PubMed Health⌕ Search

Biomedical subjects

H M Bolt

Publications and source records attributed to H M Bolt.

At least 91 records · Page 5Linked to original sources
PubMed1994

Macromolecular adducts in the use of methyl bromide as fumigant.

An HPLC method for analysis of blood protein adducts of methyl bromide was developed. With this method, the alkylated amino acid S-methylcysteine can be quantified both in globin and in serum albumin. The determination of these adducts was implemented in a field study on fumigators who use methyl bromide for the control of insects, nematodes and fungi. Sister chromatid exchange (SCE) was determined in the lymphocytes of the fumigators as an additional biomonitoring parameter. Exposure of persons living in the vicinity of fumigated objects to methyl bromide has been repeatedly reported in the past. The new method for determination of blood protein adducts can be applied for evaluation of such environmental exposure.

Blood Proteins↗
PubMed1994

Interactions between clinically used drugs and oral contraceptives.

Metabolism of contraceptive compounds may be influenced by various drugs. Of clinical importance is induction by barbiturates, by diphenylhydantoin, and especially by rifampicin, of enzymes that are responsible for degradation of estrogens. The major target is the hepatic microsomal estrogen-2-hydroxylase (cytochrome P450 3A4). Another type of interaction of drugs with disposition and effectiveness of estrogens is impairment of their enterohepatic circulation. This may be due to absorption of biliary estrogen conjugates (e.g., by cholestyramine) or to insufficient cleavage of the conjugate by intestinal bacteria, the latter being observed after administration of antibiotics (e.g., ampicillin, neomycin).

Animals↗
PubMed1994

A note on distribution of human plasma levels of ascorbic and dehydroascorbic acid.

Ascorbic acid concentrations in 102 human plasma samples ranged from 1 to 15 micrograms ml-1 with a mean concentration at about 8 micrograms ml-1, corresponding to the results of other authors. Dehydroascorbic acid was found only in traces, independent of ascorbic acid concentrations. The ascorbic acid concentrations in plasma of four persons, examined twice with a four-years interim period revealed no obvious differences over time. It is suggested that the variability of plasma ascorbic acid concentrations is mainly determined by long-term dietary habits.

Ascorbic Acid↗
PubMed1993

Polymorphism of glutathione conjugation of methyl bromide, ethylene oxide and dichloromethane in human blood: influence on the induction of sister chromatid exchanges (SCE) in lymphocytes.

A hitherto unknown glutathione-S-transferase in human erythrocytes displays polymorphism: three quarters of the population ("conjugators") possess, whereas one quarter ("non-conjugators") lack this specific activity. A standard method for the identification of conjugators and non-conjugators with the use of methyl bromide and gas chromatography (head space technique) is described. Three substrates of the polymorphic enzyme, methyl bromide, ethylene oxide and dichloromethane (methylene chloride), were incubated in vitro with individual whole blood samples of conjugators and non-conjugators. All three substances led to a marked increase of sister chromatid exchanges (SCE) in the lymphocytes of the non-conjugators but not in those of conjugators. A protective effect of the glutathione-S-transferase activity in human erythrocytes for the cytogenetic toxicity of these chemicals in vitro is thus confirmed. Since the enzyme activity is not found in erythrocytes of laboratory animals, species extrapolations for risk assessment of methyl bromide, ethylene oxide and dichloromethane should be reconsidered.

Erythrocytes↗
PubMed1993

Evaluation of DNA damage by alkaline elution technique after inhalation exposure of rats and mice to 1,3-butadiene.

The alkaline filter elution technique was used to evaluate single strand breaks (SSB), DNA-DNA (DDCL) and DNA-protein cross-links (DPCL) in liver and lung of male rats (Sprague-Dawley) and male mice (B6C3F1) after exposure to 2000 ppm 1,3-butadiene (BD) for 7 days (7 h/day and/or to 100, 250, 500, 1000) 2000 ppm BD for 7 h. SSB were detected in liver DNA of both species at 2000 ppm. Cross-links are more pronounced in mouse lung than in mouse liver. Elution rates of lung DNA from mice exposed for 7 h to different concentrations of BD revealed an increase in cross-links between 250 and 500 ppm, and a further increase in cross-links up to 2000 ppm. No such signs of genotoxicity could be observed for the lung of rats. Our data support the involvement of reactive metabolites (epoxybutene and especially diepoxybutane) in butadiene-induced carcinogenesis in the mouse but not to that extent in the rat.

