Metabolism of 1,3-butadiene: inhalation pharmacokinetics and tissue dosimetry of butadiene epoxides in rats and mice

Himmelstein, Matthew W.; Turner, Max J.; Asgharian, Bahman; Bond, James A.

doi:10.1016/0300-483x(96)03462-2

Cited by 32 publications

(33 citation statements)

References 9 publications

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“…Be that as it may, it is remarkable that A:T3 T:A transversions occurred at similar mutant fractions in the Hprt gene of mice and rats exposed to BD while G:C3 C:G transversions were significantly increased only in mice exposed to BD (current study) or DEB (Tables VI-VIII). BD-exposed mice form substantial amounts of DEB, while metabolism of BD in the rat yields little to no DEB [Himmelstein et al, 1994[Himmelstein et al, , 1995[Himmelstein et al, , 1996Thornton-Manning et al, 1995a,b, 1996. These data suggest that metabolism of BD to DEB may be one basis for BD-induced G:C3 C:G transversions, but the ultimate sources of both G:C3 C:G and A:T3 T:A transversions in BD-induced tumors remain important questions that may clarify species differences in cancer risk.…”

Section: Discussionmentioning

confidence: 92%

“…BD is an indirect alkylating agent via its in vivo metabolism to several DNA-reactive metabolites, including 1,2-epoxy-3-butene (EB; butadiene monoepoxide), 1,2:3,4-diepoxybutane (DEB; butadiene diepoxide), and 3,4-epoxy-1,2-butanediol (EBD; butadiene diol epoxide). Two of these three metabolites (i.e., EB and DEB) are present in tissues of BD-exposed mice and rats, and the greater carcinogenic susceptibility of the mouse compared with the rat correlates with the circulating levels of these genotoxic intermediates in animals exposed to the same levels of the parent compound [Himmelstein et al, 1994[Himmelstein et al, , 1995[Himmelstein et al, , 1996Thornton-Manning et al, 1995a,b, 1996. Different mutagenic efficiencies of BD metabolites have been demonstrated in in vitro studies, with the potency order of DEB ӷ EB Ͼ EBD [Cochrane and Skopek, 1994a].…”

Section: Introductionmentioning

confidence: 99%

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Characterization ofHprtmutations in cDNA and genomic DNA of T‐cell mutants from control and 1,3‐butadiene‐exposed male B6C3F1 mice and F344 rats

Meng

Walker

Scott

et al. 2004

Environ and Mol Mutagen

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A multiplex PCR procedure for analysis of genomic DNA mutations in the mouse hypoxanthine-guanine phosphoribosyltransferase (Hprt) gene was developed and then used with other established methods for the coincident identification of large- and small-scale genetic alterations in the Hprt gene of mutant T-cell isolates propagated from sham- and 1,3-butadiene (BD)-exposed mice and rats. The spectra data for RT-PCR/cDNA analysis and multiplex PCR of genomic DNA from Hprt mutants were combined, and statistical analyses of the mutant fractions for the classes of mutations identified in control versus exposed animals were conducted. Under the assumption that the mutant fractions are distributed as Poisson variates, BD exposure of mice significantly increased the frequencies of (1) nearly all types of base substitutions; (2) single-base deletions and insertions; and (3) all subcategories of deletions. Significantly elevated fractions of G:C-->C:G and A:T-->T:A transversions in the Hprt gene of BD-exposed mice were consistent with the occurrence of these substitutions as the predominant ras gene mutations in multiple tumor types increased in incidence in carcinogenicity studies of BD in mice. BD exposure of rats produced significant increases in (1) base substitutions only at A:T base pairs; (2) single-base insertions; (3) complex mutations; and (4) deletions (mainly 5' partial and complete gene deletions). Future coincident analyses of large- and small-scale mutations in rodents exposed to specific BD metabolites should help identify species differences in the sources of deletion mutations and other types of mutations induced by BD exposures in mice versus rats.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Characterization ofHprtmutations in cDNA and genomic DNA of T‐cell mutants from control and 1,3‐butadiene‐exposed male B6C3F1 mice and F344 rats

Meng

Walker

Scott

et al. 2004

Environ and Mol Mutagen

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“…Rats were loaded into nose-only tubes equipped with an opening that enabled the threading of a jugular cannula so that blood could be collected from the rat during the exposure while on the tower (Himmelstein et al, 1996). Approximately 100 µl of blood was collected from rats prior to exposure (0 min) and at ca.…”

Section: Collection Of Bloodmentioning

confidence: 99%

Blood pharmacokinetics of tertiary amyl methyl ether in male and female F344 rats and CD‐1 mice after nose‐only inhalation exposure

