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Studies on the Biological Activity of N-nitrosamines

Description: Two aspects of the biological activity of N-nitrosamines were studied. First, the effect of ascorbate on the mutagenicity of N-nitrosopiperidines was studied in the Ames Salmanella/ mammalian microsome mutagenicity test. The addition of ascorbate significantly enhanced the mutagenicity of these compounds. This enhancement was selective for N-nitrosamines suggesting a possible role of ascorbate in N-nitrosamine induced carcinogenicity. Second, the technique of velocity sedimentation in alkaline sucrose density gradients was applied to the detection of N-nitrosamine induced DNA damage in Balb/c 3T3 cells. This technique detected N-nitrosamine induced DNA damage when the cells were made permeable before treatment. This technique compares favorably with other test systems used to evaluate N-nitrosamines and should be useful in further studies of N-nitrosamines.
Date: August 1980
Creator: Barton, Rodney A. (Rodney Alan)
Partner: UNT Libraries

Induction of Aryl Hydrocarbon Hydroxylase in Ambystoma tigrinum

Description: Aryl hydrocarbon hydroxylase (AHH) was induced 15-fold in Ambystoma tigrinum by intraperitoneal injection of 3-methylcholanthrene in corn oil, or 10-fold by addition of aromatic polycyclic hydrocarbons to the aqueous environment of the neotene animal. The cytochrome P-450-associated microsomal enzyme is similar to the inducible, one-gene, autosomal-dominant system typical in the laboratory mouse and man. Differences in optimal temperature for enzyme induction and activity were noted in organ culture of human and Ambystoma tissues, and ratios of benzpyrene metabolites differed between Ambystoma and Mus. The half life of enzyme activity induced in vivo was related to the excretion of hydrocarbon metabolites.
Date: December 1974
Creator: Colvin, David P.
Partner: UNT Libraries

A Study of Aryl Hydrocarbon Hydroxylase in Cultured Human Lymphocytes

Description: Aryl hydrocarbon hydroxylase activity was studied in cultured human lymphocytes using 3-methylcholanthrene, 1,2- benzanthracene, and 4'-bromoflavone as inducers. The substrates used to run the 60 minute assay were benzo(α)pyrene and diphenyloxazole. At the optimum bromoflavone concentration for induction of aryl hydrocarbon hydroxylase, the induced enzymatic activity compared favorably with that of aryl hydrocarbon hydroxylase induced by 3MC in a 96 hour lymphocyte culture using BP as the assay substrate. The whole cell human lymphocyte system was found to have as much or more activity in 20 ml vials using Joklik's-Modified Minimum Essential Medium at a pH optimum of 7.5 with no co-factor added as did the Roswell Park assay system. The whole cell assay showed that levels of aryl hydrocarbonhydroxylase inducibility in lumphocytes from smokers and non-smokers varied without regard to the subjects' smoking habits. The assay system also indicated that intact lymphocytes generate a similar group of benzo(α)pyrene metabolites as that produced by a hepatic microsomal preparation from C57B1/6J mice.
Date: August 1976
Creator: Guyden, Jerry C.
Partner: UNT Libraries

A Study of Polynuclear Aromatic Hydrocarbon Carcinogen Transport and Deoxyribonucleic Acid Repair

Description: This investigation addresses the interrelated problems of A) Uptake and vascular transport of lipophilic chemical carcinogens, and intracellular interactions between lipoproteins and carcinogens; B) Biochemical mechanisms by which polynuclear aromatic hydrocarbon carcinogens inhibit the replicative and repair DNA synthesis in cells. The results observed in this study suggest that ingested benzo(a)pyrene (BaP) enters the gastrointestinal lymphatic drainage sequestered within lymphatic lipoproteins, and that low-density lipoproteins (LDL) play a major role in the vascular transport of BaP. BaP is taken up into cells by adsorptive endocytosis mediated by an interaction between apolipoprotein-specific receptors on the cell membrane and the specific apolipoproteins on LDL. Having entered peripheral cells sequestered within the lipid core of LDL, an electrophilic metabolite of BaP covalently binds to cellular DNA, and may interact with other cellular macro-molecules. Data presented here suggest that LDL is also absolutely required for the activation of DNA polymerase-a, which is the major enzyme of DNA excision repair necessary to correct the DNA damage caused by BaP. This study concludes that an active metabolite of the polynuclear aromatic hydrocarbon carcinogen, benzo(a)pyrene, suppresses DNA polymerase-a activity by inhibiting the binding of 2'-deoxyguanosine 5'-triphosphate to an acceptor site on the DNA polymerase-a complex with the DNA substrate, thereby competitively inhibiting interaction of 2'-deoxyguanosine 5'-triphosphate in the DNA synthetic process.
Date: December 1984
Creator: Joe, Cheol O., 1949-
Partner: UNT Libraries

