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PubMed1984

NTP Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS No. 106-99-0) in B6C3F1 Mice (Inhalation Studies).

1,3-Butadiene is used as an intermediate in the production of elastomers, polymers, and other chemicals. Of the 1,3-butadiene used in 1978, 44% was used to manufacture styrene-butadiene rubber (a substitute for natural rubber, produced by copolymerization of 1,3-butadiene with styrene), and 19% was used to produce polybutane elastomer (a substance that increases resistance of tire products to wear, heat degradation, and blowouts). Chloroprene monomer, derived from 1,3-butadiene, is used exclusively to manufacture neoprene elastomers for non-tire and latex applications. Commercial nitrile rubber, used largely in rubber hoses, seals, and gaskets for automobiles, is a copolymer of 1,3-butadiene and acrylonitrile. Acrylonitrile- butadiene- styrene resins, usually containing 20%-30% 1,3-butadiene by weight, are used to make parts for automobiles and appliances. Other polymer uses include specialty polybutadiene polymers, thermoplastic elastomers, nitrile barrier resins, and K resins(R). 1,3-Butadiene is used as an intermediate in the production of a variety of industrial chemicals, including two fungicides, captan and captofol. It is approved by the U.S. Food and Drug Administration for use in the production of adhesives used in articles for packaging, transporting, or holding food; in components of paper and paperboard that are in contact with dry food; and as a modifier in the production of semigrid and rigid vinyl chloride plastic food-contact articles. No information was located on the levels of monomer or on its elution rate from any of the commercially available polymers. It is not known if unreacted 1,3-butadiene migrated from packaging materials. Male and female B6C3F1 mice were exposed to air containing 1,3-butadiene (greater than 99% pure) at concentrations of 0-8,000 ppm in 15-day and 14-week inhalation studies. In the 15-day studies, survival was unaffected by dose, and no pathologic effects were observed; slight decreases in mean body weight occurred at the high concentrations. In the 14-week studies, mean body weight gain decreased with dose, and survival in the 5,000-ppm and 8,000-ppm groups of males was markedly reduced; no other compound-related effects were reported. Inhalation carcinogenesis studies of 1,3-butadiene were conducted by exposing groups of 50 male and female B6C3F1 mice 6 hours per day for 5 days per week to air containing the test chemical at concentrations of 0 (chamber controls), 625, or 1,250 ppm. These studies were planned for 103-week exposures but were terminated at week 60 for male mice and week 61 for female mice because of the rapidly declining survival, primarily due to neoplasia. Body weights were not affected by 1,3-butadiene. Significantly increased incidences of neoplasms at multiple sites were observed in mice exposed to 1,3-butadiene. Hemangiosarcomas of the heart occurred at increased incidences in exposed males and females (male: control, 0/50; low dose, 16/49; high dose, 7/49; female: 0/50; 11/48; 18/49). Hemangiosarcomas were also observed in the peritoneal cavity (one high dose male), subcutaneous tissue (two low dose females), and liver (one high dose female). Malignant lymphomas, diagnosed as early as week 20, were observed at increased incidences in exposed male and female mice (male: 0/50; 23/50; 29/50; female: 1/50; 10/49; 10/49). Alveolar/bronchiolar adenomas and alveolar/bronchiolar (both separately and combined) occurred at increased incidences in exposed male and female mice (combined incidences -- male: 2/50; 14/49; 15/49; female: 3/49; 12/48; 23/49). Epithelial hyperplasia of the forestomach occurred at increased incidences in dosed mice (male: 0/49; 5/40; 7/44; female: 0/49; 5/42; 9/49). Papillomas of the forestomach occurred in low dose male and in low dose and high dose female mice (male: 0/49; 5/40; 0/44; female: 0/49; 4/42; 10/49). Squamous cell carcinomas of the forestomach were observed in dosed mice (male: 0/49, 2/40, 1/44; female: 0/49, 1/42, 1/49). Acinar cell carcinomas of the mammary gland were observed at an increased incidence in high dose female reased incidence in high dose female mice (0/50; 2/49; 6/49); adenosquamous carcinomas were found in four low dose females. The incidences of granulosa cell tumors of the ovary were increased in dosed females (0/49; 6/45; 12/48). A granulosa cell carcinoma was observed in another high dose female. Gliomas were observed in two 68- to 69-week-old low dose and one high dose male mice; brain tumors are uncommon even in 2-year old mice. Liver necrosis occurred at increased incidences in dosed male and low dose female mice (male; 1/50, 8/49, 8/49; female: 6/50, 15/47, 6/49). Hepatocellular adenomas or carcinomas (combined) were observed at an increased incidence in high dose female mice (0/50, 2/47 5/49). No neoplastic lesions of the nasal cavity were observed at any dose level. The following nonneoplastic lesions of the nasal cavity occurred in mice exposed at 1,250 ppm: chronic inflammation (male, 35/50; female, 2/49); fibrosis (male, 33/50; female, 2/49); cartilaginous metaplasia (male, 16/50; female, 1/49); osseous metaplasia (male, 11/50; female, 2/49); and atrophy of the sensory epithelium (male, 32/50). No nonneoplastic lesions of the nasal cavity were found in the controls. The incidence of testicular atrophy (0/50, 19/49, 11/48) or ovarian atrophy (2/49, 40/45, 40/48) was increased in exposed male or female mice. An audit of the experimental data from these studies on 1,3-butadiene was conducted by the National Toxicology Program. No data discrepancies were found that influenced the final interpretation of these experiments. Under the conditions of these studies, there was clear evidence of carcinogenicity for 1,3-butadiene in male and female B6C3F1 mice, as shown by increased incidences and early induction of hemangiosarcomas of the heart, malignant lymphomas, alveolar/bronchiolar adenomas and carcinomas, and papillomas of the stomach in males and females; and of acinar cell carcinomas of the mammary gland, granulosa cell tumors of the ovary, and hepatocellular adenomas and adenomas or carcinomas (combined) in females. 1,3-Butadiene was associated with nonneoplastic lesions in the respiratory epithelium, liver necrosis, and testicular or ovarian atrophy. Synonyms: butadiene; biethylene; bivinyl; divinyl; erythrene; vinylethylene; pyrrolylene

