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PubMed1989

Neoplastic lesions induced by 1,3-butadiene in B6C3F1 mice.

1,3-butadiene (CAS No. 106-99-0) was evaluated for carcinogenicity and chronic toxicity by inhalation exposure in B6C3F1 mice because of its high production volume, widespread exposure of workers, and the lack of carcinogenicity and toxicity data (NTP Report #228, 1984). Butadiene (BD) had long been considered to have low toxicity. The long-term studies established that BD is a potent mouse carcinogen with multiple organ carcinogenicity (Huff et al. 1985; Melnick et al. 1988). This paper presents morphological descriptions and illustrations of the neoplastic lesions induced by 1,3-butadiene in B6C3F1 mice.

Adenocarcinoma↗
PubMed2000

Mutation analysis of the pRb pathway in 2',3'-dideoxycytidine- and 1, 3-butadiene-induced mouse lymphomas.

The pRb pathway plays a key role in controlling the G1/S transition in cell cycle progression. Aberrations of various components of the pRb pathway, such as retinoblastoma protein and its upstream actors including cyclin D1, cyclin dependence kinase-4 and p16/p15 cyclin dependent kinase inhibitors, have been reported in a variety of human tumors. Furthermore, the alterations of retinoblastoma protein and its upstream components often occur in a reciprocal manner. Previously, we have reported frequent inactivation of the Cdkn2a/Cdkn2b loci encoding p16/p15 cyclin dependent kinase inhibitors in a subset of 2',3'-dideoxycytidine- and 1, 3-butadiene-induced mouse lymphomas (S.-M. Zhuang, A. Schippert, A. Haugen-Strano, R.W. Wiseman, P. Söderkvist, Inactivation of p16(INK4a)-alpha, p16(INK4a)-beta and p15(INK4b) genes in 2', 3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas, Oncogene 16 (1998) 803-808), indicating the involvement of pRb pathway in lymphomagenesis. To investigate whether alteration of other components in pRb pathway is an alternative mechanism underlying the development of these chemically induced lymphomas, we have examined the genetic status of Rb1, Ccnd1 and Cdk4 genes that encode retinoblastoma protein, cyclin D1 and cyclin dependence kinase-4, respectively. Gross alterations of the Rb1, Ccnd1, and Cdk4 genes were not detected by Southern analysis in any of the tumors examined. In addition, single-strand conformation analysis failed to reveal point mutations in the Cdk4 amino terminal domain that is important for its association with Cdkn2a gene products. These results indicate that the mechanisms underlying the development of 2', 3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas involve inactivation of p16/p15 cyclin-dependent kinase inhibitors but not genomic alterations of the Rb1, Ccnd1 and Cdk4 genes.

Animals↗
PubMed2000

Micronuclei and gene mutations in transgenic big Blue((R)) mouse and rat fibroblasts after exposure to the epoxide metabolites of 1, 3-butadiene.

