Showing papers by "Research Triangle Park published in 1987"

Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays.

Abstract: 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.

Chromosome aberrations and sister chromatid exchanges in chinese hamster ovary cells: Evaluations of 108 chemicals

Abstract: Results from the testing of 108 coded chemicals in Chinese hamster ovary (CHO) cells for the induction of chromosome aberrations and sister chromatid exchanges (SCEs) are presented. All chemicals were tested with and without exogenous metabolic activation, using protocols designed to allow testing up to toxic doses. Cell harvest times could also be extended if chemical-induced cell cycle delay was seen. Chromosome aberrations were induced by 43 of the chemicals, and 66 induced SCEs; 37 of the chemicals were positive for both endpoints.

Estimating the recombination parameter of a finite population model without selection.

Abstract: An estimator is proposed for the parameter C = 4Nc. where N is the population size and c is the recombination rate. The estimator is appropriate for use with sequence or restriction site data from random samples from within populations. Properties of the estimator are investigated for an infinite-sites neutral model using Monte Carlo simulations. The median and mode of the distribution of the estimator are close to the true value for all parameter values examined, but large data sets are required to obtain reliable estimates.

Molecular cloning of complementary DNA encoding the lignin-forming peroxidase from tobacco: molecular analysis and tissue-specific expression

Abstract: Plant peroxidases play a major role in lignin formation and wound healing and are believed to be involved in auxin catabolism and defense to pathogen attack. The function of the anionic peroxidase isozymes is best understood in tobacco. These isozymes catalyze the formation of the lignin polymer and form rigid cross-links between lignin, cellulose, and extensin in the secondary plant cell wall. We report the purification of the anionic peroxidase isozymes from tobacco and their partial amino acid sequence. An oligonucleotide probe deduced from the amino acid sequence was used to screen a tobacco leaf cDNA library and a 1200-base-pair cDNA clone was isolated and sequenced in its entirety. The predicted amino acid sequence revealed a 22-amino acid signal peptide and a 302-amino acid mature protein (Mr, 32,311). The amino acid sequence was compared to that of the cationic peroxidases from horseradish and turnip and was found to be 52% and 46% homologous, respectively. By RNA blot analysis, the messenger for the tobacco isozyme was found to be abundant in stem tissue while expressed at very low levels in leaf and root tissue. Four distinguishable copies of the gene were found on genomic DNA blots. The gene copy number may reflect the allotetraploid nature of Nicotiana tabacum.

The impact of a vortex ring on a wall

Abstract: The flow induced by a vortex ring approaching a plane wall on a trajectory normal to the wall is investigated for an incompressible fluid which is otherwise stagnant. The detailed characteristics of the interaction of the ring with the flow near the surface have been observed experimentally for a wide variety of laminar rings, using dye in water to visualize the flow in the ring as well as near the plane surface. Numerical solutions are obtained for the trajectory of the ring as well as for the unsteady boundary-layer flow that develops on the wall. The experimental and theoretical results show that an unsteady separation develops in the boundary-layer flow, in the form of a secondary ring attached to the wall. A period of explosive boundary-layer growth then ensues and a strong viscous-inviscid interaction occurs in the form of the ejection of the secondary vortex ring from the boundary layer. The primary ring then interacts with the secondary ring and in some cases was observed to induce the formation of a third, tertiary, ring near the wall. The details of this process are investigated over a wide Reynolds number range. The results clearly show how one vortex ring can produce another, through an unsteady interaction with a viscous flow near the wall.

Tissue Specificity of Tobacco Peroxidase Isozymes and Their Induction by Wounding and Tobacco Mosaic Virus Infection

Abstract: Peroxidases (EC 1.11.1.7) have been implicated in the responses of plants to physical stress and to pathogens, as well as in a variety of cellular processes including cell wall biosynthesis. Tissue samples from leaf, root, pith, and callus of Nicotiana tabacum were assayed for specific peroxidase isozymes by analytical isoelectric focusing. Each tissue type was found to exhibit a unique isozyme fingerprint. Root tissue expressed all of the detectable peroxidase isozymes in the tobacco plant, whereas each of the other tissues examined expressed a different subset of these isozymes. In an effort to determine which peroxidase isozymes from Nicotiana tabacum are involved in cell wall biosynthesis or other normal cellular functions and which respond to stress, plants were subjected to either wounding or infection with tobacco mosaic virus. Wounding the plant triggered the expression of several cationic isozymes in the leaf and both cationic and anionic isozymes in pith tissue. Maximum enzyme activity was detected at 72 hours after wounding, and cycloheximide treatment prevented this induction. Infection of tobacco with tobacco mosaic virus induced two moderately anionic isozymes in the leaves in which virus was applied and also systemically induced in leaves which were not inoculated with virus.