Identifying and regulating carcinogens

Description: This background paper was requested by the House Government Operations Committee and its Subcommittee on Intergovernmental Relations and Human Resources. In it, OTA describes policies issued by Federal agencies concerning the identification, assessment, and regulation of carcinogenic chemicals; the chemicals that have been regulated because of carcinogenic risk; the Federal Government’s carcinogenicity testing program; and the results of OTA’s analysis of the extent of agency action on chemicals determined to be carcinogenic.
Date: November 1987
Creator: United States. Congress. Office of Technology Assessment.
Partner: UNT Libraries Government Documents Department


Description: The carcinogenic activity of the benzo[a]pyrene 1, the 7,12-dimethylbenz[a]anthracene 2 and the 3-methylcholanthrene 3 is suggested to be determine by the electrophilic attack of the active oxygen, induced by the hydroxylating enzyme systems, on the most reactive substituting carbon atom(s). The cationic intermediate(s) with the charge mainly localized on a complementary, interrelated position(s) of the hydroxyl substituted position(s) reacts further with the cellular nucleophiles. The electrophilic nature of the ultimate chemical carcinogens constitutes the common distinctive feature that correlates their different structures and allows us to understand their carcinogenicity. The formation of a covalent bond with the nucleophiles of the biological macromolecules, nucleic acids and proteins, appears to be the essential requirement in the primary process of carcinogenesis.
Date: August 1, 1970
Creator: Cavalieri, E. & Calvin, M.
Partner: UNT Libraries Government Documents Department


Description: Soils at waste sites must be evaluated for the potential of residual soil contamination to leach and migrate to the groundwater beneath the disposal area. If migration to the aquifer occurs, contaminants can travel vast distances and contaminate drinking water wells, thus exposing human receptors to harmful levels of toxins and carcinogens. To prevent groundwater contamination, a contaminant fate and transport analysis is necessary to assess the migration potential of residual soil contaminates. This type of migration analysis is usually performed using a vadose zone model to account for complex geotechnical and chemical variables including: contaminant decay, infiltration rate, soil properties, vadose zone thickness, and chemical behavior. The distinct advantage of using a complex model is that less restrictive, but still protective, soil threshold levels may be determined avoiding the unnecessary and costly remediation of marginally contaminated soils. However, the disadvantage of such modeling is the additional cost for data collection and labor required to apply these models. In order to allay these higher costs and to achieve a less restrictive but still protective clean-up level, a multiple contaminant and multi layered soil column equilibrium partitioning model was developed which is faster, simpler and less expensive to use.
Date: May 1, 2007
Creator: Rucker, G
Partner: UNT Libraries Government Documents Department

The Distribution of Radioactivity in the Mouse Following Administration of Dibenzanthracene Labeled in the 9 and 10 Positions with Carbon Fourteen

Description: Dibenzanthracene, labeled in the 9 and 10 positions with carbon fourteen has been administered to mice intravenously and by stomach tube as an aqueous colloid, and intraperitoneally, subcutaneously, and by stomach tube in tricaprylin solution. The distribution of radioactivity in the mice at various time intervals after administration of the carcinogen has been determined. The radioactivity is rapidly eliminated, largely through the feces, and ordinarily very little is absorbed. The distribution and rate of elimination depends upon the mode of administration. There is an appreciable quantity of radioactivity in tumors produced several months after a single subcutaneous injection of dibenzanthracene. There appear to be no detectable effects from the radiation of the labeled carcinogen.
Date: January 30, 1948
Creator: Heidelberger, Charles & Jones, Hardin, B.
Partner: UNT Libraries Government Documents Department

