Toxicology of 1,3-Butadiene, Chloroprene, and Isoprene

  • Harrell E. Hurst
Part of the Reviews of Environmental Contamination and Toxicology book series (RECT, volume 189)


The diene monomers 1,3-butadiene, chloroprene, and isoprene, shown in Fig. 1, are important building blocks used in the synthesis of polymers. These volatile organic compounds contribute significantly to the atmospheric burden of organic chemicals, appearing at low parts per billion (ppb)
Fig. 1.

Structures of butadiene, chloroprene, and isoprene.

concentrations in ambient air near industrial sites where they are used. Occupational exposures to these dienes occur at higher air concentrations approaching or slightly exceeding the parts per million (ppm) threshold in facilities that produce or polymerize these monomers. Such exposures present significant continuing concern to occupational hygienists and epidemiologists in the quest to provide safe working conditions during production. These three chemicals, which differ chemically only by substitution of a hydrogen, chlorine, or methyl group at the 2-carbon of the molecule, provide interesting comparisons among their physical properties, occurrence, uses, and potential health effects. This review does not attempt comprehensive review of these chemicals, as that would fill many volumes. Search of the National Library of Medicine Medline database yielded more than 1,100, 700, and 130 citations, respectively, when butadiene, isoprene, and chloroprene were sought as keywords indexed from publications between 1966 and October 2005.


PBPK Model Epoxide Hydrolase Harderian Gland Inhalation Study National Toxicology Program 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abdel-Rahman, SZ, Ammenheuser, MM, Ward, JB Jr (2001) Human sensitivity to 1,3-butadiene: role of microsomal epoxide hydrolase polymorphisms. Carcinogenesis (Oxf) 22:415–423.Google Scholar
  2. ACC Olefins Panel (2005) HPV Category Summary: Pyrolysis C3+ and Pyrolysis C4+ Category. Report 201-15092. American Chemistry Council, Arlington, VA.Google Scholar
  3. Acquavella, JF, Leonard, RC (2001) A review of the epidemiology of 1,3-butadiene and chloroprene. Chem-Biol Interact 135–136:43–52.Google Scholar
  4. Affek, HP, Yakir, D (2002) Protection by isoprene against singlet oxygen in leaves. Plant Physiol 129:269–277.Google Scholar
  5. Albertini, RJ, Sram, RJ, Vacek, PM, Lynch, J, Nicklas, JA, van Sittert, NJ, Boogaard, PJ, Henderson, RF, Swenberg, JA, Tates, AD, Ward, JB Jr, Wright, M, Ammenheuser, MM, Binkova, B, Blackwell, W, de Zwart, FA, Krako, D, Krone, J, Megens, H, Musilova, P, Rajska, G, Ranasinghe, A, Rosenblatt, JI, Rossner, P, Rubes, J, Sullivan, L, Upton, P, Zwinderman, AH (2003) Biomarkers in Czech workers exposed to 1,3-butadiene: a transitional epidemiologic study. Res Rep Health Eff Inst 116. Health Effects Institute, Boston, MA, pp 1–141.Google Scholar
  6. Ames, BN (1973) Carcinogens are mutagens: their detection and classification. Environ Health Perspect 6:115–118.Google Scholar
  7. Ames, BN, Durston, WE, Yamasaki, E, Lee, FD (1973a) Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc Natl Acad Sci USA 70:2281–2285.Google Scholar
  8. Ames, BN, Lee, FD, Durston, WE (1973b) An improved bacterial test system for the detection and classification of mutagens and carcinogens. Proc Natl Acad Sci USA 70:782–786.Google Scholar
  9. Bartsch, H, Malaveille, C, Montesano, R, Tomatis, L (1975) Tissue-mediated mutagenicity of vinylidene chloride and 2-chlorobutadiene in Salmonella typhimurium. Nature (Lond) 255:641–643.Google Scholar
  10. Bartsch, H, Malaveille, C, Barbin, A, Bresil, H, Tomatis, L, Montesano, R (1976) Mutagenicity and metabolism of vinyl chloride and related compounds. Environ Health Perspect 17:193–198.Google Scholar