Sumner¹,

Janszen²,

Asgharian³

et al. 2003

J of Applied Toxicology

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Interest in understanding the biological behavior of aliphatic ethers has increased owing to their use as gasoline additives. The purpose of this study was to investigate the blood pharmacokinetics of the oxygenate tertiary amyl methyl ether (TAME), its major metabolite tertiary amyl alcohol (TAA) and acetone in rats and mice following inhalation exposure to TAME. Species differences in the area under the curve (AUC) for TAME were significant at each exposure concentration. For rats, the blood TAME AUC increased in proportion with an increase in exposure concentration. For mice, an increase in exposure concentration (100-500 ppm) resulted in a disproportional increase in the TAME AUC. Mice had greater (two- to threefold) blood concentrations of TAA compared with rats following exposure to 2500 or 500 ppm TAME. Mice had a disproportional increase in the TAA AUC with an increase in exposure concentration (100-500 ppm). This difference could result from saturation of a process (e.g. oxidation, glucuronide conjugation) that is involved in the further metabolism of TAA. For each species, gender and exposure concentration, acetone increased during exposure and returned to control values by 16 h following exposure. The source of acetone could be both as a metabolite of TAA or an effect on endogenous metabolism produced by exposure to TAME.

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“…Seaton et al (1996) and Himmelstein et al (1996) suggested that differences in metabolic activation of BD may lead to species differences in carcinogenicity sensitivity. Thornton-Manning et al (1996) reported gender differences observed in BD metabolism of Sprague-Dawley rats.…”

Section: Introductionmentioning

confidence: 99%

“…Thornton-Manning et al (1996) reported gender differences observed in BD metabolism of Sprague-Dawley rats. Himmelstein et al (1996) identified male mice's lung and liver to be among the tissues that developed tumors at or above 62.5 ppm of BD exposure; whereas, females exposed to as low as only 6 ppm also developed tumors. In animal studies of mice and rats, pharmacokinetics models have also been used to estimate the rate of BD metabolism (Csanady et al 1996;Himmelstein et al 1996;Leavens and Bond 1996;Shargel and Yu 1999;Sweeney et al 1996).…”

Section: Introductionmentioning

confidence: 99%

Estimating metabolic rate for butadiene at steady state using a Bayesian physiologically-based pharmacokinetic model

et al. 2009

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In a study of 133 volunteer subjects, demographic, physiologic and pharmacokinetic data through exposure to 1,3-Butadiene (BD) were collected in order to estimate the percentage of BD concentration metabolized at steady state, and to determine whether this percentage varies across gender, racial, and age groups. During the 20 min of continuous exposure to 2 parts per million (ppm) of BD, five measurements of exhaled concentration were made on each subject. In the following 40 min washout period, another five measurements were collected. A Bayesian hierarchical compartmental physiologically-based pharmacokinetic model (PKPB) was used. Using prior information on the model parameters, Markov Chain Monte Carlo (MCMC) simulation was conducted to obtain posterior distributions. The overall estimate of the mean percent of BD metabolized at steady state was 12.7% (95% credible interval: 7.7-17.8%). There was no significant difference in gender with males having a mean of 13.5%, and females 12.3%. Among the racial groups, Hispanic (13.9%), White (13.0%), Asian (12.1%), and Black (10.9%), the significant difference came from the difference between Black and Hispanic with a 95% credible interval from −5.63 to −0.30%. Those older than 30 years had a mean of 12.2% versus 12.9% for the Stat (2011) 18:131-146 younger group; although this was not a statistically significant difference. Given a constant inhalation input of 2 ppm, at steady state, the overall mean exhaled concentration was estimated to be 1.75 ppm (95% credible interval: 1.64-1.84). An equivalent parameter, first-order metabolic rate constant, was also estimated and found to be consistent with the percent of BD metabolized at steady state across gender, race, and age strata.123 132 Environ Ecol

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Metabolism of 1,3-butadiene: inhalation pharmacokinetics and tissue dosimetry of butadiene epoxides in rats and mice

Cited by 32 publications

References 9 publications

Characterization ofHprtmutations in cDNA and genomic DNA of T‐cell mutants from control and 1,3‐butadiene‐exposed male B6C3F1 mice and F344 rats

Characterization ofHprtmutations in cDNA and genomic DNA of T‐cell mutants from control and 1,3‐butadiene‐exposed male B6C3F1 mice and F344 rats

Blood pharmacokinetics of tertiary amyl methyl ether in male and female F344 rats and CD‐1 mice after nose‐only inhalation exposure

Estimating metabolic rate for butadiene at steady state using a Bayesian physiologically-based pharmacokinetic model

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