1,3-Butadiene: Toxicity and Carcinogenicity in Laboratory Animals and in Humans

  • Ronald L. Melnick
  • James Huff
Part of the Reviews of Environmental Contamination and Toxicology book series (RECT, volume 124)


1,3-Butadiene, CH2=CH—CH=CH2 (CAS No. 106-99-0), is a colorless, noncorrosive gas having a boiling point of — 4.4°C and a vapor pressure of 1,900 mm Hg at 20°C (Kirshenbaum 1978). 1,3-Butadiene is a highly reactive material that can form the dimer, 4-vinyl-cyclohexene, and is flammable at atmospheric concentrations of 2% or higher. 1,3-Butadiene can form explosive peroxides in air, and therefore is shipped as a liquified gas under pressure with an inhibitor of peroxide formation, such ast-butyl catechol.


Inhalation Exposure National Toxicology Program Carcinogenicity Study Thymic Lymphoma Epoxide Intermediate 
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  1. ACGIH (1984) American Conference of Governmental Industrial Hygienists. Threshold limit values for chemical substances and physical agents in the workroom environment and biological exposure indices with intended changes for 1984–1985, Cincinnati, OH, p. 50.Google Scholar
  2. Acquavella JF (1990) Future directions in epidemiologic studies of 1,3-butadiene-exposed workers. Environ Hlth Perspect 86: 129–134.CrossRefGoogle Scholar
  3. Amoore JE, Hautula E (1983) Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J Appl Toxicol 3: 272–290.PubMedCrossRefGoogle Scholar
  4. ATSDR (1991) Toxicological profile for 1,3-butadiene. Agency for Toxic Substances and Disease Registry. US Public Health ServiceGoogle Scholar
  5. Bolt HM, Filser JG, Stormer F (1984) Inhalation pharmacokinetics based on gas uptake studies. V. Comparative pharmacokinetics of ethylene and 1,3-butadiene in rats. Arch Toxicol 55: 213–218.Google Scholar
  6. Bolt HM, Schmiedel G, Filser JG, Rolzhauser HP, Lieser K, Wistuba D, Schurig V (1983) Biological activation of 1,3-butadiene to vinyl oxirane by rat liver microsomes and expiration of the reactive metabolite by exposed rats. Cancer Res Clin Oncol 106: 112–116.CrossRefGoogle Scholar
  7. Bond JA, Dahl AR, Henderson RF, Birnbaum LS (1987) Species differences in the distribution of inhaled butadiene in tissues. Am Ind Hyg Assoc J 48: 867–872.PubMedCrossRefGoogle Scholar
  8. Bond JA, Dahl AR, Henderson RF, Dutcher JS, Mauderly JL, Birnbaum, LS (1986) Species differences in the disposition of inhaled butadiene. Toxicol Appl Pharmacol 84: 617–627.PubMedCrossRefGoogle Scholar
  9. Bond JA, Martin OS, Birnbaum LS, Dahl AR, Melnick RL, Henderson RF (1988) Metabolism of 1,3-butadiene by lung and liver microsomes of rats and mice repeatedly exposed by inhalation to 1,3-butadiene. Toxicol Lett 44: 143–151.PubMedCrossRefGoogle Scholar
  10. Carpenter CP, Shaffer CB, Weil CS, Smyth HF (1944) Studies on the inhalation of 1,3-butadiene; with a comparison of its narcotic effect with benzol, toluol, and styrene, and a note on the elimination of styrene by the human. J Ind Hyg Toxicol 26: 69–78.Google Scholar
  11. Checkoway H, Williams TM (1982) A hematology survey of workers at a styrene-butadiene synthetic rubber manufacturing plant. Am Ind Hyg Assoc J 43: 164–169.PubMedCrossRefGoogle Scholar
  12. Conner MK, Luo JE, Gutierrez de Gotera O (1983) Induction and repair of sister-chromatid exchanges in multiple murine tissues in vivo by diepoxybutane. Mutat Res 108: 251–263.PubMedGoogle Scholar
  13. Cox DR (1972) Regression models and life tables. JR Stat Soc B34: 187–220.Google Scholar
  14. Crouch CN, Pullinger DM, Gaunt IF (1979) Inhalation toxicity studies with l,3-butadiene-2. 3 month toxicity studies in rats. Am Ind Hyg Assoc J 40: 796–802.PubMedCrossRefGoogle Scholar