Animals↗
PubMed1993

[DNA methylation of monohalogenated methanes of F344 rats].

Monohalogenated methanes (methyl chloride, methyl bromide and methyl iodide) are mutagenic and carcinogenic. The possible mechanism of these effects, DNA methylation, was studied. DNA adducts from organs of F344 rats exposed to these chemicals were separated and identified with high performance liquid chromatography (HPLC) and gas-chromatography/mass-spectrometry (GC/MS). DNA adducts, 7-methylguanine (7-MeG) and O6-Methylguanine(0(6)-MeG), incorporation of 14C into de novo synthesis of nucleobases could be observed in enzymatic DNA hydrolysates by HPLC and determination of the radioactivity in the fractions. The formation of DNA adducts in the studied organs was only quantitatively different. The formation of O6-MeG was further proved by analysing the acidic hydrolysates using HPLC with non-radioactive O6-MeG as internal standard. 7-MeG and 3-MeA were identified with GC/MS analysis.

Animals↗
PubMed1993

Mechanisms of carcinogenicity of methyl halides.

Methyl chloride, bromide, and iodide are used as methylating agents. These compounds are mutagenic in short-term tests and do not require activation by exogenous S9 mix. In DNA-binding studies performed in rats and mice, 14C-labeled methyl chloride was given by inhalation, and methylation of DNA bases was examined. The compound did not lead to specific DNA adducts. In particular, methylation of DNA bases was not observed. In contrast, methyl bromide and methyl iodide, upon oral and inhalation administration to rats and mice, caused systemic DNA methylation. Specifically, 3-methyl-adenine, 7-methyl-guanine, and O6-methyl-guanine were formed. Long-term inhalation bioassays have been performed in rats and mice with methyl chloride and methyl bromide. Methyl chloride induced renal tumors, but only in male mice at the highest concentration tested (1000 ppm). Under these special conditions, a number of secondary effects occur subsequent to glutathione depletion in the target tissue, resulting in DNA damage (DNA-protein cross-links and probably DNA single-strand breaks). The particular coincidence of secondary high-dose effects precludes a risk extrapolation to man. Methyl bromide did not induce tumors in rats and mice when administered by inhalation. However, experimental data point to a possible local carcinogenic effect on the rat forestomach when the compound is given by gavage. A factor that accounts for the discrepancy between systemic DNA methylation and apparent noncarcinogenicity upon inhalation might be the preference of 7-N over O6 methylation of guanine. An extrapolation of the negative rodent inhalation bioassay of methyl bromide to man might be problematic because rodents metabolize methyl bromide very quickly whereas in humans there is a particular subpopulation that only poorly metabolizes the compound ("nonconjugators"). Such individuals can be characterized by incubation of erythrocytes with methyl chloride or methyl bromide and measurement of the substrate decline. Methyl iodide has been tested, with positive outcome, in early carcinogenicity bioassays not based on modern methodology. However, these results, along with the proven systemic methylating potency of methyl iodide, argue in favor of a carcinogenic effect of the compound.

Animals↗
PubMed1993

Interspecies differences in metabolism and kinetics of 1,3-butadiene, isobutene and styrene.

Investigations on the pharmacokinetics of inhalation of 1,3-butadiene and its primary reactive intermediate, epoxybutene, in mice and rats have demonstrated reasonably clearly that the species differences observed in the carcinogenicity of butadiene are accompanied by species differences in its metabolism. Mice metabolize butadiene to epoxybutene faster than rats but have a limited capacity for detoxification and accumulation of the reactive epoxide intermediate; these characteristics are viewed as major determinants of the greater susceptibility of mice to butadiene. The detection of alkylation products of epoxybutene and diepoxybutane with guanine residues in DNA of livers of mice exposed to butadiene indicate that eposybutene is further biotransformed to diepoxybutane in this species. This assumption is supported by the finding that butadiene induces cross-linking between DNA and proteins in mice, which can be attributed to the bifunctional alkylating diepoxybutane. Quantitative differences between rats and mice in butadiene metabolism and in the biological effectiveness of the reactive epoxide intermediates reflect the activities of different enzymes in butadiene metabolism. Epoxybutene is metabolized primarily via glutathione S-transferase-mediated pathways, resulting in glutathione depletion, increased toxicity at higher doses and covalent binding of reactive butadiene intermediates. A drastic depletion of non-protein sulfhydryl is observed in the tissues of mice but not of rats after acute exposure to butadiene. Isobutene (2-methylpropene) is converted by hepatic monooxygenase(s) to the epoxide, 2,2-dimethyloxirane. This epoxide, when appropriately tested, was mutagenic to Salmonellatyphimurium strains TA100 and TA1535. Addition of an exogenous metabolic system diminished the mutagenicity of 2,2-dimethyloxirane.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkenes↗
PubMed1992

Chromium (VI) reducing capacity of ascorbic acid and of human plasma in vitro.