1,3-Butadiene (BD) is a commodity compound and by-product in the manufacture of synthetic rubber that elicits a differential carcinogenic response in rodents after chronic exposure. Mice are up to approximately 1000-fold more sensitive to the tumorigenicity of inhaled BD than rats, thereby confounding human risk assessment analyses. Rodent transgenic in vivo and in vitro models have been recently utilized for generating genetic toxicology data in support of risk assessment studies. However, studies have not been extended to investigate multiple endpoints of genetic damage using in vitro transgenic models. The goal of this study was to evaluate possible differences in the production of genetic damage in transgenic Big Blue((R)) mouse (BBM1) and rat (BBR1) fibroblasts exposed to three predominant epoxide metabolites of BD. Analyses of cytotoxicity, micronucleus (MN) formation, cII mutant frequency (MF) and apoptosis were assessed after in vitro exposure of BBM1 and BBR1 cells exposed to various concentrations of butadiene monoepoxide (BMO), diepoxybutane (DEB) and butadiene diolepoxide (BDE). Both BMO and DEB reduced cell survival in BBM1 and BBR1 cells. However, BDE decreased cell survival only in BBM1 cells at the concentrations evaluated. Concentration-dependent increases in the formation of MN was observed in both BBM1 and BBR1 cells, with DEB being the most potent followed by BDE and then BMO. The dose-response for mutations induced at the cII locus was essentially equal after DEB exposure of BBM1 and BBR1 fibroblasts. In contrast, the cII MF was significantly increased only in BBM1 cells after exposure to either BMO or BDE. These data demonstrate a differential genetic response for gene mutations but not for MN formation in transgenic BBM1 and BBR1 fibroblasts and suggest a rodent species-specific difference in the persistence of DNA damage that results in gene mutations. In addition, apoptosis was observed in BBR1 cells but not in BBM1 cells when treated with any of the three BD epoxide metabolites. This response may partially explain the differential response to mutations induced by BMO and BDE. These data offer insight into specific differences in mouse and rat cells with respect to their response to BD epoxide metabolites. Such data may help to explain the different tumorigenicity results observed in rodent BD carcinogenicity studies.

Analysis of Variance↗
PubMed2000

Racemic and asymmetric Diels-Alder reactions of 1-(2-oxazolidinon-3-yl)-3-siloxy-1,3-butadienes.

Achiral and chiral 1-(2-oxazolidinon-3-yl)-3-siloxy-1,3-butadienes were prepared from readily available starting materials. Although more stable than the parent 1-amino-3-siloxy dienes, the 1-(2-oxazolidinon-3-yl)-3-siloxy-1,3-butadienes are still very reactive in Diels-Alder reactions, somewhat more than 1,3-dialkoxy-1, 3-butadienes (e.g., Danishefsky's diene). The cycloadditions of the achiral and chiral dienes with several different dienophiles were examined. The reactions proceeded in good yield, with modest to high endo selectivity. The chiral dienes exhibited excellent facial selectivity in cycloadditions with alpha-substituted acroleins, maleic anhydride and N-phenylmaleimide. Upon reduction and hydrolysis of the cycloadducts, substituted cyclohexenones were obtained with ee's ranging from 22% to >98%.

Acrolein↗
PubMed2003

Synthesis and characterization of peptides containing a cyclic Val adduct of diepoxybutane, a possible biomarker of human exposure to butadiene.

1,3-Butadiene, a potential human carcinogen widely used in industry, is oxidized by cytochrome P450 to diepoxybutane (DEB), which is the most mutagenic of the known butadiene metabolites. Assessment of the toxicological significance of DEB formation in humans and animals requires identification of a biomarker uniquely associated with DEB for use in molecular dosimetry studies. We wished to develop a specific and sensitive assay for one such suitable marker, the cyclic adduct 2-(3,4-dihydroxypyrrolidin-1-yl)-3-methylbutyramide (pyr-V), which is formed from addition of DEB to the terminal Val of the alpha- and beta-chains of hemoglobin. We needed to prepare a pure, rigorously characterized DEB-modified N-terminal oligopeptide for raising antibodies both to use in an immunoaffinity purification step and to standardize the assay. In addition, we needed a pure isotopomer to serve as an internal standard for quantitation by LC-MS. Direct modification of the globin sequences by reaction with DEB in vitro proved to be unproductive. We therefore opted to synthesize the cyclic Val adduct and incorporate it by FMOC chemistry into the appropriate oligopeptide sequences. In vitro and in vivo, butadiene is oxidized to enantiomeric and meso forms of DEB. A priori, all three DEB isomers are expected to form pyr-V adducts, resulting in three diastereomeric N-terminal peptides. We therefore synthesized a mixture of the cyclic Val diastereomers as their methyl esters by reaction of DEB with l-Val methyl ester hydrochloride. After protection as the di-O-tert-butyl derivatives, the mixture of 2-(3,4-di-t-butoxypyrrolidin-1-yl)-3-methylbutyric acid diastereomers was incorporated as the N-terminal residue into the 1-11 human globin alpha-chain sequence VLSPADKTNVK. The presence of the three diastereomers was confirmed by two-dimensional correlation NMR spectroscopy and temperature-dependent (1)H NMR. This strategy enabled us to obtain pure, rigorously characterized haptens in quantity for the preparation of polyclonal antibodies. Use of FMOC-protected (2)H(3)-Leu in the automated oligopeptide synthesis provided the required isotopomers for use as internal standard.

