• Factors influencing particle number concentrations, size distributions and modal parameters at a roof-level and roadside site in Leicester, UK.
    • Agus, Young, Lingard, Smalley, Tate, Goodman and Tomlin
    • Sci Total Environ
    • 386 : 1-3
    • Abstract

    Measurements of urban particle number concentrations and size distributions in the range 5-1000 nm were taken at elevated (roof-level) and roadside sampling sites on Narborough Road in Leicester, UK, along with simultaneous measurements of traffic, NO(x), CO and 1,3-butadiene concentrations and meteorological parameters. A fitting program was used to determine the characteristics of up to five modal groups present in the particle size distributions. All particle modal concentrations peaked during the morning and evening rush hours. Additional events associated with the smallest mode, that were not observed to be connected to primary emissions, were also present suggesting that this mode consisted of newly formed secondary particles. These events included peaks in concentration which coincided with peaks in solar radiation, and lower concentrations of the larger modes. Investigation into the relationships between traffic flow and occupancy indicated three flow regimes; free-flow, unstable and congested. During free-flow conditions, positive linear relationships existed between traffic flow and particle modal number concentrations. However, during unstable and congested periods, this relationship was shown to break-down. Similar trends were observed for concentrations of the gas phase pollutants NO(x), CO and 1,3-butadiene. Strong linear relationships existed between NO(x), CO, 1,3-butadiene concentrations, nucleation and Aitken mode concentrations at both sampling locations, indicating a local traffic related emission source. At the roadside, both nucleation and Aitken mode are best represented by a decreasing exponential function with wind speed, whereas at the roof-level this relationship only occurred for Aitken mode particles. The differing relationships at the two sampling locations are most likely due to a combination of meteorological factors and distance from the local emission source.

    • Ranking cancer risks of organic hazardous air pollutants in the United States.
    • Loh, Levy, Spengler, Houseman and Bennett
    • Environ Health Perspect
    • 115 : 8
    • Abstract

    BACKGROUND: In this study we compared cancer risks from organic hazardous air pollutants (HAPs) based on total personal exposure summed across different microenvironments and exposure pathways. METHODS: We developed distributions of personal exposure concentrations using field monitoring and modeling data for inhalation and, where relevant, ingestion pathways. We calculated risks for a nonoccupationally exposed and nonsmoking population using U.S. Environmental Protection Agency (EPA) and California Office of Environmental Health and Hazard Assessment (OEHHA) unit risks. We determined the contribution to risk from indoor versus outdoor sources using indoor/outdoor ratios for gaseous compounds and the infiltration factor for particle-bound compounds. RESULTS: With OEHHA's unit risks, the highest ranking compounds based on the population median are 1,3-butadiene, formaldehyde, benzene, and dioxin, with risks on the order of 10(-4)-10(-5). The highest risk compounds with the U.S. EPA unit risks were dioxin, benzene, formaldehyde, and chloroform, with risks on a similar order of magnitude. Although indoor exposures are responsible for nearly 70% of risk using OEHHA's unit risks, when infiltration is accounted for, inhalation of outdoor sources contributed 50% to total risk, on average. Additionally, 15% of risk resulted from exposures through food, mainly due to dioxin. CONCLUSIONS: Most of the polycyclic aromatic hydrocarbon, benzene, acetaldehyde, and 1,3-butadiene risk came from outdoor sources, whereas indoor sources were primarily responsible for chloroform, formaldehyde, and naphthalene risks. The infiltration of outdoor pollution into buildings, emissions from indoor sources, and uptake through food are all important to consider in reducing overall personal risk to HAPs.

    • HPLC-ESI+-MS/MS analysis of N7-guanine-N7-guanine DNA cross-links in tissues of mice exposed to 1,3-butadiene.
    • Goggin, Loeber, Park, Walker, Wickliffe and Tretyakova
    • Chem Res Toxicol
    • 20 : 5
    • Abstract

    1,3-butadiene (BD) is a major industrial chemical used in rubber and plastics production and is recognized as an animal and human carcinogen. Although the exact mechanism of BD-induced carcinogenesis is unknown, chemical reactions of epoxide metabolites of BD with DNA to form nucleobase adducts are likely to contribute to multistage carcinogenesis. Among BD-derived epoxy metabolites, 1,2:3,4-diepoxybutane (DEB) appears to be the most genotoxic and carcinogenic, probably because of its bifunctional nature. Initial DNA alkylation by DEB produces N7-(2'-hydroxy-3',4'-epoxybut-1'-yl)guanine monoadducts, which can then be hydrolyzed to N7-(2',3',4'-trihydroxy-1'-yl)guanine or can react with another site in double-stranded DNA to form 1,4-bis(guan-7-yl)-2,3-butanediol (bis-N7G-BD) cross-links. While (2',3',4'-trihydroxy-1'-yl)guanine lesions have been previously quantified in vivo, they cannot be used as a biomarker of DEB because the same lesions are also formed by another, more prevalent BD metabolite, 1,2-epoxy-3,4-butanediol. In contrast, bis-N7G-BD can only be formed from DEB, potentially providing a specific biomarker of DEB formation. We have developed a quantitative HPLC-ESI+-MS/MS method for measuring racemic and meso forms of bis-N7G-BD in DNA extracted from tissues of BD-exposed laboratory animals. In our approach, bis-N7G-BD adducts are released from DNA as free bases by neutral thermal hydrolysis, purified by solid-phase extraction, and subjected to HPLC-ESI+-MS/MS analysis. Selected reaction monitoring is performed by following the loss of a guanine moiety from protonated molecules of bis-N7G-BD and the formation of protonated guanine under collision-induced dissociation. Quantitative analysis of racemic and meso forms of bis-N7G-BD is based on isotope dilution with the corresponding 15N-labeled internal standards. The lower limit of quantification of our current method is 10-20 fmol/0.1 mg of DNA. The accuracy and precision of the new method were determined by spiking control mouse liver DNA with racemic and meso forms of bis-N7G-BD (10 fmol each), followed by sample processing and HPLC-ESI+-MS/MS analysis. Calculated amounts of racemic and meso forms of bis-N7G-BD were within 20% of the theoretical value (9.7 +/- 2 and 9.2 +/- 1.9 fmol, respectively, N = 4). DNA extracted from liver and lung tissues of mice exposed to 625 ppm butadiene for 5 days contained 3.2 +/- 0.4 and 1.8 +/- 0.5 racemic adducts per 10(6) guanines, respectively, while the amounts of meso-bis-N7G-BD were below the detection limits of our method (1 per 10(7) guanines). Control animals did not contain either bis-N7G-BD lesion. Sensitive and specific quantitative methods for bis-N7G-BD analysis developed in this work provide a unique biomarker of DEB-induced DNA alkylation following exposure to BD.