Metal inhibition of human alkylpurine-DNA-N-glycosylase activityin base excision repair

Description: Cadmium (Cd{sup 2+}), nickel (Ni{sup 2+}) and cobalt (Co{sup 2+}) are human and/or animal carcinogens. Zinc (Zn{sup 2+}) is not categorized as a carcinogen, and rather an essential element to humans. Metals were recently shown to inhibit DNA repair proteins that use metals for their function and/or structure. Here we report that the divalent ions Cd{sup 2+}, Ni{sup 2+}, and Zn{sup 2+} can inhibit the activity of a recombinant human N-methylpurine-DNA glycosylase (MPG) toward a deoxyoligonucleotide with ethenoadenine (var epsilonA). MPG removes a variety of toxic/mutagenic alkylated bases and does not require metal for its catalytic activity or structural integrity. At concentrations starting from 50 to 1000 {micro}M, both Cd{sup 2+} and Zn{sup 2+} showed metal-dependent inhibition of the MPG catalytic activity. Ni{sup 2+} also inhibited MPG, but to a lesser extent. Such an effect can be reversed with EDTA addition. In contrast, Co{sup 2+} and Mg{sup 2+} did not inhibit the MPG activity in the same dose range. Experiments using HeLa cell-free extracts demonstrated similar patterns of inactivation of the var epsilonA excision activity by the same metals. Binding of MPG to the substrate was not significantly affected by Cd{sup 2+}, Zn{sup 2+}, and Ni{sup 2+} at concentrations that show strong inhibition of the catalytic function, suggesting that the reduced catalytic activity is not due to altered MPG binding affinity to the substrate. Molecular dynamics (MD) simulations with Zn{sup 2+} showed that the MPG active site has a potential binding site for Zn{sup 2+}, formed by several catalytically important and conserved residues. Metal binding to such a site is expected to interfere with the catalytic mechanism of this protein. These data suggest that inhibition of MPG activity may contribute to metal genotoxicity and depressed repair of alkylation damage by metals in vivo.
Date: February 28, 2006
Creator: Wang, Ping; Guliaev, Anton B. & Hang, Bo
Partner: UNT Libraries Government Documents Department

Benzo[a]Pyrene Diol Epoxide Perturbation of Cell Cycle Kinetics of Synchronized Mouse Liver Epithelial Cells

Description: A cell cycle synchronization system is described for the analysis of the perturbation of cell cycle kinetics and the cycle-phase specificity of chemicals and other agents. We used the system to study the effects of ({+-})r-7, t-8-dihydroxy-t-9, 10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP diol epoxide) upon the cell cycle of mouse liver epithelial cells(NMuLi). BaP diol epoxide(0.6 uM) was added to replated cultures of NMuLi cells that had been synchronized in various stages of the cell cycle by centrifugal elutriation. DNA histograms were obtained by flow cytometry as a function of time after replating. The data were analyzed by a computer modeling routine and reduced to a few graphs illustrating the 'net effects' of the BaP diol epoxide relative to controls. BaP diol epoxide slowed S-phase traversal in all samples relative to their respective control. Traversal through G{sub 2}M was also slowed by at least 50%. BaP diol epoxide had no apparent effect upon G{sub 1} traversal by cycling cells, but delayed the recruitment of quiescent G{sub 0} cells by about 2 hrs. The methods described constitute a powerful new approach for probing the cell cycle effects of a wide variety of agents. The present system appears to be extremely sensitive and capable of characterizing the action of agents on each phase of the cell cycle. The methods are automatable and would allow for the assay and possible differential characterization of mutagens and carcinogens.
Date: July 1, 1980
Creator: Pearlman, A.L.; Navsky, B.N. & Bartholomew, J.C
Partner: UNT Libraries Government Documents Department

Localized Plasticity in the Streamlined Genomes of Vinyl Chloride Respiring Dehalococcoides