  11. Bartsch, H, Malaveille, C, Barbin, A, Planche, G (1979) Mutagenic and alkylating metabolites of halo-ethylenes, chlorobutadienes and dichlorobutenes produced by rodent or human liver tissues. Evidence for oxirane formation by P450-linked microsomal mono-oxygenases. Arch Toxicol 41:249–277.Google Scholar
  12. Bechtold, WE, Strunk, MR, Chang, IY, Ward, JB Jr, Henderson, RF (1994) Species differences in urinary butadiene metabolites: comparisons of metabolite ratios between mice, rats, and humans. Toxicol Appl Pharmacol 127:44–49.Google Scholar
  13. Begemann, P, Christova-Georgieva, NI, Sangaiah, R, Koc, H, Zhang, D, Golding, BT, Gold, A, Swenberg, JA (2004) Synthesis, characterization, and identification of N7-guanine adducts of isoprene monoepoxides in vitro. Chem Res Toxicol 17:929–936.Google Scholar
  14. Ben Porath, I, Weinberg, RA (2005) The signals and pathways activating cellular senescence. Int J Biochem Cell Biol 37:961–976.Google Scholar
  15. Bennett, DA, Waters, MD (2000) Applying biomarker research. Environ Health Perspect 108:907–910.Google Scholar
  16. Bird, MG, Rice, JM, Bond, JA (2001) Evaluation of 1,3-butadiene, isoprene and chloroprene health risks. Chem-Biol Interact 135–136:1–7.Google Scholar
  17. Blair, IA, Oe, T, Kambouris, S, Chaudhary, AK (2000) 1,3-Butadiene: cancer, mutations, and adducts. Part IV: Molecular dosimetry of 1,3-butadiene. Res Rep Health Eff Inst 92. Health Effects Institute, Boston, MA, pp 151–190.Google Scholar
  18. Bogaards, JJ, Venekamp, JC, Salmon, FG, van Bladeren, PJ (1999) Conjugation of isoprene monoepoxides with glutathione, catalyzed by alpha, mu, pi and theta-class glutathione S-transferases of rat and man. Chem-Biol Interact 117:1–14.Google Scholar
  19. Bolt, HM (1986) Metabolic activation of vinyl chloride, formation of nucleic acid adducts and relevance to carcinogenesis. IARC Sci Publ 70:261–268.Google Scholar
  20. 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. J Cancer Res Clin Oncol 106:112–116.Google Scholar
  21. Bond, JA, Medinsky, MA (2001) Insights into the toxicokinetics and toxicodynamics of 1,3-butadiene. Chem-Biol Interact 135–136:599–614.Google Scholar
  22. Bond, JA, Himmelstein, MW, Seaton, M, Boogaard, P, Medinsky, MA (1996) Metabolism of butadiene by mice, rats, and humans: a comparison of physiologically based toxicokinetic model predictions and experimental data. Toxicology 113:48–54.Google Scholar
  23. Boogaard, PJ, Bond, JA (1996) The role of hydrolysis in the detoxification of 1,2:3,4-diepoxybutane by human, rat, and mouse liver and lung in vitro. Toxicol Appl Pharmacol 141:617–627.Google Scholar
  24. Boogaard, PJ, de Kloe, KP, Booth, ED, Watson, WP (2004) DNA adducts in rats and mice following exposure to [4-14C]-1,2-epoxy-3-butene and to [2,3-14C]-1,3-butadiene. Chem-Biol Interact 148:69–92.Google Scholar
  25. Booth, ED, Kilgour, JD, Robinson, SA, Watson, WP (2004) Dose responses for DNA adduct formation in tissues of rats and mice exposed by inhalation to low concentrations of 1,3-[2,3-[(14)C]-butadiene. Chem-Biol Interact 147:195–211.Google Scholar
  26. Boysen, G, Georgieva, NI, Upton, PB, Jayaraj, K, Li, Y, Walker, VE, Swenberg, JA (2004) Analysis of diepoxide-specific cyclic N-terminal globin adducts in mice and rats after inhalation exposure to 1,3-butadiene. Cancer Res 64:8517–8520.Google Scholar
  27. California Air Resources Board (2006) 1,3-Butadiene at John Swett. (3-10-2006).Google Scholar
  28. Carmical, JR, Nechev, LV, Harris, CM, Harris, TM, Lloyd, RS (2000a) Mutagenic potential of adenine N(6) adducts of monoepoxide and diolepoxide derivatives of butadiene. Environ Mol Mutagen 35:48–56.Google Scholar