Journal Article↗
PubMed1996

Biomonitoring of 1,3-butadiene and related compounds.

The 1990 Clean Air Act Amendments list several volatile organic chemicals as hazardous air pollutants, including ethylene oxide, butadiene, styrene, and acrylonitrile. The toxicology of many of these compounds shares several common elements such as carcinogenicity in laboratory animals, genotoxicity of the epoxide intermediates, involvement of cytochrome P450 for metabolic activation (except ethylene oxide), and involvement of at least two enzymes for detoxication of the epoxides (e.g., hydrolysis or conjugation with glutathione). These similarities facilitate research strategies for identifying and developing biomarkers of exposure. This article reviews the current knowledge about biomarkers of butadiene. Butadiene is carcinogenic in mice and rats, which raises concern for potential carcinogenicity in humans. Butadiene is metabolized to DNA-reactive metabolites, including 1,2-epoxy-3-butene and diepoxybutane. These epoxides are thought to play a critical role in butadiene carcinogenicity. Butadiene and some of its metabolites (e.g., epoxybutene) are volatile. Exhalation of unchanged butadiene and excretion of butadiene metabolites in urine represent major routes of elimination. Therefore, biomonitoring of butadiene exposure could be based on chemical analysis of butadiene in exhaled breath, blood levels of butadiene epoxides, excretion of butadiene metabolites in urine, or adducts of butadiene epoxides with DNA or blood proteins. Mutation induction in specific genes (e.g., HPRT) following butadiene exposure can be potentially used as a biomarker. Excretion of 1,2-dihydroxy-4-(N-acetylcysteinyl-S)butane or the product of epoxybutene with N-7 in guanine in urine, epoxybutene-hemoglobin adducts, and HPRT mutation have been used as biomarkers in recent studies of occupational exposure to butadiene. Data in laboratory animals suggest that diepoxybutane may be a more important genotoxic metabolite than epoxybutene. Biomonitoring methods need to be developed for diepoxybutane and other putative reactive butadiene metabolites. With butadiene and related compounds, the ultimate challenge is to identify useful biomarkers of exposure in which quantitative linkages between exposure and internal dose of the important DNA-reactive metabolites are established.

Biomarkers↗
PubMed1992

1,3-Butadiene: toxicity and carcinogenicity in laboratory animals and in humans.

1,3-Butadiene is a high production volume chemical used largely in the manufacture of synthetic rubber. The production and use of 1,3-butadiene increased dramatically during World War II with the development of the synthetic rubber industry. Before the 1980s, 1,3-butadiene was not considered to be particularly hazardous to human health; therefore, OSHA established a permissible limit of 1,000 ppm for occupational exposure to this chemical. Results of recent inhalation carcinogenicity studies have demonstrated clearly that 1,3-butadiene is a multiple-organ carcinogen in Sprague-Dawley rats and in B6C3F1 mice. Particularly noteworthy in mice were the early occurrences and extensive development of lymphomas, the induction of uncommon hemangiosarcomas of the heart, and the development of malignant lung tumors at exposure concentrations as low as 6.25 ppm. Because 6.25 ppm was the lowest concentration ever used in a long-term carcinogenicity of this gas, it is likely that lower exposure levels would also cause cancers in laboratory animals. In addition, multiple organ site neoplasia was induced in mice after only 13 weeks of exposure. Two reactive epoxides, 1,2-epoxy-3-butene and diepoxybutane, have been identified as intermediates in the biotransformation of 1,3-butadiene in rats and mice. Metabolism is probably an important factor in the carcinogenicity of 1,3-butadiene, because in vitro mutagenicity of 1,3-butadiene requires metabolic activation, whereas these epoxide intermediates are direct acting mutagens in bacteria and are carcinogens in rats and mice. The metabolism of 1,3-butadiene in rats and mice is linear up to concentrations of at least 1000 ppm. Pharmacokinetic studies on 1,3-butadiene and on 1,2-epoxy-3-butene have revealed certain quantitative differences in metabolic rates between Sprague-Dawley rats and B6C3F1 mice; however, these differences were not of sufficient magnitude to account for the reported different target site carcinogenic responses in these two strains of animals. Thus, additional factors must be involved in distinguishing site specificity in the carcinogenicity of 1,3-butadiene between species. In addition to its carcinogenic effects, 1,3-butadiene is a potent in vivo genotoxic agent to mouse bone marrow cells. Hematologic changes indicative of a partially regenerative anemia were induced in mice at 62.5 and higher concentrations. 1,3-Butadiene is also a reproductive and developmental toxicant. Epidemiology studies of workers employed in the production of 1,3-butadiene or of styrene-butadiene rubber have consistently revealed associations between occupational exposure to 1,3-butadiene and excess mortality due to lymphatic and hematopoietic cancers.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗
PubMed1996

