a fraction of factors is recognized as occupational carcinogens and for each factor, there is an increased risk of cancer development associated with a specific work activity. According to the International Agency for Research on Cancer (IARC), the majority of carcinogens are classified as ‘probable’ and ‘possible’ human carcinogens, while, direct evidence of carcinogenicity is provided in epidemiological and experimental studies. In the present review, exposures to benzene, pesticides and mineral fibers are discussed as the most important cancer risk factors during work activities. PMID:27748850

  14. Formation and Repair of Tobacco Carcinogen-Derived Bulky DNA Adducts

    DOE PAGES

    Hang, Bo

    2010-01-01

    DNA adducts play a central role in chemical carcinogenesis. The analysis of formation and repair of smoking-related DNA adducts remains particularly challenging as both smokers and nonsmokers exposed to smoke are repetitively under attack from complex mixtures of carcinogens such as polycyclic aromatic hydrocarbons and N -nitrosamines. The bulky DNA adducts, which usually have complex structure, are particularly important because of their biological relevance. Several known cellular DNA repair pathways have been known to operate in human cells on specific types of bulky DNA adducts, for example, nucleotide excision repair, base excision repair, and direct reversal involving O 6 -alkylguaninemore » DNA alkyltransferase or AlkB homologs. Understanding the mechanisms of adduct formation and repair processes is critical for the assessment of cancer risk resulting from exposure to cigarette smoke, and ultimately for developing strategies of cancer prevention. This paper highlights the recent progress made in the areas concerning formation and repair of bulky DNA adducts in the context of tobacco carcinogen-associated genotoxic and carcinogenic effects.« less

  15. Estimating occupational exposure to carcinogens in Quebec.

    PubMed

    Labrèche, France; Duguay, Patrice; Ostiguy, Claude; Boucher, Alexandre; Roberge, Brigitte; Peters, Cheryl E; Demers, Paul A

    2013-09-01

    We estimated the extent of exposure to occupational carcinogens in Quebec, Canada, to help raise awareness of occupational cancers. Proportions of workers exposed to 21 recognized and 17 probable carcinogens (according to Quebec occupational health regulation and the International Agency for Research on Cancer [IARC] classification) were extracted from various sources: workplace monitoring data, research projects, a population survey, radiation protection data, exposure estimates from the Carcinogen Exposure Canada (CAREX Canada) Project database, and published exposure data. These proportions were applied to Quebec labor force data. Among the 38 studied, carcinogens with the largest proportions of exposed workers were solar radiation (6.6% of workers), night shift work/rotating shift work including nights (6.0%), diesel exhaust fumes (4.4%), wood dust (2.9%) and polycyclic aromatic hydrocarbons (2.0%). More than 15 carcinogens were identified in several industrial sectors, and up to 100,000 young workers are employed in these sectors. Although crude, estimates obtained with different data sources allow identification of research and intervention priorities for cancer in Quebec. Copyright © 2013 Wiley Periodicals, Inc.

  16. Aneuploidy: a common and early evidence-based biomarker for carcinogens and reproductive toxicants.

    PubMed

    Mandrioli, Daniele; Belpoggi, Fiorella; Silbergeld, Ellen K; Perry, Melissa J

    2016-10-12

    Aneuploidy, defined as structural and numerical aberrations of chromosomes, continues to draw attention as an informative effect biomarker for carcinogens and male reproductive toxicants. It has been well documented that aneuploidy is a hallmark of cancer. Aneuploidies in oocytes and spermatozoa contribute to infertility, pregnancy loss and a number of congenital abnormalities, and sperm aneuploidy is associated with testicular cancer. It is striking that several carcinogens induce aneuploidy in somatic cells, and also adversely affect the chromosome compliment of germ cells. In this paper we review 1) the contributions of aneuploidy to cancer, infertility, and developmental abnormalities; 2) techniques for assessing aneuploidy in precancerous and malignant lesions and in sperm; and 3) the utility of aneuploidy as a biomarker for integrated chemical assessments of carcinogenicity, and reproductive and developmental toxicity.

  17. Comparative analysis of predictive models for nongenotoxic hepatocarcinogenicity using both toxicogenomics and quantitative structure-activity relationships.

    PubMed

    Liu, Zhichao; Kelly, Reagan; Fang, Hong; Ding, Don; Tong, Weida

    2011-07-18

    The primary testing strategy to identify nongenotoxic carcinogens largely relies on the 2-year rodent bioassay, which is time-consuming and labor-intensive. There is an increasing effort to develop alternative approaches to prioritize the chemicals for, supplement, or even replace the cancer bioassay. In silico approaches based on quantitative structure-activity relationships (QSAR) are rapid and inexpensive and thus have been investigated for such purposes. A slightly more expensive approach based on short-term animal studies with toxicogenomics (TGx) represents another attractive option for this application. Thus, the primary questions are how much better predictive performance using short-term TGx models can be achieved compared to that of QSAR models, and what length of exposure is sufficient for high quality prediction based on TGx. In this study, we developed predictive models for rodent liver carcinogenicity using gene expression data generated from short-term animal models at different time points and QSAR. The study was focused on the prediction of nongenotoxic carcinogenicity since the genotoxic chemicals can be inexpensively removed from further development using various in vitro assays individually or in combination. We identified 62 chemicals whose hepatocarcinogenic potential was available from the National Center for Toxicological Research liver cancer database (NCTRlcdb). The gene expression profiles of liver tissue obtained from rats treated with these chemicals at different time points (1 day, 3 days, and 5 days) are available from the Gene Expression Omnibus (GEO) database. Both TGx and QSAR models were developed on the basis of the same set of chemicals using the same modeling approach, a nearest-centroid method with a minimum redundancy and maximum relevancy-based feature selection with performance assessed using compound-based 5-fold cross-validation. We found that the TGx models outperformed QSAR in every aspect of modeling. For example, the

  18. The carcinogenicity of 1-methyl-3(p-bromophenyl)-1-nitrosourea (Br-MPNU).

    PubMed

    Warzok, R; Martin, J; Mendel, J; Thust, R; Schwarz, H

    1983-01-01

    In long-term experiments with Hooded rats the carcinogenic potential of 1-methyl-3(p-bromophenyl)-1-nitrosourea (Br-MPNU) could be demonstrated for the first time. Br-MPNU is formed also endogenously after combined administration of 1-methyl-3(p-bromophenyl)-urea (Br-MPU) and sodium nitrite. After repeated intragastric administration of 0.33 mmol Br-MPU and 0.73 mmol NaNO2 per kg b.w. papillomas and carcinomas of the forestomach developed in 83%. After repeated administration of 0.28 mmol Br-MPNU per kg b.w. these neoplasms were observed in 88%. The comparison of results obtained in similar experiments with 1-methyl-3-phenyl-1-nitrosourea shows that bromine substitution led to a reduction of the carcinogenic activity. The present paper is part of a complex program studying the interrelationships between structure, physico-chemical properties, mutagenicity and carcinogenicity of nitrosoureas.

  19. High- to low-dose extrapolation: critical determinants involved in the dose response of carcinogenic substances.

    PubMed Central

    Swenberg, J A; Richardson, F C; Boucheron, J A; Deal, F H; Belinsky, S A; Charbonneau, M; Short, B G

    1987-01-01

    Recent investigations on mechanism of carcinogenesis have demonstrated important quantitative relationships between the induction of neoplasia, the molecular dose of promutagenic DNA adducts and their efficiency for causing base-pair mismatch, and the extent of cell proliferation in target organ. These factors are involved in the multistage process of carcinogenesis, including initiation, promotion, and progression. The molecular dose of DNA adducts can exhibit supralinear, linear, or sublinear relationships to external dose due to differences in absorption, biotransformation, and DNA repair at high versus low doses. In contrast, increased cell proliferation is a common phenomena that is associated with exposures to relatively high doses of toxic chemicals. As such, it enhances the carcinogenic response at high doses, but has little effect at low doses. Since data on cell proliferation can be obtained for any exposure scenario and molecular dosimetry studies are beginning to emerge on selected chemical carcinogens, methods are needed so that these critical factors can be utilized in extrapolation from high to low doses and across species. The use of such information may provide a scientific basis for quantitative risk assessment. PMID:3447904

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

    PubMed Central

    Cunningham, Albert R.; Trent, John O.

    2012-01-01

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

  1. Target organs in chronic bioassays of 533 chemical carcinogens

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

    Gold, L.S.; Slone, T.H.; Manley, N.B.

    1991-06-01

    A compendium of carcinogenesis bioassay results organized by target organ is presented for 533 chemicals that are carcinogenic in at least one species. This compendium is based primarily on experiments in rats or mice; results in hamsters, nonhuman primates, and dogs are also reported. The compendium can be used to identify chemicals that induce tumors at particular sites, and to determine whether target sites are the same for chemicals positive in more than one species. The Carcinogenic Potency Database (CPDB), which includes results of 3969 experiments, is used in the analysis. The published CPDB includes details on each test, andmore » literature references. Chemical carcinogens are reported for 35 different target organs in rats or mice. More than 80% of the carcinogens in each of these species are positive in at least one of the 8 most frequent target sites; liver, lung, mammary gland, stomach, vascular system, kidney, hematopoietic system, and urinary bladder. An analysis is presented of how well one can predict the carcinogenic response in mice from results in rats, or vice versa. Among chemicals tested in both species, 76% of rat carcinogens are positive in mice, and 71% of mouse carcinogens are positive in rats. Prediction is less accurate to the same target site: 52% of rat carcinogens are positive in the same site in mice, and 48% of mouse carcinogens are positive in the same site in rats. The liver is the most frequent site in common between rats and mice.« less

  2. Chromium carcinogenicity: California strategies.

    PubMed

    Alexeeff, G V; Satin, K; Painter, P; Zeise, L; Popejoy, C; Murchison, G

    1989-10-01

    Hexavalent chromium was identified by California as a toxic air contaminant (TAC) in January 1986. The California Department of Health Services (CDHS) concurred with the findings of the International Agency for Research on Cancer that there is sufficient evidence to demonstrate the carcinogenicity of chromium in both animals and humans. CDHS did not find any compelling evidence demonstrating the existence of a threshold with respect to chromium carcinogenesis. Experimental data was judged inadequate to assess potential human reproductive risks from ambient exposures. Other health effects were not expected to occur at ambient levels. The theoretically increased lifetime carcinogenic risk from a continuous lifetime exposure to hexavalent chromium fell within the range 12-146 cancer cases per nanogram hexavalent chromium per cubic meter of air per million people exposed, depending on the potency estimate used. The primary sources found to contribute significantly to the risk of exposure were chrome platers, chromic acid anodizing facilities and cooling towers utilizing hexavalent chromium as a corrosion inhibitor. Evaluation of genotoxicity data, animal studies and epidemiological studies indicates that further consideration should be given to the potential carcinogenicity of hexavalent chromium via the oral route.

  3. Occupational exposure to carcinogens: Benzene, pesticides and fibers (Review).

    PubMed

    Falzone, Luca; Marconi, Andrea; Loreto, Carla; Franco, Sabrina; Spandidos, Demetrios A; Libra, Massimo

    2016-11-01

    It is well known that the occupational exposure to contaminants and carcinogens leads to the development of cancer in exposed workers. In the 18th century, Percivall Pott was the first to hypothesize that chronic exposure to dust in the London chimney sweeps was associated with an increased risk of developing cancer. Subsequently a growing body of evidence indicated that other physical factors were also responsible for oncogenic mutations. Over the past decades, many carcinogens have been found in the occupational environment and their presence is often associated with an increased incidence of cancer. Occupational exposure involves several factors and the association between carcinogens, occupational exposure and cancer is still unclear. Only a fraction of factors is recognized as occupational carcinogens and for each factor, there is an increased risk of cancer development associated with a specific work activity. According to the International Agency for Research on Cancer (IARC), the majority of carcinogens are classified as 'probable' and 'possible' human carcinogens, while, direct evidence of carcinogenicity is provided in epidemiological and experimental studies. In the present review, exposures to benzene, pesticides and mineral fibers are discussed as the most important cancer risk factors during work activities.

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

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    .... Disposal means the safe removal of the carcinogens addressed by this section from the work environment... in an environment free of the 13 carcinogens addressed by this section. The clean change room shall... external environment. Decontamination means the inactivation of a carcinogen addressed by this section or...

  5. Carcinogen File.

    ERIC Educational Resources Information Center

    Environment, 1978

    1978-01-01

    First in a series of bulletins designed to provide information about the problem of carcinogens in the environment is on benzo(a)pyrine. Benzo(a)pyrine is a proven cancer-causing substance that has been known for over ten years to occur in broiled sausages, gas-broiled fish and beef steak, and charcoal-broiled meat. (Author/BB)

  6. Respiratory carcinogenicity assessment of soluble nickel compounds.

    PubMed Central

    Oller, Adriana R

    2002-01-01

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

  7. How many food additives are rodent carcinogens?

    PubMed

    Johnson, F M

    2002-01-01

    One generally assumes that chemical agents added to foods are reasonably free of risks to human health, and practically everyone consumes some additives in his or her food daily throughout life. In the United States, the 1958 Food Additives Amendment to the Federal Food, Drug and Cosmetic Act of 1938 requires food manufacturers to demonstrate the safety of food additives to the Food and Drug Administration (FDA). The Amendment contains a provision that prohibits approval of an additive if it is found to cause cancer in humans or animals. In the present study, data from the National Toxicology Program rodent bioassay (NTPRB) were used to identify a sample of approximately 50 rodent-tested additives and other chemicals added to food that had been evaluated independently of the FDA/food industry. Surprisingly, the sample shows more than 40% of these food chemicals to be carcinogenic in one or more rodent groups. If this percentage is extrapolated to all substances added to food in the United States, it would imply that more than 1000 of such substances are potential rodent carcinogens. The NTP and FDA test guidelines use similar, though not necessarily identical, rodent test procedures, including near lifetime exposures to the maximum tolerated dose. The FDA specifies that test chemicals should be administered by the oral route. However, the oral route includes three methods of delivering chemicals, that is, mixed in the food or water or delivered by stomach tube (gavage). The NTP data show only 1 of 18 food chemicals mixed in the food are rodent carcinogens, but 16 of 23 gavage-administered food chemicals are carcinogenic to rodents. The distribution suggests that among orally delivered chemicals, those administered in the feed will more likely prove to be noncarcinogens than chemicals given by gavage. The rodent data also reveal that effects may vary according to dose and genotype, as well as by route of administration, to further complicate extrapolation to humans

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

    PubMed

    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. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. TOPICAL REVIEW: MUTAGENICITY AND CARCINOGENICITY OF AIR

    EPA Science Inventory

    Although both outdoor and indoor airs provide exposure to mutagens and carcinogens, this review shows that the level of hazard is highly variable. Outdoor air was first shown to be carcinogenic in 1942 and mutagenic in 1975; and studies examining the genotoxicity of indoor air so...

  10. Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation

    PubMed Central

    Herceg, Zdenko

    2013-01-01

    Remarkable progress in the field of epigenetics has turned academic, medical and public attention to the potential applications of these new advances in medicine and various fields of biomedical research. The result is a broader appreciation of epigenetic phenomena in the a etiology of common human diseases, most notably cancer. These advances also represent an exciting opportunity to incorporate epigenetics and epigenomics into carcinogen identification and safety assessment. Current epigenetic studies, including major international sequencing projects, are expected to generate information for establishing the ‘normal’ epigenome of tissues and cell types as well as the physiological variability of the epigenome against which carcinogen exposure can be assessed. Recently, epigenetic events have emerged as key mechanisms in cancer development, and while our search of the Monograph Volume 100 revealed that epigenetics have played a modest role in evaluating human carcinogens by the International Agency for Research on Cancer (IARC) Monographs so far, epigenetic data might play a pivotal role in the future. Here, we review (i) the current status of incorporation of epigenetics in carcinogen evaluation in the IARC Monographs Programme, (ii) potential modes of action for epigenetic carcinogens, (iii) current in vivo and in vitro technologies to detect epigenetic carcinogens, (iv) genomic regions and epigenetic modifications and their biological consequences and (v) critical technological and biological issues in assessment of epigenetic carcinogens. We also discuss the issues related to opportunities and challenges in the application of epigenetic testing in carcinogen identification and evaluation. Although the application of epigenetic assays in carcinogen evaluation is still in its infancy, important data are being generated and valuable scientific resources are being established that should catalyse future applications of epigenetic testing. PMID:23749751

  11. Perspectives of comparing risks of environmental carcinogens

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

    Perera, F.; Boffetta, P.

    1988-10-19

    In 1987, investigators concluded that the risks of man-made industrial carcinogens and pesticides (outside of the workplace) are trivial compared with the risks of naturally occurring carcinogens found mostly in the diet. They used a ranking system based on human exposure and rodent potency (HERP) data to arrive at this conclusion. As a result, they recommend that regulatory agencies, such as the Environmental Protection Agency and the Food and Drug Administration, base their priorities in this area on their HERP system. We analyzed the assumptions and data set upon which the HERPs were based, concluding that such a simplified approachmore » to set public health policy is inappropriate given the underlying uncertainties. However, we note that when comparisons are consistently based on estimates of average daily exposure to common carcinogens, the HERP scores of many man-made pollutants are comparable to those of naturally occurring carcinogens in the diet.158 references.« less

  12. New public QSAR model for carcinogenicity

    PubMed Central

    2010-01-01

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

  13. Greek employee awareness of carcinogenic exposure.

    PubMed

    Chatzis, Christos; Karvounis, Kiki; Hatziara, Panayiota; Riza, Elena; Nikolaou, Vasilis; Linos, Athena

    2004-10-01

    Occupational risk factors contribute significantly to the development of lung cancer; however, little is known about the extent to which employees are informed of occupational exposure to carcinogenic substances. Through a case-control study, we estimated the level of awareness among Greek employees potentially exposed to known carcinogenic substances within various occupational settings. Only 6.6% of men (n = 482) employed in occupations with potential exposure to carcinogenic substances were aware of such occupational exposures. Age, education, and residence were significantly associated with awareness. Employees having at least a secondary level of education were 3.5 times more aware than those having at most 6 years of educational training. Assessing awareness among workers potentially exposed to occupational risk factors and promoting occupational health education are important steps for increasing health and safety at the workplace.

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

    NASA Astrophysics Data System (ADS)

    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

  15. Toxico-Cheminformatics and QSPR Modeling of the Carcinogenic Potency Database

    EPA Science Inventory

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

  16. Small fish models for identifying carcinogens in the aqueous environment

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

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

    1988-10-01

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

  17. Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide (Final Report)

    EPA Science Inventory

    EPA has finalized its Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide. This assessment addresses the potential carcinogenicity from long-term inhalation exposure to ethylene oxide. Now final, this assessment updates the carcinogenicity information in EPA’s 1985 Hea...

  18. Structure, function and carcinogenicity of metabolites of methylated and non-methylated polycyclic aromatic hydrocarbons: a comprehensive review.

    PubMed

    Flesher, James W; Lehner, Andreas F

    2016-01-01

    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.

  19. A novel approach: chemical relational databases, and the role of the ISSCAN database on assessing chemical carcinogenicity.

    PubMed

    Benigni, Romualdo; Bossa, Cecilia; Richard, Ann M; Yang, Chihae

    2008-01-01

    Mutagenicity and carcinogenicity databases are crucial resources for toxicologists and regulators involved in chemicals risk assessment. Until recently, existing public toxicity databases have been constructed primarily as "look-up-tables" of existing data, and most often did not contain chemical structures. Concepts and technologies originated from the structure-activity relationships science have provided powerful tools to create new types of databases, where the effective linkage of chemical toxicity with chemical structure can facilitate and greatly enhance data gathering and hypothesis generation, by permitting: a) exploration across both chemical and biological domains; and b) structure-searchability through the data. This paper reviews the main public databases, together with the progress in the field of chemical relational databases, and presents the ISSCAN database on experimental chemical carcinogens.

  20. Annual report on carcinogens (5th)

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

    Not Available

    1989-01-01

    The Fifth Annual Report on Carcinogens, prepared by the National Toxicology Program (NTP), U.S. Public Health Service, is issued by the Secretary of the Department of Health and Human Services (DHHS), pursuant to Public Law 95-622 of November 9, 1978. This law requires the Secretary to publish an annual report that contains 'a list of all substances (i) which either are known to be carcinogens or which may reasonably be anticipated to be carcinogens and (ii) to which a significant number of persons residing in the United States are exposed;...' Annual Reports should also provide available information on the naturemore » of exposures, the estimated number of persons potentially exposed, and the extent to which the implementation of Federal regulations decreases the risk to public health from exposure to these substances.« less

  1. Best practices for clinical pathology testing in carcinogenicity studies.

    PubMed

    Young, Jamie K; Hall, Robert L; O'Brien, Peter; Strauss, Volker; Vahle, John L

    2011-02-01

    The Society of Toxicologic Pathology (STP) and American Society for Veterinary Clinical Pathology (ASCVP) convened a Clinical Pathology in Carcinogenicity Studies Working Group to recommend best practices for inclusion of clinical pathology testing in carcinogenicity studies. Regulatory guidance documents and literature were reviewed, and veterinary pathologists from North America, Japan, and Europe were surveyed regarding current practices, perceived value, and recommendations for clinical pathology testing in carcinogenicity studies. For two-year rodent carcinogenicity studies, the Working Group recommends that clinical pathology testing be limited to collection of blood smears at scheduled and unscheduled sacrifices to be examined only if indicated to aid in the diagnosis of possible hematopoietic neoplasia following histopathologic evaluation. Additional clinical pathology testing is most appropriately used to address specific issues from prior toxicity studies or known test article-related class effects. Inadequate data were available to make a recommendation concerning clinical pathology testing for alternative six-month carcinogenicity assays using genetically modified mice, although the Working Group suggests that it may be appropriate to use the same approach as for two-year carcinogenicity studies since the study goal is the same.

  2. EPA's evaluation of the carcinogenic potential of glyphosate

    EPA Science Inventory

    Recently, several international agencies have evaluated the carcinogenic potential of glyphosate. In March 2015, the International Agency for Research on Cancer (IARC), a subdivision of the World Health Organization (WHO), determined that glyphosate was a probable carcinogen (gro...

  3. The effects of environmental chemical carcinogens on the microRNA machinery.

    PubMed

    Izzotti, A; Pulliero, A

    2014-07-01

    The first evidence that microRNA expression is early altered by exposure to environmental chemical carcinogens in still healthy organisms was obtained for cigarette smoke. To date, the cumulative experimental data indicate that similar effects are caused by a variety of environmental carcinogens, including polycyclic aromatic hydrocarbons, nitropyrenes, endocrine disruptors, airborne mixtures, carcinogens in food and water, and carcinogenic drugs. Accordingly, the alteration of miRNA expression is a general mechanism that plays an important pathogenic role in linking exposure to environmental toxic agents with their pathological consequences, mainly including cancer development. This review summarizes the existing experimental evidence concerning the effects of chemical carcinogens on the microRNA machinery. For each carcinogen, the specific microRNA alteration signature, as detected in experimental studies, is reported. These data are useful for applying microRNA alterations as early biomarkers of biological effects in healthy organisms exposed to environmental carcinogens. However, microRNA alteration results in carcinogenesis only if accompanied by other molecular damages. As an example, microRNAs altered by chemical carcinogens often inhibits the expression of mutated oncogenes. The long-term exposure to chemical carcinogens causes irreversible suppression of microRNA expression thus allowing the transduction into proteins of mutated oncogenes. This review also analyzes the existing knowledge regarding the mechanisms by which environmental carcinogens alter microRNA expression. The underlying molecular mechanism involves p53-microRNA interconnection, microRNA adduct formation, and alterations of Dicer function. On the whole, reported findings provide evidence that microRNA analysis is a molecular toxicology tool that can elucidate the pathogenic mechanisms activated by environmental carcinogens. Copyright © 2014 Elsevier GmbH. All rights reserved.

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

    PubMed

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

    2012-09-15

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

  5. Prediction of Chemical Carcinogenicity in Rodents from in vitro Genetic Toxicity Assays

    NASA Astrophysics Data System (ADS)

    Tennant, Raymond W.; Margolin, Barry H.; Shelby, Michael D.; Zeiger, Errol; Haseman, Joseph K.; Spalding, Judson; Caspary, William; Resnick, Michael; Stasiewicz, Stanley; Anderson, Beth; Minor, Robert

    1987-05-01

    Four widely used in vitro assays for genetic toxicity were evaluated for their ability to predict the carcinogenicity of selected chemicals in rodents. These assays were mutagenesis in Salmonella and mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Seventy-three chemicals recently tested in 2-year carcinogenicity studies conducted by the National Cancer Institute and the National Toxicology Program were used in this evaluation. Test results from the four in vitro assays did not show significant differences in individual concordance with the rodent carcinogenicity results; the concordance of each assay was approximately 60 percent. Within the limits of this study there was no evidence of complementarity among the four assays, and no battery of tests constructed from these assays improved substantially on the overall performance of the Salmonella assay. The in vitro assays which represented a range of three cell types and four end points did show substantial agreement among themselves, indicating that chemicals positive in one in vitro assay tended to be positive in the other in vitro assays. To help put this project into its proper context, we emphasize certain features of the study: 1) Standard protocols were used to mimic the major use of STTs worldwide--screening for mutagens and carcinogens; no attempt was made to optimize protocols for specific chemicals. 2) The 73 NTP chemicals and their 60% incidence of carcinogenicity are probably not representative of the universe of chemicals but rather reflect the recent chemical selection process for the NTP carcinogenicity assay. 3) The small, diverse group of chemicals precludes a meaningful evaluation of the predictive utility of chemical structure information. 4) The NTP is currently testing these same 73 chemicals in two in vivo STTs for chromosomal effects. 5) Complete data for an additional group of 30 to 40 NTP chemicals will be gathered on

  6. 29 CFR 1990.112 - Classification of potential carcinogens.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 1990.112 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS The Osha Cancer Policy § 1990.112 Classification of potential carcinogens. The following criteria...

  7. 29 CFR 1990.112 - Classification of potential carcinogens.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 1990.112 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS The Osha Cancer Policy § 1990.112 Classification of potential carcinogens. The following criteria...

  8. Fact Sheet: EPA's Guidelines for Carcinogen Risk Assessment

    EPA Science Inventory

    March 29, 2005

    FACT SHEET: EPA's GUIDELINES FOR CARCINOGEN RISK ASSESSMENT

    On March 29, 2005, EPA issued the Guidelines for Carcinogen Risk A...

  9. Carcinogens formed when Meat is Cooked

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

    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 hydrocarbonsmore » (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).« less

  10. The multitude and diversity of environmental carcinogens.

    PubMed

    Belpomme, D; Irigaray, P; Hardell, L; Clapp, R; Montagnier, L; Epstein, S; Sasco, A J

    2007-11-01

    We have recently proposed that lifestyle-related factors, screening and aging cannot fully account for the present overall growing incidence of cancer. In order to propose the concept that in addition to lifestyle related factors, exogenous environmental factors may play a more important role in carcinogenesis than it is expected, and may therefore account for the growing incidence of cancer, we overview herein environmental factors, rated as certainly or potentially carcinogenic by the International Agency for Research on Cancer (IARC). We thus analyze the carcinogenic effect of microorganisms (including viruses), radiations (including radioactivity, UV and pulsed electromagnetic fields) and xenochemicals. Chemicals related to environmental pollution appear to be of critical importance, since they can induce occupational cancers as well as other cancers. Of major concerns are: outdoor air pollution by carbon particles associated with polycyclic aromatic hydrocarbons; indoor air pollution by environmental tobacco smoke, formaldehyde and volatile organic compounds such as benzene and 1,3 butadiene, which may particularly affect children, and food pollution by food additives and by carcinogenic contaminants such as nitrates, pesticides, dioxins and other organochlorines. In addition, carcinogenic metals and metalloids, pharmaceutical medicines and cosmetics may be involved. Although the risk fraction attributable to environmental factors is still unknown, this long list of carcinogenic and especially mutagenic factors supports our working hypothesis according to which numerous cancers may in fact be caused by the recent modification of our environment.

  11. The multitude and diversity of environmental carcinogens

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

    Belpomme, D.; Cancer Research Center, Association for Research and Treatments Against Cancer; Irigaray, P.

    2007-11-15

    We have recently proposed that lifestyle-related factors, screening and aging cannot fully account for the present overall growing incidence of cancer. In order to propose the concept that in addition to lifestyle related factors, exogenous environmental factors may play a more important role in carcinogenesis than it is expected, and may therefore account for the growing incidence of cancer, we overview herein environmental factors, rated as certainly or potentially carcinogenic by the International Agency for Research on Cancer (IARC). We thus analyze the carcinogenic effect of microorganisms (including viruses), radiations (including radioactivity, UV and pulsed electromagnetic fields) and xenochemicals. Chemicalsmore » related to environmental pollution appear to be of critical importance, since they can induce occupational cancers as well as other cancers. Of major concerns are: outdoor air pollution by carbon particles associated with polycyclic aromatic hydrocarbons; indoor air pollution by environmental tobacco smoke, formaldehyde and volatile organic compounds such as benzene and 1,3 butadiene, which may particularly affect children, and food pollution by food additives and by carcinogenic contaminants such as nitrates, pesticides, dioxins and other organochlorines. In addition, carcinogenic metals and metalloids, pharmaceutical medicines and cosmetics may be involved. Although the risk fraction attributable to environmental factors is still unknown, this long list of carcinogenic and especially mutagenic factors supports our working hypothesis according to which numerous cancers may in fact be caused by the recent modification of our environment.« less

  12. Questions and Answers: EPA's Guidelines for Carcinogen Risk Assessment and Supplemental Guidance from Assessing Susceptibility from Early-Life Exposure to Carcinogens

    EPA Science Inventory

    March 29, 2005
    EPA's Guidelines for Carcinogen Risk Assessment
    And Supplemental Guidance from Assessing Susceptibility from Early-life
    Exposure to Carcinogens

    Questions and Answers

    The following questions ...

  13. Too many rodent carcinogens: Mitogenesis increases mutagenesis

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

    Ames, B.N.; Gold, L.S.

    1990-08-31

    A clarification of the mechanism of carcinogenesis is developing at a rapid rate. This new understanding undermines many assumptions of current regulatory policy toward rodent carcinogens and necessitates rethinking the utility and meaning of routine animal cancer tests. At a recent watershed meeting on carcinogenesis, much evidence was presented suggesting that mitogenesis plays a dominant role in carcinogenesis. Our own rethinking of mechanism was prompted by our findings that: spontaneous DNA damage caused by endogenous oxidants is remarkably frequent and in chronic testing at the maximum tolerated dose (MTD), more than half of all chemicals tested (both natural and synthetic)more » are carcinogens in rodents, and a high percentage of these carcinogens are not mutagens.« less

  14. Capturing Labile Sulfenamide and Sulfinamide Serum Albumin Adducts of Carcinogenic Arylamines by Chemical Oxidation

    PubMed Central

    Peng, Lijuan; Turesky, Robert J.

    2013-01-01

    Aromatic amines and heterocyclic aromatic amines (HAAs) are a class of structurally related carcinogens that are formed during the combustion of tobacco or during the high temperature cooking of meats. These procarcinogens undergo metabolic activation by N-oxidation of the exocyclic amine group to produce N-hydroxylated metabolites, which are critical intermediates implicated in toxicity and DNA damage. The arylhydroxylamines and their oxidized arylnitroso derivatives can also react with cysteine (Cys) residues of glutathione or proteins to form, respectively, sulfenamide and sulfinamide adducts. However, sulfur-nitrogen linked adducted proteins are often difficult to detect because they are unstable and undergo hydrolysis during proteolytic digestion. Synthetic N-oxidized intermediates of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogenic HAA produced in cooked meats, and 4-aminobiphenyl, a carcinogenic aromatic amine present in tobacco smoke were reacted with human serum albumin (SA) and formed labile sulfenamide or sulfinamide adducts at the Cys34 residue. Oxidation of the carcinogen-modified SA with m-chloroperoxybenzoic acid (m-CPBA) produced the arylsulfonamide adducts, which were stable to heat and the chemical reduction conditions employed to denature SA. The sulfonamide adducts of PhIP and 4-ABP were identified, by liquid chromatography/mass spectrometry, in proteolytic digests of denatured SA. Thus, selective oxidation of arylamine-modified SA produces stable arylsulfonamide-SA adducts, which may serve as biomarkers of these tobacco and dietary carcinogens. PMID:23240913

  15. Pesticides and public health: an analysis of the regulatory approach to assessing the carcinogenicity of glyphosate in the European Union.

    PubMed

    Clausing, Peter; Robinson, Claire; Burtscher-Schaden, Helmut

    2018-03-13

    The present paper scrutinises the European authorities' assessment of the carcinogenic hazard posed by glyphosate based on Regulation (EC) 1272/2008. We use the authorities' own criteria as a benchmark to analyse their weight of evidence (WoE) approach. Therefore, our analysis goes beyond the comparison of the assessments made by the European Food Safety Authority and the International Agency for Research on Cancer published by others. We show that not classifying glyphosate as a carcinogen by the European authorities, including the European Chemicals Agency, appears to be not consistent with, and in some instances, a direct violation of the applicable guidance and guideline documents. In particular, we criticise an arbitrary attenuation by the authorities of the power of statistical analyses; their disregard of existing dose-response relationships; their unjustified claim that the doses used in the mouse carcinogenicity studies were too high and their contention that the carcinogenic effects were not reproducible by focusing on quantitative and neglecting qualitative reproducibility. Further aspects incorrectly used were historical control data, multisite responses and progression of lesions to malignancy. Contrary to the authorities' evaluations, proper application of statistical methods and WoE criteria inevitably leads to the conclusion that glyphosate is 'probably carcinogenic' (corresponding to category 1B in the European Union). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  16. Immunoaffinity purification of dietary heterocyclic amine carcinogens

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

    Vanderlaan, M.; Hwang, M.; Djanegara, T.

    1993-03-01

    Cooking meats produces a family of heterocyclic aromatic amines that are carcinogens in rodents and genotoxic in many short-term assays. Concern that these compounds may be human carcinogens has prompted us to develop immunochemical methods for quantifying these compounds in the human diet and for identifying the parent compounds and metabolites in urine and feces. Previously reported monoclonal antibodies to 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 6-phenyl-2-amino-1-methylimidazo[4,5-f]pyridine (PhIP) were used to purify by immunoaffinity these known mutagens and cross-reacting structural analogs from well-done cooked beef and urine samples. Materials recovered from the immunoaffinity columns were subsequently separated by HPLC to purify the knownmore » mutagens from cross-reacting chemicals that co-purify by immunoaffinity. Immunoaffinity chromatography was found to be a rapid means of quantifying individual known mutagens, with a minimum of precolumn sample clean-up required. In addition, this procedure has yielded several new mutagens present in cooked meats that are apparently structural analogs of PhIP. Immunoaffinity techniques were also used to purify metabolites from the urine of rats and humans exposed to MeIQx or PhIP. For MeIQx-exposed rats, the combination antibodies immunoconcentrated 75% of the total urinary radioactivity. Analysis of PhIP metabolites recovered from antibody columns is facilitated by the intrinsic fluorescence of PhIP and its metabolites, providing sufficient sensitivity to monitor individuals for the levels of PhIP excreted following consumption of typical western diets. 6 refs., 3 figs.« less

  17. Carcinogenic N-Nitrosamines. Formation, Properties, and Analysis

    NASA Astrophysics Data System (ADS)

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

    1988-04-01

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

  18. Carcinogenicity of methyl-tertiary butyl ether in gasoline.

    PubMed

    Mehlman, Myron A

    2002-12-01

    Methyl tertiary butyl ether (MTBE) was added to gasoline on a nationwide scale in 1992 without prior testing of adverse, toxic, or carcinogenic effects. Since that time, numerous reports have appeared describing adverse health effects of individuals exposed to MTBE, both from inhalation of fumes in the workplace and while pumping gasoline. Leakage of MTBE, a highly water-soluble compound, from underground storage tanks has led to contamination of the water supply in many areas of the United States. Legislation has been passed by many states to prohibit the addition of MTBE to gasoline. The addition of MTBE to gasoline has not accomplished its stated goal of decreasing air pollution, and it has posed serious health risks to a large portion of the population, particularly the elderly and those with respiratory problems, asthma, and skin sensitivity. Reports of animal studies of carcinogenicity of MTBE began to appear in the 1990s, prior to the widespread introduction of MTBE into gasoline. These reports were largely ignored. In ensuing years, further studies have shown that MTBE causes various types of malignant tumors in mice and rats. The National Toxicology Program (NTP) Board of Scientific Counselors' Report on Carcinogens Subcommittee met in December 1998 to consider listing MTBE as "reasonably anticipated to be a human carcinogen." In spite of recommendations from Dr. Bailer, the primary reviewer, and other scientists on the committee, the motion to list MTBE in the report was defeated by a six to five vote, with one abstention. On the basis of animal studies, it is widely accepted that if a chemical is carcinogenic in appropriate laboratory animal test systems, it must be treated as though it were carcinogenic in humans. In the face of compelling evidence, NTP Committee members who voted not to list MTBE as "reasonably anticipated to be a human carcinogen" did a disservice to the general public; this action may cause needless exposure of many to health risks

  19. Occupational exposure to carcinogens in the European Union

    PubMed Central

    Kauppinen, T.; Toikkanen, J.; Pedersen, D.; Young, R.; Ahrens, W.; Boffetta, P.; Hansen, J.; Kromhout, H.; Blasco, J. M.; Mirabelli, D.; de la Orden-River..., V.; Pannett, B.; Plato, N.; Savela, A.; Vincent, R.; Kogevinas, M.

    2000-01-01

    OBJECTIVES—To construct a computer assisted information system for the estimation of the numbers of workers exposed to established and suspected human carcinogens in the member states of the European Union (EU).
METHODS—A database called CAREX (carcinogen exposure) was designed to provide selected exposure data and documented estimates of the number of workers exposed to carcinogens by country, carcinogen, and industry. CAREX includes data on agents evaluated by the International Agency for Research on Cancer (IARC) (all agents in groups 1 and 2A as of February 1995, and selected agents in group 2B) and on ionising radiation, displayed across the 55 industrial classes. The 1990-3 occupational exposure was estimated in two phases. Firstly, estimates were generated by the CAREX system on the basis of national labour force data and exposure prevalence estimates from two reference countries (Finland and the United States) which had the most comprehensive data available on exposures to these agents. For selected countries, these estimates were then refined by national experts in view of the perceived exposure patterns in their own countries compared with those of the reference countries.
RESULTS—About 32 million workers (23% of those employed) in the EU were exposed to agents covered by CAREX. At least 22 million workers were exposed to IARC group 1 carcinogens. The exposed workers had altogether 42 million exposures (1.3 mean exposures for each exposed worker). The most common exposures were solar radiation (9.1 million workers exposed at least 75% of working time), environmental tobacco smoke (7.5 million workers exposed at least 75% of working time), crystalline silica (3.2 million exposed), diesel exhaust (3.0 million), radon (2.7 million), and wood dust (2.6 million).
CONCLUSION—These preliminary estimates indicate that in the early 1990s, a substantial proportion of workers in the EU were exposed to carcinogens

  20. 29 CFR 1990.131 - Priority lists for regulating potential occupational carcinogens.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... carcinogens. 1990.131 Section 1990.131 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND... POTENTIAL OCCUPATIONAL CARCINOGENS Priority Setting § 1990.131 Priority lists for regulating potential occupational carcinogens. The Secretary shall establish two priority lists for regulating potential...

  1. 29 CFR 1990.131 - Priority lists for regulating potential occupational carcinogens.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... carcinogens. 1990.131 Section 1990.131 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND... POTENTIAL OCCUPATIONAL CARCINOGENS Priority Setting § 1990.131 Priority lists for regulating potential occupational carcinogens. The Secretary shall establish two priority lists for regulating potential...

  2. 29 CFR 1990.131 - Priority lists for regulating potential occupational carcinogens.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... carcinogens. 1990.131 Section 1990.131 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND... POTENTIAL OCCUPATIONAL CARCINOGENS Priority Setting § 1990.131 Priority lists for regulating potential occupational carcinogens. The Secretary shall establish two priority lists for regulating potential...

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

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... carcinogens. 1990.131 Section 1990.131 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND... POTENTIAL OCCUPATIONAL CARCINOGENS Priority Setting § 1990.131 Priority lists for regulating potential occupational carcinogens. The Secretary shall establish two priority lists for regulating potential...

  4. Is ionizing radiation regulated more stringently than chemical carcinogens

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

    Travis, C.C.; Pack, S.R.; Hattemer-Frey, H.A.

    1989-04-01

    It is widely believed that United States government agencies regulate exposure to ionizing radiation more stringently than exposure to chemical carcinogens. It is difficult to verify this perception, however, because chemical carcinogens and ionizing radiation are regulated using vastly different strategies. Chemical carcinogens are generally regulated individually. Regulators consider the risk of exposure to one chemical rather than the cumulative radiation exposure from all sources. Moreover, standards for chemical carcinogens are generally set in terms of quantities released or resultant environmental concentrations, while standards for ionizing radiation are set in terms of dose to the human body. Since chemicals andmore » ionizing radiation cannot be compared on the basis of equal dose to the exposed individual, standards regulating chemicals and ionizing radiation cannot be compared directly. It is feasible, however, to compare the two sets of standards on the basis of equal risk to the exposed individual, assuming that standards for chemicals and ionizing radiation are equivalent if estimated risk levels are equitable. This paper compares risk levels associated with current standards for ionizing radiation and chemical carcinogens. The authors do not attempt to determine whether either type of risk is regulated too stringently or not stringently enough but endeavor only to ascertain if ionizing radiation is actually regulated more strictly than chemical carcinogens.« less

  5. Nonmutagenic carcinogens induce intrachromosomal recombination in dividing yeast cells.

    PubMed

    Schiestl, R H

    1993-12-01

    A large number of animal and human carcinogens without apparent genotoxic activity exist (nonmutagenic carcinogens) that are difficult or impossible to detect with the currently used short-term tests. Because of the association of carcinogenesis with genome rearrangement, a system selecting for intrachromosomal recombination (DEL recombination) that results in genome rearrangement has been constructed in the yeast Saccharomyces cerevisiae. Because DEL recombination is under different genetic control than interchromosomal recombination and meiotic recombination, it is probably due to a different mechanism. It has been found that DEL recombination is readily inducible by 10 mutagenic carcinogens and 17 nonmutagenic carcinogens that are not detectable (false negatives) with the Ames assay. In addition, three out of four mutagens that do not cause cancer (false positives in the Ames assay) do not induce DEL recombination. DEL recombination is inducible by UV only in dividing cells but not in cells synchronized in the G1 or G2 phase of the cell cycle. Interchromosomal recombination, on the other hand, is inducible in G1 but not in G2. The nonmutagenic carcinogens induce DEL recombination only in actively growing cells, which may give some indication as to their mechanism. Further characterization of the mechanism involved in induction of DEL recombination may contribute to the understanding of the biological activity of nonmutagenic carcinogens.

  6. Clarifying carcinogenicity of ethylbenzene

    PubMed Central

    Huff, James; Chan, Po; Melnick, Ronald

    2010-01-01

    Ethylbenzene has been evaluated for carcinogenic activity in Fischer rats and B6C3F1 mice exposed by inhalation [Chan et al 1998;Chan & NTP 1999] and in Sprague-Dawley rats after oral exposure [Maltoni et al 1985,1997]. Bioassay findings are summarized below to expand on those not stated clearly or completely in Saghir et al [2010]. Overall in these three studies animals exposed to ethylbenzene had increased tumors in rats for kidneys, testes, head [including rare neuroesthesioepitheliomas], and total malignant tumors, whilst in mice tumors incidences were increased in the lung and liver [Huff,2002]. Thus ethylbenzene was carcinogenic by two exposure routes to both sexes of two species of rodents, two strains of rats, and one strain of mice, causing collectively tumors in five different target organs and a composite of “total malignant”tumors. PMID:20723573

  7. Quantitation of DNA adducts by stable isotope dilution mass spectrometry

    PubMed Central

    Tretyakova, Natalia; Goggin, Melissa; Janis, Gregory

    2012-01-01

    Exposure to endogenous and exogenous chemicals can lead to the formation of structurally modified DNA bases (DNA adducts). If not repaired, these nucleobase lesions can cause polymerase errors during DNA replication, leading to heritable mutations potentially contributing to the development of cancer. Due to their critical role in cancer initiation, DNA adducts represent mechanism-based biomarkers of carcinogen exposure, and their quantitation is particularly useful for cancer risk assessment. DNA adducts are also valuable in mechanistic studies linking tumorigenic effects of environmental and industrial carcinogens to specific electrophilic species generated from their metabolism. While multiple experimental methodologies have been developed for DNA adduct analysis in biological samples – including immunoassay, HPLC, and 32P-postlabeling – isotope dilution high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) generally has superior selectivity, sensitivity, accuracy, and reproducibility. As typical DNA adducts concentrations in biological samples are between 0.01 – 10 adducts per 108 normal nucleotides, ultrasensitive HPLC-ESI-MS/MS methodologies are required for their analysis. Recent developments in analytical separations and biological mass spectrometry – especially nanoflow HPLC, nanospray ionization MS, chip-MS, and high resolution MS – have pushed the limits of analytical HPLC-ESI-MS/MS methodologies for DNA adducts, allowing researchers to accurately measure their concentrations in biological samples from patients treated with DNA alkylating drugs and in populations exposed to carcinogens from urban air, drinking water, cooked food, alcohol, and cigarette smoke. PMID:22827593

  8. Threshold and non-threshold chemical carcinogens: A survey of the present regulatory landscape.

    PubMed

    Bevan, Ruth J; Harrison, Paul T C

    2017-08-01

    For the proper regulation of a carcinogenic material it is necessary to fully understand its mode of action, and in particular whether it demonstrates a threshold of effect. This paper explores our present understanding of carcinogenicity and the mechanisms underlying the carcinogenic response. The concepts of genotoxic and non-genotoxic and threshold and non-threshold carcinogens are fully described. We provide summary tables of the types of cancer considered to be associated with exposure to a number of carcinogens and the available evidence relating to whether carcinogenicity occurs through a threshold or non-threshold mechanism. In light of these observations we consider how different regulatory bodies approach the question of chemical carcinogenesis, looking in particular at the definitions and methodologies used to derive Occupational Exposure Levels (OELs) for carcinogens. We conclude that unless proper differentiation is made between threshold and non-threshold carcinogens, inappropriate risk management measures may be put in place - and lead also to difficulties in translating carcinogenicity research findings into appropriate health policies. We recommend that clear differentiation between threshold and non-threshold carcinogens should be made by all expert groups and regulatory bodies dealing with carcinogen classification and risk assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Chemical carcinogenesis: Too many rodent carcinogens

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

    Ames, B.N.; Gold, L.S.

    1990-10-01

    The administration of chemicals at the maximum tolerated dose (MTD) in standard animal cancer tests is postulated to increase cell division (mitogenesis), which in turn increases rates of mutagenesis and thus carcinogenesis. The animal data are consistent with this mechanism, because a high proportion{endash}about half{endash}of all chemicals tested (whether natural or synthetic) are indeed rodent carcinogens. The authors conclude that at the low doses of most human exposures, where cell killing does not occur, the hazards to humans of rodent carcinogens may be much lower than is commonly assumed.

  10. Sucralose Non-Carcinogenicity: A Review of the Scientific and Regulatory Rationale

    PubMed Central

    Berry, Colin; Brusick, David; Cohen, Samuel M.; Hardisty, Jerry F.; Grotz, V. Lee; Williams, Gary M.

    2016-01-01

    ABSTRACT Regulatory authorities worldwide have found the nonnutritive sweetener, sucralose, to be noncarcinogenic, based on a range of studies. A review of these and other studies found through a comprehensive search of electronic databases, using appropriate key terms, was conducted and results of that review are reported here. An overview of the types of studies relied upon by regulatory agencies to assess carcinogenicity potential is also provided as context. Physiochemical and pharmacokinetic/toxicokinetic studies confirm stability under conditions of use and reveal no metabolites of carcinogenic potential. In vitro and in vivo assays reveal no confirmed genotoxic activity. Long-term carcinogenicity studies in animal models provide no evidence of carcinogenic potential for sucralose. In studies in healthy adults, sucralose was well-tolerated and without evidence of toxicity or other changes that might suggest a potential for carcinogenic effects. In summary, sucralose does not demonstrate carcinogenic activity even when exposure levels are several orders of magnitude greater than the range of anticipated daily ingestion levels. PMID:27652616

  11. Sucralose Non-Carcinogenicity: A Review of the Scientific and Regulatory Rationale.

    PubMed

    Berry, Colin; Brusick, David; Cohen, Samuel M; Hardisty, Jerry F; Grotz, V Lee; Williams, Gary M

    2016-01-01

    Regulatory authorities worldwide have found the nonnutritive sweetener, sucralose, to be noncarcinogenic, based on a range of studies. A review of these and other studies found through a comprehensive search of electronic databases, using appropriate key terms, was conducted and results of that review are reported here. An overview of the types of studies relied upon by regulatory agencies to assess carcinogenicity potential is also provided as context. Physiochemical and pharmacokinetic/toxicokinetic studies confirm stability under conditions of use and reveal no metabolites of carcinogenic potential. In vitro and in vivo assays reveal no confirmed genotoxic activity. Long-term carcinogenicity studies in animal models provide no evidence of carcinogenic potential for sucralose. In studies in healthy adults, sucralose was well-tolerated and without evidence of toxicity or other changes that might suggest a potential for carcinogenic effects. In summary, sucralose does not demonstrate carcinogenic activity even when exposure levels are several orders of magnitude greater than the range of anticipated daily ingestion levels.

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

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

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

    1995-01-01

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

  13. Determination of carcinogenic herbicides in milk samples using green non-ionic silicone surfactant of cloud point extraction and spectrophotometry.

