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PubMed2006

Molecular epidemiological studies in 1,3-butadiene exposed Czech workers: female-male comparisons.

Results of a recent molecular epidemiological study of 1,3-butadiene (BD) exposed Czech workers, conducted to compare female to male responses, have confirmed and extended the findings of a previously reported males only study (HEI Research Report 116, 2003). The initial study found that urine concentrations of the metabolites 1,2-dihydroxy-4-(acetyl) butane (M1) and 1-dihydroxy-2-(N-acetylcysteinyl)-3-butene (M2) and blood concentrations of the hemoglobin adducts N-[2-hydroxy-3-butenyl] valine (HB-Val) and N-[2,3,4-trihydroxy-butyl] valine (THB-Val) constitute excellent biomarkers of exposure, both being highly correlated with BD exposure levels, and that GST genotypes modulate at least one metabolic pathway, but that irreversible genotoxic effects such as chromosome aberrations and HPRT gene mutations are neither associated with BD exposure levels nor with worker genotypes (GST [glutathione-S-transferase]-M1, GSTT1, CYP2E1 (5' promoter), CYP2E1 (intron 6), EH [epoxide hydrolase] 113, EH139, ADH [alcohol dehydrogenase]2 and ADH3). The no observed adverse effect level (NOAEL) for chromosome aberrations and HPRT mutations was 1.794 mg/m(3) (0.812 ppm)--the mean exposure level for the highest exposed worker group in this initial study. The second Czech study, reported here, initiated in 2003, included 26 female control workers, 23 female BD exposed workers, 25 male control workers and 30 male BD exposed workers (some repeats from the first study). Multiple external exposure measurements (10 full 8-h shift measures by personal monitoring per worker) over a 4-month period before biological sample collections showed that BD workplace levels were lower than in the first study. Mean 8-h TWA exposure levels were 0.008 mg/m(3) (0.0035 ppm) and 0.397 mg/m(3) (0.180 ppm) for female controls and exposed, respectively, but with individual single 8-h TWA values up to 9.793 mg/m(3) (4.45 ppm) in the exposed group. Mean male 8-h TWA exposure levels were 0.007 mg/m(3) (0.0032 ppm) and 0.808 mg/m(3) (0.370 ppm) for controls and exposed, respectively; however, the individual single 8-h TWA values up to 12.583 mg/m(3) (5.72 ppm) in the exposed group. While the urine metabolite concentrations for both M1 and M2 were elevated in exposed compared to control females, the differences were not significant, possibly due to the relatively low BD exposure levels. For males, with greater BD exposures, the concentrations of both metabolites were significantly elevated in urine from exposed compared to control workers. As in the first study, urine metabolite excretion patterns in both sexes revealed conjugation to be the minor detoxification pathway (yielding the M2 metabolite) but both M1 and M2 concentration values were lower in males in this second study compared to their concentrations in the first, reflecting the lower external exposures of males in this second study compared to the first. Of note, females showed lower concentrations of both M1 and M2 metabolites in the urine per unit of BD exposure than did males while exhibiting the same M1/(M1+M2) ratio, reflecting the same relative utilization of the hydrolytic (producing M1) and the conjugation (producing M2) detoxification pathways as males. Assays for the N,N-(2,3-dihydroxy-1,4-butadyl) valine (pyr-Val) hemoglobin (Hb) adduct, which is specific for the highly genotoxic 1,2,3,4-diepoxybutane (DEB) metabolite of BD, have been conducted on blood samples from all participants in this second Czech study. Any adduct that may have been present was below the limits of quantitation (LOQ) for this assay for all samples, indicating that production of this important BD metabolite in humans is below levels produced in both mice and rats exposed to as little as 1.0 ppm BD by inhalation (J.A. Swenberg, M.G. Bird, R.J. Lewis, Future directions in butadiene risk assessment, Chem. Biol. Int. (2006), this issue). Results of assays for the HB-Val and THB-Val hemoglobin adducts are pending. HPRT mutations, determined by cloning assays, and multiple measures of chromosome level changes (sister-chromatid exchanges [SCE], aberrations determined by conventional methods and FISH) again showed no associations with BD exposures, confirming the findings of the initial study that these irreversible genotoxic changes do not arise in humans occupationally exposed to low levels of BD. Except for lower production of both urine metabolites in females, no female-male differences in response to BD exposures were detected in this study. As in the initial study, there were no significant genotype associations with the irreversible genotoxic endpoints. However, as in the first, differences in the metabolic detoxification of BD as reflected in relative amounts of the M1 and M2 urinary metabolites were associated with genotypes, this time both GST and EH.