Metabolic interactions of 1,3-butadiene and styrene in male B6C3F1 mice.

Butadiene and styrene are a mixture of hazardous air pollutants found in the workplace of industries producing polymers such as styrene-butadiene rubber. Both butadiene and styrene require metabolic activation to exert their genotoxic effect; therefore metabolic interactions may influence their genotoxicity. Our objective was to quantitate potential metabolic interactions in mice exposed to a mixture of butadiene and styrene. The rate of metabolism of butadiene and styrene was estimated from the steady-state rate of uptake of the chemicals by male B6C3F1 mice exposed for 8 hr in a dynamic, whole-body inhalation system to 100 or 1000 ppm butadiene in combination with 0, 50, 100, or 250 ppm styrene. Styrene, styrene oxide, 1,2-epoxy-3-butene, and 1,2:3,4-diepoxybutane concentrations in blood were measured by gas chromatography-mass spectrometry at 2, 4, 6, and 8 hr of exposure. As the styrene concentration in the mixture increased, the rate of butadiene metabolism was inhibited up to 48%. 1,2-Epoxy-3-butene blood concentrations were increased by approximately 1.5-fold; however, 1,2:3,4-diepoxybutane blood concentrations were unaffected. Styrene uptake in the inhalation system was inhibited slightly by exposure with butadiene, but styrene blood concentrations increased significantly as the butadiene concentration in the mixture increased to 1000 ppm. Blood concentrations of styrene oxide increased approximately 1.6-fold for the 250-ppm styrene exposures when the butadiene concentration was increased from 0 to 1000 ppm. The data suggest that metabolic interactions occurred among the reactive metabolites (e.g., competition for detoxication pathways) as well as between butadiene and styrene in mice exposed to mixtures of butadiene and styrene. However, metabolic interactions were significant only at concentrations of butadiene and styrene higher than those typically observed in the workplace of industries producing polymers of butadiene and styrene.

Animals↗
PubMed1994

Human liver microsomes are efficient catalysts of 1,3-butadiene oxidation: evidence for major roles by cytochromes P450 2A6 and 2E1.

Previously, we provided evidence for the involvement of multiple cytochrome P450 enzymes in the metabolism of 1,3-butadiene, a rodent and possibly a human carcinogen, to butadiene monoxide in mouse and rat liver microsomes. In this study, 1,3-butadiene oxidation by seven cDNA-expressed human P450 enzymes and by human, mouse, and rat liver microsomes was characterized. Incubations with cDNA-expressed human P450 1A2, 2A6, 2B6, 2D6, and 2E1 resulted in the formation of butadiene monoxide, whereas incubations with P450 1A1 and 3A4 did not lead to the detection of any metabolite. Of the active isozymes examined, P450 2A6 and 2E1 were the most active when butadiene monoxide formation rates were normalized for the P450 content of the microsomes. With six human liver microsomal samples, 1,3-butadiene oxidation exhibited nearly threefold individual variation in the amounts of butadiene monoxide detected, and butadiene monoxide formation was NADPH- and time-dependent and was inhibited by the addition of 1-benzyl-imidazole or 4-methylpyrazole, known cytochrome P450 inhibitors. Correlation studies provided evidence for major roles by P450 2A6 and 2E1 in 1,3-butadiene oxidation in human liver microsomes. Butadiene monoxide formation rates in human liver microsomes were similar, or higher, than the rate obtained in mouse liver microsomes, whereas 1,3-butadiene oxidation rates in human and mouse liver microsomes were higher than the rate obtained in rat liver microsomes. These results provide direct evidence that 1,3-butadiene is a substrate for multiple P450 enzymes and suggest that humans may be at higher risk of expressing 1,3-butadiene toxicity compared to mice or rats. In addition, these results suggest that the mouse may be the more appropriate animal model to assess human risk.

Adult↗
PubMed1996

The use of toxicologic data in mechanistic risk assessment: 1,3-butadiene as a case study.