Amides↗
PubMed2004

Stereospecific structural perturbations arising from adenine N(6) butadiene triol adducts in duplex DNA.

Butadiene is oxidized in vivo to form stereoisomeric butadiene diol epoxides (BDE). These react with adenine N(6) in DNA yielding stereoisomeric N(6)-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl (BDT) adducts. When replicated in Escherichia coli, the (2R,3R)-N(6)-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl adduct yielded low levels of A-->G mutations whereas the (2S,3S)-N(6)-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl butadiene triol adduct yielded low levels of A-->C mutations [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutagen. 35, 48-56]. Accordingly, the structure of the (2R,3R)-N(6)-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl adduct at position X(6) in d(CGGACXAGAAG).d(CTTCTTGTCCG), the ras61 R,R-BDT-(61,2) adduct, was compared to the corresponding structure for the (2S,3S)-N(6)-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl adduct in the same sequence, the ras61 S,S-BDT-(61,2) adduct. Both the R,R-BDT-(61,2) and S,S-BDT-(61,2) adducts are oriented in the major groove of the DNA, accompanied by modest structural perturbations. However, structural refinement of the two adducts using a simulated annealing restrained molecular dynamics (rMD) approach suggests stereospecific differences in hydrogen bonding between the hydroxyl groups located at the beta- and gamma-carbons of the BDT moiety, and T(17) O(4) of the modified base pair X(6).T(17). The rMD calculations predict hydrogen bond formation between the gamma-OH and the T(17) O(4) in the R,R-BDT-(61,2) adduct whereas in the S,S-BDT-(61,2) adduct, hydrogen bond formation is predicted between the beta-OH and the T(17) O(4). This difference positions the two adducts differently in the major groove. This may account for the differential mutagenicity of the two adducts and suggests that the two adducts may interact differentially with other DNA processing enzymes. With respect to mutagenesis in E. coli, the minimal perturbation of DNA induced by both major groove adducts correlates with their facile bypass by three E. coli DNA polymerases in vitro and may account for their weak mutagenicity [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutagen. 35, 48-56].

Adenine↗
PubMed2006

Synthesis and mutagenesis of the butadiene-derived N3 2'-deoxyuridine adducts.

1,3-Butadiene is a known carcinogen and mutagen that acts through a variety of metabolic intermediates that react with DNA, forming stable and unstable lesions on dG, dA, dC, and dT. The N3 2'-deoxyuridine adducts are a highly stable, stereoisomeric mixture of adducts derived from the reaction of cytosine with the monoepoxide metabolite of butadiene, followed by spontaneous deamination. In this study, the phosphoramidites and subsequent oligodeoxynucleotides containing the N3 2'-deoxyuridine adducts have been constructed and characterized. Using a single-stranded shuttle vector DNA, the mutagenic potential of these adducts has been tested following replication in mammalian cells. Replication past the N3 2'-deoxyuridine adducts was found to be highly mutagenic with an overall mutation yield of approximately 97%. The major mutations that were observed were C to T transitions and C to A transversions. In vitro, these adducts posed a complete block to both the Klenow fragment of Escherichia coli polymerase I and polymerase epsilon, while these lesions significantly blocked polymerase delta. These data suggested a possible involvement of bypass polymerases in the in vivo replication of these lesions. Overall, these findings indicate that the N3 2'-deoxyuridine adducts are highly mutagenic lesions that may contribute to butadiene-mediated carcinogenesis.

