PubMed Health⌕ Search

Biomedical subjects

H M Bolt

Publications and source records attributed to H M Bolt.

At least 109 records · Page 6Linked to original sources

Distribution of ethylene oxide in human blood and its implications for biomonitoring.

The distribution of radioactivity following the incubation of human blood with radio-labelled ethylene oxide was investigated in vitro. After incubation, the individual blood samples were separated into lymphocytes and high (Mr greater than 10,000) and low (Mr less than 10,000) molecular fractions of erythrocyte cytoplasm and blood plasma. The radioactivity was determined in each sample by liquid scintillation counting. In erythrocyte cytoplasm, the distribution of radioactivity showed marked interindividual differences and two distinct groups could be distinguished. The coincidence of these groups with 'conjugators' and 'non-conjugators', in terms of the enzymatic conjugation of methyl halides to glutathione in erythrocytes, suggests a common principle, such as enzyme polymorphism. Such polymorphism has been described for glutathione S-transferase mu in the human liver, an enzyme that efficiently conjugates epoxides. In the other blood compartments, the interindividual differences were either less significant or were not detectable. Binding products with various macromolecules in blood, such as haemoglobin or lymphocyte DNA, are being discussed as biological monitors for occupational exposure to ethylene oxide. The observation that erythrocytes exhibit interindividual differences as described above make binding products with haemoglobin less suitable for biological monitoring of ethylene oxide exposure than, for example, DNA adducts in lymphocytes.

Blood Cells↗

A comparative investigation of the metabolism of methyl bromide and methyl iodide in human erythrocytes.

Human erythrocyte cytoplasm was incubated in head space vials with either methyl bromide or methyl iodide. The decline in concentration of the two methyl halides was monitored by gas chromatography. Simultaneously, the production of S-methylglutathione was determined by thin layer chromatography. In parallel experiments, boiled erythrocyte cytoplasm was used in order to determine non-enzymatic conjugation. Furthermore, inhibition experiments with sulfobromophthalein were performed. The results were compared with previous findings on the metabolism of methyl chloride. In contrast to methyl chloride, both methyl bromide and methyl iodide showed a significant non-enzymatic conjugation with glutathione. In addition, an enzymatic conjugation could be observed in the erythrocyte cytoplasm of the majority of the population, whereas a minority lacks this enzymatic activity. This is consistent with findings on methyl chloride. Inhibition experiments show that a minor form of the erythrocyte glutathione transferase may be responsible for the enzymatic conjugation. Of the three monohalogenated methanes, methyl bromide is the substrate with the highest affinity for the conjugating enzyme(s). In the case of methyl iodide, non-enzymatic reaction overweighs the enzymatic process. There are possible implications of the results for occupational health and the toxicity of the substances.

Cytoplasm↗

Formation and repair of DNA lesions in kidneys of male mice after acute exposure to methyl chloride.

The time-course of DNA lesions (DNA-protein cross-links, single-strand breaks) induced by high concentrations of methyl chloride (1000 ppm) was measured in renal tissue of male mice by means of the alkaline elution assay in order to gain an insight into repair processes. DNA-protein cross-links were removed at a fast rate, whereas single-strand breaks appeared to accumulate, even during repair of DNA-protein cross-links. However, 48 h after exposure to methyl chloride, neither of these lesions were detectable in mouse kidney. Both types of DNA damage were ascribed to the action of formaldehyde, an intermediate in methyl chloride metabolism which may react with nucleic acids and protein and interfere with DNA repair.

Animals↗

Inhalation pharmacokinetics of 1,3-butadiene and 1,2-epoxybutene-3 in rats and mice.