The National Research Council (NRC) recently published a report. Science and Judgment in Risk Assessment, that critiqued the current approaches to characterizing human cancer risks from exposure to chemicals. One issue raised in the report relates to the use of default options for quantitation of cancer risks. Default options are general guidelines that can be used for risk assessment when specific information about a chemical is absent. Research on 1,3-butadiene represents an interesting case study in which existing knowledge on this chemical indicates that two default options may no longer be tenable: (1) humans are as sensitive as the most sensitive animal species, and (2) the rate of metabolism is a function of body surface area rather than inherent species differences in metabolic capacity. Butadiene, a major commodity chemical used in the production of synthetic rubber, is listed as one of 189 hazardous air pollutants under the 1990 Clean Air Act Amendments. Butadiene is a carcinogen in rats and mice, with mice being substantially more sensitive than rats. The extent to which butadiene poses a cancer risk to humans exposed to this chemical is uncertain. Butadiene requires metabolic activation to DNA-reactive epoxides to exert its mutagenic and carcinogenic effects. Research is directed toward obtaining a better understanding of the cancer risks of butadiene in humans by evaluating species-dependent differences in the formation of the toxic butadiene epoxide metabolites, epoxybutene and diepoxybutane. The data include in-vitro studies on butadiene metabolism using tissues from humans, rats, and mice as well as experimental data and physiological model predictions for butadiene in blood and butadiene epoxides in blood, lung, and liver after exposure of rats and mice to inhaled butadiene. The findings suggest that humans are more like rats and less like mice regarding the formation of butadiene epoxides. The research approach employed can be a useful strategy for developing mechanistic and toxicokinetic data to supplant default options used in carcinogen risk assessments for butadiene.

Animals↗
PubMed1995

Sister-chromatid exchanges, glutathione S-transferase theta deletion and cytogenetic sensitivity to diepoxybutane in lymphocytes from butadiene monomer production workers.

The magnitude of health risks to workers associated with current and past exposures to butadiene has been the subject of considerable recent debate. Butadiene is metabolized in-vivo and in-vitro to the genotoxic intermediates 3,4-epoxybutene and diepoxybutane. Studies in animals and in-vitro systems have clearly demonstrated that 1,3-butadiene is a genotoxin and a potent inducer of sister-chromatid exchanges (SCEs). Data on the genotoxicity of butadiene in humans is, however, limited. Epidemiologic data indicate that butadiene is a probable human carcinogen. Recent work has further demonstrated that cultured lymphocytes from the approximately 20% of the Caucasian population that lack the glutathione S-transferase class theta gene (GSTT1) are relatively sensitive to the induction of cytogenetic damage by butadiene metabolites. In order to test whether butadiene exposure was associated with increases in SCE frequencies in peripheral blood lymphocytes and whether any increase observed could be affected by the DEB sensitivity-GSTT1 deletion, we studied 40 workers employed in the production of butadiene. In these workers baseline frequencies of SCEs, diepoxybutane-induced SCE frequencies and GSTT1 deletion status were assessed. Questionnaires were administered to each worker and exposure to 1,3-butadiene was determined using three separate approaches. Industrial hygiene personal sampling was used to measure breathing zone butadiene exposure and urine was collected to use in measurement of the urinary butadiene metabolite 1,2-dihydroxy-4-(N-acetylcysteinyl-S-)-butane (M1). Exposure to butadiene was generally below 2 ppm. The urinary metabolite M1 was found in all workers, but it did not correlate significantly with exposure. Six of 40 of the workers were GST theta-deleted DEB sensitive. No measure of acute or chronic exposure to butadiene was associated with an increase in SCE frequency. However, smoking and DEB sensitivity-GSTT1 null status were each significantly associated with elevations in baseline SCE frequency.

Adult↗
PubMed1991

Toxicokinetics of inhaled 1,3-butadiene in monkeys: comparison to toxicokinetics in rats and mice.

1,3-Butadiene is a potent carcinogen in mice and a weaker carcinogen in rats. People are exposed to butadiene through its industrial use--largely in rubber production (over 3 billion pounds of butadiene were produced in 1989)--and because it is common in the environment, occurring in cigarette smoke, gasoline vapor and in the effluents from fossil fuel incineration. Epidemiological studies have provided some evidence for butadiene carcinogenicity in people. Differences in the uptake and metabolism of inhaled butadiene between rodents and primates, including people, might be reflected in differences in its toxicity. In order to compare uptake and metabolism in primates to that in rodents--for which data were already available--we exposed cynomolgus monkeys (Macaca fascicularis) to 14C-labeled butadiene at concentrations of 10.1, 310 or 7760 ppm for 2 hr. Exhaled air and excreta were collected during exposure and for 96 hr after exposure. The uptake of butadiene as a result of metabolism was much lower in monkeys than in rodents. For equivalent inhalation exposures, the concentrations of total butadiene metabolites in the blood were 5-50 times lower in monkey than in the mouse, the more sensitive rodent species, and 4-14 times lower than in the rat. If the toxicokinetics of butadiene in people is more like that of the monkey than that of rodents, then our data suggest that people will receive lower doses of butadiene and its metabolites than rodents following equivalent inhalation exposures to butadiene. This has important implications for assessing the risk to humans of butadiene exposure based on animal studies.

Administration, Inhalation↗
PubMed1990

Inhalation toxicology and carcinogenicity of 1,3-butadiene in B6C3F1 mice following 65 weeks of exposure.

