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H M Bolt

Publications and source records attributed to H M Bolt.

At least 145 records · Page 8Linked to original sources
PubMed1986

Detection of 2,5-hexanedione in the urine of persons not exposed to n-hexane.

The neurotoxic n-hexane metabolite 2,5-hexanedione was detected by gas chromatography--mass spectrometry in urine samples from human subjects not exposed to n-hexane or related hydrocarbons. Quantitative determinations by multiple ion detection revealed an amount of 2,5-hexanedione ranging from 0.12 to 0.78 mg/l (0.45 +/- 0.20 mg/l; means +/- SD). The amounts of 2,5-hexanedione actually measured in urinary extracts depended on the pH employed for acid hydrolysis of the samples.

Adult↗
PubMed1986

Methodological investigations on the determination of n-hexane metabolites in urine.

Male Wistar rats were exposed to 1000 ppm n-hexane, and the excreted urinary metabolites were analyzed by capillary gas chromatography-mass spectrometry (GC-MS). 1-Hexanol, 2-hexanol, 3-hexanol, 2-hexanone, 2,5-hexanedione, 2,5-dimethyltetrahydrofuran, 2,5-dimethyl-2,3-dihydrofuran and gamma-valerolactone were identified by their retention times and their mass spectra. Quantitative gas chromatographic analyses were performed using an FID. Experiments on the hydrolysis of conjugated n-hexane metabolites revealed that enzymatic hydrolysis (in addition to acid hydrolysis) was not required, as treatment with HCl hydrolyzed conjugates sensitive to acid as well as conjugates sensitive to beta-glucuronidase. By incorporating acid hydrolysis only and by using C18-cartridges for sample extraction, a method was developed that allowed the determination of n-hexane metabolites with a sample preparation time of only 45 min. Assay precision was assessed by repeated analyses of the same urine sample. Coefficients of variation for the individual metabolites ranged from between 1.8 and 3.3.

Air Pollutants↗
PubMed1986

DNA adducts of halogenated hydrocarbons.

Although formation of DNA adducts has been postulated for several halomethanes, no chemical identification of such adducts has been performed so far. There is, however, evidence that methyl chloride does not act biologically as a DNA methylating agent. 1,2-Dichloroethane and 1,2-dibromoethane are activated through conjugation with glutathione. There is some evidence for formation on an N-7 adduct of guanine which carries an ethyl-S-cysteinyl moiety. Extensive work has been published on adducts of vinyl chloride, both in vitro and in vivo. The major DNA adduct is 7-(2-oxoethyl)guanine; a minor adduct appears to be N2,3-ethenoguanine. Other "etheno" adducts, i.e., 1,N6-ethenoadenine and 3,N4-ethenocytosine, are readily formed with DNA, vinyl chloride, and a metabolizing system in vitro and with RNA in vivo, but are usually not detected as DNA adducts in vivo. The data on DNA alkylation by vinyl chloride (and vinyl bromide) metabolites are compared with those of structurally related compounds (acrylonitrile, vinyl acetate, vinyl carbamate).

Alkylating Agents↗
PubMed1986

Alkylation of nuclear proteins and DNA after exposure of rats and mice to [1,4-14C]1,3-butadiene.

B6C3F1 mice and Wistar rats were exposed to [1,4-14C]1,3-butadiene in a closed exposure system. Based on body weight, mice metabolized the test compound at about twice the rate, compared to rats. Nucleoproteins and DNA were isolated from the livers of the animals and covalent binding of [14C]-butadiene-derived radioactivity was determined. In both species comparable amounts of radioactivity were covalently bound to liver DNA. Covalent binding to mouse-liver nucleoproteins was twice as high as in rats and thus it paralleled the higher metabolic rate for butadiene in this species.

Alkylation↗
PubMed1986

Vinyl acetate, a structural analog of vinyl carbamate, fails to induce enzyme-altered foci in rat liver.