Acetylcysteine↗
PubMed2006

N-terminal globin adducts as biomarkers for formation of butadiene derived epoxides.

The aim of this review is to summarize our recent data on butadiene (BD) derived hemoglobin adducts as biomarkers for the internal formation of the individual epoxides formed by butadiene (BD). It is well known that BD is oxidized by cytochrome P450s to several epoxides that form DNA and protein adducts. 1,2-Epoxy-3-butene (EB), 1,2;3,4-diepoxybutane (DEB) and 1,2-epoxy-3,4-butanediol (EB-diol) form N-(2-hydroxy-3-butenyl)-valine (HB-Val), N,N-(2,3-dihydroxy-1,4-butadiyl)-valine (pyr-Val) and N-(2,3,4-trihydroxybutyl)-valine (THB-Val) adducts, respectively. The analysis of HB-Val and THB-Val by the modified Edman degradation and GC-MS/MS has generated valuable insights into BD metabolism across species. In addition, a recently established method for the analysis of pyr-Val has been proven to be suitable for detection of pyr-Val in rodents exposed to BD as low as 1 ppm. These technologies have been applied to study a wide range of exposures to BD, EB, DEB, and 3-butene-1,2-diol as a precursor of EB-diol in male and female mice and rats. Altogether the data have shown that BD metabolism is species and concentration dependent, consistent with metabolism and carcinogenesis data. Mice form much more HB-Val and pyr-Val than rats, especially at low exposures. After 10 days of inhalation exposure to 3 ppm BD, mice formed 12.5-fold more pyr-Val than rats. In contrast, the amounts of THB-Val were similar in mice and rats exposed to 3 or 62.5 ppm BD. Furthermore, it appears that the formation of THB-Val is supralinear in mice and rats due to saturation of metabolic activation pathways. Gender differences in metabolism are less well established. One study with male and female rats exposed to 1000 ppm BD for 90 days demonstrated a 1.6-, 3.5- and 2.0-fold gender difference in formation of HB-Val, pyr-Val and THB-Val, respectively, with females being more efficient in epoxide formation. The analyses of BD derived protein adducts correlate well with the observed species and gender differences in BD-carcinogenesis and suggest that DEB may indeed be the most important metabolite.

Animals↗
PubMed2006

Continuous spin fractionation and characterization by size-exclusion chromatography for styrene-butadiene block copolymers.

Linear and star-shaped styrene-butadiene block copolymers synthesized by anionic polymerization of butadiene and styrene were fractionated by applying a newly developed large-scale fractionation technique, named continuous spin fractionation (CSF). Their molecular weight and polydispersity index (d=M(w)/M(n)) were measured with size-exclusion chromatography and static light scattering. For the linear triblock copolymer a fractionation via temperature variation turned out to be better suited than the usual isothermal procedure. The star-shaped polymer with the d value of 1.33 was fractionated in two CSF steps to get the targeted sample, which has a considerably more uniform structure and a narrower molecular weight distribution (d=1.11). The corresponding starting linear diblock copolymer was fractionated in one step reducing d from 1.68 to 1.17. With one set of simple laboratory equipment, 1kg polymer can be fractionated per day. Utilizing CSF, for the first time, we fractionated successfully the block copolymers.

Butadienes↗
PubMed2004

Evaluation of 1,3-butadiene dimerization and secondary reactions in the presence and absence of oxygen.

Thermal stability evaluation of exothermic chemical reactions is of great importance to the safer design and operation of chemical processes. Dominant reaction stoichiometries and their thermochemistry parameters are key elements in the evaluation process. Identification of significant reaction pathways under possible process conditions will lead to an understanding of the overall thermodynamic and kinetic behavior. The kinetics of 1,3-butadiene (BD) is an excellent example of conjugated dienes that undergo addition reactions. At elevated temperatures, 1,3-butadiene monomers can dimerize exothermally, and as temperature increases, secondary exothermic reactions will take place. The very high temperature and pressure rates that these reactions can attain may lead to a reaction runaway or even a thermal explosion. BD is a vapor at ambient conditions, usually stored as a pressurized liquid, and is a carcinogen, so the experimental evaluation is potentially difficult and hazardous. In this paper, the thermal stability of BD is evaluated. Dimerization and other secondary reactions are investigated by experimental thermal analysis using an automatic pressure adiabatic calorimeter (APTAC), by theoretical computational quantum chemistry methods, and empirical thermodynamic-energy correlations. A theoretical approach is conducted to predict some of the BD reaction behavior. Results are compared to other literature data obtained using different experimental methods.