  15. Cunningham MJ, Choy, WN, Arce GT, Rickard LB, Vlachos DA, Kinney LA, Sarrif AM (1986) In vivo sister chromatid exchange and micronucleus induction studies with 1,3-butadiene in B6C3F1 mice and Sprague-Dawley rats. Mutagenesis 1: 449–452.PubMedGoogle Scholar
  16. Dahl AR, Sun JD, Bender MA, Birnbaum LS, Bond JA, Griffith WC, Mauderly JL, Muggenburg BA, Sabourin PJ, Henderson RF, (1991) Toxicokinetics of inhaled 1,3-butadiene in monkeys: comparison to toxicokinetics in rats and mice. Toxicol Appl Pharmacol (in press).Google Scholar
  17. de Meester, Poncelet F, Roberfroid M, Mercier M (1978) Mutagenicity of butadiene and butadiene monoxide. Biochem Biophys Res Comm 80: 298–305.PubMedCrossRefGoogle Scholar
  18. de Meester, Poncelet F, Roberfroid M, Mercier M (1980) The mutagenicity of butadiene towards Salmonella typhimuriumToxicol Lett 6: 125–130.PubMedCrossRefGoogle Scholar
  19. Deutschmann S, Lair RJ (1989) 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 45: 175–183.PubMedCrossRefGoogle Scholar
  20. Dinse GE, Haseman JK (1986) Logistic regression analysis of incidental tumor data from animal carcinogenicity experiments. Fund Appl Toxicol 6: 44–52.CrossRefGoogle Scholar
  21. Divine BJ (1990) An update on mortality among workers at a 1,3-butadiene facility-Preliminary results. Environ Hlth Perspect 86: 119–128.Google Scholar
  22. Downs TD, Crane MM, Kim KW (1987) Mortality among workers at a butadiene facility. Am J Ind Med 12: 311–329.PubMedCrossRefGoogle Scholar
  23. Durchin J (1990) Sampling and analysis of the ambient air in the area of Port Neches, Jefferson County, Texas. Final Report. Sampling and Analysis Division, Monitoring Operations, Texas Air Control Board, Austin, Texas.Google Scholar
  24. Fajen JM, Roberts DR, Ungers LJ, Krishnan ER (1990) Occupational exposure of workers to 1,3-butadiene. Environ Hlth Perspect 86: 11–18.CrossRefGoogle Scholar
  25. Filser JG, Bolt HM (1984) Inhalation pharmacokinetics based on gas uptake studies. VI. Comparative evaluation of ethylene oxide and butadiene monoxide as exhaled reactive metabolites of ethylene and 1,3-butadiene in rats. Arch Toxicol 55: 219–223.Google Scholar
  26. Gart JJ, Chu KC, Tarone RE (1979) Statistical issues in interpretation of chronic bioassay tests for carcinogenicity. J Natl Cancer Inst 62: 957–974.PubMedGoogle Scholar
  27. Goodrow T, Reynolds S, Maronpot R, Anderson M (1990) 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. 50: 4818–4823.PubMedGoogle Scholar
  28. Gopinath C (1986) Spontaneous brain tumours in Sprague-Dawley rats. Food Chem Toxicol 24: 113–120.PubMedCrossRefGoogle Scholar
  29. Haseman JK, Tharrington EC, Huff JE, McConnell EE (1986) Comparison of site-specific and overall tumor incidence analyses for 81 recent National Toxicology Program carcinogenicity studies. Reg Toxicol Pharmacol 6: 155–170.CrossRefGoogle Scholar
  30. Huff J, Haseman J (1991) Long-term chemical carcinogenesis experiments for identifying potential human cancer hazards. Collective data base of the National Cancer Institute & National Toxicology Program (1976–1991). Environ Hlth Perspect (in press).Google Scholar
  31. Huff JE, Melnick RL, Solleveld HA, Haseman JK, Powers M, Miller RA (1985) Multiple organ carcinogenicity of 1,3-butadiene in B6C3F1 mice after 60 weeks of inhalation exposure. Science 227: 548–549.PubMedCrossRefGoogle Scholar
  32. Huff JE, McConnell EE, Haseman JK, Boorman GA, Eustis SL, Schwetz BA, Rao GN, Jameson CW, Hart LG, Rail DP (1988) Carcinogenesis studies: Results of 398 experiments on 104 chemicals from the U.S. National Toxicology Program. Ann NY Acad Sci 534: 1–30.PubMedCrossRefGoogle Scholar
  33. Huff JE, Cirvello J, Haseman JK, Bucher JR (1991) Chemicals associated with site-specific neoplasia in 1394 long-term carcinogenesis experiments in laboratory rodents. Environ Hlth Perspect (in press).Google Scholar