Base Sequence↗
PubMed1996

Characterization of urinary metabolites from Sprague-Dawley rats and B6C3F1 mice exposed to [1,2,3,4-13C]butadiene.

1,3-Butadiene (BD) is used in the production of synthetic rubber and other resins. Carcinogenic effects have been observed in laboratory animals exposed to BD, with mice being more sensitive than rats. Metabolic oxidation of butadiene to epoxides is believed to be a crucial step in the initiation of tumors by BD. However, limited information is available that describes the in vivo metabolism of BD. Male Sprague-Dawley rats and B6C3F1 mice were exposed to 800 ppm [1,2 3,4-13C]butadiene for 5 h, and urine was collected during and for 20 h following exposure. Urinary metabolites were characterized using 1- and 2-dimensional methods of NMR spectroscopy. Three metabolites previously detected in vivo, N-acetyl-S-(2-hydroxy-3-butenyl)-L-cysteine, N-acetyl-S-(1-(hydroxymethyl)-2-propenyl)-L-cysteine, and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine, were present in both rat and mouse urine, accounting for 87% and 73% of the total metabolites excreted, respectively. A fourth metabolite, previously detected in vitro, 3-butene-1,2-diol, was also present in both rat and mouse urine and comprised 5% and 3% of the total metabolites excreted, respectively. An additional metabolite detected only in mouse urine that is derived from glutathione conjugation with epoxybutene was identified as S-(1-(hydroxymethyl)-2-propenyl)-L-cysteine (4%). N-Acetyl-S-(1-hydroxy-3-butenyl)-L-cysteine (4%), detected in mouse urine, is a thiohemiacetal product of 3-butenal. Additionally, mice excreted N-acetyl-S-(3-hydroxypropyl)-L-cysteine (5%) and N-acetyl-S-(2-carboxyethyl)-L-cysteine (5%), which could be derived from further metabolism of N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine or from glutathione conjugation with acrolein. Mice excreted N-acetyl-S-(1-(hydroxymethyl)-3,4-dihydroxypropyl)-L-cysteine (5%), which could be derived from glutathione conjugation with diepoxybutane (BDE), while rats excreted 1,3-dihydroxypropanone (5%), which may be derived from hydrolysis of BDE. These studies indicate that reactive aldehydes are produced as metabolites of BD in vivo, in addition to the reactive monoepoxide and diepoxide of BD. The greater toxicity of BD in mice compared with rats may be attributed to the greater ability of rats to detoxify BDE via hydrolysis, and/or to the production of reactive aldehydes.

Administration, Inhalation↗
PubMed1997

Stereochemical aspects of 1,3-butadiene metabolism and toxicity in rat and mouse liver microsomes and freshly isolated rat hepatocytes.

1,3-Butadiene (BD) is a gas used heavily in the rubber and plastics industry. BD and its epoxide metabolites have been shown to be carcinogenic and mutagenic in rodents, and BD has been classified by IARC as a group 2A carcinogen. We have examined the role of stereochemistry in species-dependent metabolism and toxicity of BD. Diastereo- and enantioselective synthetic routes to butadiene monoxide (BMO), butadiene bisoxide (BBO), and 3,4-epoxybutane-1,2-diol isomers have been developed. These routes have allowed the development of chiral gas chromatographic and GC/MS analytical procedures for quantitation of these metabolites in biological experiments. We have utilized hepatic microsomes from male B6C3F1 mice and hepatic microsomes and intact hepatocytes from male Sprague-Dawley rats as experimental systems. At 30 min, BMO production from BD was two times higher in mouse hepatic microsomes than in rats, and stereoselective analysis was used to determine the relative formation of (R)- and (S)-BMO. Formation of BBO from both (R)- and (S)-BMO was characterized in rat and mouse microsomal systems. As expected, more BBO was formed in mouse hepatic microsomes (3-4-fold) than in rat hepatic microsomes. No difference in total BBO formed from either isomer was observed in rat microsomes, but in mouse microsomes significantly more BBO was produced from (S)-BMO than from (R)-BMO. The cytotoxicity of each BMO and BBO enantiomer was examined in freshly isolated rat hepatocytes. (R)-BMO showed greater cytotoxicity than (S)-BMO. Stereospecific cytotoxicity was also observed using BBO enantiomers and (meso)-BBO was more cytotoxic than either the (R:R) or the (S:S)-BBO. The results show that stereochemistry plays an important role in BD metabolism and cytotoxicity and for the purposes of risk assessment needs to be compared across species.

