Development of a high-throughput method to evaluate the impact of inhibitory compounds from lignocellulosic hydrolysates on the growth of Zymomonas mobilis.

PubMed

Franden, Mary Ann; Pienkos, Philip T; Zhang, Min

2009-12-01

Overcoming the effects of hydrolysate toxicity towards ethanologens is a key technical barrier in the biochemical conversion process for biomass feedstocks to ethanol. Despite its importance, the complexity of the hydrolysate toxicity phenomena and the lack of systematic studies, analysis and tools surrounding this issue have blocked a full understanding of relationships involving toxic compounds in hydrolysates and their effects on ethanologen growth and fermentation. In this study, we developed a quantitative, high-throughput biological growth assay using an automated turbidometer to obtain detailed inhibitory kinetics for individual compounds present in lignocellulosic biomass hydrolysate. Information about prolonged lag time and final cell densities can also be obtained. The effects of furfural, hydroxymethylfurfural (HMF), acetate and ethanol on growth rate and final cell densities of Zymomonas mobilis 8b on glucose are presented. This method was also shown to be of value in toxicity studies of hydrolysate itself, despite the highly colored nature of this material. Using this approach, we can generate comprehensive inhibitory profiles with many individual compounds and develop models that predict and examine toxic effects in the complex mixture of hydrolysates, leading to the development of improved pretreatment and conditioning processes as well as fermentation organisms.

Classifying environmental pollutants: Part 3. External validation of the classification system.

PubMed

Verhaar, H J; Solbé, J; Speksnijder, J; van Leeuwen, C J; Hermens, J L

2000-04-01

In order to validate a classification system for the prediction of the toxic effect concentrations of organic environmental pollutants to fish, all available fish acute toxicity data were retrieved from the ECETOC database, a database of quality-evaluated aquatic toxicity measurements created and maintained by the European Centre for the Ecotoxicology and Toxicology of Chemicals. The individual chemicals for which these data were available were classified according to the rulebase under consideration and predictions of effect concentrations or ranges of possible effect concentrations were generated. These predictions were compared to the actual toxicity data retrieved from the database. The results of this comparison show that generally, the classification system provides adequate predictions of either the aquatic toxicity (class 1) or the possible range of toxicity (other classes) of organic compounds. A slight underestimation of effect concentrations occurs for some highly water soluble, reactive chemicals with low log K(ow) values. On the other end of the scale, some compounds that are classified as belonging to a relatively toxic class appear to belong to the so-called baseline toxicity compounds. For some of these, additional classification rules are proposed. Furthermore, some groups of compounds cannot be classified, although they should be amenable to predictions. For these compounds additional research as to class membership and associated prediction rules is proposed.

Meta-analysis of fish early life stage tests-Association of toxic ratios and acute-to-chronic ratios with modes of action.

PubMed

Scholz, Stefan; Schreiber, Rene; Armitage, James; Mayer, Philipp; Escher, Beate I; Lidzba, Annegret; Léonard, Marc; Altenburger, Rolf

2018-04-01

Fish early life stage (ELS) tests (Organisation for Economic Co-operation and Development test guideline 210) are widely conducted to estimate chronic fish toxicity. In these tests, fish are exposed from the embryonic to the juvenile life stages. To analyze whether certain modes of action are related to high toxic ratios (i.e., ratios between baseline toxicity and experimental effect) and/or acute-to-chronic ratios (ACRs) in the fish ELS test, effect concentrations (ECs) for 183 compounds were extracted from the US Environmental Protection Agency's ecotoxicity database. Analysis of ECs of narcotic compounds indicated that baseline toxicity could be observed in the fish ELS test at similar concentrations as in the acute fish toxicity test. All nonnarcotic modes of action were associated with higher toxic ratios, with median values ranging from 4 to 9.3 × 10 4 (uncoupling < reactivity < neuromuscular toxicity < methemoglobin formation < endocrine disruption < extracellular matrix formation inhibition). Four modes of action were also found to be associated with high ACRs: 1) lysyl oxidase inhibition leading to notochord distortion, 2) putative methemoglobin formation or hemolytic anemia, 3) endocrine disruption, and 4) compounds with neuromuscular toxicity. For the prediction of ECs in the fish ELS test with alternative test systems, endpoints targeted to the modes of action of compounds with enhanced toxic ratios or ACRs could be used to trigger fish ELS tests or even replace these tests. Environ Toxicol Chem 2018;37:955-969. © 2018 SETAC. © 2018 SETAC.

A comparative assessment of the acute inhalation toxicity of vanadium compounds.

PubMed

Rajendran, N; Seagrave, J C; Plunkett, L M; MacGregor, J A

2016-11-01

Vanadium compounds have become important in industrial processes, resulting in workplace exposure potential and are present in ambient air as a result of fossil fuel combustion. A series of acute nose-only inhalation toxicity studies was conducted in both rats and mice in order to obtain comparative data on the acute toxicity potential of compounds used commercially. V 2 O 3 , V 2 O 4 , and V 2 O 5 , which have different oxidation states (+3, +4, +5, respectively), were delivered as micronized powders; the highly water-soluble and hygroscopic VOSO 4 (+4) could not be micronized and was instead delivered as a liquid aerosol from an aqueous solution. V 2 O 5 was the most acutely toxic micronized powder in both species. Despite its lower overall percentage vanadium content, a liquid aerosol of VOSO 4 was more toxic than the V 2 O 5 particles in mice, but not in rats. These data suggest that an interaction of characteristics, i.e., bioavailability, solubility and oxidation state, as well as species sensitivity, likely affect the toxicity potential of vanadium compounds. Based on clinical observations and gross necropsy findings, the lung appeared to be the target organ for all compounds. The level of hazard posed will depend on the specific chemical form of the vanadium. Future work to define the inhalation toxicity potential of vanadium compounds of various oxidation states after repeated exposures will be important in understanding how the physico-chemical and biological characteristics of specific vanadium compounds interact to affect toxicity potential and the potential risks posed to human health.

Toxicity evaluation of 2-hydroxybiphenyl and other compounds involved in studies of fossil fuels biodesulphurisation.

PubMed

Alves, L; Paixão, S M

2011-10-01

The acute toxicity of some compounds used in fossil fuels biodesulphurisation studies, on the respiration activity, was evaluated by Gordonia alkanivorans and Rhodococcus erythropolis. Moreover, the effect of 2-hydroxybiphenyl on cell growth of both strains was also determined, using batch (chronic bioassays) and continuous cultures. The IC₅₀ values obtained showed the toxicity of all the compounds tested to both strains, specially the high toxicity of 2-HBP. These results were confirmed by the chronic toxicity data. The toxicity data sets highlight for a higher sensitivity to the toxicant by the strain presenting a lower growth rate, due to a lower cells number in contact with the toxicant. Thus, microorganisms exhibiting faster generation times could be more resistant to 2-HBP accumulation during a BDS process. The physiological response of both strains to 2-HBP pulse in a steady-state continuous culture shows their potential to be used in a future fossil fuel BDS process. Copyright © 2011 Elsevier Ltd. All rights reserved.

Toxicity of N-substituted aromatics to acetoclastic methanogenic activity in granular sludge

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

Donlon, B.A.; Razo-Flores, E.; Field, J.A.

1995-11-01

N-substituted aromatics are important priority pollutants entering the environment primarily through anthropogenic activities associated associated with the industrial production of dyes, explosives, pestides, and pharmaceuticals. Anaerobic treatment of wastewaters discharged by these industries could potentially be problematical as a result of the high toxicity of N-substituted aromatics. The objective of this study was to examine the structure-toxicity relationship of N-substituted aromatic compounds to acetoclastic methanogenic bacteria. The toxicity was assayed to serum flasks by measuring methane production in granular sludge. Unacclimated cultures were used to minimize the biotransformation of the toxic organic chemicals during the test. The nature and themore » degree of the aromatic substitution were observed to have a profound effect on the toxicity of the test compound. Nitroaromatic compounds were, on the average, over 500-fold more toxic than their corresponding aromatic amines. Considering the facile reduction of nitro groups by anerobic microorganisms, a dramatic detoxification of nitroaromatics towards methanogens can be expected to occur during anaerobic wastewater treatment. While the toxicity exerted by the N-substituted aromatic compounds was closely correlated with compound apolarity (log P), it was observed that at any given log P, N-substituted phenols had a toxicity that was 2 orders of magnitude higher than that of chlorophenols and alkylphenols. This indicates that toxicity due to the chemical reactivity of nitroaromatics is much more important than partitioning effects in bacterial membranes. 41 refs., 3 figs., 1 tab.« less

Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations.

PubMed

Dolan, David G; Naumann, Bruce D; Sargent, Edward V; Maier, Andrew; Dourson, Michael

2005-10-01

A scientific rationale is provided for estimating acceptable daily intake values (ADIs) for compounds with limited or no toxicity information to support pharmaceutical manufacturing operations. These ADIs are based on application of the "thresholds of toxicological concern" (TTC) principle, in which levels of human exposure are estimated that pose no appreciable risk to human health. The same concept has been used by the US Food and Drug Administration (FDA) to establish "thresholds of regulation" for indirect food additives and adopted by the Joint FAO/WHO Expert Committee on Food Additives for flavoring substances. In practice, these values are used as a statement of safety and indicate when no actions need to be taken in a given exposure situation. Pharmaceutical manufacturing relies on ADIs for cleaning validation of process equipment and atypical extraneous matter investigations. To provide practical guidance for handling situations where relatively unstudied compounds with limited or no toxicity data are encountered, recommendations are provided on ADI values that correspond to three categories of compounds: (1) compounds that are likely to be carcinogenic, (2) compounds that are likely to be potent or highly toxic, and (3) compounds that are not likely to be potent, highly toxic or carcinogenic. Corresponding ADIs for these categories of materials are 1, 10, and 100 microg/day, respectively.

Bioenergetic strategy of microalgae for the biodegradation of tyrosol and hydroxytyrosol.

PubMed

Papazi, Aikaterini; Ioannou, Andreas; Symeonidi, Myrto; Doulis, Andreas G; Kotzabasis, Kiriakos

2017-05-01

Olive mill wastewater has significant polluting properties due to its high phenolic content [mainly tyrosol (trs) and hydroxytyrosol (htrs)]. Growth kinetics and a series of fluorescence induction measurements for Scenedesmus obliquus cultures showed that microalgae can be tolerant of these phenolic compounds. Changes in the cellular energy reserves and concentration of the phenolic compounds adjust the "toxicity" of these compounds to the microalgae and are, therefore, the main parameters that affect biodegradation. Autotrophic growth conditions of microalgae and high concentrations of trs or htrs induce higher biodegradation compared with mixotrophic conditions and lower phenolic concentrations. When microalgae face trs and htrs simultaneously, biodegradation begins from htrs, the more energetically demanding compound. All these lead to the conviction that microalgae have a "rational" management of cellular energy balance. Low toxicity levels lead to higher growth and lower biodegradation, whereas higher toxicity levels lead to lower growth and higher biodegradation. The selection of appropriate conditions (compatible to the bioenergetic strategies of microalgae) seems to be the key for a successful biodegradation of a series of toxic compounds, thus paving the way for future biotechnological applications for solving complicated pollution problems, like the detoxification of olive mill wastewater.

Investigation on modes of toxic action to rats based on aliphatic and aromatic compounds and comparison with fish toxicity based on exposure routes.

PubMed

He, Jia; Li, Jin J; Wen, Yang; Tai, Hong W; Yu, Yang; Qin, Wei C; Su, Li M; Zhao, Yuan H

2015-06-01

The modes of toxic action (MOAs) play an important role in the assessment of the ecotoxicity of organic pollutants. However, few studies have been reported on the MOAs in rat toxicity. In this paper, the toxic contributions of functional groups in 1255 aromatic compounds were calculated from regression and were then compared with the toxic contributions in aliphatic compounds. The results show that some functional groups have same toxic contributions both in aromatic and aliphatic compounds, but some have not. To investigate the MOAs in rat toxicity, the distribution of toxic ratio (TR) was examined for well-known baseline and less inert compounds and thresholds of log TR=0.3 and 0.5 were used to classify baseline, less inert and reactive compounds. The results showed that some compounds identified as baseline compounds in fish toxicity were also classified as baseline compounds in rat toxicity. Except for phenols and anilines which were identified as less inert compounds in fish toxicity, aromatic compounds with functional groups such as ether, nitrile, nitrophenol, isocyanatoe and chloro were identified as less inert chemicals in rat toxicity. Reactive compounds identified in fish toxicity exhibit greater toxicity to rats. These compounds can undergo nucleophilic substitution, acylation and Schiff base formation with biological macromolecules. The critical body residues (CBRs) calculated from absorption and bioconcentration show that log 1/CBRs in rat toxicity are not equal to that in fish for some compounds. It suggests that the exposure route can affect the identification of MOAs between these two species for these compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

Contact toxicity of twenty insecticides applied to Symmerista canicosta

Treesearch

Jacqueline L. Robertson; Robert L. Lyon; Fay L. Shon; Nancy L. Gillette

1972-01-01

Twenty insecticides were tested by topical application on mixed groups of 4th- and 5th -stage larvae of Symmerista canicosta Franclemont. Four exceeded DDT in toxicity at LD50 but only resmethrin was significantly mor toxic. Most of the compounds showed unusually high toxicities. Twelve, listed in decreasing order of toxicity...

Reclassification of Materials Listed as Transportation Health Hazards

DTIC Science & Technology

1972-08-01

f. Hyg., 7:233, 1887. 152.3 Prentiss, A. M., Chemicals in War, McGrall-Hill, N. Y., 1937. A-183 TOXICITY DATA SHEET COMPOUND: CHLORINE TRIFLUORIDE ...l%3 Chlorine Trifluoride to # 161 Diborane Highly Toxic Extrenmely Toxic 169 Fluorine 171 Hlydrazine. anhydrous Toxic- Highly Toxic. 1I 172...were run on mice and rats exposed to chlorine , anhy lrous ammonia and hydrogen sulfide. Results have been included and reflected in the

Is the bitter rejection response always adaptive?

PubMed

Glendinning, J I

1994-12-01

The bitter rejection response consists of a suite of withdrawal reflexes and negative affective responses. It is generally assumed to have evolved as a way to facilitate avoidance of foods that are poisonous because they usually taste bitter to humans. Using previously published studies, the present paper examines the relationship between bitterness and toxicity in mammals, and then assesses the ecological costs and benefits of the bitter rejection response in carnivorous, omnivorous, and herbivorous (grazing and browsing) mammals. If the bitter rejection response accurately predicts the potential toxicity of foods, then one would expect the threshold for the response to be lower for highly toxic compounds than for nontoxic compounds. The data revealed no such relationship. Bitter taste thresholds varied independently of toxicity thresholds, indicating that the bitter rejection response is just as likely to be elicited by a harmless bitter food as it is by a harmful one. Thus, it is not necessarily in an animal's best interest to have an extremely high or low bitter threshold. Based on this observation, it was hypothesized that the adaptiveness of the bitter rejection response depends upon the relative occurrence of bitter and potentially toxic compounds in an animal's diet. Animals with a relatively high occurrence of bitter and potentially toxic compounds in their diet (e.g., browsing herbivores) were predicted to have evolved a high bitter taste threshold and tolerance to dietary poisons. Such an adaptation would be necessary because a browser cannot "afford" to reject all foods that are bitter and potentially toxic without unduly restricting its dietary options. At the other extreme, animals that rarely encounter bitter and potentially toxic compounds in their diet (e.g., carnivores) were predicted to have evolved a low bitter threshold. Carnivores could "afford" to utilize such a stringent rejection mechanism because foods containing bitter and potentially toxic compounds constitute a small portion of their diet. Since the low bitter threshold would reduce substantially the risk of ingesting anything poisonous, carnivores were also expected to have a relatively low tolerance to dietary poisons. This hypothesis was supported by a comparison involving 30 mammal species, in which a suggestive relationship was found between quinine hydrochloride sensitivity and trophic group, with carnivores > omnivores > grazers > browsers. Further support for the hypothesis was provided by a comparison across browsers and grazers in terms of the production of tannin-binding salivary proteins, which probably represent an adaptation for reducing the bitterness and astringency of tannins.(ABSTRACT TRUNCATED AT 400 WORDS)

A High-Content Live-Cell Viability Assay and Its Validation on a Diverse 12K Compound Screen.

PubMed

Chiaravalli, Jeanne; Glickman, J Fraser

2017-08-01

We have developed a new high-content cytotoxicity assay using live cells, called "ImageTOX." We used a high-throughput fluorescence microscope system, image segmentation software, and the combination of Hoechst 33342 and SYTO 17 to simultaneously score the relative size and the intensity of the nuclei, the nuclear membrane permeability, and the cell number in a 384-well microplate format. We then performed a screen of 12,668 diverse compounds and compared the results to a standard cytotoxicity assay. The ImageTOX assay identified similar sets of compounds to the standard cytotoxicity assay, while identifying more compounds having adverse effects on cell structure, earlier in treatment time. The ImageTOX assay uses inexpensive commercially available reagents and facilitates the use of live cells in toxicity screens. Furthermore, we show that we can measure the kinetic profile of compound toxicity in a high-content, high-throughput format, following the same set of cells over an extended period of time.

In vitro transcriptomic prediction of hepatotoxicity for early drug discovery

PubMed Central

Cheng, Feng; Theodorescu, Dan; Schulman, Ira G.; Lee, Jae K.

2012-01-01

Liver toxicity (hepatotoxicity) is a critical issue in drug discovery and development. Standard preclinical evaluation of drug hepatotoxicity is generally performed using in vivo animal systems. However, only a small number of preselected compounds can be examined in vivo due to high experimental costs. A more efficient yet accurate screening technique which can identify potentially hepatotoxic compounds in the early stages of drug development would thus be valuable. Here, we develop and apply a novel genomic prediction technique for screening hepatotoxic compounds based on in vitro human liver cell tests. Using a training set of in vivo rodent experiments for drug hepatotoxicity evaluation, we discovered common biomarkers of drug-induced liver toxicity among six heterogeneous compounds. This gene set was further triaged to a subset of 32 genes that can be used as a multi-gene expression signature to predict hepatotoxicity. This multi-gene predictor was independently validated and showed consistently high prediction performance on five test sets of in vitro human liver cell and in vivo animal toxicity experiments. The predictor also demonstrated utility in evaluating different degrees of toxicity in response to drug concentrations which may be useful not only for discerning a compound’s general hepatotoxicity but also for determining its toxic concentration. PMID:21884709

Acute toxicity and chemical evaluation of coking wastewater under biological and advanced physicochemical treatment processes.

PubMed

Dehua, Ma; Cong, Liu; Xiaobiao, Zhu; Rui, Liu; Lujun, Chen

2016-09-01

This study investigated the changes of toxic compounds in coking wastewater with biological treatment (anaerobic reactor, anoxic reactor and aerobic-membrane bioreactor, A1/A2/O-MBR) and advanced physicochemical treatment (Fenton oxidation and activated carbon adsorption) stages. As the biological treatment stages preceding, the inhibition effect of coking wastewater on the luminescence of Vibrio qinghaiensis sp. Nov. Q67 decreased. Toxic units (TU) of coking wastewater were removed by A1/A2/O-MBR treatment process, however approximately 30 % TU remained in the biologically treated effluent. There is a tendency that fewer and fewer residual organic compounds could exert equal acute toxicity during the biological treatment stages. Activated carbon adsorption further removed toxic pollutants of biologically treated effluent but the Fenton effluent increased acute toxicity. The composition of coking wastewater during the treatment was evaluated using the three-dimensional fluorescence spectra, gas chromatography-mass spectrometry (GC-MS). The organic compounds with high polarity were the main cause of acute toxicity in the coking wastewater. Aromatic protein-like matters in the coking wastewater with low biodegradability and high toxicity contributed mostly to the remaining acute toxicity of the biologically treated effluents. Chlorine generated from the oxidation process was responsible for the acute toxicity increase after Fenton oxidation. Therefore, the incorporation of appropriate advanced physicochemical treatment process, e.g., activated carbon adsorption, should be implemented following biological treatment processes to meet the stricter discharge standards and be safer to the environment.

Toxicity, uptake, and mutagenicity of particulate and soluble nickel compounds.

PubMed Central

Fletcher, G G; Rossetto, F E; Turnbull, J D; Nieboer, E

1994-01-01

Toxicity testing in AS52 cells (24-hr exposures) gave LC50 values of 2 to 130 micrograms Ni/ml for particulate nickel compounds and 45 to 60 micrograms Ni/ml for water-soluble salts (NiCl2, NiSO4, Ni(CH3COO)2). The Ni(OH)2, NiCO3, and sulfides (Ni3S2, Ni7S6, "amorphous NiS") exhibited similar toxicities (LC50's of 2 to 8 micrograms Ni/ml), while three nickel oxides were more variable and less toxic (LC50's of 18 to 130 micrograms Ni/ml). Most compounds displayed nuclear to cytoplasmic nickel ratios of approximately 1:1.5 to 1:5 (except approximately 1:20 for nickel salts). At the LC50's, a 75-fold range in exposure levels occurred compared to a 10-fold range in cytoplasmic and nuclear nickel concentrations, [Ni]. Cellular nickel distribution indicated three groupings: inert compounds (green NiO, lithium nickel oxide, relatively low nuclear and cytosolic [Ni]); water-soluble salts (very low nuclear [Ni]; high cytosolic [Ni]), and slightly soluble compounds (relatively high cytosolic and nuclear [Ni]). Nickel compounds are considered to be only weak or equivocal mutagens. In this study, a low but significant increase in mutation rate at the gpt locus was shown. Although the results would not be sufficient to deem nickel compounds mutagenic by traditional criteria, characterization by PCR analysis indicated that the spontaneous and nickel-induced mutants exhibited different and compound-specific mutational spectra (thus confirming nickel compound involvement). The results reported illustrate some of the methodologic problems involved in testing "weak" mutagens and indicate that alternative approaches may be necessary in classifying the mutagenicity of nickel and other compounds. PMID:7843140

Fumigant toxicity of cassia and cinnamon oils and cinnamaldehyde and structurally related compounds to Dermanyssus gallinae (Acari: Dermanyssidae).

PubMed

Na, Young Eun; Kim, Soon-Il; Bang, Hea-Son; Kim, Byung-Seok; Ahn, Young-Joon

2011-06-10

The toxicity of two cassia oils, four cinnamon oils and (E)-cinnamaldehyde and (E)-cinnamic acid and 34 structurally related compounds to adult Dermanyssus gallinae (De Geer) collected from a poultry house was examined using a vapour-phase mortality bioassay. Results were compared with those of dichlorvos, a conventional acaricide. The cassia and cinnamon oils (cinnamon technical, cinnamon #500, cassia especial, cassia true, cinnamon bark and cinnamon green leaf) exhibited good fumigant toxicity (LD(50), 11.79-26.40 μg cm(-3)). α-Methyl-(E)-cinnamaldehyde (LD(50), 0.45 μg cm(-3)) and (E)-cinnamaldehyde (0.54 μg cm(-3)) were the most toxic compounds and the toxicity of these compounds was comparable to that of dichlorvos (0.30 μg cm(-3)). Potent fumigant toxicity was also observed in allyl cinnamate, ethyl-α-cyanocinnamate, (E)-2-methoxylcinnamic acid and (Z)-2-methoxylcinnamic acid (LD(50), 0.81-0.92 μg cm(-3)). Structure-activity relationships indicate that structural characteristics, such as types of functional groups and carbon skeleton rather than vapour pressure parameter, appear to play a role in determining toxicity. The essential oils and compounds described merit further study as potential acaricides for the control of D. gallinae populations as fumigants with contact action due to global efforts to reduce the level of highly toxic synthetic acaricides in the agricultural environment. Copyright © 2011. Published by Elsevier B.V.

Discovery of a novel general anesthetic chemotype using high-throughput screening.

PubMed

McKinstry-Wu, Andrew R; Bu, Weiming; Rai, Ganesha; Lea, Wendy A; Weiser, Brian P; Liang, David F; Simeonov, Anton; Jadhav, Ajit; Maloney, David J; Eckenhoff, Roderic G

2015-02-01

The development of novel anesthetics has historically been a process of combined serendipity and empiricism, with most recent new anesthetics developed via modification of existing anesthetic structures. Using a novel high-throughput screen employing the fluorescent anesthetic 1-aminoanthracene and apoferritin as a surrogate for on-pathway anesthetic protein target(s), we screened a 350,000 compound library for competition with 1-aminoanthracene-apoferritin binding. Hit compounds meeting structural criteria had their binding affinities for apoferritin quantified with isothermal titration calorimetry and were tested for γ-aminobutyric acid type A receptor binding using a flunitrazepam binding assay. Chemotypes with a strong presence in the top 700 and exhibiting activity via isothermal titration calorimetry were selected for medicinal chemistry optimization including testing for anesthetic potency and toxicity in an in vivo Xenopus laevis tadpole assay. Compounds with low toxicity and high potency were tested for anesthetic potency in mice. From an initial chemical library of more than 350,000 compounds, we identified 2,600 compounds that potently inhibited 1-aminoanthracene binding to apoferritin. A subset of compounds chosen by structural criteria (700) was successfully reconfirmed using the initial assay. Based on a strong presence in both the initial and secondary screens the 6-phenylpyridazin-3(2H)-one chemotype was assessed for anesthetic activity in tadpoles. Medicinal chemistry efforts identified four compounds with high potency and low toxicity in tadpoles, two were found to be effective novel anesthetics in mice. The authors demonstrate the first use of a high-throughput screen to successfully identify a novel anesthetic chemotype and show mammalian anesthetic activity for members of that chemotype.

Biotoxicity assessment and toxicity mechanism on coal gasification wastewater (CGW): A comparative analysis of effluent from different treatment processes.

PubMed

Ma, Weiwei; Han, Yuxing; Xu, Chunyan; Han, Hongjun; Zhu, Hao; Li, Kun; Zheng, Mengqi

2018-05-04

Even though coal gasification wastewater (CGW) treated by various biochemical treatment processes generally met the national discharge standard, its potential biotoxicity was still unknown. Therefore, in this study, bioassay with Tetrahymena thermophila (T. thermophila) was conducted to comprehensively evaluate the variation of biotoxicity in raw CGW and the treated effluent from lab-scale micro-electrolysis integrated with biological reactor (MEBR), single iron-carbon micro-electrolysis (ICME) and conventional activated sludge (CAS) processes. The results illustrated that raw CGW presented intensive acute toxicity with 24 h EC 50 value of 8.401% and toxic unit (TU) value of 11.90. Moreover, it performed significant cell membrane destruction and DNA damage even at 10% dilution concentration. The toxicant identification results revealed that multiple toxic polar compounds such as phenolic, heterocyclic and polycyclic aromatic compounds were the main contributors for biotoxicity. Furthermore, these compounds could accelerate oxidative stress, thereby inducing oxidative damage of cell membrane and DNA. As for treated effluent, TU value was decreased by 90.58% in MEBR process. An effective biotoxicity reduction was achieved in MEBR process owing to high removal efficiency in polar organic toxicants. In contrast, effluent from ICME and CAS processes presented relatively high acute toxicity and genotoxicity, because various heterocyclic and polycyclic aromatic compounds were difficult to be degraded in these processes. Therefore, it was suggested that MEBR was a potential and feasible process for improving CGW treatment and minimizing ecological risk. Copyright © 2018. Published by Elsevier B.V.

Sediment toxicity identification evaluation (TIE) studies at marine sites suspected of ordnance contamination

USGS Publications Warehouse

Carr, R.S.; Nipper, M.; Biedenbach, J.M.; Hooten, R.L.; Miller, K.; Saepoff, S.

2001-01-01

A sediment quality assessment survey and subsequent toxicity identification evaluation (TIE) study was conducted at several sites in Puget Sound, Washington. The sites were previously suspected of contamination with ordnance compounds. The initial survey employed sea urchin porewater toxicity tests to locate the most toxic stations. Sediments from the most toxic stations were selected for comprehensive chemical analyses. Based on the combined information from the toxicity and chemical data, three adjacent stations in Ostrich Bay were selected for the TIE study. The results of the phase I TIE suggested that organics and metals were primarily responsible for the observed toxicity in the sea urchin fertilization test. In addition to these contaminants, ammonia was also contributing to the toxicity for the sea urchin embryological development test. The phase II TIE study isolated the majority of the toxicity in the fraction containing nonpolar organics with high log Kow, but chemical analyses failed to identify a compound present at a concentration high enough to be responsible for the observed toxicity. The data suggest that some organic or organometallic contaminant(s) that were not included in the comprehensive suite of chemical analyses caused the observed toxicological responses.

Assessing deep and shallow learning methods for quantitative prediction of acute chemical toxicity.

PubMed

Liu, Ruifeng; Madore, Michael; Glover, Kyle P; Feasel, Michael G; Wallqvist, Anders

2018-05-02

Animal-based methods for assessing chemical toxicity are struggling to meet testing demands. In silico approaches, including machine-learning methods, are promising alternatives. Recently, deep neural networks (DNNs) were evaluated and reported to outperform other machine-learning methods for quantitative structure-activity relationship modeling of molecular properties. However, most of the reported performance evaluations relied on global performance metrics, such as the root mean squared error (RMSE) between the predicted and experimental values of all samples, without considering the impact of sample distribution across the activity spectrum. Here, we carried out an in-depth analysis of DNN performance for quantitative prediction of acute chemical toxicity using several datasets. We found that the overall performance of DNN models on datasets of up to 30,000 compounds was similar to that of random forest (RF) models, as measured by the RMSE and correlation coefficients between the predicted and experimental results. However, our detailed analyses demonstrated that global performance metrics are inappropriate for datasets with a highly uneven sample distribution, because they show a strong bias for the most populous compounds along the toxicity spectrum. For highly toxic compounds, DNN and RF models trained on all samples performed much worse than the global performance metrics indicated. Surprisingly, our variable nearest neighbor method, which utilizes only structurally similar compounds to make predictions, performed reasonably well, suggesting that information of close near neighbors in the training sets is a key determinant of acute toxicity predictions.

Hydrogel tissue construct-based high-content compound screening.

PubMed

Lam, Vy; Wakatsuki, Tetsuro

2011-01-01

Current pharmaceutical compound screening systems rely on cell-based assays to identify therapeutic candidates and potential toxicities. However, cells grown on 2D substrata or in suspension do not exhibit the mechanical or physiological properties of cells in vivo. To address this limitation, the authors developed an in vitro, high-throughput, 3D hydrogel tissue construct (HTC)-based assay system to quantify cell and tissue mechanical properties and multiple parameters of physiology. HTC mechanics was quantified using an automated device, and physiological status was assessed using spectroscopy-based indicators that were read on microplate readers. To demonstrate the application of this system, the authors screened 4 test compounds--rotenone (ROT), cytochalasin D (CD), 2,4-dinitrophenol (DNP), and Rho kinase inhibitor (H-1152)--for their ability to modulate HTC contractility without affecting actin integrity, mitochondrial membrane potential (MMP), or viability. All 4 compounds dose-dependently reduced HTC contractility. However, ROT was toxic, DNP dissipated MMP, and CD reduced both intracellular F-actin and viability. H-1152 was found to be the best candidate compound since it reduced HTC contractility with minimal side effects. The authors propose that their HTC-based assay system can be used to screen for compounds that modulate HTC contractility and assess the underlying physiological mechanism(s) of compound activity and toxicity.

Considerations for Incorporating Bioavailability in Effect-Directed Analysis and Toxicity Identification Evaluation.

EPA Science Inventory

In order to avoid a bias toward highly toxic but poorly bioavailable compounds in the effect-directed analysis (EDA) of soils and sediments, approaches are discussed to consider bioavailability in EDA procedures. In parallel, complimentary approaches for making toxicity identific...

Red turpentine Dendroctonus valens P450s: Diversity, midgut location, and response to alfa-pinene enantiomers

Treesearch

M. Fernanda López; Viviana Cerrillo; Zulema Gómez; M. Shibayama; Olga-Arciniega; Gerardo Zúñiga

2007-01-01

Bark beetle colonization action is a biotic stress to the host, which responds to this action by secreting oleoresin. This mixture of several compounds can be highly toxic for the insects. We hypothesized that the first physiological reaction of the insects to these toxic compounds is to metabolize and subsequently use some of them as pheromone precursors. Epithelial...

Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

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

Diaz, Dolores, E-mail: diaz.dolores@gene.com; Ford, Kevin A.; Hartley, Dylan P.

Several toxicities are clearly driven by free drug concentrations in plasma, such as toxicities related to on-target exaggerated pharmacology or off-target pharmacological activity associated with receptors, enzymes or ion channels. However, there are examples in which organ toxicities appear to correlate better with total drug concentrations in the target tissues, rather than with free drug concentrations in plasma. Here we present a case study in which a small molecule Met inhibitor, GEN-203, with significant liver and bone marrow toxicity in preclinical species was modified with the intention of increasing the safety margin. GEN-203 is a lipophilic weak base as demonstratedmore » by its physicochemical and structural properties: high LogD (distribution coefficient) (4.3) and high measured pKa (7.45) due to the basic amine (N-ethyl-3-fluoro-4-aminopiperidine). The physicochemical properties of GEN-203 were hypothesized to drive the high distribution of this compound to tissues as evidenced by a moderately-high volume of distribution (Vd > 3 l/kg) in mouse and subsequent toxicities of the compound. Specifically, the basicity of GEN-203 was decreased through addition of a second fluorine in the 3-position of the aminopiperidine to yield GEN-890 (N-ethyl-3,3-difluoro-4-aminopiperidine), which decreased the volume of distribution of the compound in mouse (Vd = 1.0 l/kg), decreased its tissue drug concentrations and led to decreased toxicity in mice. This strategy suggests that when toxicity is driven by tissue drug concentrations, optimization of the physicochemical parameters that drive tissue distribution can result in decreased drug concentrations in tissues, resulting in lower toxicity and improved safety margins. -- Highlights: ► Lower pKa for a small molecule: reduced tissue drug levels and toxicity. ► New analysis tools to assess electrostatic effects and ionization are presented. ► Chemical and PK drivers of toxicity can be leveraged to improve safety.« less

Genetic toxicology of thallium: a review.

PubMed

Rodríguez-Mercado, Juan José; Altamirano-Lozano, Mario Agustín

2013-07-01

This review summarizes the current knowledge about the general toxicity of thallium (Tl) and its environmental sources, with special emphasis placed on its potential mutagenic, genotoxic, and cytotoxic effects on both eukaryotic and prokaryotic cells. Tl is a nonessential heavy metal that poses environmental and occupational threats as well as therapeutic hazards because of its use in medicine. It is found in two oxidation states, thallous (Tl(+)) and thallic (Tl(3+)), both of which are considered highly toxic to human beings and domestic and wild organisms. Many Tl compounds are colorless, odorless and tasteless, and these characteristics, combined with the high toxicity of TI compounds, have led to their use as poisons. Because of its similarity to potassium ions (K(+)), plants and mammals readily absorb Tl(+) through the skin and digestive and respiratory systems. In mammals, it can cross the placental, hematoencephalic, and gonadal barriers. Inside cells, Tl can accumulate and interfere with the metabolism of potassium and other metal cations, mimicking or inhibiting their action. The effects of Tl on genetic material have not yet been thoroughly explored, and few existing studies have focused exclusively on Tl(+). Both in vivo and in vitro studies indicate that Tl compounds can have a weak mutagenic effect, but no definitive effect on the induction of primary DNA damage or chromosomal damage has been shown. These studies have demonstrated that Tl compounds are highly toxic and lead to changes in cell-cycle progression.

Fluoroacetate-mediated toxicity of fluorinated ethanes.

PubMed

Keller, D A; Roe, D C; Lieder, P H

1996-04-01

A series of 1-(di)halo-2-fluoroethanes reported in the literature to be nontoxic or of low toxicity were found to be highly toxic by the inhalation route. Experiments were performed that showed the compounds, 1,2-difluoroethane, 1-chloro-2-fluoroethane, 1-chloro-1,2-difluoroethane, and 1-bromo-2-fluoroethane to be highly toxic to rats upon inhalation for 4 hr. All four compounds had 4-hr approximate lethal concentrations of < or = 100 ppm in rats. In contrast, 1,1-difluoroethane (commonly referred to as HFC-152a) has very low acute toxicity with a 4-hr LC50 of > 400,000 ppm in rats. Rats exposed to the selected toxic fluoroethanes showed clinical signs of fluoroacetate toxicity (lethargy, hunched posture, convulsions). 1,2-Difluoroethane, 1-chloro-2-fluoroethane, 1-chloro-1,2-difluoroethane, and 1-bromo-2-fluoroethane were shown to increase concentrations of citrate in serum and heart tissue, a hallmark of fluoroacetate intoxication. 19F NMR analysis confirmed that fluoroacetate was present in the urine of rats exposed to each toxic compound. Fluorocitrate, a condensation product of fluoroacetate and oxaloacetate, was identified in the kidney of rats exposed to 1,2-difluoroethane. There was a concentration-related elevation of serum and heart citrate in rats exposed to 0-1000 ppm 1,2-fluoroethane. Serum citrate was increased up to 5-fold and heart citrate was increased up to 11-fold over control citrate levels. Metabolism of 1,2-difluoroethane by cytochrome P450 (most likely CYP2E1) is suspected because pretreatment of rats or mice with SKF-525F, disulfiram, or dimethyl sulfoxide prevented or delayed the toxicity observed in rats not pretreated. Experimental evidence indicates that the metabolism of the toxic fluoroethanes is initiated at the carbon-hydrogen bond, with metabolism to fluoroacetate via an aldehyde or an acyl fluoride. The results of these studies show that 1-(di)halo-2-fluoroethanes are highly toxic to rats and should be considered a hazard to humans unless demonstrated otherwise.

Discovery of a Novel General Anesthetic Chemotype Using High-throughput Screening

PubMed Central

McKinstry-Wu, Andrew R.; Bu, Weiming; Rai, Ganesha; Lea, Wendy A.; Weiser, Brian P.; Liang, David F.; Simeonov, Anton; Jadhav, Ajit; Maloney, David J.; Eckenhoff, Roderic G.

2014-01-01

Background The development of novel anesthetics has historically been a process of combined serendipity and empiricism, with most recent new anesthetics developed via modification of existing anesthetic structures. Methods Using a novel high-throughput screen employing the fluorescent anesthetic 1-aminoanthracene (1-AMA) and apoferritin as a surrogate for on-pathway anesthetic protein target(s), we screened a 350,000 compound library for competition with 1-AMA-apoferritin binding. Hit compounds meeting structural criteria had their binding affinities for apoferritin quantified with isothermal titration calorimetry and were tested for γ-aminobutyric acid type A-receptor binding using a flunitrazepam binding assay. Chemotypes with a strong presence in the top 700 and exhibiting activity via isothermal titration calorimetry were selected for medicinal chemistry optimization including testing for anesthetic potency and toxicity in an in vivo Xenopus laevis tadpole assay. Compounds with low toxicity and high potency were tested for anesthetic potency in mice. Results From an initial chemical library of over 350,000 compounds, we identified 2,600 compounds that potently inhibited 1-AMA binding to apoferritin. A subset of compounds chosen by structural criteria (700) was successfully reconfirmed using the initial assay. Based upon a strong presence in both the initial and secondary screens the 6-phenylpyridazin-3(2H)-one chemotype was assessed for anesthetic activity in tadpoles. Medicinal chemistry efforts identified four compounds with high potency and low toxicity in tadpoles, two were found to be effective novel anesthetics in mice. Conclusions We demonstrate the first use of a high-throughput screen to successfully identify a novel anesthetic chemotype and show mammalian anesthetic activity for members of that chemotype. PMID:25603205

Elucidating compound mechanism of action by network perturbation analysis | Office of Cancer Genomics

Cancer.gov

Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor intensive and mostly limited to elucidating high-affinity binding target proteins.

An integrated approach to improved toxicity prediction for the safety assessment during preclinical drug development using Hep G2 cells

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

Noor, Fozia; Niklas, Jens; Mueller-Vieira, Ursula

2009-06-01

Efficient and accurate safety assessment of compounds is extremely important in the preclinical development of drugs especially when hepatotoxicty is in question. Multiparameter and time resolved assays are expected to greatly improve the prediction of toxicity by assessing complex mechanisms of toxicity. An integrated approach is presented in which Hep G2 cells and primary rat hepatocytes are compared in frequently used cytotoxicity assays for parent compound toxicity. The interassay variability was determined. The cytotoxicity assays were also compared with a reliable alternative time resolved respirometric assay. The set of training compounds consisted of well known hepatotoxins; amiodarone, carbamazepine, clozapine, diclofenac,more » tacrine, troglitazone and verapamil. The sensitivity of both cell systems in each tested assay was determined. Results show that careful selection of assay parameters and inclusion of a kinetic time resolved assay improves prediction for non-metabolism mediated toxicity using Hep G2 cells as indicated by a sensitivity ratio of 1. The drugs with EC{sub 50} values 100 {mu}M or lower were considered toxic. The difference in the sensitivity of the two cell systems to carbamazepine which causes toxicity via reactive metabolites emphasizes the importance of human cell based in-vitro assays. Using the described system, primary rat hepatocytes do not offer advantage over the Hep G2 cells in parent compound toxicity evaluation. Moreover, respiration method is non invasive, highly sensitive and allows following the time course of toxicity. Respiration assay could serve as early indicator of changes that subsequently lead to toxicity.« less

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity.

PubMed

Rabanal, Francesc; Grau-Campistany, Ariadna; Vila-Farrés, Xavier; Gonzalez-Linares, Javier; Borràs, Miquel; Vila, Jordi; Manresa, Angeles; Cajal, Yolanda

2015-05-29

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

Fish embryo toxicity test: identification of compounds with weak toxicity and analysis of behavioral effects to improve prediction of acute toxicity for neurotoxic compounds.

PubMed

Klüver, Nils; König, Maria; Ortmann, Julia; Massei, Riccardo; Paschke, Albrecht; Kühne, Ralph; Scholz, Stefan

2015-06-02

The fish embryo toxicity test has been proposed as an alternative for the acute fish toxicity test, but concerns have been raised for its predictivity given that a few compounds have been shown to exhibit a weak acute toxicity in the fish embryo. In order to better define the applicability domain and improve the predictive capacity of the fish embryo test, we performed a systematic analysis of existing fish embryo and acute fish toxicity data. A correlation analysis of a total of 153 compounds identified 28 compounds with a weaker or no toxicity in the fish embryo test. Eleven of these compounds exhibited a neurotoxic mode of action. We selected a subset of eight compounds with weaker or no embryo toxicity (cyanazine, picloram, aldicarb, azinphos-methyl, dieldrin, diquat dibromide, endosulfan, and esfenvalerate) to study toxicokinetics and a neurotoxic mode of action as potential reasons for the deviating fish embryo toxicity. Published fish embryo LC50 values were confirmed by experimental analysis of zebrafish embryo LC50 according to OECD guideline 236. Except for diquat dibromide, internal concentration analysis did not indicate a potential relation of the low sensitivity of fish embryos to a limited uptake of the compounds. Analysis of locomotor activity of diquat dibromide and the neurotoxic compounds in 98 hpf embryos (exposed for 96 h) indicated a specific effect on behavior (embryonic movement) for the neurotoxic compounds. The EC50s of behavior for neurotoxic compounds were close to the acute fish toxicity LC50. Our data provided the first evidence that the applicability domain of the fish embryo test (LC50s determination) may exclude neurotoxic compounds. However, neurotoxic compounds could be identified by changes in embryonic locomotion. Although a quantitative prediction of acute fish toxicity LC50 using behavioral assays in fish embryos may not yet be possible, the identification of neurotoxicity could trigger the conduction of a conventional fish acute toxicity test or application of assessment factors while considering the very good fish embryo-acute fish toxicity correlation for other compounds.

Differential sensitivity of plasma carboxylesterase-null mice to parathion, chlorpyrifos and chlorpyrifos oxon, but not to diazinon, dichlorvos, diisopropylfluorophosphate, cresyl saligenin phosphate, cyclosarin thiocholine, tabun thiocholine, and carbofuran

PubMed Central

Duysen, Ellen G.; Cashman, John R.; Schopfer, Lawrence M.; Nachon, Florian; Masson, Patrick; Lockridge, Oksana

2012-01-01

Mouse blood contains four esterases that detoxify organophosphorus compounds: carboxylesterase, butyrylcholinesterase, acetylcholinesterase, and paraoxonase-1. In contrast human blood contains the latter three enzymes but not carboxylesterase. Organophosphorus compound toxicity is due to inhibition of acetylcholinesterase. Symptoms of intoxication appear after approximately 50% of the acetylcholinesterase is inhibited. However, complete inhibition of carboxylesterase and butyrylcholinesterase has no known effect on an animal’s well being. Paraoxonase hydrolyzes organophosphorus compounds and is not inhibited by them. Our goal was to determine the effect of plasma carboxylesterase deficiency on response to sublethal doses of 10 organophosphorus toxicants and one carbamate pesticide. Homozygous plasma carboxylesterase deficient ES1−/− mice and wild-type littermates were observed for toxic signs and changes in body temperature after treatment with a single sublethal dose of toxicant. Inhibition of plasma acetylcholinesterase, butyrylcholinesterase, and plasma carboxylesterase was measured. It was found that wild-type mice were protected from the toxicity of 12.5 mg/kg parathion applied subcutaneously. However, both genotypes responded similarly to paraoxon, cresyl saligenin phosphate, diisopropylfluorophosphate, diazinon, dichlorvos, cyclosarin thiocholine, tabun thiocholine, and carbofuran. An unexpected result was the finding that transdermal application of chlorpyrifos at 100 mg/kg and chlorpyrifos oxon at 14 mg/kg was lethal to wild-type but not to ES1−/− mice, showing that with this organochlorine, the presence of carboxylesterase was harmful rather than protective. It was concluded that carboxylesterase in mouse plasma protects from high toxicity agents, but the amount of carboxylesterase in plasma is too low to protect from low toxicity compounds that require high doses to inhibit acetylcholinesterase. PMID:22209767

Identification of acute toxicants in New Bedford Harbor sediments

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

Ho, K.T.; McKinney, R.A.; Kuhn, A.

1997-03-01

New Bedford Harbor (NBH) is a marine Superfund site contaminated with high concentrations of polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) and metals. Experiments were conducted to determine the causal toxic agent(s) in pore waters from New Bedford Harbor sediments to amphipods and mysid shrimp. Chemical manipulations to characterize toxicity revealed that pore-water toxicity was organic in nature. Fractionation and subsequent mass spectral identification of peaks in the toxic fraction indicated that PCBs. PAHs, and unknown compounds were present. Comparisons of PAH LC50s and PAH concentrations in this fraction indicated that the toxicity was not due to PAHs because themore » PAH concentrations were much lower than the reported PAH LC50s. One unknown peak was positively identified as bis(2-ethylhexyl) phthalate, and the other tentatively identified as pyrazole. Toxicity tests and comparison of toxicity in the blank and toxic fractions eliminated the two unknowns as toxic causal agents. The authors determined the range of PCB LC50s to fall between 10 and 110 ppb for Mysidopsis bahia and Ampelisca abdita. Concentrations of PCBs for the toxic fractions ranged from 12 to 27 ppb. This range falls within the observed PCB LC50s for M. bahia and A. abdita. Based upon these PCB concentrations, they concluded that PCBs were the acute toxic agents in NBH pore waters. Other compounds in the toxic fractions, or compounds that coeluted and were undistinguished from PCBs had minor contributions to the measured toxicity.« less

Pathway Profiling and Tissue Modeling of Developmental Toxicity

EPA Science Inventory

High-throughput and high-content screening (HTS-HCS) studies are providing a rich source of data that can be applied to in vitro profiling of chemical compounds for biological activity and potential toxicity. EPA’s ToxCast™ project, and the broader Tox21 consortium, in addition t...

Virtual Embryo: Systems Modeling in Developmental Toxicity

EPA Science Inventory

High-throughput and high-content screening (HTS-HCS) studies are providing a rich source of data that can be applied to in vitro profiling of chemical compounds for biological activity and potential toxicity. EPA’s ToxCast™ project, and the broader Tox21 consortium, in addition t...

Response of Bioluminescent Bacteria to Alkyltin Compounds.

DTIC Science & Technology

1987-12-01

found in the butyltiri series of compounds; tributyltin was (’Stimes more toxic than dibutyltin and (- 50 times more toxic than (mono)butyltin. When...correlations between compounds, tributyltin was -35 tine more Kicrotxit and fish bLoessays for pure toxic than dibutyltin end -750 times More compounds and...the compounds as a decrease in toxicity (5) tributyltin compounds ea -150 tines more and a method to study synergistic andtoxic than trinethyltia

Small Molecule Fluoride Toxicity Agonists

PubMed Central

Nelson1, James W.; Plummer, Mark S.; Blount, Kenneth F.; Ames, Tyler D.; Breaker, Ronald R.

2015-01-01

SUMMARY Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch-reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. PMID:25910244

The taste of toxicity: A quantitative analysis of bitter and toxic molecules.

PubMed

Nissim, Ido; Dagan-Wiener, Ayana; Niv, Masha Y

2017-12-01

The role of bitter taste-one of the few basic taste modalities-is commonly assumed to signal toxicity and alert animals against consuming harmful compounds. However, it is known that some toxic compounds are not bitter and that many bitter compounds have negligible toxicity while having important health benefits. Here we apply a quantitative analysis of the chemical space to shed light on the bitterness-toxicity relationship. Using the BitterDB dataset of bitter molecules, The BitterPredict prediction tool, and datasets of toxic compounds, we quantify the identity and similarity between bitter and toxic compounds. About 60% of the bitter compounds have documented toxicity and only 56% of the toxic compounds are known or predicted to be bitter. The LD 50 value distributions suggest that most of the bitter compounds are not very toxic, but there is a somewhat higher chance of toxicity for known bitter compounds compared to known nonbitter ones. Flavonoids and alpha acids are more common in the bitter dataset compared with the toxic dataset. In contrast, alkaloids are more common in the toxic datasets compared to the bitter dataset. Interestingly, no trend linking LD 50 values with the number of activated bitter taste receptors (TAS2Rs) subtypes is apparent in the currently available data. This is in accord with the newly discovered expression of TAS2Rs in several extra-oral tissues, in which they might be activated by yet unknown endogenous ligands and play non-gustatory physiological roles. These results suggest that bitter taste is not a very reliable marker for toxicity, and is likely to have other physiological roles. © 2017 IUBMB Life, 69(12):938-946, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

Toxicity of insecticides to tsetse flies

PubMed Central

Hadaway, A. B.

1972-01-01

New insecticides have been evaluated for toxicity to tsetse flies and compared with organochlorine compounds currently in use. The most toxic compounds and their estimated median lethal doses in nanograms per fly by topical application in solution to teneral Glossina austeni were: resmethrin 4, fenthion 8, dieldrin 10, propoxur 12, chlorfenvinphos 12, tetrachlorvinphos 20, and dichlorvos 20. There was little variation in the susceptibility of teneral male and female flies, young fed flies, and fed stud males with all the compounds tested (dieldrin, resmethrin, tetrachlorvinphos, bromophos, and propoxur) and increased tolerance in old fed pregnant flies occurred only with dieldrin and resmethrin. There was also little variation in the susceptibility of teneral flies of the two species G. austeni and G. morsitans. In contact toxicity tests with water dispersible powder deposits on plywood, propoxur was highly active initially but lost its effectiveness after only a few weeks, whereas tetrachlorvinphos was less active initially but more persistent. PMID:4537853

Discrimination of excess toxicity from baseline level for ionizable compounds: Effect of pH.

PubMed

Li, Jin J; Zhang, Xu J; Wang, Xiao H; Wang, Shuo; Yu, Yang; Qin, Wei C; Su, Li M; Zhao, Yuan H

2016-03-01

The toxic effect can be affected by pH in water through affecting the degree of ionization of ionizable compounds. Wrong classification of mode of action can be made from the apparent toxicities. In this paper, the toxicity data of 61 compounds to Daphnia magna determined at three pH values were used to investigate the effect of pH on the discrimination of excess toxicity. The results show that the apparent toxicities are significantly less than the baseline level. Analysis on the effect of pH on bioconcentration factor (BCF) shows that the log BCF values are significantly over-estimated for the strongly ionizable compounds, leading to the apparent toxicities greatly less than the baseline toxicities and the toxic ratios greatly less than zero. A theoretical equation between the apparent toxicities and pH has been developed basing on the critical body residue (CBR). The apparent toxicities are non-linearly related to pH, but linearly to fraction of unionized form. The determined apparent toxicities are well fitted with the toxicities predicted by the equation. The toxicities in the unionized form calculated from the equation are close to, or greater than the baseline level for almost all the strongly ionizable compounds, which are very different from the apparent toxicities. The studied ionizable compounds can be either classified as baseline, less inert or reactive compounds in D. magna toxicity. Some ionizable compounds do not exhibit excess toxicity at a certain pH, due not to their poor reactivity with target molecules, but because of the ionization in water. Copyright © 2015 Elsevier Ltd. All rights reserved.

Contact and fumigant toxicity of Armoracia rusticana essential oil, allyl isothiocyanate and related compounds to Dermatophagoides farinae.

PubMed

Yun, Yeon-Kyeong; Kim, Hyun-Kyung; Kim, Jun-Ran; Hwang, Kumnara; Ahn, Young-Joon

2012-05-01

The toxicity to adult Dermatophagoides farinae of allyl isothiocyanate identified in horseradish, Armoracia rusticana, oil and another 27 organic isothiocyanates was evaluated using contact + fumigant and vapour-phase mortality bioassays. Results were compared with those of two conventional acaricides, benzyl benzoate and dibutyl phthalate. Horseradish oil (24 h LC(50), 1.54 µg cm(-2)) and allyl isothiocyanate (2.52 µg cm(-2)) were highly toxic. Benzyl isothiocyanate (LC(50) , 0.62 µg cm(-2)) was the most toxic compound, followed by 4-chlorophenyl, 3-bromophenyl, 3,5-bis(trifluoromethyl)phenyl, cyclohexyl, 2-chlorophenyl, 4-bromophenyl and 2-bromophenyl isothiocyanates (0.93-1.41 µg cm(-2)). All were more effective than either benzyl benzoate (LC(50) , 4.58 µg cm(-2)) or dibutyl phthalate (24.49 µg cm(-2)). The structure-activity relationship indicates that types of functional group and chemical structure appear to play a role in determining the isothiocyanate toxicities to adult D. farinae. In the vapour-phase mortality bioassay, these isothiocyanates were consistently more toxic in closed versus open containers, indicating that their mode of delivery was, in part, a result of vapour action. In the light of global efforts to reduce the level of highly toxic synthetic acaricides in indoor environments, the horseradish oil-derived compounds and the isothiocyanates described herein merit further study as potential acaricides for the control of house dust mite populations as fumigants with contact action. Copyright © 2011 Society of Chemical Industry.

Identification of compounds in heavy fuel oil that are chronically toxic to rainbow trout embryos by effects-driven chemical fractionation.

PubMed

Adams, Julie; Bornstein, Jason M; Munno, Keenan; Hollebone, Bruce; King, Thomas; Brown, R Stephen; Hodson, Peter V

2014-04-01

The present study isolated and identified compounds in heavy fuel oil 7102 (HFO 7102) that are bioavailable and chronically toxic to rainbow trout embryos (Oncorhynchus mykiss). An effects-driven chemical fractionation combined the chemical separation of oil with toxicity testing and chemical analyses of each fraction to identify the major classes of compounds associated with embryo toxicity. Toxicity was assessed with 2 exposure methods, a high-energy chemical dispersion of oil in water, which included oil droplets in test solutions, and water accommodated fractions which were produced by oiled gravel desorption columns, and which did not contain visible oil droplets. Fractions of HFO with high concentrations of naphthalenes, alkanes, asphaltenes, and resins were nontoxic to embryos over the range of concentrations tested. In contrast, fractions enriched with 3- to 4-ringed alkyl polycyclic aromatic hydrocarbons (PAHs) were embryotoxic, consistent with published studies of crude oils and individual alkyl PAHs. The rank order of fraction toxicity did not vary between the exposure methods and was consistent with their PAH content; fractions with higher-molecular weight alkyl PAHs were the most toxic. Exposure of juvenile trout to most fractions of HFO induced higher activities of cytochrome P450 enzymes, with a rank order of potency that varied with exposure method and differed somewhat from that of embryotoxicity. Induction reflected the bioavailability of PAHs but did not accurately predict embryotoxicity. © 2013 SETAC.

Using ultrahigh-resolution mass spectrometry and toxicity identification techniques to characterize the toxicity of oil sands process-affected water: The case for classical naphthenic acids.

PubMed

Hughes, Sarah A; Mahaffey, Ashley; Shore, Bryon; Baker, Josh; Kilgour, Bruce; Brown, Christine; Peru, Kerry M; Headley, John V; Bailey, Howard C

2017-11-01

Previous assessments of oil sands process-affected water (OSPW) toxicity were hampered by lack of high-resolution analytical analysis, use of nonstandard toxicity methods, and variability between OSPW samples. We integrated ultrahigh-resolution mass spectrometry with a toxicity identification evaluation (TIE) approach to quantitatively identify the primary cause of acute toxicity of OSPW to rainbow trout (Oncorhynchus mykiss). The initial characterization of OSPW toxicity indicated that toxicity was associated with nonpolar organic compounds, and toxicant(s) were further isolated within a range of discrete methanol fractions that were then subjected to Orbitrap mass spectrometry to evaluate the contribution of naphthenic acid fraction compounds to toxicity. The results showed that toxicity was attributable to classical naphthenic acids, with the potency of individual compounds increasing as a function of carbon number. Notably, the mass of classical naphthenic acids present in OSPW was dominated by carbon numbers ≤16; however, toxicity was largely a function of classical naphthenic acids with ≥17 carbons. Additional experiments found that acute toxicity of the organic fraction was similar when tested at conductivities of 400 and 1800 μmhos/cm and that rainbow trout fry were more sensitive to the organic fraction than larval fathead minnows (Pimephales promelas). Collectively, the results will aid in developing treatment goals and targets for removal of OSPW toxicity in water return scenarios both during operations and on mine closure. Environ Toxicol Chem 2017;36:3148-3157. © 2017 SETAC. © 2017 SETAC.

Analysis of Pfizer compounds in EPA's ToxCast chemicals-assay space.

PubMed

Shah, Falgun; Greene, Nigel

2014-01-21

The U.S. Environmental Protection Agency (EPA) launched the ToxCast program in 2007 with the goal of evaluating high-throughput in vitro assays to prioritize chemicals that need toxicity testing. Their goal was to develop predictive bioactivity signatures for toxic compounds using a set of in vitro assays and/or in silico properties. In 2009, Pfizer joined the ToxCast initiative by contributing 52 compounds with preclinical and clinical data for profiling across the multiple assay platforms available. Here, we describe the initial analysis of the Pfizer subset of compounds within the ToxCast chemical (n = 1814) and in vitro assay (n = 486) space. An analysis of the hit rate of Pfizer compounds in the ToxCast assay panel allowed us to focus our mining of assays potentially most relevant to the attrition of our compounds. We compared the bioactivity profile of Pfizer compounds to other compounds in the ToxCast chemical space to gain insights into common toxicity pathways. Additionally, we explored the similarity in the chemical and biological spaces between drug-like compounds and environmental chemicals in ToxCast and compared the in vivo profiles of a subset of failed pharmaceuticals having high similarity in both spaces. We found differences in the chemical and biological spaces of pharmaceuticals compared to environmental chemicals, which may question the applicability of bioactivity signatures developed exclusively based on the latter to drug-like compounds if used without prior validation with the ToxCast Phase-II chemicals. Finally, our analysis has allowed us to identify novel interactions for our compounds in particular with multiple nuclear receptors that were previously not known. This insight may help us to identify potential liabilities with future novel compounds.

Novel Polyfluorinated Compounds Identified Using High Resolution Mass Spectrometry Downstream of Manufacturing Facilities near Decatur, Alabama

EPA Science Inventory

Concern over persistence, bioaccumulation, and toxicity has led to international regulation and phase-outs of certain perfluorinated compounds and little is known about their replacement products. High resolution mass spectrometry was used to investigate the occurrence and identi...

Prediction of metabolism-induced hepatotoxicity on three-dimensional hepatic cell culture and enzyme microarrays.

PubMed

Yu, Kyeong-Nam; Nadanaciva, Sashi; Rana, Payal; Lee, Dong Woo; Ku, Bosung; Roth, Alexander D; Dordick, Jonathan S; Will, Yvonne; Lee, Moo-Yeal

2018-03-01

Human liver contains various oxidative and conjugative enzymes that can convert nontoxic parent compounds to toxic metabolites or, conversely, toxic parent compounds to nontoxic metabolites. Unlike primary hepatocytes, which contain myriad drug-metabolizing enzymes (DMEs), but are difficult to culture and maintain physiological levels of DMEs, immortalized hepatic cell lines used in predictive toxicity assays are easy to culture, but lack the ability to metabolize compounds. To address this limitation and predict metabolism-induced hepatotoxicity in high-throughput, we developed an advanced miniaturized three-dimensional (3D) cell culture array (DataChip 2.0) and an advanced metabolizing enzyme microarray (MetaChip 2.0). The DataChip is a functionalized micropillar chip that supports the Hep3B human hepatoma cell line in a 3D microarray format. The MetaChip is a microwell chip containing immobilized DMEs found in the human liver. As a proof of concept for generating compound metabolites in situ on the chip and rapidly assessing their toxicity, 22 model compounds were dispensed into the MetaChip and sandwiched with the DataChip. The IC 50 values obtained from the chip platform were correlated with rat LD 50 values, human C max values, and drug-induced liver injury categories to predict adverse drug reactions in vivo. As a result, the platform had 100% sensitivity, 86% specificity, and 93% overall predictivity at optimum cutoffs of IC 50 and C max values. Therefore, the DataChip/MetaChip platform could be used as a high-throughput, early stage, microscale alternative to conventional in vitro multi-well plate platforms and provide a rapid and inexpensive assessment of metabolism-induced toxicity at early phases of drug development.

Synthetic antimicrobial peptides as agricultural pesticides for plant-disease control.

PubMed

Montesinos, Emilio; Bardají, Eduard

2008-07-01

There is a need of antimicrobial compounds in agriculture for plant-disease control, with low toxicity and reduced negative environmental impact. Antimicrobial peptides are produced by living organisms and offer strong possibilities in agriculture because new compounds can be developed based on natural structures with improved properties of activity, specificity, biodegradability, and toxicity. Design of new molecules has been achieved using combinatorial-chemistry procedures coupled to high-throughput screening systems and data processing with design-of-experiments (DOE) methodology to obtain QSAR equation models and optimized compounds. Upon selection of best candidates with low cytotoxicity and moderate stability to protease digestion, anti-infective activity has been evaluated in plant-pathogen model systems. Suitable compounds have been submitted to acute toxicity testing in higher organisms and exhibited a low toxicity profile in a mouse model. Large-scale production can be achieved by solution organic or chemoenzymatic procedures in the case of very small peptides, but, in many cases, production can be performed by biotechnological methods using genetically modified microorganisms (fermentation) or transgenic crops (plant biofactories).

Small molecule fluoride toxicity agonists.

PubMed

Nelson, James W; Plummer, Mark S; Blount, Kenneth F; Ames, Tyler D; Breaker, Ronald R

2015-04-23

Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here, we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. Copyright © 2015 Elsevier Ltd. All rights reserved.

Investigations of chemical warfare agents and toxic industrial compounds with proton-transfer-reaction mass spectrometry for a real-time threat monitoring scenario.

PubMed

Kassebacher, Thomas; Sulzer, Philipp; Jürschik, Simone; Hartungen, Eugen; Jordan, Alfons; Edtbauer, Achim; Feil, Stefan; Hanel, Gernot; Jaksch, Stefan; Märk, Lukas; Mayhew, Chris A; Märk, Tilmann D

2013-01-30

Security and protection against terrorist attacks are major issues in modern society. One especially challenging task is the monitoring and protection of air conditioning and heating systems of buildings against terrorist attacks with toxic chemicals. As existing technologies have low selectivity, long response times or insufficient sensitivity, there is a need for a novel approach such as we present here. We have analyzed various chemical warfare agents (CWAs) and/or toxic industrial compounds (TICs) and related compounds, namely phosgene, diphosgene, chloroacetone, chloroacetophenone, diisopropylaminoethanol, and triethyl phosphate, utilizing a high-resolution proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOFMS) instrument with the objective of finding key product ions and their intensities, which will allow a low-resolution quadrupole mass spectrometry based PTR-MS system to be used with high confidence in the assignment of threat agents in the atmosphere. We obtained high accuracy PTR-TOFMS mass spectra of the six compounds under study at two different values for the reduced electric field in the drift tube (E/N). From these data we have compiled a table containing product ions, and isotopic and E/N ratios for highly selective threat compound detection with a compact and cost-effective quadrupole-based PTR-MS instrument. Furthermore, using chloroacetophenone (tear gas), we demonstrated that this instrument's response is highly linear in the concentration range of typical Acute Exposure Guideline Levels (AEGLs). On the basis of the presented results it is possible to develop a compact and cost-effective PTR-QMS instrument that monitors air supply systems and triggers an alarm as soon as the presence of a threat agent is detected. We hope that this real-time surveillance device will help to seriously improve safety and security in environments vulnerable to terrorist attacks with toxic chemicals. Copyright © 2012 John Wiley & Sons, Ltd.

Comparison of toxicity of class-based organic chemicals to algae and fish based on discrimination of excess toxicity from baseline level.

PubMed

Li, Jin J; Tai, Hong W; Yu, Yang; Wen, Yang; Wang, Xiao H; Zhao, Yuan H

2015-07-01

Toxicity data to fish and algae were used to investigate excess toxicity between species. Results show that chemicals exhibiting excess toxicity to fish also show excess toxicity to algae for most of the compounds. This indicates that they share the same mode of action between species. Similar relationships between logKOW and toxicities to fish and algae for baseline and less inert compounds suggest that they have similar critical body residues in the two species. Differences in excess toxicity for some compounds suggest that there is a difference of physiological structure and metabolism between fish and algae. Some reactive compounds (e.g. polyamines) exhibit greater toxic effects for algae than those for fish because of relatively low bio-uptake potential of these hydrophilic compounds in fish as compared with that in algae. Esters exhibiting greater toxicity in fish than that in algae indicate that metabolism can affect the discrimination of excess toxicity from baseline level. Algae growth inhibition is a very good surrogate for fish lethality. This is not only because overall toxicity sensitivity to algae is greater than that to fish, but also the excess toxicity calculated from algal toxicity can better reflect reactivity of compounds with target molecules than fish toxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

Toxicity of new generation flame retardants to Daphnia magna.

PubMed

Waaijers, Susanne L; Hartmann, Julia; Soeter, A Marieke; Helmus, Rick; Kools, Stefan A E; de Voogt, Pim; Admiraal, Wim; Parsons, John R; Kraak, Michiel H S

2013-10-01

There is a tendency to substitute frequently used, but relatively hazardous brominated flame retardants (BFRs) with halogen-free flame retardants (HFFRs). Consequently, information on the persistence, bioaccumulation and toxicity (PBT) of these HFFRs is urgently needed, but large data gaps and inconsistencies exist. Therefore, in the present study the toxicity of a wide range of HFFRs to the water flea Daphnia magna was investigated. Our results revealed that four HFFRs were showing no effect at their Sw (saturated water concentration) and three had a low toxicity (EC50>10 mg L(-1)), suggesting that these compounds are not hazardous. Antimony trioxide had a moderate toxicity (EC50=3.01 mg L(-1), 95% CL: 2.76-3.25) and triphenyl phosphate and the brominated reference compound tetra bromobisphenol A were highly toxic to D. magna (EC50=0.55 mg L(-1), 95% CL: 0.53-0.55 and EC50=0.60 mg L(-1), 95% CL: 0.24-0.97 respectively). Aluminum trihydroxide and bisphenol A bis(diphenyl phosphate) caused limited mortality at Sw (26 and 25% respectively) and have a low solubility (<10 mg L(-1)). Hence, increased toxicity of these compounds may be observed when for instance decreasing pH could increase solubility. By testing all compounds under identical conditions we provided missing insights in the environmental hazards of new generation flame retardants and propose as best candidates for BFR replacements: APP, ALPI, DOPO, MHO, MPP, ZHS and ZS. © 2013 Elsevier B.V. All rights reserved.

High-Content, High-Throughput Screening for the Identification of Cytotoxic Compounds Based on Cell Morphology and Cell Proliferation Markers

PubMed Central

Martin, Heather L.; Adams, Matthew; Higgins, Julie; Bond, Jacquelyn; Morrison, Ewan E.; Bell, Sandra M.; Warriner, Stuart; Nelson, Adam; Tomlinson, Darren C.

2014-01-01

Toxicity is a major cause of failure in drug discovery and development, and whilst robust toxicological testing occurs, efficiency could be improved if compounds with cytotoxic characteristics were identified during primary compound screening. The use of high-content imaging in primary screening is becoming more widespread, and by utilising phenotypic approaches it should be possible to incorporate cytotoxicity counter-screens into primary screens. Here we present a novel phenotypic assay that can be used as a counter-screen to identify compounds with adverse cellular effects. This assay has been developed using U2OS cells, the PerkinElmer Operetta high-content/high-throughput imaging system and Columbus image analysis software. In Columbus, algorithms were devised to identify changes in nuclear morphology, cell shape and proliferation using DAPI, TOTO-3 and phosphohistone H3 staining, respectively. The algorithms were developed and tested on cells treated with doxorubicin, taxol and nocodazole. The assay was then used to screen a novel, chemical library, rich in natural product-like molecules of over 300 compounds, 13.6% of which were identified as having adverse cellular effects. This assay provides a relatively cheap and rapid approach for identifying compounds with adverse cellular effects during screening assays, potentially reducing compound rejection due to toxicity in subsequent in vitro and in vivo assays. PMID:24505478

Investigation of Acute and Chronic Toxicity Trends of Pesticides Using High-Throughput Bioluminescence Assay Based on the Test Organism Vibrio fischeri.

PubMed

Westlund, Paul; Nasuhoglu, Deniz; Isazadeh, Siavash; Yargeau, Viviane

2018-05-01

High-throughput acute and chronic toxicity tests using Vibrio fischeri were used to assess the toxicity of a variety of fungicides, herbicides, and neonicotinoids. The use of time points beyond the traditional 30 min of an acute test highlighted the sensitivity and applicability of the chronic toxicity test and indicated that for some compounds toxicity is underestimated using only the acute test. The comparison of EC 50 values obtained from acute and chronic tests provided insight regarding the toxicity mode of action, either being direct or indirect. Using a structure-activity relationship approach similar to the one used in hazard assessments, the relationship between toxicity and key physicochemical properties of pesticides was investigated and trends were identified. This study not only provides new information regarding acute toxicity of some pesticides but also is one of the first studies to investigate the chronic toxicity of pesticides using the test organism V. fischeri. The findings demonstrated that the initial bioluminescence has a large effect on the calculated effective concentrations for target compounds in both acute and chronic tests, providing a way to improve and standardize the test protocol. In addition, the findings emphasize the need for additional investigation regarding the relationship between a toxicant's physicochemical properties and mode of action in nontarget organisms.

A possible link between Balkan endemic nephropathy and the leaching of toxic organic compounds from Pliocene lignite by groundwater: Preliminary investigation

USGS Publications Warehouse

Orem, W.H.; Feder, G.L.; Finkelman, R.B.

1999-01-01

Balkan endemic nephropathy (BEN) is a fatal kidney disease that is known to occur only in clusters of villages in alluvial valleys of tributaries of the Danube River in Bulgaria, Romania, Yugoslavia, Bosnia, and Croatia. The confinement of this disease to a specific geographic area has led to speculation that an environmental factor may be involved in the etiology of BEN. Numerous environmental factors have been suggested as causative agents for producing BEN, including toxic metals in drinking water, metal deficiency in soils of BEN areas, and environmental mycotoxins to name a few. These hypotheses have either been disproved or have failed to conclusively demonstrate a connection to the etiology of BEN, or the clustering of BEN villages. In previous work, we observed a distinct geographic relationship between the distribution of Pliocene lignites in the Balkans and BEN villages. We hypothesized that the long-term consumption of well water containing toxic organic compounds derived from the leaching of nearby Pliocene lignites by groundwater was a primary factor in the etiology of BEN. In our current work, chemical analysis using 13C nuclear magnetic resonance (13CNMR) spectroscopy indicated a high degree of organic functionality in Pliocene lignite from the Balkans, and suggested that groundwater can readily leach organic matter from these coal beds. Semi-quantitative gas chromatography/mass spectroscopy analysis of solvent extracts of groundwater from shallow wells in BEN villages indicated the presence of potentially toxic aromatic compounds, such as napthalene, fluorene, phenanthrene, and pyrene at concentrations in the ppb range. Laboratory leaching of Balkan Pliocene lignites with distilled water yielded soluble organic matter (> 500 MW) containing large amounts of aromatic structures similar to the simple/discrete aromatic compounds detected in well water from BEN villages. These preliminary results are permissive of our hypothesis and suggest that further work on the possible relationship between the etiology of BEN and toxic aromatic substances leached from Pliocene lignites in well water is warranted.A distinct geographic relationship between the distribution of Pliocene lignites in the Balkans and villages where Balkan endemic nephropathy (BEN) occurs has been observed, indicating a possible link between BEN and the long-term consumption of well water containing toxic organic compounds derived from the leaching of nearby Pliocene lignites. Preliminary investigations by NMR spectroscopy, gas chromatography/mass spectroscopy and leaching experiments show a high degree of organic functionality in the Pliocene lignites, high-leachability by groundwater of organic matter from these beds, and the presence of toxic aromatic compounds.

Bacterial bio-resources for remediation of hexachlorocyclohexane.

