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PubMed1996

Toxicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344 rats and B6C3F(1) mice.

Chloroprene (2-chloro-1,3-butadiene) is a high production chemical used almost exclusively in the production of polychloroprene (neoprene) elastomer. Because of its structural similarity to isoprene (2-methyl-1,3-butadiene) and to 1,3-butadiene, a potent trans-species carcinogen, inhalation studies were performed on chloroprene to characterize its toxicological potential and to provide a basis for selecting exposure concentrations for chronic toxicity and carcinogenicity studies. Thirteen-week inhalation toxicology studies were conducted in male and female F344 rats and B6C3F(1) mice at exposure concentrations of 0, 5, 12, 32 or 80 ppm (6 h/day; 5 days/week). A 200 ppm exposure group was also included for rats only, because a previous study showed that this concentration of chloroprene is lethal to mice. In mice, exposure to 80 ppm chloroprene caused a marginal decrease in body weight gain in males and epithelial hyperplasia of the forestomach in males and females. This lesion has been observed in mice exposed to isoprene or 1,3-butadiene. In rats, exposure to 80 ppm chloroprene or higher concentrations caused degeneration and metaplasia of the olfactory epithelium and exposure to 200 ppm caused anemia, hepatocellular necrosis and reduced sperm motility. These lesions have not been observed in rats exposed to isoprene or 1,3-butadiene. The profile of toxic effects of chloroprene is considerably different from that of isoprene or 1,3-butadiene; this may be due to differences in exposure concentrations that were used in toxicology studies of these compounds and /or to the influence of the chlorine substitution on the toxicokinetics of these compounds, on their biotransformation, or on the reactivity of metabolic intermediates with tissue macromolecules.

Administration, Inhalation↗
PubMedDate not supplied

Synthesis and biochemical characterization of N1-, N2-, and N7-guanosine adducts of butadiene monoxide.

1,3-Butadiene is a known rodent carcinogen, but the molecular mechanisms of its carcinogenicity are poorly understood. Butadiene monoxide (BM), a known mutagenic metabolite of 1,3-butadiene, was previously shown to react with guanosine to yield two N7-guanine adducts. In the present study, eight guanosine adducts of BM were purified and characterized as diastereomeric pairs of N7-(2-hydroxy-3-buten-1-yl)guanosine (G-1 and G-3), N7-(1-hydroxy-3-buten-2-yl)guanosine (G-2 and G-5), N2-(1-hydroxy-3-buten-2-yl)guanosine (G-4 and G-7), and N1-(1-hydroxy-3-buten-2-yl)guanosine (G-6 and G-8) on the basis of stability studies and analyses by UV, 1H NMR, and fast atom bombardment mass spectrometry. While the N7-adducts exhibited half-lives of approximately 50 (G-1 and G-3) and 90 h (G-2 and G-5) upon incubation for 192 h in 100 mM phosphate buffer (pH 7.4) at 37 degrees C, the N1- and N2-adducts remained stable. When guanosine was reacted with excess BM in phosphate buffer (pH 7.4) at 37 degrees C, adduct formation exhibited pseudo-first-order kinetics, with the N7-adducts being formed approximately 10-fold more favorably than the N1- and N2-adducts. When incubations were carried out at lower BM concentrations, the N7-adducts remained the major detectable adducts, but the N2-adducts were also detectable at equimolar BM and guanosine concentrations, and the N1-adducts were detectable at a 5-fold molar excess of BM. These results, which provide clear evidence that guanosine can be alkylated at multiple sites following 1,3-butadiene exposure, may aid in the development of useful biomarkers for exposure to 1,3-butadiene. The results may also contribute to a better understanding of the molecular mechanisms of 1,3-butadiene-induced carcinogenicity.

Carcinogens↗
PubMed2006

Isomers and polymorphs of (E,E)-1,4-bis(nitrophenyl)-2,3-diaza-1,3-butadienes.