Description: Vinyl chloride (VC) is a human carcinogen and widespread priority pollutant. Here we report the first, to our knowledge, complete genome sequences of microorganisms able to respire VC, Dehalococcoides sp. strains VS and BAV1. Notably, the respective VC reductase encoding genes, vcrAB and bvcAB, were found embedded in distinct genomic islands (GEIs) with different predicted integration sites, suggesting that these genes were acquired horizontally and independently by distinct mechanisms. A comparative analysis that included two previously sequenced Dehalococcoides genomes revealed a contextually conserved core that is interrupted by two high plasticity regions (HPRs) near the Ori. These HPRs contain the majority of GEIs and strain-specific genes identified in the four Dehalococcoides genomes, an elevated number of repeated elements including insertion sequences (IS), as well as 91 of 96 rdhAB, genes that putatively encode terminal reductases in organohalide respiration. Only three core rdhA orthologous groups were identified, and only one of these groups is supported by synteny. The low number of core rdhAB, contrasted with the high rdhAB numbers per genome (up to 36 in strain VS), as well as their colocalization with GEIs and other signatures for horizontal transfer, suggests that niche adaptation via organohalide respiration is a fundamental ecological strategy in Dehalococccoides. This adaptation has been exacted through multiple mechanisms of recombination that are mainly confined within HPRs of an otherwise remarkably stable, syntenic, streamlined genome among the smallest of any free-living microorganism.
Date: June 30, 2009
Creator: McMurdie, Paul J.; Behrens, Sebastien F.; Muller, Jochen A.; Goke, Jonathan; Ritalahti, Kirsti M.; Wagner, Ryan et al.
Partner: UNT Libraries Government Documents Department

Health hazards associated with the use of di-(2-ethylhexyl) phthalate (commonly referred to as DOP) in HEPA filter test

Description: Di-(2-ethylhexyl) phthalate (DEHP), commonly referred to as di-octyl phthalate, is an important production chemical in the US. In addition to its major use as an additive in plastics, DEHP is widely used to evaluate the effectiveness of high efficiency particulate air (HEPA) filters. Historically, DEHP was also used in quantitative fit testing for respirators. Evaluations of this compound a decade ago showed that it can induce hepatocellular carcinomas in laboratory animals. Although most Department of Energy (DOE) facilities have since discontinued using DEHP in respirator fit testing, DEHP continues to be used for evaluating HEPA filters. This report summarizes available information on the toxicity, mutagenicity, carcinogenicity, and other hazards and problems posed by DEHP, specifically with reference to HEPA filter testing. Information on work practice improvements as well as the availability and suitability of DEHP substitutes are also presented. This material should assist the DOE in the safe use of this material.
Date: January 1, 1995
Partner: UNT Libraries Government Documents Department

Assessment of Technologies for Determining Cancer Risks From the Environment

Description: A report by the Office of Technology Assessment (OTA) that "discusses the strengths and weaknesses of data sources used for determining trends in cancer occurrence and mortality, and reviews estimates of the contribution of various factors-behaviors and exposures-associated with cancer in this country" (p. iii).
Date: June 1981
Creator: United States. Congress. Office of Technology Assessment.
Partner: UNT Libraries Government Documents Department

Toxicology profiles of chemical and radiological contaminants at Hanford

Description: This document summarizes toxicology information required under Section 3.3 (Toxicity Assessment) of HSRAM, and can also be used to develop the short toxicology profiles required in site assessments (described in HSRAM, Section 3.3.5). Toxicology information is used in the dose-response step of the risk assessment process. The dose-response assessment describes the quantitative relationship between the amount of exposure to a substance and the extent of toxic injury or disease. Data are derived from animal studies or, less frequently, from studies in exposed human populations. The risks of a substance cannot be ascertained with any degree of confidence unless dose-response relations are quantified. This document summarizes dose-response information available from the US Environmental Protection Agency (EPA). The contaminants selected for inclusion in this document represent most of the contaminants found at Hanford (both radiological and chemical), based on sampling and analysis performed during site investigations, and historical information on waste disposal practices at the Hanford Site.
Date: July 1, 1995
Creator: Harper, B.L.; Strenge, D.L.; Stenner, R.D.; Maughan, A.D. & Jarvis, M.K.
Partner: UNT Libraries Government Documents Department

