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PubMed1993

Examination of the structure-toxicity relationships of L-cysteine-S-conjugates of halogenated alkenes and their corresponding mercapturic acids in rat renal tissue slices.

Rat kidney slices were produced using a modified version of a mechanical tissue slicer. The slices were incubated with various concentrations of L-cysteine conjugates and mercapturic acids of halogenated alkenes in a submersion incubation system. The slices showed a time- and concentration-dependent toxicity to the nephrotoxic conjugates. The five L-cysteine conjugates tested: S-(1,2-dichlorovinyl)-L-cysteine (1,2-DCVC), S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), S-(1-chloro-1,2,2-trifluoroethyl)-L-cysteine (CTFEC), S-(1,1-dichloro-2,2-difluoroethyl)-L-cysteine (DCDFEC) and S-(1,1-dibromo-2,2-difluoroethyl)-L-cysteine (DBDFEC) were more toxic compared to the corresponding mercapturic acids. Comparing the in vitro toxicity data with the in vivo data for the same compounds results in similar ranking for the relative nephrotoxicity of the conjugates.

Acetylcysteine↗
PubMed1995

Halogenated aromatic hydrocarbon-induced suppression of the plaque-forming cell response in B6C3F1 splenocytes cultured with allogenic mouse serum: Ah receptor structure activity relationships.

The immunosuppressive effects of halogenated aromatic hydrocarbons (HAHs) were investigated in B6C3F1 female mice and in mouse splenocytes cultured with allogenic mouse serum using the Mishell-Dutton model for in vitro immunization to trinitrophenyl-lipopolysaccharide (TNP-LPS). Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 1,2,3,7,8-PeCDF, 1,3,6,8-tetrachlorodibenzofuran (TCDF), 3,3',4,4',5-pentachlorobiphenyl (pentaCB), or 3,3',4,4',5,5'-hexaCB resulted in a dose-dependent suppression of the splenic plaque-forming cell (PFC) response both in vivo and in vitro. The effective dose required to decrease 50% (ED50) of the response to 2,3,7,8-TCDD, 2,3,4,7,8-PeCDF, 1,2,3,7,8-PeCDF, 1,3,6,8-TCDF, 3,3',4,4',5-pentaCB, or 3,3',4,4',5,5'-hexaCB in vivo was 14.1, 5.5, 1695, 34,800, 21, and 19 nmol/kg, respectively, and in vitro was 7.0, 10.6, 149, 2325, 9.1 and 9.1 nM, respectively. There was an excellent rank order and linear correlation between the in vivo versus in vitro activities for these HAHs (r < 0.99) and the relative immunosuppressive potencies of these compounds paralleled their binding affinities for the aryl hydrocarbon (Ah) receptor. These results show that splenocytes cultured with allogenic mouse serum is an Ah-responsive in vitro assay which can be used for quantitating the immunosuppressive effects of HAHs.

Analysis of Variance↗
PubMed1978

Chemical structure and biodegradability of halogenate aromatic compounds. Substituent effects on 1,2-dioxygenation of benzoic acid.

Dioxygenation of substituted benzoic acids by whole cells of 3-chlorobenzoate-utilizing Pseudomonas sp. B 13, benzoate-induced cells of Alcaligenes eutrophus B 9 and toluate-grown cells of Pseudomonas putida mt-2 was examined. Electron-attracting substituents like halogen decreased the reaction rates of benzoate 1,2-dioxygenation. Dioxygenation of substituted benzoic acids by P. putida mt-2 was mostly undisturbed by steric effects of the substituents. Good correlation resulted between the log Vrel values and the Hammett substituent constant sigma. In contrast the reaction rates of dioxygenation by Pseudomonas sp. B 13 and A. eutrophus were decreased predominantly by steric effects of substituents. A non-polar reaction mechanism of benzoate 1,2-dioxygenation is discussed. Results from inhibition studies demonstrate high stereospecificities for the 1,2-dioxygenation by Pseudomonas sp. B 13 of benzoic acids with substituents in ortho- or para-position. In the case of P. putida mt-2 steric handrance by substituents was observed only with orth-substituted benzoic acids. Stereospecificities of the benzoate 1,2-dioxygenation by Pseudomonas sp. B 13 and P. putida mt-2 are illustrated schematically.

