The impact of physical and mental activity on toxicokinetics and toxicodynamics of workplace chemicals.
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Humans↗
Biomedical subjects
H M Bolt
Publications and source records attributed to H M Bolt.
Analysis of macromolecular ethylene oxide adducts.
Ethylene oxide is a carcinogenic compound which is also an ethylene metabolite. Ethylene oxide forms macromolecular adducts with proteins and nucleic acids. Targets in proteins are the amino acids cysteine, histidine and valine (if N-terminal, as in hemoglobin). The major DNA adduct is 7-(2-hydroxyethyl)-guanine. Methods for detection of this adduct include radiolabelling and GC-MS. The sensitivity of current GC/MS methods can be improved by selective enrichment of adducts from DNA samples. Studies in this direction are presently being performed.
Alkylation↗
Biochemical effects of methyl chloride in relation to its tumorigenicity.
The biochemical effects of methyl chloride were investigated in tissues of F-344 rats and B6C3F1 mice (both sexes). Activities of GST were 2-3 times higher in livers of male B6C3F1 mice, compared with those of female mice, and with rats of both sexes. In kidneys GST activities of (male) mice were about 7 times lower than those found in livers. The activity of FDH was higher in livers of mice (both sexes) than in those of rats. No obvious sex difference was found in livers of rats and mice with respect to FDH. In kidneys, however, (minor) differences in FDH activities occurred between male and female B6C3F1 mice (4.7 vs. 3.1 nmol/min per mg). Sex differences of FDH activity in kidneys were not observed in F-344 rats. The microsomal transformation (by cytochrome P-450) of methyl chloride and S-methyl-L-cysteine to formaldehyde in tissues of B6C3F1 mice occurred preferentially in the liver. More formaldehyde was produced in liver microsomes of male, compared to those of female mice. Kidney microsomes metabolized methyl chloride to formaldehyde much less than liver microsomes. After a single exposure of mice of both sexes to 1000 ppm methyl chloride no elevation in formaldehyde concentrations was observed in livers and kidneys ex vivo. The determination of DNA lesions, using the alkaline elution technique, revealed no DNA-protein crosslinks in kidneys of male B6C3F1 mice after exposure to methyl chloride (1000 ppm, 6 h day-1, 4 days) and gave only minor evidence of single-strand breaks. Lipid peroxidation (production of TBA reactive material), induced by single exposure to methyl chloride (1000 ppm, 6 h), was very pronounced in livers of male and female mice. Smaller increases in peroxidation were observed in the kidneys of exposed mice. The theory that renal tumors observed in male mice after chronic exposure of the test animals to high (1000 ppm) concentrations of methyl chloride, are evoked by intermediates and in situ produced formaldehyde is proven unlikely by our results.
5-Methylcytosine↗
Depletion of hepatic non-protein sulfhydryl content during exposure of rats and mice to butadiene.
B6C3F1 mice, Sprague-Dawley and Wistar rats were exposed to 1,3-butadiene in a closed exposure system. Exposure concentrations were kept above 2000 ppm to ensure saturation of butadiene metabolism in both species (Vmax conditions). Hepatic non-protein sulfhydryl (NPSH) content was determined in butadiene-exposed animals (and air-exposed controls) after exposures for 0, 7 and 15 h. Depletion of hepatic NPSH content was different for the species and strains investigated. In mice, hepatic NPSH content declined to about 20% after 7 h and was further depleted to about 4% at 15 h when signs of acute toxicity were observed. After a 7 h exposure of rats to butadiene, hepatic NPSH content was depleted to about 65% (Wistar) or 80% (Sprague-Dawley) of the corresponding controls but remained practically stable after a 15 h exposure to butadiene. The time-courses of depletion by butadiene of hepatic NPSH support previous findings on differences in butadiene metabolism between rats and mice and offer an additional explanation for the considerable species differences observed in the toxicity and carcinogenicity of this compound.
Animals↗
Roles of etheno-DNA adducts in tumorigenicity of olefins.
