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. 1993 Dec;101(Suppl 6):161–167. doi: 10.1289/ehp.93101s6161

A brief survey of butadiene health effects: a role for metabolic differences.

L S Birnbaum 1
PMCID: PMC1520015  PMID: 8020440

Abstract

1,3-Butadiene is a major monomer in the rubber and plastics industry and is one of the highest-production industrial chemicals in the United States. Although not highly acutely toxic to rodents, inhalation of concentrations as low as 6.25 ppm causes tumors in mice. Butadiene is oncogenic in rats, but much higher exposure concentrations are required than in mice. Chronic toxicity targets the gonads and hematopoietic system. Butadiene is also a potent mutagen and clastogen. Differences in the absorption, distribution, and elimination of butadiene appear to be relatively minor between rats and mice, although mice do retain more butadiene and its metabolites after exposure to the same concentration and have a higher rate of metabolic elimination. Recent studies have demonstrated that major species differences appear to occur in the rate of detoxication of the primary metabolite, 3-epoxybutene (butadiene monoepoxide [BDMO]). Mice have the greatest rate of production of BDMO as compared to other species, but the rate of removal of BDMO appears to be less than in other species. Mice have low levels of epoxide hydrolase; rats have intermediate levels; monkeys and humans appear to have high levels of this detoxifying enzyme. Thus, while only low levels of butadiene exposure may result in an accumulation of BDMO in the mouse, much higher levels would be required to result in an elevation of circulating BDMO in other species. The level of this reactive metabolite may be correlated with the species differences in butadiene sensitivity.

