Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “BUTADIENE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources
PubMed1996

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

Significant species differences exist in the susceptibility to butadiene (BD)-induced cancer in rats and mice, and metabolism is likely a critical determinant for species sensitivity. This study measured the in vivo concentrations of, (1) BD in blood; (2) epoxybutene (EB) and diepoxybutane (DEB) in blood, lung and liver; and (3) glutathione (GSH) in lung and liver of male B6C3F1 mice and Sprague-Dawley rats during and after 6-h exposure to 62.5, 625, 1250, and 8000 (rat only) ppm BD. Mice had higher concentrations of EB and DEB in blood and tissues than did rats, DEB could not be detected in blood or tissues of rats, and the greatest depletion of GSH occurred in the lungs of mice. During exposure, the peak concentrations of EB in mice compared with rats were 4- to 8-fold higher in blood, 13- to 15-fold higher in lung, and 5- to 8-fold higher in liver. These data suggest that higher levels of BD epoxides in blood and tissues of mice compared with rats may explain, in part, the greater sensitivity of mice than rats to BD-induced carcinogenicity.

Administration, Inhalation↗
PubMed2001

Urinary metabolites and haemoglobin adducts as biomarkers of exposure to 1,3-butadiene: a basis for 1,3-butadiene cancer risk assessment.

Since 1,3-butadiene (BD) is a suspected human carcinogen, exposure to BD should be minimised and controlled. This study aimed at comparing the suitability of biomarkers for low levels of exposure to BD, and at exploration of the relative pathways of human metabolism of BD for comparison with experimental animals. Potentially sensitive biomarkers for BD are its urinary metabolites 1,2-dihydroxybutyl mercapturic acid (DHBMA, also referred to as MI) and 1- and 2-monohydroxy-3-butenyl mercapturic acid (MHBMA, also referred to as MII) and its haemoglobin (Hb) adducts 1- and 2-hydroxy-3-butenyl valine (MHBVal). In two field studies in BD-workers, airborne BD, MHBMA, DHBMA and MHBVal were determined. MHBMA proved more sensitive than DHBMA for monitoring recent exposures to BD and could measure 8-h time weighted average exposures as low as 0.13 ppm (0.29 mg/m(3)). The sensitivity of DHBMA was restricted by relatively high natural background levels in urine, of which the origin is currently unknown. MHBVal proved a sensitive method for monitoring cumulative exposures to BD at or above 0.35 ppm (0.77 mg/m(3)). Statistically significant relationships were found between either MHBMA or DHBMA and 8-h airborne BD levels, and between MHBVal adducts and average airborne BD levels over 60 days. The data showed a much higher rate of hydrolytic metabolism of BD in humans compared to animals, which was reflected in a much higher DHBMA/(MHBMA+DHBMA) ratio, and in much lower levels of MHBVal in humans, confirming in vitro results. Assuming a genotoxic mechanism, the data of this study coupled with our recent data on DNA and Hb binding in rodents, suggest that the cancer risk for humans from exposure to BD will be less than for the rat, and much less than for the mouse.

Air Pollutants, Occupational↗
PubMed1992

Species differences in urinary butadiene metabolites; identification of 1,2-dihydroxy-4-(N-acetylcysteinyl)butane, a novel metabolite of butadiene.

1,3-Butadiene (BD) is used in the manufacture of styrene-BD and polybutadiene rubber. Differences seen in chronic toxicity studies in the susceptibility of B6C3F1 mice and Sprague-Dawley rats to BD raise the question of how to use the rodent toxicology data to predict the health risk of BD in humans. The purpose of this study was to determine if there are species differences in the metabolism of BD to urinary metabolites that might help to explain the differences in the toxicity of BD. The major urinary metabolites of BD in F344/N rats, Sprague-Dawley rats, B6C3F1 mice, Syrian hamsters, and cynomolgus monkeys were identified as 1,2-dihydroxy-4-(N-acetylcysteinyl)-butane (I) and the N-acetylcysteine conjugate of BD monoxide [1-hydroxy-2-(N-acetylcysteinyl)-3-butene] (II). These mercapturic acids are formed by addition of glutathione at either the double bond (I) or the epoxide (II) respectively. When exposed to approximately 8000 p.p.m. of BD for 2 h, the mice excreted 3-4 times as much metabolite II as I, the hamster and the rats produced approximately 1.5 times as much metabolite II as I, while the monkeys produced primarily metabolite I. The ratio of formation of metabolite I to the total formation of the two mercapturic acids correlated well with the known hepatic epoxide hydrolase activity in the different species. These data suggest that (i) the availability of the monoepoxide for conjugation with glutathione is highest in the mouse, followed by the hamster and the rat, and is lowest in the monkey; and (ii) the epoxide availability is inversely related to the hepatic activity of epoxide hydrolase, the enzyme that removes the epoxide by hydrolysis. The ratio of the two mercapturic acids in human urine following BD exposure may indicate the pathways of BD metabolism in humans and may aid in the determination of the most appropriate animal model for BD toxicity.