PubMed

Alvarez, Analía; Benimeli, Claudia S; Saez, Juliana M; Fuentes, María S; Cuozzo, Sergio A; Polti, Marta A; Amoroso, María J

2012-11-15

In the last few decades, highly toxic organic compounds like the organochlorine pesticide (OP) hexachlorocyclohexane (HCH) have been released into the environment. All HCH isomers are acutely toxic to mammals. Although nowadays its use is restricted or completely banned in most countries, it continues posing serious environmental and health concerns. Since HCH toxicity is well known, it is imperative to develop methods to remove it from the environment. Bioremediation technologies, which use microorganisms and/or plants to degrade toxic contaminants, have become the focus of interest. Microorganisms play a significant role in the transformation and degradation of xenobiotic compounds. Many Gram-negative bacteria have been reported to have metabolic abilities to attack HCH. For instance, several Sphingomonas strains have been reported to degrade the pesticide. On the other hand, among Gram-positive microorganisms, actinobacteria have a great potential for biodegradation of organic and inorganic toxic compounds. This review compiles and updates the information available on bacterial removal of HCH, particularly by Streptomyces strains, a prolific genus of actinobacteria. A brief account on the persistence and deleterious effects of these pollutant chemical is also given.

Bacterial Bio-Resources for Remediation of Hexachlorocyclohexane

PubMed Central

Alvarez, Analía; Benimeli, Claudia S.; Saez, Juliana M.; Fuentes, María S.; Cuozzo, Sergio A.; Polti, Marta A.; Amoroso, María J.

2012-01-01

In the last few decades, highly toxic organic compounds like the organochlorine pesticide (OP) hexachlorocyclohexane (HCH) have been released into the environment. All HCH isomers are acutely toxic to mammals. Although nowadays its use is restricted or completely banned in most countries, it continues posing serious environmental and health concerns. Since HCH toxicity is well known, it is imperative to develop methods to remove it from the environment. Bioremediation technologies, which use microorganisms and/or plants to degrade toxic contaminants, have become the focus of interest. Microorganisms play a significant role in the transformation and degradation of xenobiotic compounds. Many Gram-negative bacteria have been reported to have metabolic abilities to attack HCH. For instance, several Sphingomonas strains have been reported to degrade the pesticide. On the other hand, among Gram-positive microorganisms, actinobacteria have a great potential for biodegradation of organic and inorganic toxic compounds. This review compiles and updates the information available on bacterial removal of HCH, particularly by Streptomyces strains, a prolific genus of actinobacteria. A brief account on the persistence and deleterious effects of these pollutant chemical is also given. PMID:23203113

NITROGEN DIOXIDE, PULMONARY FUNCTION, AND RESPIRATORY DISEASE

EPA Science Inventory

Concern as to the toxicity of the oxides of nitrogen has been frequently expressed in clinical and toxicological literature. Oxides of nitrogen are highly reactive compounds and suggest toxic effects on biological systems. The earliest evidence for potential damage to man occurre...

Phenotypic Characterization of Toxic Compound Effects on Liver Spheroids Derived from iPSC Using Confocal Imaging and Three-Dimensional Image Analysis.

PubMed

Sirenko, Oksana; Hancock, Michael K; Hesley, Jayne; Hong, Dihui; Cohen, Avrum; Gentry, Jason; Carlson, Coby B; Mann, David A

2016-09-01

Cell models are becoming more complex to better mimic the in vivo environment and provide greater predictivity for compound efficacy and toxicity. There is an increasing interest in exploring the use of three-dimensional (3D) spheroids for modeling developmental and tissue biology with the goal of accelerating translational research in these areas. Accordingly, the development of high-throughput quantitative assays using 3D cultures is an active area of investigation. In this study, we have developed and optimized methods for the formation of 3D liver spheroids derived from human iPS cells and used those for toxicity assessment. We used confocal imaging and 3D image analysis to characterize cellular information from a 3D matrix to enable a multi-parametric comparison of different spheroid phenotypes. The assay enables characterization of compound toxicities by spheroid size (volume) and shape, cell number and spatial distribution, nuclear characterization, number and distribution of cells expressing viability, apoptosis, mitochondrial potential, and viability marker intensities. In addition, changes in the content of live, dead, and apoptotic cells as a consequence of compound exposure were characterized. We tested 48 compounds and compared induced pluripotent stem cell (iPSC)-derived hepatocytes and HepG2 cells in both two-dimensional (2D) and 3D cultures. We observed significant differences in the pharmacological effects of compounds across the two cell types and between the different culture conditions. Our results indicate that a phenotypic assay using 3D model systems formed with human iPSC-derived hepatocytes is suitable for high-throughput screening and can be used for hepatotoxicity assessment in vitro.

Acute lethal toxicity of environmental pollutants to aquatic organisms.

PubMed

Yen, Jui-Hung; Lin, Kuo-Hsiung; Wang, Yei-Shung

2002-06-01

The acute lethal toxicity of environment pollutants including chlorophenol, haloalkane, quinone, and substituted nitrobenzene (i.e., nitrophenol, nitrobenzene, nitrotoluene, and aniline) compounds to aquatic organisms was determined. Determination of toxicity of chemicals was performed with chlorella, daphnia, carp, and tilapia. The toxicity of chlorophenols had no relation to the number of chlorine atoms on the benzene ring, but monochlorophenol had lower activity than more chlorine-substituted compounds. The tolerance levels of daphnia and carp to haloalkanes was found to be higher than that of chlorella; toxicity to chlorella was several hundred times higher than to daphnia. The toxicity of naphthoquinone compounds to chlorella and carp was higher than that of anthraquinone. A compound with a monochloride substitution on anthraquinone ring was less toxic to carp than those substituted with amine, hydroxyl, and dichlorine groups. Nitrobenzene compounds with an additional substitution group on the p position were extremely toxic to daphnia and carp. (c) 2002 Elsevier Science (USA).

Larvicidal and antifeedant activity of some plant-derived compounds to Lymantria dispar L. (Lepidoptera: Limantriidae).

PubMed

Kostić, Miroslav; Popović, Zorica; Brkić, Dejan; Milanović, Slobodan; Sivcev, Ivan; Stanković, Sladjan

2008-11-01

Ethanol solutions of essential oil of Ocimum basilicum and its main component, linalool (both isomer forms), all in three concentrations, as well as botanical standard Bioneem (0.5%), were tested for their toxicity and antifeedant activity against the second instar gypsy moth larvae in the laboratory bioassay. The essential oil of O. basilicum was subjected to gas chromatography analysis, and totally 37 compounds were detected, of which linalool was predominantly present. All tested solutions showed low to moderate larvicidal effect in both residual toxicity test and in chronic larval mortality bioassay. Chronic mortality tests showed that obtained mortality was a consequence of starving rather than ingestion of treated leaves. However, antifeedant index achieved by application of tested solutions in feeding choice assay was remarkable. Foliar application of all tested compounds deterred feeding by L2 in the same percent as Bioneem. Antifeedant index was relatively high at all tested treatments (85-94%); moreover, the larval desensitization to repelling volatiles has not occurred after five days of observation. Low toxic and high antifeedant properties make these plant-derived compounds suitable for incorporation in integrated pest management programs, especially in urban environments.

Vanadium distribution in rats and DNA cleavage by vanadyl complex: implication for vanadium toxicity and biological effects.

PubMed Central

Sakurai, H

1994-01-01

Vanadium ion is toxic to animals. However, vanadium is also an agent used for chemoprotection against cancers in animals. To understand both the toxic and beneficial effects we studied vanadium distribution in rats. Accumulation of vanadium in the liver nuclei of rats given low doses of compounds in the +4 or +5 oxidation state was greater than in the liver nuclei of rats given high doses of vanadium compounds or the vanadate (+5 oxidation state) compound. Vanadium was incorporated exclusively in the vanadyl (+4 oxidation state) form. We also investigated the reactions of vanadyl ion and found that incubation of DNA with vanadyl ion and hydrogen peroxide (H2O2) led to intense DNA cleavage. ESR spin trapping demonstrated that hydroxyl radicals are generated during the reactions of vanadyl ion and H2O2. Thus, we propose that the mechanism for vanadium-dependent toxicity and antineoplastic action is due to DNA cleavage by hydroxyl radicals generated in living systems. PMID:7843133

Comparison of Toxicities to Vibrio fischeri and Fish Based on Discrimination of Excess Toxicity from Baseline Level

PubMed Central

Wang, Xiao H.; Yu, Yang; Huang, Tao; Qin, Wei C.; Su, Li M.; Zhao, Yuan H.

2016-01-01

Investigations on the relationship of toxicities between species play an important role in the understanding of toxic mechanisms to environmental organisms. In this paper, the toxicity data of 949 chemicals to fish and 1470 chemicals to V. fischeri were used to investigate the modes of action (MOAs) between species. The results show that although there is a positive interspecies correlation, the relationship is poor. Analysis on the excess toxicity calculated from toxic ratios (TR) shows that many chemicals have close toxicities and share the same MOAs between the two species. Linear relationships between the toxicities and octanol/water partition coefficient (log KOW) for baseline and less inert compounds indicate that the internal critical concentrations (CBRs) approach a constant both to fish and V. fischeri for neutral hydrophobic compounds. These compounds share the same toxic mechanisms and bio-uptake processes between species. On the other hand, some hydrophilic compounds exhibit different toxic effects with greatly different log TR values between V. fischeri and fish species. These hydrophilic compounds were identified as reactive MOAs to V. fischeri, but not to fish. The interspecies correlation is improved by adding a hydrophobic descriptor into the correlation equation. This indicates that the differences in the toxic ratios between fish and V. fischeri for these hydrophilic compounds can be partly attributed to the differences of bioconcentration between the two species, rather than the differences of reactivity with the target macromolecules. These hydrophilic compounds may more easily pass through the cell membrane of V. fischeri than the gill and skin of fish, react with the target macromolecules and exhibit excess toxicity. The compounds with log KOW > 7 exhibiting very low toxicity (log TR < –1) to both species indicate that the bioconcentration potential of a chemical plays a very important role in the identification of excess toxicity and MOAs. PMID:26901437

Identification of chalcone-based antileishmanial agents targeting trypanothione reductase.

PubMed

Ortalli, Margherita; Ilari, Andrea; Colotti, Gianni; De Ionna, Ilenia; Battista, Theo; Bisi, Alessandra; Gobbi, Silvia; Rampa, Angela; Di Martino, Rita M C; Gentilomi, Giovanna A; Varani, Stefania; Belluti, Federica

2018-05-02

All currently used first-line and second-line drugs for the treatment of leishmaniasis exhibit several drawbacks including toxicity, high costs and route of administration. Furthermore, some drugs are associated with the emergence of drug resistance. Thus, the development of new treatments for leishmaniasis is a priority in the field of neglected tropical diseases. The present work highlights the use of natural derived products, i.e. chalcones, as potential source of antileishmanial agents. Thirty-one novel chalcone compounds have been synthesized and their activity has been evaluated against promastigotes of Leishmania donovani; 16 compounds resulted active against L. donovani in a range from 3.0 to 21.5 μM, showing low toxicity against mammalian cells. Among these molecules, 6 and 16 showed good inhibitory activity on both promastigotes and intracellular amastigotes, coupled with an high selectivity index. Furthermore, compounds 6 and 16 inhibited the promastigote growth of other leishmanial species, including L. tropica, L. major and L. infantum. Finally, 6 and 16 interacted with high affinity with trypanothione reductase (TR), an essential enzyme for the leishmanial parasite and compound 6 inhibited TR with sub-micromolar potency. Thus, the effective inhibitory activity against Leishmania, the lack of toxicity on mammalian cells and the ability to block a crucial parasite's enzyme, highlight the potential for compound 6 to be optimized as novel drug candidate against leishmaniasis. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Effects of three related amides on microecosystem stability

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

Flum, T.F.; Shannon, L.J.

1987-04-01

Three related amides (diuron, 2-(octyloxy) acetanilide, and salicylanilide) were evaluated for toxicity to aquatic microcosm communities. Effects were measured at the ecosystem level using changes in pH, Eh (redox potential), and dissolved oxygen as indicators of toxicity. These values were used to calculate the resistance, resilience, and relative instability of the microecosystems to each compound at comparable dose levels of approximately 2500 micrograms/liter. Such measures have often been used in a theoretical context, but have not received wide practical application. The systems showed low resistance and no resilience to diuron, high resistance and low resilience to 2-(octyloxy) acetanilide, and nomore » response to salicylanilide. At a higher exposure level (9800 micrograms/liter salicylanilide), the systems showed low resistance and high resilience. Both this approach and more traditional dose-response measures of toxicity indicated that diuron was clearly the most toxic compound, followed by 2-(octyloxy) acetanilide and salicylanilide. While microcosm toxicity tests were slightly less sensitive than some single species tests, they provided important additional information on the extent of perturbations and the rate of ecosystem recovery.« less

Effect of Simulated Weathering and Aging of TNT in Amended Sandy Loam Soil on Toxicity to the Enchytraeid Worm, Enchytreaeus Crypticus

DTIC Science & Technology

2006-05-01

high bioavailability of organic compounds. However, amended SSL soil was analyzed for presence of metabolic transformation products from nitroaromatic...Phillips, C.; Checkai, R. 1999. Comparison of malathion toxicity using enchytraeid reproduction test and earthworm toxicity test in different soil ...OF TNT IN AMENDED SANDY LOAM SOIL ON TOXICITY TO THE ENCHYTRAEID WORM, ENCHYTRAEUS CRYPTICUS Roman G. Kuperman Ronald T. Checkai Michael Simini

Physicochemical characterization and toxicity of decursin and their derivatives from Angelica gigas.

PubMed

Mahat, Bimit; Chae, Jung-Woo; Baek, In-Hwan; Song, Gyu-Yong; Song, Jin-Sook; Cho, Seong-Kwon; Kwon, Kwang-Il

2012-01-01

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The present study provided a physicochemical and toxicological characterization of compounds in A. gigas NAKAI (decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin). Diketone decursin (173.16 μg/mL) and epoxide decursin (122.12 μg/mL) exhibited >100 μg/mL kinetic solubility after applying nephelometry, suggesting a highly soluble compound. The Student’s t-test revealed significant differences in the pKa ranges of the compounds by automatic titration from capillary electrophoresis (p<0.05). Diketone decursin, epoxide decursin and oxim decursin might be formulated into an oral dosage form (log P: 0-3) by an automatic titration analysis. A parallel artificial membrane permeability assay demonstrated permeability coefficients of <10 x 10⁻⁶ cm/s for all of the compounds, suggesting poor permeability. Ether decursin exhibited a toxic effect after being applied to mouse (NIH 3T3, EC₅₀: 57.9 μM) and human (HT-29, EC₅₀: 36.1 μM; Hep-G2, EC₅₀: 4.92 μM) cells. Additionally, epoxide and oxim decursin were toxic through acute oral toxicity (four and three deaths of Institute of Cancer Research (ICR) mice) and mutation toxicity testing by applying Salmonella typhimurium cells with and without S9. Although diketone decursin exhibited less permeability, it is potentially valuable pharmacological compound that should be investigated.

Loading and removal of PAHs, fragrance compounds, triclosan and toxicity by composting process from sewage sludge.

PubMed

Ozaki, Noriatsu; Nakazato, Akihiro; Nakashima, Kazuki; Kindaichi, Tomonori; Ohashi, Akiyoshi

2017-12-15

Although the production of compost from sewage sludge is well established in developed countries, the use of sludge-based compost may represent a source of pollutants. The present study assessed the levels of potentially harmful compounds in compost as well as their rates of decrease during composting. The concentrations of 16 polycyclic aromatic hydrocarbons (PAHs), three fragrance compounds (OTNE, HHCB and AHTN) and triclosan were determined in the initial sewage sludge and in compost over the span of 1year. Simultaneously, the toxicity to luminescent bacteria (Aliivibrio fischeri) and aryl hydrocarbon receptor reactivity of organic solvent extracts of sludge and compost samples were assessed. Higher PAH, fragrance compounds, and triclosan concentrations were found in sewage sludge from urban areas compared with rural regions, and the urban sludge was also more toxic than the rural sludge. The high pollutant concentrations in urban sludge raised the concentrations of these compounds in the raw materials for composting and in the resulting composts. The organic matter was decomposed by 65% during the composting process, and the measured toxic substances were decreased by a similar amount, with the exception of triclosan, which decreased by only 35%. The toxicity to A. fischeri decreased to a greater extent (90%) than did the organic matter, while the aryl hydrocarbon receptor reactivity decreased by only 35%. This lower decrease coincided with that of the aryl hydrocarbon receptor-reactive PAHs (37%). Copyright © 2017 Elsevier B.V. All rights reserved.

Acute Toxicity and Environmental Risks of Five Veterinary Pharmaceuticals for Aquatic Macroinvertebrates.

PubMed

Bundschuh, Mirco; Hahn, Torsten; Ehrlich, Bert; Höltge, Sibylla; Kreuzig, Robert; Schulz, Ralf

2016-02-01

Due to the high use of antibiotics and antiparasitics for the treatment of livestock, there is concern about the potential impacts of the release of these compounds into freshwater ecosystems. In this context, the present study quantified the acute toxicity of two antibiotics (sulfadiazine and sulfadimidine), and three antiparasitic agents (flubendazole, fenbendazole, ivermectin) for nine freshwater invertebrate species. These experiments revealed a low degree of toxicity for the sulfonamide antibiotics, with limited implications in the survival of all test species at the highest test concentrations (50 and 100 mg/L). In contrast, all three antiparasitic agents indicated on the basis of their acute toxicity risks for the aquatic environment. Moreover, chronic toxicity data from the literature for antiparasitics, including effects on reproduction in daphnids, support the concern about the integrity of aquatic ecosystems posed by releases of these compounds. Thus, these pharmaceuticals warrant further careful consideration by environmental risk managers.

Discriminating modes of toxic action in mice using toxicity in BALB/c mouse fibroblast (3T3) cells.

PubMed

Huang, Tao; Yan, Lichen; Zheng, Shanshan; Wang, Yue; Wang, Xiaohong; Fan, Lingyun; Li, Chao; Zhao, Yuanhui; Martyniuk, Christopher J

2017-12-01

The objective of this study was to determine whether toxicity in mouse fibroblast cells (3T3 cells) could predict toxicity in mice. Synthesized data on toxicity was subjected to regression analysis and it was observed that relationship of toxicities between mice and 3T3 cells was not strong (R 2  = 0.41). Inclusion of molecular descriptors (e.g. ionization, pKa) improved the regression to R 2  = 0.56, indicating that this relationship is influenced by kinetic processes of chemicals or specific toxic mechanisms associated to the compounds. However, to determine if we were able to discriminate modes of action (MOAs) in mice using the toxicities generated from 3T3 cells, compounds were first classified into "baseline" and "reactive" guided by the toxic ratio (TR) for each compound in mice. Sequence, binomial and recursive partitioning analyses provided strong predictions of MOAs in mice based upon toxicities in 3T3 cells. The correct classification of MOAs based on these methods was 86%. Nearly all the baseline compounds predicted from toxicities in 3T3 cells were identified as baseline compounds from the TR in mice. The incorrect assignment of MOAs for some compounds is hypothesized to be due to experimental uncertainty that exists in toxicity assays for both mice and 3T3 cells. Conversely, lack of assignment can also arise because some reactive compounds have MOAs that are different in mice compared to 3T3 cells. The methods developed here are novel and contribute to efforts to reduce animal numbers in toxicity tests that are used to evaluate risks associated with organic pollutants in the environment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Addressing the selectivity and toxicity of antiviral nucleosides.

PubMed

Feng, Joy Y

2018-01-01

Nucleoside and nucleotide analogs have played significant roles in antiviral therapies and are valued for their impressive potency and high barrier to resistance. They have been approved for treatment of herpes simplex virus-1, HIV, HBV, HCV, and influenza, and new drugs are being developed for the treatment of RSV, Ebola, coronavirus MERS, and other emerging viruses. However, this class of compounds has also experienced a high attrition rate in clinical trials due to toxicity. In this review, we discuss the utility of different biochemical and cell-based assays and provide recommendations for assessing toxicity liability before entering animal toxicity studies.

Toxicity and repellency to rats of actidione

USGS Publications Warehouse

Traub, R.; DeWitt, J.B.; Welch, J.F.; Newman, D.

1950-01-01

The antibiotic actidione was found to be highly repellent to laboratory rats and to significantly reduce gnawing attacks upon treated paperboards. Rats refused to accept food or water containing this material even under conditions of acute starvation and died of starvation and thirst,rather than accept water containing l.0 mg. of actidione per liter. The compound is highly toxic to .rats with the minimum .lethal dose by oral administration being approximately l.0 mg./Kg body weight. Paperboard treated with the compound resisted gnawing attacks by specially trained and motivated rats for periods of two hundred hours, although similar .untreated boards were pierced within thirty-to sixty minutes.

Antibacterial properties of soap containing some fatty acid esters.

PubMed

Pandey, N K; Natraj, C V; Kalle, G P; Nambudiry, M E

1985-02-01

Synopsis Chemical microbial inhibitors compatible with formulations of soaps and deodorant perfumes are more effective if they are substantive to the skin. However, highly effective inhibitors are toxic and their substantivity on skin may accentuate the toxicity. Natural compounds such as short to medium chain fatty acids and their derivatives, which are known to be germicidal, offer a viable alternative to chemical inhibitors. We report here the synthesis of sodium 2-lauroyloxy propionate and an in vivo method to test its substantivity on skin following its incorporation in soaps. Among several compounds tested, sodium 2-lauroyloxy propionate was found to be highly substantive in soap formulation.

Allylglucosinolate and herbivorous caterpillars: a contrast in toxicity and tolerance.

PubMed

Blau, P A; Feeny, P; Contardo, L; Robson, D S

1978-06-16

Allylglucosinolate, found in many cruciferous plants, is acutely toxic to Papilio polyxenes larvae, which do not normally attack crucifers. By contrast, larval growth of Pieris rapae, a crucifer specialist, is not affected even by artificially high concentrations of allylglucosinolate. Larval growth of Spodoptera eridania, a generalist feeder, is inhibited by high but not by low concentrations of the compound.

Comparison of the mouse Embryonic Stem cell Test, the rat Whole Embryo Culture and the Zebrafish Embryotoxicity Test as alternative methods for developmental toxicity testing of six 1,2,4-triazoles

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

Jong, Esther de, E-mail: Esther.de.Jong@rivm.nl; Laboratory for Health Protection Research, National Institute for Public Health and the Environment; Barenys, Marta

2011-06-01

The relatively high experimental animal use in developmental toxicity testing has stimulated the search for alternatives that are less animal intensive. Three widely studied alternative assays are the mouse Embryonic Stem cell Test (EST), the Zebrafish Embryotoxicity Test (ZET) and the rat postimplantation Whole Embryo Culture (WEC). The goal of this study was to determine their efficacy in assessing the relative developmental toxicity of six 1,2,4-triazole compounds, flusilazole, hexaconazole, cyproconazole, triadimefon, myclobutanil and triticonazole. For this purpose, we analyzed effects and relative potencies of the compounds in and among the alternative assays and compared the findings to their known inmore » vivo developmental toxicity. Triazoles are antifungal agents used in agriculture and medicine, some of which are known to induce craniofacial and limb abnormalities in rodents. The WEC showed a general pattern of teratogenic effects, typical of exposure to triazoles, mainly consisting of reduction and fusion of the first and second branchial arches, which are in accordance with the craniofacial malformations reported after in vivo exposure. In the EST all triazole compounds inhibited cardiomyocyte differentiation concentration-dependently. Overall, the ZET gave the best correlation with the relative in vivo developmental toxicities of the tested compounds, closely followed by the EST. The relative potencies observed in the WEC showed the lowest correlation with the in vivo developmental toxicity data. These differences in the efficacy between the test systems might be due to differences in compound kinetics, in developmental stages represented and in the relative complexity of the alternative assays.« less

Comparison of the mouse Embryonic Stem cell Test, the rat Whole Embryo Culture and the Zebrafish Embryotoxicity Test as alternative methods for developmental toxicity testing of six 1,2,4-triazoles.

PubMed

de Jong, Esther; Barenys, Marta; Hermsen, Sanne A B; Verhoef, Aart; Ossendorp, Bernadette C; Bessems, Jos G M; Piersma, Aldert H

2011-06-01

The relatively high experimental animal use in developmental toxicity testing has stimulated the search for alternatives that are less animal intensive. Three widely studied alternative assays are the mouse Embryonic Stem cell Test (EST), the Zebrafish Embryotoxicity Test (ZET) and the rat postimplantation Whole Embryo Culture (WEC). The goal of this study was to determine their efficacy in assessing the relative developmental toxicity of six 1,2,4-triazole compounds,(1) flusilazole, hexaconazole, cyproconazole, triadimefon, myclobutanil and triticonazole. For this purpose, we analyzed effects and relative potencies of the compounds in and among the alternative assays and compared the findings to their known in vivo developmental toxicity. Triazoles are antifungal agents used in agriculture and medicine, some of which are known to induce craniofacial and limb abnormalities in rodents. The WEC showed a general pattern of teratogenic effects, typical of exposure to triazoles, mainly consisting of reduction and fusion of the first and second branchial arches, which are in accordance with the craniofacial malformations reported after in vivo exposure. In the EST all triazole compounds inhibited cardiomyocyte differentiation concentration-dependently. Overall, the ZET gave the best correlation with the relative in vivo developmental toxicities of the tested compounds, closely followed by the EST. The relative potencies observed in the WEC showed the lowest correlation with the in vivo developmental toxicity data. These differences in the efficacy between the test systems might be due to differences in compound kinetics, in developmental stages represented and in the relative complexity of the alternative assays. Copyright © 2011 Elsevier Inc. All rights reserved.

Fumigant toxicity of basil oil compounds and related compounds to Thrips palmi and Orius strigicollis.

PubMed

Kim, Kwang-Ho; Yi, Chang-Geun; Ahn, Young-Joon; Kim, Soon Il; Lee, Sang-Guei; Kim, Jun-Ran

2015-09-01

This study was aimed at assessing the fumigant toxicity to adult Thrips palmi (a serious insect pest) and Orius strigicollis (a beneficial predator insect) of basil (Ocimum basilicum) essential oil compounds and structurally related compounds using vapour-phase toxicity bioassays. Against adult T. palmi, linalool (LD50 0.0055 mg cm(-3) ) was the most toxic fumigant and was 15.2-fold more effective than dichlorvos (0.0837 mg cm(-3) ). Strong fumigant toxicity was also observed in pulegone (0.0095 mg cm(-3) ), (±)-camphor (0.0097 mg cm(-3) ) and 1,8-cineole (0.0167 mg cm(-3) ). Moderate toxicity was produced by camphene, 3-carene, (-)-menthone, (+)-α-pinene, (+)-β-pinene, α-terpineol and (-)-α-thujone (0.0215-0.0388 mg cm(-3) ). Against adult O. strigicollis, dichlorvos (LD50 9.0 × 10(-10) mg cm(-3) ) was the most toxic fumigant, whereas the LD50 values of these compounds ranged from 0.0127 to >0.23 mg cm(-3) . Based upon the selective toxicity ratio, the compounds described are more selective than dichlorvos. The basil oil compounds described merit further study as potential insecticides for control of T. palmi in greenhouses because of their generally lower toxicity to O. strigicollis and their greater activity as a fumigant than dichlorvos. © 2014 Society of Chemical Industry.

NQO2 Is a Reactive Oxygen Species Generating Off-Target for Acetaminophen

PubMed Central

2014-01-01

The analgesic and antipyretic compound acetaminophen (paracetamol) is one of the most used drugs worldwide. Acetaminophen overdose is also the most common cause for acute liver toxicity. Here we show that acetaminophen and many structurally related compounds bind quinone reductase 2 (NQO2) in vitro and in live cells, establishing NQO2 as a novel off-target. NQO2 modulates the levels of acetaminophen derived reactive oxygen species, more specifically superoxide anions, in cultured cells. In humans, NQO2 is highly expressed in liver and kidney, the main sites of acetaminophen toxicity. We suggest that NQO2 mediated superoxide production may function as a novel mechanism augmenting acetaminophen toxicity. PMID:25313982

ToxiFly: Can Fruit Flies be Used to Identify Toxicity Pathways for Airborne Chemicals?

EPA Science Inventory

Current high-throughput and alternative screening assays for chemical toxicity are unable to test volatile organic compounds (VOCs), thus limiting their scope. Further, the data generated by these assays require mechanistic information to link effects at molecular targets to adve...

VIRTUAL EMBRYO: SYSTEMS MODELING IN DEVELOPMENTAL TOXICITY - Symposium: SOT 2012

EPA Science Inventory

High-throughput screening (HTS) studies are providing a rich source of data that can be applied to in vitro profiling of chemical compounds for biological activity and potential toxicity. Chemical profiling in ToxCast covered 965 drugs-chemicals in over 500 diverse assays testing...

Aflatoxin Toxicity Reduction in Feed by Enhanced Binding to Surface-Modified Clay Additives

PubMed Central

Jaynes, William F.; Zartman, Richard E.

2011-01-01

Animal feeding studies have demonstrated that clay additives, such as bentonites, can bind aflatoxins in ingested feed and reduce or eliminate the toxicity. Bentonite deposits are found throughout the world and mostly consist of expandable smectite minerals, such as montmorillonite. The surfaces of smectite minerals can be treated with organic compounds to create surface-modified clays that more readily bind some contaminants than the untreated clay. Montmorillonites treated with organic cations, such as hexadecyltrimethylammonium (HDTMA) and phenyltrimethylammonium (PTMA), more effectively remove organic contaminants, such as benzene and toluene, from water than untreated clay. Similarly, montmorillonite treated with PTMA (Kd = 24,100) retained more aflatoxin B1 (AfB1) from aqueous corn flour than untreated montmorillonite (Kd = 944). Feed additives that reduced aflatoxin toxicity in animal feeding studies adsorbed more AfB1 from aqueous corn flour than feed additives that were less effective. The organic cations HDTMA and PTMA are considered toxic and would not be suitable for clay additives used in feed or food, but other non-toxic or nutrient compounds can be used to prepare surface-modified clays. Montmorillonite (SWy) treated with choline (Kd = 13,800) and carnitine (Kd = 3960) adsorbed much more AfB1 from aqueous corn flour than the untreated clay (Kd = 944). A choline-treated clay prepared from a reduced-charge, high-charge montmorillonite (Kd = 20,100) adsorbed more AfB1 than the choline-treated high-charge montmorillonite (Kd = 1340) or the untreated montmorillonite (Kd = 293). Surface-modified clay additives prepared using low-charge smectites and nutrient or non-toxic organic compounds might be used to more effectively bind aflatoxins in contaminated feed or food and prevent toxicity. PMID:22069725

Aflatoxin toxicity reduction in feed by enhanced binding to surface-modified clay additives.

PubMed

Jaynes, William F; Zartman, Richard E

2011-06-01

Animal feeding studies have demonstrated that clay additives, such as bentonites, can bind aflatoxins in ingested feed and reduce or eliminate the toxicity. Bentonite deposits are found throughout the world and mostly consist of expandable smectite minerals, such as montmorillonite. The surfaces of smectite minerals can be treated with organic compounds to create surface-modified clays that more readily bind some contaminants than the untreated clay. Montmorillonites treated with organic cations, such as hexadecyltrimethylammonium (HDTMA) and phenyltrimethylammonium (PTMA), more effectively remove organic contaminants, such as benzene and toluene, from water than untreated clay. Similarly, montmorillonite treated with PTMA (K(d) = 24,100) retained more aflatoxin B1 (AfB1) from aqueous corn flour than untreated montmorillonite (K(d) = 944). Feed additives that reduced aflatoxin toxicity in animal feeding studies adsorbed more AfB1 from aqueous corn flour than feed additives that were less effective. The organic cations HDTMA and PTMA are considered toxic and would not be suitable for clay additives used in feed or food, but other non-toxic or nutrient compounds can be used to prepare surface-modified clays. Montmorillonite (SWy) treated with choline (K(d) = 13,800) and carnitine (K(d) = 3960) adsorbed much more AfB1 from aqueous corn flour than the untreated clay (K(d) = 944). A choline-treated clay prepared from a reduced-charge, high-charge montmorillonite (K(d) = 20,100) adsorbed more AfB1 than the choline-treated high-charge montmorillonite (K(d) = 1340) or the untreated montmorillonite (K(d) = 293). Surface-modified clay additives prepared using low-charge smectites and nutrient or non-toxic organic compounds might be used to more effectively bind aflatoxins in contaminated feed or food and prevent toxicity.

Adaptation of High-Throughput Screening in Drug Discovery—Toxicological Screening Tests

PubMed Central

Szymański, Paweł; Markowicz, Magdalena; Mikiciuk-Olasik, Elżbieta

2012-01-01

High-throughput screening (HTS) is one of the newest techniques used in drug design and may be applied in biological and chemical sciences. This method, due to utilization of robots, detectors and software that regulate the whole process, enables a series of analyses of chemical compounds to be conducted in a short time and the affinity of biological structures which is often related to toxicity to be defined. Since 2008 we have implemented the automation of this technique and as a consequence, the possibility to examine 100,000 compounds per day. The HTS method is more frequently utilized in conjunction with analytical techniques such as NMR or coupled methods e.g., LC-MS/MS. Series of studies enable the establishment of the rate of affinity for targets or the level of toxicity. Moreover, researches are conducted concerning conjugation of nanoparticles with drugs and the determination of the toxicity of such structures. For these purposes there are frequently used cell lines. Due to the miniaturization of all systems, it is possible to examine the compound’s toxicity having only 1–3 mg of this compound. Determination of cytotoxicity in this way leads to a significant decrease in the expenditure and to a reduction in the length of the study. PMID:22312262

Fluorescent Chemosensors for Toxic Organophosphorus Pesticides: A Review

PubMed Central

Obare, Sherine O.; De, Chandrima; Guo, Wen; Haywood, Tajay L.; Samuels, Tova A.; Adams, Clara P.; Masika, Noah O.; Murray, Desmond H.; Anderson, Ginger A.; Campbell, Keith; Fletcher, Kenneth

2010-01-01

Many organophosphorus (OP) based compounds are highly toxic and powerful inhibitors of cholinesterases that generate serious environmental and human health concerns. Organothiophosphates with a thiophosphoryl (P=S) functional group constitute a broad class of these widely used pesticides. They are related to the more reactive phosphoryl (P=O) organophosphates, which include very lethal nerve agents and chemical warfare agents, such as, VX, Soman and Sarin. Unfortunately, widespread and frequent commercial use of OP-based compounds in agricultural lands has resulted in their presence as residues in crops, livestock, and poultry products and also led to their migration into aquifers. Thus, the design of new sensors with improved analyte selectivity and sensitivity is of paramount importance in this area. Herein, we review recent advances in the development of fluorescent chemosensors for toxic OP pesticides and related compounds. We also discuss challenges and progress towards the design of future chemosensors with dual modes for signal transduction. PMID:22163587

Fluorescent chemosensors for toxic organophosphorus pesticides: a review.

PubMed

Obare, Sherine O; De, Chandrima; Guo, Wen; Haywood, Tajay L; Samuels, Tova A; Adams, Clara P; Masika, Noah O; Murray, Desmond H; Anderson, Ginger A; Campbell, Keith; Fletcher, Kenneth

2010-01-01

Many organophosphorus (OP) based compounds are highly toxic and powerful inhibitors of cholinesterases that generate serious environmental and human health concerns. Organothiophosphates with a thiophosphoryl (P=S) functional group constitute a broad class of these widely used pesticides. They are related to the more reactive phosphoryl (P=O) organophosphates, which include very lethal nerve agents and chemical warfare agents, such as, VX, Soman and Sarin. Unfortunately, widespread and frequent commercial use of OP-based compounds in agricultural lands has resulted in their presence as residues in crops, livestock, and poultry products and also led to their migration into aquifers. Thus, the design of new sensors with improved analyte selectivity and sensitivity is of paramount importance in this area. Herein, we review recent advances in the development of fluorescent chemosensors for toxic OP pesticides and related compounds. We also discuss challenges and progress towards the design of future chemosensors with dual modes for signal transduction.

Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes.

PubMed

Zhang, Xiangming; Liu, Huijuan; Sun, Bo; Sun, Yan; Zhong, Weilong; Liu, Yanrong; Chen, Shuang; Ling, Honglei; Zhou, Lei; Jing, Xiangyan; Qin, Yuan; Xiao, Ting; Sun, Tao; Zhou, Honggang; Yang, Cheng

2016-11-17

Peroxisome proliferator-activated receptor γ (PPARγ) is recognized as a key regulator of insulin resistance. In this study, we searched for novel PPARγ agonists in a library of structurally diverse organic compounds and determined that podophyllotoxin exhibits partial agonist activity toward PPARγ. Eight novel podophyllotoxin-like derivatives were synthesized and assayed for toxicity and functional activity toward PPARγ to reduce the possible systemic toxic effects of podophyllotoxin and to maintain partial agonist activity toward PPARγ. Cell-based transactivation assays showed that compounds (E)-3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-4-(4(trifluoromethyl)styryl)dihydrofuran-2(3H)-one (3a) and (E)-4-(3-acetylstyryl)-3-(hydroxyl (3,4,5-trimethoxyphenyl)methyl)dihydrofuran-2(3H)-one (3f) exhibited partial agonist activity. An experiment using human hepatocarcinoma cells (HepG2) that were induced to become an insulin-resistant model showed that compounds 3a and 3f improved insulin sensitivity and glucose consumption. In addition, compounds 3a and 3f significantly improved hyperglycemia and insulin resistance in high-fat diet-fed streptozotocin (HFD-STZ)-induced type 2 diabetic rats at a dose of 15 mg/kg/day administered orally for 45 days, without significant weight gain. Cell toxicity testing also showed that compounds 3a and 3f exhibited weaker toxicity than pioglitazone. These findings suggested that compounds 3a and 3f improved insulin resistance in vivo and in vitro and that the compounds exhibited potential for the treatment of type 2 diabetes mellitus.

DETECTION OF TOXICANT(S) ON BUILDING SURFACES FOLLOWING CHEMICAL ATTACK

EPA Science Inventory

A critical step prior to reoccupation of any facility following a chemical attack is monitoring for toxic compounds on surfaces within that facility. Low level detection of toxicant(s) is necessary to ensure that these compounds have been eliminated after building decontaminatio...

Organochlorine pesticides, their toxic effects on living organisms and their fate in the environment

PubMed Central

Megha, Pankajshan; Sreedev, Puthur

2016-01-01

Organochlorine (OC) pesticides are synthetic pesticides widely used all over the world. They belong to the group of chlorinated hydrocarbon derivatives, which have vast application in the chemical industry and in agriculture. These compounds are known for their high toxicity, slow degradation and bioaccumulation. Even though many of the compounds which belong to OC were banned in developed countries, the use of these agents has been rising. This concerns particularly abuse of these chemicals which is in practice across the continents. Though pesticides have been developed with the concept of target organism toxicity, often non-target species are affected badly by their application. The purpose of this review is to list the major classes of pesticides, to understand organochlorine pesticides based on their activity and persistence, and also to understand their biochemical toxicity. PMID:28652852

The U.S. EPA's ToxCast Chemical Screening Program and Predictive Modeling of Toxicity

EPA Science Inventory

The ToxCast program was developed by the U.S. EPA's National Center for Computational Toxicology to provide cost-effective high-throughput screening for the potential toxicity of thousands of chemicals. Phase I screened 309 compounds in over 500 assays to evaluate concentration-...

Building predictive models of developmental toxicity from ToxRefDB and ToxCast

EPA Science Inventory

EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that are highly correlated with observed in vivo toxicity. We hypothesize that cell signaling pathways underlying development are primary targets f...

Toward antituberculosis drugs: in silico screening of synthetic compounds against Mycobacterium tuberculosisl,d-transpeptidase 2.

PubMed

Billones, Junie B; Carrillo, Maria Constancia O; Organo, Voltaire G; Macalino, Stephani Joy Y; Sy, Jamie Bernadette A; Emnacen, Inno A; Clavio, Nina Abigail B; Concepcion, Gisela P

2016-01-01

Mycobacterium tuberculosis (Mtb) the main causative agent of tuberculosis, is the main reason why this disease continues to be a global public health threat. It is therefore imperative to find a novel antitubercular drug target that is unique to the structural machinery or is essential to the growth and survival of the bacterium. One such target is the enzyme l,d-transpeptidase 2, also known as LdtMt2, a protein primarily responsible for the catalysis of 3→3 cross-linkages that make up the mycolyl-arabinogalactan-peptidoglycan complex of Mtb. In this study, structure-based pharmacophore screening, molecular docking, and in silico toxicity evaluations were employed in screening compounds from a database of synthetic compounds. Out of the 4.5 million database compounds, 18 structures were identified as high-scoring, high-binding hits with very satisfactory absorption, distribution, metabolism, excretion, and toxicity properties. Two out of the 18 compounds were further subjected to in vitro bioactivity assays, with one exhibiting a good inhibitory activity against the Mtb H37Ra strain.

Mechanism Profiling of Hepatotoxicity Caused by Oxidative Stress Using Antioxidant Response Element Reporter Gene Assay Models and Big Data.

PubMed

Kim, Marlene Thai; Huang, Ruili; Sedykh, Alexander; Wang, Wenyi; Xia, Menghang; Zhu, Hao

2016-05-01

Hepatotoxicity accounts for a substantial number of drugs being withdrawn from the market. Using traditional animal models to detect hepatotoxicity is expensive and time-consuming. Alternative in vitro methods, in particular cell-based high-throughput screening (HTS) studies, have provided the research community with a large amount of data from toxicity assays. Among the various assays used to screen potential toxicants is the antioxidant response element beta lactamase reporter gene assay (ARE-bla), which identifies chemicals that have the potential to induce oxidative stress and was used to test > 10,000 compounds from the Tox21 program. The ARE-bla computational model and HTS data from a big data source (PubChem) were used to profile environmental and pharmaceutical compounds with hepatotoxicity data. Quantitative structure-activity relationship (QSAR) models were developed based on ARE-bla data. The models predicted the potential oxidative stress response for known liver toxicants when no ARE-bla data were available. Liver toxicants were used as probe compounds to search PubChem Bioassay and generate a response profile, which contained thousands of bioassays (> 10 million data points). By ranking the in vitro-in vivo correlations (IVIVCs), the most relevant bioassay(s) related to hepatotoxicity were identified. The liver toxicants profile contained the ARE-bla and relevant PubChem assays. Potential toxicophores for well-known toxicants were created by identifying chemical features that existed only in compounds with high IVIVCs. Profiling chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources. Kim MT, Huang R, Sedykh A, Wang W, Xia M, Zhu H. 2016. Mechanism profiling of hepatotoxicity caused by oxidative stress using antioxidant response element reporter gene assay models and big data. Environ Health Perspect 124:634-641; http://dx.doi.org/10.1289/ehp.1509763.

Mechanism Profiling of Hepatotoxicity Caused by Oxidative Stress Using Antioxidant Response Element Reporter Gene Assay Models and Big Data

PubMed Central

Kim, Marlene Thai; Huang, Ruili; Sedykh, Alexander; Wang, Wenyi; Xia, Menghang; Zhu, Hao

2015-01-01

Background: Hepatotoxicity accounts for a substantial number of drugs being withdrawn from the market. Using traditional animal models to detect hepatotoxicity is expensive and time-consuming. Alternative in vitro methods, in particular cell-based high-throughput screening (HTS) studies, have provided the research community with a large amount of data from toxicity assays. Among the various assays used to screen potential toxicants is the antioxidant response element beta lactamase reporter gene assay (ARE-bla), which identifies chemicals that have the potential to induce oxidative stress and was used to test > 10,000 compounds from the Tox21 program. Objective: The ARE-bla computational model and HTS data from a big data source (PubChem) were used to profile environmental and pharmaceutical compounds with hepatotoxicity data. Methods: Quantitative structure–activity relationship (QSAR) models were developed based on ARE-bla data. The models predicted the potential oxidative stress response for known liver toxicants when no ARE-bla data were available. Liver toxicants were used as probe compounds to search PubChem Bioassay and generate a response profile, which contained thousands of bioassays (> 10 million data points). By ranking the in vitro–in vivo correlations (IVIVCs), the most relevant bioassay(s) related to hepatotoxicity were identified. Results: The liver toxicants profile contained the ARE-bla and relevant PubChem assays. Potential toxicophores for well-known toxicants were created by identifying chemical features that existed only in compounds with high IVIVCs. Conclusion: Profiling chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources. Citation: Kim MT, Huang R, Sedykh A, Wang W, Xia M, Zhu H. 2016. Mechanism profiling of hepatotoxicity caused by oxidative stress using antioxidant response element reporter gene assay models and big data. Environ Health Perspect 124:634–641; http://dx.doi.org/10.1289/ehp.1509763 PMID:26383846

Tandem screening of toxic compounds on GFP-labeled bacteria and cancer cells in microtiter plates.

PubMed

Montoya, Jessica; Varela-Ramirez, Armando; Shanmugasundram, Muthian; Martinez, Luis E; Primm, Todd P; Aguilera, Renato J

2005-09-23

A 96-well fluorescence-based assay has been developed for the rapid screening of potential cytotoxic and bacteriocidal compounds. The assay is based on detection of green fluorescent protein (GFP) in HeLa human carcinoma cells as well as gram negative (Escherichia coli) and gram positive bacteria (Mycobacterium avium). Addition of a toxic compound to the GFP marked cells resulted in the loss of the GFP fluorescence which was readily detected by fluorometry. Thirty-nine distinct naphthoquinone derivatives were screened and several of these compounds were found to be toxic to all cell types. Apart from differences in overall toxicity, two general types of toxic compounds were detected, those that exhibited toxicity to two or all three of the cell types and those that were primarily toxic to the HeLa cells. Our results demonstrate that the parallel screening of both eukaryotic and prokaryotic cells is not only feasible and reproducible but also cost effective.

Synthesis and structure-activity relationship of di-(3, 8-diazabicyclo[3.2.1]octane) diquaternary ammonium salts as unique analgesics.

PubMed

Liu, Hong; Cheng, Tie-Ming; Zhang, Hong-Mei; Li, Run-Tao

2003-11-01

Based on the structure characteristics of the lead compounds, 1, 1' octanedioyl-4, 4'-dimethyl-4, 4'-dibenzyl dipiperazinium dibromide (2) and 3, 8-disubstituted-3, 8-diazabicyclo [3.2.1]octanes (DBO), di-(3, 8-diazabicyclo [3.2.1]octane) diquaternary ammonium salts 3 a-c were designed and synthesized through a highly practical procedure. Target compounds 3 a-c and the hydrochloride salts of their precursors 10 a-c were evaluated for their in vivo analgesic and sedative activities. Interestingly, the introduction of an endoethylenic bridge in the piperazine of lead compound 2 causes loss of the analgesic activity and increases the toxicity dramatically. This result shows that the flexible conformation of piperazine in compound 2 is favorable for interaction with the receptor, and the quaternization of compounds 10 a-c is the main reason for the toxicity increase.

Inhibitory effects of toxic compounds on nitrification process for cokes wastewater treatment.

PubMed

Kim, Young Mo; Park, Donghee; Lee, Dae Sung; Park, Jong Moon

2008-04-15

Cokes wastewater is one of the most toxic industrial effluents since it contains high concentrations of toxic compounds such as phenols, cyanides and thiocyanate. Although activated sludge process has been adapted to treat this wastewater, nitrification process has been occasionally upset by serious inhibitory effects of toxic compounds. In this study, therefore, we examined inhibitory effects of ammonia, thiocyanate, free cyanide, ferric cyanide, phenol and p-cresol on nitrification in an activated sludge system, and then correlated their threshold concentrations with the full-scale pre-denitrification process for treating cokes wastewater. Ammonia below 350 mg/L did not cause substrate inhibition for nitrifying bacteria. Thiocyanate above 200mg/L seemed to inhibit nitrification, but it was due to the increased loading of ammonia produced from its biodegradation. Free cyanide above 0.2mg/L seriously inhibited nitrification, but ferric cyanide below 100mg/L did not. Phenol and p-cresol significantly inhibited nitrification above 200 mg/L and 100mg/L, respectively. Meantime, activated carbon was added to reduce inhibitory effects of phenol and free cyanide.

Acute Oral Toxicity Evaluations of Some Zinc(II) Complexes Derived from 1-(2-Salicylaldiminoethyl)piperazine Schiff Bases in Rats

PubMed Central

Salga, Muhammad Saleh; Ali, Hapipah Mohd; Abdulla, Mahmood Ameen; Abdelwahab, Siddig Ibrahim

2012-01-01

The current study described the synthesis and the in vivo acute oral toxicity evaluations in Sprague Dawley rats. The compounds were characterized by elemental analyses, LC-MS, FTIR, 1H NMR, 13C NMR and UV-visible spectroscopy. In the acute toxicity study, a single administration of the compounds was performed orally to the rats at the single doses of 2000 mg/kg and they were then monitored for possible side effects, mortality or behavioral changes up to 14 days. The serum level of aspartate (AST), alanine aminotransferases (ALT), alkaline phosphate (ALP), triglyceride, high density lipoprotein (HDL), immunoglobulins (GAM) and the C-reactive proteins did not significantly change. The hematological indices white blood cells (WBC), haematocrit (HCT), red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), and mean corpuscular hemoglobin (MCH) were within the normal range. The renal function indices examined were also within the reference range. Generally, the compounds exhibited low toxic effects as required for further in vivo therapeutic studies. PMID:22408397

Organic waste compounds in streams: Occurrence and aquatic toxicity in different stream compartments, flow regimes, and land uses in southeast Wisconsin, 2006–9

USGS Publications Warehouse

Baldwin, Austin K.; Corsi, Steven R.; Richards, Kevin D.; Geis, Steven W.; Magruder, Christopher

2013-01-01

An assessment of organic chemicals and aquatic toxicity in streams located near Milwaukee, Wisconsin, indicated high potential for adverse impacts on aquatic organisms that could be related to organic waste compounds (OWCs). OWCs used in agriculture, industry, and households make their way into surface waters through runoff, leaking septic-conveyance systems, regulated and unregulated discharges, and combined sewage overflows, among other sources. Many of these compounds are toxic at elevated concentrations and (or) known to have endocrine-disrupting potential, and often they occur as complex mixtures. There is still much to be learned about the chronic exposure effects of these compounds on aquatic populations. During 2006–9, the U.S. Geological Survey, in cooperation with the Milwaukee Metropolitan Sewerage District (MMSD), conducted a study to determine the occurrence and potential toxicity of OWCs in different stream compartments and flow regimes for streams in the Milwaukee area. Samples were collected at 17 sites and analyzed for a suite of 69 OWCs. Three types of stream compartments were represented: water column, streambed pore water, and streambed sediment. Water-column samples were subdivided by flow regime into stormflow and base-flow samples. One or more compounds were detected in all 196 samples collected, and 64 of the 69 compounds were detected at least once. Base-flow samples had the lowest detection rates, with a median of 12 compounds detected per sample. Median detection rates for stormflow, pore-water, and sediment samples were more than double that of base-flow samples. Compounds with the highest detection rates include polycyclic aromatic hydrocarbons (PAHs), insecticides, herbicides, and dyes/pigments. Elevated occurrence and concentrations of some compounds were detected in samples from urban sites, as compared with more rural sites, especially during stormflow conditions. These include the PAHs and the domestic waste-water-indicator compounds, among others. Urban runoff and storm-related leaks of sanitary sewers and (or) septic systems may be important sources of these and other compounds to the streams. The Kinnickinnic River, a highly urbanized site, had the highest detection rates and concentrations of compounds of all the sampled sites. The Milwaukee River near Cedarburg—one of the least urban sites—and the Outer Milwaukee Harbor site had the lowest detection rates and concentrations. Aquatic-toxicity benchmarks were exceeded for 12 of the 25 compounds with known benchmarks. The compounds with the greatest benchmark exceedances were the PAHs, both in terms of exceedance frequency (up to 93 percent for some compounds in sediment samples) and magnitude (concentrations up to 1,024 times greater than the benchmark value). Other compounds with toxicity-benchmark exceedances include Bis(2-ethylhexyl) phthalate (a plasticizer), 2-Methylnapthalene (a component of fuel and oil), phenol (an antimicrobial disinfectant with diverse uses), and 4-Nonylphenol (sum of all isomers; a detergent metabolite, among other uses). Analyzed as a mixture, the suite of PAH compounds were found to be potentially toxic for most non-base-flow samples. Bioassay tests were conducted on samples from 14 streams: Ceriodaphnia dubia in base-flow samples, Ceriodaphnia dubia and Hyallela azteca in pore-water samples, and Hyallela azteca and Chironomus tentans in sediment samples. The greatest adverse effect was observed in tests with Chironomus tentans from sediment samples. The weight of Chironomus tentans after exposure to sediments decreased with increased OWC concentrations. This was most evident in the relation between PAH results and Chironomus tentans bioassay results for the majority of samples; however, solvents and flame retardants appeared to be important for one site each. These results for PAHs were consistent with assessment of PAH potency factors for sediment, indicating that PAHs were likely to have adverse effects on aquatic organisms in many of the streams studied.

Human exposure, biomarkers, and fate of organotins in the environment.

PubMed

Okoro, Hussein K; Fatoki, Olalekan S; Adekola, Folahan A; Ximba, Bhekumusa J; Snyman, Reinette G; Opeolu, Beatrice

2011-01-01

Organotin compounds result from the addition of organic moieties to inorganic tin.Thus, one or more tin-carbon bonds exist in each organotin molecule. The organo-tin compounds are ubiquitous in the environment. Organotin compounds have many uses, including those as fungicides and stabilizers in plastics, among others in industry. The widespread use of organotins as antifouling agents in boat paints has resulted in pollution of freshwater and marine ecosystems. The presence of organotin compounds in freshwater and marine ecosystems is now understood to be a threat, because of the amounts found in water and the toxicity of some organotin compounds to aquatic organisms, and perhaps to humans as well. Organotin com-pounds are regarded by many to be global pollutants of a stature similar to biphenyl,mercury, and the polychlorinated dibenzodioxins. This stature results from the high toxicity, persistence, bioaccumulation, and endocrine disruptive features of even very low levels of selected organotin compounds.Efforts by selected governmental agencies and others have been undertaken to find a global solution to organotin pollution. France was the first country to ban the use of the organotins in 1980. This occurred before the international maritime organization (IMO) called for a global treaty to ban the application of tributyltin (TBT)-based paints. In this chapter, we review the organotin compounds with emphasis on the human exposure, fate, and distribution of them in the environment. The widespread use of the organotins and their high stability have led to contamination of some aquatic ecosystems. As a result, residues of the organotins may reach humans via food consumption. Notwithstanding the risk of human exposure, only limited data are available on the levels at which the organotins exist in foodstuffs consumed by humans. Moreover, the response of marine species to the organotins, such as TBT, has not been thoroughly investigated. Therefore, more data on the organotins and the consequences of exposure to them are needed. In particular, we believe the following areas need attention: expanded toxicity testing in aquatic species, human exposure, human body burdens, and the research to identify biomarkers for testing the toxicity of the organotins to marine invertebrates.

Plant-Associated Bacterial Degradation of Toxic Organic Compounds in Soil

PubMed Central

McGuinness, Martina; Dowling, David

2009-01-01

A number of toxic synthetic organic compounds can contaminate environmental soil through either local (e.g., industrial) or diffuse (e.g., agricultural) contamination. Increased levels of these toxic organic compounds in the environment have been associated with human health risks including cancer. Plant-associated bacteria, such as endophytic bacteria (non-pathogenic bacteria that occur naturally in plants) and rhizospheric bacteria (bacteria that live on and near the roots of plants), have been shown to contribute to biodegradation of toxic organic compounds in contaminated soil and could have potential for improving phytoremediation. Endophytic and rhizospheric bacterial degradation of toxic organic compounds (either naturally occurring or genetically enhanced) in contaminated soil in the environment could have positive implications for human health worldwide and is the subject of this review. PMID:19742157

Microbial toxicity and biodegradability of perfluorooctane sulfonate (PFOS) and shorter chain perfluoroalkyl and polyfluoroalkyl substances (PFASs).

PubMed

Ochoa-Herrera, Valeria; Field, Jim A; Luna-Velasco, Antonia; Sierra-Alvarez, Reyes

2016-09-14

Perfluorooctane sulfonate (PFOS) and related perfluoroalkyl and polyfluoroalkyl substances (PFASs) are emerging contaminants that have been widely applied in consumer and industrial applications for decades. However, PFOS has raised public concern due to its high bioaccumulative character, environmental persistence, and toxicity. Shorter PFASs such as perfluorobutane sulfonate (PFBS) and polyfluoroalkyl compounds have been proposed as alternatives to PFOS but it is unclear whether these fluorinated substances pose a risk for public health and the environment. The objective of this research was to investigate the microbial toxicity and the susceptibility to microbial degradation of PFOS and several related fluorinated compounds, i.e., short-chain perfluoroalkyl and polyfluoroalkyl sulfonic and carboxylic acids. None of the compounds tested were toxic to the methanogenic activity of anaerobic wastewater sludge even at very high concentrations (up to 500 mg L -1 ). All PFASs evaluated were highly resistant to microbial degradation. PFOS was not reductively dehalogenated by the anaerobic microbial consortium even after very long periods of incubation (3.4 years). Similarly, the tested short chain perfluoroalkyl substances (i.e., PFBS and trifluoroacetic acid) and a polyfluoroalkyl PFOS analogue, 6 : 2 fluorotelomer sulfonic acid (FTSA) were also resistant to anaerobic biodegradation. Likewise, no conclusive evidence of microbial degradation was observed under aerobic conditions for any of the short-chain perfluoroalkyl and polyfluoroalkyl carboxylic acids tested after 32 weeks of incubation. Collectively, these results indicate that PFOS and its alternatives such as short chain perfluoroalkyl sulfonates and carboxylates and their polyfluorinated homologues are highly resistant to microbial degradation.

NMR-based urine analysis in rats: prediction of proximal tubule kidney toxicity and phospholipidosis.

PubMed

Lienemann, Kai; Plötz, Thomas; Pestel, Sabine

2008-01-01

The aim of safety pharmacology is early detection of compound-induced side-effects. NMR-based urine analysis followed by multivariate data analysis (metabonomics) identifies efficiently differences between toxic and non-toxic compounds; but in most cases multiple administrations of the test compound are necessary. We tested the feasibility of detecting proximal tubule kidney toxicity and phospholipidosis with metabonomics techniques after single compound administration as an early safety pharmacology approach. Rats were treated orally, intravenously, inhalatively or intraperitoneally with different test compounds. Urine was collected at 0-8 h and 8-24 h after compound administration, and (1)H NMR-patterns were recorded from the samples. Variation of post-processing and feature extraction methods led to different views on the data. Support Vector Machines were trained on these different data sets and then aggregated as experts in an Ensemble. Finally, validity was monitored with a cross-validation study using a training, validation, and test data set. Proximal tubule kidney toxicity could be predicted with reasonable total classification accuracy (85%), specificity (88%) and sensitivity (78%). In comparison to alternative histological studies, results were obtained quicker, compound need was reduced, and very importantly fewer animals were needed. In contrast, the induction of phospholipidosis by the test compounds could not be predicted using NMR-based urine analysis or the previously published biomarker PAG. NMR-based urine analysis was shown to effectively predict proximal tubule kidney toxicity after single compound administration in rats. Thus, this experimental design allows early detection of toxicity risks with relatively low amounts of compound in a reasonably short period of time.

The effects of plant essential oils on escape response and mortality rate of Aedes aegypti and Anopheles minimus.

PubMed

Sathantriphop, Sunaiyana; Achee, Nicole L; Sanguanpong, Unchalee; Chareonviriyaphap, Theeraphap

2015-12-01

The High Throughput Screening System (HITSS) has been applied in insecticide behavioral response studies with various mosquito species. In general, chemical or natural compounds can produce a range of insect responses: contact irritancy, spatial repellency, knock-down, and toxicity. This study characterized these actions in essential oils derived from citronella, hairy basil, catnip, and vetiver in comparison to DEET and picaridin against Aedes aegypti and Anopheles minimus mosquito populations. Results indicated the two mosquito species exhibited significantly different (P<0.05) contact irritant escape responses between treatment and control for all tested compound concentrations, except with the minimum dose of picaridin (P>0.05) against Ae. aegypti. Spatial repellency responses were elicited in both mosquito species when exposed to all compounds, but the strength of the repellent response was dependent on compound and concentration. Data show that higher test concentrations had greatest toxic effects on both mosquito populations, but vetiver had no toxic effect on Ae. aegypti and picaridin did not elicit toxicity in either Ae. aegypti or An. minimus at any test concentration. Ultimately, this study demonstrates the ability of the HITSS assay to guide selection of effective plant essential oils for repelling, irritating, and killing mosquitoes. © 2015 The Society for Vector Ecology.

Heavy Metals in ToxCast: Relevance to Food Safety (SOT) ...

EPA Pesticide Factsheets

Human exposure to heavy metals occurs through food contamination due to industrial processes, vehicle emissions and farming methods. Specific toxicity endpoints have been associated with metal exposures, e.g. lead and neurotoxicity; however, numerous varieties of heavy metals have not been systematically examined for potential toxicities. We describe results from testing a large set of heavy metal-containing compounds in extensive suites of in vitro assays to suggest possible molecular initiating events in toxicity pathways. A broad definition of heavy metals that includes As, Se and organometallics or inorganic salts containing metals in Group III or higher (MW > 40) was used to identify 75 different compounds tested in the EPA’s ToxCast assays encompassing biochemical, cellular and model organism assays. These 75, plus an additional 100 metal-containing compounds, were tested in Tox21 quantitative high-throughput screening (qHTS) assays covering nuclear receptor and stress pathways. Known activities were confirmed such as activation of stress pathways and nuclear receptors (RXR, PPARg) as well as overt cytotoxicity. Specifically, organotin and organomercury were among the most potent of over 8K chemicals tested. The HTS results support known toxicities, including promiscuous GPCR activity for mercury compounds consistent with the neuropsychiatric effects seen in mercury poisoning (Mad Hatter’s Syndrome). As such, HTS approaches provide an efficient method

Mixtures of diflubenzuron and p-chloroaniline changes the activities of enzymes biomarkers on tilapia fish (Oreochromis niloticus) in the presence and absence of soil.

PubMed

Dantzger, Darlene D; Jonsson, Claudio M; Aoyama, Hiroshi

2018-02-01

The insecticide Diflubenzuron (DFB), used by many fish farming, when metabolized or degraded produces the extremely toxic compound p-chloroaniline (PCA). Once in the aquatic environment, these compounds can form mixtures and their bioavailability depends on factors such as the presence of soil. The toxic effects of the isolated compounds and their mixtures in the proportions: 75%, 50%, and 25% of PCA were analyzed in tilapia (Oreochromis niloticus) in the presence and absence of soil after 96h. The enzymes catalase (CAT), acid (AcP) and alkaline (AlP) phosphatases and alanine (ALT) and aspartate (AST) aminotransferases of the liver of the tilapia (Oreochromis niloticus) were used as biomarkers. DFB and the mixture containing 75% of this compound did not present high toxicity to fish; however, 25mg/L of PCA alone and 15mg/L of the mixture with 75% of this compound promoted 50% mortality of tilapia (Oreochromis niloticus). In the presence of soil, these toxicity values decreased to 37 and 25mg/L, respectively. Independent of the presence of soil, a synergistic effect was observed when the proportion of PCA was 75% and to the mixture, with 25% PCA was observed the antagonistic effect. Different concentrations of the compounds and their mixtures induced CAT activity independently of the presence of soil. Additionally, increases in phosphatases and transaminases activities were observed. In some cases, the enzymes also had their activities decreased and the dose-dependence effects were not observed. This research showed that the presence of soil influenced the toxicity of the compounds but not altered interaction type among them. Diflubenzuron, p-chloroaniline, and mixtures thereof caused disorders in enzymes important for the health of tilapia (Oreochromis niloticus). Copyright © 2017 Elsevier Inc. All rights reserved.

Development of marine toxicity data for ordnance compounds

USGS Publications Warehouse

Nipper, M.; Carr, R.S.; Biedenbach, J.M.; Hooten, R.L.; Miller, K.; Saepoff, S.

2001-01-01

A toxicity database for ordnance compounds was generated using eight compounds of concern and marine toxicity tests with five species from different phyla. Toxicity tests and endpoints included fertilization success and embryological development with the sea urchin Arbacia punctulata; zoospore germination, germling length, and cell number with the green macroalga Ulva fasciata; survival and reproductive success of the polychaete Dinophilus gyrociliatus; larvae hatching and survival with the redfish Sciaenops ocellatus; and survival of juveniles of the opossum shrimp Americamysis bahia (formerly Mysidopsis bahia). The studied ordnance compounds were 2,4- and 2,6-dinitrotoluene, 2,4,6-trinitrotoluene, 1,3-dinitrobenzene, 1,3,5-trinitrobenzene, 2,4,6-trinitrophenylmethylnitramine (tetryl), 2,4,6-trinitrophenol (picric acid), and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). The most sensitive toxicity test endpoints overall were the macroalga zoospore germination and the polychaete reproduction tests. The most toxic ordnance compounds overall were tetryl and 1,3,5-trinitrobenzene. These were also the most degradable compounds, often being reduced to very low or below-detection levels at the end of the test exposure. Among the dinitro- and trinitrotoluenes and benzenes, toxicity tended to increase with the level of nitrogenation. Picric acid and RDX were the least toxic chemicals tested overall.

Anaerobic Microbial Transformation of Aromatic Hydrocarbons and Mixtures of Aromatic Hydrocarbons and Halogenated Solvents.

DTIC Science & Technology

1992-08-25

High initial concentrations of these compounds may be toxic or inhibitory to the microflora, especially if the microorganisms have not been exposed to...these compounds before. Slow acclimation of the microflora to lower concentrations of these compounds , that occur at the outskirts of contamination...acceptors such as nitrate or sulfate may impair the capability of the microorganisms to degrade these compounds , although anaerobic respiration -- in theory

Antiviral Nucleotide Incorporation by Recombinant Human Mitochondrial RNA Polymerase Is Predictive of Increased In Vivo Mitochondrial Toxicity Risk

PubMed Central

Lin, Xiaodong; Yokokawa, Fumiaki; Sweeney, Zachary; Saunders, Oliver; Xie, Lili; Lim, Siew Pheng; Uteng, Marianne; Uehara, Kyoko; Warne, Robert; Gang, Wang; Jones, Christopher; Yendluri, Satya; Gu, Helen; Mansfield, Keith; Boisclair, Julie; Heimbach, Tycho; Catoire, Alexandre; Bracken, Kathryn; Weaver, Margaret; Moser, Heinz; Zhong, Weidong

2016-01-01

Nucleoside or nucleotide inhibitors are a highly successful class of antivirals due to selectivity, potency, broad coverage, and high barrier to resistance. Nucleosides are the backbone of combination treatments for HIV, hepatitis B virus, and, since the FDA approval of sofosbuvir in 2013, also for hepatitis C virus (HCV). However, many promising nucleotide inhibitors have advanced to clinical trials only to be terminated due to unexpected toxicity. Here we describe the in vitro pharmacology of compound 1, a monophosphate prodrug of a 2′-ethynyluridine developed for the treatment of HCV. Compound 1 inhibits multiple HCV genotypes in vitro (50% effective concentration [EC50], 0.05 to 0.1 μM) with a selectivity index of >300 (50% cytotoxic concentration [CC50], 30 μM in MT-4 cells). The active triphosphate metabolite of compound 1, compound 2, does not inhibit human α, β, or γ DNA polymerases but was a substrate for incorporation by the human mitochondrial RNA polymerase (POLRMT). In dog, the oral administration of compound 1 resulted in elevated serum liver enzymes and microscopic changes in the liver. Transmission electron microscopy showed significant mitochondrial swelling and lipid accumulation in hepatocytes. Gene expression analysis revealed dose-proportional gene signature changes linked to loss of hepatic function and increased mitochondrial dysfunction. The potential of in vivo toxicity through mitochondrial polymerase incorporation by nucleoside analogs has been previously shown. This study shows that even moderate levels of nucleotide analog incorporation by POLRMT increase the risk of in vivo mitochondrial dysfunction. Based on these results, further development of compound 1 as an anti-HCV compound was terminated. PMID:27645237

Schistosomiasis Control Using Piplartine against Biomphalaria glabrata at Different Developmental Stages

PubMed Central

Rapado, Ludmila Nakamura; Pinheiro, Alessandro de Sá; Lopes, Priscila Orechio de Moraes Victor; Fokoue, Harold Hilarion; Scotti, Marcus Tullius; Marques, Joaquim Vogt; Ohlweiler, Fernanda Pires; Borrely, Sueli Ivone; Pereira, Carlos Alberto de Bragança; Kato, Massuo Jorge; Nakano, Eliana; Yamaguchi, Lydia Fumiko

2013-01-01

Background Schistosomiasis is one of the most significant diseases in tropical countries and affects almost 200 million people worldwide. The application of molluscicides to eliminate the parasite's intermediate host, Biomphalaria glabrata, from infected water supplies is one strategy currently being used to control the disease. Previous studies have shown a potent molluscicidal activity of crude extracts from Piper species, with extracts from Piper tuberculatum being among the most active. Methods and Findings The molluscicidal activity of P. tuberculatum was monitored on methanolic extracts from different organs (roots, leaves, fruit and stems). The compounds responsible for the molluscicidal activity were identified using 1H NMR and ESIMS data and multivariate analyses, including principal component analysis and partial least squares. These results indicated that the high molluscicidal activity displayed by root extracts (LC50 20.28 µg/ml) was due to the presence of piplartine, a well-known biologically-active amide. Piplartine was isolated from P. tuberculatum root extracts, and the molluscicidal activity of this compound on adults and embryos of B. glabrata was determined. The compound displayed potent activity against all developmental stages of B. glabrata. Next, the environmental toxicity of piplartine was evaluated using the microcrustacean Daphnia similis (LC50 7.32 µg/ml) and the fish Danio rerio (1.69 µg/ml). The toxicity to these organisms was less compared with the toxicity of niclosamide, a commercial molluscicide. Conclusions The development of a new, natural molluscicide is highly desirable, particularly because the commercially available molluscicide niclosamide is highly toxic to some organisms in the environment (LC50 0.25 µg/ml to D. similis and 0.12 µg/ml to D. rerio). Thus, piplartine is a potential candidate for a natural molluscicide that has been extracted from a tropical plant species and showed less toxic to environment. PMID:23755312

The chemical nature of phenolic compounds determines their toxicity and induces distinct physiological responses in Saccharomyces cerevisiae in lignocellulose hydrolysates

PubMed Central

2014-01-01

We investigated the severity of the inhibitory effects of 13 phenolic compounds usually found in spruce hydrolysates (4-hydroxy-3-methoxycinnamaldehyde, homovanilyl alcohol, vanillin, syringic acid, vanillic acid, gallic acid, dihydroferulic acid, p-coumaric acid, hydroquinone, ferulic acid, homovanillic acid, 4-hydroxybenzoic acid and vanillylidenacetone). The effects of the selected compounds on cell growth, biomass yield and ethanol yield were studied and the toxic concentration threshold was defined for each compound. Using Ethanol Red, the popular industrial strain of Saccharomyces cerevisiae, we found the most toxic compound to be 4-hydroxy-3-methoxycinnamaldehyde which inhibited growth at a concentration of 1.8 mM. We also observed that toxicity did not generally follow a trend based on the aldehyde, acid, ketone or alcohol classification of phenolic compounds, but rather that other structural properties such as additional functional groups attached to the compound may determine its toxicity. Three distinctive growth patterns that effectively clustered all the compounds involved in the screening into three categories. We suggest that the compounds have different cellular targets, and that. We suggest that the compounds have different cellular targets and inhibitory mechanisms in the cells, also compounds who share similar pattern on cell growth may have similar inhibitory effect and mechanisms of inhibition. PMID:24949277

Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity.

PubMed

Good, James A D; Silver, Jim; Núñez-Otero, Carlos; Bahnan, Wael; Krishnan, K Syam; Salin, Olli; Engström, Patrik; Svensson, Richard; Artursson, Per; Gylfe, Åsa; Bergström, Sven; Almqvist, Fredrik

2016-03-10

The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Herein, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 ≤ 100 nM) in attenuating infectivity across multiple serovars of C. trachomatis without host cell toxicity. The lead compound 21a exhibits reduced lipophilicity versus 1 and did not affect the growth or viability of representative commensal flora at 50 μM. In microscopy studies, a highly active fluorescent analogue 37 localized inside the parasitiphorous inclusion, indicative of a specific targeting of bacterial components. In summary, we present a class of small molecules to enable the development of specific treatments for C. trachomatis.

The identification of polar organic compounds found in consumer products and their toxicological properties.

PubMed

Cooper, S D; Raymer, J H; Pellizzari, E D; Thomas, K W

1995-01-01

Exposure to volatile organic compounds (VOCs) in the indoor environment has received substantial research attention in the past several years, with the goal of better understanding the impact of such exposures on human health and well-being. Many VOCs can arise from consumer products used within the indoor environment. The VOCs emitted from five representative consumer products were collected onto Tenax-GC and subjected to thermal desorption and analysis by gas chromatography, in combination with low-resolution mass spectrometry (MS), high-resolution MS, and matrix-isolation Fourier transform infrared spectroscopy for structural characterization. An emphasis was placed on the polar organic compounds often used to provide fragrance in these products. The structures of a number of these compounds were confirmed, and an electronic literature search was carried out on them to determine any known toxic properties. The search revealed that many of the VOCs possess toxic properties when studied at acute, relatively high-level exposures. In addition, toxic effects were reported for a few of the chemicals, such as benzaldehyde, alpha-terpineol, benzyl acetate, and ethanol, at relatively low dose levels of 9-14 mg/kg. In general, the data were unclear as to the effect of chronic, low-level exposures. The widespread use of such chemicals suggests that the health effects of chronic exposures need to be determined. Validated analytical methods for the quantitative characterization of polar organic compounds at low concentrations will be required to make such work possible.

