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PubMed1995

Preparation, characterization and 32P-postlabeling of butadiene monoepoxide N6-adenine adducts.

Butadiene monoepoxide, an active metabolite of 1,3-butadiene, was reacted with deoxyadenosine, deoxyadenosine 3'-monophosphate and DNA. The nucleoside reaction products were isolated and using various spectroscopic techniques were determined to be the N6-substituted deoxyadenosine adducts. Deoxyadenosine 3'-monophosphate products were identified by treating the modified nucleotide products with alkaline phosphatase, resulting in nucleoside adducts with HPLC retention times similar to those of the deoxyadenosine adducts. Monophosphate products were also identified through MS/MS techniques by comparing the daughter ions derived from the base moieties of N6-alkylated nucleosides and nucleotides. The reaction mechanism in aqueous solution was studied using optically active butadiene monoepoxides. Using the alkylated monophosphate standards and an HPLC/32P postlabeling assay the N6-alkylated adenine adducts were detected in calf thymus DNA exposed to butadiene monoepoxide.

Adenine↗
PubMed2003

A model of sensitivity: 1,3-butadiene increases mutant frequencies and genomic damage in mice lacking a functional microsomal epoxide hydrolase gene.

The specific role that polymorphisms in xenobiotic metabolizing enzymes play in modulating sensitivity to 1,3-butadiene (BD) genotoxicity has been relatively unexplored. The enzyme microsomal epoxide hydrolase (mEH) is important in detoxifying the mutagenic epoxides of BD (butadiene monoepoxide [BDO], butadiene diepoxide [BDO(2)]). Polymorphisms in the human mEH gene appear to affect the function of the enzyme. We exposed mice with normal mEH activity (WT) and knockout mice without mEH activity (KO) to 20 ppm BD (inhalation) or 30 mg/kg BDO(2) (intraperitoneal [IP] injection). We then compared Hprt mutant frequencies (MFs) among these groups. KO mice exposed to BD exhibited a significant (P < 0.05) 12.4-fold increase in MF over controls and a significant 5.4-fold increase in MF over exposed WT mice. Additionally, KO mice exposed to BDO(2) exhibited a significant 4.5-fold increase in MF over controls and a significant 1.7-fold increase in MF over exposed WT mice. We also compared genomic damage in WT and KO mice (comet tail moment) following IP exposure to 3 mg/kg and 30 mg/kg BDO(2). KO mice exposed to 3 mg/kg exhibited significantly more DNA damage than controls (7.5-12.1-fold increase) and exposed WT mice (3 mg/kg; 4.8-fold increase). KO mice exposed to 30 mg/kg BDO(2) exhibited significantly more DNA damage than all other groups (2.3-27.9-fold increase). Correlation analysis indicated that a significant, positive relationship (r(2) = 0.92) exists between comet-measured damage and Hprt MFs. The lack of mEH activity increases the genetic sensitivity of mice exposed to BD and BDO(2). This model should facilitate a mechanistic understanding of the observed variation in human genetic sensitivity following exposure to BD.

Administration, Inhalation↗
PubMed2004

Characterization of alkyl-cobalamins formed on trapping of epoxide metabolites of 1,3-butadiene.

Analytical methods facilitating studies of electrophilically reactive and genotoxic compounds in vitro and in vivo are needed. The strong nucleophile, cob(I)alamin, formed by reduction of Vitamin B12 [cob(III)alamin], may be used for trapping and analysis of 1,2-epoxides and other electrophiles. In the present study, cob(I)alamin is evaluated as an analytical tool for 1,2-epoxide metabolites (oxiranes) of 1,3-butadiene. Products of reaction of cob(I)alamin with 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 1,2-epoxy-3,4-butanediol (EBdiol) have been analyzed by reversed phase high performance liquid chromatography (HPLC) coupled on-line to electrospray ionization mass spectrometry (ESI-MS) and ultraviolet diode array detection (UV-DAD). It was shown that a specific alkyl-CbI complex is formed for each metabolite and that it was possible to discriminate between the products by HPLC-UV and by LC-MS. Quantification of DEB with the method by use of another 1,2-epoxide as an internal standard was successfully performed. The possibility of using cob(I)alamin for trapping and analysis of the three oxirane metabolites of 1,3-butadiene will facilitate quantitative comparisons of species in vitro with regard to metabolism of 1,3-butadiene.