The structures of five of the possible six isomers of (E,E)-1,4-bis(nitrophenyl)-2,3-diaza-1,3-butadiene are reported, including two polymorphs of one of the isomers. (E,E)-1,4-Bis(2-nitrophenyl)-2,3-diaza-1,3-butadiene, C(14)H(10)N(4)O(4) (I), crystallizes in two polymorphic forms (Ia) and (Ib) in which the molecules lie across centres of inversion in space groups P2(1)/n and P2(1)/c, respectively: the molecules in (Ia) and (Ib) are linked into chains by aromatic pi...pi stacking interactions and C-H...pi(arene) hydrogen bonds, respectively. Molecules of (E,E)-1-(2-nitrophenyl)-4-(3-nitrophenyl)-2,3-diaza-1,3-butadiene (II) are linked into sheets by two independent C-H...O hydrogen bonds. The molecules of (E,E)-1,4-bis(3-nitrophenyl)-2,3-diaza-1,3-butadiene (III) lie across inversion centres in the space group P2(1)/n, and a combination of a C-H...O hydrogen bond and a pi...pi stacking interaction links the molecules into sheets. A total of four independent C-H...O hydrogen bonds link the molecules of (E,E)-1-(3-nitrophenyl)-4-(4-nitrophenyl)-2,3-diaza-1,3-butadiene (IV) into sheets. In (E,E)-1,4-bis(4-nitrophenyl)-2,3-diaza-1,3-butadiene (V) the molecules, which lie across centres of inversion in the space group P2(1)/n, are linked by just two independent C-H...O hydrogen bonds into a three-dimensional framework.

Journal Article↗
PubMed1991

NTP technical report on the toxicity studies of Hexachloro-1,3-butadiene in B6C3F1 Mice (Feed Studies) (CAS No. 87-68-3).

Two-week and 13-week toxicity studies of hexachloro-1,3-butadiene incorporated in the diet were conducted in B6C3F1 mice. Groups of five mice of each sex received diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm hexachloro-1,3-butadiene for 15 days. Toxic responses in the 2-week studies, primarily in the higher dose groups, included abnormal clinical signs (lethargy, hunched posture, rough hair coats, light sensitivity, and/or in coordination), deaths (all mice in the two highest dose groups died by day 7), body and organ weight depression, and gross and histopathologic changes. The most prevalent microscopic lesion, seen in all hexachloro-1,3-butadiene-dosed mice, was renal tubular cell necrosis and/or regeneration. Regeneration was seen in lower dose groups. In addition to kidney lesions, histopathologic changes were also seen in the liver (hepatocyte necrosis, cytoplasmic vacuolization), lymphoid tissues (lymph node necrosis, depletion), and testis (seminiferous tubule giant cells) of mice in the two highest dose groups which died during the first week of the studies. Thirteen-week studies were conducted in which groups of 10 mice per sex received 0,1, 3,10, 30, or 100 ppm hexachloro-1,3-butadiene in feed (corresponding to doses of 0, 0.1, 0.4, 1.5, 4.9, or 16.8 mg/kg per day for males and 0.2, 0.5, 1.8, 4.5, or 19.2 mg/kg per day for females). No compound-related clinical signs or deaths were observed. Compared with controls, body weight gain was reduced in males receiving 30 and 100 ppm (-49% and -56%, respectively) and females receiving 100 ppm (-47%). Kidney weights were reduced in the males receiving 30 and 100 ppm and females receiving 100 ppm. A compound-related increase in tubular cell regeneration in the renal cortex occurred in male and female mice. This lesion, characterized by a diffuse increase in basophilia of the tubular epithelial cytoplasm and an increase in the number of nuclei, increased in severity with increased dose. The motility of sperm from dosed mice was lower, though not dose related, than that from controls. Female mice were more susceptible to the toxicity of hexachloro-1,3-butadiene than male mice. Based on the histopathologic evaluations, the no-observed-adverse-effect level appeared to be 10 ppm for the male mice in this 13-week study; no such level was identified for the female mice. Synonyms: HCBD; hexachlorobutadiene; 1,1,2,3,4,4-hexachloro-1,3- butadiene; perchlorobutadiene; C 46; Dolen-Pur, (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)

Journal Article↗
PubMedDate not supplied

Solvolytic formation of 1,2-dichloro-3,4-epoxybutane from butadiene monoxide under physiological conditions.