3'-azido-3'-deoxythymidine triphosphate as an inhibitor and substrate of purified human immunodeficiency virus reverse transcriptase

Abstract: Reverse transcriptase was purified from human immunodeficiency virus (HIV). It utilized the artificial primer-template poly(rA)-oligo(dT)12-18 more efficiently than activated calf thymus DNA, poly(rI)-oligo(dC)12-18, poly(rC)-oligo(dG)12-18, or poly(rCm)-oligo(dG)12-18. Maximum activity was observed at pH 7.0 to 7.6 in the presence of 5 mM MgCl2 and 100 mM KCl. 39-Azido-39-deoxythymidine triphosphate competed with dTTP for binding to HIV reverse transcriptase. Different kinetic constants were obtained with different primer-templates. Km and Ki values of 2.8 and 0.04 microM, respectively, were obtained with poly(rA)-oligo(dT)12-18. The corresponding values were 1.2 and 0.3 microM, respectively, with activated calf thymus DNA and 0.3 and 0.01 microM, respectively, with extracted virus and native template. Inhibition of the host cell DNA polymerases alpha and beta was considerably weaker. The Km and Ki values obtained with activated calf thymus DNA as the primer-template were 2.4 and 230 microM, respectively, for DNA polymerase alpha and 6.0 and 73 microM, respectively, for DNA polymerase beta. 39-Azido-39-deoxythymidine triphosphate could also serve as an alternate substrate for HIV reverse transcriptase. The resulting incorporation of 39-azido-39-deoxythymidine triphosphate into poly(rA)-oligo(dT)12-18 caused chain termination and premature deceleration of the reaction. The terminated primer could not be elongated when incubated with dTTP and HIV reverse transcriptase. Images

Ribavirin antagonizes the effect of azidothymidine on HIV replication

Abstract: Azidothymidine and ribavirin both inhibit replication of human immunodeficiency virus in vitro and show promise of clinical utility in patients infected with this virus. In this study, the possible interactions of these drugs were examined in vitro, and a reproducible antagonism between azidothymidine and ribavirin was found to occur under a variety of experimental conditions. The mechanism responsible for this antagonism appeared to be inhibition of azidothymidine phosphorylation by ribavirin. Because similar effects may occur in vivo, clinical trials of these two drugs in combination must be performed only under carefully controlled conditions.

Efficacy of Beclomethasone Nasal Solution, Flunisolide, and Cromolyn in Relieving Symptoms of Ragweed Allergy

Abstract: Although three effective topical treatments for allergic rhinitis are available, little information to assist the clinician in choosing among them has been reported. Therefore, we conducted a randomized clinical trial to compare beclomethasone nasal solution, flunisolide, and cromolyn with placebo in 120 patients with hay fever during the ragweed season of 1984. We found that all three agents were superior to placebo ( P P

Adhesion and Removal of Fine Particles on Surfaces

Abstract: Particles on surfaces containing microelectronic circuits interfere with the circuit operation thus reducing product yield. Adhesion of particles to such surface as well as to other surfaces in production environments needs to be understood so that effective ways for preventing deposition and cleaning contaminated surfaces may be devised. Adhesive forces result from molecular and electrostatic interaction and are influenced by the surrounding medium and the composition. The magnitude of adhesive forces relative to the particle mass increases significantly for micrometer-and submicrometer-sized particles, and their removal is therefore difficult. Experimental techniques for adhesion measurement are marginal, and new developments are urgently needed. Considerable new research is needed to develop new cleaning media and techniques.

A method to quantitate the relative initiating and promoting potencies of hepatocarcinogenic agents in their dose-response relationships to altered hepatic foci.