    PubMed

    Mohd, N I; Zain, N N M; Raoov, M; Mohamad, S

    2018-04-01

    A new cloud point methodology was successfully used for the extraction of carcinogenic pesticides in milk samples as a prior step to their determination by spectrophotometry. In this work, non-ionic silicone surfactant, also known as 3-(3-hydroxypropyl-heptatrimethylxyloxane), was chosen as a green extraction solvent because of its structure and properties. The effect of different parameters, such as the type of surfactant, concentration and volume of surfactant, pH, salt, temperature, incubation time and water content on the cloud point extraction of carcinogenic pesticides such as atrazine and propazine, was studied in detail and a set of optimum conditions was established. A good correlation coefficient ( R 2 ) in the range of 0.991-0.997 for all calibration curves was obtained. The limit of detection was 1.06 µg l -1 (atrazine) and 1.22 µg l -1 (propazine), and the limit of quantitation was 3.54 µg l -1 (atrazine) and 4.07 µg l -1 (propazine). Satisfactory recoveries in the range of 81-108% were determined in milk samples at 5 and 1000 µg l -1 , respectively, with low relative standard deviation, n  = 3 of 0.301-7.45% in milk matrices. The proposed method is very convenient, rapid, cost-effective and environmentally friendly for food analysis.

  14. Mycotoxins as human carcinogens-the IARC Monographs classification.

    PubMed

    Ostry, Vladimir; Malir, Frantisek; Toman, Jakub; Grosse, Yann

    2017-02-01

    Humans are constantly exposed to mycotoxins (e.g. aflatoxins, ochratoxins), mainly via food intake of plant and animal origin. The health risks stemming from mycotoxins may result from their toxicity, in particular their carcinogenicity. In order to prevent these risks, the International Agency for Research on Cancer (IARC) in Lyon (France)-through its IARC Monographs programme-has performed the carcinogenic hazard assessment of some mycotoxins in humans, on the basis of epidemiological data, studies of cancer in experimental animals and mechanistic studies. The present article summarizes the carcinogenic hazard assessments of those mycotoxins, especially aflatoxins (aflatoxin B 1 , B 2 , G 1 , G 2 and M 1 ), fumonisins (fumonisin B 1 and B 2 ) and ochratoxin A (OTA). New information regarding the genotoxicity of OTA (formation of OTA-DNA adducts), the role of OTA in oxidative stress and the identification of epigenetic factors involved in OTA carcinogenesis-should they indeed provide strong evidence that OTA carcinogenicity is mediated by a mechanism that also operates in humans-could lead to the reclassification of OTA.

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

    PubMed Central

    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 transgenic rodent models incorporating such mechanisms are used to identify mechanisms involved in tumor formation and as selective tests for carcinogens. Transgenic methods can be considered an extension of genetic manipulation by selective breeding, which long has been employed in science and agriculture. The use of two rodent species in carcinogenicity testing is especially important for identifying transspecies carcinogens. The capacity of a substance to induce neoplasia across species suggests that the mechanism(s) involved in the induction of the neoplasia are conserved and therefore may have significance for humans. Based on available information there is sufficient experience with some in vivo transgenic rodent carcinogenicity models to support their application as complementary second species studies in conjunction with a single 2-year rodent carcinogenicity study. The optional substitution of a second 2-year rodent carcinogenicity study with an alternative study such as an in vivo transgenic carcinogenicity study is part of the International Conference on Harmonization guidance S1B: Testing for Carcinogenicity of Pharmaceuticals. This guidance is intended to be flexible enough to accommodate a wide range of possible carcinogenicity assessment models currently under consideration or models that may be developed in the future. The use of an in vivo transgenic mouse model in place of a second 2-year mouse study will improve the assessment of carcinogenic risk by contributing

  16. Dietary Carcinogens and Anticarcinogens.

    ERIC Educational Resources Information Center

    Ames, Bruce N.

    1983-01-01

    Describes 16 mutagens/carcinogens found in plant food and coffee as well as several anticarcinogens also found in such food. Speculates on relevant biochemical mechanisms, particularly the role of oxygen radicals and their inhibitors in the fat/cancer relationship, promotion, anticarcinogenesis, and aging. (JN)

  17. Reducing the use of carcinogens: the Massachusetts experience.

    PubMed

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

    2014-01-01

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

  18. Guidelines for Carcinogen Risk Assessment

    EPA Pesticide Factsheets

    The Guidelines for Carcinogen Risk Assessment provide EPA staff with guidance for developing and using risk assessments. They also provide basic information to the public about the Agency's risk assessment methods.

  19. Contributions of Human Enzymes in Carcinogen Metabolism

    PubMed Central

    Rendic, Slobodan; Guengerich, F. Peter

    2012-01-01

    Considerable support exists for roles of metabolism in modulating the carcinogenic properties of chemicals. In particular, many of these compounds are procarcinogens that require activation to electrophilic forms to exert genotoxic effects. We systematically analyzed the existing literature on metabolism of carcinogens by human enzymes, which has been developed largely in the past 25 years. The metabolism and especially bioactivation of carcinogens are dominated by cytochrome P450 enzymes (66% of bioactivations). Within this group, six P450s—1A1, 1A2, 1B1, 2A6, 2E1, and 3A4—accounted for 77% of the P450 activation reactions. The roles of these P450s can be compared with those estimated for drug metabolism and should be considered in issues involving enzyme induction, chemoprevention, molecular epidemiology, inter-individual variations, and risk assessment. PMID:22531028

  20. Cytogenetic studies of mice chronically fed carcinogens

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

    Director, A.E.; Ramsey, M.J.; Tucker, J.D.

    1997-10-01

    Over the past few years, we have carried out chronic feeding studies in C57BL/6 female mice. These experiments examined the effect of the chronic ingestion of a single chemical carcinogen on chromosomes. The carcinogens studied were PhIP,MeIQx, cyclophosphamide and urethane. These studies used traditional assays, such as SCEs and MN, as well as chromosome painting. In all four cases, the traditional assays showed an increase in the frequency of lesions, demonstrating that the chemicals, and/or their reactive metabolites, reached the target nuclei. This, however, seemed at odds with the data obtained from chromosome painting, which did not show an increasemore » in the frequency of stable chromosome aberrations. This discrepancy between traditional assays and chromosome painting may be due to the nature of the lesions that each assay identifies. The traditional assays tend to identify lesions on the chromatid level, where as chromosome painting identifies lesions on the chromosome level requires two or more DNA double strand breaks occurring proximally in both time and space. In other words, for exposure to a chemical carcinogen to induce an increase in chromosome aberrations as measured by chromosome painting, the chemical, or its metabolites, would have to cause a large number of double strand breaks. By applying this logic to the data obtained from the four chronic feeding studies, one can infer that the chronic ingestion of chemical carcinogens does not result in the frequent formation of double strand breaks and therefore, does not result in the frequent formation of double strand breaks and therefore, does not result in increased frequencies of stable chromosome aberrations. We must, therefore, look elsewhere for the mechanism(s) underlying carcinogenesis due to chronic exposure to chemical carcinogens.« less

  1. Recent Advances in In Vivo Genotoxicity Testing: Prediction of Carcinogenic Potential Using Comet and Micronucleus Assay in Animal Models

    PubMed Central

    Kang, Seung Hun; Kwon, Jee Young; Lee, Jong Kwon; Seo, Young Rok

    2013-01-01

    Genotoxic events have been known as crucial step in the initiation of cancer. To assess the risk of cancer, genotoxicity assays, including comet, micronucleus (MN), chromosomal aberration, bacterial reverse, and sister chromatid exchange assay, can be performed. Compared with in vitro genotoxicity assay, in vivo genotoxicity assay has been used to verify in vitro assay result and definitely provide biological significance for certain organs or cell types. The comet assay can detect DNA strand breaks as markers of genotoxicity. Methods of the in vivo comet assay have been established by Japanese Center for the Validation of Alternative Methods (JaCVAM) validation studies depending on tissue and sample types. The MN can be initiated by segregation error and lagging acentric chromosome fragment. Methods of the in vivo MN assay have been established by Organization for Economic Co-operation and Development (OECD) test guidelines and many studies. Combining the in vivo comet and MN assay has been regarded as useful methodology for evaluating genetic damage, and it has been used in the assessment of potential carcinogenicity by complementarily presenting two distinct endpoints of the in vivo genotoxicity individual test. Few studies have investigated the quantitative relation between in vivo genotoxicity results and carcinogenicity. Extensive studies emphasizes that positive correlation is detectable. This review summarizes the results of the in vivo comet and MN assays that have investigated the genotoxicity of carcinogens as classified by the International Agency for Research on Cancer (IARC) carcinogenicity database. As a result, these genotoxicity data may provide meaningful information for the assessment of potential carcinogenicity and for implementation in the prevention of cancer. PMID:25337557

  2. The linearized multistage model and the future of quantitative risk assessment.

    PubMed

    Crump, K S

    1996-10-01

    The linearized multistage (LMS) model has for over 15 years been the default dose-response model used by the U.S. Environmental Protection Agency (USEPA) and other federal and state regulatory agencies in the United States for calculating quantitative estimates of low-dose carcinogenic risks from animal data. The LMS model is in essence a flexible statistical model that can describe both linear and non-linear dose-response patterns, and that produces an upper confidence bound on the linear low-dose slope of the dose-response curve. Unlike its namesake, the Armitage-Doll multistage model, the parameters of the LMS do not correspond to actual physiological phenomena. Thus the LMS is 'biological' only to the extent that the true biological dose response is linear at low dose and that low-dose slope is reflected in the experimental data. If the true dose response is non-linear the LMS upper bound may overestimate the true risk by many orders of magnitude. However, competing low-dose extrapolation models, including those derived from 'biologically-based models' that are capable of incorporating additional biological information, have not shown evidence to date of being able to produce quantitative estimates of low-dose risks that are any more accurate than those obtained from the LMS model. Further, even if these attempts were successful, the extent to which more accurate estimates of low-dose risks in a test animal species would translate into improved estimates of human risk is questionable. Thus, it does not appear possible at present to develop a quantitative approach that would be generally applicable and that would offer significant improvements upon the crude bounding estimates of the type provided by the LMS model. Draft USEPA guidelines for cancer risk assessment incorporate an approach similar to the LMS for carcinogens having a linear mode of action. However, under these guidelines quantitative estimates of low-dose risks would not be developed for

  3. Carcinogenic agents in snuff.

    PubMed

    Hoffmann, D; Harley, N H; Fisenne, I; Adams, J D; Brunnemann, K D

    1986-03-01

    The oral use of snuff has been associated with an increased-risk for cancer of the oral cavity and pharynx. The five most popular U.S. snuff brands were analyzed for alkaloids, volatile and tobacco-specific N-nitrosamines (TSNA), benzo[a]pyrene (CAS: 50-32-8), and polonium-210. The carcinogenic TSNA in the five snuff brands ranged from 9,600 to 289,000 ppb. These concentrations exceed the nitrosamine concentrations of other consumer products by at least 2 orders of magnitude. Polonium amounted to 0.16-1.22 pCi/g dry snuff. Trace amounts of benzo[a]pyrene (0.1-63 ppb) were indicative of contamination of the tobacco with thermal degradation products, probably due to fire curing or flue curing. The findings from this study, the biologic activity of snuff in animal models, and the epidemiologic studies on snuff use and oral cancer strongly suggest the need for reduction of carcinogens and especially of nitrosamines and polonium-210 in snuff.

  4. Exposure to carcinogens for defined job categories in Norway's offshore petroleum industry, 1970 to 2005.

    PubMed

    Steinsvåg, Kjersti; Bråtveit, Magne; Moen, Bente E

    2007-04-01

    To identify and describe the exposure to selected known and suspected carcinogenic agents, mixtures and exposure circumstances for defined job categories in Norway's offshore petroleum industry from 1970 to 2005, in order to provide exposure information for a planned cohort study on cancer. Background information on possible exposure was obtained through company visits, including interviewing key personnel (n = 83) and collecting monitoring reports (n = 118) and other relevant documents (n = 329). On the basis of a previous questionnaire administered to present and former offshore employees in 1998, 27 job categories were defined. This study indicated possible exposure to 18 known and suspected carcinogenic agents, mixtures or exposure circumstances. Monitoring reports were obtained on seven agents (benzene, mineral oil mist and vapour, respirable and total dust, asbestos fibres, refractory ceramic fibres, formaldehyde and tetrachloroethylene). The mean exposure level of 367 personal samples of benzene was 0.037 ppm (range: less than the limit of detection to 2.6 ppm). Asbestos fibres were detected (0.03 fibres/cm3) when asbestos-containing brake bands were used in drilling draw work in 1988. Personal samples of formaldehyde in the process area ranged from 0.06 to 0.29 mg/m3. Descriptions of products containing known and suspected carcinogens, exposure sources and processes were extracted from the collected documentation and the interviews of key personnel. This study described exposure to 18 known and suspected carcinogenic agents, mixtures and exposure circumstances for 27 job categories in Norway's offshore petroleum industry. For a planned cohort study on cancer, quantitative estimates of exposure to benzene, and mineral oil mist and vapour might be developed. For the other agents, information in the present study can be used for further assessment of exposure, for instance, by expert judgement. More systematic exposure surveillance is needed in this industry

  5. 29 CFR 1915.1003 - 13 carcinogens (4-Nitrobiphenyl, etc.).

    Code of Federal Regulations, 2010 CFR

    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 applicable...

  6. 29 CFR 1915.1003 - 13 carcinogens (4-Nitrobiphenyl, etc.).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 7 2014-07-01 2014-07-01 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 applicable...

  7. 29 CFR 1926.1103 - 13 carcinogens (4-Nitrobiphenyl, etc.).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 8 2012-07-01 2012-07-01 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 construction...

  8. 29 CFR 1926.1103 - 13 carcinogens (4-Nitrobiphenyl, etc.).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 8 2011-07-01 2011-07-01 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 construction...

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

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 8 2013-07-01 2013-07-01 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 construction...

  10. 29 CFR 1926.1103 - 13 carcinogens (4-Nitrobiphenyl, etc.).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 8 2014-07-01 2014-07-01 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 construction...

  11. 29 CFR 1915.1003 - 13 carcinogens (4-Nitrobiphenyl, etc.).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 7 2013-07-01 2013-07-01 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 applicable...

  12. 29 CFR 1915.1003 - 13 carcinogens (4-Nitrobiphenyl, etc.).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 7 2011-07-01 2011-07-01 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 applicable...

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

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 7 2012-07-01 2012-07-01 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 applicable...

  14. Chemical carcinogens and inhibitors of carcinogenesis in the human diet

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

    Carr, B.I.

    1985-01-01

    The induction of cancer by chemicals as presently understood involves a series of steps, some of which require the passage of time. Many substances that are potent carcinogens in experimental animals are known to exist in nature and occur as part of the human diet. In addition, many of the substances that are known to inhibit experimental carcinogenesis also exist in the human diet. Thus, in addition to industrially produced carcinogens, humans can be presumed to have evolved in an environment that contains both carcinogens and anti-carcinogens. There is also a great deal of experimental and human epidemiologic data onmore » the influence of lipids, proteins and carbohydrates on cancer incidence rates; however, much of those data are confusing and conflicting.« less

  15. Carcinogen-induced trans activation of gene expression.

    PubMed Central

    Kleinberger, T; Flint, Y B; Blank, M; Etkin, S; Lavi, S

    1988-01-01

    We report a new mechanism of carcinogen action by which the expression of several genes was concomitantly enhanced. This mechanism involved the altered activity of cellular factors which modulate the expression of genes under their control. The increased expression was regulated at least in part on the transcriptional level and did not require amplification of the overexpressed genes. This phenomenon was transient; it was apparent as early as 24 h after carcinogen treatment and declined a few days later. Images PMID:2835673

  16. Genotoxic chemical carcinogens target inducible genes in vivo

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

    Hamilton, J.W.; McCaffrey, J.; Caron, R.M.

    1994-12-31

    Our laboratory is interested in whether carcinogen-induced DNA damage is distributed nonrandomly in the genome - that is, {open_quotes}targeted{close_quotes} to specific genes or gene regions in vivo. As an indirect measure of whether targeting occurs at the gene level, we have examined whether carcinogens differentially alter the expression of individual genes. We have compared the effects of model genotoxic carcinogens that principally induce either strand breaks, simple alkylations, bulky lesions, or DNA cross-links on the expression of several constitutive and inducible genes in a simple in vivo system, the chick embryo. Each agent was examined for its effects on genemore » expression over a 24 hour period corresponding to the period of maximal DNA damage and repair induced by each compound. The doses used in these studies represented the maximum doses that caused no overt toxicity over a 96 hour period but that induced significant levels of DNA damage. Our results demonstrate that inducible genes are targeted by chemical carcinogens. We hypothesize that such effects may be a result of DNA damage specifically altering DNA-protein interactions within the promoters of inducible genes.« less

  17. Combination Effects of Forty Carcinogens Administered at Low Doses to Male Rats

    PubMed Central

    Takayama, Shozo; Hasegawa, Hirokazu; Ohgaki, Hiroko

    1989-01-01

    An investigation was conducted to determine whether a mixture of low doses of forty carcinogens that target different organs, including the liver, intestine, thyroid, urinary bladder, and skin, is effective for tumor induction in F344/DuCrj rats. The dose of each carcinogen in the diet was 1/50 of the TD50 value, treatment being continued for 102 weeks. Significant numbers of neoplastic nodules of the liver and follicular cell tumors of the thyroid developed in the animals exposed to the carcinogen mixture, although the question of whether the observed carcinogenic effects were synergistic or additive could not be answered. The results serve to evaluate carcinogenic risk in the search for causes of human cancer. PMID:2511179

  18. METABOLISM, GENOTOXICITY, AND CARCINOGENICITY OF COMFREY

    PubMed Central

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

    2018-01-01

    Comfrey has been consumed by humans as a vegetable and a tea and used as an herbal medicine for more than 2000 years. Comfrey, however, produces hepatotoxicity in livestock and humans and carcinogenicity in experimental animals. Comfrey contains as many as 14 pyrrolizidine alkaloids (PA), including 7-acetylintermedine, 7-acetyllycopsamine, echimidine, intermedine, lasiocarpine, lycopsamine, myoscorpine, symlandine, symphytine, and symviridine. The mechanisms underlying comfrey-induced genotoxicity and carcinogenicity are still not fully understood. The available evidence suggests that the active metabolites of PA in comfrey interact with DNA in liver endothelial cells and hepatocytes, resulting in DNA damage, mutation induction, and cancer development. Genotoxicities attributed to comfrey and riddelliine (a representative genotoxic PA and a proven rodent mutagen and carcinogen) are discussed in this review. Both of these compounds induced similar profiles of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and similar mutation spectra. Further, the two agents share common mechanisms of drug metabolism and carcinogenesis. Overall, comfrey is mutagenic in liver, and PA contained in comfrey appear to be responsible for comfrey-induced toxicity and tumor induction. PMID:21170807

  19. Relationship between molecular connectivity and carcinogenic activity: a confirmation with a new software program based on graph theory.

    PubMed Central

    Malacarne, D; Pesenti, R; Paolucci, M; Parodi, S

    1993-01-01

    For a database of 826 chemicals tested for carcinogenicity, we fragmented the structural formula of the chemicals into all possible contiguous-atom fragments with size between two and eight (nonhydrogen) atoms. The fragmentation was obtained using a new software program based on graph theory. We used 80% of the chemicals as a training set and 20% as a test set. The two sets were obtained by random sorting. From the training sets, an average (8 computer runs with independently sorted chemicals) of 315 different fragments were significantly (p < 0.125) associated with carcinogenicity or lack thereof. Even using this relatively low level of statistical significance, 23% of the molecules of the test sets lacked significant fragments. For 77% of the molecules of the test sets, we used the presence of significant fragments to predict carcinogenicity. The average level of accuracy of the predictions in the test sets was 67.5%. Chemicals containing only positive fragments were predicted with an accuracy of 78.7%. The level of accuracy was around 60% for chemicals characterized by contradictory fragments or only negative fragments. In a parallel manner, we performed eight paired runs in which carcinogenicity was attributed randomly to the molecules of the training sets. The fragments generated by these pseudo-training sets were devoid of any predictivity in the corresponding test sets. Using an independent software program, we confirmed (for the complex biological endpoint of carcinogenicity) the validity of a structure-activity relationship approach of the type proposed by Klopman and Rosenkranz with their CASE program. Images Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. PMID:8275991

  20. Relationship between increasing concentrations of two carcinogens and statistical image descriptors of foci morphology in the cell transformation assay.

    PubMed

    Callegaro, Giulia; Corvi, Raffaella; Salovaara, Susan; Urani, Chiara; Stefanini, Federico M

    2017-06-01

    Cell Transformation Assays (CTAs) have long been proposed for the identification of chemical carcinogenicity potential. The endpoint of these in vitro assays is represented by the phenotypic alterations in cultured cells, which are characterized by the change from the non-transformed to the transformed phenotype. Despite the wide fields of application and the numerous advantages of CTAs, their use in regulatory toxicology has been limited in part due to concerns about the subjective nature of visual scoring, i.e. the step in which transformed colonies or foci are evaluated through morphological features. An objective evaluation of morphological features has been previously obtained through automated digital processing of foci images to extract the value of three statistical image descriptors. In this study a further potential of the CTA using BALB/c 3T3 cells is addressed by analysing the effect of increasing concentrations of two known carcinogens, benzo[a]pyrene and NiCl 2 , with different modes of action on foci morphology. The main result of our quantitative evaluation shows that the concentration of the considered carcinogens has an effect on foci morphology that is statistically significant for the mean of two among the three selected descriptors. Statistical significance also corresponds to visual relevance. The statistical analysis of variations in foci morphology due to concentration allowed to quantify morphological changes that can be visually appreciated but not precisely determined. Therefore, it has the potential of providing new quantitative parameters in CTAs, and of exploiting all the information encoded in foci. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

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

    PubMed

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

    2012-11-01

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

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

    NASA Astrophysics Data System (ADS)

    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.

  3. Polycyclic Aromatic Hydrocarbons In Edible Mushrooms from Niger Delta, Nigeria: Carcinogenic and Non-Carcinogenic Health Risk Assessment

    PubMed

    Igbiri, Sorbari; Udowelle, Nnaemeka Arinze; Ekhator, Osazuwa Clinton; Asomugha, Rose Ngozi; Igweze, Zelinjo Nkeiruka; Orisakwe, Orish Ebere

    2017-02-01

    In the oil-rich Niger Delta, hydrocarbon pollution and oil spillages, gas flaring and sundry anthropogenic activities constitute sources of polycyclic aromatic hydrocarbons (PAHs), with food contamination playing a major role in human exposure. In this study we assessed PAH levels in wild and cultivated edible mushroom species consumed by the general population from the oil producing Niger Delta, Nigeria. The concentrations of USEPA-16 PAHs were determined by gas chromatography and carcinogenic and non-carcinogenic health risks were calculated. The concentrations of USEPA-16 PAHs ranged from 0.02 mg/kg – 3.37 mg/kg. The dietary intake of carcinogenic and non-carcinogenic USEPA-16 PAHs (Naphthalene, Acenaphthylene, Acenaphthene, Anthracene, Phenanthrene, Flourene, Flouranthene, Pyrene, Benzo[a]Anthracene, Chrysene, Benzo[a]Pyrene, Benzo[b]Flouranthene, Benzo[K]Flouranthene, Benzo[g,h,i] Perylene, Dibenz[a,h]Anthracene and Ideno[1,2,3-cd]Pyrene) for adults, adolescents and seniors ranged from 0.00 – 0.05 mg/kg/day, 0.00 – 0.06 mg/kg/day and 0.00 – 0.07 mg/kg/day. The BaPeq ranged from 0.02 – 2.76 with margin of exposure MOE values of BaP ranging from 3,500,000 to 700,000, 3,500,000 and 3,500,000 to 7,000,000 for adults, adolescents and seniors indicating very insignificant health risk. The incremental lifetime cancer risk was within the safe range of 1.56x10-8 – 1.73x10-6 with the highest calculated risk found for wild Pleurotus ostreatus mushroom species from the study area. Creative Commons Attribution License

  4. Workshop on problem areas associated with developing carcinogen guidelines

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

    Not Available

    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)

  5. Evaluation of the potential carcinogenicity of benzotrichloride (97-07-7). Final report

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

    Not Available

    1988-06-01

    Benzotrichloride is a probable human carcinogen, classified as weight-of-evidence Group B1 under the EPA Guidelines for Carcinogen Risk Assessment. Evidence on potential carcinogenicity from animal studies is Sufficient, and the evidence from human studies is Limited. The potency factor (F) for benzotrichloride is estimated to be 58.0 (mg/kg/day)(-1), placing it in potency group 2 according to the CAG's methodology for evaluating potential carcinogens. Combining the weight-of-evidence group and the potency group, benzotrichloride is assigned a MEDIUM hazard ranking.

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

    PubMed

    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. © 2013.

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

    PubMed Central

    Rusyn, Ivan; Chiu, Weihsueh A.; Lash, Lawrence H.; 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 forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including from 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. 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's 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

  8. CAREX Canada: an enhanced model for assessing occupational carcinogen exposure

    PubMed Central

    Peters, Cheryl E; Ge, Calvin B; Hall, Amy L; Davies, Hugh W; Demers, Paul A

    2015-01-01

    Objectives To estimate the numbers of workers exposed to known and suspected occupational carcinogens in Canada, building on the methods of CARcinogen EXposure (CAREX) projects in the European Union (EU). Methods CAREX Canada consists of estimates of the prevalence and level of exposure to occupational carcinogens. CAREX Canada includes occupational agents evaluated by the International Agency for Research on Cancer as known, probable or possible human carcinogens that were present and feasible to assess in Canadian workplaces. A Canadian Workplace Exposure Database was established to identify the potential for exposure in particular industries and occupations, and to create exposure level estimates among priority agents, where possible. CAREX EU data were reviewed for relevance to the Canadian context and the proportion of workers likely to be exposed by industry and occupation in Canada was assigned using expert assessment and agreement by a minimum of two occupational hygienists. These proportions were used to generate prevalence estimates by linkage with the Census of Population for 2006, and these estimates are available by industry, occupation, sex and province. Results CAREX Canada estimated the number of workers exposed to 44 known, probable and suspected carcinogens. Estimates of levels of exposure were further developed for 18 priority agents. Common exposures included night shift work (1.9 million exposed), solar ultraviolet radiation exposure (1.5 million exposed) and diesel engine exhaust (781 000 exposed). Conclusions A substantial proportion of Canadian workers are exposed to known and suspected carcinogens at work. PMID:24969047

  9. An evaluation of risk estimation procedures for mixtures of carcinogens

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

    Hwang, J.S.; Chen, J.J.

    1999-12-01

    The estimation of health risks from exposure to a mixture of chemical carcinogens is generally based on the combination of information from several available single compound studies. The current practice of directly summing the upper bound risk estimates of individual carcinogenic components as an upper bound on the total risk of a mixture is known to be generally too conservative. Gaylor and Chen (1996, Risk Analysis) proposed a simple procedure to compute an upper bound on the total risk using only the upper confidence limits and central risk estimates of individual carcinogens. The Gaylor-Chen procedure was derived based on anmore » underlying assumption of the normality for the distributions of individual risk estimates. IN this paper the authors evaluated the Gaylor-Chen approach in terms the coverages of the upper confidence limits on the true risks of individual carcinogens. In general, if the coverage probabilities for the individual carcinogens are all approximately equal to the nominal level, then the Gaylor-Chen approach should perform well. However, the Gaylor-Chen approach can be conservative or anti-conservative if some of all individual upper confidence limit estimates are conservative or anti-conservative.« less

  10. Cell-type-dependent activities of regulatory regions and E2 proteins derived from carcinogenic and non-carcinogenic human alphapapillomaviruses.

    PubMed

    Schenker, Astrid; Straub, Elke; Iftner, Thomas; Stubenrauch, Frank

    2013-06-01

    A large number of studies have revealed that persistent infections with certain human papillomavirus (HPV) types are necessary for the development of invasive cancer of the cervix. Recent studies have shown that not only do the major carcinogenic HPV types 16 and 18 encode E6 and E7 oncoproteins with immortalizing activity but also the very weakly or non-carcinogenic types 53, 66, 70 and 82. Currently, it is unknown whether transcriptional differences exist between these viruses that account for carcinogenicity in vivo. Therefore, we compared for the first time the activities of the upstream regulatory regions (URRs) that drive E6 and E7 expression derived from HPV16, -18, -31, -53, -66, -70 and -82 in the absence and presence of the viral E2 transcriptional regulator. URR activities in the absence of E2 varied widely and were further modulated by the cellular background. The co-expression of homologous E2 proteins resulted in repression of the URRs of only some HPV types and this varied with cell type. Activation by E2 proteins was less cell-type dependent but differed in an HPV-type-dependent manner. However, basal URR activity, repression of the URR by E2 and transcriptional activation by E2 did not correlate with HPV carcinogenicity in vivo. In summary, our data do not support the model that the transcriptional activity of human alphapapillomavirus types correlates with epidemiological risk classification.

  11. Carcinogenic potential of hydrotreated petroleum aromatic extracts.

    PubMed Central

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

    1985-01-01

    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

  12. An Evaluation of the Human Carcinogenic Potential of ...

    EPA Pesticide Factsheets

    This position paper, An Evaluation of the Human Carcinogenic Potential of Ethylene Glycol Butyl Ether, was developed in support of the EPA's evaluation of a petition from the American Chemistry Council requesting to delist EGBE per the Clean Air Act Amendments (CAAA), Title III, section 112(b)(1). The position paper was a key component of the Agency's recent determination to grant this petition. It will also be used in the Agency's IRIS assessment of ethylene glycol butyl ether (EGBE). An NTP (1998; 2000) study has reported some evidence of carcinogenic activity in male B6C3F1 mice based on increased incidence of hemangiosarcomas of the liver, and some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidence of forestomach squamous cell papillomas or carcinomas.

  13. In silico quantitative structure-toxicity relationship study of aromatic nitro compounds.

    PubMed

    Pasha, Farhan Ahmad; Neaz, Mohammad Morshed; Cho, Seung Joo; Ansari, Mohiuddin; Mishra, Sunil Kumar; Tiwari, Sharvan

    2009-05-01

    Small molecules often have toxicities that are a function of molecular structural features. Minor variations in structural features can make large difference in such toxicity. Consequently, in silico techniques may be used to correlate such molecular toxicities with their structural features. Relative to nine different sets of aromatic nitro compounds having known observed toxicities against different targets, we developed ligand-based 2D quantitative structure-toxicity relationship models using 20 selected topological descriptors. The topological descriptors have several advantages such as conformational independency, facile and less time-consuming computation to yield good results. Multiple linear regression analysis was used to correlate variations of toxicity with molecular properties. The information index on molecular size, lopping centric index and Kier flexibility index were identified as fundamental descriptors for different kinds of toxicity, and further showed that molecular size, branching and molecular flexibility might be particularly important factors in quantitative structure-toxicity relationship analysis. This study revealed that topological descriptor-guided quantitative structure-toxicity relationship provided a very useful, cost and time-efficient, in silico tool for describing small-molecule toxicities.

  14. Risk-based indicators of Canadians' exposures to environmental carcinogens.

    PubMed

    Setton, Eleanor; Hystad, Perry; Poplawski, Karla; Cheasley, Roslyn; Cervantes-Larios, Alejandro; Keller, C Peter; Demers, Paul A

    2013-02-12

    Tools for estimating population exposures to environmental carcinogens are required to support evidence-based policies to reduce chronic exposures and associated cancers. Our objective was to develop indicators of population exposure to selected environmental carcinogens that can be easily updated over time, and allow comparisons and prioritization between different carcinogens and exposure pathways. We employed a risk assessment-based approach to produce screening-level estimates of lifetime excess cancer risk for selected substances listed as known carcinogens by the International Agency for Research on Cancer. Estimates of lifetime average daily intake were calculated using population characteristics combined with concentrations (circa 2006) in outdoor air, indoor air, dust, drinking water, and food and beverages from existing monitoring databases or comprehensive literature reviews. Intake estimates were then multiplied by cancer potency factors from Health Canada, the United States Environmental Protection Agency, and the California Office of Environmental Health Hazard Assessment to estimate lifetime excess cancer risks associated with each substance and exposure pathway. Lifetime excess cancer risks in excess of 1 per million people are identified as potential priorities for further attention. Based on data representing average conditions circa 2006, a total of 18 carcinogen-exposure pathways had potential lifetime excess cancer risks greater than 1 per million, based on varying data quality. Carcinogens with moderate to high data quality and lifetime excess cancer risk greater than 1 per million included benzene, 1,3-butadiene and radon in outdoor air; benzene and radon in indoor air; and arsenic and hexavalent chromium in drinking water. Important data gaps were identified for asbestos, hexavalent chromium and diesel exhaust in outdoor and indoor air, while little data were available to assess risk for substances in dust, food and beverages. The ability to

  15. IARC classes 1 and 2 carcinogens are successfully identified by an alternative strategy that detects DNA-reactivity and cell transformation ability of chemicals.

    PubMed

    Benigni, Romualdo; Bossa, Cecilia; Battistelli, Chiara Laura; Tcheremenskaia, Olga

    2013-12-12

    For decades, traditional toxicology has been the ultimate source of information on the carcinogenic potential of chemicals; however with increasing demand on regulation of chemicals and decreasing resources for testing, opportunities to accept "alternative" approaches have dramatically expanded. The need for tools able to identify carcinogens in shorter times and at a lower cost in terms of animal lives and money is still an open issue, and the present strategies and regulations for carcinogenicity pre-screening do not adequately protect human health. In previous papers, we have proposed an integrated in vitro/in silico strategy that detects DNA-reactivity and tissue disorganization/disruption by chemicals, and we have shown that the combination of Salmonella and Structural Alerts for the DNA-reactive carcinogens, and in vitro cell transformation assays for nongenotoxic carcinogens permits the identification of a very large proportion (up to 95%) of rodent carcinogens, while having a considerable specificity with the rodent noncarcinogens. In the present paper we expand the previous investigation and show that this alternative strategy identifies correctly IARC Classes 1 and 2 carcinogens. If implemented, this alternative strategy can contribute to improve the protection of human health while decreasing the use of animals. Copyright © 2013 Elsevier B.V. All rights reserved.

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

    PubMed Central

    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 methanesulfonate, methyl methanesulfonate, ethyl nitrosourea, benzo[a]pyrene, trichloroethylene, benzene, and sodium arsenate. The latter three carcinogens are not detectable with several in vitro or in vivo mutagenesis assays. We studied the molecular mechanism of the carcinogen-induced reversion events by cDNA analysis using reverse transcriptase–PCR method and identified the induced reversion events as deletions. DNA deletion assays may be sensitive indicators for carcinogen exposure. PMID:9114032

  17. Occupational exposure limits for carcinogens--variant approaches by different countries

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

    Cook, W.A.

    1989-09-01

    The differences in treatment of occupational exposure limits for carcinogens by 24 countries is described along with a discussion of the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit values (TLV) treatment, the similar treatment of the new Occupational Safety and Health Administration (OSHA) standard, and the treatment by provinces of Canada. The unique listing by the Federal Republic of Germany of so-called technical guiding concentrations of a group of carcinogens is discussed with the note that Austria used this same system. Publications on justification for establishing occupational exposure limits for certain carcinogens are discussed also.

  18. Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide ...

    EPA Pesticide Factsheets

    EPA has finalized its Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide. This assessment addresses the potential carcinogenicity from long-term inhalation exposure to ethylene oxide. Now final, this assessment updates the carcinogenicity information in EPA’s 1985 Health Assessment Document. EPA’s program and regional offices may use this assessment to inform decisions to protect human health. The Toxicological Review and charge were reviewed internally by EPA and by other federal agencies and White House Offices before public release. Consistent with the May 2009 IRIS assessment development process, all written comments on IRIS assessments submitted by other federal agencies and White House Offices are made publicly available. Accordingly, interagency comments and the interagency science consultation materials provided to other agencies, including interagency review drafts of the IRIS Toxicological Review of Ammonia and the charge to external peer reviewers, are posted on this site.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

    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

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

    PubMed

    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.

  2. The influence of thresholds on the risk assessment of carcinogens in food.

    PubMed

    Pratt, Iona; Barlow, Susan; Kleiner, Juliane; Larsen, John Christian

    2009-08-01

    The risks from exposure to chemical contaminants in food must be scientifically assessed, in order to safeguard the health of consumers. Risk assessment of chemical contaminants that are both genotoxic and carcinogenic presents particular difficulties, since the effects of such substances are normally regarded as being without a threshold. No safe level can therefore be defined, and this has implications for both risk management and risk communication. Risk management of these substances in food has traditionally involved application of the ALARA (As Low as Reasonably Achievable) principle, however ALARA does not enable risk managers to assess the urgency and extent of the risk reduction measures needed. A more refined approach is needed, and several such approaches have been developed. Low-dose linear extrapolation from animal carcinogenicity studies or epidemiological studies to estimate risks for humans at low exposure levels has been applied by a number of regulatory bodies, while more recently the Margin of Exposure (MOE) approach has been applied by both the European Food Safety Authority and the Joint FAO/WHO Expert Committee on Food Additives. A further approach is the Threshold of Toxicological Concern (TTC), which establishes exposure thresholds for chemicals present in food, dependent on structure. Recent experimental evidence that genotoxic responses may be thresholded has significant implications for the risk assessment of chemicals that are both genotoxic and carcinogenic. In relation to existing approaches such as linear extrapolation, MOE and TTC, the existence of a threshold reduces the uncertainties inherent in such methodology and improves confidence in the risk assessment. However, for the foreseeable future, regulatory decisions based on the concept of thresholds for genotoxic carcinogens are likely to be taken case-by-case, based on convincing data on the Mode of Action indicating that the rate limiting variable for the development of cancer

  3. Maximum workplace concentration values and carcinogenicity classification for mixtures.

    PubMed Central

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

    1998-01-01

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

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

    NASA Technical Reports Server (NTRS)

    Giner-Sorolla, A.; Oro, J.

    1981-01-01

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

  5. Genotoxicity of Swimming Pool Water and Carcinogenicity of Drinking Water

    EPA Science Inventory

    Among the 11 disinfection by-products (DBPs) in drinking water that are regulated by the U.S. EPA, (a) 2 DBPs (chloroaceticacid and chlorite) are not carcinogenic-in either of2 species; (b) chlorite is not carcinogenic in 3 rodent assays and has never been tested for genotoxicity...

  6. Genotoxicity of Swimming Pool Water and Carcinogenicity of Drinking Water**

    EPA Science Inventory

    Among the 11 disinfection by-products (DBPs) in drinking water that are regulated by the U.S. EPA, (a) 2 DBPs (chloroaceticacid and chlorite) are not carcinogenic-in either of2 species; (b) chlorite is not carcinogenic in 3 rodent assays and has never been tested for genotoxicity...

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

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

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

    1992-01-01

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

  8. Exposure to carcinogens for defined job categories in Norway's offshore petroleum industry, 1970 to 2005

    PubMed Central

    Steinsvåg, Kjersti; Bråtveit, Magne; Moen, Bente E

    2007-01-01

    Objectives To identify and describe the exposure to selected known and suspected carcinogenic agents, mixtures and exposure circumstances for defined job categories in Norway's offshore petroleum industry from 1970 to 2005, in order to provide exposure information for a planned cohort study on cancer. Methods Background information on possible exposure was obtained through company visits, including interviewing key personnel (n = 83) and collecting monitoring reports (n = 118) and other relevant documents (n = 329). On the basis of a previous questionnaire administered to present and former offshore employees in 1998, 27 job categories were defined. Results This study indicated possible exposure to 18 known and suspected carcinogenic agents, mixtures or exposure circumstances. Monitoring reports were obtained on seven agents (benzene, mineral oil mist and vapour, respirable and total dust, asbestos fibres, refractory ceramic fibres, formaldehyde and tetrachloroethylene). The mean exposure level of 367 personal samples of benzene was 0.037 ppm (range: less than the limit of detection to 2.6 ppm). Asbestos fibres were detected (0.03 fibres/cm3) when asbestos‐containing brake bands were used in drilling draw work in 1988. Personal samples of formaldehyde in the process area ranged from 0.06 to 0.29 mg/m3. Descriptions of products containing known and suspected carcinogens, exposure sources and processes were extracted from the collected documentation and the interviews of key personnel. Conclusions This study described exposure to 18 known and suspected carcinogenic agents, mixtures and exposure circumstances for 27 job categories in Norway's offshore petroleum industry. For a planned cohort study on cancer, quantitative estimates of exposure to benzene, and mineral oil mist and vapour might be developed. For the other agents, information in the present study can be used for further assessment of exposure, for instance, by expert judgement. More

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

    PubMed

    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. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. The Regulation of Carcinogenic Hazards.

    ERIC Educational Resources Information Center

    Gori, Gio Batta

    1980-01-01

    It is suggested that a system of relative standards be formulated which would compare utility of substances to their relative risk as carcinogens. This would define a range of use restrictions. Substances intended for specific uses would then be regulated according to these standards. (Author/RE)

  11. EPA (Environmental Protection Agency) programs and the regulation of carcinogens: Methods and philosophies. Technical report

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

    Jackson, M.; Johnson, L.; Kelly, J.

    1988-01-01

    This paper discusses the manner in which the EPA identifies, assesses risk for, and regulates substances determined to cause cancer in humans. The report provides an overall perspective of the carcinogen standard-setting process as it is affected by scientific, legal, and political influences. Discussed are: history and methods of carcinogen regulation; toxicological methods for determining carcinogenicity; the use of human-exposure data to regulate carcinogens; an overview of the agency's system for classifying chemical agents suspected or known to cause cancer; significant Federal court cases and decisions that have influenced attempts by Federal agencies to regulate carcinogens; and factors affecting EPAsmore » regulation of carcinogens.« less

  12. Heterocyclic amines: Mutagens/carcinogens produced during cooking of meat and fish.

    PubMed

    Sugimura, Takashi; Wakabayashi, Keiji; Nakagama, Hitoshi; Nagao, Minako

    2004-04-01

    Research leading to the discovery of a series of mutagenic and carcinogenic heterocyclic amines (HCAs) was inspired by the idea that smoke produced during cooking of food, especially meat or fish, might be carcinogenic. More than ten kinds of HCAs, actually produced by cooking or heating of meat or fish, have now been isolated and their structures determined, most being previously unregistered compounds. They are highly mutagenic towards Salmonella typhimurium in the presence of S9 mix and are also mutagenic in vitro and in vivo toward mammalian cells. HCAs have now been chemically synthesized in quantity and subjected to long-term animal testing. When HCAs were fed in the diet, rodents developed cancers in many organs, including the colon, breast and prostate, and one HCA produced hepatomas in monkeys. The lesions exhibited alteration in genes including Apc, beta-catenin and Ha-ras, and these changes provide clues to the induction mechanisms. The HCAs are oxidized to hydroxyamino derivatives by cytochrome P450s, and further converted to ester forms by acetyltransferase and sulfotransferase. Eventually, they produce DNA adducts through the formation of N-C bonds at guanine bases. There are HCA-sensitive and resistant strains of rodents and a search for the responsible genes is now under way. While the content of HCAs in dishes consumed in ordinary life is low and not sufficient in itself to explain human cancer, the coexistence of many other mutagens/carcinogens of either autobiotic or xenobiotic type and the possibility that HCAs induce genomic instability and heightened sensitivity to tumor promoters suggest that avoidance of exposure to HCAs or reduction of HCAs' biological effects as far as possible are to be highly recommended. Usage of microwave ovens for cooking and supplementation of the diet, for example with soy-isoflavones, which have been found to suppress the occurrence of HCA-induced breast cancers, should be encouraged. Advice to the general public

  13. The contribution of molecular epidemiology to the identification of human carcinogens: current status and future perspectives.

    PubMed

    Boffetta, P; Islami, F

    2013-04-01

    The use of biological-based markers of exposure, intermediate effect, outcome, and susceptibility has become standard practice in cancer epidemiology, which has contributed to identification of several carcinogenic agents. Nevertheless, with the exception of biological agents, this contribution, in terms of providing sufficiently strong evidence as required by the International Agency for Research on Cancer (IARC) monographs, has been modest. We discuss the overall contribution of molecular epidemiology to identification of carcinogens, with focus on IARC monographs. For many carcinogens, valid biological markers of exposure and mechanisms of actions are not available. Molecular markers are usually assessed in single biological samples, which may not represent the actual exposure or biological events related to carcinogens. The contribution of molecular epidemiology to identification of carcinogens has mainly been limited to the carcinogens acting through a genotoxic mechanism, i.e. when carcinogens induce DNA damage. A number of factors, including certain hormones and overweight/obesity, may show carcinogenic effects through nongenotoxic pathways, for which mechanisms of carcinogenicity are not well identified and their biomarkers are sparse. Longitudinal assessment of biomarkers may provide more informative data in molecular epidemiology studies. For many carcinogens and mechanistic pathways, in particular nongenotoxic carcinogenicity, valid biological markers still need to be identified.

  14. Theoretical and experimental approaches to possible thresholds of response in carcinogenicity

    EPA Science Inventory

    The determination and utilization of the actual low dose-response relationship for chemical carcinogens has long interested toxicologists, experimental pathologists, modelers and risk assessors. To date, no unequivocal examples of carcinogenic thresholds in humans are known. Ho...

  15. Novel naïve Bayes classification models for predicting the carcinogenicity of chemicals.

    PubMed

    Zhang, Hui; Cao, Zhi-Xing; Li, Meng; Li, Yu-Zhi; Peng, Cheng

    2016-11-01

    The carcinogenicity prediction has become a significant issue for the pharmaceutical industry. The purpose of this investigation was to develop a novel prediction model of carcinogenicity of chemicals by using a naïve Bayes classifier. The established model was validated by the internal 5-fold cross validation and external test set. The naïve Bayes classifier gave an average overall prediction accuracy of 90 ± 0.8% for the training set and 68 ± 1.9% for the external test set. Moreover, five simple molecular descriptors (e.g., AlogP, Molecular weight (M W ), No. of H donors, Apol and Wiener) considered as important for the carcinogenicity of chemicals were identified, and some substructures related to the carcinogenicity were achieved. Thus, we hope the established naïve Bayes prediction model could be applied to filter early-stage molecules for this potential carcinogenicity adverse effect; and the identified five simple molecular descriptors and substructures of carcinogens would give a better understanding of the carcinogenicity of chemicals, and further provide guidance for medicinal chemists in the design of new candidate drugs and lead optimization, ultimately reducing the attrition rate in later stages of drug development. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Estimated prevalence of exposure to occupational carcinogens in Australia (2011-2012).

    PubMed

    Carey, Renee N; Driscoll, Timothy R; Peters, Susan; Glass, Deborah C; Reid, Alison; Benke, Geza; Fritschi, Lin

    2014-01-01

    Although past studies of workplace exposures have contributed greatly to our understanding of carcinogens, significant knowledge gaps still exist with regard to the actual extent of exposure among current workers, with no routinely collected population-based data being available in most countries. This study, the Australian Work Exposures Study (AWES), aimed to investigate the current prevalence of occupational exposure to carcinogens. A random sample of men and women aged between 18 and 65, who were currently in paid employment, were invited to participate in a telephone interview collecting information about their current job and various demographic factors. Interviews were conducted using a web-based application (OccIDEAS). OccIDEAS uses the expert exposure method in which participants are asked about their job tasks and predefined algorithms are used to automatically assign exposures. Responses were obtained from 5023 eligible Australian residents, resulting in an overall response rate of 53%. 1879 respondents (37.6%) were assessed as being exposed to at least one occupational carcinogen in their current job. Extrapolation of these figures to the Australian working population suggested 3.6 million (40.3%) current workers could be exposed to carcinogens in their workplace. Exposure prevalence was highest among farmers, drivers, miners and transport workers, as well as men and those residing in regional areas. This study demonstrates a practical, web-based approach to collecting population information on occupational exposure to carcinogens and documents the high prevalence of current exposure to occupational carcinogens in the general population.

  17. Reducing carcinogens in public schools: A non-regulatory approach by a regulatory agency

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

    Roche, L.M.

    1995-05-01

    The New Jersey Public Employees` Occupational Safety and Health Program identified 318 public school districts that reported any of 10 selected carcinogens on their 1990 New Jersey Right to Know Survey of hazardous substances. After obtaining more information about the school districts` use of these carcinogens from a 10% random sample phone survey, a letter recommending substitution of less hazardous substances was sent to the 318 school districts. Individualized to reflect information provided by the schools in the 1990 survey, a form requesting additional information on the status of containers holding the carcinogens was also sent. There were 1,303 reportsmore » of the 10 carcinogens from the 272 (86%) school districts that completed the form. Most were disposed of (668, 51%), used completely (65, 5%), or were slated for disposal (287, 22%). This is an example of a successful project by a regulatory agency to reduce potential exposure to carcinogens in public schools. The 10 most reported carcinogens were arsenic, arsenic trioxide, asbestos, benzene, benzidine, lead chromate, sodium arsenate, sodium arsenite, sodium dichromate, and vinyl chloride.« less

  18. FACTORS INFLUENCING AGE AND STRAIN-RELATED SUSCEPTIBILITY TO 3-METHYLCHOLANTHRENE CARCINOGENICITY

    EPA Science Inventory

    Fetal mice are more sensitive to chemical carcinogens than are adults. Further, some strains of mice are more susceptible to chemical carcinogens than others. We have been conducting studies to understand the interactions between age and genetic background underlying these suscep...

  19. 29 CFR 1990.131 - Priority lists for regulating potential occupational carcinogens.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... POTENTIAL OCCUPATIONAL CARCINOGENS Priority Setting § 1990.131 Priority lists for regulating potential occupational carcinogens. The Secretary shall establish two priority lists for regulating potential... 29 Labor 9 2010-07-01 2010-07-01 false Priority lists for regulating potential occupational...