Butadienes↗
PubMed1998

Stereochemical aspects of the conjugation of epoxide metabolites of butadiene with glutathione in rat liver cytosol and freshly isolated rat hepatocytes.

1,3-Butadiene (BD), a gas used widely in production and synthesis of rubber, plastics, and resins, is metabolized to three different epoxide metabolites: butadiene monoxide (BMO), butadiene bisoxide (BBO) and epoxybutanediol (ED). We have examined the role of stereochemistry in the chemical and enzyme-mediated conjugation of R- and S-BMO; RR-, SS-, and meso-BBO; and SR-, RS-, RR-, and SS-ED with glutathione (GSH) using liver cytosol and freshly isolated hepatocytes from male Sprague-Dawley rats. Chemical and enzyme-mediated reactivity of BD-epoxides (5 mM) with GSH (0.1 mM) was assessed by measuring remaining GSH in solution using dithiobisnitrobenzoic acid (DTNB). Chemical reactivity of BD epoxides with GSH was modest while addition of cytosol resulted in increased removal of GSH following exposure to each BD-epoxide. BBO stereoisomers resulted in the greatest cytosol-mediated removal of GSH (40-70%). BMO enantiomers removed 40-60% and ED stereoisomers removed 10-35% of GSH. Cytosol-mediated reactions with GSH were predictive of results observed in isolated hepatocytes where stereoselective depletion of GSH was observed following treatment with each class of epoxide metabolites. R-BMO depleted cellular GSH more rapidly and to a greater extent than S-BMO, SS- and meso-BBO were more potent than RR-BBO and SS- and SR-ED were more potent than RS- and RR-ED. These data demonstrate that enzyme-mediated reactions represent the primary mechanism of conjugation of BD-epoxides with GSH and that these reactions display marked stereoselectivity.

Animals↗
PubMed1994

Mutagenicity of 1,3-butadiene inhalation in somatic and germinal cells of mice.

Inhalation exposure of mice to 50, 200, 500 or 1300 ppm of 1,3-butadiene for 6 h per day for 5 consecutive days caused micronuclei in mouse bone marrow and peripheral blood erythrocytes. The dose response was non-linear. The slope of the curve flattened with increasing exposure concentration. Coat color spots were found in the mouse spot test after exposure of pregnant females on pregnancy days 8-12 to 500 ppm of 1,3-butadiene. Dominant lethal mutations were induced in spermatozoa and late spermatids after exposure of male mice to 1300 ppm with the 5-day exposure regimen. Thus, in the mouse 1,3-butadiene is a somatic and germ cell mutagen.

Administration, Inhalation↗
PubMed1995

Chromosome aberrations and response to gamma-ray challenge in lymphocytes of workers exposed to 1,3-butadiene.