Protein adducts of the prostate carcinogen PhIP in children

Description: Prostate cancer is the second leading cause of cancer death in men in the United States. few epidemiology studies have indicated that exposure to PhIP, a rodent prostate carcinogen formed in meat during cooking, may be an important risk factor for prostate cancer in humans. Therefore, a highly sensitive biomarker assay is urgently needed to clarify the role of PhIP in prostate cancer. The goal of this project is to develop an assay that can be used to more accurately quantify human exposure to PhIP and potential prostate cancer risk. Our hypothesis is that an Accelerator Mass Spectrometry-based method can be developed to measure protein adducts of PhIP in the blood of humans. This will provide a measure of the internal dose, as well as the capacity for carcinogen bioactivation to a form that can initiate the cancer process. Towards this goal, we have characterized an adduct formed by PhIP in vitro with the amino acid cysteine. This adduct should provide a biomarker of dietary PhIP exposure and potential prostate cancer risk that could be used to identify individuals for prevention and for monitoring the effect chemoprevention strategies.
Date: February 20, 2004
Creator: Laboratory, Lawrence Livermore National
Partner: UNT Libraries Government Documents Department


Description: In the class of the polycondensed aromatic hydrocarbons, the concept of localized charge in a {sigma}-complex, e.g., the carbonium ion formed by addition of a proton or other electrophile to an aromatic ring, has so far received experimental evidence only in the case of anthracene. The ultraviolet spectrum of this compound in sulfuric acid is similar to that of the benzhydryl cation. Ph{sub c}C{sup +}Me. This result implies the protonation of anthracene at one meso-carbon atom and the localization of the positive charge at the other. The {sigma}-complex of the potent carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) in acidic medium offers another example of this type of charge localization. The determination of structure was achieved by comparing the NMR spectra of DMBA in neutral and acidic solvents. The ratio of the integrated intensities of the proton peaks in the spectrum of DMBA is, from right to left, 3:3:5:1:1:2:1. The assignment of the 7-CH{sub 3} ({sigma}3.00) and 12-CH{sub 3} ({sigma}3.29) resonances was made by comparison with the spectra of 7-methylbenz[a]anthracene (7-CH{sub 3}, {sigma}3.03) and 12-methylbenz[a]anthracene (12-CH{sub 3}, {sigma}3.32) under the same conditions. A good general correlation exists between the methyl chemical shifts of the twelve monosubstituted methylbenzanthrancenes and the corresponding aryl protons of benzanthracene.
Date: April 1, 1971
Creator: Cavalieri, Ercole & Calvin, Melvin.
Partner: UNT Libraries Government Documents Department

Subtask 1.1 - Characterization of Erionite

Description: Zeolites are an economical mineral used in several applications, primarily as molecular sieves because of their crystalline structure. Southwestern North Dakota has several localities of volcanic ash deposits (tuffs) that have undergone physical and chemical changes forming some zeolites in the process. Of particular interest is the zeolite mineral erionite, but not because of its economic potential. Erionite is highly carcinogenic and was found to be responsible for extremely high mortality rates in two Turkish villages in close proximity to erionite rock and dust. Erionite has traditionally been identified using x-ray diffraction (XRD) methods. The presence of swelling clays can interfere with the identification of erionite by XRD giving false positive results. Scanning electron microscopy (SEM) was used to identify the distinctive needlelike form of erionite. In some cases, erionite was identified using SEM techniques where erionite was present, but in quantities that are lower than the lower detection limits. Conversely, erionite was identified by XRD in some instances where the erionite was somewhat masked in a clay matrix. Both XRD and SEM methods should be used to properly identify erionite. Erionite was identified in sandstones and siltstones from buttes in Dunn, Stark, and Slope Counties of North Dakota, but no definitive correlation was noted between these occurrences and health effects that may be attributed to erionite.
Date: November 30, 2009
Creator: Eylands, Kurt; Azenkeng, Alexander; Mibeck, Blaise & Raymond, Laura
Partner: UNT Libraries Government Documents Department