    • Mutagenesis of the supF gene by stereoisomers of 1,2,3,4-diepoxybutane.
    • Kim, Tretyakova and Wogan
    • Chem Res Toxicol
    • 20 : 5
    • Abstract

    1,2,3,4-diepoxybutane (DEB) is a key metabolite of the important industrial chemical and environmental contaminant, 1,3-butadiene (BD). Although all three optical isomers of DEB, S,S-, R,R-, and meso-DEB, are produced by metabolic processing of BD, S,S-DEB exhibits the most potent genotoxicity and cytotoxicity, followed by R,R- and then meso-DEB. Our previous studies suggested that the observed differences between the biological effects of DEB optical isomers may be structural in their origin. Although S,S- and R,R-DEB produced mainly 1,3-interstrand 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) cross-links, meso-diepoxide induced equal numbers of intrastrand and interstrand bis-N7G-BD lesions. In the present study, the mutagenicity of the three DEB stereoisomers in the supF gene was investigated. We found that S,S-DEB was the most potent mutagen. Interestingly, mutation specificity and mutant spectra were strongly dependent on DEB stereochemistry. Although A:T to T:A transversions were the major form of mutation observed following treatment with each of the three stereoisomers (35-40%), S,S-DEB induced higher numbers of G:C to A:T transitions, whereas R,R-DEB treatment resulted in a greater frequency of G:C to T:A transversions. Our results are consistent with the stereospecific induction of promutagenic nucleobase adducts other than G-G cross-links by DEB stereoisomers.

    • 1,3-Butadiene exposure and cardiovascular disease.
    • Penn and Snyder
    • Mutat Res
    • 621 : 1-2
    • Abstract
    • Development of a physiologically based toxicokinetic model for butadiene and four major metabolites in humans: global sensitivity analysis for experimental design issues.
    • Brochot, Smith and Bois
    • Chem Biol Interact
    • 167 : 3
    • Abstract

    1,3-Butadiene (BD) is metabolized in humans and rodents to mutagenic and carcinogenic species. Our previous work has focused on developing a physiologically based toxicokinetic (PBTK) model for BD to estimate its metabolic rate to 1,2-epoxy-3-butene (EB), using exhaled breath BD concentrations in human volunteers exposed by inhalation. In this paper, we extend our BD model to describe the kinetics of its four major metabolites EB, 1,2:3,4-diepoxybutane (DEB), 3-butene-1,2-diol (BDD), and 3,4-epoxy-1,2-butanediol (EBD), and to test whether the extended model and experimental data (to be collected for BD and metabolites in humans) are together adequate to estimate the metabolic rate constants of each of the above chemicals. Global sensitivity analyses (GSA) were conducted to evaluate the relative importance of the model parameters on model outputs during the 20min of exposure and the 40min after exposure ended. All model parameters were studied together with various potentially measurable model outputs: concentrations of BD and EB in exhaled air, concentrations of BD and all metabolites in venous blood, and cumulated amounts of urinary metabolites excreted within 24h. Our results show that pulmonary absorption of BD and subsequent distribution and metabolism in the well-perfused tissues compartment are the critical processes in the toxicokinetics of BD and metabolites. In particular, three parameters influence numerous outputs: the blood:air partition coefficient for BD, the metabolic rate of BD to EB, and the volume of the well-perfused tissues. Other influential parameters include other metabolic rates, some partition coefficients, and parameters driving the gas exchanges (in particular, for BD outputs). GSA shows that the impact of the metabolic rate of BD to EB on the BD concentrations in exhaled air is greatly increased if a few of the model's important parameters (such as the blood:air partition coefficient for BD) are measured experimentally. GSA also shows that all the transformation pathways described in the PBTK model may not be estimable if only data on the studied outputs are collected, and that data on a specific output for a chemical may not inform all the transformations involving that chemical.

    • Site specific N6-(2-hydroxy-3,4-epoxybut-1-yl)adenine oligodeoxynucleotide adducts of 1,2,3,4-diepoxybutane: synthesis and stability at physiological pH.
    • Antsypovich, Quirk-Dorr, Pitts and Tretyakova
    • Chem Res Toxicol
    • 20 : 4
    • Abstract

    1,2,3,4-Diepoxybutane (DEB) is an important metabolite of 1,3-butadiene, a high volume industrial chemical classified as a human and animal carcinogen. DEB is a bifunctional alkylating agent that exhibits both mutagenic and cytotoxic activity, presumably a result of its ability to form bifunctional DNA adducts. Initial reactions of DEB with DNA produce 2-hydroxy-3,4-epoxybut-1-yl (HEB) lesions at guanine and adenine nucleobases. The epoxy group of the monoadduct is inherently reactive and can then undergo further reactions, for example, hydrolysis to the corresponding 2,3,4-trihydroxybutyl adducts and/or second alkylation to yield 2,3-butanediol cross-links. In the present work, synthetic DNA 16-mers containing structurally defined racemic N6-(2-hydroxy-3,4-epoxybut-1-yl)-2'-deoxyadenosine (N6-HEB-dA) adducts (5'-AATTATGTXACGGTAG-3', where X = N6-HEB-dA) were prepared by coupling 6-chloropurine-containing oligodeoxynucleotides with 1-amino-2-hydroxy-3,4-epoxybutane. The latter was generated in situ from the corresponding Fmoc-protected amino epoxide. The N6-HEB-dA-containing DNA oligomer was isolated by reverse-phase HPLC, and the presence of N6-HEB-dA in its structure was confirmed by molecular weight determination and by HPLC-UV-ESI+-MS/MS analyses of enzymatic digests. An independently prepared N6-HEB-dA nucleoside served as an authentic standard. The fate of N6-HEB-dA within DNA at physiological conditions in the presence of various nucleophiles (e.g., cysteine, dG, and the complementary DNA strand) was investigated. Under all conditions tested, N6-HEB-dA rapidly cyclized to produce previously unidentified exocyclic dA lesions (t1/2 < 2 h at physiological conditions). Only trace amounts of hydrolyzed and cross-linked products were detected, suggesting that the rate of cyclization was much greater than the rates of other reactions at the epoxide ring. These results indicate that DEB-induced alkylation of N6-adenine in DNA is unlikely to lead to DNA-DNA cross-linking but instead can result in the formation of exocyclic dA adducts.