An integrated population monitoring study was initiated to investigate whether occupational exposure to current low levels of butadiene is mutagenic to workers. Ten exposed workers (mean production area concentration of 3.5 ppm) and 10 matched plant controls (mean exposure to 0.03 ppm) were selected and blood samples were collected for our study. The standard cytogenetic assay was used to determine chromosome aberration frequencies. In addition, a challenge assay was used to determine response to gamma-rays as an indication of DNA repair deficiencies. In the latter assay, cells were exposed to gamma-rays at the G1 phase of the cell cycle in vitro and the frequencies of chromosome aberrations in the first post-irradiation metaphase cells were quantitated. Based on results of the cytogenetic assay, the exposed group had a higher frequency of cells with chromosome aberrations and higher chromatid breaks per 100 cells compared with the control. However, the difference was not significant (p > 0.1). With the challenge assay, the exposed group had a higher frequency of aberrant cells (p < 0.04), chromatid breaks (p < 0.05), deletions (p < 0.07), and dicentrics (p < 0.02) than the controls. In addition, the dicentric frequencies from workers were significantly correlated with the presence of a butadiene metabolite [1,2-dihydroxy-4-(N-acetylcysteinyl-S)butane] in urine with a correlation of coefficient of 0.6 (p < 0.01). Two outliers were identified and our interpretation of their responses will be discussed. This study indicates that the workers had exposure-induced mutagenic effects. Together with the observation of gene mutation in a subset of the present population, this study indicates that the current occupational exposure to butadiene may not be safe to workers.

Adult↗
PubMed1996

Biological effect monitoring in industrial workers from the Czech Republic exposed to low levels of butadiene.

Blood samples were collected twice (in 1993 and 1994) from 19 workers exposed to 1,3-butadiene and 19 matched controls. Three exposed and three control subjects were the same in 1993 and 1994. Personal passive dosimetry was performed in 1993 and twice in 1994 on the day preceding blood sampling. Mean exposure level in 1994 was 1.76 +/- 4.20 ppm (S.D.) and individual exposure levels ranged between 0.012 ppm (detection limit) and 19.77 ppm. Using the clonal assay, geometric mean of hprt mutant frequencies adjusted for cloning efficiency, age and smoking were, respectively, 7.85 (+/- 7.09) x 10(-6) and 10.14 (+/- 9.16) x 10(-6) in pooled (1993 plus 1994) exposed and control subjects. The difference was not statistically significant indicating that 1,3-butadiene did not induce a detectable increase in mutations at the hprt locus. A similar result was obtained for the 1994 subjects alone. There was no difference between adjusted geometric mean mutant frequencies of exposed and unexposed non-smokers or between exposed and unexposed smokers. Analysis of chromosomal aberrations in lymphocytes from 1994 subjects indicated that the percentage of aberrant cells was significantly enhanced in exposed subjects. In 1993 (data not shown), it was impossible to demonstrate a significant increase of aberrant cells in subjects exposed to 1,3-butadiene. Frequencies of micronuclei in cytochalasin-B blocked binucleate lymphocytes in exposed and unexposed 1994 subjects were not significantly different. This was also the case for earlier samples analyzed in the same plant. Using the comet assay for 1994 subjects, no statistically significant difference was found between the whole group of exposed and unexposed subjects. This was true for both the comet tail length and the percentage of DNA in the tail. In exposed smokers, however, the comet tail length was significantly longer than in unexposed smokers. Unexpectedly, in unexposed smokers the tail length was significantly shorter than in unexposed non-smokers. It was also unexpected that the percentage of DNA in the comet tail was significantly lower in exposed non-smokers than in unexposed non-smokers.

Adult↗
PubMed1996

Biological monitoring of butadiene exposure by measurement of haemoglobin adducts.

The measurement of haemoglobin (Hb) adducts is an important tool for monitoring exposures to industrial chemicals such as ethylene, ethylene oxide and propylene oxide. The aim of the present study was to use this method to monitor occupational exposure to butadiene. The methodology was evaluated with Hb samples obtained by reacting butadiene monoepoxide (BMO), the primary reactive metabolite of 1,3-butadiene, with blood and by dosing BMO to rats and mice. The Hb adducts: N-(2-hydroxy-3-buten-1-yl)valine and N-(1-hydroxy-3-buten-2-yl)valine were determined as the pentaflurophenylthiohydantoin derivatives using the modified Edman degradation procedure and gas chromatography with negative ion chemical ionisation mass spectrometry. The adducts were quantified using d4-N-(2-hydroxyethyl)valine as an internal reference chemical. Relatively high background signals were observed which made accurate quantitation difficult. The lower limit of detection was estimated as 10-20 pmol/g globin. The experiments have demonstrated that appropriate reference samples are required for accurate quantitation and the method requires further refinement to improve the sensitivity of the analysis.