  34. IISRP (1981a) The toxicity and carcinogenicity of butadiene gas administered to rats by inhalation for approximately 24 months. International Institute of Synthetic Rubber Producers. Report No. 2653-522/2.Google Scholar
  35. IISRP (1981b) 1,3-Butadiene: Inhalation teratogenicity study in the rat. International Institute of Synthetic Rubber Producers. Report No. 2788-522/3.Google Scholar
  36. Irons RD, Smith CN, Stillman WS, Shah RS, Steinhagen WH, Leiderman LJ (1986a) Macrocytic-megaloblastic anemia in male B6C3F1 mice following chronic exposure to 1,3-butadiene. Toxicol Appl Pharmacol 83: 95–100.PubMedCrossRefGoogle Scholar
  37. Irons RD, Smith CN, Stillman WS, Shah RS, Steinhagen WH, Leiderman LJ (1986b) Macrocytic-megaloblastic anemia in male NIH Swiss mice following repeated exposure to 1,3-butadiene. Toxicol Appl Pharmacol 85: 450–455.PubMedCrossRefGoogle Scholar
  38. Irons RD (1990) Studies on the mechanism of 1,3-butadiene-induced leukemogenesis: The potential role of endogenous murine leukemia virus. Environ Hlth Perspect 86: 49–55.CrossRefGoogle Scholar
  39. Irons RD, Cathro HP, Stillman WS, Steinhagen WH, Shah RS (1989) Susceptibility to 1,3-butadiene-induced leukemogenesis correlates with endogenous ecotropic retroviral background in the mouse. Toxicol Appl Pharmacol 101: 170–176.PubMedCrossRefGoogle Scholar
  40. Irons RD, Stillman WS, Cloyd MW (1987) Selective activation of endogenous ecotropic retrovirus in hematopoietic tissues of B6C3F1 mice during the preleukemic phase of 1,3-butadiene exposure. Virology 161: 457–462.PubMedCrossRefGoogle Scholar
  41. Jelitto B, Vangala RR, Laib RJ (1989) Species differences in DNA damage by butadiene: Role of diepoxybutane. Arch Toxicol, Suppl 13: 246–249.Google Scholar
  42. Kirshenbaum I (1978) Butadiene. In: Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 4,3rd ed. John Wiley & Sons, Inc., New York, NY, pp. 313–337.Google Scholar
  43. Kreiling R, Laib RJ, Bolt HM (1986) Alkylation of nuclear proteins and DNA after exposure of rats and mice to [1,4-14C] 1,3-butadiene. Toxicol Lett 30: 131–136.PubMedCrossRefGoogle Scholar
  44. Kreiling R, Laib RJ, Bolt HM (1988) Depletion of hepatic non-protein sulfhydryl content during exposure of rats and mice to butadiene. Toxicol Lett 41: 209–214.PubMedCrossRefGoogle Scholar
  45. Kreiling R, Laib RJ, Filser JG, Bolt HM (1986) Species differences in butadiene metabolism between mice and rats evaluated by inhalation pharmacokinetics. Arch Toxicol 58: 235–238.PubMedCrossRefGoogle Scholar
  46. Kreiling R, Laib RJ, Filser JG, Bolt HM (1987) Inhalation pharmacokinetics of 1,2-epoxybutene-3 reveal species differences between rats and mice sensitive to butadiene-induced carcinogenesis. Arch Toxicol 61: 7–11.PubMedCrossRefGoogle Scholar
  47. Krinke G, Naylor DC, Schmid S, Frohlich E, Schnider K (1985) The incidence of naturally-occurring primary brain tumours in the laboratory rat. J Comp Path. 95: 175–192.PubMedCrossRefGoogle Scholar
  48. Laib RH, Filser JG, Kreiling R, Vangala, RR, Bolt HM (1990) Inhalation pharmacokinetics of 1,3-butadiene and 1,2-epoxybutene-3 in rats and mice. Environ Hlth Perspect 86: 57–63.CrossRefGoogle Scholar
  49. Landrigan PJ (1990) Critical assessment of epidemiologic studies on the human carcinogenicity of 1,3-butadiene. Environ Hlth Perspect 86: 143–148.CrossRefGoogle Scholar
  50. Lorenz J, Glatt HR, Fleischmann R, Ferlinz R, Oesch F (1984) 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 32: 43–56.PubMedCrossRefGoogle Scholar
  51. Maldotti A, Chiorboli C, Agnozzi A, Bartocci C, Carassiti V (1980) Photooxidation of 1,3-butadiene containing systems: rate constant determinations for the reaction of acrolein with OH radicals. Int J Chem Kinet 12: 905–913.CrossRefGoogle Scholar