  20. The carcinogenic effects of aspartame: The urgent need for regulatory re-evaluation.

    PubMed

    Soffritti, Morando; Padovani, Michela; Tibaldi, Eva; Falcioni, Laura; Manservisi, Fabiana; Belpoggi, Fiorella

    2014-04-01

    Aspartame (APM) is an artificial sweetener used since the 1980s, now present in >6,000 products, including over 500 pharmaceuticals. Since its discovery in 1965, and its first approval by the US Food and Drugs Administration (FDA) in 1981, the safety of APM, and in particular its carcinogenicity potential, has been controversial. The present commentary reviews the adequacy of the design and conduct of carcinogenicity bioassays on rodents submitted by G.D. Searle, in the 1970s, to the FDA for market approval. We also review how experimental and epidemiological data on the carcinogenic risks of APM, that became available in 2005 motivated the European Commission (EC) to call the European Food and Safety Authority (EFSA) for urgent re-examination of the available scientific documentation (including the Searle studies). The EC has further requested that, if the results of the evaluation should suggest carcinogenicity, major changes must be made to the current APM specific regulations. Taken together, the studies performed by G.D. Searle in the 1970s and other chronic bioassays do not provide adequate scientific support for APM safety. In contrast, recent results of life-span carcinogenicity bioassays on rats and mice published in peer-reviewed journals, and a prospective epidemiological study, provide consistent evidence of APM's carcinogenic potential. On the basis of the evidence of the potential carcinogenic effects of APM herein reported, a re-evaluation of the current position of international regulatory agencies must be considered an urgent matter of public health. © 2014 Wiley Periodicals, Inc.

  1. Application of bacterial reverse mutation assay for detection of non-genotoxic carcinogens.

    PubMed

    Kanode, Rewan; Chandra, Saurabh; Sharma, Sharad

    2017-06-01

    Non-genotoxic carcinogens may play a significant role in development of cancer. Currently short-term assays for mutagenicity classify genotoxic carcinogens and lack the abilities to detect epigenetic carcinogens. The need to develop an endpoint always remains to recognize potentially carcinogenic agents employing rapid and practical bioassays. For this, the present study utilized TA98 and TA1537 tester strains of Salmonella typhimurium to evaluate four non-genotoxic carcinogenic agents (Coumarin, β-Myrcene, Bis(2-ethylhexyl) phthalate and trans-anethole). These chemicals were tested individually and in combination with promutagens 2-aminoanthracene (2AA) and benzo(a)pyrene (BP) in presence of metabolic activation system (S9) by plate incorporation method. Exposure to all four test chemicals revealed marked increase of revertant colonies in promutagen combined groups as compared to promutagens alone. However significantly greater fold responses were observed with 2AA combination groups (Coumarin +2AA, β-Myrcene +2AA, Bis(2-ethylhexyl) phthalate +2AA and trans-anethole +2AA) with TA98 strain as compared with TA1537, which seems to have enhanced the mutagenic response of 2AA in metabolically activated conditions. It is concluded that out of both tester strains TA98 strain of Salmonella typhimurium has the potential to detect non-genotoxic carcinogens when combined with potent promutgens either by inhibiting or modulating activities of liver microsomal enzymes biochemically which may indirectly contribute to neoplastic alterations. Further this simple, short-term alternative assay may provide rapid information during extrapolative toxicology for differentiating genotoxic and non-genotoxic carcinogens.

  2. Toxic and carcinogenic agents in dry and moist snuff.

    PubMed

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

    1987-12-01

    The oral use of snuff is causatively associated with cancer of the oral cavity. Since most epidemiologic studies to date relate to the long-term use of dry snuff, which has dominated the U.S. smokeless tobacco market in the past, the concentrations of several toxic and carcinogenic agents in the three most popular dry snuff brands have been compared with those in the five most popular moist snuff brands sold in the United States. All eight samples were analyzed for nitrate, alkaloids, polyphenols, volatile carbonyl compounds, lead, cadmium, selenium, and the carcinogenic compounds benzo[a]pyrene (CAS: 50-32-8), polonium-210 (CAS: 13981-52-7), volatile N-nitrosamines (VNAs), N-nitrosodiethanolamine (CAS: 1116-54-7), and the tobacco-specific N-nitrosamines (TSNAs). Most of the snuff brands were rich in nitrate (greater than or equal to 1.5%), total polyphenols (greater than 2%), and in nicotine (greater than or equal to 1.5%), which is the habituating factor in tobacco use. Concentrations of the VNAs were significantly above the permissible limits set for some food products; the concentrations of the TSNAs in both snuff types exceeded the levels of nitrosamines in other consumer products by at least two to three orders of magnitude. The extremely high levels of the TSNAs in snuff have remained unchanged during the last decade and present the major carcinogenic risk factor for the oral use of snuff. Polonium-210 contributes further to the carcinogenic risk associated with snuff. The chemical-analytical data presented in this study do not indicate marked differences in the carcinogenic potential of moist snuff compared to dry snuff.

  3. [Principles of establishing occupational exposure limits for carcinogens in Poland and in other EU countries].

    PubMed

    Skowroń, Jolanta; Czerczak, Slawomir

    2013-01-01

    The principles of determining exposure limits for carcinogens adopted in Poland, the European Union and in other selected countries of the EC are discussed in this article. Carcinogens and/or mutagens pose a direct health risk to people exposed to them. If carcinogens cannot be eliminated from the work and living environments, their exposure should be kept at the lowest possible level. To assess health risk for carcinogens it is necessary to determine the probability of developing a disease or of death from cancer as a result of occupational exposure to carcinogenic substances.

  4. Risk assessment of DNA-reactive carcinogens in food.

    PubMed

    Jeffrey, A M; Williams, G M

    2005-09-01

    Risk assessment of DNA-reactive carcinogens in food requires knowledge of the extent of DNA damage in the target organ which results from the competition between DNA adduct formation and repair. Estimates of DNA adduct levels can be made by direct measurement or indirectly as a consequence of their presence, for example, by tumor formation in animal models or exposed populations epidemiologically. Food-borne DNA-reactive carcinogens are present from a variety of sources. They are generally not intrinsically DNA-reactive but require bioactivation to DNA-reactive metabolites a process which may be modulated by the compound itself or the presence of other xenobiotics. A single DNA reactant may form several distinct DNA adducts each undergoing different rates of repair. Some DNA reactants may be photochemically activated or produce reactive oxygen species and thus indirect oxidative DNA damage. The levels of DNA adducts arising from exposures influenced by variations in the doses, the frequency with which an individual is exposed, and rates of DNA repair for specific adducts. Each adduct has a characteristic efficiency with which it induces mutations. Based on experience with the well-studied DNA-reactive food carcinogen aflatoxin B(1) (AFB(1)), a limit of 20 ppb or approximately 30 microg/day has been set and is considered a tolerable daily intake (TDI). Since AFB(1) is considered a potent carcinogen, doses of <1.5 microg of unknown compounds are considered TDIs. Most DNA-reactants, including acrylamide, heterocyclic amines, and alpha,beta-unsaturated carbonyl are below this value. Above that value, measurement of actual DNA adducts levels in either experimental animals with a risk assessment, or, when this occurs, exposed humans are needed. A number of approaches to undertake this are described including immunological, mass spectrometric and (32)P-postlabeling or the use of surrogates such as hemoglobin adducts, together with approaches to evaluate the results. A

  5. Risk assessment of DNA-reactive carcinogens in food

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

    Jeffrey, A.M.; Williams, G.M.

    2005-09-01

    Risk assessment of DNA-reactive carcinogens in food requires knowledge of the extent of DNA damage in the target organ which results from the competition between DNA adduct formation and repair. Estimates of DNA adduct levels can be made by direct measurement or indirectly as a consequence of their presence, for example, by tumor formation in animal models or exposed populations epidemiologically. Food-borne DNA-reactive carcinogens are present from a variety of sources. They are generally not intrinsically DNA-reactive but require bioactivation to DNA-reactive metabolites a process which may be modulated by the compound itself or the presence of other xenobiotics. Amore » single DNA reactant may form several distinct DNA adducts each undergoing different rates of repair. Some DNA reactants may be photochemically activated or produce reactive oxygen species and thus indirect oxidative DNA damage. The levels of DNA adducts arising from exposures influenced by variations in the doses, the frequency with which an individual is exposed, and rates of DNA repair for specific adducts. Each adduct has a characteristic efficiency with which it induces mutations. Based on experience with the well-studied DNA-reactive food carcinogen aflatoxin B{sub 1} (AFB{sub 1}), a limit of 20 ppb or {approx}30 {mu}g/day has been set and is considered a tolerable daily intake (TDI). Since AFB{sub 1} is considered a potent carcinogen, doses of <1.5 {mu}g of unknown compounds are considered TDIs. Most DNA-reactants, including acrylamide, heterocyclic amines, and {alpha},{beta}-unsaturated carbonyl are below this value. Above that value, measurement of actual DNA adducts levels in either experimental animals with a risk assessment, or, when this occurs, exposed humans are needed. A number of approaches to undertake this are described including immunological, mass spectrometric and {sup 32}P-postlabeling or the use of surrogates such as hemoglobin adducts, together with approaches to

  6. Report on carcinogens monograph on 1-bromopropane.

    PubMed

    2013-09-01

    The National Toxicology Program conducted a cancer evaluation on 1 bromopropane for possible listing in the Report on Carcinogens (RoC). The cancer evaluation is captured in the RoC monograph, which was peer reviewed in a public forum. The monograph consists of two components: (Part 1) the cancer evaluation, which reviews the relevant scientific information, assesses its quality, applies the RoC listing criteria to the scientific information, and provides the NTP recommendation for listing status for 1 bromopropane in the RoC, and (Part 2) the substance profile proposed for the RoC, containing the NTP's listing status recommendation, a summary of the scientific evidence considered key to reaching that decision, and data on properties, use, production, exposure, and Federal regulations and guidelines to reduce exposure to 1-bromopropane. This monograph provides an assessment of the available scientific information on 1 bromopropane, including human exposure and properties, disposition and toxicokinetics, cancer studies in experimental animals, and studies of mechanisms and other related effects, including relevant toxicological effects, genetic toxicology, and mechanisms of carcinogenicity. From this assessment, the NTP recommended that 1 bromopropane be listed as reasonably anticipated to be a human carcinogen in the RoC based on sufficient evidence from studies in experimental animals, which found inhalation exposure to 1-bromopropane caused skin tumors in male rats, large intestine tumors in female and male rats, and lung tumors in female mice. Also noted was that 1 bromopropane, either directly or via reactive metabolites, caused molecular alterations that typically are associated with carcinogenesis, including genotoxicity, oxidative stress, and glutathione depletion. These alterations, observed in mainly in vitro and toxicity studies in rodents, are relevant to possible mechanisms of human carcinogenicity and support the relevance of the cancer studies in

  7. Application of the key characteristics of carcinogens in cancer hazard identification.

    PubMed

    Guyton, Kathryn Z; Rusyn, Ivan; Chiu, Weihsueh A; Corpet, Denis E; van den Berg, Martin; Ross, Matthew K; Christiani, David C; Beland, Frederick A; Smith, Martyn T

    2018-04-05

    Smith et al. (Env. Health Perspect. 124: 713, 2016) identified 10 key characteristics (KCs), one or more of which are commonly exhibited by established human carcinogens. The KCs reflect the properties of a cancer-causing agent, such as 'is genotoxic,' 'is immunosuppressive' or 'modulates receptor-mediated effects,' and are distinct from the hallmarks of cancer, which are the properties of tumors. To assess feasibility and limitations of applying the KCs to diverse agents, methods and results of mechanistic data evaluations were compiled from eight recent IARC Monograph meetings. A systematic search, screening and evaluation procedure identified a broad literature encompassing multiple KCs for most (12/16) IARC Group 1 or 2A carcinogens identified in these meetings. Five carcinogens are genotoxic and induce oxidative stress, of which pentachlorophenol, hydrazine and malathion also showed additional KCs. Four others, including welding fumes, are immunosuppressive. The overall evaluation was upgraded to Group 2A based on mechanistic data for only two agents, tetrabromobisphenol A and tetrachloroazobenzene. Both carcinogens modulate receptor-mediated effects in combination with other KCs. Fewer studies were identified for Group 2B or 3 agents, with the vast majority (17/18) showing only one or no KCs. Thus, an objective approach to identify and evaluate mechanistic studies pertinent to cancer revealed strong evidence for multiple KCs for most Group 1 or 2A carcinogens but also identified opportunities for improvement. Further development and mapping of toxicological and biomarker endpoints and pathways relevant to the KCs can advance the systematic search and evaluation of mechanistic data in carcinogen hazard identification.

  8. Health effects of coal mining and combustion: carcinogens and cofactors.

    PubMed Central

    Falk, H L; Jurgelski, W

    1979-01-01

    Some polynuclear aromatics (PNA) have been found to be potent carcinogens for all tissues and organs of experimental animals that have been exposed to them, but different dose levels are needed for these effects. They have been known for decades to cause cancer at the site of application but also at certain sites distant from the area of contact. Although some hydrocarbons are potent and complete carcinogens, the majority of related hydrocarbons was originally found to be inactive. Since they generally appear together, it was important to know more about their interaction, particularly whether they would synergize, or antagonize. The polycyclic hydrocarbons have been studied by subcutaneous injection, where they prove very potent carcinogens. They are also very active on the skin of mice where they produce cancer on prolonged application. Inhalation studies, require larger doses yielded negative results until particulate matter was introduced which facilitated the development of lung tumors. Although iron oxide dust was used initially, other dusts were also capable of enhancing the response of the tissue to benzo(a)pyrene carcinogenesis. This point is of importance, particularly since the inhalation of PNA in situations of air pollution or coal mining involves particulates, although of a different type. Soot is not a homogenous substance and several factors determine its properties. Soots will lose some of the absorbed chemicals during their residence in air, but they retain their PNAs for long periods of time when they reach the soil. The carcinogenicity of PNAs in the adsorbed state may be completely absent, depending on particle size of the soot and availability of eluting capability of the tissues or cells in contact with the soot. Whenever the carcinogenic polynuclear aromatics can be eluted they will be active in producing cancer if their residence is adequate. There seems to be no reason to assume that a large increase in coal combustion in the future will

  9. Comparisons of carcinogenicities of nickel compounds in rats

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

    Sunderman, F.W. Jr.; Maenza, R.M.

    This study demonstrates marked differences in the incidences of sarcomas in Fischer rats within 2 years after a single im injection of 4 insoluble nickel-containing powders amorphous nickel monosulfide (NiS), nickel subsulfide (..cap alpha..Ni/sub 3/S/sub 2/), partially converted nickel-iron sulfide matte, and metallic nickel. The powders (<2 ..mu..m median particle diameters) were administered in penicillin suspension, and each powder was tested at 2 dosages. Whereas ..cap alpha..Ni/sub 3/S/sub 2/ was highly carcinogenic, amorphous NiS did not induce any tumors. The carcinogenic potency of partially converted nickel-iron sulfide matte was less than ..cap alpha..Ni/sub 3/S/sub 2/ but greater than Ni powder.more » No sarcomas occurred at the injection site in two groups of control rats that received im injections of penicillin or Fe powder. The observed differences in carcinogenic potencies of ..cap alpha..Ni/sub 3/S/sub 2/ and amorphous NiS may provide an experimental approach to elucidate the molecular mechanisms of nickel carcinogenesis.« less

  10. Detection of genotoxic and non-genotoxic carcinogens in Xpc(-/-)p53(+/-) mice.

    PubMed

    Melis, Joost P M; Speksnijder, Ewoud N; Kuiper, Raoul V; Salvatori, Daniela C F; Schaap, Mirjam M; Maas, Saskia; Robinson, Joke; Verhoef, Aart; van Benthem, Jan; Luijten, Mirjam; van Steeg, Harry

    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. Copyright © 2012 Elsevier Inc. All rights reserved.

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

    PubMed Central

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

    2012-01-01

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

  12. Carcinogen derived biomarkers: applications in studies of human exposure to secondhand tobacco smoke

    PubMed Central

    Hecht, S

    2004-01-01

    Objective: To review the literature on carcinogen derived biomarkers of exposure to secondhand tobacco smoke (SHS). These biomarkers are specifically related to known carcinogens in tobacco smoke and include urinary metabolites, DNA adducts, and blood protein adducts. Method: Published reviews and the current literature were searched for relevant articles. Results: The most consistently elevated biomarker in people exposed to SHS was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Gluc), urinary metabolites of the tobacco specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The tobacco specificity of this biomarker as well as its clear relation to an established lung carcinogen are particularly appropriate for its application in studies of SHS exposure. Conclusion: The results of the available carcinogen derived biomarker studies provide biochemical data which support the conclusion, based on epidemiologic investigations, that SHS causes lung cancer in non-smokers. PMID:14985617

  13. Antagonistic interactions of an arsenic-containing mixture in a multiple organ carcinogenicity bioassay.

    PubMed

    Pott, W A; Benjamin, S A; Yang, R S

    1998-11-27

    Inorganic arsenic (As), 1,2-dichloroethane (DCE), vinyl chloride (VC) and trichloroethylene (TCE) are frequently identified as groundwater contaminants near hazardous waste disposal sites. While the carcinogenicity of each of these chemicals has been extensively studied individually, little information exists regarding their carcinogenic potential in combination. Therefore, we investigated the carcinogenic promoting potential of chemical mixtures containing arsenic, DCE, VC and TCE following multiple initiator administration in a multiple organ carcinogenicity bioassay (N. Ito, T. Shirai, S. Fukushima, Medium-term bioassay for carcinogens using multiorgan models, in: N. Ito, H. Sugano (Eds.), Modification of Tumor Development in Rodents, Prog. Exp. Tumor Res., 33, 41-57, Basel, Karger, 1991). Our results reveal a dose-responsive antagonistic effect of this four-chemical mixture on the development of preneoplastic hepatic lesions (altered hepatocellular foci and glutathione S-transferase pi positive foci) as well as bronchioalveolar hyperplasia and adenoma formation.

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

    PubMed

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

    2012-02-01

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

  15. [The National Registry of Occupational Exposures to Carcinogens (SIREP): information system and results].

    PubMed

    Scarselli, Alberto

    2011-01-01

    The recording of occupational exposure to carcinogens is a fundamental step in order to assess exposure risk factors in workplaces. The aim of this paper is to describe the characteristics of the Italian register of occupational exposures to carcinogen agents (SIREP). The core data collected in the system are: firm characteristics, worker demographics, and exposure information. Statistical descriptive analyses were performed by economic activity sector, carcinogen agent and geographic location. Currently, the information recorded regard: 12,300 firms, 130,000 workers, and 250,000 exposures. The SIREP database has been set up in order to assess, control and reduce the carcinogen risk at workplace.

  16. Indoor air - assessment: Methods of analysis for environmental carcinogens

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

    Peterson, M.R.; Naugle, D.F.; Berry, M.A.

    1990-06-01

    The monograph describes, in a general way, published sampling procedures and analytical approaches for known and suspected carcinogens. The primary focus is upon carcinogens found in indoor air, although the methods described are applicable to other media or environments. In cases where there are no published methods for a particular pollutant in indoor air, methods developed for the workplace and for ambient air are included since they should be adaptable to indoor air. Known and suspected carcinogens have been grouped into six categories for the purposes of this and related work. The categories are radon, asbestos, organic compounds, inorganic species,more » particles, and non-ionizing radiation. Some methods of assessing exposure that are not specific to any particular pollutant category are covered in a separate section. The report is the fifth in a series of EPA/Environmental Criteria and Assessment Office Monographs.« less

  17. Risk assessment for carcinogens under California's Proposition 65

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

    Pease, W.S.; Zeise, L.; Kelter, A.

    1990-06-01

    Risk assessments for carcinogens are being developed through an accelerated process in California as a part of the state's implementation of Proposition 65, the Safe Drinking Water and Toxic Enforcement Act. Estimates of carcinogenic potency made by the California Department of Health Services (CDHS) are generally similar to estimates made by the U.S. Environmental Protection Agency (EPA). The largest differences are due to EPA's use of the maximum likelihood estimate instead of CDHS' use of the upper 95% confidence bounds on potencies derived from human data and to procedures used to correct for studies of short duration or with earlymore » mortality. Numerical limits derived from these potency estimates constitute no significant risk levels, which govern exemption from Proposition 65's discharge prohibition and warning requirements. Under Proposition 65 regulations, lifetime cancer risks less than 10(-5) are not significant and cumulative intake is not considered. Following these regulations, numerical limits for a number of Proposition 65 carcinogens that are applicable to the control of toxic discharges are less stringent than limits under existing federal water pollution control laws. Thus, existing federal limits will become the Proposition 65 levels for discharge. Chemicals currently not covered by federal and state controls will eventually be subject to discharge limitations under Proposition 65. No significant risk levels (expressed in terms of daily intake of carcinogens) also trigger warning requirements under Proposition 65 that are more extensive than existing state or federal requirements. A variety of chemical exposures from multiple sources are identified that exceed Proposition 65's no significant risk levels.« less

  18. Lifetime carcinogenicity study of 1- and 2-naphthylamine in dogs.

    PubMed Central

    Purchase, I. F.; Kalinowski, A. E.; Ishmael, J.; Wilson, J.; Gore, C. W.; Chart, I. S.

    1981-01-01

    Groups of male and female beagle dogs were given daily doses of 400 mg of various mixtures of naphthylamines for up to 109 months. Survivors were killed at 128 months. A variety of pathological conditions was diagnosed, but the only effect related to treatment was the induction of bladder neoplasms. All dogs which received pure 2-naphthylamine developed transitional-cell carcinomas of the bladder within 34 months. Two of 8 dogs receiving 6% 2-naphthylamine in 1-naphthylamine developed early carcinoma and 2/8 dogs receiving 0.5% 2-naphthylamine in 1-naphthylamine developed haemangioma of the bladder. Some of the dogs receiving 1-naphthylamine (total dose 950 g) and the controls had focal cystitis or hyperplasia, but no neoplasia of the bladder. These results confirm the carcinogenicity of 2-naphthylamine to dogs. No carcinogenic effect of 1-naphthylamine was observed, indicating that it is at least 200 times less potent as a carcinogen than 2-naphthylamine. The incidence of bladder cancer in dogs fed mixtures of both naphthylamines explains why previous experimental and epidemiological studies of impure 1-naphthylamine have revealed carcinogenicity. Images Fig. 1 Fig. 2 PMID:7326199

  19. Application of the key characteristics of carcinogens in cancer hazard identification

    PubMed Central

    Guyton, Kathryn Z; Rusyn, Ivan; Chiu, Weihsueh A; Corpet, Denis E; van den Berg, Martin; Ross, Matthew K; Christiani, David C; Beland, Frederick A; Smith, Martyn T

    2018-01-01

    Abstract Smith et al. (Env. Health Perspect. 124: 713, 2016) identified 10 key characteristics (KCs), one or more of which are commonly exhibited by established human carcinogens. The KCs reflect the properties of a cancer-causing agent, such as ‘is genotoxic,’ ‘is immunosuppressive’ or ‘modulates receptor-mediated effects,’ and are distinct from the hallmarks of cancer, which are the properties of tumors. To assess feasibility and limitations of applying the KCs to diverse agents, methods and results of mechanistic data evaluations were compiled from eight recent IARC Monograph meetings. A systematic search, screening and evaluation procedure identified a broad literature encompassing multiple KCs for most (12/16) IARC Group 1 or 2A carcinogens identified in these meetings. Five carcinogens are genotoxic and induce oxidative stress, of which pentachlorophenol, hydrazine and malathion also showed additional KCs. Four others, including welding fumes, are immunosuppressive. The overall evaluation was upgraded to Group 2A based on mechanistic data for only two agents, tetrabromobisphenol A and tetrachloroazobenzene. Both carcinogens modulate receptor-mediated effects in combination with other KCs. Fewer studies were identified for Group 2B or 3 agents, with the vast majority (17/18) showing only one or no KCs. Thus, an objective approach to identify and evaluate mechanistic studies pertinent to cancer revealed strong evidence for multiple KCs for most Group 1 or 2A carcinogens but also identified opportunities for improvement. Further development and mapping of toxicological and biomarker endpoints and pathways relevant to the KCs can advance the systematic search and evaluation of mechanistic data in carcinogen hazard identification. PMID:29562322

  20. MicroRNA Responses to the Genotoxic Carcinogens Aflatoxin B1 and Benzo[a]pyrene in Human HepaRG Cells.

    PubMed

    Marrone, April K; Tryndyak, Volodymyr; Beland, Frederick A; Pogribny, Igor P

    2016-02-01

    Recent advances in toxicogenomics present an opportunity to develop new in vitro testing methodologies to identify human carcinogens. We have investigated microRNA expression responses to the treatment of human liver HepaRG cells with the human genotoxic carcinogens aflatoxin B1 (AFB1) and benzo[a]pyrene (B[a]P), and the structurally similar compounds aflatoxin B2 (AFB2) and benzo[e]pyrene (B[e]P) that exhibit minimal carcinogenic potential. We demonstrate that treatment of HepaRG cells with AFB1 or B[a]P resulted in specific changes in the expression of miRNAs as compared with their non-carcinogenic analogues, particularly in a marked over-expression of miR-410. An additional novel finding is the dose- and time-dependent inhibition of miR-122 in AFB1-treated HepaRG cells. Mechanistically, the AFB1-induced down-regulation of miR-122 was attributed to inhibition of the HNF4A/miR-122 regulatory pathway. These results demonstrate that HepaRG cells can be used to investigate miRNA responses to xenobiotic exposure, and illustrate the existence of early non-genotoxic events, in addition to a well-established genotoxic mode of action changes, in the mechanism of AFB1 and B[a]P carcinogenicity. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

  1. Carcinogens Report Adds Seven Agents.

    PubMed

    2017-01-01

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

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

    PubMed

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

    2005-01-01

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

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

    PubMed

    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.

  4. Small difference in carcinogenic potency between GBP nanomaterials and GBP micromaterials.

    PubMed

    Gebel, Thomas

    2012-07-01

    Materials that can be described as respirable granular biodurable particles without known significant specific toxicity (GBP) show a common mode of toxicological action that is characterized by inflammation and carcinogenicity in chronic inhalation studies in the rat. This study was carried out to compare the carcinogenic potency of GBP nanomaterials (primary particle diameter 1-100 nm) to GBP micromaterials (primary particle diameter >100 nm) in a pooled approach. For this purpose, the positive GBP rat inhalation carcinogenicity studies have been evaluated. Inhalation studies on diesel engine emissions have also been included due to the fact that the mode of carcinogenic action is assumed to be the same. As it is currently not clear which dose metrics may best explain carcinogenic potency, different metrics have been considered. Cumulative exposure concentrations related to mass, surface area, and primary particle volume have been included as well as cumulative lung burden metrics related to mass, surface area, and primary particle volume. In total, 36 comparisons have been conducted. Including all dose metrics, GBP nanomaterials were 1.33- to 1.69-fold (mean values) and 1.88- to 3.54-fold (median values) more potent with respect to carcinogenicity than GBP micromaterials, respectively. Nine of these 36 comparisons showed statistical significance (p < 0.05, U test), all of which related to dose metrics based on particle mass. The maximum comparative potency factor obtained for one of these 9 dose metric comparisons based on particle mass was 4.71. The studies with diesel engine emissions did not have a major impact on the potency comparison. The average duration of the carcinogenicity studies with GBP nanomaterials was 4 months longer (median values 30 vs. 26 months) than the studies with GBP micromaterials, respectively. Tumor rates increase with age and lung tumors in the rat induced by GBP materials are known to appear late, that is, mainly after study

  5. Towards health impact assessment of drinking-water privatization--the example of waterborne carcinogens in North Rhine-Westphalia (Germany).

    PubMed Central

    Fehr, Rainer; Mekel, Odile; Lacombe, Martin; Wolf, Ulrike

    2003-01-01

    Worldwide there is a tendency towards deregulation in many policy sectors - this, for example, includes liberalization and privatization of drinking-water management. However, concerns about the negative impacts this might have on human health call for prospective health impact assessment (HIA) on the management of drinking-water. On the basis of an established generic 10-step HIA procedure and on risk assessment methodology, this paper aims to produce quantitative estimates concerning health effects from increased exposure to carcinogens in drinking-water. Using data from North Rhine-Westphalia in Germany, probabilistic estimates of excess lifetime cancer risk, as well as estimates of additional cases of cancer from increased carcinogen exposure levels are presented. The results show how exposure to contaminants that are strictly within current limits could increase cancer risks and case-loads substantially. On the basis of the current analysis, we suggest that with uniform increases in pollutant levels, a single chemical (arsenic) is responsible for a large fraction of expected additional risk. The study also illustrates the uncertainty involved in predicting the health impacts of changes in water quality. Future analysis should include additional carcinogens, non-cancer risks including those due to microbial contamination, and the impacts of system failures and of illegal action, which may be increasingly likely to occur under changed management arrangements. If, in spite of concerns, water is privatized, it is particularly important to provide adequate surveillance of water quality. PMID:12894324

  6. Comparison of Reversibility of Rat Forestomach Lesions Induced by Genotoxic and Non‐genotoxic Carcinogens

    PubMed Central

    Kagawa, Masataka; Hakoi, Kazuo; Yamamoto, Atsushi; Futakuchi, Mitsuru

    1993-01-01

    Reversibility of forestomach lesions induced by genotoxic and non‐genotoxic carcinogens was compared histopathologically. Groups of 30 to 33 male F344 rats were given dietary 0.1% 8‐nitroquinoline, dietary 0.4–0.2% 2‐(2‐furyl)‐3‐(5‐nitro‐2‐furyl)acrylamide, an intragastric dose of 20 mg/kg body weight N‐methyl‐N′‐nitro‐N‐nitrosoguanidine once a week, or 20 ppm N‐methylnitrosourethane in the drinking water as a genotoxic carcinogen, or 2% butylated hydroxyanisole, 2% caffeic acid, 2% sesamol or 2% 4‐methoxyphenol in the diet as a non‐genotoxic carcinogen for 24 weeks. Ten or 11 rats in each group were killed at week 24. Half of the remainder were maintained on basal diet alone for an additional 24 weeks and the other half were given the same chemical for 48 weeks, and then killed. Forestomach lesions induced by genotoxic carcinogens did not regress after removal of carcinogens. In contrast, simple or papillary hyperplasia (SPH), but not basal cell hyperplasia (BCH), induced by non‐genotoxic carcinogens clearly regressed after cessation of insult. SFH labeling indices in the non‐genotoxic carcinogen‐treated cases decreased after removal of the carcinogenic stimulus whereas BCH values were low irrespective of treatment. Atypical hyperplasia (AH), observed at high incidences in rats treated with genotoxic carcinogens, was also evident in animals receiving non‐genotoxic agents, even after their withdrawal, albeit at low incidences. AH labeling indices remained high even without continued insult. These results indicate that even with non‐genotoxic carcinogens, heritable alterations at the DNA level could occur during strong cell proliferation and result in AH development. This putative preneoplastic lesion might then progress to produce carcinomas. PMID:8276717

  7. Major carcinogenic pathways identified by gene expression analysis of peritoneal mesotheliomas following chemical treatment in F344 rats

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

    Kim, Yongbaek; Thai-Vu Ton; De Angelo, Anthony B.

    2006-07-15

    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-PCRmore » 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/{beta}-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.« less

  8. Occupational exposure to carcinogens in Australian road transport workers.

    PubMed

    Si, Si; Carey, Renee; Reid, Alison; Peters, Susan; Glass, Deborah D; Driscoll, Timothy; Darcey, Ellie; Fritschi, Lin

    2016-01-01

    Road transport workers (RTWs) are at high risk of exposure to several occupational carcinogens. However, there are gaps in knowledge regarding the extent and the circumstances of exposure. As a sub-study of the Australian Work Exposures Study, this study investigated the prevalence of occupational exposure in Australian RTWs. A random sample of Australian working population was invited to a telephone interview regarding their current jobs. An automated expert-assessment procedure was applied to self-reported job-related tasks using a web-based application. 162 RTWs were included in this study. RTWs were exposed to diesel exhaust (97%), solar ultraviolet radiation (78%), environmental tobacco smoke (55%), benzene (29%), silica (15%), and asbestos (10%) at work. Besides driving on roads, vehicle maintenance-related tasks were the major source of carcinogen exposures among RTWs. Most RTWs are exposed to at least one carcinogen at work. We have identified tasks where the use of control measures could potentially reduce exposures. © 2015 Wiley Periodicals, Inc.

  9. Carcinogenic and non-carcinogenic health risks of metal(oid)s in tap water from Ilam city, Iran.

    PubMed

    Fakhri, Yadolah; Saha, Narottam; Ghanbari, Sahebeh; Rasouli, Milad; Miri, Ali; Avazpour, Moayed; Rahimizadeh, Aziz; Riahi, Seyed-Mohammad; Ghaderpoori, Mansour; Keramati, Hassan; Moradi, Bigard; Amanidaz, Nazak; Mousavi Khaneghah, Amin

    2018-04-20

    One of the most important pathways for exposure to metals is drinking water ingestion. Chronic or acute exposure to metals can endanger the health of the exposed population, and hence, estimation of human health risks is crucial. In the current study for the first time, the concentrations of Mercury (Hg), Arsenic (As), Zinc (Zn), Lead (Pb) and Cobalt (Co) in 120 collected tap water samples (2015, July-November) from Ilam city, Iran were investigated using flame atomic absorption spectrophotometer. Also, the metal-induced carcinogenic and non-carcinogenic risks for consumers exposed to tap drinking water were calculated. The average (range) concentrations of Hg, Zn, As, Pb and Co were defined as 0.40 ± 0.10 μg/L (ND-0.9 μg/L), 5014 ± 5707 μg/L (2900.00-5668.33 μg/L), 21.008 ± 2.876 μg/L (3.5-62 μg/L), 30.38 ± 5.56 μg/L (6-87 μg/L), and 11.34 ± 1.61 μg/L (0.1-50 μg/L), respectively. Average concentrations of all examined metals were significantly higher than WHO and national standard recommended limits. The ranking order of metals concentrations in the tap drinking water was Zn > Pb > As > Co > Hg. Except for Hg and Co, at least one age group consumers were at considerable non-carcinogenic risks induced by Zn, As and Pb [Target Hazard Quotient (THQ > 1)]. The rank order of age groups consumers based on THQ and Incremental lifetime cancer risk (ILCR) was <1 years >1-9 years > 20 + years > 10-19 years. The calculated ILCR for As in all age groups were higher than 10 -3 value. All age groups of consumers in Ilam city, especially infants (<1 years) and children (1-10 years), are at considerable non-carcinogenic and carcinogenesis risk. Copyright © 2018 Elsevier Ltd. All rights reserved.

  10. USING PROTEOMICS TO MONITOR PROTEIN EXPRESSION IN HUMAN CELLS EXPOSED TO CARCINOGENS

    EPA Science Inventory

    People are continuously exposed exogenously to varying amounts of chemicals that have been shown to have carcinogenic properties in experimental systems. It has been estimated that exposure to environmental chemical carcinogens in the environment may contribute significantly to t...

  11. PREDICTING TOXICOLOGICAL ENDPOINTS OF CHEMICALS USING QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSARS)

    EPA Science Inventory

    Quantitative structure-activity relationships (QSARs) are being developed to predict the toxicological endpoints for untested chemicals similar in structure to chemicals that have known experimental toxicological data. Based on a very large number of predetermined descriptors, a...

  12. Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane

    PubMed Central

    Bauman, Julie E.; Zang, Yan; Sen, Malabika; Li, Changyou; Wang, Lin; Egner, Patricia A.; Fahey, Jed W.; Normolle, Daniel P.; Grandis, Jennifer R.; Kensler, Thomas W.; Johnson, Daniel E.

    2016-01-01

    Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSEs) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared to vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC. PMID:27339168

  13. Carcinogenicity of chromium and chemoprevention: a brief update

    PubMed Central

    Gu, Yuanliang; Song, Xin; Zhao, Jinshun

    2017-01-01

    Chromium has two main valence states: hexavalent chromium (Cr[VI]) and trivalent chromium (Cr[III]). Cr(VI), a well-established human carcinogen, can enter cells by way of a sulfate/phosphate anion-transport system, and then be reduced to lower-valence intermediates consisting of pentavalent chromium (Cr[V]), tetravalent chromium (Cr[IV]) or Cr(III) via cellular reductants. These intermediates may directly or indirectly result in DNA damage or DNA–protein cross-links. Although Cr(III) complexes cannot pass easily through cell membranes, they have the ability to accumulate around cells to induce cell-surface morphological alteration and result in cell-membrane lipid injuries via disruption of cellular functions and integrity, and finally to cause DNA damage. In recent years, more research, including in vitro, in vivo, and epidemiological studies, has been conducted to evaluate the genotoxicity/carcinogenicity induced by Cr(VI) and/or Cr(III) compounds. At the same time, various therapeutic agents, especially antioxidants, have been explored through in vitro and in vivo studies for preventing chromium-induced genotoxicity/carcinogenesis. This review aims to provide a brief update on the carcinogenicity of Cr(VI) and Cr(III) and chemoprevention with different antioxidants. PMID:28860815

  14. [New perspectives in monitoring of exposures to carcinogens].

    PubMed

    Pavanello, Sofia; Lotti, Marcello

    2011-01-01

    Biomonitoring occupational and environmental exposures to carcinogens is a common practice and several biomarkers have been developed for risk assessment. However, in particular, because of the lack of prospective studies, the place of these biomarkers within the complex scenario of the gene-environment interactions leading to cancer cannot be defined. New opportunities and suggestions for biomonitoring exposures to carcinogens could derive from exploring the exposome, from the results of genomewide association and omic studies. Based on these premises it is possible to envisage personalized biomonitoring procedures, as those already actuated in nutrition and clinical oncology, allowing a better predictivity of biomarkers in the preventive settings.

  15. U.S. EPA framework for determining mutagenic mode of action for carcinogens

    EPA Science Inventory

    U.S. EPA's Guidelines for Carcinogen Risk Assessment (Cancer Guidelines) specify that information on a chemical's mode of action (MOA) is key to the risk assessment process. MOA determines conditions under which a chemical is considered to be carcinogenic, appropriate low dose ex...

  16. /sup 32/P-postlabeling assay in mice of transplacental DNA damage induced by the environmental carcinogens safrole, 4-aminobiphenyl, and benzo(a)pyrene

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

    Lu, L.J.; Disher, R.M.; Reddy, M.V.

    1986-06-01

    Transplacental exposure of fetuses to carcinogens is known to induce tumors in the offspring, often with a high incidence and short latency. While covalent adduction of DNA appears to be essential for tumor initiation, little is known about the binding of carcinogens to the DNA of fetal tissues. A sensitive /sup 32/P-postlabeling method enabled us to study the binding of the environmental carcinogens safrole (600 mumol/kg p.o.), 4-aminobiphenyl (800 mumol/kg), and benzo(a)pyrene (200 mumol/kg) to the DNA of various maternal and fetal tissues after administration of test carcinogens to pregnant ICR mice on day 18 of gestation. The results showmore » that these carcinogens bound to the DNA of maternal and fetal liver, lung, kidney, heart, brain, intestine, skin, maternal uterus, and placenta, with organ-specific quantitative and qualitative differences. It was possible for the first time to analyze DNA adduct patterns in minute amounts of tissue, for example those available from fetal heart. The covalent binding index 24 h after safrole treatment was estimated for the different organs and ranged from 0.1 to 247 and 0.1 to 5.8 for maternal and fetal DNA, respectively. Covalent binding index values of 0.2 to 13 and 0.1 to 0.3 for maternal and fetal DNA, respectively, were found for 4-aminobiphenyl. Benzo(a)pyrene treatment yielded covalent binding index values of 0.6 to 6.5 and 0.3 to 0.7 for maternal and fetal DNA, respectively. In both maternal and fetal tissues, safrole exhibited preferential binding to liver DNA. 4-Aminobiphenyl bound preferentially to DNA of maternal liver and kidney but showed no preference among fetal tissues. Benzo(a)pyrene exhibited weak tissue preference in both maternal and fetal organs.« less

  17. Reductive Detoxication of Arylhydroxylamine Carcinogens by Human NADH Cytochrome b5 Reductase and Cytochrome b5

    PubMed Central

    Kurian, Joseph R.; Chin, Nathaniel A.; Longlais, Brett J.; Hayes, Kristie L.; Trepanier, Lauren A.

    2008-01-01

    Heterocyclic and aromatic amine carcinogens are thought to lead to tumor initiation via the formation of DNA adducts, and bioactivation to arylhydroxylamine metabolites is necessary for reactivity with DNA. Carcinogenic arylhydroxylamine metabolites are cleared by a microsomal, NADH-dependent, oxygen-insensitive reduction pathway in humans, which may be a source of inter-individual variability in response to aromatic amine carcinogens. The purpose of this study was to characterize the identity of this reduction pathway in human liver. Based on our findings with structurally similar arylhydroxylamine metabolites of therapeutic drugs, we hypothesized that the reductive detoxication of arylhydroxylamine carcinogens was catalyzed by NADH cytochrome b5 reductase (b5R) and cytochrome b5 (cyt b5). We found that reduction of the carcinogenic hydroxylamines of the aromatic amine 4-aminobiphenyl (4-ABP; found in cigarette smoke) and the heterocyclic amine 2- amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP; found in grilled meats) was indeed catalyzed by a purified system containing only human b5R and cyt b5. Specific activities were 56 to 346-fold higher in the purified system compared to human liver microsomes (HLM), with similar Michaelis-Menten constants (Km values) in both systems. The stoichiometry for b5R and cyt b5 that yielded the highest activity in the purified system was also similar to that found in native HLM (∼1:8 to 1:10). Polyclonal antisera to either b5R or cyt b5 significantly inhibited N-hydroxy-4-aminobiphenyl (NHOH-4-ABP) reduction by 95 and 89%, respectively, and immunoreactive cyt b5 protein content in individual HLM was significantly correlated with individual reduction of both NHOH-4-ABP and N-hydroxy-PhIP (NHOH-PhIP). Finally, titration of HLM into the purified b5R/cyt b5 system did not enhance the efficiency of reduction activity. We conclude that b5R and cyt b5 are together solely capable of the reduction of arylhydroxylamine carcinogens

  18. Is benzene exposure from gasoline carcinogenic?

    PubMed

    Jamall, Ijaz S; Willhite, Calvin C

    2008-02-01

    This article questions the basis for benzene as the carcinogenic surrogate in deriving health risk-based 'clean-up levels' for gasoline-impacted soil and groundwater at leaking underground storage tank properties. The epidemiological evidence suggests that acute myelogenous leukemia (AML) associated with chronic occupational benzene exposure can be best described by sigmoid dose-response relationships. A review of the molecular toxicology and kinetics of benzene points to the existence of threshold mechanisms in the induction of leukemia. The toxicological and epidemiological literature on chronic exposure to unleaded gasoline indicates that the benzene exposures required to induce a measurable carcinogenic response are substantially greater than exposures likely to be encountered from exposure to gasoline at contaminated properties. Thus, assuming that theoretical cancer risks associated with exposure to benzene from gasoline reflect actual health risks associated with such environmental exposures to gasoline and using these theoretical cancer risks and cancer potency factors for benzene to dictate soil and groundwater clean up of gasoline are not scientifically defensible.

  19. Proposed changes in the classification of carcinogenic chemicals in the work area.

    PubMed

    Neumann, H G; Thielmann, H W; Filser, J G; Gelbke, H P; Greim, H; Kappus, H; Norpoth, K H; Reuter, U; Vamvakas, S; Wardenbach, P; Wichmann, H E

    1997-12-01

    Carcinogenic chemicals in the work area are currently classified into three categories in Section III of the German List of MAK and BAT Values. This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these Categories--IIIA1, IIIA2, and IIIB--be retained as Categories 1, 2, and 3, to conform with EU regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, it is now proposed that these three categories be supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not convey a significant risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. It is proposed that chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures be classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose-response relationships and toxicokinetics and for which risk at low doses can be assessed will be classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented. The proposed changes in classifying carcinogenic chemicals in the work area are presented for further discussion.

  20. A proposed framework for consistent regulation of public exposures to radionuclides and other carcinogens

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

    Kocher, D.C.; Hoffman, F.O.

    1991-12-31

    This paper discusses a proposed framework for consistent regulation of carcinogenic risks to the public based on establishing de manifestis (i.e., unacceptable) and de minimis (i.e., trivial) lifetime risks from exposure to any carcinogens at levels of about 10{sup {minus}1}--10{sup {minus}3} and 10{sup {minus}4}--10{sup {minus}6}, respectively, and reduction of risks above de minimis levels as low as reasonably achievable (ALARA). We then discuss certain differences in the way risks from exposure to radionuclides and other carcinogens currently are regulated or assessed which would need to be considered in implementing the proposed regulatory framework for all carcinogens.

  1. A proposed framework for consistent regulation of public exposures to radionuclides and other carcinogens

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

    Kocher, D.C.; Hoffman, F.O.

    1991-01-01

    This paper discusses a proposed framework for consistent regulation of carcinogenic risks to the public based on establishing de manifestis (i.e., unacceptable) and de minimis (i.e., trivial) lifetime risks from exposure to any carcinogens at levels of about 10{sup {minus}1}--10{sup {minus}3} and 10{sup {minus}4}--10{sup {minus}6}, respectively, and reduction of risks above de minimis levels as low as reasonably achievable (ALARA). We then discuss certain differences in the way risks from exposure to radionuclides and other carcinogens currently are regulated or assessed which would need to be considered in implementing the proposed regulatory framework for all carcinogens.

  2. Universal structural parameter to quantitatively predict metallic glass properties

    DOE PAGES

    Ding, Jun; Cheng, Yong-Qiang; Sheng, Howard; ...

    2016-12-12

    Quantitatively correlating the amorphous structure in metallic glasses (MGs) with their physical properties has been a long-sought goal. Here we introduce flexibility volume' as a universal indicator, to bridge the structural state the MG is in with its properties, on both atomic and macroscopic levels. The flexibility volume combines static atomic volume with dynamics information via atomic vibrations that probe local configurational space and interaction between neighbouring atoms. We demonstrate that flexibility volume is a physically appropriate parameter that can quantitatively predict the shear modulus, which is at the heart of many key properties of MGs. Moreover, the new parametermore » correlates strongly with atomic packing topology, and also with the activation energy for thermally activated relaxation and the propensity for stress-driven shear transformations. These correlations are expected to be robust across a very wide range of MG compositions, processing conditions and length scales.« less

  3. 78 FR 68849 - Draft Current Intelligence Bulletin “Update of NIOSH Carcinogen Classification and Target Risk...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-15

    ...; Docket Number NIOSH 240-A] Draft Current Intelligence Bulletin ``Update of NIOSH Carcinogen... document for public comment entitled ``Current Intelligence Bulletin: Update of NIOSH Carcinogen... obtain comments on the draft document, ``Current Intelligence Bulletin: Update of NIOSH Carcinogen...

  4. Identifying carcinogens: the tobacco industry and regulatory politics in the United States.

    PubMed

    Cook, Daniel M; Bero, Lisa A

    2006-01-01

    The process of identifying carcinogens for purposes of health and safety regulation has been contested internationally. The U.S. government produces a "Report on Carcinogens" every two years, which lists known and likely human carcinogenic substances. In the late 1990s the tobacco industry responded to the proposed listing of secondhand smoke with a multi-part strategy. Despite industry efforts to challenge both the substance of the report and the agency procedures, environmental tobacco smoke was declared by the agency in 2000 to be a known human carcinogen. A subsequent lawsuit, launched by chemical interests but linked to the tobacco industry, failed, but it produced a particular legal precedent of judicial review that is favorable to all regulated industries. The authors argue that, in this case, tobacco industry regulation contradicts academic expectations of business regulatory victories. However, the tobacco industry's participation in the regulatory process influenced the process in favor of all regulated industry.

  5. [D.lgsl. 625/1994--Protection against carcinogenic agents: the obligation to educate].

    PubMed

    Fucci, P; Anselmi, E; Bracci, C; Comba, P

    1997-01-01

    According to act 626/1994, employers have the duty to inform and train workers and their representatives. The implementation of training activities requires the following points: planning the training program according to the needs of the target population, use of the methods aimed at promoting learning and the adoption of safe behaviour, setting-up of evaluation tools. The disciplines of risk perception and communication and adult training may provide useful contribution in this frame. At the light of the preliminary experiences in this field, the importance of the following items for workers, workers representatives and employers is emphasized: probabilistic causality models, role of cognitive and emotional factors in the learning process, definition of carcinogenic according to national and international organisation, meaning of TLV with respect to carcinogenic exposure, interaction between carcinogens in the case of multiple exposition, risk evaluation, preventive measures, transfer of carcinogen risk from workplace to domestic environment, due to lack of compliance with basic hygienic rules such proper use of work clothes.

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  8. Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane.

    PubMed

    Bauman, Julie E; Zang, Yan; Sen, Malabika; Li, Changyou; Wang, Lin; Egner, Patricia A; Fahey, Jed W; Normolle, Daniel P; Grandis, Jennifer R; Kensler, Thomas W; Johnson, Daniel E

    2016-07-01

    Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSE) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared with vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC. Cancer Prev Res; 9(7); 547-57. ©2016 AACR. ©2016 American Association for Cancer Research.

  9. Studies on carcinogenic and toxic effects of ochratoxin A in chicks.

    PubMed

    Stoev, Stoycho D

    2010-04-01

    Carcinogenic/toxic effects of ochratoxin A (OTA) in various internal organs of Plymouth Rock chicks were determined. The number of OTA-induced neoplasms was similar in chicks given 25 ppm L-β-phenylalanine (PHE) in addition to 5 ppm OTA compared to chicks given only 5 ppm OTA, which showed that PHE cannot be used as a real protector against the carcinogenic or toxic effects of OTA in chicks. OTA was found to provoke strong degenerative changes in liver and kidneys, degenerative changes and depletion of cells in lymphoid organs, oedematous and degenerative changes in the brain, muscular haemorrhages and fatty changes in the bone marrow. The target organs for carcinogenic effect of OTA in chicks were found to be kidneys and liver.