Animals↗
PubMed1998

Inactivations of p16INK4a-alpha, p16INK4a-beta and p15INK4b genes in 2',3'-dideoxycytidine- and 1,3-butadiene-induced murine lymphomas.

The p16INK4a (alpha and beta form) and p15INK4b genes were analysed for homozygous deletion, hypermethylation and point mutation in B6C3F1 mouse lymphomas induced by 2',3'-dideoxycytidine or 1,3-butadiene. Although the p16INK4a-alpha gene appeared normal in DNA from 2',3'-dideoxycytidine-induced lymphomas, Southern analyses revealed homozygous deletions or rearrangements of the p16INK4a-beta and/or p15INK4b genes in four of 16 tumours. Surprisingly, two of these lymphomas showed exclusive deletions of the p16INK4a EIbeta exon. The p15INK4b promoter region was hypermethylated in two additional 2',3'-dideoxycytidine-induced lymphomas. In contrast, homozygous deletions spanning the p16INK4a and p15INK4b loci were observed in only two of 31 1,3-butadiene-induced tumours. Thus, these cyclin dependent kinase inhibitor genes may play a significant role in chemically induced mouse lymphomas and support the contention of tumour suppressor activity for the p19ARF protein encoded by the p16INK4a-beta gene. Different genetic pathways may be involved in the development of these chemically induced tumours since we have previously shown that mutations in p53 and ras genes are common in 1,3-butadiene- but not 2',3'-dideoxycytidine-induced lymphomas.

Animals↗
PubMed2002

Frequent mutations of the Trp53, Hras1 and beta-catenin (Catnb) genes in 1,3-butadiene-induced mammary adenocarcinomas in B6C3F1 mice.

DNAs from 1,3-butadiene-induced mammary adenocarcinomas of B6C3F1 mice were examined for mutations in the Trp53 gene, the ras gene family and several components of the Wnt signaling pathway, including beta-catenin (Catnb), Apc and Axin. Trp53 mutations were detected in 41% (7 out of 17) of tumors. Each tumor with a Trp53 mutation also exhibited loss of the wild-type Trp53 allele, supporting the importance of Trp53 inactivation during development of these tumors. Analyses of the Hras1, Kras2 and Nras proto-oncogenes revealed Hras1 mutations in 53% (9 out of 17) of tumors. Seven of these mutations were a G-->C transversion in Hras1 codon 13, consistent with a 1,3-butadiene-specific Kras2 mutation previously reported in several other tumor types. Mutation screens in Catnb exon 2, the Apc mutation cluster region and the Catnb-binding domain of the Axin gene identified Catnb missense mutations in 3 out of 17 (18%) tumors. In total, mutations of the Trp53, Hras1 and/or Catnb genes were identified in 15 out of 17 1,3-butadiene-induced mammary adenocarcinomas. These results indicate that multiple genetic pathways are disrupted in chemically induced mammary tumors, and that studies in mouse models may help to understand the etiology of human breast cancers.

Adenocarcinoma↗
PubMed2005

Coexistence of 1,3-butadiene conformers in ionization energies and Dyson orbitals.