    • The importance of 3,4-epoxy-1,2-butanediol and hydroxymethylvinyl ketone in 3-butene-1,2-diol associated mutagenicity.
    • Powley, Walker, Li, Upton and Swenberg
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    1,2:3,4-Diepoxybutane is hypothesized to be the main intermediate involved in mutagenicity following exposure to low levels of 1,3-butadiene (BD) in mice, while metabolites of 3-butene-1,2-diol (BD-diol) are thought to become involved in both rats and mice at higher exposures. BD-diol is biotransformed to hydroxymethylvinyl ketone (HMVK), a potentially mutagenic metabolite, and 3,4-epoxy-1,2-butanediol (EB-diol), a known mutagen. To determine the relative importance of HMVK and EB-diol in BD-diol associated mutagenesis, we have examined the dosimetry of a HMVK derived DNA adduct, as well as EB-diol derived DNA and hemoglobin adducts, in rodents exposed to BD-diol. We previously demonstrated similarities in the shapes of the dose-response curves for EB-diol derived DNA adducts, hemoglobin adducts, and Hprt mutant frequencies in BD-diol exposed rodents, indicating that EB-diol was involved in the mutagenic response associated with BD-diol exposure. To examine the role of HMVK in BD-diol mutagenicity, a method to quantify the alpha-regioisomer of HMVK derived 1,N(2)-propanodeoxyguanosine (alpha-HMVK-dGuo) was developed. The method involved enzymatic hydrolysis of DNA, HPLC purification, and adduct measurement by liquid chromatography - tandem mass spectrometry. Intra- and inter-experimental variabilities were determined to be 2.3-18.2 and 4.1%, respectively. The limit of detection was approximately 5 fmol of analyte standard injected onto the column or 5 fmol/200 microg DNA. The method was used to analyze liver DNA from control female F344 rats and female F344 rats exposed to 36 ppm BD-diol. In addition, liver samples from female Sprague-Dawley rats exposed to 1000 ppm BD were analyzed. alpha-HMVK-dGuo was not detected in any of the samples analyzed. Several possible explanations exist for the negative results including the possibility that alpha-HMVK-dGuo may be a minor adduct or may be efficiently repaired. Alternatively, HMVK itself may be readily detoxified by glutathione (GSH) conjugation. While experiments must be conducted to understand the exact mechanism(s), these results, in addition to published EB-diol derived adduct dosimetry and existing HMVK derived mercapturic acid data, suggest that EB-diol is primarily responsible for BD-diol induced mutagenicity in rodents.

    • Future directions in butadiene risk assessment and the role of cross-species internal dosimetry.
    • Swenberg, Boysen, Georgieva, Bird and Lewis
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • International Symposium on the Evaluation of Butadiene and Chloroprene Health Risks.
    • Himmelstein, Baan, Albertini, Bird and Lewis
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Development and testing of a chemical mechanism for atmospheric photochemical transformations of 1,3-butadiene.
    • Sexton, Doyle, Jeffries and Ebersviller
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    1,3-Butadiene (BD) in the atmosphere is a highly reactive hazardous air pollutant, which has a short lifetime and is quickly transformed to reaction products, some of which are also toxic. The ability to predict exposure to BD and its' products requires models with chemical mechanisms which can simulate these transformations. The atmospheric photochemical reactions of BD have been studied in the University of North Carolina Outdoor smog chamber, which has been used for over 30 years to test photochemical mechanisms for air quality simulation models for ozone. Experiments have been conducted under conditions of real sunlight and realistic temperature and humidity to study the transformations of BD and to develop and test chemical mechanisms for the simulation of these processes. Experimental observation of time-concentration data of BD decay and the formation of many products is compared to simulation results. This chemical mechanism can be incorporated into air quality simulation models which can be used to estimate ambient concentrations needed for exposure estimates.

    • PBPK models in risk assessment--A focus on chloroprene.
    • DeWoskin
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Measurement of plasma or urinary metabolites and Hprt mutant frequencies following inhalation exposure of mice and rats to 3-butene-1,2-diol.
    • Walker, McDonald, Meng, Kracko, Bauer, Seilkop, Walker, Henderson and Walker
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    Studies were performed to determine if the detoxification pathway of 1,3-butadiene (BD) through 3-butene-1,2-diol (BD-diol) is a major contributor to mutagenicity in BD-exposed mice and rats. First, female and male mice and rats (4-5 weeks old) were exposed by nose-only for 6h to 0, 62.5, 200, 625, or 1250 ppm BD or to 0, 6, 18, 24, or 36 ppm BD-diol primarily to establish BD and BD-diol exposure concentrations that yielded similar plasma levels of BD-diol, and then animals were exposed in inhalation chambers for 4 weeks to BD-diol to determine the mutagenic potency estimates for the same exposure levels and to compare these estimates to those reported for BD-exposed female mice and rats where comparable blood levels of BD-diol were achieved. Measurements of plasma levels of BD-diol (via GC/MS methodology) showed that (i) BD-diol accumulated in a sub-linear fashion during single 6-h exposures to >200 ppm BD; (ii) BD-diol accumulated in a linear fashion during single or repeated exposures to 6-18 ppm BD and then in a sub-linear fashion with increasing levels of BD-diol exposure; and (iii) exposures of mice and rats to 18 ppm BD-diol were equivalent to those produced by 200 ppm BD exposures (with exposures to 36 ppm BD-diol yielding plasma levels approximately 25% of those produced by 625 ppm BD exposures). Measurements of Hprt mutant frequencies (via the T cell cloning assay) showed that repeated exposures to 18 and 36 ppm BD-diol were significantly mutagenic in mice and rats. The resulting data indicated that BD-diol derived metabolites (especially, 1,2-dihydroxy-3,4-epoxybutane) have a narrow range of mutagenic effects confined to high-level BD (>or=200 ppm) exposures, and are responsible for nearly all of the mutagenic response in the rat and for a substantial portion of the mutagenic response in the mouse following high-level BD exposures.

    • Identification of covalent modifications in P450 2E1 by 1,2-epoxy-3-butene in vitro.
    • Boysen, Scarlett, Temple, Combs, Brooks, Borchers and Swenberg
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    1,3-Butadiene is metabolized mainly by cytochrome P450 2E1 to several epoxides that are considered toxic and carcinogenic. The first step of BD metabolism is oxidation to 1,2-epoxy-3-butene (EB), a reactive metabolite. It has been shown that P450s can be inactivated by covalent binding of reactive metabolites to protein or heme. Molecular dosimetry studies have clearly shown that BD metabolism follows a supralinear dose response, suggestive of saturation of metabolic activation. In this study, potential binding sites of EB in human P450 2E1 were identified and modeled to test whether EB covalently binds to residues important for enzyme activity. Commercially available human P450 2E1 was reacted with EB, digested with trypsin and the resulting peptides were analyzed by Matrix-Assisted Laser Desorption/Ionization tandem Time-of-Flight mass spectrometry (MALDI-MS). The identity of EB modified peptides was confirmed by Matrix-Assisted Laser Desorption/Ionization tandem mass spectrometry (MALDI-MS/MS) sequencing. It was shown that EB binds to four histidine and two tyrosine residues. All modification sites were assigned by at least two adjacent and a minimum of eight peptide specific fragments. Protein modeling revealed that two of these covalent modifications (His(109), His(370)) are clearly associated with the active site, and that their Calpha atoms are located less than 9A from a known inhibitor binding site. In addition, the side chain of His(370) is within 4A of the heme group and its modification is expected to influence the orientation of the heme. The Calpha atom of Tyr(71) is within 14A of the potential inhibitor binding site and within 7A of the flap undergoing conformational change upon ligand binding, potentially placing Tyr(71) near the substrate as it enters and leaves the active site. The data support the hypothesis that EB can inactivate P450 2E1 by covalent modifications and thus add an additional regulatory mechanism for BD metabolism.