Acetylcysteine↗
PubMed1994

Mutagenicity of butadiene and its epoxide metabolites: II. Mutational spectra of butadiene, 1,2-epoxybutene and diepoxybutane at the hprt locus in splenic T cells from exposed B6C3F1 mice.

The mutagenic potential and mutational spectra of butadiene (BD), 1,2-epoxybutene (EB), and diepoxybutane (DEB) were determined in splenic T cells from exposed B6C3F1 mice. Mice exposed by inhalation to 625 p.p.m. BD for 2 weeks displayed an average hprt- mutation frequency of 6.2 x 10(-6) compared to 1.2 x 10(-6) in controls. Mice were also given three daily i.p. doses of 60, 80 and 100 mg EB/kg or 7, 14 and 21 mg DEB/kg. Average hprt- frequencies of 5.4 x 10(-6), 4.1 x 10(-6) and 8.6 x 10(-6) were seen in the EB groups, respectively, while average frequencies of 4.6 x 10(-6), 9.4 x 10(-6) and 13 x 10(-6) were seen in the DEB groups. DNA sequencing revealed that approximately half of the mutations induced in vivo by BD, EB and DEB were frameshift mutations. A +1 frameshift 'hotspot' in six consecutive guanine bases in exon 3 was observed with all three compounds. The remaining mutations produced by BD, EB and DEB were transition and transversion mutations at both AT and GC base pairs. Base pair substitutions induced by BD were biased in favor of mutation at AT base pairs. The mutational spectra produced by BD, EB and DEB were very similar to that observed previously with ethylene oxide, suggesting that these epoxide agents may be working through a similar mutagenic mechanism.

Animals↗
PubMed2000

1,3-butadiene: cancer, mutations, and adducts. Part III: In vivo mutation of the endogenous hprt genes of mice and rats by 1,3-butadiene and its metabolites.

1,3-Butadiene (BD), an important chemical used mainly in the production of synthetic rubber, is a potent carcinogen in mice, a weak carcinogen in rats, and a suspected carcinogen in humans. To provide a better understanding of the mutagenic mechanisms involved in interspecies differences in BD-induced carcinogenesis, studies were conducted in rodents to test two hypotheses: (a) the mutagenic potency of BD at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus of T lymphocytes (T cells) can be used to quantify interspecies differences in BD-induced carcinogenicity in exposed rodents and (b) comparison of the mutagenic potency and specificity of BD and racemic mixtures of two epoxy metabolites, 1,2-epoxy-3-butene (BDO) and 1,2,3,4-diepoxybutane (BDO2), at the hprt locus of T cells can be used to define the relative contribution of each intermediate to observed BD mutagenicity in each species. The first hypothesis was investigated by determining the effects of exposure duration and elapsed time after exposures on hprt mutant frequencies (MFs) in T cells from thymus and spleen of female B6C3F1 mice and F344 rats (4 to 5 weeks old). In this study, rodents were exposed by inhalation to 0 or 1,250 parts per million (ppm) BD for up to 2 weeks, or to 0 or 625 ppm BD for up to 4 weeks (with all exposures 6 hours/day, 5 days/week). The second hypothesis was examined by defining the effects of exposure concentration and elapsed time after exposures on the hprt MFs in splenic T cells from mice and rats exposed by inhalation to BD (0, 20, 62.5, or 625 ppm), BDO (0, 2.5, or 25 ppm), or BDO2 (0, 2, or 4 ppm) for 4 weeks (all exposures 6 hours/day, 5 days/week). The hprt MFs were measured weekly or biweekly using the T cell cloning assay for up to 10 weeks after the last exposure. The mutagenic potency of BD (represented by the difference in the areas under the mutant T cell "manifestation" curves [or the "change in MFs over time"] of exposed versus control animals) was significantly greater in mice (4.4-fold) than in rats following 2 weeks of exposure to 1,250 ppm BD. Mutagenic potency in mice was 8.5-fold greater than that in rats following 4 weeks of exposure to 625 ppm BD. These hprt MF data provide the first evidence that BD is mutagenic in the rat, albeit the mutagenic response was significantly less than that observed in similarly exposed mice. In addition, the MF data from the two exposure-duration studies indicate that both exposure concentration and exposure duration are important in determining the magnitude of the mutagenic response to BD. The relative contribution of BDO versus BDO2 to overall BD mutagenicity was evaluated by exposing mice and rats to carefully chosen concentrations of BD and racemic mixtures of BDO and BDO2 (that is, 62.5, 2.5, and 4.0 ppm, respectively) and comparing the mutagenic potency of each compound when comparable blood levels of metabolites were achieved. The resulting MF data indicate that (+/-)-BDO2 is a major contributor to the mutagenicity of BD in mice at lower BD exposure levels (< or = 62.5 ppm), whereas other metabolites and stereochemical configurations are responsible for mutations in BD-exposed rats and for the incremental mutagenic effects at higher exposure levels in mice. Molecular analysis of hprt cDNA from expanded T cell clones from control and BD-exposed mice demonstrated an increased frequency of large deletions in exposed animals (p = 0.016), presumably associated with in situ formation of (+/-)-BDO2, meso-BDO2, or both. Results of these mutagenicity experiments, along with data from collaborative studies of DNA adducts from the same animals, should provide a better understanding of the interspecies variation in carcinogenic response to BD and improve the extrapolation of rodent data to the estimation of cancer risk in exposed persons.