Animals↗
PubMed1996

Male-mediated F1 effects in mice exposed to 1,3-butadiene.

We examined the effects on dominant lethality, the incidence of fetal abnormalities and tumour incidence in surviving offspring of acute and subchronic exposure of male mice by inhalation to the industrial monomer, 1,3-butadiene. In the acute study, CD-1 mice were exposed to atmospheres containing 0 (n = 25), 1250 (n = 25) or 6250 ppm (n = 50) for 6 h, and each male was caged 5 days later for 1 week with two untreated virgin females. One of the females was killed humanely on day 17 of gestation. The other was allowed to deliver and rear her litter and the litters were monitored throughout adulthood. The killed female was examined for the number of live foetuses, the number of post implantation deaths (early and late) and the number and type of any gross malformations. In the subchronic study, males were exposed to 0 (n = 25), 12.5 (n = 25) or 1250 (n = 50) for 6 h per day on 5 days per week for 10 weeks and then mated the next morning. Mating and observation details were as for the acute study. Acute exposure to butadiene resulted in only a small decrease in implantations; after 10 weeks' subchronic exposure with either the high or low concentration, however, a wide variety of statistically significant effects was seen. At 1250' ppm, the number of implantations was reduced, dominant lethal mutations were induced, and the incidences of early and late deaths were increased; some of the live foetuses were malformed. The low dose also increased the frequency of malformations and late deaths but it did not affect the number of early deaths. Skeletal examination of malformed foetuses, randomly selected normal litter mates and controls confirmed the abnormalities seen at necropsy in malformed foetuses. However, karyotypic analysis of foetal liver from malformed foetuses, randomly selected normal litter mates and controls showed no karyotypic abnormalities. The number of gross suspected tumours in the F1 adults did not appear to reveal an increase over control values. Thus, butadiene is mutagenic in the germ cells of male mice, as shown by the induction of dominant lethality at 1250 ppm, and the frequencies of late deaths and congenital malformations appear to be increased at the subchronic level of 12.5 ppm and skeletal examination of malformed foetuses confirmed the macroscopic abnormalities.

Abnormalities, Drug-Induced↗
PubMed1996

Butadiene epidemiology: a summary of results and outstanding issues.

Published epidemiologic studies of butadiene workers, individually and in aggregate, find rates similar to expected for essentially all forms of cancer, with the possible exception of lymphohematopoietic cancers. Reviewers of the literature have disagreed about whether butadiene is a cause of human lymphohematopoietic cancers. This article reviews the available butadiene epidemiologic studies and focuses on the bases for disagreement among reviewers. The disagreement seems to be due to different conventions in applying, explicitly or implicitly, Hill's causal criteria, fostered, in part, by deficiencies in the available epidemiologic studies. Many of these deficiencies will be remedied by updated studies presented at this Symposium or are remediable by other analyses of the existing data.

Butadienes↗
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↗
PubMed2006

Some insights into the mode of action of butadiene by examining the genotoxicity of its metabolites.