    • Chloroprene: overview of studies under consideration for the development of an IRIS assessment.
    • Pagan
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • A follow-up study of women in the synthetic rubber industry: study methods.
    • Sathiakumar and Delzell
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    BACKGROUND: Concerns about the possible toxic effects of workplace exposures in the synthetic rubber industry have centered on 1,3-butadiene (BD), styrene and dimethyldithiocarbamate (DMDTC). Our previous mortality studies of over 17,000 male synthetic rubber workers found an excess of leukemia that may be due to BD or BD plus other chemicals. Experimental studies have shown that BD produces mammary tumors in female mice and rats and ovarian tumors in female mice. AIM: This paper presents the methods of a follow-up study that evaluates the mortality experience of women employed in the North American synthetic rubber industry. METHODS: Women employed for at least 1 day at any of eight North American styrene-butadiene rubber plants were followed up from 1943 to 2002. Identifying and work history information were obtained from personnel records. Estimated quantitative exposure to BD, styrene and DMDTC, developed for our previous study of men, were used in this study. External analyses use the standardized mortality ratios (SMRs) to compare the cohort's cause-specific mortality rates to the rates of the female general population of the states or the province where the plants are located. Internal analyses use the Poisson regression and Cox proportional hazards models to examine specific cancer mortality rates in relation to BD, styrene and DMDTC exposure, by comparing an exposed cohort subgroup with the rate of unexposed cohort members.

    • 1,3-Butadiene and leukemia among synthetic rubber industry workers: exposure-response relationships.
    • Cheng, Sathiakumar, Graff, Matthews and Delzell
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    Previous research updated the mortality experience of North American synthetic rubber industry workers during the period 1944-1998, determined if leukemia and other cancers were associated with several employment factors and carried out Poisson regression analysis to examine exposure-response associations between estimated exposure to 1,3-butadiene (BD) or other chemicals and cancer. The present study used Cox regression procedures to examine further the exposure-response relationship between several unlagged and lagged, continuous, time-dependent BD exposure indices (BD parts per million (ppm)-years, the total number of exposures to BD concentrations >100 ppm ("peaks") and average intensity of BD) and leukemia, lymphoid neoplasms and myeloid neoplasms. All three BD exposure indices were associated positively with leukemia. Using continuous, untransformed BD ppm-years the regression coefficient (beta) from an analysis that controlled only for age was 2.9 x 10(-4) (p<0.01); the regression coefficient adjusted for all covariates (age, year of birth, race, plant, years since hire and dimethyldithiocarbamate) was similar in magnitude (beta=3.0 x 10(-4), p=0.04). Lagging exposure had minimal impact on the results for leukemia for any of the three BD exposure indices. In models that controlled only for age, lymphoid neoplasms were associated with BD ppm-years and myeloid neoplasms, with BD peaks, but neither trend was statistically significant after adjusting for multiple covariates. The present results support the presence of a causal relationship between high cumulative exposure and high intensity of exposure to BD and leukemia.

    • Validation of 1,3-butadiene exposure estimates for workers at a synthetic rubber plant.
    • Sathiakumar, Delzell, Cheng, Lynch, Sparks and Macaluso
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    PURPOSE: This investigation assessed the validity of estimates of exposure to 1,3-butadiene (BD) developed for a plant included in a study of mortality among synthetic rubber industry workers. The estimates were developed without using historical measurement data and have not been validated previously. METHODS: Personal BD measurements came from an exposure-monitoring program initiated in 1977. For each job, we computed the year-specific difference between the BD estimate and the mean of BD measurements. We also computed rank correlation coefficients and calculated the mean, across all measurements, of the difference between the estimate and the measurement. RESULTS: The mean BD concentration was 5.2 ppm for 4978 measurements and 4.7 ppm for the corresponding estimates. The mean difference between estimates and measurements was -0.50 ppm (standard deviation, 26.5 ppm) overall and ranged from -227.9 to +27.0 ppm among all 306 job/year combinations. Estimates were correlated with measurements for all 306 combinations (rank correlation coefficient, r=0.45, p<0.0001), for 82 combinations pertaining to jobs that were well-defined by a specific set of tasks and typically found in styrene-BD rubber (SBR) plants (r=0.81, p<0.0001), for 70 combinations pertaining to jobs that were well-defined but not typical (r=0.29, p=0.01) and for 92 combinations pertaining to poorly-defined jobs typically found in SBR plants (r=0.56, <0.0001). Estimates were not correlated with measurements for poorly defined jobs not typically found in SBR plants (r=0.01, p=0.93). For well-defined typical SBR jobs with measurement means that were over 7.0 ppm, estimates were consistently lower than measurements. CONCLUSIONS: Possible reasons for differences between estimates and measurements included faulty assumptions used in developing BD estimates, unstable or nonrepresentive measurements and errors in linking measurement data to the job-exposure matrix. Exposure misclassification may have been more severe for subjects from the validation study plant than for subjects from other plants in the mortality study. BD estimates for typical SBR jobs, which comprise most operations at all but one of the plants in the mortality study, appeared to be useful for ranking workers by cumulative exposure. Uncertainty analyses would enhance the utility of the BD exposure estimates for quantitative risk assessment.