Animals↗
PubMed2000

1,3-butadiene: cancer, mutations, and adducts. Part IV: Molecular dosimetry of 1,3-butadiene.

Analysis of N7-guanine adducts derived from 1,3-butadiene (BD) was conducted with use of liquid chromatography-mass spectrometry (LC-MS) in combination with stable isotope methods. The N7-guanine adducts were shown to undergo spontaneous depurination from DNA in vitro in both calf-thymus DNA and TK6-cell DNA. A comparison was made between BD-derived N7-guanine adduct concentrations both in liver DNA and urine of rats and mice exposed to BD. This has provided insight into the exposure of the animals to 1,2-epoxy-3-butene (BDO), 1,2,3,4-diepoxybutane (BDO2), and 1,2-dihydroxy-3,4-epoxybutane (BDO-diol), the three oxidative metabolites of BD thought to be responsible for BD-mediated carcinogenesis. The liver DNA of mice contained more of the two N7-guanine adducts of BDO--N7-2-hydroxy-3-butenyl-1-guanine (2HB1G) and N7-1-hydroxy-3-butenyl-2-guanine (1HB2G)--than the amounts in rats during the 10-day BD exposure and the 6 days after exposure that were monitored. An excess of 1HB2G over 2HB1G by a factor of approximately 10 in the rat liver and a factor of approximately 5 in the mouse liver was also observed. This regioselective difference was apparent during both the 10-day exposure and the 6 days after exposure. The half-lives of 2HB1G and 1HB2G were estimated as 4.3 days and 3.5 days, respectively, in the DNA of BD-exposed mice and rats. Higher amounts of 2HB1G and 1HB2G appeared in rat urine compared with mouse urine after the 10-day exposure to 1,250 ppm BD. Analysis of liver DNA for N7-guanine adducts derived from BDO2 revealed the presence of two diastereomeric forms of N7-(2,3,4-trihydroxybutyl)-1-guanine (THBG). One of the diastereomers [(+/-)-THBG] was formed by reaction of DNA with (+/-)-BDO2 or BDO-diol, and the other diastereomer (meso-THBG) was formed by reaction of DNA with meso-BDO2 or BDO-diol. There was more (+/-)-THBG and meso-THBG in liver DNA of mice compared with amounts in rats during the 10 days of BD exposure and the 6 days after exposure. A twofold excess of (+/-)-THBG over meso-THBG in rat liver was found at all of the time points monitored. After 10 days of exposure to BD, (+/-)-THBG in mouse liver was also present in an almost twofold excess over meso-THBG. At 6 days after exposure to BD, however, (+/-)-THBG and meso-THBG were present in almost equal amounts in mouse liver. Furthermore, amounts of the two THBG diastereomers in mouse liver 6 days after exposure to BD were almost fivefold greater than amounts in rat liver. The half-lives of (+/-)-THBG and meso-THBG appeared to be longer in mouse liver (4.1 days and 5.5 days, respectively) than in rat liver (3.6 days and 4.0 days, respectively). Higher amounts of (+/-)-THBG were excreted in rat urine compared with mouse urine. It is noteworthy that each of the N7-guanine adducts derived from BD was present in higher concentrations in the liver DNA of mice exposed to 1,250 ppm BD than in the liver DNA of rats exposed to the same dose. Conversely, each of the adducts was present in higher concentrations in the urine of rats compared with the urine of mice after exposure to 1,250 ppm BD.