1,3-Butadiene (BTD) is an important commodity chemical and air pollutant that has been shown to be a potent carcinogen in mice, and to a lesser extent, a carcinogen in rats. To better assess butadiene's carcinogenic risk to humans, it is important to understand its mode of action and how this relates to differences in responses among species. In a series of in vitro experiments, lymphocytes from rats, mice, and humans were exposed to 3,4-epoxy-1-butene (EB) or 1,2:3,4-diepoxybutane (DEB) for 1h at the G(0) stage of the cell cycle, stimulated to divide, and cultured to assess the ability of these metabolites to induce sister chromatid exchange (SCE) and chromosome aberrations (CAs). EB induced no increases in SCEs or CAs in the cells from the three species. DEB was a potent SCE- and CA-inducer, with the results being similar in each rodent species. The response for SCEs seen in the human cells was more complex, with genetic polymorphism for glutathione-S-transferases (GST) possibly modulating the response. The single cell gel electrophoresis assay was used on genetically engineered V79 cell lines to investigate a possible influence of GST status. Experiments were also conducted to investigate the reason for EB's failure to induce SCEs or CAs in G(0) cells. The results indicate that EB-induced DNA damage was repaired before DNA synthesis in unstimulated lymphocytes, but EB caused a large increase in SCEs if actively cycling cells were treated. Thus, the results indicate that DEB damage is persistent in G(0) cells, and DEB is a much more potent genotoxicant than EB. The carcinogenic effect of butadiene will most likely depend on the degree to which DEB is produced and reaches target tissues, and to a lesser extent on the ability of EB to reach actively dividing or repair deficient cells.

Animals↗
PubMed2006

Evaluation of genetic alterations in cancer-related genes in lung and brain tumors from B6C3F1 mice exposed to 1,3-butadiene or chloroprene.

1,3-Butadiene and chloroprene are multisite carcinogens in B6C3F1 mice with the strongest tumor response being the induction of lung neoplasms in females. Incidence of brain tumors in mice exposed to 1,3-butadiene was equivocal. This article reviews the efforts of our laboratory and others to uncover the mechanisms of butadiene and chloroprene induced lung and brain tumor responses in the B6C3F1 mouse. The formation of lung tumors by these chemicals involved mutations in the K-ras cancer gene and loss of heterozygosity in the region of K-ras on distal chromosome 6, while alterations in p53 and p16 were implicated in brain tumorigenesis.

Alleles↗
PubMed2001

Significance of 1,3-butadiene to the US air toxics regulatory effort.

Because of its prevalence, particularly as a combustion by-product, 1,3-butadiene is a particularly important air toxic. It plays a significant role in all air toxics regulatory efforts in the US. The various requirements of the Federal Clean Air Act (CAA) dealing with air toxics are reviewed and the significance of 1,3-butadiene in each area is discussed in light of what is known about its emissions and health effects. The impacts of the changes in the understanding of 1,3-butadiene cancer potency over the past 15 years demonstrates the possible impact of such benchmarks and the importance of using the best science in understanding public health risks.

Air Pollution↗
PubMed2001

Development of a preliminary physiologically based toxicokinetic (PBTK) model for 1,3-butadiene risk assessment.

Potential health effects of human exposure to 1,3-butadiene (BD) are of concern due to the use of BD in industry and its low-level presence throughout the environment. Physiologically based toxicokinetic (PBTK) models of BD in rodents have been developed by multiple research groups in an effort to explain species differences in toxicity (especially carcinogenic potency) through toxicokinetics. PBTK modeling of dose metrics related to a non-cancer endpoint, ovotoxicity in experimental animals, was conducted. The cumulative area under the blood concentration vs. time curve (AUC) for the metabolite diepoxybutane (butadiene diepoxide, DEB) was found to be consistent with ovotoxicity in mice and rats exposed to BD by inhalation or epoxybutene (butadiene monoepoxide, EB) or DEB by intraperitoneal injection. This suggests that cumulative DEB AUC may also be an appropriate metric for possible human risk. A preliminary human PBTK model was assembled for the eventual assessment of reproductive risk to humans and for prioritizing the determination of model parameters. The preliminary model accurately predicted published data on exhaled breath BD concentrations in a human volunteer exposed to BD by inhalation. The fit was relatively insensitive to the rate constant for BD epoxidation. Sensitivity analyses were conducted on this human PBTK model. Using a range of published rate constants, human blood DEB was found to be sensitive to rates of epoxidation of EB to DEB and hydrolysis of EB and DEB, but not BD epoxidation. Because of the large ranges of rates measured in vitro for these reactions, different combinations of in-vitro rates produce varying predictions of blood DEB concentration. Thus, validation of a human PBTK model with human biomonitoring data will be essential to produce a PBTK model that can be applied to risk assessment.