Butadienes↗
PubMed2006

Chrome-tanned leather shavings as a filler of butadiene-acrylonitrile rubber.

The noxious wastes from the tanning industry such as chrome-tanned leather shavings were used as the only filler of rubber mixes containing carboxylated butadiene-acrylonitrile rubber (XNBR) or butadiene-acrylonitrile rubber (NBR), and a dispersing agent Limanol PEV (Schill & Seilacher). The best form addition of leather powder to the rubber mixes is mixed the waste protein with zinc oxide. The leather powder added to the rubber mixes improves the mechanical properties: tensile strength (T(s)), elongation at break (epsilon(b)) and increase the cross-linking density of carboxylated XNBR and NBR rubber mixes. Satisfactory results of these studies are presented in this work.

Acrylic Resins↗
PubMed2005

Inhibition of cell proliferation, cytotoxicity and induction of apoptosis of 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene in gastrointestinal tumour cell lines and preliminary evaluation of its toxicity in vivo.

Our preliminary data suggested that 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene [Viale M, Ottone M, Chiavarina B, Mariggiò MA, Prevosto C, Dell'Erba C, et al. Preliminary evaluation in vitro of the inhibition of cell proliferation, cytotoxicity and induction of apoptosis by 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene. Invest New Drug 2004;22:359-67] (Naph-DNB), possesses good characteristics in terms of inhibition of cell proliferation in two cell lines derived from colon and gastric cancers. On this basis and to confirm the specificity of our compound towards gastrointestinal malignancies, we have analyzed the inhibition of cell proliferation, the cytotoxicity and the induction of apoptosis by Naph-DNB in seven cell lines derived from human colon (DLD-1, Lovo, HCT-8 and Colo 741), stomach (HGC-27) and pancreas (Panc-1 and Hup-T4) tumours. For the sake of comparison, cells have also been exposed to four anticancer drugs utilized for the treatment of gastrointestinal malignancies (oxaliplatin, irinotecan, gemcitabine and 5-fluorouracil). Moreover, toxicological data have been obtained in order to define the lethal dose (LD) and maximal tolerated dose (MTD) values and the spectrum of tissue alterations caused by the intraperitoneal (i.p.) and intravenous (i.v.) administration of Naph-DNB. IC50 data obtained by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay suggest that Naph-DNB is generally more active than two or more of the anticancer drugs above in most cell lines: it displayed the lowest activity only in HGC-27 cells, although data concerning the IC75 parameter enlighten a significantly better activity than irinotecan and 5-fluorouracil. Using the equitoxic concentrations IC50 and IC75, we have also evaluated the ability of Naph-DNB and of the other anticancer drugs to kill cells and to induce apoptosis. Our data show that at these concentrations Naph-DNB has a cytotoxic activity comparable or even better than that of some anticancer drugs. Similarly, Naph-DNB induces apoptosis better than the other anticancer drugs in HCT-8 and HGC-27 cells, while in Lovo and Panc-1 cells the induction is comparable. On the basis of toxicological data we defined the LD10, LD50, LD90 (i.p., 17.6, 36.1 and 54.1 mg kg(-1), respectively; i.v., 6.1, 14.1 and 22.0 mg kg(-1), respectively) and the MTD (i.p., 15 mg kg(-1); i.v., 5 mg kg(-1)) parameters. Histochemical analysis has shown that, in general, the administration of even toxic doses of Naph-DNB does not cause great structural injuries, although it can have some effects on the metabolism of glicogen and iron in organs as liver and spleen. In conclusion, our preclinical studies in vitro suggest that Naph-DNB may represent a good anticancer compound for the treatment of generally unresponsive tumours such as those of pancreas, stomach and colon. Moreover, the analysis of its toxic effects has allowed the definition of LD and MTD parameters, which will be used in further experiments in vivo for the definition of its antitumour activity.