Animals↗
PubMed2000

1,3-butadiene: cancer, mutations, and adducts. Part V: Hemoglobin adducts as biomarkers of 1,3-butadiene exposure and metabolism.

1,3-Butadiene (BD) is an important chemical used largely in the manufacture of synthetic rubber and thermoplastic resins. In addition, it has been identified in cigarette smoke, automobile exhaust, and gasoline vapor. The objective of this research was to develop highly sensitive and specific assays for the detection and quantitation of hemoglobin adducts of three BD metabolites: 1,2-epoxy-3-butene (BDO), 1,2,3,4-diepoxybutane (BDO2), and 1,2-dihydroxy-3,4-epoxybutane (BDO-diol). We have successfully developed an assay for both N-(2-hydroxy-3-butenyl)valine (HBVal) and N-(2,3,4-trihydroxybutyl)valine (THBVal) in hemoglobin. The six adducts measured were the two diastereomers (isomers I and II) of HBVal and the four diastereomers of THBVal (isomers I through IV, which were eluted as three peaks, 1, 2, and 3). HBVal and THBVal were measured in control and exposed B6C3F1 mice and Sprague-Dawley rats (1,000 ppm BD for 13 weeks at 6 hours/day, 5 days/week). In a second set of animal exposures, total THBVal was determined in B6C3F1 female mice (n = 5) exposed to 1,250 ppm BD for 1, 5, or 10 days (6 hours/day, 5 days/week). THBVal adducts were also monitored in occupationally exposed Chinese workers and nonoccupationally exposed U.S. laboratory workers. This study utilized the modified Edman degradation method of Törnqvist and colleagues (1986). Briefly, the samples were subjected to Edman degradation, Centricon-30 ultrafiltration, washing on C18 columns, and acetylation for isomers of THBVal only, followed by gas chromatography-mass spectrometry (GC-MS) quantitation. For the HBVal assay, an authentic internal standard globin alkylated with [2H6]BDO was used; for the THBVal assay, a synthesized external standard, THB[13C5]Val, was used after Edman degradation. The mean +/- SD amounts of total HBVal measured in exposed mice (in pmol/g globin) were 16,560 +/- 3,910 for female mice (n = 4) and 12,400 +/- 2,030 for male mice (n = 5). The corresponding values for rats were 8,690 +/- 930 for female rats (n = 5) and 5,480 +/- 2,880 for male rats (n = 3). The total amount of THBVal (eluted peaks 1, 2, and 3) in male mice (n = 5) was 78,900 +/- 13,700; and in females (n = 2) was 56,100 +/- 100. In male rats (n = 3), the detected value was 9,650 +/- 1,620 and in females (n = 3) the value was 21,600 +/- 6,780. In control male mice (n = 4), the total level of THBVal isomers was approximately 27 pmol/g globin. In a control male rat, total THBVal was approximately 15 pmol/g globin. In the time course study, the amount of THBVal adducts increased linearly with exposure, resulting in values of 4,200 +/- 830, 19,760 +/- 1,780, and 35,940 +/- 3,460 pmol/g globin following 1, 5, or 10 days of exposure to 1,250 ppm BD, respectively. Detection of HBVal in human samples was difficult due to low concentrations of adducts and a high background in the chromatograms. In a pooled sample from 4 individuals, we performed multiple separations with high-pressure liquid chromatography (HPLC) of the derivatized adducts and detected 4.6 pmol/g globin (that is, 2.7 and 1.9 pmol/g globin for isomers I and II, respectively). We measured the amounts of THBVal in both nonoccupationally exposed U.S. laboratory workers and occupationally exposed workers from a polybutadiene plant in China. The mean total amount of THBVal among the U.S. laboratory workers was 36 +/- 23 pmol/g globin for nonsmokers (n = 7) and 40 +/- 9 for smokers (n = 4), compared with a mean total amount of 39 +/- 13 pmol/g globin in a control set of Chinese workers (n = 25). These control values are overestimations of the true values because the amounts of THBVal in globin samples from other unexposed individuals (15 of 51) were below our limit of detection. BD-exposed Chinese workers had a total amount of 88 +/- 59 pmol/g globin THBVal. The difference between smokers and nonsmokers was not significant, whereas the difference between control and exposed Chinese workers was highly significant (p < 0.001).

Animals↗
PubMed1984

Toxicity of the components of styrene polymers: polystyrene, acrylonitrile-butadiene-styrene (ABS) and styrene-butadiene-rubber (SBR). Reactants and additives.