Bacteria↗
PubMed1988

Modeling the tissue solubilities and metabolic rate constant (Vmax) of halogenated methanes, ethanes, and ethylenes.

Experimental solvent:air and tissue:air partition coefficients for 25 halogenated methanes, ethanes, and ethylenes in saline solution; olive oil; and rat blood, muscle, liver, and fat tissues have been examined using theoretical molecular modeling techniques. The metabolic rate constant, Vmax, was also investigated by these techniques for 19 chlorinated compounds in this group. Two graph theoretical approaches (the distance method of Wiener and the connectivity index method of Randic, Kier, and Hall) and an approach utilizing ad hoc molecular descriptors were employed. Satisfactory regression models for solubility were obtained with both the Randic-Kier-Hall approach and the ad hoc descriptors approach. Fluorine substituents decrease tissue solubilities, whereas both clorine and bromine substituents increase tissue solubilities, with the relative influence being Cl less than Br. Tissue solubilities can also be represented conveniently in terms of contributions from oil and saline solubilities, a procedure reinforced by factor analysis of the data. Equations derived by these methods adequately estimated the solubilities for eight additional compounds. No approach could successfully model Vmax for all 19 compounds, but a subset of 16 compounds was modeled using the connectivity indices. The equation is limited in its use but indicated future modeling directions for Vmax.

Adipose Tissue↗
PubMed1995

Metabolic transformation of halogenated and other alkenes--a theoretical approach. Estimation of metabolic reactivities for in vivo conditions.

Olefinic hydrocarbons are metabolized in vivo by cytochrome P450-dependent monooxygenases to the corresponding epoxides. The maximum in vivo metabolic rate, which is an important toxicokinetic parameter, has been used to define the apparent rate constant (kapp) describing in vivo metabolic reactivity of alkenes. To derive kapp, the metabolic rate normalized per body weight was divided by the corresponding average alkene concentration in the body at saturation conditions of 90%. Toxicokinetic data obtained in rats for 13 compounds (ethene, 1-fluoroethene, 1,1-difluoroethene, 1-chloroethene, 1,1-dichloroethene, cis-1,2-dichloroethene, trans-1,2-dichloroethene, 1,1,2-trichloroethene, perchloroethene, propene, isoprene, 1,3-butadiene and styrene) have been used to calculate kapp values. A theoretical model, based on the assumption that in vivo epoxidation can be described as a cytochrome P450-mediated electrophilic reaction, has been developed. Using the olefinic hydrocarbons as an example it has been shown that kapp can be explained solely by the following molecular parameters: ionization potential, dipole moment and pi-electron density. These molecular parameters were calculated by a quantum chemical method or were taken from the literature. Furthermore, the model was tested also by predicting kapp for isobutene, an alkene which was not used for the model development. The predicted value of kapp agrees with the one derived experimentally, demonstrating that molecular parameters of halogenated and other alkenes can be used to predict in vivo metabolic reactivity. The model presented here is a first contribution to the ultimate goal to predict toxicokinetic parameters for in vivo conditions based on physicochemical parameters of enzymes and compounds exclusively.

Alkenes↗
PubMed1994

Structure-metabolism relationships of ring-A halogenated analogues of 17 alpha-ethynyloestradiol.