Animals↗
PubMed2004

Determination of molecular parameters for 1,3-butadiene and propylene using infrared tunable diode laser absorption spectroscopy.

A technique has been developed for the determination of molecular parameters, including infrared absorption line positions, strengths, and nitrogen-broadened half-widths for 1,3-butadiene (C(4)H(6)) and propylene (C(3)H(6)). The parameters for these two molecules are required for quantitation using Tunable Diode Laser Absorption Spectroscopy (TDLAS). These molecules have populations of highly overlapping infrared absorption lines in their room temperature spectra. The technique reported here provides a procedure for estimating the molecular parameters for these overlapping absorption lines from quantitative reference spectra taken with the TDLAS instrument at different pressures and concentrations. The system was developed for the quantitation of gaseous constituents in a single puff of cigarette smoke and this paper will describe the procedure and some of the factors that influence the accuracy of quantitation for 1,3-butadiene, including the approach taken to minimize the adverse effects of the absorption due to propylene in the same spectral region.

Alkenes↗
PubMed2001

N7-guanine adducts of the epoxy metabolites of 1,3-butadiene in mice lung.

Epoxy metabolites of 1,3-butadiene are electrophilic and can bind to nucleophilic sites in DNA forming DNA adducts. In this study, guanine N7 adducts of epoxy butene and guanine N7 adducts of epoxy butanediol were measured in lung tissues of mice inhalation exposed to various concentrations of 1,3-butadiene. 32P-postlabeling of DNA adducts were used to demonstrate that the DNA adducts derived from epoxybutene and epoxybutanediol were formed in a dose dependent manner. More than 98% of all adducts detected were formed from epoxybutanediol. Enantiomeric distribution of the adducts formed in vivo differs from that of in vitro experiments demonstrated before. In the case of epoxybutene most of the adducts were formed to the terminal carbon of the S-epoxybutene enantiomer. Most of the adducts derived from epoxybutanediol were formed from the 2S-3R enantiomer. The data demonstrates that enzymatic processes involved with activation and/or detoxification of the metabolites are enantiospecific and/or DNA repair machinery repairs the damage with stereochemical considerations. These are the crucial factors if interspecies differences in tumor sensitiveness is concerned.

Administration, Inhalation↗
PubMed2001

Assessment of butadiene exposure in synthetic rubber manufacturing workers in Texas using frequencies of hprt mutant lymphocytes as a biomarker.

1,3-Butadiene (BD), which is used to manufacture synthetic rubber, is a mutagen and carcinogen. Because past occupational exposures have been associated with an increased risk of leukemia, there has been a dramatic reduction in workplace exposure standards. The health benefits of these reduced levels of occupational exposure to BD will be difficult to evaluate using relatively insensitive traditional epidemiological studies; however, biomarkers can be used to determine whether there are genotoxic effects associated with recent exposures to BD. In past studies of BD-exposed workers in Southeast Texas, we observed an increase in the frequency of lymphocytes with mutations in a reporter gene, hprt. Frequencies of hprt mutant cells correlated with air levels of BD and with the concentration of a BD metabolite in urine. Average exposures to 1-3 parts per million (p.p.m.) of BD were associated with a threefold increase in hprt variant (mutant) frequencies (Vfs). We now report results from a follow-up study of workers in a synthetic rubber plant in Southeast Texas. Thirty-seven workers were evaluated on three occasions over a 2-week period for exposure to BD by the use of personal organic vapor monitors and by determining the concentration of a BD metabolite in urine. The frequency of hprt mutants was determined, by autoradiography, with lymphocyte samples collected 2 weeks after the final exposure measurement. Based on their work locations, the study participants were assigned to high-exposure (N=22) or low-exposure (N=15) groups. The BD exposure, +/-standard error, of the workers in the high-exposure group (1.65+/-0.52 p.p.m.) was significantly greater than the low-exposure group (0.07+/-0.03 p.p.m.; P<0.01). The frequency of hprt mutant lymphocytes was also significantly different in the two groups (high, 10.67+/-1.5 x 10(-6); low, 3.54+/-0.6 x 10(-6); P<0.001). The concentration of the urine metabolite was greater in the high-exposure group, but the difference was not significant. The correlation coefficient between hprt Vf and BD exposure levels was r=0.44 (CI(95), 0.11-0.69; P=0.011). This study reproduced the findings from a previous study at this plant. Although studies of butadiene-exposed workers in other countries have not detected an effect of exposure on frequencies of hprt mutant lymphocytes, we have repeatedly observed this result in our studies in Texas.