    • Exposure and risk assessment of 1,3-butadiene in Japan.
    • Higashino, Mita, Yoshikado, Iwata and Nakanishi
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    1,3-Butadiene is on the list of Substances Requiring Priority Action published by the Central Environmental Council of Japan in 1996. Emission of 1,3-butadiene has been controlled by a voluntary reduction program since 1997. Although the industrial emission of 1,3-butadiene in Japan has decreased in recent years, primarily due to a voluntary industrial emissions reduction program, the risks of exposure to it remain largely unknown. We assessed the risks and consequences of exposure to 1,3-butadiene on human health. A remarkable advantage of our risk assessment approach is the detailed assessment of exposure. Previously, we developed two different models that can be applied for the assessment of exposure: the first, the AIST-ADMER model estimates regional concentration distributions, whereas the second, the METI-LIS model estimates concentration distributions in the vicinity of factories. Both models were used for the assessment of exposure to 1,3-butadiene. Using exposure concentration and carcinogenic potency determined and reported by Environment Canada and Health Canada, we evaluated the excess lifetime cancer risk for persons exposed to 1,3-butadiene over the course of a lifetime. The results suggested that the majority of the population in Japan has an excess lifetime cancer risk of less than 10(-5), whereas a small number of people living close to industrial sources had a risk of greater than 10(-5). The results of the present assessment also showed that 1,3-butadiene in the general environment originates primarily from automobile emissions, such that a countermeasure of reducing emissions from cars is expected to be effective at reducing the total cancer risk among Japanese. On the other hand, individual risks among a population living in the vicinity of certain industrial sources were found to be significantly higher than those of the population living elsewhere, such that a reduction in emissions from a small number of specific industrial sources should be realized in order to reduce the high level of individual risk. Based on the results of our assessment, the Industrial Structure Council of the Ministry of Economy, Trade and Industry (METI) in Japan decided to announce that the voluntary reduction program had been successful, and that emissions reductions should no longer be targeted across all industries in general, but instead that such reductions should be carried out in a small number of selected factories that emit excessively large amounts of emissions.

    • Chromosomal aberration frequencies determined by conventional methods: Parallel increases over time in the region of a petrochemical industry and throughout the Czech Republic.
    • Sram, Rössner, Beskid, Bavorova, Ocadlikova, Solansky and Albertini
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Spatial and temporal trend evaluation of ambient concentrations of 1,3-butadiene and chloroprene in Texas.
    • Grant, Leopold, McCant and Honeycutt
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Molecular epidemiological studies in 1,3-butadiene exposed Czech workers: female-male comparisons.
    • Albertini, Sram, Vacek, Lynch, Rossner, Nicklas, McDonald, Boysen, Georgieva and Swenberg
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Age-, gender-, and species-dependent mutagenicity in T cells of mice and rats exposed by inhalation to 1,3-butadiene.
    • Meng, Walker, McDonald, Henderson, Carter, Cook, McCash, Torres, Bauer, Seilkop, Upton, Georgieva, Boysen, Swenberg and Walker
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    Experiments were performed: (i) to investigate potential age- and gender-dependent differences in mutagenic responses in T cells following exposures of B6C3F1 mice and F344 rats by inhalation for 2 weeks to 0 or 1250 ppm butadiene (BD), and (ii) to determine if exposures for 2 weeks to 62.5 ppm BD produce a mutagenic effect in female rats. To evaluate the effect of age on mutagenic response, mutant manifestation curves for splenic T cells of female mice exposed at 8-9 weeks of age were defined by measuring Hprt mutant frequencies (MFs) at multiple time points after BD exposure using a T cell cloning assay and comparing the resulting mutagenic potency estimate (calculated as the difference of areas under the mutant manifestation curves of treated versus control animals) to that reported for female mice exposed to BD in the same fashion beginning at 4-5 weeks of age. The shapes of the mutant T cell manifestation curves for spleens were different [e.g., the maximum BD-induced MFs in older mice (8.0+/-1.0 [S.D.]x10(-6)) and younger mice (17.8+/-6.1 x 10(-6)) were observed at 8 and 5 weeks post-exposure, respectively], but the mutagenic burden was the same for both age groups. To assess the effect of gender on mutagenic response, female and male rodents were exposed to BD at 4-5 weeks of age and Hprt MFs were measured when maximum MFs are expected to occur post-exposure. The resulting data demonstrated that the pattern for mutagenic susceptibility from high-level BD exposure is female mice>male mice>female rats>male rats. Exposures of female rats to 62.5 ppm BD caused a minor but significant mutagenic response compared with controls (n=16/group; P=0.03). These results help explain part of the differing outcomes/interpretations of data in earlier Hprt mutation studies in BD-exposed rodents.

    • Effect of n-hexane on the disposition and toxicity of the 1,3-butadiene metabolite 3-butene-1,2-diol.
    • Iba and Bird
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    3-Butene-1,2-diol (butenediol), a major metabolite of 1,3-butadiene (butadiene), can undergo either detoxification or biotransformation to potentially toxic metabolites, including 3,4-epoxy-1,2-butanediol and hydroxymethylvinyl ketone (HMVK). Butadiene exposure can occur concomitantly with hexanes, which share common biotransformation pathways with butadiene. To determine the potential influence of hexane co-exposure on butadiene toxicity, the present study examined the effect of n-hexane on butenediol disposition [as measured by urinary excretion of (N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine) (MI level)] and genotoxicity (as measured by the frequency of bone marrow micronucleated erythrocytes) and acute toxicity (as measured by body weight changes) in the rat. The results show that butenediol was not genotoxic to adult or immature rats but was acutely toxic to adult but not immature rats. The results also suggest that n-hexane co-exposure may attenuate the acute toxicity by butenediol in adult rats and that immature rats may be less sensitive than adults to the acute toxicity.

    • Cancer risk assessment for 1,3-butadiene: dose-response modeling from an epidemiological perspective.
    • Sielken, Valdez-Flores, Gargas, Kirman, Teta and Delzell
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    The dose-response assessment of the association between 1,3-butadiene (BD) and leukemia mortality among workers in the North American synthetic rubber industry is explored. Analyses are based on the most recent University of Alabama at Birmingham epidemiological study and exposure estimation. The U.S. EPA Science Advisory Board recommendations of using the most recent data and giving consideration to peak exposures to BD have been followed. If cumulative BD ppm-years is to be used as the predictor of the leukemia rate ratio, then the performance of that predictor is statistically significantly improved if the slope in the predictor is estimated with age and the cumulative number of BD peaks (where a BD peak is any exposure, regardless of duration, to a BD concentration above 100 ppm) added as categorical covariates. After age and the cumulative number of BD peaks are incorporated as categorical covariates in the Poisson regression model, the estimated concentration (EC(001)) corresponding to an excess risk of 0.001 as a result of continuous environmental exposure is 11.2 ppm; however, the estimated slope for BD cumulative ppm-years in the linear rate ratio for leukemia used to derive this EC(001) is not statistically significantly different from zero. Sensitivity analyses using alternative models indicate either essentially no risk or estimated EC(001) values of 9 and 77 ppm. Analyses suggesting the absence of a statistically significant low-dose risk versus cumulative BD ppm-years are presented. Sensitivity analyses of other malignant neoplasms of lymphatic and hematopoietic tissue (specifically, lymphoid and myeloid neoplasms) resulted in conclusions about the dose-response modeling methodology that were supportive of the methodology used for leukemia.