The toxicity of the components of styrene polymers, e.g., polystyrene, ABS and SBR, were reviewed with primary focus on the reactive monomers (except styrene) (e.g., acrylonitrile, butadiene) as well as on impurities and solvents such as benzene, hexane and methylethyl ketone, and additives such as phenyl-2-naphthylamine, di-n-butyl phthalate, and a number of peroxide initiators and flame retardants (e.g., 2,3-dibromopropanol, decadibromodiphenyl oxide and antimony trioxide). It is stressed that toxicity data are generally lacking for the majority of additives employed in the production of styrene polymers. Information is also lacking as to the numbers of individuals at potential risk and the extent of their exposure to the large number of additives employed.

1-Naphthylamine↗
PubMed1999

Mutagenicity of the racemic mixtures of butadiene monoepoxide and butadiene diepoxide at the Hprt locus of T-lymphocytes following inhalation exposures of female mice and rats.

The purpose of this study was to determine if Hprt mutant frequency (Mf) data from rodents exposed directly to individual epoxy metabolites of 1,3-butadiene (BD) can be used to identify the relative significance of each intermediate in the mutagenicity of BD in mice vs. rats. To this end, the relative contributions of the racemic mixtures of BD monoepoxide (BDO) and BD diepoxide (BDO(2)) to BD-induced mutagenicity was investigated by exposing mice and rats to selected concentrations of BDO and BDO(2) (i.e., 2.5 and 4.0 ppm, respectively) and comparing the mutagenic potency of each intermediate to that of BD (at 62.5 ppm) when comparable blood levels of metabolites are achieved (in the mouse). Female B6C3F1 mice and F344 rats (4-5 weeks old) were exposed to rac-BDO (0, 2.5, or 25 ppm) or (+/-)-BDO(2) (0, 2, 4 ppm) by inhalation for 4 weeks (6 h/day, 5 days/week), and then groups of control and exposed animals (n=3-12/group) were necropsied at multiple time points post-exposure for measuring Hprt Mfs in splenic lymphocytes (via the T-cell cloning assay) and estimating mutagenic potencies (represented by the difference in the areas under the mutant T-cell 'manifestation' curves of treated vs. control animals). The resulting Mf data, along with the extant metabolism data, suggest that at lower BD exposures (</=62.5 ppm) (+/-)-BDO(2) is a major contributor to the mutagenicity of BD in mice, whereas other metabolites and stereochemical configurations are responsible for mutations in BD-exposed rats and for the incremental mutagenic effects at higher BD exposures in mice. These studies indicate that additional work is needed to determine more definitively the relative contributions of these and other metabolites and stereochemical forms to BD-induced mutagenicity. Also, the novel approach of measuring mutagenic potencies as the change in Hprt Mfs over time in T-cells of exposed vs. control animals, as used in this study, can be valuable for predicting the potential role of these intermediates in each species.