High-resolution MS and MS(n) investigation of ozone oxidation products from phenazone-type pharmaceuticals and metabolites.

PubMed

Favier, Maxime; Dewil, Raf; Van Eyck, Kwinten; Van Schepdael, Ann; Cabooter, Deirdre

2015-10-01

Phenazone-type pharmaceuticals, such as aminopyrine, metamizole, phenazone and propyphenazone, are widely used analgesics that have been detected in wastewater treatment plant effluents in μg L(-1) concentrations. Acetamido antipyrine (AAA) and formyl aminoantipyrine (FAA) - the main metabolites of aminopyrine and metamizole - have also been detected in sub μg L(-1) concentrations in environmental water bodies and in resources used to produce drinking water, suggesting their highly persistent character. In this study phenazone, propyphenazone, AAA and FAA were treated with ozone under laboratory conditions and 17 degradation products were identified by an elucidation approach based on high-resolution mass spectrometry (LTQ Orbitrap). Typical oxidation of carbon-carbon double bonds by ozone was observed among other mechanisms of ring opening. It was demonstrated that reactivity of these compounds with ozone is high (rate constants kO3 ranging from 6.5×10(4) to 2.4×10(6) M(-1) s(-1)). The toxicity of the degradation products from ozonation was estimated by quantitative structure-activity relationships (QSAR). It was shown that, when the carbon-carbon double bond is partially oxidized to an epoxy, the toxicity towards fish and daphnids is higher than that of the parent compound. By further oxidizing the molecules, a common degradation product - 1-acetyl-1-methyl-2-phenylhydrazide (AMPH) - was also found to be more toxic than its parent compounds, which is of concern since this compound has previously been reported in environmental waters. Copyright © 2015 Elsevier Ltd. All rights reserved.

Predicting Developmental Toxicity of ToxCast Phase I Chemicals Using Human Embryonic Stem Cells and Metabolomics

EPA Science Inventory

EPA’s ToxRefDB contains prenatal guideline study data from rats and rabbits for over 240 chemicals that overlap with the ToxCast in vitro high throughput screening project. A subset of these compounds were tested in Stemina Biomarker Discovery's developmental toxicity platform, a...

Quadrennial Review of Military Compensation (5th). Volume 3. Special and Incentive Pays.

DTIC Science & Technology

1984-01-01

Airlines, Inc. ..- Professional Pilot Magazine President’s Private Sector Survey Cost Control Group REHAB , Inc. "p Taylor Diving and Salvage Co...compensation to per- * 0 , sonnel performing duty involving highly toxic pesticides. Duty requiring the use of pesticides of high acute toxicity...The compounding effects of continual exposure to jumping result . in spinal disc, knee, shoulder, ankle , and general bone problems. Doctors

EFFECTS OF BENZO[A]PYRENE EXPOSURE ON A FISH POPULATION RESISTANT TO THE TOXIC EFFECTS OF DIOXIN-LIKE COMPOUNDS

EPA Science Inventory

Effects of a model polycyclic aromatic hydrocarbon (PAH) were compared in populations of the estuarine fish Fundulus heteroclitus indigenous to a reference site and one highly contaminated with polychlorinated biphenyls (PCBs) and other compounds. The fish population resident to ...

Predicting acute contact toxicity of pesticides in honeybees (Apis mellifera) through a k-nearest neighbor model.

PubMed

Como, F; Carnesecchi, E; Volani, S; Dorne, J L; Richardson, J; Bassan, A; Pavan, M; Benfenati, E

2017-01-01

Ecological risk assessment of plant protection products (PPPs) requires an understanding of both the toxicity and the extent of exposure to assess risks for a range of taxa of ecological importance including target and non-target species. Non-target species such as honey bees (Apis mellifera), solitary bees and bumble bees are of utmost importance because of their vital ecological services as pollinators of wild plants and crops. To improve risk assessment of PPPs in bee species, computational models predicting the acute and chronic toxicity of a range of PPPs and contaminants can play a major role in providing structural and physico-chemical properties for the prioritisation of compounds of concern and future risk assessments. Over the last three decades, scientific advisory bodies and the research community have developed toxicological databases and quantitative structure-activity relationship (QSAR) models that are proving invaluable to predict toxicity using historical data and reduce animal testing. This paper describes the development and validation of a k-Nearest Neighbor (k-NN) model using in-house software for the prediction of acute contact toxicity of pesticides on honey bees. Acute contact toxicity data were collected from different sources for 256 pesticides, which were divided into training and test sets. The k-NN models were validated with good prediction, with an accuracy of 70% for all compounds and of 65% for highly toxic compounds, suggesting that they might reliably predict the toxicity of structurally diverse pesticides and could be used to screen and prioritise new pesticides. Copyright © 2016 Elsevier Ltd. All rights reserved.

DETECTION OF TOXICANTS ON BUILDING SURFACES FOLLOWING CHEMICAL ATTACK

EPA Science Inventory

A critical step prior to reoccupation of any facility following a chemical attack will be the monitoring of toxic compounds on surfaces within that facility. Low level detection of toxicant(s) is necessary to ensure that these compounds have been eliminated after decontamination...

Optimal choice of pH for toxicity and bioaccumulation studies of ionizing organic chemicals.

PubMed

Rendal, Cecilie; Kusk, Kresten Ole; Trapp, Stefan

2011-11-01

It is recognized that the pH of exposure solutions can influence the toxicity and bioaccumulation of ionizing compounds. The present study investigates whether it can be considered a general rule that an ionizable compound is more toxic and more bioaccumulative when in the neutral state. Three processes were identified to explain the behavior of ionizing compounds with changing pH: the change in lipophilicity when a neutral compound becomes ionized, electrical attraction, and the ion trap. The literature was screened for bioaccumulation and toxicity tests of ionizing organic compounds performed at multiple pH levels. Toxicity and bioconcentration factors (BCFs) were higher for acids at lower pH values, whereas the opposite was true for bases. The effect of pH was most pronounced when pH - pK(a) was in the range of -1 to 3 for acids, and -3 to 1 for bases. The factor by which toxicity and BCF changed with pH was correlated with the lipophilicity of the compound (log K(OW) of the neutral compound). For both acids and bases, the correlation was positive, but it was significant only for acids. Because experimental data in the literature were limited, results were supplemented with model simulations using a dynamic flux model based on the Fick-Nernst-Planck diffusion equation known as the cell model. The cell model predicts that bases with delocalized charges may in some cases show declining bioaccumulation with increasing pH. Little information is available for amphoteric and zwitterionic compounds; however, based on simulations with the cell model, it is expected that the highest toxicity and bioaccumulation of these compounds will be found where the compounds are most neutral, at the isoelectric point. Copyright © 2011 SETAC.

Identification of compounds protective against G93A-SOD1 toxicity for the treatment of amyotrophic lateral sclerosis.

PubMed

Benmohamed, Radhia; Arvanites, Anthony C; Kim, Jinho; Ferrante, Robert J; Silverman, Richard B; Morimoto, Richard I; Kirsch, Donald R

2011-03-01

The underlying cause of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder, remains unknown. However, there is strong evidence that one pathophysiological mechanism, toxic protein misfolding and/or aggregation, may trigger motor neuron dysfunction and loss. Since the clinical and pathological features of sporadic and familial ALS are indistinguishable, all forms of the disease may be better understood and ultimately treated by studying pathogenesis and therapy in models expressing mutant forms of SOD1. We developed a cellular model in which cell death depended on the expression of G93A-SOD1, a mutant form of superoxide dismutase found in familial ALS patients that produces toxic protein aggregates. This cellular model was optimized for high throughput screening to identify protective compounds from a >50,000 member chemical library. Three novel chemical scaffolds were selected for further study following screen implementation, counter-screening and secondary testing, including studies with purchased analogs. All three scaffolds blocked SOD1 aggregation in high content screening assays and data on the optimization and further characterization of these compounds will be reported separately. These data suggest that optimization of these chemicals scaffolds may produce therapeutic candidates for ALS patients.

Structure-activity relationships for a series of compounds that inhibit aggregation of the Alzheimer's peptide, Aβ42.

PubMed

McKoy, Angela F; Chen, Jermont; Schupbach, Trudi; Hecht, Michael H

2014-11-01

Inhibiting aggregation of the amyloid-beta (Aβ) peptide may be an effective strategy for combating Alzheimer's disease. As the high-resolution structure of the toxic Aβ aggregate is unknown, rational design of small molecule inhibitors is not possible, and inhibitors are best isolated by high-throughput screening. We applied high-throughput screening to a collection of 65,000 compounds to identify compound D737 as an inhibitor of Aβ aggregation. D737 diminished the formation of oligomers and fibrils, and reduced Aβ42-induced cytotoxicity. Most importantly, D737 increased the life span and locomotive ability of transgenic flies in a Drosophila melanogaster model of Alzheimer's disease (J Biol Chem, 287, 2012, 38992). To explore the chemical features that make D737 an effective inhibitor of Aβ42 aggregation and toxicity, we tested a small collection of eleven analogues of D737. Overall, the ability of a compound to inhibit Aβ aggregation was a good predictor of its efficacy in prolonging the life span and locomotive ability of transgenic flies expressing human Aβ42 in the central nervous system. Two compounds (D744 and D830) with fluorine substitutions on an aromatic ring were effective inhibitors of Aβ42 aggregation and increased the longevity of transgenic flies beyond that observed for the parent compound, D737. © 2014 John Wiley & Sons A/S.

Organotin compounds and aquatic bacteria: A review

NASA Astrophysics Data System (ADS)

Cooney, J. J.

1995-03-01

Organotins are toxic to microorganisms. Trisubstituted organotins (R3SnX) are considered more toxic than disubstituted (R2SnX2) or monosubstituted (RSnX3) compounds, and tetrasubstituted compounds (R4Sn) are not considered toxic. In the R3Sn series propyl-, butyl-, pentyl-, phenyl- and cyclohexyltins are the most toxic to microorganisms. Toxicity towards aerobes in the R3Sn series is related to total molecular surface area and to the octanol: water partition coefficient, Kow, which is a measure of hydrophobicity. Care must be taken when testing the toxicity of tin compounds in the laboratory, for a number of biological, chemical and physical factors can influence the apparent toxicity. Although TBT is generally the most toxic of the butyltins, there are instances where monobutyltin (MBT) is as toxic, or more toxic, than TBT to microorganisms. Thus, debutylation in the sequence TBT→DBT→MBT→Sn does not detoxity TBT for all microorganisms. Some microorganisms can methylate inorganic or organic tins under aerobic or anaerobic conditions. Methylation can also occur by chemical means and the relative contributions of biotic and abiotic mechanisms are not clear. It is difficult to isolate a pure culture which can methylate tin compounds aerobically, and it is difficult to isolate a pure culture which degrades TBT, suggesting that microbial consortiums may be involved in transformations of organotins in the aquatic environment. Methylation and debutylation alter the adsorbtivity and solubility of tin compounds; thus microorganisms can influence the environmental mobility of tin. TBT-resistant microorganisms can be isolated, and in some of them resistance to TBT can be plasmid-mediated.

A Review of the Toxicity of Compounds Found in Herbal Dietary Supplements.

PubMed

Hudson, Amy; Lopez, Elizabeth; Almalki, Ahmad J; Roe, Amy L; Calderón, Angela I

2018-07-01

Use of herbal dietary supplements by the public is common and has been happening for centuries. In the United States, the Food and Drug Administration has a limited scope of regulation over marketed herbal dietary supplements, which may contain toxic botanical compounds that pose a public health risk. While the Food and Drug Administration has made efforts to prohibit the sale of unsafe herbal dietary supplements, numerous reports have proliferated of adverse events due to these supplements. This literature review investigates bioactive plant compounds commonly used in herbal dietary supplements and their relative toxicities. Using primarily the National Library of Medicine journal database and SciFinder for current reports, 47 toxic compounds in 55 species from 46 plant families were found to demonstrate harmful effects due to hepatic, cardiovascular, central nervous system, and digestive system toxicity. This review further contributes a novel and comprehensive view of toxicity across the botanical dietary market, and investigates the toxicity of the top ten botanical dietary supplements purchased in the United States of America to gauge the exposure risk of toxicity to the public. The criteria of measuring toxicity in this review (plant compound, family, quantity, and toxicity effects) across the entire market in the United States, with special attention to those supplements whose exposure to the consumer is maximal, provides a unique contribution to the investigation of botanical supplements. Georg Thieme Verlag KG Stuttgart · New York.

Ecotoxicology of organic contaminants to amphibians

USGS Publications Warehouse

Sparling, D.W.; Sparling, Donald W.; Linder, Greg L.; Bishop, Christine A.

2000-01-01

The effects of organic contaminants on amphibians are poorly known but of considerable interest. These contaminants include the highly toxic dioxins and furans as well as PCBs, PAHs and organochlorine pesticides. Although these compounds may have lower acute toxicity than dioxins and furans, they have been implicated in several problems associated with genotoxicity, endocrine disruption, malformations and reduced growth. There is evidence that amphibian tadpoles bioaccumulate these organic compounds and may have biological concentrating factors ranging in the hundreds. This chapter reviews what is known about the effects and concentrations of organic contaminants in amphibians and provides recommendations for further research

Phenolic profile and antioxidant activity from non-toxic Mexican Jatropha curcas L. shell methanolic extracts.

PubMed

Perea-Domínguez, Xiomara Patricia; Espinosa-Alonso, Laura Gabriela; Hosseinian, Farah; HadiNezhad, Mehri; Valdez-Morales, Maribel; Medina-Godoy, Sergio

2017-03-01

Jatropha curcas seed shells are the by-product obtained during oil extraction process. Recently, its chemical composition has gained attention since its potential applications. The aim of this study was to identify phenolic compounds profile from a non-toxic J. curcas shell from Mexico, besides, evaluate J. curcas shell methanolic extract (JcSME) antioxidant activity. Free, conjugate and bound phenolics were fractionated and quantified (606.7, 193.32 and 909.59 μg/g shell, respectively) and 13 individual phenolic compounds were detected by HPLC. The radical-scavenging activity of JcSME was similar to Trolox and ascorbic acid by DPPH assay while by ABTS assay it was similar to BHT. Effective antioxidant capacity by ORAC was found (426.44 ± 53.39 μmol Trolox equivalents/g shell). The Mexican non-toxic J. curcas shell is rich in phenolic compounds with high antioxidant activity; hence, it could be considerate as a good source of natural antioxidants.

Boron-containing acids: preliminary evaluation of acute toxicity and access to the brain determined by Raman scattering spectroscopy.

PubMed

Soriano-Ursúa, Marvin A; Farfán-García, Eunice D; López-Cabrera, Yessica; Querejeta, Enrique; Trujillo-Ferrara, José G

2014-01-01

Boron-containing compounds (BCCs), particularly boron containing acids (BCAs), have become attractive moieties or molecules in drug development. It has been suggested that when functional groups with boron atoms are added to well-known drugs, the latter are conferred with greater potency and efficacy in relation to their target receptors. However, the use of BCAs in drug development is limited due to the lack of a toxicological profile. Consequently, the aim of the present study was to evaluate the acute toxicity of boric and boronic acids. Thus, a determination was made of the lethal dose (LD50) of test compounds in male CD1 mice, as well as the effective dose required to negatively affect spontaneous motor activity and to produce notable behavioral abnormalities. After treatment of animals at different doses, macroscopic observations were made from a necropsy, and Raman scattering spectroscopic studies were carried out on brain tissue samples. In general, the results show that most of the tested BCAs have very low toxicity, evidenced by the high doses required to induce notable toxic effects (greater than 100 mg/kg of body weight for all compounds, except for 3-thyenilboronic acid). Such toxic effects, presumably mediated by action on the CNS, include eye damage, gastrointestinal effects (e.g., gastric-gut dilatation and fecal retention), sedation, hypnosis and/or trembling. This preliminary toxicological profile suggests that BCAs can be considered potential therapeutic agents or moieties to be added to other compounds in the development of new drugs. Future studies are required to explore possible chronic toxicity of BCCs. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparative in vitro toxicity assessment of perfluorinated carboxylic acids.

PubMed

Mahapatra, Cecon T; Damayanti, Nur P; Guffey, Samuel C; Serafin, Jennifer S; Irudayaraj, Joseph; Sepúlveda, Maria S

2017-06-01

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are synthetic fluorinated compounds that are highly bioaccumulative and persistent organic pollutants. Perfluorooctanoic acid (PFOA), an eight-carbon chain perfluorinated carboxylic acid, was used heavily for the production of fluoropolymers, but concerns have led to its replacement by shorter carbon chain homologues such as perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid (PFBA). However, limited toxicity data exist for these substitutes. We evaluated the toxicity of PFOA, PFHxA and PFBA on a zebrafish liver cell line and investigated the effects of exposure on cell metabolism. Gross toxicity after 96 h of exposure was highest for PFOA and PFO - , while PFHxA and PFBA exhibited lower toxicity. Although the structural similarity of these compounds to fatty acids suggests the possibility of interference with the transport and metabolism of lipids, we could not detect any differential expression of peroxisome proliferator-activated receptor (ppar-α, -β and -γ), fabp3 and crot genes after 96 h exposure to up to 10 ppm of the test compounds. However, we observed localized lipid droplet accumulation only in PFBA-exposed cells. To study the effects of these compounds on cell metabolism, we conducted fluorescence lifetime imaging microscopy using naturally fluorescent biomarkers, NADH and FAD. The fluorescence lifetimes of NADH and FAD and the bound/free ratio of each of these coenzymes decreased in a dose- and carbon length-dependent manner, suggesting disruption of cell metabolism. In sum, our study revealed that PFASs with shorter carbon chains are less toxic than PFOA, and that exposure to sublethal dosage of PFOA, PFHxA or PFBA affects cell metabolism. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Validation of visualized transgenic zebrafish as a high throughput model to assay bradycardia related cardio toxicity risk candidates.

PubMed

Wen, Dingsheng; Liu, Aiming; Chen, Feng; Yang, Julin; Dai, Renke

2012-10-01

Drug-induced QT prolongation usually leads to torsade de pointes (TdP), thus for drugs in the early phase of development this risk should be evaluated. In the present study, we demonstrated a visualized transgenic zebrafish as an in vivo high-throughput model to assay the risk of drug-induced QT prolongation. Zebrafish larvae 48 h post-fertilization expressing green fluorescent protein in myocardium were incubated with compounds reported to induce QT prolongation or block the human ether-a-go-go-related gene (hERG) K⁺ current. The compounds sotalol, indapaminde, erythromycin, ofoxacin, levofloxacin, sparfloxacin and roxithromycin were additionally administrated by microinjection into the larvae yolk sac. The ventricle heart rate was recorded using the automatic monitoring system after incubation or microinjection. As a result, 14 out of 16 compounds inducing dog QT prolongation caused bradycardia in zebrafish. A similar result was observed with 21 out of 26 compounds which block hERG current. Among the 30 compounds which induced human QT prolongation, 25 caused bradycardia in this model. Thus, the risk of compounds causing bradycardia in this transgenic zebrafish correlated with that causing QT prolongation and hERG K⁺ current blockage in established models. The tendency that high logP values lead to high risk of QT prolongation in this model was indicated, and non-sensitivity of this model to antibacterial agents was revealed. These data suggest application of this transgenic zebrafish as a high-throughput model to screen QT prolongation-related cardio toxicity of the drug candidates. Copyright © 2012 John Wiley & Sons, Ltd.

Literature-based compound profiling: application to toxicogenomics.

PubMed

Frijters, Raoul; Verhoeven, Stefan; Alkema, Wynand; van Schaik, René; Polman, Jan

2007-11-01

To reduce continuously increasing costs in drug development, adverse effects of drugs need to be detected as early as possible in the process. In recent years, compound-induced gene expression profiling methodologies have been developed to assess compound toxicity, including Gene Ontology term and pathway over-representation analyses. The objective of this study was to introduce an additional approach, in which literature information is used for compound profiling to evaluate compound toxicity and mode of toxicity. Gene annotations were built by text mining in Medline abstracts for retrieval of co-publications between genes, pathology terms, biological processes and pathways. This literature information was used to generate compound-specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes after compound administration. To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with 11 hepatotoxicants. Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat aspecific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. A more detailed analysis of the keyword profiles of diethylhexylphthalate, dimethylnitrosamine and methapyrilene (MPy) showed that the differences in the keyword fingerprints of these three compounds are based upon known distinct modes of action. Visualization of MPy-linked keywords and MPy-induced genes in a literature network enabled us to construct a mode of toxicity proposal for MPy, which is in agreement with known effects of MPy in literature. Compound keyword fingerprinting based on information retrieved from literature is a powerful approach for compound profiling, allowing evaluation of compound toxicity and analysis of the mode of action.

In view of an optimal gut antifungal therapeutic strategy: an in vitro susceptibility and toxicity study testing a novel phyto-compound.

PubMed

Metugriachuk, Yussef; Kuroi, Olivia; Pavasuthipaisit, Kanok; Tsuchiya, Junji; Minelli, Emilio; Okura, Ruichi; Fesce, Edoardo; Marotta, F

2005-01-01

In view of the raising concern for gut fungal infection, the aim of the present research was to carry out a systematic in vitro study testing the antifungal activity and possible toxicity of a polygodyal-anethole compound (Kolorex) in several strains of Candida albicans and in other fungal pathogens. The in vitro susceptibility tests were carried out on 4 strains of C. albicans (C. krusei, C. lipolytica, C. tropicalis, C. utilis), Aspergillus flavus and A. fumigatus. Cultures were also analyzed by varying medium, pH and inoculum size, and a time-course killing test was carried out. In the present study the polygodyal-anethole compound showed remarkable in vitro activity against the most common fungi, which was significantly better than polygodyal alone. Moreover, such mixture compound was shown to exert its activity against a wide spectrum of fungi, including C. lipolytica and C. tropicalis, which required significantly higher MIC of polygodyal to be unfeasible in clinical application. The activity of the polygodyal-anethole compound was significantly better than polygodyal alone with high inoculum size and low pH. Moreover, it proved to exert a significantly faster biological activity against low inoculum. This study suggests that the mixture compound Kolorex has a very good profile of antifungal activity in terms of effectiveness and spectrum of action while being devoid of any significant toxicity.

Toxicity of nonylphenol diethoxylate in lab-scale anaerobic digesters.

PubMed

Bozkurt, Hande; Sanin, F Dilek

2014-06-01

Nonylphenol compounds have high commercial, industrial and domestic uses owing to their surface active properties. In addition to their toxic, carcinogenic and persistent characteristics; they have drawn the attention of scientists lately due to their endocrine disrupting properties. Their widespread use and disposal cause them to enter wastewater treatment systems at high concentrations. Since they are highly persistent and hydrophobic, they accumulate mostly on sludge. In this study using Anaerobic Toxicity Assay (ATA) tests, the toxicity of a model nonylphenol compound, nonylphenol diethoxylate (NP2EO), for anaerobic digestion of sludge was determined. The test bottles were dosed with NP2EO in acetone, with concentrations ranging from 1 mg L(-1) to 30 mg L(-1). During the tests, gas productions and compositions in terms of methane and carbon dioxide were monitored. To be able to judge about the fate, the target compounds were extracted from water and sludge and analyzed using GC/MS. The sludge samples used for assembling the reactors were found to contain NP and NP1EO but no NP2EO. After the assay was completed, all the NP2EO spiked into the live reactors was found to disappear. The increase seen in NP1EO and NP and further accumulation of NP in the system, indicated the conversion of NP2EO to these metabolites. On the other hand, no conversion was observed in abiotic reactors. Inhibition of NP2EO for anaerobic microorganisms was not observed throughout the tests considering the biogas production of the test reactors in comparison to the control reactors. Copyright © 2013 Elsevier Ltd. All rights reserved.

Improvement of ethanol productivity and energy efficiency by degradation of inhibitors using recombinant Zymomonas mobilis (pHW20a-fdh).

PubMed

Dong, Hong-Wei; Fan, Li-Qiang; Luo, Zichen; Zhong, Jian-Jiang; Ryu, Dewey D Y; Bao, Jie

2013-09-01

Toxic compounds, such as formic acid, furfural, and hydroxymethylfurfural (HMF) generated during pretreatment of corn stover (CS) at high temperature and low pH, inhibit growth of Zymomonas mobilis and lower the conversion efficiency of CS to biofuel and other products. The inhibition of toxic compounds is considered as one of the major technical barriers in the lignocellulose bioconversion. In order to detoxify and/or degrade these toxic compounds by the model ethanologenic strain Z. mobilis itself in situ the fermentation medium, we constructed a recombinant Z. mobilis ZM4 (pHW20a-fdh) strain that is capable of degrading toxic inhibitor, formate. This is accomplished by cloning heterologous formate dehydrogenase gene (fdh) from Saccharomyces cerevisiae and by coupling this reaction of NADH regeneration reaction system with furfural and HMF degradation in the recombinant Z. mobilis strain. The NADH regeneration reaction also improved both the energy efficiency and cell physiological activity of the recombinant organism, which were definitely confirmed by the improved cell growth, ethanol yield, and ethanol productivity during fermentation with CS hydrolysate. Copyright © 2013 Wiley Periodicals, Inc.

Diaryltriazine non-nucleoside reverse transcriptase inhibitors are potent candidates for pre-exposure prophylaxis in the prevention of sexual HIV transmission.

PubMed

Ariën, Kevin K; Venkatraj, Muthusamy; Michiels, Johan; Joossens, Jurgen; Vereecken, Katleen; Van der Veken, Pieter; Abdellati, Saïd; Cuylaerts, Vicky; Crucitti, Tania; Heyndrickx, Leo; Heeres, Jan; Augustyns, Koen; Lewi, Paul J; Vanham, Guido

2013-09-01

Pre-exposure prophylaxis and topical microbicides are important strategies in the prevention of sexual HIV transmission, especially since partial protection has been shown in proof-of-concept studies. In search of new candidate drugs with an improved toxicity profile and with activity against common non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV, we have synthesized and investigated a library of 60 new diaryltriazine analogues. From this library, 15 compounds were evaluated in depth using a broad armamentarium of in vitro assays that are part of a preclinical testing algorithm for microbicide development. Antiviral activity was assessed in a cell line, and in primary human cells, against both subtype B and subtype C HIV-1 and against viruses resistant to therapeutic NNRTIs and the candidate NNRTI microbicide dapivirine. Toxicity towards primary blood-derived cells, cell lines originating from the female reproductive tract and female genital microflora was also studied. We identified several compounds with highly potent antiviral activity and toxicity profiles that are superior to that of dapivirine. In particular, compound UAMC01398 is an interesting new candidate that warrants further investigation because of its superior toxicity profile and potent activity against dapivirine-resistant viruses.

Design and Biological Evaluation of Antifouling Dihydrostilbene Oxime Hybrids.

PubMed

Moodie, Lindon W K; Cervin, Gunnar; Trepos, Rozenn; Labriere, Christophe; Hellio, Claire; Pavia, Henrik; Svenson, Johan

2018-04-01

By combining the recently reported repelling natural dihydrostilbene scaffold with an oxime moiety found in many marine antifoulants, a library of nine antifouling hybrid compounds was developed and biologically evaluated. The prepared compounds were shown to display a low antifouling effect against marine bacteria but a high potency against the attachment and growth of microalgae down to MIC values of 0.01 μg/mL for the most potent hybrid. The mode of action can be characterized as repelling via a reversible non-toxic biostatic mechanism. Barnacle cyprid larval settlement was also inhibited at low μg/mL concentrations with low levels or no toxicity observed. Several of the prepared compounds performed better than many reported antifouling marine natural products. While several of the prepared compounds are highly active as antifoulants, no apparent synergy is observed by incorporating the oxime functionality into the dihydrostilbene scaffold. This observation is discussed in light of recently reported literature data on related marine natural antifoulants and antifouling hybrids as a potentially general strategy for generation of improved antifoulants.

Acute photo-induced toxicity and toxicokinetics of single compounds and mixtures of polycyclic aromatic hydrocarbons in zebrafish.

PubMed

Willis, Alison M; Oris, James T

2014-09-01

The present study examined photo-induced toxicity and toxicokinetics for acute exposure to selected polycyclic aromatic hydrocarbons (PAHs) in zebrafish. Photo-enhanced toxicity from co-exposure to ultraviolet (UV) radiation and PAHs enhanced the toxicity and exhibited toxic effects at PAH concentrations orders of magnitude below effects observed in the absence of UV. Because environmental exposure to PAHs is usually in the form of complex mixtures, the present study examined the photo-induced toxicity of both single compounds and mixtures of PAHs. In a sensitive larval life stage of zebrafish, acute photo-induced median lethal concentrations (LC50s) were derived for 4 PAHs (anthracene, pyrene, carbazole, and phenanthrene) to examine the hypothesis that phototoxic (anthracene and pyrene) and nonphototoxic (carbazole and phenanthrene) pathways of mixtures could be predicted from single exposures. Anthracene and pyrene were phototoxic as predicted; however, carbazole exhibited moderate photo-induced toxicity and phenanthrene exhibited weak photo-induced toxicity. The toxicity of each chemical alone was used to compare the toxicity of mixtures in binary, tertiary, and quaternary combinations of these PAHs, and a predictive model for environmental mixtures was generated. The results indicated that the acute toxicity of PAH mixtures was additive in phototoxic scenarios, regardless of the magnitude of photo-enhancement. Based on PAH concentrations found in water and circumstances of high UV dose to aquatic systems, there exists potential risk of photo-induced toxicity to aquatic organisms. © 2014 SETAC.

The Generation of Diazo Compounds in Continuous-Flow.

PubMed

Hock, Katharina J; Koenigs, Rene M

2018-03-25

Toxic, cancerogenic and explosive - these attributes are typically associated with diazo compounds. Nonetheless, diazo compounds are nowadays a highly demanded class of reagents for organic synthesis, yet the concerns with regards to safe and scalable transformations of these compounds are still exceptionally high. Lately, the research area of the continuous-flow synthesis of diazo compounds attracted significant interest and a whole variety of protocols for their "on-demand" preparation have been realized to date. This concept article focuses on the recent developments using continuous-flow technologies to access diazo compounds; thus minimizing risks and hazards when working with this particular class of compounds. In this article we discuss these concepts and highlight different pre-requisites to access and to perform downstream functionalization reaction. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Development and application of freshwater sediment-toxicity benchmarks for currently used pesticides

USGS Publications Warehouse

Nowell, Lisa H.; Norman, Julia E.; Ingersoll, Christopher G.; Moran, Patrick W.

2016-01-01

Sediment-toxicity benchmarks are needed to interpret the biological significance of currently used pesticides detected in whole sediments. Two types of freshwater sediment benchmarks for pesticides were developed using spiked-sediment bioassay (SSB) data from the literature. These benchmarks can be used to interpret sediment-toxicity data or to assess the potential toxicity of pesticides in whole sediment. The Likely Effect Benchmark (LEB) defines a pesticide concentration in whole sediment above which there is a high probability of adverse effects on benthic invertebrates, and the Threshold Effect Benchmark (TEB) defines a concentration below which adverse effects are unlikely. For compounds without available SSBs, benchmarks were estimated using equilibrium partitioning (EqP). When a sediment sample contains a pesticide mixture, benchmark quotients can be summed for all detected pesticides to produce an indicator of potential toxicity for that mixture. Benchmarks were developed for 48 pesticide compounds using SSB data and 81 compounds using the EqP approach. In an example application, data for pesticides measured in sediment from 197 streams across the United States were evaluated using these benchmarks, and compared to measured toxicity from whole-sediment toxicity tests conducted with the amphipod Hyalella azteca (28-d exposures) and the midge Chironomus dilutus (10-d exposures). Amphipod survival, weight, and biomass were significantly and inversely related to summed benchmark quotients, whereas midge survival, weight, and biomass showed no relationship to benchmarks. Samples with LEB exceedances were rare (n = 3), but all were toxic to amphipods (i.e., significantly different from control). Significant toxicity to amphipods was observed for 72% of samples exceeding one or more TEBs, compared to 18% of samples below all TEBs. Factors affecting toxicity below TEBs may include the presence of contaminants other than pesticides, physical/chemical characteristics of sediment, and uncertainty in TEB values. Additional evaluations of benchmarks in relation to sediment chemistry and toxicity are ongoing.

Prioritizing pesticide compounds for analytical methods development

USGS Publications Warehouse

Norman, Julia E.; Kuivila, Kathryn; Nowell, Lisa H.

2012-01-01

The U.S. Geological Survey (USGS) has a periodic need to re-evaluate pesticide compounds in terms of priorities for inclusion in monitoring and studies and, thus, must also assess the current analytical capabilities for pesticide detection. To meet this need, a strategy has been developed to prioritize pesticides and degradates for analytical methods development. Screening procedures were developed to separately prioritize pesticide compounds in water and sediment. The procedures evaluate pesticide compounds in existing USGS analytical methods for water and sediment and compounds for which recent agricultural-use information was available. Measured occurrence (detection frequency and concentrations) in water and sediment, predicted concentrations in water and predicted likelihood of occurrence in sediment, potential toxicity to aquatic life or humans, and priorities of other agencies or organizations, regulatory or otherwise, were considered. Several existing strategies for prioritizing chemicals for various purposes were reviewed, including those that identify and prioritize persistent, bioaccumulative, and toxic compounds, and those that determine candidates for future regulation of drinking-water contaminants. The systematic procedures developed and used in this study rely on concepts common to many previously established strategies. The evaluation of pesticide compounds resulted in the classification of compounds into three groups: Tier 1 for high priority compounds, Tier 2 for moderate priority compounds, and Tier 3 for low priority compounds. For water, a total of 247 pesticide compounds were classified as Tier 1 and, thus, are high priority for inclusion in analytical methods for monitoring and studies. Of these, about three-quarters are included in some USGS analytical method; however, many of these compounds are included on research methods that are expensive and for which there are few data on environmental samples. The remaining quarter of Tier 1 compounds are high priority as new analytes. The objective for analytical methods development is to design an integrated analytical strategy that includes as many of the Tier 1 pesticide compounds as possible in a relatively few, cost-effective methods. More than 60 percent of the Tier 1 compounds are high priority because they are anticipated to be present at concentrations approaching levels that could be of concern to human health or aquatic life in surface water or groundwater. An additional 17 percent of Tier 1 compounds were frequently detected in monitoring studies, but either were not measured at levels potentially relevant to humans or aquatic organisms, or do not have benchmarks available with which to compare concentrations. The remaining 21 percent are pesticide degradates that were included because their parent pesticides were in Tier 1. Tier 1 pesticide compounds for water span all major pesticide use groups and a diverse range of chemical classes, with herbicides and their degradates composing half of compounds. Many of the high priority pesticide compounds also are in several national regulatory programs for water, including those that are regulated in drinking water by the U.S. Environmental Protection Agency under the Safe Drinking Water Act and those that are on the latest Contaminant Candidate List. For sediment, a total of 175 pesticide compounds were classified as Tier 1 and, thus, are high priority for inclusion in analytical methods available for monitoring and studies. More than 60 percent of these compounds are included in some USGS analytical method; however, some are spread across several research methods that are expensive to perform, and monitoring data are not extensive for many compounds. The remaining Tier 1 compounds for sediment are high priority as new analytes. The objective for analytical methods development for sediment is to enhance an existing analytical method that currently includes nearly half of the pesticide compounds in Tier 1 by adding as many additional Tier 1 compounds as are analytically compatible. About 35 percent of the Tier 1 compounds for sediment are high priority on the basis of measured occurrence. A total of 74 compounds, or 42 percent, are high priority on the basis of predicted likelihood of occurrence according to physical-chemical properties, and either have potential toxicity to aquatic life, high pesticide useage, or both. The remaining 22 percent of Tier 1 pesticide compounds were either degradates of Tier 1 parent compounds or included for other reasons. As with water, the Tier 1 pesticide compounds for sediment are distributed across the major pesticide-use groups; insecticides and their degradates are the largest fraction, making up 45 percent of Tier 1. In contrast to water, organochlorines, at 17 percent, are the largest chemical class for Tier 1 in sediment, which is to be expected because there is continued widespread detection in sediments of persistent organochlorine pesticides and their degradates at concentrations high enough for potential effects on aquatic life. Compared to water, there are fewer available benchmarks with which to compare contaminant concentrations in sediment, but a total of 19 Tier 1 compounds have at least one sediment benchmark or screening value for aquatic organisms. Of the 175 compounds in Tier 1, 77 percent have high aquatic-life toxicity, as defined for this process. This evaluation of pesticides and degradates resulted in two lists of compounds that are priorities for USGS analytical methods development, one for water and one for sediment. These lists will be used as the basis for redesigning and enhancing USGS analytical capabilities for pesticides in order to capture as many high-priority pesticide compounds as possible using an economically feasible approach.

Toxicities of emamectin benzoate homologues and photodegradates to Lepidoptera.

PubMed

Argentine, Joseph A; Jansson, Richard K; Starner, Van R; Halliday, W Ross

2002-12-01

The toxicity of a number of emamectin benzoate homologues and photodegradates to five species of Lepidoptera was investigated using diet and foliar bioassays. The emamectin benzoate homologues B1a and B1b were equally toxic in the diet and foliar assays to Spodoptera exigua (Hübner), Heliothis virescens (F.), Tricoplusia ni (Hübner), and Spodoptera frugiperda (J. E. Smith), within each of these species. Plutella xylostella (L.) was the most sensitive species to emamectin benzoate. The AB1a photodegradate of emamectin benzoate was as toxic as the parent compound in the diet assay. However, in the foliage assay AB1a was 4.4-fold less toxic to S. exigua than the parent compound. The MFB1a photodegradate of emamectin benzoate was as toxic as the parent compound to P. xylostella, and 3.1 to 6.2 times as toxic as the parent compound to the other species in the diet assay. The order of toxicity of the photodegradates were AB1a > MFB1a > FAB1a > 8,9-Z-MAB1a > PAB1a.

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

PubMed

Balaji, S; Chempakam, B

2010-10-01

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

Investigation and molecular docking studies of Bassianolide from Lecanicillium lecanii against Plutella xylostella (Lepidoptera: Plutellidae).

PubMed

Ravindran, Keppanan; Sivaramakrishnan, Sivaperumal; Hussain, Mubasher; Dash, Chandra Kanta; Bamisile, Bamisope Steve; Qasim, Muhammad; Liande, Wang

2018-04-01

Entomopathogenic fungi are rich sources of bioactive secondary metabolites that possess insecticidal properties. The present study reported a novel approach for the identification of insecticidal compounds produced by Lecanicillium lecanii 09 and to assess their toxicity against the diamondback moth Plutella xylostella L. The cyclic peptides groups of toxic substances were separated from L. lecanii 09 through submerged liquid state fermentation. The most abundant toxic metabolite, Bassianolide was purified by high-performance liquid chromatography (HPLC) and its molecular weight and purity were determined by Liquid chromatography - mass spectroscopy (LC-MS), Fourier transformed infrared spectroscopy (FT-IR), and H 1 nuclear magnetic resonance (NMR) respectively. Subsequently, the toxicity of bassianolide was tested against third instar larvae of P. xylostella at three different concentrations (0.01, 0.1, 0.5 mg/ml). The results showed that higher concentration of 0.5 mg/ml had significant maximum mortality at 120 hour post inoculation. Furthermore, we investigated the ligand-target interaction of secondary metabolite binding with target insect immune receptor proteins and predicted the role of toxicity against insect host. This is the first study to report the infection process and the interaction of fungal mediated cyclicdepsipeptide compound (bassianolide) from L. lecanii 09 against the insect host P. xylostella. This novel approach provides a potential impact on biological control using natural toxic compound which acts as good inhibitor on pest insect and prevents toxicity hazards, pollution as well as ecocidal effects killing several beneficial insects. Copyright © 2018 Elsevier Inc. All rights reserved.

Two Host-Induced Ralstonia solanacearum Genes, acrA and dinF, Encode Multidrug Efflux Pumps and Contribute to Bacterial Wilt Virulence▿ †

PubMed Central

Brown, Darby G.; Swanson, Jill K.; Allen, Caitilyn

2007-01-01

Multidrug efflux pumps (MDRs) are hypothesized to protect pathogenic bacteria from toxic host defense compounds. We created mutations in the Ralstonia solanacearum acrA and dinF genes, which encode putative MDRs in the broad-host-range plant pathogen. Both mutations reduced the ability of R. solanacearum to grow in the presence of various toxic compounds, including antibiotics, phytoalexins, and detergents. Both acrAB and dinF mutants were significantly less virulent on the tomato plant than the wild-type strain. Complementation restored near-wild-type levels of virulence to both mutants. Addition of either dinF or acrAB to Escherichia coli MDR mutants KAM3 and KAM32 restored the resistance of these strains to several toxins, demonstrating that the R. solanacearum genes can function heterologously to complement known MDR mutations. Toxic and DNA-damaging compounds induced expression of acrA and dinF, as did growth in both susceptible and resistant tomato plants. Carbon limitation also increased expression of acrA and dinF, while the stress-related sigma factor RpoS was required at a high cell density (>107 CFU/ml) to obtain wild-type levels of acrA expression both in minimal medium and in planta. The type III secretion system regulator HrpB negatively regulated dinF expression in culture at high cell densities. Together, these results show that acrAB and dinF encode MDRs in R. solanacearum and that they contribute to the overall aggressiveness of this phytopathogen, probably by protecting the bacterium from the toxic effects of host antimicrobial compounds. PMID:17337552

Two host-induced Ralstonia solanacearum genes, acrA and dinF, encode multidrug efflux pumps and contribute to bacterial wilt virulence.

PubMed

Brown, Darby G; Swanson, Jill K; Allen, Caitilyn

2007-05-01

Multidrug efflux pumps (MDRs) are hypothesized to protect pathogenic bacteria from toxic host defense compounds. We created mutations in the Ralstonia solanacearum acrA and dinF genes, which encode putative MDRs in the broad-host-range plant pathogen. Both mutations reduced the ability of R. solanacearum to grow in the presence of various toxic compounds, including antibiotics, phytoalexins, and detergents. Both acrAB and dinF mutants were significantly less virulent on the tomato plant than the wild-type strain. Complementation restored near-wild-type levels of virulence to both mutants. Addition of either dinF or acrAB to Escherichia coli MDR mutants KAM3 and KAM32 restored the resistance of these strains to several toxins, demonstrating that the R. solanacearum genes can function heterologously to complement known MDR mutations. Toxic and DNA-damaging compounds induced expression of acrA and dinF, as did growth in both susceptible and resistant tomato plants. Carbon limitation also increased expression of acrA and dinF, while the stress-related sigma factor RpoS was required at a high cell density (>10(7) CFU/ml) to obtain wild-type levels of acrA expression both in minimal medium and in planta. The type III secretion system regulator HrpB negatively regulated dinF expression in culture at high cell densities. Together, these results show that acrAB and dinF encode MDRs in R. solanacearum and that they contribute to the overall aggressiveness of this phytopathogen, probably by protecting the bacterium from the toxic effects of host antimicrobial compounds.

Persistent and High-Level Expression of Human Liver Prolidase in Vivo in Mice Using Adenovirus

DTIC Science & Technology

2013-01-01

types of nerve agents and pesticide compounds, is mostly exported into the circulation [11]. Similarly, human paraoxonase1, a promising enzyme in the...of human butyrylcholinesetrase results in persistent high-level transgene expression in vivo, Chem. Biol. Interact. 175 (2008) 327– 331. [11] K...paraoxonase1 gene transfer to provide protection against the toxicity of the organophosphorus pesticide toxicant diazoxon, Gene Ther. 18 (2011) 250–257. [14

Thermochemical Wastewater Valorization via Enhanced Microbial Toxicity Tolerance

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

Beckham, Gregg T; Thelhawadigedara, Lahiru Niroshan Jayakody; Johnson, Christopher W

Thermochemical (TC) biomass conversion processes such as pyrolysis and liquefaction generate considerable amounts of wastewater, which often contains highly toxic compounds that are incredibly challenging to convert via standard wastewater treatment approaches such as anaerobic digestion. These streams represent a cost for TC biorefineries, and a potential valorization opportunity, if effective conversion methods are developed. The primary challenge hindering microbial conversion of TC wastewater is toxicity. In this study, we employ a robust bacterium, Pseudomonas putida, with TC wastewater streams to demonstrate that aldehydes are the most inhibitory compounds in these streams. Proteomics, transcriptomics, and fluorescence-based immunoassays of P. putidamore » grown in a representative wastewater stream indicate that stress results from protein damage, which we hypothesize is a primary toxicity mechanism. Constitutive overexpression of the chaperone genes, groEL, groES, and clpB, in a genome-reduced P. putida strain improves the tolerance towards multiple TC wastewater samples up to 200-fold. Moreover, the concentration ranges of TC wastewater are industrially relevant for further bioprocess development for all wastewater streams examined here, representing different TC process configurations. Furthermore, we demonstrate proof-of-concept polyhydroxyalkanoate production from the usable carbon in an exemplary TC wastewater stream. Overall, this study demonstrates that protein quality control machinery and repair mechanisms can enable substantial gains in microbial tolerance to highly toxic substrates, including heterogeneous waste streams. When coupled to other metabolic engineering advances such as expanded substrate utilization and enhanced product accumulation, this study generally enables new strategies for biological conversion of highly-toxic, organic-rich wastewater via engineered aerobic monocultures or designer consortia.« less

Remote detection of human toxicants in real time using a human-optimized, bioluminescent bacterial luciferase gene cassette bioreporter

NASA Astrophysics Data System (ADS)

Close, Dan; Webb, James; Ripp, Steven; Patterson, Stacey; Sayler, Gary

2012-06-01

Traditionally, human toxicant bioavailability screening has been forced to proceed in either a high throughput fashion using prokaryotic or lower eukaryotic targets with minimal applicability to humans, or in a more expensive, lower throughput manner that uses fluorescent or bioluminescent human cells to directly provide human bioavailability data. While these efforts are often sufficient for basic scientific research, they prevent the rapid and remote identification of potentially toxic chemicals required for modern biosecurity applications. To merge the advantages of high throughput, low cost screening regimens with the direct bioavailability assessment of human cell line use, we re-engineered the bioluminescent bacterial luciferase gene cassette to function autonomously (without exogenous stimulation) within human cells. Optimized cassette expression provides for fully endogenous bioluminescent production, allowing continuous, real time monitoring of the bioavailability and toxicology of various compounds in an automated fashion. To access the functionality of this system, two sets of bioluminescent human cells were developed. The first was programed to suspend bioluminescent production upon toxicological challenge to mimic the non-specific detection of a toxicant. The second induced bioluminescence upon detection of a specific compound to demonstrate autonomous remote target identification. These cells were capable of responding to μM concentrations of the toxicant n-decanal, and allowed for continuous monitoring of cellular health throughout the treatment process. Induced bioluminescence was generated through treatment with doxycycline and was detectable upon dosage at a 100 ng/ml concentration. These results demonstrate that leveraging autonomous bioluminescence allows for low-cost, high throughput direct assessment of toxicant bioavailability.

[Assessment of the relationship of properties of chemical compounds and their toxicity to a unified hygienic standardization for chemicals].

PubMed

Trushkov, V F; Perminov, K A; Sapozhnikova, V V; Ignatova, O L

2013-01-01

The connection of thermodynamic properties and parameters of toxicity of chemical substances was determined. Obtained data are used for the evaluation of toxicity and hygienic rate setting of chemical compounds. The relationship between enthalpy and toxicity of chemical compounds has been established. Orthogonal planning of the experiment was carried out in the course of the investigations. Equation of unified hygienic rate setting in combined, complex, conjunct influence on the organism is presented. Prospects of determination of toxicity and methodology of unified hygienic rate setting in combined, complex, conjunct influence on the organism are presented

Prediction of human population responses to toxic compounds by a collaborative competition.

PubMed

Eduati, Federica; Mangravite, Lara M; Wang, Tao; Tang, Hao; Bare, J Christopher; Huang, Ruili; Norman, Thea; Kellen, Mike; Menden, Michael P; Yang, Jichen; Zhan, Xiaowei; Zhong, Rui; Xiao, Guanghua; Xia, Menghang; Abdo, Nour; Kosyk, Oksana; Friend, Stephen; Dearry, Allen; Simeonov, Anton; Tice, Raymond R; Rusyn, Ivan; Wright, Fred A; Stolovitzky, Gustavo; Xie, Yang; Saez-Rodriguez, Julio

2015-09-01

The ability to computationally predict the effects of toxic compounds on humans could help address the deficiencies of current chemical safety testing. Here, we report the results from a community-based DREAM challenge to predict toxicities of environmental compounds with potential adverse health effects for human populations. We measured the cytotoxicity of 156 compounds in 884 lymphoblastoid cell lines for which genotype and transcriptional data are available as part of the Tox21 1000 Genomes Project. The challenge participants developed algorithms to predict interindividual variability of toxic response from genomic profiles and population-level cytotoxicity data from structural attributes of the compounds. 179 submitted predictions were evaluated against an experimental data set to which participants were blinded. Individual cytotoxicity predictions were better than random, with modest correlations (Pearson's r < 0.28), consistent with complex trait genomic prediction. In contrast, predictions of population-level response to different compounds were higher (r < 0.66). The results highlight the possibility of predicting health risks associated with unknown compounds, although risk estimation accuracy remains suboptimal.

Effects of seven antifouling compounds on photosynthesis and inorganic carbon use in sugar kelp Saccharina latissima (Linnaeus).

PubMed

Johansson, Per; Eriksson, Karl Martin; Axelsson, Lennart; Blanck, Hans

2012-10-01

Macroalgae depend on carbon-concentrating mechanisms (CCMs) to maintain a high photosynthetic activity under conditions of low carbon dioxide (CO(2)) availability. Because such conditions are prevalent in marine environments, CCMs are important for upholding the macroalgal primary productivity in coastal zones. This study evaluated the effects of seven antifouling compounds-chlorothalonil, DCOIT, dichlofluanid, diuron, irgarol, tolylfluanid, and zinc pyrithione (ZnTP)-on the photosynthesis and CCM of sugar kelp (Saccharina latissima (L.)). Concentration-response curves of these toxicants were established using inhibition of carbon incorporation, whereas their effects over time and their inhibition of the CCM were studied using inhibition of O(2) evolution. We demonstrate that exposure to all compounds except ZnTP (< 1000 nM) resulted in toxicity to photosynthesis of S. latissima. However, carbon incorporation and O(2) evolution differed in their ability to detect toxicity from some of the compounds. Diuron, irgarol, DCOIT, tolylfluanid, and, to some extent, dichlofluanid inhibited carbon incorporation. Chlorothalonil did not inhibit carbon incorporation but clearly inhibited oxygen (O(2)) evolution. Photosynthesis showed only little recovery during the 2-h postexposure period. Inhibition of photosynthesis even increased after the end of exposure to chlorothalonil and tolylfluanid. Through changes in pH of the medium, toxic effects on the CCM could be studied isolated from photosynthesis effects. The CCM of S. latissima was inhibited by chlorothalonil, DCOIT, dichlofluanid, and tolylfluanid. Such inhibition of the CCM, or the absence thereof, deepens the understanding the mechanism of action of the studied compounds.

In vitro screening of organotin compounds and sediment extracts for cytotoxicity to fish cells.

PubMed

Giltrap, Michelle; Macken, Ailbhe; McHugh, Brendan; McGovern, Evin; Foley, Barry; Davoren, Maria

2011-01-01

The present study reports an in vitro screening method for contaminants in sediment samples utilizing an RTG-2 cell line. This technique integrates cytotoxicity testing with analytical chemistry with the aim of achieving a toxicity evaluation of the sediment sample. The toxic effect of individual organotin (OT) compounds and their presence in the sediment sample is the focus of the present study; however, other contaminants are also discussed. The following OT compounds: tributyltin (TBT), dibutyltin (DBT), monobutyltin (MBT), triphenyltin (TPT), diphenyltin (DPT), and a sediment solvent extract are exposed to the RTG-2 fish cell line. Both the alamar blue (AB) and neutral red (NR) assays are used to assess cytotoxicity after 24-h and 96-h exposure. Methodology for preparation of a sediment solvent extract suitable for biological testing and analytical determination is also described. With the RTG-2 cells, the AB and NR assays had comparable sensitivity for each individual OT compound exposure after 24 h, with TPT being the most toxic compound tested. The individual OT compound concentrations required to induce a 50% toxic effect on the cells (369 ng ml⁻¹ TBT, 1,905 ng ml⁻¹ DBT) did not equate to the concentrations of these contaminants present in the sediment extract that induced a 50% effect on the cells (294 ng ml⁻¹ TBT, 109 ng ml⁻¹ DBT). The solvent extract therefore exhibited a greater toxicity, and this suggests that the toxic effects observed were not due to OT compounds alone. The presence of other contaminants in the solvent extract is confirmed with chemical analysis, warranting further toxicity testing of contaminant mixtures and exposure to the cell line to further elucidate a complete toxicity evaluation. © 2010 SETAC.

Collapsing Aged Culture of the Cyanobacterium Synechococcus elongatus Produces Compound(s) Toxic to Photosynthetic Organisms

PubMed Central

Cohen, Assaf; Sendersky, Eleonora; Carmeli, Shmuel; Schwarz, Rakefet

2014-01-01

Phytoplankton mortality allows effective nutrient cycling, and thus plays a pivotal role in driving biogeochemical cycles. A growing body of literature demonstrates the involvement of regulated death programs in the abrupt collapse of phytoplankton populations, and particularly implicates processes that exhibit characteristics of metazoan programmed cell death. Here, we report that the cell-free, extracellular fluid (conditioned medium) of a collapsing aged culture of the cyanobacterium Synechococcus elongatus is toxic to exponentially growing cells of this cyanobacterium, as well as to a large variety of photosynthetic organisms, but not to eubacteria. The toxic effect, which is light-dependent, involves oxidative stress, as suggested by damage alleviation by antioxidants, and the very high sensitivity of a catalase-mutant to the conditioned medium. At relatively high cell densities, S. elongatus cells survived the deleterious effect of conditioned medium in a process that required de novo protein synthesis. Application of conditioned medium from a collapsing culture caused severe pigment bleaching not only in S. elongatus cells, but also resulted in bleaching of pigments in a cell free extract. The latter observation indicates that the elicited damage is a direct effect that does not require an intact cell, and therefore, is mechanistically different from the metazoan-like programmed cell death described for phytoplankton. We suggest that S. elongatus in aged cultures are triggered to produce a toxic compound, and thus, this process may be envisaged as a novel regulated death program. PMID:24959874

Design, Synthesis, and Antifouling Activity of Glucosamine-Based Isocyanides.

PubMed

Umezawa, Taiki; Hasegawa, Yuki; Novita, Ira S; Suzuki, Junya; Morozumi, Tatsuya; Nogata, Yasuyuki; Yoshimura, Erina; Matsuda, Fuyuhiko

2017-06-29

Biofouling, an undesirable accumulation of organisms on sea-immersed structures such as ship hulls and fishing nets, is a serious economic issue whose effects include oil wastage and clogged nets. Organotin compounds were utilized since the 1960s as an antifouling material; however, the use of such compounds was later banned by the International Maritime Organization (IMO) due to their high toxicity toward marine organisms, resulting in masculinization and imposex. Since the ban, there have been extensive efforts to develop environmentally benign antifoulants. Natural antifouling products obtained from marine creatures have been the subject of considerable attention due to their potent antifouling activity and low toxicity. These antifouling compounds often contain isocyano groups, which are well known to have natural antifouling properties. On the basis of our previous total synthesis of natural isocyanoterpenoids, we envisaged the installation of an isocyano functional group onto glucosamine to produce an environmentally friendly antifouling material. This paper describes an effective synthetic method for various glucosamine-based isocyanides and evaluation of their antifouling activity and toxicity against cypris larvae of the barnacle Amphibalanus amphitrite . Glucosamine isocyanides with an ether functionality at the anomeric position exhibited potent antifouling activity, with EC 50 values below 1 μg/mL, without detectable toxicity even at a high concentration of 10 μg/mL. Two isocyanides had EC 50 values of 0.23 and 0.25 μg/mL, comparable to that of CuSO₄, which is used as a fouling inhibitor (EC 50 = 0.27 μg/mL).

Field monitoring of toxic organic pollution in the sediments of Pearl River estuary and its tributaries.

PubMed

Fu, J; Wang, Z; Mai, B; Kang, Y

2001-01-01

Field monitoring of the toxic organic compounds (PCBs, PAHs, organochlorine pesticides) in the top sediments of Pearl River Estuary and its up-streams were made. It was found that the highest concentrations of these toxic organic compounds occurred in the sediment sampled at Macau inner harbor (ZB013), which is a sink of suspended fine particles transported from the upstream waterways. Because of the affinity of the hydrophobic organic compounds (PAHs, PCBs) for the solid phase, these fine particle depositions led to accumulation of these compounds in the sediment of Macau. The atmospheric dry deposition may be another source of the toxic organic pollution in the sediment.

Bilayer Effects of Antimalarial Compounds

PubMed Central

Ramsey, Nicole B.; Andersen, Olaf S.

2015-01-01

Because of the perpetual development of resistance to current therapies for malaria, the Medicines for Malaria Venture developed the Malaria Box to facilitate the drug development process. We tested the 80 most potent compounds from the box for bilayer-mediated effects on membrane protein conformational changes (a measure of likely toxicity) in a gramicidin-based stopped flow fluorescence assay. Among the Malaria Box compounds tested, four compounds altered membrane properties (p< 0.05); MMV007384 stood out as a potent bilayer-perturbing compound that is toxic in many cell-based assays, suggesting that testing for membrane perturbation could help identify toxic compounds. In any case, MMV007384 should be approached with caution, if at all. PMID:26551613

Bilayer Effects of Antimalarial Compounds.

PubMed

Ramsey, Nicole B; Andersen, Olaf S

2015-01-01

Because of the perpetual development of resistance to current therapies for malaria, the Medicines for Malaria Venture developed the Malaria Box to facilitate the drug development process. We tested the 80 most potent compounds from the box for bilayer-mediated effects on membrane protein conformational changes (a measure of likely toxicity) in a gramicidin-based stopped flow fluorescence assay. Among the Malaria Box compounds tested, four compounds altered membrane properties (p< 0.05); MMV007384 stood out as a potent bilayer-perturbing compound that is toxic in many cell-based assays, suggesting that testing for membrane perturbation could help identify toxic compounds. In any case, MMV007384 should be approached with caution, if at all.

Assessment of toxicological profiles of the municipal wastewater effluents using chemical analyses and bioassays.

PubMed

Smital, Tvrtko; Terzic, Senka; Zaja, Roko; Senta, Ivan; Pivcevic, Branka; Popovic, Marta; Mikac, Iva; Tollefsen, Knut Erik; Thomas, Kevin V; Ahel, Marijan

2011-05-01

The hazardous chemical contamination of untreated wastewater and secondary effluent from the wastewater treatment plant (WWTP) of the city of Zagreb, Croatia was comprehensively characterized using large-volume solid-phase extraction (SPE) and silica gel fractionation, followed by a detailed analysis of the resulting extracts by a combination of chemical and bioassay methods. Over 100 individual contaminants or closely related-contaminant groups were identified by high-resolution gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-QTOF). Ecotoxicity profiling of the investigated samples, including cytotoxicity, chronic toxicity and EROD activity; inhibition of the multixenobiotic resistance (MXR), genotoxicity and estrogenic potential, revealed the most significant contribution of toxic compounds to be present in polar fractions. Wastewater treatment using conventional activated sludge process reduced the initial toxicity of raw wastewater to various extents, ranging from 28% for algal toxicity to 73.2% for an estrogenic activity. The most efficient toxicity removal was observed for the polar compounds. Copyright © 2010 Elsevier Inc. All rights reserved.

Cyclodextrin-enhanced degradation of toluene and p-toluic acid by Pseudomonas putida.

PubMed Central

Schwartz, A; Bar, R

1995-01-01

Degradation of an immiscible aromatic solvent, toluene, and a water-soluble aromatic compound, p-toluic acid, by a Pseudomonas putida strain in the presence of beta-cyclodextrin (beta-CD) was investigated. The ability of CDs to interact with hydrophobic organics and form inclusion compounds was exploited in this study to remove or alleviate the toxicities of substrates and consequently to enable or enhance degradation. Liquid toluene was found to be highly toxic to P. putida. However, this phase toxicity was removed when crystalline beta-CD-complexed toluene was provided as the substrate. The latter was fully degraded at a concentration of up to 10 g/liter. Degradation of toluene vapors was enhanced in the presence of beta-CD as a result of reduced molecular toxicity and facilitated absorption of the gaseous substrate. Similarly, beta-CD alleviated the inhibitory effect of p-toluic acid on P. putida. This protective effect of CD was remarkably more prominent when the microbial culture was shock loaded with an otherwise toxic dose of p-toluic acid (1.8 g/liter). PMID:7618884

Acute toxicity assessment of perfluorinated carboxylic acids towards the Baltic microalgae.

PubMed

Latała, Adam; Nędzi, Marcin; Stepnowski, Piotr

2009-09-01

The presence of high-energy carbon-fluorine bonds in perfluoro compounds lends them great stability and causes them to be environmentally persistent. Relatively little is known about the acute toxicity of perfluorinated carboxylic acids (PFCAs) to ecotoxicological markers such as aquatic plants and animals. This study tested the toxicity of these compounds to the green alga Chlorella vulgaris, the diatom Skeletonema marinoi and the blue-green alga Geitlerinema amphibium, which are species representative of the algal flora of the Baltic Sea. The EC(50) values obtained range from 0.28 mM to 12.84 mM. A distinct relationship between hydrophobicity and toxicity is demonstrated. For every extra perfluoromethylene group in the alkyl chain, the toxicity increases twofold. LogEC(50) values are very well correlated linearly with both the number of carbon atoms in the perfluoroalkyl chain and the partition coefficients. The results also indicate that there are clear differences between the responses of particular taxonomic groups of algae: blue-green algae and diatoms are far more sensitive to PFCAs than green algae, probably because of differences in cell wall structure.

A BIOGENIC ROLE IN EXPOSURE TO TWO TOXIC COMPOUNDS

EPA Science Inventory

Biogenic sources play an important role in ozone and particulate concentrations through emissions of volatile organic compounds. The same emissions also contribute to chronic toxic exposures from formaldehyde and acetaldehyde because each compound arises through primary and se...

Toxicity of selenium (Na sub 2 SeO sub 3 ) and mercury (HgCl sub 2 ) on the planarian Dugesia gonocephala

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

Congiu, A.M.; Casu, S.; Ugazio, G.

1989-10-01

The toxicity of selenium (Na{sub 2}SeO{sub 3}) and mercury (HgCl{sub 2}) was determined by using a freshwater planarian which is particularly sensitive to pollution, and belongs to a fissiparous breed of Dugesia gonocephala. The mortality and fissiparity frequency of the subjects were studied. They were exposed to intense treatments (48 hours) or for medium to long periods of time (21 days) to either the single compounds or a combination of both, and were fed or fasting. The lethal effect of sodium selenite is correlated to the food intake, whereas the toxicity of mercurous chloride is probably the result of amore » fixative effect which does not depend on feeding. The 21-day treatment with the first compound has a non-negligible lethal effect which is probably due to an accumulation phenomenon. At doses where an antioxidant effect prevails, fissiparity is stimulated. On the other hand, the second compound reduces reproduction frequency to half the base values. Compared to the Paracentrotus lividus, the Dugesia gonocephala offers various advantages concerning toxicological experiments; besides being easier to handle in the laboratory, it is available all year round and is not subject to seasonal cycles. It is also more susceptible to the toxic effect of mercury, which is a common and highly toxic pollutant, than the sea urchin.« less

Effects of Organoboron Antifoulants on Oyster and Sea Urchin Embryo Development

PubMed Central

Tsunemasa, Noritaka; Tsuboi, Ai; Okamura, Hideo

2013-01-01

Prohibition of Ot (organotin) compounds was introduced in Japan in 1997 and worldwide from September 2008. This meant that the production of paints containing TBT compounds was stopped and alternatives to the available Ot antifoulants had to be developed. It has been claimed that the degradation by-products of these alternative antifoulants were less toxic than those of Ot compounds. Since the introduction of the alternative antifoulants, the accumulation of these compounds has been reported in many countries. However, the toxicity of these compounds was still largely unreported. In this research, the toxicity of the alternative Ot antifoulants TPBP (triphenylborane pyridine) and TPBOA (triphenylborane octadecylamine) and their degradation products on Crassostea gigas and Hemicentrotus pulcherrimus were tested. The results showed that toxic effects in Crassostea gigas was higher for each antifouling biocide than that in Hemicentrotus pulcherrimus. Also, while the toxicity of the Organoboron antifoulants and the Ots were the same, the former’s degradation products were much less harmful. PMID:23263671

Space- and time-resolved raman and breakdown spectroscopy: advanced lidar techniques

NASA Astrophysics Data System (ADS)

Silviu, Gurlui; Marius Mihai, Cazacu; Adrian, Timofte; Oana, Rusu; Georgiana, Bulai; Dimitriu, Dan

2018-04-01

DARLIOES - the advanced LIDAR is based on space- and time-resolved RAMAN and breakdown spectroscopy, to investigate chemical and toxic compounds, their kinetics and physical properties at high temporal (2 ns) and spatial (1 cm) resolution. The high spatial and temporal resolution are needed to resolve a large variety of chemical troposphere compounds, emissions from aircraft, the self-organization space charges induced light phenomena, temperature and humidity profiles, ice nucleation, etc.

Identifying developmental vascular disruptor compounds using a predictive signature and alternative toxicity models

EPA Science Inventory

Identifying Developmental Vascular Disruptor Compounds Using a Predictive Signature and Alternative Toxicity Models Presenting Author: Tamara Tal Affiliation: U.S. EPA/ORD/ISTD, RTP, NC, USA Chemically induced vascular toxicity during embryonic development can result in a wide...

Predictive ecotoxicity of MoA 1 of organic chemicals using in silico approaches.

PubMed

de Morais E Silva, Luana; Alves, Mateus Feitosa; Scotti, Luciana; Lopes, Wilton Silva; Scotti, Marcus Tullius

2018-05-30

Persistent organic products are compounds used for various purposes, such as personal care products, surfactants, colorants, industrial additives, food, pesticides and pharmaceuticals. These substances are constantly introduced into the environment and many of these pollutants are difficult to degrade. Toxic compounds classified as MoA 1 (Mode of Action 1) are low toxicity compounds that comprise nonreactive chemicals. In silico methods such as Quantitative Structure-Activity Relationships (QSARs) have been used to develop important models for prediction in several areas of science, as well as aquatic toxicity studies. The aim of the present study was to build a QSAR model-based set of theoretical Volsurf molecular descriptors using the fish acute toxicity values of compounds defined as MoA 1 to identify the molecular properties related to this mechanism. The selected Partial Least Squares (PLS) results based on the values of cross-validation coefficients of determination (Q cv 2 ) show the following values: Q cv 2 = 0.793, coefficient of determination (R 2 ) = 0.823, explained variance in external prediction (Q ext 2 ) = 0.87. From the selected descriptors, not only the hydrophobicity is related to the toxicity as already mentioned in previously published studies but other physicochemical properties combined contribute to the activity of these compounds. The symmetric distribution of the hydrophobic moieties in the structure of the compounds as well as the shape, as branched chains, are important features that are related to the toxicity. This information from the model can be useful in predicting so as to minimize the toxicity of organic compounds. Copyright © 2018. Published by Elsevier Inc.

Computer-assisted engineering of the synthetic pathway for biodegradation of a toxic persistent pollutant.

PubMed

Kurumbang, Nagendra Prasad; Dvorak, Pavel; Bendl, Jaroslav; Brezovsky, Jan; Prokop, Zbynek; Damborsky, Jiri

2014-03-21

Anthropogenic halogenated compounds were unknown to nature until the industrial revolution, and microorganisms have not had sufficient time to evolve enzymes for their degradation. The lack of efficient enzymes and natural pathways can be addressed through a combination of protein and metabolic engineering. We have assembled a synthetic route for conversion of the highly toxic and recalcitrant 1,2,3-trichloropropane to glycerol in Escherichia coli, and used it for a systematic study of pathway bottlenecks. Optimal ratios of enzymes for the maximal production of glycerol, and minimal toxicity of metabolites were predicted using a mathematical model. The strains containing the expected optimal ratios of enzymes were constructed and characterized for their viability and degradation efficiency. Excellent agreement between predicted and experimental data was observed. The validated model was used to quantitatively describe the kinetic limitations of currently available enzyme variants and predict improvements required for further pathway optimization. This highlights the potential of forward engineering of microorganisms for the degradation of toxic anthropogenic compounds.

Extraction of antioxidants from olive mill wastewater and electro-coagulation of exhausted fraction to reduce its toxicity on anaerobic digestion.

PubMed

Khoufi, Sonia; Aloui, Fathi; Sayadi, Sami

2008-03-01

Liquid-liquid extraction was used in order to recover phenolic compounds from centrifuged olive mill wastewater (OMW), a polluting by-product of olive oil production process, and to reduce their toxicity for a subsequent aerobic or anaerobic digestion. Phenolic compounds were identified in untreated and treated OMW by gas chromatography coupled to mass spectrometry (GC-MS). The experimental results of ethyl acetate extraction showed that the monomers recovery efficiency was over 90%. This pre-treatment resulted in the removal of the major LMM phenolic compounds and a small part of HMM polyphenols. The aerobic treatment of the exhausted OMW fraction removed 78.7% of the soluble COD. In the case of anaerobic digestion at OLR ranged from 1 to 3.5 gCOD l(-1)day(-1), methanisation process exhibited high methane yield as 0.3 l CH4 produced per g COD introduced and high COD removal (80%). However, a disruption of the process was observed when the OLR was increased to 4.5 gCODl(-1)day(-1). A pre-treatment by electro-coagulation resulted in decreasing the toxicity and enhancing the performance of methanisation operated at higher OLR from 4 to 7.5 gCODl(-1)day(-1).

A New Approach in Applying Systems Engineering Tools and Analysis to Determine Hepatocyte Toxicogenomics Risk Levels to Human Health.

PubMed

Gigrich, James; Sarkani, Shahryar; Holzer, Thomas

2017-03-01

There is an increasing backlog of potentially toxic compounds that cannot be evaluated with current animal-based approaches in a cost-effective and expeditious manner, thus putting human health at risk. Extrapolation of animal-based test results for human risk assessment often leads to different physiological outcomes. This article introduces the use of quantitative tools and methods from systems engineering to evaluate the risk of toxic compounds by the analysis of the amount of stress that human hepatocytes undergo in vitro when metabolizing GW7647 1 over extended times and concentrations. Hepatocytes are exceedingly connected systems that make it challenging to understand the highly varied dimensional genomics data to determine risk of exposure. Gene expression data of peroxisome proliferator-activated receptor-α (PPARα) 2 binding was measured over multiple concentrations and varied times of GW7647 exposure and leveraging mahalanombis distance to establish toxicity threshold risk levels. The application of these novel systems engineering tools provides new insight into the intricate workings of human hepatocytes to determine risk threshold levels from exposure. This approach is beneficial to decision makers and scientists, and it can help reduce the backlog of untested chemical compounds due to the high cost and inefficiency of animal-based models.

Toxicological evaluation of the natural products and some semisynthetic derivatives of Heterotheca inuloides Cass (Asteraceae).