1,3-Butadiene, a large-production volume chemical used mainly in the manufacture of synthetic rubber, was found to induce multiple-organ carcinogenicity in male and female B6C3F1 mice at exposure concentrations (625 and 1250 ppm) equivalent to and below the OSHA standard of 1000 ppm. Since this study was terminated after 60 weeks of exposure because of reduced survival due to fatal tumors, and because dose-response relationships for 1,3-butadiene-induced neoplastic and nonneoplastic lesions were not clearly established, a second long-term inhalation study of 1,3-butadiene in B6C3F1 mice was conducted at lower exposure concentrations, ranging from 6.25 to 625 ppm. Both the histopathological findings from animals dying through week 65 and the results of evaluations of animals exposed for 40 and 65 weeks are presented in this report. Exposure to 1,3-butadiene caused a regenerative anemia at concentrations of 62.5 ppm and higher. Testicular atrophy was induced at 625 ppm, and ovarian atrophy was observed at 20 ppm and higher. During the first 50 weeks of the study, lymphocytic lymphoma was the major cause of death of mice exposed to 625 ppm 1,3-butadiene. Neoplasms of the heart, forestomach, lung, Harderian gland, mammary gland, ovary, and liver were frequently observed in 1,3-butadiene-exposed mice that died between week 40 and week 65 of the study. Studies in which exposure to 1,3-butadiene was stopped after limited periods were also included to assess the relationship between exposure levels and duration of exposures on the outcome of 1,3-butadiene-induced carcinogenicity. In these studies, lymphocytic lymphomas were induced in male mice exposed to 625 ppm 1,3-butadiene for only 13 weeks. The incidence of lymphocytic lymphoma in male mice exposed to 625 ppm 1,3-butadiene for 26 weeks was two times that in mice exposed to 625 ppm for 13 weeks. However, when the exposure concentration was reduced by half to 312 ppm and the exposure duration extended to 52 weeks, the incidence of lymphocytic lymphoma was reduced by 90%. Thus, the multiple of the exposure concentration times the exposure duration did not predict the incidence of lymphocytic lymphoma in mice. The early mortalities resulting from lymphocytic lymphomas in male mice exposed to 625 ppm 1,3-butadiene limited the expression of tumors at other sites. A clearer dose-response for 1,3-butadiene-induced neoplasia should be apparent from experiments in mice exposed to lower concentrations of this chemical for 2 years.

Air Pollutants, Occupational↗
PubMed1986

Species differences in the disposition of inhaled butadiene.

Recent chronic inhalation carcinogenicity studies of butadiene indicated that B6C3F1 mice are more sensitive to the tumorigenic effects of inhaled butadiene than are Sprague-Dawley rats. Tumors in mice included lymphomas, hemangiosarcomas, alveolar/bronchiolar adenomas and carcinomas, and hepatocellular adenomas and carcinomas whereas in rats tumors included mammary tumors, thyroid follicular cell adenomas, uterine tumors, and exocrine pancreatic adenomas. The purpose of this investigation was to determine if there were differences in the uptake and disposition of inhaled butadiene between rats and mice and if these differences were consistent with the differences in the species susceptibility to inhaled butadiene. Male Sprague-Dawley rats and B6C3F1 mice were exposed nose only to concentrations in the range of 0.14 to 13,000 micrograms [14C]butadiene/liter air (0.08 to 7100 ppm; 25 degrees C, 620 torr) for 6 hr. Blood samples were taken during exposure and urine, feces, and expired air were collected for up to 65 hr after exposure. In both rats and mice there was a significant (p less than 0.001) concentration-related decrease in the percentage of butadiene retained at the cessation of a 6-hr exposure with increasing butadiene exposure concentration, suggesting saturable metabolism of this chemical. At all concentrations of butadiene tested, mice retained about 4 to 7 times the amount (mumol/kg body wt) of butadiene and metabolites than did rats. In both species and at all butadiene concentrations tested, urine and exhaled air were the major routes of excretion of 14C, together accounting for 75 to 85% of the total 14C eliminated. In mice, for all concentrations tested, elimination of 14C in urine, feces, and exhaled air increased with increasing butadiene exposure concentration, although the increase was not proportional to exposure concentration. However, exposure of rats to 13,000 micrograms butadiene/liter air resulted in a leveling off in the amount of 14C that was eliminated in urine and a concomitant increase in exhalation of 14CO2. Analysis of blood samples taken during exposure indicated that the blood of mice contained 2 to 5 times the concentration of 1,2-epoxy-3-butene than did the blood of rats. The data from this study indicate that species differences exist in the amount retained and metabolism of inhaled butadiene.

Absorption↗
PubMed2000

Genotoxic markers among butadiene polymer workers in China.