Administration, Inhalation↗
PubMed1993

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

1,3-Butadiene is produced in large volumes for use in the manufacture of synthetic rubber and of thermoplastic resins. In previous inhalation studies conducted by the NTP (NTP, 1984) there was clear evidence of multiple organ carcinogenicity in male and female mice exposed to 625 or 1,250 ppm 1,3-butadiene for 60 or 61 weeks. To better characterize exposure-response relationships for neoplasms and nonneoplastic lesions, toxicology and carcinogenesis studies were conducted by exposing groups of male and female B6C3F1 mice to air containing 1,3-butadiene (greater than 99% pure) for up to 2 years. An additional study in male B6C3F1 mice, in which exposure to 1,3-butadiene was stopped after limited exposure periods (13, 26, 40, or 52 weeks), was performed to assess the effects of varying concentration and duration of exposure on the incidences of 1,3-butadiene-induced neoplasms. In vitro genetic toxicology studies were conducted in Salmonella typhimurium and mouse lymphoma cells. In vivo genetic effects were assayed in germ cells of male Drosophila melanogaster and in bone marrow and peripheral blood cells of B6C3F1 mice. 2-Year Studies: Groups of 70 male and 70 female mice were exposed to air containing 0, 6.25, 20, 62.5, or 200 ppm 1,3-butadiene for 6 hours per day, 5 days per week for up to 2 years; groups of 90 male and 90 female mice were exposed to 625 ppm 1,3-butadiene on the same schedule. Up to 10 animals from each group were examined after 9 and 15 months of exposure. Survival and Body Weight in the 2-Year Studies: Two-year survival was decreased for males and females exposed to concentrations of 20 ppm or above, primarily due to the development of chemical-related malignant neoplasms. No female mice exposed to 200 or 625 ppm or males exposed to 625 ppm survived to the end of the studies (males: 35/50, 39/50, 24/50, 22/50, 4/50, 0/70; females: 37/50, 33/50, 24/50, 11/50, 0/50, 0/70). Mean body weights of exposed male and female mice were similar to those of the controls. Hematologic Effects in the 2-Year Studies: Hematologic parameters were evaluated after 9 and 15 months of exposure. At 9 months, decreases in erythrocyte counts, hemoglobin concentration, and packed red cell volume were observed in male mice exposed to 62.5 ppm or above and in female mice exposed to 200 or 625 ppm. Mean erythrocyte volume was increased in male mice exposed to 625 ppm and in females exposed to 200 or 625 ppm. At 15 months, decreases in erythrocyte counts, hemoglobin concentration, and packed red cell volume and increases in mean erythrocyte volume were observed in male and female mice exposed to 625 ppm. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: Exposure of mice to 1,3-butadiene induced benign and malignant neoplasms at multiple sites. Statistically significant increases in the incidences of neoplasms at one or more sites were seen at concentrations of 20 ppm and higher in males and 6.25 ppm and higher in females. There was no exposure level in this study at which a significant carcinogenic response was not observed. Statistically significant increases occurred in the incidences of malignant lymphoma; histiocytic sarcoma; cardiac hemangiosarcoma; harderian gland adenoma; hepatocellular adenoma and carcinoma; alveolar/bronchiolar adenoma and carcinoma; mammary gland carcinoma, adenoacanthoma, and malignant mixed tumor (females only); benign and malignant ovarian granulosa cell tumor; and forestomach squamous cell papilloma and carcinoma. Low incidences of uncommon neoplasms also occurred in exposed male and female mice, including intestinal carcinomas in males, renal tubule adenomas in males and females, skin sarcomas (all types combined) in females, and Zymbal's gland adenomas and carcinomas in females. Lymphocytic lymphomas appeared as early as week 23 and were the principal cause of death of male and female mice exposed to 625 ppm 1,3-butadiene. The early and extensive development of lethal lymphocytic lymphomas in mice exposed to 625 ppm resulted in a reduced number of mice at risk for neoplasms developing laterg later at other sites. Exposure-response relationships for 1,3-butadiene-induced neoplasms were more clearly characterized at concentrations below 625 ppm and after adjustment for intercurrent mortality. Increased incidences of nonneoplastic lesions in exposed mice included bone marrow atrophy; testicular atrophy; ovarian atrophy, angiectasis, germinal epithelial hyperplasia, and granulosa cell hyperplasia; uterine atrophy; cardiac endothelial hyperplasia and mineralization; alveolar epithelial hyperplasia; forestomach epithelial hyperplasia; and harderian gland hyperplasia. Stop-Exposure Study: The stop-exposure study consisted of groups of 50 male mice exposed to 1,3-butadiene at concentrations of 200 ppm for 40 weeks, 625 ppm for 13 weeks, 312 ppm for 52 weeks, or 625 ppm for 26 weeks. After the exposures were completed, these groups were placed in control chambers for the remainder of the 2-year study. The total exposure of 1,3-butadiene (concentration times duration of exposure) of the 13- and 40-week stop-exposure groups was approximately 8,000 ppm-weeks, while that of the 26- and 52-week stop-exposure groups was approximately 16,000 ppm-weeks. The survival of all stop-exposure groups was markedly lower than that of the controls. The incidences of lymphocytic lymphoma, histiocytic sarcoma, cardiac hemangiosarcoma, alveolar/bronchiolar adenoma and carcinoma, forestomach squamous cell papilloma and carcinoma, hepatocellular adenoma, harderian gland adenoma and adenocarcinoma, and preputial gland carcinoma were significantly increased. Neoplasms were induced at most of these sites after only 13 weeks of exposure to 1,3-butadiene. Additionally, low numbers of malignant gliomas and neuroblastomas of the brain and Zymbal's gland carcinomas occurred in one or more stop-exposure groups. At similar total exposures, the incidence of lymphocytic lymphoma was greater with exposure to a higher concentration of 1,3-butadiene for a short time compared with exposure to a lower concentration for an extended period (34&percnt; at 625 ppm for 13 weeks versus 12&percnt; at 200 ppm for 40 weeks; 60&percnt; at 625 ppm for 26 weeks versus 8&percnt; at 312 ppm for 52 weeks). Genetic Toxicology: 1,3-Butadiene has been tested both in vitro and in vivo for mutagenic activity. In vitro, positive results were obtained in the Salmonella typhimurium gene mutation assay with strain TA1535; mutagenic activity was not observed in other S. typhimurium strains (TA100, TA97, and TA98). 1,3-Butadiene was negative in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells with and without S9. In vivo, 1,3-butadiene did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster; however, it did induce significant increases in chromosomal aberrations and sister chromatid exchanges in bone marrow cells of mice exposed for 2 weeks by inhalation. In addition, significant increases in micronucleated erythrocytes were observed in peripheral blood samples obtained from male and female mice exposed to 1,3-butadiene for 2 or 13 weeks or 15 months by inhalation. Conclusions: The previous inhalation studies of 1,3-butadiene (TR-288) in male and female B6C3F1 mice provided clear evidence of carcinogenicity at exposure concentrations of 625 or 1,250 ppm. The present inhalation studies - 2-year exposures of 6.25, 20, 62.5, 200, or 625 ppm or shorter duration exposures of 200, 312, or 625 ppm - provide a better characterization of the concentration-dependent responses for 1,3-butadiene-induced neoplasms and nonneoplastic lesions. The present studies confirmed the clear evidence of carcinogenicity of 1,3-butadiene in male B6C3F1 mice based on increased incidences of neoplasms in the hematopoietic system, heart, lung, forestomach, liver, harderian gland, preputial gland, brain, and kidney. There was clear evidence of carcinogenicity of 1,3-butadiene in female B6C3F1 mice based on increased incidences of neoplasms in the hematopoietic system, heart, lung, forestomach, liver, harderian gland, ovary, and mammary gland. Low incidences of intestinal carcinomas in male mice, Zymbal's gland carcinomas in male and female mice, and renal tubule adenomas and skin sarcomas in female mice may also have been related to administration of 1,3-butadiene. Synonyms: alpha,gamma-Butadiene; bivinyl; divinyl; erythrene; vinylethylene; biethylene; pyrrolylene