Butadiene monoxide, a presumed carcinogenic metabolite of butadiene, is stable in water or phosphate buffer, but was found to rapidly disappear from the headspace of solutions (10(-6) to 10(-4) M) in phosphate-buffered saline incubated at 37 degrees C. The process was first order with respect to monoxide concentration, with an apparent rate constant of 6.6 x 10(-4) sec-1. Mass spectrometric examination of the major product formed indicated it to be 1,2-dichloro-3,4-epoxybutane, which was confirmed by synthesis. Formation of the dichloro epoxide was linearly dependent on chloride ion concentration of the medium, but independent of dissolved oxygen. The formation of the dichloro epoxide is explained by slow solvolytic formation of a chloronium ion from butadiene monoxide, which is followed by attack of chloride ion to generate chlorine and butadiene. The chlorine is than rapidly trapped by second molecule of butadiene monoxide. This was confirmed by competitive trapping of generated chlorine by inclusion of crotyl alcohol in the incubation. A similar pathway has recently been demonstrated for reversible formation of bromine from solvolytically generated bromonium ions. The facile formation of dichloroepoxybutane under physiological conditions may be of significance in the toxicity of butadiene.

Bromine↗
PubMed1992

Pharmacokinetic interaction between 1,3-butadiene and styrene in Sprague-Dawley rats.

Gas uptake studies were carried out to evaluate kinetic interactions between 1,3-butadiene and styrene in Sprague-Dawley rats. The animals were co-exposed by inhalation to a mixture of 1,3-butadiene between 20 and 6000 ppm (v/v) and styrene between 0 and 500 ppm. The data demonstrate that metabolism of 1,3-butadiene was partially inhibited by styrene. The inhibition was competitive at atmospheric concentrations of styrene up to 90 ppm. Higher concentrations of styrene resulted in a small additional inhibition only. The apparent Michaelis-Menten constant for 1,3-butadiene, related to the average concentration in the organism of the animals, was Kmapp = 1.17 +/- 0.37 (mumol/l of tissue) and the corresponding atmospheric concentration at steady state was 560 ppm. The inhibition constant of styrene was found to be Ki = 0.23 +/- 0.30 (mumol/l of tissue). The maximal metabolic rate for 1,3-butadiene was 230 +/- 10 (mu/kg/h).

Air↗
PubMed2003

Comparison of breath, blood and urine concentrations in the biomonitoring of environmental exposure to 1,3-butadiene, 2,5-dimethylfuran, and benzene.

OBJECTIVES: To investigate and compare alveolar, blood, and urine concentrations of 1,3-butadiene, 2,5 dimethylfuran, and benzene, in non-occupational exposure to these products. METHODS: Benzene, 2,5-dimethylfuran and 1,3-butadiene were measured in the breath, blood, and urine samples of 61 subjects living in small mountain villages. All 61 were regularly employed as forestry workers. Sampling was done during the long winter-season non-working period. Samples were collected after overnight rest and analysed by headspace and GC-mass spectrometry methods. RESULTS: The median 1,3-butadiene level was 1.2 ng/l (range: <0.8-13.2 ng/l) in alveolar air, 2.2 ng/l (range: <0.5-50.2 ng/l) in blood, and 1.1 ng/l (range: <1-8.9 ng/l) in urine. The median benzene level was 5.7 ng/l (range: <1-24.9 ng/l) in alveolar air, 62.3 ng/l (range: 33.5-487.2 ng/l) in blood, and 63.4 ng/l (range: 25.8-1099.1 ng/l) in urine. The median 2,5-dimethylfuran level was 0.5 ng/l (range: <1-12.5 ng/l) in alveolar air, 2.5 ng/l (range: <5-372.9 ng/l) in blood, and 51.8 ng/l (range: <5-524.9 ng/l) in urine. In several cases, 2,5-dimethylfuran levels were below the detection limit in alveolar air and blood, especially in non-smokers. 1,3-Butadiene, 2,5-dimethylfuran and benzene levels were significantly higher in smokers than non-smokers in all biological media. CONCLUSIONS: 1,3-Butadiene and benzene, as ubiquitous pollutants, are detectable and quantifiable in human alveolar air, blood and urine. 2,5-Dimethylfuran, which is not a usual environmental pollutant, is almost always detectable in biological media, but only in smokers.