The metabolic fates of 2-chloro-, 2-bromo-, 4-bromo- and 2-iodo-17 alpha-ethynyloestradiol (EE2) in rats were determined. 6,7-3H-labelled analogues (0.1-2.0 mumol/kg) were administered i.v. to anaesthetized animals. The metabolites of all four compounds were rapidly and extensively excreted in bile (79-93% of the dose over 6 h). Unlike EE2 and 2-fluoro-EE2 (2-FEE2), neither 2-chloro(Cl)-(2.0 mumol/kg),2-bromo(Br)-(0.1 mumol/kg), nor 2-iodo(I)-EE2-(0.1 mumol/kg) underwent C-2 hydroxylation in female rats; 2-BrEE2 was similarly refractory in male rats; females, was subject to approx. 2-fold greater C-2 hydroxylation than 2-FEE2 but this equalled only approx. 60% of that undergone by EE2. All three of the C-2 halogenated derivatives were substantially excreted unchanged except for conjugation. 2-ClEE2 alone was C-4 hydroxylated to an appreciable extent. The oxidative metabolism of 2- and 4-BrEE2 in rats was sexually differentiated: 2-BrEE2 yielded an alkyl hydroxylated metabolite and a two-component dihydroxylated fraction in the ratio 1:0.09 and 1:0.76 in males and females, respectively; 4-BrEE2 underwent C-2 and alicyclic (C-15) hydroxylation in the ratio 1:4.8 and 1:0.07 in males and females, respectively. 2-ClEE2 formed much less alkyl monohydroxylated metabolite (C-16 hydroxylated for 2-Cl- and 2-IEE2) than did either 2-BrEE2 or 2-IEE2. The observed structure-metabolism relationships are discussed.

Animals↗
PubMed2006

Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death.

We have previously identified the naturally occurring non-toxic antitussive phthalideisoquinoline alkaloid, noscapine as a tubulin-binding agent that arrests mitosis and induces apoptosis. Here we present high-yield efficient synthetic methods and an evaluation of anticancer activity of halogenated noscapine analogs. Our results show that all analogs display higher tubulin-binding activity than noscapine and inhibit proliferation of human cancer cells (MCF-7, MDA-MB-231 and CEM). Surprisingly, the bromo-analog is approximately 40-fold more potent than noscapine in inhibiting cellular proliferation of MCF-7 cells. The ability of these analogs to inhibit cellular proliferation is mediated by cell cycle arrest at the G2/M phase, in that all analogs except 9-iodonoscapine, caused selective mitotic arrest with a higher efficiency than noscapine followed by apoptotic cell death as shown by immunofluorescence and quantitative FACS analyses. Furthermore, our results reveal the appearance of numerous fragmented nuclei as evidenced by DAPI staining. Thus, our data indicate a great potential of these compounds for studying microtubule-mediated processes and as chemotherapeutic agents for the management of human cancers.

Antineoplastic Agents↗
PubMed2006

Synthesis and receptor binding studies of halogenated N,N-dialkylel-(2-phenyl-1H-indol-3-yl)glyoxylamides to visualize peripheral benzodiazepine receptors with SPECT or PET.

A library of halogenated 2-arylindolyl-3-oxocarboxamides was prepared to develop radioligands to visualize cerebral PBR by SPECT and PET imaging. In vitro evaluation showed that most of the synthesized compounds were selective,high-affinity PBR ligands with adequate lipophilicity (log D7.4 in the range of 1.6-2.4). The iodinated derivative 11 (Ki = 2.6 nM) and the fluorinated analog 26 (Ki = 6.2 nM) displayed higher affinity than reference compounds.

Alkylation↗
PubMed2006

Genotoxic activity of halogenated phenylglycine derivatives.

The discovery of genotoxic amino acids derived from phenylglycine, and possessing halogen substituents, is described. The utility of hypervalent iodine reagents in the synthesis of this class of compounds is highlighted. The mechanism of action of the (haloaryl)glycines was studied in Saccharomyces cerevisiae.

Benzamidines↗
PubMed2004

Aqueous solubility, Henry's law constants and air/water partition coefficients of n-octane and two halogenated octanes.

New data on the aqueous solubility of n-octane, 1-chlorooctane and 1-bromooctane are reported between 1 degree C and 45 degrees C. Henry's law constants, K(H), and air/water partition coefficients, K(AW), were calculated by associating the measured solubility values to vapor pressures taken from literature. The mole fraction aqueous solubility varies between (1.13-1.60)x10(-7) for n-octane with a minimum at approximately 23 degrees C, (3.99-5.07)x10(-7) for 1-chlorooctane increasing monotonically with temperature and (1.60-3.44)x10(-7) for 1-bromooctane with a minimum near 18 degrees C. The calculated air-water partition coefficients increase with temperature and are two orders of magnitude lower for the halogenated derivatives compared to octane. The precision of the results, taken as the average absolute deviations of the aqueous solubility, the Henry's law constants, or the air/water partition coefficients, from appropriate smoothing equations as a function of temperature is of 3% for n-octane and of 2% and 4% for 1-chlorooctane and 1-bromooctane, respectively. A new apparatus based on the dynamic saturation column method was used for the solubility measurements. Test measurements with n-octane indicated the capability of measuring solubilities between 10(-6) and 10(-10) in mole fraction, with an estimated accuracy better than +/-10%. A thorough thermodynamic analysis of converting measured data to air/water partition coefficients is presented.