Journal Article↗
PubMed2001

Ambient concentrations of 1,3-butadiene in the UK.

This paper assesses the current knowledge of 1,3-butadiene as an atmospheric pollutant, considers measurement techniques and reviews available data on 1,3-butadiene monitoring and emissions estimates. Atmospheric chemistry, sources of emission, current legislation, measurement techniques and monitoring programmes for 1,3-butadiene are reviewed. There have been comparatively few studies of the products of oxidation of 1,3-butadiene in the atmosphere. However, on the basis of the available information, and by analogy with the oxidation mechanism for the widely-studied and structurally similar natural hydrocarbon isoprene (2-methyl-1,3-butadiene), it is possible to define some features of the likely oxidation pathways for 1,3-butadiene. The total UK 1,3-butadiene emission to the atmosphere for 1996 has been estimated at 10.60 kTonnes. 1,3-Butadiene is a product of petrol and diesel combustion; consequently this total is dominated by road transport exhaust emissions (accounting for some 68% of the total). Off-road vehicles and machinery are responsible for 14% of the total UK emission. 1,3-Butadiene is used in the manufacture of numerous rubber compounds, and consequently emissions arise from both the manufacture and use of 1,3-butadiene in industrial processes. Emissions from the chemical industry account for 18% of the UK total emission- 8% from 1,3-butadiene manufacture and 10% from 1,3-butadiene use. The United Kingdom Expert Panel on Air Quality Standards (EPAQS) has published a report on 1,3-butadiene, and recommended a national air quality standard of 1.0 ppb (expressed as an annual rolling mean). This was adopted by the Government as part of the National Air Quality Strategy (NAQS) in 1997, and a target of compliance by 2005 was set. Work conducted for the review of the NAQS (1999) indicated that it was likely that all locations would be compliant with the national standard by the end of 2003. As a result, the review updated the air quality objective for 1,3-butadiene, with the deadline for compliance being brought forward to 31/12/2003. The UK Hydrocarbon Monitoring Network provides continuous hourly measurements of 1,3-butadiene at 13 sites, and has been operational since 1993. The dataset that is available allows spatial and temporal trends to be evaluated, and has proved to be invaluable in characterising the current ambient levels of 1,3-butadiene in the UK. Hourly maximum concentrations of 1,3-butadiene of up to 10 ppb (1 ppb=1 ppb, i.e. 1 vol. of 1,3-butadiene in 1,000,000,000 vol. of air. 1 ppb of 1,3-butadiene is ca. equal to 2.25 microg m(-3) at 20 degrees C) may be measured for several hours at the sites. Monthly mean concentrations are typically 0.1-0.4 ppbv. At most sites, these levels are driven by emissions from motor vehicles. Occasionally emissions of 1,3-butadiene from industrial sources may elevate 1,3-butadiene concentrations to several tens of ppb. Trend analysis of the data suggests that ambient concentrations of 1,3-butadiene in the UK are declining at about 10% per year.