Adult↗
PubMed1996

Leukemia and cumulative exposure to butadiene, styrene and benzene among workers in the synthetic rubber industry.

Retrospective, quantitative estimates of exposure to 1,3-butadiene, styrene and benzene were developed for a follow-up study of leukemia mortality among 16610 subjects employed at six North American styrene-butadiene rubber manufacturing plants (418846 person-years, 58 leukemia deaths). The estimation procedure entailed identifying work areas within each manufacturing process, historical changes in exposure potential and specific tasks involving exposure, and using mathematical models to calculate job- and time-period-specific average exposures. The resulting estimates were linked with the subjects' work histories to obtain cumulative exposure estimates, which were employed in stratified and Poisson regression analyses of mortality rates. Mantel-Haenszel rate ratios adjusted by race, age, and cumulative styrene exposure increase with cumulative butadiene exposure from 1 in the nonexposed category to 4.5 in the category of 80 ppm-years or more (P = 0.01). The risk pattern is less clear and statistically nonsignificant for styrene exposure. A trend of increasing risk with butadiene exposure is still present after exclusion of the nonexposed category (P = 0.03). A parsimonious interpretation of the findings presented here, in light of previous epidemiologic studies, is that exposure to butadiene in the synthetic rubber industry produces a dose-related increase in the occurrence of leukemia.

Benzene↗
PubMed1996

Butadiene and isoprene: future studies and implications.

Based on the symposium on 1,-3-butadiene and isoprene at Blaine, WA, the following areas need special attention for future research: (1) discrepancies in PBPK modelling by different groups should be solved; (2) potential human target tissues (bone marrow, lymphatic tissues) should be better integrated into PBPK models; (3) the present rapid development in research on human genetic interindividual differences in 1,3-butadiene metabolism and toxicity should be supported, with the intention to determine human subgroups of differential susceptibility and to integrate this into epidemiological research; (4) further validation of past exposures in the epidemiologically studied corhorts is very desirable; (5) the question of possibly differential effects in 1,3-butadiene monomer workers and styrene-butadiene-rubber workers (lymphosarcoma?, reticulosarcoma?, leukemia?) should be resolved in future epidemiological studies; (6) potential human target tissues (bone marrow, lymphatic tissues) should be better integrated into PBPK modelling; (7) risk assessment of isoprene and, by quantitative comparison, of 1,3-butadiene in humans should consider the physiological background of endogenous isoprene production; and (8) future research on biomarkers should establish practical tools for medical surveillance of presently exposed persons.

Animals↗
PubMed2004

Dose responses for the formation of hemoglobin adducts and urinary metabolites in rats and mice exposed by inhalation to low concentrations of 1,3-[2,3-(14)C]-butadiene.