  52. Malvoisin E, Lhoest G, Poncelet F, Roberfroid M, Mercier M (1979) Identification and quantitation of 1,2-epoxybutene-3 as the primary metabolite of 1,3-butadiene. J Chromatogr 178: 419–425.CrossRefGoogle Scholar
  53. Malvoisin E, Roberfroid M (1982) Hepatic microsomal metabolism of 1,3-butadiene. Xenobiotica 12: 137–144.PubMedCrossRefGoogle Scholar
  54. Matanoski GM, Schwartz L (1987) Mortality of workers in styrene-butadiene polymer production. J Occup Med 29: 675–680.PubMedGoogle Scholar
  55. Matanoski GM, Santos-Burgoa C, Schwartz L (1990) Mortality of a cohort of workers in the styrene-butadiene polymer manufacturing industry (1943–1982). Environ Hlth Perspect 86: 107–117.CrossRefGoogle Scholar
  56. Matanoski GM, Santos-Burgoa C, Zeger SL, Schwartz L (1989) Epidemiologic data related to health effects of 1,3-butadiene. In: Mohr U, Bates DV, Dungworth DLGoogle Scholar
  57. Lee PN, McCellan RO, Roe FJC (eds.). Assessment of Inhalation Hazards, Springer-Verlag, New York. pp. 201–214.Google Scholar
  58. Meinhardt TJ, Lemen RA, Crandall MS, Young RJ (1982) Environmental epidemiologic investigation of the styrene-butadiene rubber industry. Scand J Work Environ Hlth 8: 250–259.Google Scholar
  59. Melnick RL, Huff JE, Bird MG, Acquavella JF (1990a) Symposium overview: Toxicology, carcinogenesis, and human health aspects of 1,3-butadiene. Environ Hlth Perspect 86: 3–5.CrossRefGoogle Scholar
  60. Melnick RL, Huff JE, Roycroft JH, Chou BJ, Miller RA (1990b) Inhalation toxicology and carcinogenicity of 1,3-butadiene in B6C3F1 mice following 65 weeks of exposure. Environ Hlth Perspect 86: 27–36.Google Scholar
  61. Melnick RL, Huff J, Chou BJ, Miller R (1990c) Carcinogenicity of 1,3-butadiene in C57BL/6 x C3H F1 mice at low exposure concentrations. Cancer Res 50: 6592–6599.PubMedGoogle Scholar
  62. Miller LM (1978) Investigations of selected potential environmental contaminants: butadiene and its oligomers. In: EPA-560/2-78-008. US Environmental Protection Agency, Washington, DC.Google Scholar
  63. Miller RA, Boorman GA (1990) Morphology of neoplastic lesions induced by 1,3-butadiene in B6C3F1 mice. Environ Hlth Perspect 86: 37–48.Google Scholar
  64. Morrissey RE, Schwetz BA, Hackett PL, Sikov MR, Hardin BD, McClanahan BJ, Decker JR, Mast TJ (1990) Overview of reproductive and developmental toxicity studies of 1,3-butadiene in rodents. Environ Hlth Perspect 86: 79–84.CrossRefGoogle Scholar
  65. Morrow NL (1990) The industrial production and use of 1,3-butadiene. Environ Hlth Perspect 86: 7–8.CrossRefGoogle Scholar
  66. Mullins JA (1990) Industrial emissions of 1,3-butadiene. Environ Hlth Perspect 86: 9–10.CrossRefGoogle Scholar
  67. NIOSH (1989) National Occupational Exposure Survey. National Institute for Occupational Safety and Health, Cincinnati, OHGoogle Scholar
  68. NTP (1984) Toxicology and carcinogenesis studies of 1,3-butadiene (CAS No. 106-99-0) in B6C3F1 mice (inhalation studies). In: National Toxicology Program TR No. 288, pp. 1–111, National Institutes of Health, Bethesda, MDGoogle Scholar
  69. OSHA (1990) Occupational exposure to 1,3-butadiene; proposed rule and notice of hearing. Occupational Safety and Health Administration. Fed. Reg. 55: 32736–32826.Google Scholar
  70. Ott MG (1990) Assessment of 1,3-butadiene epidemiology studies. Environ Hlth Perspect 86: 135–141.CrossRefGoogle Scholar
  71. Owen PE, Glaister JR, Gaunt IF, Pullinger DH (1987) Inhalation toxicity studies with 1,3-butadiene. 3. Two-year toxicity/carcinogenicity studies in rats. Am Ind Hyg Assoc J 48: 407–413.Google Scholar