Studies were conducted on inhalation pharmacokinetics of 1,3-butadiene and of its primary reactive metabolic intermediate 1,2-epoxybutene-3 in rats (Sprague-Dawley) and mice (B6C3F1). Investigations of inhalation pharmacokinetics of 1,3-butadiene revealed saturation kinetics of 1,3-butadiene metabolism in both species. For rats and mice linear pharmacokinetics apply at exposure concentrations below 1000 ppm 1,3-butadiene; saturation of 1,3-butadiene metabolism is observed at atmospheric concentrations of about 2000 ppm. The estimated maximal metabolic elimination rates were 400 mumole/hr/kg for mice and 200 mumole/hr/kg for rats. This shows that 1,3-butadiene is metabolized by mice at about twice the rate of rats. Investigations of inhalation pharmacokinetics of 1,2-epoxybutene-3 revealed major differences in metabolism of this compound between both species. No indication of saturation kinetics of 1,2-epoxybutene-3 metabolism could be observed in rats up to exposure concentrations of 5000 ppm, whereas in mice the saturation of epoxybutene metabolism became apparent at atmospheric concentrations of about 500 ppm. The estimated maximal metabolic rate for 1,2-epoxybutene-3 was 350 mumole/hr/kg in mice and greater than 2600 mumole/hr/kg in rats. When the animals are exposed to high concentrations of 1,3-butadiene, 1,2-epoxybutene-3 is exhaled by rats and mice. For rats 1,2-epoxybutene-3 concentration in the gas phase of the system reaches a plateau at about 4 ppm. For mice, 1,2-epoxybutene-3 concentration increases with exposure time until, at about 10 ppm, signs of acute toxicity are observed. Under these conditions hepatic nonprotein sulfhydryl compounds are virtually depleted in mice but not in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

Inhalation pharmacokinetics of isoprene in rats and mice.

Studies on inhalation pharmacokinetics of isoprene were conducted in rats (Wistar) and mice (B6C3F1) to investigate possible species differences in metabolism of this compound. Pharmacokinetic analysis of isoprene inhaled by rats and mice revealed saturation kinetics of isoprene metabolism in both species. For rats and mice, linear pharmacokinetics apply at exposure concentrations below 300 ppm isoprene. Saturation of isoprene metabolism is practically complete at atmospheric concentrations of about 1000 ppm in rats and about 2000 ppm in mice. In the lower concentration range where first-order metabolism applies, metabolic clearance (related to the concentration in the atmosphere) of inhaled isoprene per kilogram body weight was 6200 mL/hr for rats and 12,000 mL/hr for mice. The estimated maximal metabolic elimination rates were 130 mumole/hr/kg for rats and 400 mumole/hr/kg for mice. This shows that the rate of isoprene metabolism in mice is about two or three times that in rats. When the untreated animals are kept in a closed all-glass exposure system, the exhalation of isoprene into the system can be measured. This shows that the isoprene endogenously produced by the animals is systemically available within the animal organism. From such experiments the endogenous production rate of isoprene was calculated to be 1.9 mumole/hr/kg for rats and 0.4 mumole/hr/kg for mice. Our data indicate that the endogenous production of isoprene should be accounted for when discussing a possible carcinogenic or mutagenic risk of this compound.

Administration, Inhalation↗

Increased alkylation of liver DNA and cell turnover in young versus old rats exposed to vinyl chloride correlates with cancer susceptibility.

To investigate the factors responsible for the high sensitivity of the livers of young rats to the carcinogenic stimulus of vinyl chloride (VC) adult and 11-day-old Wistar rats were exposed to [1,2-14C] VC. Adult rats received either a single 6-h exposure, or 2 single 6-h exposures separated by a treatment-free time interval of 15 h. Eleven-day-old rats received 2 single 6-h exposures, according to the same treatment schedule. The animals were sacrificed 1 h after the end of the corresponding exposure period; liver DNA was isolated, enzymatically hydrolyzed and analyzed by column chromatography. Incorporation of [14C]VC-derived radioactivity into the physiological deoxyribonucleosides (presumably reflecting the activity of DNA replication) was observed for all three sets of experiments. Virtually no difference in 14C-incorporation was observed between adult rats sacrificed immediately after one single 6-h exposure to [14C]VC and those which received a second exposure on the following day. In contrast, an about 8-fold increase in 14C-incorporation into the physiological purines of DNA of young versus adult rats was detected. This difference is indicative of a significantly elevated DNA synthesis/cell replication in the liver of young (11-d) rats. Radioactivity associated with 7-(2-oxoethyl)guanine was taken as an indicator of DNA alkylation by [14C]VC. Analysis of 7-(2-oxoethyl)guanine revealed that in adult animals the amount of this alkylation product formed is increased by a second exposure to VC. About 5-fold of the amount of 7-(2-oxoethyl)guanine present in adults could be determined in liver DNA of young (11-d) animals exposed under the same exposure conditions. Our results suggest that the high sensitivity of young rats to VC-induced hepatocarcinogenesis can reasonably be explained by enhanced DNA-alkylation and by increased cellular proliferation at an early age.