While 1,3-butadiene is carcinogenic in rodents, cancer causation in humans is less certain. We examined a spectrum of genotoxic outcomes in 41 butadiene polymer production workers and 38 non-exposed controls, in China, to explore the role of butadiene in human carcinogenesis. Because in vitro studies suggest that genetic polymorphisms in glutathione S-transferase enzymes influence genotoxic effects of butadiene, we also related genotoxicity to genetic polymorphisms in GSTT1 and GSTM1. Among butadiene-exposed workers, median air exposure was 2 p.p.m. (6 h time-weighted average), due largely to intermittent high level exposures. Compared with unexposed subjects, butadiene-exposed workers had greater levels of hemoglobin N-(2,3,4-trihydroxybutyl)valine (THBVal) adducts (P < 0.0001) and adduct levels tended to correlate, among butadiene-exposed workers, with air measures (P = 0.03). Butadiene-exposed workers did not differ, however, from unexposed workers with respect to frequency of uninduced or diepoxybutane-induced sister chromatid exchanges, aneuploidy as measured by fluorescence in situ hybridization of chromosomes 1, 7, 8 and 12, glycophorin A variants or lymphocyte hprt somatic mutation. Also among the exposed, greater THBVal levels were not associated with increases in uninduced sister chromatid exchanges, aneuploidy, glycophorin A or hprt mutations. Butadiene-exposed workers had greater lymphocyte (P = 0.002) and platelet counts (P = 0.07) and lymphocytes as a percentage of white blood cells were moderately correlated with greater THBVal levels (Spearman's phi = 0.32, P = 0.07). Among butadiene-exposed workers, neither GSTM1 nor GSTT1 genotype status predicted urinary mercapturic acid butanediol formation, THBVal adducts, uninduced sister chromatid exchanges, aneuploidy or mutations in the glycophorin A or hprt genes. Overall, the study demonstrated exposure to butadiene in these workers, by a variety of short-term and long-term measures, but did not show specific genotoxic effects, at the chromosomal or gene levels, related to that exposure.

Adult↗
PubMed2004

Analysis of diepoxide-specific cyclic N-terminal globin adducts in mice and rats after inhalation exposure to 1,3-butadiene.

1,3-Butadiene is an important industrial chemical used in the production of synthetic rubber and is also found in gasoline and combustion products. It is a multispecies, multisite carcinogen in rodents, with mice being the most sensitive species. 1,3-Butadiene is metabolized to several epoxides that form DNA and protein adducts. Previous analysis of 1,2,3-trihydroxybutyl-valine globin adducts suggested that most adducts resulted from 3-butene-1,2-diol metabolism to 3,4-epoxy-1,2-butanediol, rather than from 1,2;3,4-diepoxybutane. To specifically examine metabolism of 1,3-butadiene to 1,2;3,4-diepoxybutane, the formation of the 1,2;3,4-diepoxybutane-specific adduct N,N-(2,3-dihydroxy-1,4-butadiyl)-valine was evaluated in mice treated with 3, 62.5, or 1250 ppm 1,3-butadiene for 10 days and rats exposed to 3 or 62.5 ppm 1,3-butadiene for 10 days, or to 1000 ppm 1,3-butadiene for 90 days, using a newly developed immunoaffinity liquid chromatography tandem mass spectrometry assay. In addition, 2-hydroxy-3-butenyl-valine and 1,2,3-trihydroxybutyl-valine adducts were determined. The analyses of several adducts derived from 1,3-butadiene metabolites provided new insight into species and exposure differences in 1,3-butadiene metabolism. Mice formed much higher amounts of N,N-(2,3-dihydroxy-1,4-butadiyl)-valine than rats. The formation of 2-hydroxy-3-butenyl-valine and N,N-(2,3-dihydroxy-1,4-butadiyl)-valine was similar in mice exposed to 3 or 62.5 ppm 1,3-butadiene, whereas 2-hydroxy-3-butenyl-valine was 3-fold higher at 1250 ppm. In both species, 1,2,3-trihydroxybutyl-valine adducts were much higher than 2-hydroxy-3-butenyl-valine and N,N-(2,3-dihydroxy-1,4-butadiyl)-valine. Together, these data show that 1,3-butadiene is primarily metabolized via the 3-butene-1,2-diol pathway, but that mice are much more efficient at forming 1,2;3,4-diepoxybutane than rats, particularly at low exposures. This assay should also be readily adaptable to molecular epidemiology studies on 1,3-butadiene-exposed workers.

Amino Acid Sequence↗
PubMed1990

Species differences in the metabolism and disposition of inhaled 1,3-butadiene and isoprene.

Species differences in sensitivity to carcinogenic effects from inhaled 1,3-butadiene might stem, at least in part, from differences in uptake, metabolism, and distribution of 1,3-butadiene. To examine this possibility, rats, mice, and monkeys were exposed to stepped concentrations of 14C-labeled 1,3-butadiene and the chemically related compound, isoprene. Respiratory data were collected during exposure and were used to determine fractional uptake. Rates and routes of excretion of retained radioactivity were also determined and blood levels of potentially toxic metabolites were measured. In some cases, the concentrations of hemoglobin adducts were determined. For rodents, the tissue distribution of metabolites was examined. Some results from these continuing studies to date are: a) mice achieve higher blood concentrations of reactive metabolites than do rats; b) blood levels of toxic metabolites are lower in monkeys than in rodents; c) uptake and retention of 1,3-butadiene is nonlinear in the range where long-term toxicity studies have been conducted; d) the efficiency of production of reactive metabolites decreases with increased inhaled concentrations of 1,3-butadiene; e) repeated exposure to 1,3-butadiene does not induce the metabolism of 1,3-butadiene in rodents; f) hemoglobin adducts of 1,3-butadiene are potential dosimeters of exposure; and g) rats inhaling isoprene produce reactive metabolites analogous to those produced during inhalation of 1,3-butadiene. The available data indicate that major differences in the biological fate of inhaled 1,3-butadiene occur among species, and these differences, at least in part, account for those in species sensitivity to the toxicity of inhaled 1,3-butadiene.