The development of hepatic enzyme-altered foci (ATPase, GGTase) was investigated after dosing vinyl acetate (200 and 400 mg/kg per day, orally) to newborn rats for 3 weeks, with or without subsequent promotion by phenobarbital. Whereas the structurally related compounds vinyl carbamate and vinyl chloride induce enzyme-altered foci under comparable experimental conditions, no foci were observed in vinyl acetate-treated animals at the age of 14 weeks. This is consistent with investigations on metabolism and pharmacokinetics of vinyl acetate which show that this compound, after entering the organism, is immediately split by blood esterases and thus may not be available for epoxidation to an ultimately carcinogenic metabolite.

Adenosine Triphosphatases↗
PubMed1986

Disposition of a soluble chromate in the isolated perfused rat liver.

The uptake of potassium dichromate in the isolated perfused rat liver was almost complete after one hour of perfusion. No significant sex differences in chromium distribution were observed. At the end of the experiments (one hour), about 60% of the applied Cr(VI) dose (312 micrograms Cr/liver) was located in the cytosol, 14% was in the mitochondria, 9% in the microsomal pellet and 2% was associated with the nuclei. Gel chromatography of the cytosol showed that most of the chromium was in fractions with an apparent molecular weight of 6000 Da and absorption maxima at 410 nm and 548 nm. Similar optical properties and molecular weight are characteristic of GSH-Cr complexes formed by reaction of Cr(VI) with GSH in vitro.

Animals↗
PubMed1986

Metabolic activation of vinyl chloride, formation of nucleic acid adducts and relevance to carcinogenesis.

Comparative experiments with vinyl chloride and 2,2'-dichlorodiethyl ether confirm that chloroacetaldehyde, which is formed during metabolism of both compounds, binds covalently to proteins, but not to nucleic acids. The putative nucleic-acid-binding agent, chloroethylene oxide, is formed from vinyl chloride, not from 2,2'-dichlorodiethyl ether. The degree of potential carcinogenicity of epoxides formed from substituted ethylenes is considered to be determined by factors of stability/reactivity and by the rate of breakdown of epoxide and the rate of its formation. Hence, pharmacokinetic data are of considerable importance in assessing the comparative carcinogenic potencies of ethylene derivatives.

Animals↗
PubMed1985

Covalent interaction of reactive metabolites with cytosolic coenzyme A as mechanism of haloethylene-induced acetonemia.

Previous experiments have shown that a number of xenobiotics such as halogenated ethylenes cause an experimental acetonemia. In addition, under exposure of rats to vinylidene fluoride (one of the agents producing this effect), the urinary excretion rates of acetoacetate and 3-hydroxybutyrate are enhanced. The enhanced formation of ketone bodies is theoretically explained by a covalent interaction of reactive metabolites of the applied xenobiotic with hepatic cytosolic coenzyme A. This theory is further corroborated by the following experiments: Microsomal incubations of [14C]vinyl chloride and [3H]coenzyme A lead to one metabolite containing 2 moles vinyl chloride/mole coenzyme A and two other with equimolar ratios of both components. Exposure of rats to vinyl chloride leads to a progressive depletion of hepatic cytosolic CoASH, but not of CoASH in mitochondria. In the cytosol acetyl-CoA is also diminished after vinyl chloride exposure. These changes may cause secondary effects in lipid metabolism which are regarded as responsible for the enhancement of ketone bodies.

Acetoacetates↗
PubMed1985

The formation of glutathione-chromium complexes and their possible role in chromium disposition.

The reduction of Cr(VI) to Cr(III) by glutathione (GSH) in vitro resulted in the formation of two different GSH-chromium complexes with an approximate molecular-weight of 10,000 and 5000, respectively. Both complexes exhibited strong fluorescence. The molar ratio between oxidized glutathione (GSSG) and chromium was calculated by determining the chromium content of the two isolated complex species by flameless Atomic Absorption Spectrometry (AAS).

Chromates↗
PubMed1985

Fast uptake kinetics in vitro of 51Cr (VI) by red blood cells of man and rat.