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Selected References

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  1. Bolt H. M., Filser J. G., Störmer F. Inhalation pharmacokinetics based on gas uptake studies. V. Comparative pharmacokinetics of ethylene and 1,3-butadiene in rats. Arch Toxicol. 1984 Oct;55(4):213–218. doi: 10.1007/BF00341013. [DOI] [PubMed] [Google Scholar]
  2. Bolt H. M., Schmiedel G., Filser J. G., Rolzhäuser H. P., Lieser K., Wistuba D., Schurig V. Biological activation of 1,3-butadiene to vinyl oxirane by rat liver microsomes and expiration of the reactive metabolite by exposed rats. J Cancer Res Clin Oncol. 1983;106(2):112–116. doi: 10.1007/BF00395388. [DOI] [PubMed] [Google Scholar]
  3. Bond J. A., Dahl A. R., Henderson R. F., Birnbaum L. S. Species differences in the distribution of inhaled butadiene in tissues. Am Ind Hyg Assoc J. 1987 Oct;48(10):867–872. doi: 10.1080/15298668791385723. [DOI] [PubMed] [Google Scholar]
  4. Bond J. A., Dahl A. R., Henderson R. F., Dutcher J. S., Mauderly J. L., Birnbaum L. S. Species differences in the disposition of inhaled butadiene. Toxicol Appl Pharmacol. 1986 Jul;84(3):617–627. doi: 10.1016/0041-008x(86)90268-1. [DOI] [PubMed] [Google Scholar]
  5. Bond J. A., Martin O. S., Birnbaum L. S., Dahl A. R., Melnick R. L., Henderson R. F. Metabolism of 1,3-butadiene by lung and liver microsomes of rats and mice repeatedly exposed by inhalation to 1,3-butadiene. Toxicol Lett. 1988 Nov;44(1-2):143–151. doi: 10.1016/0378-4274(88)90140-3. [DOI] [PubMed] [Google Scholar]
  6. Checkoway H., Williams T. M. A hematology survey of workers at a styrene-butadiene synthetic rubber manufacturing plant. Am Ind Hyg Assoc J. 1982 Mar;43(3):164–169. doi: 10.1080/15298668291409550. [DOI] [PubMed] [Google Scholar]
  7. Crouch C. N., Pullinger D. H., Gaunt I. F. Inhalation toxicity studies with 1,3-butadiene -- 2. 3 month toxicity study in rats. Am Ind Hyg Assoc J. 1979 Sep;40(9):796–802. doi: 10.1080/15298667991430316. [DOI] [PubMed] [Google Scholar]
  8. Csanády G. A., Guengerich F. P., Bond J. A. Comparison of the biotransformation of 1,3-butadiene and its metabolite, butadiene monoepoxide, by hepatic and pulmonary tissues from humans, rats and mice. Carcinogenesis. 1992 Jul;13(7):1143–1153. doi: 10.1093/carcin/13.7.1143. [DOI] [PubMed] [Google Scholar]
  9. Dahl A. R., Bechtold W. E., Bond J. A., Henderson R. F., Mauderly J. L., Muggenburg B. A., Sun J. D., Birnbaum L. S. Species differences in the metabolism and disposition of inhaled 1,3-butadiene and isoprene. Environ Health Perspect. 1990 Jun;86:65–69. doi: 10.1289/ehp.908665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dahl A. R., Sun J. D., Birnbaum L. S., Bond J. A., Griffith W. C., Jr, Mauderly J. L., Muggenburg B. A., Sabourin P. J., Henderson R. F. Toxicokinetics of inhaled 1,3-butadiene in monkeys: comparison to toxicokinetics in rats and mice. Toxicol Appl Pharmacol. 1991 Aug;110(1):9–19. doi: 10.1016/0041-008x(91)90285-m. [DOI] [PubMed] [Google Scholar]
  11. Deutschmann S., Laib R. J. Concentration-dependent depletion of non-protein sulfhydryl (NPSH) content in lung, heart and liver tissue of rats and mice after acute inhalation exposure to butadiene. Toxicol Lett. 1989 Feb;45(2-3):175–183. doi: 10.1016/0378-4274(89)90007-6. [DOI] [PubMed] [Google Scholar]
  12. Divine B. J. An update on mortality among workers at a 1,3-butadiene facility--preliminary results. Environ Health Perspect. 1990 Jun;86:119–128. doi: 10.1289/ehp.9086119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Elfarra A. A., Duescher R. J., Pasch C. M. Mechanisms of 1,3-butadiene oxidations to butadiene monoxide and crotonaldehyde by mouse liver microsomes and chloroperoxidase. Arch Biochem Biophys. 1991 Apr;286(1):244–251. doi: 10.1016/0003-9861(91)90036-i. [DOI] [PubMed] [Google Scholar]