Blood and urine were obtained from male Sprague-Dawley rats and B6C3F1 mice exposed to either a single 6 h or multiple daily (5 x 6 h) nose-only doses of 1,3-[2,3- (14)C]-butadiene at atmospheric concentrations of 1, 5 or 20 ppM. Globin was isolated from erythrocytes of exposed animals and analyzed for total radioactivity and also for N-(1,2,3-trihydroxybut-4-yl)-valine adducts. The modified Edman degradation procedure coupled with GC-MS was used for the adduct analysis. Linear relationships were observed between the exposures to 1,3-[2,3-(14)C]-butadiene and the total radioactivity measured in globin and the level of trihydroxybutyl valine adducts in globin. A greater level of radioactivity (ca. 1.3-fold) was found in rat globin compared with mouse globin. When analyzed for specific amino acid adducts, higher levels of trihydroxybutyl valine adducts were found in mouse globin compared with rat globin. Average levels of trihydroxybutyl valine adduct measured in globin from rats and mice exposed for 5 x 6 h at 1, 5 and 20 ppM 1,3-[2,3-(14)C]-butadiene were, respectively, for rats: 80, 179, 512 pM/g globin and for mice: 143, 351, 1100 pM/g globin. The profiles of urinary metabolites for rats and mice exposed at the different concentrations of butadiene were obtained by reverse phase HPLC analysis on urine collected 24 h after the start of exposure and were compared with results of a previous similar study carried out for 6 h at 200 ppM butadiene. Whilst there were qualitative and quantitative differences between the profiles for rats and mice, the major metabolites detected in both cases were those representing products of epoxide hydrolase mediated hydrolysis and glutathione (GSH) conjugation of the metabolically formed 1,2-epoxy-3-butene. These were 4-(N-acetyl-l-cysteine-S-yl)-1,2-dihydroxy butane and (R)-2-(N-acetyl-l-cystein-S-yl)-1-hydroxybut-3-ene, 1-(N-acetyl-l-cystein-S-yl)-2-(S)-hydroxybut-3-ene, 1-(N-acetyl-l-cystein-S-yl)-2-(R)-hydroxybut-3-ene, (S)-2-(N-acetyl-l-cystein-S-yl)-1-hydroxybut-3-ene, respectively. The former pathway showed a greater predominance in the rat. The profiles of metabolites were similar at exposure concentration in the range 1-20 ppM. There were however some subtle differences compared with results of exposure to the higher 200 ppM concentrations. Overall the results provide the basis for cross species comparison of low exposures in the range of occupational exposures, with the wealth of data available from high exposure studies.

Administration, Inhalation↗
PubMed2006

Effect of n-hexane on the disposition and toxicity of the 1,3-butadiene metabolite 3-butene-1,2-diol.

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.

Acetylcysteine↗
PubMed2006

Micronuclei, DNA single-strand breaks and DNA-repair activity in mice exposed to 1,3-butadiene by inhalation.

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).

Administration, Inhalation↗
PubMed2001

Health risk assessment of 1,3-butadiene as a Priority Substance in Canada.

1,3-Butadiene was included in the second list of Priority Substances to be assessed under the Canadian Environmental Protection Act. Potential hazards to human health were characterized on the basis of critical examination of available data on health effects in experimental animals and occupationally exposed human populations, as well as information on mode of action. Based on consideration of all relevant data identified as of April 1998, butadiene was considered highly likely to be carcinogenic to humans, and likely to be a somatic and germ cell genotoxicant in humans. In addition, butadiene may also be a reproductive toxicant in humans. Estimates of the potency of butadiene to induce these effects have been derived on the basis of quantitation of observed exposure-response relationships for the purposes of characterization of risk to the general population in Canada exposed to butadiene in the ambient environment.

Animals↗
PubMed2001

Physiological modeling of butadiene disposition in mice and rats.