Air Pollutants, Occupational↗
PubMed2001

Occupational exposure to butadiene, isoprene and chloroprene.

Workers are exposed to butadiene, isoprene and chloroprene in the manufacture of these monomers and in their use in the production of various elastomers. These include styrene butadiene rubber, polybutadiene, polyisoprene, butyl rubber and neoprene. Monomer production and extraction are done in typical closed chemical process units where low background levels of the monomers are the result of minor leaks in valves and pumps. Occasionally, higher levels occur as a result of planned or unplanned events that cause releases. Polymer production is also a closed process, but the occasional clogging of pipes and equipment with polymer requiring maintenance operations where some release is likely occurs much more often than for monomer production. For this reason, exposure levels are generally higher on polymer production units. Polymer finishing is essentially an open process, but almost all monomer should have been stripped from the polymer before finishing. Where small amounts of solvents or monomers remain in the polymer and are volatilized in finishing, they are captured by vapor control systems. As a result, exposures in finishing are typically low. Measured levels of exposure in recent years are presented. In general, modern levels of exposure are well below OSHA, ACGIH and other applicable limits. Few measurements were made prior to the 1970s, but epidemiological estimates made by modeling suggest that levels could have been quite high in the 1940s and 1950s. In these years, manual reactor cleaning was common, and pumps often leaked.

Air Pollutants, Occupational↗
PubMed2001

Insights into the toxicokinetics and toxicodynamics of 1,3-butadiene.

1,3 Butadiene (BD) is a colorless gas used in the production of synthetic rubber and plastics. BD is carcinogenic in rats and mice, however, there are striking species differences in cancer potency and spectrum of tumors, with mice being more susceptible to tumor induction than rats. Epidemiology studies suggest an excess incidence of leukemia in workers in the styrene-butadiene rubber industry. Consideration of mechanisms of BD carcinogenicity can provide insights into differences in cancer potency between rodents and serve to elucidate the extent to which BD exposure may cause cancer in humans. Mechanistic research in the areas of biochemical toxicology, molecular biology, molecular dosimetry, and susceptibility factors can impact BD cancer risk assessment for humans. This research has focused on quantitating species differences in the metabolism of BD and BD epoxides, defining molecular lesions produced by BD epoxides, identifying biomarkers for BD exposure to explore metabolic pathways in humans, and determining potential risk factors for sensitive subpopulations. BD is activated by P450 isozymes, including CYP2E1, to at least two genotoxic metabolites, epoxybutene (EB) and diepoxybutane (DEB). Dosimetry data from several laboratories on EB and DEB following inhalation exposure to BD indicate that blood concentrations of EB were four-eight-fold higher in mice compared with rats and that blood concentrations of DEB were 25-100-fold higher in mice than in rats. The higher levels of these two DNA-reactive metabolites in mice compared with rats probably contribute to the species differences in carcinogenic effects of BD between mice and rats. In vitro metabolism studies of BD in rats, mice, and human tissues indicate that there are significant quantitative species differences in the metabolic activation of BD to EB and DEB and the detoxication of EB and DEB. Activation/detoxication ratios calculated using in vitro kinetic constants reveal that ratios in mice were greater than in both rats and humans. In vitro data are consistent with in vivo dosimetry data and cancer potency for rodents, and suggest that humans may be at a decreased risk. Data on mutagenicity and mutational spectra of BD epoxides show mechanistic differences between EB- and DEB-induced mutational events suggesting involvement of DEB in the development of cancer. Concentrations of DEB that are genotoxic in vitro are within the range of concentrations measured in mice in vivo, whereas concentrations of EB that are genotoxic in vitro are ten-100-fold greater than concentrations observed in vivo. Characterization of molecular events indicate that EB-induced genotoxicity is due to point mutations and small deletions, while DEB induces point mutations, small deletions, and large-scale deletions involving many base pairs. The extent to which epoxybutanediol is involved in BD carcinogenesis is not known. Molecular dosimetry studies in rodents and humans have focused on urinary metabolites and DNA and hemoglobin adducts. Data from these studies are consistent with in vivo and in vitro metabolism data providing further support for the differences in metabolic activation and deactivation of BD and BD epoxides across species and the role of DEB in tumor development. Research on potential susceptibility factors points to other P450 isozymes, in addition to CYP2E1, that are involved in both the metabolic activation and mutagenicity of BD. Taken together, mechanistic data on BD toxicokinetics and toxicodynamics provide an integrated insight into critical steps in initiation of cancer, metabolites responsible for cancer, sensitive biomarkers for exposure, and potential risk factors for individual susceptibility. Available evidence suggests that BD is unlikely to be a human carcinogen at the low exposure concentrations currently encountered in the environment or workplace.