PubMed

Rodríguez-Chávez, José Luis; Coballase-Urrutia, Elvia; Sicilia-Argumedo, Gloria; Ramírez-Apan, Teresa; Delgado, Guillermo

2015-12-04

Heterotheca ineuloides Cass (Asteraceae), popularly known as árnica mexicana, is widely used in Mexican traditional medicine to treat bruises, dermatological problems, rheumatic pains, and other disorders as cancer. The major constituents in H. inuloides are cadinane type sesquiterpenes, flavonoids and phytosterols. Compounds with a cadinane skeleton have been proved to possess cytotoxic activity against human-tumor cell lines and brine shrimp, and display toxic effects in different animal species. Although this plant has been widely used, there is little available information on the safety and toxicity especially of pure compounds. Evaluate the potential toxicity of the natural products isolated from H. inuloides and some semisynthetic derivatives. The toxic aspects of the following natural products isolated from dried flowers of H. inuloides: 7-hydroxy-3,4-dihydrocadalene (1), 7-hydroxycadalene (2), 3,7-dihydroxy-3(4H)-isocadalen-4-one (3), (1R,4R)-1-hydroxy-4H-1,2,3,4- tetrahydrocadalen-15-oic acid (4), D-chiro-inositol (5), quercetin (6), quercetin-3,7,3'-trimethyl ether (7), quercetin-3,7,3',4'-tetramethyl ether (8), eriodictyol-7,4'-dimethyl ether (9), α-spinasterol (10), caryolan-1,9β-diol (11) and 7-(3,3-dimethylallyloxy)-coumarin (12) as well as the toxic aspects of the semisynthetic compounds 7-acetoxy-3,4-dihydrocadalene (13), 7-benzoxy-3,4-dihydrocadalene (14), 7-acetoxycadalene (15), 7-benzoxycadalene (16), quercetin pentaacetate (17), 7-hydroxycalamenene (18), 3,8-dimethyl-5-(1-methylethyl)-1,2-naphthoquinone (19), and 4-isopropyl-1,6-dimethylbenzo[c]oxepine-7,9-dione (20). Toxic activities of compounds were determined by sulforhodamine B (SRB) assay, Artemia salina assay, RAW264.7 macrophage cells. Additionally, the acute toxicity in mouse of compound 1, the major natural sesquiterpene isolated from the acetone extract, was evaluated. The best cytotoxicity activity was observed for mansonone C (19) on K562 cell line with IC50 1.45 ± 0.14 μM, for 7-hydroxycadalene (2) on HCT-15 cell line with IC50 18.89 ± 1.2 μM, and for quercetin pentaacetate (17) on MCF-7 cell line with IC50 22.57 ± 2.4 μM. Sesquiterpenes mansonone C (19) and 7-hydroxy-3,4-dihydrocadalene (1) caused the strongest deleterious effects against A. salina with IC50 39.4 ± 1.07, and 45.47 ± 1.74 μM, respectively. The number of viable RAW 264.7 cells was reduced with sesquiterpenes 1 and 2 by more than 90%. In addition, the acute study of 1 revealed no lethal effects at 300 mg/kg body weight, however, a reduction in the body weight of mice, morphological changes in the tissues of the liver and kidney and toxic signs were observed at very high doses (2000 mg/kg). The results provided evidence for the cytotoxicity of Mexican arnica (H. inuloides) metabolites and may be correlated with one of the popular uses of this plant, in traditional Mexican medicine, as anticancer remedy. Among the active compounds contained in the acetone extract, the cytotoxic activity is mainly ascribable to cadinene type sesquiterpenes. In addition, evidence of acute toxicity suggests that 7-hydroxy-3,4-dihydrocadalene (1) may lead to toxicity at very high doses. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Composition, distribution, and potential toxicity of organochlorine mixtures in bed sediments of streams

USGS Publications Warehouse

Phillips, Patrick J.; Nowell, Lisa H.; Gilliom, Robert J.; Nakagaki, Naomi; Murray, Karen; VanAlstyne, Carolyn

2010-01-01

Mixtures of organochlorine compounds have the potential for additive or interactive toxicity to organisms exposed in the stream. This study uses a variety of methods to identify mixtures and a modified concentration-addition approach to estimate their potential toxicity at 845 stream sites across the United States sampled between 1992 and 2001 for organochlorine pesticides and polychlorinated biphenyls (PCBs) in bed sediment. Principal-component (PC) analysis identified five PCs that account for 77% of the total variance in 14 organochlorine compounds in the original dataset. The five PCs represent: (1) chlordane-related compounds and dieldrin; (2) p,p′-DDT and its degradates; (3) o,p′-DDT and its degradates; (4) the pesticide degradates oxychlordane and heptachlor epoxide; and (5) PCBs. The PC analysis grouped compounds that have similar chemical structure (such as parent compound and degradate), common origin (in the same technical pesticide mixture), and(or) similar relation of concentrations to land use. For example, the highest concentrations of chlordane compounds and dieldrin occurred at urban sites, reflecting past use of parent pesticides for termite control. Two approaches to characterizing mixtures—PC-based mixtures and unique mixtures—were applied to all 299 samples with a detection of two or more organochlorine compounds. PC-based mixtures are defined by the presence (in the sample) of one or more compounds associated with that PC. Unique mixtures are defined as a specific combination of two or more compounds detected in a sample, regardless of how many other compounds were also detected in that sample. The simplest PC-based mixtures (containing compounds from 1 or 2 PCs) commonly occurred in a variety of land use settings. Complex mixtures (containing compounds from 3 or more PCs) were most common in samples from urban and mixed/urban sites, especially in the Northeast, reflecting high concentrations of multiple chlordane, dieldrin, DDT-related compounds, and(or) PCBs. The most commonly occurring unique mixture (p,p′-DDE, p,p′-DDD) occurred in both simple and complex PC-based mixtures, and at both urban and agricultural sites. Mean Probable Effect Concentration Quotients (PEC-Q) values, which estimate the potential toxicity of organochlorine contaminant mixtures, were highest for complex mixtures. Mean PEC-Q values were highest for urban sites in the Northeast, followed by mixed/urban sites in the Northeast and agricultural sites in cotton growing areas. These results demonstrate that the PEC-Q approach can be used in combination with PC-based and unique mixture analyses to relate potential aquatic toxicity of contaminant mixtures to mixture complexity, land use, and other surrogates for contaminant sources.

Comparison of the toxicity of fluoridation compounds in the nematode Caenorhabditis elegans.

PubMed

Rice, Julie R; Boyd, Windy A; Chandra, Dave; Smith, Marjolein V; Den Besten, Pamela K; Freedman, Jonathan H

2014-01-01

Fluorides are commonly added to drinking water in the United States to decrease the incidence of dental caries. Silicofluorides, such as sodium hexafluorosilicate (Na2 SiF6 ) and fluorosilicic acid (H2 SiF6 ), are mainly used for fluoridation, although fluoride salts such as sodium fluoride (NaF) are also used. Interestingly, only the toxicity of NaF has been examined and not that of the more often used silicofluorides. In the present study, the toxicities of NaF, Na2 SiF6 , and H2 SiF6 were compared. The toxicity of these fluorides on the growth, feeding, and reproduction in the alternative toxicological testing organism Caenorhabditis elegans was examined. Exposure to these compounds produced classic concentration-response toxicity profiles. Although the effects of the fluoride compounds varied among the 3 biological endpoints, no differences were found between the 3 compounds, relative to the fluoride ion concentration, in any of the assays. This suggests that silicofluorides have similar toxicity to NaF. © 2013 SETAC.

A32A-0126: A BIOGENIC ROLE IN EXPOSURE TO TWO TOXIC COMPOUNDS

EPA Science Inventory

Biogenic sources play an important role in ozone and particulate concentrations through emissions of volatile organic compounds. The same emissions also contribute to chronic toxic exposures from formaldehyde and acetaldehyde because each compound arises through primary and sec...

Neurotoxic effects of perfluoroalkylated compounds: mechanisms of action and environmental relevance.

PubMed

Mariussen, Espen

2012-09-01

Perfluoroalkylated compounds (PFCs) are used in fire-fighting foams, treatment of clothes, carpets and leather products, and as lubricants, pesticides, in paints and medicine. Recent developments in chemical analysis have revealed that fluorinated compounds have become ubiquitously spread and are regarded as a potential threats to the environment. Due to the carbon-fluorine bond, which has a very high bond strength, these chemicals are extremely persistent towards degradation and some PFCs have a potential for bioaccumulation in organisms. Of particular concern has been the developmental toxicity of PFOS and PFOA, which has been manifested in rodent studies as high mortality of prenatally exposed newborn rats and mice within 24 h after delivery. The nervous system appears to be one of the most sensitive targets of environmental contaminants. The serious developmental effects of PFCs have lead to the upcoming of studies that have investigated neurotoxic effects of these substances. In this review the major findings of the neurotoxicity of the main PFCs and their suggested mechanisms of action are presented. The neurotoxic effects are discussed in light of other toxic effects of PFCs to indicate the significance of PFCs as neurotoxicants. The main findings are that PFCs may induce neurobehavioral effects, particularly in developmentally exposed animals. The effects are, however, subtle and inconclusive and are often induced at concentrations where other toxic effects also are expected. Mechanistic studies have shown that PFCs may affect the thyroid system, influence the calcium homeostasis, protein kinase C, synaptic plasticity and cellular differentiation. Compared to other environmental toxicants the human blood levels of PFCs are high and of particular concern is that susceptible groups may be exposed to a cocktail of substances that in combination reach harmful concentrations.

Environmental contamination and human exposure to dioxin-related compounds in e-waste recycling sites of developing countries.

PubMed

Tue, Nguyen Minh; Takahashi, Shin; Subramanian, Annamalai; Sakai, Shinichi; Tanabe, Shinsuke

2013-07-01

E-waste recycling using uncontrolled processes is a major source of dioxin-related compounds (DRCs), including not only the regulated polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) but also non-regulated brominated and mixed halogenated compounds (PBDD/Fs and PXDD/Fs). Various studies at informal e-waste recycling sites (EWRSs) in Asian developing countries found the soil contamination levels of PCDD/Fs from tens to ten thousand picogram TCDD-equivalents (TEQ) per gram and those of DL-PCBs up to hundreds of picogram TEQ per gram. The air concentration of PCDD/Fs was reported as high as 50 pg TEQ per m(3) in Guiyu, the largest Chinese EWRS. Non-regulated compounds also contributed substantially to the total DL toxicity of the DRC mixtures from e-waste, as evidenced by the high TEQ levels estimated for the currently identifiable PBDD/Fs as well as the large portion of unexplained bioassay-derived TEQ levels in soils/dusts from EWRSs. Considering the high exposure levels estimated for EWRS residents, especially children, comprehensive emission inventories of DRCs from informal e-waste recycling, the identities and toxic potencies of unidentified DRCs released, and their impacts on human health need to be investigated in future studies.

Toxic and hormetic-like effects of three components of citrus essential oils on adult Mediterranean fruit flies (Ceratitis capitata)

PubMed Central

Papanastasiou, Stella A.; Bali, Eleftheria-Maria D.; Ioannou, Charalampos S.; Papachristos, Dimitrios P.; Zarpas, Kostas D.

2017-01-01

Plant essential oils (EOs) and a wide range of their individual components are involved in a variety of biological interactions with insect pests including stimulatory, deterrent, toxic and even hormetic effects. Both the beneficial and toxic properties of citrus EOs on the Mediterranean fruit fly (medfly) have been experimentally evidenced over the last years. However, no information is available regarding the toxic or beneficial effects of the major components of citrus EOs via contact with the adults of the Mediterranean fruit fly. In the present study, we explored the toxicity of limonene, linalool and α-pinene (3 of the main compounds of citrus EOs) against adult medflies and identified the effects of sub-lethal doses of limonene on fitness traits in a relaxed [full diet (yeast and sugar)] and in a stressful (sugar only) feeding environment. Our results demonstrate that all three compounds inferred high toxicity to adult medflies regardless of the diet, with males being more sensitive than females. Sub-lethal doses of limonene (LD20) enhanced the lifespan of adult medflies when they were deprived of protein. Fecundity was positively affected when females were exposed to limonene sub-lethal doses. Therefore, limonene, a major constituent of citrus EOs, induces high mortality at increased doses and positive effects on life history traits of medfly adults through contact at low sub-lethal doses. A hormetic-like effect of limonene to adult medflies and its possible underlying mechanisms are discussed. PMID:28520791

Chemical Compounds Toxic to Invertebrates Isolated from Marine Cyanobacteria of Potential Relevance to the Agricultural Industry

PubMed Central

Essack, Magbubah; Alzubaidy, Hanin S.; Bajic, Vladimir B.; Archer, John A. C.

2014-01-01

In spite of advances in invertebrate pest management, the agricultural industry is suffering from impeded pest control exacerbated by global climate changes that have altered rain patterns to favour opportunistic breeding. Thus, novel naturally derived chemical compounds toxic to both terrestrial and aquatic invertebrates are of interest, as potential pesticides. In this regard, marine cyanobacterium-derived metabolites that are toxic to both terrestrial and aquatic invertebrates continue to be a promising, but neglected, source of potential pesticides. A PubMed query combined with hand-curation of the information from retrieved articles allowed for the identification of 36 cyanobacteria-derived chemical compounds experimentally confirmed as being toxic to invertebrates. These compounds are discussed in this review. PMID:25356733

Chemical compounds toxic to invertebrates isolated from marine cyanobacteria of potential relevance to the agricultural industry.

PubMed

Essack, Magbubah; Alzubaidy, Hanin S; Bajic, Vladimir B; Archer, John A C

2014-10-29

In spite of advances in invertebrate pest management, the agricultural industry is suffering from impeded pest control exacerbated by global climate changes that have altered rain patterns to favour opportunistic breeding. Thus, novel naturally derived chemical compounds toxic to both terrestrial and aquatic invertebrates are of interest, as potential pesticides. In this regard, marine cyanobacterium-derived metabolites that are toxic to both terrestrial and aquatic invertebrates continue to be a promising, but neglected, source of potential pesticides. A PubMed query combined with hand-curation of the information from retrieved articles allowed for the identification of 36 cyanobacteria-derived chemical compounds experimentally confirmed as being toxic to invertebrates. These compounds are discussed in this review.

Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound.

PubMed

Kamimura, Hidetaka; Ito, Satoshi

2016-01-01

1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery. 2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans. 3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes. 4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2). 5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

Screening of agelasine D and analogs for inhibitory activity against pathogenic protozoa; identification of hits for visceral leishmaniasis and Chagas disease.

PubMed

Vik, Anders; Proszenyák, Agnes; Vermeersch, Marieke; Cos, Paul; Maes, Louis; Gundersen, Lise-Lotte

2009-01-08

There is an urgent need for novel and improved drugs against several tropical diseases caused by protozoa. The marine sponge (Agelas sp.) metabolite agelasine D, as well as other agelasine analogs and related structures were screened for inhibitory activity against Plasmodium falciparum, Leishmania infantum, Trypanosoma brucei and T. cruzi, as well as for toxicity against MRC-5 fibroblast cells. Many compounds displayed high general toxicity towards both the protozoa and MRC-5 cells. However, two compounds exhibited more selective inhibitory activity against L. infantum (IC(50) <0.5 microg/mL) while two others displayed IC(50) <1 microg/mL against T. cruzi in combination with relatively low toxicity against MRC-5 cells. According to criteria set up by the WHO Special Programme for Research & Training in Tropical Diseases (TDR), these compounds could be classified as hits for leishmaniasis and for Chagas disease, respectively. Identification of the hits as well as other SAR data from this initial screening will be valuable for design of more potent and selective potential drugs against these neglected tropical diseases.

Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability

PubMed Central

Hendriks, Delilah F. G.; Fredriksson Puigvert, Lisa; Messner, Simon; Mortiz, Wolfgang; Ingelman-Sundberg, Magnus

2016-01-01

Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound’s potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days. In contrast, no such synergism was observed after both 8 and 14 days of exposure to the BA mixture for compounds that cause non-cholestatic hepatotoxicity. Mechanisms behind the toxicity of the cholestatic compound chlorpromazine were accurately detected in both spheroid models, including intracellular BA accumulation, inhibition of ABCB11 expression and disruption of the F-actin cytoskeleton. Furthermore, the observed synergistic toxicity of chlorpromazine and BA was associated with increased oxidative stress and modulation of death receptor signalling. Combined, our results demonstrate that the hepatic spheroid models presented here can be used to detect and study compounds with cholestatic liability. PMID:27759057

Weighted Feature Significance: A Simple, Interpretable Model of Compound Toxicity Based on the Statistical Enrichment of Structural Features

PubMed Central

Huang, Ruili; Southall, Noel; Xia, Menghang; Cho, Ming-Hsuang; Jadhav, Ajit; Nguyen, Dac-Trung; Inglese, James; Tice, Raymond R.; Austin, Christopher P.

2009-01-01

In support of the U.S. Tox21 program, we have developed a simple and chemically intuitive model we call weighted feature significance (WFS) to predict the toxicological activity of compounds, based on the statistical enrichment of structural features in toxic compounds. We trained and tested the model on the following: (1) data from quantitative high–throughput screening cytotoxicity and caspase activation assays conducted at the National Institutes of Health Chemical Genomics Center, (2) data from Salmonella typhimurium reverse mutagenicity assays conducted by the U.S. National Toxicology Program, and (3) hepatotoxicity data published in the Registry of Toxic Effects of Chemical Substances. Enrichments of structural features in toxic compounds are evaluated for their statistical significance and compiled into a simple additive model of toxicity and then used to score new compounds for potential toxicity. The predictive power of the model for cytotoxicity was validated using an independent set of compounds from the U.S. Environmental Protection Agency tested also at the National Institutes of Health Chemical Genomics Center. We compared the performance of our WFS approach with classical classification methods such as Naive Bayesian clustering and support vector machines. In most test cases, WFS showed similar or slightly better predictive power, especially in the prediction of hepatotoxic compounds, where WFS appeared to have the best performance among the three methods. The new algorithm has the important advantages of simplicity, power, interpretability, and ease of implementation. PMID:19805409

Predicting the aquatic toxicity mode of action using logistic regression and linear discriminant analysis.

PubMed

Ren, Y Y; Zhou, L C; Yang, L; Liu, P Y; Zhao, B W; Liu, H X

2016-09-01

The paper highlights the use of the logistic regression (LR) method in the construction of acceptable statistically significant, robust and predictive models for the classification of chemicals according to their aquatic toxic modes of action. Essentials accounting for a reliable model were all considered carefully. The model predictors were selected by stepwise forward discriminant analysis (LDA) from a combined pool of experimental data and chemical structure-based descriptors calculated by the CODESSA and DRAGON software packages. Model predictive ability was validated both internally and externally. The applicability domain was checked by the leverage approach to verify prediction reliability. The obtained models are simple and easy to interpret. In general, LR performs much better than LDA and seems to be more attractive for the prediction of the more toxic compounds, i.e. compounds that exhibit excess toxicity versus non-polar narcotic compounds and more reactive compounds versus less reactive compounds. In addition, model fit and regression diagnostics was done through the influence plot which reflects the hat-values, studentized residuals, and Cook's distance statistics of each sample. Overdispersion was also checked for the LR model. The relationships between the descriptors and the aquatic toxic behaviour of compounds are also discussed.

A History of Space Toxicology Mishaps: Lessons Learned and Risk Management

NASA Technical Reports Server (NTRS)

James, John T.

2009-01-01

After several decades of human spaceflight, the community of space-faring nations has accumulated a diverse and sometimes harrowing history of toxicological events that have plagued human space endeavors almost from the very beginning. Lessons have been learned in ground-based test beds and others were discovered the hard way - when human lives were at stake in space. From such lessons one can build a risk-management framework for toxicological events to minimize the probability of a harmful exposure, while recognizing that we cannot foresee all events. Space toxicologists have learned that relatively harmless compounds can be converted by air revitalization systems into compounds that cause serious harm to the crew. Our toxic risk management strategy now includes an assessment of the fate of any compound that might be released into the atmosphere. Propellants are highly toxic compounds, yet we have not always been able to thoroughly isolate the crew from exposure to these toxicants. Leakage of fluids from systems has resulted in hazardous conditions at times, and the behavior of such compounds inside a spacecraft has taught us how to manage potentially harmful escapes should they occur. Potential combustion events are an ever-present threat to the wellbeing of the crew. Such events have been sufficiently common that we have learned that one cannot judge the health threat of a given fire by the magnitude of the event. Management of such risks demands monitoring of combustion products. In the category of unpredictable toxic events, if one assumes that fires are predictable, we can place experience with toxic microbial metabolites, upsets during repair operations, and discharges from filters that have accumulated a substantial load of pollutants in their absorption beds. Management of such events requires a broad-spectrum, real-time analytical capability to discern the identity and concentrations of pollutants if they enter the atmosphere. Adverse events are an integral part of any human activity, and the spacefaring community must learn as much as possible from mistakes and near misses.

Compound-specific effects of diverse neurodevelopmental toxicants on global gene expression in the neural embryonic stem cell test (ESTn)

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

Theunissen, P.T., E-mail: Peter.Theunissen@rivm.nl; Department of Toxicogenomics, Maastricht University, Maastricht; Robinson, J.F.

Alternative assays for developmental toxicity testing are needed to reduce animal use in regulatory toxicology. The in vitro murine neural embryonic stem cell test (ESTn) was designed as an alternative for neurodevelopmental toxicity testing. The integration of toxicogenomic-based approaches may further increase predictivity as well as provide insight into underlying mechanisms of developmental toxicity. In the present study, we investigated concentration-dependent effects of six mechanistically diverse compounds, acetaldehyde (ACE), carbamazepine (CBZ), flusilazole (FLU), monoethylhexyl phthalate (MEHP), penicillin G (PENG) and phenytoin (PHE), on the transcriptome and neural differentiation in the ESTn. All compounds with the exception of PENG altered ESTnmore » morphology (cytotoxicity and neural differentiation) in a concentration-dependent manner. Compound induced gene expression changes and corresponding enriched gene ontology biological processes (GO–BP) were identified after 24 h exposure at equipotent differentiation-inhibiting concentrations of the compounds. Both compound-specific and common gene expression changes were observed between subsets of tested compounds, in terms of significance, magnitude of regulation and functionality. For example, ACE, CBZ and FLU induced robust changes in number of significantly altered genes (≥ 687 genes) as well as a variety of GO–BP, as compared to MEHP, PHE and PENG (≤ 55 genes with no significant changes in GO–BP observed). Genes associated with developmentally related processes (embryonic morphogenesis, neuron differentiation, and Wnt signaling) showed diverse regulation after exposure to ACE, CBZ and FLU. In addition, gene expression and GO–BP enrichment showed concentration dependence, allowing discrimination of non-toxic versus toxic concentrations on the basis of transcriptomics. This information may be used to define adaptive versus toxic responses at the transcriptome level.« less

Dual Effect of Phenolic Nectar on Three Floral Visitors of Elsholtzia rugulosa (Lamiaceae) in SW China.

PubMed

Zhang, Feng-Ping; Yang, Qiu-Yun; Zhang, Shi-Bao

2016-01-01

Some plants secrete toxic nectar to appeal to most effective pollinators and deter non-pollinators or nectar thieves; however available information about ecological function of toxic nectar remains scarce. Elsholtzia rugulosa stands out as a plant with toxic nectar recorded in SW China. We focused on the functional significance of the phenolic compound that imparts toxic to the nectar of E. rugulosa. The effects of phenolic nectar were studied in three visitors of the flowers of the winter-blooming E. rugulosa Hemsl. (Lamiaceae) in SW China. The pollinating species Apis cerana Fabricius (Apidae; Asian honey bee) and two occasional visitors, Vespa velutina Lepeletier (Vespidae; yellow-legged Asian hornet) and Bombus eximius Smith (Apidae; a bumble bee) were tested for their preferences for low and high concentrations of 4-hydroxybenzoic acid in hexose and sucrose solutions. The pollinator is important for the plant, which is dependent on pollinator visits to attain a higher seed production and it is most likely that the combination of phenolic toxic nectar and the adaptation to phenolic nectar by A. cerana delivers an evolutionary advantage to both actors. The low and high concentrations of the phenolic acid were nearly totally refused by both occasional visitors V. velutina and B. eximius and were preferred by the pollinator A. cerana. E. rugulosa gains by having a much higher seed production and the pollinating honey bee by having an exclusive and reliable food source during the winter season at high altitudes in SW China. We found that the function of the toxic phenolic compound has dual roles by appealing to legitimate pollinators and deterring non-pollinators of E. rugulosa.

Reproductive activities of Heliotropium indicum isolate against Helopeltis theivora and toxicity evaluation in mice.

PubMed

Dolui, A K; Debnath, Manabendra; De, B; Kumar, Atul

2012-05-01

A new compound E was isolated from the methanolic extract of the leaves of Heliotropium indicum by chromatographic fractionation. In the present study, the effect of the compound E on reproduction of Helopeltis theivora has been evaluated. The acute toxicity study (LD50) and sub-acute toxicity studies (haematological, biochemical and histopathological parameters) in albino Swiss mice were carried out to evaluate the safety aspect of the compound E. The compound showed significant inhibitory effect on the reproductive life of H. theivora. The oviposition period, fecundity and hatching percentage of H. theivora were found to be 15.67 days, 39.33 and 28.00% respectively after treatment with 2% compound E, whereas the control value were found to be 20.33 days, 77.67 and 77.33% respectively. The LD50 of the compound was found to be 780 mg kg(-1) in Swiss albino female mice. The compound did not show any toxicity in mice at sub-lethal dose treatment (78 mg kg(-1) b. wt., once daily) for 21 days as evident from different haematological, biochemical and histopathological parameters in compound E treated group when compared with control.

Understanding the toxicological potential of aerosol organic compounds using informatics based screening

NASA Astrophysics Data System (ADS)

Topping, David; Decesari, Stefano; Bassan, Arianna; Pavan, Manuela; Ciacci, Andrea

2016-04-01

Exposure to atmospheric particulate matter is responsible for both short-term and long-term adverse health effects. So far, all efforts spent in achieving a systematic epidemiological evidence of specific aerosol compounds determining the overall aerosol toxicity were unsuccessful. The results of the epidemiological studies apparently conflict with the laboratory toxicological analyses which have highlighted very different chemical and toxicological potentials for speciated aerosol compounds. Speciation remains a problem, especially for organic compounds: it is impossible to conduct screening on all possible molecular species. At the same time, research on toxic compounds risks to be biased towards the already known compounds, such as PAHs and dioxins. In this study we present results from an initial assessment of the use of in silico methods (i.e. (Q)SAR, read-across) to predict toxicity of atmospheric organic compounds including evaluation of applicability of a variety of popular tools (e.g. OECD QSAR Toolbox) for selected endpoints (e.g. genotoxicity). Compounds are categorised based on the need of new experimental data for the development of in silico approaches for toxicity prediction covering this specific chemical space, namely the atmospheric aerosols. Whilst only an initial investigation, we present recommendations for continuation of this work.

Biocides in hydraulic fracturing fluids: a critical review of their usage, mobility, degradation, and toxicity.

PubMed

Kahrilas, Genevieve A; Blotevogel, Jens; Stewart, Philip S; Borch, Thomas

2015-01-06

Biocides are critical components of hydraulic fracturing ("fracking") fluids used for unconventional shale gas development. Bacteria may cause bioclogging and inhibit gas extraction, produce toxic hydrogen sulfide, and induce corrosion leading to downhole equipment failure. The use of biocides such as glutaraldehyde and quaternary ammonium compounds has spurred a public concern and debate among regulators regarding the impact of inadvertent releases into the environment on ecosystem and human health. This work provides a critical review of the potential fate and toxicity of biocides used in hydraulic fracturing operations. We identified the following physicochemical and toxicological aspects as well as knowledge gaps that should be considered when selecting biocides: (1) uncharged species will dominate in the aqueous phase and be subject to degradation and transport whereas charged species will sorb to soils and be less bioavailable; (2) many biocides are short-lived or degradable through abiotic and biotic processes, but some may transform into more toxic or persistent compounds; (3) understanding of biocides' fate under downhole conditions (high pressure, temperature, and salt and organic matter concentrations) is limited; (4) several biocidal alternatives exist, but high cost, high energy demands, and/or formation of disinfection byproducts limits their use. This review may serve as a guide for environmental risk assessment and identification of microbial control strategies to help develop a sustainable path for managing hydraulic fracturing fluids.

Review on fate and mechanism of removal of pharmaceutical pollutants from wastewater using biological approach.

PubMed

Tiwari, Bhagyashree; Sellamuthu, Balasubramanian; Ouarda, Yassine; Drogui, Patrick; Tyagi, Rajeshwar D; Buelna, Gerardo

2017-01-01

Due to research advancement and discoveries in the field of medical science, maintains and provides better human health and safer life, which lead to high demand for production of pharmaceutical compounds with a concomitant increase in population. These pharmaceutical (biologically active) compounds were not fully metabolized by the body and excreted out in wastewater. This micro-pollutant remains unchanged during wastewater treatment plant operation and enters into the receiving environment via the discharge of treated water. Persistence of pharmaceutical compounds in both surface and ground waters becomes a major concern due to their potential eco-toxicity. Pharmaceuticals (emerging micro-pollutants) deteriorate the water quality and impart a toxic effect on living organisms. Therefore, from last two decades, plenty of studies were conducted on the occurrence, impact, and removal of pharmaceutical residues from the environment. This review provides an overview on the fate and removal of pharmaceutical compounds via biological treatment process. Copyright © 2016 Elsevier Ltd. All rights reserved.

(Q)SARs to predict environmental toxicities: current status and future needs.

PubMed

Cronin, Mark T D

2017-03-22

The current state of the art of (Quantitative) Structure-Activity Relationships ((Q)SARs) to predict environmental toxicity is assessed along with recommendations to develop these models further. The acute toxicity of compounds acting by the non-polar narcotic mechanism of action can be well predicted, however other approaches, including read-across, may be required for compounds acting by specific mechanisms of action. The chronic toxicity of compounds to environmental species is more difficult to predict from (Q)SARs, with robust data sets and more mechanistic information required. In addition, the toxicity of mixtures is little addressed by (Q)SAR approaches. Developments in environmental toxicology including Adverse Outcome Pathways (AOPs) and omics responses should be utilised to develop better, more mechanistically relevant, (Q)SAR models.

PHILIS (PORTABLE HIGH-THROUGHPUT INTEGRATED LABORATORY IDENTIFICATION SYSTEM)

EPA Pesticide Factsheets

These mobile laboratory assets, for the on-site analysis of chemical warfare agent (CWA) and toxic industrial compound (TIC) contaminated environmental samples, are part of the evolving Environmental Response Laboratory Network (ERLN).

Exploitation of deep-sea resources: the urgent need to understand the role of high pressure in the toxicity of chemical pollutants to deep-sea organisms.

PubMed

Mestre, Nélia C; Calado, Ricardo; Soares, Amadeu M V M

2014-02-01

The advent of industrial activities in the deep sea will inevitably expose deep-sea organisms to potentially toxic compounds. Although international regulations require environmental risk assessment prior to exploitation activities, toxicity tests remain focused on shallow-water model species. Moreover, current tests overlook potential synergies that may arise from the interaction of chemicals with natural stressors, such as the high pressures prevailing in the deep sea. As pressure affects chemical reactions and the physiology of marine organisms, it will certainly affect the toxicity of pollutants arising from the exploitation of deep-sea resources. We emphasize the need for environmental risk assessments based on information generated from ecotoxicological trials that mimic, as close as possible, the deep-sea environment, with emphasis to a key environmental factor - high hydrostatic pressure. Copyright © 2013 Elsevier Ltd. All rights reserved.

Synthesis and toxicity evaluation of hydrophobic ionic liquids for volatile organic compounds biodegradation in a two-phase partitioning bioreactor.

PubMed

Rodriguez Castillo, Alfredo Santiago; Guihéneuf, Solène; Le Guével, Rémy; Biard, Pierre-François; Paquin, Ludovic; Amrane, Abdeltif; Couvert, Annabelle

2016-04-15

Synthesis of several hydrophobic ionic liquids (ILs), which might be selected as good candidates for degradation of hydrophobic volatile organic compounds in a two-phase partitioning bioreactor (TPPB), were carried out. Several bioassays were also realized, such as toxicity evaluation on activated sludge and zebrafish, cytotoxicity, fluoride release in aqueous phase and biodegradability in order to verify their possible effects in case of discharge in the aquatic environment and/or human contact during industrial manipulation. The synthesized compounds consist of alkylimidazoliums, functionalized imidazoliums, isoqinoliniums, triazoliums, sulfoniums, pyrrolidiniums and morpholiniums and various counter-ions such as: PF6(-), NTf2(-) and NfO(-). Toxicity evaluation on activated sludge of each compound (5% v/v of IL) was assessed by using a glucose uptake inhibition test. Toxicity against zebrafish and cytotoxicity were evaluated by the ImPACCell platform of Rennes (France). Fluoride release in water was estimated by regular measurements using ion chromatography equipment. IL biodegradability was determined by measuring BOD28 of aqueous samples (compound concentration,1mM). All ILs tested were not biodegradable; while some of them were toxic toward activated sludge. Isoquinolinium ILs were toxic to human cancerous cell lines. Nevertheless no toxicity was found against zebrafish Danio rerio. Only one IL released fluoride after long-time agitation. Copyright © 2016 Elsevier B.V. All rights reserved.

Evaluation of Toxicological Effects of an Aqueous Extract of Shells from the Pecan Nut Carya illinoinensis (Wangenh.) K. Koch and the Possible Association with Its Inorganic Constituents and Major Phenolic Compounds.

PubMed

Porto, Luiz Carlos S; da Silva, Juliana; Sousa, Karen; Ambrozio, Mariana L; de Almeida, Aline; Dos Santos, Carla Eliete I; Dias, Johnny F; Allgayer, Mariangela C; Dos Santos, Marcela S; Pereira, Patrícia; Ferraz, Alexandre B F; Picada, Jaqueline N

2016-01-01

Background. Industrial processing of the pecan nut Carya illinoinensis K. Koch generated a large amount of shells, which have been used to prepare nutritional supplements and medicinal products; however, the safe use of shells requires assessment. This study evaluated the toxic, genotoxic, and mutagenic effects of pecan shell aqueous extract (PSAE) and the possible contribution of phenolic compounds, ellagic and gallic acids, and inorganic elements present in PSAE to induce toxicity. Results. Levels of inorganic elements like K, P, Cl, and Rb quantified using the Particle-Induced X-Ray Emission method were higher in PSAE than in pecan shells, while Mg and Mn levels were higher in shells. Mice showed neurobehavioral toxicity when given high PSAE doses (200-2,000 mg kg(-1)). The LD50 was 1,166.3 mg kg(-1). However, PSAE (50-200 mg·kg(-1)) and the phenolic compounds (10-100 mg·kg(-1)) did not induce DNA damage or mutagenicity evaluated using the comet assay and micronucleus test. Treatment with ellagic acid (10-100 mg·kg(-1)) decreased triglyceride and glucose levels, while treatments with PSAE and gallic acid had no effect. Conclusion. Pecan shell toxicity might be associated with high concentrations of inorganic elements such as Mn, Al, Cu, and Fe acting on the central nervous system, besides phytochemical components, suggesting that the definition of the safe dose should take into account the consumption of micronutrients.

Evaluation of Toxicological Effects of an Aqueous Extract of Shells from the Pecan Nut Carya illinoinensis (Wangenh.) K. Koch and the Possible Association with Its Inorganic Constituents and Major Phenolic Compounds

PubMed Central

Porto, Luiz Carlos S.; Sousa, Karen; Ambrozio, Mariana L.; de Almeida, Aline; dos Santos, Carla Eliete I.; Dias, Johnny F.; Allgayer, Mariangela C.; dos Santos, Marcela S.; Pereira, Patrícia; Picada, Jaqueline N.

2016-01-01

Background. Industrial processing of the pecan nut Carya illinoinensis K. Koch generated a large amount of shells, which have been used to prepare nutritional supplements and medicinal products; however, the safe use of shells requires assessment. This study evaluated the toxic, genotoxic, and mutagenic effects of pecan shell aqueous extract (PSAE) and the possible contribution of phenolic compounds, ellagic and gallic acids, and inorganic elements present in PSAE to induce toxicity. Results. Levels of inorganic elements like K, P, Cl, and Rb quantified using the Particle-Induced X-Ray Emission method were higher in PSAE than in pecan shells, while Mg and Mn levels were higher in shells. Mice showed neurobehavioral toxicity when given high PSAE doses (200–2,000 mg kg−1). The LD50 was 1,166.3 mg kg−1. However, PSAE (50–200 mg·kg−1) and the phenolic compounds (10–100 mg·kg−1) did not induce DNA damage or mutagenicity evaluated using the comet assay and micronucleus test. Treatment with ellagic acid (10–100 mg·kg−1) decreased triglyceride and glucose levels, while treatments with PSAE and gallic acid had no effect. Conclusion. Pecan shell toxicity might be associated with high concentrations of inorganic elements such as Mn, Al, Cu, and Fe acting on the central nervous system, besides phytochemical components, suggesting that the definition of the safe dose should take into account the consumption of micronutrients. PMID:27525021

Design, Synthesis, and Antifouling Activity of Glucosamine-Based Isocyanides

PubMed Central

Hasegawa, Yuki; Novita, Ira S.; Suzuki, Junya; Morozumi, Tatsuya; Nogata, Yasuyuki; Yoshimura, Erina; Matsuda, Fuyuhiko

2017-01-01

Biofouling, an undesirable accumulation of organisms on sea-immersed structures such as ship hulls and fishing nets, is a serious economic issue whose effects include oil wastage and clogged nets. Organotin compounds were utilized since the 1960s as an antifouling material; however, the use of such compounds was later banned by the International Maritime Organization (IMO) due to their high toxicity toward marine organisms, resulting in masculinization and imposex. Since the ban, there have been extensive efforts to develop environmentally benign antifoulants. Natural antifouling products obtained from marine creatures have been the subject of considerable attention due to their potent antifouling activity and low toxicity. These antifouling compounds often contain isocyano groups, which are well known to have natural antifouling properties. On the basis of our previous total synthesis of natural isocyanoterpenoids, we envisaged the installation of an isocyano functional group onto glucosamine to produce an environmentally friendly antifouling material. This paper describes an effective synthetic method for various glucosamine-based isocyanides and evaluation of their antifouling activity and toxicity against cypris larvae of the barnacle Amphibalanus amphitrite. Glucosamine isocyanides with an ether functionality at the anomeric position exhibited potent antifouling activity, with EC50 values below 1 μg/mL, without detectable toxicity even at a high concentration of 10 μg/mL. Two isocyanides had EC50 values of 0.23 and 0.25 μg/mL, comparable to that of CuSO4, which is used as a fouling inhibitor (EC50 = 0.27 μg/mL). PMID:28661419

High-throughput screening, predictive modeling and computational embryology

EPA Science Inventory

High-throughput screening (HTS) studies are providing a rich source of data that can be applied to profile thousands of chemical compounds for biological activity and potential toxicity. EPA’s ToxCast™ project, and the broader Tox21 consortium, in addition to projects worldwide,...

Predicting adult fish acute lethality with the zebrafish embryo: relevance of test duration, endpoints, compound properties, and exposure concentration analysis.

PubMed

Knöbel, Melanie; Busser, Frans J M; Rico-Rico, Angeles; Kramer, Nynke I; Hermens, Joop L M; Hafner, Christoph; Tanneberger, Katrin; Schirmer, Kristin; Scholz, Stefan

2012-09-04

The zebrafish embryo toxicity test has been proposed as an alternative for the acute fish toxicity test, which is required by various regulations for environmental risk assessment of chemicals. We investigated the reliability of the embryo test by probing organic industrial chemicals with a wide range of physicochemical properties, toxicities, and modes of toxic action. Moreover, the relevance of using measured versus nominal (intended) exposure concentrations, inclusion of sublethal endpoints, and different exposure durations for the comparability with reported fish acute toxicity was explored. Our results confirm a very strong correlation of zebrafish embryo to fish acute toxicity. When toxicity values were calculated based on measured exposure concentrations, the slope of the type II regression line was 1 and nearly passed through the origin (1 to 1 correlation). Measured concentrations also explained several apparent outliers. Neither prolonged exposure (up to 120 h) nor consideration of sublethal effects led to a reduced number of outliers. Yet, two types of compounds were less lethal to embryos than to adult fish: a neurotoxic compound acting via sodium channels (permethrin) and a compound requiring metabolic activation (allyl alcohol).

Environmental levels, toxicity and human exposure to tributyltin (TBT)-contaminated marine environment. a review. b_antizar@hotmail.com.

PubMed

Antizar-Ladislao, Blanca

2008-02-01

Tributyltin (TBT) is a toxic chemical used for various industrial purposes such as slime control in paper mills, disinfection of circulating industrial cooling waters, antifouling agents, and the preservation of wood. Due to its widespread use as an antifouling agent in boat paints, TBT is a common contaminant of marine and freshwater ecosystems exceeding acute and chronic toxicity levels. TBT is the most significant pesticide in marine and freshwaters in Europe and consequently its environmental level, fate, toxicity and human exposure are of current concern. Thus, the European Union has decided to specifically include TBT compounds in its list of priority compounds in water in order to control its fate in natural systems, due to their toxic, persistent, bioaccumulative and endocrine disruptive characteristics. Additionally, the International Maritime Organization has called for a global treaty that bans the application of TBT-based paints starting 1 of January 2003, and total prohibition by 1 of January 2008. This paper reviews the state of the science regarding TBT, with special attention paid to the environmental levels, toxicity, and human exposure. TBT compounds have been detected in a number of environmental samples. In humans, organotin compounds have been detected in blood and in the liver. As for other persistent organic pollutants, dietary intake is most probably the main route of exposure to TBT compounds for the general population. However, data concerning TBT levels in foodstuffs are scarce. It is concluded that investigations on experimental toxicity, dietary intake, potential human health effects and development of new sustainable technologies to remove TBT compounds are clearly necessary.

Fate and effects of picric acid and 2,6-DNT in marine environments: toxicity of degradation products.

PubMed

Nipper, Marion; Carr, R Scott; Biedenbach, James M; Hooten, Russell L; Miller, Karen

2005-11-01

The toxicity of transformation products of 2,6-dinitrotoluene (2,6-DNT) and 2,4,6-trinitrophenol (picric acid) were assessed in spiked sandy and fine-grained marine sediments and in seawater. Toxicity of pore water from sediments spiked with 2,6-DNT decreased for the macro-alga, Ulva fasciata, zoospores as biotransformation proceeded, but increased for the copepod, Schizopera knabeni, nauplii. The primary biotransformation product of 2,6-DNT, 2-amino-6-nitrotoluene, was also more toxic than the parent compound to copepod nauplii, but not to alga zoospores, in spiked seawater tests. Two biotransformation products of picric acid, picramic acid and 2,4-DNP, were more toxic than their parent compound. Porewater toxicity from picric acid-spiked sediments decreased significantly at the end of six-months incubation. Fine-grained sediment spiked with either ordnance compound had lower toxicity than its sandy counterpart after six months, suggesting faster microbial transformation in the former and production of less toxic products. Photo-transformation of 2,6-DNT in seawater resulted in a reduction in toxicity.

Catalytic Destruction Of Toxic Organic Compounds

NASA Technical Reports Server (NTRS)

Voecks, Gerald E.

1990-01-01

Proposed process disposes of toxic organic compounds in contaminated soil or carbon beds safely and efficiently. Oxidizes toxic materials without producing such other contaminants as nitrogen oxides. Using air, fuel, catalysts, and steam, system consumes less fuel and energy than decontamination processes currently in use. Similar process regenerates carbon beds used in water-treatment plants.

Mercury toxicity reduced by selenium

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

Not Available

1973-01-01

A methylmercury compound added to a tuna-corn-soya ration fed to Japanese quail was less toxic than an equivalent amount of the compound added to the basal corn-soya ration. Selenium present in the tuna is apparently the factor that reduces mercury toxicity, since it was also reduced or prevented by addition of selenium to the diets.

Predictive models in hazard assessment of Great Lakes contaminants for fish

USGS Publications Warehouse

Passino, Dora R. May

1986-01-01

A hazard assessment scheme was developed and applied to predict potential harm to aquatic biota of nearly 500 organic compounds detected by gas chromatography/mass spectrometry (GC/MS) in Great Lakes fish. The frequency of occurrence and estimated concentrations of compounds found in lake trout (Salvelinus namaycush) and walleyes (Stizostedion vitreum vitreum) were compared with available manufacturing and discharge information. Bioconcentration potential of the compounds was estimated from available data or from calculations of quantitative structure-activity relationships (QSAR). Investigators at the National Fisheries Research Center-Great Lakes also measured the acute toxicity (48-h EC50's) of 35 representative compounds to Daphnia pulex and compared the results with acute toxicity values generated by QSAR. The QSAR-derived toxicities for several chemicals underestimated the actual acute toxicity by one or more orders of magnitude. A multiple regression of log EC50 on log water solubility and molecular volume proved to be a useful predictive model. Additional models providing insight into toxicity incorporate solvatochromic parameters that measure dipolarity/polarizability, hydrogen bond acceptor basicity, and hydrogen bond donor acidity of the solute (toxicant).

Growth of Pure Cultures of Marine Phytoplankton in the Presence of Toxicants

PubMed Central

Ukeles, Ravenna

1962-01-01

The effects of 17 toxicants on the growth of five species of algae in pure culture were studied. The two species displaying the greatest sensitivity to the action of each of the compounds tested were Monochrysis lutheri and Phaeodactylum tricornutum, and the most resistant species was Protococcus. Of eight different classes of toxicants tested, substituted urea compounds and a mercuric compound were most effective in inhibiting growth of all algal species at the lowest concentrations. PMID:13995259

Evaluation of “Dream Herb,” Calea zacatechichi, for Nephrotoxicity Using Human Kidney Proximal Tubule Cells

PubMed Central

Flynn, Thomas J.; Vohra, Sanah; Wiesenfeld, Paddy; Sprando, Robert L.

2016-01-01

A recent surge in the use of dietary supplements, including herbal remedies, necessitates investigations into their safety profiles. “Dream herb,” Calea zacatechichi, has long been used in traditional folk medicine for a variety of purposes and is currently being marketed in the US for medicinal purposes, including diabetes treatment. Despite the inherent vulnerability of the renal system to xenobiotic toxicity, there is a lack of safety studies on the nephrotoxic potential of this herb. Additionally, the high frequency of diabetes-associated kidney disease makes safety screening of C. zacatechichi for safety especially important. We exposed human proximal tubule HK-2 cells to increasing doses of this herb alongside known toxicant and protectant control compounds to examine potential toxicity effects of C. zacatechichi relative to control compounds. We evaluated both cellular and mitochondrial functional changes related to toxicity of this dietary supplement and found that even at low doses evidence of cellular toxicity was significant. Moreover, these findings correlated with significantly elevated levels of nephrotoxicity biomarkers, lending further support for the need to further scrutinize the safety of this herbal dietary supplement. PMID:27703475

Toxic effects of two essential oils and their constituents on the mealworm beetle, Tenebrio molitor.

PubMed

Martínez, L C; Plata-Rueda, A; Colares, H C; Campos, J M; Dos Santos, M H; Fernandes, F L; Serrão, J E; Zanuncio, J C

2017-12-14

The study identified insecticidal effects from the cinnamon and clove essential oils in Tenebrio molitor L. (Coleoptera: Tenebrionidae). The lethal concentrations (LC50 and LC90), lethal time, and repellent effect on larvae, pupae, and adults of T. molitor after exposure to six concentrations of each essential oil and toxic compounds were evaluated. The chemical composition of the cinnamon oil was also determined and primary compounds were eugenol (10.19%), trans-3-caren-2-ol (9.92%), benzyl benzoate (9.68%), caryophyllene (9.05%), eugenyl acetate (7.47%), α-phellandrene (7.18%), and α-pinene (6.92%). In clove essential oil, the primary compounds were eugenol (26.64%), caryophyllene (23.73%), caryophyllene oxide (17.74%), 2-propenoic acid (11.84%), α-humulene (10.48%), γ-cadinene (4.85%), and humulene oxide (4.69%). Cinnamon and clove essential oils were toxic to T. molitor. In toxic chemical compounds, eugenol have stronger contact toxicity in larvae, pupae, and adult than caryophyllene oxide, followed by α-pinene, α-phellandrene, and α-humulene. In general, the two essential oils were toxic and repellent to adult T. molitor. Cinnamon and clove essential oils and their compounds caused higher mortality and repellency on T. molitor and, therefore, have the potential for integrated management programs of this insect.

A new sensor for the assessment of personal exposure to volatile organic compounds

NASA Astrophysics Data System (ADS)

Chen, Cheng; Driggs Campbell, Katherine; Negi, Indira; Iglesias, Rodrigo A.; Owens, Patrick; Tao, Nongjian; Tsow, Francis; Forzani, Erica S.

2012-07-01

To improve our understanding of indoor and outdoor personal exposures to common environmental toxicants released into the environment, new technologies that can monitor and quantify the toxicants anytime anywhere are needed. This paper presents a wearable sensor to provide such capabilities. The sensor can communicate with a common smart phone and provides accurate measurement of volatile organic compound concentration at a personal level in real-time, providing environmental toxicants data every three minutes. The sensor has high specificity and sensitivity to aromatic, alkyl, and chlorinated hydrocarbons with a resolution as low as 4 parts-per-billion (ppb), with a detection range of 4 ppb-1000 ppm (parts-per-million). The sensor's performance was validated using Gas Chromatography and Selected Ion Flow Tube - Mass Spectrometry reference methods in a variety of environments and activities with overall accuracy higher than 81% (r2 > 0.9). Field tests examined personal exposure in various scenarios including: indoor and outdoor environments, traffic exposure in different cities which vary from 0 to 50 ppmC (part-per-million carbon from hydrocarbons), and pollutants near the 2010 Deepwater Horizon's oil spill. These field tests not only validated the performance but also demonstrated unprecedented high temporal and spatial toxicant information provided by the new technology.

A New Sensor for the Assessment of Personal Exposure to Volatile Organic Compounds

PubMed Central

Chen, Cheng; Campbell, Katherine Driggs; Negi, Indira; Iglesias, Rodrigo A.; Owens, Patrick; Tao, Nongjian; Tsow, Francis; Forzani, Erica

2012-01-01

To improve our understanding of indoor and outdoor personal exposures to common environmental toxicants released into the environment, new technologies that can monitor and quantify the toxicants anytime anywhere are needed. This paper presents a wearable sensor to provide such capabilities. The sensor can communicate with a common smart phone and provides accurate measurement of volatile organic compound concentration at a personal level in real time, providing environmental toxicants data every three minutes. The sensor has high specificity and sensitivity to aromatic, alkyl, and chlorinated hydrocarbons with a resolution as low as 4 parts per billion (ppb), with a detection range of 4 ppb to 1000 ppm (parts per million). The sensor's performance was validated using Gas Chromatography and Selected Ion Flow Tube - Mass Spectrometry reference methods in a variety of environments and activities with overall accuracy higher than 81% (r2 > 0.9). Field tests examined personal exposure in various scenarios including: indoor and outdoor environments, traffic exposure in different cities which vary from 0 to 50 ppmC (part-per-million carbon from hydrocarbons), and pollutants near the 2010 Deepwater Horizon's oil spill. These field tests not only validated the performance but also demonstrated unprecedented high temporal and spatial toxicant information provided by the new technology. PMID:22736952

Evaluation of semiochemical toxicity to houseflies and stable flies (Diptera: Muscidae).

PubMed

Mann, Rajinder S; Kaufman, Phillip E; Butler, Jerry F

2010-08-01

The housefly, Musca domestica L., and stable fly, Stomoxys calcitrans (L.) are cosmopolitan pests of both farm and home environments. Houseflies have been shown to be resistant to a variety of insecticides, and new chemistries are slow to emerge on the market. Toxicities of selected semiochemicals with molecular structures indicative of insecticidal activity were determined against adults from an insecticide-susceptible laboratory strain of houseflies. The three most active semiochemicals were also evaluated against recently colonized housefly and stable fly strains. Nineteen semiochemicals classified as aliphatic alcohols, terpenoids, ketones and carboxylic esters showed toxicity to houseflies and stable flies. Rosalva (LC(50) = 25.98 microg cm(-2)) followed by geranyl acetone and citronellol (LC(50) = 49.97 and 50.02 microg cm(-2)) were identified as the most toxic compounds to houseflies. Permethrin was up to 144-fold more toxic than rosalva on the susceptible strain. However, it was only 35-fold more toxic to the insecticide-tolerant field strain. The compounds generated high toxicity to stable flies, with LC(50) values ranging from 16.30 to 40.41 microg cm(-2). Quantification of LC(50) values of rosalva, citronellol and geranyl acetone against susceptible housefly and field-collected housefly and stable fly strains showed that semiochemicals could serve as potent insecticides for fly control programs. Copyright (c) 2010 Society of Chemical Industry.

IMMUNOCHEMICAL DETERMINATION OF DIOXINS IN SEDIMENT SAMPLES

EPA Science Inventory

Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are considered highly toxic contaminants with the environmental monitoring of these compounds being of great importance. Immunoassay procedures such as the enzyme-linked immunosorbent assay (ELIS...

Flavoring Compounds Dominate Toxic Aldehyde Production during E-Cigarette Vaping.

PubMed

Khlystov, Andrey; Samburova, Vera

2016-12-06

The growing popularity of electronic cigarettes (e-cigarettes) raises concerns about the possibility of adverse health effects to primary users and people exposed to e-cigarette vapors. E-Cigarettes offer a very wide variety of flavors, which is one of the main factors that attract new, especially young, users. How flavoring compounds in e-cigarette liquids affect the chemical composition and toxicity of e-cigarette vapors is practically unknown. Although e-cigarettes are marketed as safer alternatives to traditional cigarettes, several studies have demonstrated formation of toxic aldehydes in e-cigarette vapors during vaping. So far, aldehyde formation has been attributed to thermal decomposition of the main components of e-cigarette e-liquids (propylene glycol and glycerol), while the role of flavoring compounds has been ignored. In this study, we have measured several toxic aldehydes produced by three popular brands of e-cigarettes with flavored and unflavored e-liquids. We show that, within the tested e-cigarette brands, thermal decomposition of flavoring compounds dominates formation of aldehydes during vaping, producing levels that exceed occupational safety standards. Production of aldehydes was found to be exponentially dependent on concentration of flavoring compounds. These findings stress the need for a further, thorough investigation of the effect of flavoring compounds on the toxicity of e-cigarettes.

Assessing the risk associated with the presence of emerging organic contaminants in sludge-amended soil: A country-level analysis.

PubMed

Thomaidi, Vasiliki S; Stasinakis, Athanasios S; Borova, Viola L; Thomaidis, Nikolaos S

2016-04-01

Greece was used as case study and the environmental risk associated with the existence of 99 emerging organic contaminants (EOCs) in sludge-amended soil was estimated using risk quotient (RQ) approach. Data on the concentration levels of EOCs in sewage sludge was collected after literature review. Chemical analyses were also conducted for 50 pharmaceuticals and illicit drugs in sludge samples from Athens Sewage Treatment Plant. Risk assessment was based on both terrestrial and aquatic acute toxicity data, using both the maximum and the average measured concentrations of the target compounds. EC50/LC50 values were collected through literature review or using the ECOSAR program in cases that experimental values were not available. Triclosan seems to pose an environmental risk on the soil environment, as its RQ values exceeded 1, both in terrestrial and aquatic toxicity data based risk assessment. Calculations based on aquatic toxicity data showed that another eleven compounds had RQs higher than 1, most of them belonging to the classes of synthetic phenolic compounds and siloxanes. Tetradecamethylhexasiloxane presented the highest RQ, while high RQs were also calculated for decamethylcyclopentasiloxane and caffeine. No environmental risk for the terrestrial environment is expected due to the individual action of illicit drugs, perfluorinated compounds and benzotriazoles. The sludge source and the day of sampling affected the estimated threat due to nonylphenolic compounds; however these factors did not affect the estimated risk for siloxanes, caffeine and ofloxacin. Calculation of RQ values for the mixture of EOCs, using either the maximum or the average concentrations, far exceeded 1 (253 and 209, respectively), indicating a presumable threat for the terrestrial environment due to the baseline toxicity of these compounds. Countries that reuse sludge for agricultural purposes should include specific EOCs in national monitoring campaigns and study more thoroughly on their effects to the terrestrial environment. Copyright © 2016 Elsevier B.V. All rights reserved.

Natural compounds and combination therapy in colorectal cancer treatment.

PubMed

Rejhová, A; Opattová, A; Čumová, A; Slíva, D; Vodička, P

2018-01-20

Colorectal cancer (CRC) therapy using conventional chemotherapeutics represents a considerable burden for the patient's organism because of high toxicity while the response is relatively low. Our review summarizes the findings about natural compounds as chemoprotective agents for decreasing risk of CRC. It also identifies natural compounds which possess anti-tumor effects of various characteristics, mainly in vitro on colorectal cell lines or in vivo studies on experimental models, but also in a few clinical trials. Many of natural compounds suppress proliferation by inducing cell cycle arrest or induce apoptosis of CRC cells resulting in the inhibition of tumor growth. A novel employment of natural substances is a so-called combination therapy - administration of two or more substances - conventional chemotherapeutics and a natural compound or more natural compounds at a time. Some natural compounds may sensitize to conventional cytotoxic therapy, reinforce the drug effective concentration, intensify the combined effect of both administered therapeutics or exert cytotoxic effects specifically on tumor cells. Moreover, combined therapy by targeting multiple signaling pathways, uses various mechanisms to reduce the development of resistance to antitumor drugs. The desired effect could be to diminish burden on the patient's organism by replacing part of the dose of a conventional chemotherapeutic with a natural substance with a defined effect. Many natural compounds are well tolerated by the patients and do not cause toxic effects even at high doses. Interaction of conventional chemotherapeutics with natural compounds introduces a new aspect in the research and therapy of cancer. It could be a promising approach to potentially achieve improvements, while minimizing of adverse effects associated with conventional chemotherapy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The comparative toxicity of DDT and analogues to susceptible and resistant houseflies and mosquitos*

PubMed Central

Metcalf, R. L.; Fukuto, T. R.

1968-01-01

Studies of the comparative toxicity of more than 120 DDT analogues to susceptible and insecticide-resistant houseflies (Musca domestica L.) and mosquitos (Culex fatigans Wiedemann and Anopheles albimanus Wiedemann) have shown that the relative effectiveness of these compounds against DDT-resistant insects is correlated with the susceptibility of the molecule to attack by DDT-ase at the benzylic hydrogen. Compounds highly effective against DDT-resistant flies and mosquitos are produced by blocking this detoxication mechanism by o-chlorination, α-fluorination, and by altering the aliphatic portion of the molecule as in the nitropropyl, neopentyl, dichlorocyclopropyl, and trichlorobenzanilide derivatives. These compounds offer practical possibilities for the control of DDT-resistant insects. The correlation of structure, DDT-like activity, and resistance ratios gives new insight into the mode of action of DDT and the nature of DDT resistance. PMID:4386201

Predicting mixture toxicity of seven phenolic compounds with similar and dissimilar action mechanisms to Vibrio qinghaiensis sp.nov.Q67.

PubMed

Huang, Wei Ying; Liu, Fei; Liu, Shu Shen; Ge, Hui Lin; Chen, Hong Han

2011-09-01

The predictions of mixture toxicity for chemicals are commonly based on two models: concentration addition (CA) and independent action (IA). Whether the CA and IA can predict mixture toxicity of phenolic compounds with similar and dissimilar action mechanisms was studied. The mixture toxicity was predicted on the basis of the concentration-response data of individual compounds. Test mixtures at different concentration ratios and concentration levels were designed using two methods. The results showed that the Weibull function fit well with the concentration-response data of all the components and their mixtures, with all relative coefficients (Rs) greater than 0.99 and root mean squared errors (RMSEs) less than 0.04. The predicted values from CA and IA models conformed to observed values of the mixtures. Therefore, it can be concluded that both CA and IA can predict reliable results for the mixture toxicity of the phenolic compounds with similar and dissimilar action mechanisms. Copyright © 2011 Elsevier Inc. All rights reserved.

Novel endotoxin-sequestering compounds with terephthalaldehyde-bis-guanylhydrazone scaffolds.

PubMed

Khownium, Kriangsak; Wood, Stewart J; Miller, Kelly A; Balakrishna, Rajalakshmi; Nguyen, Thuan B; Kimbrell, Matthew R; Georg, Gunda I; David, Sunil A

2006-03-01

We have shown that lipopolyamines bind to the lipid A moiety of lipopolysaccharide, a constituent of Gram-negative bacterial membranes, and neutralize its toxicity in animal models of endotoxic shock. In an effort to identify non-polyamine scaffolds with similar endotoxin-recognizing features, we had observed an unusually high frequency of hits containing guanylhydrazone scaffolds in high-throughput screens. We now describe the syntheses and preliminary structure-activity relationships in a homologous series of bis-guanylhydrazone compounds decorated with hydrophobic functionalities. These first-generation compounds bind and neutralize lipopolysaccharide with a potency comparable to that of polymyxin B, a peptide antibiotic known to sequester LPS.

Photo-oxidation method using MoS2 nanocluster materials

DOEpatents

Wilcoxon, Jess P.

2001-01-01

A method of photo-oxidizing a hydrocarbon compound is provided by dispersing MoS.sub.2 nanoclusters in a solvent containing a hydrocarbon compound contaminant to form a stable solution mixture and irradiating the mixture to photo-oxide the hydrocarbon compound. Hydrocarbon compounds of interest include aromatic hydrocarbon and chlorinated hydrocarbons. MoS.sub.2 nanoclusters with an average diameter less than approximately 10 nanometers are shown to be effective in decomposing potentially toxic aromatic and chlorinated hydrocarbons, such as phenol, pentachlorophenol, chlorinated biphenols, and chloroform, into relatively non-toxic compounds. The irradiation can occur by exposing the MoS.sub.2 nanoclusters and hydrocarbon compound mixture with visible light. The MoS.sub.2 nanoclusters can be introduced to the toxic hydrocarbons as either a MoS.sub.2 solution or deposited on a support material.

Application of solar photo-Fenton toward toxicity removal and textile wastewater reuse.

PubMed

Starling, Maria Clara V M; Dos Santos, Paulo Henrique Rodrigues; de Souza, Felipe Antônio Ribeiro; Oliveira, Sílvia Corrêa; Leão, Mônica M D; Amorim, Camila C

2017-05-01

Solar photo-Fenton represents an innovative and low-cost option for the treatment of recalcitrant industrial wastewater, such as the textile wastewater. Textile wastewater usually shows high acute toxic and variability and may be composed of many different chemical compounds. This study aimed at optimizing and validating solar photo-Fenton treatment of textile wastewater in a semi-pilot compound parabolic collector (CPC) for toxicity removal and wastewater reclamation. In addition, treated wastewater reuse feasibility was investigated through pilot tests. Experimental design performed in this study indicated optimum condition for solar photo-Fenton reaction (20 mg L -1 of Fe 2+ and 500 mg L -1 of H 2 O 2 ; pH 2.8), which achieved 96 % removal of dissolved organic carbon (DOC) and 99 % absorbance removal. A toxicity peak was detected during treatment, suggesting that highly toxic transformation products were formed during reaction. Toxic intermediates were properly removed during solar photo-Fenton (SPF) treatment along with the generation of oxalic acid as an ultimate product of degradation and COS increase. Different samples of real textile wastewater were treated in order to validate optimized treatment condition with regard to wastewater variability. Results showed median organic carbon removal near 90 %. Finally, reuse of treated textile wastewater in both dyeing and washing stages of production was successful. These results confirm that solar photo-Fenton, as a single treatment, enables wastewater reclamation in the textile industry. Graphical abstract Solar photo-Fenton as a revolutionary treatment technology for "closing-the-loop" in the textile industry.

Mammalian Toxicity of Munitions Compounds. Phase II. Effects of Multiple Doses Part II. 2,4-Dinitrotoluene

DTIC Science & Technology

1978-11-01

middle, or high levels of 2,4-DNT in the feed averaged 34, 93, or 266 mg/kg/day, respectively. The female rats consumed an average of 38, 108, or 145 mg...intake of males fed the low, middle or high levels of 2,4-DNT in the feed averaged 47, 137, or 413 mg/kg/day, respectively. The female mice consumed an...Experimental Procedures All dogs were observed daily for behavioral changes and toxic signs. Body weights of all dogs were recorded weekly. Blood

The first evidence of deinoxanthin from Deinococcus sp. Y35 with strong algicidal effect on the toxic dinoflagellate Alexandrium tamarense.

PubMed

Li, Yi; Zhu, Hong; Lei, Xueqian; Zhang, Huajun; Guan, Chengwei; Chen, Zhangran; Zheng, Wei; Xu, Hong; Tian, Yun; Yu, Zhiming; Zheng, Tianling

2015-06-15

Harmful algal blooms (HABs) could be deemed hazardous materials in aquatic environment. Alexandrium tamarense is a toxic HAB causing alga, which causes serious economic losses and health problems. In this study, the bacterium Deinococcus xianganensis Y35 produced a new algicide, showing a high algicidal effect on A. tamarense. The algicidal compound was identified as deinoxanthin, a red pigment, based on high resolution mass spectrometry and NMR after the active compound was isolated and purified. Deinoxanthin exhibited an obvious inhibitory effect on algal growth, and showed algicidal activity against A. tamarense with an EC50 of 5.636 μg/mL with 12h treatment time. Based on the unique structure and characteristics of deinoxanthin, the content of reactive oxygen species (ROS) increased after 0.5h exposure, the structure of organelles including chloroplasts and mitochondria were seriously damaged. All these results firstly confirmed that deinoxanthin as the efficient and eco-environmental algicidal compound has potential to be used for controlling harmful algal blooms through overproduction of ROS. Copyright © 2015 Elsevier B.V. All rights reserved.

Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach.

PubMed

Nara, Hiroshi; Sato, Kenjiro; Naito, Takako; Mototani, Hideyuki; Oki, Hideyuki; Yamamoto, Yoshio; Kuno, Haruhiko; Santou, Takashi; Kanzaki, Naoyuki; Terauchi, Jun; Uchikawa, Osamu; Kori, Masakuni

2014-11-13

Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid inhibitor 21k exhibited excellent potency and selectivity for MMP-13 over other MMPs. An effort to convert compound 21k to the mono sodium salt 38 was promising in all animal species studied. Moreover, no overt toxicity was observed in a preliminary repeat dose oral toxicity study of compound 21k in rats. A single oral dose of compound 38 significantly reduced degradation products (CTX-II) released from articular cartilage into the joint cavity in a rat MIA model in vivo. In this article, we report the discovery of highly potent, selective, and orally bioavailable MMP-13 inhibitors as well as their detailed structure-activity data.

Toxicity identification evaluation of cosmetics industry wastewater.

PubMed

de Melo, Elisa Dias; Mounteer, Ann H; Leão, Lucas Henrique de Souza; Bahia, Renata Cibele Barros; Campos, Izabella Maria Ferreira

2013-01-15

The cosmetics industry has shown steady growth in many developing countries over the past several years, yet little research exists on toxicity of wastewaters it generates. This study describes a toxicity identification evaluation conducted on wastewater from a small Brazilian hair care products manufacturing plant. Physicochemical and ecotoxicological analyses of three wastewater treatment plant inlet and outlet samples collected over a six month period revealed inefficient operation of the treatment system and thus treated wastewater organic matter, suspended solids and surfactants contents consistently exceeded discharge limits. Treated wastewater also presented high acute toxicity to Daphnia similis and chronic toxicity to Ceriodaphnia dubia and Pseudokirchneriella subcapitata. This toxicity was associated with suspended solids, volatile or sublatable and non-polar to moderately polar organic compounds that could be recovered in filtration and aeration residues. Seven surfactants used in the largest quantities in the production process were highly toxic to P. subcapitata and D. similis. These results indicated that surfactants, important production raw materials, are a probable source of toxicity, although other possible sources, such as fragrances, should not be discarded. Improved treatment plant operational control may reduce toxicity and lower impact of wastewater discharge to receiving waters. Copyright © 2012 Elsevier B.V. All rights reserved.

Toxicity and fate of two munitions constituents in spiked sediment exposures with the marine amphipod Eohaustorius estuarius.

PubMed

Rosen, Gunther; Lotufo, Guilherme R

2005-11-01

The lethal toxicity of the explosive compounds 14C-labeled 2,4,6-trinitrotoluene (TNT) and nonradiolabeled hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) to the estuarine amphipod Eohaustorius estuarius was investigated in 10-d spiked sediment exposures. The 10-d median lethal concentration (LC50) was determined using the sum molar initial concentration of TNT, aminodinitrotoluenes (ADNTs), and diaminonitrotoluenes (DANTs), as determined by high-performance liquid chromatography (HPLC), and collectively referred to as HPLC-TNT*. Despite expectations of higher toxicity in sandy sediment (Yaquina Bay [YB], OR, USA) compared to relatively fine-grained sediment (San Diego Bay [SDB], CA, USA), LC50 values were similar: 159 and 125 micromol/kg, for YB and SDB sediments, respectively. When expressed as the sum of TNT and all its degradation products (14C-TNT*), LC50s were approximately two times the corresponding LC50s determined by HPLC. The HPLC-TNT* fraction likely corresponds to the most bioavailable and toxic transformation products. The concentrations of 14C-TNT* in tissues were substantially higher than those for HPLC-TNT*, suggesting that compounds other than TNT and its major aminated transformation products were prevalent. Critical body residues were similar for exposures to SDB (11.7 micromol/kg) and YB sediments (39.4 micromol/kg), despite marked differences in the nature of compounds available for uptake in the exposure media. The critical body residues for E. estuarius are lower than those reported for other aquatic invertebrates (83-172 micromol/kg). Unlike observations for TNT, RDX was only loosely associated with SDB sediment, with near complete recovery of the parent compound by chemical analysis. Exposure to RDX did not result in significant mortality even at the highest measured sediment concentration of 10,800 micromol/kg dry weight, nor tissue concentrations as high as 96 micromol/kg wet weight. The lack of RDX lethal effects in this study is consistent with results reported for other invertebrate species.

Determination of drugs in surface water and wastewater samples by liquid chromatography-mass spectrometry: Methods and preliminary results including toxicity studies with Vibrio fischeri

USGS Publications Warehouse

Farre, M.; Ferrer, I.; Ginebreda, A.; Figueras, M.; Olivella, L.; Tirapu, L.; Vilanova, M.; Barcelo, D.

2001-01-01

In the present work a combined analytical method involving toxicity and liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) was developed for the determination of pharmaceutical compounds in water samples. The drugs investigated were the analgesics: ibuprofen, ketoprofen, naproxen, and diclofenac, the decomposition product of the acetyl salicylic acid: salicylic acid and one lipid lowering agent, gemfibrozil. The selected compounds are acidic substances, very polar and all of them are analgesic compounds that can be purchased without medical prescription. The developed protocol consisted, first of all, on the use Microtox?? and ToxAlert??100 toxicity tests with Vibrio fischeri for the different pharmaceutical drugs. The 50% effective concentration (EC50) values and the toxicity units (TU) were determined for every compound using both systems. Sample enrichment of water samples was achieved by solid-phase extraction procedure (SPE), using the Merck LiChrolut?? EN cartridges followed by LC-ESI-MS. Average recoveries loading 1 l of samples with pH=2 varied from 69 to 91% and the detection limits in the range of 15-56 ng/l. The developed method was applied to real samples from wastewater and surface-river waters of Catalonia (north-east of Spain). One batch of samples was analyzed in parallel also by High Resolution Gas Chromatography coupled with Mass Spectrometry (HRGC-MS) and the results have been compared with the LC-ESI-MS method developed in this work. ?? 2001 Elsevier Science B.V. All rights reserved.

Medicinal Uses, Phytochemistry, and Pharmacology of Origanum onites (L.): A Review.

PubMed

Tepe, Bektas; Cakir, Ahmet; Sihoglu Tepe, Arzuhan

2016-05-01

Origanum onites L., known as Turkish oregano, has great traditional, medicinal, preservative, and commercial importance. It is used for the treatment of several kinds of ailments, such as gastrointestinal disorders, diabetes, high cholesterol, leukemia, bronchitis, etc. In this review, traditional use, phytochemistry, and pharmacology of O. onites reported between 1988 and 2014 were discussed. This review was prepared based on literature survey on scientific journals and books from libraries and electronic sources, such as Web of Science, PubMed, Scopus, Google Scholar, etc. All databases were searched up to June 2014. Several different classes of terpenoids, triterpene acids, phenolic acids, hydroquinones, flavonoids, hydrocarbons, sterols, pigments, fatty acids, tocopherols, and inorganic compounds were detected mainly in the aerial parts of this plant. Pharmacological studies revealed that extracts obtained from several solvents and individual compounds exhibited antimicrobial, antiviral, antioxidant, insecticidal, anticancer, hepatoprotective, genotoxic, antidiabetic, cholinesterase inhibitory, anti-inflammatory, analgesic activities, etc. O. onites, in general, exhibited remarkable activity potential in almost all test systems. The results of toxicity studies indicated that O. onites did not show any significant toxicity and mutagenicity on Drosophila and Salmonella. Toxicity of the extracts/essential oils and also individual compounds should be evaluated on mammalian cells to ensure their safety. The bioactivity of individual compounds aside from terpenoids should also be assessed in detail. Additionally, mode of action for the bioactive compounds should be evaluated to understand the complex pharmacological effects of these phytochemicals. © 2016 Verlag Helvetica Chimica Acta AG, Zürich.

Granulated decontamination formulations

DOEpatents

Tucker, Mark D.

2007-10-02

A decontamination formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a sorbent additive, and water. A highly adsorbent sorbent additive (e.g., amorphous silica, sorbitol, mannitol, etc.) is used to "dry out" one or more liquid ingredients into a dry, free-flowing powder that has an extended shelf life, and is more convenient to handle and mix in the field.

Ecotoxicity of quinoline and hydroxylated derivatives and their occurrence in groundwater of a tar-contaminated field site.

PubMed

Neuwoehner, Judith; Reineke, Anne-Kirsten; Hollender, Juliane; Eisentraeger, Adolf

2009-03-01

In the groundwater of a timber impregnation site higher concentrations of hydroxylated quinolines compared to their parent compounds quinoline and isoquinoline were found. Studying the toxicity of parent compounds and metabolites, genotoxicity was found with metabolic activation in the SOS-Chromotest and Ames fluctuation test only for quinoline. An adverse effect on algae was observed only for the parent compounds quinoline and isoquinoline, while in the Daphnia magna immobilization assay most hydroxylated quinoline derivatives showed toxicity. The highest ecotoxic potential was observed in the Vibrio fischeri luminescence-inhibition assay. Comparing experimental EC50-values with QSAR predicted ones, for all compounds apart from isoquinoline and 2(1H)-quinolinone in the V. fischeri test baseline toxicity or polar nacrosis is indicated. In conclusion, the hydroxylation of quinoline leads to a detoxification of the genotoxic potential, while taken additive mixture toxicity and a safety factor into account parent compounds and metabolites are found of ecotoxicological relevance in the groundwater.

A high throughput drug screening assay to identify compounds that promote oligodendrocyte differentiation using acutely dissociated and purified oligodendrocyte precursor cells.

PubMed

Lariosa-Willingham, Karen D; Rosler, Elen S; Tung, Jay S; Dugas, Jason C; Collins, Tassie L; Leonoudakis, Dmitri

2016-09-05

Multiple sclerosis is caused by an autoimmune response resulting in demyelination and neural degeneration. The adult central nervous system has the capacity to remyelinate axons in part through the generation of new oligodendrocytes (OLs). To identify clinical candidate compounds that may promote remyelination, we have developed a high throughput screening (HTS) assay to identify compounds that promote the differentiation of oligodendrocyte precursor cells (OPCs) into OLs. Using acutely dissociated and purified rat OPCs coupled with immunofluorescent image quantification, we have developed an OL differentiation assay. We have validated this assay with a known promoter of differentiation, thyroid hormone, and subsequently used the assay to screen the NIH clinical collection library. We have identified twenty-seven hit compounds which were validated by dose response analysis and the generation of half maximal effective concentration (EC50) values allowed for the ranking of efficacy. The assay identified novel promoters of OL differentiation which we attribute to (1) the incorporation of an OL toxicity pre-screen to allow lowering the concentrations of toxic compounds and (2) the utilization of freshly purified, non-passaged OPCs. These features set our assay apart from other OL differentiation assays used for drug discovery efforts. This acute primary OL-based differentiation assay should be of use to those interested in screening large compound libraries for the identification of drugs for the treatment of MS and other demyelinating diseases.