The earliest physiological models of 1,3-butadiene disposition reproduced uptake of the gas from closed chambers but over-predicted steady-state circulating concentrations of the mutagenic intermediates 1,2-epoxybut-3-ene and 1,2:3,4-diepoxybutane. A preliminary model based on the observation of a transient complex between cytochrome P450 and microsomal epoxide hydrolase on the endoplasmic reticulum membrane reproduced the blood epoxide concentrations as well as the chamber uptake data. This model was enhanced by the addition of equations for the production and detoxication of 3,4-epoxybutane-1,2-diol in the liver, lungs, and kidneys. The model includes flow-restricted delivery of butadiene and its metabolites to compartments for lungs, liver, fat, kidneys, gastrointestinal tract, other rapidly perfused tissues, and other slowly perfused tissues. Blood was distributed among compartments for arterial, venous, and tissue capillary spaces. Channeling of the three bound epoxides to epoxide hydrolase and their release from the endoplasmic reticulum are competing processes in this model. Parameters were estimated to fit data for chamber uptake of butadiene and epoxybutene, steady-state blood concentrations of epoxybutene and diepoxybutane, and the fractions of the inhaled dose of butadiene that appears as various excreted metabolites. The optimal values of the apparent K(m)s of membrane-bound epoxides for epoxide hydrolase were only 5% of the values for the cytosolic substrate, consistent with the observation of a transient complex between epoxide hydrolase and the cytochrome P450 that produces the epoxide. This proximity effect corresponds to the notion that epoxides produced in situ have privileged access to epoxide hydrolase. The model also predicts considerable accumulation of epoxybutanediol, in agreement with the observation that most of the DNA adducts in animals exposed to butadiene arise from this metabolite.

Animals↗
PubMed2001

A mortality, morbidity, and hematology study of petrochemical employees potentially exposed to 1,3-butadiene monomer.

This three-part study is an update of a previous report that examined the mortality, morbidity, and hematological data of employees from a petrochemical facility in Texas who had potential exposure to 1,3-butadiene monomer. The first part describes the updated cause-specific mortality of 614 workers. Vital status for each cohort member was ascertained through 1998, a 9-year extension of the previous study. The second part is an examination of the morbidity experience of cohort members who were still working during 1992-1998, including 289 of the 614 mortality cohort members. The third part is an evaluation of the hematological results from routine health surveillance and/or medical examinations. Approximately 430 of the 614 employees who had complete blood count (CBC) data as of December 1999 were included in the hematological evaluations. The most recent examination containing CBC data was used and compared with similar data for over 2600 other employees from this facility. Overall mortality during the follow-up period, 1948-1998, was significantly lower than for the local comparison population (standardized mortality ratio (SMR) of 0.55 with a 95% confidence interval (CI) of 0.42-0.70). Mortality for all cancer was also significantly lower (SMR, 0.57; 95% CI, 0.32-0.92). Mortality for all lymphohematopoietic cancer was about the same as the comparison population (SMR, 1.06; 95% CI, 0.22-3.11). None of the cause-specific morbidity was in excess compared with an internal comparison group. There were no differences in the distribution or mean values of hematological variables (e.g. white blood cells, red blood cells, hemoglobin, platelets, mean corpuscular volume) between the butadiene cohort and the comparison group, or between a subgroup of workers in jobs with the highest potential for butadiene exposure (i.e. shipping) and the rest of the butadiene cohort. The findings of this study suggest that the butadiene exposure at this facility in the last 20 years does not pose a health hazard to employees.

Blood Cell Count↗
PubMed2001

The influence of co-exposure to dimethyldithiocarbamate on butadiene metabolism.

Treatment of rats and mice with a single oral dose of dimethyldithiocarbamate (DMDTC; 250 mg/kg) had a marked effect on hepatic CYP2E1 and aldehyde dehydrogenase activities, measured in vitro, for up to 24 h after dosing. The same treatment did not affect CYP2A6, glutathione S-transferase, epoxide hydrolase, alcohol dehydrogenase activities or hepatic glutathione levels. As a consequence of the loss of CYP2E1 activity, butadiene metabolism in liver fractions from DMDTC treated rats and mice was markedly reduced, as was the metabolism of the mono-epoxide to the di-epoxide in mouse liver. The conversion of the mono-epoxide to the diol by epoxide hydrolases was not affected by DMDTC treatment. Urinary excretion of radioactivity, following dosing with DMDTC and exposure to 200 ppm C-14 butadiene for 6 h, was markedly reduced in rats, but increased in mice. The profiles of urinary metabolites were qualitatively similar from mice exposed to butadiene to those exposed after dosing with DMDTC. In the rat, pre-dosing with DMDTC resulted in the formation of three additional urinary metabolites following exposure to butadiene. Overall, DMDTC appears to impact qualitatively and quantitatively on the metabolism of butadiene. The nature and full significance of these changes has yet to be characterised.