Administration, Inhalation↗
PubMed1992

1,3-Butadiene oxidation by human myeloperoxidase. Role of chloride ion in catalysis of divergent pathways.

1,3-Butadiene was oxidized by human myeloperoxidase in the absence of KCl to yield butadiene monoxide (BM) and crotonaldehyde (CA), but at KCl concentrations higher than 50 mM, 1-chloro-2-hydroxy-3-butene (CHB) was the major metabolite detected; metabolite formation was dependent on incubation time, pH, KCl, 1,3-butadiene, and H2O2 concentrations. The data are best explained by 1,3-butadiene being oxidized by myeloperoxidase by two different mechanisms. First, oxygen transfer from the hemoprotein would occur to either C-1 or C-4 of 1,3-butadiene to form an intermediate which may cyclize to form BM or undergo a hydrogen shift to form 3-butenal, an unstable precursor of CA. Further evidence for this mechanism was provided by the inability to detect methyl vinyl ketone, a possible product of an oxygen transfer reaction to C-2 or C-3 of 1,3-butadiene, and by the finding that CA was not simply a decomposition product of BM under assay conditions. In the second mechanism, however, chloride ion is oxidized by myeloperoxidase to HOCl which reacts with 1,3-butadiene to yield CHB. Further evidence for this mechanism was provided by the finding that CHB was readily formed when 1,3-butadiene was added to the filtrate of a myeloperoxidase/H2O2/KCl incubation and when 1,3-butadiene was allowed to react with authentic HOCl. In addition, CHB was not detected when BM or CA was incubated with myeloperoxidase, H2O2, and KCl for up to 60 min, or when 1,3-butadiene and KCl were incubated with chloroperoxidase and H2O2 or with mouse liver microsomes and NADPH, enzyme systems which catalyze 1,3-butadiene oxidation to BM and CA, but unlike myeloperoxidase, do not catalyze chloride ion oxidation to HOCl. These results provide clear evidence for novel olefinic oxidation reactions by myeloperoxidase.

Aldehydes↗
PubMed1993

Species differences in the metabolism of 1,3-butadiene in vivo.

The metabolism of 1,3-butadiene in vivo was studied in mice, rats and primates. The percentage of inhaled butadiene that is absorbed by exposed animals depends in large part on its rate of metabolism. Uptake of inhaled butadiene was 20% in B6C3F1 mice but only 4% in Sprague-Dawley rats and 3% in cynomolgus monkeys exposed to low levels (10 ppm 14C-butadiene or less). The routes of excretion of the carbon-14 retained after completion of the exposures were similar in rats and mice, one-half of the material being excreted in urine, 5-10% in faeces, 5-10% exhaled as carbon dioxide, 15-20% exhaled as volatile metabolites and 10-20% retained in the body. Monkeys, however, appeared to metabolize the retained 14C-butadiene more completely, as one-half of the internal dose of butadiene was exhaled as 14C-carbon dioxide. With equivalent exposures, blood metabolite levels were much higher in mice than in monkeys. In mice, the only species examined thus far, bone marrow was found to have much higher levels of butadiene monoepoxide per gram of tissue than did the blood, suggesting formation of the butadiene monoepoxide in the marrow in situ. The major urinary metabolites were two mercapturic acids (called M-I and M-II), formed from the glutathione conjugates of either butadiene monoepoxide (M-II) or the butenediol hydrolysis product of butadiene monoepoxide (M-I). Mice excrete three times as much M-II as M-I, corroborating the finding in vitro that mice are more efficient at forming the glutathione conjugate of butadiene monoepoxide than in hydrolysing it to the butenediol.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed2003

Metabolic distribution of radioactivity in Sprague-Dawley rats and B6C3F1 mice exposed to 1,3-[2,3-14C]-butadiene by whole body exposure.