Air Pollutants↗
PubMed1993

Research strategy for assessing target tissue dosimetry of 1,3-butadiene in laboratory animals and humans.

1,3-Butadiene is carcinogenic to rats and mice, although mice are more sensitive than rats. It is not known if butadiene poses a carcinogenic risk to humans. Butadiene requires metabolic activation to reactive epoxides that can bind to DNA to initiate a series of events that lead to tumour formation. Species differences in activation and detoxification must be considered in estimating human risks from exposure to butadiene. A research strategy for assessing the role of metabolic factors in the carcinogenicity of butadiene involves studies in laboratory animals in vivo, supplemented with studies in vitro with tissues from both laboratory animals and humans. In experiments conducted on liver and lung tissues from Sprague-Dawley rats, B6C3F1 mice and humans, we characterized the oxidation of butadiene and butadiene monoepoxide by cytochrome P450-dependent mono-oxygenases and the detoxification of butadiene monoepoxide by epoxide hydrolases and glutathione transferases. B6C3F1 mouse liver microsomes displayed a capacity for butadiene oxidation exceeding that seen in either human or rat liver microsomes. Except in mice, oxidation of butadiene occurred at rates significantly lower with lung than with liver microsomes. In general, human liver microsomes hydrolysed butadiene monoepoxide at higher rates than either rats or mice. The capacity for glutathione conjugation with butadiene monoepoxide was higher in mice than in humans or rats. The ratios of butadiene activation (P450):detoxication (hydrolysis and conjugation) are markedly different in mouse (74:1), rat (6:1) and human (6:1) liver tissues. The differences in the ratios between mice and rats are consistent with the higher carcinogenic sensitivity of mice than rats to butadiene. Factors in addition to metabolism, however, probably play a role in the carcinogenicity of butadiene in rats and mice. Metabolic rate constants for butadiene and butadiene monoepoxide oxidation and for butadiene monoepoxide hydrolysis and conjugation with glutathione, determined from physiological pharmacokinetic model simulations of butadiene-exposed rats and mice, were for the most part similar to the constants determined in vitro. The same trends that were noted in vitro were seen in vivo. The physiological dosimetry model for butadiene that includes in-vitro vitro metabolic constants can stimulate behaviour in vivo and can be used to predict blood and tissue concentrations of butadiene and its monoepoxide.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Genotoxicity and cytotoxicity in male B6C3F1 mice following exposure to mixtures of 1,3-butadiene and styrene.

1,3-Butadiene and styrene are oxidized, in part, by cytochrome P450 2E1 and have been shown to metabolically interact in rodents exposed by inhalation to mixtures of both compounds. Because the reactive metabolites of butadiene and styrene are thought to be responsible for the toxicity of each compound, metabolic interactions may alter the response in animals exposed to mixtures of butadiene and styrene compared with the response in animals exposed to butadiene alone or styrene alone. The purpose of this study was to quantitate alterations in genotoxicity and cytotoxicity in male B6C3F1 mice exposed to mixtures of butadiene and styrene. Male B6C3F1 mice were exposed to 6.25, 62.5, 200, or 625 ppm butadiene alone, 50 ppm styrene alone, or mixtures of 6.25, 62.5, 200, or 625 ppm butadiene and 50 ppm styrene. Genotoxicity was assessed by quantitating the frequency of micronucleated polychromatic erythrocytes in bone marrow. Cytotoxicity was assessed by counting total spleen and thymus cells and by quantitating the frequency of polychromatic erythrocytes in the peripheral blood. Butadiene and mixtures of butadiene and styrene were genotoxic in mice, as shown by a significant increase in the frequency of micronucleated polychromatic erythrocytes. The increased frequency following exposure to mixtures of butadiene and styrene was not significantly different compared with the frequency following exposure to butadiene alone. Styrene and mixtures of butadiene and styrene were cytotoxic in mice, as shown by significantly decreased number of spleen cells. Exposure to mixtures of butadiene and styrene with butadiene concentrations of 62.5 or 625 ppm significantly reduced the number of thymus cells. Exposure to 200 ppm or 625 ppm butadiene alone, or to mixtures of 200 ppm or 625 ppm butadiene and 50 ppm styrene, significantly reduced the frequency of polychromatic erythrocytes in the peripheral blood. The results of the study demonstrate that exposure to mixture of butadiene and styrene does not reduce the respective genotoxicity of butadiene or cytotoxicity of styrene.

Animals↗