  29. Carmical, JR, Zhang, M, Nechev, L, Harris, CM, Harris, TM, Lloyd, RS (2000b) Mutagenic potential of guanine N2 adducts of butadiene mono-and diolepoxide. Chem Res Toxicol 13:18–25.Google Scholar
  30. CEN (2005) Facts & figures from the chemical industry. (4-10-2006).Google Scholar
  31. Chiappe, C, De Rubertis, A, Tinagli, V, Amato, G, Gervasi, PG (2000) Stereochemical course of the biotransformation of isoprene monoepoxides and of the corresponding diols with liver microsomes from control and induced rats. Chem Res Toxicol 13:831–838.Google Scholar
  32. Clary, JJ, Feron, VJ, Reuzel, PG (1978) Toxicity of beta-chloroprene (2-chlorobutadiene-1,3): acute and subacute toxicity. Toxicol Appl Pharmacol 46:375–384.Google Scholar
  33. Cochrane, JE, Skopek, TR (1994a) Mutagenicity of butadiene and its epoxide metabolites: I. Mutagenic potential of 1,2-epoxybutene, 1,2,3,4-diepoxybutane and 3,4-epoxy-1,2-butanediol in cultured human lymphoblasts. Carcinogenesis (Oxf) 15:713–717.Google Scholar
  34. Cochrane, JE, Skopek, TR (1994b) Mutagenicity of butadiene and its epoxide metabolites: II. Mutational spectra of butadiene, 1,2-epoxybutene and diepoxybutane at the hprt locus in splenic T cells from exposed B6C3F1 mice. Carcinogenesis (Oxf) 15:719–723.Google Scholar
  35. Coon, MJ (2005) Cytochrome P450: nature’s most versatile biological catalyst. Annu Rev Pharmacol Toxicol 45:1–25.Google Scholar
  36. Cottrell, L, Golding, BT, Munter, T, Watson, WP (2001) In vitro metabolism of chloroprene: species differences, epoxide stereochemistry and a de-chlorination pathway. Chem Res Toxicol 14:1552–1562.Google Scholar
  37. Creech, JL Jr, Johnson, MN (1974) Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Occup Med 16:150–151.Google Scholar
  38. Csanady, GA, Guengerich, FP, Bond, JA (1992) Comparison of the biotransformation of 1,3-butadiene and its metabolite, butadiene monoepoxide, by hepatic and pulmonary tissues from humans, rats and mice. Carcinogenesis (Oxf) 13:1143–1153.Google Scholar
  39. Csanady, GA, Kreuzer, PE, Baur, C, Filser, JG (1996) A physiological toxicokinetic model for 1,3-butadiene in rodents and man: blood concentrations of 1,3-butadiene, its metabolically formed epoxides, and of haemoglobin adducts — relevance of glutathione depletion. Toxicology 113:300–305.Google Scholar
  40. Dahl, AR, Birnbaum, LS, Bond, JA, Gervasi, PG, Henderson, RF (1987) The fate of isoprene inhaled by rats: comparison to butadiene. Toxicol Appl Pharmacol 89:237–248.Google Scholar
  41. Del Monte, M, Citti, L, Gervasi, PG (1985) Isoprene metabolism by liver microsomal mono-oxygenases. Xenobiotica 15:591–597.Google Scholar
  42. Delzell, E, Sathiakumar, N, Macaluso, M, Hovinga, M, Larson, R, Barone, F, Beall, C, Julian, J, Muir, D (1995) A follow-up study of synthetic rubber workers. Prepared for the International Institute of Synthetic Rubber Workers, Houston, TX.Google Scholar
  43. Delzell, E, Sathiakumar, N, Hovinga, M, Macaluso, M, Julian, J, Larson, R, Cole, P, Muir, DC (1996) A follow-up study of synthetic rubber workers. Toxicology 113:182–189.Google Scholar
  44. Drevon, C, Kuroki, T (1979) Mutagenicity of vinyl chloride, vinylidene chloride and chloroprene in V79 Chinese hamster cells. Mutat Res 67:173–182.Google Scholar
  45. Duescher, RJ, Elfarra, AA (1994) Human liver microsomes are efficient catalysts of 1,3-butadiene oxidation: evidence for major roles by cytochromes P450 2A6 and 2E1. Arch Biochem Biophys 311:342–349.Google Scholar
  46. Elfarra, AA, Sharer, JE, Duescher, RJ (1995) Synthesis and characterization of N-acetyl-l-cysteine S-conjugates of butadiene monoxide and their detection and quantitation in urine of rats and mice given butadiene monoxide. Chem Res Toxicol 8:68–76.Google Scholar