  10. Evidence of carcinogenicity in humans of water-soluble nickel salts

    PubMed Central

    2010-01-01

    Background Increased risks of nasal cancer and lung cancer in nickel refiners have been investigated scientifically and discussed since they were detected in the 1930s. Nickel compounds are considered to be the main cause of the cancer excess. Parts of the nickel producing industry and their consultants oppose the classification of water-soluble nickel salts as human carcinogens, and argue that the risk in exposed workers should be ascribed to other occupational exposures and smoking. Discussion Respiratory cancer risks in Welsh, Finnish, and Norwegian nickel refiners add to the evidence of carcinogenicity of water-soluble nickel. In Norwegian refiners, the first epidemiological study in 1973 identified high risks of lung cancer and nasal cancer among long-term electrolysis workers. Risk analyses based on exposure estimates developed in the 1980s supported the view that water-soluble nickel compounds were central in the development of cancer. Recently, new exposure estimates were worked out for the same cohort based on personal monitoring of total nickel and chemical determination of four forms of nickel. Additional data have been collected on life-time smoking habits, and on exposure to arsenic, asbestos, sulphuric acid mists, cobalt, and occupational lung carcinogens outside the refinery. After adjustment for these potential confounding exposures in case-control analyses, the risk pattern added to the evidence of an important role of water-soluble nickel compounds as causes of lung cancer. These Norwegian cancer studies rely on national Cancer Registry data, considered close to complete from 1953 onwards; and on National Population Register data continuously updated with mortality and emigration. Canadian mortality studies--perceived to offer the strongest support to the industry position not to recognise carcinogenicity of water-soluble nickel--appear to suffer from limitations in follow-up time, loss to follow-up, absence of risk analysis with individual

  11. The Role of Tobacco-Derived Carcinogens in Pancreas Cancer

    PubMed Central

    Lochan, Rajiv; Reeves, Helen L.; Daly, Anne K.; Charnley, Richard M.

    2011-01-01

    The extremely poor outcome from pancreas cancer is well known. However, its aetiology less well appreciated, and the molecular mechanisms underlying this are poorly understood. Tobacco usage is one of the strongest risk factors for this disease, and this is a completely avoidable hazard. In addition, there are well described hereditary diseases which predispose, and familial pancreas cancer. We have sought here to summarise the role of tobacco-derived carcinogens and the mode of their tumorigenic action on the pancreas. There is compelling evidence from animal and human studies (laboratory including cell line studies and epidemiologic) that tobacco derived carcinogens cause pancreas cancer. However, the manner in which they do so is not entirely apparent. There is also compelling evidence that synergism with genetic and other life-style factors—like diet obesity—results in a multifactorial causation of the disease. Ascertaining the role of tobacco carcinogens in the development of this cancer and their interaction with other risk factors will enable novel therapeutic and preventative strategies to improve outcome from this appalling malignancy. PMID:22084727

  12. Binding of environmental carcinogens to asbestos and mineral fibres.

    PubMed Central

    Harvey, G; Pagé, M; Dumas, L

    1984-01-01

    A rapid method has been developed for measuring the binding capacity of asbestos and other mineral fibres for environmental carcinogens. Benzo(alpha)pyrene (B(alpha)P), nitrosonornicotine (NNN), and N-acetyl-2-aminofluorene (NAAF) were assayed in the presence of Canadian grade 4T30 chrysotile, chrysotile A, amosite, crocidolite, glass microfibres, glasswool, attapulgite, and titanium dioxide. Chrysotile binds significantly more carcinogens than the other mineral fibres. This binding assay is reproducible with coefficients of variation of less than 8% and 6% respectively for inter and intra assay. The influence of pH was also studied, and there is good correlation between the carcinogen binding and the charge of the tested mineral fibres. The in vitro cytotoxicity on macrophage like cell line P388D1 and the haemolytic activity of various mineral fibres were also measured; a good correlation was found between the binding capacity and the cytotoxicity of tested mineral fibres on P388D1 cells. These results give some explanations for the reported synergism between exposure to asbestos and the smoking habits of workers. PMID:6331497

  13. OVERVIEW OF DRINKING WATER MUTAGENICITY AND CARCINOGENICITY AND RISK FOR BLADDER CANCER

    EPA Science Inventory

    Among the 11 disinfection by-products (DBPs) in drinking water that are regulated by the U.S. EPA, (a) 2 DBPs (chloroacetic acid and chlorite) are not carcinogenic-in either of 2 species; (b) chlorite is not carcinogenic in 3 rodent assays and has never been tested for genotoxici...

  14. Reproducibility of Quantitative Structural and Physiological MRI Measurements

    DTIC Science & Technology

    2017-08-09

    per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and...Journal Article 3. DATES COVERED (From – To) January 2015 – July 2017 4. TITLE AND SUBTITLE Reproducibility of Quantitative Structural and...NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) USAF School of Aerospace Medicine Aeromedical Research Dept/FHOH 2510 Fifth St., Bldg

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

    PubMed

    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.

  16. Partitioning and lipophilicity in quantitative structure-activity relationships.

    PubMed Central

    Dearden, J C

    1985-01-01

    The history of the relationship of biological activity to partition coefficient and related properties is briefly reviewed. The dominance of partition coefficient in quantitation of structure-activity relationships is emphasized, although the importance of other factors is also demonstrated. Various mathematical models of in vivo transport and binding are discussed; most of these involve partitioning as the primary mechanism of transport. The models describe observed quantitative structure-activity relationships (QSARs) well on the whole, confirming that partitioning is of key importance in in vivo behavior of a xenobiotic. The partition coefficient is shown to correlate with numerous other parameters representing bulk, such as molecular weight, volume and surface area, parachor and calculated indices such as molecular connectivity; this is especially so for apolar molecules, because for polar molecules lipophilicity factors into both bulk and polar or hydrogen bonding components. The relationship of partition coefficient to chromatographic parameters is discussed, and it is shown that such parameters, which are often readily obtainable experimentally, can successfully supplant partition coefficient in QSARs. The relationship of aqueous solubility with partition coefficient is examined in detail. Correlations are observed, even with solid compounds, and these can be used to predict solubility. The additive/constitutive nature of partition coefficient is discussed extensively, as are the available schemes for the calculation of partition coefficient. Finally the use of partition coefficient to provide structural information is considered. It is shown that partition coefficient can be a valuable structural tool, especially if the enthalpy and entropy of partitioning are available. PMID:3905374

  17. Quantitative structure-property relationship (correlation analysis) of phosphonic acid-based chelates in design of MRI contrast agent.

    PubMed

    Tiwari, Anjani K; Ojha, Himanshu; Kaul, Ankur; Dutta, Anupama; Srivastava, Pooja; Shukla, Gauri; Srivastava, Rakesh; Mishra, Anil K

    2009-07-01

    Nuclear magnetic resonance imaging is a very useful tool in modern medical diagnostics, especially when gadolinium (III)-based contrast agents are administered to the patient with the aim of increasing the image contrast between normal and diseased tissues. With the use of soft modelling techniques such as quantitative structure-activity relationship/quantitative structure-property relationship after a suitable description of their molecular structure, we have studied a series of phosphonic acid for designing new MRI contrast agent. Quantitative structure-property relationship studies with multiple linear regression analysis were applied to find correlation between different calculated molecular descriptors of the phosphonic acid-based chelating agent and their stability constants. The final quantitative structure-property relationship mathematical models were found as--quantitative structure-property relationship Model for phosphonic acid series (Model 1)--log K(ML) = {5.00243(+/-0.7102)}- MR {0.0263(+/-0.540)}n = 12 l r l = 0.942 s = 0.183 F = 99.165 quantitative structure-property relationship Model for phosphonic acid series (Model 2)--log K(ML) = {5.06280(+/-0.3418)}- MR {0.0252(+/- .198)}n = 12 l r l = 0.956 s = 0.186 F = 99.256.

  18. Quantitative Restoration of the Evolution of Mantle Structures Using Data Assimilation

    NASA Astrophysics Data System (ADS)

    Ismail-Zadeh, A.; Schubert, G.; Tsepelev, I.

    2008-12-01

    Rapid progress in imaging deep Earth structures and in studies of physical and chemical properties of mantle rocks facilitates research in assimilation of data related to mantle dynamics. We present a quantitative approach to assimilation of geophysical and geodetic data, which allows for incorporating observations and unknown initial conditions for mantle temperature and flow into a three-dimensional dynamic model in order to determine the initial conditions in the geological past. Once the conditions are determined the evolution of mantle structures can be restore backward in time. We apply data assimilation techniques to model the evolution of mantle plumes and lithospheric slabs. We show that the geometry of the mantle structures changes with time diminishing the degree of surface curvature of the structures, because the heat conduction smoothes the complex thermal surfaces of mantle bodies with time. Present seismic tomography images of mantle structures do not allow definition of the sharp shapes of these structures. Assimilation of mantle temperature and flow to the geological past instead provides a quantitative tool to restore thermal shapes of prominent structures in the past from their diffusive shapes at present.

  19. The carcinogenic action of crystalline silica: a review of the evidence supporting secondary inflammation-driven genotoxicity as a principal mechanism.

    PubMed

    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

  20. Genotoxicity and carcinogenicity of cobalt-, nickel- and copper-based nanoparticles

    PubMed Central

    MAGAYE, RUTH; ZHAO, JINSHUN; BOWMAN, LINDA; DING, MIN

    2012-01-01

    The nanotechnology industry has matured and expanded at a rapid pace in the last decade, leading to the research and development of nanomaterials with enormous potential. The largest source of these nanomaterials is the transitional metals. It has been revealed that numerous properties of these nano-sized elements are not present in their bulk states. The nano size of these particles means they are easily transported into biological systems, thus, raising the question of their effects on the susceptible systems. Although advances have been made and insights have been gained on the effect of transitional metals on susceptible biological systems, there still is much ground to be covered, particularly with respect to our knowledge on the genotoxic and carcinogenic effects. Therefore, this review intends to summarize the current knowledge on the genotoxic and carcinogenic potential of cobalt-, nickel- and copper-based nanoparticles indicated in in vitro and in vivo mammalian studies. In the present review, we briefly state the sources, use and exposure routes of these nanoparticles and summarize the current literature findings on their in vivo and in vitro genotoxic and carcinogenic effects. Due to the increasing evidence of their role in carcinogenicity, we have also included studies that have reported epigenetic factors, such as abnormal apoptosis, enhanced oxidative stress and pro-inflammatory effects involving these nanoparticles. PMID:23170105

  1. The limits of two-year bioassay exposure regimens for identifying chemical carcinogens.

    PubMed

    Huff, James; Jacobson, Michael F; Davis, Devra Lee

    2008-11-01

    Chemical carcinogenesis bioassays in animals have long been recognized and accepted as valid predictors of potential cancer hazards to humans. Most rodent bioassays begin several weeks after birth and expose animals to chemicals or other substances, including workplace and environmental pollutants, for 2 years. New findings indicate the need to extend the timing and duration of exposures used in the rodent bioassay. In this Commentary, we propose that the sensitivity of chemical carcinogenesis bio-assays would be enhanced by exposing rodents beginning in utero and continuing for 30 months (130 weeks) or until their natural deaths at up to about 3 years. Studies of three chemicals of different structures and uses-aspartame, cadmium, and toluene-suggest that exposing experimental animals in utero and continuing exposure for 30 months or until their natural deaths increase the sensitivity of bioassays, avoid false-negative results, and strengthen the value and validity of results for regulatory agencies. Government agencies, drug companies, and the chemical industry should conduct and compare the results of 2-year bioassays of known carcinogens or chemicals for which there is equivocal evidence of carcinogenicity with longer-term studies, with and without in utero exposure. If studies longer than 2 years and/or with in utero exposure are found to better identify potential human carcinogens, then regulatory agencies should promptly revise their testing guidelines, which were established in the 1960s and early 1970s. Changing the timing and dosing of the animal bioassay would enhance protection of workers and consumers who are exposed to potentially dangerous workplace or home contaminants, pollutants, drugs, food additives, and other chemicals throughout their lives.

  2. The Limits of Two-Year Bioassay Exposure Regimens for Identifying Chemical Carcinogens

    PubMed Central

    Huff, James; Jacobson, Michael F.; Davis, Devra Lee

    2008-01-01

    Background Chemical carcinogenesis bioassays in animals have long been recognized and accepted as valid predictors of potential cancer hazards to humans. Most rodent bioassays begin several weeks after birth and expose animals to chemicals or other substances, including workplace and environmental pollutants, for 2 years. New findings indicate the need to extend the timing and duration of exposures used in the rodent bioassay. Objectives In this Commentary, we propose that the sensitivity of chemical carcinogenesis bio-assays would be enhanced by exposing rodents beginning in utero and continuing for 30 months (130 weeks) or until their natural deaths at up to about 3 years. Discussion Studies of three chemicals of different structures and uses—aspartame, cadmium, and toluene—suggest that exposing experimental animals in utero and continuing exposure for 30 months or until their natural deaths increase the sensitivity of bioassays, avoid false-negative results, and strengthen the value and validity of results for regulatory agencies. Conclusions Government agencies, drug companies, and the chemical industry should conduct and compare the results of 2-year bioassays of known carcinogens or chemicals for which there is equivocal evidence of carcinogenicity with longer-term studies, with and without in utero exposure. If studies longer than 2 years and/or with in utero exposure are found to better identify potential human carcinogens, then regulatory agencies should promptly revise their testing guidelines, which were established in the 1960s and early 1970s. Changing the timing and dosing of the animal bioassay would enhance protection of workers and consumers who are exposed to potentially dangerous workplace or home contaminants, pollutants, drugs, food additives, and other chemicals throughout their lives. PMID:19057693

  3. Quantitative aspects of the causes of the main human cancers in the light of initiating and promoting mechanisms.

    PubMed

    Weisburger, J H

    1985-02-01

    The early work in the field of chemical carcinogenesis accomplished by Dr. Boyland has provided us with key concepts that can be applied today in the prevention of many kinds of human cancer. Broad understanding of the complex processes of cancer causation was achieved in the last 50 years. Thus, research on the action of chemical carcinogens through their reactive metabolites, the detection of such agents through rapid in vitro bioassays by the product of their interaction with DNA, and the consequences related thereto, has been applied to the qualitative and quantitative implications of such an interaction in relation to the etiology of human cancers. Beginning knowledge of the mechanisms of tumor promotion provides further means of controlling neoplastic processes because of the distinct qualitative and quantitative properties of promoters. The promotion phenomenon contributes extensively to the development of human cancer of the lung and nutritionally-linked cancers such as those in the colon, breast, or prostate. Their quantitative effects may be easier to limit than those due to genotoxic carcinogens, which would help substantially to lower the incidence of these important cancers.

  4. It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco

    PubMed Central

    Hecht, Stephen S.

    2014-01-01

    The Family Smoking Prevention and Tobacco Control Act gives the Food and Drug Administration power to regulate tobacco products. This commentary calls for immediate regulation of the carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N’-nitrosonornicotine (NNN) in cigarette tobacco as a logical path to cancer prevention. NNK and NNN, powerful carcinogens in laboratory animals, have been evaluated as “carcinogenic to humans” by the International Agency for Research on Cancer. NNK and NNN are present in the tobacco of virtually all marketed cigarettes; levels in cigarette smoke are directly proportional to the amounts in tobacco. The NNK metabolite NNAL, itself a strong carcinogen, is present in the urine of smokers and non-smokers exposed to secondhand smoke. Some of the highest levels of NNK and NNN are found in U.S. products. It is well established that factors such as choice of tobacco blend, agricultural conditions, and processing methods influence levels of NNK and NNN in cigarette tobacco and cigarette smoke. Therefore, it is time to control these factors and produce cigarettes with 100 ppb or less each of NNK and NNN in tobacco, which would result in an approximate 15-20 fold reduction of these carcinogens in the mainstream smoke of popular cigarettes sold in the United States. PMID:24806664

  5. Replication of a carcinogenic nitropyrene DNA lesion by human Y-family DNA polymerase

    PubMed Central

    Kirouac, Kevin N.; Basu, Ashis K.; Ling, Hong

    2013-01-01

    Nitrated polycyclic aromatic hydrocarbons are common environmental pollutants, of which many are mutagenic and carcinogenic. 1-Nitropyrene is the most abundant nitrated polycyclic aromatic hydrocarbon, which causes DNA damage and is carcinogenic in experimental animals. Error-prone translesion synthesis of 1-nitropyrene–derived DNA lesions generates mutations that likely play a role in the etiology of cancer. Here, we report two crystal structures of the human Y-family DNA polymerase iota complexed with the major 1-nitropyrene DNA lesion at the insertion stage, incorporating either dCTP or dATP nucleotide opposite the lesion. Polι maintains the adduct in its active site in two distinct conformations. dCTP forms a Watson–Crick base pair with the adducted guanine and excludes the pyrene ring from the helical DNA, which inhibits replication beyond the lesion. By contrast, the mismatched dATP stacks above the pyrene ring that is intercalated in the helix and achieves a productive conformation for misincorporation. The intra-helical bulky pyrene mimics a base pair in the active site and facilitates adenine misincorporation. By structure-based mutagenesis, we show that the restrictive active site of human polη prevents the intra-helical conformation and A-base misinsertions. This work provides one of the molecular mechanisms for G to T transversions, a signature mutation in human lung cancer. PMID:23268450

  6. Aberrant activation of M phase proteins by cell proliferation-evoking carcinogens after 28-day administration in rats.

    PubMed

    Yafune, Atsunori; Taniai, Eriko; Morita, Reiko; Hayashi, Hitomi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2013-06-07

    We have previously reported that hepatocarcinogens increase liver cells expressing p21(Cip1), a G1 checkpoint protein and M phase proteins after 28-day treatment in rats. This study aimed to identify early prediction markers of carcinogens available in many target organs after 28-day treatment in rats. Immunohistochemical analysis was performed on Ki-67, p21(Cip1) and M phase proteins [nuclear Cdc2, phospho-Histone H3 (p-Histone H3), Aurora B and heterochromatin protein 1α (HP1α)] with carcinogens targeting different organs. Carcinogens targeting thyroid (sulfadimethoxine; SDM), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole; BHA), glandular stomach (catechol; CC), and colon (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and chenodeoxycholic acid) were examined using a non-carcinogenic toxicant (caprolactam) and carcinogens targeting other organs as negative controls. All carcinogens increased Ki-67(+), nuclear Cdc2(+), p-Histone H3(+) or Aurora B(+) carcinogenic target cells, except for both colon carcinogens, which did not increase cell proliferation. On the other hand, p21(Cip1+) cells increased with SDM and CC. HP1α responded only to BHA. Results revealed carcinogens evoking cell proliferation concurrently induced cell cycle arrest at M phase or showing chromosomal instability reflecting aberration in cell cycle regulation, irrespective of target organs, after 28-day treatment. Therefore, M phase proteins may be early prediction markers of carcinogens evoking cell proliferation in many target organs. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  7. Interaction between carcinogenic and anti-carcinogenic trace elements in the scalp hair samples of different types of Pakistani female cancer patients.

    PubMed

    Wadhwa, Sham Kumar; Kazi, Tasneem Gul; Afridi, Hassan Imran; Talpur, Farah Naz; Naeemullah

    2015-01-15

    It was investigated that carcinogenic processes are linked with the imbalances of essential trace and toxic elements in body fluid and tissues of human. In this study, the relationship between carcinogenic elements, arsenic (As), cadmium (Cd), and nickel (Ni), and anti-carcinogenic elements, selenium (Se) and zinc (Zn), in the scalp hair of different female cancer patients (breast, cervix, mouth and ovarian) was studied. The scalp hair samples were collected from cancer patients and referent female subjects of the same age group and socioeconomic status. The scalp hair samples were oxidized by 65% nitric acid and 30% hydrogen peroxide by microwave oven and analyzed by atomic absorption spectrometry. The validity and accuracy of the methodology were checked using certified reference material of human hair (BCR 397). The mean concentrations of As, Cd, and Ni were found to be significantly higher in the scalp hair samples of cancerous patients as compared to referents, while reverse results were obtained in the case of Zn and Se (p<0.01). The study revealed that low level of trace elements (Se, Zn) and high level of heavy elements (As, Cd, and Ni) were associated with increased risk of cancer. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. [QUANTITATIVE DNA EVALUATION OF THE HIGH CARCINOGENIC RISK OF HUMAN PAPILLOMA VIRUSES AND HUMAN HERPES VIRUSES IN MALES WITH FERTILITY DISORDERS].

    PubMed

    Evdokimov, V V; Naumenko, V A; Tulenev, Yu A; Kurilo, L F; Kovalyk, V P; Sorokina, T M; Lebedeva, A L; Gomberg, M A; Kushch, A A

    2016-01-01

    Infertility is an actual medical and social problem. In 50% of couples it is associated with the male factor and in more than 50% of cases the etiology of the infertility remains insufficiently understood. The goal of this work was to study the prevalence and to perform quantitative analysis of the human herpes viruses (HHV) and high carcinogenic risk papilloma viruses (HR HPV) in males with infertility, as well as to assess the impact of these infections on sperm parameters. Ejaculate samples obtained from 196 males fall into 3 groups. Group 1 included men with the infertility of unknown etiology (n = 112); group 2, patients who had female partners with the history of spontaneous abortion (n = 63); group 3 (control), healthy men (n = 21). HHV and HR HPV DNA in the ejaculates were detected in a total of 42/196 (21.4%) males: in 31 and 11 patients in groups 1 and 2, respectively (p > 0.05) and in none of healthy males. HHV were detected in 24/42; HR HPV, in 18/42 males (p > 0.05) without significant difference between the groups. Among HR HPV genotypes of the clade A9 in ejaculate were more frequent (14/18, p = 0.04). Comparative analysis of the sperm parameters showed that in the ejaculates of the infected patients sperm motility as well as the number of morphologically normal cells were significantly reduced compared with the healthy men. The quantification of the viral DNA revealed that in 31% of the male ejaculates the viral load was high: > 3 Ig10/100000 cells. Conclusion. The detection of HHV and HR HPV in the ejaculate is associated with male infertility. Quantification of the viral DNA in the ejaculate is a useful indicator for monitoring viral infections in infertility and for decision to start therapy.

  9. Prevalence of occupational exposure to carcinogens among workers of Arabic, Chinese and Vietnamese ancestry in Australia.

    PubMed

    Boyle, Terry; Carey, Renee N; Glass, Deborah C; Peters, Susan; Fritschi, Lin; Reid, Alison

    2015-09-01

    Although job-related diseases result in more deaths per year than job-related injuries, most research concerning ethnic minority workers has concerned accidents and injuries rather than disease-causing exposures such as carcinogens. We conducted a telephone-based cross-sectional survey to estimate the prevalence of occupational exposure to carcinogens among a sample of ethnic minority workers in Australia, and compared their exposure prevalence to that of a sample of the general Australian-born working population ('Australian workers'). One-third of the ethnic minority workers were exposed to at least one carcinogen at work. The likelihood of exposure to carcinogens was not significantly different from that of Australian workers, although the likelihood of exposure to individual carcinogens varied by ethnicity. Knowing the prevalence of exposure to carcinogens in the workplace in different ethnic groups will allow better targeted and informed occupational health and safety measures to be implemented where necessary. © 2015 Wiley Periodicals, Inc.

  10. Carcinogenicity and mode of action evaluation for alpha-hexachlorocyclohexane: Implications for human health risk assessment.

    PubMed

    Bradley, Ann E; Shoenfelt, Joanna L; Durda, Judi L

    2016-04-01

    Alpha-hexachlorocyclohexane (alpha-HCH) is one of eight structural isomers that have been used worldwide as insecticides. Although no longer produced or used agriculturally in the United States, exposure to HCH isomers is of continuing concern due to legacy usage and persistence in the environment. The U.S. Environmental Protection Agency (EPA) classifies alpha-HCH as a probable human carcinogen and provides a slope factor of 6.3 (mg/kg-day)(-1) for the compound, based on hepatic nodules and hepatocellular carcinomas observed in male mice and derived using a default linear approach for modeling carcinogens. EPA's evaluation, last updated in 1993, does not consider more recently available guidance that allows for the incorporation of mode of action (MOA) for determining a compound's dose-response. Contrary to the linear approach assumed by EPA, the available data indicate that alpha-HCH exhibits carcinogenicity via an MOA that yields a nonlinear, threshold dose-response. In our analysis, we conducted an MOA evaluation and dose-response analysis for alpha-HCH-induced liver carcinogenesis. We concluded that alpha-HCH causes liver tumors in rats and mice through an MOA involving increased promotion of cell growth, or mitogenesis. Based on these findings, we developed a threshold, cancer-based, reference dose (RfD) for alpha-HCH. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Report on carcinogens monograph on cumene.

    PubMed

    2013-09-01

    The National Toxicology Program conducted a cancer evaluation on cumene for possible listing in the Report on Carcinogens (RoC). The cancer evaluation is captured in the RoC monograph, which was peer reviewed in a public forum. The monograph consists of two components: (Part 1) the cancer evaluation, which reviews the relevant scientific information, assesses its quality, applies the RoC listing criteria to the scientific information, and provides the NTP recommendation for listing status for cumene in the RoC, and (Part 2) the substance profile proposed for the RoC, containing the NTP's listing status recommendation, a summary of the scientific evidence considered key to reaching that decision, and data on properties, use, production, exposure, and Federal regulations and guidelines to reduce exposure to cumene. This monograph provides an assessment of the available scientific information on cumene, including human exposure and properties, disposition and toxicokinetics, cancer studies in experimental animals, and studies of mechanisms and other related effects, including relevant toxicological effects, genetic toxicology, and mechanisms of carcinogenicity. From this assessment, the NTP recommended that cumene be listed as reasonably anticipated to be a human carcinogen in the RoC based on sufficient evidence from studies in experimental animals, which found that cumene exposure caused lung tumors in male and female mice and liver tumors in female mice. Several proposed mechanisms of carcinogenesis support the relevance to humans of the lung and liver tumors observed in experimental animals. Specifically, there is evidence that humans and experimental animals metabolize cumene through similar metabolic pathways. In addition, mutations of the K-ras oncogene and p53 tumor-suppressor gene observed in cumene-induced lung tumors in mice, along with altered expression of many other genes, resemble molecular alterations found in human lung and other cancers.

  12. Evaluation of the dermal carcinogenicity of lubricant base oils by the mouse skin painting bioassay and other proposed methods.

    PubMed

    Chasey, K L; McKee, R H

    1993-01-01

    Lubricant base oils are petroleum products that are predominantly derived from the vacuum distillation of crude oil. Various types of refinement can be employed during the manufacturing process, and evidence suggests that certain of the associated process streams produce skin cancer. Polycyclic aromatic compounds (PACs), some of which are considered as the causative agents, are removed, concentrated or chemically converted during the refinement process. In order to understand the effects of various types of refinement processes on carcinogenic potential, 94 oils were evaluated in the mouse epidermal cancer bioassay. This Exxon database is unique, because of the wide range of crude oils and processing histories represented. Seven processing history classifications are described, and conclusions concerning the impacts of each refinement process on dermal carcinogenicity are discussed. This research also included an evaluation of selected biological and chemical test methods for predicting carcinogenic potential. These included a modified version of the Ames test for mutagenicity, as well as analytical characterizations of the polycyclic aromatic structures in the oils. For classification purposes, a sample was considered to be carcinogenic if it resulted in the production of two or more tumor-bearing animals (in test groups of either 40 or 50 animals). The modified Ames test was considered to be positive if the mutagenicity index was > or = 2.0, and PAC analyses were similarly designated as positive or negative according to proposed guidelines. All of the alternative test methods showed similar agreement with dermal carcinogenicity bioassay data; concordance values were > or = 80%. However, each test was incorrect in ca. 10%-20% of the cases evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

    PubMed Central

    Chappell, Grace; Pogribny, Igor P.; Guyton, Kathryn Z.; Rusyn, Ivan

    2016-01-01

    Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as “carcinogenic to humans” (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments. PMID:27234561

  14. Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review.

    PubMed

    Chappell, Grace; Pogribny, Igor P; Guyton, Kathryn Z; Rusyn, Ivan

    2016-01-01

    Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as "carcinogenic to humans" (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    PubMed

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

    2014-05-01

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

  16. Ozonation of mutagenic and carcinogenic polyaromatic amines and polyaromatic hydrocarbons in water

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

    Burleson, G.R.; Caulfield, M.J.; Pollard, M.

    1979-06-01

    The Salmonella-microsome assay for mutagenesis was used to determine the effect of ozone on the mutagenesis of selected carcinogens and mutagens in water. Short periods of ozonation were shown to completely inactivate the mutagenicity of several polyaromatic amine mutagens including acriflavine, proflavine, and beta-naphthylamine. Selected polyaromatic hydrocarbons were also sensitive to ozonation. Kinetic studies revealed that the mutagenicity of benzo(a)pyrene, 3-methylcholanthrene, and 7,12-dimethylbenz(a)anthracene was destroyed after short periods of ozonation. To correlate loss of mutagenicity with loss of carcinogenicity, two polyaromatic hydrocarbons were treated with ozone, extracted from water with hexane, and tested for carcinogenicity in mice. When 7,12-dimethyl-benz(a)anthracene andmore » 3-methyl-cholanthrene were treated with ozone, there was a substantial reduction in carcinogenicity compared to control groups treated with oxygen alone. However, a small number of tumors developed in the group of animals receiving a hexane extract of ozonated 7,12-dimethylbenz(a)anthracene. This activity may be due to breakdown products of 7,12-dimethylbenz(a)anthracene that are not mutagenic.« less

  17. Availability of epidemiologic data on humans exposed to animal carcinogens. II. Chemical uses and production volume

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

    Karstadt, M.; Bobal, R.

    1982-01-01

    We report further findings of a survey of manufacturers, processors, and importers of chemicals determined by the International Agency for Research on Cancer (IARC) to be animal carcinogens, but whose carcinogenicity in humans was considered uncertain because of inadequate epidemiologic data. We requested epidemiologic studies from the companies marketing or using any of the 75 IARC animal carcinogens in commerce in the United States. Eighteen of the 75 IARC animal carcinogens had volumes listed of 10(6) lb/year or greater, with 8 of the 13 chemicals for which studies had been completed or are in progress in this ''high volume'' category.more » The use category with the largest number of chemicals was drugs--19 of the 75 IARC animal carcinogens were in this category. However, none of the 13 chemicals included in epidemiologic studies was a drug. Seven of the 13 chemicals included in studies were used primarily as pesticides. We received little information on dyes and dye intermediates, experimental carcinogens, and drugs, all of which are produced in relatively low volumes; these categories represent 42 of the 75 IARC animal carcinogens. Low volumes and declining usage/production appear to be barriers to performance of epidemiologic studies. Information we received suggests that sometimes the problem of low production volume may be avoided by studying users rather than production workers. Overall, however, we expect few additional epidemiologic studies of the 75 IARC animal carcinogens.« less

  18. [Carcinogenic N-nitrosamines in the tire industry].

    PubMed

    Sokol?kaia, N N; Krivosheeva, L V; Khesing, A Ia; Piven, V A; Kavun, S M

    1993-01-01

    The level of volatile carcinogenic N-nitrosamines (NA) was studied in the air of various technological sites of tyre production. Reported total levels of NA in air exceeded MACs set in certain countries for the same enterprises. For example, German total MAC for 12 carcinogenic NA is 1 g/m3. N-nitrosomorpholine appeared to have the highest level (91 g/m3), probably, because its derivatives are used as raw material for technological process. Relative rate of volatile NA release from rubber samples containing 4-nitrosodiphenylamine (modifier) was studied. The parameter was reported to have no influence on NA outlet in conditions simulating technological process. NA was detected by means of gas chromatography with thermal energy detector TEA 502A provided by Thermo Electron Corporation, USA. The article necessitates regulation of NA in tyre production and better rubber mixtures to control the pollution of atmosphere.

  19. Dietary Carcinogens and Breast Cancer.

    DTIC Science & Technology

    1997-07-01

    11) proposed that L-proyl-tRNA synthetase could esterify N-hydroxy heterocyclic amines and that ATP was required to add the amino acid to the 16...need to be depleted of endogenous amino acids . To test this notion, tRNA synthetase substrates were removed by dialysis in one experiment, and activation...carcinogens in pyrolysates of amino acids and proteins and cooked foods: heterocyclic aromatic amines. In: Y.T. Woo (ed.) Chemical Induction of Cancer

  20. Mequindox Induced Genotoxicity and Carcinogenicity in Mice

    PubMed Central

    Liu, Qianying; Lei, Zhixin; Wu, Qin; Huang, Deyu; Xie, Shuyu; Wang, Xu; Pan, Yuanhu; Yuan, Zonghui

    2018-01-01

    Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N-oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (KM) mice (50 mice/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for one and a half years. The result showed adverse effects on body weights, feed consumption, hematology, serum chemistry, organ weights, relative organ weights, and incidence of tumors during most of the study period. Treatment-related changes in hematology, serum chemistry, relative weights and histopathological examinations revealed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive system, were the main targets after MEQ administration. Additionally, MEQ significantly increased the frequency of micronucleated normochromatic erythrocytes in bone marrow cells of mice. Furthermore, MEQ increased the incidence of tumors, including mammary fibroadenoma, breast cancer, corticosuprarenaloma, haemangiomas, hepatocarcinoma, and pulmonary adenoma. Interestingly, the higher incidence of tumors was noted in M25 mg/kg group, the lowest dietary concentration tested, which was equivalent to approximately 2.25 and 1.72 mg/kg b.w./day in females and males, respectively. It was assumed that the lower toxicity might be a reason for its higher tumor incidence in M25 mg/kg group. This finding suggests a potential relationships among the dose, general toxicity and carcinogenicity in vivo, and further study is required to reveal this relationship. In conclusion, the present study demonstrates that MEQ is a genotoxic carcinogen in KM mice. PMID:29692735

  1. Mequindox Induced Genotoxicity and Carcinogenicity in Mice.

    PubMed

    Liu, Qianying; Lei, Zhixin; Wu, Qin; Huang, Deyu; Xie, Shuyu; Wang, Xu; Pan, Yuanhu; Yuan, Zonghui

    2018-01-01

    Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N -oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (KM) mice (50 mice/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for one and a half years. The result showed adverse effects on body weights, feed consumption, hematology, serum chemistry, organ weights, relative organ weights, and incidence of tumors during most of the study period. Treatment-related changes in hematology, serum chemistry, relative weights and histopathological examinations revealed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive system, were the main targets after MEQ administration. Additionally, MEQ significantly increased the frequency of micronucleated normochromatic erythrocytes in bone marrow cells of mice. Furthermore, MEQ increased the incidence of tumors, including mammary fibroadenoma, breast cancer, corticosuprarenaloma, haemangiomas, hepatocarcinoma, and pulmonary adenoma. Interestingly, the higher incidence of tumors was noted in M25 mg/kg group, the lowest dietary concentration tested, which was equivalent to approximately 2.25 and 1.72 mg/kg b.w./day in females and males, respectively. It was assumed that the lower toxicity might be a reason for its higher tumor incidence in M25 mg/kg group. This finding suggests a potential relationships among the dose, general toxicity and carcinogenicity in vivo , and further study is required to reveal this relationship. In conclusion, the present study demonstrates that MEQ is a genotoxic carcinogen in KM mice.

  2. Regulation of priority carcinogens and reproductive or developmental toxicants

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

    Hooper, K.; LaDou, J.; Rosenbaum, J.S.

    In California, 370 carcinogens and 112 reproductive/developmental toxicants have been identified as a result of the State's Safe Drinking Water and Toxic Enforcement Act of 1986. They include pesticides, solvents, metals, industrial intermediates, environmental mixtures, and reactive agents. Occupational, environmental, and consumer product exposures that involve these agents are regulated under the Act. At levels of concern, businesses must provide warnings for and limit discharges of those chemicals. The lists of chemicals were compiled following systematic review of published data, including technical reports from the U.S. Public Health Service--National Toxicology Program (NTP), and evaluation of recommendations from authoritative bodies suchmore » as the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency (USEPA). Given the large number of chemicals that are carcinogens or reproductive/developmental toxicants, regulatory concerns should focus on those that have high potential for human exposure, e.g., widely distributed or easily absorbed solvents, metals, environmental mixtures, or reactive agents. In this paper, we present a list of 33 potential priority carcinogens and reproductive/developmental toxicants, including alcoholic beverages, asbestos, benzene, chlorinated solvents, formaldehyde, glycol ethers, lead, tobacco smoke, and toluene.« less

  3. Regulation of priority carcinogens and reproductive or developmental toxicants.

    PubMed

    Hooper, K; LaDou, J; Rosenbaum, J S; Book, S A

    1992-01-01

    In California, 370 carcinogens and 112 reproductive/developmental toxicants have been identified as a result of the State's Safe Drinking Water and Toxic Enforcement Act of 1986. They include pesticides, solvents, metals, industrial intermediates, environmental mixtures, and reactive agents. Occupational, environmental, and consumer product exposures that involve these agents are regulated under the Act. At levels of concern, businesses must provide warnings for and limit discharges of those chemicals. The lists of chemicals were compiled following systematic review of published data, including technical reports from the U.S. Public Health Service--National Toxicology Program (NTP), and evaluation of recommendations from authoritative bodies such as the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency (USEPA). Given the large number of chemicals that are carcinogens or reproductive/developmental toxicants, regulatory concerns should focus on those that have high potential for human exposure, e.g., widely distributed or easily absorbed solvents, metals, environmental mixtures, or reactive agents. In this paper, we present a list of 33 potential priority carcinogens and reproductive/developmental toxicants, including alcoholic beverages, asbestos, benzene, chlorinated solvents, formaldehyde, glycol ethers, lead, tobacco smoke, and toluene.

  4. Source contributions to total concentrations and carcinogenic potencies of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in ambient air: a case study in Suzhou City, China.

    PubMed

    Xuan, Zhiqiang; Bi, Chenglu; Li, Jiafu; Nie, Jihua; Chen, Zhihai

    2017-10-01

    The potential source categories and source contributions of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in ambient air from Suzhou City, China, were performed by principal component analysis-multiple linear regression (PCA-MLR) and positive matrix factorization (PMF). The carcinogenic potencies of PCDD/Fs were quantitatively apportioned based on the positive matrix factorization-toxic equivalent concentration (PMF-TEQ) method. The results of the present study were summarized as follows. (1) The total concentrations and toxic equivalent concentrations of PCDD/Fs (∑PCDD/Fs and TEQ) in ambient air from Suzhou City were 1.34-42.80 pg N m -3 and 0.081-1.22 pg I-TEQ N m -3 , respectively. (2) PCA-MLR suggested that industrial combustion (IC), electric arc furnaces (EAFs) and secondary aluminum smelters (ALSs), unleaded gas-fueled vehicle sources (UGFVs), ALSs, and hazardous solid waste incinerators (HSWIs) could be the primary PCDD/F contributors, accounting for 13.2, 16.7, 35.5, 19.4, and 15.2% of ∑PCDD/Fs, respectively. (3) PMF and PMF-TEQ indicated that EAFs (carbon steel), UGFVs, IC, ALSs, municipal solid waste incinerators (MSWIs) and hospital waste incinerators (HWIs), and HSWIs contributed 10.9, 10.9, 42.8, 11.3, 10.7, and 13.4% to ∑PCDD/Fs, but contributed 8.3, 12.3, 50.3, 12.7, 6.0, and 10.4% to carcinogenic potencies of PCDD/Fs. This study was the first attempt to quantitatively apportion the source-specific carcinogenic potencies of PCDD/Fs in ambient air.

  5. Ptaquiloside, the major carcinogen of bracken fern, in the pooled raw milk of healthy sheep and goats: an underestimated, global concern of food safety.

    PubMed

    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.

  6. Detection of rare and possibly carcinogenic human papillomavirus genotypes as single infections in invasive cervical cancer.

    PubMed

    Geraets, Daan; Alemany, Laia; Guimera, Nuria; de Sanjose, Silvia; de Koning, Maurits; Molijn, Anco; Jenkins, David; Bosch, Xavier; Quint, Wim

    2012-12-01

    The contribution of carcinogenic human papillomavirus (HPV) types to the burden of cervical cancer has been well established. However, the role and contribution of phylogenetically related HPV genotypes and rare variants remains uncertain. In a recent global study of 8977 HPV-positive invasive cervical carcinomas (ICCs), the genotype remained unidentified in 3.7% by the HPV SPF10 PCR-DEIA-LiPA25 (version 1) algorithm. The 331 ICC specimens with unknown genotype were analysed by a novel sequence methodology, using multiple selected short regions in L1. This demonstrated HPV genotypes that have infrequently or never been detected in ICC, ie HPV26, 30, 61, 67, 68, 69, 73 and 82, and rare variants of HPV16, 18, 26, 30, 34, 39, 56, 67, 68, 69, 82 and 91. These are not identified individually by LiPA25 and only to some extent by other HPV genotyping assays. Most identified genotypes have a close phylogenetic relationship with established carcinogenic HPVs and have been classified as possibly carcinogenic by IARC. Except for HPV85, all genotypes in α-species 5, 6, 7, 9 and 11 were encountered as single infections in ICCs. These species of established and possibly carcinogenic HPV types form an evolutionary clade. We have shown that the possibly carcinogenic types were detected only in squamous cell carcinomas, which were often keratinizing and diagnosed at a relatively higher mean age (55.3 years) than those associated with established carcinogenic types (50.9 years). The individual frequency of the possibly carcinogenic types in ICCs is low, but together they are associated with 2.25% of the 8338 included ICCs with a single HPV type. This fraction is greater than seven of the established carcinogenic types individually. This study provides evidence that possibly carcinogenic HPV types occur as single infections in invasive cervical cancer, strengthening the circumstantial evidence of a carcinogenic role. Copyright © 2012 Pathological Society of Great Britain and

  7. Morpho-chemical characterization and surface properties of carcinogenic zeolite fibers.

    PubMed

    Mattioli, Michele; Giordani, Matteo; Dogan, Meral; Cangiotti, Michela; Avella, Giuseppe; Giorgi, Rodorico; Dogan, A Umran; Ottaviani, Maria Francesca

    2016-04-05

    Erionite belonging to the zeolite family is a human health-hazard, since it was demonstrated to be carcinogenic. Conversely, offretite family zeolites were suspected carcinogenic. Mineralogical, morphological, chemical, and surface characterizations were performed on two erionites (GF1, MD8) and one offretite (BV12) fibrous samples and, for comparison, one scolecite (SC1) sample. The specific surface area analysis indicated a larger availability of surface sites for the adsorption onto GF1, while SC1 shows the lowest one and the presence of large pores in the poorly fibrous zeolite aggregates. Selected spin probes revealed a high adsorption capacity of GF1 compared to the other zeolites, but the polar/charged interacting sites were well distributed, intercalated by less polar sites (Si-O-Si). MD8 surface is less homogeneous and the polar/charged sites are more interacting and closer to each other compared to GF1. The interacting ability of BV12 surface is much lower than that found for GF1 and MD8 and the probes are trapped in small pores into the fibrous aggregates. In comparison with the other zeolites, the non-carcinogenic SC1 shows a poor interacting ability and a lower surface polarity. These results helped to clarify the chemical properties and the surface interacting ability of these zeolite fibers which may be related to their carcinogenicity. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Genotoxicity and carcinogenicity of acrylamide: a critical review.

    PubMed

    Carere, Angelo

    2006-01-01

    In 2002, public health concerns were raised by Swedish studies showing that relatively high levels of acrylamide were formed during the frying, roasting, or baking of a variety of foods, including potatoes, cereal products and coffee at temperatures above 120 degrees C. Acrylamide possesses a range of hazardous properties, the key effects being carcinogenicity, genotoxicity, neurotoxicity and reproductive toxicity. Acrylamide is clearly carcinogenic in studies in animals, in which it causes increased tumour incidence at a variety of sites. Although the mechanisms for tumour induction in experimental animals have not yet fully elucidated, the in vivo genotoxicity at gene and chromosome level in somatic and germ cells in rodents cannot be discounted from contributing to it. At this time, there is no information to indicate any significant difference between rodents and humans in sensitivity to cancer formation from acrylamide. The present available epidemiological studies of human industrial and accidental exposures have to be considered not suitable for use in the cancer risk assessment of acrylamide in food, due to several limitations. In reviewing the genotoxicity and carcinogenicity of acrylamide, the author has taken into account also the evaluations made by the IARC in 1994, the FAO/WHO in 2002 by the European Commission Scientific Committee on Food (SCF) in 2002 and by the Joint FAO/WHO Expert Committee on Food Additive (JECFA) in 2005.

  9. Genotoxicity and carcinogenicity of the light emitted by artificial illumination systems.

    PubMed

    De Flora, Silvio

    2013-03-01

    The light delivered by artificial illumination systems, and in particular by halogen quartz bulbs, contains UVA, UVB, and UVC radiation, is genotoxic to both bacterial and human cells and is potently carcinogenic to hairless mice. Since IARC has classified UV radiation in Group 1, any source of UV light poses a carcinogenic hazard to humans. Suitable regulations would be needed in order to control the safety of the light emitted by artificial light sources.

  10. QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS FOR CHEMICAL REDUCTIONS OF ORGANIC CONTAMINANTS

    EPA Science Inventory

    Sufficient kinetic data on abiotic reduction reactions involving organic contaminants are now available that quantitative structure-activity relationships (QSARs) for these reactions can be developed. Over 50 QSARs have been reported, most in just the last few years, and they ar...

  11. Quantitation of exposure to benzo[a]pyrene with monoclonal antibodies.

    PubMed Central

    Santella, R M; Hsieh, L L; Lin, C D; Viet, S; Weinstein, I B

    1985-01-01

    It is now possible to quantitate carcinogen adducts on DNA by highly sensitive immunoassays. These techniques are particularly useful for screening human populations for exposure to potential environmental carcinogens. We have developed a panel of monoclonal antibodies that react with benzo(a)pyrene (BP) modified DNA to be used in an enzyme linked immunoassay (ELISA) to quantitate adduct levels of both human and animal samples. BALBc/Cr mice were immunized with either DNA modified by 7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9, 10-tetrahydrobenzo(a)pyrene (BPDE-I-DNA) complexed electrostatically to methylated bovine serum albumin or with BPDE-I-modified guanosine conjugated with bovine serum albumin (BPDE-I-G-BSA). Four stable clones were produced from the spleen cells of animals immunized with BPDE-I-DNA and one from BPDE-I-G-BSA immunized animals. All antibodies were shown to be highly specific for BPDE-I-DNA and did not crossreact with nonmodified DNA or with N-2-acetylaminofluorene or 1-aminopyrene modified DNA. The antibodies differed in their sensitivity to BPDE-II-DNA, BPDE-I-poly G, BPDE-I-tetraols and BPDE-I-dG. In general, all the antibodies showed the greatest affinity for their original antigen. Those generated against modified DNA showed highest reactivity against modified DNA while the one antibody generated against the monoadduct showed highest reactivity with the monoadduct. These antibodies are currently being used in a highly sensitive competitive ELISA to quantitate levels of BP-DNA adducts in various animal and human tissue samples. PMID:4085452

  12. Single molecule quantitation and sequencing of rare translocations using microfluidic nested digital PCR.

    PubMed

    Shuga, Joe; Zeng, Yong; Novak, Richard; Lan, Qing; Tang, Xiaojiang; Rothman, Nathaniel; Vermeulen, Roel; Li, Laiyu; Hubbard, Alan; Zhang, Luoping; Mathies, Richard A; Smith, Martyn T

    2013-09-01

    Cancers are heterogeneous and genetically unstable. New methods are needed that provide the sensitivity and specificity to query single cells at the genetic loci that drive cancer progression, thereby enabling researchers to study the progression of individual tumors. Here, we report the development and application of a bead-based hemi-nested microfluidic droplet digital PCR (dPCR) technology to achieve 'quantitative' measurement and single-molecule sequencing of somatically acquired carcinogenic translocations at extremely low levels (<10(-6)) in healthy subjects. We use this technique in our healthy study population to determine the overall concentration of the t(14;18) translocation, which is strongly associated with follicular lymphoma. The nested dPCR approach improves the detection limit to 1×10(-7) or lower while maintaining the analysis efficiency and specificity. Further, the bead-based dPCR enabled us to isolate and quantify the relative amounts of the various clonal forms of t(14;18) translocation in these subjects, and the single-molecule sensitivity and resolution of dPCR led to the discovery of new clonal forms of t(14;18) that were otherwise masked by the conventional quantitative PCR measurements. In this manner, we created a quantitative map for this carcinogenic mutation in this healthy population and identified the positions on chromosomes 14 and 18 where the vast majority of these t(14;18) events occur.

  13. Review of the carcinogenic activity of diethanolamine and evidence of choline deficiency as a plausible mode of action.

    PubMed

    Leung, Hon-Wing; Kamendulis, Lisa M; Stott, William T

    2005-12-01

    more susceptible than other mammalian species including humans. These differences are attributed to quantitative differences in the enzyme kinetics controlling choline metabolism. The fact that DEA was carcinogenic in mice but not in rats also has important implications for human risk assessment. DEA has been shown to be less readily absorbed across rat and human skin than mouse skin. Since a no observed effect level for DEA-induced choline deficiency in mice has been established to be 10 mg/kg/d, this indicates that there is a critical level of DEA that must be attained in order to affect choline homeostasis. The lack of a carcinogenic response in rats suggests that exposure to DEA did not reach this critical level. Since rodents are far more sensitive to choline deficiency than humans, it can be concluded that the hepatocarcinogenic effect of DEA in mice is not predictive of similar susceptibility in humans.