Environmental labeling of car tires--toxicity to Daphnia magna can be used as a screening method.

PubMed

Wik, Anna; Dave, Göran

2005-02-01

Car tires contain several water-soluble compounds that can leach into water and have toxic effects on aquatic organisms. Due to tire wear, 10,000 tonnes of rubber particles end up along the Swedish roads every year. This leads to a diffuse input of emissions of several compounds. Emissions of polyaromatic hydrocarbons (PAHs) are of particular concern. PAHs are ingredients of the high aromatic oil (HA oil) that is used in the rubber as a softener and as a filler. The exclusion of HA oils from car tires has started, and an environmental labeling of tires could make HA oils obsolete. The toxicity to Daphnia magna from 12 randomly selected car tires was tested in this study. Rubber from the tread of the tires was grated into small pieces, to simulate material from tire wear, and the rubber was equilibrated with dilution water for 72 h before addition of test organisms. The 24-h EC50s of the rubber pieces ranged from 0.29 to 32 gl-1, and the 48-h EC50s ranged from 0.0625 to 2.41 gl-1. Summer tires were more toxic than winter tires. After the 48-h exposure, the daphnids were exposed to UV-light for 2 h, to determine if the tires contained compounds that were phototoxic. After UV-activation the EC50s ranged from 0.0625 to 0.38 gl-1. Four of the 12 tires had a very distinct photoactivation, with a toxicity increase of >10 times. This study has shown that the used method for toxicity testing with Daphnia magna according to ISO 6341 could be used as a basis for environmental labeling of car tires.

Where does the toxicity come from in saponin extract?

PubMed

Jiang, Xiaogang; Cao, Yi; Jørgensen, Louise von Gersdorff; Strobel, Bjarne W; Hansen, Hans Chr Bruun; Cedergreen, Nina

2018-08-01

Saponin-rich plant extracts contain bioactive natural compounds and have many applications, e.g. as biopesticides and biosurfactants. The composition of saponin-rich plant extracts is very diverse, making environmental monitoring difficult. In this study various ecotoxicity data as well as exposure data have been collected to explore which compounds in the plant extract are relevant as plant protection agents and furthermore to clarify which compounds may cause undesired side-effects due to their toxicity. Hence, we quantified the toxicity of different fractions (saponins/non-saponins) in the plant extracts on the aquatic crustacean Daphnia magna and zebrafish (Danio rerio) embryos. In addition, we tested the toxicity changes during saponin degradation as well. The results confirm that saponins are responsible for the majority of toxicity (85.1-93.6%) of Quillaja saponaria extract. We, therefore, suggest saponins to be the main target of saponin-rich plant extracts, for instance in the saponin-based biopesticide regulation. Furthermore, we suggest that an abundant saponin fraction, QS-18 from Q. saponaria, can be a key monitoring target to represent the environmental concentration of the saponins, as it contributes with 26% and 61% of the joint toxicity to D. magna and D. rerio, respectively out of the total saponins. The degradation products of saponins are 3-7 times less toxic than the parent compound; therefore the focus should be mainly on the parent compounds. Copyright © 2018 Elsevier Ltd. All rights reserved.

Synthesis and biological evaluation of febrifugine analogues as potential antimalarial agents.

PubMed

Zhu, Shuren; Zhang, Quan; Gudise, Chandrashekar; Wei, Lai; Smith, Erika; Zeng, Yuling

2009-07-01

Febrifugine is an alkaloid isolated from Dichroa febrifuga Lour as the active component against Plasmodium falciparum. Adverse side effects have precluded febrifugine as a potential clinical drug. In this study novel febrifugine analogues were designed and synthesized. Lower toxicity was achieved by reducing or eliminating the tendency of forming chemically reactive and toxic intermediates and metabolites. Synthesized compounds were evaluated for acute toxicity and in vitro and in vivo antimalarial efficacy. Some compounds are much less toxic than the natural product febrifugine and existing antimalarial drug chloroquine and are expected to possess wide therapeutic windows. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.

Effects-driven chemical fractionation of heavy fuel oil to isolate compounds toxic to trout embryos.

PubMed

Bornstein, Jason M; Adams, Julie; Hollebone, Bruce; King, Thomas; Hodson, Peter V; Brown, R Stephen

2014-04-01

Heavy fuel oil (HFO) spills account for approximately 60% of ship-source oil spills and are up to 50 times more toxic than medium and light crude oils. Heavy fuel oils contain elevated concentrations of polycyclic aromatic hydrocarbons (PAHs) and alkyl-PAHs, known to be toxic to fish; however, little direct characterization of HFO toxicity has been reported. An effects-driven chemical fractionation was conducted on HFO 7102 to separate compounds with similar chemical and physical properties, including toxicity, to isolate the groups of compounds most toxic to trout embryos. After each separation, toxicity tests directed the next phase of fractionation, and gas chromatography-mass spectrometry analysis correlated composition with toxicity, with a focus on PAHs. Low-temperature vacuum distillation permitted the separation of HFO into 3 fractions based on boiling point ranges. The most toxic of these fractions underwent wax precipitation to remove long-chain n-alkanes. The remaining PAH-rich extract was further separated using open column chromatography, which provided distinct fractions that were grouped according to increasing aromatic ring count. The most toxic of these fractions was richest in PAHs and alkyl-PAHs. The results of the present study were consistent with previous crude oil studies that identified PAH-rich fractions as the most toxic. © 2013 SETAC.

HIGHLY SENSITIVE DIOXIN IMMUNOASSAY AND ITS APPLICATIONS TO SOIL AND BIOTA SAMPLES. (R825433)

EPA Science Inventory

Tetrachlorodibenzo-p-dioxin (TCDD) is a well-known highly toxic compound that is present in nearly all components of the global ecosystem, including air, soil, sediment, fish and humans. Dioxin analysis is equipment intensive and expensive requiring low ppt or even ppq ...

Cottonseed meal with high level of (+)-Gossypol as diet for broilers

USDA-ARS?s Scientific Manuscript database

Cottonseed is composed of ~22.5% of a high quality protein. This represents 3.5 MMT of protein that could be available for human consumption. Cottonseed protein currently is underutilized because of the presence of a toxic compound called gossypol. Gossypol is biosynthesized by the free radical co...

Genetics Home Reference: acatalasemia

MedlinePlus

... oxygen and water. Hydrogen peroxide is produced through chemical reactions within cells. At low levels, it is involved in several chemical signaling pathways, but at high levels it is toxic to cells. ... reactions convert it into compounds called reactive oxygen species ...

High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells.

PubMed

Liang, Shenxuan; Yin, Lei; Shengyang Yu, Kevin; Hofmann, Marie-Claude; Yu, Xiaozhong

2017-01-01

Bisphenol A (BPA), an endocrine-disrupting compound, was found to be a testicular toxicant in animal models. Bisphenol S (BPS), bisphenol AF (BPAF), and tetrabromobisphenol A (TBBPA) were recently introduced to the market as alternatives to BPA. However, toxicological data of these compounds in the male reproductive system are still limited so far. This study developed and validated an automated multi-parametric high-content analysis (HCA) using the C18-4 spermatogonial cell line as a model. We applied these validated HCA, including nuclear morphology, DNA content, cell cycle progression, DNA synthesis, cytoskeleton integrity, and DNA damage responses, to characterize and compare the testicular toxicities of BPA and 3 selected commercial available BPA analogues, BPS, BPAF, and TBBPA. HCA revealed BPAF and TBBPA exhibited higher spermatogonial toxicities as compared with BPA and BPS, including dose- and time-dependent alterations in nuclear morphology, cell cycle, DNA damage responses, and perturbation of the cytoskeleton. Our results demonstrated that this specific culture model together with HCA can be utilized for quantitative screening and discriminating of chemical-specific testicular toxicity in spermatogonial cells. It also provides a fast and cost-effective approach for the identification of environmental chemicals that could have detrimental effects on reproduction. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Lignocellulosic ethanol production by starch-base industrial yeast under PEG detoxification

PubMed Central

Liu, Xiumei; Xu, Wenjuan; Mao, Liaoyuan; Zhang, Chao; Yan, Peifang; Xu, Zhanwei; Zhang, Z. Conrad

2016-01-01

Cellulosic ethanol production from lignocellulosic biomass offers a sustainable solution for transition from fossil based fuels to renewable alternatives. However, a few long-standing technical challenges remain to be addressed in the development of an economically viable fermentation process from lignocellulose. Such challenges include the needs to improve yeast tolerance to toxic inhibitory compounds and to achieve high fermentation efficiency with minimum detoxification steps after a simple biomass pretreatment. Here we report an in-situ detoxification strategy by PEG exo-protection of an industrial dry yeast (starch-base). The exo-protected yeast cells displayed remarkably boosted vitality with high tolerance to toxic inhibitory compounds, and with largely improved ethanol productivity from crude hydrolysate derived from a pretreated lignocellulose. The PEG chemical exo-protection makes the industrial S. cerevisiae yeast directly applicable for the production of cellulosic ethanol with substantially improved productivity and yield, without of the need to use genetically modified microorganisms. PMID:26837707

Non-toxic liquid scintillators with high light output based on phenyl-substituted siloxanes

NASA Astrophysics Data System (ADS)

Dalla Palma, M.; Carturan, S. M.; Degerlier, M.; Marchi, T.; Cinausero, M.; Gramegna, F.; Quaranta, A.

2015-04-01

The work describes the development of a new class of liquid scintillators based on polysiloxane liquid compounds. These materials are characterized by low toxicity, chemical inertness, very low volatility and low flammability, allowing their use without concerns even at high temperatures in vacuum. In this view different polysiloxane based liquids have been tested, with variable content and distribution of phenyl lateral substituents and added with suitable dyes, namely 2,5-diphenyloxazole (PPO) and Lumogen Violet (LV). Absorption and fluorescence spectroscopy have been used in order to study the emission feature of the various compounds and to investigate the spectral matching between siloxane solvents and dissolved primary dyes. Scintillation efficiency towards 60Co and 137Cs gamma rays, relative to commercial liquid scintillator (EJ-309), has been measured and the results have been related to the energy transfer and energy migration mechanism from monomer and excimer forming sites in liquid siloxanes.

Lignocellulosic ethanol production by starch-base industrial yeast under PEG detoxification

NASA Astrophysics Data System (ADS)

Liu, Xiumei; Xu, Wenjuan; Mao, Liaoyuan; Zhang, Chao; Yan, Peifang; Xu, Zhanwei; Zhang, Z. Conrad

2016-02-01

Cellulosic ethanol production from lignocellulosic biomass offers a sustainable solution for transition from fossil based fuels to renewable alternatives. However, a few long-standing technical challenges remain to be addressed in the development of an economically viable fermentation process from lignocellulose. Such challenges include the needs to improve yeast tolerance to toxic inhibitory compounds and to achieve high fermentation efficiency with minimum detoxification steps after a simple biomass pretreatment. Here we report an in-situ detoxification strategy by PEG exo-protection of an industrial dry yeast (starch-base). The exo-protected yeast cells displayed remarkably boosted vitality with high tolerance to toxic inhibitory compounds, and with largely improved ethanol productivity from crude hydrolysate derived from a pretreated lignocellulose. The PEG chemical exo-protection makes the industrial S. cerevisiae yeast directly applicable for the production of cellulosic ethanol with substantially improved productivity and yield, without of the need to use genetically modified microorganisms.

The draft genome sequence and annotation of the desert woodrat Neotoma lepida.

PubMed

Campbell, Michael; Oakeson, Kelly F; Yandell, Mark; Halpert, James R; Dearing, Denise

2016-09-01

We present the de novo draft genome sequence for a vertebrate mammalian herbivore, the desert woodrat (Neotoma lepida). This species is of ecological and evolutionary interest with respect to ingestion, microbial detoxification and hepatic metabolism of toxic plant secondary compounds from the highly toxic creosote bush (Larrea tridentata) and the juniper shrub (Juniperus monosperma). The draft genome sequence and annotation have been deposited at GenBank under the accession LZPO01000000.

Toxicity of certain new compounds to insecticide-resistant houseflies*

PubMed Central

Georghiou, G. P.; Metcalf, R. L.; von Zboray, E. P.

1965-01-01

Houseflies in poultry ranches in certain areas of California are now resistant to most insecticides licensed for use in these establishments, and this resistance problem appears likely to spread to other areas in the future. The authors have therefore studied the contact and oral toxicity of 19 new compounds that have shown interesting properties against resistant flies. These compounds were selected from among several hundred submitted by various laboratories for evaluation under a co-operative programme sponsored by the World Health Organization. Five compounds were found to be as toxic to three insecticide-resistant strains as to a susceptible strain, and showed strikingly steep log-dosage/probit mortality lines against the resistant strains. The authors suggest that these compounds be further studied for fly control in field trials. PMID:5294994

Chemical Characterization of Compounds Released by Marine Mammals.

DTIC Science & Technology

1983-08-01

Glucose . . . 30 Lactose . . . 30 Mannose . . . 31 Xylose . . . 31 TOXICITY AND DISCUSSION OF COMPOUNDS WHICH ARE INSOLUBLE IN WATER AND/OR UNSAFE...glycine; urea; mannose; glycerol; inositol; arabitol; erythritol; mannitol; sorbitol; xylitol; . erythrose; galactose; glucose ; lactose; xylose...of marine mam- mals . 26 15. Summary of physical properties and toxicity information for compounds insoluble in water and/or considered unsafe . . . 27

Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice

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

Porter, J.B.; Morgan, J.; Hoyes, K.P.

1990-12-01

The relationship between the oral efficacy and the acute toxicity of hydroxypyridin-4-one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing 59Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.3 in the iron-free form with a trend of increasing oral efficacy with increasing Kpart values (r = .6). However, this is achieved at a cost of increasing acute toxicity, as shown bymore » a linear correlation between 59Fe excretion increase per unit dose and 1/LD50 (r = .83). A sharp increase in the LD50 values is observed for compounds with Kpart values above 1.0, suggesting that such compounds are unlikely to possess a sufficient therapeutic safety margin. Below a Kpart of 1.0, acute toxicity is relatively independent of lipid solubility. All the compounds are less toxic by the oral route than by the intraperitoneal route, although iron excretion is not significantly different by these two routes. At least five compounds (CP51, CP94, CP93, CP96, and CP21) are more effective orally than the same dose of intraperitoneal desferrioxamine (DFO) (P less than or equal to .02) or orally administered L1(CP20) (P less than or equal to .02).« less

Chemical characteristics of urban stormwater sediments and implications for environmental management, Maricopa County, Arizona

USGS Publications Warehouse

Parker, J.T.C.; Fossum, K.D.; Ingersoll, T.L.

2000-01-01

Investigations of the chemical characteristics of urban stormwater sediments in the rapidly growing Phoenix metropolitan area of Maricopa County, Arizona, showed that the inorganic component of these sediments generally reflects geologic background values. Some concentrations of metals were above background values, especially cadmium, copper, lead, and zinc, indicating an anthropogenic contribution of these elements to the sediment chemistry. Concentrations, however, were not at levels that would require soil remediation according to guidelines of the U.S. Environmental Protection Agency. Arsenic concentrations generally were above recommended values for remediation at a few sites, but these concentrations seem to reflect geologic rather than anthropogenic factors. Several organochlorine compounds no longer in use were ubiquitous in the Phoenix area, although concentrations generally were low. Chlordane, DDT and its decay products DDE and DDD, dieldrin, toxaphene, and PCBs were found at almost all sites sampled, although some of the pesticides in which these compounds are found have been banned for almost 30 years. A few sites showed exceptionally high concentrations of organochlorine compounds. On the basis of published guidelines, urban stormwater sediments do not appear to constitute a major regional environmental problem with respect to the chemical characteristics investigated here. At individual sites, high concentrations of organic compounds - chlordane, dieldrin, PCBs, and toxaphene - may require some attention. The possible environmental hazard presented by low-level organochlorine contamination is not addressed in this paper; however, high levels of toxicity in urban sediments are difficult to explain. Sediment toxicity varied significantly with time, which indicates that these tests should be evaluated carefully before they are used for management decisions.Investigations of the chemical characteristics of urban stormwater sediments in the rapidly growing Phoenix metropolitan area of Maricopa County, Arizona, showed that the inorganic component of these sediments generally reflects geologic background values. Some concentrations of metals were above background values, especially cadmium, copper, lead, and zinc, indicating an anthropogenic contribution of these elements to the sediment chemistry. Concentrations, however, were not at levels that would require soil remediation according to guidelines of the U.S. Environmental Protection Agency. Arsenic concentrations generally were above recommended values for remediation at a few sites, but these concentrations seem to reflect geologic rather than anthropogenic factors. Several organochlorine compounds no longer in use were ubiquitous in the Phoenix area, although concentrations generally were low. Chlordane, DDT and its decay products DDE and DDD, dieldrin, toxaphene, and PCBs were found at almost all sites sampled, although some of the pesticides in which these compounds are found have been banned for almost 30 years. A few sites showed exceptionally high concentrations of organochlorine compounds. On the basis of published guidelines, urban stormwater sediments do not appear to constitute a major regional environmental problem with respect to the chemical characteristics investigated here. At individual sites, high concentrations of organic compounds - chlordane, dieldrin, PCBs, and toxaphene - may require some attention. The possible environmental hazard presented by low-level organochlorine contamination is not addressed in this paper; however, high levels of toxicity in urban sediments are difficult to explain. Sediment toxicity varied significantly with time, which indicates that these tests should be evaluated carefully before they are used for management decisions.

Organic compounds in produced waters from coalbed natural gas wells in the Powder River Basin, Wyoming, USA

USGS Publications Warehouse

Orem, W.H.; Tatu, C.A.; Lerch, H.E.; Rice, C.A.; Bartos, T.T.; Bates, A.L.; Tewalt, S.; Corum, M.D.

2007-01-01

The organic composition of produced water samples from coalbed natural gas (CBNG) wells in the Powder River Basin, WY, sampled in 2001 and 2002 are reported as part of a larger study of the potential health and environmental effects of organic compounds derived from coal. The quality of CBNG produced waters is a potential environmental concern and disposal problem for CBNG producers, and no previous studies of organic compounds in CBNG produced water have been published. Organic compounds identified in the produced water samples included: phenols, biphenyls, N-, O-, and S-containing heterocyclic compounds, polycyclic aromatic hydrocarbons (PAHs), aromatic amines, various non-aromatic compounds, and phthalates. Many of the identified organic compounds (phenols, heterocyclic compounds, PAHs) are probably coal-derived. PAHs represented the group of organic compounds most commonly observed. Concentrations of total PAHs ranged up to 23 ??g/L. Concentrations of individual compounds ranged from about 18 to <0.01 ??g/L. Temporal variability of organic compound concentrations was documented, as two wells with relatively high organic compound contents in produced water in 2001 had much lower concentrations in 2002. In many areas, including the PRB, coal strata provide aquifers for drinking water wells. Organic compounds observed in produced water are also likely present in drinking water supplied from wells in the coal. Some of the organic compounds identified in the produced water samples are potentially toxic, but at the levels measured in these samples are unlikely to have acute health effects. The human health effects of low-level, chronic exposure to coal-derived organic compounds in drinking water are currently unknown. Continuing studies will evaluate possible toxic effects from low level, chronic exposure to coal-derived organic compounds in drinking water supplies.

Multi-class Mode of Action Classification of Toxic Compounds Using Logic Based Kernel Methods.

PubMed

Lodhi, Huma; Muggleton, Stephen; Sternberg, Mike J E

2010-09-17

Toxicity prediction is essential for drug design and development of effective therapeutics. In this paper we present an in silico strategy, to identify the mode of action of toxic compounds, that is based on the use of a novel logic based kernel method. The technique uses support vector machines in conjunction with the kernels constructed from first order rules induced by an Inductive Logic Programming system. It constructs multi-class models by using a divide and conquer reduction strategy that splits multi-classes into binary groups and solves each individual problem recursively hence generating an underlying decision list structure. In order to evaluate the effectiveness of the approach for chemoinformatics problems like predictive toxicology, we apply it to toxicity classification in aquatic systems. The method is used to identify and classify 442 compounds with respect to the mode of action. The experimental results show that the technique successfully classifies toxic compounds and can be useful in assessing environmental risks. Experimental comparison of the performance of the proposed multi-class scheme with the standard multi-class Inductive Logic Programming algorithm and multi-class Support Vector Machine yields statistically significant results and demonstrates the potential power and benefits of the approach in identifying compounds of various toxic mechanisms. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Organic compounds removal and toxicity reduction of landfill leachate by commercial bakers' yeast and conventional bacteria based membrane bioreactor integrated with nanofiltration.

PubMed

Reis, Beatriz Gasparini; Silveira, Amanda Lemes; Tostes Teixeira, Luiza Procópio; Okuma, Adriana Akemi; Lange, Liséte Celina; Amaral, Miriam Cristina Santos

2017-12-01

This study aimed to compare the performance of a commercial bakers' yeast (MBRy) and conventional bacteria (MBRb) based membrane bioreactor integrated with nanofiltration (NF) in the removal of landfill leachate toxicity. Performances were evaluated using physicochemical analyses, toxicity tests and identification of organic compounds. The MBR b and MBR y were operated with a hydraulic retention time (HRT) of 48h and solids retention time (SRT) of 60 d. The MBR y demonstrated better removal efficiencies for COD (69±7%), color (54±11%) and ammoniacal nitrogen (34±7%) compared to MBR b , which showed removal efficiencies of 27±5%, 33±4% and 27±7%, for COD, color and ammoniacal nitrogen. Although the MBR y seems to be the configuration that presented the highest efficiency; it generated toxic permeate whose toxicity cannot be explained by physicochemical results. The identification of compounds shows that there is a wide range of compounds in the landfill leachate in addition to others that are produced in the biological treatment steps. The NF plays a crucial role in the polishing of the final effluents by the either complete or partial retention of compounds, that attribute toxicity to the leachate, and inorganic contaminants. Copyright © 2017 Elsevier Ltd. All rights reserved.

A perspective on the toxicology of marine toxins.

PubMed

Botana, Luis M

2012-09-17

Although there has been much progress with regard to marine toxins from dinoflagellates, much remains to be done. Because these compounds are a seafood consumer risk, the demands cover from legislative to scientific aspects. Legislation is required for all new toxins that appear in the coasts. On the other hand, it is important to understand the toxicity of the different analogues, in terms of both the relative toxicity to reference compounds and the mechanism of toxicity itself, both acute and long-term. For this, a uniform approach to do toxic studies is necessary, especially acute toxicity. The need for pure standards in sufficient supply and the understanding of the mode of action of some of the compounds (such as yessotoxin or azaspiracids) will help the development of another important field, the use of marine toxins as drug leads, and the chemistry around them.

Does lipophilicity of toxic compounds determine effects on drought tolerance of the soil collembolan Folsomia candida?

PubMed

Skovlund, Gitte; Damgaard, Christian; Bayley, Mark; Holmstrup, Martin

2006-12-01

The ability of Collembola to survive drought stress is crucial for their distribution in the terrestrial environment. Previous studies have suggested that several toxic compounds affect the drought tolerance of Folsomia candida in a synergistic manner and that these compounds have the feature in common that they elicit their toxicity by causing membrane damage. We hypothesised that the detrimental effect of toxic chemicals on drought tolerance in F. candida depends on the lipophilicity (log K(ow)) of the compound because a higher log K(ow) would mean a closer interaction with membranes. In this study the three chemicals 4-nonylphenol, pyrene and p,p'-DDE were tested. Surprisingly, 4-nonylphenol, with the lowest log K(ow), was the most potent with respect to reducing drought tolerance followed by pyrene, suggesting that interactions between drought tolerance and chemical stress do not depend on lipophilicity alone.

Evaluation of antimicrobial activity of glycerol monolaurate nanocapsules against American foulbrood disease agent and toxicity on bees.

PubMed

Lopes, Leonardo Q S; Santos, Cayane G; de Almeida Vaucher, Rodrigo; Gende, Liesel; Raffin, Renata P; Santos, Roberto C V

2016-08-01

The American Foulbrood Disease (AFB) is a fatal larval bee infection. The etiologic agent is the bacterium Paenibacillus larvae. The treatment involves incineration of all contaminated materials, leading to high losses. The Glycerol Monolaurate (GML) is a known antimicrobial potential compound, however its use is reduced due to its low solubility in water and high melting point. The nanoencapsulation of some drugs offers several advantages like improved stability and solubility in water. The present study aimed to evaluate the antimicrobial activity against P. larvae and the toxicity in bees of GML nanoparticles. The nanocapsules were produced and presented mean diameter of 210 nm, polydispersity index of 0.044, and zeta potential of -23.4 mV demonstrating the acceptable values to predict a stable system. The microdilution assay showed that it is necessary 142 and 285 μg/mL of GML nanocapsules to obtain a bacteriostatic and bactericidal effect respectively. The time-kill curve showed the controlled release of compound, exterminating the microorganism after 24 h. The GML nanocapsules were able to kill the spore form of Paenibacillus larvae while the GML do not cause any effect. The assay in bees showed that the GML has a high toxicity while the GML nanoparticles showed a decrease on toxic effects. Concluding, the formulation shows positive results in the action to combat AFB besides not causing damage to bees. Copyright © 2016 Elsevier Ltd. All rights reserved.

Biotransformation of macrolide antibiotics using enriched activated sludge culture: Kinetics, transformation routes and ecotoxicological evaluation.

PubMed

Terzic, Senka; Udikovic-Kolic, Nikolina; Jurina, Tamara; Krizman-Matasic, Ivona; Senta, Ivan; Mihaljevic, Ivan; Loncar, Jovica; Smital, Tvrtko; Ahel, Marijan

2018-05-05

The biotransformation of three prominent macrolide antibiotics (azithromycin, clarithromycin and erythromycin) by an activated sludge culture, which was adapted to high concentrations of azithromycin (10 mg/L) was investigated. The study included determination of removal kinetics of the parent compounds, identification of their major biotransformation products (TPs) and assessment of ecotoxicological effects of biotransformation. The chemical analyses were performed by ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry, which enabled a tentative identification of TPs formed during the experiments. The ecotoxicological evaluation included two end-points, residual antibiotic activity and toxicity to freshwater algae. The enriched activated sludge culture was capable of degrading all studied macrolide compounds with high removal efficiencies (>99%) of the parent compounds at elevated concentrations (10 mg/L). The elimination of all three macrolide antibiotics was associated with the formation of different TPs, including several novel compounds previously unreported in the literature. Some of the TPs were rather abundant and contributed significantly to the overall mass balance at the end of the biodegradation experiments. Biodegradation of all investigated macrolides was associated with a pronounced reduction of the residual antibiotic activity and algal toxicity, indicating a rather positive ecotoxicological outcome of the biotransformation processes achieved by the enriched sludge culture. Copyright © 2018 Elsevier B.V. All rights reserved.

Embryotoxicity of nitrophenols to the early life stages of zebrafish (Danio rerio).

PubMed

Ceylan, Zeynep; Şişman, Turgay; Yazıcı, Zehra; Altıkat, Aysun Özen

2016-08-01

The nitrophenols (NPs) are water-soluble compounds. These compounds pose a significant health threat since they are priority environmental pollutants. In this study, 2-Nitrophenol (2NP) and 2,4-dinitrophenol (DNP) were examined for embryo and early life stage toxicity in zebrafish (Danio rerio). Acute toxicity and teratogenicity of 2NP and DNP were tested for 4 days using zebrafish embryos. The typical lesions observed were no somite formation, incomplete eye and head development, tail curvature, weak pigmentation (≤48 hours postfertilization (hpf)), kyphosis, scoliosis, yolk sac deformity, and nonpigmentation (72 hpf). Also, embryo and larval mortality increased and hatching success decreased. The severity of abnormalities and mortalities were concentration- and compound-dependent. Of the compounds tested, 2,4-DNP was found to be highly toxic to the fish embryos following exposure. The median lethal concentrations and median effective concentrations for 2NP are 18.7 mg/L and 7.9 mg/L, respectively; the corresponding values for DNP are 9.65 mg/L and 3.05 mg/L for 48 h. The chorda deformity was the most sensitive endpoint measured. It is suggested that the embryotoxicity may be mediated by an oxidative phosphorylation uncoupling mechanism. This article is the first to describe the teratogenicity and embryotoxicity of two NPs to the early life stages of zebrafish. © The Author(s) 2014.

Safety profiles of old and new antimicrobials for the treatment of MRSA infections.

PubMed

Bassetti, Matteo; Righi, Elda

2016-01-01

Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of severe nosocomial and community-acquired infections. Various adverse effects have been associated with compounds that are commonly used in the treatment of MRSA. Prolonged use of high-dose vancomycin has been linked with nephrotoxicity. Linezolid use has been associated with lactic acidosis in regimens longer than 14 days and occurrence of thrombocytopenia in patients with renal impairment. Daptomycin use correlates with reversible and often asymptomatic myopathy. Among new compounds, telavancin has shown increased toxicity compared to vancomycin, especially in patients with severe renal impairment, while a low rate of adverse effects was reported others glycolipopeptides such as dalbavancin and oritavancin and for new cephalosporins. Recently studied oxazolidinones (tedizolid and radezolid) also showed mild adverse effects in Phase 2 and 3 clinical trials. Due to the constant increase in antimicrobial resistance, the use of higher doses and prolonged regimens of antibiotics employed in the treatment of Gram-positive infections has become more common and linked to increased toxicity. Furthermore, new compounds with MRSA activity have been recently approved and will be regularly employed in clinical practice. The knowledge of the adverse effects and risk factors for the development of toxicity associated with anti-MRSA antimicrobials is paramount for the correct use of old and new compounds, especially in the treatment of severe infections.

Machine learning prioritizes synthesis of primaquine ureidoamides with high antimalarial activity and attenuated cytotoxicity.

PubMed

Levatić, Jurica; Pavić, Kristina; Perković, Ivana; Uzelac, Lidija; Ester, Katja; Kralj, Marijeta; Kaiser, Marcel; Rottmann, Matthias; Supek, Fran; Zorc, Branka

2018-02-25

Primaquine (PQ) is a commonly used drug that can prevent the transmission of Plasmodium falciparum malaria, however toxicity limits its use. We prepared five groups of PQ derivatives: amides 1a-k, ureas 2a-k, semicarbazides 3a,b, acylsemicarbazides 4a-k and bis-ureas 5a-v, and evaluated them for antimalarial activity in vitro against the erythrocytic stage of P. falciparum NF54. Particular substituents, such as trityl (in 2j and 5r) and methoxybenzhydryl (in 3b and 5v) were associated with a favorable cytotoxicity-to-activity ratio. To systematically link structural features of PQ derivatives to antiplasmodial activity, we performed a quantitative structure-activity relationship (QSAR) study using the Support Vector Machines machine learning method. This yielded a highly accurate statistical model (R 2  = 0.776 in cross-validation), which was used to prioritize novel candidate compounds. Seven novel PQ-ureidoamides 10a-g were synthesized and evaluated for activity, highlighting the benzhydryl ureidoamides 10e and 10f derived from p-chlorophenylglycine. Further experiments on human cell lines revealed that 10e and 10f are an order of magnitude less toxic than PQ in vitro while having antimalarial activity indistinguishable from PQ. The toxicity profile of novel compounds 10 toward human cells was particularly favorable when the glucose-6-phosphate dehydrogenase (G6PD) was inhibited, while toxicity of PQ was exacerbated by G6PD inhibition. Our work therefore highlights promising lead compounds for the development of effective antimalarial drugs that may also be safer for G6PD-deficient patients. In addition, we provide computational inferences of antimalarial activity and cytotoxicity for thousands of PQ-like molecular structures. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Toxicity of Anacostia River, Washington, D.C., USA, sediment fed to mute swans (Cygnus olor)

USGS Publications Warehouse

Beyer, W.N.; Day, D.; Melancon, M.J.; Sileo, L.

2000-01-01

Sediment ingestion is sometimes the principal route by which waterfowl are exposed to environmental contaminants, and at severely contaminated sites waterfowl have been killed by ingesting sediment. Mute swans (Cygnus olor) were fed a diet for 6 weeks with a high but environmentally realistic concentration (24%) of sediment from the moderately polluted Anacostia River in the District of Columbia, USA, to estimate the sediment's toxicity. Control swans were fed the same diet without the sediment. Five organochlorine compounds were detected in the treated diets, but none of 22 organochlorine compounds included in the analyses was detected in livers of the treated swans. The concentrations of 24 polynuclear aromatic hydrocarbons measured in the treated diet were as high as 0.80 mg/kg, and they were thought to have been responsible for the observed induction of hepatic microsomal monooxygenase activity in livers. A concentration of 85 mg/kg of lead in the diet was enough to decrease red blood cell ALAD activity but was not high enough to cause more serious effects of lead poisoning. The dietary concentrations of Al, Fe, V, and Ba were high compared to the concentrations of these elements known to be toxic in laboratory feeding studies. However, the lack of accumulation in the livers of the treated swans suggested that these elements were not readily available from the ingested sediment. We did not study all potential toxic effects, but, on the basis of those that we did consider, we concluded that the treated swans were basically healthy after a chronic exposure to the sediment.

Identification of Three Classes of Heteroaromatic Compounds with Activity against Intracellular Trypanosoma cruzi by Chemical Library Screening

PubMed Central

Bettiol, Esther; Samanovic, Marie; Murkin, Andrew S.; Raper, Jayne; Buckner, Frederick; Rodriguez, Ana

2009-01-01

The development of new drugs against Chagas disease is a priority since the currently available medicines have toxic effects, partial efficacy and are targeted against the acute phase of disease. At present, there is no drug to treat the chronic stage. In this study, we have optimized a whole cell-based assay for high throughput screening of compounds that inhibit infection of mammalian cells by Trypanosoma cruzi trypomastigotes. A 2000-compound chemical library was screened using a recombinant T. cruzi (Tulahuen strain) expressing β-galactosidase. Three hits were selected for their high activity against T. cruzi and low toxicity to host cells in vitro: PCH1, NT1 and CX1 (IC50: 54, 190 and 23 nM, respectively). Each of these three compounds presents a different mechanism of action on intracellular proliferation of T. cruzi amastigotes. CX1 shows strong trypanocidal activity, an essential characteristic for the development of drugs against the chronic stage of Chagas disease where parasites are found intracellular in a quiescent stage. NT1 has a trypanostatic effect, while PCH1 affects parasite division. The three compounds also show high activity against intracellular T. cruzi from the Y strain and against the related kinetoplastid species Leishmania major and L. amazonensis. Characterization of the anti–T. cruzi activity of molecules chemically related to the three library hits allowed the selection of two compounds with IC50 values of 2 nM (PCH6 and CX2). These values are approximately 100 times lower than those of the medicines used in patients against T. cruzi. These results provide new candidate molecules for the development of treatments against Chagas disease and leishmaniasis. PMID:19238193

Identification of three classes of heteroaromatic compounds with activity against intracellular Trypanosoma cruzi by chemical library screening.

PubMed

Bettiol, Esther; Samanovic, Marie; Murkin, Andrew S; Raper, Jayne; Buckner, Frederick; Rodriguez, Ana

2009-01-01

The development of new drugs against Chagas disease is a priority since the currently available medicines have toxic effects, partial efficacy and are targeted against the acute phase of disease. At present, there is no drug to treat the chronic stage. In this study, we have optimized a whole cell-based assay for high throughput screening of compounds that inhibit infection of mammalian cells by Trypanosoma cruzi trypomastigotes. A 2000-compound chemical library was screened using a recombinant T. cruzi (Tulahuen strain) expressing beta-galactosidase. Three hits were selected for their high activity against T. cruzi and low toxicity to host cells in vitro: PCH1, NT1 and CX1 (IC(50): 54, 190 and 23 nM, respectively). Each of these three compounds presents a different mechanism of action on intracellular proliferation of T. cruzi amastigotes. CX1 shows strong trypanocidal activity, an essential characteristic for the development of drugs against the chronic stage of Chagas disease where parasites are found intracellular in a quiescent stage. NT1 has a trypanostatic effect, while PCH1 affects parasite division. The three compounds also show high activity against intracellular T. cruzi from the Y strain and against the related kinetoplastid species Leishmania major and L. amazonensis. Characterization of the anti-T. cruzi activity of molecules chemically related to the three library hits allowed the selection of two compounds with IC(50) values of 2 nM (PCH6 and CX2). These values are approximately 100 times lower than those of the medicines used in patients against T. cruzi. These results provide new candidate molecules for the development of treatments against Chagas disease and leishmaniasis.

ADMET in silico modelling: towards prediction paradise?

PubMed

van de Waterbeemd, Han; Gifford, Eric

2003-03-01

Following studies in the late 1990s that indicated that poor pharmacokinetics and toxicity were important causes of costly late-stage failures in drug development, it has become widely appreciated that these areas should be considered as early as possible in the drug discovery process. However, in recent years, combinatorial chemistry and high-throughput screening have significantly increased the number of compounds for which early data on absorption, distribution, metabolism, excretion (ADME) and toxicity (T) are needed, which has in turn driven the development of a variety of medium and high-throughput in vitro ADMET screens. Here, we describe how in silico approaches will further increase our ability to predict and model the most relevant pharmacokinetic, metabolic and toxicity endpoints, thereby accelerating the drug discovery process.

Toxicity to Daphnia pulex and QSAR predictions for polycyclic hydrocarbons representative of Great Lakes contaminants

USGS Publications Warehouse

Passino-Reader, D.R.; Hickey, J.P.; Ogilvie, L.M.

1997-01-01

The objectives of this study were (1) to determine the toxicity of several types of polycyclic hydrocarbons characteristic of Great Lakes samples to Daphnia pulex, a Great Lakes zooplankter, (2) to investigate the influence of different structural characteristics on toxicity, and (3) to determine the linear solvation energy relationship (LSER) parameters and model that describe these compounds. These results will be related to comparative toxicity of other Great Lakes environmental compounds and to their application in site specific risk assessment.

Acute Oral Toxicity of Trimethylolethane Trinitrate (TMETN) in Sprague- Dawley Rats

DTIC Science & Technology

1989-07-01

classification scheme of Hodge and Steiner, these results indicate that TMETN is a slightly toxic compound.1 20. ON-RIBUTION /AVAILABILITY OF ABSTRACT 21. ABSTRACT...the classification scheme of Hodge and Sterner, these results indcate that TMETN is a slightly toxic compound. KEY WORDS: Acute Oral Toxicit-y...Dawley rats and 1027.4 63.7 mg/kg in female Sprague-Dawley rats. These MLD values place TMETN in the "slightly toxic" range by the system of Hodge and

Toxicity potential of disinfection agent in tannery wastewater.

PubMed

Tisler, Tatjana; Zagorc-Koncan, Jana; Cotman, Magda; Drolc, Andreja

2004-09-01

Wastewater from a tannery was investigated using chemical-specific analyses and assessment of the acute toxicity of the whole effluent over a 2-year period. The wastewater samples were overloaded with organic and inorganic compounds, and measured concentrations of the chemical parameters as well as dilution factors estimating acute toxicity, frequently exceeded the permissible limits for the discharge of wastewater from a tannery into the receiving stream. In the later part of the monitoring programme, the toxicity of the samples was significantly increased in comparison to the previous samples. The agent for hide disinfection was assumed to be the reason for the increased toxicity of the wastewater samples, and the extremely high acute and chronic toxicity of the agent to bacteria, algae, daphnids, and fish confirmed this suspicion. The most sensitive species was Daphnia magna; the 48 h EC50 was 0.70 x 10(-5)v/v% and the 21d IC25 was 0.40 x 10(-6)v/v% of the agent. After withdrawal of this highly toxic agent for hide disinfection from the technological process in the tannery, the toxicity of the wastewater declined to the previous level.

Highly hydroxylated steroids of the starfish Archaster typicus from the Vietnamese waters.

PubMed

Ivanchina, Natalia V; Kicha, Alla A; Huong, Trinh T T; Kalinovsky, Anatoly I; Dmitrenok, Pavel S; Agafonova, Irina G; Long, Pham Q; Stonik, Valentin A

2010-12-01

Five new steroidal compounds, including an unusual glucoside, along with several known steroids were isolated from the starfish Archaster typicus collected in shallow waters of Quang Ninh province (Vietnam). Three new compounds are 27-nor-cholestane derivatives and the other two are 24,26-dihydroxycholestane derivatives. A biogenesis pathway for the unusual side chain of 27-nor-cholestane derivatives is proposed. Isolated compounds presented moderate toxic effects in the sperm- and 8-blastomere tests on embryonal development of the sea urchin Strongylocentrotusintermedius. Copyright 2010 Elsevier Inc. All rights reserved.

Fluorinated Compounds in U.S. Fast Food Packaging

EPA Science Inventory

Per- and polyfluoroalkyl substances (PFASs) are highly persistent synthetic chemicals, some of which have been associated with cancer, developmental toxicity, immunotoxicity, and other health effects. PFASs in grease-resistant food packaging can leach into food and increase dieta...

IMMUNOCHEMICAL DETERMINATION OF DIOXINS IN SEDIMENT AND SERUM SAMPLES

EPA Science Inventory

Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are considered highly toxic contaminants and the environmental and biological monitoring of these compounds is of great concern. Immunoassays may be used as screening methods to satisfy the gro...

PRACTICAL APPROACHES TO REMEDIATION OF POLYCHLORINATED BIPHENYLS IN SEDIMENTS

EPA Science Inventory

Polychlorinated biphenyls (PCBs) are one group of persistent organic pollutants (POPs) of international concern because of global distribution, persistence, and toxicity. Removal of these compounds from the environment presents a very tough challenge because they are highly hydro...

Demonstration of carboxylesterase in cytology samples of human nasal respiratory epithelium

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

Rodgers, D.A.; Nikula, K.J.; Avila, K.

1995-12-01

The epithelial lining of the nasal airways is a target for responses induced by a variety of toxicant exposures. The high metabolic capacity of this tissue has been suggested to play a role in both protection of the airways through detoxication of certain toxicants, as well as in activation of other compounds to more toxic metabolites. Specifically, nasal carboxylesterase (CE) has been shown to mediate the toxicity of inhaled esters and acrylates by converting them to more toxic acid and alcohol metabolites which can be cytotoxic and/or carcinogenic to the nasal mucosa. Due to difficulties in extrapolating rodent models tomore » human, new paradigms using human cells and tissues are essential to understanding and evaluating the metabolic processes in human nasal epithelium.« less

Acute Neurobehavorial Toxicity of Flame Retardant Replacement Compounds in Zebrafish Larvae

EPA Science Inventory

As polybrominated diphenyl ethers (PBDEs) are phased out, numerous compounds areemerging as potential replacement flame retardants for use in consumer and electronicproducts. Little is known, however, about the neurobehavioral toxicity of thesereplacements. This study evaluated t...

Nicotine, aerosol particles, carbonyls and volatile organic compounds in tobacco- and menthol-flavored e-cigarettes.

PubMed

Lee, Mi-Sun; LeBouf, Ryan F; Son, Youn-Suk; Koutrakis, Petros; Christiani, David C

2017-04-27

We aimed to assess the content of electronic cigarette (EC) emissions for five groups of potentially toxic compounds that are known to be present in tobacco smoke: nicotine, particles, carbonyls, volatile organic compounds (VOCs), and trace elements by flavor and puffing time. We used ECs containing a common nicotine strength (1.8%) and the most popular flavors, tobacco and menthol. An automatic multiple smoking machine was used to generate EC aerosols under controlled conditions. Using a dilution chamber, we targeted nicotine concentrations similar to that of exposure in a general indoor environment. The selected toxic compounds were extracted from EC aerosols into a solid or liquid phase and analyzed with chromatographic and spectroscopic methods. We found that EC aerosols contained toxic compounds including nicotine, fine and nanoparticles, carbonyls, and some toxic VOCs such as benzene and toluene. Higher mass and number concentrations of aerosol particles were generated from tobacco-flavored ECs than from menthol-flavored ECs. We found that diluted machine-generated EC aerosols contain some pollutants. These findings are limited by the small number of ECs tested and the conditions of testing. More comprehensive research on EC exposure extending to more brands and flavor compounds is warranted.

Protective effects of a natural herbal compound quercetin against snake venom-induced hepatic and renal toxicities in rats.

PubMed

Al-Asmari, Abdulrahman K; Khan, Haseeb A; Manthiri, Rajamohamed A; Al-Khlaiwi, Ahmad A; Al-Asmari, Bayan A; Ibrahim, Khalid E

2018-05-08

Echis pyramidum is a highly poisonous viper snake. Previous studies have shown acute phase hepatic and renal toxicities of Echis pyramidum venom (EPV) in rats. This study reports the protective effects of a natural herbal compound quercetin (QRC) on EPV-induced hepatic and renal toxicities in rats. A singly injection of EPV (4.76 mg/kg) caused significant increase in serum biomarkers of liver and kidney function. Pre-treatment of QRC (10 mg/kg) significantly reduced the toxic effects of EPV on functional impairment in liver and kidneys of rats. Administration of QRC also reversed EPV-induced increase in lipid peroxidation and decrease in total thiols. The histopathology of liver showed fat accumulation, focal degeneration and cytoplasmic vacuolation of hepatocytes in EPV treated rats. EPV also caused renal tubular dilation and focal atrophy of glomerular tufts in rat kidneys. Administration of QRC prevented EPV-induced structural tissue damage in liver and kidneys of rats. In conclusion, QRC significantly inhibited the acute phase toxic effects of EPV on liver and kidneys of rats by preventing the oxidative stress in these organs. QRC is also known for its anti-inflammatory, anti-edema, anti-hemorrhagic and PLA2-inhibitory properties and therefore may be regarded as a multi-action antidote against snake venom toxicity. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Best Extraction Technique for Kaempferol and Quercetin Isolation from Guava Leaves (Psidium guajava)

NASA Astrophysics Data System (ADS)

Batubara, I.; Suparto, I. H.; Wulandari, N. S.

2017-03-01

Guava leaves contain various compounds that have biological activity such as kaempferol and quercetin as anticancer. Twelve extraction techniques were performed to obtain the best extraction technique to isolate kaempferol and quercetin from the guava leaves. Toxicity of extracts was tested against Artemia salina larvae. All extracts were toxic (LC50 value less than 1000 ppm) except extract of direct soxhletation on guava leaves, and extract of sonication and soxhletation using n-hexane. The extract with high content of total phenols and total flavonoids, low content of tannins, intense color of spot on thin layer chromatogram was selected for high performance liquid chromatography analysis. Direct sonication of guava leaves was chosen as the best extraction technique with kampferol and quercetin content of 0.02% and 2.15%, respectively. In addition to high content of kaempferol and quercetin, direct sonication was chosen due to the shortest extraction time, lesser impurities and high toxicity.

Oral LD50 toxicity modeling and prediction of per- and polyfluorinated chemicals on rat and mouse.

PubMed

Bhhatarai, Barun; Gramatica, Paola

2011-05-01

Quantitative structure-activity relationship (QSAR) analyses were performed using the LD(50) oral toxicity data of per- and polyfluorinated chemicals (PFCs) on rodents: rat and mouse. PFCs are studied under the EU project CADASTER which uses the available experimental data for prediction and prioritization of toxic chemicals for risk assessment by using the in silico tools. The methodology presented here applies chemometrical analysis on the existing experimental data and predicts the toxicity of new compounds. QSAR analyses were performed on the available 58 mouse and 50 rat LD(50) oral data using multiple linear regression (MLR) based on theoretical molecular descriptors selected by genetic algorithm (GA). Training and prediction sets were prepared a priori from available experimental datasets in terms of structure and response. These sets were used to derive statistically robust and predictive (both internally and externally) models. The structural applicability domain (AD) of the models were verified on 376 per- and polyfluorinated chemicals including those in REACH preregistration list. The rat and mouse endpoints were predicted by each model for the studied compounds, and finally 30 compounds, all perfluorinated, were prioritized as most important for experimental toxicity analysis under the project. In addition, cumulative study on compounds within the AD of all four models, including two earlier published models on LC(50) rodent analysis was studied and the cumulative toxicity trend was observed using principal component analysis (PCA). The similarities and the differences observed in terms of descriptors and chemical/mechanistic meaning encoded by descriptors to prioritize the most toxic compounds are highlighted.

Lethal and sub-lethal evaluation of Indigo Carmine dye and byproducts after TiO2 photocatalysis in the immune system of Eisenia andrei earthworms.

PubMed

Genázio Pereira, Patrícia Christina; Reimão, Roberta Valoura; Pavesi, Thelma; Saggioro, Enrico Mendes; Moreira, Josino Costa; Veríssimo Correia, Fábio

2017-09-01

The Indigo carmine (IC) dye has been widely used in textile industries, even though it has been considered toxic for rats, pigs and humans. Owing to its toxicity, wastes containing this compound should be treated to minimize or eliminate their toxic effects on the biota. As an alternative to wastewater treatment, advanced oxidative processes (AOPs) have been highlighted due to their high capacity to destruct organic molecules. In this context, this study aimed to evaluate Indigo Carmine toxicity to soil organisms using the earthworm Eisenia andrei as a model-organism and also verify the efficiency of AOP in reducing its toxicity to these organisms. To this end, lethal (mortality) and sub-lethal (loss or gain of biomass, reproduction, behavior, morphological changes and immune system cells) effects caused by this substance and its degradation products in these annelids were evaluated. Morphological changes were observed even in organisms exposed to low concentrations, while mortality was the major effect observed in individuals exposed to high levels of indigo carmine dye. The organisms exposed to the IC during the contact test showed mortality after 72h of exposure (LC 50 = 75.79mgcm - 2 ), while those exposed to photoproducts showed mortality after 48h (LC 50 = 243min). In the chronic study, the organisms displayed a mortality rate of 14%, while those exposed to the photoproduct reached up to 32.7%. A negative influence of the dye on the reproduction rate was observed, while by-products affected juvenile survival. A loss of viability and alterations in the cellular proportion was verified during the chronic test. However, the compounds did not alter the behavior of the annelids in the leak test (RL ranged from 20% to 30%). Although photocatalysis has been presented as an alternative technology for the treatment of waste containing the indigo carmine dye, this process produced byproducts even more toxic than the original compounds to E. andrei. Copyright © 2017 Elsevier Inc. All rights reserved.

Application of Caenorhabditis elegans (nematode) and Danio rerio embryo (zebrafish) as model systems to screen for developmental and reproductive toxicity of Piperazine compounds.

PubMed

Racz, Peter I; Wildwater, Marjolein; Rooseboom, Martijn; Kerkhof, Engelien; Pieters, Raymond; Yebra-Pimentel, Elena Santidrian; Dirks, Ron P; Spaink, Herman P; Smulders, Chantal; Whale, Graham F

2017-10-01

To enable selection of novel chemicals for new processes, there is a recognized need for alternative toxicity screening assays to assess potential risks to man and the environment. For human health hazard assessment these screening assays need to be translational to humans, have high throughput capability, and from an animal welfare perspective be harmonized with the principles of the 3Rs (Reduction, Refinement, Replacement). In the area of toxicology a number of cell culture systems are available but while these have some predictive value, they are not ideally suited for the prediction of developmental and reproductive toxicology (DART). This is because they often lack biotransformation capacity, multicellular or multi- organ complexity, for example, the hypothalamus pituitary gonad (HPG) axis and the complete life cycle of whole organisms. To try to overcome some of these limitations in this study, we have used Caenorhabditis elegans (nematode) and Danio rerio embryos (zebrafish) as alternative assays for DART hazard assessment of some candidate chemicals being considered for a new commercial application. Nematodes exposed to Piperazine and one of the analogs tested showed a slight delay in development compared to untreated animals but only at high concentrations and with Piperazine as the most sensitive compound. Total brood size of the nematodes was also reduced primarily by Piperazine and one of the analogs. In zebrafish Piperazine and analogs showed developmental delays. Malformations and mortality in individual fish were also scored. Significant malformations were most sensitively identified with Piperazine, significant mortality was only observed in Piperazine and only at the higest dose. Thus, Piperazine seemed the most toxic compound for both nematodes and zebrafish. The results of the nematode and zebrafish studies were in alignment with data obtained from conventional mammalian toxicity studies indicating that these have potential as developmental toxicity screening systems. The results of these studies also provided reassurance that none of the Piperazines tested are likely to have any significant developmental and/or reproductive toxicity issues to humans when used in their commercial applications. Copyright © 2017. Published by Elsevier Ltd.

Combinatorial QSAR Modeling of Rat Acute Toxicity by Oral Exposure

EPA Science Inventory

Quantitative Structure-Activity Relationship (QSAR) toxicity models have become popular tools for identifying potential toxic compounds and prioritizing candidates for animal toxicity tests. However, few QSAR studies have successfully modeled large, diverse mammalian toxicity end...

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

Szluha, A.; Morrison, A.; Heckman, C.

Physico-chemical criteria were established and subjected to the chemical compounds listed in CHRIS to select those chemicals which are immiscible and float on water. This information was compiled in a menu-driven data base for easy access. As the result of this work, 294 CHRIS chemicals were found to be floaters. A literature review was conducted also to review available spill containment and recovery equipment and techniques for the application toward floating hazardous chemical spills. No single technology or equipment was found to effectively apply for the containment and recovery of spilled floating chemicals. Specific deficiencies and problems inherent in existingmore » technologies were identified. A hazard and toxicity ranking system was developed and applied to the floating chemicals for groupings by degrees of flammability and toxicity hazards. These groupings include highly flammable through noncombustible and highly toxic through non-toxic and the combination of degrees of hazards.« less

Light-stick: A problem of marine pollution in Brazil.

PubMed

Cesar-Ribeiro, Caio; Rosa, Helena Costi; Rocha, Daniele Oliveira; Dos Reis, Camila Galli Baldini; Prado, Tabata Sarti; Muniz, Daniela Hernandes Coimbra; Carrasco, Raquel; Silva, Flávia Milão; Martinelli-Filho, José Eduardo; Palanch-Hans, Maria Fernanda

2017-04-15

Light-sticks are used as bait in surface long-line fishing, to capture swordfish and other large pelagic predators. When discharged in the ocean, it may reach the beaches. The traditional Brazilian community of Costa dos Coqueiros, Bahia, use light-sticks as a medicine for rheumatism, vitiligo and mycoses. It may affect the marine life when its content leak in the open ocean. This work evaluated and identified the acute and chronic toxicity of the light-stick. A high acute toxicity was observed in the mobility/mortality of Artemia sp.; in the fertilization of sea urchin eggs, and a high chronic toxicity in the development of the pluteus larvae of the same sea urchin. The main compounds that probably caused toxicity were the volatiles such as the fluorescent PAH and oxidants such as the hydrogen peroxide. Its disposal in the open ocean is a potential threat for marine life. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparative Analysis between Ecotoxicity of Nitrogen-, Phosphorus-, and Potassium-Based Fertilizers and Their Active Ingredients

PubMed Central

Simplício, Nathan de Castro Soares; Muniz, Daphne Heloísa de Freitas; Rocha, Fernanda Regina Moreira; Martins, Denis Cavalcanti; Dias, Zélia Malena Barreira; Farias, Bruno Pereira da Costa; Oliveira-Filho, Eduardo Cyrino

2016-01-01

This study aimed to analyze the ecotoxicity of nitrogen-, phosphorus-, and potassium-based compounds to organisms of two different trophic levels in order to compare the toxic effect between high-purity substances and these substances as components of fertilizers. Dilutions were made with the fertilizers’ potassium chloride, potassium nitrate, superphosphate, urea, and their equivalent reagents, to conduct assays to establish the acute lethal concentration for half of the population (LC50). Ten individuals of the benthic snail Biomphalaria glabrata and the fish Danio rerio were exposed to each concentration of tested compounds. As a result, the toxicity levels of potassium chloride, potassium nitrate, and urea were obtained for B. glabrata and D. rerio, with the fish being more susceptible to potassium chloride in the fertilizer and the snail to potassium nitrate and urea, in both commercial and reagent forms. Regarding superphosphate, no significant toxicity was found. This study concluded that among the tested substances, KNO3 and KCl were the most toxic substances and urea the least toxic. It was not possible to establish the most sensitive species since, for KCl, the fish were more susceptible to the fertilizer and the snail to the reagent, while for KNO3 the opposite was observed. PMID:29051434

Use of the ciliated protozoan Tetrahymena pyriformis for the assessment of toxicity and quantitative structure--activity relationships of xenobiotics: comparison with the Microtox test.

PubMed

Bogaerts, P; Bohatier, J; Bonnemoy, F

2001-07-01

Cytotoxicity and quantitative structure-activity relationships of 13 inorganic and 21 organic substances were determined using three bioassays performed on the ciliated protozoan Tetrahymena pyriformis and the luminescent bacterium Vibrio fischeri. The best concordance of toxicity results was observed between the T. pyriformis FDA--esterase activity and population growth inhibition tests for the organic compounds. The sensitivity of these two assays is compared with that of the Microtox test. The T. pyriformis FDA test showed a high sensitivity is most cases. The aim of the current research was to determine whether the relative toxicity of metal ions and organic molecules, with these three bioassays, was predictable using three ion characteristics and hydrophobicity, respectively. For metal ions, the variable that best modeled the toxicity data obtained with the two T. pyriformis tests was the softness index [sigma(p), i.e., (coordinate bond energy of the metal fluoride--coordinate bond energy of the metal iodide)/(coordinate bond energy of the metal fluoride)]. No correlation was found with the Microtox test. For organic compounds, a significant correlation was observed between the hydrophobicity coefficient and the toxicity data. This correlation is closer with the two tests using Tetrahymena. Copyright 2001 Academic Press.

Harnessing the medicinal properties of Andrographis paniculata for diseases and beyond: a review of its phytochemistry and pharmacology

PubMed Central

Okhuarobo, Agbonlahor; Falodun, Joyce Ehizogie; Erharuyi, Osayemwenre; Imieje, Vincent; Falodun, Abiodun; Langer, Peter

2014-01-01

Andrographis paniculata Wall (family Acanthaceae) is one of the most popular medicinal plants used traditionally for the treatment of array of diseases such as cancer, diabetes, high blood pressure, ulcer, leprosy, bronchitis, skin diseases, flatulence, colic, influenza, dysentery, dyspepsia and malaria for centuries in Asia, America and Africa continents. It possesses several photochemical constituents with unique and interesting biological properties. This review describes the past and present state of research on Andrographis paniculata with respect to the medicinal usage, phytochemistry, pharmacological activities, toxicity profile and therapeutic usage, in order to bridge the gap requiring future research opportunities. This review is based on literature study on scientific journals and books from library and electronic sources. Diterpenes, flavonoids, xanthones, noriridoides and other miscellaneous compounds have been isolated from the plant. Extract and pure compounds of the plant have been reported for their anti-microbial, cytotoxicity, anti-protozoan, anti-inflammatory, anti-oxidant, immunostimulant, anti-diabetic, anti-infective, anti-angiogenic, hepato-renal protective, sex hormone/sexual function modulation, liver enzymes modulation insecticidal and toxicity activities. The results of numerous toxicity evaluations of extracts and metabolites isolated from this plant did not show any significant acute toxicity in experimental animals. Detailed and more comprehensive toxicity profile on mammalian tissues and organs is needed in future studies.

Plant-derived compounds in treatment of leishmaniasis

PubMed Central

Oryan, A

2015-01-01

Leishmaniasis is a neglected public health problem caused by the protozoan species belonging to the genus Leishmania affecting mostly the poor populations of developing countries. The causative organism is transmitted by female sandflies. Cutaneous, mucocutaneous, and visceral clinical manifestations are the most frequent forms of leishmaniasis. Chemotherapy still relies on the use of pentavalent antimonials, amphotericin B, paromomycin, miltefosin and liposomal amphotericin B. However, the application of these drugs is limited due to low efficacy, life-threatening side effects, high toxicity, induction of parasite resistance, length of treatment and high cost. Given the fact that antileishmanial vaccines may not become available in the near future, the search for better drugs should be continued. Natural products may offer an unlimited source of chemical diversity to identify new drug modules. New medicines should be less toxic or non-toxic, safe, more efficient, less expensive and readily available antileishmanial agents, especially for low-income populations. In the present review, special focus is on medicinal plants used against leishmanaiasis. The bioactive phytocompounds present in the plant derivatives including the crude extracts, essential oils, and other useful compounds can be a good source for discovering and producing new antileishmanial medicines. PMID:27175144

Petroleomic analysis of the treatment of naphthenic organics in oil sands process-affected water with buoyant photocatalysts.

PubMed

Leshuk, Tim; Peru, Kerry M; de Oliveira Livera, Diogo; Tripp, Austin; Bardo, Patrick; Headley, John V; Gu, Frank

2018-05-10

The persistence of toxicity associated with the soluble naphthenic organic compounds (NOCs) of oil sands process-affected water (OSPW) implies that a treatment solution may be necessary to enable safe return of this water to the environment. Due to recent advances in high-resolution mass spectrometry (HRMS), the majority of the toxicity of OSPW is currently understood to derive from a subset of toxic classes, comprising only a minority of the total NOCs. Herein, oxidative treatment of OSPW with buoyant photocatalysts was evaluated under a petroleomics paradigm: chemical changes across acid-, base- and neutral-extractable organic fractions were tracked throughout the treatment with both positive and negative ion mode electrospray ionization (ESI) Orbitrap MS. Elimination of detected OS + and NO + classes of concern in the earliest stages of the treatment, along with preferential degradation of high carbon-numbered O 2 - acids, suggest that photocatalysis may detoxify OSPW with higher efficiency than previously thought. Application of petroleomic level analysis offers unprecedented insights into the treatment of petroleum impacted water, allowing reaction trends to be followed across multiple fractions and thousands of compounds simultaneously. Copyright © 2018 Elsevier Ltd. All rights reserved.

Toxicity of phenol and monochlorophenols to growth and metabolic activities of Pseudomonas

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

Huang, D.S.; Tseng, I.C.

1996-07-01

Phenolic compounds are toxic to many organisms and are often present in the effluents from oil refineries, the petrochemical, pesticide, and color and textile industries. Several authors have demonstrated a characteristic pattern of behavioral responses in fishes during phenol exposure. Others have also evaluated the toxicity of halogenated phenolic compounds by screening for effects on the specific growth rates (SGR) and the dehydrogenase activity (DHA) of Escherichia coli. However, little work has been done to determine the effects on biota from short exposures at relatively high concentrations of phenol or monochlorophenols that might occur following a deliberate or accidental dischargemore » to a receiving water. Microorganisms with phenol-degrading capacity have been studied intensively, including cyanobacteria such as Nostoc linckia, yeast such as Trichosporon cutaneum, bacteria such as Pseudomonas putida, and other unidentified species. Among these Pseudomonas has received the most attention and several mutants have been prepared to degrade substituted phenols. This study investigates the initial response of Pseudomonas upon exposure to high concentrations of phenol and chlorophenols by measuring the oxygen uptake rates. A series growth experiment was also conducted in order to compare the kinetic results with standard microbial tests. 12 refs., 3 figs., 1 tab.« less

Ecotoxicological assessment of a high energetic and insensitive munitions compound: 2,4-dinitroanisole (DNAN).

PubMed

Dodard, Sabine G; Sarrazin, Manon; Hawari, Jalal; Paquet, Louise; Ampleman, Guy; Thiboutot, Sonia; Sunahara, Geoffrey I

2013-11-15

The high explosive nitroaromatic 2,4-dinitroanisole (DNAN) is less shock sensitive than 2,4,6-trinitrotoluene (TNT), and is proposed as a TNT replacement for melt-cast formulations. Before using DNAN in munitions and potentially leading to environmental impact, the present study examines the ecotoxicity of DNAN using selected organisms. In water, DNAN decreased green algae Pseudokirchneriella subcapitata growth (EC50 = 4.0mg/L), and bacteria Vibrio fischeri bioluminescence (Microtox, EC50 = 60.3mg/L). In soil, DNAN decreased perennial ryegrass Lolium perenne growth (EC50 =7 mg/kg), and is lethal to earthworms Eisenia andrei (LC50 = 47 mg/kg). At sub-lethal concentrations, DNAN caused an avoidance response (EC50 = 31 mg/kg) by earthworms. The presence of DNAN and 2-amino-4-nitroanisole in earthworms and plants suggested a role of these compounds in DNAN toxicity. Toxicity of DNAN was compared to TNT, tested under the same experimental conditions. These analyses showed that DNAN was equally, or even less deleterious to organism health than TNT, depending on the species and toxicity test. The present studies provide baseline toxicity data to increase the understanding of the environmental impact of DNAN, and assist science-based decision makers for improved management of potential DNAN contaminated sites. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Microarray analysis in rat liver slices correctly predicts in vivo hepatotoxicity.

PubMed

Elferink, M G L; Olinga, P; Draaisma, A L; Merema, M T; Bauerschmidt, S; Polman, J; Schoonen, W G; Groothuis, G M M

2008-06-15

The microarray technology, developed for the simultaneous analysis of a large number of genes, may be useful for the detection of toxicity in an early stage of the development of new drugs. The effect of different hepatotoxins was analyzed at the gene expression level in the rat liver both in vivo and in vitro. As in vitro model system the precision-cut liver slice model was used, in which all liver cell types are present in their natural architecture. This is important since drug-induced toxicity often is a multi-cellular process involving not only hepatocytes but also other cell types such as Kupffer and stellate cells. As model toxic compounds lipopolysaccharide (LPS, inducing inflammation), paracetamol (necrosis), carbon tetrachloride (CCl(4), fibrosis and necrosis) and gliotoxin (apoptosis) were used. The aim of this study was to validate the rat liver slice system as in vitro model system for drug-induced toxicity studies. The results of the microarray studies show that the in vitro profiles of gene expression cluster per compound and incubation time, and when analyzed in a commercial gene expression database, can predict the toxicity and pathology observed in vivo. Each toxic compound induces a specific pattern of gene expression changes. In addition, some common genes were up- or down-regulated with all toxic compounds. These data show that the rat liver slice system can be an appropriate tool for the prediction of multi-cellular liver toxicity. The same experiments and analyses are currently performed for the prediction of human specific toxicity using human liver slices.

Microarray analysis in rat liver slices correctly predicts in vivo hepatotoxicity

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

Elferink, M.G.L.; Olinga, P.; Draaisma, A.L.

2008-06-15

The microarray technology, developed for the simultaneous analysis of a large number of genes, may be useful for the detection of toxicity in an early stage of the development of new drugs. The effect of different hepatotoxins was analyzed at the gene expression level in the rat liver both in vivo and in vitro. As in vitro model system the precision-cut liver slice model was used, in which all liver cell types are present in their natural architecture. This is important since drug-induced toxicity often is a multi-cellular process involving not only hepatocytes but also other cell types such asmore » Kupffer and stellate cells. As model toxic compounds lipopolysaccharide (LPS, inducing inflammation), paracetamol (necrosis), carbon tetrachloride (CCl{sub 4}, fibrosis and necrosis) and gliotoxin (apoptosis) were used. The aim of this study was to validate the rat liver slice system as in vitro model system for drug-induced toxicity studies. The results of the microarray studies show that the in vitro profiles of gene expression cluster per compound and incubation time, and when analyzed in a commercial gene expression database, can predict the toxicity and pathology observed in vivo. Each toxic compound induces a specific pattern of gene expression changes. In addition, some common genes were up- or down-regulated with all toxic compounds. These data show that the rat liver slice system can be an appropriate tool for the prediction of multi-cellular liver toxicity. The same experiments and analyses are currently performed for the prediction of human specific toxicity using human liver slices.« less

Broad activity of diphenyleneiodonium analogues against Mycobacterium tuberculosis, malaria parasites and bacterial pathogens.

PubMed

Nguyen, Nghi; Wilson, Danny W; Nagalingam, Gayathri; Triccas, James A; Schneider, Elena K; Li, Jian; Velkov, Tony; Baell, Jonathan

2018-03-25

In this study, a structure-activity relationship (SAR) compound series based on the NDH-2 inhibitor diphenyleneiodonium (DPI) was synthesised. Compounds were evaluated primarily for in vitro efficacy against Gram-positive and Gram-negative bacteria, commonly responsible for nosocomial and community acquired infections. In addition, we also assessed the activity of these compounds against Mycobacterium tuberculosis (Tuberculosis) and Plasmodium spp. (Malaria). This led to the discovery of highly potent compounds active against bacterial pathogens and malaria parasites in the low nanomolar range, several of which were significantly less toxic to mammalian cells. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Antifungal Compounds against Candida Infections from Traditional Chinese Medicine

PubMed Central

2017-01-01

Infections caused by Candida albicans, often refractory and with high morbidity and mortality, cause a heavy burden on the public health while the current antifungal drugs are limited and are associated with toxicity and resistance. Many plant-derived molecules including compounds isolated from traditional Chinese medicine (TCM) are reported to have antifungal activity through different targets such as cell membrane, cell wall, mitochondria, and virulence factors. Here, we review the recent progress in the anti-Candida compounds from TCM, as well as their antifungal mechanisms. Considering the diverse targets and structures, compounds from TCM might be a potential library for antifungal drug development. PMID:29445739

IMPROVEMENT IN AIR TOXICS METHODS FOR VOLATILE ORGANIC COMPOUNDS

EPA Science Inventory

Innovative and customized monitoring methods for air toxic volatile organic compounds (VOCs) are being developed for applications in exposure and trends monitoring. This task addresses the following applications of specific interest:

o Contributions to EPA Regional Monit...

Essential Oils of Hyptis pectinata Chemotypes: Isolation, Binary Mixtures and Acute Toxicity on Leaf-Cutting Ants.

PubMed

Feitosa-Alcantara, Rosana B; Bacci, Leandro; Blank, Arie F; Alves, Péricles B; Silva, Indira Morgana de A; Soares, Caroline A; Sampaio, Taís S; Nogueira, Paulo Cesar de L; Arrigoni-Blank, Maria de Fátima

2017-04-12

Leaf-cutting ants are pests of great economic importance due to the damage they cause to agricultural and forest crops. The use of organosynthetic insecticides is the main form of control of these insects. In order to develop safer technology, the objective of this work was to evaluate the formicidal activity of the essential oils of two Hyptis pectinata genotypes (chemotypes) and their major compounds on the leaf-cutting ants Acromyrmex balzani Emery and Atta sexdens rubropilosa Forel. Bioassays of exposure pathways (contact and fumigation) and binary mixtures of the major compounds were performed. The major compounds identified in the essential oils of H. pectinata were β-caryophyllene, caryophyllene oxide and calamusenone. The essential oils of H. pectinata were toxic to the ants in both exposure pathways. Essential oils were more toxic than their major compounds alone. The chemotype calamusenone was more toxic to A. balzani in both exposure pathways. A. sexdens rubropilosa was more susceptible to the essential oil of the chemotype β-caryophyllene in both exposure pathways. In general, the binary mixtures of the major compounds resulted in additive effect of toxicity. The essential oils of H. pectinata is a raw material of great potential for the development of new insecticides.

Consideration of reactivity to acute fish toxicity of α,β-unsaturated carbonyl ketones and aldehydes.

PubMed

Furuhama, A; Aoki, Y; Shiraishi, H

2012-01-01

To understand the key factor for fish toxicity of 11 α,β-unsaturated carbonyl aldehydes and ketones, we used quantum chemical calculations to investigate their Michael reactions with methanethiol or glutathione. We used two reaction schemes, with and without an explicit water molecule (Scheme-1wat and Scheme-0wat, respectively), to account for the effects of a catalytic water molecule on the reaction pathway. We determined the energies of the reactants, transition states (TS), and products, as well as the activation energies of the reactions. The acute fish toxicities of nine of the carbonyl compounds were evaluated to correlate with their hydrophobicities; no correlation was observed for acrolein and crotonaldehyde. The most toxic compound, acrolein, had the lowest activation energy. The activation energy of the reaction could be estimated with Scheme-1wat but not with Scheme-0wat. The complexity of the reaction pathways of the compounds was reflected in the difficulty of the TS structure searches when Scheme-1wat was used with the polarizable continuum model. The theoretical estimations of activation energies of α,β-unsaturated carbonyl compounds with catalytic molecules or groups including hydrogen-bond networks may complement traditional tools for predicting the acute aquatic toxicities of compounds that cannot be easily obtained experimentally.

Air toxics evaluation of ABB Combustion Engineering Low-Emission Boiler Systems

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

Wesnor, J.D.

1993-10-26

The specific goals of the program are to identify air toxic compounds that might be emmitted from the new boiler with its various Air Pollution Control device for APCD alternatives in levels of regulatory concern. For the compounds thought to be of concern, potential air toxic control methodologies will be suggested and a Test Protocol will be written to be used in the Proof of Concept and full scale tests. The following task was defined: Define Replations and Standards; Identify Air Toxic Pollutants of Interest to Interest to Utility Boilers; Assesment of Air Toxic By-Products; State of the Art Assessmentmore » of Toxic By-Product Control Technologies; and Test Protocol Definition.« less

Toxicity and accumulation of selenite in four microalgae

NASA Astrophysics Data System (ADS)

Wang, Dazhi; Cheng, Zhaodi; Li, Shaojing; Gao, Yahui

2003-09-01

The toxicity and bioaccumulation of selenite in four microalgae, Spirulina platensis, Dunaliella salina, Dunaliella bardawill and Phaeodactylum tricornutum cultured in the presence of selenite were investigated. Lower concentrations of selenite were generally nontoxic and frequently stimulated algal growth, while higher concentrations of selenite inhibited algal growth. Selenite was more toxic to D. salina and D. bardawill than to S. platensis and P. Tricornutum. All algae cultured in selenite were able to incorporate Se to different degrees, which depended on algal species. The distributions of selenite among intracellular macromolecular compounds were different among algal species: most of the selenite was associated with proteins in S. platensis, D. salina and D. bardawill, while most of the selenite was associated with lipids in P. tricornutum, which reflected the physiological differences among the algae. These observations suggest that algae are able to accumulate selenite and bind it with intracellular macromolecular compounds when exposed to high concentration of selenite. This may represent a form of storage or detoxification of selenite by the algae.