  14. Fajen J. M., Roberts D. R., Ungers L. J., Krishnan E. R. Occupational exposure of workers to 1,3-butadiene. Environ Health Perspect. 1990 Jun;86:11–18. doi: 10.1289/ehp.908611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Filser J. G., Bolt H. M. Inhalation pharmacokinetics based on gas uptake studies. I. Improvement of kinetic models. Arch Toxicol. 1981 Jul;47(4):279–292. doi: 10.1007/BF00332394. [DOI] [PubMed] [Google Scholar]
  16. Goodrow T., Reynolds S., Maronpot R., Anderson M. Activation of K-ras by codon 13 mutations in C57BL/6 X C3H F1 mouse tumors induced by exposure to 1,3-butadiene. Cancer Res. 1990 Aug 1;50(15):4818–4823. [PubMed] [Google Scholar]
  17. Huff J. E., Melnick R. L., Solleveld H. A., Haseman J. K., Powers M., Miller R. A. Multiple organ carcinogenicity of 1,3-butadiene in B6C3F1 mice after 60 weeks of inhalation exposure. Science. 1985 Feb 1;227(4686):548–549. doi: 10.1126/science.3966163. [DOI] [PubMed] [Google Scholar]
  18. Irons R. D., Cathro H. P., Stillman W. S., Steinhagen W. H., Shah R. S. Susceptibility to 1,3-butadiene-induced leukemogenesis correlates with endogenous ecotropic retroviral background in the mouse. Toxicol Appl Pharmacol. 1989 Oct;101(1):170–176. doi: 10.1016/0041-008x(89)90222-6. [DOI] [PubMed] [Google Scholar]
  19. Irons R. D., Smith C. N., Stillman W. S., Shah R. S., Steinhagen W. H., Leiderman L. J. Macrocytic-megaloblastic anemia in male B6C3F1 mice following chronic exposure to 1,3-butadiene. Toxicol Appl Pharmacol. 1986 Mar 30;83(1):95–100. doi: 10.1016/0041-008x(86)90326-1. [DOI] [PubMed] [Google Scholar]
  20. Jelitto B., Vangala R. R., Laib R. J. Species differences in DNA damage by butadiene: role of diepoxybutane. Arch Toxicol Suppl. 1989;13:246–249. doi: 10.1007/978-3-642-74117-3_42. [DOI] [PubMed] [Google Scholar]
  21. Kreiling R., Laib R. J., Bolt H. M. Alkylation of nuclear proteins and DNA after exposure of rats and mice to [1,4-14C]1,3-butadiene. Toxicol Lett. 1986 Feb;30(2):131–136. doi: 10.1016/0378-4274(86)90095-0. [DOI] [PubMed] [Google Scholar]
  22. Kreiling R., Laib R. J., Bolt H. M. Depletion of hepatic non-protein sulfhydryl content during exposure of rats and mice to butadiene. Toxicol Lett. 1988 Jun;41(3):209–214. doi: 10.1016/0378-4274(88)90056-2. [DOI] [PubMed] [Google Scholar]
  23. Kreiling R., Laib R. J., Filser J. G., Bolt H. M. Inhalation pharmacokinetics of 1,2-epoxybutene-3 reveal species differences between rats and mice sensitive to butadiene-induced carcinogenesis. Arch Toxicol. 1987;61(1):7–11. doi: 10.1007/BF00324541. [DOI] [PubMed] [Google Scholar]
  24. Kreiling R., Laib R. J., Filser J. G., Bolt H. M. Species differences in butadiene metabolism between mice and rats evaluated by inhalation pharmacokinetics. Arch Toxicol. 1986 Apr;58(4):235–238. doi: 10.1007/BF00297112. [DOI] [PubMed] [Google Scholar]
  25. Kreuzer P. E., Kessler W., Welter H. F., Baur C., Filser J. G. Enzyme specific kinetics of 1,2-epoxybutene-3 in microsomes and cytosol from livers of mouse, rat, and man. Arch Toxicol. 1991;65(1):59–67. doi: 10.1007/BF01973504. [DOI] [PubMed] [Google Scholar]
  26. Lorenz J., Glatt H. R., Fleischmann R., Ferlinz R., Oesch F. Drug metabolism in man and its relationship to that in three rodent species: monooxygenase, epoxide hydrolase, and glutathione S-transferase activities in subcellular fractions of lung and liver. Biochem Med. 1984 Aug;32(1):43–56. doi: 10.1016/0006-2944(84)90007-3. [DOI] [PubMed] [Google Scholar]
  27. Malvoisin E., Roberfroid M. Hepatic microsomal metabolism of 1,3-butadiene. Xenobiotica. 1982 Feb;12(2):137–144. doi: 10.3109/00498258209046787. [DOI] [PubMed] [Google Scholar]