The minimum-energy structures on the torsional potential-energy surface of 1,3-butadiene have been studied quantum mechanically using a range of models including ab initio Hartree-Fock and second-order Møller-Plesset theories, outer valence Green's function, and density-functional theory with a hybrid functional and statistical average orbital potential model in order to understand the binding-energy (ionization energy) spectra and orbital cross sections observed by experiments. The unique full geometry optimization process locates the s-trans-1,3-butadiene as the global minimum structure and the s-gauche-1,3-butadiene as the local minimum structure. The latter possesses the dihedral angle of the central carbon bond of 32.81 degrees in agreement with the range of 30 degrees-41 degrees obtained by other theoretical models. Ionization energies in the outer valence space of the conformer pair have been obtained using Hartree-Fock, outer valence Green's function, and density-functional (statistical average orbital potentials) models, respectively. The Hartree-Fock results indicate that electron correlation (and orbital relaxation) effects become more significant towards the inner shell. The spectroscopic pole strengths calculated in the Green's function model are in the range of 0.85-0.91, suggesting that the independent particle picture is a good approximation in the present study. The binding energies from the density-functional (statisticaly averaged orbital potential) model are in good agreement with photoelectron spectroscopy, and the simulated Dyson orbitals in momentum space approximated by the density-functional orbitals using plane-wave impulse approximation agree well with those from experimental electron momentum spectroscopy. The coexistence of the conformer pair under the experimental conditions is supported by the approximated experimental binding-energy spectra due to the split conformer orbital energies, as well as the orbital momentum distributions of the mixed conformer pair observed in the orbital cross sections of electron momentum spectroscopy.

Butadienes↗
PubMed1979

Inhalation toxicity studies with 1,3-butadiene -- 1. Atmosphere generation and control.

1,3-butadiene, which is used extensively in the synthetic rubber industry, is a highly reactive, potentially explosive compound, presenting particular problems for the design and execution of inhalation toxicity studies. Before undertaking inhalation studies with butadiene, it was necessary to develop safe systems for the generation and control of stable exposure chamber atmospheres. Infrared and gas chromatographic analytical methods were adapted for monitoring the concentration and distribution of butadiene in exposure chambers, and for analysis of known impurities, particularly, t-butyl catechol and 4-vinyl-1-cyclohexene, in atmospheres generated for inhalation tests.

Air Pollutants↗
PubMed1982

A hematology survey of workers at a styrene-butadiene synthetic rubber manufacturing plant.

A previous epidemiologic study of the U.S. rubber industry indicated that there has been an excess of leukemia and lymphoma mortality among hourly workers at one styrene-butadiene rubber manufacturing plant. This investigation was a combined industrial hygiene and hematology cross-sectional survey at the same plant. The objectives of the survey were to quantify exposure levels for styrene, butadiene, benzene and toluene, and to relate these levels to hematologic variation. Personal air samples and blood specimens were obtained from 157 production workers. All exposure levels for the four chemicals assayed were well below recommended standards. The higher mean styrene (13.67 ppm) and butadiene (20.03 ppm) concentrations were found in the Tank Farm area; in all other departments the mean levels for the four chemicals were less than 2 ppm. The Tank Farm workers had slightly lower levels of circulating erythrocytes, hemoglobin, platelets and neutrophils, and slightly higher mean corpuscular red cell volumes and neutrophil band counts than the other workers. Overall, in this population there was no pronounced evidence of hematologic abnormality, as determined from examination of peripheral blood.

Adult↗
PubMed1994

In vivo metabolism of butadiene by mice and rats: a comparison of physiological model predictions and experimental data.