Fast transport kinetics of 51Cr (VI) into red blood cells (RBCs) in vitro were studied. No significant species differences were found between RBCs of man and rat. The uptake of 51Cr (VI) by RBCs in whole blood was composed of two different first order processes of different velocities (apparent t 1/2 of 22.7 s and 10.4 min for man and 6.9 s and 10.1 min for rat, respectively). However, even after longer time periods a fixed portion of approximately 15% of the administered dose remained in the plasma and did not penetrate into RBCs Over the entire concentration range studied (10 microM-50 mM), the fast initial uptake followed Michaelis-Menten kinetics. The maximal capacity of this Cr(VI) transport into RBCs of man and rat was 3.1 X 10(8) CrO4(2-) ions X cell-1 X min-1 and 2.5 X 10(8) CrO4(-2) ions X cell-1 X min-1, respectively. It is likely that Cr(VI) is transported into RBCs via a physiological anion carrier ("band-3-protein").

Animals↗
PubMed1985

Metabolism and pharmacokinetics of vinyl acetate.

The hydrolysis of vinyl acetate (formation of acetic acid) has been studied in vitro with rat liver and lung microsomes, rat and human plasma and purified esterases (such as acetylcholine esterase, butyrylcholine esterase, carboxyl esterase). Characterization of the kinetic parameters revealed that rat liver microsomes and purified carboxyl esterase (from porcine liver) displayed the highest activity. In order to establish the rate of metabolism of vinyl acetate in vivo, rats were exposed in closed desiccator jar chambers, and gas uptake kinetics were studied. The decay of vinyl acetate was dose-dependent, indicating possible saturation of metabolic pathway(s). The maximal clearance (at lower concentrations) of vinyl acetate from the system (30 000 ml/h per kg body weight) was similar to the maximal ventilation rate in this species. This indicated that under conditions when metabolic enzymes are not saturated the metabolic rate is mainly determined by pulmonary uptake. The exposure of rats to vinyl acetate resulted in a transient exhalation of significant amounts of acetaldehyde into to the closed exposure system. This indicates the presence of this metabolic intermediate of vinyl acetate in the organism in vivo.

Animals↗
PubMed1985

DNA-binding assay of methyl chloride.

Fischer-344 rats and B6C3F1 mice of both sexes were exposed in closed chambers to 14C-labeled methyl chloride. Different clearance values from the gas phase of the system indicated that, based on body weight, mice metabolized the test compound much faster than rats. After isolation of DNA and nucleoproteins from liver and kidneys radioactivity was found in all macromolecular samples; this was ascribed to metabolic C1-incorporation. Radioactivity incorporation was particularly high in DNA of mouse kidneys, suggesting a high turnover to active C1 bodies (formaldehyde, formate) in this tissue. Analyses of DNA samples from kidneys of female and male mice showed neither 7-N-methylguanine nor O6-methylguanine. Hence, the formation of tumors in B6C3F1 mice exposed to high concentrations of methyl chloride is not based on methylation of DNA in this tissue.

Animals↗
PubMed1985

Effect of antidotes of the acute toxicity of methacrylonitrile.

When rats were exposed for 30 min to methacrylonitrile at concentrations between 3180 and 5700 ppm, the clinical symptoms observed suggested a toxic activity of metabolically formed cyanide. This is in contrast to the signs of toxicity observed in the same species after inhalation of acrylonitrile where metabolic cyanide formation plays only a minor role. The acute toxicity of methacrylonitrile could be antagonized with cyanide antidotes (4-dimethylaminophenol plus sodium thiosulfate) as well as with N-acetyl-cysteine which directly reacts with alpha,beta-unsaturated nitriles.

Acrylates↗
PubMed1985

Vinyl acetate: DNA-binding assay in vivo.