  14. Databases applicable to quantitative hazard/risk assessment-Towards a predictive systems toxicology

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

    Waters, Michael; Jackson, Marcus

    2008-11-15

    The Workshop on The Power of Aggregated Toxicity Data addressed the requirement for distributed databases to support quantitative hazard and risk assessment. The authors have conceived and constructed with federal support several databases that have been used in hazard identification and risk assessment. The first of these databases, the EPA Gene-Tox Database was developed for the EPA Office of Toxic Substances by the Oak Ridge National Laboratory, and is currently hosted by the National Library of Medicine. This public resource is based on the collaborative evaluation, by government, academia, and industry, of short-term tests for the detection of mutagens andmore » presumptive carcinogens. The two-phased evaluation process resulted in more than 50 peer-reviewed publications on test system performance and a qualitative database on thousands of chemicals. Subsequently, the graphic and quantitative EPA/IARC Genetic Activity Profile (GAP) Database was developed in collaboration with the International Agency for Research on Cancer (IARC). A chemical database driven by consideration of the lowest effective dose, GAP has served IARC for many years in support of hazard classification of potential human carcinogens. The Toxicological Activity Profile (TAP) prototype database was patterned after GAP and utilized acute, subchronic, and chronic data from the Office of Air Quality Planning and Standards. TAP demonstrated the flexibility of the GAP format for air toxics, water pollutants and other environmental agents. The GAP format was also applied to developmental toxicants and was modified to represent quantitative results from the rodent carcinogen bioassay. More recently, the authors have constructed: 1) the NIEHS Genetic Alterations in Cancer (GAC) Database which quantifies specific mutations found in cancers induced by environmental agents, and 2) the NIEHS Chemical Effects in Biological Systems (CEBS) Knowledgebase that integrates genomic and other biological data

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

    PubMed

    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.

  16. Evaluation of the potential carcinogenicity of 4-chloro-o-toluidine hydrochloride (3165-93-3). Final report

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

    Not Available

    1988-06-01

    4-Chloro-o-toluidine hydrochloride is a probable human carcinogen, classified as weight-of-evidence Group B2 under the EPA Guidelines for Carcinogen Risk Assessment. Evidence on potential carcinogenicity from animal studies is Sufficient, and the evidence from human studies is No Data. The potency factor (F) for 4-chloro-o-toluidine hydrochloride is estimated to be 0.40 (mg/kg/day)(-1), placing it in potency group 3 according to the CAG's methodology for evaluating potential carcinogens. Combining the weight-of-evidence group and the potency group, 4-chloro-o-toluidine hydrochloride is assigned a LOW hazard ranking.

  17. Use of human peripheral blood lymphocytes to measure DNA binding capacity of chemical carcinogens

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

    Gupta, R.C.; Earley, K.; Sharma, S.

    1988-05-01

    Although animal models have been used successfully to study metabolic activation and binding of carcinogens to DNA, only limited studies have been done in human systems. To circumvent the problems associated with the inaccessibility of human tissues and a lack of sensitive methods to detect DNA damage, the authors have investigated the capability of human peripheral blood lymphocytes in vitro to metabolize carcinogens to their DNA binding species by a {sup 32}P-labeled adduct assay. Freshly isolated lymphocytes were exposed at 37{degree}C for 18 hr to 4-aminobiphenyl, 2-aminofluorene, 2-anthramine, 2-acetylaminophenanthrene, benzidine, 1-nitropyrene, 1,2-benzanthracene, triphenylene, 7,12-dimethylbenz(a)anthracene, or benzo(a)pyrene at 30 {mu}M each,more » compounds that are shown or suspected to be carcinogenic in experimental animals. The data indicate that all test carcinogens formed readily measurable levels of DNA adducts. Analysis of exposed DNAs by {sup 32}P-labeling after digestion and adduct enrichment showed exclusively or predominantly one major adduct for all test carcinogens, except for 2-anthramine, triphenylene, and 7,12-dimethylbenz(a)anthracene, which showed two or three adducts. From 12 lymphocyte specimens studied thus far, significant interindividual variations were observed. The lymphocyte system in combination with the {sup 32}P-adduct assay may prove to be an ultrasensitive means to determine interindividual variations in the ability to biotransform carcinogens.« less

  18. Systematic network assessment of the carcinogenic activities of cadmium

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

    Chen, Peizhan; Duan, Xiaohua; Li, Mian

    Cadmium has been defined as type I carcinogen for humans, but the underlying mechanisms of its carcinogenic activity and its influence on protein-protein interactions in cells are not fully elucidated. The aim of the current study was to evaluate, systematically, the carcinogenic activity of cadmium with systems biology approaches. From a literature search of 209 studies that performed with cellular models, 208 proteins influenced by cadmium exposure were identified. All of these were assessed by Western blotting and were recognized as key nodes in network analyses. The protein-protein functional interaction networks were constructed with NetBox software and visualized with Cytoscapemore » software. These cadmium-rewired genes were used to construct a scale-free, highly connected biological protein interaction network with 850 nodes and 8770 edges. Of the network, nine key modules were identified and 60 key signaling pathways, including the estrogen, RAS, PI3K-Akt, NF-κB, HIF-1α, Jak-STAT, and TGF-β signaling pathways, were significantly enriched. With breast cancer, colorectal and prostate cancer cellular models, we validated the key node genes in the network that had been previously reported or inferred form the network by Western blotting methods, including STAT3, JNK, p38, SMAD2/3, P65, AKT1, and HIF-1α. These results suggested the established network was robust and provided a systematic view of the carcinogenic activities of cadmium in human. - Highlights: • A cadmium-influenced network with 850 nodes and 8770 edges was established. • The cadmium-rewired gene network was scale-free and highly connected. • Nine modules were identified, and 60 key signaling pathways related to cadmium-induced carcinogenesis were found. • Key mediators in the network were validated in multiple cellular models.« less

  19. Potential late health effects of depleted uranium and tungsten used in armor-piercing munitions: comparison of neoplastic transformation and genotoxicity with the known carcinogen nickel.

    PubMed

    Miller, Alexandra C; Xu, Jiaquan; Stewart, Michael; Prasanna, Pataje G S; Page, Natalie

    2002-02-01

    Limited data exist to permit an accurate assessment of risks for carcinogenesis and mutagenesis from embedded fragments or inhaled particulates of depleted uranium (DU). Ongoing studies have been designed to provide information about the carcinogenic potential of DU using in vitro and in vivo assessments of morphological transformation as well as cytogenetic, mutagenic, and oncogenic effects. For comparison, we also examined tungsten alloys used in military projectiles and the known carcinogen nickel. Quantitative and qualitative in vitro transformation studies were done to assess the carcinogenic potential of radiation and chemical hazards. Using a human osteosarcoma cell model, we demonstrated that soluble and insoluble DU compounds can transform cells to the tumorigenic phenotype, as characterized by morphological, biochemical, and oncogenic changes consistent with tumor cell behavior. Tungsten alloys and nickel were also shown to be neoplastic transforming agents, although at a frequency less than that of DU. Sister chromatid exchange, micronuclei, and alkaline filter elution assays showed DU and tungsten alloys were genotoxic. Exposure to a nontoxic, nontransforming dose of DU induced a small but statistically significant increase in the number of dicentrics formed in cells. These results suggest that long-term exposure to DU or tungsten alloys could be critical to the development of neoplastic disease in humans and that additional studies are needed.

  20. A Novel Strategy to Predict Carcinogenicity of Antiparasitics Based on a Combination of DNA Lesions and Bacterial Mutagenicity Tests

    PubMed Central

    Liu, Qianying; Lei, Zhixin; Zhu, Feng; Ihsan, Awais; Wang, Xu; Yuan, Zonghui

    2017-01-01

    Genotoxicity and carcinogenicity testing of pharmaceuticals prior to commercialization is requested by regulatory agencies. The bacterial mutagenicity test was considered having the highest accuracy of carcinogenic prediction. However, some evidences suggest that it always results in false-positive responses when the bacterial mutagenicity test is used to predict carcinogenicity. Along with major changes made to the International Committee on Harmonization guidance on genotoxicity testing [S2 (R1)], the old data (especially the cytotgenetic data) may not meet current guidelines. This review provides a compendium of retrievable results of genotoxicity and animal carcinogenicity of 136 antiparasitics. Neither genotoxicity nor carcinogenicity data is available for 84 (61.8%), while 52 (38.2%) have been evaluated in at least one genotoxicity or carcinogenicity study, and only 20 (14.7%) in both genotoxicity and carcinogenicity studies. Among 33 antiparasitics with at least one old result in in vitro genotoxicity, 15 (45.5%) are in agreement with the current ICH S2 (R1) guidance for data acceptance. Compared with other genotoxicity assays, the DNA lesions can significantly increase the accuracy of prediction of carcinogenicity. Together, a combination of DNA lesion and bacterial tests is a more accurate way to predict carcinogenicity. PMID:29170735

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

    PubMed

    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. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    PubMed

    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. © The Author(s) 2015.

  3. RESPIRATORY CARCINOGENICITY OF DIESEL FUEL EMISSIONS. FINAL REPORT

    EPA Science Inventory

    An experiment was carried out to compare the carcinogenicity of diesel exhaust particles (administered by fifteen weekly intratracheal instillations) to that of organic extracts of diesel particles, coke oven emissions, roofing tar condensate and cigarette smoke condensate. Appro...

  4. Carcinogenicity study of 3-monochloropropane-1, 2-diol (3-MCPD) administered by drinking water to B6C3F1 mice showed no carcinogenic potential.

    PubMed

    Jeong, Jayoung; Han, Beom Seok; Cho, Wan-Seob; Choi, Mina; Ha, Chang-Su; Lee, Byoung-Seok; Kim, Yong-Bum; Son, Woo-Chan; Kim, Choong-Yong

    2010-09-01

    3-Monochloropropane-1, 2-diol (or 3-chloro-1,2-propanediol, 3-MCPD) is a well-known food processing contaminant found in a wide range of foods and ingredients. It has been classified as non-genotoxic carcinogen but its carcinogenic potential in the rodents has been controversial. The carcinogenicity to B6C3F1 mice by drinking water administration was assessed over a period of 104 weeks. Three groups, each comprising 50 male and 50 female mice received 3-MCPD at dosages of 30, 100 or 300 ppm up to Day 100 and 200 ppm onward (4.2, 14.3 and 33.0 mg/kg for males; 3.7, 12.2, and 31.0 mg/kg for females), were allocated. Survival was good, with at least 80% of males and 72% of females in each group surviving 104 weeks. Body weights and body weight gain were decreased in males and females receiving 200 ppm. Water and food consumptions of both sexes at 300/200 ppm were lowered. Emaciated or crouching position was observed for animals of both sexes exposed to 200 ppm. There were some differences in hematology and serum biochemistry compared with controls, although there was no histopathological evidence to support those changes. Histopathological examination did not reveal any neoplastic or non-neoplastic findings attributable to treatment with 3-MCPD. It is concluded that drinking water administration of 3-MCPD for 104 weeks revealed no evidence of carcinogenic potential.

  5. Comparative statistical analysis of carcinogenic and non-carcinogenic effects of uranium in groundwater samples from different regions of Punjab, India.

    PubMed

    Saini, Komal; Singh, Parminder; Bajwa, Bikramjit Singh

    2016-12-01

    LED flourimeter has been used for microanalysis of uranium concentration in groundwater samples collected from six districts of South West (SW), West (W) and North East (NE) Punjab, India. Average value of uranium content in water samples of SW Punjab is observed to be higher than WHO, USEPA recommended safe limit of 30µgl -1 as well as AERB proposed limit of 60µgl -1 . Whereas, for W and NE region of Punjab, average level of uranium concentration was within AERB recommended limit of 60µgl -1 . Average value observed in SW Punjab is around 3-4 times the value observed in W Punjab, whereas its value is more than 17 times the average value observed in NE region of Punjab. Statistical analysis of carcinogenic as well as non carcinogenic risks due to uranium have been evaluated for each studied district. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. [Cardiovascular risk, occupation and exposure to occupational carcinogens in a group of workers in Salamanca].

    PubMed

    González-Sánchez, Jesús

    2015-01-01

    Identify the cardiovascular risk factors in a group of workers in the province of Salamanca, protected by external prevention services, as regards exposure to occupational carcinogens, by sector of activity and gender. An observational descriptive epidemiological study was conducted. The sample selection was by stratified random sampling in each entity. The variables collected by questionnaire were, sociodemographic characteristics, exposure to occupational carcinogens, and cardiovascular risk factors (smoking, hypertension, dyslipidemia, and diabetes), using the clinical-work histories as a source of information. Statistically significant differences were observed in cardiovascular risk according to the exposure to occupational carcinogens (p <0.001), primarily among workers in the industry sector. A total of 32% of the workers in the province of Salamanca was exposed to some occupational carcinogen. Women were more exposed in the service sector and men in the agriculture and livestock sector. Nearly one third of the workers belonging to the external prevention services of the province of Salamanca, were exposed to some kind of occupational carcinogens. The most frequent being biological risks, solvent products, and silica, which were above the national mean of exposure. It is important to consider the exposure to occupational carcinogens in the implementation of interventions in the prevention of cardiovascular risk in the work place. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  7. Chemical structure determines target organ carcinogenesis in rats

    PubMed Central

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

    2012-01-01

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

  8. Quantitative structural MRI for early detection of Alzheimer’s disease

    PubMed Central

    McEvoy, Linda K; Brewer, James B

    2011-01-01

    Alzheimer’s disease (AD) is a common progressive neurodegenerative disorder that is not currently diagnosed until a patient reaches the stage of dementia. There is a pressing need to identify AD at an earlier stage, so that treatment, when available, can begin early. Quantitative structural MRI is sensitive to the neurodegeneration that occurs in mild and preclinical AD, and is predictive of decline to dementia in individuals with mild cognitive impairment. Objective evidence of ongoing brain atrophy will be critical for risk/benefit decisions once potentially aggressive, disease-modifying treatments become available. Recent advances have paved the way for the use of quantitative structural MRI in clinical practice, and initial clinical use has been promising. However, further experience with these measures in the relatively unselected patient populations seen in clinical practice is needed to complete translation of the recent enormous advances in scientific knowledge of AD into the clinical realm. PMID:20977326

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

    PubMed Central

    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 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

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

    NASA Astrophysics Data System (ADS)

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

    2017-11-01

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

  11. CARCINOGENIC EFFECTS OF LOW DOSES OF IONIZING RADIATION

    EPA Science Inventory

    Carcinogenic Effects of Low Doses of Ionizing Radiation

    R Julian Preston, Environmental Carcinogenesis Division, NHEERL, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

    The form of the dose-response curve for radiation-induced cancers, particu...

  12. Age-Related Differences in Susceptibility to Carcinogenesis. II. Approaches for Application and Uncertainty Analyses for Individual Genetically Acting Carcinogens

    PubMed Central

    Hattis, Dale; Goble, Robert; Chu, Margaret

    2005-01-01

    In an earlier report we developed a quantitative likelihood-based analysis of the differences in sensitivity of rodents to mutagenic carcinogens across three life stages (fetal, birth to weaning, and weaning to 60 days) relative to exposures in adult life. Here we draw implications for assessing human risks for full lifetime exposures, taking into account three types of uncertainties in making projections from the rodent data: uncertainty in the central estimates of the life-stage–specific sensitivity factors estimated earlier, uncertainty from chemical-to-chemical differences in life-stage–specific sensitivities for carcinogenesis, and uncertainty in the mapping of rodent life stages to human ages/exposure periods. Among the uncertainties analyzed, the mapping of rodent life stages to human ages/exposure periods is most important quantitatively (a range of several-fold in estimates of the duration of the human equivalent of the highest sensitivity “birth to weaning” period in rodents). The combined effects of these uncertainties are estimated with Monte Carlo analyses. Overall, the estimated population arithmetic mean risk from lifetime exposures at a constant milligrams per kilogram body weight level to a generic mutagenic carcinogen is about 2.8-fold larger than expected from adult-only exposure with 5–95% confidence limits of 1.5-to 6-fold. The mean estimates for the 0- to 2-year and 2- to 15-year periods are about 35–55% larger than the 10- and 3-fold sensitivity factor adjustments recently proposed by the U.S. Environmental Protection Agency. The present results are based on data for only nine chemicals, including five mutagens. Risk inferences will be altered as data become available for other chemicals. PMID:15811844

  13. Development of human cell models for assessing the carcinogenic potential of chemicals

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

    Pang Yaqin; Li Wenxue; Ma Rulin

    2008-11-01

    To develop human cell models for assessing the carcinogenic potential of chemicals, we established transgenic human cell lines and tested the sensitivity of known carcinogens using a cell transformation assay. A retroviral vector encoding an oncogenic allele of H-Ras (HBER) or c-Myc (HBEM) was introduced into human bronchial epithelial cells (HBE) immortalized by SV40 large T (LT) antigen, leading to increased cell proliferation but failing to confer a transformed phenotype characterized by anchorage-independent cell growth and tumor formation of immunodeficient mice. When these pre-transformed cells were treated with nickel sulfate (NiSO{sub 4}), we found that it shortened the latency ofmore » malignant transformation at least by 19 wk in HBER cells or 16 wk in HBEM cells compared to vector control cells. Similarly, the latency of cell transformation was shorter by 15 wk in HBER cells or 9 wk in HBEM cells when cells were treated with benzo(a)pyrenediol epoxide (BPDE). HBER cells appeared to be more sensitive to TPA, NiSO{sub 4} or BPDE-induced cell transformation compared to human embryonic kidney cells expressing H-Ras (HEKR), implying that cell-type specificity is one of important factors determining the effectiveness of the assay. Using AFB{sub 1} and BaP as the representative pro-carcinogens, we also compared the efficiency of three different metabolic conditions in mediating cell transformation. Low dose chemical induction seems to be a prospective system used for metabolic activation of pro-carcinogens. Our findings provided direct evidence that a genetically modified human cell transformation model can be applied to the assessment of potent carcinogens.« less

  14. Biomarkers of susceptibility to chemical carcinogens: the example of non-Hodgkin lymphomas.

    PubMed

    Kelly, Rachel S; Vineis, Paolo

    2014-09-01

    Genetic susceptibly to suspected chemical and environmental carcinogens may modify the response to exposure. The aim of this review was to explore the issues involved in the study of gene-environment interactions, and to consider the use of susceptibility biomarkers in cancer epidemiology, using non-Hodgkin lymphoma (NHL) as an example. PubMed, EMBASE and Web of Science were searched for peer-reviewed articles considering biomarkers of susceptibility to chemical, agricultural and industrial carcinogens in the aetiology of NHL. The results suggest a modifying role for genetic susceptibility to a number of occupational and environmental exposures including organochlorines, chlorinated solvents, chlordanes and benzene in the aetiology of NHL. The potential importance of these gene-environment interactions in NHL may help to explain the lack of definitive carcinogens identified to date for this malignancy. Although a large number of genetic variants and gene-environment interactions have been explored for NHL, to date replication is lacking and therefore the findings remain to be validated. These findings highlight the need for novel standardized methodologies in the study of genetic susceptibility to chemical carcinogens. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis

    PubMed Central

    Ochieng, Josiah; Nangami, Gladys N.; Ogunkua, Olugbemiga; Miousse, Isabelle R.; Koturbash, Igor; Odero-Marah, Valerie; McCawley, Lisa; Nangia-Makker, Pratima; Ahmed, Nuzhat; Luqmani, Yunus; Chen, Zhenbang; Papagerakis, Silvana; Wolf, Gregory T.; Dong, Chenfang; Zhou, Binhua P.; Brown, Dustin G.; Colacci, Annamaria; Hamid, Roslida A.; Mondello, Chiara; Raju, Jayadev; Ryan, Elizabeth P.; Woodrick, Jordan; Scovassi, Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Salem, Hosni K.; Amedei, Amedeo; Al-Temaimi, Rabeah; Al-Mulla, Fahd; Bisson, William H.; Eltom, Sakina E.

    2015-01-01

    The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial–mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis. PMID:26106135

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

    PubMed

    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.

  17. Mechanism-based classification of PAH mixtures to predict carcinogenic potential

    DOE PAGES

    Tilton, Susan C.; Siddens, Lisbeth K.; Krueger, Sharon K.; ...

    2015-04-22

    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 two-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 profilesmore » measured in skin of mice collected 12 h post-initiation were compared to 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<0.05) 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. As a result, 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.« less

  18. Critical effective methods to detect genotoxic carcinogens and neoplasm-promoting agents.

    PubMed

    Weisburger, J H; Williams, G M

    1991-01-01

    Neoplasia in fish can result from contamination of waters with carcinogens and promoters. Cancer in fish, therefore, is a possible indicator of cancer risk to man and serves as a guide to the need for preventive approaches involving improved means of waste disposal and environmental hygiene. Moreover, cancer in fish indicates that this important food source may be contaminated. Detection of genotoxic carcinogens to which fish are exposed can be achieved quickly and efficiently by carefully selected batteries of complementary in vitro and in vivo bioassays. One such battery consists of the Ames test, a reverse mutation assay in prokaryotic Salmonella typhimurium, and the Williams test, involving DNA repair in freshly explanted metabolically highly competent liver cells from diverse species, including humans. Determination of DNA-carcinogen adducts by varied techniques, including 32P-postlabeling, as well as DNA breakage, mammalian cell mutagenicity, chromosome aberrations, sister chromatid exchange, or cell transformation represent additional approaches, each with its own advantages and disadvantages. More research is needed on systems to apprehend neoplasm promoters, but tests to determine interruption of intercellular communications through gap junctions appear promising. Other approaches rely on measurement of enzymes such as ornithine decarboxylase and protein kinase C. Approaches to the definition of risk to fish or humans require characterization of the genotoxic or nongenotoxic properties of a chemical, relative potency data obtained in select, limited rodent bioassays, and knowledge of prevailing environmental concentrations of specific carcinogens.

  19. Critical effective methods to detect genotoxic carcinogens and neoplasm-promoting agents

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

    Weisburger, J.H.; Williams, G.M.

    1991-01-01

    Neoplasia in fish can result from contamination of waters with carcinogens and promoters. Cancer in fish, therefore, is a possible indicator of cancer risk to man and serves as a guide to the need for preventative approaches involving improved means of waste disposal and environmental hygiene. Moreover, cancer in fish indicates that this important food source may be contaminated. Detection of genotoxic carcinogens to which fish are exposed can be achieved quickly and efficiently by carefully selected batteries of complementary in vitro and in vivo bioassays. One such battery consists of the Ames test, a reverse mutation assay in prokaryoticmore » Salmonella typhimurium, and the Williams test, involving DNA repair in freshly explanted metabolically highly competent liver cells from diverse species, including humans. Determination of DNA-carcinogen adducts by varied techniques, including {sup 32}P-postlabeling, as well as DNA breakage, mammalian cell mutagenicity, chromosome aberrations, sister chromatid exchange, or cell transformation represent additional approaches, each with its own advantages and disadvantages. More research is needed on systems to apprehend neoplasm promoters, but tests to determine interruption of intercellular communications through gap junctions appear promising. Other approaches rely on measurement of enzymes such as ornithine decarboxylase and protein kinase C. Approaches to the definition of risk to fish or humans require characterization of the genotoxic or nongenotoxic properties of a chemical, relative potency data obtained in select, limited rodent bioassays, and knowledge of prevailing environmental concentrations of specific carcinogens.« less

  20. Glyphosate rodent carcinogenicity bioassay expert panel review.

    PubMed

    Williams, Gary M; Berry, Colin; Burns, Michele; de Camargo, Joao Lauro Viana; Greim, Helmut

    2016-09-01

    Glyphosate has been rigorously and extensively tested for carcinogenicity by administration to mice (five studies) and to rats (nine studies). Most authorities have concluded that the evidence does not indicate a cancer risk to humans. The International Agency for Research on Cancer (IARC), however, evaluated some of the available data and concluded that glyphosate probably is carcinogenic to humans. The expert panel convened by Intertek assessed the findings used by IARC, as well as the full body of evidence and found the following: (1) the renal neoplastic effects in males of one mouse study are not associated with glyphosate exposure, because they lack statistical significance, strength, consistency, specificity, lack a dose-response pattern, plausibility, and coherence; (2) the strength of association of liver hemangiosarcomas in a different mouse study is absent, lacking consistency, and a dose-response effect and having in high dose males only a significant incidence increase which is within the historical control range; (3) pancreatic islet-cell adenomas (non-significant incidence increase), in two studies of male SD rats did not progress to carcinomas and lacked a dose-response pattern (the highest incidence is in the low dose followed by the high dose); (4) in one of two studies, a non-significant positive trend in the incidence of hepatocellular adenomas in male rats did not lead to progression to carcinomas; (5) in one of two studies, the non-significant positive trend in the incidence of thyroid C-cell adenomas in female rats was not present and there was no progression of adenomas to carcinomas at the end of the study. Application of criteria for causality considerations to the above mentioned tumor types and given the overall weight-of-evidence (WoE), the expert panel concluded that glyphosate is not a carcinogen in laboratory animals.

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

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

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

    1990-01-01

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

  2. Identification of EBP50 as a Specific Biomarker for Carcinogens Via the Analysis of Mouse Lymphoma Cellular Proteome

    PubMed Central

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

    2012-01-01

    To identify specific biomarkers generated upon exposure of L5178Y mouse lymphoma cells to carcinogens, 2-DE and MALDI-TOF MS analysis were conducted using the cellular proteome of L5178Y cells that had been treated with the known carcinogens, 1,2-dibromoethane and O-nitrotoluene and the noncarcinogens, emodin and D-mannitol. Eight protein spots that showed a greater than 1.5-fold increase or decrease in intensity following carcinogen treatment compared with treatment with noncarcinogens were selected. Of the identified proteins, we focused on the candidate biomarker ERM-binding phosphoprotein 50 (EBP50), the expression of which was specifically increased in response to treatment with the carcinogens. The expression level of EBP50 was determined by western analysis using polyclonal rabbit anti-EBP50 antibody. Further, the expression level of EBP50 was increased in cells treated with seven additional carcinogens, verifying that EBP50 could serve as a specific biomarker for carcinogens. PMID:22434383

  3. Identification of EBP50 as a specific biomarker for carcinogens via the analysis of mouse lymphoma cellular proteome.

    PubMed

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

    2012-03-01

    To identify specific biomarkers generated upon exposure of L5178Y mouse lymphoma cells to carcinogens, 2-DE and MALDI-TOF MS analysis were conducted using the cellular proteome of L5178Y cells that had been treated with the known carcinogens, 1,2-dibromoethane and O-nitrotoluene and the noncarcinogens, emodin and D-mannitol. Eight protein spots that showed a greater than 1.5-fold increase or decrease in intensity following carcinogen treatment compared with treatment with noncarcinogens were selected. Of the identified proteins, we focused on the candidate biomarker ERM-binding phosphoprotein 50 (EBP50), the expression of which was specifically increased in response to treatment with the carcinogens. The expression level of EBP50 was determined by western analysis using polyclonal rabbit anti-EBP50 antibody. Further, the expression level of EBP50 was increased in cells treated with seven additional carcinogens, verifying that EBP50 could serve as a specific biomarker for carcinogens.

  4. An Alternative to Formaldehyde. Avoiding the Carcinogenic Risks.

    ERIC Educational Resources Information Center

    Ealy, Julie B.

    1991-01-01

    Demonstrations in which glyoxal may be substituted for formaldehyde, a known carcinogen, are presented. An acid-base clock reaction and a copper mirror on the inside of a test tube are described. Directions for the demonstrations and safety precautions are included. (KR)

  5. A high-throughput next-generation sequencing-based method for detecting the mutational fingerprint of carcinogens.

    PubMed

    Besaratinia, Ahmad; Li, Haiqing; Yoon, Jae-In; Zheng, Albert; Gao, Hanlin; Tommasi, Stella

    2012-08-01

    Many carcinogens leave a unique mutational fingerprint in the human genome. These mutational fingerprints manifest as specific types of mutations often clustering at certain genomic loci in tumor genomes from carcinogen-exposed individuals. To develop a high-throughput method for detecting the mutational fingerprint of carcinogens, we have devised a cost-, time- and labor-effective strategy, in which the widely used transgenic Big Blue mouse mutation detection assay is made compatible with the Roche/454 Genome Sequencer FLX Titanium next-generation sequencing technology. As proof of principle, we have used this novel method to establish the mutational fingerprints of three prominent carcinogens with varying mutagenic potencies, including sunlight ultraviolet radiation, 4-aminobiphenyl and secondhand smoke that are known to be strong, moderate and weak mutagens, respectively. For verification purposes, we have compared the mutational fingerprints of these carcinogens obtained by our newly developed method with those obtained by parallel analyses using the conventional low-throughput approach, that is, standard mutation detection assay followed by direct DNA sequencing using a capillary DNA sequencer. We demonstrate that this high-throughput next-generation sequencing-based method is highly specific and sensitive to detect the mutational fingerprints of the tested carcinogens. The method is reproducible, and its accuracy is comparable with that of the currently available low-throughput method. In conclusion, this novel method has the potential to move the field of carcinogenesis forward by allowing high-throughput analysis of mutations induced by endogenous and/or exogenous genotoxic agents.

  6. A differential mobility spectrometry/mass spectrometry platform for the rapid detection and quantitation of DNA adduct dG-ABP.

    PubMed

    Kafle, Amol; Klaene, Joshua; Hall, Adam B; Glick, James; Coy, Stephen L; Vouros, Paul

    2013-07-15

    There is continued interest in exploring new analytical technologies for the detection and quantitation of DNA adducts, biomarkers which provide direct evidence of exposure and genetic damage in cells. With the goal of reducing clean-up steps and improving sample throughput, a Differential Mobility Spectrometry/Mass Spectrometry (DMS/MS) platform has been introduced for adduct analysis. A DMS/MS platform has been utilized for the analysis of dG-ABP, the deoxyguanosine adduct of the bladder carcinogen 4-aminobiphenyl (4-ABP). After optimization of the DMS parameters, each sample was analyzed in just 30 s following a simple protein precipitation step of the digested DNA. A detection limit of one modification in 10^6 nucleosides has been achieved using only 2 µg of DNA. A brief comparison (quantitative and qualitative) with liquid chromatography/mass spectrometry is also presented highlighting the advantages of using the DMS/MS method as a high-throughput platform. The data presented demonstrate the successful application of a DMS/MS/MS platform for the rapid quantitation of DNA adducts using, as a model analyte, the deoxyguanosine adduct of the bladder carcinogen 4-aminobiphenyl. Copyright © 2013 John Wiley & Sons, Ltd.

  7. Carcinogenicity and mutagenicity of chromium.

    PubMed

    Léonard, A; Lauwerys, R R

    1980-11-01

    Occupational exposure represents the main source of human contamination by chromium. For non-occupationally exposed people the major environmental exposure to chromium occurs as a consequence of its presence in food. Chromium must be considered as an essential element. Its deficiency impairs glucose metabolism. Trivalent chromium salts are poorly absorbed through the gastro-intestinal and respiratory tracts because they do not cross membranes easily. Hexavalent chromium can be absorbed by the oral and pulmonary routes and probably also through the skin. After its absorption, hexavalent chromium is rapidly reduced to the trivalent form which is probably the only form to be found in biological material. Epidemiological studies have shown that some chromium salts (mainly the slightly soluble hexavalent salts) are carcinogens. Lung cancers have, indeed, often been reported among workers in chromate-producing industry and, to a lesser extent, in workers from the chrome-pigment industry. The first attempts to produce cancers in experimental animals by inhalation or parenteral introduction gave negative or equivocal results but, from 1960, positive results have been obtained with various chromium compounds. As for the carcinogenic activity, the mutagenicity of chromium has mainly been found with hexavalent salts. In the majority of assay systems used, trivalent chromium appears inactive. It can be considered as evident, however, that the ultimate mutagen which binds to the genetic material is the trivalent form produced intracellularly from hexavalent chromium, the apparent lack of activity of the trivalent form being due to its poor cellular uptake.

  8. Identification and classification of carcinogens: procedures of the Chemical Substances Threshold Limit Value Committee, ACGIH. American Conference of Governmental Industrial Hygienists.

    PubMed Central

    Spirtas, R; Steinberg, M; Wands, R C; Weisburger, E K

    1986-01-01

    The Chemical Substances Threshold Limit Value Committee of the American Conference of Governmental Industrial Hygienists has refined its procedures for evaluating carcinogens. Types of epidemiologic and toxicologic evidence used are reviewed and a discussion is presented on how the Committee evaluates data on carcinogenicity. Although it has not been conclusively determined whether biological thresholds exist for all types of carcinogens, the Committee will continue to develop guidelines for permissible exposures to carcinogens. The Committee will continue to use the safety factor approach to setting Threshold Limit Values for carcinogens, despite its shortcomings. A compilation has been developed for lists of substances considered to be carcinogenic by several scientific groups. The Committee will use this information to help to identify and classify carcinogens for its evaluation. PMID:3752326

  9. 40 CFR Appendix C to Part 132 - Great Lakes Water Quality Initiative Methodologies for Development of Human Health Criteria and...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... organisms where higher doses or concentrations resulted in an adverse effect. Quantitative structure... probable or possible human carcinogen, when, because of major qualitative or quantitative limitations, the... quantitative risk assessment, but for which data are inadequate for Tier I criterion development due to a tumor...

  10. 40 CFR Appendix C to Part 132 - Great Lakes Water Quality Initiative Methodologies for Development of Human Health Criteria and...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... organisms where higher doses or concentrations resulted in an adverse effect. Quantitative structure... probable or possible human carcinogen, when, because of major qualitative or quantitative limitations, the... quantitative risk assessment, but for which data are inadequate for Tier I criterion development due to a tumor...

  11. 40 CFR Appendix C to Part 132 - Great Lakes Water Quality Initiative Methodologies for Development of Human Health Criteria and...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... organisms where higher doses or concentrations resulted in an adverse effect. Quantitative structure... probable or possible human carcinogen, when, because of major qualitative or quantitative limitations, the... quantitative risk assessment, but for which data are inadequate for Tier I criterion development due to a tumor...

  12. Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents

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

    Brink, Willem van den; Emerenciana, Annette

    Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products (exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using nonlinearmore » mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation and C-cell hyperplasia after 2 years of treatment. The predictive performance of the model was evaluated using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation for all four products, which is not possible with traditional data analysis methods. It can be concluded that both pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity. The concept is promising for application to other drug classes. - Highlights: • An integrative PKPD model is

  13. Quantitative NDE of Composite Structures at NASA

    NASA Technical Reports Server (NTRS)

    Cramer, K. Elliott; Leckey, Cara A. C.; Howell, Patricia A.; Johnston, Patrick H.; Burke, Eric R.; Zalameda, Joseph N.; Winfree, William P.; Seebo, Jeffery P.

    2015-01-01

    The use of composite materials continues to increase in the aerospace community due to the potential benefits of reduced weight, increased strength, and manufacturability. Ongoing work at NASA involves the use of the large-scale composite structures for spacecraft (payload shrouds, cryotanks, crew modules, etc). NASA is also working to enable the use and certification of composites in aircraft structures through the Advanced Composites Project (ACP). The rapid, in situ characterization of a wide range of the composite materials and structures has become a critical concern for the industry. In many applications it is necessary to monitor changes in these materials over a long time. The quantitative characterization of composite defects such as fiber waviness, reduced bond strength, delamination damage, and microcracking are of particular interest. The research approaches of NASA's Nondestructive Evaluation Sciences Branch include investigation of conventional, guided wave, and phase sensitive ultrasonic methods, infrared thermography and x-ray computed tomography techniques. The use of simulation tools for optimizing and developing these methods is also an active area of research. This paper will focus on current research activities related to large area NDE for rapidly characterizing aerospace composites.

  14. Carcinogenic Effects of Benzene: An Update (Draft Report)

    EPA Science Inventory

    The major issue addressed in this document involves the nature and magnitude of the risk of cancer to humans exposed to low levels of benzene. Occupational studies continue to provide the bulk of evidence of benzenes carcinogenicity. Workers are exposed at much higher levels than...

  15. UPPER BOUND RISK ESTIMATES FOR MIXTURES OF CARCINOGENS

    EPA Science Inventory

    The excess cancer risk that might result from exposure to a mixture of chemical carcinogens usually is estimated with data from experiments conducted on individual chemicals. An upper bound on the total excess risk is estimated commonly by summing individual upper bound risk esti...

  16. Impact of occupational carcinogens on lung cancer risk in a general population

    PubMed Central

    De Matteis, Sara; Consonni, Dario; Lubin, Jay H; Tucker, Margaret; Peters, Susan; Vermeulen, Roel CH; Kromhout, Hans; Bertazzi, Pier Alberto; Caporaso, Neil E; Pesatori, Angela C; Wacholder, Sholom; Landi, Maria Teresa

    2012-01-01

    Background Exposure to occupational carcinogens is an important preventable cause of lung cancer. Most of the previous studies were in highly exposed industrial cohorts. Our aim was to quantify lung cancer burden attributable to occupational carcinogens in a general population. Methods We applied a new job–exposure matrix (JEM) to translate lifetime work histories, collected by personal interview and coded into standard job titles, into never, low and high exposure levels for six known/suspected occupational lung carcinogens in the Environment and Genetics in Lung cancer Etiology (EAGLE) population-based case–control study, conducted in Lombardy region, Italy, in 2002–05. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in men (1537 cases and 1617 controls), by logistic regression adjusted for potential confounders, including smoking and co-exposure to JEM carcinogens. The population attributable fraction (PAF) was estimated as impact measure. Results Men showed an increased lung cancer risk even at low exposure to asbestos (OR: 1.76; 95% CI: 1.42–2.18), crystalline silica (OR: 1.31; 95% CI: 1.00–1.71) and nickel–chromium (OR: 1.18; 95% CI: 0.90–1.53); risk increased with exposure level. For polycyclic aromatic hydrocarbons, an increased risk (OR: 1.64; 95% CI: 0.99–2.70) was found only for high exposures. The PAFs for any exposure to asbestos, silica and nickel–chromium were 18.1, 5.7 and 7.0%, respectively, equivalent to an overall PAF of 22.5% (95% CI: 14.1–30.0). This corresponds to about 1016 (95% CI: 637–1355) male lung cancer cases/year in Lombardy. Conclusions These findings support the substantial role of selected occupational carcinogens on lung cancer burden, even at low exposures, in a general population. PMID:22467291

  17. Impact of occupational carcinogens on lung cancer risk in a general population.

    PubMed

    De Matteis, Sara; Consonni, Dario; Lubin, Jay H; Tucker, Margaret; Peters, Susan; Vermeulen, Roel Ch; Kromhout, Hans; Bertazzi, Pier Alberto; Caporaso, Neil E; Pesatori, Angela C; Wacholder, Sholom; Landi, Maria Teresa

    2012-06-01

    Exposure to occupational carcinogens is an important preventable cause of lung cancer. Most of the previous studies were in highly exposed industrial cohorts. Our aim was to quantify lung cancer burden attributable to occupational carcinogens in a general population. We applied a new job-exposure matrix (JEM) to translate lifetime work histories, collected by personal interview and coded into standard job titles, into never, low and high exposure levels for six known/suspected occupational lung carcinogens in the Environment and Genetics in Lung cancer Etiology (EAGLE) population-based case-control study, conducted in Lombardy region, Italy, in 2002-05. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in men (1537 cases and 1617 controls), by logistic regression adjusted for potential confounders, including smoking and co-exposure to JEM carcinogens. The population attributable fraction (PAF) was estimated as impact measure. Men showed an increased lung cancer risk even at low exposure to asbestos (OR: 1.76; 95% CI: 1.42-2.18), crystalline silica (OR: 1.31; 95% CI: 1.00-1.71) and nickel-chromium (OR: 1.18; 95% CI: 0.90-1.53); risk increased with exposure level. For polycyclic aromatic hydrocarbons, an increased risk (OR: 1.64; 95% CI: 0.99-2.70) was found only for high exposures. The PAFs for any exposure to asbestos, silica and nickel-chromium were 18.1, 5.7 and 7.0%, respectively, equivalent to an overall PAF of 22.5% (95% CI: 14.1-30.0). This corresponds to about 1016 (95% CI: 637-1355) male lung cancer cases/year in Lombardy. These findings support the substantial role of selected occupational carcinogens on lung cancer burden, even at low exposures, in a general population.

  18. Identification and classification of carcinogens: procedures of the Chemical Substances Threshold Limit Value Committee, ACGIH. American Conference of Governmental Industrial Hygienists

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

    Spirtas, R.; Steinberg, M.; Wands, R.C.

    1986-10-01

    The Chemical Substances Threshold Limit Value Committee of the American Conference of Governmental Industrial Hygienists has refined its procedures for evaluating carcinogens. Types of epidemiologic and toxicologic evidence used are reviewed and a discussion is presented on how the Committee evaluates data on carcinogenicity. Although it has not been conclusively determined whether biological thresholds exist for all types of carcinogens, the Committee will continue to develop guidelines for permissible exposures to carcinogens. The Committee will continue to use the safety factor approach to setting Threshold Limit Values for carcinogens, despite its shortcomings. A compilation has been developed for lists ofmore » substances considered to be carcinogenic by several scientific groups. The Committee will use this information to help to identify and classify carcinogens for its evaluation.« less

  19. Local structure in LaMnO3 and CaMnO3 perovskites: A quantitative structural refinement of Mn K -edge XANES data

    NASA Astrophysics Data System (ADS)

    Monesi, C.; Meneghini, C.; Bardelli, F.; Benfatto, M.; Mobilio, S.; Manju, U.; Sarma, D. D.

    2005-11-01

    Hole-doped perovskites such as La1-xCaxMnO3 present special magnetic and magnetotransport properties, and it is commonly accepted that the local atomic structure around Mn ions plays a crucial role in determining these peculiar features. Therefore experimental techniques directly probing the local atomic structure, like x-ray absorption spectroscopy (XAS), have been widely exploited to deeply understand the physics of these compounds. Quantitative XAS analysis usually concerns the extended region [extended x-ray absorption fine structure (EXAFS)] of the absorption spectra. The near-edge region [x-ray absorption near-edge spectroscopy (XANES)] of XAS spectra can provide detailed complementary information on the electronic structure and local atomic topology around the absorber. However, the complexity of the XANES analysis usually prevents a quantitative understanding of the data. This work exploits the recently developed MXAN code to achieve a quantitative structural refinement of the Mn K -edge XANES of LaMnO3 and CaMnO3 compounds; they are the end compounds of the doped manganite series LaxCa1-xMnO3 . The results derived from the EXAFS and XANES analyses are in good agreement, demonstrating that a quantitative picture of the local structure can be obtained from XANES in these crystalline compounds. Moreover, the quantitative XANES analysis provides topological information not directly achievable from EXAFS data analysis. This work demonstrates that combining the analysis of extended and near-edge regions of Mn K -edge XAS spectra could provide a complete and accurate description of Mn local atomic environment in these compounds.

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

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

    Melis, Joost P.M.; Leiden University Medical Center, Department of Toxicogenetics, Leiden; Speksnijder, Ewoud N.

    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 themore » 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.« less

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

    PubMed Central

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

    1981-01-01

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

  2. Genotoxicity and potential carcinogenicity of cyanobacterial toxins - a review.

    PubMed

    Zegura, Bojana; Straser, Alja; Filipič, Metka

    2011-01-01

    The occurrence of cyanobacterial blooms has increased significantly in many regions of the world in the last century due to water eutrophication. These blooms are hazardous to humans, animals, and plants due to the production of cyanotoxins, which can be classified in five different groups: hepatotoxins, neurotoxins, cytotoxins, dermatotoxins, and irritant toxins (lipopolysaccharides). There is evidence that certain cyanobacterial toxins are genotoxic and carcinogenic; however, the mechanisms of their potential carcinogenicity are not well understood. The most frequently occurring and widespread cyanotoxins in brackish and freshwater blooms are the cyclic heptapeptides, i.e., microcystins (MCs), and the pentapeptides, i.e., nodularins (NODs). The main mechanism associated with potential carcinogenic activity of MCs and NOD is the inhibition of protein phosphatases, which leads to the hyperphosphorylation of cellular proteins, which is considered to be associated with their tumor-promoting activity. Apart from this, MCs and NOD induce increased formation of reactive oxygen species and, consequently, oxidative DNA damage. There is also evidence that MCs and NOD induce micronuclei, and NOD was shown to have aneugenic activity. Both cyanotoxins interfere with DNA damage repair pathways, which, along with DNA damage, is an important factor involved in the carcinogenicity of these agents. Furthermore, these toxins increase the expression of TNF-α and early-response genes, including proto-oncogenes, genes involved in the response to DNA damage, cell cycle arrest, and apoptosis. Rodent studies indicate that MCs and NOD are tumor promotors, whereas NOD is thought to have also tumor-initiating activity. Another cyanobacterial toxin, cylindrospermopsin (CYN), which has been neglected for a long time, is lately being increasingly found in the freshwater environment. The principal mechanism of its toxicity is the irreversible inhibition of protein synthesis. It is pro

  3. Quantitative Structure-Antifungal Activity Relationships for cinnamate derivatives.

    PubMed

    Saavedra, Laura M; Ruiz, Diego; Romanelli, Gustavo P; Duchowicz, Pablo R

    2015-12-01

    Quantitative Structure-Activity Relationships (QSAR) are established with the aim of analyzing the fungicidal activities of a set of 27 active cinnamate derivatives. The exploration of more than a thousand of constitutional, topological, geometrical and electronic molecular descriptors, which are calculated with Dragon software, leads to predictions of the growth inhibition on Pythium sp and Corticium rolfsii fungi species, in close agreement to the experimental values extracted from the literature. A set containing 21 new structurally related cinnamate compounds is prepared. The developed QSAR models are applied to predict the unknown fungicidal activity of this set, showing that cinnamates like 38, 28 and 42 are expected to be highly active for Pythium sp, while this is also predicted for 28 and 34 in C. rolfsii. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    PubMed

    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. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. A high-throughput next-generation sequencing-based method for detecting the mutational fingerprint of carcinogens

    PubMed Central

    Besaratinia, Ahmad; Li, Haiqing; Yoon, Jae-In; Zheng, Albert; Gao, Hanlin; Tommasi, Stella

    2012-01-01

    Many carcinogens leave a unique mutational fingerprint in the human genome. These mutational fingerprints manifest as specific types of mutations often clustering at certain genomic loci in tumor genomes from carcinogen-exposed individuals. To develop a high-throughput method for detecting the mutational fingerprint of carcinogens, we have devised a cost-, time- and labor-effective strategy, in which the widely used transgenic Big Blue® mouse mutation detection assay is made compatible with the Roche/454 Genome Sequencer FLX Titanium next-generation sequencing technology. As proof of principle, we have used this novel method to establish the mutational fingerprints of three prominent carcinogens with varying mutagenic potencies, including sunlight ultraviolet radiation, 4-aminobiphenyl and secondhand smoke that are known to be strong, moderate and weak mutagens, respectively. For verification purposes, we have compared the mutational fingerprints of these carcinogens obtained by our newly developed method with those obtained by parallel analyses using the conventional low-throughput approach, that is, standard mutation detection assay followed by direct DNA sequencing using a capillary DNA sequencer. We demonstrate that this high-throughput next-generation sequencing-based method is highly specific and sensitive to detect the mutational fingerprints of the tested carcinogens. The method is reproducible, and its accuracy is comparable with that of the currently available low-throughput method. In conclusion, this novel method has the potential to move the field of carcinogenesis forward by allowing high-throughput analysis of mutations induced by endogenous and/or exogenous genotoxic agents. PMID:22735701

  6. MATline: a job-exposure matrix for carcinogenic chemicals.

    PubMed

    Gilardi, Luisella; Falcone, Umberto; Santoro, Silvano; Coffano, Elena

    2008-01-01

    MATline is a tool that can be used to predict which industrial processes can be expected to involve the use of a substance that is considered carcinogenic as documented in the literature. The database includes agents carrying risk phrases R45, R49 and R40 according to the method of classification adopted by the EU and/or agents in categories 1, 2A and 2B as classified by the International Agency for Research on Cancer (IARC). Each agent is associated with a list of industrial processes coded according to the tariff headings used by the National Institute of Insurance against Occupational Injuries and Diseases (Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, INAIL). The main sources of information are the IARC Monographs and databases available through the National Library of Medicine's TOXNET portal. The matrix currently includes 600 carcinogenic agents, 23 classes of agents and some 7000 links between agents and industrial processes. MATline can be viewed on the www.dors.it website.

  7. The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis.

    PubMed

    Ochieng, Josiah; Nangami, Gladys N; Ogunkua, Olugbemiga; Miousse, Isabelle R; Koturbash, Igor; Odero-Marah, Valerie; McCawley, Lisa J; Nangia-Makker, Pratima; Ahmed, Nuzhat; Luqmani, Yunus; Chen, Zhenbang; Papagerakis, Silvana; Wolf, Gregory T; Dong, Chenfang; Zhou, Binhua P; Brown, Dustin G; Colacci, Anna Maria; Hamid, Roslida A; Mondello, Chiara; Raju, Jayadev; Ryan, Elizabeth P; Woodrick, Jordan; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Salem, Hosni K; Amedei, Amedeo; Al-Temaimi, Rabeah; Al-Mulla, Fahd; Bisson, William H; Eltom, Sakina E

    2015-06-01

    The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial-mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Carcinogenicity of Embedded Tungsten Alloys in Mice

    DTIC Science & Technology

    2011-03-01

    year carcinogenicity (Aim 1) and serial euthanasia (Aim 2) studies were analyzed for metal content using inductively coupled-plasma mass spectrometry...inductively coupled- plasma mass spectrometer (PQ ExCell ICPMS System, ThermoElemental, Franklin, MA) equipped with a Cetac ASX500 Autosampler. High...Metal analysis using inductively coupled-plasma mass spectrometry showed that both the tungsten/nickel/cobalt and tungsten/nickel/iron

  9. Mutagens and carcinogens in foods. Epidemiologic review.

    PubMed Central

    Hislop, T. G.

    1993-01-01

    Evidence that diet contributes to the development of cancer is strengthening. This paper examines mutagens and carcinogens, such as naturally occurring substances, products of cooking and food processing, intentional and unintentional additives, and contaminants, found in foods. Such substances are present in minute quantities in the diets of average Canadians. Indication of health risk is largely limited to experimental laboratory evidence. PMID:8499796

  10. Tumor susceptibility in two mouse strains with varying doses of carcinogen

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

    Bernfeld, P.; Homburger, F.