1,3-Butadiene (BD), a rodent carcinogen, is metabolized to mutagenic and potentially DNA-reactive epoxides, including butadiene monoepoxide (BMO) and butadiene diepoxide. A physiological model containing five tissue groups (liver, lung, fat, slowly perfused tissues and rapidly perfused tissues) and blood was developed to describe uptake and metabolism of inhaled BD and BMO. Maximal rates for hepatic and pulmonary metabolism of BD and hepatic metabolism of BMO incorporated into the model were extrapolated from in vitro data (Csanády et al., Carcinogenesis, 13, 1143-1153, 1992). Apparent enzyme affinities used in the model were identified to the values measured in vitro. Model stimulations for BD and BMO uptake were compared to results from experiments in which groups of male Sprague-Dawley rats and B6C3F1 mice were exposed to initial concentrations of 50-5000 p.p.m. BD in closed chamber experiments and published data on BMO uptake by rats and mice. Metabolic rate constants extrapolated from in vitro data stimulated both BMO and BD uptake from closed chambers. The Vmax for hepatic metabolism of BD extrapolated from in vitro studies was 62 mumol/kg/h for rats and 340 mumol/kg/h for mice, while the Vmax for pulmonary metabolism of BD was 1.0 and 22 for rats and mice, respectively. These results demonstrate the usefulness of data derived in vitro for predicting in vivo behavior. Model simulations were also conducted in which only hepatic metabolism of BD was incorporated. These simulations underestimated BD uptake for mice, but not rats. Inclusion of in vitro-derived rates of pulmonary metabolism of BD into the model improved the fit to the data for mice. Since mice, but not rats, develop lung tumors after exposure to BD, these results point to the need for further characterize the metabolic capacity and target cells in the lung for BD and its metabolites. Once characterized, these models can be extended to predict in vivo behavior of BD in humans.

Animals↗
PubMed1995

Gender differences in the metabolism of 1,3-butadiene in Sprague-Dawley rats following a low level inhalation exposure.

1,3-Butadiene (BD), a compound used extensively in the rubber industry, is carcinogenic in the male and female Sprague-Dawley rats after chronic exposures to 1000 and 8000 p.p.m. In terms of incidence of tumors the majority were in mammary tissue, thus the incidence of tumors in female rats exceeded that in males in chronic carcinogenicity studies. In the present study the production and disposition of butadiene monoepoxide (BDO) and butadiene diepoxide (BDO2), mutagenic BD metabolites, were examined in male and female Sprague-Dawley rats following a low level inhalation exposure to BD. The rats were exposed to a target concentration of 62.5 p.p.m. BD by nasal inhalation for 6 h. Immediately after exposure blood, bone marrow, lung and fat samples were removed from all the animals and mammary tissue was removed from females. The samples were prepared by cryogenic-vacuum line distillation and analyzed for the epoxides using multidimensional gas chromatography-mass spectrometry. Levels of BDO in the blood were 25.9 +/- 2.9 and 29.4 +/- 2 pmol/g in male and females respectively. The levels of this metabolite were also similar in males and females in the other tissues examined. The greatest amounts of BDO were in fat (175 +/- 21 and 203 +/- 13 pmol/g in males and females respectively). Levels of BDO2 were approximately 5-fold greater in the blood of female rats compared with male rats. In the other tissues examined BDO2 was also consistently greater in tissues from females. In fat BDO2 was present at a concentration of 7.7 +/- 1.3 and 1.1 +/- 0.1 pmol/g tissue in females and males respectively. Mammary tissue from female rats contained 10.5 +/- 2.4 pmol/g BDO2, a level slightly lower than that observed in blood. The ratios of the two epoxides differed markedly between males and females in all tissues examined. Differences were most pronounced in lung and fat tissues, where BDO/BDO2 ratios were 9 and 0.6 (lung) and 159 and 26 (fat) for males and females respectively. This study is the first to describe a gender difference in the metabolism of BD. The greater production of the highly mutagenic BDO2 in females may play a role in the increased incidence of mammary tumors after chronic exposure to BD.

Administration, Inhalation↗
PubMed1995

Epidemiological and mechanistic data suggest that 1,3-butadiene will not be carcinogenic to humans at exposures likely to be encountered in the environment or workplace.