  72. Peto R, Pike MC, Day WE, Gray RG, Lee PN, Parish S, Peto J, Richards S, Wahrendorf S (1980) Guidelines for simple, sensitive significance tests for carcinogenic effects in long term animal experiments. Long-Term and Short-Term Screening Assays for Carcinogens: A Critical Appraisal, IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Supplement 2, pp. 311–426. International Agency for Research on Cancer, Lyon, France.Google Scholar
  73. Portier CJ, Bailer AJ (1989) Testing for increased carcinogenicity using a survival-adjusted quantal response test. Fund Appl Toxicol 12: 731–737.CrossRefGoogle Scholar
  74. Reynolds SH, Stowers SJ, Patterson RM, Maronpot RR, Aaronson SA, Anderson MW (1987) Activated oncogenes in B6C3F1 mouse liver tumors: implications for risk assessment. Science 237: 1309–1316.PubMedCrossRefGoogle Scholar
  75. Ristau C, Deutschmann S, Laib RJ, Ottenwalder H (1990) Detection of diepoxybutane-induced DNA-DNA crosslinks by cesium trifloroacetate (CsTFA) density-gradient centrifugation. Arch Toxicol 64: 343–344.PubMedCrossRefGoogle Scholar
  76. Schmidt U, Loeser E (1985) Species differences in the formation of butadiene monoxide from 1,3-butadiene. Arch Toxicol 57: 222–225.PubMedCrossRefGoogle Scholar
  77. Sharief Y, Brown AM, Backer LC, Campbell JA, Westbrook-Collins B, Stead AG, Allen JW (1986) Sister chromatid exchange and chromosome aberration analyses in mice after in vivo exposure to acrylonitrile, styrene, or butadiene monoxide. Environ Mut 8: 439–448.CrossRefGoogle Scholar
  78. Shelby MD (1990) Results of NTP-sponsored mouse cytogenetic studies on 1,3-butadiene, isoprene, and chloroprene. Environ Hlth Perspectives 86: 71–73.CrossRefGoogle Scholar
  79. Shugaev BB (1969) Concentrations of hydrocarbons in tissues as a measure of toxicity. Arch Environ Hlth 18: 878–882.Google Scholar
  80. Thurmond LM, Lauer LD, House RV, Stillman WS, Irons RD, Steinhagen WH, Dean JH (1986) Effect of short-term inhalation exposure to 1,3-butadiene on murine immune functions. Toxicol Appl Pharmacol 86: 170–179.PubMedCrossRefGoogle Scholar
  81. Tice RR, Boucher R, Luke CA, Shelby MD (1987) Comparative cytogenetic analysis of bone marrow damage induced in male B6C3F1 mice by multiple exposures to gaseous 1,3-butadiene. Environ Mut 9: 235–250.CrossRefGoogle Scholar
  82. USITC (1990) United States International Trade Commission. Synthetic Organic Chemicals; United States Production and Sales, 1989. Publ. 2338. U.S. Government Printing Office, Washington, DC.Google Scholar
  83. Van Duuren BL, Langseth L, Orris L, Teebor G, Nelson N, Kuschner K (1966) Carcinogenicity of epoxides, lactones, and peroxy compounds. IV. Tumor response in epithelial and connective tissue in mice and rats. J Natl Cancer Inst 37: 825–838.Google Scholar
  84. Van Duuren BL, Nelson N, Orris L, Palmes ED, Schmitt FL (1963) Carcinogenicity of epoxides, lactones, and peroxy compounds. J Natl Cancer Inst 31: 41–55.Google Scholar
  85. Voogd CE, van der Stel JJ, Jacobs JJJAA (1981) The mutagenic action of aliphatic epoxides. Mutat Res 89: 269–282.PubMedCrossRefGoogle Scholar
  86. Wade MJ, Moyer JW, Hine CH (1979) Mutagenic action of a series of epoxides. Mutat Res 66: 367–371.PubMedCrossRefGoogle Scholar
  87. Wiseman RW, Barrett JC (1990) Loss of heterozygosity on chromosome 4 in butadiene-induced lung tumors of B6C3F1 mice. Am Assoc Cancer Res 31: 317.Google Scholar
  88. Yin S, Li G-L, Tain F-D, Fu Z-I, Jin C, Chen Y-J, Luo S-J, Ye P-Z, Zhang J-Z, Wang G-C, Zhang X-C, Wu H-N, Zhong Q-C (1989) A retrospective cohort study of leukemia and other causes in benzene workers. Environ Hlth Perspect 82: 207–213.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 1992

Authors and Affiliations

  • Ronald L. Melnick
    • 1
  • James Huff
    • 1
  1. 1.National Institute of Environmental Health SciencesUSA

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