Age Factors↗

Nick translation studies on DNA strand breaks in pBR322 plasmid induced by different chromium species.

Single strand breaks are DNA defects caused by various chemicals. DNA strand breaks induced in vitro by chromium(VI) during the reduction of this chromium species with glutathione or hydrogen peroxide were examined. Using DNA agarose gel electrophoresis and a nick translation assay, strand breaks were detected only when chromium(VI) was reduced by hydrogen peroxide. The reduction of chromium(VI) by an excess of glutathione led to no alteration in the DNA agarose gel electrophoresis pattern of the double-stranded plasmid pBR322 DNA and in the nick translation assay, indicating that no strand breaks had occurred under these conditions. No strand breaks could be detected during the reduction by hydrogen peroxide after the addition of superoxide dismutase. This indicates that hydroxyl radicals from peroxochromium complexes may be a relevant reactive species involved in chromate genotoxicity.

Chromium↗

Combined effects of shiftwork and environmental hazards (heat, noise, toxic agents).

The paper deals with the results of studies or discussions concerning the problem of nightwork combined with other adverse working conditions. Special emphasis is laid on the untoward effect of high temperature during nightwork, as well as on noise and exposure to chemicals. It is shown that there is no substantial influence of heat stress on the circadian rhythm of adrenaline excretion under sitting working conditions with the subject performing a difficult mental task at warm climates up to 30 degrees C BET. Shiftwork and noise induce independent different effects which can be explained in terms of activation for shiftwork and in terms of tension for noise. The combination of both adverse exposures is therefore partly subtractive but partly additive as night work and noise negatively affect daysleep. Practical experience in the field of combined effects of shiftwork and chemical agents is lacking, but theoretical speculations lead to the conclusion that there may exist a time of day dependence of some chemicals, used at workplaces.

Adult↗

Recent advances in biological monitoring of hexavalent chromium compounds.

Intratracheal instillation of 51CrCl3 in anaesthetized rabbits resulted in partial absorption. In blood, the absorbed material was entirely confined to the plasma compartment. By contrast, after similar application of Na251CrO4 the bulk of blood radioactivity was present in red blood cells (RBC). It is suggested that Cr (VI) may enter the body not reduced via the lung and may be deposited in RBC for the cell's lifetime (approximately 110 d). Since inhalation of Cr (VI)-containing aerosols or particles is the main occupational exposure route for man, it is concluded that the chromium content of RBC could be used as a selective biological indicator for exposures to (carcinogenic) hexavalent chromium. The new theoretical concept was confirmed in a pilot study with workers of a dye pigment plant. Elevated chromium content of whole blood evoked by exposure to chromate particles correlated strongly with increased chromium values in RBC (correlation coefficient: 0.86).

Animals↗

Uptake of 51Cr(VI) by human erythrocytes: evidence for a carrier-mediated transport mechanism.

Uptake of 20 micron 51Cr(VI) by resuspended red blood cells (RBC) (0.9% saline) was studied. Inhibition of the specific anion carrier system "band-3-protein" of RBC membrane with "SITS" (4-acetamido-4'-cyanatostilbene-2,2'-disulphonic acid) resulted in a non-competitive type of inhibition for chromium uptake. It is concluded that Cr(VI) is transported by participation with this system. Intracellularly, chromium is almost quantitatively bound to hemoglobin and trapped for the cell's lifetime. Glutathione (GSH) is possibly involved in this process as indicated by incubation experiments of RBC with 10 mM Na2(51)CrO4. In these experiments, a rapid decrease of GSH content of the cells was observed.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