Abstract: The relative response to various initiating doses of diethylnitrosamine (DEN) and dimethylbenz[a]anthracene of the induction of numbers and size (vol. % of liver) of altered hepatic foci (AHF) in livers of adult female rats of the Sprague-Dawley and Fischer 344 (F-344) strains was studied by methods of quantitative stereology in the presence and absence of the promoting agent, phenobarbital (PB, 0.05% in the diet). In all cases, a relatively linear response with dose, even at the lowest doses employed, was obtained except for the numbers of AHF at the highest dose of DEN (30 mg/kg), which was not significantly different from that at a dose of 10 mg/kg in F-344 female rats. Similar dose-response data were obtained at various doses of two promoting agents effective in hepatocarcinogenesis, PB and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in livers of F-344 female rats following initiation with DEN (10 mg/kg) 24 h post-70% hepatectomy. The response to these agents exhibited threshold levels below which no increase in number or vol. % of liver of AHF was noted in comparison with that in livers of animals not treated with the promoting agents. At several subthreshold doses of both PB and TCDD an inhibition of AHF formation and growth (measured as vol. % of liver) was observed. Based on quantitative stereologic calculations, parameters for the estimation for the relative potency of chemicals as initiating or promoting agents have been established. These are defined as: initiation index = no. of foci induced X liver-1 X [mmol/kg body wt]-1 and promotion index = Vf/Vc X mmol-1 X weeks-1, where Vf is the total volume fraction (%) occupied by AHF in the livers of rats treated with the test agent and Vc is the total volume of AHF in control animals which have only been initiated. These parameters were calculated for a number of agents based on data published in the literature and from those reported herein. Neither parameter varied significantly with the dose of the initiating agent based on the data in this paper. The range of promotion indices extended over more than eight orders of magnitude, whereas that of initiation indices was much less variable. Such parameters may be useful as quantitative estimates of the potency of hepatocarcinogenic agents, such values having potential application to risk estimations.

Summary review of the health effects associated with phenol.

Abstract: Phenol, a monohydroxy derivative of benzene, occurs naturally in animal waste and by decomposition of organic wastes. It is also produced by man, originally by fractional distillation of coal tar, but more recently by cumene hydroperoxidation and toluene oxi dation. As a result of large production volume and natural sources, occupational and environmental exposure to phenol is likely. Phenol poisoning can occur by skin absorption, vapor inhalation, or ingestion, and, regardless of route of exposure, can result in det rimental health effects. Acute toxicity has been observed in man and experimental animals, resulting in muscle weakness, convul sions, and coma. In addition, studies have shown that although teratogenic effects have not been associated with exposure to phenol by either inhalation or oral route, high doses of phenol are fetotoxic. This paper addresses these studies and others in an attempt to determine if human health is at risk to those levels of phenol present in the environment and workplac...

Exposures to Benzene and Other Volatile Compounds from Active and Passive Smoking

Abstract: Personal exposures and breath concentrations of approximately 20 volatile organics were measured for 200 smokers and 322 nonsmokers in New Jersey and California. Smokers displayed significantly elevated breath levels of benzene, styrene, ethylbenzene, m + p-xylene, o-xylene, and octane. Significant increases in breath concentration with number of cigarettes smoked were noted for the first four aromatic compounds. Based on direct measurements of benzene in mainstream cigarette smoke, it is calculated that a typical smoker inhales 2 mg benzene daily, compared to 0.2 mg/day for the nonsmoker. Thus, cigarette smoking may be the most important source of exposure to benzene for about 50 million citizens of the United States. Passive smokers exposed at work had significantly elevated levels of aromatics in their breath. Indoor air levels in homes with smokers were significantly greater than in nonsmoking homes during fall and winter but not during spring and summer. The average annual increase in homes with smokers was 3.6 microgram/m3 for benzene and 0.5 microgram/m3 for styrene--an approximate 50% relative increase in each case. Thus, exposure to benzene and styrene may be increased for the approximately 60% of children and other nonsmokers living in homes with smokers.

Fault-Tolerant SoFtware Reliability Modeling

Abstract: In situations in which computers are used to manage life-critical situations, software errors that could arise due to inadequate or incomplete testing cannot be tolerated. This paper examines three methods of creating fault-tolerant software systems, Recovery Block, N-Version Programming, and Consensus Recovery Block, and it presents reliability models for each. The models are used to show that one method, the Consensus Recovery Block, is more reliable than the other two.