Mapping the Human Toxome by Systems Toxicology

PubMed Central

Bouhifd, Mounir; Hogberg, Helena T.; Kleensang, Andre; Maertens, Alexandra; Zhao, Liang; Hartung, Thomas

2014-01-01

Toxicity testing typically involves studying adverse health outcomes in animals subjected to high doses of toxicants with subsequent extrapolation to expected human responses at lower doses. The low-throughput of current toxicity testing approaches (which are largely the same for industrial chemicals, pesticides and drugs) has led to a backlog of more than 80,000 chemicals to which human beings are potentially exposed whose potential toxicity remains largely unknown. Employing new testing strategies that employ the use of predictive, high-throughput cell-based assays (of human origin) to evaluate perturbations in key pathways, referred as pathways of toxicity, and to conduct targeted testing against those pathways, we can begin to greatly accelerate our ability to test the vast “storehouses” of chemical compounds using a rational, risk-based approach to chemical prioritization, and provide test results that are more predictive of human toxicity than current methods. The NIH Transformative Research Grant project Mapping the Human Toxome by Systems Toxicology aims at developing the tools for pathway mapping, annotation and validation as well as the respective knowledge base to share this information. PMID:24443875

New isocoumarins from a cold-adapted fungal strain mucor sp. and their developmental toxicity to zebrafish embryos.

PubMed

Feng, Chun-Chi; Chen, Guo-Dong; Zhao, Yan-Qiu; Xin, Sheng-Chang; Li, Song; Tang, Jin-Shan; Li, Xiao-Xia; Hu, Dan; Liu, Xing-Zhong; Gao, Hao

2014-07-01

Three new isocoumarin derivatives, mucorisocoumarins A-C (1-3, resp.), together with seven known compounds, 4-10, were isolated from the cold-adapted fungal strain Mucor sp. (No. XJ07027-5). The structures of the new compounds were identified by detailed IR, MS, and 1D- and 2D-NMR analyses. It was noteworthy that compounds 1, 2, 4, and 5 were successfully resolved by chiral HPLC, indicating that 1-7 should exist as enantiomers. In an embryonic developmental toxicity assay using a zebrafish model, compound 3 produced developmental abnormalities in the zebrafish embryos. This is the first report of isocoumarins with developmental toxicity to zebrafish embryos. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.

Sensitivity assessment of freshwater macroinvertebrates to pesticides using biological traits.

PubMed

Ippolito, A; Todeschini, R; Vighi, M

2012-03-01

Assessing the sensitivity of different species to chemicals is one of the key points in predicting the effects of toxic compounds in the environment. Trait-based predicting methods have proved to be extremely efficient for assessing the sensitivity of macroinvertebrates toward compounds with non specific toxicity (narcotics). Nevertheless, predicting the sensitivity of organisms toward compounds with specific toxicity is much more complex, since it depends on the mode of action of the chemical. The aim of this work was to predict the sensitivity of several freshwater macroinvertebrates toward three classes of plant protection products: organophosphates, carbamates and pyrethroids. Two databases were built: one with sensitivity data (retrieved, evaluated and selected from the U.S. Environmental Protection Agency ECOTOX database) and the other with biological traits. Aside from the "traditional" traits usually considered in ecological analysis (i.e. body size, respiration technique, feeding habits, etc.), multivariate analysis was used to relate the sensitivity of organisms to some other characteristics which may be involved in the process of intoxication. Results confirmed that, besides traditional biological traits, related to uptake capability (e.g. body size and body shape) some traits more related to particular metabolic characteristics or patterns have a good predictive capacity on the sensitivity to these kinds of toxic substances. For example, behavioral complexity, assumed as an indicator of nervous system complexity, proved to be an important predictor of sensitivity towards these compounds. These results confirm the need for more complex traits to predict effects of highly specific substances. One key point for achieving a complete mechanistic understanding of the process is the choice of traits, whose role in the discrimination of sensitivity should be clearly interpretable, and not only statistically significant.

Biodegradation and detoxification of naphthenic acids in oil sands process affected waters.

PubMed

Yue, Siqing; Ramsay, Bruce A; Wang, Jiaxi; Ramsay, Juliana A

2016-12-01

After oil sands process affected water (OSPW) was treated in a continuous flow biofilm reactor, about 40% of the organic compounds in the acid extractable fraction (AEF) including naphthenic acids (NAs) were degraded resulting in a reduction of 73% in the Microtox acute toxicity and of 22% in the yeast estrogenic assay. Using effect directed analysis, treated and untreated OSPW were fractionated by solid phase extraction and the fractions with the largest decrease in toxicity and estrogenicity were selected for analysis by electrospray ionization combined with linear ion trap and a high-resolution Orbitrap mass spectrometer (negative ion mode). The aim of this study was to determine whether compositional changes between the untreated and treated fractions provide insight related to biodegradation and detoxification of NAs. The O2S, O3S and O4S compounds were either not major contributors of toxicity or estrogenicity or the more toxic or estrogenic ones were biodegraded. The O3- and O4-NAs seem to be more readily metabolized than O2NAs and their degradation would contribute to detoxification. The decrease in acute toxicity may be associated with the degradation of C12 and C13 bicyclic and C12-C14 tricyclic NAs while the decrease in estrogenicity may be linked to the degradation of C16 O2-NAs with double bond equivalents (DBE)=5 and 6, C16 and 17 O2-NAs with DBE=7, and C19-O2-NAs with DBE=8. The residual acute toxicity may be caused by recalcitrant components and/or degradation products such as the O2 bicyclic and tricyclic NAs, particularly the C14 and C15 bicyclic and C14-C16 tricyclic NAs as well as the polycyclic aromatic NAs (DBE≥5 compounds). The decrease in estrogenicity may be linked to the degradation of the O3 and O4 oxidized NAs while much of the residual estrogenicity may be due to the recalcitrant polycyclic aromatic O2-NAs. Hence, treatment to further detoxify OSPW should target these compounds. Copyright © 2016 Elsevier B.V. All rights reserved.

Toxicology, structure-function relationship, and human and environmental health impacts of polychlorinated biphenyls: progress and problems.

PubMed Central

Safe, S

1993-01-01

Polychlorinated biphenyls (PCBs) are industrial compounds that have been detected as contaminants in almost every component of the global ecosystem including the air, water, sediments, fish, and wildlife and human adipose tissue, milk, and serum. PCBs in commercial products and environmental extracts are complex mixtures of isomers and congeners that can now be analyzed on a congener-specific basis using high-resolution gas chromatographic analysis. PCBs are metabolized primarily via mixed-function oxidases into a broad spectrum of metabolites. The results indicate that metabolic activation is not required for PCB toxicity, and the parent hydrocarbons are responsible for most of the biochemical and toxic responses elicited by these compounds. Some of these responses include developmental and reproductive toxicity, dermal toxicity, endocrine effects, hepatotoxicity, carcinogenesis, and the induction of diverse phase I and phase II drug-metabolizing enzymes. Many of the effects observed for the commercial PCBs are similar to those reported for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Structure-function relationships for PCB congeners have identified two major structural classes of PCBs that elicit "TCDD-like" responses, namely, the coplanar PCBs (e.g., 3,3',4,4'-tetraCB, 3,3'4,4',5-pentaCB and 3,3',4,4',5,5'-hexaCB) and their mono-ortho coplanar derivatives. These compounds competitively bind to the TCDD or aryl hydrocarbon (Ah) receptor and exhibit Ah receptor agonist activity. In addition, other structural classes of PCBs elicit biochemical and toxic responses that are not mediated through the Ah receptor. The shor-term effects of PCBs on occupationally exposed humans appear to be reversible, and no consistent changes in overall mortality and cancer mortality have been reported. Recent studies have demonstrated that some developmental deficits in infants and children correlated with in utero exposure to PCBs; however, the etiologic agent(s) or structural class of PCBs responsible for these effects have not been delineated. In contrast, based on a toxic equivalency factor approach, the reproductive and developmental problems in certain wildlife populations appear to be related to the TCDD-like PCB congeners. PMID:8354174

Chemical & Material Risk Management Initiatives: Reach & Cr6+ Strategies (Briefing Charts)

DTIC Science & Technology

2011-02-01

Definition Acquisition, Technology and Logistics 17 DoD Hexavalent Chromium Minimization Strategy Non‐ Chrome  Primer Acquisition, Technology and...Logistics 18 Hexavalent Chromium (Cr6+) - Some Facts • Cr6+ compounds are wonderful corrosion inhibitors • Cr6+ compounds are highly toxic – We’ve learned...and Logistics 21 DoD Hexavalent Chromium Minimization Policy Acquisition, Technology and Logistics 22 Myth-busters • The DoD policy does not ban the

Treatment of mycosis fungoides with topical nitrosourea compounds: Further studies.

PubMed

Zackheim, H S; Epstein, E H

1975-12-01

Twenty-six patients with mycosis fungoides were treated topically with three nitrosourea compounds: carmustine (BCNU), lomustine (CCNU), and 1-methyl-1-nitrosourea. A high percentage experienced good to excellent results. Remissions following treatment of individual lesions varied from one month to at least three years. Remissions following total body surface treatment varied from two weeks to at least four months. Two of 13 patients treated over the entire body suffered temporary bone marrow depression, indluding one with severe pancytopenia. This toxic effect was attributed to lomustine and was not seen in patients treated with carmustine alone. Thirteen patients highly allergic to mechlorethamine hydrochloride showed no cross-sensitivity to nitrosourea compounds. A primary irritant dermatitis occurred in about one half of the patients and telangiectasia in two. Two patients developed hypersensitivity to nitrosourea compounds. Carmustine is the preferred nitrosourea compound for topical therapy of mycosis fungoides.

Lipid reducing activity and toxicity profiles of a library of polyphenol derivatives.

PubMed

Urbatzka, Ralph; Freitas, Sara; Palmeira, Andreia; Almeida, Tiago; Moreira, João; Azevedo, Carlos; Afonso, Carlos; Correia-da-Silva, Marta; Sousa, Emilia; Pinto, Madalena; Vasconcelos, Vitor

2018-05-10

Obesity is an increasing epidemic worldwide and novel treatments are urgently needed. Polyphenols are natural compounds derived from plants, which are known in particular for their antioxidant properties. However, some polyphenols were described to possess anti-obesity activities in vitro and in vivo. In this study, we aimed to screen a library of 85 polyphenol derivatives for their lipid reducing activity and toxicity. Compounds were analyzed at 5 μM with the zebrafish Nile red fluorescence fat metabolism assay and for general toxicity in vivo. To improve the safety profile, compounds were screened at 50 μM in murine preadipocytes in vitro for cytotoxicity. Obtained activity data were used to create a 2D-QSAR (quantitative structure activity relationship) model. 38 polyphenols showed strong lipid reducing activity. Toxicity analysis revealed that 18 of them did not show any toxicity in vitro or in vivo. QSAR analysis revealed the importance of the number of rings, fractional partial positively charged surface area, relative positive charge, relative number of oxygen atoms, and partial negative surface area for lipid-reducing activity. The five most potent compounds with EC 50 values in the nanomolar range for lipid reducing activity and without any toxic effects are strong candidates for future research and development into anti-obesity drugs. Molecular profiling for fasn, sirt1, mtp and ppary revealed one compound that reduced significantly fasn mRNA expression. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Detoxification of olive mill wastewater by electrocoagulation and sedimentation processes.

PubMed

Khoufi, Sonia; Feki, Firas; Sayadi, Sami

2007-04-02

Olive mill wastewater (OMW) is characterised by its high suspended solids content (SS), high turbidity (NTU), chemical oxygen demand (COD) concentration up to 100 gl(-1) and toxic phenolic compounds concentration up to 10 gl(-1). This study examined the effect of a physico-electrochemical method to detoxify olive mill wastewater prior an anaerobic biotreatment process. The proposed pre-treatment process consisted in a preliminary electrocoagulation step in which most phenolic compounds were polymerised, followed by a sedimentation step. The BOD(5)/COD ratio of the electrocoagulated OMW increased from 0.33, initial value, to 0.58. Furthermore, the sedimentation step yielded the removal of 76.2%, 75% and 71% of phenolic compounds, turbidity and suspended solid, respectively, after 3 days of plain settling. The combination of electrocoagulation and sedimentation allowed a COD reduction and decoloration of about 43% and 90%, respectively. This pre-treatment decreases the inhibition of Vibrio fisheri luminescence by 66.4%. Continuous anaerobic biomethanization experiments conducted in parallel with raw OMW and electrocoagulated OMW before and after sedimentation at a loading rate of 6g COD l(-1)day(-1), proved that the final pre-treated OMW was bioconverted into methane at high yield while raw OMW was very toxic to anaerobic microorganisms.

Teratological Effects of a Panel of Sixty Water-Soluble Toxicants on Zebrafish Development

PubMed Central

Ali, Shaukat; Aalders, Jeffrey

2014-01-01

Abstract The zebrafish larva is a promising whole-animal model for safety pharmacology, environmental risk assessment, and developmental toxicity. This model has been used for the high-throughput toxicity screening of various compounds. Our aim here is to identify possible phenotypic markers of teratogenicity in zebrafish embryos that could be used for the assaying compounds for reproductive toxicity. We have screened a panel of 60 water-soluble toxicants to examine their effects on zebrafish development. A total of 22,080 wild-type zebrafish larvae were raised in 250 μL defined buffer in 96-well plates at a plating density of one embryo per well. They were exposed for a 96-h period starting at 24 h post-fertilization. A logarithmic concentration series was used for range-finding, followed by a narrower geometric series for developmental toxicity assessment. A total of 9017 survivors were analyzed at 5 days post-fertilization for nine phenotypes, namely, (1) normal, (2) pericardial oedema, (3) yolk sac oedema, (4) melanophores dispersed, (5) bent tail tip, (6) bent body axis, (7) abnormal Meckel's cartilage, (8) abnormal branchial arches, and (9) uninflated swim bladder. For each toxicant, the EC50 (concentration required to produce one or more of these abnormalities in 50% of embryos) was also calculated. For the majority of toxicants (55/60) there was, at the population level, a statistically significant, concentration-dependent increase in the incidence of abnormal phenotypes among survivors. The commonest abnormalities were pericardial oedema, yolk sac oedema, dispersed melanophores, and uninflated swim bladder. It is possible therefore that these could prove to be general indicators of reproductive toxicity in the zebrafish embryo assay. PMID:24650241

Enhanced formulations for neutralization of chemical, biological and industrial toxants

DOEpatents

Tucker, Mark D [Albuqueque, NM

2008-06-24

An enhanced formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The enhanced formulation according to the present invention is non-toxic and non-corrosive and can be delivered by a variety of means and in different phases. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a bleaching activator and water.

Weathering the storm: how lodgepole pine trees survive mountain pine beetle outbreaks.

PubMed

Erbilgin, Nadir; Cale, Jonathan A; Hussain, Altaf; Ishangulyyeva, Guncha; Klutsch, Jennifer G; Najar, Ahmed; Zhao, Shiyang

2017-06-01

Recent mountain pine beetle outbreaks in western North America killed millions of lodgepole pine trees, leaving few survivors. However, the mechanism underlying the ability of trees to survive bark beetle outbreaks is unknown, but likely involve phytochemicals such as monoterpenes and fatty acids that can drive beetle aggregation and colonization on their hosts. Thus, we conducted a field survey of beetle-resistant lodgepole pine (Pinus contorta) trees to retrospectively deduce whether these phytochemicals underlie their survival by comparing their chemistry to that of non-attacked trees in the same stands. We also compared beetle attack characteristics between resistant and beetle-killed trees. Beetle-killed trees had more beetle attacks and longer ovipositional galleries than resistant trees, which also lacked the larval establishment found in beetle-killed trees. Resistant trees contained high amounts of toxic and attraction-inhibitive compounds and low amounts of pheromone-precursor and synergist compounds. During beetle host aggregation and colonization, these compounds likely served three critical roles in tree survival. First, low amounts of pheromone-precursor (α-pinene) and synergist (mycrene, terpinolene) compounds reduced or prevented beetles from attracting conspecifics to residual trees. Second, high amounts of 4-allyanisole further inhibited beetle attraction to its pheromone. Finally, high amounts of toxic limonene, 3-carene, 4-allyanisole, α-linolenic acid, and linoleic acid inhibited beetle gallery establishment and oviposition. We conclude that the variation of chemotypic expression of local plant populations can have profound ecological consequences including survival during insect outbreaks.

Potent Antifouling Marine Dihydroquinolin-2(1H)-one-Containing Alkaloids from the Gorgonian Coral-Derived Fungus Scopulariopsis sp.

PubMed

Shao, Chang-Lun; Xu, Ru-Fang; Wang, Chang-Yun; Qian, Pei-Yuan; Wang, Kai-Ling; Wei, Mei-Yan

2015-08-01

Marine biofouling has a major economic impact, especially when it occurs on ship hulls or aquaculture facilities. Since the International Maritime Organization (IMO) treaty to ban the application of organotin-based paints to ships went into effect in 2008, there is an urgent demand for the development of efficient and environmentally friendly antifouling agents. Marine microorganisms have proved to be a potential source of antifouling natural compounds. In this study, six dihydroquinolin-2-one-containing alkaloids, three monoterpenoids combined with a 4-phenyl-3,4-dihydroquinolin-2(1H)-one (1-3) and three 4-phenyl-3,4-dihydroquinolin-2(1H)-one alkaloids (4-6), were isolated from the gorgonian coral-derived fungus Scopulariopsis sp. collected in the South China Sea. These dihydroquinolin-2-one-containing alkaloids were evaluated against the larval settlement of barnacle Balanus amphitrite, and antifouling activity was detected for the first time for this class of metabolites. All of them except 6 showed strong antifouling activity. Compounds 1 and 2 were discovered to be the most promising non-toxic antilarval settlement candidates. Especially, compound 1 is the strongest antifouling compound in nature until now which showed highly potent activity with picomolar level (EC50 17.5 pM) and a very safety and high therapeutic ratio (LC50/EC50 1200). This represents an effective non-toxic, anti-larval settlement structural class of promising antifouling lead compound.

Isolation, Purification, and Characterization of Five Active Diketopiperazine Derivatives from Endophytic Streptomyces SUK 25 with Antimicrobial and Cytotoxic Activities.

PubMed

Alshaibani, Muhanna; Zin, Noraziah; Jalil, Juriyati; Sidik, Nik; Ahmad, Siti Junaidah; Kamal, Nurkhalida; Edrada-Ebel, Ruangelie

2017-07-28

In our search for new sources of bioactive secondary metabolites from Streptomyces sp., the ethyl acetate extracts from endophytic Streptomyces SUK 25 afforded five active diketopiperazine (DKP) compounds. The aim of this study was to characterize the bioactive compounds isolated from endophytic Streptomyces SUK 25 and evaluate their bioactivity against multiple drug resistance (MDR) bacteria such as Enterococcus raffinosus, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter spp., and their cytotoxic activities against the human hepatoma (HepaRG) cell line. The production of secondary metabolites by this strain was optimized through Thornton's medium. Isolation, purification, and identification of the bioactive compounds were carried out using high-performance liquid chromatography, high-resolution mass liquid chromatography-mass spectrometry, Fourier transform infrared spectroscopy, and nuclear magnetic resonance, and cryopreserved HepaRG cells were selected to test the cytotoxicity. The results showed that endophytic Streptomyces SUK 25 produces four active DKP compounds and an acetamide derivative, which were elucidated as cyclo -( L -Val- L -Pro), cyclo -( L -Leu- L -Pro), cyclo -( L -Phe- L -Pro), cyclo -( L -Val- L -Phe), and N -(7-hydroxy-6-methyl-octyl)-acetamide. These active compounds exhibited activity against methicillin-resistant S. aureus ATCC 43300 and Enterococcus raffinosus , with low toxicity against human hepatoma HepaRG cells. Endophytic Streptomyces SUK 25 has the ability to produce DKP derivatives biologically active against some MDR bacteria with relatively low toxicity against HepaRG cells line.

Radioprotection by metals: Selenium

NASA Astrophysics Data System (ADS)

Weiss, J. F.; Srinivasan, V.; Kumar, K. S.; Landauer, M. R.

The need exists for compounds that will protect individuals from high-dose acute radiation exposure in space and for agents that might be less protective but less toxic and longer acting. Metals and metal derivatives provide a small degree of radioprotection (dose reduction factor <= 1.2 for animal survival after whole-body irradiation). Emphasis is placed here on the radioprotective potential of selenium (Se). Both the inorganic salt, sodium selenite, and the organic Se compound, selenomethionine, enhance the survival of irradiated mice (60Co, 0.2 Gy/min) when injected IP either before (-24 hr and -1 hr) or shortly after (+15 min) radiation exposure. When administered at equitoxic doses (one-fourth LD10; selenomethionine = 4.0 mg/kg Se, sodium selenite = 0.8 mg/kg Se), both drugs enhanced the 30-day survival of mice irradiated at 9 Gy. Survival after 10-Gy exposure was significantly increased only after selenomethionine treatment. An advantage of selenomethionine is lower lethal and behavioral toxicity (locomotor activity depression) compared to sodium selenite, when they are administered at equivalent doses of Se. Sodium selenite administered in combination with WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioic acid, enhances the radioprotective effect and reduces the lethal toxicity, but not the behavioral toxicity, of WR-2721. Other studies on radioprotection and protection against chemical carcinogens by different forms of Se are reviewed. As additional animal data and results from human chemoprevention trials become available, consideration also can be given to prolonged administration of Se compounds for protection against long-term radiation effects in space.

Aspidosperma (Apocynaceae) plant cytotoxicity and activity towards malaria parasites. Part II: experimental studies withAspidosperma ramiflorum in vivo and in vitro.

PubMed

Aguiar, Anna C C; Cunha, Ananda C; Ceravolo, Isabela Penna; Gonçalves, Regina A Correia; Oliveira, Arildo J B; Krettli, Antoniana Ursine

2015-11-01

Several species of Aspidosperma plants are used to treat diseases in the tropics, including Aspidosperma ramiflorum, which acts against leishmaniasis, an activity that is experimentally confirmed. The species, known as guatambu-yellow, yellow peroba, coffee-peroba and matiambu, grows in the Atlantic Forest of Brazil in the South to the Southeast regions. Through a guided biofractionation of A. ramiflorum extracts, the plant activity against Plasmodium falciparum was evaluated in vitro for toxicity towards human hepatoma G2 cells, normal monkey kidney cells and nonimmortalised human monocytes isolated from peripheral blood. Six of the seven extracts tested were active at low doses (half-maximal drug inhibitory concentration < 3.8 µg/mL); the aqueous extract was inactive. Overall, the plant extracts and the purified compounds displayed low toxicity in vitro. A nonsoluble extract fraction and one purified alkaloid isositsirikine (compound 5) displayed high selectivity indexes (SI) (= 56 and 113, respectively), whereas compounds 2 and 3 were toxic (SI < 10). The structure, activity and low toxicity of isositsirikine in vitro are described here for the first time in A. ramiflorum, but only the neutral and precipitate plant fractions were tested for activity, which caused up to 53% parasitaemia inhibition of Plasmodium berghei in mice with blood-induced malaria. This plant species is likely to be useful in the further development of an antimalarial drug, but its pharmacological evaluation is still required.

Acute toxicity of polybrominated diphenyl ethers (PBDEs) for turbot (Psetta maxima) early life stages (ELS).

PubMed

Mhadhbi, Lazhar; Fumega, José; Boumaiza, Moncef; Beiras, Ricardo

2012-03-01

The environmental presence of polybrominated diphenyl ethers (PBDEs), among which BDE-47 and BDE-99 are particularly abundant, makes toxicity data necessary to assess the hazard risk posed by PBDE to aquatic organisms. This study examines the effects of BDE-47 and BDE-99 on embryo-larval stages of the marine flatfish turbot. The turbot embryos were exposed at nominal concentrations of BDE-47 and BDE-99 for 6 days. Selected dose levels were relevant for investigating sublethal and lethal effects. Both tested compounds caused lethal toxicity as well as non-lethal malformations during embryo development. We found a high toxic potency of BDE-47 compared to BDE-99 (LC₅₀ values for embryos and larvae, respectively, BDE-47: 27.35 and 14.13 μg L⁻¹; BDE-99: 38.28 and 29.64 μg L⁻¹). The present study shows high sensitivity of fish early life stages (ELS) to PBDE compounds. Based on environmental concentrations of dissolved PBDEs from various aquatic ecosystems, waterborne BDE-47 and BDE-99 pose little risk of acute toxicity to marine fish at relevant environmental concentrations. Turbot fish ELS proved to be an excellent model for the study of ecotoxicity of contaminants in seawater. The results demonstrate harmful effects of PBDE on turbot ELS at concentrations in the range of parts per billion units. In the perspective of risk assessment, ELS endpoints provide rapid, cost-effective and ecologically relevant information, and links should be sought between these short-term tests and effects of long-term exposures in more realistic scenarios.

Degradation of trifluoroacetate in oxic and anoxic sediments

USGS Publications Warehouse

Visscher, P.T.; Culbertson, C.W.; Oremland, R.S.

1994-01-01

THE deleterious effect of chlorofluorocarbons on stratospheric ozone has led to international cooperation to end their use. The search for acceptable alternatives has focused on hydrofluorocarbons (HFCs) or hydrochlorofluorocarbons (HCFCs) which are attractive because they have relatively short atmospheric residence times. HFCs and HCFCs are attacked by tropospheric hydroxyl radicals, leading to the formation of trifluoroacetate (TFA). Most of the atmospheric TFA is deposited at the Earth's surface, where it is thought to be highly resistant to bacterial attack. Therefore, use of HCFCs and HFCs may lead to accumulation of TFA in soils, where it could prove toxic or inhibitory to plants and soil microbial communities. Although little is known about the toxicity of TFA, monofluoroacetate, which occurs at low levels in some plants and which is susceptible to slow attack by aerobic soil microbes, is known to be acutely toxic. Here we report that TFA can be rapidly degraded microbially under anoxic and oxic conditions. These results imply that significant microbial sinks exist in nature for the elimination of TFA from the environment. We also show that oxic degradation of TFA leads to the formation of fluoroform, a potential ozone-depleting compound with a much longer atmospheric lifetime than the parent compounds.The deleterious effect of chlorofluorcarbons on stratospheric ozone has led to international cooperation to end their use. The search for acceptable alternatives has focused on hydroflnorocarbons (HFCs) or hydrochloroflnorcarbons (HCFs) which are attractive because they have relatively short atmospheric residence times. HFCs and HCFs are attacked by tropospheric hydroxyl radicals, leading to the formation of trifluoroacetate (TFA). Most of the atmospheric TFA is deposited at the Earth's surface, where it is thought to be highly resistant to bacterial attack. Therefore, use of HCFs and HCFs may lead to accummulation of TFA in soils, where it could prove toxic or inhibitory to plants and soil microbial communities. Although little is known about the toxicity of TFA, monofluoracetate, which occurs at low levels in some plants and which is susceptible to slow attack by aerobic soil microbes, is known to be acutely toxic. Here we report that TFA can be rapidly degraded microbially under anoxic and oxic conditions. These results imply that significant microbial sinks exist in nature for the elimination of TFA from the environment. We also show that oxic degradation of TFA leads to the formation of fluoroform, a potential ozone-depleting compound with a much longer atmospheric lifetime than the parent compounds.

Experimental validation of a model for diffusion-controlled absorption of organic compounds in the trachea

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

Gerde, P.; Muggenburg, B.A.; Thornton-Manning, J.R.

1995-12-01

Most chemically induced lung cancer originates in the epithelial cells in the airways. Common conceptions are that chemicals deposited on the airway surface are rapidly absorbed through mucous membranes, limited primarily by the rate of blood perfusion in the mucosa. It is also commonly thought that for chemicals to induce toxicity at the site of entry, they must be either rapidly reactive, readily metabolizable, or especially toxic to the tissues at the site of entry. For highly lipophilic toxicants, there is a third option. Our mathematical model predicts that as lipophilicity increases, chemicals partition more readily into the cellular lipidmore » membranes and diffuse more slowly through the tissues. Therefore, absorption of very lipophilic compounds will be almost entirely limited by the rate of diffusion through the epithelium rather than by perfusion of the capillary bed in the subepithelium. We have reported on a preliminary model for absorption through mucous membranes of any substance with a lipid/aqueous partition coefficient larger than one. The purpose of this work was to experimentally validate the model in Beagle dogs. This validated model on toxicant absorption in the airway mucosa will improve risk assessment of inhaled« less

Nursing protects honeybee larvae from secondary metabolites of pollen

PubMed Central

Lucchetti, Matteo A.; Kilchenmann, Verena; Glauser, Gaetan; Praz, Christophe

2018-01-01

The pollen of many plants contains toxic secondary compounds, sometimes in concentrations higher than those found in the flowers or leaves. The ecological significance of these compounds remains unclear, and their impact on bees is largely unexplored. Here, we studied the impact of pyrrolizidine alkaloids (PAs) found in the pollen of Echium vulgare on honeybee adults and larvae. Echimidine, a PA present in E. vulgare pollen, was isolated and added to the honeybee diets in order to perform toxicity bioassays. While adult bees showed relatively high tolerance to PAs, larvae were much more sensitive. In contrast to other bees, the honeybee larval diet typically contains only traces of pollen and consists predominantly of hypopharyngeal and mandibular secretions produced by nurse bees, which feed on large quantities of pollen-containing bee bread. We quantified the transfer of PAs to nursing secretions produced by bees that had previously consumed bee bread supplemented with PAs. The PA concentration in these secretions was reduced by three orders of magnitude as compared to the PA content in the nurse diet and was well below the toxicity threshold for larvae. Our results suggest that larval nursing protects honeybee larvae from the toxic effect of secondary metabolites of pollen. PMID:29563265

Pemetrexed degradation by photocatalytic process: Kinetics, identification of transformation products and estimation of toxicity.

PubMed

Secrétan, Philippe-Henri; Karoui, Maher; Levi, Yves; Sadou-Yayé, Hassane; Tortolano, Lionel; Solgadi, Audrey; Yagoubi, Najet; Do, Bernard

2018-05-15

This study employed a UV-A/visible/TiO 2 system to investigate the degradation of pemetrexed, an antifolate agent used in chemotherapy. The laboratory-scale method employed a photostability chamber that could be used to study multiple samples. Reversed-phase HPLC coupled with high-resolution ESI-LTQ-Orbitrap mass spectrometry was used to determine the transformation products (TPs) of PEME. Based on the identified TPs and existing chemical knowledge, the mechanism of degradation of the target compound was proposed. Concentrations were monitored as a function of time, and the degradation kinetics were compared. The structures of seven TPs, four of which have not been described to date, were proposed. Most of the TPs stemmed from OH radical additions to the dihydropyrrole moiety and oxidative decarboxylation of the glutamate residue. Based on the elucidated structures, a computational toxicity assessment was performed, showing that the TPs with higher log D values than the parent compound are more toxic than the PEME itself. To support these findings, the toxicities of irradiated samples on Vibrio fischeri were monitored over time. The experimental results corresponded well with the results of previous computational studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Multi-parameter optimization of aza-follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 2: Impact of lipophilicity on promiscuity and in vivo toxicity.

PubMed

Beaulieu, Pierre L; Bolger, Gordon; Deon, Dan; Duplessis, Martin; Fazal, Gulrez; Gagnon, Alexandre; Garneau, Michel; LaPlante, Steven; Stammers, Timothy; Kukolj, George; Duan, Jianmin

2015-03-01

We describe our efforts to identify analogs of thumb pocket 1 HCV NS5B inhibitor 1 (aza-analog of BI 207524) with improved plasma to liver partitioning and a predicted human half-life consistent with achieving a strong antiviral effect at a reasonable dose in HCV-infected patients. Compounds 3 and 7 were identified that met these criteria but exhibited off-target promiscuity in an in vitro pharmacology screen and in vivo toxicity in rats. High lipophilicity in this class was found to correlate with increased probability for promiscuous behavior and toxicity. The synthesis of an 8×11 matrix of analogs allowed the identification of C3, an inhibitor that displayed comparable potency to 1, improved partitioning to the liver and reduced lipophilicity. Although C3 displayed reduced propensity for in vitro off-target inhibition and the toxicity profile in rats was improved, the predicted human half-life of this compound was short, resulting in unacceptable dosing requirements to maintain a strong antiviral effect in patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

Nursing protects honeybee larvae from secondary metabolites of pollen.

PubMed

Lucchetti, Matteo A; Kilchenmann, Verena; Glauser, Gaetan; Praz, Christophe; Kast, Christina

2018-03-28

The pollen of many plants contains toxic secondary compounds, sometimes in concentrations higher than those found in the flowers or leaves. The ecological significance of these compounds remains unclear, and their impact on bees is largely unexplored. Here, we studied the impact of pyrrolizidine alkaloids (PAs) found in the pollen of Echium vulgare on honeybee adults and larvae. Echimidine, a PA present in E. vulgare pollen, was isolated and added to the honeybee diets in order to perform toxicity bioassays. While adult bees showed relatively high tolerance to PAs, larvae were much more sensitive. In contrast to other bees, the honeybee larval diet typically contains only traces of pollen and consists predominantly of hypopharyngeal and mandibular secretions produced by nurse bees, which feed on large quantities of pollen-containing bee bread. We quantified the transfer of PAs to nursing secretions produced by bees that had previously consumed bee bread supplemented with PAs. The PA concentration in these secretions was reduced by three orders of magnitude as compared to the PA content in the nurse diet and was well below the toxicity threshold for larvae. Our results suggest that larval nursing protects honeybee larvae from the toxic effect of secondary metabolites of pollen. © 2018 The Authors.

Acaricidal Activity of Eugenol Based Compounds against Scabies Mites

PubMed Central

Pasay, Cielo; Mounsey, Kate; Stevenson, Graeme; Davis, Rohan; Arlian, Larry; Morgan, Marjorie; Vyszenski-Moher, DiAnn; Andrews, Kathy; McCarthy, James

2010-01-01

Backgound Human scabies is a debilitating skin disease caused by the “itch mite” Sarcoptes scabiei. Ordinary scabies is commonly treated with topical creams such as permethrin, while crusted scabies is treated with topical creams in combination with oral ivermectin. Recent reports of acaricide tolerance in scabies endemic communities in Northern Australia have prompted efforts to better understand resistance mechanisms and to identify potential new acaricides. In this study, we screened three essential oils and four pure compounds based on eugenol for acaricidal properties. Methodology/Principal Findings Contact bioassays were performed using live permethrin-sensitive S. scabiei var suis mites harvested from pigs and permethrin-resistant S. scabiei var canis mites harvested from rabbits. Results of bioassays showed that clove oil was highly toxic against scabies mites. Nutmeg oil had moderate toxicity and ylang ylang oil was the least toxic. Eugenol, a major component of clove oil and its analogues –acetyleugenol and isoeugenol, demonstrated levels of toxicity comparable to benzyl benzoate, the positive control acaricide, killing mites within an hour of contact. Conclusions The acaricidal properties demonstrated by eugenol and its analogues show promise as leads for future development of alternative topical acaricides to treat scabies. PMID:20711455

Industrial toxicants and Parkinson’s disease

PubMed Central

Caudle, W. Michael; Guillot, Thomas S.; Lazo, Carlos R.; Miller, Gary W.

2012-01-01

The exposure of the human population to environmental contaminants is recognized as a significant contributing factor for the development of Parkinson’s disease (PD) and other forms of parkinsonism. While pesticides have repeatedly been identified as risk factors for PD, these compounds represent only a subset of environmental toxicants that we are exposed to on a regular basis. Thus, non-pesticide contaminants, such as metals, solvents, and other organohalogen compounds have also been implicated in the clinical and pathological manifestations of these movement disorders and it is these non-pesticide compounds that are the subject of this review. As toxic exposures to these classes of compounds can result in a spectrum of PD or PD-related disorders, it is imperative to appreciate shared clinico-pathological characteristics or mechanisms of action of these compounds in order to further delineate the resultant disorders as well as identify improved preventive strategies or therapeutic interventions. PMID:22309908

[The VR, the Russian version of the nerve agent VX].

PubMed

Cuquel, A-C; Dorandeu, F; Ceppa, F; Renard, C; Burnat, P

2015-05-01

A product of the arms race during the Cold War, the Russian VX, or VR, is an organophosphorus compound that is a structural isomer of the western VX compound (or A4), with which it shares a very high toxicity. It is much less studied and known than VX because the knowledge of its existence is relatively recent. A very low volatility and high resistance in the environment make it a persistent agent. Poisoning occurs mainly following penetration through skin and mucosa but vapour inhalation is a credible risk in some circumstances. The clinical presentation may be differed by several hours and despite the absence of signs and symptoms, the casualty should not be considered as contamination or intoxication-free. This agent has a long residence time in blood, a characteristics that clearly differentiates it from other compounds such as sarin. The protocols for antidote administration may thus have to be changed accordingly. The fact that VR poisoned individuals will less respond to the current oxime therapy used in France, the 2-PAM and that VR represents a higher threat than VX, being probably possessed by some proliferating states, justify the interest for this toxic product. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Antifungal activity of ionic liquids based on (-)-menthol: a mechanism study.

PubMed

Suchodolski, Jakub; Feder-Kubis, Joanna; Krasowska, Anna

2017-04-01

The mechanism of toxicity of chiral ionic liquids with (1R,2S,5R)-(-)-menthol [C n -Am-Men][Cl] (n=10, 11 or 12) in the fungus Candida albicans is reported here. Ionic liquids were more toxic towards Candida strain lacking all identified multidrug resistance efflux pumps. Moreover, the compounds tested inhibited C. albicans filamentation at the concentration at which detached fungal cells also adhered to the plastic surface. Our results showed the high activity of all the tested chiral ionic liquids in the permeabilization of C. albicans' membranes and in the digestion and interruption of the cell wall. The investigated ionic liquids thus have potential as disinfectants because besides their antifungal and antiadhesive action these compounds do not cause hemolysis. Copyright © 2017 Elsevier GmbH. All rights reserved.

Combination of cheminformatics and bioinformatics to explore the chemical basis of the rhizomes and aerial parts of Dioscorea nipponica Makino.

PubMed

Li, Xu-Zhao; Zhang, Shuai-Nan; Yang, Xu-Yan

2017-12-01

This study was aimed to explore the chemical basis of the rhizomes and aerial parts of Dioscorea nipponica Makino (DN). The pharmacokinetic profiles of the compounds from DN were calculated via ACD/I-Lab and PreADMET program. Their potential therapeutic and toxicity targets were screened through the DrugBank's or T3DB's ChemQuery structure search. Eleven of 48 compounds in the rhizomes and over half of the compounds in the aerial parts had moderate or good human oral bioavailability. Twenty-three of 48 compounds in the rhizomes and 40/43 compounds from the aerial parts had moderate or good permeability to intestinal cells. Forty-three of 48 compounds from the rhizomes and 18/43 compounds in the aerial parts bound weakly to the plasma proteins. Eleven of 48 compounds in the rhizomes and 36/43 compounds of the aerial parts might pass across the blood-brain barrier. Forty-three 48 compounds in the rhizomes and 18/43 compounds from the aerial parts showed low renal excretion ability. The compounds in the rhizomes possessed 391 potential therapeutic targets and 216 potential toxicity targets. Additionally, the compounds from the aerial parts possessed 101 potential therapeutic targets and 183 potential toxicity targets. These findings indicated that combination of cheminformatics and bioinformatics may facilitate achieving the objectives of this study. © 2017 Royal Pharmaceutical Society.

Exploring anaerobic environments for cyanide and cyano-derivatives microbial degradation.

PubMed

Luque-Almagro, Víctor M; Cabello, Purificación; Sáez, Lara P; Olaya-Abril, Alfonso; Moreno-Vivián, Conrado; Roldán, María Dolores

2018-02-01

Cyanide is one of the most toxic chemicals for living organisms described so far. Its toxicity is mainly based on the high affinity that cyanide presents toward metals, provoking inhibition of essential metalloenzymes. Cyanide and its cyano-derivatives are produced in a large scale by many industrial activities related to recovering of precious metals in mining and jewelry, coke production, steel hardening, synthesis of organic chemicals, and food processing industries. As consequence, cyanide-containing wastes are accumulated in the environment becoming a risk to human health and ecosystems. Cyanide and related compounds, like nitriles and thiocyanate, are degraded aerobically by numerous bacteria, and therefore, biodegradation has been offered as a clean and cheap strategy to deal with these industrial wastes. Anaerobic biological treatments are often preferred options for wastewater biodegradation. However, at present very little is known about anaerobic degradation of these hazardous compounds. This review is focused on microbial degradation of cyanide and related compounds under anaerobiosis, exploring their potential application in bioremediation of industrial cyanide-containing wastes.

Interferon induction by and toxicity of polyriboinosinic acid [poly(rI)].polyribocytidylic acid [poly (rC)], mismatched analog poly (rI).poly[r(C12Uracil)n], and poly(rI).poly(rC) L-lysine complexed with carboxymethylcellulose.

PubMed Central

Stringfellow, D A; Weed, S D

1980-01-01

The ability of polyriboinosionic acid [poly(rI)].polyribocytidylic acid [poly(rC)], mismatched analog poly (rI).poly[r(C12Uracil)n], and poly(rI).poly(rC) complexed with poly L-lysine and carboxymethylcellulose [poly(ICLc)] to induce interferon and the comparative toxicity of each in cats were evaluated. Each induced high levels of circulating interferon, although poly(ICLC) injected intravenously at 1 to 4 mg/kg induced up to 10 times more interferon than the other compounds. Each compound was pyrogenic and caused a transient decrease in leukocyte numbers. Poly(rI).poly(rC) and the mismatched analog caused severe diarrhea and nausea at the highest drug concentrations (1 to 4 mg/kg), but poly (ICLC) did not. Each compound also caused depression and lethargy and impaired coordination. PMID:6157363

Leishmanicidal compounds of Nectria pseudotrichia, an endophytic fungus isolated from the plant Caesalpinia echinata (Brazilwood).

PubMed

Cota, Betania Barros; Tunes, Luiza Guimarães; Maia, Daniela Nabak Bueno; Ramos, Jonas Pereira; Oliveira, Djalma Menezes de; Kohlhoff, Markus; Alves, Tânia Maria de Almeida; Souza-Fagundes, Elaine Maria; Campos, Fernanda Fraga; Zani, Carlos Leomar

2018-02-01

BACKGROUND In a screen of extracts from plants and fungi to detect antileishmanial activity, we found that the ethyl acetate extract of the fungus Nectria pseudotrichia, isolated from the tree Caesalpinia echinata (Brazilwood), is a promising source of bioactive compounds. OBJECTIVES The aims of this study were to isolate and determine the chemical structures of the compounds responsible for the antileishmanial activity of the organic extract from N. pseudotrichia. METHODS Compounds were isolated by chromatographic fractionation using semi-preparative high-performance liquid chromatography, and their chemical structures were determined by analytical and spectral data and by comparison with published data. The antileishmanial activity of the isolated compounds was evaluated in intracellular amastigote forms of Leishmania (Viannia) braziliensis expressing firefly luciferase as reporter gene, and cytotoxicity was determined in Vero and THP-1 mammalian cell lines by MTT assay. FINDINGS Fractionation of the extract yielded seven compounds: 10-acetyl trichoderonic acid A (1), 6'-acetoxy-piliformic acid (2), 5',6'-dehydropiliformic acid (3), piliformic acid (4), hydroheptelidic acid (5), xylaric acid D (6), and cytochalasin D (7). Compounds 1, 2 and 3 are reported here for the first time. Compounds 1, 2, and 5 were more active, with IC50 values of 21.4, 28.3, and 24.8 µM, respectively, and showed low toxicity to Vero and THP-1 cells. MAIN CONCLUSIONS N. pseudotrichia produces secondary metabolites that are more toxic to intracellular amastigote forms of L. (V.) braziliensis than to mammalian cells.

Photocatalytic Degradation of 4-Nitrophenol by C, N-TiO2: Degradation Efficiency vs. Embryonic Toxicity of the Resulting Compounds

NASA Astrophysics Data System (ADS)

Osin, Oluwatomiwa A.; Yu, Tianyu; Cai, Xiaoming; Jiang, Yue; Peng, Guotao; Cheng, Xiaomei; Li, Ruibin; Qin, Yao; Lin, Sijie

2018-06-01

The photocatalytic activity of TiO2 based photocatalysts can be improved by structural modification and elemental doping. In this study, through rational design, one type of carbon and nitrogen co-doped TiO2 (C, N-TiO2) photocatalyst with mesoporous structure was synthesized with improved photocatalytic activity in degrading 4-nitrophenol under simulated sunlight irradiation. The photocatalytic degradation efficiency of the C, N-TiO2 was much higher than the anatase TiO2 (A-TiO2) based on absorbance and HPLC analyses. Moreover, using zebrafish embryos, we showed that the intermediate degradation compounds generated by photocatalytic degradation of 4-nitrophenol had higher toxicity than the parent compound. A repeated degradation process was necessary to render complete degradation and non-toxicity to the zebrafish embryos. Our results demonstrated the importance of evaluating the photocatalytic degradation efficiency in conjunction with the toxicity assessment of the degradation compounds.

In vitro approaches to evaluate toxicity induced by organotin compounds tributyltin (TBT), dibutyltin (DBT), and monobutyltin (MBT) in neuroblastoma cells.

PubMed

Ferreira, Martiña; Blanco, Lucía; Garrido, Alejandro; Vieites, Juan M; Cabado, Ana G

2013-05-01

The toxic effects of the organotin compounds (OTCs) monobutyltin (MBT), dibutyltin (DBT), and tributyltin (TBT) were evaluated in vitro in a neuroblastoma human cell line. Mechanisms of cell death, apoptosis versus necrosis, were studied by using several markers: inhibition of cell viability and proliferation, F-actin, and mitochondrial membrane potential changes as well as reactive oxygen species (ROS) production and DNA fragmentation. The most toxic effects were detected with DBT and TBT even at very low concentrations (0.1-1 μM). In contrast, MBT induced lighter cytotoxic changes at the higher doses tested. None of the studied compounds stimulated propidium iodide uptake, although the most toxic chemical, TBT, caused lactate dehydrogenase release at the higher concentrations tested. These findings suggest that in neuroblastoma, OTC-induced cytotoxicity involves different pathways depending on the compound, concentration, and incubation time. A screening method for DBT and TBT quantification based on cell viability loss was developed, allowing a fast detection alternative to complex methodology.

Photocatalytic Degradation of 4-Nitrophenol by C, N-TiO2: Degradation Efficiency vs. Embryonic Toxicity of the Resulting Compounds.

PubMed

Osin, Oluwatomiwa A; Yu, Tianyu; Cai, Xiaoming; Jiang, Yue; Peng, Guotao; Cheng, Xiaomei; Li, Ruibin; Qin, Yao; Lin, Sijie

2018-01-01

The photocatalytic activity of TiO 2 based photocatalysts can be improved by structural modification and elemental doping. In this study, through rational design, one type of carbon and nitrogen co-doped TiO 2 (C, N-TiO 2 ) photocatalyst with mesoporous structure was synthesized with improved photocatalytic activity in degrading 4-nitrophenol under simulated sunlight irradiation. The photocatalytic degradation efficiency of the C, N-TiO 2 was much higher than the anatase TiO 2 (A-TiO 2 ) based on absorbance and HPLC analyses. Moreover, using zebrafish embryos, we showed that the intermediate degradation compounds generated by photocatalytic degradation of 4-nitrophenol had higher toxicity than the parent compound. A repeated degradation process was necessary to render complete degradation and non-toxicity to the zebrafish embryos. Our results demonstrated the importance of evaluating the photocatalytic degradation efficiency in conjunction with the toxicity assessment of the degradation compounds.

Natural compounds isolated from Brazilian plants are potent inhibitors of hepatitis C virus replication in vitro.

PubMed

Jardim, A C G; Igloi, Z; Shimizu, J F; Santos, V A F F M; Felippe, L G; Mazzeu, B F; Amako, Y; Furlan, M; Harris, M; Rahal, P

2015-03-01

Compounds extracted from plants can provide an alternative approach to new therapies. They present characteristics such as high chemical diversity, lower cost of production and milder or inexistent side effects compared with conventional treatment. The Brazilian flora represents a vast, largely untapped, resource of potential antiviral compounds. In this study, we investigate the antiviral effects of a panel of natural compounds isolated from Brazilian plants species on hepatitis C virus (HCV) genome replication. To do this we used firefly luciferase-based HCV sub-genomic replicons of genotypes 2a (JFH-1), 1b and 3a and the compounds were assessed for their effects on both HCV replication and cellular toxicity. Initial screening of compounds was performed using the maximum non-toxic concentration and 4 compounds that exhibited a useful therapeutic index (favourable ratio of cytotoxicity to antiviral potency) were selected for extra analysis. The compounds APS (EC50=2.3μM), a natural alkaloid isolated from Maytrenus ilicifolia, and the lignans 3(∗)43 (EC50=4.0μM), 3(∗)20 (EC50=8.2μM) and 5(∗)362 (EC50=38.9μM) from Peperomia blanda dramatically inhibited HCV replication as judged by reductions in luciferase activity and HCV protein expression in both the subgenomic and infectious systems. We further show that these compounds are active against a daclatasvir resistance mutant subgenomic replicon. Consistent with inhibition of genome replication, production of infectious JFH-1 virus was significantly reduced by all 4 compounds. These data are the first description of Brazilian natural compounds possessing anti-HCV activity and further analyses are being performed in order to investigate the mode of action of those compounds. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

DECHLORINATION OF POLYCHLORINATED BIPHENYLS IN SEDIMENT SLURRIES BY PALLADIUM MODIFIED ZEROVALENT IRON

EPA Science Inventory

Polychlorinated biphenyls (PCBs) are one group of persistent organic pollutants (POPs) of international concern because of global distribution, persistence, and toxicity. Removal of these compounds from the environment presents a very tough challenge because they are highly hydro...

A Literature Review - Problem Definition Studies on Selected Toxic Chemicals. Volume 2. Occupational Health and Safety Aspects of Phosphorus Smoke Compounds

DTIC Science & Technology

1978-04-01

1945. 24. Schautz, R.: [Occurrence of necrosis of both feet following local phosphorus burns.] Arztl Wchnschr 8:362-365, 1953 (German). 25...been found to be highly toxic to bcth experimental animals and humans. Occupational exposure to white phosphorus vapors has produced necrosis of the... necrosis of the jaw ("phossy jaw") among workers. There have been no reported cases of carcinogenicity in humans after white phos-. phorus intoxication

Study of oil-water partitioning of a chemical dispersant using an acute bioassay with marine crustaceans

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

Wells, P.G.; Abernethy, S.; Mackay, D.

1982-01-01

The toxicity of seawater dispersions of a chemical dispersant to two marine crustaceans was investigated in the presence and absence of various quantities of a non-toxic mineral oil. From the results and a physical-chemical partitioning analysis, a limiting value of the oil-water partition coefficient of the toxic compounds is deduced suggesting that essentially all of the toxic compounds in the dispersant will partition into solution in water following dispersant application to an oil spill. This conclusion simplifies interpretation and prediction of the toxic effects of a dispersed oil spill. The combined bioassay-partitioning procedure may have applications to the study ofmore » the toxicity of other complex mixtures such as industrial effluents.« less

Identification of endocrine disrupting chemicals acting on human aromatase.

PubMed

Baravalle, Roberta; Ciaramella, Alberto; Baj, Francesca; Di Nardo, Giovanna; Gilardi, Gianfranco

2018-01-01

Human aromatase is the cytochrome P450 catalysing the conversion of androgens into estrogens playing a key role in the endocrine system. Due to this role, it is likely to be a target of the so-called endocrine disrupting chemicals, a series of compounds able to interfere with the hormone system with toxic effects. If on one side the toxicity of some compounds such as bisphenol A is well known, on the other side the toxic concentrations of such compounds as well as the effect of the many other molecules that are in contact with us in everyday life still need a deep investigation. The availability of biological assays able to detect the interaction of chemicals with key molecular targets of the endocrine system represents a possible solution to identify potential endocrine disrupting chemicals. Here the so-called alkali assay previously developed in our laboratory is applied to test the effect of different compounds on the activity of human aromatase. The assay is based on the detection of the alkali product that forms upon strong alkali treatment of the NADP + released upon enzyme turnover. Here it is applied on human aromatase and validated using anastrozole and sildenafil as known aromatase inhibitors. Out of the small library of compounds tested, resveratrol and ketoconazole resulted to inhibit aromatase activity, while bisphenol A and nicotine were found to exert an inhibitory effect at relatively high concentrations (100μM), and other molecules such as lindane and four plasticizers did not show any significant effect. These data are confirmed by quantification of the product estrone in the same reaction mixtures through ELISA. Overall, the results show that the alkali assay is suitable to screen for molecules that interfere with aromatase activity. As a consequence it can also be applied to other molecular targets of EDCs that use NAD(P)H for catalysis in a high throughput format for the fast screening of many different compounds as endocrine disrupting chemicals. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. Copyright © 2017 Elsevier B.V. All rights reserved.

The contribution of low tar cigarettes to environmental tobacco smoke

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

Chortyk, O.T.; Schlotzhauer, W.S.

A series of low tar cigarettes (LTC) were smoked and the quantities of condensable mainstream (inhaled) and sidestream (between puffs) smoke compounds were determined and compared to those produced by a high tar, nonfilter cigarette. It was found that the LTC produced large quantities of sidestream smoke condensates, about equal to the high tar cigarette, and contained very high levels of toxic or cocarcinogenic phenols. On an equal weight basis, the LTC emitted more of these hazardous compounds into sidestream and environmental tobacco smoke. Higher smoke yields of a flavor additive and a sugar degradation product indicated addition of suchmore » compounds during the manufacture of LTC. It was concluded that, compared to a high tar cigarette, smoking LTC may be better for the smoker, but not for the nearby nonsmoker. Information should be developed to allow smokers to choose LTC that produce lower levels of hazardous compounds in their environmentally emitted sidestream smoke.« less

In vitro assessment of the structure-activity relationship of tyrosinase-dependent cytotoxicity of a series of substituted phenols.

PubMed

Naish-Byfield, S; Cooksey, C J; Latter, A M; Johnson, C I; Riley, P A

1991-01-01

The rate of oxidation by purified mushroom tyrosinase of 30 compounds was measured by oximetry, and the tyrosinase-dependent cytotoxicity of each estimated in an in vitro assay using exposure of non-melanogenic cells to the agents in the presence and absence of tyrosinase. Cytotoxicity was estimated by immediate inhibition of DNA synthesis; 4-hydroxyanisole was used as the reference material. Compounds that were not oxidized by tyrosinase were found to be non-toxic but there was no direct relationship between the rate of oxidation and the relative cytotoxicity of those materials that acted as substrates for the enzyme. Thioethers were found to be more cytotoxic than the corresponding phenoxyethers. This was partly due to their greater rate of oxidation by tyrosinase and, in the case of propylthiophenol, the consequence of higher effective toxicity of the lipophilic species. The optimum chain length for the side chain of the oxyethers was three saturated carbon atoms and the toxicity appeared to be influenced by the lipophilicity of the compounds, possibly reflecting the relative lipid solubility of the putative toxic ortho-quinones generated from them. The maximum tyrosinase-dependent toxicity observed was in the range 5-6 times the relative toxicity of 4-hydroxyanisole. Sulphinyl and sulphonyl derivatives were inactive. In addition to oxyethers and thioethers, esters and glycosides of oxyethers were also examined and were found to be toxic in the presence of tyrosinase when hydrolysed. The succinates were found to be oxidized and toxic in our test system, suggesting that they rapidly underwent spontaneous hydrolysis. Oximetry data suggest that slight spontaneous hydrolysis of the other compounds occurs but they were not toxic in our assay. Ring-methylated phenoxyethers were oxidized relatively slowly and were non-toxic. Fluorine-substituted phenoxyethers were oxidized slightly more rapidly and exhibited clear toxicity in our system. Sesamol was oxidized to a black pigment but was non-toxic in our assay. A water-soluble vitamin E derivative was not oxidized and was non-toxic. Allyl hydroquinone was not oxidized but exhibited significant direct toxicity.

Are luminescent bacteria suitable for online detection and monitoring of toxic compounds in drinking water and its sources?

PubMed

Woutersen, Marjolijn; Belkin, Shimshon; Brouwer, Bram; van Wezel, Annemarie P; Heringa, Minne B

2011-05-01

Biosensors based on luminescent bacteria may be valuable tools to monitor the chemical quality and safety of surface and drinking water. In this review, an overview is presented of the recombinant strains available that harbour the bacterial luciferase genes luxCDABE, and which may be used in an online biosensor for water quality monitoring. Many bacterial strains have been described for the detection of a broad range of toxicity parameters, including DNA damage, protein damage, membrane damage, oxidative stress, organic pollutants, and heavy metals. Most lux strains have sensitivities with detection limits ranging from milligrams per litre to micrograms per litre, usually with higher sensitivities in compound-specific strains. Although the sensitivity of lux strains can be enhanced by various molecular manipulations, most reported detection thresholds are still too high to detect levels of individual contaminants as they occur nowadays in European drinking waters. However, lux strains sensing specific toxic effects have the advantage of being able to respond to mixtures of contaminants inducing the same effect, and thus could be used as a sensor for the sum effect, including the effect of compounds that are as yet not identified by chemical analysis. An evaluation of the suitability of lux strains for monitoring surface and drinking water is therefore provided.

Rapid Assessment of the Toxicity of Fungal Compounds Using Luminescent Vibrio qinghaiensis sp. Q67

PubMed Central

Jian, Qijie; Gong, Liang; Li, Taotao; Wang, Yong; Wu, Yu; Chen, Feng; Qu, Hongxia; Duan, Xuewu

2017-01-01

Most tropical fruits after harvest are very perishable because of fungal infection. Since some pathogenic fungi can produce hazardous compounds such as mycotoxins, novel rapid and effective methods to assess those hazardous compounds are urgently needed. Herein we report that Vibrio qinghaiensis sp. Q67, a luminescent bacterium, can be used to rapidly assess the toxicities of mycotoxins and cultures from mycotoxin-producing pathogens. A good correlation (R2 > 0.98) between concentrations of the mycotoxins (fumonisin B1, deoxynivalenol, zearalenone, ochratoxin A, patulin, and citrinin) and the luminous intensity of V. qinghaiensis sp. Q67 was obtained. Furthermore, significant correlations (R2 > 0.96) between the amount of mycotoxin and the luminous intensity from the cultures of 10 major mycotoxin-producing pathogens were also observed. In addition, Fusarium proliferatum (half-maximal inhibitory concentration (IC50) = 17.49%) exhibited greater luminescence suppression than Fusarium semitectum (IC50 = 92.56%) or Fusarium oxysporum (IC50 = 28.61%), which was in agreement with the existing higher levels of fumonisin B1, fumonisin B2, and deoxynivalenol, which were measured by high-performance liquid chromatography-tandem mass spectrometry. These results suggest that V. qinghaiensis sp. Q67 is a promising alternative for the rapid evaluation of the toxicity of fungal mycotoxins. PMID:29065469

Rapid Assessment of the Toxicity of Fungal Compounds Using Luminescent Vibrio qinghaiensis sp. Q67.

PubMed

Jian, Qijie; Gong, Liang; Li, Taotao; Wang, Yong; Wu, Yu; Chen, Feng; Qu, Hongxia; Duan, Xuewu; Jiang, Yueming

2017-10-21

Most tropical fruits after harvest are very perishable because of fungal infection. Since some pathogenic fungi can produce hazardous compounds such as mycotoxins, novel rapid and effective methods to assess those hazardous compounds are urgently needed. Herein we report that Vibrio qinghaiensis sp. Q67, a luminescent bacterium, can be used to rapidly assess the toxicities of mycotoxins and cultures from mycotoxin-producing pathogens. A good correlation ( R ² > 0.98) between concentrations of the mycotoxins (fumonisin B1, deoxynivalenol, zearalenone, ochratoxin A, patulin, and citrinin) and the luminous intensity of V. qinghaiensis sp. Q67 was obtained. Furthermore, significant correlations ( R ² > 0.96) between the amount of mycotoxin and the luminous intensity from the cultures of 10 major mycotoxin-producing pathogens were also observed. In addition, Fusarium proliferatum (half-maximal inhibitory concentration (IC 50 ) = 17.49%) exhibited greater luminescence suppression than Fusarium semitectum (IC 50 = 92.56%) or Fusarium oxysporum (IC 50 = 28.61%), which was in agreement with the existing higher levels of fumonisin B1, fumonisin B2, and deoxynivalenol, which were measured by high-performance liquid chromatography-tandem mass spectrometry. These results suggest that V. qinghaiensis sp. Q67 is a promising alternative for the rapid evaluation of the toxicity of fungal mycotoxins.

Comparative Toxicity of Selected Aviation Fuels as Measured by Insect Bioassay

DTIC Science & Technology

1982-07-01

structure in termites , ants, and bees can be used to contrast the toxicity of a compound. A comparative study of toxicity can also be made using a...and also serve as sex pheromones , kairomones, and defensive compounds. Cuticular hydrocarbons vary significantly in structure and amount by species...in flour beetles. Flour beetles contain hydrocarbons which function as sex pheromones and also contain a significant amount of 1-pentadecene which

Specific detection of membrane-toxic substances with a conductivity assay.

PubMed

Eich, J; Dürholt, H; Steger-Hartmann, T; Wagner, E

2000-03-01

A conductivity assay that represents a new biotest able to detect the effects of membrane-toxic compounds, e.g., detergents, organic solvents, and radical formers, on various organisms was previously described and developed. The conductivity assay measures ion leakage from cells, tissues, or whole plant and animal organisms whose membrane systems have been damaged by membrane-toxic compounds. In this study the specificity of the conductivity assay for membrane-toxic compounds was tested by comparing the electrolyte efflux from Elodea canadensis leaves during incubation with a well-known detergent (benzalkonium chloride) using different plant physiological and biochemical techniques (photochemical efficiency, plasmolysis capacity, NBT reduction, and electron microscopy of membranes of E. canadensis leaves). The comparison of the different methods proved that the electrolyte loss during benzalkonium chloride incubation determined in the conductivity assay is due to membrane impairment. The observed electrolyte loss correlated with a reduction of photochemical efficiency and a decrease in both plasmolysis and NBT reduction capacity. Furthermore, a disintegration of the plasmalemma could be seen in the electron micrographs. These results indicate that the measured electrolyte loss in the conductivity assay is a specific effect of membrane-toxic compounds. Copyright 2000 Academic Press.

Can Dietary Polyphenols Prevent the Formation of Toxic Compounds from Maillard Reaction?

PubMed

Del Turco, Serena; Basta, Giuseppina

2016-01-01

Polyphenols are functional compounds in edible vegetable and food such as tea, coffee and red wine and increasing evidence demonstrates a positive link between consumption of polyphenol-rich foods and disease prevention. In this review we have focused on the current knowledge of the potential anti-glycation effects of polyphenols, particularly in regard to their influence on Maillard reaction, a non-enzymatic reaction between amino acids and reducing sugars that contributes to the production of toxic compounds, mainly reactive carbonyl species, advanced glycation end-products (AGEs) and other toxicants. The Maillard reaction occurs in the human body during hyperglycemic condition, but it is well known as browning reaction in thermally processed foods and it is responsible for flavor and toxicant formation. Dietary polyphenols can have anti-glycation effects and actively participate in Maillard reaction, mitigating the AGE formation and the heat-induced production of toxic compounds. In a time in which the role of a healthy diet in the prevention of chronic diseases is welcome and the borderline between food and medicine is becoming very thin, an improved mechanistic knowledge of how polyphenols can function to reduce harmful and unhealthy substances is mandatory.

Biodegradation and toxicity of a maize herbicide mixture: mesotrione, nicosulfuron and S-metolachlor.

PubMed

Carles, Louis; Joly, Muriel; Bonnemoy, Frédérique; Leremboure, Martin; Donnadieu, Florence; Batisson, Isabelle; Besse-Hoggan, Pascale

2018-04-21

The prediction of chemical mixture toxicity is a major concern regarding unintentional mixture of pesticides from agricultural lands treated with various such compounds. We focused our work on a mixture of three herbicides commonly applied on maize crops within a fortnight, namely mesotrione (β-triketone), nicosulfuron (sulfonylurea) and S-metolachlor (chloroacetanilide). The metabolic pathways of mesotrione and nicosulfuron were qualitatively and quantitatively determined with a bacterial strain (Bacillus megaterium Mes11). This strain was isolated from an agricultural soil and able to biotransform both these herbicides. Although these pathways were unaffected in the case of binary or ternary herbicide mixtures, kinetics of nicosulfuron disappearance and also of mesotrione and nicosulfuron metabolite formation was strongly modulated. The toxicity of the parent compounds and metabolites was evaluated for individual compounds and mixtures with the standardized Microtox® test. Synergistic interactions were evidenced for all the parent compound mixtures. Synergistic, antagonistic or additive toxicity was obtained depending on the metabolite mixture. Overall, these results emphasize the need to take into account the active ingredient and metabolites all together for the determination of environmental fate and toxicity of pesticide mixtures. Copyright © 2018 Elsevier B.V. All rights reserved.

Zebrafish embryo toxicity of anaerobic biotransformation products from the insensitive munitions compound 2,4-dinitroanisole.

PubMed

Olivares, Christopher I; Sierra-Alvarez, Reyes; Abrell, Leif; Chorover, Jon; Simonich, Michael; Tanguay, Robert L; Field, Jim A

2016-11-01

2,4-Dinitroanisole (DNAN) is an emerging insensitive munitions compound that readily undergoes anaerobic nitro-group reduction to 2-methoxy-5-nitroaniline (MENA) and 2,4-diaminoanisole (DAAN), followed by formation of unique azo dimers. Currently there is little knowledge on the ecotoxicity of DNAN (bio)transformation products. In the present study, mortality, development, and behavioral effects of DNAN (bio)transformation products were assessed using zebrafish (Danio rerio) embryos. The authors tested individual products, MENA and DAAN, as well as dimer and trimer surrogates. As pure compounds, 3-nitro-4-methoxyaniline and 2,2'-dimethoxy-4,4'-azodianiline caused statistically significant effects, with lowest-observable-adverse effect levels (LOAEL) at 6.4 μM on 1 or 2 developmental endpoints, respectively. The latter had 6 additional statistically significant developmental endpoints with LOAELs of 64 μM. Based on light-to-dark swimming behavioral tests, DAAN (640 μM) caused reduction in swimming, suggestive of neurotoxicity. No statistically significant mortality occurred (≤64 μM) for any of the individual compounds. However, metabolite mixtures formed during different stages of MENA (bio)transformation in soil were characterized using high-resolution mass spectrometry in parallel with zebrafish embryo toxicity assays, which demonstrated statistically significant mortality during the onset of azo-dimer formation. Overall the results indicate that several DNAN (bio)transformation products cause different types of toxicity to zebrafish embryos. Environ Toxicol Chem 2016;35:2774-2781. © 2016 SETAC. © 2016 SETAC.

EFFECT OF IRRADIANCE SPECTRA ON THE PHOTOINDUCED TOXICITY OF THREE POLYCYCLIC AROMATIC HYDROCARBONS

EPA Science Inventory

Photoinduced toxicity of polycyclic aromatic hydrocarbons (PAHs) is dependent on the concentration of compounds present and the dose of light received. Of the light present, only those wavelengths absorbed by the compound have the potential to initiate the photochemical events un...

THE EFFECT OF IRRADIANCE SPECTRA ON THE PHOTOACTIVATED TOXICITY OF THREE POLYCYCLIC AROMATIC HYDROCARBONS

EPA Science Inventory

Photoinduced toxicity of polycyclic aromatic hydrocarbons (PAHs) is dependent on the concentration of compounds present and the dose of light recieved. Of the light present, only those wavelengths absorbed by the compound have the potential to initiate the photochemical events un...

Draft genome sequence of Coniochaeta ligniaria NRRL 30616, a lignocellulolytic fungus for bioabatement of inhibitors in plant biomass hydrolysates

USDA-ARS?s Scientific Manuscript database

Here, we report the first draft genome sequence (42.38 Mb that contains 13,657 genes) of Coniochaeta ligniaria NRRL30616, an ascomycete with high biotechnological relevance in the bioenergy field given its high potential for bioabatement of toxic furanic compounds in plant biomass hydrolysates and i...

Design, discovery, modelling, synthesis, and biological evaluation of novel and small, low toxicity s-triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors.

PubMed

Viira, Birgit; Selyutina, Anastasia; García-Sosa, Alfonso T; Karonen, Maarit; Sinkkonen, Jari; Merits, Andres; Maran, Uko

2016-06-01

A set of top-ranked compounds from a multi-objective in silico screen was experimentally tested for toxicity and the ability to inhibit the activity of HIV-1 reverse transcriptase (RT) in cell-free assay and in cell-based assay using HIV-1 based virus-like particles. Detailed analysis of a commercial sample that indicated specific inhibition of HIV-1 reverse transcription revealed that a minor component that was structurally similar to that of the main compound was responsible for the strongest inhibition. As a result, novel s-triazine derivatives were proposed, modelled, discovered, and synthesised, and their antiviral activity and cellular toxicity were tested. Compounds 18a and 18b were found to be efficient HIV-1 RT inhibitors, with an IC50 of 5.6±1.1μM and 0.16±0.05μM in a cell-based assay using infectious HIV-1, respectively. Compound 18b also had no detectable toxicity for different human cell lines. Their binding mode and interactions with the RT suggest that there was strong and adaptable binding in a tight (NNRTI) hydrophobic pocket. In summary, this iterative study produced structural clues and led to a group of non-toxic, novel compounds to inhibit HIV-RT with up to nanomolar potency. Copyright © 2016 Elsevier Ltd. All rights reserved.

IPM-compatibility of foliar insecticides for citrus: Indices derived from toxicity to beneficial insects from four orders

PubMed Central

Michaud, J.P.; Grant, A.K.

2003-01-01

A series of compounds representing four major pesticide groups were tested for toxicity to beneficial insects representing four different insect orders: Coleoptera (Coccinellidae), Hemiptera (Anthocoridae), Hymenoptera (Aphelinidae), and Neuroptera (Chrysopidae). These materials included organophosphates (methidathion, esfenvalerate and phosmet), carbamates (carbofuran, methomyl and carbaryl), pyrethroids (bifenthrin, fenpropathrin, zeta-cypermethrin, cyfluthrin and permethrin) and the oxadiazine indoxacarb. Toxicity to coccinellid and lacewing species was assessed by treating 1st instar larvae with the recommended field rate of commercial products, and two 10 fold dilutions of these materials, in topical spray applications. Adult Aphytis melinus Debach and 2nd instar Orius insidiosus (Say) were exposed to leaf residues of the same concentrations for 24 h. ANOVA performed on composite survival indices derived from these data resolved significant differences among materials with respect to their overall toxicity to beneficial insects. Cyfluthrin, fenpropathrin and zeta-cypermethrin all increased the developmental time of the lacewing and one or more coccinellid species for larvae that survived topical applications. Bifenthrin increased developmental time for two coccinellid species and decreased it in a third. Indoxacarb (Avaunt® WG, DuPont Corp.) ranked highest overall for safety to beneficial insects, largely because of its low dermal toxicity to all species tested. Zeta-cypermethrin (Super Fury®, FMC Corporation) received the second best safety rating, largely because of its low toxicity as a leaf residue to A. melinus and O. insidiosus. Phosmet (Imidan® 70W, Gowan Co.) and methidathion (Supracide® 25W, Gowan Co.) ranked high for safety to coccinellid species, but compounds currently recommended for use in citrus such as fenpropathrin (Danitol® 2.4EC, Sumimoto Chem. Co.) and carbaryl (Sevin® XLR EC, Rhone Poulenc Ag. Co.) ranked very low for IPM-compatibility based on their relatively high toxicity to all species tested. Abbreviation: FR field rate PMID:15841234

Acute toxicity of 31 different nanoparticles to zebrafish (Danio rerio) tested in adulthood and in early life stages – comparative study

PubMed Central

Kovrižnych, Jevgenij A.; Zeljenková, Dagmar; Rollerová, Eva; Szabová, Elena; Wimmerová, Soňa

2013-01-01

At present, nanoparticles are beginning to influence our lives in many ways and understanding the environmental health and safety aspect of nanomaterials has become a crucial issue. The aim of the work was to assess and compare the acute toxicity of 31 different nanomaterials to fish mature individuals Danio rerio with that to fish early life stages on using evaluation of the 48- and 96- hour LC50 values. A further aim was to evaluate teratogenicity of the nanoparticles tested to fish eggs. The nanoparticles tested were: 8 pure metals, 10 metal oxides, 5 other metal compounds and their mixtures, 2 silicon compounds, 3 calcium compounds, and 3 carbon compounds. Using 48-h and 96-h tests of acute toxicity (according to OECD 203), we evaluated mortality data, LC50 values, occurrence of malformations, as well as hatching time. In our study, 6 kinds of nanoparticles – calcium oxide, copper, copper in the form of oxide and CuZnFe4O4, magnesium oxide, and nickel – caused cumulative mortality. Two kinds of nanoparticles – copper and silver – were toxic for fish with LC50 values of approximately 3 mg/L. We did not observe marked differences between the 48-hour and 96-hour acute toxicity LC50 values, yet the possibility to evaluate hatching time in the 96-h acute fish toxicity test seems to be an advantage against that of the 48-hour toxicity. PMID:24179431

ION COMPOSITION ELUCIDATION (ICE): A HIGH ...