Animals↗
PubMed2001

Hemoglobin adducts as biomarkers of 1,3-butadiene in occupationally low exposed Italian workers and a few diesel-exposed miners.

Hemoglobin adducts were determined as biomarkers of 1,3-butadiene (BD) in 30 workers and 10 controls from an Italian BD plant and in 14 diesel-exposed miners. N-(2,3,4-trihydroxybutyl)valine (THBVal), an N-terminal valine globin adduct of reactive butadiene metabolites, was analyzed by gas chromatography/high resolution mass spectrometry after a modified Edman degradation and further acetylation. The BD exposure for the plant workers was 31 microg/m(3) (personal sampling). Whereas there was no detectable difference in hemoglobin adduct levels (range 17.7-61.4 pmol/g globin) between the total group of exposed and controls, slight but significant differences could be found between two subgroups of workers from different production units as well as one subgroup and controls (P<0.05), between smoking (n=13) and non-smoking exposed workers (n=17; P=0.066) as well as between smoking exposed workers and controls (P=0.055). Adduct levels of the miners (all non-smokers) were in the same range as those of the Italian BD-workers and controls. The internal exposure and strain measured by THBVal levels resulting from a very low occupational BD exposure was in the range of the contribution of moderate smoking.

Biomarkers↗
PubMed2001

Comparative toxicity of dithiocarbamates and butadiene metabolites in human lymphoid and bone marrow cells.

Apparent differences in the pattern of leukemia risk have been observed between workers employed in 1,3-butadiene (BD) monomer production and those working in styrene-butadiene rubber production (SBR). There are a number of possible explanations for these discrepancies, including differences in disease classification and diagnosis as well as possible quantitative and qualitative differences in occupational exposure between these two industries. This led us to evaluate the possibility that the pattern of disease observed in SBR might be influenced by the presence of an important class of biologically reactive chemicals, dithiocarbamates (DTC), that were present in SBR but not BD monomer production. Therefore, we compared the immunotoxic and hematotoxic activities of DTC and BD metabolites in human immune and hematopoietic cells. Relative to the mouse, human CD34+ bone marrow cells are relatively resistant to the direct effects of BD metabolites, with only the bis-oxide producing any evidence of suppression of clonogenic response at concentrations between 1 and 10 microM. Similarly, treatment of human CD4+ lymphocytes with known (2,3-epoxybutene) and putative BD metabolites (D,L-butane-bis-oxide, (2S,3R)-3-epoxybutane-1,2-diol) does not result in appreciable T-cell toxicity at concentrations likely to be encountered in vivo. In contrast, treatment of human cells with DTC at concentrations as low as 100 nM results in significant suppression of hematopoietic clonogenic response and T-lymphocyte function. Additional studies in our laboratory and others suggest a role for copper in DTC toxicity in both human lymphocytes and bone marrow cells, although the pattern of altered transcriptional regulation observed is markedly different in these two cell populations. These results are consistent with the pattern of DTC toxicity previously observed in clinical and molecular studies.

Animals↗
PubMed1998

Dose response study for 1,3-butadiene-induced dominant lethal mutations and heritable translocations in germs cells of male mice.