    Administration of 3-methylcholanthrene to C3H/HeJ and C57BL/6J mice at four dose levels over a 1:125 range resulted in a practically equal tumor response in both strains at all dose levels. Using a different method of carcinogen administration, a reversal of tumor susceptibility was found when varying the dose of carcinogen, a phenomenon not observed by us. Our study suggests that Prehn and Lawler's results may have been influenced, at least in part, by the practice of the latter authors to exclude data of substantial numbers of tumor-free mice from the evaluation. (JMT)

  11. Decrease of 5-hydroxymethylcytosine in rat liver with subchronic exposure to genotoxic carcinogens riddelliine and aristolochic acid.

    PubMed

    Lian, Christine Guo; Xu, Shuyun; Guo, Weimin; Yan, Jian; Frank, Maximilian Y M; Liu, Robert; Liu, Cynthia; Chen, Ying; Murphy, George F; Chen, Tao

    2015-11-01

    The level of 5-hydroxymethylcytosine (5-hmC) converted by ten-eleven translocation (TET) family is decreased in cancers. However, whether 5-hmC level is perturbed in early stages of carcinogenesis caused by genotoxic carcinogens is not defined. 5-hmC levels and TET2 expression were measured in liver of rats treated with genotoxic carcinogens, riddelliine, or aristolochic acid. Levels of 5-hmC and TET2 expression decreased in the liver of the carcinogens-treated rats. Loss of 5-hmC correlates well with documented induction of genetic mutations by the carcinogens, suggesting that TET2-mediated 5-hydroxymethylation plays an epigenetic role in early state of carcinogenesis. © 2014 Wiley Periodicals, Inc.

  12. Decrease of 5-Hydroxymethylcytosine in Rat Liver with Subchronic Exposure to Genotoxic Carcinogens Riddelliine and Aristolochic Acid

    PubMed Central

    Lian, Christine Guo; Xu, Shuyun; Guo, Weimin; Yan, Jian; Frank, Maximilian Y M; Liu, Robert; Liu, Cynthia; Chen, Ying; Murphy, George F.; Chen, Tao

    2018-01-01

    The level of 5-hydroxymethylcytosine (5-hmC) converted by ten-eleven translocation (TET) family is decreased in cancers. However, whether 5-hmC level is perturbed in early stages of carcinogenesis caused by genotoxic carcinogens is not defined. 5-hmC levels and TET2 expression were measured in liver of rats treated with genotoxic carcinogens, riddelliine, or aristolochic acid. Levels of 5-hmC and TET2 expression decreased in the liver of the carcinogens-treated rats. Loss of 5-hmC correlates well with documented induction of genetic mutations by the carcinogens, suggesting that TET2-mediated 5-hydroxymethylation plays an epigenetic role in early state of carcinogenesis. PMID:25154389

  13. Carcinogenicity of Disinfection By-products and Research Needs

    EPA Science Inventory

    A review by S.D. Richardson et al. (Mutat. Res. 636:178, 2007) presents the first analysis of the 30-year literature on the genotoxicity, carcinogenicity, and occurrence of 87 disinfection by-products (DBPs) identified in drinking water. Of these, 11 are regulated by the U.S. EP...

  14. Tannin structural elucidation and quantitative ³¹P NMR analysis. 1. Model compounds.

    PubMed

    Melone, Federica; Saladino, Raffaele; Lange, Heiko; Crestini, Claudia

    2013-10-02

    Tannins and flavonoids are secondary metabolites of plants that display a wide array of biological activities. This peculiarity is related to the inhibition of extracellular enzymes that occurs through the complexation of peptides by tannins. Not only the nature of these interactions, but more fundamentally also the structure of these heterogeneous polyphenolic molecules are not completely clear. This first paper describes the development of a new analytical method for the structural characterization of tannins on the basis of tannin model compounds employing an in situ labeling of all labile H groups (aliphatic OH, phenolic OH, and carboxylic acids) with a phosphorus reagent. The ³¹P NMR analysis of ³¹P-labeled samples allowed the unprecedented quantitative and qualitative structural characterization of hydrolyzable tannins, proanthocyanidins, and catechin tannin model compounds, forming the foundations for the quantitative structural elucidation of a variety of actual tannin samples described in part 2 of this series.

  15. Carcinogenicity and Immunotoxicity of Embedded Depleted Uranium and Heavy-Metal Tungsten Alloy in Rodents

    DTIC Science & Technology

    2006-10-01

    Embedded Depleted Uranium and Heavy-Metal Tungsten Alloy in Rodents PRINCIPAL INVESTIGATOR: John F. Kalinich, Ph.D...Carcinogenicity and Immunotoxicity of Embedded Depleted Uranium and Heavy- Metal Tungsten Alloy in Rodents 5b. GRANT NUMBER DAMD17-01-1-0821 5c...ABSTRACT This study investigated the carcinogenic and immunotoxic potential of embedded fragments of depleted uranium (DU) and a heavy-metal tungsten

  16. USE OF GENE PROFILING TO DIFFERENTIATE A CARCINOGENIC FROM A NONCARCINOGENIC ALDEHYDE IN THE RAT NOSE

    EPA Science Inventory

    Abstract
    Formaldehyde (FA) is cytotoxic and is carcinogenic to the rat nasal respiratory epithelium producing tumors after twelve months of exposure. In contrast, glutaraldehyde (GA) is also cytotoxic but not carcinogenic to nasal epithelium after 2 yrs of exposure. Other...

  17. [Occupational exposure to carcinogens: analysis of the application of the CAREX information system to Catalonia].

    PubMed

    de Grado Andrés, Adolfo; Molinero Ruiz, Emilia; van der Haar, Rudolf

    2014-01-01

    The objective of this study is to estimate occupational exposures to human carcinogens in Catalonia in 2009, taking as a reference the CAREX ESP 2007 information system, and to evaluate the suitability of extrapolating these data to Catalonia. The reference population is the number of people registered with the Social Security system in Catalonia in 2009. Carcinogens considered are those which the International Agency for Research on Cancer (IARC) classified into groups 1 and 2A and are related to occupational exposures. The exposure prevalences from the CAREX ESP 2007, adapted to the Catalonian Industrial Classification (CCAE 09), were used. Technical survey reports from the Occupational Safety and Health Centers of the Catalonian local government, and related databases were consulted. The most frequent occupational exposures to human carcinogens were solar radiation, crystalline silica, diesel exhaust, radon and wood dust, although based mainly on data not considered adequate for extrapolation to Catalonia. Around 217 exposure situations for 25 carcinogens, not previously considered in CAREX ESP 2007, were identified. The estimated number of workers exposed to human carcinogens in Catalonia in 2009 based on the CAREX ESP 2007 system could differ from the real situation. Development of a CAREX CAT system that incorporates exposure data from Catalonia is recommended. Copyright belongs to the Societat Catalana de Seguretat i Medicina del Treball.

  18. TOXNET: Toxicology Data Network

    MedlinePlus

    ... 4. Supporting Data for Carcinogenicity Expand II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure II. ... of Confidence (Carcinogenicity, Oral Exposure) Expand II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure II. ...

  19. Quantitative structure-activation barrier relationship modeling for Diels-Alder ligations utilizing quantum chemical structural descriptors.

    PubMed

    Nandi, Sisir; Monesi, Alessandro; Drgan, Viktor; Merzel, Franci; Novič, Marjana

    2013-10-30

    In the present study, we show the correlation of quantum chemical structural descriptors with the activation barriers of the Diels-Alder ligations. A set of 72 non-catalysed Diels-Alder reactions were subjected to quantitative structure-activation barrier relationship (QSABR) under the framework of theoretical quantum chemical descriptors calculated solely from the structures of diene and dienophile reactants. Experimental activation barrier data were obtained from literature. Descriptors were computed using Hartree-Fock theory using 6-31G(d) basis set as implemented in Gaussian 09 software. Variable selection and model development were carried out by stepwise multiple linear regression methodology. Predictive performance of the quantitative structure-activation barrier relationship (QSABR) model was assessed by training and test set concept and by calculating leave-one-out cross-validated Q2 and predictive R2 values. The QSABR model can explain and predict 86.5% and 80% of the variances, respectively, in the activation energy barrier training data. Alternatively, a neural network model based on back propagation of errors was developed to assess the nonlinearity of the sought correlations between theoretical descriptors and experimental reaction barriers. A reasonable predictability for the activation barrier of the test set reactions was obtained, which enabled an exploration and interpretation of the significant variables responsible for Diels-Alder interaction between dienes and dienophiles. Thus, studies in the direction of QSABR modelling that provide efficient and fast prediction of activation barriers of the Diels-Alder reactions turn out to be a meaningful alternative to transition state theory based computation.

  20. Accurate characterization of carcinogenic DNA adducts using MALDI tandem time-of-flight mass spectrometry

    NASA Astrophysics Data System (ADS)

    Barnes, Charles A.; Chiu, Norman H. L.

    2009-01-01

    Many chemical carcinogens and their in vivo activated metabolites react readily with genomic DNA, and form covalently bound carcinogen-DNA adducts. Clinically, carcinogen-DNA adducts have been linked to various cancer diseases. Among the current methods for DNA adduct analysis, mass spectroscopic method allows the direct measurement of unlabeled DNA adducts. The goal of this study is to explore the use of matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS) to determine the identity of carcinogen-DNA adducts. Two of the known carcinogenic DNA adducts, namely N-(2'-deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenyl-imidazo [4,5-b] pyridine (dG-C8-PhIP) and N-(2'-deoxyguanosin-8yl)-4-aminobiphenyl (dG-C8-ABP), were selected as our models. In MALDI-TOF MS measurements, the small matrix ion and its cluster ions did not interfere with the measurements of both selected dG adducts. To achieve a higher accuracy for the characterization of selected dG adducts, 1 keV collision energy in MALDI-TOF/TOF MS/MS was used to measure the adducts. In comparison to other MS/MS techniques with lower collision energies, more extensive precursor ion dissociations were observed. The detection of the corresponding fragment ions allowed the identities of guanine, PhIP or ABP, and the position of adduction to be confirmed. Some of the fragment ions of dG-C8-PhIP have not been reported by other MS/MS techniques.

  1. Quantitative Structure--Activity Relationship Modeling of Rat Acute Toxicity by Oral Exposure

    EPA Science Inventory

    Background: Few Quantitative Structure-Activity Relationship (QSAR) studies have successfully modeled large, diverse rodent toxicity endpoints. Objective: In this study, a combinatorial QSAR approach has been employed for the creation of robust and predictive models of acute toxi...

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

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

    Qi, Xiaozhe; Yu, Tao; Zhu, Liye

    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 inmore » 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.« less

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

    PubMed Central

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

    2014-01-01

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

  4. Use of in vivo/in vitro unscheduled DNA synthesis for identification of organ-specific carcinogens

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

    Furihata, C.; Matsushima, T.

    1987-01-01

    There are still only a few in vivo short-term assay methods for predicting potential organ-specific carcinogens and mutagens in mammals, although such methods are required for evaluating the in vivo effects of in vitro mutagens. In the in vivo/in vitro UDS assay methods described here, chemicals are given to experimental animals and induction of UDS in target organs is determined by in vitro organ culture or primary cell culture in the presence of (/sup 3/H)dThd. Incorporation of (/sup 3/H)dThd into DNA is measured with a liquid scintillation counter or by autoradiography. These methods have now been applied to the glandularmore » stomach, forestomach, colon, liver, kidney, pancreas, tracheal epithelium, nasal epithelium, and spermatocytes. With minor modifications, they may also be applied to other organs. The present review shows that induction of UDS in various organs correlated well with the induction of cancer in these organs. The present authors have used the present methods to identify some potential organ-specific mutagens and carcinogens in mammals. The present authors found that three dicarbonyl compounds, glyoxal, methylglyoxal, and diacetyl, induced apparent UDS and TDS in the glandular stomach, and other groups found that 2-NT, MA6BT, and CNEt6BT induced UDS in the liver. These in vivo/in vitro UDS assays are better than in vitro UDS assay for identification of potential organ-specific mutagens and carcinogens in mammals and are especially useful for identifying potential mutagens and carcinogens that are specific for certain organs, such as the stomach, liver, and kidney. They are also useful for examining the potential mutagenicities and carcinogenicities of carcinogen analogs. However, these methods are not suitable for general in vivo screening because they are not yet available for all organs. 113 references.« less

  5. Carcinogenicity of airborne combustion products observed in subcutaneous tissue and lungs of laboratory rodents.

    PubMed Central

    Pott, F; Stöber, W

    1983-01-01

    Most air pollution in West Germany is caused by combustion products. Particulate organic matter released by incomplete combustion is suspected to contribute to the "urban factor" of lung cancer frequency in urban-industrial centers. The carcinogenic potential of single components, groups of compounds and total source emissions of combustion processes was investigated in laboratory animals by subcutaneous injection, intratracheal instillation or inhalation. Tests by subcutaneous injection of condensates of automobile exhaust, extracts of coal furnace emissions and of airborne particles and different fractions of these extracts showed that the polycyclic aromatic hydrocarbons (PAH) with four to six benzene rings have the strongest experimental carcinogenicity. However, polar compounds (heterocyclic nitrogen-containing PAH, phenols, and others) also show remarkable carcinogenic potency. There were large differences between the dose-response relationships of several PAHs. In the subcutaneous tissue, benzo(a)pyrene and dibenz(a,h)anthracene are the most carcinogenic of the tested airborne PAHs. Furthermore, they can induce high tumor rates in the lung after subcutaneous injection in newborn mice and after intratracheal instillation of mice or hamsters. The tumor rate of benzo(a)pyrene did not further increase after simultaneous instillation of carbon black, but lead chloride may have a promoting effect. Far more than 100 PAHs are found in the urban atmosphere. However, because of the remarkable similarity of the PAH profiles in the examined samples, it may be sufficient to measure just a few stable PAHs in the urban air in order to facilitate an assessment of the carcinogenic potency of the PAH content in the atmosphere. To examine the carcinogenic or cocarcinogenic effects of gas and vapor emissions, studies with a two-phase model were carried out: phase 1 relates to the induction of a basic tumor rate in the lung by a well known carcinogen, while phase 2 is

  6. Carcinogenicity of airborne combustion products observed in subcutaneous tissue and lungs of laboratory rodents.

    PubMed

    Pott, F; Stöber, W

    1983-01-01

    Most air pollution in West Germany is caused by combustion products. Particulate organic matter released by incomplete combustion is suspected to contribute to the "urban factor" of lung cancer frequency in urban-industrial centers. The carcinogenic potential of single components, groups of compounds and total source emissions of combustion processes was investigated in laboratory animals by subcutaneous injection, intratracheal instillation or inhalation. Tests by subcutaneous injection of condensates of automobile exhaust, extracts of coal furnace emissions and of airborne particles and different fractions of these extracts showed that the polycyclic aromatic hydrocarbons (PAH) with four to six benzene rings have the strongest experimental carcinogenicity. However, polar compounds (heterocyclic nitrogen-containing PAH, phenols, and others) also show remarkable carcinogenic potency. There were large differences between the dose-response relationships of several PAHs. In the subcutaneous tissue, benzo(a)pyrene and dibenz(a,h)anthracene are the most carcinogenic of the tested airborne PAHs. Furthermore, they can induce high tumor rates in the lung after subcutaneous injection in newborn mice and after intratracheal instillation of mice or hamsters. The tumor rate of benzo(a)pyrene did not further increase after simultaneous instillation of carbon black, but lead chloride may have a promoting effect. Far more than 100 PAHs are found in the urban atmosphere. However, because of the remarkable similarity of the PAH profiles in the examined samples, it may be sufficient to measure just a few stable PAHs in the urban air in order to facilitate an assessment of the carcinogenic potency of the PAH content in the atmosphere. To examine the carcinogenic or cocarcinogenic effects of gas and vapor emissions, studies with a two-phase model were carried out: phase 1 relates to the induction of a basic tumor rate in the lung by a well known carcinogen, while phase 2 is

  7. Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents.

    PubMed

    Hurley, P M

    1998-08-01

    Of 240 pesticides screened for carcinogenicity by the U.S. Environmental Protection Agency Office of Pesticide Programs, at least 24 (10%) produce thyroid follicular cell tumors in rodents. Thirteen of the thyroid carcinogens also induce liver tumors, mainly in mice, and 9 chemicals produce tumors at other sites. Some mutagenic data are available on all 24 pesticides producing thyroid tumors. Mutagenicity does not seem to be a major determinant in thyroid carcinogenicity, except for possibly acetochlor; evidence is less convincing for ethylene thiourea and etridiazole. Studies on thyroid-pituitary functioning, including indications of thyroid cell growth and/or changes in thyroxine, triiodothyronine, or thyroid-stimulating hormone levels, are available on 19 pesticides. No such antithyroid information is available for etridiazole, N-octyl bicycloheptene dicarboximide, terbutryn, triadimefon, and trifluralin. Of the studied chemicals, only bromacil lacks antithyroid activity under study conditions. Intrathyroidal and extrathyroidal sites of action are found: amitrole, ethylene thiourea, and mancozeb are thyroid peroxidase inhibitors; and acetochlor, clofentezine, fenbuconazole, fipronil, pendimethalin, pentachloronitrobenzene, prodiamine, pyrimethanil, and thiazopyr seem to enhance the hepatic metabolism and excretion of thyroid hormone. Thus, with 12 pesticides that mode of action judgments can be made, 11 disrupt thyroid-pituitary homeostasis only; no chemical is mutagenic only; and acetochlor may have both antithyroid and some mutagenic activity. More information is needed to identify other potential antithyroid modes of thyroid carcinogenic action.

  8. Evaluation of the carcinogenic risks at the influence of POPs.

    PubMed

    Nazhmetdinova, Aiman; Kassymbayev, Adlet; Chalginbayeva, Altinay

    2017-12-20

    Kazakhstan is included in the list of environmentally vulnerable countries and Kyzylorda oblast in particular. This is due to its geographical, spatial and temporal and socioeconomic features. As part of the program "Integrated approaches in the management of public health in the Aral region", we have carried out an expertise on many samples of natural environments and products. Samples were selected in accordance with sampling procedures according to regulatory documents by specialists of the Pesticide Toxicology Laboratory. It is accredited by the State Standard of the Republic of Kazakhstan, for compliance with ST RK ISO/IEC 17025-2007 "General requirements for the competence of test and calibration laboratories". Gas chromatograph was used for the determination of residues of organochlorine pesticides. For the determination of dioxins, polychlorinated biphenyl was conducted on the gas chromatomass spectrometer with quadruple detector produce by Agilent Company, USA. To assess the risk, we carried out the mathematical calculations according to the risk of chemicals polluting (No P 2.1.10.1920-04, Russia). Calculation of the carcinogenic risk was carried out with the use of data on the size of the exposure and meanings of carcinogenic potential factors (slope factor and unit risk). The evaluation of persistent organic pollutants (POPs), based on the previous results of the research concerning water, soil and food products, was held in five population settlements in Kyzylorda oblast villages: Ayteke bi, Zhalagash, Zhosaly, Shieli and Aralsk town. Pollution with the POPs in the environmental objects by means of exposition and evaluation of the carcinogenic risk to human health is confirmed by the data of the statistical reporting about some morbidity in Kyzylorda oblast, such as skin diseases and subcutaneous tissue, endocrine system diseases, pregnancy complications etc. The received levels of carcinogenic risks, which were first carried out in the Republic of

  9. Aberrant activation of ubiquitin D at G2 phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats.

    PubMed

    Taniai, Eriko; Yafune, Atsunori; Hayashi, Hitomi; Itahashi, Megu; Hara-Kudo, Yukiko; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2012-01-01

    We have previously reported that renal carcinogens examined in rats increase tubular cell proliferation and topoisomerase (Topo) IIα(+) cells. The present study was aimed at identifying early prediction markers of carcinogens after 28-day treatment in rats. Following gene expression screening by microarrays in renal tubules with renal carcinogens, immunohistochemical analysis and TUNEL-assay were performed with carcinogens targeting different organs. All renal carcinogens tested (ferric nitrilotriacetic acid, ochratoxin A (OTA), monuron, tris(2-chloroethyl) phosphate, and potassium bromate) increased tubular cells immunoreactive for minichromosome maintenance 3 (Mcm3) or ubiquitin D (Ubd) or those showing apoptosis, compared with untreated controls or non-carcinogenic renal toxicants. Carcinogens targeting the liver (thioacetamide (TAA), fenbendazole, piperonyl butoxide (PBO) and methyleugenol), thyroid (sulfadimethoxine), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole), glandular stomach (catechol), and colon (chenodeoxycholic acid and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) were examined for induction of Mcm3, Ubd, Topo IIα, Ki-67 and apoptosis using non-carcinogenic toxicants as negative controls. All carcinogens increased Mcm3(+), Ubd(+), Topo IIα(+), Ki-67(+) or TUNEL(+) cells, except for hepatocarcinogen PBO and both colon carcinogens, which did not increase cell proliferation. Ubd(+) cells co-expressing Topo IIα was increased without changing phospho-Histone H3-co-expressing cell population as examined with OTA and TAA. Results revealed cooperative responses of Topo IIα, Ubd and apoptosis by carcinogens inducing high proliferation activity, irrespective of target organs, examined here after a 28-day administration. Aberrant expression of Ubd at G(2) phase and increased apoptosis reflecting aberrant cell cycle regulation may be the common feature of these carcinogens.

  10. On the International Agency for Research on Cancer classification of glyphosate as a probable human carcinogen.

    PubMed

    Tarone, Robert E

    2018-01-01

    The recent classification by International Agency for Research on Cancer (IARC) of the herbicide glyphosate as a probable human carcinogen has generated considerable discussion. The classification is at variance with evaluations of the carcinogenic potential of glyphosate by several national and international regulatory bodies. The basis for the IARC classification is examined under the assumptions that the IARC criteria are reasonable and that the body of scientific studies determined by IARC staff to be relevant to the evaluation of glyphosate by the Monograph Working Group is sufficiently complete. It is shown that the classification of glyphosate as a probable human carcinogen was the result of a flawed and incomplete summary of the experimental evidence evaluated by the Working Group. Rational and effective cancer prevention activities depend on scientifically sound and unbiased assessments of the carcinogenic potential of suspected agents. Implications of the erroneous classification of glyphosate with respect to the IARC Monograph Working Group deliberative process are discussed.

  11. Electron-density descriptors as predictors in quantitative structure--activity/property relationships and drug design.

    PubMed

    Matta, Chérif F; Arabi, Alya A

    2011-06-01

    The use of electron density-based molecular descriptors in drug research, particularly in quantitative structure--activity relationships/quantitative structure--property relationships studies, is reviewed. The exposition starts by a discussion of molecular similarity and transferability in terms of the underlying electron density, which leads to a qualitative introduction to the quantum theory of atoms in molecules (QTAIM). The starting point of QTAIM is the topological analysis of the molecular electron-density distributions to extract atomic and bond properties that characterize every atom and bond in the molecule. These atomic and bond properties have considerable potential as bases for the construction of robust quantitative structure--activity/property relationships models as shown by selected examples in this review. QTAIM is applicable to the electron density calculated from quantum-chemical calculations and/or that obtained from ultra-high resolution x-ray diffraction experiments followed by nonspherical refinement. Atomic and bond properties are introduced followed by examples of application of each of these two families of descriptors. The review ends with a study whereby the molecular electrostatic potential, uniquely determined by the density, is used in conjunction with atomic properties to elucidate the reasons for the biological similarity of bioisosteres.

  12. 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.

    PubMed

    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 <1.0, 4.8±0.1, 6.7±0.3, and 2.7±0.1 h, respectively. CG-2 decomposed primarily via a retro-Michael reaction to produce dG and CBO, with only a small fraction of CG-2 degrading to CG-3. Decomposition of CG-4 proceeded via a cyclization reaction and/or replacement of the chlorine atom by a hydroxyl group to form 1,N2-(1-hydroxy-1-hydroxymethylpropan-1,3-diyl)-2'-deoxyguanosine (CG-4D1) and N(2)-(4-hydroxy-3-oxobutyl)-2'-deoxyguanosine (CG-4D2), whereas decomposition of CG-5/6 yielded CG-1. Collectively, the newly characterized CBO adducts could be used to investigate the role of CBO in the mechanism of BD carcinogenicity and could also be used to develop biomarkers for BD exposure. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  13. Medical follow-up of workers exposed to lung carcinogens: French evidence-based and pragmatic recommendations.

    PubMed

    Delva, Fleur; Margery, Jacques; Laurent, François; Petitprez, Karine; Pairon, Jean-Claude

    2017-02-14

    The aim of this work was to establish recommendations for the medical follow-up of workers currently or previously exposed to lung carcinogens. A critical synthesis of the literature was conducted. Occupational lung carcinogenic substances were listed and classified according to their level of lung cancer risk. A targeted screening protocol was defined. A clinical trial, National Lung Screnning Trial (NLST), showed the efficacy of chest CAT scan (CT) screening for populations of smokers aged 55-74 years with over 30 pack-years of exposure who had stopped smoking for less than 15 years. To propose screening in accordance with NLST criteria, and to account for occupational risk factors, screening among smokers and former smokers needs to consider the types of occupational exposure for which the risk level is at least equivalent to the risk of the subjects included in the NLST. The working group proposes an algorithm that estimates the relative risk of each occupational lung carcinogen, taking into account exposure to tobacco, based on available data from the literature. Given the lack of data on bronchopulmonary cancer (BPC) screening in occupationally exposed workers, the working group proposed implementing a screening experiment for bronchopulmonary cancer in subjects occupationally exposed or having been occupationally exposed to lung carcinogens who are confirmed as having high risk factors for BPC. A specific algorithm is proposed to determine the level of risk of BPC, taking into account the different occupational lung carcinogens and tobacco smoking at the individual level.

  14. Cyclodextrin-enhanced extraction and energy transfer of carcinogens in complex oil environments.

    PubMed

    Serio, Nicole; Chanthalyma, Chitapom; Prignano, Lindsey; Levine, Mindy

    2013-11-27

    Reported herein is the use of γ-cyclodextrin for two tandem functions: (a) the extraction of carcinogenic polycyclic aromatic hydrocarbons (PAHs) from oil samples into aqueous solution and (b) the promotion of highly efficient energy transfer from the newly extracted PAHs to a high-quantum-yield fluorophore. The extraction proceeded in moderate to good efficiencies, and the resulting cyclodextrin-promoted energy transfer led to a new, brightly fluorescent signal in aqueous solution. The resulting dual-function system (extraction followed by energy transfer) has significant relevance in the environmental detection and cleanup of oil-spill-related carcinogens.

  15. Supplement to the Carcinogenic Potency Database (CPDB): results of animal bioassays published in the general literature in 1993 to 1994 and by the National Toxicology Program in 1995 to 1996.

    PubMed Central

    Gold, L S; Manley, N B; Slone, T H; Rohrbach, L

    1999-01-01

    The Carcinogenic Potency Database (CPDB) is a systematic and unifying analysis of results of chronic, long-term cancer tests. This paper presents a supplemental plot of the CPDB, including 513 experiments on 157 test compounds published in the general literature in 1993 and 1994 and in Technical Reports of the National Toxicology Program in 1995 and 1996. The plot standardizes the experimental results (whether positive or negative for carcinogenicity), including qualitative data on strain, sex, route of compound administration, target organ, histopathology, and author's opinion and reference to the published paper, as well as quantitative data on carcinogenic potency, statistical significance, tumor incidence, dose-response curve shape, length of experiment, duration of dosing, and dose rate. A numerical description of carcinogenic potency, the TD(subscript)50(/subscript), is estimated for each set of tumor incidence data reported. When added to the data published earlier, the CPDB now includes results of 5,620 experiments on 1,372 chemicals that have been reported in 1,250 published papers and 414 National Cancer Institute/National Toxicology Program Technical Reports. The plot presented here includes detailed analyses of 25 chemicals tested in monkeys for up to 32 years by the National Cancer Institute. Half the rodent carcinogens that were tested in monkeys were not carcinogenic, despite usually strong evidence of carcinogenicity in rodents and/or humans. Our analysis of possible explanatory factors indicates that this result is due in part to the fact that the monkey studies lacked power to detect an effect compared to standard rodent bioassays. Factors that contributed to the lack of power are the small number of animals on test; a stop-exposure protocol for model rodent carcinogens; in a few cases, toxic doses that resulted in stoppage of dosing or termination of the experiment; and in a few cases, low doses administered to monkeys or early termination of the

  16. The Syrian hamster embryo cells transformation assay identifies efficiently nongenotoxic carcinogens, and can contribute to alternative, integrated testing strategies.

    PubMed

    Benigni, Romualdo; Bossa, Cecilia; Tcheremenskaia, Olga; Battistelli, Chiara Laura; Giuliani, Alessandro

    2015-02-01

    The long-term carcinogenesis bioassays have played a central role in protecting human health, but for ethical and practical reasons their use is dramatically diminishing and the genotoxicity short-term tests have taken the pivotal role in the pre-screening of chemical carcinogenicity. However, this strategy cannot detect nongenotoxic carcinogens. Since up to 25% of IARC human carcinogens are recognized to have nongenotoxic mechanisms of action, the risk they pose to human health cannot be disregarded, and it is urgent to fill the gap in the tools for alternative testing. In this paper, we analyze from different perspectives the ability of Cell Transformation Assays to identify nongenotoxic carcinogens, and we conclude that the Syrian hamster embryo cells test is able to identify nongenotoxic carcinogens with 80-90% efficiency, and thus, can play an important role in integrated, alternative testing strategies. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. UVA radiation induced ultrafast electron transfer from a food carcinogen benzo[a]pyrene to organic molecules, biological macromolecules, and inorganic nano structures.

    PubMed

    Banerjee, Soma; Sarkar, Soumik; Lakshman, Karthik; Dutta, Joydeep; Pal, Samir Kumar

    2013-04-11

    Reactions involving electron transfer (ET) and reactive oxygen species (ROS) play a pivotal role in carcinogenesis and cancer biochemistry. Our present study emphasizes UVA radiation induced ET reaction as one of the key aspects of a potential carcinogen, benzo[a]pyrene (BP), in the presence of a wide variety of molecules covering organic p-benzoquinone (BQ), biological macromolecules like calf-thymus DNA (CT-DNA), human serum albumin (HSA) protein, and inorganic zinc oxide (ZnO) nanorods (NRs). Steady-state and picosecond-resolved fluorescence spectroscopy have been used to monitor such ET reactions. Physical consequences of BP association with CT-DNA have been investigated through temperature-dependent circular dichroism (CD) spectroscopy. The temperature-dependent steady-state, picosecond-resolved fluorescence lifetime and anisotropy studies reveal the effect of temperature on the perturbation of such ET reactions from BP to biological macromolecules, highlighting their temperature-dependent association. Furthermore, the electron-donating property of BP has been corroborated by measuring wavelength-dependent photocurrent in a BP-anchored ZnO NR-based photodevice, offering new physical insights for the carcinogenic study of BP.

  18. A study of tobacco carcinogenesis XLVIII. Carcinogenicity of N'-nitrosonornicotine in mink (Mustela vison).

    PubMed

    Koppang, N; Rivenson, A; Reith, A; Dahle, H K; Evensen, O; Hoffmann, D

    1992-11-01

    During tobacco processing and smoking, nicotine and nornicotine give rise to N'-nitrosonornicotine (NNN), a highly abundant, strong carcinogen. NNN is known to exert carcinogenic activity in mice, rats and hamsters. Major target organs for NNN carcinogenicity in the rat are the esophagus and the nasal mucosa, and in the Syrian golden hamster trachea and nasal mucosa. In comparison with the rat, the mink (Mustela vison) has a markedly expanded nasal mucosa. Therefore, we explored in this study whether the mink could serve as a non-rodent model for nasal carcinogenesis using NNN as the carcinogen. Twenty random-bred mink, beginning at the age of 3 weeks, received twice weekly s.c. injections of NNN, a total dose of 11.9 mM per animal over a 38 week period. All of the 19 mink at risk developed malignant tumors of both the respiratory and the olfactory region of the nose within 3.5 years. In most animals the malignant tumors, primarily esthesioneuroepithelioma, invaded the brain. Remarkably, NNN induced no other tumors in the mink. None of the control animals developed nasal tumors nor tumors at other sites during the 3.5 years of the assay. The historical data from the farm did not reveal any spontaneous occurrence of nasal tumors in mink at any age. This study supports the concept that NNN is a proven carcinogen for multiple species of mammals and that the mink can serve as a non-rodent, non-inbred animal model for nasal carcinogenesis, especially since NNN induces only tumors in the nasal cavity in this species and not at other sites, as it does in mice, rats and hamsters.

  19. INSIGHTS INTO THE CARCINOGENIC MODE OF ACTION OF ARSENIC

    EPA Science Inventory

    That arsenic can induce cancer in humans has been known since the late 17th century, yet how arsenic induces cancer has been the subject of numerous scientific publications. Various modes of action (MOA) have been proposed for arsenic's carcinogenicity. In this paper we review o...

  20. Evaluation of the sensitivity and specificity of in vivo erythrocyte micronucleus and transgenic rodent gene mutation tests to detect rodent carcinogens.

    PubMed

    Morita, Takeshi; Hamada, Shuichi; Masumura, Kenichi; Wakata, Akihiro; Maniwa, Jiro; Takasawa, Hironao; Yasunaga, Katsuaki; Hashizume, Tsuneo; Honma, Masamitsu

    2016-05-01

    Sensitivity and/or specificity of the in vivo erythrocyte micronucleus (MN) and transgenic rodent mutation (TGR) tests to detect rodent carcinogens and non-carcinogens were investigated. The Carcinogenicity and Genotoxicity eXperience (CGX) dataset created by Kirkland et al. was used for the carcinogenicity and in vitro genotoxicity data, i.e., Ames and chromosome aberration (CA) tests. Broad literature surveys were conducted to gather in vivo MN or TGR test data to add to the CGX dataset. Genotoxicity data in vitro were also updated slightly. Data on 379 chemicals (293 carcinogens and 86 non-carcinogens) were available for the in vivo MN test; sensitivity, specificity or concordances were calculated as 41.0%, 60.5% or 45.4%, respectively. For the TGR test, data on 80 chemicals (76 carcinogens and 4 non-carcinogens) were available; sensitivity was calculated as 72.4%. Based on the recent guidance on genotoxicity testing strategies, performance (sensitivity/specificity) of the following combinations was calculated; Ames+in vivo MN (68.7%/45.3%), Ames+TGR (83.8%/not calculated (nc)), Ames+in vitro CA+in vivo MN (80.8%/21.3%), Ames+in vitro CA+TGR (89.1%/nc), Ames+in vivo MN+TGR (87.5%/nc), Ames+in vitro CA+in vivo MN+TGR (89.3%/nc). Relatively good balance in performance was shown by the Ames+in vivo MN in comparison with Ames+in vitro CA (74.3%/37.5%). Ames+TGR and Ames+in vivo MN+TGR gave even higher sensitivity, but the specificity could not be calculated (too few TGR data on non-carcinogens). This indicates that in vivo MN and TGR tests are both useful as in vivo tests to detect rodent carcinogens. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Structure modification and functionality of whey proteins: quantitative structure-activity relationship approach.

    PubMed

    Nakai, S; Li-Chan, E

    1985-10-01

    According to the original idea of quantitative structure-activity relationship, electric, hydrophobic, and structural parameters should be taken into consideration for elucidating functionality. Changes in these parameters are reflected in the property of protein solubility upon modification of whey proteins by heating. Although solubility is itself a functional property, it has been utilized to explain other functionalities of proteins. However, better correlations were obtained when hydrophobic parameters of the proteins were used in conjunction with solubility. Various treatments reported in the literature were applied to whey protein concentrate in an attempt to obtain whipping and gelling properties similar to those of egg white. Mapping simplex optimization was used to search for the best results. Improvement in whipping properties by pepsin hydrolysis may have been due to higher protein solubility, and good gelling properties resulting from polyphosphate treatment may have been due to an increase in exposable hydrophobicity. However, the results of angel food cake making were still unsatisfactory.

  2. A Review of the Carcinogenic Potential of Bisphenol A

    PubMed Central

    Seachrist, Darcie D; Bonk, Kristen W.; Ho, Shuk-Mei; Prins, Gail S.; Soto, Ana M.; Keri, Ruth A.

    2015-01-01

    The estrogenic properties of bisphenol A (BPA), a ubiquitous synthetic monomer that can leach into the food and water supply, have prompted considerable research into exposure-associated health risks in humans. Endocrine-disrupting properties of BPA suggest it may impact developmental plasticity during early life, predisposing individuals to disease at doses below the oral reference dose (RfD) established by the Environmental Protection Agency in 1982. Herein, we review the current in vivo literature evaluating the carcinogenic properties of BPA. We conclude that there is substantial evidence from rodent studies indicating that early-life BPA exposures below the RfD lead to increased susceptibility to mammary and prostate cancer. Based on the definitions of “carcinogen” put forth by the International Agency for Research on Cancer and the National Toxicology Program, we propose that BPA may be reasonably anticipated to be a human carcinogen in the breast and prostate due to its tumor promoting properties. PMID:26493093

  3. Carcinogenicity of multi-walled carbon nanotubes: challenging issue on hazard assessment.

    PubMed

    Fukushima, Shoji; Kasai, Tatsuya; Umeda, Yumi; Ohnishi, Makoto; Sasaki, Toshiaki; Matsumoto, Michiharu

    2018-01-25

    This report reviews the carcinogenicity of multi-walled carbon nanotubes (MWCNTs) in experimental animals, concentrating on MWNT-7, a straight fibrous MWCNT. MWCNTs were administered to mice and rats by intraperitoneal injection, intrascrotal injection, subcutaneous injection, intratracheal instillation and inhalation. Intraperitoneal injection of MWNT-7 induced peritoneal mesothelioma in mice and rats. Intrascrotal injection induced peritoneal mesothelioma in rats. Intratracheal instillation of MWCNT-N (another straight fibrous MWCNT) induced both lung carcinoma and pleural mesothelioma in rats. In the whole body inhalation studies, in mice MWNT-7 promoted methylcholanthrene-initiated lung carcinogenesis. In rats, inhalation of MWNT-7 induced lung carcinoma and lung burdens of MWNT-7 increased with increasing concentration of airborne MWNT-7 and increasing duration of exposure. Straight, fibrous MWCNTs exerted carcinogenicity in experimental animals. Phagocytosis of MWCNT fibers by macrophages was very likely to be a principle factor in MWCNT lung carcinogenesis. Using no-observed-adverse-effect level-based approach, we calculated that the occupational exposure limit (OEL) of MWNT-7 for cancer protection is 0.15 μg/m 3 for a human worker. Further studies on the effects of the shape and size of MWCNT fibers and mode of action on the carcinogenicity are required.

  4. Carcinogenicity of airborne fine particulate benzo(a)pyrene: an appraisal of the evidence and the need for control.

    PubMed Central

    Perera, F

    1981-01-01

    Benzo(a)pyrene(BaP) originating from fossil fuel and other organic combustion processes is largely adsorbed on fine particulate and hence is a widespread atmospheric pollutant. Available emissions and air quality data are based on the total weight of particulate matter without reference to size and give little information on trends and concentrations of fine particulate BaP. Greater reliance on coal, synfuels and diesel fuel for energy production and transportation will significantly increase ambient levels of BaP. Because of the particulate size, BaP is substantially deposited in the lower lung and readily eluted into surrounding tissue. After elution in the lung, BaP is metabolically activated to its electrophilic, carcinogenic from by a complex enzyme system whose activity is increased by prior exposure to air pollutants, cigarette smoke and certain drugs. The resultant diol epoxide metabolite has been shown to bind covalently with the DNA of the lung. In experimental animals, BaP is a potent initiating carcinogen whose action is enhanced by sulfur dioxide, promoting agents and carrier fine particles. The effect of small, divided doses of BaP has been shown to be greater than that of a single high dose; no threshold has been established. Epidemiological studies show that mixtures containing BaP (such as urban air, industrial emissions and cigarette smoke) are carcinogenic and may interact synergistically. Occupational studies indicate that the action of BaP-containing mixtures is enhanced in the presence of SO2. However, quantitative risk assessment for BaP is precluded by problems in extrapolating to the general population from small-scale animal studies; uncertainties in findings of epidemiology; and imprecise exposure data. Existing stationary and mobile controls preferentially remove coarse particulate matter and are inefficient collectors of the particulate BaP. In the current absence of health and environmental standards for BaP, there is little incentive

  5. Developing a Multiplexed Quantitative Cross-Linking Mass Spectrometry Platform for Comparative Structural Analysis of Protein Complexes.

    PubMed

    Yu, Clinton; Huszagh, Alexander; Viner, Rosa; Novitsky, Eric J; Rychnovsky, Scott D; Huang, Lan

    2016-10-18

    Cross-linking mass spectrometry (XL-MS) represents a recently popularized hybrid methodology for defining protein-protein interactions (PPIs) and analyzing structures of large protein assemblies. In particular, XL-MS strategies have been demonstrated to be effective in elucidating molecular details of PPIs at the peptide resolution, providing a complementary set of structural data that can be utilized to refine existing complex structures or direct de novo modeling of unknown protein structures. To study structural and interaction dynamics of protein complexes, quantitative cross-linking mass spectrometry (QXL-MS) strategies based on isotope-labeled cross-linkers have been developed. Although successful, these approaches are mostly limited to pairwise comparisons. In order to establish a robust workflow enabling comparative analysis of multiple cross-linked samples simultaneously, we have developed a multiplexed QXL-MS strategy, namely, QMIX (Quantitation of Multiplexed, Isobaric-labeled cross (X)-linked peptides) by integrating MS-cleavable cross-linkers with isobaric labeling reagents. This study has established a new analytical platform for quantitative analysis of cross-linked peptides, which can be directly applied for multiplexed comparisons of the conformational dynamics of protein complexes and PPIs at the proteome scale in future studies.

  6. Potential carcinogenic hazards of non-regulated disinfection by-products: haloquinones, halo-cyclopentene and cyclohexene derivatives, N-halamines, halonitriles, and heterocyclic amines.

    PubMed

    Bull, Richard J; Reckhow, David A; Li, Xingfang; Humpage, Andrew R; Joll, Cynthia; Hrudey, Steve E

    2011-08-15

    Drinking water disinfectants react with natural organic material (NOM) present in source waters used for drinking water to produce a wide variety of by-products. Several hundred disinfections by-products (DBPs) have been identified, but none have been identified with sufficient carcinogenic potency to account for the cancer risks projected from epidemiological studies. In a search for DBPs that might fill this risk gap, the present study projected reactions of chlorine and chloramine that could occur with substructures present in NOM to produce novel by-products. A review of toxicological data on related compounds, supplemented by use of a quantitative structure toxicity relationship (QSTR) program TOPKAT®) identified chemicals with a high probability of being chronically toxic and/or carcinogenic among 489 established and novel DBPs. Classes of DBPs that were specifically examined were haloquinones (HQs), related halo-cyclopentene and cyclohexene (HCP&H) derivatives, halonitriles (HNs), organic N-chloramines (NCls), haloacetamides (HAMs), and nitrosamines (NAs). A review of toxicological data available for quinones suggested that HQs and HCP&H derivatives appeared likely to be of health concern and were predicted to have chronic lowest observed adverse effect levels (LOAELs) in the low μg/kg day range. Several HQs were predicted to be carcinogenic. Some have now been identified in drinking water. The broader class of HNs was explored by considering current toxicological data on haloacetonitriles and extending this to halopropionitriles. 2,2-dichloropropionitrile has been identified in drinking water at low concentrations, as well as the more widely recognized haloacetonitriles. The occurrence of HAMs has been previously documented. The very limited toxicological data on HAMs suggests that this class would have toxicological potencies similar to the dihaloacetic acids. Organic N-halamines are also known to be produced in drinking water treatment and have

  7. THE CARCINOGENIC RESPONSE TO A MIXTURE OF DRINKING WATER DISINFECTION BY-PRODUCTS (DBP) WAS LESS THAN ADDITIVE

    EPA Science Inventory

    THE CARCINOGENIC RESPONSE TO A MIXTURE OF DRINKING WATER DISINFECTION BY -PRODUCTS (DBP) W AS LESS THAN ADDITIVE.

    Current default risk assessments for chemical mixtures assume additivity of carcinogenic effects but this may under or over represent the actual biological res...

  8. Asian Americans and disproportionate exposure to carcinogenic hazardous air pollutants: A national study.

    PubMed

    Grineski, Sara E; Collins, Timothy W; Morales, Danielle X

    2017-07-01

    Studies have demonstrated disparate exposures to carcinogenic hazardous air pollutants (HAPs) in neighborhoods with high densities of Black and Hispanic residents in the US. Asians are the fastest growing racial/ethnic group in the US, yet they have been underemphasized in previous studies of environmental health and injustice. This cross-sectional study investigated possible disparities in residential exposure to carcinogenic HAPs among Asian Americans, including Asian American subgroups in the US (including all 50 states and the District of Columbia, n = 71,208 US census tracts) using National Air Toxics Assessment and US Census data. In an unadjusted analysis, Chinese and Korean Americans experience the highest mean cancer risks from HAPs, followed by Blacks. The aggregated Asian category ranks just below Blacks and above Hispanics, in terms of carcinogenic HAP risk. Multivariate models adjusting for socioeconomic status, population density, urban location, and geographic clustering show that an increase in proportion of Asian residents in census tracts is associated with significantly greater cancer risk from HAPs. Neighborhoods with higher proportions (as opposed to lower proportions) of Chinese, Korean, and South Asian residents have significantly greater cancer risk burdens relative to Whites. Tracts with higher concentrations of Asians speaking a non-English language and Asians that are US-born have significantly greater cancer risk burdens. Asian Americans experience substantial residential exposure to carcinogenic HAPs in US census tracts and in the US more generally. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    DTIC Science & Technology

    2005-08-01

    QSAR in Environmental Researth was accepted and published in April of 2005. The manuscript described the cat -SAR program in detail. We note the...analysis of this data yielded a very good model. As such, this was a suitable dataset on which to develop and test the cat -SAR program. A copy of the...developed and validated (i.e., a-c) as planned in MCASE and then with the cat -SAR program. We have also updated rodent carcinogenicity models so that

  10. Consumption of organic meat does not diminish the carcinogenic potential associated with the intake of persistent organic pollutants (POPs).

    PubMed

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

    2017-02-01

    Numerous studies have shown an epidemiological link between meat consumption and the incidence of cancer, and it has been suggested that this relationship may be motivated by the presence of carcinogenic contaminants on it. Among the most frequently detected contaminants in meat are several types of persistent organic pollutants (POPs), and it is well known that many of them are carcinogenic. On the other hand, an increasing number of consumers choose to feed on what are perceived as healthier foods. Thus, the number of consumers of organic food is growing. However, environmental contamination by POPs is ubiquitous, and it is therefore unlikely that the practices of organic food production are able to prevent this contamination. To test this hypothesis, we acquired 76 samples of meat (beef, chicken, and lamb) of two modes of production (organic and conventional) and quantified their levels of 33 carcinogenic POPs. On this basis, we determined the human meat-related daily dietary exposure to these carcinogens using as a model a population with a high consumption of meat, such as the Spanish population. The maximum allowable meat consumption for this population and the carcinogenic risk quotients associated with the current pattern of consumption were calculated. As expected, no sample was completely free of carcinogenic contaminants, and the differences between organically and conventionally produced meats were minimal. According to these results, the current pattern of meat consumption exceeded the maximum limits, which are set according to the levels of contaminations, and this is associated with a relevant carcinogenic risk. Strikingly, the consumption of organically produced meat does not diminish this carcinogenic risk, but on the contrary, it seems to be even higher, especially that associated with lamb consumption.

  11. Vaccinia virus, herpes simplex virus, and carcinogens induce DNA amplification in a human cell line and support replication of a helpervirus dependent parvovirus

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

    Schlehofer, J.R.; Ehrbar, M.; zur Hausen, H.

    1986-07-15

    The SV40-transformed human kidney cell line, NB-E, amplifies integrated as well as episomal SV40 DNA upon treatment with chemical (DMBA) or physical (uv irradiation) carcinogens (initiators) as well as after infection with herpes simplex virus (HSV) type 1 or with vaccinia virus. In addition it is shown that vaccinia virus induces SV40 DNA amplification also in the SV40-transformed Chinese hamster embryo cell line, CO631. These findings demonstrate that human cells similar to Chinese hamster cells amplify integrated DNA sequences after treatment with carcinogens or infection with specific viruses. Furthermore, a poxvirus--vaccinia virus--similar to herpes group viruses induces DNA amplification. Asmore » reported for other systems, the vaccinia virus-induced DNA amplification in NB-E cells is inhibited by coinfection with adeno-associated virus (AAV) type 5. This is in line with previous studies on inhibition of carcinogen- or HSV-induced DNA amplification in CO631 cells. The experiments also demonstrate that vaccinia virus, in addition to herpes and adenoviruses acts as a helper virus for replication and structural antigen synthesis of AAV-5 in NB-E cells.« less

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

    EPA Science Inventory

    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(...

  13. Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents.

    PubMed

    van den Brink, Willem; Emerenciana, Annette; Bellanti, Francesco; Della Pasqua, Oscar; van der Laan, Jan Willem

    2017-04-01

    Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products (exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using nonlinear mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation and C-cell hyperplasia after 2years of treatment. The predictive performance of the model was evaluated using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation for all four products, which is not possible with traditional data analysis methods. It can be concluded that both pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity. The concept is promising for application to other drug classes. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Nonparametric modeling of longitudinal covariance structure in functional mapping of quantitative trait loci.