Cyclic DNA adducts bearing an "etheno" structure have been described to occur after interaction with metabolites of halogenated olefins. Extensive work has been published on adducts of vinyl chloride, both in vitro and in vivo. The major DNA adduct of vinyl chloride is 7-(2-oxoethyl)guanine, but an important 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 usually are not detected as DNA adducts in vivo. Other compounds that have been studied with respect to possible formation of etheno DNA adducts are vinyl bromide (which is more or less completely analogous to vinyl chloride), acrylonitrile, vinyl acetate and vinyl carbamate. Proposals of possible structures of DNA adducts with an etheno structure have been promutagenic potential of these lesions which may lead to misincorporation of wrong DNA bases in newly synthesized DNA.
Alkenes↗
[Current status of the tumor risk from oral contraception. The statement of the Standing Committee on Hormone Toxicology of the German Society for Endocrinology].
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Breast Neoplasms↗
4,5-Dihydroxy-2-hexanone: a new metabolite of N-hexane and of 2,5-hexanedione in rat urine.
Male Wistar rats were exposed to 2000 ppm n-hexane or were treated with a single dose of 2,5-hexanedione (200 mg kg-1). Analysis of the urine collected after both treatments revealed the formation of 4,5-dihydroxy-2-hexanone via 5-hydroxy-2-hexanone or 2,5-hexanedione, respectively. Identification of this new n-hexane metabolite included enzymatic hydrolysis of the excreted glucuronide, derivatization of the keto group with O-methylhydroxylamine, and subsequent GC-MS analysis. The chemical structure derived from the mass spectra obtained was confirmed by further analysis of the methoxime-TMS derivatives and of deuterated 4,5-dihydroxy-2-hexanone excreted after treating rats with 2,5-[2H10]-hexanedione. 4,5-Dihydroxy-2-hexanone is proposed to be identical with a urinary constituent that is excreted by rats after n-hexane exposure and is converted to 2,5-dimethylfuran or 2,5-hexanedione, respectively, depending on the conditions of urine treatment prior to GC-MS analysis.
Acetates↗
Pharmacokinetic factors and their implication in the induction of mouse liver tumors by halogenated hydrocarbons.
The presently available data on pharmacokinetics of halogenated solvents which produce hepatic tumors in B6C3F1 mice, but not in rats, are reviewed. Such compounds are trichloroethylene, perchloroethylene, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, and dichloromethane. It seems likely that higher metabolic rates in mice (compared with other species) may lead to a species-selective toxicity of such compounds. Recurrent cytotoxicity which leads to stimulation of cell replication seems to be a contributing factor in the pathogenesis of mouse liver tumors. However, it is likely that more than one factor contributes to the unique tumor response of the B6C3F1 mouse.
Animals↗
Kinetics and disposition in toxicology. Example: carcinogenic risk estimate for ethylene.
Pharmacokinetic analysis of the behaviour of xenobiotics in living organisms is the basis for the understanding of dose (concentration-) response relationships. Risk estimates may lead to erroneous results if pharmacokinetic principles are neglected. The pharmacokinetic behaviour of a xenobiotic should be known before planning long-term experiments on toxicity and carcinogenicity. This is demonstrated using ethylene as an example. On the basis of the pharmacokinetics in rats of ethylene and ethylene oxide, its carcinogenic metabolite, we estimated the theoretical risk for the carcinogenic potential of ethylene. Our results demonstrate that exposure of rats to ethylene concentrations higher than 1000 ppm correspond to a (theoretical) exposure to 5.6 ppm ethylene oxide: exposures to ethylene at 40 ppm are equivalent to ethylene oxide exposures of 1 ppm, which is the (new) TLV for ethylene oxide.
Animals↗
Pharmacokinetics of the neurotoxin n-hexane in rat and man.
The pharmacokinetics of inhaled n-hexane in rat and man were compared. In the rat metabolism was saturable. Up to 300 ppm, the metabolic rate was directly proportional to the concentration in the atmosphere, reaching 47 mumol/(h X kg). Only 17% of n-hexane was exhaled unchanged. Above 300 ppm, the amount of n-hexane in the body rose with increasing atmospheric concentrations from 1.6 up to a limiting value of 9.6, which corresponded to the thermodynamic distribution coefficient of n-hexane between the organism and the atmosphere. Up to 3000 ppm, the rate of metabolism increased to 245 mumol/(h X kg); only a slow further increase was found up to 7000 ppm (285 mumol/(h X kg]. In man the steady-state concentrations of n-hexane were about 1 ppm. The metabolic clearance was 132 1/h, and n-hexane accumulated to a factor of 2.3 in the organism. The thermodynamic distribution coefficient was calculated to be 12. Twenty per cent of n-hexane in the body was exhaled unchanged. At low concentrations the rate of metabolism of n-hexane is limited in both species by transport to the enzyme system. Under these conditions the rate of metabolism of n-hexane should not be influenced by xenobiotics which induce the n-hexane metabolizing enzyme system.