Animals↗
PubMed1989

Mutagenic activity of ultraviolet-irradiated mixtures of nitrogen dioxide and propene or butadiene.

The mutagenic activities of mixtures of nitrogen dioxide and 1,3-butadiene or propene were investigated after uv-irradiation in a small, laboratory-bench scale flow-through gas exposure system. The tester organism was Salmonella typhimurium, principally strain TA100. The photoreaction products from 1,3-butadiene and nitrogen dioxide were more mutagenic than those from propene and nitrogen dioxide. Approximately 0.25 ppm butadiene, compared to 100 ppm propene, was needed to give a significant mutagenic effect with 0.25 ppm NO2 after 6 hr exposure. The influence of different experimental conditions on mutagenic activity was studied using propene plus nitrogen dioxide. Increasing the mean reaction time from 40 min to 1 hr 20 min or 3 hr 20 min by reduction of the flow rate through the 20-liter reaction vessel did not appreciably increase the sensitivity of the system, nor did humidification of the air, omission of the metabolic system (S9 mix), or spreading of the bacteria on the agar surface. Prolongation of the exposure time from 6 to 16 or 24 hr did, however, give an increased mutagenic response. With prolonged exposure, a slight mutagenic effect could also be detected with ethene + NO2 + uv. Ozone addition did not appreciably enhance the mutagenic response.

Alkenes↗
PubMed1998

DNA adducts in mouse testis and lung after inhalation exposure to 1,3-butadiene.

1,3-Butadiene is a widely used industrial chemical and also an environmental contaminant. Recent findings have shown that butadiene can also be a male germ cell mutagen. In this study, DNA adduct formation in testis and lung has been explored by using N7-alkylated guanines as a marker of biological effective dose. The adducts measured were the four structurally different guanine N7-adducts alkylated by butadienemonoepoxide, the main metabolite of 1,3-butadiene. This study demonstrates the dose-dependent adduct formation in lung and testis. At lower exposures (50 and 200 ppm) the adduct levels were about the same in the two organs, but at 500 ppm the adduct level was significantly (p < 0.03) higher in testis than in lung. The enantiomeric composition of the adducts detected was also different. In lung, all 4 possible adducts were present (S-C-1" dominating, 49%), but in testis only two out of four adducts were detected (S-C-2" being the most abundant adduct, 71%). These novel observations indicate that the DNA repair is different in these two organs studied and that heritable genetic effects observed may be mediated through the DNA adducts.

Alkylation↗
PubMed1989

Determination of benzene, toluene and 1,3-butadiene in cigarette smoke by GC-MDS.

An analytical procedure was devised for the determination of selected gas phase constituents in cigarette smoke utilizing capillary gas chromatography and mass selective detection (GC-MSD); the MSD was used in the selective ion monitoring mode (SIM). The gas of freshly generated mainstream smoke was analyzed via a 10-port gas sampling valve on a puff-by-puff basis. Benzene, toluene, and 1,3-butadiene were found in the range of 6-73, 5-88, and 16-75 micrograms/cigarette, respectively. The gas phase of sidestream smoke was trapped in methanol using 3 midget impingers at -78 degrees C. Benzene in sidestream smoke was found in the range of 490-840 micrograms/cigarette; toluene and 1,3-butadiene levels were 1,090-1,690 and 300-470 micrograms/cigarette, respectively. Environmental tobacco smoke (ETS), sampled in a smoke-filled bar, was analyzed using the cold trap method. The concentrations of benzene and toluene in this indoor air were found to be 26-36 and 41-80 micrograms/m3, respectively, while 1,3-butadiene was present at 3.3-4.5 micrograms/m3.

Benzene↗