The question of carcinogenicity of vinyl acetate led us to perform a DNA binding assay in vivo in rats, using 14C-labelled vinyl acetate. After administration of [14C]vinyl acetate to male and female Fischer-344 rats, either orally or by inhalation, no specific hepatic DNA adducts, known to occur after administration of labelled vinyl halides or vinyl carbamates, could be detected in hepatic tissues.

Animals↗
PubMed1985

The rat liver foci bioassay: I. Age-dependence of induction by vinyl chloride of ATPase-deficient foci.

The age-dependence of the induction of pre-neoplastic enzyme-altered hepatic foci was investigated. Rats were exposed (8 h/day, 7 days/week) to 2000 p.p.m. vinyl chloride (VC) either 'transplacentally' (exposure of pregnant females), or immediately after birth for different time intervals (5, 11, 17, 47, 83 days) or from an age of 7 or 21 days onwards. The animals were then kept without further treatment; livers were evaluated for ATPase-deficient foci at the age of 4 months. 'Transplacental' exposure and exposure from day 1 through 5 caused no increase over controls in ATPase-deficient foci, probably due to the lack of hepatocellular proliferation and the low rate of VC metabolism at this developmental stage. However, foci area was steeply increased when newborn rats were exposed for 11 and 17 days; but this was not further enhanced by a 47- or 83-day exposure. Only a few ATPase-deficient foci occurred when exposure started 21 days after birth. Exposure of adult rats did not result in more ATPase-deficient foci than were seen in untreated controls; control values could not be increased by a preceding partial hepatectomy. The results indicate that the induction of pre-neoplastic hepatocellular lesions in rats by VC is restricted to a well defined period (approximately day 7-21) in the early lifetime of the animals. This period of highest sensitivity is characterized by the beginning of rapid liver growth.

Adenosine Triphosphatases↗
PubMed1985

The rat liver foci bioassay: II. Investigations on the dose-dependent induction of ATPase-deficient foci by vinyl chloride at very low doses.

In order to study the dose-dependence of the genotoxic effect of vinyl chloride (VC) hepatocellular ATPase-deficient foci were evaluated after subchronic exposure of newborn rats. Wistar rats were exposed from day 1 after birth over 10 weeks to 10, 40, 70, 150, 500 and 2000 p.p.m. VC (8 h/day; 5 days/week). One week after cessation of exposure hepatic ATPase-deficient foci were quantitated. For a subsequent investigation lower dose range groups of female and male Wistar and Sprague-Dawley rats were exposed (8 h/day; 5 days/week) to 2.5, 5, 10, 20, 40 and 80 p.p.m. VC. Exposure started at day 3 of life and lasted for 3 weeks. After cessation of exposure the animals were maintained for 10 weeks without further treatment until ATPase-deficient foci were quantitated. Both sets of experiments revealed a straight linear relationship between the dose of VC and the % foci area induced. Within the dose range investigated, no obvious threshold for the induction of pre-neoplastic foci by VC was observed.

Adenosine Triphosphatases↗
PubMed1984

Inhalation pharmacokinetics based on gas uptake studies. V. Comparative pharmacokinetics of ethylene and 1,3-butadiene in rats.

The pharmacokinetics of ethylene and 1,3-butadiene were studied in male Sprague-Dawley rats by use of a closed inhalation chamber system. Both compounds showed saturable metabolism when untreated rats were used. "Linear" pharmacokinetics applied at exposure concentrations below 800 ppm ethylene and below 1,000 ppm 1,3-butadiene. A constant elimination rate, indicative of metabolic saturation, occurred at concentrations higher than 1,000 ppm ethylene or 1,500 ppm 1,3-butadiene. Pretreatment with aroclor 1254 (polychlorinated biphenyls) increased Vmax for both compounds. For 1,3-butadiene, no saturation of metabolic capacity was observed with exposure concentrations up to 12,000 ppm when the rats were pretreated with aroclor 1254. A comparison with previous studies on ethane and n-pentane suggested that introduction of a double bond into a saturated aliphatic hydrocarbon increased the rate of metabolism under conditions in vivo.

Animals↗