Understanding the Mechanism of Human P450 CYP1A2 Using Coupled Quantum-Classical Simulations in a Dynamical Environment

Description: The reaction mechanism of the human P450 CYP1A2 enzyme plays a fundamental role in understanding the effects of environmental carcinogens and mutagens on humans. Despite extensive experimental research on this enzyme system, key questions regarding its catalytic cycle and oxygen activation mechanism remain unanswered. In order to elucidate the reaction mechanism in human P450, new computational methods are needed to accurately represent this system. To enable us to perform computational simulations of unprecedented accuracy on these systems, we developed a dynamic quantum-classical (QM/MM) hybrid method, in which ab initio molecular dynamics are coupled with classical molecular mechanics. This will provide the accuracy needed to address such a complex, large biological system in a fully dynamic environment. We also present detailed calculations of the P450 active site, including the relative charge transfer between iron porphine and tetraphenyl porphyrin.
Date: February 10, 2006
Creator: Draeger, E W; Bennion, B; Gygi, F & Lightstone, F
Partner: UNT Libraries Government Documents Department

Ionizing radiation predisposes non-malignant human mammaryepithelial cells to undergo TGF beta-induced epithelial to mesenchymaltransition

Description: Transforming growth factor {beta}1 (TGF{beta}) is a tumor suppressor during the initial stage of tumorigenesis, but it can switch to a tumor promoter during neoplastic progression. Ionizing radiation (IR), both a carcinogen and a therapeutic agent, induces TGF{beta}, activation in vivo. We now show that IR sensitizes human mammary epithelial cells (HMEC) to undergo TGF{beta}-mediated epithelial to mesenchymal transition (EMT). Non-malignant HMEC (MCF10A, HMT3522 S1 and 184v) were irradiated with 2 Gy shortly after attachment in monolayer culture, or treated with a low concentration of TGF{beta} (0.4 ng/ml), or double-treated. All double-treated (IR+TGF{beta}) HMEC underwent a morphological shift from cuboidal to spindle-shaped. This phenotype was accompanied by decreased expression of epithelial markers E-cadherin, {beta}-catenin and ZO-1, remodeling of the actin cytoskeleton, and increased expression of mesenchymal markers N-cadherin, fibronectin and vimentin. Furthermore, double-treatment increased cell motility, promoted invasion and disrupted acinar morphogenesis of cells subsequently plated in Matrigel{trademark}. Neither radiation nor TGF{beta} alone elicited EMT, even though IR increased chronic TGF{beta} signaling and activity. Gene expression profiling revealed that double treated cells exhibit a specific 10-gene signature associated with Erk/MAPK signaling. We hypothesized that IR-induced MAPK activation primes non-malignant HMEC to undergo TGF{beta}-mediated EMT. Consistent with this, Erk phosphorylation were transiently induced by irradiation, persisted in irradiated cells treated with TGF{beta}, and treatment with U0126, a Mek inhibitor, blocked the EMT phenotype. Together, these data demonstrate that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression.
Date: April 6, 2007
Creator: Andarawewa, Kumari L.; Erickson, Anna C.; Chou, William S.; Costes, Sylvain; Gascard, Philippe; Mott, Joni D. et al.
Partner: UNT Libraries Government Documents Department

Ionization in liquids. Final technical report, November 1, 1993--December 31, 1995

Description: The objective of these studies which began in 1993 was to provide new information on electron and ion transport and reactions in model liquids and biomimetic systems that is pertinent to the roles of charged species in inducing radiobiological damage and to elucidate the interrelationship among the carcinogenicity, mutagenicity and electrophilicity of chemicals. This final report summarizes research efforts in the following areas: electrons in biological systems; and electron and ion transport and reactions in model liquids. In biological systems attention was focused on the following: excess electrons as probes of carcinogen electrophilicity; cost effectiveness of k{sub e} as a carcinogen-screening test; and conversion of k{sub e} to a carcinogen-screening electronic device. In model liquids, research was focused on two areas. The first investigated radiation-induced dimerization of fullerenes. The second area studied radiolytic synthesis of fullerene derivatives.
Date: March 29, 1996
Creator: Bakale, G.
Partner: UNT Libraries Government Documents Department