In the metabolism of chromium(VI) its reduction in human plasma is of importance; an extracellular reduction of Cr(VI) is regarded as a detoxification step. Ascorbic acid has been suggested to represent the majority of the Cr(VI)-reducing capacity of human plasma. Therefore the kinetics of the reaction of Cr(VI) with ascorbic acid, at biologically realistic concentrations were studied. Ascorbic acid, in 0.2 M HEPES buffer and at concentrations ranging from 14.2 to 113.6 nmol ml-1 (2.5-20.0 microgram ml-1), was mixed with Cr(VI) (0.4-1.5 nmol ml-1) and incubated at pH 7.4 and 37 degrees C. In addition, chromate solutions at different concentrations [1.5-100 nmol ml-1 Cr(VI)], were incubated at 37 degrees C with freshly drawn blood. From these incubates, ascorbic acid and its oxidized form, dehydroascorbic acid, were simultaneously analyzed by HPLC and post-column derivatization. Chromate was determined by flow injection analysis. The reaction kinetics of ascorbic acid in HEPES buffer with Cr(VI) is of pseudo-first order at higher concentrations, whilst apparently at lower concentrations kinetics are consistent with an autocatalyzed reaction. Results obtained after spiking human plasma are similar. However, when Cr(VI) was reacted with human plasma, no changes in the intrinsic contents of ascorbic acid of the plasma samples occurred. Also, comparing different plasma samples the intrinsic plasma contents of ascorbic acid and the reduction capacities for Cr(VI) [ranging between 0.48 and 0.63 nmol ml-1 Cr(VI) to be reduced] did not correlate. This shows that the reduction of Cr(VI) in native human plasma is complex and is not only determined by the plasma ascorbic acid levels. This is in contrast to the situation in lung lavage fluids (Suzuki 1988; Suzuki and Fukuda 1990) where the concentrations of ascorbic acid are much higher than in blood.

Ascorbic Acid↗
PubMed1991

Tumors of the urinary bladder in painters: a case-control study.

In a case-control study, 403 male patients with a diagnosis of "bladder tumor" and (as controls) 426 patients suffering from prostate disease were investigated. The results of this study indicate that past employment as a painter was associated with an excess risk of bladder tumor. The relative risk of bladder tumor estimated for painters was 2.76. The possible role of benzidine-based azodyes (or azodyes based on substituted benzidines) as a carcinogenic risk factor for painters is discussed.

Adult↗
PubMed1991

Formation of DNA adducts in F-344 rats after oral administration or inhalation of [14C]methyl bromide.

The genotoxic effects of methyl bromide were investigated in a DNA-binding study. [14C]Methyl bromide was administered to male and female F-344 rats orally, or by inhalation from a closed exposure system. DNA adducts were detected in the liver, lung, stomach and forestomach. [14C]3-Methyladenine, [14C]7-methylguanine and [14C]O6-methylguanine were identified using a combination of three different methods of hydrolysing DNA, followed by HPLC or gas chromatography-mass spectrometry. After both oral and inhalation exposure, the highest levels of methylated guanines, especially those of [14C]O6-methylguanine, were found in the stomach and forestomach of the rats. These results clearly demonstrate a systemic DNA-alkylating potential of methyl bromide.

Administration, Inhalation↗
PubMed1991

DNA binding of methyl iodide in male and female F344 rats.

The genotoxic potency of methyl iodide was investigated in a DNA binding study. Male and female F344 rats were exposed to 14C-labelled methyl iodide orally or by inhalation in a closed exposure system. DNA adducts were detected in the liver, lung, stomach and forestomach of the exposed animals. [14C]3-Methyladenine, [14C]7-methylguanine and [14C]O6-methylguanine could be identified by a combination of three different methods of hydrolysing DNA and subsequent HPLC or GC/MS analysis. The highest values of methylated guanines were determined in the stomach and forestomach of the animals following both oral and inhalative exposure. These results demonstrate a systemic genotoxic effect of methyl iodide.

Adenine↗