Administration, Oral↗
PubMed2001

Comparative carcinogenicity of 1,3-butadiene, isoprene, and chloroprene in rats and mice.

1,3-Butadiene, isoprene (2-methyl-1,3-butadiene), and chloroprene (2-chloro-1,3-butadiene) are high-production-volume chemicals used mainly in the manufacture of synthetic rubber. Inhalation studies have demonstrated multiple organ tumorigenic effects with each of these chemicals in mice and rats. Sites of tumor induction by these epoxide-forming chemicals were compared to each other and to ethylene oxide, a chemical classified by the National Toxicology Program (NTP) and by the International Agency for Research on Cancer (IARC) as carcinogenic to humans. For this group of chemicals, there are substantial species differences in sites of neoplasia; neoplasia of the mammary gland is the only common tumorigenic effect in rats and mice. Within each species, there are several common sites of tumor induction; these include the hematopoietic system, circulatory system, lung, liver, forestomach, Harderian gland, and mammary gland in mice, and the mammary gland and possibly the brain, thyroid, testis, and kidney in rats. For studies in which individual animal data were available, mortality-adjusted tumor rates were calculated, and estimates were made of the shape of the exposure-response curves and ED10 values (i.e. exposure concentrations associated with an excess risk of 10% at each tumor site). Most tumorigenic effects reported here were consistent with linear or supralinear models. For chloroprene and butadiene, the most potent response was for the induction of lung neoplasms in female mice, with ED10 values of 0.3 ppm. Based on animal cancer data, isoprene and chloroprene are listed in the NTP's Report on Carcinogens (RoC) as reasonably anticipated to be a human carcinogen. Butadiene is listed in the RoC as known to be a human carcinogen 'based on sufficient evidence of carcinogenicity from studies in humans, including epidemiological and mechanistic information', with support from experimental studies in laboratory animals. Epidemiology data for isoprene and chloroprene are not considered adequate to evaluate the potential carcinogenicity of these agents in humans.

Administration, Inhalation↗
PubMed2001

Using DNA and hemoglobin adducts to improve the risk assessment of butadiene.

The purpose of this paper is to review what we know about various biomarkers of butadiene in animal, human and in vitro studies, and to draw inferences from these data that impact on the accurate assessment of human risks for cancer. Studies comparing the DNA and hemoglobin adducts of butadiene with exposure, metabolism and genotoxicity have provided a great deal of insight that is applicable to biologically based risk assessment. First, the DNA and hemoglobin adduct data strongly support the conclusion that 3,4-epoxy-1,2-butanediol is the major electrophile available for binding to these macromolecules. Biomarker studies have also provided insight into the possibility of a sensitive population associated with the GSTT1 null genotype. While it is clear that lymphocytes from GSTT1 null individuals are more sensitive for the induction of sister chromatid exchanges (SCE) following in vitro exposure to 1,2,3,4-diepoxybutane, there was no such increase in SCE or other biomarkers of genotoxicity in workers exposed to 1-3 p.p.m. butadiene, regardless of GST genotype. The globin adduct data also demonstrate that there is roughly a tenfold range for interindividual differences in the metabolism of butadiene. This type of analysis represents an excellent means for providing scientific data for this critical determinant. Another useful application of hemoglobin adducts in risk assessment was demonstrated by regressing data for various endpoints for genotoxicity against that individual's biologically effective dose, thereby providing an independent mechanism for evaluation that excludes any possible confounding by inappropriate controls. Finally, biomarker studies have identified critical gaps in our knowledge that are needed for the accurate assessment of butadiene. Most notable of these is the lack of diepoxide-specific biomarkers in mice, rats and humans.

Animals↗