1,3-Butadiene (BD) is a carcinogen in both rats and mice with mice being substantially more sensitive than rats. It is not known if BD poses a carcinogenic risk for humans. Findings from exposure assessment studies indicate that potential industrial exposure to BD in monomer, polymer, and end-user industries is typically < 2 p.p.m. Epidemiologic studies of persons occupationally exposed to BD are inconclusive. In vitro metabolism of BD in rats, mice and human tissues indicate that there are significant quantitative species differences in the metabolic activation of BD to butadiene monoepoxide (BMO) and butadiene diepoxide (BDE) and the detoxication of BMO. Activation/detoxication ratios calculated using in vitro kinetic constants reveal that ratios in mice were 12-fold greater than rats and humans. In rats and mice exposed to BD, concentrations of BMO in blood and tissues of mice were up to 14-fold higher than in rats and BDE was only detected in mice thereby providing a strong argument for why mice are highly sensitive to BD carcinogenicity. The fact that human tissues do not appear to metabolize BMO to BDE to any significant extent suggest that humans may not be sensitive to BD carcinogenicity. In mice, BDE is a more potent carcinogen than BMO. BDE is mutagenic in vitro at the hprt locus in human TK6 lymphoblasts at concentrations that were 100-fold less than the concentration of BMO required to yield a similar mutation frequency. Importantly, the concentrations of BDE that were genotoxic in vitro are nearly identical to the concentrations of BDE measured in blood and tissues of mice exposed to BD by inhalation. BD is genotoxic in mice, but not rats, following inhalation exposure and this is paralleled by species differences in observed tumor susceptibility. BD is not genotoxic in occupationally-exposed workers. The genetic basis for BD carcinogenicity appears to be primarily through induction of point mutations and deletion events mediated via the potent genotoxic metabolite, BDE. The genotoxic endpoints induced by BDE (e.g., deletion and point mutations) rather than BMO (e.g., point mutations) likely represent the underlying mechanism responsible for the striking species differences observed in the genotoxicity and carcinogenicity of BD in mice versus rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Physiologically based pharmacokinetic modeling of 1,3-butadiene, 1,2-epoxy-3-butene, and 1,2:3,4-diepoxybutane toxicokinetics in mice and rats.

1,3-Butadiene (BD) is a more potent tumor inducer in mice than in rats. BD also shows striking differences in metabolic activation, with substantially higher blood concentrations of 1,2:3,4-diepoxybutane (butadiene diepoxide; BDE) in BD-exposed mice than in similarly exposed rats. The objective of this study was to develop a single mechanistic model structure capable of describing BD disposition in both species. To achieve this objective, known pathways of 1,2-epoxy-3-butene (butadiene monoepoxide; BMO) and BDE metabolism were incorporated into a physiologically based pharmacokinetic model by scaling rates determined in vitro. With this model structure, epoxide clearance was underestimated for both rats and mice. Improved simulation of blood epoxide concentrations was achieved by addition of first-order metabolism in the slowly perfused tissues, verified by simulation of data on the time course for BMO elimination after i.v. injection of BMO. Blood concentrations of BD were accurately predicted for mice and rats exposed by inhalation to constant concentrations of BD. However, if all BD was assumed to be metabolized to BMO, blood concentrations of BMO were overpredicted. By assuming that only a fraction of BD metabolism produces BMO, blood concentrations of BMO could be predicted over a range of BD exposure concentrations for both species. In vitro and in vivo studies suggest an alternative cytochrome P-450-mediated pathway for BD metabolism that does not yield BMO. Including an alternative pathway for BD metabolism in the model also gave accurate predictions of blood BDE concentrations after inhalation of BD. Blood concentrations of BMO and BDE observed in both mice and rats are best explained by the existence of an alternative pathway for BD metabolism which does not produce BMO.

Administration, Inhalation↗