    PubMed

    Yap, John Stephen; Fan, Jianqing; Wu, Rongling

    2009-12-01

    Estimation of the covariance structure of longitudinal processes is a fundamental prerequisite for the practical deployment of functional mapping designed to study the genetic regulation and network of quantitative variation in dynamic complex traits. We present a nonparametric approach for estimating the covariance structure of a quantitative trait measured repeatedly at a series of time points. Specifically, we adopt Huang et al.'s (2006, Biometrika 93, 85-98) approach of invoking the modified Cholesky decomposition and converting the problem into modeling a sequence of regressions of responses. A regularized covariance estimator is obtained using a normal penalized likelihood with an L(2) penalty. This approach, embedded within a mixture likelihood framework, leads to enhanced accuracy, precision, and flexibility of functional mapping while preserving its biological relevance. Simulation studies are performed to reveal the statistical properties and advantages of the proposed method. A real example from a mouse genome project is analyzed to illustrate the utilization of the methodology. The new method will provide a useful tool for genome-wide scanning for the existence and distribution of quantitative trait loci underlying a dynamic trait important to agriculture, biology, and health sciences.

  15. Biological monitoring of carcinogens: current status and perspectives.

    PubMed

    Pavanello, Sofia; Lotti, Marcello

    2012-04-01

    Biomonitoring exposures to carcinogens is common practice and a variety of biomarkers have been developed to assess both exposures and biochemical/biological effects. However, their clinical and preventive relevance is still uncertain. The understanding of cancer as a genetic disease has dramatically evolved during last decades, showing that cancer cell types acquire their characteristics with different strategies, time frames and microenvironments. Therefore, the place of current biomarkers within this complex scenario of gene-environment interactions leading to cancer cannot be defined. Reasons are manifold. Most studies assessed cancer risk on a group basis through snapshots taken at unknown time-points of the postulated chain of events. Little attention has been paid to the variety and variability of exposures, and no prospective study validated the indicators of biochemical/biological effects. New opportunities and suggestions for biomonitoring exposures to carcinogens could derive from exploring the exposome that combines exposures from all sources both external and internal. The discovery of new biomarkers and the identification of relevant gene-specific pathways could be achieved through metabolomic and genome-wide studies. In conclusion, it is possible to envisage personalized biomonitoring procedures, such as those already implemented in the context of nutrition and clinical oncology.

  16. Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide ...

    EPA Pesticide Factsheets

    In December 2016, EPA finalized its Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide. EPA’s evaluation was reviewed internally by EPA and by other federal agencies and White House Offices in October 2016, before public release. Consistent with the May 2009 IRIS assessment development process, all written comments on IRIS assessments submitted by other federal agencies and White House Offices are made publicly available. Accordingly, interagency comments and the interagency science discussion materials provided to other agencies, including interagency review drafts of the EPA’s Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide, are posted on this site. Note: No major science comments were received on the Interagency Science Discussion Draft. The Toxicological Review and charge were reviewed internally by EPA and by other federal agencies and White House Offices before public release. Consistent with the May 2009 IRIS assessment development process, all written comments on IRIS assessments submitted by other federal agencies and White House Offices are made publicly available. Accordingly, interagency comments and the interagency science consultation materials provided to other agencies, including interagency review drafts of the IRIS Toxicological Review of Ammonia and the charge to external peer reviewers, are posted on this site.

  17. Quantification of the carcinogenic effect of polycyclic aromatic hydrocarbons in used engine oil by topical application onto the skin of mice.

    PubMed

    Grimmer, G; Dettbarn, G; Brune, H; Deutsch-Wenzel, R; Misfeld, J

    1982-01-01

    The purpose of this investigation was to identify the substances mainly responsible for the carcinogenic effect of used engine oil from gasoline engines using topical application as a carcinogen-specific bioassay. This was performed by comparison of the tumorigenic effect of single fractions with that of an unseparated sample of the lubricating oil. The probit analysis of the results shows: 1) The used engine oil, from gasoline-driven automobiles, investigated provoked local tumors after long-term application to the dorsal skin of mice. The incidence of carcinoma depended on the dose of the oil. 2) The fraction of the polycyclic aromatic hydrocarbons (PAH) containing more than three rings accounts for about 70% of the total carcinogenicity in the case of crankcase oil. This fraction constitutes only up to 1.14% by weight of the total oil sample. 3) The content of benzo(a)pyrene (216.8 mg/kg) accounts for 18% of the total carcinogenicity of the used oil. 4) Regarding the reduced carcinogenicity of the oil sample, which was reconstituted from all fractions, it seems possible that some of the carcinogenic substances were lost due to volatility, with evaporation of the solvents from the oil-fractionation processes. 5) Regarding the small effect of the PAH-free fraction, as well as the equal carcinogenic effects of the PAH-fraction (containing more than three rings) and the reconstituted oil sample, no hints for a co-carcinogenic activity were obtained.

  18. Quantitative analysis of voids in percolating structures in two-dimensional N-body simulations

    NASA Technical Reports Server (NTRS)

    Harrington, Patrick M.; Melott, Adrian L.; Shandarin, Sergei F.

    1993-01-01

    We present in this paper a quantitative method for defining void size in large-scale structure based on percolation threshold density. Beginning with two-dimensional gravitational clustering simulations smoothed to the threshold of nonlinearity, we perform percolation analysis to determine the large scale structure. The resulting objective definition of voids has a natural scaling property, is topologically interesting, and can be applied immediately to redshift surveys.

  19. Quantitative Understanding of SHAPE Mechanism from RNA Structure and Dynamics Analysis.

    PubMed

    Hurst, Travis; Xu, Xiaojun; Zhao, Peinan; Chen, Shi-Jie

    2018-05-10

    The selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) method probes RNA local structural and dynamic information at single nucleotide resolution. To gain quantitative insights into the relationship between nucleotide flexibility, RNA 3D structure, and SHAPE reactivity, we develop a 3D Structure-SHAPE Relationship model (3DSSR) to rebuild SHAPE profiles from 3D structures. The model starts from RNA structures and combines nucleotide interaction strength and conformational propensity, ligand (SHAPE reagent) accessibility, and base-pairing pattern through a composite function to quantify the correlation between SHAPE reactivity and nucleotide conformational stability. The 3DSSR model shows the relationship between SHAPE reactivity and RNA structure and energetics. Comparisons between the 3DSSR-predicted SHAPE profile and the experimental SHAPE data show correlation, suggesting that the extracted analytical function may have captured the key factors that determine the SHAPE reactivity profile. Furthermore, the theory offers an effective method to sieve RNA 3D models and exclude models that are incompatible with experimental SHAPE data.

  20. [Quantitative relationship between gas chromatographic retention time and structural parameters of alkylphenols].

    PubMed

    Ruan, Xiaofang; Zhang, Ruisheng; Yao, Xiaojun; Liu, Mancang; Fan, Botao

    2007-03-01

    Alkylphenols are a group of permanent pollutants in the environment and could adversely disturb the human endocrine system. It is therefore important to effectively separate and measure the alkylphenols. To guide the chromatographic analysis of these compounds in practice, the development of quantitative relationship between the molecular structure and the retention time of alkylphenols becomes necessary. In this study, topological, constitutional, geometrical, electrostatic and quantum-chemical descriptors of 44 alkylphenols were calculated using a software, CODESSA, and these descriptors were pre-selected using the heuristic method. As a result, three-descriptor linear model (LM) was developed to describe the relationship between the molecular structure and the retention time of alkylphenols. Meanwhile, the non-linear regression model was also developed based on support vector machine (SVM) using the same three descriptors. The correlation coefficient (R(2)) for the LM and SVM was 0.98 and 0. 92, and the corresponding root-mean-square error was 0. 99 and 2. 77, respectively. By comparing the stability and prediction ability of the two models, it was found that the linear model was a better method for describing the quantitative relationship between the retention time of alkylphenols and the molecular structure. The results obtained suggested that the linear model could be applied for the chromatographic analysis of alkylphenols with known molecular structural parameters.

  1. Differences in the Rate of In Situ Mammary Gland Development and Other Developmental Endpoints in Three Strains of Female Rat Commonly Used in Mammary Carcinogenesis Studies: Implications for Timing of Carcinogen Exposure

    PubMed Central

    Stanko, Jason P.; Kissling, Grace E.; Chappell, Vesna A.; Fenton, Suzanne E.

    2016-01-01

    The potential of chemicals to alter susceptibility to mammary tumor formation is often assessed using a carcinogen-induced study design in various rat strains. The rate of mammary gland development must be considered so that the timing of carcinogen administration is impactful. In this study, in situ mammary gland (MG) development was assessed in females of the Harlan Sprague Dawley (Hsd:SD), Charles River Sprague Dawley (Crl:SD), and Charles River Long Evans (Crl:LE) rat strains at postnatal day (PND) 25, 33, and 45. Development was evaluated by physical assessment of growth parameters, developmental scoring, and quantitative morphometric analysis. Though body weight was consistently lower and day of vaginal opening (VO) occurred latest in female Hsd:SD rats, they exhibited accelerated pre-and peripubertal MG development compared to other strains. Glands of Crl:SD and Crl:LE rats exhibited significantly more terminal end buds (TEBs) and TEB/mm than Hsd:SD rats around the time of VO. These data suggest a considerable difference in rate of MG development across commonly used strains, which is independent of body weight and timing of VO. In mammary tumor induction studies employing these strains, administration of the carcinogen should be timed appropriately, based on strain, to specifically target the peak of TEB occurrence. PMID:27613105

  2. Role of Mutagenicity in Asbestos Fiber-Induced Carcinogenicity and Other Diseases

    PubMed Central

    Huang, Sarah X. L.; Jaurand, Marie-Claude; Kamp, David W.; Whysner, John; Hei, Tom K.

    2011-01-01

    The cellular and molecular mechanisms of how asbestos fibers induce cancers and other diseases are not well understood. Both serpentine and amphibole asbestos fibers have been shown to induce oxidative stress, inflammatory responses, cellular toxicity and tissue injuries, genetic changes, and epigenetic alterations in target cells in vitro and tissues in vivo. Most of these mechanisms are believe to be shared by both fiber-induced cancers and noncancerous diseases. This article summarizes the findings from existing literature with a focus on genetic changes, specifically, mutagenicity of asbestos fibers. Thus far, experimental evidence suggesting the involvement of mutagenesis in asbestos carcinogenicity is more convincing than asbestos-induced fibrotic diseases. The potential contributions of mutagenicity to asbestos-induced diseases, with an emphasis on carcinogenicity, are reviewed from five aspects: (1) whether there is a mutagenic mode of action (MOA) in fiber-induced carcinogenesis; (2) mutagenicity/carcinogenicity at low dose; (3) biological activities that contribute to mutagenicity and impact of target tissue/cell type; (4) health endpoints with or without mutagenicity as a key event; and finally, (5) determinant factors of toxicity in mutagenicity. At the end of this review, a consensus statement of what is known, what is believed to be factual but requires confirmation, and existing data gaps, as well as future research needs and directions, is provided. PMID:21534089

  3. Genomic alterations in spontaneous and carcinogen-induced murine melanoma cell lines.

    PubMed

    Melnikova, Vladislava O; Bolshakov, Svetlana V; Walker, Christopher; Ananthaswamy, Honnavara N

    2004-03-25

    We have conducted an analysis of genetic alterations in spontaneous murine melanoma cell line B16F0 and its two metastatic clones, B16F1 and B16F10 and the carcinogen-induced murine melanoma cell lines CM519, CM3205, and K1735. We found that unlike human melanomas, the murine melanoma cell lines did not have activating mutations in the Braf oncogene at exon 11 or 15. However, there were distinct patterns of alterations in the ras, Ink4a/Arf, and p53 genes in the two melanoma groups. In the spontaneous B16 melanoma cell lines, expression of p16Ink4a and p19Arf tumor suppressor proteins was lost as a consequence of a large deletion spanning Ink4a/Arf exons 1alpha, 1beta, and 2. In contrast, the carcinogen-induced melanoma cell lines expressed p16Ink4a but had inactivating mutations in either p19Arf (K1735) or p53 (CM519 and CM3205). Inactivation of p19Arf or p53 in carcinogen-induced melanomas was accompanied by constitutive activation of mitogen-activated protein kinases (MAPKs) and/or mutation-associated activation of N-ras. These results indicate that genetic alterations in p16Ink4a/p19Arf, p53 and ras-MAPK pathways can cooperate in the development of murine melanoma.

  4. Studies on glyphosate-induced carcinogenicity in mouse skin: a proteomic approach.

    PubMed

    George, Jasmine; Prasad, Sahdeo; Mahmood, Zafar; Shukla, Yogeshwer

    2010-03-10

    Glyphosate is a widely used broad spectrum herbicide, reported to induce various toxic effects in non-target species, but its carcinogenic potential is still unknown. Here we showed the carcinogenic effects of glyphosate using 2-stage mouse skin carcinogenesis model and proteomic analysis. Carcinogenicity study revealed that glyphosate has tumor promoting activity. Proteomic analysis using 2-dimensional gel electrophoresis and mass spectrometry showed that 22 spots were differentially expressed (>2 fold) on glyphosate, 7, 12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) application over untreated control. Among them, 9 proteins (translation elongation factor eEF-1 alpha chain, carbonic anhydrase III, annexin II, calcyclin, fab fragment anti-VEGF antibody, peroxiredoxin-2, superoxide dismutase [Cu-Zn], stefin A3, and calgranulin-B) were common and showed similar expression pattern in glyphosate and TPA-treated mouse skin. These proteins are known to be involved in several key processes like apoptosis and growth-inhibition, anti-oxidant responses, etc. The up-regulation of calcyclin, calgranulin-B and down-regulation of superoxide dismutase [Cu-Zn] was further confirmed by immunoblotting, indicating that these proteins can be good candidate biomarkers for skin carcinogenesis induced by glyphosate. Altogether, these results suggested that glyphosate has tumor promoting potential in skin carcinogenesis and its mechanism seems to be similar to TPA. Copyright (c) 2009 Elsevier B.V. All rights reserved.

  5. [Painting in construction and exposure to carcinogenic chemical agents: an Italian study in Lombardy].

    PubMed

    Cirla, P E; Martinotti, I; Firmi, A M; Cirla, A M

    2012-01-01

    The risk associated with exposure to chemical carcinogens (as classified by International Agency for Research on Cancer and/or the European Union), during painting activities in construction seems controversial. This study included all 43 activities of professional painting in this sector existing in the area of Cremona, in Lombardy region. The aim was to consider and promote preventive technical and medical solutions, basing on efficacy. The occupational exposure and the already adopted preventive measures were evaluated by investigations at workplaces, supported by standardized questionnaires and registrations. 860 commercial products (402 chemical substances) were classified: in 38% of cases the ingredients were not listed in the Material Safety Data Sheets (retrieved by the manufacturer). The real possibility of a risk exposure to carcinogens has been reported in a small proportion of situations. In all companies the presence of carcinogens was unrecognized or at least had not been taken into account in the risk assessment of workers.

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

    PubMed

    Godderis, Lode; Thomas, Reuben; Hubbard, Alan E; Tabish, Ali M; Hoet, Peter; Zhang, Luoping; Smith, Martyn T; Veulemans, Hendrik; McHale, Cliona M

    2012-01-01

    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.

  7. Effect of Chemical Mutagens and Carcinogens on Gene Expression Profiles in Human TK6 Cells

    PubMed Central

    Godderis, Lode; Thomas, Reuben; Hubbard, Alan E.; Tabish, Ali M.; Hoet, Peter; Zhang, Luoping; Smith, Martyn T.; Veulemans, Hendrik; McHale, Cliona M.

    2012-01-01

    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. PMID:22723965

  8. OSHA Confronts Carcinogens in the Workplace as Inflation Fighters Confront OSHA.

    ERIC Educational Resources Information Center

    Heller, Ilene

    1978-01-01

    Discusses the apparently opposing forces of worker safety, as represented by the Occupational Safety and Health Administration (OSHA), and economic inflation spawned by expensive industrial processes needed to limit the emission of carcinogens. (CP)

  9. Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan

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

    Jackson, Anna Francina, E-mail: Francina.Jackson@hc-sc.gc.ca; Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa K1S 5B6; Williams, Andrew, E-mail: Andrew.Williams@hc-sc.gc.ca

    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 inmore » 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

  10. MUTAGENICITY AND CARCINOGENICITY ASSESSMENT OF 1,3-BUTADIENE. REVIEW DRAFT

    EPA Science Inventory

    The Mutagenicity and Carcinogenicity Assessment of 1,3-Butadiene was prepared to serve as a source document for Agency-wide use. In the development of this assessment document, the scientific literature has been inventoried, key studies have been evaluated, and the summary and co...

  11. Cell transformation and mutability of different genetic loci in mammalian cells by metabolically activated carcinogenic polycylic hydrocarbons

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

    Huberman, E.

    1977-01-01

    Treatment of experimental animals with chemical carcinogens, including some polycyclic hydrocarbons, can result in the formation of malignant tumors. The process whereby some chemicals induce malignancy is as yet unknown. However, in a model system using mammalian cells in culture, it was possible to show that the chemical carcinogens induce malignant transformation rather than select for pre-existing tumor cells. In the process of the in vitro cell transformation, the normal cells, which have an oriented pattern of cell growth, a limited life-span in vitro, and are not tumorigenic, are converted into cells that have a hereditary random pattern of cellmore » growth, the ability to grow continuously in culture, and the ability to form tumors in vivo. This stable heritable phenotype of the transformed cells is similar to that of cells derived from spontaneous or experimentally induced tumors. Such stable heritable phenotype changes may arise from alteration in gene expression due to a somatic mutation after interaction of the carcinogen with cellular DNA. In the present experiments we have shown that metabolically activated carcinogenic polycyclic hydrocarbons which have been shown to bind to cellular DNA induce somatic mutations at different genetic loci in mammalian cells and that there is a relationship between the degree of mutant induction and the degree of carcinogenicity of the different hydrocarbons tested.« less

  12. Quantitative magneto-optical investigation of superconductor/ferromagnet hybrid structures

    NASA Astrophysics Data System (ADS)

    Shaw, G.; Brisbois, J.; Pinheiro, L. B. G. L.; Müller, J.; Blanco Alvarez, S.; Devillers, T.; Dempsey, N. M.; Scheerder, J. E.; Van de Vondel, J.; Melinte, S.; Vanderbemden, P.; Motta, M.; Ortiz, W. A.; Hasselbach, K.; Kramer, R. B. G.; Silhanek, A. V.

    2018-02-01

    We present a detailed quantitative magneto-optical imaging study of several superconductor/ferromagnet hybrid structures, including Nb deposited on top of thermomagnetically patterned NdFeB and permalloy/niobium with erasable and tailored magnetic landscapes imprinted in the permalloy layer. The magneto-optical imaging data are complemented with and compared to scanning Hall probe microscopy measurements. Comprehensive protocols have been developed for calibrating, testing, and converting Faraday rotation data to magnetic field maps. Applied to the acquired data, they reveal the comparatively weaker magnetic response of the superconductor from the background of larger fields and field gradients generated by the magnetic layer.

  13. Quantitation of pyridyloxobutyl-DNA adducts in tissues of rats treated chronically with (R)- or (S)-N’-nitrosonornicotine (NNN) in a carcinogenicity study

    PubMed Central

    Zhao, Lijiao; Balbo, Silvia; Wang, Mingyao; Upadhyaya, Pramod; Khariwala, Samir S.; Villalta, Peter W.; Hecht, Stephen S.

    2013-01-01

    We quantified DNA adducts resulting from 2’-hydroxylation of enantiomers of the tobacco-specific nitrosamine N’-nitrosonornicotine (NNN) in tissues of male F-344 rats after 10, 30, 50, and 70 weeks of treatment with 14 ppm in the drinking water. These rats were in subgroups of a carcinogenicity study in which (S)-NNN was highly tumorigenic in the oral cavity and esophagus while (R)-NNN was relatively weakly active. DNA adducts were quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry in six tissues – oral mucosa, esophageal mucosa, nasal respiratory mucosa, nasal olfactory mucosa, liver, and lung. O2-[4-(3-Pyridyl)-4-oxobut-1-yl]thymidine (O2-POB-dThd, 7) and 7-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxyguanosine (7-POB-dGuo, 8), the latter as 7-[4-(3-pyridyl)-4-oxobut-1-yl]guanine (7-POB-Gua, 11), were detected at each time point in each tissue. In the target tissues for carcinogenicity, oral mucosa and esophageal mucosa, levels of 7-POB-Gua (11) and O2-POB-dThd (7) were similar, or 11 predominated, while in all other tissues at all time points for both enantiomers, 7 was clearly present in greater amounts than 11. Total measured DNA adduct levels in esophageal mucosa and oral mucosa were higher in rats treated with (S)-NNN than (R)-NNN. The highest adduct levels were found in the nasal respiratory mucosa. DNA adducts generally persisted in all tissues without any sign of substantial decreases throughout the 70 week time course. The results of this study suggest that inefficient repair of 7-POB-dGuo (8) in the rat oral cavity and esophagus may be important in carcinogenesis by NNN and support the development of these DNA adducts as potential biomarkers of NNN metabolic activation in people who use tobacco products. PMID:24001146

  14. Efficacy of computerized discrimination between structure-related and non-structure-related echoes in ultrasonographic images for the quantitative evaluation of the structural integrity of superficial digital flexor tendons in horses.

    PubMed

    van Schie, H T; Bakker, E M; Jonker, A M; van Weeren, P R

    2001-07-01

    To evaluate effectiveness of computerized discrimination between structure-related and non-structure-related echoes in ultrasonographic images for quantitative evaluation of tendon structural integrity in horses. 4 superficial digital flexor tendons (2 damaged tendons, 2 normal tendons). Transverse ultrasonographic images that precisely matched histologic sections were obtained in fixed steps along the long axis of each tendon. Distribution, intensity, and delineation of structure-related echoes, quantitatively expressed as the correlation ratio and steadiness ratio , were compared with histologic findings in tissue that was normal or had necrosis, early granulation, late granulation, early fibrosis, or inferior repair. In normal tendon, the even distribution of structure-related echoes with high intensity and sharp delineation yielded high correlation ratio and steadiness ratio. In areas of necrosis, collapsed endotendon septa yielded solid but blurred structure-related echoes (high correlation ration and low steadiness ratio). In early granulation tissue, complete lack of organization caused zero values for both ratios. In late granulation tissue, reorganization and swollen endotendon septa yielded poorly delineated structure-related echoes (high correlation ratio, low steadiness ratio). In early fibrosis, rearrangement of bundles resulted in normal correlation ration and slightly low steadiness ratio. In inferior repair, the almost complete lack of structural reorganization resulted in heterogeneous poorly delineated low-intensity echoes (low correlation ratio and steadiness ratio). The combination of correlation ratio and steadiness ratio accurately reflects histopathologic findings, making computerized correlation of ultrasonographic images an efficient tool for quantitative evaluation of tendon structural integrity.

  15. Quantitative Analysis of Cellular Metabolic Dissipative, Self-Organized Structures

    PubMed Central

    de la Fuente, Ildefonso Martínez

    2010-01-01

    One of the most important goals of the postgenomic era is understanding the metabolic dynamic processes and the functional structures generated by them. Extensive studies during the last three decades have shown that the dissipative self-organization of the functional enzymatic associations, the catalytic reactions produced during the metabolite channeling, the microcompartmentalization of these metabolic processes and the emergence of dissipative networks are the fundamental elements of the dynamical organization of cell metabolism. Here we present an overview of how mathematical models can be used to address the properties of dissipative metabolic structures at different organizational levels, both for individual enzymatic associations and for enzymatic networks. Recent analyses performed with dissipative metabolic networks have shown that unicellular organisms display a singular global enzymatic structure common to all living cellular organisms, which seems to be an intrinsic property of the functional metabolism as a whole. Mathematical models firmly based on experiments and their corresponding computational approaches are needed to fully grasp the molecular mechanisms of metabolic dynamical processes. They are necessary to enable the quantitative and qualitative analysis of the cellular catalytic reactions and also to help comprehend the conditions under which the structural dynamical phenomena and biological rhythms arise. Understanding the molecular mechanisms responsible for the metabolic dissipative structures is crucial for unraveling the dynamics of cellular life. PMID:20957111

  16. Development of a screening tool to prioritize testing for the carcinogenic hazard of residual aromatic extracts and related petroleum streams.

    PubMed

    Goyak, Katy O; Kung, Ming H; Chen, Min; Aldous, Keith K; Freeman, James J

    2016-12-15

    Residual aromatic extracts (RAE) are petroleum substances with variable composition predominantly containing aromatic hydrocarbons with carbon numbers greater than C25. Because of the high boiling nature of RAEs, the aromatics present are high molecular weight, with most above the range of carcinogenic polycyclic aromatic hydrocarbons (PAHs). However, refinery distillations are imperfect; some PAHs and their heteroatom-containing analogs (collectively referred to as polycyclic aromatic content or PAC) may remain in the parent stream and be extracted into the RAE, and overall PAC content is related to the carcinogenic potential of an RAE. We describe here a real-time analytical chemistry-based tool to assess the carcinogenic hazard of RAE via the development of a functional relationship between carcinogenicity and boiling point. Samples representative of steps along the RAE manufacturing process were obtained from five refineries to evaluate relationships between mutagenicity index (MI), PAC ring content and gas chromatographic distillation (GCD) curves. As expected, a positive linear relationship between MI and PAC ring content occurred, most specifically for 3-6 ring PAC (R 2 =0.68). A negative correlation was found between MI and temperature at 5% vaporization by GCD (R 2 =0.72), indicating that samples with greater amounts of lower boiling constituents were more likely to be carcinogenic. The inverse relationship between boiling range and carcinogenicity was further demonstrated by fractionation of select RAE samples (MI=0.50+0.07; PAC=1.70+0.51wt%; n=5) into low and high boiling fractions, where lower boiling fractions were both more carcinogenic than the higher boiling fractions (MI=2.36±0.55 and 0.17±0.11, respectively) and enriched in 3-6 ring PACs (5.20+0.70wt% and 0.97+0.35wt%, respectively). The criteria defining carcinogenicity was established as 479°C for the 5% vaporization points by GCD, with an approximate 95% probability of a future sample having

  17. The Temporal Structure of Scientific Consensus Formation

    PubMed Central

    Shwed, Uri; Bearman, Peter S.

    2011-01-01

    This article engages with problems that are usually opaque: What trajectories do scientific debates assume, when does a scientific community consider a proposition to be a fact, and how can we know that? We develop a strategy for evaluating the state of scientific contestation on issues. The analysis builds from Latour’s black box imagery, which we observe in scientific citation networks. We show that as consensus forms, the importance of internal divisions to the overall network structure declines. We consider substantive cases that are now considered facts, such as the carcinogenicity of smoking and the non-carcinogenicity of coffee. We then employ the same analysis to currently contested cases: the suspected carcinogenicity of cellular phones, and the relationship between vaccines and autism. Extracting meaning from the internal structure of scientific knowledge carves a niche for renewed sociological commentary on science, revealing a typology of trajectories that scientific propositions may experience en route to consensus. PMID:21886269

  18. Electrochemical methods for monitoring of environmental carcinogens.

    PubMed

    Barek, J; Cvacka, J; Muck, A; Quaiserová, V; Zima, J

    2001-04-01

    The use of modern electroanalytical techniques, namely differential pulse polarography, differential pulse voltammetry on hanging mercury drop electrode or carbon paste electrode, adsorptive stripping voltammetry and high performance liquid chromatography with electrochemical detection for the determination of trace amounts of carcinogenic N-nitroso compounds, azo compounds, heterocyclic compounds, nitrated polycyclic aromatic hydrocarbons and aromatic and heterocyclic amines is discussed. Scope and limitations of these methods are described and some practical applications based on their combination with liquid-liquid or solid phase extraction are given.

  19. DNA-REACTIVE CARCINOGENS: MODE OF ACTION AND HUMAN CANCER HAZARD

    EPA Science Inventory

    It has been known for decades that mutagenicity plays an important role in the activity of most carcinogens. This mutagenicity can result from direct damage to DNA through a chemical being DNA-reactive or from indirect effects, such as through the production of oxygen radicals th...

  20. Cellular distribution of cell cycle-related molecules in the renal tubules of rats treated with renal carcinogens for 28 days: relationship between cell cycle aberration and carcinogenesis.

    PubMed

    Taniai, Eriko; Hayashi, Hitomi; Yafune, Atsunori; Watanabe, Maiko; Akane, Hirotoshi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2012-09-01

    Some renal carcinogens can induce karyomegaly, which reflects aberrant cell division in the renal tubules, from the early stages of exposure. To clarify the cell cycle-related changes during the early stages of renal carcinogenesis, we performed immunohistochemical analysis of tubular cells in male F344 rats treated with carcinogenic doses of representative renal carcinogens for 28 days. For this purpose, the karyomegaly-inducing carcinogens ochratoxin A (OTA), ferric nitrilotriacetic acid, and monuron, and the non-karyomegaly-inducing carcinogens tris(2-chloroethyl) phosphate and potassium bromate were examined. For comparison, a karyomegaly-inducing non-carcinogen, p-nitrobenzoic acid, and a non-carcinogenic non-karyomegaly-inducing renal toxicant, acetaminophen, were also examined. The outer stripe of the outer medulla (OSOM) and the cortex + OSOM were subjected to morphometric analysis of immunoreactive proximal tubular cells. Renal carcinogens, irrespective of their karyomegaly-inducing potential, increased proximal tubular cell proliferation accompanied by an increase in topoisomerase IIα-immunoreactive cells, suggesting a reflection of cell proliferation. Karyomegaly-inducing carcinogens increased nuclear Cdc2-, γH2AX-, and phosphorylated Chk2-immunoreactive cells in both areas, the former two acting in response to DNA damage and the latter one suggestive of sustained G₂. OTA, an OSOM-targeting carcinogen, could easily be distinguished from untreated controls and non-carcinogens by evaluation of molecules responding to DNA damage and G₂/M transition in the OSOM. Thus, all renal carcinogens examined facilitated proximal tubular proliferation by repeated short-term treatment. Among these, karyomegaly-inducing carcinogens may cause DNA damage and G₂ arrest in the target tubular cells.

  1. Carcinogenicity of consumption of red meat and processed meat: A review of scientific news since the IARC decision.

    PubMed

    Domingo, José L; Nadal, Martí

    2017-07-01

    In October 2015, the International Agency for Research on Cancer (IARC) issued a press release on the results of the evaluation of the carcinogenicity of red and processed meat. Based on the accumulated scientific literature, the consumption of red meat was classified as "probably carcinogenic to humans" and processed meat as "carcinogenic to humans". Given the importance of this topic, this review was aimed at revising the current state-of-the-art on the carcinogenicity of red and processed meat, some time after the IARC decision. Some new epidemiological studies and new reviews clearly supporting the IARC decision have been published during these months. However, a number of gaps still exist. It is basic to establish the mechanisms leading to the increased risk of colorectal cancer (CRC) and other cancers arising from red and processed meat consumption. Another important pending issue is to establish the role of known/suspected carcinogens contained in uncooked or unprocessed meats, as well as the influence of cooking. Finally, it would be highly recommended to conduct new epidemiological studies to elucidate whether the consumption of white meat, such as pork and/or poultry, are -positively or inversely-associated with an increased risk of CRC and other types of cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Comprehensive review of epidemiological and animal studies on the potential carcinogenic effects of nicotine per se.

    PubMed

    Haussmann, Hans-Juergen; Fariss, Marc W

    2016-09-01

    The effects of long-term use of nicotine per se on cancer risk, in the absence of tobacco extract or smoke, are not clearly understood. This review evaluates the strength of published scientific evidence, in both epidemiological and animal studies, for the potential carcinogenic effects of nicotine per se; that is to act as a complete carcinogen or as a modulator of carcinogenesis. For human studies, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a carcinogenic effect due to the limited information available. In animal studies, limited evidence suggests an association between long-term nicotine exposure and a lack of a complete carcinogenic effect. Conclusive studies using current bioassay guidelines, however, are missing. In studies using chemical/physical carcinogens or transgenic models, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a modulating (stimulating) effect on carcinogenesis. This is primarily due to the large number of conflicting studies. In contrast, a majority of studies provides sufficient evidence for an association between nicotine exposure and enhanced carcinogenesis of cancer cells inoculated in mice. This modulating effect was especially prominent in immunocompromized mice. Overall, taking the human and animal studies into consideration, there appears to be inadequate evidence to conclude that nicotine per se does or does not cause or modulate carcinogenesis in humans. This conclusion is in agreement with the recent US Surgeon General's 2014 report on the health consequences of nicotine exposure.

  3. Comprehensive review of epidemiological and animal studies on the potential carcinogenic effects of nicotine per se

    PubMed Central

    Haussmann, Hans-Juergen; Fariss, Marc W.

    2016-01-01

    Abstract The effects of long-term use of nicotine per se on cancer risk, in the absence of tobacco extract or smoke, are not clearly understood. This review evaluates the strength of published scientific evidence, in both epidemiological and animal studies, for the potential carcinogenic effects of nicotine per se; that is to act as a complete carcinogen or as a modulator of carcinogenesis. For human studies, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a carcinogenic effect due to the limited information available. In animal studies, limited evidence suggests an association between long-term nicotine exposure and a lack of a complete carcinogenic effect. Conclusive studies using current bioassay guidelines, however, are missing. In studies using chemical/physical carcinogens or transgenic models, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a modulating (stimulating) effect on carcinogenesis. This is primarily due to the large number of conflicting studies. In contrast, a majority of studies provides sufficient evidence for an association between nicotine exposure and enhanced carcinogenesis of cancer cells inoculated in mice. This modulating effect was especially prominent in immunocompromized mice. Overall, taking the human and animal studies into consideration, there appears to be inadequate evidence to conclude that nicotine per se does or does not cause or modulate carcinogenesis in humans. This conclusion is in agreement with the recent US Surgeon General’s 2014 report on the health consequences of nicotine exposure. PMID:27278157

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

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

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

    1989-03-01

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

  5. Use of reduction rate as a quantitative knob for controlling the twin structure and shape of palladium nanocrystals.

    PubMed

    Wang, Yi; Peng, Hsin-Chieh; Liu, Jingyue; Huang, Cheng Zhi; Xia, Younan

    2015-02-11

    Kinetic control is a powerful means for maneuvering the twin structure and shape of metal nanocrystals and thus optimizing their performance in a variety of applications. However, there is only a vague understanding of the explicit roles played by reaction kinetics due to the lack of quantitative information about the kinetic parameters. With Pd as an example, here we demonstrate that kinetic parameters, including rate constant and activation energy, can be derived from spectroscopic measurements and then used to calculate the initial reduction rate and further have this parameter quantitatively correlated with the twin structure of a seed and nanocrystal. On a quantitative basis, we were able to determine the ranges of initial reduction rates required for the formation of nanocrystals with a specific twin structure, including single-crystal, multiply twinned, and stacking fault-lined. This work represents a major step forward toward the deterministic syntheses of colloidal noble-metal nanocrystals with specific twin structures and shapes.

  6. Computational modeling approaches to quantitative structure-binding kinetics relationships in drug discovery.

    PubMed

    De Benedetti, Pier G; Fanelli, Francesca

    2018-03-21

    Simple comparative correlation analyses and quantitative structure-kinetics relationship (QSKR) models highlight the interplay of kinetic rates and binding affinity as an essential feature in drug design and discovery. The choice of the molecular series, and their structural variations, used in QSKR modeling is fundamental to understanding the mechanistic implications of ligand and/or drug-target binding and/or unbinding processes. Here, we discuss the implications of linear correlations between kinetic rates and binding affinity constants and the relevance of the computational approaches to QSKR modeling. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Quantitative structure parameters from the NMR spectroscopy of quadrupolar nuclei

    DOE PAGES

    Perras, Frederic A.

    2015-12-15

    Here, nuclear magnetic resonance (NMR) spectroscopy is one of the most important characterization tools in chemistry, however, 3/4 of the NMR active nuclei are underutilized due to their quadrupolar nature. This short review centers on the development of methods that use solid-state NMR of quadrupolar nuclei for obtaining quantitative structural information. Namely, techniques using dipolar recoupling as well as the resolution afforded by double-rotation are presented for the measurement of spin–spin coupling between quadrupoles, enabling the measurement of internuclear distances and connectivities.

  8. IARC monographs: 40 years of evaluating carcinogenic hazards to humans.

    PubMed

    Pearce, Neil; 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

    2015-06-01

    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. 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. 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. The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.

  9. Production of carcinogenic acetaldehyde by Candida albicans from patients with potentially malignant oral mucosal disorders.

    PubMed

    Gainza-Cirauqui, M L; Nieminen, M T; Novak Frazer, L; Aguirre-Urizar, J M; Moragues, M D; Rautemaa, R

    2013-03-01

    Production of carcinogenic acetaldehyde by Candida has been suggested to contribute to epithelial dysplasia and oral carcinogenesis. Oral lichen planus (OLP), oral lichenoid lesion (OLL) and oral leukoplakia (OL) are potentially carcinogenic oral diseases where colonisation by Candida is common, but acetaldehyde production by Candida has not been studied. Acetaldehyde production in ethanol (11 mM), glucose (100 mM), ethanol-glucose (11 mM and 100 mM) or red wine (1200 mM ethanol) incubation by Candida albicans from patients with OLL (n = 6), OLP (n = 16), OL (n = 6) and controls (n = 6) was measured by gas chromatography. Participants completed a questionnaire regarding their smoking habits and alcohol consumption. All Candida albicans isolates produced potentially carcinogenic levels of acetaldehyde (>100 μM) in all incubations containing ethanol. The control group isolates produced the highest acetaldehyde levels. Isolates from smokers produced more acetaldehyde in all incubations than those from non-smokers. The difference was significant in ethanol-glucose incubation. Isolates from patients who were both smokers and drinkers produced the highest amounts when incubated in ethanol, ethanol-glucose and wine. Candida albicans isolated from potentially carcinogenic oral diseases can produce mutagenic amounts of acetaldehyde. Cigarette smoking and alcohol consumption may favour adaptational changes resulting in the upregulation of candidal acetaldehyde metabolism. © 2012 John Wiley & Sons A/S. All rights reserved.

  10. Chemical Sensor Array Response Modeling Using Quantitative Structure-Activity Relationships Technique

    NASA Astrophysics Data System (ADS)

    Shevade, Abhijit V.; Ryan, Margaret A.; Homer, Margie L.; Zhou, Hanying; Manfreda, Allison M.; Lara, Liana M.; Yen, Shiao-Pin S.; Jewell, April D.; Manatt, Kenneth S.; Kisor, Adam K.

    We have developed a Quantitative Structure-Activity Relationships (QSAR) based approach to correlate the response of chemical sensors in an array with molecular descriptors. A novel molecular descriptor set has been developed; this set combines descriptors of sensing film-analyte interactions, representing sensor response, with a basic analyte descriptor set commonly used in QSAR studies. The descriptors are obtained using a combination of molecular modeling tools and empirical and semi-empirical Quantitative Structure-Property Relationships (QSPR) methods. The sensors under investigation are polymer-carbon sensing films which have been exposed to analyte vapors at parts-per-million (ppm) concentrations; response is measured as change in film resistance. Statistically validated QSAR models have been developed using Genetic Function Approximations (GFA) for a sensor array for a given training data set. The applicability of the sensor response models has been tested by using it to predict the sensor activities for test analytes not considered in the training set for the model development. The validated QSAR sensor response models show good predictive ability. The QSAR approach is a promising computational tool for sensing materials evaluation and selection. It can also be used to predict response of an existing sensing film to new target analytes.

  11. Toxicogenomics and cancer risk assessment: a framework for key event analysis and dose-response assessment for nongenotoxic carcinogens.

    PubMed

    Bercu, Joel P; Jolly, Robert A; Flagella, Kelly M; Baker, Thomas K; Romero, Pedro; Stevens, James L

    2010-12-01

    In order to determine a threshold for nongenotoxic carcinogens, the traditional risk assessment approach has been to identify a mode of action (MOA) with a nonlinear dose-response. The dose-response for one or more key event(s) linked to the MOA for carcinogenicity allows a point of departure (POD) to be selected from the most sensitive effect dose or no-effect dose. However, this can be challenging because multiple MOAs and key events may exist for carcinogenicity and oftentimes extensive research is required to elucidate the MOA. In the present study, a microarray analysis was conducted to determine if a POD could be identified following short-term oral rat exposure with two nongenotoxic rodent carcinogens, fenofibrate and methapyrilene, using a benchmark dose analysis of genes aggregated in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) biological processes, which likely encompass key event(s) for carcinogenicity. The gene expression response for fenofibrate given to rats for 2days was consistent with its MOA and known key events linked to PPARα activation. The temporal response from daily dosing with methapyrilene demonstrated biological complexity with waves of pathways/biological processes occurring over 1, 3, and 7days; nonetheless, the benchmark dose values were consistent over time. When comparing the dose-response of toxicogenomic data to tumorigenesis or precursor events, the toxicogenomics POD was slightly below any effect level. Our results suggest that toxicogenomic analysis using short-term studies can be used to identify a threshold for nongenotoxic carcinogens based on evaluation of potential key event(s) which then can be used within a risk assessment framework. Copyright © 2010 Elsevier Inc. All rights reserved.

  12. Carcinogenicity of benzyl chloride, benzal chloride, benzotrichloride and benzoyl chloride in mice by skin application.

    PubMed

    Fukuda, K; Matsushita, H; Sakabe, H; Takemoto, K

    1981-10-01

    The carcinogenicity of benzyl chloride (BYC), benzal chloride (BAC), benzotrichloride (BTC) and benzoyl chloride (BOC), which were suspected as causative agents of lung cancer and maxillary malignant lymphoma of workers employed in factories producing BOC, was examined by skin applications in female ICR mice. After rather high dose exposure, BTC exhibited leukemogenic and pulmonary tumorigenic activities as well as potent dermal carcinogenic activity. After administration of the chemicals at the dose of 2.3 microliter/animal, twice a week for 50 weeks, BTC induced 68% incidence of skin cancers and 58% incidence of pulmonary tumors (including 10% of lung carcinomas) within 399 days. Incidence of skin cancers was 58% for BAC, 15% for BYC and 10% for BOC within 560 days. Considering the extent of possible exposure of the workers to these chemicals in the working environment and the carcinogenic potency of the chemicals tested, it can be concluded that BTC was very probably responsible for causing the cancers seen int he workers employed in manufacturing BOC.

  13. Quantitative structure-antifungal activity relationships of some benzohydrazides against Botrytis cinerea.

    PubMed

    Reino, José L; Saiz-Urra, Liane; Hernandez-Galan, Rosario; Aran, Vicente J; Hitchcock, Peter B; Hanson, James R; Gonzalez, Maykel Perez; Collado, Isidro G

    2007-06-27

    Fourteen benzohydrazides have been synthesized and evaluated for their in vitro antifungal activity against the phytopathogenic fungus Botrytis cinerea. The best antifungal activity was observed for the N',N'-dibenzylbenzohydrazides 3b-d and for the N-aminoisoindoline-derived benzohydrazide 5. A quantitative structure-activity relationship (QSAR) study has been developed using a topological substructural molecular design (TOPS-MODE) approach to interpret the antifungal activity of these synthetic compounds. The model described 98.3% of the experimental variance, with a standard deviation of 4.02. The influence of an ortho substituent on the conformation of the benzohydrazides was investigated by X-ray crystallography and supported by QSAR study. Several aspects of the structure-activity relationships are discussed in terms of the contribution of different bonds to the antifungal activity, thereby making the relationships between structure and biological activity more transparent.

  14. Mutagenicity of food-derived carcinogens and the effect of antioxidant vitamins.

    PubMed

    Montgomery, Beverly A; Murphy, Jessica; Chen, James J; Desai, Varsha G; McGarrity, Lynda; Morris, Suzanne M; Casciano, Daniel A; Aidoo, Anane

    2002-01-01

    The food-derived heterocyclic amines (HCAs) 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are mutagenic in the Ames test and produce tumors in laboratory animals, including monkeys. These HCAs have also been shown to induce gene mutations in vivo. To assess the antimutagenic effects of dietary antioxidant vitamins, beta-carotene, ascorbic acid (vitamin C), and alpha-tocopherol (vitamin E), on food-borne mutagenes/carcinogens, we evaluated the mutagenic activity of the compounds alone or combined with antioxidant vitamins. We utilized the rat lymphocyte mutation assay at the hypoxanthine guanine phosphoribosyl transferase (Hprt) locus. Female Fischer 344 rats treated with different doses (0, 2.5, 5.0, 25.0, and 50.0 mg/kg) of the carcinogens were sacrificed 5 wk after mutagen treatment. Although IQ and MeIQ slightly increased mutation frequency (MF) at some doses, a significant (P < 0.0009) increase in MF was found in animals exposed to MeIQx at 25 mg/kg. PhIP was the most mutagenic of the HCAs, with increases (P < 0.0001) in MF detected at all dose levels compared with controls. Because PhIP was the most mutagenic, it was selected for studies using the dietary antioxidant vitamins. Addition of antioxidant vitamins, singly or in a mixture, caused a significant (P < 0.0001) decrease in PhIP-induced Hprt MF. Vitamin E was the most effective at decreasing Hprt MF. In addition, we determined whether carcinogen metabolism would be affected by ingestion of vitamins. The activities of endogenous detoxification enzymes, glutathione S-transferase and glutathione peroxidase (GPx), were thus examined. Intake of beta-carotene and vitamin C without the carcinogen resulted in an increase (P < 0.05) in GPx activity. Also a modest increase in GPx activity was seen in animals that received the antioxidant mixture alone

  15. Quantitative Structure-Cytotoxicity Relationship of Oleoylamides.

    PubMed

    Sakagami, Hiroshi; Uesawa, Yoshihiro; Ishihara, Mariko; Kagaya, Hajime; Kanamoto, Taisei; Terakubo, Shigemi; Nakashima, Hideki; Takao, Koichi; Sugita, Yoshiaki

    2015-10-01

    Eighteen oleoylamides were subjected to quantitative structure-activity relationship analysis based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to assess their biological activities. Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and five human oral normal cells (gingival fibroblast, periodontal ligament fibroblast, pulp cell, oral keratinocyte, primary gingival epithelial cells) was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor-selectivity (TS) was evaluated by the ratio of the mean 50% cytotoxic concentration (CC50) against normal human oral cells to that against OSCC cell lines. Potency-selectivity expression (PSE) was determined by the ratio of TS to CC50 against OSCC. Anti-HIV activity was evaluated by the ratio of CC50 to the concentration leading to 50% cytoprotection from HIV infection (EC50). Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by the LowModeMD method. Among 18 derivatives, compounds 8: with a catechol group) and 18: with a (2-pyridyl)amino group) had the highest TS. On the other hand, doxorubicin and 5-fluorouracil (5-FU) were more highly cytotoxic to normal epithelial cells, displaying unexpectedly lower TS and PSE values. None of the compounds had anti-HIV activity. Among 330 chemical descriptors, 75, 73 and 19 descriptors significantly correlated to the cytotoxicity to normal and tumor cells, and TS, respectively. Multivariate statistics with chemical descriptors for molecular polarization and hydrophobicity may be useful for the evaluation of cytotoxicity and TS of oleoylamides. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  16. Application of Key Events and Analysis to Chemical Carcinogens and Noncarcinogens

    EPA Science Inventory

    The existence of thresholds for toxicants is a matter of debate in chemical rsk assessment and regulation. Current risk assessment methods are based on the assumption that, in the basense of sufficient data, carcinogenesis does not have a threshold, while non-carcinogenic endpoi...

  17. CARCINOGENICITY OF HOUSEHOLD SOLID FUEL COMBUSTION AND OF HIGH-TEMPERATURE FRYING

    EPA Science Inventory

    In October, 2006, 19 scientists from eight countries met at the International Agency for Research on Cancer (IARC) in Lyon, France, to assess the carcinogenicity of household solid fuel combustion (coal and biomass) and of high-temperature frying. These assessments will be publi...

  18. Carcinogenic and non-carcinogenic risk assessments of arsenic contamination in drinking water of Ardabil city in the Northwest of Iran.

    PubMed

    Sadeghi, Fatemeh; Nasseri, Simin; Yunesian, Masud; Nabizadeh, Ramin; Mosaferi, Mohammad; Mesdaghinia, Alireza

    2018-04-16

    Based on the environmental health assessment framework of the United State Environmental Protection Agency, a quantitative health risk assessment of arsenic in contaminated drinking water in a city in the northwest of Iran has been carried out. In the exposure assessment step, arsenic concentrations in drinking water were determined during four seasons. In addition, the water ingestion rate for different age groups in this region was determined. The concentration of arsenic in 163 collected samples from different locations during four seasons ranged from 0 to 99 μg L -1 . Furthermore, a high percentage of the samples manifested higher levels than the permissible limit of 10 μg L -1 . The total daily water intake rates of four age groups 1 to <2 (group 1), 2 to <6 (group 2), 6 to <16 (group 3), and ≥16 years (group 4) were estimated as 0.86, 1.49, 2.00, and 2.33 L day -1 , respectively. Calculating the lifetime average daily dose of arsenic indicated that adults (group 4) had the highest and children (group 1) had the lowest daily intake of arsenic in their entire life. The results of risk characteristic showed that the order of excess lifetime cancer risk via arsenic exposure in the four groups was 4 > 3 > 2 > 1. The estimated risks for all age groups were higher than the acceptable range (1E-6 to 1E-4). The hazard quotient values for all of the classified groups were lower than the recommended limit values (<1), but it cannot be concluded that potential non-carcinogenicity risks are non-existent since the possible exposure to arsenic via food and skin may also pose the risk.

  19. ARSENIC: CARCINOGENIC MECHANISMS, RISK ASSESSMENT AND THE MAXIMUM CONTAMINANT LEVEL (MCL)

    EPA Science Inventory


    This workshop will provide an up-to-date overview on key issues related to cancer risk assessment of arsenic: carcinogenic mechanisms; application of mechanistic information to risk assessment models; and the development of the MCL for arsenic in drinking water. The two prese...