  28. Matanoski G. M., Santos-Burgoa C., Schwartz L. Mortality of a cohort of workers in the styrene-butadiene polymer manufacturing industry (1943-1982). Environ Health Perspect. 1990 Jun;86:107–117. doi: 10.1289/ehp.9086107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Meinhardt T. J., Lemen R. A., Crandall M. S., Young R. J. Environmental epidemiologic investigation of the styrene-butadiene rubber industry. Mortality patterns with discussion of the hematopoietic and lymphatic malignancies. Scand J Work Environ Health. 1982 Dec;8(4):250–259. doi: 10.5271/sjweh.2469. [DOI] [PubMed] [Google Scholar]
  30. Melnick R. L., Huff J., Chou B. J., Miller R. A. Carcinogenicity of 1,3-butadiene in C57BL/6 x C3H F1 mice at low exposure concentrations. Cancer Res. 1990 Oct 15;50(20):6592–6599. [PubMed] [Google Scholar]
  31. Morrissey R. E., Schwetz B. A., Hackett P. L., Sikov M. R., Hardin B. D., McClanahan B. J., Decker J. R., Mast T. J. Overview of reproductive and developmental toxicity studies of 1,3-butadiene in rodents. Environ Health Perspect. 1990 Jun;86:79–84. doi: 10.1289/ehp.908679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Owen P. E., Glaister J. R., Gaunt I. F., Pullinger D. H. Inhalation toxicity studies with 1,3-butadiene. 3. Two year toxicity/carcinogenicity study in rats. Am Ind Hyg Assoc J. 1987 May;48(5):407–413. doi: 10.1080/15298668791384959. [DOI] [PubMed] [Google Scholar]
  33. Recio L., Osterman-Golkar S., Csanády G. A., Turner M. J., Myhr B., Moss O., Bond J. A. Determination of mutagenicity in tissues of transgenic mice following exposure to 1,3-butadiene and N-ethyl-N-nitrosourea. Toxicol Appl Pharmacol. 1992 Nov;117(1):58–64. doi: 10.1016/0041-008x(92)90217-g. [DOI] [PubMed] [Google Scholar]
  34. Ristau C., Deutschmann S., Laib R. J., Ottenwälder H. Detection of diepoxybutane-induced DNA-DNA crosslinks by cesium trifluoracetate (CsTFA) density-gradient centrifugation. Arch Toxicol. 1990;64(4):343–344. doi: 10.1007/BF01972998. [DOI] [PubMed] [Google Scholar]
  35. Sharer J. E., Duescher R. J., Elfarra A. A. Formation, stability, and rearrangements of the glutathione conjugates of butadiene monoxide: evidence for the formation of stable sulfurane intermediates. Chem Res Toxicol. 1991 Jul-Aug;4(4):430–436. doi: 10.1021/tx00022a006. [DOI] [PubMed] [Google Scholar]
  36. Shugaev B. B. Concentrations of hydrocarbons in tissues as a measure of toxicity. Arch Environ Health. 1969 Jun;18(6):878–882. doi: 10.1080/00039896.1969.10665509. [DOI] [PubMed] [Google Scholar]
  37. Thurmond L. M., Lauer L. D., House R. V., Stillman W. S., Irons R. D., Steinhagen W. H., Dean J. H. Effect of short-term inhalation exposure to 1,3-butadiene on murine immune functions. Toxicol Appl Pharmacol. 1986 Nov;86(2):170–179. doi: 10.1016/0041-008x(86)90047-5. [DOI] [PubMed] [Google Scholar]
  38. Tice R. R., Boucher R., Luke C. A., Shelby M. D. Comparative cytogenetic analysis of bone marrow damage induced in male B6C3F1 mice by multiple exposures to gaseous 1,3-butadiene. Environ Mutagen. 1987;9(3):235–250. doi: 10.1002/em.2860090303. [DOI] [PubMed] [Google Scholar]
  39. de Meester C. Genotoxic properties of 1,3-butadiene. Mutat Res. 1988 May;195(3):273–281. doi: 10.1016/0165-1110(88)90005-x. [DOI] [PubMed] [Google Scholar]
  40. de Meester C., Poncelet F., Roberfroid M., Mercier M. Mutagenicity of butadiene and butadiene monoxide. Biochem Biophys Res Commun. 1978 Jan 30;80(2):298–305. doi: 10.1016/0006-291x(78)90676-9. [DOI] [PubMed] [Google Scholar]
  41. de Meester C., Poncelet F., Roberfroid M., Mercier M. The mutagenicity of butadiene towards Salmonella typhimurium. Toxicol Lett. 1980 Aug;6(3):125–130. doi: 10.1016/0378-4274(80)90179-4. [DOI] [PubMed] [Google Scholar]

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