Treatment of human viral infections

Abstract: Treatment of AIDS or humans carrying or infected with the AIDS virus or having antibodies to the AIDS virus is disclosed using the compound 3'-azido-3'-deoxythymidine or a pharmaceutically acceptable basic salt thereof. Also disclosed is the use of the 5'-mono-, di- and triphosphate of 3'-azido-3'-deoxythymidine or a pharmaceutically acceptable basic salt thereof for the same purpose. Additionally, there is disclosed the treatment of Kaposi's sarcoma with 3'-azido-3'-deoxythymidine (AZT) and the synergistic activity in the treatment of humans infected with HTLV-III of AZT and interferon as well as AZT and acyclovir and AZT and 2-amino-9-(2-hydroxyethoxymethyl)purine or an ester thereof.

Comparative cytogenetic analysis of bone marrow damage induced in male B6C3F1 mice by multiple exposures to gaseous 1,3-butadiene.

Abstract: Groups of male B6C3F1 mice (N = 12) were exposed to ambient air or to gaseous 1,3-butadiene (BD) at 6.25, 62.5, and 625 ppm for 10 exposure days (6 hr + T90/day). Exposure to BD induced in bone marrow: 1) a significant increase in the frequency of chromosomal aberrations (CA); 2) a significant elevation in the frequency of sister chromatid exchanges (SCE); 3) a significant lengthening of the average generation time (AGT); 4) a significant depression in the mitotic index (MI); and, as measured in the peripheral blood, 5) a significant increase in the proportion of circulating polychromatic erythrocytes (%PCE), and 6) a significant increase in the level of micronucleated PCE (MN-PCE) and micronucleated normochromatic erythrocytes (MN-NCE). The most sensitive indicator of genotoxic damage was the frequency of SCE (significant at 6.25 ppm), followed by MN-PCE levels (significant at 62.5 ppm), and then by CA and MN-NCE frequencies (significant at 625 ppm). The most sensitive measure of cytotoxic damage was AGT (significant at 62.5 ppm), followed by %PCE (significant at 625 ppm), and then by MI (significant by trend test only). Because each cytogenetic endpoint was evaluated in every animal, a correlation analysis was conducted to evaluate the degree of concordance among the various indicators of genotoxic and cytotoxic damage. The extent of concordance ranged from a very good correlation between the induction of MN-PCE and the induction of SCE (correlation coefficient r = 0.9562) to the lack of a significant correlation between the depression in the MI and any other endpoint (r less than 0.37).

Liver lesions in B6C3F1 mice: the National Toxicology Program, experience and position

Abstract: The spectrum of hepatocellular proliferative lesions in B6C3F1 (C57BL/6N X C3H/HeN MTV-) mice used in National Toxicology Program (NTP) two-year carcinogenicity studies includes foci of cellular alteration, adenoma, carcinoma, and hepatoblastoma. The diagnosis of hepatocellular hyperplasia is reserved for those non-neoplastic proliferative lesions which are believed to occur secondary to necrosis or a degenerative process in the liver. Diagnostic criteria, similar to those previously published, are used during the NTP peer review of these lesions. Incidences of liver tumors in control mice have been established from the NTP database and the frequency of enhanced liver tumor responses in treated mice has been determined based on 278 two-year carcinogenicity studies. Although alternative rodent strains are being examined, at the present time there is no acceptable alternative to the B6C3F1 mouse for NTP carcinogenicity studies. Interim sacrifices and "stop" studies are incorporated into two-year studies to gain knowledge about the biological behavior of mouse liver neoplasia. Also, data are being gathered relative to the pattern of oncogene activation in spontaneous and chemically induced liver tumors in B6C3F1 mice.

Plant antitumor agents. 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogues. Structure-activity correlations.

Abstract: Nineteen racemic ring A substituted analogues of the antitumor agent 20(S)-camptothecin were prepared by total synthesis and evaluated for in vitro cytotoxic activity against KB cell culture and in vivo antileukemic activity against L1210. These compounds bore a wide variety of substituents at C11 designed to confer upon the ring system a broad range of combinations of electronic, steric, and lipophilic effects. A few C10-substituted derivatives as well as C10,C11-disubstituted analogues prepared as part of a concurrent study have also been included for general comparison. With the notable exception of the cyano derivative, the 11-substituted compounds displayed only modest in vitro and in vivo activities, and there was a remarkable insensitivity toward the nature of the substituent. In contrast, the 9- and 10-substituted compounds exhibited a considerably higher level of dose potency and activity both in vitro and in vivo.