Hydrocarbons, Halogenated↗
PubMed2006

Toxicity of three halogenated flame retardants to nitrifying bacteria, red clover (Trifolium pratense), and a soil invertebrate (Enchytraeus crypticus).

Halogenated flame retardants have a high sorption affinity to particles, making soils and sediments important sinks. Here, three of the most commonly used flame retardants have been tested for sub-lethal toxicity towards soil nitrifying bacteria, a terrestrial plant (seed emergence and growth of the red clover, Trifolium pratense), and a soil invertebrate (survival and reproduction of Enchytraeus crypticus). Tetrabromobisphenol A (TBBPA) was quite toxic to enchytraeids, with significant effects on reproduction detected already at the 10 mgkg(-1) exposure level (EC(10)=2.7 mgkg(-1)). In contrast, decabromodiphenyl ether (DeBDE) was not toxic at all, and short-chain chloroparaffins (CP(10-13)) only affected soil nitrifying bacteria at the highest test concentration (EC(10)=570 mgkg(-1)). Exposure concentrations were verified by chemical analysis for TBBPA and DeBDE, but not for CP(10-13), as a reliable method was not available. Based on the generated data, a PNEC for soil organisms can be estimated at 0.3 mgkg(-1) for TBBPA and 57 mgkg(-1) for short-chain chloroparaffins. No PNEC could be estimated for DeBDE. Measurements of TBBPA in soil are not available, but measured concentrations in Swedish sludge are all lower than the estimated threshold value for biological effects in soil.

Animals↗
PubMed2006

Bioremediation of halogenated compounds: comparison of dehalogenating bacteria and improvement of catalyst stability.

Five bacterial strains were compared for halogenated compounds conversion in aqueous media. Depending on the strain, the optimal temperature for dehalogenase activity of resting cells varied from 30 to 45 degrees C, while optimal pH raised from 8.4 to 9.0. The most effective dehalogenase activity for 1-chlorobutane conversion was detected with Rhodococcus erythropolis NCIMB13064 and Escherichia coli BL21 (DE3) (DhaA). The presence of 2-chlorobutane or propanal in the aqueous media could inhibit the 1-chlorobutane transformation.

Biodegradation, Environmental↗
PubMed2003

Qualitative evaluation of thermal desorption-programmable temperature vaporization-comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry for the analysis of selected halogenated contaminants.

The separation of 38 toxic and predominant polychlorinated biphenyl (PCB) congeners, 11 persistent halogenated pesticides, 1 brominated biphenyl (BB), and 8 polybrominated diphenyl ethers (PBDEs) has been optimized using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC x GC-TOFMS). A thermal desorption-programmable temperature vaporization (TD-PTV) step was used for the injection. Different column sets were investigated, and a 100% dimethylpolysiloxane (15 m x 0.25 mm i.d. x 0.25 microm film thickness) narrowbore capillary column coupled to a high temperature (8% phenyl)-polycarborane-siloxane (2 m x 0.10 mm i.d. x 0.10 microm film thickness) microbore column set was selected. Of the 58 compounds investigated, only one pair of PCBs was not resolved. All other analytes were either baseline separated into the chromatographic plane or were virtually separated using the deconvolution capability of the TOFMS.

Gas Chromatography-Mass Spectrometry↗
PubMed2006

Development of a purge and trap continuous flow system for the stable carbon isotope analysis of volatile halogenated organic compounds in water.