Administration, Inhalation↗
Inhalation pharmacokinetics of 1,2-epoxybutene-3 reveal species differences between rats and mice sensitive to butadiene-induced carcinogenesis.
Comparative investigations of inhalation pharmacokinetics of 1,2-epoxybutene-3 (vinyl oxirane, the primary reactive intermediate of butadiene) revealed major differences in metabolism of this compound between rats and mice. Whereas in rats no indication of saturation kinetics of epoxybutene metabolism could be observed up to exposure concentrations of 5000 ppm, in mice saturation of epoxybutene metabolism becomes apparent at atmospheric concentrations of about 500 ppm. The estimated maximal metabolic rate (Vmax) in mice for epoxybutene was only 350 mumol X h-1 X kg-1 (rats: greater than 2600 mumol X h-1 X kg-1). In the lower concentration range where first order metabolism applies (up to about 500 ppm) epoxybutene is metabolized by mice at higher rates compared to rats (metabolic clearance per kg body weight, mice: 24,900 ml X h-1, rats: 13,400 ml X h-1). Under these conditions the steady state concentration of epoxybutene in the mouse is about 10 times that in the rat. When mice are exposed to high concentrations of butadiene (greater than 2000 ppm; conditions of saturation of butadiene metabolism; closed exposure system) epoxybutene is exhaled by the animals, and its concentration in the gas phase increases with exposure time. At about 10 ppm epoxybutene signs of acute toxicity are observed. When rats are exposed to butadiene under similar conditions, the epoxybutene concentration reaches a plateau at about 4 ppm. Under these conditions hepatic non-protein sulfhydryl compounds are virtually depleted in mice but not in rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗
DNA binding assay with 11-aminoundecanoic acid-[11-14C] in F-344 rats.
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Amino Acids↗
Experimental toxicology of formaldehyde.
Formaldehyde is a reactive chemical which undergoes spontaneous reactions with various cellular constituents. Mutagenicity data may be interpreted on the background of this behavior. Mice are better able to reduce the irritating effect of formaldehyde than rats and to reduce their ventilation rate when formaldehyde acts on the respiratory tract. Subacute exposure of rats to concentrations higher than 2 ppm inhibits mucociliary clearance of the nasal epithelium and leads to progressive histological and ultrastructural lesions at this site. The occurrence of squamous cell carcinomas of the nasal epithelium of rats after 2 years inhalation of 14.3 ppm formaldehyde (CIIT study) is probably the result of chronic and recurrent local toxicity; this is supported by species differences in susceptibility to the tissue damaging and carcinogenic effect of formaldehyde (rat, mouse, hamster). Data on formaldehyde-DNA interaction further support the argument that a direct risk extrapolation from the formaldehyde effects in rats to those expected for man is not possible.
Animals↗
The relevance of 4,5-dihydroxy-2-hexanone in the excretion kinetics of n-hexane metabolites in rat and man.
Male Wistar rats were exposed to n-hexane concentrations between 50 and 3000 ppm for 8 h, and urinary excretion kinetics of the n-hexane metabolites 1-hexanol, 2-hexanol, 3-hexanol, 2-hexanone, 2,5-hexanedione, and 4,5-dihydroxy-2-hexanone were assessed. The amounts of metabolites excreted were linearly dependent on the n-hexane exposure concentration, up to an exposure of about 300 ppm. Above 300 ppm exposure the metabolite excretion indicated saturation kinetics in the metabolism of n-hexane. In its quantity, the newly described 4,5-dihydroxy-2-hexanone was the second metabolite, its amount in the urine being about ten times higher than that of excreted 2,5-hexanedione. Using gas chromatography-mass spectrometry the occurrence of 4,5-dihydroxy-2-hexanone as an n-hexane metabolite in urine of man was confirmed after exposure of a male volunteer to a mean of 217 ppm n-hexane for 4 h (laboratory exposure). Twenty-six hours after starting this exposure the excretion of 4,5-dihydroxy-2-hexanone (as a result of the n-hexane exposure) reached a level which was four times higher than the excretion of 2,5-hexanedione. The results in both rat and man indicate the relevance of 4,5-dihydroxy-2-hexanone as a metabolite of n-hexane metabolism. Formation of this metabolite may be viewed as a route of detoxification.