  20. A review of experimental evidence for the carcinogenicity of man-made vitreous fibers.

    PubMed

    Davis, J M

    1986-01-01

    This paper reviews experimental studies on the carcinogenicity of man-made vitreous fibers. Long-term inhalation studies using several animal species and dust preparations of fibrous glass, rock wool or slag wool have produced little evidence of pulmonary fibrosis or pulmonary tumors. While some intratracheal injection studies found almost no pathological changes in lung tissue, some showed that pulmonary fibrosis can occur. Only one intratracheal injection study has reported that vitreous fibers can be carcinogenic; in contrast, many workers have reported that, following intrapleural or intraperitoneal injection, man-made vitreous fibers are highly carcinogenic, and tumor production appears to be closely related to fiber size. In vitro tests confirm that vitreous fibers can be toxic and can cause neoplastic transformation of cultured cells. The discrepancies between some experimental studies probably result from the relatively high solubility of most vitreous fibers. It seems likely that, while these fibers can survive in body cavities long enough to cause tumor production, they dissolve in lung tissue fast enough to have relatively little harmful effect. Rock-wool fibers appear more durable than glass- or slag-wool fibers, and, with similar fiber numbers and sizes in any dust cloud, this material is the most likely to have harmful potential.

  1. Chronic exposure to combined carcinogens enhances breast cell carcinogenesis with mesenchymal and stem-like cell properties.

    PubMed

    Pluchino, Lenora Ann; Wang, Hwa-Chain Robert

    2014-01-01

    Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens.

  2. Chronic Exposure to Combined Carcinogens Enhances Breast Cell Carcinogenesis with Mesenchymal and Stem-Like Cell Properties

    PubMed Central

    Pluchino, Lenora Ann; Wang, Hwa-Chain Robert

    2014-01-01

    Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens. PMID:25372613

  3. Fragment-based quantitative structure-activity relationship (FB-QSAR) for fragment-based drug design.

    PubMed

    Du, Qi-Shi; Huang, Ri-Bo; Wei, Yu-Tuo; Pang, Zong-Wen; Du, Li-Qin; Chou, Kuo-Chen

    2009-01-30

    In cooperation with the fragment-based design a new drug design method, the so-called "fragment-based quantitative structure-activity relationship" (FB-QSAR) is proposed. The essence of the new method is that the molecular framework in a family of drug candidates are divided into several fragments according to their substitutes being investigated. The bioactivities of molecules are correlated with the physicochemical properties of the molecular fragments through two sets of coefficients in the linear free energy equations. One coefficient set is for the physicochemical properties and the other for the weight factors of the molecular fragments. Meanwhile, an iterative double least square (IDLS) technique is developed to solve the two sets of coefficients in a training data set alternately and iteratively. The IDLS technique is a feedback procedure with machine learning ability. The standard Two-dimensional quantitative structure-activity relationship (2D-QSAR) is a special case, in the FB-QSAR, when the whole molecule is treated as one entity. The FB-QSAR approach can remarkably enhance the predictive power and provide more structural insights into rational drug design. As an example, the FB-QSAR is applied to build a predictive model of neuraminidase inhibitors for drug development against H5N1 influenza virus. (c) 2008 Wiley Periodicals, Inc.

  4. Chemical graphs, molecular matrices and topological indices in chemoinformatics and quantitative structure-activity relationships.

    PubMed

    Ivanciuc, Ovidiu

    2013-06-01

    Chemical and molecular graphs have fundamental applications in chemoinformatics, quantitative structureproperty relationships (QSPR), quantitative structure-activity relationships (QSAR), virtual screening of chemical libraries, and computational drug design. Chemoinformatics applications of graphs include chemical structure representation and coding, database search and retrieval, and physicochemical property prediction. QSPR, QSAR and virtual screening are based on the structure-property principle, which states that the physicochemical and biological properties of chemical compounds can be predicted from their chemical structure. Such structure-property correlations are usually developed from topological indices and fingerprints computed from the molecular graph and from molecular descriptors computed from the three-dimensional chemical structure. We present here a selection of the most important graph descriptors and topological indices, including molecular matrices, graph spectra, spectral moments, graph polynomials, and vertex topological indices. These graph descriptors are used to define several topological indices based on molecular connectivity, graph distance, reciprocal distance, distance-degree, distance-valency, spectra, polynomials, and information theory concepts. The molecular descriptors and topological indices can be developed with a more general approach, based on molecular graph operators, which define a family of graph indices related by a common formula. Graph descriptors and topological indices for molecules containing heteroatoms and multiple bonds are computed with weighting schemes based on atomic properties, such as the atomic number, covalent radius, or electronegativity. The correlation in QSPR and QSAR models can be improved by optimizing some parameters in the formula of topological indices, as demonstrated for structural descriptors based on atomic connectivity and graph distance.

  5. CarcinoPred-EL: Novel models for predicting the carcinogenicity of chemicals using molecular fingerprints and ensemble learning methods.

    PubMed

    Zhang, Li; Ai, Haixin; Chen, Wen; Yin, Zimo; Hu, Huan; Zhu, Junfeng; Zhao, Jian; Zhao, Qi; Liu, Hongsheng

    2017-05-18

    Carcinogenicity refers to a highly toxic end point of certain chemicals, and has become an important issue in the drug development process. In this study, three novel ensemble classification models, namely Ensemble SVM, Ensemble RF, and Ensemble XGBoost, were developed to predict carcinogenicity of chemicals using seven types of molecular fingerprints and three machine learning methods based on a dataset containing 1003 diverse compounds with rat carcinogenicity. Among these three models, Ensemble XGBoost is found to be the best, giving an average accuracy of 70.1 ± 2.9%, sensitivity of 67.0 ± 5.0%, and specificity of 73.1 ± 4.4% in five-fold cross-validation and an accuracy of 70.0%, sensitivity of 65.2%, and specificity of 76.5% in external validation. In comparison with some recent methods, the ensemble models outperform some machine learning-based approaches and yield equal accuracy and higher specificity but lower sensitivity than rule-based expert systems. It is also found that the ensemble models could be further improved if more data were available. As an application, the ensemble models are employed to discover potential carcinogens in the DrugBank database. The results indicate that the proposed models are helpful in predicting the carcinogenicity of chemicals. A web server called CarcinoPred-EL has been built for these models ( http://ccsipb.lnu.edu.cn/toxicity/CarcinoPred-EL/ ).

  6. Carcinogenic Tobacco-Specific N-Nitrosamines in U.S. Cigarettes -Three Decades of Remarkable Neglect by the Tobacco Industry

    PubMed Central

    Stepanov, Irina; Knezevich, Aleksandar; Zhang, Liqin; Watson, Clifford; Hatsukami, Dorothy K.; Hecht, Stephen S.

    2013-01-01

    Modification of tobacco curing methods and other changes in cigarette manufacturing techniques could substantially reduce the levels of tobacco-specific nitrosamines (TSNA), a group of potent carcinogens, in cigarette smoke. In 1999, two major U.S. cigarette manufacturers stated their intent to move towards using tobaccos low in TSNA. Since there is no information available on current TSNA levels in tobacco of various cigarettes available in the U.S., we examined the levels of these carcinogens in currently marketed brands. Seventeen brands of cigarettes were purchased in April of 2010 from retail stores in Minnesota. In all brands, the sum of two potent carcinogenic TSNA – 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N′-nitrosonornicotine – in cigarette filler averaged 2.54 (±1.05) μg/g tobacco. This value is virtually identical to the sum of these two carcinogens reported for the tobacco of a U.S. filtered cigarette in 1979. TSNA levels in smoke positively correlated with those in tobacco filler of the same cigarettes. We found no indication that any meaningful attempt was made to reduce or even control TSNA levels in the new varieties of the popular brands Marlboro and Camel introduced over the last decade. In light of the recently granted regulatory authority to the FDA over tobacco products, regulation of TSNA levels in cigarette tobacco should be strongly considered to reduce the levels of these potent carcinogens in cigarette smoke. PMID:21602537

  7. Chemical characteristic of PM2.5 emission and inhalational carcinogenic risk of domestic Chinese cooking.

    PubMed

    Zhang, Nan; Han, Bin; He, Fei; Xu, Jia; Zhao, Ruojie; Zhang, Yujuan; Bai, Zhipeng

    2017-08-01

    To illustrate chemical characteristic of PM 2.5 emission and assess inhalational carcinogenic risk of domestic Chinese cooking, 5 sets of duplicate cooking samples were collected, using the most used 5 types of oil. The mass abundance of 14 elements, 5 water-soluble ions, organic carbon (OC), elemental carbon (EC) and 11 polycyclic aromatic hydrocarbons (PAHs) were calculated; the signature and diagnostic ratio of cooking in the domestic kitchen were analyzed; and carcinogenic risks of heavy metals and PAHs via inhalation were assessed in two scenarios. The analysis showed that OC was the primary composition in the chemical profile; Na was the most abundant element that might be due to the usage of salt; Cr and Pb, NO 3 - and SO 4 2- , Phe, FL and Pyr were the main heavy metals/water-soluble ions/PAHs, respectively. Phe and FL could be used to separate cooking and stationary sources, while diagnostic ratios of BaA/(BaA + CHR), BaA/CHR, BaP/BghiP and BaP/BeP should be applied with caution, as they were influenced by various cooking conditions. Carcinogenic risks of heavy metals and PAHs were evaluated in two scenarios, simulating the condition of cooking with no ventilation and with the range hood on, respectively. The integrated risk of heavy metals and PAHs was 2.7 × 10 -3 and 5.8 × 10 -6 , respectively, during cooking with no ventilation. While with the usage of range hood, only Cr(VI), As and Ni might induce potential carcinogenic risk. The difference in the chemical abundance in cooking sources found between this and other studies underlined the necessity of constructing locally representative source profiles under real conditions. The comparison of carcinogenic risk suggested that the potentially adverse health effects induced by inorganic compositions from cooking sources should not be ignored. Meanwhile, intervention methods, such as the operation of range hood, should be applied during cooking for health protection. Copyright © 2017 Elsevier Ltd

  8. 3D-quantitative structure-activity relationship study for the design of novel enterovirus A71 3C protease inhibitors.

    PubMed

    Nie, Quandeng; Xu, Xiaoyi; Zhang, Qi; Ma, Yuying; Yin, Zheng; Shang, Luqing

    2018-06-07

    A three-dimensional quantitative structure-activity relationships model of enterovirus A71 3C protease inhibitors was constructed in this study. The protein-ligand interaction fingerprint was analyzed to generate a pharmacophore model. A predictive and reliable three-dimensional quantitative structure-activity relationships model was built based on the Flexible Alignment of AutoGPA. Moreover, three novel compounds (I-III) were designed and evaluated for their biochemical activity against 3C protease and anti-enterovirus A71 activity in vitro. III exhibited excellent inhibitory activity (IC 50 =0.031 ± 0.005 μM, EC 50 =0.036 ± 0.007 μM). Thus, this study provides a useful quantitative structure-activity relationships model to develop potent inhibitors for enterovirus A71 3C protease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  9. Occurrence of Pineal Gland Tumors in Combined Chronic Toxicity/Carcinogenicity Studies in Wistar Rats.

    PubMed

    Treumann, Silke; Buesen, Roland; Gröters, Sibylle; Eichler, Jens-Olaf; van Ravenzwaay, Bennard

    2015-08-01

    Pineal gland tumors are very rare brain lesions in rats as well as in other species including humans. A total of 8 (out of 1,360 examined) Wistar rats from 3 different combined chronic toxicity/carcinogenicity or mere carcinogenicity studies revealed pineal gland tumors. The tumors were regarded to be spontaneous and unrelated to treatment. The morphology and immunohistochemical evaluation led to the diagnosis malignant pinealoma. The main characteristics that were variably developed within the tumors were the following: cellular atypia, high mitotic index, giant cells, necrosis, Homer Wright rosettes, Flexner-Wintersteiner rosettes and pseudorosettes, positive immunohistochemical reaction for synaptophysin, and neuron-specific enolase. The pineal gland is not a protocol organ for histopathological examination in carcinogenicity studies. Nevertheless, the pineal gland can occasionally be encountered on the routine brain section or if it is the origin of a tumor protruding into the brain, the finding will be recorded. Therefore, although known to be a rare tumor in rats, pineal neoplasms should be included in the list of possible differential diagnoses for brain tumors, especially when the tumor is located in the region of the pineal body. © 2015 by The Author(s).

  10. Quantitative Acoustic Model for Adhesion Evaluation of Pmma/silicon Film Structures

    NASA Astrophysics Data System (ADS)

    Ju, H. S.; Tittmann, B. R.

    2010-02-01

    A Poly-methyl-methacrylate (PMMA) film on a silicon substrate is a main structure for photolithography in semiconductor manufacturing processes. This paper presents a potential of scanning acoustic microscopy (SAM) for nondestructive evaluation of the PMMA/Si film structure, whose adhesion failure is commonly encountered during the fabrication and post-fabrication processes. A physical model employing a partial discontinuity in displacement is developed for rigorously quantitative evaluation of the interfacial weakness. The model is implanted to the matrix method for the surface acoustic wave (SAW) propagation in anisotropic media. Our results show that variations in the SAW velocity and reflectance are predicted to show their sensitivity to the adhesion condition. Experimental results by the v(z) technique and SAW velocity reconstruction verify the prediction.

  11. Chemistry of carcinogenic metals.

    PubMed Central

    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 use of equilibrium data to determine the speciation of metal ions and complexes under varying solution conditions are described. Methods for assessing the interferences by hydrogen ion, competing metal ions, hydrolysis, and precipitation are explained, and are applied to systems containing iron(III) chelates of fourteen chelating agents designed for effective binding of the ferric ion. The donor groups available for the building up of multidentate ligands are presented, and the ways in which they may be combined to achieve high affinity and selectivity for certain types of metal ions are explained. PMID:6791915

  12. Oxidative Stress Mechanisms Do Not Discriminate between Genotoxic and Nongenotoxic Liver Carcinogens.

    PubMed

    Deferme, Lize; Wolters, Jarno; Claessen, Sandra; Briedé, Jacco; Kleinjans, Jos

    2015-08-17

    It is widely accepted that in chemical carcinogenesis different modes-of-action exist, e.g., genotoxic (GTX) versus nongenotoxic (NGTX) carcinogenesis. In this context, it has been suggested that oxidative stress response pathways are typical for NGTX carcinogenesis. To evaluate this, we examined oxidative stress-related changes in gene expression, cell cycle distribution, and (oxidative) DNA damage in human hepatoma cells (HepG2) exposed to GTX-, NGTX-, and noncarcinogens, at multiple time points (4-8-24-48-72 h). Two GTX (azathriopine (AZA) and furan) and two NGTX (tetradecanoyl-phorbol-acetate, (TPA) and tetrachloroethylene (TCE)) carcinogens as well as two noncarcinogens (diazinon (DZN, d-mannitol (Dman)) were selected, while per class one compound was deemed to induce oxidative stress and the other not. Oxidative stressors AZA, TPA, and DZN induced a 10-fold higher number of gene expression changes over time compared to those of furan, TCE, or Dman treatment. Genes commonly expressed among AZA, TPA, and DZN were specifically involved in oxidative stress, DNA damage, and immune responses. However, differences in gene expression between GTX and NGTX carcinogens did not correlate to oxidative stress or DNA damage but could instead be assigned to compound-specific characteristics. This conclusion was underlined by results from functional readouts on ROS formation and (oxidative) DNA damage. Therefore, oxidative stress may represent the underlying cause for increased risk of liver toxicity and even carcinogenesis; however, it does not discriminate between GTX and NGTX carcinogens.

  13. Interpretation of the margin of exposure for genotoxic carcinogens - elicitation of expert knowledge about the form of the dose response curve at human relevant exposures.

    PubMed

    Boobis, Alan; Flari, Villie; Gosling, John Paul; Hart, Andy; Craig, Peter; Rushton, Lesley; Idahosa-Taylor, Ehi

    2013-07-01

    The general approach to risk assessment of genotoxic carcinogens has been to advise reduction of exposure to "as low as reasonably achievable/practicable" (ALARA/P). However, whilst this remains the preferred risk management option, it does not provide guidance on the urgency or extent of risk management actions necessary. To address this, the "Margin of Exposure" (MOE) approach has been proposed. The MOE is the ratio between the point of departure for carcinogenesis and estimated human exposure. However, interpretation of the MOE requires implicit or explicit consideration of the shape of the dose-response curve at human relevant exposures. In a structured elicitation exercise, we captured expert opinion on available scientific evidence for low dose-response relationships for genotoxic carcinogens. This allowed assessment of: available evidence for the nature of dose-response relationships at human relevant exposures; the generality of judgments about such dose-response relationships; uncertainties affecting judgments on the nature of such dose-response relationships; and whether this last should differ for different classes of genotoxic carcinogens. Elicitation results reflected the variability in experts' views on the form of the dose-response curve for low dose exposure and major sources of uncertainty affecting the assumption of a linear relationship. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Quantitative ultrasonic evaluation of concrete structures using one-sided access

    NASA Astrophysics Data System (ADS)

    Khazanovich, Lev; Hoegh, Kyle

    2016-02-01

    Nondestructive diagnostics of concrete structures is an important and challenging problem. A recent introduction of array ultrasonic dry point contact transducer systems offers opportunities for quantitative assessment of the subsurface condition of concrete structures, including detection of defects and inclusions. The methods described in this paper are developed for signal interpretation of shear wave impulse response time histories from multiple fixed distance transducer pairs in a self-contained ultrasonic linear array. This included generalizing Kirchoff migration-based synthetic aperture focusing technique (SAFT) reconstruction methods to handle the spatially diverse transducer pair locations, creating expanded virtual arrays with associated reconstruction methods, and creating automated reconstruction interpretation methods for reinforcement detection and stochastic flaw detection. Interpretation of the reconstruction techniques developed in this study were validated using the results of laboratory and field forensic studies. Applicability of the developed methods for solving practical engineering problems was demonstrated.

  15. Tannin structural elucidation and quantitative ³¹P NMR analysis. 2. Hydrolyzable tannins and proanthocyanidins.

    PubMed

    Melone, Federica; Saladino, Raffaele; Lange, Heiko; Crestini, Claudia

    2013-10-02

    An unprecedented analytical method that allows simultaneous structural and quantitative characterization of all functional groups present in tannins is reported. In situ labeling of all labile H groups (aliphatic and phenolic hydroxyls and carboxylic acids) with a phosphorus-containing reagent (Cl-TMDP) followed by quantitative ³¹P NMR acquisition constitutes a novel fast and reliable analytical tool for the analysis of tannins and proanthocyanidins with significant implications for the fields of food and feed analyses, tannery, and the development of natural polyphenolics containing products.

  16. Exposure to meat-derived carcinogens and bulky DNA adduct levels in normal-appearing colon mucosa.

    PubMed

    Ho, Vikki; Brunetti, Vanessa; Peacock, Sarah; Massey, Thomas E; Godschalk, Roger W L; van Schooten, Frederik J; Ashbury, Janet E; Vanner, Stephen J; King, Will D

    2017-09-01

    Meat consumption is a risk factor for colorectal cancer. This research investigated the relationship between meat-derived carcinogen exposure and bulky DNA adduct levels, a biomarker of DNA damage, in colon mucosa. Least squares regression was used to examine the relationship between meat-derived carcinogen exposure (PhIP and meat mutagenicity) and bulky DNA adduct levels in normal-appearing colon tissue measured using 32 P-postlabelling among 202 patients undergoing a screening colonoscopy. Gene-diet interactions between carcinogen exposure and genetic factors relevant to biotransformation and DNA repair were also examined. Genotyping was conducting using the MassARRAY ® iPLEX ® Gold SNP Genotyping assay. PhIP and higher meat mutagenicity exposures were not associated with levels of bulky DNA adducts in colon mucosa. The XPC polymorphism (rs2228001) was found to associate with bulky DNA adduct levels, whereby genotypes conferring lower DNA repair activity were associated with higher DNA adduct levels than the normal activity genotype. Among individuals with genotypes associated with lower DNA repair (XPD, rs13181 and rs1799179) or detoxification activity (GSTP1, rs1695), higher PhIP or meat mutagenicity exposures were associated with higher DNA adduct levels. Significant interactions between the XPC polymorphism (rs2228000) and both dietary PhIP and meat mutagenicity on DNA adduct levels was observed, but associations were inconsistent with the a priori hypothesized direction of effect. Exposure to meat-derived carcinogens may be associated with increased DNA damage occurring directly in the colon among genetically susceptible individuals. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Influence of the physicochemical and aromatic properties on the chemical reactivity and its relation with carcinogenic and anticoagulant effect of 17β-aminoestrogens

    NASA Astrophysics Data System (ADS)

    Soriano-Correa, Catalina; Raya, Angélica; Barrientos-Salcedo, Carolina; Esquivel, Rodolfo O.

    2014-06-01

    Activity of steroid hormones is dependent upon a number of factors, as solubility, transport and metabolism. The functional differences caused by structural modifications could exert an influence on the chemical reactivity and biological effect. The goal of this work is to study the influence of the physicochemical and aromatic properties on the chemical reactivity and its relation with the carcinogenic risk that can associate with the anticoagulant effect of 17β-aminoestrogens using quantum-chemical descriptors at the DFT-B3LYP, BH&HLYP and M06-2X levels. The relative acidity of (H1) of the hydroxyl group increases with electron-withdrawing groups. Electron-donor groups favor the basicity. The steric hindrance of the substituents decreases the aromatic character and consequently diminution the carcinogenic effect. Density descriptors: hardness, electrophilic index, atomic charges, molecular orbitals, electrostatic potential and their geometric parameters permit analyses of the chemical reactivity and physicochemical features and to identify some reactive sites of 17β-aminoestrogens.

  18. [Exposure to carcinogens in work environment today. State of the art, problems and prospects raised by the Law 626/94].

    PubMed

    Carnevale, F; Baldasseroni, A

    1998-01-01

    The implementation in our country of recent legislation on carcinogenic risk assessment and management (VIIth title of Law 626/94) is considered. The authors describe potentialities and limits of the new legislation and of the derived Guidelines issued by the Regions. The health policy in this field and possible evolution in the near future are outlined, bearing in mind the experience of other countries. A short list of questions is suggested as a contribution to the discussion on the future scenario: whether exposure to carcinogens should be lower in the working environment than in the general environment; what is the relative importance of multifactoriality, individual biological variability, individual life-style in the genesis of cancers; whether medical health surveillance is worthwhile in terms of primary prevention; is it always true that there is no threshold limit value for carcinogens; what is the role of individual attitudes to prevention in exposure to carcinogens compared to "objective" protection; which balance between costs and benefits should be aimed at.

  19. Investigating the epigenetic effects of a prototype smoke-derived carcinogen in human cells.

    PubMed

    Tommasi, Stella; Kim, Sang-in; Zhong, Xueyan; Wu, Xiwei; Pfeifer, Gerd P; Besaratinia, Ahmad

    2010-05-12

    Global loss of DNA methylation and locus/gene-specific gain of DNA methylation are two distinct hallmarks of carcinogenesis. Aberrant DNA methylation is implicated in smoking-related lung cancer. In this study, we have comprehensively investigated the modulation of DNA methylation consequent to chronic exposure to a prototype smoke-derived carcinogen, benzo[a]pyrene diol epoxide (B[a]PDE), in genomic regions of significance in lung cancer, in normal human cells. We have used a pulldown assay for enrichment of the CpG methylated fraction of cellular DNA combined with microarray platforms, followed by extensive validation through conventional bisulfite-based analysis. Here, we demonstrate strikingly similar patterns of DNA methylation in non-transformed B[a]PDE-treated cells vs control using high-throughput microarray-based DNA methylation profiling confirmed by conventional bisulfite-based DNA methylation analysis. The absence of aberrant DNA methylation in our model system within a timeframe that precedes cellular transformation suggests that following carcinogen exposure, other as yet unknown factors (secondary to carcinogen treatment) may help initiate global loss of DNA methylation and region-specific gain of DNA methylation, which can, in turn, contribute to lung cancer development. Unveiling the initiating events that cause aberrant DNA methylation in lung cancer has tremendous public health relevance, as it can help define future strategies for early detection and prevention of this highly lethal disease.

  20. Investigating the Epigenetic Effects of a Prototype Smoke-Derived Carcinogen in Human Cells

    PubMed Central

    Tommasi, Stella; Kim, Sang-in; Zhong, Xueyan; Wu, Xiwei; Pfeifer, Gerd P.; Besaratinia, Ahmad

    2010-01-01

    Global loss of DNA methylation and locus/gene-specific gain of DNA methylation are two distinct hallmarks of carcinogenesis. Aberrant DNA methylation is implicated in smoking-related lung cancer. In this study, we have comprehensively investigated the modulation of DNA methylation consequent to chronic exposure to a prototype smoke-derived carcinogen, benzo[a]pyrene diol epoxide (B[a]PDE), in genomic regions of significance in lung cancer, in normal human cells. We have used a pulldown assay for enrichment of the CpG methylated fraction of cellular DNA combined with microarray platforms, followed by extensive validation through conventional bisulfite-based analysis. Here, we demonstrate strikingly similar patterns of DNA methylation in non-transformed B[a]PDE-treated cells vs control using high-throughput microarray-based DNA methylation profiling confirmed by conventional bisulfite-based DNA methylation analysis. The absence of aberrant DNA methylation in our model system within a timeframe that precedes cellular transformation suggests that following carcinogen exposure, other as yet unknown factors (secondary to carcinogen treatment) may help initiate global loss of DNA methylation and region-specific gain of DNA methylation, which can, in turn, contribute to lung cancer development. Unveiling the initiating events that cause aberrant DNA methylation in lung cancer has tremendous public health relevance, as it can help define future strategies for early detection and prevention of this highly lethal disease. PMID:20485678

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

    DTIC Science & Technology

    2004-08-01

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

  2. Carcinogenic and neurotoxic risks of acrylamide consumed through caffeinated beverages among the lebanese population.

    PubMed

    El-Zakhem Naous, Ghada; Merhi, Areej; Abboud, Martine I; Mroueh, Mohamad; Taleb, Robin I

    2018-06-06

    The present study aims to quantify acrylamide in caffeinated beverages including American coffee, Lebanese coffee, espresso, instant coffee and hot chocolate, and to determine their carcinogenic and neurotoxic risks. A survey was carried for this purpose whereby 78% of the Lebanese population was found to consume at least one type of caffeinated beverages. Gas Chromatography Mass Spectrometry analysis revealed that the average acrylamide level in caffeinated beverages is 29,176 μg/kg sample. The daily consumption of acrylamide from Lebanese coffee (10.9 μg/kg-bw/day), hot chocolate (1.2 μg/kg-bw/day) and Espresso (7.4 μg/kg-bw/day) was found to be higher than the risk intake for carcinogenicity and neurotoxicity as set by World Health Organization (WHO; 0.3-2 μg/kg-bw/day) at both the mean (average consumers) and high (high consumers) dietary exposures. On the other hand, American coffee (0.37 μg/kg-bw/day) was shown to pose no carcinogenic or neurotoxic risks among the Lebanese community for consumers with a mean dietary exposure. The study shows alarming results that call for regulating the caffeinated product industry by setting legislations and standard protocols for product preparation in order to limit the acrylamide content and protect consumers. In order to avoid carcinogenic and neurotoxic risks, we propose that WHO/FAO set acrylamide levels in caffeinated beverages to 7000 μg acrylamide/kg sample, a value which is 4-folds lower than the average acrylamide levels of 29,176 μg/kg sample found in caffeinated beverages sold in the Lebanese market. Alternatively, consumers of caffeinated products, especially Lebanese coffee and espresso, would have to lower their daily consumption to 0.3-0.4 cups/day. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. Fetal Exposure to Carcinogens With Tobacco Use in Pregnancy: Phase 1 MAW Study Findings.

    PubMed

    Flanagan, Christie A; Koller, Kathryn R; Wolfe, Abbie W; Thomas, Timothy K; Benowitz, Neal L; Renner, Caroline C; Hughes, Christine; Hatsukami, Dorothy K; Bronars, Carrie; Murphy, Neil J; Day, Gretchen; Decker, Paul A; Patten, Christi A

    2016-11-01

    The high prevalence of smoking and smokeless tobacco (ST) use during pregnancy in Alaska Native (AN) women is concerning due to the detrimental effects of these products to the mother and the developing fetus. We sought to correlate maternal cotinine levels with fetal exposure to a tobacco-specific carcinogen to incorporate in a biomarker feedback intervention to motivate tobacco cessation during pregnancy. Demographic and tobacco use data were collected from a convenience sample of pregnant AN smokers, ST users, and non-users. Maternal and neonatal urine were collected at delivery. Maternal urine cotinine and neonatal urine total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, a tobacco-specific carcinogen) levels in smokers and ST users were analyzed and their correlations determined by Spearman correlation coefficients. During 2012-2014, we enrolled 64 non-users, 54 smokers, and 30 ST (20 homemade iqmik; 10 commercial ST) users (n = 148). Analyses of paired maternal-infant urine samples obtained for 36 smokers demonstrated a moderate to strong correlation (r = 0.73, P < .001) between maternal cotinine and infant NNAL levels. The correlation was not significant for 25 iqmik users (r = 0.36, P = .17) or 9 commercial ST users (r = 0.60, P = .09). No analysis was conducted for 55 non-users with cotinine and NNAL levels < limits of quantification. There is a moderate to strong correlation between maternal smoking and fetal exposure to the tobacco-specific carcinogen NNAL. The correlation between maternal smoking and fetal carcinogen exposure may provide an education tool to help motivate smoking cessation among pregnant AN women. Further investigation is warranted to determine correlations between maternal commercial ST and iqmik use and neonatal NNAL. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

    PubMed Central

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

    2015-01-01

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

  5. Polymorphisms in carcinogen metabolism enzymes, fish intake, and risk of prostate cancer

    PubMed Central

    Stern, Mariana C.

    2012-01-01

    Cooking fish at high temperature can produce potent carcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons. The effects of these carcinogens may undergo modification by the enzymes responsible for their detoxification and/or activation. In this study, we investigated genetic polymorphisms in nine carcinogen metabolism enzymes and their modifying effects on the association between white or dark fish consumption and prostate cancer (PCA) risk. We genotyped 497 localized and 936 advanced PCA cases and 760 controls from the California Collaborative Case–Control Study of Prostate Cancer. Three polymorphisms, EPHX1 Tyr113His, CYP1B1 Leu432Val and GSTT1 null/present, were associated with localized PCA risk. The PTGS2 765 G/C polymorphism modified the association between white fish consumption and advanced PCA risk (interaction P 5 0.002), with high white fish consumption being positively associated with risk only among carriers of the C allele. This effect modification by PTGS2 genotype was stronger when restricted to consumption of well-done white fish (interaction P 5 0.021). These findings support the hypotheses that changes in white fish brought upon by high-temperature cooking methods, such as carcinogen accumulation and/or fatty acid composition changes, may contribute to prostate carcinogenesis. However, the gene–diet interactions should be interpreted with caution given the limited sample size. Thus, our findings require further validation with additional studies. Abbreviations: AA African American; BMI body mass index; CI confidence interval; CNV copy number variant; EPIC European Prospective Investigation into Cancer and Nutrition; HCA heterocyclic amine; HCFA Health Care Financing Administration; LAC Los Angeles county; MAF minor allele frequency; NHW non-Hispanic White; OR odds ratio; PAH polycyclic aromatic hydrocarbon; PCA prostate cancer; PTGS2 prostaglandin- endoperoxide synthase 2; PUFA polyunsaturated fatty acids; RDD

  6. Quantitative theory of hydrophobic effect as a driving force of protein structure

    PubMed Central

    Perunov, Nikolay; England, Jeremy L

    2014-01-01

    Various studies suggest that the hydrophobic effect plays a major role in driving the folding of proteins. In the past, however, it has been challenging to translate this understanding into a predictive, quantitative theory of how the full pattern of sequence hydrophobicity in a protein shapes functionally important features of its tertiary structure. Here, we extend and apply such a phenomenological theory of the sequence-structure relationship in globular protein domains, which had previously been applied to the study of allosteric motion. In an effort to optimize parameters for the model, we first analyze the patterns of backbone burial found in single-domain crystal structures, and discover that classic hydrophobicity scales derived from bulk physicochemical properties of amino acids are already nearly optimal for prediction of burial using the model. Subsequently, we apply the model to studying structural fluctuations in proteins and establish a means of identifying ligand-binding and protein–protein interaction sites using this approach. PMID:24408023

  7. Temporal aspects of tumorigenic response to individual and mixed carcinogens. Comprehensive progress report, June 1, 1975--May 31, 1978. [Mouse skin, rats, hamsters

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

    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 amore » 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.« less

  8. Quantitative structure-cytotoxicity relationship of phenylpropanoid amides.

    PubMed

    Shimada, Chiyako; Uesawa, Yoshihiro; Ishihara, Mariko; Kagaya, Hajime; Kanamoto, Taisei; Terakubo, Shigemi; Nakashima, Hideki; Takao, Koichi; Saito, Takayuki; Sugita, Yoshiaki; Sakagami, Hiroshi

    2014-07-01

    A total of 12 phenylpropanoid amides were subjected to quantitative structure-activity relationship (QSAR) analysis, based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to investigate on their biological activities. Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and three human oral normal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor selectivity was evaluated by the ratio of the mean CC50 (50% cytotoxic concentration) against normal oral cells to that against OSCC cell lines. Anti-HIV activity was evaluated by the ratio of CC50 to EC50 (50% cytoprotective concentration from HIV infection). Physicochemical, structural, and quantum-chemical parameters were calculated based on the conformations optimized by the LowModeMD method followed by density functional theory (DFT) method. Twelve phenylpropanoid amides showed moderate cytotoxicity against both normal and OSCC cell lines. N-Caffeoyl derivatives coupled with vanillylamine and tyramine exhibited relatively higher tumor selectivity. Cytotoxicity against normal cells was correlated with descriptors related to electrostatic interaction such as polar surface area and chemical hardness, whereas cytotoxicity against tumor cells correlated with free energy, surface area and ellipticity. The tumor-selective cytotoxicity correlated with molecular size (surface area) and electrostatic interaction (the maximum electrostatic potential). The molecular size, shape and ability for electrostatic interaction are useful parameters for estimating the tumor selectivity of phenylpropanoid amides. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  9. Evidence supporting product standards for carcinogens in smokeless tobacco products

    PubMed Central

    Hatsukami, Dorothy K.; Stepanov, Irina; Severson, Herb; Jensen, Joni A.; Lindgren, Bruce R.; Horn, Kimberly; Khariwala, Samir S.; Martin, Julia; Carmella, Steven G.; Murphy, Sharon E.; Hecht, Stephen S.

    2014-01-01

    Smokeless tobacco (ST) products sold in the U.S. vary significantly in yields of nicotine and tobacco-specific nitrosamines (TSNA). With the passage of the Family Smoking Prevention and Tobacco Control Act, the Food and Drug Administration now has the authority to establish product standards. However, limited data exist determining the relative roles of pattern of ST use versus constituent levels in the ST product in exposure of users to carcinogens. In this study, ST users of brands varying in nicotine and TSNA content were recruited from three different regions in the U.S. Participants underwent two assessment sessions. During these sessions, demographic and ST use history information along with urine samples to assess biomarkers of exposure and effect were collected. During the time between data collection, ST users recorded the amount and duration of ST use on a daily basis using their diary cards. Results showed that independent of pattern of ST use and nicotine yields, levels of TSNA in ST products played a significant role in carcinogen exposure levels. Product standards for reducing levels of TSNA in ST products are necessary to decrease exposure to these toxicants and potentially to reduce risk for cancer. PMID:25524878

  10. Quantitative structure-toxicity relationship (QSTR) studies on the organophosphate insecticides.

    PubMed

    Can, Alper

    2014-11-04

    Organophosphate insecticides are the most commonly used pesticides in the world. In this study, quantitative structure-toxicity relationship (QSTR) models were derived for estimating the acute oral toxicity of organophosphate insecticides to male rats. The 20 chemicals of the training set and the seven compounds of the external testing set were described by means of using descriptors. Descriptors for lipophilicity, polarity and molecular geometry, as well as quantum chemical descriptors for energy were calculated. Model development to predict toxicity of organophosphate insecticides in different matrices was carried out using multiple linear regression. The model was validated internally and externally. In the present study, QSTR model was used for the first time to understand the inherent relationships between the organophosphate insecticide molecules and their toxicity behavior. Such studies provide mechanistic insight about structure-toxicity relationship and help in the design of less toxic insecticides. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Environmental exposure to human carcinogens in teenagers and the association with DNA damage

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

    Franken, Carmen, E-mail: carmen.franken@vito.be

    Background: We investigated whether human environmental exposure to chemicals that are labeled as (potential) carcinogens leads to increased (oxidative) damage to DNA in adolescents. Material and methods: Six hundred 14–15-year-old youngsters were recruited all over Flanders (Belgium) and in two areas with important industrial activities. DNA damage was assessed by alkaline and formamidopyrimidine DNA glycosylase (Fpg) modified comet assays in peripheral blood cells and analysis of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels. Personal exposure to potentially carcinogenic compounds was measured in urine, namely: chromium, cadmium, nickel, 1-hydroxypyrene as a proxy for exposure to other carcinogenic polycyclic aromatic hydrocarbons (PAHs), t,t-muconic acid asmore » a metabolite of benzene, 2,5-dichlorophenol (2,5-DCP), organophosphate pesticide metabolites, and di(2-ethylhexyl) phthalate (DEHP) metabolites. In blood, arsenic, polychlorinated biphenyl (PCB) congeners 118 and 156, hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT) and perfluorooctanoic acid (PFOA) were analyzed. Levels of methylmercury (MeHg) were measured in hair. Multiple linear regression models were used to establish exposure-response relationships. Results: Biomarkers of exposure to PAHs and urinary chromium were associated with higher levels of both 8-OHdG in urine and DNA damage detected by the alkaline comet assay. Concentrations of 8-OHdG in urine increased in relation with increasing concentrations of urinary t,t-muconic acid, cadmium, nickel, 2,5-DCP, and DEHP metabolites. Increased concentrations of PFOA in blood were associated with higher levels of DNA damage measured by the alkaline comet assay, whereas DDT was associated in the same direction with the Fpg-modified comet assay. Inverse associations were observed between blood arsenic, hair MeHg, PCB 156 and HCB, and urinary 8-OHdG. The latter exposure biomarkers were also associated with higher fish intake. Urinary

  12. Most cancer in firefighters is due to radio-frequency radiation exposure not inhaled carcinogens.

    PubMed

    Milham, S

    2009-11-01

    Recent reviews and reports of cancer incidence and mortality in firefighters conclude that they are at an increased risk of a number of cancers. These include leukemia, multiple myeloma, non-Hodgkin's lymphoma, male breast cancer, malignant melanoma, and cancers of the brain, stomach, colon, rectum, prostate, urinary bladder, testes, and thyroid. Firefighters are exposed to a long list of recognized or probable carcinogens in combustion products and the presumed route of exposure to these carcinogens is by inhalation. Curiously, respiratory system cancers and diseases are usually not increased in firefighters as they are in workers exposed to known inhaled carcinogens. The list of cancers with increased risk in firefighters strongly overlaps the list of cancers at increased risk in workers exposed to electromagnetic fields (EMF) and radiofrequency radiation (RFR). Firefighters have increased exposure to RFR in the course of their work, from the mobile two-way radio communications devices which they routinely use while fighting fires, and at times from firehouse and fire vehicle radio transmitters. I suggest that some of the increased cancer risk in firefighters is caused by RFR exposure, and is therefore preventable. The precautionary principle should be applied to reduce the risk of cancer in firefighters, and workman's compensation rules will necessarily need to be modified.

  13. [The register of exposed workers to carcinogens: legislative framework and data analysis].

    PubMed

    Scarselli, A; Di Marzio, D; Marinaccio, A; Iavicoli, S

    2010-01-01

    On the basis of the law which introduced the registration of occupational exposures to carcinogens (Legislative Decree 626/94), the National Institute for Occupational Safety and Prevention designed and implemented an information system for collecting and recording such information. The Ministry of Health Decree No 155/2007, which established the procedures for record keeping and transmission of registers of exposed workers, regulated the legislative fJamework in this field. The aim of the study was to illustrate some of the major legislative issues and toprovide summary statistics, after one year of entry into force of this Decree. The main information to record is: the carcinogenic agents used, the type of occupational exposure and data on the environmental measurements. Descriptive statistical analysis were carried out, by sector of economic activity, carcinogen agent and worker's occupation. As at 31 December 2008 the information recorded, altogether, covered: 6000 firms, 79,000 workers, 164,000 exposures and 100,000 measurements. Most of the exposures occurred in the manufacturing and construction industries and in commercial activities. Such surveillance system, established as a result of the institution of exposure registers, makes it possible to plan analytical studies, both for monitoring the effects of exposure, even at low doses, and for assessing the prevention and protection measures. It is hoped that the recent readjustment law (Legislative Decree 81/2008) will promote awareness of all subjects involved in the recording procedures (employers, physicians, local health units, research institutes, etc.), thus increasing the quality and coverage of data transmission.

  14. A Quantitative Structure-Property Relationship (QSPR) Study of Aliphatic Alcohols by the Method of Dividing the Molecular Structure into Substructure

    PubMed Central

    Liu, Fengping; Cao, Chenzhong; Cheng, Bin

    2011-01-01

    A quantitative structure–property relationship (QSPR) analysis of aliphatic alcohols is presented. Four physicochemical properties were studied: boiling point (BP), n-octanol–water partition coefficient (lg POW), water solubility (lg W) and the chromatographic retention indices (RI) on different polar stationary phases. In order to investigate the quantitative structure–property relationship of aliphatic alcohols, the molecular structure ROH is divided into two parts, R and OH to generate structural parameter. It was proposed that the property is affected by three main factors for aliphatic alcohols, alkyl group R, substituted group OH, and interaction between R and OH. On the basis of the polarizability effect index (PEI), previously developed by Cao, the novel molecular polarizability effect index (MPEI) combined with odd-even index (OEI), the sum eigenvalues of bond-connecting matrix (SX1CH) previously developed in our team, were used to predict the property of aliphatic alcohols. The sets of molecular descriptors were derived directly from the structure of the compounds based on graph theory. QSPR models were generated using only calculated descriptors and multiple linear regression techniques. These QSPR models showed high values of multiple correlation coefficient (R > 0.99) and Fisher-ratio statistics. The leave-one-out cross-validation demonstrated the final models to be statistically significant and reliable. PMID:21731451

  15. THE USE OF NON-TUMOR DATA IN CANCER RISK ASSESSMENT: REFLECTIONS ON BENZENE, BUTADIENE AND VINYL CHLORIDE

    EPA Science Inventory



    1.0 Introduction. Quantitative estimation of human cancer risk from exposure to chemicals has traditionally been almost exclusively based on tumor incidence in experimental animals. While improvements in carcinogenicity testing in experimental animals (1,2) and structure-...

  16. An analysis of pharmaceutical experience with decades of rat carcinogenicity testing: support for a proposal to modify current regulatory guidelines.

    PubMed

    Sistare, Frank D; Morton, Daniel; Alden, Carl; Christensen, Joel; Keller, Douglas; Jonghe, Sandra De; Storer, Richard D; Reddy, M Vijayaraj; Kraynak, Andrew; Trela, Bruce; Bienvenu, Jean-Guy; Bjurström, Sivert; Bosmans, Vanessa; Brewster, David; Colman, Karyn; Dominick, Mark; Evans, John; Hailey, James R; Kinter, Lewis; Liu, Matt; Mahrt, Charles; Marien, Dirk; Myer, James; Perry, Richard; Potenta, Daniel; Roth, Arthur; Sherratt, Philip; Singer, Thomas; Slim, Rabih; Soper, Keith; Fransson-Steen, Ronny; Stoltz, James; Turner, Oliver; Turnquist, Susan; van Heerden, Marjolein; Woicke, Jochen; DeGeorge, Joseph J

    2011-06-01

    Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.

  17. Identification of cancer chemopreventive isothiocyanates as direct inhibitors of the arylamine N-acetyltransferase-dependent acetylation and bioactivation of aromatic amine carcinogens.

    PubMed

    Duval, Romain; Xu, Ximing; Bui, Linh-Chi; Mathieu, Cécile; Petit, Emile; Cariou, Kevin; Dodd, Robert H; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

    2016-02-23

    Aromatic amines (AAs) are chemicals of industrial, pharmacological and environmental relevance. Certain AAs, such as 4-aminobiphenyl (4-ABP), are human carcinogens that require enzymatic metabolic activation to reactive chemicals to form genotoxic DNA adducts. Arylamine N-acetyltransferases (NAT) are xenobiotic metabolizing enzymes (XME) that play a major role in this carcinogenic bioactivation process. Isothiocyanates (ITCs), including benzyl-ITC (BITC) and phenethyl-ITC (PEITC), are phytochemicals known to have chemopreventive activity against several aromatic carcinogens. In particular, ITCs have been shown to modify the bioactivation and subsequent mutagenicity of carcinogenic AA chemicals such as 4-ABP. However, the molecular and biochemical mechanisms by which these phytochemicals may modulate AA carcinogens bioactivation and AA-DNA damage remains poorly understood. This manuscript provides evidence indicating that ITCs can decrease the metabolic activation of carcinogenic AAs via the irreversible inhibition of NAT enzymes and subsequent alteration of the acetylation of AAs. We demonstrate that BITC and PEITC react with NAT1 and inhibit readily its acetyltransferase activity (k(i) = 200 M(-1).s(-1) and 66 M(-1).s(-1) for BITC and PEITC, respectively). Chemical labeling, docking approaches and substrate protection assays indicated that inhibition of the acetylation of AAs by NAT1 was due to the chemical modification of the enzyme active site cysteine. Moreover, analyses of AAs acetylation and DNA adducts in cells showed that BITC was able to modulate the endogenous acetylation and bioactivation of 4-ABP. In conclusion, we show that direct inhibition of NAT enzymes may be an important mechanism by which ITCs exert their chemopreventive activity towards AA chemicals.

  18. Science, politics, and health in the brave new world of pharmaceutical carcinogenic risk assessment: Technical progress or cycle of regulatory capture?

    PubMed Central

    Abraham, John; Ballinger, Rachel

    2012-01-01

    The carcinogenicity (cancer-inducing potential) of pharmaceuticals is an important risk factor for health when considering whether thousands of patients on drug trials or millions/billions of consumers in the marketplace should be exposed to a new drug. Drawing on fieldwork involving over 50 interviews and documentary research spanning 2002–2010 in Europe and the US, and on regulatory capture theory, this article investigates how the techno-regulatory standards for carcinogenicity testing of pharmaceuticals have altered since 1998. It focuses on the replacement of long-term carcinogenicity tests in rodents (especially mice) with shorter-term tests involving genetically-engineered mice (GEM). Based on evidence regarding financial/organizational control, methodological design, and interpretation of the validation and application of these new GEM tests, it is argued that regulatory agencies permitted the drug industry to shape such validation and application in ways that prioritized commercial interests over the need to protect public health. Boundary-work enabling industry scientists to define some standards of public-health policy facilitated such capture. However, as the scientific credibility of GEM tests as tools to protect public health by screening out carcinogens became inescapably problematic, a regulatory resurgence, impelled by reputational concerns, exercised more control over industry’s construction and use of the tests, The extensive problems with GEM tests as public-health protective regulatory science raises the spectre that alterations to pharmaceutical carcinogenicity-testing standards since the 1990s may have been boundary-work in which the political project of decreasing the chance that companies’ products are defined as carcinogenic has masqueraded as techno-science. PMID:22784375

  19. The use of dose-response data in a margin of exposure approach to carcinogenic risk assessment for genotoxic chemicals in food.

    PubMed

    Benford, Diane J

    2016-05-01

    Genotoxic substances are generally not permitted for deliberate use in food production. However, an appreciable number of known or suspected genotoxic substances occur unavoidably in food, e.g. from natural occurrence, environmental contamination and generation during cooking and processing. Over the past decade a margin of exposure (MOE) approach has increasingly been used in assessing the exposure to substances in food that are genotoxic and carcinogenic. The MOE is defined as a reference point on the dose-response curve (e.g. a benchmark dose lower confidences limit derived from a rodent carcinogenicity study) divided by the estimated human intake. A small MOE indicates a higher concern than a very large MOE. Whilst the MOE cannot be directly equated to risk, it supports prioritisation of substances for further research or for possible regulatory action, and provides a basis for communicating to the public. So far, the MOE approach has been confined to substances for which carcinogenicity data are available. In the absence of carcinogenicity data, evidence of genotoxicity is used only in hazard identification. The challenge to the genetic toxicology community is to develop approaches for characterising risk to human health based on data from genotoxicity studies. In order to achieve wide acceptance, it would be important to further address the issues that have been discussed in the context of dose-response modelling of carcinogenicity data in order to assign levels of concern to particular MOE values, and also whether it is possible to make generic conclusions on how potency in genotoxicity assays relates to carcinogenic potency. © Crown copyright 2015.

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

    PubMed Central

    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 are conducted by injecting rodents with a single dose of 2.5 to 10 μmol of pure NNK; the amount of NNK contained in all of the mainstream smoke from about 3700 to 14,800 typical U.S. cigarettes. Extrapolated to a 70-kg smoker, the carcinogenic dose of pure NNK administered to rodents would be equivalent to the amount of NNK in all of the mainstream smoke of 22 to 87 million typical U.S. cigarettes. Furthermore, extrapolating results from rodent studies based on a single injection of pure NNK to establish a causative role for NNK in the carcinogenicity of chronic tobacco smoke exposure in humans is not consistent with basic pharmacological and toxicological principles. For example, such an approach fails to consider the effect of other smoke constituents upon the toxicity of NNK. In vitro studies demonstrate that nicotine, cotinine, and aqueous cigarette “tar” extract (ACTE) all inhibit the mutagenic activity of NNK. In vivo studies reveal that the formation of pulmonary DNA adducts in mice injected with NNK is inhibited by the administration of cotinine and mainstream cigarette smoke. Cigarette smoke has been shown to modulate the metabolism of NNK, providing a mechanism for the inhibitory effects of cigarette smoke and cigarette smoke constituents on NNK-induced tumorigenesis. NNK-related pulmonary DNA adducts have not been detected in rodents exposed to cigarette smoke, nor has the toxicity of tobacco smoke or tobacco smoke condensate containing marked reductions in TSNA