    • Evaluation of genetic alterations in cancer-related genes in lung and brain tumors from B6C3F1 mice exposed to 1,3-butadiene or chloroprene.
    • Ton, Hong, Devereux, Melnick, Sills and Kim
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Quantitative analysis of N-terminal valine peptide adducts specific for 1,2-epoxy-3-butene.
    • Georgieva, Boysen, Upton, Jayaraj, Gold and Swenberg
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    Butadiene (BD) metabolism shows gender, species and concentration dependency, making the extrapolation of animal results to humans complex. BD is metabolized mainly by cytochrome P450 2E1 to three epoxides, 1,2-epoxy-3-butene (EB), 1,2;3,4-diepoxybutane (DEB) and 1,2-epoxy-butanediol (EB-diol). For accurate risk assessment it is important to elucidate species differences in the internal formation of the individual epoxides in order to assign the relative risks associated with their different mutagenic potencies. Analysis of N-terminal globin adducts is a common approach for monitoring the internal formation of BD derived epoxides. Our long term strategy is to develop an LC-MS/MS method for simultaneous detection of all three BD hemoglobin adducts. This approach is modeled after the recently reported immunoaffinity LC-MS/MS method for the cyclic N,N-(2,3-dihydroxy-1,4-butadyil)-valine (pyr-Val, derived from DEB). We report herein the analysis of the EB-derived 2-hydroxyl-3-butenyl-valine peptide (HB-Val). The procedure utilizes trypsin hydrolysis of globin and immunoaffinity (IA) purification of alkylated heptapeptides. Quantitation is based on LC-MS/MS monitoring of the transition from the singly charged molecular ion of HB-Val (1-7) to the a(1) fragment. Human HB-Val (1-11) was synthesized and used for antibody production. As internal standard, the labeled rat-[(13)C(5)(15)N]-Val (1-11) was prepared through direct alkylation of the corresponding peptide with EB. Standards were characterized and quantified by LC-MS/MS and LC-UV. The method was validated with different amounts of human HB-Val standard. The recovery was >75% and coefficient of variation <25%. The LOQ was set to 100 fmol/injection. For a proof of principal experiment, globin samples from male and female rats exposed to 1000 ppm BD for 90 days were analyzed. The amounts of HB-Val present were 268.2+/-56 and 350+/-70 pmol/g (mean+/-S.D.) for males and females, respectively. No HB-Val was detected in controls. These data are much lower compared to previously reported values measured by GC-MS/MS. The difference may be due higher specificity of the LC-MS/MS method to the N-terminal peptide from the alpha-chain versus derivatization of both alpha- and beta-chain by Edman degradation, and possible instability of HB-Val adducts during long term storage (about 10 years) between the analyses. These differences will be resolved by examining recently collected samples, using the same internal standard for parallel analysis by GC-MS/MS and LC-MS/MS. Based on our experience with pyr-Val adduct assay we anticipate that this assay will be suitable for evaluation of HB-Val in multiple species.

    • Atmospheric photochemical transformations enhance 1,3-butadiene-induced inflammatory responses in human epithelial cells: The role of ozone and other photochemical degradation products.
    • Doyle, Sexton, Jeffries and Jaspers
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    Chemistry of hazardous air pollutants has been studied for many years, yet little is known about how these chemicals, once reacted within urban atmospheres, affect healthy and susceptible individuals. Once released into the atmosphere, 1,3-butadiene (BD) reacts with hydroxyl radicals and ozone (created by photochemical processes), to produce many identified and unidentified products. Once this transformation has occurred, the toxic potential of atmospheric pollutants such as BD in the ambient environment is currently unclear. During this study, environmental irradiation chambers (also called smog chambers), utilizing natural sunlight, were used to create photochemical transformations of BD. The smog chamber/in vitro exposure system was designed to investigate the toxicity of chemicals before and after photochemical reactions and to investigate interactions with the urban atmosphere using representative in vitro samples. In this study, we determined the relative toxicity and inflammatory gene expression induced by coupling smog chamber atmospheres with an in vitro system to expose human respiratory epithelial cells to BD, BDs photochemical degradation products, or the equivalent ozone generated within the photochemical mixture. Exposure to the photochemically generated products of BD (primarily acrolein, acetaldehyde, formaldehyde, furan and ozone) induced significant increases in cytotoxicity, IL-8, and IL-6 gene expression compared to a synthetic mixture of primary products that was created by injecting the correct concentrations of the detected products from the irradiation experiments. Interestingly, exposure to the equivalent levels of ozone generated during the photochemical transformation of BD did not induce the same level of inflammatory cytokine release for either exposure protocol, suggesting that the effects from ozone alone do not account for the entire response in the irradiation experiments. These results indicate that BDs full photochemical product generation and interactions, rather than ozone alone, must be carefully evaluated when investigating the possible adverse health effects to BD exposures. The research presented here takes into account that photochemical transformations of hazardous air pollutants (HAPs) does generate a dynamic exposure system and therefore provides a more realistic approach to estimate the toxicity of ambient air pollutants once they are released into the atmosphere.

    • Mutagenicity of stereochemical configurations of 1,2-epoxybutene and 1,2:3,4-diepoxybutane in human lymphblastoid cells.
    • Meng, Redetzke, Hackfeld, Hodge, Walker and Walker
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    The carcinogenicity of 1,3-butadiene (BD) is related to its bioactivation to several DNA-reactive metabolites; accumulating evidence suggests that the stereochemistry of these BD intermediates may play a significant role in the mutagenic and carcinogenic actions of the parent compound. The objective of this study was to evaluate the cytotoxicity and mutagenicity of stereochemical forms of 1,2-epoxybutene (EB) and 1,2:3,4-diepoxybutane (DEB), two genotoxic BD metabolites, in a human lymphoblastoid cell line, TK6. Cytotoxicity was measured by comparing cloning efficiencies in chemical-exposed cells versus those in control cells. The hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK) mutant frequencies (MFs) were measured using a cell cloning assay. HPRT mutants collected from cells exposed to the three forms of DEB were analyzed by PCR to characterize large genetic alterations. All the three stereoisomers of DEB caused increased HPRT and TK MFs compared to the concurrent control samples. There were no significant differences in cytotoxicity or mutagenicity among the three isomers of DEB in TK6 cells. Molecular analysis of HPRT mutants revealed similar distributions of types of mutations among the three isomers of DEB. There were also no statistically significant differences in mutagenic efficiencies between the two isomers of EB in TK6 cells. These results were consistent with the in vivo findings that there was little difference in the mutagenic efficiencies of racemic-DEB versus meso-DEB in rodents. Thus, in terms of mutagenic efficiency, stereochemical configurations of EB and DEB are not likely to play a significant role in the mutagenicity and carcinogenicity of BD.