The uptake of 1,3-[2,3-(14)C]-butadiene and its disposition, measured as radioactivity in urine, faeces, exhaled volatiles and CO(2) during and following 6 h whole body exposure to 20 ppm butadiene has been investigated in male Sprague-Dawley rats and B6C3F1 mice. Whilst there were similarities between the two species, the uptake and metabolic distribution of butadiene were somewhat different for rats and mice. The major differences observed were in the urinary excretion of radioactivity and in the exhalation of 14C-CO(2). After 42 h from the start of exposure, 51.1% of radioactivity was eliminated in rat urine compared with 39.5% for mouse urine. 34.9% of the recovered radioactivity was exhaled by rats as 14C-CO(2), compared with 48.7% by mice. Excretion of radioactivity in faeces was similar for both species (3.8% for rats and 3.4% for mice). The tissue concentrations of 14C-butadiene equivalents measured in liver, testes, lung and blood of exposed mice were 0.493, 0460, 0.457, and 1.626 nmol/g tissue, respectively. The values for the corresponding rat tissues were 0.869, 0.329, 0.457, and 1.626 nmol butadiene equivalents/g tissue, respectively. For rats, 6.2% of recovered radioactivity (0.288 nmol butadiene equivalents/g tissue) was retained in carcasses whereas for mice the amount was 3.6% (0.334 nmol butadiene equivalents/g tissue). There were also some significant differences between the metabolic conversion of 1,3-[2,3-(14)C]-butadiene and excretion by mice following the 20 ppm whole body exposure compared to previously reported data for nose-only exposure to 200 ppm butadiene [Richardson et al., Toxicol. Sci. 49 (1999) 186]. The main difference between the high- and low-exposure studies was in the exhalation of 14C-CO(2). At the 200 ppm exposure, 40% of the radioactivity was exhaled as 14C-CO(2) by rats whereas 6% was measured by this route for mice. The proportional conversion of butadiene to CO(2) by mice was significantly greater at the low exposure concentration compared with that reported for the higher concentration. This shift was not observed for rats. The difference between species could be caused by a saturation of metabolism in mice between 20 and 200 ppm for the pathways leading to CO(2). Restraint or error in collection of CO(2) in the 200 ppm study could also be factors.

Animals↗
PubMed1997

Abnormal DNA repair activities in lymphocytes of workers exposed to 1,3-butadiene.

Exposure to high concentrations of butadiene has been shown to cause cancer among exposed workers. We have conducted a biomarker study to elucidate whether current butadiene exposure conditions are hazardous to workers. Twenty-four workers exposed consistently to butadiene were matched with 19 co-workers who had much less contact with butadiene and who served as our controls. In the standard cytogenetic assay, there was no difference in chromosome aberration frequencies between the exposed and control groups. In the challenge assay, the exposed group shows a consistent, but non-significant, increase in chromosome aberrations indicating some abnormality in DNA repair response. The observed dicentric frequency in the challenge assay (indicative of abnormal repair of damaged chromosomes) is significantly correlated with a butadiene metabolite, 1,2-dihydroxy-4-(N-acetylcysteinyl)butane, in urine (r = 0.52; p = 0.04). Furthermore, cigarette smokers had consistently abnormal repair response compared with non-smokers for both the control and exposed groups. A small subset of the studied workers were evaluated for toxicant-induced DNA repair deficiency using an independent cat-host cell reactivation (CAT-HCR) assay. When cigarette smokers and non-smokers were combined in our analysis, we observed that the exposed group (n = 9) had a significant reduction of DNA repair activities (p = 0.009) compared with the control group (n = 6). Cigarette smoking contributed significantly to the effect as exposed smokers (n = 4) had a significant reduction in DNA repair activities (p = 0.04) compared with exposed non-smokers. The results from the two independently conducted assays support each other and confirm the previously reported abnormal DNA repair response in another group of butadiene workers. In conclusion, our data indicates that exposure to environmental toxicants, such as butadiene, can cause DNA repair defects. Therefore, the current butadiene exposure conditions are still hazardous to workers. However, our data indicates that butadiene is not a potent genotoxic agent. Furthermore, the butadiene-induced effect is significantly enhanced by the cigarette smoking habit.

Adult↗
PubMed1987

Species differences in the distribution of inhaled butadiene in tissues.

1,3-Butadiene is produced commercially for use in the manufacture of elastomers, polymers and other chemicals. Recent inhalation carcinogenicity studies of butadiene indicate that B6C3F1 mice are more sensitive to the tumorigenic effects of inhaled butadiene than are Sprague Dawley rats. The purpose of this investigation was to determine if there were differences in distribution in tissues of inhaled butadiene between rats and mice. Male Sprague Dawley rats and B6C3F1 mice were exposed nose-only for 3.4 hr to (mean +/- SE) 1220 +/- 71 micrograms 14C-butadiene/L air and 121 +/- 2 micrograms 14C-butadiene/L air, respectively. Radioactivity was distributed widely in tissues immediately following exposure of both rats and mice to 14C-butadiene. In both species, respiratory tract tissue (lung, trachea, nasal turbinates), gastrointestinal tract (small and large intestine), liver, kidneys, urinary bladder and pancreas contained high concentrations of radioactivity within 1 hr after the end of exposure. In all cases, tissues of mice contained 15 to 100 times the concentration of 14C-butadiene equivalents per mumole of butadiene inhaled than did rats. For both rats and mice, elimination of 14C from tissues and blood was rapid, with 77% to 99% of the initial tissue burden being eliminated with half-times of 2 to 10 hr. Within 1 hr after the end of exposure, all rat tissues retained a substantial amount of 14C that was associated with volatile material (20% to 40% of the total 14C in tissues) that was probably butadiene and/or metabolites. A similar observation was noted in mouse liver, the only tissue of mice examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