EPA Pesticide Factsheets

Unidentified Organic Compounds. For target analytes, standards are purchased, extraction and clean-up procedures are optimized, and mass spectra and retention times for the chromatographic separation are obtained for comparison to the target compounds in environmental sample extracts. This is an efficient approach and selective extraction and clean-up can decrease detection limits for the target compounds relative to analyzing a raw extract containing compounds that yield mass interferences. But selection of a class of compounds for study ignores many potentially toxic compounds. All compounds should be considered, because even trace amounts of compounds found to be endocrine disrupting chemicals might influence embryonic development. Before the toxicology of the hundreds of compounds found in sewage treatment effluents and water reservoirs can be studied alone and in mixtures, they must first be identified. A given compound might be one of the 3800 high production volume chemicals used commercially, a human or microorganism metabolite of such a compound, a photochemical degradation, hydrolysis, or thermal decomposition product, a chlorination or ozonolysis byproduct for drinking water samples, or a naturally occurring compound. Numerous researchers targeting assorted classes of analytes could easily overlook or be unable to identify many of these compounds. Most non-targeted compounds will not be in mass spectral libraries and can seldom be tentatively identifi

Toxicity evaluation of the process effluent streams of a petrochemical industry.

PubMed

Reis, J L R; Dezotti, M; Sant'Anna, G L

2007-02-01

The physico-chemical characteristics and the acute toxicity of several wastewater streams, generated in the industrial production of synthetic rubber, were determined. The acute toxicity was evaluated in bioassays using different organisms: Danio rerio (fish), Lactuca sativa (lettuce) and Brachionus calyciflorus (rotifer). The removal of toxicity attained in the industrial wastewater treatment plant was also determined upstream and downstream of the activated sludge process. The results obtained indicate that the critical streams in terms of acute toxicity are the effluents from the liquid polymer unit and the spent caustic butadiene washing stage. The biological treatment was able to partially remove the toxicity of the industrial wastewater. However, a residual toxicity level persisted in the biotreated wastewater. The results obtained with Lactuca sativa showed a high degree of reproducibility, using root length or germination index as evaluation parameters. The effect of volatile pollutants on the toxicity results obtained with lettuce seeds was assessed, using ethanol as a model compound. Modifications on the assay procedure were proposed. A strong correlation between the toxic responses of Lactuca sativa and Danio rerio was observed for most industrial effluent streams.

Synthesis, analgesic activity, and binding properties of some epibatidine analogs with a tropine skeleton.

PubMed

Rádl, S; Hafner, W; Budesínsky, M; Hejnová, L; Krejcí, I

2000-06-01

A series of epibatidine analogs and their positional isomers bearing an 8-azabicyclo[3.2.1]octane moiety is described. Also some of their simplified analogs bearing a 3-piperidine moiety are reported. Their receptor binding profiles (5-HT1A, 5-HT1B, M1, M2, neuronal nicotinic receptor) and analgesic activity (hot plate, acetic acid induced writhing) have been studied. Some of the compounds, especially those containing an 8-azabicyclo[3.2.1]oct-2-ene moiety possess high afinity for the nicotinic cholinergic receptor. The most analgesically active compounds are also highly toxic. Optimized structures (PM3-MOPAC, Alchemy 2000, Tripos Inc.) of compounds 1-9 were compared with that of epibatidine.

Acute toxicity of some nerve agents and pesticides in rats.

PubMed

Misik, Jan; Pavlikova, Ruzena; Cabal, Jiri; Kuca, Kamil

2015-01-01

Highly toxic organophosphorus compounds (V- and G-nerve agents) were originally synthesized for warfare or as agricultural pesticides. Data on their acute toxicity are rare and patchy. Therefore, there is a need for integrated summary comparing acute toxicity of organophosphates using different administration routes in the same animal model with the same methodology. Based on original data, a summary of in vivo acute toxicity of selected V- and G-nerve agents (tabun, sarin, soman, VX, Russian VX) and organophosphates paraoxon (POX) and diisopropyl fluorophosphate (DFP) in rats has been investigated. Male Wistar rats were exposed to organophosphates in several administration routes (i.m., i.p., p.o, s.c., p.c.). The acute toxicity was evaluated by the assessment of median lethal dose (LD50, mg kg(-1)) 2, 4, and 24 hours post exposure. V-agents were the most toxic presented with LD50 ranged from 0.0082 mg kg(-1) (VX, i.m.) to 1.402 mg kg(-1) (Russian VX, p.o.), followed by G-agents (LD50 = 0.069 mg kg(-1)/soman, i.m./ - 117.9 mg kg(-1)/sarin, p.c./), organophosphate POX and DFP (LD50 = 0.321 mg kg(-1)/POX, i.m./ - 420 mg kg(-1)/DFP, p.c./). Generally, i.m. administration was the most toxic throughout all tested agents and ways of administration (LD50 = 0.0082 mg kg(-1)/VX/ - 1.399 mg kg(-1)/DFP/) whereas p.c. way was responsible for lowest acute toxicity (LD50 = 0.085 mg kg(-1)/VX/ - 420 mg kg(-1)/DFP/). The acute toxicity of selected organophosphorus compounds is summarized throughout this study. Although the data assessed in rats are rather illustrative prediction for human, it presents a valuable contribution, indicating the toxic potential and harmfulness of organophosphates.

High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection.

PubMed

Islam, Md Koushikul; Baudin, Maria; Eriksson, Jonas; Öberg, Christopher; Habjan, Matthias; Weber, Friedemann; Överby, Anna K; Ahlm, Clas; Evander, Magnus

2016-04-01

Rift Valley fever virus (RVFV) is an emerging virus that causes serious illness in humans and livestock. There are no approved vaccines or treatments for humans. The purpose of the study was to identify inhibitory compounds of RVFV infection without any preconceived idea of the mechanism of action. A whole-cell-based high-throughput drug screening assay was developed to screen 28,437 small chemical compounds targeting RVFV infection. To accomplish both speed and robustness, a replication-competent NSs-deleted RVFV expressing a fluorescent reporter gene was developed. Inhibition of fluorescence intensity was quantified by spectrophotometry and related to virus infection in human lung epithelial cells (A549). Cell toxicity was assessed by the Resazurin cell viability assay. After primary screening, 641 compounds were identified that inhibited RVFV infection by ≥80%, with ≥50% cell viability at 50 µM concentration. These compounds were subjected to a second screening regarding dose-response profiles, and 63 compounds with ≥60% inhibition of RVFV infection at 3.12 µM compound concentration and ≥50% cell viability at 25 µM were considered hits. Of these, six compounds with high inhibitory activity were identified. In conclusion, the high-throughput assay could efficiently and safely identify several promising compounds that inhibited RVFV infection. © 2016 Society for Laboratory Automation and Screening.

Metallo-organic decomposition films

NASA Technical Reports Server (NTRS)

Gallagher, B. D.

1985-01-01

A summary of metallo-organic deposition (MOD) films for solar cells was presented. The MOD materials are metal ions compounded with organic radicals. The technology is evolving quickly for solar cell metallization. Silver compounds, especially silver neodecanoate, were developed which can be applied by thick-film screening, ink-jet printing, spin-on, spray, or dip methods. Some of the advantages of MOD are: high uniform metal content, lower firing temperatures, decomposition without leaving a carbon deposit or toxic materials, and a film that is stable under ambient conditions. Molecular design criteria were explained along with compounds formulated to date, and the accompanying reactions for these compounds. Phase stability and the other experimental and analytic results of MOD films were presented.

Activity profiles of 676 ToxCast Phase II compounds in 231 biochemical high-throughput screening assays

EPA Science Inventory

Understanding potential health risks posed by environmental chemicals is a significant challenge elevated by large numbers of diverse chemicals with generally uncharacterized exposures, mechanisms and toxicities. The present study is a performance evaluation and critical analysis...

Understanding the Biology and Technology of ToxCast and Tox21 Assays

EPA Science Inventory

The ToxCast high-throughput toxicity (HTT) testing methods have been developed to evaluate the hazard potential of diverse environmental, industrial and consumer product chemicals. The main goal is prioritizing the compounds of greatest concern for more detailed toxicological stu...

Prediction of mutagenic toxicity by combination of Recursive Partitioning and Support Vector Machines.

PubMed

Liao, Quan; Yao, Jianhua; Yuan, Shengang

2007-05-01

The study of prediction of toxicity is very important and necessary because measurement of toxicity is typically time-consuming and expensive. In this paper, Recursive Partitioning (RP) method was used to select descriptors. RP and Support Vector Machines (SVM) were used to construct structure-toxicity relationship models, RP model and SVM model, respectively. The performances of the two models are different. The prediction accuracies of the RP model are 80.2% for mutagenic compounds in MDL's toxicity database, 83.4% for compounds in CMC and 84.9% for agrochemicals in in-house database respectively. Those of SVM model are 81.4%, 87.0% and 87.3% respectively.

Mechanistic Investigation of the Non-Cytochrome P450 Mediated Metabolism of Triadimefon and Implications for Toxicity

EPA Science Inventory

Triazole containing compounds have been used for decades as agricultural and medicinal fungicides. Recently, emphasis has been placed on the potential adverse effects of these compounds within mammalian systems and an effort has been made to understand their toxic mode of action...

Consensus Modeling of Oral Rat Acute Toxicity

EPA Science Inventory

An acute toxicity dataset (oral rat LD50) with about 7400 compounds was compiled from the ChemIDplus database. This dataset was divided into a modeling set and a prediction set. The compounds in the prediction set were selected so that they were present in the modeling set used...

TOXIC EQUIVALENCY APPROACH FOR DIOXINS: AN EXAMPLE OF DOSE ADDITIVITY

EPA Science Inventory

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is often called the most toxic man-made compound. However, it is but the prototype for a family of structurally related compounds which have a common mechanism of action, induce a common spectrum of biological responses, and are...

Understanding the tolerance of the industrial yeast Saccharomyces cerevisiae against a major class of toxic aldehyde compounds

USDA-ARS?s Scientific Manuscript database

Development of the next-generation biocatalyst is vital for fermentation-based industrial applications and a sustainable bio-based economy. Overcoming the major class of toxic compounds associated with lignocellulose-to-biofuels conversion is one of the significant challenges for new strain developm...

THE DEVELOPMENT AND APPLICATION OF AN IC-ICP-MS METHOD FOR THE SPECIATION OF METHYLTINS.

EPA Science Inventory

The determination of organotin compounds in environmental samples is of concern as the species have varying degrees of toxicity. Generally, the most toxic organotin compounds belong to the tri alkyl substituted variety followed by the di- and mono-substituted organotins. The low...

PARAMETRIC EVALUATION OF VOC/HAP (VOLATILE ORGANIC COMPOUNDS-HAZARDOUS/TOXIC AIR POLLUTANTS) DESTRUCTION VIA CATALYTIC INCINERATION

EPA Science Inventory

The report describes the use of a pilot-scale catalytic incineration unit/solvent generation system to investigate the effectiveness of catalytic incineration as a way to destroy volatile organic compounds (VOCs) and hazardous/toxic air pollutants (HAPs). Objectives of the study ...

Identification of organic compounds in landfill leachate treated by advanced oxidation processes.

PubMed

Scandelai, Ana Paula Jambers; Sloboda Rigobello, Eliane; Oliveira, Beatriz Lopes Corso de; Tavares, Célia Regina Granhen

2017-11-27

Landfill leachates are considered to be complex effluents of a variable composition containing many biorecalcitrant and highly toxic compounds. Considering the shortage of studies concerning the treatment of landfill leachates using ozone, as well as its combination with catalysts, the aim of this paper was to identify the organic compounds in this effluent treated with advanced oxidation processes (AOPs) of ozonation (O 3 ), and heterogeneous catalytic ozonation with TiO 2 (O 3 /TiO 2 ) and with ZnO (O 3 /ZnO). In addition, this study sought to assess the efficiency of the removal of the organic matter present in the leachate. For the pre- and post-AOPs, the leachate was characterized through physicochemical parameters and identification of organic compounds using gas chromatography coupled to the mass spectrometry (GC-MS). The three processes studied (O 3 , O 3 /TiO 2 , and O 3 /ZnO) presented color removal, turbidity, BOD above 95%, and lower COD removals (19%, 24%, and 33%, respectively). All AOPs studied promoted a similar reduction of organic compounds from leachate, some of which with toxic and carcinogenic potential, such as p-cresol, bisphenol A, atrazine, and hexazinone. In addition, upon the removal of organic matter and organic compounds, the heterogeneous catalytic ozonation processes proved more efficient than the process carried out only with ozone.

Effects of vehicle type and fuel quality on real world toxic emissions from diesel vehicles

NASA Astrophysics Data System (ADS)

Nelson, Peter F.; Tibbett, Anne R.; Day, Stuart J.

Diesel vehicles are an important source of emissions of air pollutants, particularly oxides of nitrogen (NO x), particulate matter (PM), and toxic compounds with potential health impacts including volatile organic compounds (VOCs) such as benzene and aldehydes, and polycyclic aromatic hydrocarbons (PAHs). Current developments in engine design and fuel quality are expected to reduce these emissions in the future, but many vehicles exceed 10 years of age and may make a major contribution to urban pollutant concentrations and related health impacts for many years. In this study, emissions of a range of toxic compounds are reported using in-service vehicles which were tested using urban driving cycles developed for Australian conditions. Twelve vehicles were chosen from six vehicle weight classes and, in addition, two of these vehicles were driven through the urban drive cycle using a range of diesel fuel formulations. The fuels ranged in sulphur content from 24 to 1700 ppm, and in total aromatics from 7.7 to 33 mass%. Effects of vehicle type and fuel composition on emissions are reported. The results show that emissions of these toxic species were broadly comparable to those observed in previous dynamometer and tunnel studies. Emissions of VOCs and smaller PAHs such as naphthalene, which are derived largely from the combustion process, appear to be related, and show relatively little variability when compared with the variability in emissions of aldehydes and larger PAHs. In particular, aldehyde emissions are highly variable and may be related to engine operating conditions. Fuels of lower sulphur and aromatic content did not have a significant influence on emissions of VOCs and aldehydes, but tended to result in lower emissions of PAHs. The toxicity of vehicle exhaust, as determined by inhalation risk and toxic equivalency factor (TEF)-weighted PAH emissions, was reduced with fuels of lower aromatic content.

The use of cultured hepatocytes to investigate the metabolism of drugs and mechanisms of drug hepatotoxicity.

PubMed

Gómez-Lechón, M J; Ponsoda, X; Bort, R; Castell, J V

2001-01-01

Hepatotoxins can be classified as intrinsic when they exert their effects on all individuals in a dose-dependent manner, and as idiosyncratic when their effects are the consequence of an abnormal metabolism of the drug by susceptible individuals (metabolic idiosyncrasy) or of an immune-mediated injury to hepatocytes (allergic hepatitis). Some xenobiotics are electrophilic, and others are biotransformed by the liver into highly reactive metabolites that are usually more toxic than the parent compound. This activation process is the key to many hepatotoxic phenomena. Mitochondria are a frequent target of hepatotoxic drugs, and the alteration of their function has immediate effects on the energy balance of cells (depletion of ATP). Lipid peroxidation, oxidative stress, alteration of Ca(2+) homeostasis, and covalent binding to cell macromolecules are the molecular mechanisms that are frequently involved in the toxicity of xenobiotics. Against these potential hazards, cells have their own defence mechanisms (for example, glutathione, DNA repair, suicide inactivation). Ultimately, toxicity is the balance between bioactivation and detoxification, which determines whether a reactive metabolite elicits a toxic effect. The ultimate goal of in vitro experiments is to generate the type of scientific information needed to identify compounds that are potentially toxic to man. For this purpose, both the design of the experiments and the interpretation of the results are critical.

Formulation and characterization of garlic (Allium sativum L.) essential oil nanoemulsion and its acaricidal activity on eriophyid olive mites (Acari: Eriophyidae).

PubMed

Mossa, Abdel-Tawab H; Afia, Sahar I; Mohafrash, Samia M M; Abou-Awad, Badawi A

2018-04-01

Green and nanoacaricides including essential oil (EO) nanoemulsions are important compounds to provide new, active, safe acaricides and lead to improvement of avoiding the risk of synthetic acaricides. This study was carried out for the first time on eriophyid mites to develop nanoemulsion of garlic essential oil by ultrasonic emulsification and evaluate its acaricidal activity against the two eriophyid olive mites Aceria oleae Nalepa and Tegolophus hassani (Keifer). Acute toxicity of nanoemulsion was also studied on male rats. Garlic EO was analyzed by gas chromatography-mass spectrometry (GC-MS), and the major compounds were diallyl sulfide (8.6%), diallyl disulfide (28.36%), dimethyl tetrasulfide (15.26%), trisulfide,di-2-propenyl (10.41%), and tetrasulfide,di-2-propenyl (9.67%). Garlic oil nanoemulsion with droplet size 93.4 nm was formulated by ultrasonic emulsification for 35 min. Emulsification time and oil and surfactant ratio correlated to the emulsion droplet size and stability. The formulated nanoemulsion showed high acaricidal activity against injurious eriophyid mites with LC 50 298.225 and 309.634 μg/ml, respectively. No signs of nanoemulsion toxicity were noted in treating rats; thus, it may be considered non-toxic to mammals. Stability of garlic oil nanoemulsion, high acaricidal activity, and the absence of organic toxic solvents make the formulation that may be a possible acaricidal product. Results suggest the possibility of developing suitable natural nanoacaricide from garlic oil.

Toxicity of municipal wastewater effluents contaminated by pentachlorophenol in southwest Missouri

USGS Publications Warehouse

Wylie, G.D.; Finger, S.E.; Crawford, R.W.

1990-01-01

Toxicity of effluents from two sewage treatment plants in Joplin, Missouri, was tested using Ceriodaphnia dubia and Pimephales promelas. No test organisms survived in effluents from either plant, in effluents diluted with water from Turkey Creek (the receiving stream), or in water from Turkey Creek. Mortality was complete in all but the most dilute treatments of effluents, in which reconstituted water was used as the diluent. High concentrations of pentachlorophenol (130–970 μg liter−1) in effluents and the receiving stream likely caused mortality during the 7-day tests. Detectable concentrations of other phenolic compounds indicated the presence in Turkey Creek of other toxic by-products of pentachlorophenol manufacture. This study demonstrated the utility of biological tests of whole effluents to determine toxicity of wastewater effluents.

Ecotoxicological assessment of soils polluted with chemical waste from lindane production: Use of bacterial communities and earthworms as bioremediation tools.

PubMed

Muñiz, Selene; Gonzalvo, Pilar; Valdehita, Ana; Molina-Molina, José Manuel; Navas, José María; Olea, Nicolás; Fernández-Cascán, Jesús; Navarro, Enrique

2017-11-01

An ecotoxicological survey of soils that were polluted with wastes from lindane (γ-HCH) production assessed the effects of organochlorine compounds on the metabolism of microbial communities and the toxicity of these compounds to a native earthworm (Allolobophora chlorotica). Furthermore, the bioremediation role of earthworms as facilitators of soil washing and the microbial degradation of these organic pollutants were also studied. Soil samples that presented the highest concentrations of ε-HCH, 2,4,6-trichlorophenol, pentachlorobenzene and γ-HCH were extremely toxic to earthworms in the short term, causing the death of almost half of the population. In addition, these soils inhibited the heterotrophic metabolic activity of the microbial community. These highly polluted samples also presented substances that were able to activate cellular detoxification mechanisms (measured as EROD and BFCOD activities), as well as compounds that were able to cause endocrine disruption. A few days of earthworm activity increased the extractability of HCH isomers (e.g., γ-HCH), facilitating the biodegradation of organochlorine compounds and reducing the intensity of endocrine disruption in soils that had low or medium contamination levels. Copyright © 2017 Elsevier Inc. All rights reserved.

Poly-3-hydroxybutyrate (PHB) production from alkylphenols, mono and poly-aromatic hydrocarbons using Bacillus sp. CYR1: A new strategy for wealth from waste.

PubMed

Venkateswar Reddy, M; Mawatari, Yasuteru; Yajima, Yuka; Seki, Chigusa; Hoshino, Tamotsu; Chang, Young-Cheol

2015-09-01

In the present study five different types of alkylphenols, each of the two different types of mono and poly-aromatic hydrocarbons were selected for degradation, and conversion into poly-3-hydroxybutyrate (PHB) using the Bacillus sp. CYR1. Strain CYR1 showed growth with various toxic organic compounds. Degradation pattern of all the organic compounds at 100 mg/l concentration with or without addition of tween-80 were analyzed using high pressure liquid chromatography (HPLC). Strain CYR1 showed good removal of compounds in the presence of tween-80 within 3 days, but it took 6 days without addition of tween-80. Strain CYR1 showed highest PHB production with phenol (51 ± 5%), naphthalene (42 ± 4%), 4-chlorophenol (32 ± 3%) and 4-nonylphenol (29 ± 3%). The functional groups, structure, and thermal properties of the produced PHB were analyzed. These results denoted that the strain Bacillus sp. CYR1 can be used for conversion of different toxic compounds persistent in wastewaters into useable biological polyesters. Copyright © 2015 Elsevier Ltd. All rights reserved.

Structure-activity models of oral clearance, cytotoxicity, and LD50: a screen for promising anticancer compounds

PubMed Central

Boik, John C; Newman, Robert A

2008-01-01

Background Quantitative structure-activity relationship (QSAR) models have become popular tools to help identify promising lead compounds in anticancer drug development. Few QSAR studies have investigated multitask learning, however. Multitask learning is an approach that allows distinct but related data sets to be used in training. In this paper, a suite of three QSAR models is developed to identify compounds that are likely to (a) exhibit cytotoxic behavior against cancer cells, (b) exhibit high rat LD50 values (low systemic toxicity), and (c) exhibit low to modest human oral clearance (favorable pharmacokinetic characteristics). Models were constructed using Kernel Multitask Latent Analysis (KMLA), an approach that can effectively handle a large number of correlated data features, nonlinear relationships between features and responses, and multitask learning. Multitask learning is particularly useful when the number of available training records is small relative to the number of features, as was the case with the oral clearance data. Results Multitask learning modestly but significantly improved the classification precision for the oral clearance model. For the cytotoxicity model, which was constructed using a large number of records, multitask learning did not affect precision but did reduce computation time. The models developed here were used to predict activities for 115,000 natural compounds. Hundreds of natural compounds, particularly in the anthraquinone and flavonoids groups, were predicted to be cytotoxic, have high LD50 values, and have low to moderate oral clearance. Conclusion Multitask learning can be useful in some QSAR models. A suite of QSAR models was constructed and used to screen a large drug library for compounds likely to be cytotoxic to multiple cancer cell lines in vitro, have low systemic toxicity in rats, and have favorable pharmacokinetic properties in humans. PMID:18554402

Structure-activity models of oral clearance, cytotoxicity, and LD50: a screen for promising anticancer compounds.

PubMed

Boik, John C; Newman, Robert A

2008-06-13

Quantitative structure-activity relationship (QSAR) models have become popular tools to help identify promising lead compounds in anticancer drug development. Few QSAR studies have investigated multitask learning, however. Multitask learning is an approach that allows distinct but related data sets to be used in training. In this paper, a suite of three QSAR models is developed to identify compounds that are likely to (a) exhibit cytotoxic behavior against cancer cells, (b) exhibit high rat LD50 values (low systemic toxicity), and (c) exhibit low to modest human oral clearance (favorable pharmacokinetic characteristics). Models were constructed using Kernel Multitask Latent Analysis (KMLA), an approach that can effectively handle a large number of correlated data features, nonlinear relationships between features and responses, and multitask learning. Multitask learning is particularly useful when the number of available training records is small relative to the number of features, as was the case with the oral clearance data. Multitask learning modestly but significantly improved the classification precision for the oral clearance model. For the cytotoxicity model, which was constructed using a large number of records, multitask learning did not affect precision but did reduce computation time. The models developed here were used to predict activities for 115,000 natural compounds. Hundreds of natural compounds, particularly in the anthraquinone and flavonoids groups, were predicted to be cytotoxic, have high LD50 values, and have low to moderate oral clearance. Multitask learning can be useful in some QSAR models. A suite of QSAR models was constructed and used to screen a large drug library for compounds likely to be cytotoxic to multiple cancer cell lines in vitro, have low systemic toxicity in rats, and have favorable pharmacokinetic properties in humans.

Photoenhanced Toxicity of Oil to Larval Fish

EPA Science Inventory

Photoenhanced toxicity is the increase in the toxicity of a chemical in the presence of ultraviolet light (UV), compared to toxicity elicited under conditions of minimal UV. Oil products, weathered oils, combusted oil products, and specific polycyclic aromatic compounds in oil ha...

Three dimensional quantitative structure-toxicity relationship modeling and prediction of acute toxicity for organic contaminants to algae.

PubMed

Jin, Xiangqin; Jin, Minghao; Sheng, Lianxi

2014-08-01

Although numerous chemicals have been identified to have significant toxicological effect on aquatic organisms, there is still lack of a reliable, high-throughput approach to evaluate, screen and monitor the presence of organic contaminants in aquatic system. In the current study, we proposed a synthetic pipeline to automatically model and predict the acute toxicity of chemicals to algae. In the procedure, a new alignment-free three dimensional (3D) structure characterization method was described and, with this method, several 3D-quantitative structure-toxicity relationship (3D-QSTR) models were developed, from which two were found to exhibit strong internal fitting ability and high external predictive power. The best model was established by Gaussian process (GP), which was further employed to perform extrapolation on a random compound library consisting of 1014 virtually generated substituted benzenes. It was found that (i) substitution number can only exert slight influence on chemical׳s toxicity, but low-substituted benzenes seem to have higher toxicity than those of high-substituted entities, and (ii) benzenes substituted by nitro group and halogens exhibit high acute toxicity as compared to other substituents such as methyl and carboxyl groups. Subsequently, several promising candidates suggested by computational prediction were assayed by using a standard algal growth inhibition test. Consequently, four substituted benzenes, namely 2,3-dinitrophenol, 2-chloro-4-nitroaniline, 1,2,3-trinitrobenzene and 3-bromophenol, were determined to have high acute toxicity to Scenedesmus obliquus, with their EC50 values of 2.5±0.8, 10.5±2.1, 1.4±0.2 and 42.7±5.4μmol/L, respectively. Copyright © 2014 Elsevier Ltd. All rights reserved.

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.

Transcriptomic analysis in the developing zebrafish embryo after compound exposure: Individual gene expression and pathway regulation

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

Hermsen, Sanne A.B., E-mail: Sanne.Hermsen@rivm.nl; Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht; Institute for Risk Assessment Sciences

2013-10-01

The zebrafish embryotoxicity test is a promising alternative assay for developmental toxicity. Classically, morphological assessment of the embryos is applied to evaluate the effects of compound exposure. However, by applying differential gene expression analysis the sensitivity and predictability of the test may be increased. For defining gene expression signatures of developmental toxicity, we explored the possibility of using gene expression signatures of compound exposures based on commonly expressed individual genes as well as based on regulated gene pathways. Four developmental toxic compounds were tested in concentration-response design, caffeine, carbamazepine, retinoic acid and valproic acid, and two non-embryotoxic compounds, D-mannitol andmore » saccharin, were included. With transcriptomic analyses we were able to identify commonly expressed genes, which were mostly development related, after exposure to the embryotoxicants. We also identified gene pathways regulated by the embryotoxicants, suggestive of their modes of action. Furthermore, whereas pathways may be regulated by all compounds, individual gene expression within these pathways can differ for each compound. Overall, the present study suggests that the use of individual gene expression signatures as well as pathway regulation may be useful starting points for defining gene biomarkers for predicting embryotoxicity. - Highlights: • The zebrafish embryotoxicity test in combination with transcriptomics was used. • We explored two approaches of defining gene biomarkers for developmental toxicity. • Four compounds in concentration-response design were tested. • We identified commonly expressed individual genes as well as regulated gene pathways. • Both approaches seem suitable starting points for defining gene biomarkers.« less

Evaluation of a novel automated water analyzer for continuous monitoring of toxicity and chemical parameters in municipal water supply.

PubMed

Bodini, Sergio F; Malizia, Marzio; Tortelli, Annalisa; Sanfilippo, Luca; Zhou, Xingpeng; Arosio, Roberta; Bernasconi, Marzia; Di Lucia, Stefano; Manenti, Angela; Moscetta, Pompeo

2018-08-15

A novel tool, the DAMTA analyzer (Device for Analytical Monitoring and Toxicity Assessment), designed for fully automated toxicity measurements based on luminescent bacteria as well as for concomitant determination of chemical parameters, was developed and field-tested. The instrument is a robotic water analyzer equipped with a luminometer and a spectrophotometer, integrated on a thermostated reaction plate which contains a movable carousel with 80 cuvettes. Acute toxicity is measured on-line using a wild type Photobacterium phosphoreum strain with measurable bioluminescence and unaltered sensitivity to toxicants lasting up to ten days. The EC50 values of reference compounds tested were consistent with A. fischeri and P. phosphoreum international standards and comparable to previously published data. Concurrently, a laboratory trial demonstrated the feasibility of use of the analyzer for the determination of nutrients and metals in parallel to the toxicity measurements. In a prolonged test, the system was installed only in toxicity mode at the premises of the World Fair "Expo Milano-2015″, a high security site to ensure the quality of the supplied drinking water. The monitoring program lasted for six months during which ca. 2400 toxicity tests were carried out; the results indicated a mean non-toxic outcome of -5.5 ± 6.2%. In order to warrant the system's robustness in detecting toxic substances, Zn was measured daily with highly reproducible inhibition results, 70.8 ± 13.6%. These results assure that this novel toxicity monitor can be used as an early warning system for protection of drinking water sources from emergencies involving low probability/high impact contamination events in source water or treated water. Copyright © 2018 Elsevier Inc. All rights reserved.

Detoxification of cancerogenic compounds by lactic acid bacteria strains.

PubMed

Lili, Zhao; Junyan, Wei; Hongfei, Zhao; Baoqing, Zhu; Bolin, Zhang

2017-10-20

Carcinogens in food are an important issue that threat people's health right now. Lactic acid bacteria (LAB) strains as well-known probiotics have shown numerous perspectives in being used as a good food additive to confront cancerogenic compounds in recent years. Some LAB strains can remove cancerogenic compounds from medium environment via direct physical binding and avoid re-pollution of poisonous secondary metabolites which are generated from degradation of cancerogenic compounds. This article presents a whole overview of the physical-binding of LAB strains to such common cancerogenic compounds existed in food and feed environments as mycotoxins, polycyclic aromatic hydrocarbons (PAHs), heterocyclic amines (HAs) and pthalic acid esters (PAEs).In most cases, summaries of these published researches show that the binding of LAB strains to cancerogenic compounds is a physical process. Binding sites generally take place in cell wall, and peptidoglycan from LAB cells is the chief binding site. The adsorption of lactic acid bacteria to cancerogenic compounds is strain-specific. Specially, the strains from the two genera Lactobacillus and Bifidobacterium show a better potential in binding cancerogenic compounds. Moreover, we firstly used molecular dynamic computer model as a highly potential tool to simulate the binding behavior of peptidoglycan from Lactobacillus acidophilus to DBP, one of pthalic acid esters with genetic toxicity. It was seen that the theoretical data were quite consistent with the experimental results in terms of the ability of this bacterium to bind DBP. Also, the toxicity reduction of cancerogenic compounds by LAB strains could be achieved either in gastrointestinal model or animal tests and clinical researches as well. In conclusion, carefully selected LAB strains should be a good solution as one of safety strategies to reduce potential risk of cancerogenic compounds from food-based products.

The Aromatic Head Group of Spider Toxin Polyamines Influences Toxicity to Cancer Cells

PubMed Central

Wilson, David; McIntyre, Lachlan; Smith, Jennifer J.; Tribolet, Leon; Loukas, Alex; Liddell, Michael J.; Daly, Norelle L.

2017-01-01

Spider venoms constitute incredibly diverse libraries of compounds, many of which are involved in prey capture and defence. Polyamines are often prevalent in the venom and target ionotropic glutamate receptors. Here we show that a novel spider polyamine, PA366, containing a hydroxyphenyl-based structure is present in the venom of several species of tarantula, and has selective toxicity against MCF-7 breast cancer cells. By contrast, a polyamine from an Australian funnel-web spider venom, which contains an identical polyamine tail to PA366 but an indole-based head-group, is only cytotoxic at high concentrations. Our results suggest that the ring structure plays a role in the cytotoxicity and that modification to the polyamine head group might lead to more potent and selective compounds with potential as novel cancer treatments. PMID:29077051

The Aromatic Head Group of Spider Toxin Polyamines Influences Toxicity to Cancer Cells.

PubMed

Wilson, David; Boyle, Glen M; McIntyre, Lachlan; Nolan, Matthew J; Parsons, Peter G; Smith, Jennifer J; Tribolet, Leon; Loukas, Alex; Liddell, Michael J; Rash, Lachlan D; Daly, Norelle L

2017-10-27

Spider venoms constitute incredibly diverse libraries of compounds, many of which are involved in prey capture and defence. Polyamines are often prevalent in the venom and target ionotropic glutamate receptors. Here we show that a novel spider polyamine, PA 366 , containing a hydroxyphenyl-based structure is present in the venom of several species of tarantula, and has selective toxicity against MCF-7 breast cancer cells. By contrast, a polyamine from an Australian funnel-web spider venom, which contains an identical polyamine tail to PA 366 but an indole-based head-group, is only cytotoxic at high concentrations. Our results suggest that the ring structure plays a role in the cytotoxicity and that modification to the polyamine head group might lead to more potent and selective compounds with potential as novel cancer treatments.

Organogel polymers from 10-undecenoic acid and poly(vinyl acetate)

USDA-ARS?s Scientific Manuscript database

Organogels are used in a variety of high value applications including the removal of toxic solvents from aqueous environments and the time-controlled release of compounds. One of the most promising gelators is a polyvinyl polymer containing medium chain length carboxylic acids. The existing producti...

Oxidation-reduction catalyst and its process of use

NASA Technical Reports Server (NTRS)

Schryer, Jacqueline L. (Inventor); Oglesby, Donald M. (Inventor); Jordan, Jeffrey D. (Inventor); Watkins, Anthony Neal (Inventor)

2008-01-01

This invention relates generally to a ruthenium stabilized oxidation-reduction catalyst useful for oxidizing carbon monoxide, and volatile organic compounds, and reducing nitrogen oxide species in oxidizing environments, substantially without the formation of toxic and volatile ruthenium oxide species upon said oxidizing environment being at high temperatures.

Adaptation of the Estuarine Fish, Fundulus heterclitus (Atlantic Killifish) to Polychlorinated Biphenyls (PCBs)

EPA Science Inventory

To characterize intra-specific variation in sensitivity to highly toxic pollutants in the non-migratory estuarine Atlantic killifish (Fundulus heteroclitus), we compared early life stage responses to the prototypical dioxin-like compound, 3,3’4,4’,5 hexachlorobiphenyl (PCB126). ...

CATALYTIC DECHLORINATION OF 2-CL BP IN SEDIMENTS AND WATER-SOLVENT SYSTEMS BY FE/PD BIMETAL

EPA Science Inventory

Polychlorinated biphenyls (PCBs) are one group of persistent organic pollutants (POPs) of international concern because of global distribution, persistence, and toxicity. Removal of these compounds from the environment presents a very tough challenge because they are highly hydro...

The ToxCast Chemical Prioritization Program at the US EPA (UCLA Molecular Toxicology Program)

EPA Science Inventory

To meet the needs of chemical regulators reviewing large numbers of data-poor chemicals for safety, the EPA's National Center for Computational Toxicology is developing a means of efficiently testing thousands of compounds for potential toxicity. High-throughput bioactivity profi...

Use of soil fumigants and air quality issues in California, USA

USDA-ARS?s Scientific Manuscript database

Many high value cash crops use soil fumigants for profitable production.The primary fumigants used in California are 1,3-dichloropropene (Telone®), chloropicrin, metam salts (sodium or potassium), and methyl bromide. Most of these toxic chemicals and their formulations are volatile compounds (VOCs),...

Photoactivation and toxicity of mixtures of polycyclic aromatic hydrocarbon compounds in marine sediment

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

Swartz, R.C.; Ferraro, S.P.; Lamberson, J.O.

1997-10-01

The direct toxicity and photoinduced toxicity of sediment-associated acenaphthene, phenanthrene, fluoranthene, and pyrene were determined for the marine amphipod Rhepoxynius abronius. The four polycyclic aromatic hydrocarbons (PAHs) were spiked into sediment in a concentration series of either single compounds or as approximately equitoxic mixtures of all four compounds. Standard 10-d sediment toxicity tests were conducted under fluorescent lighting. After 10 d, survivors were exposed for 1 h to ultraviolet (UV) radiation in the absence of sediment and then tested for their ability to bury in uncontaminated sediment. The 10-d median lethal concentrations (LC50s) were 2.31 mg acenaphthene/g organic carbon (OC),more » 2.22 mg phenanthrene/g OC, 3.31 mg fluoranthene/g OC, and 2.81 mg pyrene/g OC. These LC50s were used to calculate the sum of toxic units ({Sigma}TU) of the four PAHs in the approximately equitoxic mixtures. The {Sigma}TU LC50 was then calculated for the mixture treatments. If the toxicologic interaction of a mixture of contaminants is additive, {Sigma}TU LC50 = 1.0. The observed LC50 (1.55 {Sigma}TU) was slightly, but significantly, greater than unity, indicating that the interaction of PAHs in the mixture was less than additive. Exposure to UV radiation enhanced the toxic effects of fluoranthene and pyrene, but did not affect the toxicity of acenaphthene and phenanthrene. Effects of UV radiation on the toxicity of the mixture of four PAHs could be explained by the photoactivation of fluoranthene and pyrene alone. These results are consistent with predictions based on photophysical properties of PAH compounds.« less

In vitro Toxicity and Inflammatory Response Induced by Copper Nanoparticles in Rat Alveolar Macrophages

DTIC Science & Technology

2008-03-01

the cupric form is most prevalent (Linder and Hazegh-Azam, 1996:797S). Cupric compounds are blue-green in color and highly soluble in water...reduced clearance of particles due to macrophage damage after exposure to various doses of titanium dioxide ( TiO2 )(5, 50, and 250 mg/m3) (Warheit, et al...viability. The assay measures cell viability when the tetrazolium compound is bioreduced by viable cells to a colored formazan product (see Figure 3

[Chemicals toxic to the olfactory system. Analysis and description].

PubMed

Norès, J M; Biacabe, B; Bonfils, P

2000-10-28

AN IMPORTANT PROBLEM: Occupational exposure to chemical products can have toxic effects on the olfactory system. An important number of patients have experienced olfactory disorders subsequent to the development of the chemical industry and atmospheric pollution. EPIDEMIOLOGY DATA: Straightforward data are difficult to collect because several cofactors other than the toxic product are involved. Two lists of toxic products can be made. The first list includes products for which scientific data is available and the second products for which data is lacking. Olfactory tests also differ between authors and countries. TWO TYPES OF TOXICITY: Acute, accidental toxicity is evidenced by the lesions caused by inhalation of high-doses of strongly toxic agents. Chronic intoxication caused by lower concentrations of these inhaled agents does not produce a trigeminal reflex leading to a modified respiratory rate reducing the airborne aggression. APPROXIMATIONS: Clinical data describing the olfactory toxicity of certain industrial and chemical compounds are very significant but often cannot prove a cause and effect relationship. Data obtained with experimental models in rodents are difficult to extrapolate to humans.

Toxicity to Eisenia andrei and Folsomia candida of a metal mixture applied to soil directly or via an organic matrix.

PubMed

Natal-da-Luz, T; Ojeda, G; Pratas, J; Van Gestel, C A M; Sousa, J P

2011-09-01

Regulatory limits for chemicals and ecological risk assessment are usually based on the effects of single compounds, not taking into account mixture effects. The ecotoxicity of metal-contaminated sludge may, however, not only be due to its metal content. Both the sludge matrix and the presence of other toxicants may mitigate or promote metal toxicity. To test this assumption, the toxicity of soils recently amended with an industrial sludge predominantly contaminated with chromium, copper, nickel, and zinc and soils freshly spiked with the same mixture of metals was evaluated through earthworm (Eisenia andrei) and collembolan (Folsomia candida) reproduction tests. The sludge was less toxic than the spiked metal mixture for E. andrei but more toxic for F. candida. Results obtained for the earthworms suggest a decrease in metal bioavailability promoted by the high organic matter content of the sludge. The higher toxicity of the sludge for F. candida was probably due to the additive toxic effect of other pollutants. Copyright © 2011 Elsevier Inc. All rights reserved.

Decontamination formulation with sorbent additive

DOEpatents

Tucker; Mark D. , Comstock; Robert H.

2007-10-16

A decontamination formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a bleaching activator, a sorbent additive, and water. The highly adsorbent, water-soluble sorbent additive (e.g., sorbitol or mannitol) is used to "dry out" one or more liquid ingredients, such as the liquid bleaching activator (e.g., propylene glycol diacetate or glycerol diacetate) and convert the activator into a dry, free-flowing powder that has an extended shelf life, and is more convenient to handle and mix in the field.

Acute toxicity, twenty-eight days repeated dose toxicity and genotoxicity of vanadyl trehalose in kunming mice.

PubMed

Jiang, Pingzhe; Ni, Zaizhong; Wang, Bin; Ma, Baicheng; Duan, Huikun; Li, Xiaodan; Ma, Xiaofeng; Wei, Qian; Ji, Xiangzhen; Liu, Qiqi; Xing, Shuguang; Li, Minggang

2017-04-01

A new trend has been developed using vanadium and organic ligands to form novel compounds in order to improve the beneficial actions and reduce the toxicity of vanadium compounds. In present study, vanadyl trehalose was explored the oral acute toxicity, 28 days repeated dose toxicity and genotoxicity in Kunming mice. The Median Lethal Dose (LD 50 ) of vanadyl trehalose was revealed to be 1000 mg/kg body weight in fasted Kunming mice. Stomach and intestine were demonstrated to be the main target organs of vanadyl trehalose through 28 days repeated dose toxicity study. And vanadyl trehalose also showed particular genotoxicity through mouse bone marrow micronucleus and mouse sperm malformation assay. In brief, vanadyl trehalose presented certain, but finite toxicity, which may provide experimental basis for the clinical application. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of the toxic effects of four anti-cancer drugs in plant bioassays and its potency for screening in the context of waste water reuse for irrigation.

PubMed

Lutterbeck, Carlos Alexandre; Kern, Deivid Ismael; Machado, Ênio Leandro; Kümmerer, Klaus

2015-09-01

Anti-cancer drugs are compounds that are of high environmental relevance because of their lack of specific mode of action. They can be extremely harmful to living organisms even at low concentrations. The present study evaluated the toxic effects of four frequently used anti-cancer drugs against plant seedlings, namely Cyclophosphamide (CP), Methotrexate (MTX), 5-Fluorouracil (5-FU) and Imatinib (IM). The phytotoxicity experiments were performed with Lactuca sativa seedlings whereas cytotoxicity, genotoxicity and mutagenicity investigations were performed with the well-established Allium cepa assays. MTX was the most phytotoxic compound, followed by 5-FU, CP and IM. Significant differences in the Mitotic Indexes (MI) were observed in three of the studied compounds (MTX, 5-FU and CP), indicating potential cytotoxic activity of these substances. Chromosome aberrations were registered in cells that were exposed to 5-FU, CP and IM. All the four compounds caused the formation of micronucleated cells indicating mutagenic potential. Besides, the assays performed with MTX samples presented a high number of cell apoptosis (cell death). Although it is unlikely that the pharmaceuticals concentrations measured in the environment could cause lethal effects in plants, the obtained results indicate that these compounds may affect the growth and normal development of these plants. So, both tests can constitute important tools for a fast screening of environmental contamination e.g. in the context of the reuse of treated wastewater and biosolids of agricultural purpose. Copyright © 2015 Elsevier Ltd. All rights reserved.

40 CFR 227.32 - Liquid, suspended particulate, and solid phases of a material.

Code of Federal Regulations, 2014 CFR

2014-07-01

... interact with ocean water to form insoluble matter or new toxic compounds, or materials which may release toxic compounds upon deposition, the Administrator, Regional Administrator, or the District Engineer, as... the material be performed upon a mixture of the waste with ocean water rather than on the material...

40 CFR 227.32 - Liquid, suspended particulate, and solid phases of a material.

Code of Federal Regulations, 2012 CFR

2012-07-01

... interact with ocean water to form insoluble matter or new toxic compounds, or materials which may release toxic compounds upon deposition, the Administrator, Regional Administrator, or the District Engineer, as... the material be performed upon a mixture of the waste with ocean water rather than on the material...

40 CFR 227.32 - Liquid, suspended particulate, and solid phases of a material.

Code of Federal Regulations, 2013 CFR

2013-07-01

... interact with ocean water to form insoluble matter or new toxic compounds, or materials which may release toxic compounds upon deposition, the Administrator, Regional Administrator, or the District Engineer, as... the material be performed upon a mixture of the waste with ocean water rather than on the material...

THE 2005 WORLD HEALTH ORGANIZATION RE-EVALUATION OF HUMAN AND MAMMALIAN TOXIC EQUIVALENCY FACTORS FOR DIOXINS AND DIOXIN-LIKE COMPOUNDS

EPA Science Inventory

In June 2005 a WHO-IPCS expert meeting was held in Geneva during which the toxic equivalency factors (TEFs) for dioxin like compounds, including some polychlorinated biphenyls (PCBs), were re-evaluated. For this re-evaluation process the refined TEF database recently published by...

Supercritical fluid chromatography-tandem mass spectrometry for the analysis of lipid A

USDA-ARS?s Scientific Manuscript database

Food safety and defense applications require the availability of methods of detection for a variety of toxic compounds in foods. One compound of concern is lipid A, an endotoxin from Gram-negative bacteria, which can cause human illness if it is present at acutely toxic levels in food. The chosen ...

DEVELOPMENTAL TOXICITY OF TCDD AND RELATED COMPOUNDS: SENSITIVITIES AND DIFFERENCES

EPA Science Inventory

The issue of the developmental toxicity of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) and related compounds has been the subject of two recent reviews (Morrissey and Schwetz, 1989; Couture et al., 1990a). here is little doubt that TCDD is one of the most potent developmental tox...

Greener Alternative to Qualitative Analysis for Cations without H[subscript 2]S and Other Sulfur-Containing Compounds

ERIC Educational Resources Information Center

Sidhwani, Indu Tucker; Chowdhury, Sushmita

2008-01-01

Qualitative analysis of inorganic salts and mixtures is an essential experiment carried out in high school, undergraduate, and postgraduate levels all over the world especially in India and South Asia. The classical technique uses H[subscript 2]S, which is highly toxic and has adverse effects on humans and the environment. Increasing awareness…

Fluoroacetic acid in guar gum.

PubMed

Vartiainen, T; Gynther, J

1984-04-01

The toxicity of guar gum, derived from the Indian leguminous plant Cyamopsis tetragonolobus, is thought to be due to a globulin which can be denaturated and made non-toxic. Another very toxic compound, fluoroacetic acid, has been detected at a low level in raw samples of guar gum (0.07-1.42 micrograms fluoroacetic acid/g). A sample of a guar-gum pharmaceutical formulation contained only 0.08 ppm fluoroacetate. One exceptionally high value of 9.5 micrograms/g was found in a guar-gum powder. The low concentrations of fluoroacetate found in guar gum dispel any considerations about possible health risks associated with fluoroacetate during the prolonged use of guar gum at the recommended doses.

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

Kasschau, M.R.; Skaggs, M.M.; Chen, E.C.M.

Stress has been reported to accelerate protein catabolism in man and animals and as a result one can expect to observe changes in certain amino acids pools of these organisms. In the present study, the Gulf Coast sea anemone, Bunodosoma cavernata, was used as the test animal and free amino acid levels of whole animals were measured following stressed conditions. Sea anemones were chosen as the test animals since they are sessile and, due to the nature of their morphology, they have few mechanisms by which they can escape environmental stress. The animals were exposed to sublethal concentrations of mercuricmore » chloride and cadmium chloride and the organic amines, aniline, diethanol amine (DEA), and ethylene diamine (EDA). Chloride salts of mercury and cadmium were chosen rather than other anions since chloride is the most abundant anion in seawater. These two particular metals were chosen as challenge compounds due to their high toxicity in aquatic systems. The three organic amines were chosen for their relatively high water solubility and low vapor pressure in an aqueous solution, thus insuring that the toxic compound is retained in the test solution. Since organic amines are used extensively in the Gulf Coast industrial complex, there is a high probability of these compounds contaminating the marine environment. Results indicate that the reaction of B. cavernata to stress from organic amines is similar to the response to heavy metals, only more extensive.« less

Leishmanicidal compounds of Nectria pseudotrichia, an endophytic fungus isolated from the plant Caesalpinia echinata (Brazilwood)

PubMed Central

Cota, Betania Barros; Tunes, Luiza Guimarães; Maia, Daniela Nabak Bueno; Ramos, Jonas Pereira; de Oliveira, Djalma Menezes; Kohlhoff, Markus; Alves, Tânia Maria de Almeida; Souza-Fagundes, Elaine Maria; Campos, Fernanda Fraga; Zani, Carlos Leomar

2018-01-01

BACKGROUND In a screen of extracts from plants and fungi to detect antileishmanial activity, we found that the ethyl acetate extract of the fungus Nectria pseudotrichia, isolated from the tree Caesalpinia echinata (Brazilwood), is a promising source of bioactive compounds. OBJECTIVES The aims of this study were to isolate and determine the chemical structures of the compounds responsible for the antileishmanial activity of the organic extract from N. pseudotrichia. METHODS Compounds were isolated by chromatographic fractionation using semi-preparative high-performance liquid chromatography, and their chemical structures were determined by analytical and spectral data and by comparison with published data. The antileishmanial activity of the isolated compounds was evaluated in intracellular amastigote forms of Leishmania (Viannia) braziliensis expressing firefly luciferase as reporter gene, and cytotoxicity was determined in Vero and THP-1 mammalian cell lines by MTT assay. FINDINGS Fractionation of the extract yielded seven compounds: 10-acetyl trichoderonic acid A (1), 6′-acetoxy-piliformic acid (2), 5′,6′-dehydropiliformic acid (3), piliformic acid (4), hydroheptelidic acid (5), xylaric acid D (6), and cytochalasin D (7). Compounds 1, 2 and 3 are reported here for the first time. Compounds 1, 2, and 5 were more active, with IC50 values of 21.4, 28.3, and 24.8 µM, respectively, and showed low toxicity to Vero and THP-1 cells. MAIN CONCLUSIONS N. pseudotrichia produces secondary metabolites that are more toxic to intracellular amastigote forms of L. (V.) braziliensis than to mammalian cells. PMID:29236928

[Impact of microdose clinical trials in the preclinical stage].

PubMed

Kim, Soonih

2014-01-01

A microdose clinical trial may be useful as a safe early-phase exploratory study using doses as low as 100 μg or less for determination of the disposition of a candidate compound in humans in a short period of time. This may increase confidence in candidate compounds, especially those for which it is difficult to predict disposition based on the results of in vitro or preclinical studies. In this study, we examined microdose trials performed in the preclinical stage for two first-in-class compounds with a new mechanism of action. These compounds showed species difference in first pass metabolism in the digestive tract and liver, causing uncertainty in prediction of disposition in humans. For this reason, first-in-human microdose clinical trials were performed. The results showed that the two compounds had effective blood concentrations after oral administration at a dose of 100 mg qd. Administration of an extremely small dose of one (14)C-labeled compound permitted identification of major metabolites. No toxic metabolites were detected. The preclinical toxic dose was determined based on prediction of blood exposure at the estimated maximum clinical dose. For the other candidate compound, the findings of the microdose trial indicated a high bioavailability after oral administration and low hepatic clearance after intravenous administration. These results suggested only a small risk of a change in disposition in patients with hepatic disorder. The data obtained for the two compounds suggest that microdose clinical trials can be useful for improving the process of candidate selection in the preclinical stage.

Treating Diabetes Mellitus: Pharmacophore Based Designing of Potential Drugs from Gymnema sylvestre against Insulin Receptor Protein

PubMed Central

Hossain, Mohammad Uzzal; Khan, Md. Arif; Rakib-Uz-Zaman, S. M.; Ali, Mohammad Tuhin; Islam, Md. Saidul; Keya, Chaman Ara; Salimullah, Md.

2016-01-01

Diabetes mellitus (DM) is one of the most prevalent metabolic disorders which can affect the quality of life severely. Injectable insulin is currently being used to treat DM which is mainly associated with patient inconvenience. Small molecules that can act as insulin receptor (IR) agonist would be better alternatives to insulin injection. Herein, ten bioactive small compounds derived from Gymnema sylvestre (G. sylvestre) were chosen to determine their IR binding affinity and ADMET properties using a combined approach of molecular docking study and computational pharmacokinetic elucidation. Designing structural analogues were also performed for the compounds associated with toxicity and less IR affinity. Among the ten parent compounds, six were found to have significant pharmacokinetic properties with considerable binding affinity towards IR while four compounds were associated with toxicity and less IR affinity. Among the forty structural analogues, four compounds demonstrated considerably increased binding affinity towards IR and less toxicity compared with parent compounds. Finally, molecular interaction analysis revealed that six parent compounds and four analogues interact with the active site amino acids of IR. So this study would be a way to identify new therapeutics and alternatives to insulin for diabetic patients. PMID:27034931

Treating Diabetes Mellitus: Pharmacophore Based Designing of Potential Drugs from Gymnema sylvestre against Insulin Receptor Protein.

PubMed

Hossain, Mohammad Uzzal; Khan, Md Arif; Rakib-Uz-Zaman, S M; Ali, Mohammad Tuhin; Islam, Md Saidul; Keya, Chaman Ara; Salimullah, Md

2016-01-01

Diabetes mellitus (DM) is one of the most prevalent metabolic disorders which can affect the quality of life severely. Injectable insulin is currently being used to treat DM which is mainly associated with patient inconvenience. Small molecules that can act as insulin receptor (IR) agonist would be better alternatives to insulin injection. Herein, ten bioactive small compounds derived from Gymnema sylvestre (G. sylvestre) were chosen to determine their IR binding affinity and ADMET properties using a combined approach of molecular docking study and computational pharmacokinetic elucidation. Designing structural analogues were also performed for the compounds associated with toxicity and less IR affinity. Among the ten parent compounds, six were found to have significant pharmacokinetic properties with considerable binding affinity towards IR while four compounds were associated with toxicity and less IR affinity. Among the forty structural analogues, four compounds demonstrated considerably increased binding affinity towards IR and less toxicity compared with parent compounds. Finally, molecular interaction analysis revealed that six parent compounds and four analogues interact with the active site amino acids of IR. So this study would be a way to identify new therapeutics and alternatives to insulin for diabetic patients.

Detoxification of furfural in Corynebacterium glutamicum under aerobic and anaerobic conditions.

PubMed

Tsuge, Yota; Hori, Yoshimi; Kudou, Motonori; Ishii, Jun; Hasunuma, Tomohisa; Kondo, Akihiko

2014-10-01

The toxic fermentation inhibitors in lignocellulosic hydrolysates raise serious problems for the microbial production of fuels and chemicals. Furfural is considered to be one of the most toxic compounds among these inhibitors. Here, we describe the detoxification of furfural in Corynebacterium glutamicum ATCC13032 under both aerobic and anaerobic conditions. Under aerobic culture conditions, furfuryl alcohol and 2-furoic acid were produced as detoxification products of furfural. The ratio of the products varied depending on the initial furfural concentration. Neither furfuryl alcohol nor 2-furoic acid showed any toxic effect on cell growth, and both compounds were determined to be the end products of furfural degradation. Interestingly, unlike under aerobic conditions, most of the furfural was converted to furfuryl alcohol under anaerobic conditions, without affecting the glucose consumption rate. Both the NADH/NAD(+) and NADPH/NADP(+) ratio decreased in the accordance with furfural concentration under both aerobic and anaerobic conditions. These results indicate the presence of a single or multiple endogenous enzymes with broad and high affinity for furfural and co-factors in C. glutamicum ATCC13032.

Discovery of a novel acyl-CoA: cholesterol acyltransferase inhibitor: the synthesis, biological evaluation, and reduced adrenal toxicity of (4-phenylcoumarin)acetanilide derivatives with a carboxylic acid moiety.

PubMed

Ogino, Masaki; Nakada, Yoshihisa; Negoro, Nobuyuki; Itokawa, Shigekazu; Nishimura, Satoshi; Sanada, Tsukasa; Satomi, Tomoko; Kita, Shunbun; Kubo, Kazuki; Marui, Shogo

2011-01-01

As a part of our research for novel potent and orally available acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors that can be used as anti-atherosclerotic agents, we recently reported the discovery of the (4-phenylcoumarine)acetanilide derivative 1. However, compound 1 showed adrenal toxicity in animal models. In order to search for safer ACAT inhibitors that do not have adrenal toxicity, we examined the inhibitory activity of ACAT in human macrophage and adrenal cells. The introduction of a carboxylic acid moiety on the pendant phenyl ring and the adjustment of the lipophilicity led to the discovery of (2E)-3-[7-chloro-3-[2-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]acrylic acid (21e), which showed potent ACAT inhibitory activity in macrophages and a selectivity of around 30-fold over adrenal cells. In addition, compound 21e showed high adrenal safety in guinea pigs.

Cleaner co-combustion of lignite-biomass-waste blends by utilising inhibiting compounds of toxic emissions.

PubMed

Skodras, G; Palladas, A; Kaldis, S P; Sakellaropoulos, G P

2007-04-01

In this paper, the co-combustion behaviour of coal with wastes and biomass and the related toxic gaseous emissions were investigated. The objective of this work is to add on towards a cleaner co-combustion of lignite-waste-biomass blends by utilizing compounds that could inhibit the formation of toxic pollutants. A series of co-combustion tests was performed in a pilot scale incinerator, and the emissions of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) were measured. The co-combustion behaviour of lignite with olive kernels, MDF and sawdust was studied and the ability of additives such as urea, almond shells and municipal sewage sludge to reduce the PCDD/F emissions was examined. All blends were proven good fuels and reproducible combustion conditions were achieved. The addition of inhibitors prior to combustion showed in some cases, relatively high PCDD/F emissions reduction. Among the inhibitors tested, urea seems to achieve a reduction of PCDD/F emissions for all fuel blends, while an unstable behaviour was observed for the others.

Photoenhanced Toxicity of Petroleum to Aquatic Invertebrates and Fish

EPA Science Inventory

Photoenhanced toxicity is a distinct mechanism of petroleum toxicity that is mediated by the interaction of solar radiation with specific polycyclic aromatic compounds in oil. Phototoxicity is observed as a twofold to greater than 1000-fold increase in chemical toxicity to aquati...

Extended evaluation on the ES-D3 cell differentiation assay combined with the BeWo transport model, to predict relative developmental toxicity of triazole compounds.

PubMed

Li, Hequn; Flick, Burkhard; Rietjens, Ivonne M C M; Louisse, Jochem; Schneider, Steffen; van Ravenzwaay, Bennard

2016-05-01

The mouse embryonic stem D3 (ES-D3) cell differentiation assay is based on the morphometric measurement of cardiomyocyte differentiation and is a promising tool to detect developmental toxicity of compounds. The BeWo transport model, consisting of BeWo b30 cells grown on transwell inserts and mimicking the placental barrier, is useful to determine relative placental transport velocities of compounds. We have previously demonstrated the usefulness of the ES-D3 cell differentiation assay in combination with the in vitro BeWo transport model to predict the relative in vivo developmental toxicity potencies of a set of reference azole compounds. To further evaluate this combined in vitro toxicokinetic and toxicodynamic approach, we combined ES-D3 cell differentiation data of six novel triazoles with relative transport rates obtained from the BeWo model and compared the obtained ranking to the developmental toxicity ranking as derived from in vivo data. The data show that the combined in vitro approach provided a correct prediction for in vivo developmental toxicity, whereas the ES-D3 cell differentiation assay as stand-alone did not. In conclusion, we have validated the combined in vitro approach for developmental toxicity, which we have previously developed with a set of reference azoles, for a set of six novel triazoles. We suggest that this combined model, which takes both toxicodynamic and toxicokinetic aspects into account, should be further validated for other chemical classes of developmental toxicants.

Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro

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

Spicer, Timothy P.; Jiang, Jianwen; Taylor, Alexander B.

Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. Here, as a result of high-throughput screening and structure$-$activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S 1' subsite and in an S 1/S 2* subsite. Type II collagen- andmore » cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Lastly, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug$-$drug interactions in humans.« less

Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro

DOE PAGES

Spicer, Timothy P.; Jiang, Jianwen; Taylor, Alexander B.; ...

2014-10-20

Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. Here, as a result of high-throughput screening and structure$-$activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S 1' subsite and in an S 1/S 2* subsite. Type II collagen- andmore » cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Lastly, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug$-$drug interactions in humans.« less

Percutaneous penetration and pharmacodynamics: Wash-in and wash-off of sunscreen and insect repellent.

PubMed

Rodriguez, Jocelyn; Maibach, Howard I

2016-01-01

Increased awareness of skin cancer and mosquito-transmitted diseases has increased use of insect repellents and sunscreens. The challenge in setting recommendations for use and reapplication, especially when used concomitantly, lies in finding the balance between applying a durable product effective in withstanding natural and physical factors such as water, sweat, temperature and abrasion, while limiting percutaneous absorption and decreasing risk of potential dermal and systemic toxicity. Inorganic sunscreens show no or little percutaneous absorption or toxic effects in comparison to organic sunscreens, which show varying levels of dermal penetration and cutaneous adverse effects. An alternative to N,N-diethyl-m-toluamide (DEET), the traditional gold standard compound in insect repellents, picaridin appears as efficacious, has lower risk of toxicity, and when used simultaneously with sunscreen may decrease percutaneous absorption of both compounds. Conversely, combined use of DEET and sunscreen results in significantly higher absorption of both compounds. It is important to increase consumer awareness of "washing in" of various compounds leading to increased risk of toxicity, as well as differences in reapplication need due to "washing off" caused by water, sweat and abrasion. Although much remains to be studied, to maximize efficacy and decrease toxicity, contemporary research tools, including dermatopharmokinetics, should aid these prospective advances.

Cinnamaldehyde and related phenylpropanoids, natural repellents and insecticides against Sitophilus zeamais (Motsch.). A chemical structure-bioactivity relationship.

PubMed

Zaio, Yésica P; Gatti, Gerardo; Ponce, Andrés A; Saavedra Larralde, Natalia A; Martinez, María J; Zunino, María P; Zygadlo, Julio A

2018-05-13

Insecticidal activity and repellent effects on adults of Sitophilus zeamais of 12 cinnamaldehyde-related compounds was evaluated by contact toxicity bioassays and a two-choice olfactometer, respectively. To determine non-toxicity in mammals, additionally, body weight, serum biochemical profiles, liver weight, physiological parameters, sperm motility and histopathological data were obtained as complementary information in C57BL/6 mice, treated with the best natural compound. Based on 24h LC 95 and LC 50 values, alpha-methyl-cinnamaldehyde and cinnamaldehyde, respectively, exhibited better insecticidal activity than the other compounds. The best repellent effect was observed with alpha-bromo-cinnamaldehyde, which even repelled at the lowest concentration studied (0.28 μM). The evaluation of a quantitative structure-activity relationship showed a linear relationship between the LC 50 values for adult weevil toxicity and dipolo with Q (difference between orbital electronegativity carbon 1 and orbital electronegativity carbon 3 of the molecule) values in cinnamaldehyde-related compounds. In addition, the polar surface and Log P descriptors also revealed a linear relationship with the S. zeamais repellent effect for cinnamaldehyde analogues. Besides, cinnamaldehyde did not show toxicity in the parameters evaluated in mice. From the phenylpropanoid components studied, the natural compound which had the best insecticidal and repellent activity against S. zeamais was cinnamaldehyde and presented no mammalian toxicity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

ProTox: a web server for the in silico prediction of rodent oral toxicity

PubMed Central

Drwal, Malgorzata N.; Banerjee, Priyanka; Dunkel, Mathias; Wettig, Martin R.; Preissner, Robert

2014-01-01

Animal trials are currently the major method for determining the possible toxic effects of drug candidates and cosmetics. In silico prediction methods represent an alternative approach and aim to rationalize the preclinical drug development, thus enabling the reduction of the associated time, costs and animal experiments. Here, we present ProTox, a web server for the prediction of rodent oral toxicity. The prediction method is based on the analysis of the similarity of compounds with known median lethal doses (LD50) and incorporates the identification of toxic fragments, therefore representing a novel approach in toxicity prediction. In addition, the web server includes an indication of possible toxicity targets which is based on an in-house collection of protein–ligand-based pharmacophore models (‘toxicophores’) for targets associated with adverse drug reactions. The ProTox web server is open to all users and can be accessed without registration at: http://tox.charite.de/tox. The only requirement for the prediction is the two-dimensional structure of the input compounds. All ProTox methods have been evaluated based on a diverse external validation set and displayed strong performance (sensitivity, specificity and precision of 76, 95 and 75%, respectively) and superiority over other toxicity prediction tools, indicating their possible applicability for other compound classes. PMID:24838562

Levels of selected carcinogens and toxicants in vapour from electronic cigarettes.

PubMed

Goniewicz, Maciej Lukasz; Knysak, Jakub; Gawron, Michal; Kosmider, Leon; Sobczak, Andrzej; Kurek, Jolanta; Prokopowicz, Adam; Jablonska-Czapla, Magdalena; Rosik-Dulewska, Czeslawa; Havel, Christopher; Jacob, Peyton; Benowitz, Neal

2014-03-01

Electronic cigarettes, also known as e-cigarettes, are devices designed to imitate regular cigarettes and deliver nicotine via inhalation without combusting tobacco. They are purported to deliver nicotine without other toxicants and to be a safer alternative to regular cigarettes. However, little toxicity testing has been performed to evaluate the chemical nature of vapour generated from e-cigarettes. The aim of this study was to screen e-cigarette vapours for content of four groups of potentially toxic and carcinogenic compounds: carbonyls, volatile organic compounds, nitrosamines and heavy metals. Vapours were generated from 12 brands of e-cigarettes and the reference product, the medicinal nicotine inhaler, in controlled conditions using a modified smoking machine. The selected toxic compounds were extracted from vapours into a solid or liquid phase and analysed with chromatographic and spectroscopy methods. We found that the e-cigarette vapours contained some toxic substances. The levels of the toxicants were 9-450 times lower than in cigarette smoke and were, in many cases, comparable with trace amounts found in the reference product. Our findings are consistent with the idea that substituting tobacco cigarettes with e-cigarettes may substantially reduce exposure to selected tobacco-specific toxicants. E-cigarettes as a harm reduction strategy among smokers unwilling to quit, warrants further study. (To view this abstract in Polish and German, please see the supplementary files online.).

Lethal and sublethal effects of marine sediment extracts on fish cells and chromosomes

NASA Astrophysics Data System (ADS)

Landolt, Marsha L.; Kocan, Richard M.

1984-03-01

The cost of conducting conventional chronic bioassays with every potentially toxic compound found in marine ecosystems is prohibitive; therefore short-term toxicity tests which can be used for rapid screening were developed. The tests employ cultured fish cells to measure lethal, sublethal or genotoxic effects of pure compounds and complex mixtures. The sensitivity of these tests has been proven under laboratory conditions; the following study used two of these tests, the anaphase aberration test and a cytotoxicity assay, under field conditions. Sediment was collected from 97 stations within Puget Sound, Washington. Serial washings of the sediment in methanol and dichloromethane yielded an organic extract which was dried, dissolved in DMSO and incubated as a series of dilutions with rainbow trout gonad (RTG-2) cells. The toxic effects of the extract were measured by examining the rate of cell proliferation and the percentage of damaged anaphase figures. Anaphase figures were considered to be abnormal if they exhibited non-disjunctions, chromosome fragments, or chromosome bridges. A second cell line (bluegill fry, BF-2) was also tested for cell proliferation and was included because, unlike the RTG-2 cell line, it contains little or no mixed function oxygenase activity. Of 97 stations tested, 35 showed no genotoxic activity, 42 showed high genotoxic activity (P≤.01) and the remainder were intermediate. Among the toxic sites were several deep water stations adjacent to municipal sewage outfalls and four urban waterways contaminated by industrial and municipal effluents. Extracts from areas that showed genotoxic effects also inhibited cell proliferation and were cytotoxic to RTG-2 cells. Few effects were noted in the MFO deficient BF-2 cells. Short term in vitro tests provide aquatic toxicologists with a versatile and cost effective tool for screening complex environments. Through these tests one can identify compounds or geographic regions that exhibit high cytotoxic or genotoxic potential.

Inhibition of toxic actions of phospholipase A2 isolated & characterized from the Indian Banded Krait (Bungarus fasciatus) venom by synthetic herbal compounds

PubMed Central

Gomes, Antony; Bhattacharya, Shamik; Mukherjee, Sanghamitra; Inn-ho-Tsai; Gomes, Aparna

2012-01-01

Background & objectives: Phospholipase A2 (PLA2) is one of the major constituents of krait venom associated with several pathophysiological actions like myotoxicity, cardiotoxicity, neurotoxicity, etc. As there was no specific antiserum available against Bungarus fasciatus venom, this study was done with synthetic herbal compounds, anti PLA2 rabbit antiserum and commercial polyvalent snake venom antiserum to neutralize the PLA2 induced toxicities in experimental models. Methods: B. fasciatus venom phospholipase A2 fraction 38 (BF-38) was isolated by ion exchange chromatography, molecular weight was determined by mass spectrometry and its N terminal amino acid sequence was identified. Monospecific rabbit antiserum was raised against the PLA2 in presence of Freund complete adjuvant. The neutralization of PLA2 induced toxicities was done in in vitro and in in vivo models using synthetic herbal compounds, anti PLA2 rabbit antiserum and commercial polyvalent snake venom antiserum. Results: A toxic PLA2 (BF-38) was purified from the B. fasciatus venom by CM-cellulose and HPLC, of 13.17 kDa and a minor band of 7.3 kDa using ESI-MS. The 13.17 kDa PLA2 sequence was NLYQFKNMIQC. The 7.3 kDa toxin sequence was RKCLTKYSQDNES and was found to be <10 per cent w/w. Anti PLA2 rabbit antiserum produced faint precipitant band in immunogel diffusion and showed low titre value. The commercial polyvalent snake venom antiserum, anti PLA2 rabbit antiserum and the synthetic herbal compounds neutralized the PLA 2 induced toxicities at different intensities. Interpretation & conclusions: Our results suggested that synthetic herbal compound (BA) along with antiserum might provide effective protection against PLA2 induced toxicities of B. fasciatus venom. PMID:22885262

Acute bioassays and hazard evaluation of representative contaminants detected in Great Lakes fish

USGS Publications Warehouse

Passino, Dora R. May; Smith, Stephen B.

1987-01-01

We have provided a hazard ranking for 19 classes of compounds representing many of the nearly 500 organic compounds identified by gas chromatography-mass spectrometry in lake trout (Salvelinus namaycush) and walleye (Stizostedion vitreum vitreum) from the Great Lakes and Lake St. Clair. We initially made a provisional hazard ranking based on available published and unpublished information on aquatic toxicity, bioaccumulation, occurrence and sources. Acute toxicity tests with Daphnia pulex at 17A°C in reconstituted hard water were performed with 30 compounds representative of the 19 classes that were highest in the provisional ranking. The resulting toxicity data, along with information on the compounds' occurrence in Great Lakes fish and their sources, were ranked and weighted and then used in calculating the revised hazard ranking. The 10 most hazardous classes, in descending order, are as follows (values shown are mean 48-h EC50s, in μ/ml): arene halides (e.g., polychlorinated biphenyls, DDT), 0.0011; phthalate esters, 0.133; chlorinated camphenes (toxaphene), 0.0082; polyaromatic hydrocarbons (PAHs; e.g., dimethylnaphthalene) and reduced derivatives, 1.01; chlorinated fused polycyclics (e.g., trans-nonachlor), 0.022; nitrogen-containing compounds (e.g., O-methylhydroxyl-amine), 1.35; alkyl halides (e.g., (bromomethyl)cyclohexene), 10.1; cyclic alkanes (e.g., cyclododecane), 20.9; silicon-containing compounds (e.g., dimethyldiethoxy silane), 1.25; and heterocyclic nitrogen compounds (e.g., nicotine), 2.48. We recommend that chronic bioassays be conducted with fish and invertebrates to determine the sublethal effects of the following classes of compounds, for which few toxicity data are available: PAHs, heterocyclic nitrogen compounds, other nitrogen-containing compounds, alkyl halides, cyclic alkanes and silicon-containing compounds. Information from these types of studies will aid researchers in determining the possible causal role these contaminants play in the decline and reproductive impairment of Great Lakes fish.

In silico discovery and in vitro activity of inhibitors against Mycobacterium tuberculosis 7,8-diaminopelargonic acid synthase (Mtb BioA).

PubMed

Billones, Junie B; Carrillo, Maria Constancia O; Organo, Voltaire G; Sy, Jamie Bernadette A; Clavio, Nina Abigail B; Macalino, Stephani Joy Y; Emnacen, Inno A; Lee, Alexandra P; Ko, Paul Kenny L; Concepcion, Gisela P

2017-01-01

Computer-aided drug discovery and development approaches such as virtual screening, molecular docking, and in silico drug property calculations have been utilized in this effort to discover new lead compounds against tuberculosis. The enzyme 7,8-diaminopelargonic acid aminotransferase (BioA) in Mycobacterium tuberculosis ( Mtb ), primarily involved in the lipid biosynthesis pathway, was chosen as the drug target due to the fact that humans are not capable of synthesizing biotin endogenously. The computational screening of 4.5 million compounds from the Enamine REAL database has ultimately yielded 45 high-scoring, high-affinity compounds with desirable in silico absorption, distribution, metabolism, excretion, and toxicity properties. Seventeen of the 45 compounds were subjected to bioactivity validation using the resazurin microtiter assay. Among the 4 actives, compound 7 (( Z )- N -(2-isopropoxyphenyl)-2-oxo-2-((3-(trifluoromethyl)cyclohexyl)amino)acetimidic acid) displayed inhibitory activity up to 83% at 10 μg/mL concentration against the growth of the Mtb H37Ra strain.