    • Synthesis and mutagenesis of the butadiene-derived N3 2'-deoxyuridine adducts.
    • Fernandes, Hackfeld, Kozekov, Hodge and Lloyd
    • Chem Res Toxicol
    • 19 : 7
    • Abstract

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

    • Micronuclei, DNA single-strand breaks and DNA-repair activity in mice exposed to 1,3-butadiene by inhalation.
    • Vodicka, Stetina, Smerak, Vodickova, Naccarati, Barta and Hemminki
    • Mutat Res
    • 608 : 1
    • Abstract

    We investigated single-strand breaks and endonuclease III-sensitive sites in DNA along with gamma-irradiation-specific DNA-repair activity in hepatocytes and frequencies of micronuclei in polychromatic bone-marrow erythrocytes of male NMRI mice (2 months old, weight 30-35 g) during sub-acute inhalation exposure to 1,3-butadiene (28 days, 500 mg/m3) and up to 28 days after the exposure. Concentrations of 1,3-butadiene in blood, an indicator of internal exposure, moderately increased during the exposure period. The most interesting finding was that gamma-irradiation-specific DNA-repair activity gradually increased during exposure, being significantly higher compared with control levels on days 7 and 28 of exposure (P = 0.005 and 0.035, respectively), reaching a maximum on day 1 after the termination of exposure (P = 0.003) and then returning to control levels. A significant correlation between gamma-irradiation-specific DNA-repair activity and the concentration of 1,3-butadiene in blood (R = 0.866, P = 0.050) supports a possible induction of DNA-repair activity by the exposure to 1,3-butadiene and formation of its metabolites. The initial increase in micronucleus frequency (micronuclei per 1000 cells) in the exposed mice continuously decreased from 20.4 +/- 5.1 (day 3) to 15.1 +/- 3.2 (day 28) within the exposure period, and subsequently from 12.4 +/- 5.1 to 4.6 +/- 1.6 in the period following termination of the 1,3-butadiene exposure, while micronucleus frequencies in control animals were significantly lower (from 1.7 +/- 1.5 to 4.2 +/- 0.8).

    • Synthesis of DNA oligodeoxynucleotides containing structurally defined N6-(2-hydroxy-3-buten-1-yl)-adenine adducts of 3,4-epoxy-1-butene.
    • Dorr, Murphy and Tretyakova
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract

    3,4-Epoxy-1-butene (EB) is generated by cytochrome P450-mediated epoxidation of 1,3-butadiene (BD), an important environmental and industrial chemical classified as a probable human carcinogen. The ability of EB to induce point mutations at GC and AT base pairs has been attributed to its reactions with DNA to form covalent nucleobase adducts. Guanine alkylation is preferred at the endocyclic N7 nitrogen, while adenine can be modified at the N1-, N3-, N7-, and the N6 positions. For each of these sites, a pair of regioisomeric 2-hydroxy-3-buten-1-yl and 1-hydroxy-3-buten-2-yl adducts is produced as a result of epoxide ring opening at the terminal C-4 or the internal C-3 carbon position of EB, respectively. The N6-EB-adenine adducts are of particular interest because of their stability in DNA, potentially leading to their accumulation in vivo. In the present work, synthetic DNA oligomers containing structurally defined N6-(2-hydroxy-3-buten-1-yl)-dA (N6-HB-dA) adducts were prepared for the first time by a postoligomerization approach that involved coupling 6-chloropurine-containing DNA with synthetic 1-amino-3-buten-2-ol. N6-HB-dA-containing DNA oligomers were isolated by reversed phase HPLC, and the presence of N6-HB-dA in their structure was confirmed by molecular weight determination from HPLC-ESI- -MS of the intact strands and by HPLC-ESI+-MS/MS and MS/MS/MS analyses of the enzymatic digests using synthetic N6-HB-dA as an authentic standard. N6-HB-dA-containing oligomers generated in this study will be used for structural and biological studies.