Adult↗
Pharmacokinetics of isoprene in mice and rats.
Pharmacokinetic analysis of isoprene inhaled by male Wistar rats and male B6C3F1 mice showed saturation kinetics in both species. Below atmospheric concentrations of 300 ppm in rats and in mice the rate of metabolism is directly proportional to the concentration. The low accumulation of isoprene in the body at low atmospheric concentrations suggests transport limitation of the metabolism. Only small amounts of isoprene taken up are exhaled as unchanged substance (15% in rats and 25% in mice). Its half life in rats is 6.8 min and in mice 4.4 min. At concentrations above 300 ppm the rate of metabolism does not increase further in proportion to the atmospheric concentration. It finally approaches maximal values of 130 mumol/(h X kg) body weight at atmospheric concentrations above 1500 ppm in rats, and 400 mumol/(h X kg) body weight at concentrations above 2000 ppm in mice. This indicates limited production of the two possible mono-epoxides of isoprene at high concentrations. Isoprene is endogenously produced and is systemically available. Its production rate is 1.9 mumol/(h X kg) in rats, and 0.4 mumol/(h X kg) in mice, respectively. Part of the endogenous isoprene is exhaled by the animals but it is metabolized to a greater extent: the rate of metabolism of endogenously produced and systemically available isoprene is 1.6 mumol/(h X kg) (rats) and 0.3 mumol/(h X kg) (mice).
Administration, Inhalation↗
Synthesis and genotoxicity of acetoxyoxirane, the epoxide of vinyl acetate.
Acetoxyoxirane, the epoxide of vinyl acetate and a potential reactive intermediate, was synthesized and characterized by 13C-nuclear magnetic resonance (13C-NMR) and mass spectroscopy. The compound induced lesions (endonuclease-sensitive and alkali-labile sites) in supercoiled PM2 DNA in vitro and was directly mutagenic toward Salmonella typhimurium TA100. The mutagenicity of the epoxide in phosphate buffer (pH 7.4, 37 degrees C) decreased, with an initial half-life of 2.8 minutes, and mutagenicity was completely abolished by addition of S-9 mix. Acetoxyoxirane did not induce unscheduled DNA synthesis on incubation with Syrian hamster embryo fibroblasts (SHE cells). These findings may possibly be explained by an effective inactivation of acetoxyoxirane by esterases when these are present in the biological system. This view is consistent with the lack of acetoxyoxirane detected in rat liver microsomal incubations of vinyl acetate.
Animals↗
Biological reactive metabolites in human toxicity.
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Acrylates↗
Species differences in butadiene metabolism between mice and rats evaluated by inhalation pharmacokinetics.
Metabolism of 1,3-butadiene to 1,2-epoxybutene-3 in rats follows saturation kinetics. Comparative investigation of inhalation pharmacokinetics in mice also revealed a saturation pattern. For both species "linear" pharmacokinetics apply at exposure concentrations below 1000 ppm 1,3-butadiene; saturation of butadiene metabolism is observed at atmospheric concentrations of about 2000 ppm. For mice metabolic clearance per kg body weight in the lower concentration range where first order metabolism applies was 7300 ml X h-1 (rat: 4500 ml X h-1. Maximal metabolic elimination rate (Vmax) was 400 mumol X h-1 X kg-1 (rat: 220 mumol X h-1 X kg-1. This shows that 1,3-butadiene is metabolized by mice at higher rates compared to rats. Based on these investigations, the metabolic elimination rates of butadiene in both species were calculated for the exposure concentrations applied in two inhalation bioassays with rats and with mice. The results show that the higher rate of butadiene metabolism in mice when compared to rats may only in part be responsible for the considerable difference in the susceptibility of both species to butadiene-induced carcinogenesis.
Animals↗