A purge and trap (P&T) continuous flow system was developed in order to concentrate high volumes of water for trace analyses and stable carbon isotope measurements of volatile halogenated organic compounds (VHOCs) in seawater. The P&T parameters were evaluated regarding quality parameters, extraction efficiency and isotope fractionation. Precision (about 20%), linearity (>0.9676), and recoveries (between 75% and 99%) were reasonable within the large concentration range tested. Isotope fractionation was between 1 per thousand and 3 per thousand. Finally, the developed system was successfully applied to the quantitative and stable carbon isotope analysis of three water samples of different origin.

Carbon Isotopes↗
PubMed2006

A method for measuring semi- and non-volatile organic halogens by combustion ion chromatography.

Recent studies have shown that various semi- and non-volatile organohalogen compounds are ubiquitous in the environment: these include halogenated dioxins including chlorinated dioxins, other persistent organic pollutants (POPs), brominated flame retardants (BFRs), and perfluorooctane sulfonate (PFOS). However, monitoring and assessment of these compounds by the analyses of individual compounds and their isomers is onerous because of their low environmental concentrations and large number of compounds. In this study, we have developed a new method that is capable of screening and monitoring an array of organohalogen compounds efficiently by combustion ion chromatography (CIC) - the new analyzer that serially connects combustion furnace and ion chromatograph. Analyzer performance was evaluated in terms of its applicability, reproducibility, and sensitivity as limit of detection (LOD). Recoveries of organochlorine, organobromine, and organoiodine compounds by the CIC were between 97 and 105%; those of organofluorine compounds were from 86 to 91%. In all cases, the relative standard deviation of five analyses was 4% or smaller. The analyzer would exhibit good sensitivity for various environmental matrices (e.g., 2.8-31ng-X/g-soil, 1.4-16ng-X/L-water, and 9.2-100ng-X/m3N-gas). The method is fast and can provide information regarding the occurrence of organohalogen compounds within 1 or 2 days after sampling. Applicability of the new method for the assessment of contamination in flue gas and fly ash was also demonstrated. Our results show that the method is efficient to investigate emission sources and areas contaminated by organohalogen compounds.

Chromatography↗
PubMed2004

Screening of halogenated aromatic compounds in some raw material lots for an aluminium recycling plant.

Four samples of scrap raw materials for an aluminium recycling plant were screened for the occurrence of persistent halogenated aromatic compounds. The samples contained waste from handling of electric and electronic plastics, filter dust from electronic crusher, cyclone dust from electronic crusher and light fluff from car shredder. In our screening analyses, brominated flame retardants were observed in all samples. Polybrominated diphenyl ethers (PBDE) were identified in all samples in amounts of 245-67450 ng/g. The major PBDE congeners found were decabromo- and pentabromodiphenyl ethers. 1,1-bis(2,4,6-tribromophenoxy)ethane, hexabromobenzene, ethyl-pentabromobenzene, tetrabromobisphenol-A, pentabromotoluene and dimethyl tetrabromobenzene were observed in all scrap samples. The concentrations of PCBs, PCNs (polychlorinated naphthalenes) and nona- to undecachlorinated terphenyls in some of these scrap samples were remarkably high.

Aluminum↗
PubMed2006

Halogenated organic contaminants and mercury in northern fulmars (Fulmarus glacialis): levels, relationships to dietary descriptors and blood to liver comparison.

The northern fulmar (Fulmarus glacialis) is an interesting candidate for the study of patterns and levels of halogenated organic contaminants (HOCs) since they accumulate high levels of certain HOCs. In the present study we characterized a suite of established and novel HOCs in northern fulmars breeding on Bjørnøya in the Norwegian Arctic. A comparison between blood and liver HOC levels was made, and the levels were related to the ratios of heavier to lighter stable isotopes of nitrogen (15)N/(14)N (delta(15)N) and carbon (13)C/(12)C (delta(13)C) in muscle. A significant difference in congener patterns between blood and liver was found. The delta(13)C was not related to HOCs, neither in liver nor in blood. Weak correlations were found between delta(15)N and liver HOC levels. The 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents (TEQs) in northern fulmars were well above thresholds for reproductive effects in seabirds.

Animals↗