In silico discovery and in vitro activity of inhibitors against Mycobacterium tuberculosis 7,8-diaminopelargonic acid synthase (Mtb BioA)

PubMed Central

Billones, Junie B; Carrillo, Maria Constancia O; Organo, Voltaire G; Sy, Jamie Bernadette A; Clavio, Nina Abigail B; Macalino, Stephani Joy Y; Emnacen, Inno A; Lee, Alexandra P; Ko, Paul Kenny L; Concepcion, Gisela P

2017-01-01

Computer-aided drug discovery and development approaches such as virtual screening, molecular docking, and in silico drug property calculations have been utilized in this effort to discover new lead compounds against tuberculosis. The enzyme 7,8-diaminopelargonic acid aminotransferase (BioA) in Mycobacterium tuberculosis (Mtb), primarily involved in the lipid biosynthesis pathway, was chosen as the drug target due to the fact that humans are not capable of synthesizing biotin endogenously. The computational screening of 4.5 million compounds from the Enamine REAL database has ultimately yielded 45 high-scoring, high-affinity compounds with desirable in silico absorption, distribution, metabolism, excretion, and toxicity properties. Seventeen of the 45 compounds were subjected to bioactivity validation using the resazurin microtiter assay. Among the 4 actives, compound 7 ((Z)-N-(2-isopropoxyphenyl)-2-oxo-2-((3-(trifluoromethyl)cyclohexyl)amino)acetimidic acid) displayed inhibitory activity up to 83% at 10 μg/mL concentration against the growth of the Mtb H37Ra strain. PMID:28280303

Measurement of volatile organic compounds in human blood.

PubMed Central

Ashley, D L; Bonin, M A; Cardinali, F L; McCraw, J M; Wooten, J V

1996-01-01

Volatile organic compounds (VOCs) are an important public health problem throughout the developed world. Many important questions remain to be addressed in assessing exposure to these compounds. Because they are ubiquitous and highly volatile, special techniques must be applied in the analytical determination of VOCs. The analytical methodology chosen to measure toxicants in biological materials must be well validated and carefully carried out; poor quality assurance can lead to invalid results that can have a direct bearing on treating exposed persons. The pharmacokinetics of VOCs show that most of the internal dose of these compounds is quickly eliminated, but there is a fraction that is only slowly removed, and these compounds may bioaccumulate. VOCs are found in the general population at the high parts-per-trillion range, but some people with much higher levels have apparently been exposed to VOC sources away from the workplace. Smoking is the most significant confounder to internal dose levels of VOCs and must be considered when evaluating suspected cases of exposure. PMID:8933028

Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists Devoid of Carboxylic Acids

PubMed Central

2011-01-01

Antagonism of the CRTH2 receptor represents a very attractive target for a variety of allergic diseases. Most CRTH2 antagonists known to date possess a carboxylic acid moiety, which is essential for binding. However, potential acid metabolites O-acyl glucuronides might be linked to idiosynchratic toxicity in humans. In this communication, we describe a new series of compounds that lack the carboxylic acid moiety. Compounds with high affinity (Ki < 10 nM) for the receptor have been identified. Subsequent optimization succeeded in reducing the high metabolic clearance of the first compounds in human and rat liver microsomes. At the same time, inhibition of the CYP isoforms was optimized, giving rise to stable compounds with an acceptable CYP inhibition profile (IC50 CYP2C9 and 2C19 > 1 μM). Taken together, these data show that compounds devoid of carboxylic acid groups could represent an interesting alternative to current CRTH2 antagonists in development. PMID:24900284

The effects of characteristics of substituents on toxicity of the nitroaromatics: HiT QSAR study

NASA Astrophysics Data System (ADS)

Kuz'min, Victor E.; Muratov, Eugene N.; Artemenko, Anatoly G.; Gorb, Leonid; Qasim, Mohammad; Leszczynski, Jerzy

2008-10-01

The present study applies the Hierarchical Technology for Quantitative Structure-Activity Relationships (HiT QSAR) for (i) evaluation of the influence of the characteristics of 28 nitroaromatic compounds (some of which belong to a widely known class of explosives) as to their toxicity; (ii) prediction of toxicity for new nitroaromatic derivatives; (iii) analysis of the effects of substituents in nitroaromatic compounds on their toxicity in vivo. The 50% lethal dose concentration for rats (LD50) was used to develop the QSAR models based on simplex representation of molecular structure. The preliminary 1D QSAR results show that even the information on the composition of molecules reveals the main tendencies of changes in toxicity. The statistic characteristics for partial least squares 2D QSAR models are quite satisfactory ( R 2 = 0.96-0.98; Q 2 = 0.91-0.93; R 2 test = 0.89-0.92), which allows us to carry out the prediction of activity for 41 novel compounds designed by the application of new combinations of substituents represented in the training set. The comprehensive analysis of toxicity changes as a function of substituent position and nature was carried out. Molecular fragments that promote and interfere with toxicity were defined on the basis of the obtained models. It was shown that the mutual influence of substituents in the benzene ring plays a crucial role regarding toxicity. The influence of different substituents on toxicity can be mediated via different C-H fragments of the aromatic ring.

From data point timelines to a well curated data set, data mining of experimental data and chemical structure data from scientific articles, problems and possible solutions.

PubMed

Ruusmann, Villu; Maran, Uko

2013-07-01

The scientific literature is important source of experimental and chemical structure data. Very often this data has been harvested into smaller or bigger data collections leaving the data quality and curation issues on shoulders of users. The current research presents a systematic and reproducible workflow for collecting series of data points from scientific literature and assembling a database that is suitable for the purposes of high quality modelling and decision support. The quality assurance aspect of the workflow is concerned with the curation of both chemical structures and associated toxicity values at (1) single data point level and (2) collection of data points level. The assembly of a database employs a novel "timeline" approach. The workflow is implemented as a software solution and its applicability is demonstrated on the example of the Tetrahymena pyriformis acute aquatic toxicity endpoint. A literature collection of 86 primary publications for T. pyriformis was found to contain 2,072 chemical compounds and 2,498 unique toxicity values, which divide into 2,440 numerical and 58 textual values. Every chemical compound was assigned to a preferred toxicity value. Examples for most common chemical and toxicological data curation scenarios are discussed.

Toxicology of organophosphorus compounds in view of an increasing terrorist threat.

PubMed

Worek, Franz; Wille, Timo; Koller, Marianne; Thiermann, Horst

2016-09-01

The implementation of the Chemical Weapon Convention (CWC), prohibiting the development, production, storage and use of chemical weapons by 192 nations and the ban of highly toxic OP pesticides, especially class I pesticides according to the WHO classification, by many countries constitutes a great success of the international community. However, the increased interest of terrorist groups in toxic chemicals and chemical warfare agents presents new challenges to our societies. Almost seven decades of research on organophosphorus compound (OP) toxicology was mainly focused on a small number of OP nerve agents despite the fact that a huge number of OP analogues, many of these agents having comparable toxicity to classical nerve agents, were synthesized and published. Only limited physicochemical, toxicological and medical information on nerve agent analogues is available in the open literature. This implies potential gaps of our capabilities to detect, to decontaminate and to treat patients if nerve agent analogues are disseminated and may result in inadequate effectiveness of newly developed countermeasures. In summary, our societies may face new, up to now disregarded, threats by toxic OP which calls for increased awareness and appropriate preparedness of military and civilian CBRN defense, a broader approach for new physical and medical countermeasures and an integrated system of effective detection, decontamination, physical protection and treatment.

Photodegradation applied to the treatment of phenol and derived substances catalyzed by TiO2/BiPO4 and biological toxicity analysis.

PubMed

Zaidan, Léa Elias Mendes Carneiro; de Lima Sales, Renata Vitória; de Almeida Salgado, Júlia Barbosa; da Silva, Ana Maria Ribeiro Bastos; Napoleão, Daniella Carla; Rodríguez-Díaz, Joan Manuel; Marques, Olga Martins; Benachour, Mohand; da Silva, Valdinete Lins

2017-03-01

For this work, a phenol solution model was treated by an advanced oxidation process (AOPs), using the heterogeneous catalyst TiO 2 /BiPO 4 and hydrogen peroxide combined with UVA for 240 min. An annular reactor containing a UVA lamp (80 W) was employed. A central composite rotacional design was developed employing a TiO 2 /BiPO 4 concentration of 87 mg L -1 and a hydrogen peroxide concentration of 1800 mg L -1 , being evaluated by the degradation percentage and phenol mineralization percentage as responses; 94.30 and 67.00 % were obtained for the phenol degradation and total organic carbon (TOC) conversion, respectively. The lumped kinetic model (LKM) was applied and a satisfactory profile of the residual fractions of the organic compounds present in the liquid phase as a time function with a determination coefficient (R 2  = 0.9945). The toxicity tests employing microbiological species indicated that the organisms tested for the evaluation of the toxic compounds present in the contaminated samples presented a practical low cost test, rapid execution, and high sensibility as an indicator of the presence of toxic substances in liquid effluents.

Toxicity of ar-curcumene and epi-β-bisabolol from Hedychium larsenii (Zingiberaceae) essential oil on malaria, chikungunya and St. Louis encephalitis mosquito vectors.

PubMed

AlShebly, Mashael Marzouq; AlQahtani, Fatma Saeed; Govindarajan, Marimuthu; Gopinath, Kasi; Vijayan, Periasamy; Benelli, Giovanni

2017-03-01

Mosquitoes act as vectors of key pathogens and parasites. Plant essential oils have been recognized as important sources of biopesticides, which do not induce resistance and have limited toxic effects on human health and non-target organisms. In this research, we evaluated the larvicidal and oviposition deterrence activity of Hedychium larsenii essential oil (EO) and its major compounds ar-curcumene and epi-β-bisabolol. Both molecules showed high toxicity against early third instars of Anopheles stephensi (LC 50 =10.45 and 14.68µg/ml), Aedes aegypti (LC 50 =11.24 and 15.83µg/ml) and Culex quinquefasciatus (LC 50 =12.24 and 17.27µg/ml). In addition, low doses of ar-curcumene and epi-β-bisabolol were effective as oviposition deterrents against the three tested mosquito species. Notably, the acute toxicity of H. larsenii oil and its major compounds against the mosquito biocontrol agent Poecilia reticulata was low, with LC 50 higher than 1500ppm. Overall, the results from this study revealed that ar-curcumene and epi-β-bisabolol from the H. larsenii oil can be considered for the development of novel and effective mosquito larvicides. Copyright © 2016 Elsevier Inc. All rights reserved.

Biotransformation and toxicity of aniline and aniline derivatives of cyanobacteria.

PubMed

Cerniglia, C E; Freeman, J P; Van Baalen, C

1981-12-01

Agmenellum quadruplicatum strain PR-6 and Oscillatoria sp. strain JCM grown photoautotrophically in the presence of aniline metabolized the aromatic amine to formanilide, acetanilide and p-aminophenol. The metabolites were isolated by either thin-layer, gas-liquid or high pressure liquid chromatography and identified by comparison of their chromatographic, ultraviolet absorbance and mass spectral properties with those of authentic compounds. The toxicity of aniline derivatives towards Agmenellum quadruplicatum strain PR-6 indicated that the cyanobacterium was extremely sensitive to o-, m- and p-aminophenols, and phenylhydroxylamine.

Determination of perfluoroalkyl ether carboxylic acids (PFECAs) and sulfonic acids (PFESAs) in North Carolina surface water using high resolution mass spectrometry

EPA Science Inventory

Many per- and polyfluorinated compounds have been shown to be globally distributed with some also having the additional undesirable properties of persistence, bioaccumulation, and toxicity. To address these concerns, many industrial manufacturers have moved away from their tradi...

20180416 - Understanding the Biology and Technology of ToxCast and Tox21 Assays (SETAC Durham NC)

EPA Science Inventory

The ToxCast high-throughput toxicity (HTT) testing methods have been developed to evaluate the hazard potential of diverse environmental, industrial and consumer product chemicals. The main goal is prioritizing the compounds of greatest concern for more detailed toxicological stu...

Portable Sensor for Chemical Nerve Agents and Organophosphorus Compounds

DTIC Science & Technology

2015-08-18

as pesticides in crop, livestock, and poultry products and as chemical and biological warfare agents. As a result of the high toxicity and the...agents have been exploited for use as pesticides in crop, livestock, and poultry products and as chemical and biological warfare agents. As a result of

Development of a Computational (in silico) Model of Ocular Teratogenesis

EPA Science Inventory

EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that are highly correlated with observed in vivo toxicity. In silico models provide a framework for interpreting the in vitro results and for simul...

ENDOGENOUS REDUCTANTS SUPPORT THE CATALYTIC FUNCTION OF REOMBINANT RAT CYT119, AN ARSENIC METHYLTRANSFERASE

EPA Science Inventory

The postulated scheme for the metabolism of inorganic As involves alternating steps of oxidative methylation and of reduction of As from the pentavalent to the trivalent oxidation state, producing methylated compounds containing AsIII that are highly reactive and toxic. S-adenosy...

Formation of Toxic Iodinated Disinfection By-Products from Compounds Used in Medical Imaging

EPA Science Inventory

Iodinated X-ray contrast media (ICM) were investigated as a source of iodine in the formation of iodo-trihalomethane (iodo-THM) and iodo-acid disinfection byproducts (DBPs), both of which are highly genotoxic and/or cytotoxic in mammalian cells. ICM are widely used at medical cen...

Exposures to multiple air toxics in New York City.

PubMed Central

Kinney, Patrick L; Chillrud, Steven N; Ramstrom, Sonja; Ross, James; Spengler, John D

2002-01-01

Efforts to assess health risks associated with exposures to multiple urban air toxics have been hampered by the lack of exposure data for people living in urban areas. The TEACH (Toxic Exposure Assessment, a Columbia/Harvard) study was designed to characterize levels of and factors influencing personal exposures to urban air toxics among high school students living in inner-city neighborhoods of New York City and Los Angeles, California. This present article reports methods and data for the New York City phase of TEACH, focusing on the relationships between personal, indoor, and outdoor concentrations in winter and summer among a group of 46 high school students from the A. Philip Randolph Academy, a public high school located in the West Central Harlem section of New York City. Air pollutants monitored included a suite of 17 volatile organic compounds (VOCs) and aldehydes, particulate matter with a mass median aerodynamic diameter

Exposures to multiple air toxics in New York City.

PubMed

Kinney, Patrick L; Chillrud, Steven N; Ramstrom, Sonja; Ross, James; Spengler, John D

2002-08-01

Efforts to assess health risks associated with exposures to multiple urban air toxics have been hampered by the lack of exposure data for people living in urban areas. The TEACH (Toxic Exposure Assessment, a Columbia/Harvard) study was designed to characterize levels of and factors influencing personal exposures to urban air toxics among high school students living in inner-city neighborhoods of New York City and Los Angeles, California. This present article reports methods and data for the New York City phase of TEACH, focusing on the relationships between personal, indoor, and outdoor concentrations in winter and summer among a group of 46 high school students from the A. Philip Randolph Academy, a public high school located in the West Central Harlem section of New York City. Air pollutants monitored included a suite of 17 volatile organic compounds (VOCs) and aldehydes, particulate matter with a mass median aerodynamic diameter

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

PubMed

Pieniazek, Danuta; Bukowska, Bozena; Duda, Wirgiliusz

2003-01-01

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

Schiff Bases of Benzothiazol-2-ylamine and Thiazolo[5,4-b] pyridin-2-ylamine as Anticonvulsants: Synthesis, Characterization and Toxicity Profiling.

PubMed

Shukla, Rashmi; Singh, Ajeet P; Sonar, Pankaj K; Mishra, Mudita; Saraf, Shailendra K

2016-01-01

Schiff bases have a broad spectrum of biological activities like antiinflammatory, analgesic, antimicrobial, anticonvulsant, antitubercular, anticancer, antioxidant, anthelmintic and so forth. Thus, after a thorough perusal of literature, it was decided to conjugate benzothiazol-2-ylamine/thiazolo [5, 4-b] pyridin-2-ylamine with aromatic and heteroaromatic aldehydes to get a series of Schiff bases. Synthesis, characterization, in-silico toxicity profiling and anticonvulsant activity of the Schiff bases of Benzothiazol-2-ylamine and Thiazolo [5, 4-b] pyridin-2-ylamine. Aniline/4-aminopyridine was converted to the corresponding thiourea derivatives, which were cyclized to obtain benzothiazol-2-ylamine/thiazolo [5, 4-b] pyridin-2-ylamine. Finally, these were condensed with various aromatic and heteroaromatic aldehydes to obtain Schiff bases of benzothiazol-2-ylamine and thiazolo [5, 4-b] pyridin-2-ylamine. The synthesized compounds were characterized and screened for their anticonvulsant activity using maximal electroshock (MES) test and isoniazid (INH) induced convulsions test. In-silico toxicity profiling of all the synthesized compounds was done through "Lazar" and "Osiris" properties explorer. Majority of the compounds were more potent against MES induced convulsions than INH induced convulsions. Schiff bases of benzothiazol-2-ylamine were more effective than thiazolo [5, 4-b] pyridin-2-ylamine against MES induced convulsions. The compound benzothiazol-2-yl-(1H-indol-2-ylmethylene)-amine (VI) was the most potent member of the series against both types of convulsions. Compound VI exhibited the most significant activity profile in both the models. The compounds did not exhibit any carcinogenicity or acute toxicity in the in-silico studies. Thus, it may be concluded that the Schiff bases of benzothiazol-2-ylamine exhibit the potential to be promising and non-toxic anticonvulsant agents.

Toxicity of basil oil constituents and related compounds and the efficacy of spray formulations to Dermatophagoides farinae (Acari: Pyroglyphidae).

PubMed

Perumalsamy, Haribalan; Kim, Jae Yeon; Kim, Jun-Ran; Hwang, Kum Na Ra; Ahn, Young-Joon

2014-05-01

Pyroglyphid house dust mites are the most common cause of allergic symptoms in humans. An assessment was made of the toxicity of basil, Ocimum basilicum L, essential oil, 11 basil oil constituents, seven structurally related compounds, and another 22 previously known basil oil constituents to adult American house dust mites, Dermatophagoides farinae Hughes. The efficacy of four experimental spray formulations containing basil oil (1, 2, 3, and 4% sprays) was also assessed. Results were compared with those of two conventional acaricides benzyl benzoate and N,N-diethyl-3-methylbenzamide. The active principles of basil oil were determined to be citral, alpha-terpineol, and linalool. Citral (24 h LC50, 1.13 microg/cm2) and menthol (1.69 microg/cm2) were the most toxic compounds, followed by methyl eugenol (5.78 microg/cm2). These compounds exhibited toxicity greater than benzyl benzoate (LC50, 8.41 microg/cm2) and N,N-diethyl-3-methylbenzamide (37.67 microg/cm2). Potent toxicity was also observed with eugenol, menthone, spathulenol, alpha-terpineol, nerolidol, zerumbone, and nerol (LC50, 12.52-21.44 microg/cm2). Interestingly, the sesquiterpenoid alpha-humulene, lacking only the carbonyl group present in zerumbone, was significantly less effective than zerumbone, indicating that the alpha,beta-unsaturated carbonyl group of zerumbone is a prerequisite component for toxicity. These compounds were consistently more toxic in closed versus open containers, indicating that their mode of delivery was largely a result of vapor action. Basil oil applied as 3 and 4% sprays provided 97 and 100% mortality against the mites, respectively, whereas permethrin (cis:trans, 25:75) 2.5 g/liter spray treatment resulted in 17% mortality. Our results indicate that practical dust mite control in indoor environments can be achieved by basil oil spray formulations (3 and 4% sprays) as potential contact-action fumigants.

Novel amidines and analogues as promising agents against intracellular parasites: a systematic review.

PubMed

Soeiro, M N C; Werbovetz, K; Boykin, D W; Wilson, W D; Wang, M Z; Hemphill, A

2013-07-01

Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.

Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants.

PubMed

Krug, Anne K; Balmer, Nina V; Matt, Florian; Schönenberger, Felix; Merhof, Dorit; Leist, Marcel

2013-12-01

Organ-specific in vitro toxicity assays are often highly sensitive, but they lack specificity. We evaluated here examples of assay features that can affect test specificity, and some general procedures are suggested on how positive hits in complex biological assays may be defined. Differentiating human LUHMES cells were used as potential model for developmental neurotoxicity testing. Forty candidate toxicants were screened, and several hits were obtained and confirmed. Although the cells had a definitive neuronal phenotype, the use of a general cell death endpoint in these cultures did not allow specific identification of neurotoxicants. As alternative approach, neurite growth was measured as an organ-specific functional endpoint. We found that neurite extension of developing LUHMES was specifically inhibited by diverse compounds such as colchicine, vincristine, narciclasine, rotenone, cycloheximide, or diquat. These compounds reduced neurite growth at concentrations that did not compromise cell viability, and neurite growth was affected more potently than the integrity of developed neurites of mature neurons. A ratio of the EC50 values of neurite growth inhibition and cell death of >4 provided a robust classifier for compounds associated with a developmental neurotoxic hazard. Screening of unspecific toxicants in the test system always yielded ratios <4. The assay identified also compounds that accelerated neurite growth, such as the rho kinase pathway modifiers blebbistatin or thiazovivin. The negative effects of colchicine or rotenone were completely inhibited by a rho kinase inhibitor. In summary, we suggest that assays using functional endpoints (neurite growth) can specifically identify and characterize (developmental) neurotoxicants.

Synthesis and evaluation of phosphorus containing, specific CDK9/CycT1 inhibitors.

PubMed

Németh, Gábor; Greff, Zoltán; Sipos, Anna; Varga, Zoltán; Székely, Rita; Sebestyén, Mónika; Jászay, Zsuzsa; Béni, Szabolcs; Nemes, Zoltán; Pirat, Jean-Luc; Volle, Jean-Noël; Virieux, David; Gyuris, Ágnes; Kelemenics, Katalin; Ay, Eva; Minarovits, Janos; Szathmary, Susan; Kéri, György; Orfi, László

2014-05-22

Although there is a significant effort in the design of a selective CDK9/CycT1 inhibitor, no compound has been proven to be a specific inhibitor of this kinase so far. The aim of this research was to develop novel and selective phosphorus containing CDK9/CycT1 inhibitors. Molecules bearing phosphonamidate, phosphonate, and phosphinate moieties were synthesized. Prepared compounds were evaluated in an enzymatic CDK9/CycT1 assay. The most potent molecules were tested in cell-based toxicity and HIV proliferation assays. Selectivity of shortlisted compounds against CDKs and other kinases was tested. The best compound was shown to be a highly specific, ATP-competitive inhibitor of CDK9/CycT1 with antiviral activity.

Fumigant toxicity and acetylcholinesterase inhibitory activity of 4 Asteraceae plant essential oils and their constituents against Japanese termite (Reticulitermes speratus Kolbe).

PubMed

Seo, Seon-Mi; Kim, Junheon; Kang, Jaesoon; Koh, Sang-Hyun; Ahn, Young-Joon; Kang, Kyu-Suk; Park, Il-Kwon

2014-07-01

This study investigated the fumigant toxicity of 4 Asteraceae plant essential oils and their constituents against the Japanese termite Reticulitermes speratus Kolbe. Fumigant toxicity varied with plant essential oils or constituents, exposure time, and concentration. Among the tested essential oils, those from Chamaemelum nobile exhibited the strongest fumigant toxicity, followed by those from Santolina chamaecyparissus, Ormenis multicaulis, and Eriocephalus punctulatus at 2 days after treatment. In all, 15, 24, 19, and 9 compounds were identified in the essential oils from C. nobile, E. punctulatus, O. multicaulis, and S. chamaecyparissus, respectively, by using gas chromatography, gas chromatography-mass spectrometry, or open-column chromatography. The identified compounds were tested individually for their fumigant toxicity against Japanese termites. Among the test compounds, trans-pinocarveol, caryophyllene oxide, sabinene hydrate, and santolina alcohol showed strong fumigant toxicity against Japanese termites. Acetylcholinesterase (AChE) inhibition activity of the identified compounds from C. nobile, E. punctulatus, O. multicaulis, and S. chamaecyparissus essential oils were tested to determine the mode of their action. The IC50 values of (+)-α-pinene, (-)-limonene, (-)-α-pinene, β-pinene, and β-phellandrene against Japanese termite AChE were 0.03, 0.13, 0.41, 0.42, and 0.67mg/mL, respectively. Further studies are warranted to determine the potential of these essential oils and their constituents as fumigants for termite control. Copyright © 2014 Elsevier Inc. All rights reserved.

Novel Phenoxazinones as potent agonist of PPAR-α: design, synthesis, molecular docking and in vivo studies.

PubMed

Ugwu, David I; Okoro, Uchechukwu C; Mishra, Narendra K; Okafor, Sunday N

2018-05-22

The use of statin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for the treatment of dyslipidemia has been associated with dose limiting hepatoxicity, mytotoxicity and tolerability due to myalgias thereby necessitating the synthesis of new drug candidates for the treatment of lipid disorder. The reaction of appropriate benzenesulphonamide with substituted phenoxazinone in the presence of phenylboronic acid gave the targeted compounds. The molecular docking study were carried out using autodock tool against peroxisome proliferator activated receptor alpha. The in vivo lipid profile were assayed using conventional methods. The kidney and liver function test were carried out to assess the effect of the derivatives on the organs. The LD 50 of the most active derivatives were determined using mice. The targeted compounds were successfully synthesized in excellent yields and characterized using spectroscopic techniques. The results of the molecular docking experiment showed that they were good stimulant of peroxisome proliferator activated receptor alpha. Compound 9f showed activity at Ki of 2.8 nM and binding energy of 12.6 kcal/mol. All the compounds tested reduced triglyceride, total cholesterol, low density lipoprotein cholesterol and very low density lipoprotein cholesterol level in the mice model. Some of the reported compounds also increased high density lipoprotein cholesterol level in the mice. The compounds did not have appreciable effect on the kidney and liver of the mice used. The LD 50 showed that the novel compounds have improved toxicity profile. The synthesis of fifteen new derivatives of carboxamides bearing phenoxazinone and sulphonamide were successful. The compounds possessed comparable activity to gemfibrozil. The reported compounds had better toxicity profile than gemfibrozil and could serve as a replacement for the statins and fibrate class of lipid agents.

Novel Polyfluorinated Compounds Identified Using High ...

EPA Pesticide Factsheets

Concern over persistence, bioaccumulation, and toxicity has led to international regulation and phase-outs of certain perfluorinated compounds and little is known about their replacement products. High resolution mass spectrometry was used to investigate the occurrence and identity of replacement fluorinated compounds in surface water and sediment of the Tennessee River near Decatur, Alabama. Analysis of legacy Per- and polyfluoroalkyl substances (PFASs) revealed a marked increase in concentrations downstream of manufacturing facilities, with the most abundant compounds being perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate (PFBS), and perfluorooctanoic acid (PFOA) as high as 220 ng L–1, 160 ng L–1, and 120 ng L–1, respectively. A series of nine polyfluorinated carboxylic acids was discovered, each differing by CF2CH2. These acids are likely products or byproducts of a manufacturing process that uses 1,1-difluoroethene, which is registered to a manufacturing facility in the area. Two other predominant compounds discovered have structures consistent with perfluorobutanesulfonate and perfluoroheptanoic acid but have a single hydrogen substituted for a fluorine someplace in their structure. A polyfluoroalkyl sulfate with differing mixes of hydrogen and fluorine substitution was also observed. N-methyl perfluorobutane sulfonamidoacetic acid (MeFBSAA) was observed at high concentrations and several other perfluorobutane sulfonamido substances were pres

In vitro and in silico antioxidant and toxicological activities of Achyrocline satureioides.

PubMed

Salgueiro, Andréia C F; Folmer, Vanderlei; da Rosa, Hemerson S; Costa, Márcio T; Boligon, Aline A; Paula, Fávero R; Roos, Daniel H; Puntel, Gustavo O

2016-12-24

Achyrocline satureioides ("macela or marcela") is a medicinal plant, traditionally collected in "Good Friday" before sunrise. In traditional medicine, dried flowers of A. satureioides are used as anti-dyspeptic, antispasmodic and anti-inflammatory. To evaluate the phytochemical profile and to present an in vitro and in silico approach about toxicity and antioxidant potential of A. satureioides flowers extract and its major phytoconstituents. Plant were collected according to the popular tradition. Extract were obtained by infusion and analyzed from high-performance liquid chromatography. Toxicity was evaluated in Artemia salina and human lymphocytes. Extract antioxidant activity was determined with total antioxidant capacity, DPPH • and ABTS +• scavenging, ferric reducing antioxidant power, deoxyribose degradation assay, and thiobarbituric acid reactive substances (TBA-RS) assay. TBA-RS inhibitions were evaluated in brain of rats for A. satureioides extract and its major phytoconstituents. Predictions of activity spectra for substances and in silico toxicity evaluation from major phytoconstituents were performed via computer simulation. Chromatographic data indicated isoquercitrin, quercetin and caffeic acid as main compounds in flowers extract. Toxicity tests demonstrated a very low toxic potential of A. satureioides. Extract exhibited antioxidant activities in low concentrations. Both extract and major phytochemicals standards showed protection against lipid peroxidation in brain of rats. Computer simulations pointed some biological activities in agreement with traditional use, as well as some experimental results found in this work. Moreover, in silico toxic predictions showed that the A. satureioides major compounds had low probability for toxic risk. Our results indicate that A. satureioides infusion possesses low toxicological potential and an effective antioxidant activity. These findings confirm the traditional use of this plant in the folk medicine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Identification of compounds bound to suspended solids causing sub-lethal toxic effects in Daphnia magna. A field study on re-suspended particles during river floods in Ebro River.

PubMed

Rivetti, Claudia; Gómez-Canela, Cristian; Lacorte, Silvia; Díez, Sergi; Lázaro, Wilkinson L; Barata, Carlos

2015-04-01

Identifying chemicals causing adverse effects in organisms present in water remains a challenge in environmental risk assessment. This study aimed to assess and identify toxic compounds bound to suspended solids re-suspended during a prolonged period of flushing flows in the lower part of Ebro River (NE, Spain). This area is contaminated with high amounts of organochlorine and mercury sediment wastes. Chemical characterization of suspended material was performed by solid phase extraction using a battery of non-polar and polar solvents and analyzed by GC-MS/MS and LC-MS/MS. Mercury content was also determined for all sites. Post-exposure feeding rates of Daphnia magna were used to assess toxic effects of whole and filtered water samples and of re-constituted laboratory water with re-suspended solid fractions. Organochlorine and mercury residues in the water samples increased from upstream to downstream locations. Conversely, toxic effects were greater at the upstream site than downstream of the superfund Flix reservoir. A further analysis of the suspended solid fraction identified a toxic component eluted within the 80:20 methanol:water fraction. Characterization of that toxic component fraction by LC-MS/MS identified the phytotoxin anatoxin-a, whose residue levels were correlated with observed feeding inhibition responses. Further feeding inhibition assays conducted in the lab using anatoxin-a produced from Planktothrix agardhii, a filamentous cyanobacteria, confirmed field results. This study provides evidence that in real field situation measured contaminant residues do not always agree with toxic effects. Copyright © 2015 Elsevier B.V. All rights reserved.

Disposition of toxic PCB congeners in snapping turtle eggs: expressed as toxic equivalents of TCDD

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

Bryan, A.M.; Stone, W.B.; Olafsson, P.G.

1987-11-01

Studies of snapping turtles, taken from the region of the Upper Hudson River, in New York State, revealed exceedingly high levels of PCBs in the adipose tissue. There is evidence to suggest that large reserves of fat provide protection against chlorinated hydrocarbon toxicity. Such storage may protect snapping turtle eggs from disposition of toxic PCB congeners and account for the apparent absence of reports regarding detrimental effects on the hatchability of eggs from turtles living in the vicinity of the upper Hudson River. The present study was undertaken to determine if indeed these eggs are protected against disposition of toxicmore » PCB congeners by the presence of large reserves of fat. Although tissue volumes play an important role in determining the initial site of disposition, the major factor controlling the elimination of these compounds involves metabolism. For simple halogenated benzenes as well as for more complex halogenated biphenyls, oxidative metabolism catalyzed by P-448, occurs primarily at the site of two adjacent unsubstituted carbon atoms via arene oxide formation leading to the formation of water soluble metabolites. Toxicological studies have demonstrated that the most toxic PCB congeners, isosteriomers of tetrachlorodibenzo-p-dioxin (TCDD), require no metabolic activation. These compounds have chlorine atoms in the meta and para positions of both rings. It may be concluded that the structures of PCB congeners and isomers which favor induction of cytochrome P-448 are also those which are toxic and resist metabolism. It is the objective of the present study to determine if the heavy fat bodies of the female turtle provide a sufficiently large sink to retain the toxic congeners and prevent their incorporation into the eggs.« less

Ambrosia artemisiifolia as a potential resource for management of golden apple snails, Pomacea canaliculata (Lamarck).

PubMed

Ding, Wenbing; Huang, Rui; Zhou, Zhongshi; He, Hualiang; Li, Youzhi

2018-04-01

Ambrosia artemisiifolia, an invasive weed in Europe and Asia, is highly toxic to the golden apple snail (GAS; Pomacea canaliculata) in laboratory tests. However, little is known about the chemical components of A. artemisiifolia associated with the molluscicidal activity or about its potential application for GAS control in rice fields. This study evaluated the molluscicidal activities of powders, methanol extracts, and individual compounds from A. artemisiifolia against GAS in rice fields and under laboratory conditions. Ambrosia artemisiifolia powders did not negatively affect the growth and development of rice but they reduced damage to rice caused by GAS. Extracts had moderate acute toxicity but potent chronic toxicity. The 24-h 50% lethal concentration (LC 50 ) of the extracts against GAS was 194.0 mg L -1 , while the weights, lengths and widths of GAS were significantly affected by exposure to a sublethal concentration (100 mg/mL). Psilostachyin, psilostachyin B, and axillaxin were identified as the most active molluscicide components in the aerial parts of A. artemisiifolia, and the 24-h LC 50 values of these purified compounds were 15.9, 27.0, and 97.0 mg/L, respectively. The results indicate that chemical compounds produced by A. artemisiifolia may be useful for population management of GAS in rice fields. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Embryotoxic and teratogenic effects of petroleum hydrocarbons in mallards (Anas platyrhynchos)

USGS Publications Warehouse

Hoffman, D.J.

1979-01-01

Egg surface applications of microliter quantities of crude and refined oils of high aromatic content are embryotoxic to mallards (Anas platyrhynchos) and other avian species; applications of aliphatic hydrocarbons have virtually no effect. Mallard eggs at 72 h of development were exposed to a mixture of aromatic hydrocarbons or to aromatic compounds representative to those present in crude oil to assess their toxicity. The class composition of the mixture was similar to that of South Louisiana crude oil, an American Petroleum Institute reference oil. Application of 20 microliter of the mixture reduced embryonic survival by nearly 70%. The temporal pattern of embryonic death was similar to that after exposure to South Louisiana crude oil. Embryonic growth was stunted, as reflected by weight, crown-rump length, and bill length, and there was a significant increase in the incidence of abnormal survivors. When individual classes of aromatic hydrocarbons were tested, tetracyclics caused some embryonic death at the concentrations in the mixture. When classes were tested in all possible combinations of two, no combination appeared to be as toxic as the entire mixture. Addition of the tetracyclic compound chrysene to the aromatic mixture considerably enhanced embryotoxicity, but could not completely account for the toxicity of the crude oil. The presence of additional unidentified polycyclic aromatic hydrocarbons as well as methylated derivatives of polycyclic aromatic compounds such as chrysene may further account for the embryotoxicity of the crude oil.

Gramicidin D enhances the antibacterial activity of fluoride.

PubMed

Nelson, James W; Zhou, Zhiyuan; Breaker, Ronald R

2014-07-01

Fluoride is a toxic anion found in many natural environments. One of the major bacterial defenses against fluoride is the cell envelope, which limits passage of the membrane-impermeant fluoride anion. Accordingly, compounds that enhance the permeability of bacterial membranes to fluoride should also enhance fluoride toxicity. In this study, we demonstrate that the pore-forming antibiotic gramicidin D increases fluoride uptake in Bacillus subtilis and that the antibacterial activity of this compound is potentiated by fluoride. Polymyxin B, another membrane-targeting antibiotic with a different mechanism of action, shows no such improvement. These results, along with previous findings, indicate that certain compounds that destabilize bacterial cell envelopes can enhance the toxicity of fluoride. Copyright © 2014 Elsevier Ltd. All rights reserved.

Ecotoxicological evaluation of the risk posed by bisphenol A, triclosan, and 4-nonylphenol in coastal waters using early life stages of marine organisms (Isochrysis galbana, Mytilus galloprovincialis, Paracentrotus lividus, and Acartia clausi).

PubMed

Tato, Tania; Salgueiro-González, Noelia; León, Víctor M; González, Sergio; Beiras, Ricardo

2018-01-01

This study assessed the environmental risk on coastal ecosystems posed by three phenolic compounds of special environmental and human health concern used in plastics and household products: bisphenol A (BPA), triclosan (TCS) and 4-nonylphenol (4-NP). These three chemicals are among the organic contaminants most frequently detected in wastewater. The most toxic compound tested was 4-NP, with 10% effective concentration at 11.1 μg L -1 for Isochrysis galbana, 110.5 μg L -1 for Mytilus galloprovincialis, 53.8 μg L -1 for Paracentrotus lividus, and 29.0 μg L -1 for Acartia clausi, followed by TCS (14.6 μg L -1 for I. galbana, 149.8 μg L -1 for M. galloprovincialis, 129.9 μg L -1 for P. lividus, and 64.8 μg L -1 for A. clausi). For all species tested, BPA was the less toxic chemical, with toxicity thresholds ranging between 400 and 1200 μg L -1 except for A. clausi nauplii (186 μg L -1 ). The relatively narrow range of variation in toxicity considering the broad physiological differences among the biological models used point at non-selective mechanisms of toxicity for these aromatic organics. Microalgae, the main primary producers in pelagic ecosystems, showed particularly high susceptibility to the chemicals tested. When the toxicity thresholds experimentally obtained were compared to the maximum environmental concentrations reported in coastal waters, the risk quotients obtained correspond to very low or low risk for BPA and TCS, and from low to high for 4-NP. Copyright © 2017 Elsevier Ltd. All rights reserved.

40 CFR 401.15 - Toxic pollutants.

Code of Federal Regulations, 2012 CFR

2012-07-01

.... Mercury and compounds 46. Naphthalene 47. Nickel and compounds 48. Nitrobenzene 49. Nitrophenols.... Tetrachloroethylene 60. Thallium and compounds 61. Toluene 62. Toxaphene 1 63. Trichloroethylene 64. Vinyl chloride 65...

40 CFR 401.15 - Toxic pollutants.

Code of Federal Regulations, 2014 CFR

2014-07-01

.... Mercury and compounds 46. Naphthalene 47. Nickel and compounds 48. Nitrobenzene 49. Nitrophenols.... Tetrachloroethylene 60. Thallium and compounds 61. Toluene 62. Toxaphene 1 63. Trichloroethylene 64. Vinyl chloride 65...

40 CFR 401.15 - Toxic pollutants.

Code of Federal Regulations, 2013 CFR

2013-07-01

.... Mercury and compounds 46. Naphthalene 47. Nickel and compounds 48. Nitrobenzene 49. Nitrophenols.... Tetrachloroethylene 60. Thallium and compounds 61. Toluene 62. Toxaphene 1 63. Trichloroethylene 64. Vinyl chloride 65...

Abcb4 acts as multixenobiotic transporter and active barrier against chemical uptake in zebrafish (Danio rerio) embryos

PubMed Central

2013-01-01

Background In mammals, ABCB1 constitutes a cellular “first line of defense” against a wide array of chemicals and drugs conferring cellular multidrug or multixenobiotic resistance (MDR/MXR). We tested the hypothesis that an ABCB1 ortholog serves as protection for the sensitive developmental processes in zebrafish embryos against adverse compounds dissolved in the water. Results Indication for ABCB1-type efflux counteracting the accumulation of chemicals in zebrafish embryos comes from experiments with fluorescent and toxic transporter substrates and inhibitors. With inhibitors present, levels of fluorescent dyes in embryo tissue and sensitivity of embryos to toxic substrates were generally elevated. We verified two predicted sequences from zebrafish, previously annotated as abcb1, by cloning; our synteny analyses, however, identified them as abcb4 and abcb5, respectively. The abcb1 gene is absent in the zebrafish genome and we explored whether instead Abcb4 and/or Abcb5 show toxicant defense properties. Quantitative real-time polymerase chain reaction (qPCR) analyses showed the presence of transcripts of both genes throughout the first 48 hours of zebrafish development. Similar to transporter inhibitors, morpholino knock-down of Abcb4 increased accumulation of fluorescent substrates in embryo tissue and sensitivity of embryos toward toxic compounds. In contrast, morpholino knock-down of Abcb5 did not exert this effect. ATPase assays with recombinant protein obtained with the baculovirus expression system confirmed that dye and toxic compounds act as substrates of zebrafish Abcb4 and inhibitors block its function. The compounds tested comprised model substrates of human ABCB1, namely the fluorescent dyes rhodamine B and calcein-am and the toxic compounds vinblastine, vincristine and doxorubicin; cyclosporin A, PSC833, MK571 and verapamil were applied as inhibitors. Additionally, tests were performed with ecotoxicologically relevant compounds: phenanthrene (a polycyclic aromatic hydrocarbon) and galaxolide and tonalide (two polycyclic musks). Conclusions We show that zebrafish Abcb4 is a cellular toxicant transporter and provides protection of embryos against toxic chemicals dissolved in the water. Zebrafish Abcb4 thus is functionally similar to mammalian ABCB1, but differs from mammalian ABCB4, which is not involved in cellular resistance to chemicals but specifically transports phospholipids in the liver. Our data have important implications: Abcb4 could affect bioavailability - and thus toxicologic and pharmacologic potency - of chemicals to zebrafish embryos and inhibition of Abcb4 therefore causes chemosensitization, that is, enhanced sensitivity of embryos to toxicants. These aspects should be considered in (eco)toxicologic and pharmacologic chemical screens with the zebrafish embryo, a major vertebrate model. PMID:23773777

Recreational inhalation of butane and propane in adolescents: Two forensic cases of accidental death.

PubMed

Sironi, Luca; Amadasi, Alberto; Zoja, Riccardo

2016-09-01

The recreational use of inhalants is a fairly widespread habit among adolescents because of the ease of availability and methods of assumption. Their use is however not free of risks, both for direct toxicity on several target organs and for a mechanism of gas replacement with lack of oxygen. The first case concerns a 12-year-old boy who died suddenly after sniffing a mix of butane and propane contained in a can of air freshener. The second case concerns a 14-year-old boy who died by acute poisoning by the same mixture contained in a refill for lighters. High concentrations of the compounds were found in the tissues by analysis with gas chromatography-mass spectrometry. The compounds found in tissues and biological fluids were perfectly compatible with those contained in the containers used for the inhalation. The mechanisms of death were therefore assessed in a combination of the direct toxicity of the compound and oxygen replacement, thus highlighting the crucial help that toxicological analyses can provide in such cases. Copyright © 2016. Published by Elsevier Ireland Ltd.

FudC, a protein primarily responsible for furfural detoxification in Corynebacterium glutamicum.

PubMed

Tsuge, Yota; Kudou, Motonori; Kawaguchi, Hideo; Ishii, Jun; Hasunuma, Tomohisa; Kondo, Akihiko

2016-03-01

Lignocellulosic hydrolysates contain compounds that inhibit microbial growth and fermentation, thereby decreasing the productivity of biofuel and biochemical production. In particular, the heterocyclic aldehyde furfural is one of the most toxic compounds found in these hydrolysates. We previously demonstrated that Corynebacterium glutamicum converts furfural into the less toxic compounds furfuryl alcohol and 2-furoic acid. To date, however, the genes involved in these oxidation and reduction reactions have not been identified in the C. glutamicum genome. Here, we show that Cgl0331 (designated FudC) is mainly responsible for the reduction of furfural into furfuryl alcohol in C. glutamicum. Deletion of the gene encoding FudC markedly diminished the in vivo reduction of furfural to furfuryl alcohol. Purified His-tagged FudC protein from Escherichia coli was also shown to convert furfural into furfuryl alcohol in an in vitro reaction utilizing NADPH, but not NADH, as a cofactor. Kinetic measurements demonstrated that FudC has a high affinity for furfural but has a narrow substrate range for other aldehydes compared to the protein responsible for furfural reduction in E. coli.

Using Pareto points for model identification in predictive toxicology

PubMed Central

2013-01-01

Predictive toxicology is concerned with the development of models that are able to predict the toxicity of chemicals. A reliable prediction of toxic effects of chemicals in living systems is highly desirable in cosmetics, drug design or food protection to speed up the process of chemical compound discovery while reducing the need for lab tests. There is an extensive literature associated with the best practice of model generation and data integration but management and automated identification of relevant models from available collections of models is still an open problem. Currently, the decision on which model should be used for a new chemical compound is left to users. This paper intends to initiate the discussion on automated model identification. We present an algorithm, based on Pareto optimality, which mines model collections and identifies a model that offers a reliable prediction for a new chemical compound. The performance of this new approach is verified for two endpoints: IGC50 and LogP. The results show a great potential for automated model identification methods in predictive toxicology. PMID:23517649

Predicting drug-induced liver injury using ensemble learning methods and molecular fingerprints.

PubMed

Ai, Haixin; Chen, Wen; Zhang, Li; Huang, Liangchao; Yin, Zimo; Hu, Huan; Zhao, Qi; Zhao, Jian; Liu, Hongsheng

2018-05-21

Drug-induced liver injury (DILI) is a major safety concern in the drug-development process, and various methods have been proposed to predict the hepatotoxicity of compounds during the early stages of drug trials. In this study, we developed an ensemble model using three machine learning algorithms and 12 molecular fingerprints from a dataset containing 1,241 diverse compounds. The ensemble model achieved an average accuracy of 71.1±2.6%, sensitivity of 79.9±3.6%, specificity of 60.3±4.8%, and area under the receiver operating characteristic curve (AUC) of 0.764±0.026 in five-fold cross-validation and an accuracy of 84.3%, sensitivity of 86.9%, specificity of 75.4%, and AUC of 0.904 in an external validation dataset of 286 compounds collected from the Liver Toxicity Knowledge Base (LTKB). Compared with previous methods, the ensemble model achieved relatively high accuracy and sensitivity. We also identified several substructures related to DILI. In addition, we provide a web server offering access to our models (http://ccsipb.lnu.edu.cn/toxicity/HepatoPred-EL/).

Safety of Traditional Arab Herbal Medicine

PubMed Central

Saad, Bashar; Azaizeh, Hassan; Abu-Hijleh, Ghassan; Said, Omar

2006-01-01

Herbal remedies are widely used for the treatment and prevention of various diseases and often contain highly active pharmacological compounds. Many medicinal herbs and pharmaceutical drugs are therapeutic at one dose and toxic at another. Toxicity related to traditional medicines is becoming more widely recognized as these remedies become popular in the Mediterranean region as well as worldwide. Most reports concerning the toxic effects of herbal medicines are associated with hepatotoxicity although reports of other toxic effects including kidney, nervous system, blood, cardiovascular and dermatologic effects, mutagenicity and carcinogenicity have also been published in the medical literature. This article presents a systematic review on safety of traditional Arab medicine and the contribution of Arab scholars to toxicology. Use of modern cell biological, biochemical, in vitro and in vivo techniques for the evaluation of medicinal plants safety is also discussed. PMID:17173106

Resources and biological activities of natural polyphenols.

PubMed

Li, An-Na; Li, Sha; Zhang, Yu-Jie; Xu, Xiang-Rong; Chen, Yu-Ming; Li, Hua-Bin

2014-12-22

The oxidative stress imposed by reactive oxygen species (ROS) plays an important role in many chronic and degenerative diseases. As an important category of phytochemicals, phenolic compounds universally exist in plants, and have been considered to have high antioxidant ability and free radical scavenging capacity, with the mechanism of inhibiting the enzymes responsible for ROS production and reducing highly oxidized ROS. Therefore, phenolic compounds have attracted increasing attention as potential agents for preventing and treating many oxidative stress-related diseases, such as cardiovascular diseases, cancer, ageing, diabetes mellitus and neurodegenerative diseases. This review summarizes current knowledge of natural polyphenols, including resource, bioactivities, bioavailability and potential toxicity.

Resources and Biological Activities of Natural Polyphenols

PubMed Central

Li, An-Na; Li, Sha; Zhang, Yu-Jie; Xu, Xiang-Rong; Chen, Yu-Ming; Li, Hua-Bin

2014-01-01

The oxidative stress imposed by reactive oxygen species (ROS) plays an important role in many chronic and degenerative diseases. As an important category of phytochemicals, phenolic compounds universally exist in plants, and have been considered to have high antioxidant ability and free radical scavenging capacity, with the mechanism of inhibiting the enzymes responsible for ROS production and reducing highly oxidized ROS. Therefore, phenolic compounds have attracted increasing attention as potential agents for preventing and treating many oxidative stress-related diseases, such as cardiovascular diseases, cancer, ageing, diabetes mellitus and neurodegenerative diseases. This review summarizes current knowledge of natural polyphenols, including resource, bioactivities, bioavailability and potential toxicity. PMID:25533011

Evidence for paralytic shellfish poisons in the freshwater cyanobacterium Lyngbya wollei (Farlow ex Gomont) comb. nov.

PubMed

Carmichael, W W; Evans, W R; Yin, Q Q; Bell, P; Moczydlowski, E

1997-08-01

Lyngbya wollei (Farlow ex Gomont) comb. nov., a perennial mat-forming filamentous cyanobacterium prevalent in lakes and reservoirs of the southeastern United States, was found to produce a potent, acutely lethal neurotoxin when tested in the mouse bioassay. Signs of poisoning were similar to those of paralytic shellfish poisoning. As part of the Tennessee Valley Authority master plan for Guntersville Reservoir, the mat-forming filamentous cyanobacterium L. wollei, a species that had recently invaded from other areas of the southern United States, was studied to determine if it could produce any of the known cyanotoxins. Of the 91 field samples collected at 10 locations at Guntersville Reservoir, Ala., on the Tennessee River, over a 3-year period, 72.5% were toxic. The minimum 100% lethal doses of the toxic samples ranged from 150 to 1,500 mg kg of lyophilized L. wollei cells-1, with the majority of samples being toxic at 500 mg kg-1. Samples bioassayed for paralytic shellfish toxins by the Association of Official Analytical Chemists method exhibited saxitoxin equivalents ranging from 0 to 58 micrograms g (dry weight)-1. Characteristics of the neurotoxic compound(s), such as the lack of adsorption by C18 solid-phase extraction columns, the short retention times on C18 high-performance liquid chromatography (HPLC) columns, the interaction of the neurotoxins with saxiphilin (a soluble saxitoxin-binding protein), and external blockage of voltage-sensitive sodium channels, led to our discovery that this neurotoxin(s) is related to the saxitoxins, the compounds responsible for paralytic shellfish poisonings. The major saxitoxin compounds thus far identified by comparison of HPLC fluorescence retention times are decarbamoyl gonyautoxins 2 and 3. There was no evidence of paralytic shellfish poison C toxins being produced by L. wollei. Fifty field samples were placed in unialgal culture and grown under defined culture conditions. Toxicity and signs of poisoning for these laboratory-grown strains of L. wollei were similar to those of the field collection samples.

Effects of harmful cyanobacteria on the freshwater pathogenic free-living amoeba Acanthamoeba castellanii.

PubMed

Urrutia-Cordero, Pablo; Agha, Ramsy; Cirés, Samuel; Lezcano, María Ángeles; Sánchez-Contreras, María; Waara, Karl-Otto; Utkilen, Hans; Quesada, Antonio

2013-04-15

Grazing is a major regulating factor in cyanobacterial population dynamics and, subsequently, considerable effort has been spent on investigating the effects of cyanotoxins on major metazoan grazers. However, protozoan grazers such as free-living amoebae can also feed efficiently on cyanobacteria, while simultaneously posing a major threat for public health as parasites of humans and potential reservoirs of opportunistic pathogens. In this study, we conducted several experiments in which the freshwater amoeba Acanthamoeba castellanii was exposed to pure microcystin-LR (MC-LR) and six cyanobacterial strains, three MC-producing strains (MC-LR, MC-RR, MC-YR, MC-WR, [Dha7] MC-RR) and three strains containing other oligopeptides such as anabaenopeptins and cyanopeptolins. Although the exposure to high concentrations of pure MC-LR yielded no effects on amoeba, all MC-producing strains inflicted high mortality rates on amoeba populations, suggesting that toxic effects must be mediated through the ingestion of toxic cells. Interestingly, an anabaenopeptin-producing strain caused the greatest inhibition of amoeba growth, indicating that toxic bioactive compounds other than MCs are of great importance for amoebae grazers. Confocal scanning microscopy revealed different alterations in amoeba cytoskeleton integrity and as such, the observed declines in amoeba densities could have indeed been caused via a cascade of cellular events primarily triggered by oligopeptides with protein-phosphatase inhibition capabilities such as MCs or anabaenopeptins. Moreover, inducible-defense mechanisms such as the egestion of toxic, MC-producing cyanobacterial cells and the increase of resting stages (encystation) in amoebae co-cultivated with all cyanobacterial strains were observed in our experiments. Consequently, cyanobacterial strains showed different susceptibilities to amoeba grazing which were possibly influenced by the potentiality of their toxic secondary metabolites. Hence, this study shows the importance of cyanobacterial toxicity against amoeba grazing and, that cyanobacteria may contain a wide range of chemical compounds capable of negatively affect free-living, herbivorous amoebae. Moreover, this is of high importance for understanding the interactions and population dynamics of such organisms in aquatic ecosystems. Copyright © 2012 Elsevier B.V. All rights reserved.

Turning the Tide on Toxics in the Home.

ERIC Educational Resources Information Center

Washington State Dept. of Ecology, Olympia.

This booklet provides a guide for the safe use and disposal of toxic chemicals found around the home. Toxicity ratings given to compounds are explained along with the amount needed for a probable fatal dose for a 150-pound person. Each category of hazardous waste is provided with typical examples of the toxicants, a toxicity rating, several…

High Throughput, High Content Screening for Novel Pigmentation Regulators Using a Keratinocyte/Melanocyte Co-culture System

PubMed Central

Lee, Ju Hee; Chen, Hongxiang; Kolev, Vihren; Aull, Katherine H.; Jung, Inhee; Wang, Jun; Miyamoto, Shoko; Hosoi, Junichi; Mandinova, Anna; Fisher, David E.

2014-01-01

Skin pigmentation is a complex process including melanogenesis within melanocytes and melanin transfer to the keratinocytes. To develop a comprehensive screening method for novel pigmentation regulators, we used immortalized melanocytes and keratinocytes in co-culture to screen large numbers of compounds. High-throughput screening plates were subjected to digital automated microscopy to quantify the pigmentation via brightfield microscopy. Compounds with pigment suppression were secondarily tested for their effects on expression of MITF and several pigment regulatory genes, and further validated in terms of non-toxicity to keratinocytes/melanocytes and dose dependent activity. The results demonstrate a high-throughput, high-content screening approach, which is applicable to the analysis of large chemical libraries using a co-culture system. We identified candidate pigmentation inhibitors from 4,000 screened compounds including zoxazolamine, 3-methoxycatechol, and alpha-mangostin, which were also shown to modulate expression of MITF and several key pigmentation factors, and are worthy of further evaluation for potential translation to clinical use. PMID:24438532

Chemical Protection Against Radiation Damage

ERIC Educational Resources Information Center

Campaigne, Ernest

1969-01-01

Discusses potential war time and medical uses for chemical compounds giving protection against radiation damage. Describes compounds known to protect, research aimed at discovering such compounds, and problems of toxicity. (EB)

Modulation of the Substitution Pattern of 5-Aryl-2-Aminoimidazoles Allows Fine-Tuning of Their Antibiofilm Activity Spectrum and Toxicity

PubMed Central

Peeters, Elien; Hooyberghs, Geert; Robijns, Stijn; Waldrant, Kai; De Weerdt, Ami; Delattin, Nicolas; Liebens, Veerle; Kucharíková, Soňa; Tournu, Hélène; Verstraeten, Natalie; Dovgan, Barbara; Girandon, Lenart; Fröhlich, Mirjam; De Brucker, Katrijn; Michiels, Jan; Cammue, Bruno P. A.; Thevissen, Karin; Vanderleyden, Jozef; Van der Eycken, Erik

2016-01-01

We previously synthesized several series of compounds, based on the 5-aryl-2-aminoimidazole scaffold, that showed activity preventing the formation of Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa biofilms. Here, we further studied the activity spectrum of a number of the most active N1- and 2N-substituted 5-aryl-2-aminoimidazoles against a broad panel of biofilms formed by monospecies and mixed species of bacteria and fungi. An N1-substituted compound showed very strong activity against the biofilms formed by Gram-negative and Gram-positive bacteria and the fungus Candida albicans but was previously shown to be toxic against various eukaryotic cell lines. In contrast, 2N-substituted compounds were nontoxic and active against biofilms formed by Gram-negative bacteria and C. albicans but had reduced activity against biofilms formed by Gram-positive bacteria. In an attempt to develop nontoxic compounds with potent activity against biofilms formed by Gram-positive bacteria for application in antibiofilm coatings for medical implants, we synthesized novel compounds with substituents at both the N1 and 2N positions and tested these compounds for antibiofilm activity and toxicity. Interestingly, most of these N1-,2N-disubstituted 5-aryl-2-aminoimidazoles showed very strong activity against biofilms formed by Gram-positive bacteria and C. albicans in various setups with biofilms formed by monospecies and mixed species but lost activity against biofilms formed by Gram-negative bacteria. In light of application of these compounds as anti-infective coatings on orthopedic implants, toxicity against two bone cell lines and the functionality of these cells were tested. The N1-,2N-disubstituted 5-aryl-2-aminoimidazoles in general did not affect the viability of bone cells and even induced calcium deposition. This indicates that modulating the substitution pattern on positions N1 and 2N of the 5-aryl-2-aminoimidazole scaffold allows fine-tuning of both the antibiofilm activity spectrum and toxicity. PMID:27550355

[Concentrations of alkaloids, cyanogenic glycosides, polyphenols and saponins in selected medicinal plants from Ecuador and their relationship with acute toxicity against Artemia salina].

PubMed

Jaramillo Jaramillo, Carmita; Jaramillo Espinoza, Anyi; D'Armas, Haydelba; Troccoli, Luis; Rojas de Astudillo, Luisa

2016-09-01

Alkaloids, polyphenols, cyanogenic glycosides and saponins are among the main chemical compounds synthesized by plants but not considered essential for their basic metabolism. These compounds have different functions in plants, and have been recognized with medicinal and pharmacological properties. In this research, concentrations of the mentioned secondary metabolites were determined in the medicinal plants Artemisia absinthium, Cnidoscolus aconitifolius, Parthenium hysterophorus, Piper carpunya and Taraxacum officinale, from Ecuador, and related with cytotoxic effects against Artemia salina. Alcoholic and aqueous extracts from leaves of these selected plants were prepared at different concentrations. To assess cytotoxicity of these extracts, different bioassays with A. salina were undertaken, and the mortality rates and LC50 were obtained. Besides, concentrations of alkaloids, cyanogenic glycosides, phenols, tannins and saponins were determined by spectrophotometric methods; this constituted the first report of quantification of secondary metabolites in the selected plants from Ecuador. T. officinale had the highest concentration of total phenols (22.30 ± 0.23 mg/g) and tannins (11.70 ± 0.10 mg/g), C. aconitifolius of cyanogenic glycosides (5.02 ± 0.37 µg/g) and P. hysterophorus of saponins (6.12 ± 0.02 mg/g). Tannins values obtained were not adverse to their consumption. Alcoholic and aqueous extracts of selected plants had hemolytic activity depending on the concentration of saponins. Although the values of cyanogenic glycosides were permissible, it was necessary to monitor the presence of this metabolite in plants to minimize health problems. LC50 values ranged from extremely toxic (3.37 µg/mL) to highly toxic (274.34 μg/mL), in P. carpunya and T. officinale, respectively. From correlation analysis, it was observed that increase values of alkaloids concentrations had highly significant (p<0.001) acute toxicity against A. salina, while at a higher polyphenol concentration the level of plants cytotoxicity decreased significantly (p<0.001). The results of principal component analysis showed that saponins apparently were in synergy with polyphenols to decrease cytotoxicity, but antagonize with alkaloids and cyanogenic glycosides, indicating that these secondary metabolites present variability in the mechanisms of action against A. salina, as cytotoxic compounds. These results also demonstrate that polyphenols and saponins can be lethal at low concentrations, demonstrating the potential of brine shrimp bioassay as a model to evaluate plant extracts containing low concentrations of chemical compounds with high polarities. The significant positive correlation between cytotoxicity and concentration of alkaloids confirmed by the bioassay of brine shrimp can be useful to identify promising sources of antitumor compounds, and to evaluate tolerable limits not affecting other benign cells. Contents of secondary metabolites found in the selected plants confer them great pharmacologic values.

Synthesis, antimalarial activity, heme binding and docking studies of N-substituted 4-aminoquinoline-pyrimidine molecular hybrids.

PubMed

Maurya, Shiv Shyam; Khan, Shabana I; Bahuguna, Aparna; Kumar, Deepak; Rawat, Diwan S

2017-03-31

A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Metabolic enzyme microarray coupled with miniaturized cell-culture array technology for high-throughput toxicity screening.

PubMed

Lee, Moo-Yeal; Dordick, Jonathan S; Clark, Douglas S

2010-01-01

Due to poor drug candidate safety profiles that are often identified late in the drug development process, the clinical progression of new chemical entities to pharmaceuticals remains hindered, thus resulting in the high cost of drug discovery. To accelerate the identification of safer drug candidates and improve the clinical progression of drug candidates to pharmaceuticals, it is important to develop high-throughput tools that can provide early-stage predictive toxicology data. In particular, in vitro cell-based systems that can accurately mimic the human in vivo response and predict the impact of drug candidates on human toxicology are needed to accelerate the assessment of drug candidate toxicity and human metabolism earlier in the drug development process. The in vitro techniques that provide a high degree of human toxicity prediction will be perhaps more important in cosmetic and chemical industries in Europe, as animal toxicity testing is being phased out entirely in the immediate future.We have developed a metabolic enzyme microarray (the Metabolizing Enzyme Toxicology Assay Chip, or MetaChip) and a miniaturized three-dimensional (3D) cell-culture array (the Data Analysis Toxicology Assay Chip, or DataChip) for high-throughput toxicity screening of target compounds and their metabolic enzyme-generated products. The human or rat MetaChip contains an array of encapsulated metabolic enzymes that is designed to emulate the metabolic reactions in the human or rat liver. The human or rat DataChip contains an array of 3D human or rat cells encapsulated in alginate gels for cell-based toxicity screening. By combining the DataChip with the complementary MetaChip, in vitro toxicity results are obtained that correlate well with in vivo rat data.

Computational Selection of Inhibitors of A-beta Aggregation and Neuronal Toxicity

PubMed Central

Chen, Deliang; Martin, Zane S.; Soto, Claudio; Schein, Catherine H.

2009-01-01

Alzheimer’s Disease (AD) is characterized by the cerebral accumulation of misfolded and aggregated amyloid-β protein (Aβ). Disease symptoms can be alleviated, in vitro and in vivo, by “β-sheet breaker” pentapeptides that reduce plaque volume. However the peptide nature of these compounds, made them biologically unstable and unable to penetrate membranes with high efficiency. The main goal of this study was to use computational methods to identify small molecule mimetics with better drug-like properties. For this purpose, the docked conformations of the active peptides were used to identify compounds with similar activities. A series of related β-sheet breaker peptides were docked to solid state NMR structures of a fibrillar form of Aβ. The lowest energy conformations of the active peptides were used to design three dimensional (3D)-pharmacophores, suitable for screening the NCI database with Unity. Small molecular weight compounds with physicochemical features in a conformation similar to the active peptides were selected, ranked by docking solubility parameters. Of 16 diverse compounds selected for experimental screening, 2 prevented and reversed Aβ aggregation at 2–3 μM concentration, as measured by Thioflavin T (ThT) fluorescence and ELISA assays. They also prevented the toxic effects of aggregated Aβ on neuroblastoma cells. Their low molecular weight and aqueous solubility makes them promising lead compounds for treating AD. PMID:19540126

Stability studies of endocrine disrupting tributyltin and triphenyltin compounds in an artificial sea water model.

PubMed

Novotny, Ladislav; Sharaf, Leyla; Abdel-Hamid, Mohammed E; Brtko, Julius

2018-01-01

Triorganotins belong to toxic components present predominantly in antifouling paints for marine vessels. Tributyltin/triphenyltin at pico- or nanomolar concentrations in sea water are known to induce an irreversible sexual abnormality in females of over 190 marine species, an "imposex" phenomenon - the superimposition of male genitalia on a female. Moreover, trialkyltins and triaryltins function as potent nuclear retinoid X receptors (RXR) agonists. In mammals, triorganotin compounds induce immunosuppressive, metabolic, reproductive or developmental effects. Toxic effects of triorganotins warrant the need for monitoring of their long-lasting presence in the environment. This study brings novel data on the stability of two triorganotin compounds in artificial sea water model obtained by applying ultra-pressure liquid chromatography (UPLC) and gas chromatography-mass spectrometry (GC-MS) methods. Stability of tributyltin and triphenyltin chlorides was studied for 180 days and the degradation kinetic parameters were obtained. Tributyltin chloride was the less stable with the degradation kinetic parameters Kdeg = 0.00014 day-1 and t1/2 = 4950 days (13.6 years). Kdeg of the more stable triphenyltin chloride was determined to be Kdeg = 0.00006 day-1 with t1/2 = 11550 days (31.6 years). Since similar stability data of triorganotin compounds were not published previously, we report high stability for both tested compounds, which indicates a significant environmental problem when these substances enter sea water and later coastal sediments.

Marinobacter sp. from marine sediments produce highly stable surface-active agents for combatting marine oil spills.

PubMed

Raddadi, Noura; Giacomucci, Lucia; Totaro, Grazia; Fava, Fabio

2017-11-02

The application of chemical dispersants as a response to marine oil spills is raising concerns related to their potential toxicity also towards microbes involved in oil biodegradation. Hence, oil spills occurring under marine environments necessitate the application of biodispersants that are highly active, stable and effective under marine environment context. Biosurfactants from marine bacteria could be good candidates for the development of biodispersant formulations effective in marine environment. This study aimed at establishing a collection of marine bacteria able to produce surface-active compounds and evaluating the activity and stability of the produced compounds under conditions mimicking those found under marine environment context. A total of 43 different isolates were obtained from harbor sediments. Twenty-six of them produced mainly bioemulsifiers when glucose was used as carbon source and 16 were biosurfactant/bioemulsifiers producers after growth in the presence of soybean oil. Sequencing of 16S rRNA gene classified most isolates into the genus Marinobacter. The produced emulsions were shown to be stable up to 30 months monitoring period, in the presence of 300 g/l NaCl, at 4 °C and after high temperature treatment (120 °C for 20 min). The partially purified compounds obtained after growth on soybean oil-based media exhibited low toxicity towards V. fischeri and high capability to disperse crude oil on synthetic marine water. To the best of our knowledge, stability characterization of bioemulsifiers/biosurfactants from the non-pathogenic marine bacterium Marinobacter has not been previously reported. The produced compounds were shown to have potential for different applications including the environmental sector. Indeed, their high stability in the presence of high salt concentration and low temperature, conditions characterizing the marine environment, the capability to disperse crude oil and the low ecotoxicity makes them interesting for the development of biodispersants to be used in combatting marine oil spills.

Identification of Inhibitors in Lignocellulosic Slurries and Determination of Their Effect on Hydrocarbon-Producing Microorganisms

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

Yang, Shihui; Franden, Mary A; Yang, Qing

The aim of this work was to identify inhibitors in pretreated lignocellulosic slurries, evaluate high-throughput screening strategies, and investigate the impact of inhibitors on potential hydrocarbon-producing microorganisms. Compounds present in slurries that could inhibit microbial growth were identified through a detailed analysis of saccharified slurries by applying a combination of approaches of high-performance liquid chromatography, GC-MS, LC-DAD-MS, and ICP-MS. Several high-throughput assays were then evaluated to generate toxicity profiles. Our results demonstrated that Bioscreen C was useful for analyzing bacterial toxicity but not for yeast. AlamarBlue reduction assay can be a useful high-throughput assay for both bacterial and yeast strainsmore » as long as medium components do not interfere with fluorescence measurements. In addition, this work identified two major inhibitors (furfural and ammonium acetate) for three potential hydrocarbon-producing bacterial species that include Escherichia coli, Cupriavidus necator, and Rhodococcus opacus PD630, which are also the primary inhibitors for ethanologens. Here, this study was strived to establish a pipeline to quantify inhibitory compounds in biomass slurries and high-throughput approaches to investigate the effect of inhibitors on microbial biocatalysts, which can be applied for various biomass slurries or hydrolyzates generated through different pretreatment and enzymatic hydrolysis processes or different microbial candidates.« less

Identification of Inhibitors in Lignocellulosic Slurries and Determination of Their Effect on Hydrocarbon-Producing Microorganisms

DOE PAGES

Yang, Shihui; Franden, Mary A; Yang, Qing; ...

2018-04-04

The aim of this work was to identify inhibitors in pretreated lignocellulosic slurries, evaluate high-throughput screening strategies, and investigate the impact of inhibitors on potential hydrocarbon-producing microorganisms. Compounds present in slurries that could inhibit microbial growth were identified through a detailed analysis of saccharified slurries by applying a combination of approaches of high-performance liquid chromatography, GC-MS, LC-DAD-MS, and ICP-MS. Several high-throughput assays were then evaluated to generate toxicity profiles. Our results demonstrated that Bioscreen C was useful for analyzing bacterial toxicity but not for yeast. AlamarBlue reduction assay can be a useful high-throughput assay for both bacterial and yeast strainsmore » as long as medium components do not interfere with fluorescence measurements. In addition, this work identified two major inhibitors (furfural and ammonium acetate) for three potential hydrocarbon-producing bacterial species that include Escherichia coli, Cupriavidus necator, and Rhodococcus opacus PD630, which are also the primary inhibitors for ethanologens. Here, this study was strived to establish a pipeline to quantify inhibitory compounds in biomass slurries and high-throughput approaches to investigate the effect of inhibitors on microbial biocatalysts, which can be applied for various biomass slurries or hydrolyzates generated through different pretreatment and enzymatic hydrolysis processes or different microbial candidates.« less

Zebrafish: A Model for the Study of Toxicants Affecting Muscle Development and Function

PubMed Central

Dubińska-Magiera, Magda; Daczewska, Małgorzata; Lewicka, Anna; Migocka-Patrzałek, Marta; Niedbalska-Tarnowska, Joanna; Jagla, Krzysztof

2016-01-01

The rapid progress in medicine, agriculture, and allied sciences has enabled the development of a large amount of potentially useful bioactive compounds, such as drugs and pesticides. However, there is another side of this phenomenon, which includes side effects and environmental pollution. To avoid or minimize the uncontrollable consequences of using the newly developed compounds, researchers seek a quick and effective means of their evaluation. In achieving this goal, the zebrafish (Danio rerio) has proven to be a highly useful tool, mostly because of its fast growth and development, as well as the ability to absorb the molecules diluted in water through its skin and gills. In this review, we focus on the reports concerning the application of zebrafish as a model for assessing the impact of toxicants on skeletal muscles, which share many structural and functional similarities among vertebrates, including zebrafish and humans. PMID:27869769

Selenium toxicity in plants and its detoxification by phosphorus

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

Singh, M.; Singh, N.

1978-11-01

A study was undertaken to determine selenium toxicity and the effect of phosphorus application on selenium in wheat (Triticum aestivum). Selenium in a compound was applied at 0, 2.5, 5, and 10 ppm to wheat in a greenhouse using sandy soil. Phosphorus in a compound was applied at 0, 50, and 100 ppm to the experimental plants. Sunflower (Helianthus annuus) was grown after wheat to determine the residual effect of selenium and phosphorus. Results indicated that high amounts (2.5 ppm and above) of added and residual selenium in soil decreased the growth of wheat and sunflower, decreased the absorption ofmore » zinc, copper, iron, manganese, sulfur, and nitrogen, and decreased the synthesis of nucleic acids, chlorophyll, and protein. The application of phosphorus decreased the harmful effects of selenium and increased all the above parameters. (3 graphs, 21 references, 4 tables)« less

Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets

PubMed Central

Pratheeshkumar, Poyil; Sreekala, Chakkenchath; Zhang, Zhuo; Budhraja, Amit; Ding, Songze; Son, Young-Ok; Wang, Xin; Hitron, Andrew; Hyun-Jung, Kim; Wang, Lei; Lee, Jeong-Chae; Shi, Xianglin

2016-01-01

Cancer is the second leading cause of death worldwide. There is greater need for more effective and less toxic therapeutic and preventive strategies. Natural products are becoming an important research area for novel and bioactive molecules for drug discovery. Phytochemicals and dietary compounds have been used for the treatment of cancer throughout history due to their safety, low toxicity, and general availability. Many active phytochemicals are in human clinical trials. Studies have indicated that daily consumption of dietary phytochemicals have cancer protective effects against carcinogens. They can inhibit, delay, or reverse carcinogenesis by inducing detoxifying and antioxidant enzymes systems, regulating inflammatory and proliferative signaling pathways, and inducing cell cycle arrest and apoptosis. Epidemiological studies have also revealed that high dietary intakes of fruits and vegetables reduce the risk of cancer. This review discusses potential natural cancer preventive compounds, their molecular targets, and their mechanisms of actions. PMID:22583402