    • Analyses of (1-chloroethenyl)oxirane headspace and hemoglobin N-valine adducts in erythrocytes indicate selective detoxification of (1-chloroethenyl)oxirane enantiomers.
    • Hurst and Ali
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Mass spectral analyses of hemoglobin adducts formed after in vitro exposure of erythrocytes to hydroxymethylvinyl ketone.
    • Barshteyn, Krause and Elfarra
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Detoxification of olefinic epoxides and nucleotide excision repair of epoxide-mediated DNA damage: Insights from animal models examining human sensitivity to 1,3-butadiene.
    • Wickliffe, Herring, Hallberg, Galbert, Masters, Ammenheuser, Xie, Friedberg, Lloyd, Abdel-Rahman and Ward
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Some insights into the mode of action of butadiene by examining the genotoxicity of its metabolites.
    • Kligerman and Hu
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Cross-linking of the human DNA repair protein O6-alkylguanine DNA alkyltransferase to DNA in the presence of 1,2,3,4-diepoxybutane.
    • Loeber, Rajesh, Fang, Pegg and Tretyakova
    • Chem Res Toxicol
    • 19 : 5
    • Abstract
    • Cancer risk assessment for 1,3-butadiene: data integration opportunities.
    • Preston
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Metabolism of 1,3-butadiene to toxicologically relevant metabolites in single-exposed mice and rats.
    • Filser, Hutzler, Meischner, Veereshwarayya and Csanády
    • Chem Biol Interact
    • 166 : 1-3
    • Abstract
    • Characterization of 1,2,3,4-diepoxybutane-2'-deoxyguanosine cross-linking products formed at physiological and nonphysiological conditions.
    • Zhang and Elfarra
    • Chem Res Toxicol
    • 19 : 4
    • Abstract
    • Urinary biomarkers of 1,3-butadiene in environmental settings using liquid chromatography isotope dilution tandem mass spectrometry.
    • Sapkota, Halden, Dominici, Groopman and Buckley
    • Chem Biol Interact
    • 160 : 1
    • Abstract
    • Lack of genotoxic effect in workers exposed to very low doses of 1,3-butadiene.
    • Lovreglio, Bukvic, Fustinoni, Ballini, Drago, Foà, Guanti and Soleo
    • Arch Toxicol
    • 80 : 6
    • Abstract
    • Protection of rats against 3-butene-1,2-diol-induced hepatotoxicity and hypoglycemia by N-acetyl-l-cysteine.
    • Sprague and Elfarra
    • Toxicol Appl Pharmacol
    • 207 : 3
    • Abstract
    • Reaction of 1,2,3,4-diepoxybutane with 2'-deoxyguanosine: initial products and their stabilities and decomposition patterns under physiological conditions.
    • Zhang and Elfarra
    • Chem Res Toxicol
    • 18 : 8
    • Abstract
    • 3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice.
    • Wickliffe, Galbert, Ammenheuser, Herring, Xie, Masters, Friedberg, Lloyd and Ward
    • Environ Mol Mutagen
    • 47 : 1
    • Abstract
    • Combustion-derived ultrafine particles transport organic toxicants to target respiratory cells.
    • Penn, Murphy, Barker, Henk and Penn
    • Environ Health Perspect
    • 113 : 8
    • Abstract
    • Male-mediated developmental toxicity.
    • Anderson
    • Toxicol Appl Pharmacol
    • 207 : 2 Suppl
    • Abstract
    • Hemoglobin adducts and micronuclei in rodents after treatment with isoprene monoxide or butadiene monoxide.
    • Fred, Grawé and Törnqvist
    • Mutat Res
    • 585 : 1-2
    • Abstract
    • Quantification of DNA and hemoglobin adducts of 3,4-epoxy-1,2-butanediol in rodents exposed to 3-butene-1,2-diol.
    • Powley, Li, Upton, Walker and Swenberg
    • Carcinogenesis
    • 26 : 9
    • Abstract
    • Variability in human sensitivity to 1,3-butadiene: influence of polymorphisms in the 5'-flanking region of the microsomal epoxide hydrolase gene (EPHX1).
    • Abdel-Rahman, Ammenheuser, Omiecinski, Wickliffe, Rosenblatt and Ward
    • Toxicol Sci
    • 85 : 1
    • Abstract
    • Acute exposure of human lung cells to 1,3-butadiene diepoxide results in G1 and G2 cell cycle arrest.
    • Schmiederer, Knutson, Muganda and Albrecht
    • Environ Mol Mutagen
    • 45 : 4
    • Abstract
    • Guanine-adenine DNA cross-linking by 1,2,3,4-diepoxybutane: potential basis for biological activity.
    • Park, Hodge, Anderson and Tretyakova
    • Chem Res Toxicol
    • 17 : 12
    • Abstract
    • A new role for glutathione: protection of vitamin B12 from depletion by xenobiotics.
    • Watson, Munter and Golding
    • Chem Res Toxicol
    • 17 : 12
    • Abstract
    • Analysis of diepoxide-specific cyclic N-terminal globin adducts in mice and rats after inhalation exposure to 1,3-butadiene.
    • Boysen, Georgieva, Upton, Jayaraj, Li, Walker and Swenberg
    • Cancer Res
    • 64 : 23
    • Abstract
    • Carcinogenic activity of cigarette smoke gas phase and its modulation by beta-carotene and N-acetylcysteine.
    • Witschi
    • Toxicol Sci
    • 84 : 1
    • Abstract
    • Effects of 1,3-butadiene, isoprene, and their photochemical degradation products on human lung cells.
    • Doyle, Sexton, Jeffries, Bridge and Jaspers
    • Environ Health Perspect
    • 112 : 15
    • Abstract
    • Markers of individual susceptibility and DNA repair rate in workers exposed to xenobiotics in a tire plant.
    • Vodicka, Kumar, Stetina, Musak, Soucek, Haufroid, Sasiadek, Vodickova, Naccarati, Sedikova, Sanyal, Kuricova, Brsiak, Norppa, Buchancova and Hemminki
    • Environ Mol Mutagen
    • 44 : 4
    • Abstract
    • Activation of bis-electrophiles to mutagenic conjugates by human O6-alkylguanine-DNA alkyltransferase.
    • Valadez, Liu, Loktionova, Pegg and Guengerich
    • Chem Res Toxicol
    • 17 : 7
    • Abstract
    • DNA adducts in rats and mice following exposure to [4-14C]-1,2-epoxy-3-butene and to [2,3-14C]-1,3-butadiene.
    • Boogaard, de Kloe, Booth and Watson
    • Chem Biol Interact
    • 148 : 1-2
    • Abstract
    • Mercapturic acid urinary metabolites of 3-butene-1,2-diol as in vivo evidence for the formation of hydroxymethylvinyl ketone in mice and rats.
    • Sprague and Elfarra
    • Chem Res Toxicol
    • 17 : 6
    • Abstract
    • Delivery levels and behavior of 1,3-butadiene, acrylonitrile, benzene, and other toxic volatile organic compounds in mainstream tobacco smoke from two brands of commercial cigarettes.
    • Pankow, Luo, Tavakoli, Chen and Isabelle
    • Chem Res Toxicol
    • 17 : 6
    • Abstract
    • Hemoglobin adduct levels in rat and mouse treated with 1,2:3,4-diepoxybutane.
    • Fred, Kautiainen, Athanassiadis and Törnqvist
    • Chem Res Toxicol
    • 17 : 6
    • Abstract
    • Species and tissue differences in the toxicity of 3-butene-1,2-diol in male Sprague-Dawley rats and B6C3F1 mice.
    • Sprague, Phillips, Young and Elfarra
    • Toxicol Sci
    • 80 : 1
    • Abstract
    • Biological monitoring in occupational exposure to low levels of 1,3-butadiene.
    • Fustinoni, Perbellini, Soleo, Manno and Foà
    • Toxicol Lett
    • 149 : 1-3
    • Abstract

    Exposure to 1,3-butadiene (BD), a probable carcinogen to humans, was investigated in two groups of subjects working in a petrochemical plant where BD is produced and used to prepare polymers: 42 occupationally exposed workers and 43 internal non-occupationally exposed controls. BD personal exposure was very low but significantly different in the two groups (median airborne BD 1.5 and 0.4 microg/m(3) in exposed and controls, respectively). Similarly, BD in blood and urine, but not in exhaled air, was higher in the exposed workers than in controls (blood BD 3.7 ng/l versus <1.8 ng/l, urinary BD 2.4 ng/l versus <1.0 ng/l). These three biomarkers correlated significantly with personal exposure ( 0.283 < or = Pearson's r < or = 0.383) and between them (0.780 < or = r < or = 0.896). Excretion of urinary mercapturic acids N-acetyl-S-(3,4-hydroxybutyl)-l-cysteine (MI), N-acetyl-S-(1-hydroxymethyl-2-propenyl)-l-cysteine and N-acetyl-S-(2-hydroxy-3-butenyl)-l-cysteine (MII), chromosomal aberrations (CA), and sister chromatid exchanges (SCE) in peripheral blood lymphocytes were not influenced by occupational exposure. Our results show that unmetabolised BD in biological fluids, and particularly urinary