Butadiene (BD) and its metabolites have extensively been studied in the EU sponsored research project "Multi-endpoint analysis of genetic damage induced by 1,3-butadiene and its major metabolites". Within this project a dominant lethal test and a heritable translocation test were performed with male mice to study the dose-response relationships for the respective endpoints. BD concentrations of 130 and 500 ppm were tested in the dominant lethal assay by exposing male mice on 6 h/day for five consecutive days resulting in doses of 3900 and 15,000 ppmh, respectively. Males were mated for four consecutive weeks at a ratio of 1:2 to untreated females. A positive dominant lethal effect was observed in the first mating week in the experiment with 15,000 ppmh but no dominant lethality was found with the lower dose of 3900 ppmh. The present dominant lethal data have to be viewed together with the data already published for a BD dose of 39,000 ppmh (1300 ppm at 6 h/day on 5 consecutive days) [1]. The main difference between results with the highest and the middle dose is that mating weeks one and two (sperm and late spermatids) showed an effect at 39,000 ppmh while only mating week one (sperm) showed an effect at 15,000 ppmh. In the heritable translocation assay, males mice were exposed with a BD dose of 15,000 ppmh and mated for one week to untreated females. Among 434 F1 offspring, we found 5 translocation carriers (1.15% vs. 0.05% in the historical control, p < 0.001). In the previous heritable translocation experiment with a BD dose of 39,000 ppmh of DB exposure, 2.7% of the offspring carried a reciprocal translocation [2]. These data can be used for quantification of genetic risk. The dose response for BD-induced heritable translocations in sperm and late spermatids of mice was linear (Y = 0.05 + 6.9 x 10(-5)X) and a doubling dose of 725 ppmh could be calculated.

Animals↗
PubMed1988

Effects of AT-125 on the nephrotoxicity of hexachloro-1,3-butadiene in rats.

The role of gamma-glutamyl transpeptidase (gamma-GTP) in the nephrotoxicity of hexachloro-1,3-butadiene (HCBD) was studied using male Sprague-Dawley rats pretreated with AT-125 (Acivicin; L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid). Inhibition of gamma-GTP by more than 95% did not affect urine output, glomerular filtration rate, or tubular reabsorption of filtrate, sodium, or glucose. Nephrotoxicity observed during the first 24 hr after HCBD was not decreased by inhibition of gamma-GTP and beyond 24 hr nephrotoxicity was increased, rather than decreased, in the AT-125-pretreated group. HCBD impairs glucose reabsorption and this was greatly increased in the AT-125-pretreated group, indicating that function of the initial segment of the nephron is impaired by HCBD. Since inhibition of gamma-GTP did not protect against HCBD nephrotoxicity, it is concluded that gamma-GTP inhibition does not limit the formation of metabolites(s) which cause HCBD nephrotoxicity. Therefore, distribution of gamma-glutamyltranspeptidase does not account for the selective nephrotoxicity of hexachloro-1,3-butadiene.

Animals↗
PubMed1996

Monophosphate 32P-postlabeling assay of DNA adducts from 1,2:3,4-diepoxybutane, the most genotoxic metabolite of 1,3-butadiene: in vitro methodological studies and in vivo dosimetry.

Among the main DNA-reactive metabolites of 1,3-butadiene (BD), both 1,2:3,4-butadiene diepoxide (BDE) and 1,2-epoxy-3-butene (BME) have been reported in mice and rats exposed to BD, but blood and tissue levels of these metabolites are much higher in mice than in rats under similar exposure conditions. BDE, being more reactive and genotoxic than BME, is thought to be responsible for the greater susceptibility of mice to BD carcinogenicity. While BDE is a DNA-alkylating agent and some BDE adducts have been characterized, no sufficiently sensitive method has been reported for studying BDE-DNA binding in vivo. In the present investigation, a modified dinucleotide/monophosphate version of the 32P-postlabeling assay was applied to detect BDE-DNA adducts, which were prepared by reacting BDE with calf thymus DNA or deoxyribooligonucleotides [(AC)10, (AG)10, (CCT)7 and (GGT)7] in vitro or with skin DNA of mice in vivo upon topical treatment. Optimal resolution by 2-D PEI-cellulose TLC of the highly polar 5'-monophosphate adducts was achieved at +4 degrees C using 0.3 M LiCI (DI) and 0.4 M NaCl, 0.04 M H3BO3, pH 7.6 (D2). The profiles of the 32P-postlabeled adducts were similar for calf thymus and skin DNA, with 3 major spots being detected. Adducts obtained in in vitro and in vivo experiments were compared by re- and cochromatography in 4 or 5 different solvents, and these experiments provided evidence that corresponding BDE adducts, for the most part, were identical and represented adenine derivatives. Guanine adducts were not detected by this method although literature data indicate their formation. Quantitatively, the assay responded linearly to adduct concentration, as shown in an experiment where BDE-modified skin DNA was serially diluted up to 81-fold with control DNA. The limit of detection was approximately 1 adduct in 10(8) normal nucleotides. Further, in an in vivo dosimetry study, skin DNA from groups of 8 individual mice treated with different doses of BDE (1.9, 5.7, 17, 51 and 153 mumol/mouse) for 3 days exhibited a linear relationship (r > or = 0.992) between adduct levels and dose. The results suggest that the 32P-postlabeling assay described herein will have utility in mechanistic studies and biomonitoring of DNA adduct formation from BDE and possibly other polar epoxides.

Animals↗
PubMed1997

Micronucleus induction in germ and somatic cells of the mouse after exposure to the butadiene metabolites diepoxybutane and epoxybutene.

The genotoxicity of diepoxibutane (DEB) and epoxybutene (EB), two of the main metabolites of 1,3-butadiene, was tested in the germ and somatic cells of the mouse by applying an MN assay in early spermatids, and in peripheral blood reticulocytes of a subgroup of the same animals. DEB (0.17 and 0.35 mmol/kg) and EB (0.35, 0.70 and 1.04 mmol/kg) were administered i.p. In the germ cell assay, significant increases of MN were observed after treatment of premeiotic S-phase cells with both butadiene metabolites, but DEB was shown to be more powerful than EB in the induction of chromosomal damage. A weak effect of the same compounds was also found after treatment of late spermatocytes, approaching the meiotic divisions. From the MN assay in peripheral blood reticulocytes, a statistically significant increase of the frequency of MN was detected at each dose tested for both chemicals. However, the results have again shown that DEB is much more efficient than EB in inducing chromosome damage.

Animals↗
PubMedDate not supplied

A mechanistic assessment of 1,3-butadiene diepoxide-induced inhibition of uterine deciduoma proliferation in pseudopregnant rats.

Butadiene diepoxide (BDE), a reactive metabolite of 1,3-butadiene that is an important industrial chemical used in synthetic rubber production causes a dose-dependent inhibition of deciduoma development in pseudopregnant Sprague-Dawley rats. This study used 4 daily i.p. BDE doses of 0.20, 0.25, 0.30, 0.35, or 0.40 to characterize mechanisms that may be responsible for the antideciduoma effect. Pseudopregnant rats were treated either before (pseudopregnancy [PPG] days 1-4) or after (PPG days 5-9) deciduoma induction by endometrial trauma with a blunt needle. Animals were killed on PPG day 9 and evaluated for serum progesterone and endometrial protein and DNA. RT-PCR was used to measure message for estrogen receptor (ER) alpha and pituitary adenylate cyclase-activating polypeptide (PACAP). Substrate zymography and Western blotting were used respectively to measure matrix metalloproteinase (MMP)-9 and inducible nitric oxide synthase. The antideciduoma effects of BDE were associated with decreases in endometrial weight, protein, and DNA, with decreases in serum progesterone, and with decreases in PACAP message and MMP-9. A reduction in NOS was identified at the highest dose of BDE. Message for estrogen receptor (ER) alpha was not affected at any dose. We conclude that the reduction in decidual proliferation was direct and appeared to be associated with either 1) a decrease in the effectiveness of the deciduogenic stimulation and/or a weakened endometrial sensitivity to the stimulus; or 2) an effect on deciduoma development. Molecular mechanisms that apparently contributed to BDE inhibition of decidual metabolism included the synthesis of protein and DNA involved in decidual growth, the synthesis and activation of a matrix metalloproteinase for degradation of the extracellular matrix that is essential for tissue remodeling during deciduoma development, and the nitric oxide/nitric oxide synthase and pituitary adenylate cyclase-activating peptide systems that are involved in promoting vasodilation and increased vascular permeability to enhance the availability of substrates for maximal deciduoma growth. The ovotoxicity of BDE, which has previously been established, may indirectly affect decidual proliferation by reducing progesterone, the preeminent endocrine regulator of deciduoma development. The findings also suggest that BDE may possess no estrogenic action since it was associated with endometrial weight loss and unaltered levels of the estrogen receptor alpha mRNA expression.

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