  47. Elfarra, AA, Krause, RJ, Selzer, RR (1996) Biochemistry of 1,3-butadiene metabolism and its relevance to 1,3-butadiene-induced carcinogenicity. Toxicology 113:23–30.Google Scholar
  48. Elfarra, AA, Krause, RJ, Kemper, RA (2001a) Cellular and molecular basis for species, sex and tissue differences in 1,3-butadiene metabolism. Chem-Biol Interact 135–136:239–248.Google Scholar
  49. Elfarra, AA, Moll, TS, Krause, RJ, Kemper, RA, Selzer, RR (2001b) Reactive metabolites of 1,3-butadiene: DNA and hemoglobin adduct formation and potential roles in carcinogenicity. Adv Exp Med Biol 500:93–103.Google Scholar
  50. Evans, T, Hart, MJ, Cerione, RA (1991) The Ras superfamilies: regulatory proteins and posttranslational modifications. Curr Opin Cell Biol 3:185–191.Google Scholar
  51. Falk, H, Creech, JL Jr, Heath, CW Jr, Johnson, MN, Key, MM (1974) Hepatic disease among workers at a vinyl chloride polymerization plant. JAMA 230:59–63.Google Scholar
  52. Filser, JG, Johanson, G, Kessler, W, Kreuzer, PE, Stei, P, Baur, C, Csanady, GA (1993) A pharmacokinetic model to describe toxicokinetic interactions between 1,3-butadiene and styrene in rats: predictions for human exposure. IARC Sci Publ 127:65–78.Google Scholar
  53. Fred, C, Cantillana, T, Henderson, AP, Golding, BT, Tornqvist, M (2004a) Adducts of N-terminal valines in hemoglobin with isoprene diepoxide, a metabolite of isoprene. Rapid Commun Mass Spectrom 18:2177–2184.Google Scholar
  54. Fred, C, Kautiainen, A, Athanassiadis, I, Tornqvist, M (2004b) Hemoglobin adduct levels in rat and mouse treated with 1,2:3,4-diepoxybutane. Chem Res Toxicol 17:785–794.Google Scholar
  55. Fred, C, Grawe, J, Tornqvist, M (2005) Hemoglobin adducts and micronuclei in rodents after treatment with isoprene monoxide or butadiene monoxide. Mutat Res 585:21–32.Google Scholar
  56. Fustinoni, S, Soleo, L, Warholm, M, Begemann, P, Rannug, A, Neumann, HG, Swenberg, JA, Vimercati, L, Colombi, A (2002) Influence of metabolic genotypes on biomarkers of exposure to 1,3-butadiene in humans. Cancer Epidemiol Biomark Prev 11:1082–1090.Google Scholar
  57. Gervasi, PG, Longo, V (1990) Metabolism and mutagenicity of isoprene. Environ Health Perspect 86:85–87.Google Scholar
  58. Gervasi, PG, Citti, L, Del Monte, M, Longo, V, Benetti, D (1985) Mutagenicity and chemical reactivity of epoxidic intermediates of the isoprene metabolism and other structurally related compounds. Mutat Res 156:77–82.Google Scholar
  59. Golding, BT, Cottrell, L, Mackay, D, Zhang, D, Watson, WP (2003) Stereochemical and kinetic comparisons of mono-and diepoxide formation in the in vitro metabolism of isoprene by liver microsomes from rats, mice, and humans. Chem Res Toxicol 16:933–944.Google Scholar
  60. 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.Google Scholar
  61. Graff, JJ, Sathiakumar, N, Macaluso, M, Maldonado, G, Matthews, R, Delzell, E (2005) Chemical exposures in the synthetic rubber industry and lymphohematopoietic cancer mortality. J Occup Environ Med 47:916–932.Google Scholar
  62. Guengerich, FP (1997) Comparisons of catalytic selectivity of cytochrome P450 subfamily enzymes from different species. Chem-Biol Interact 106:161–182.Google Scholar
  63. Guengerich, FP (2003) Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions. Arch Biochem Biophys 409:59–71.Google Scholar
  64. Gwinner, LM, Laib, RJ, Filser, JG, Bolt, HM (1983) Evidence of chloroethylene oxide being the reactive metabolite of vinyl chloride towards DNA: comparative studies with 2,2′-dichlorodiethylether. Carcinogenesis (Oxf) 4:1483–1486.Google Scholar
  65. Hayes, JD, Flanagan, JU, Jowsey, IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88.Google Scholar
  66. Hayes, RB, Zhang, L, Yin, S, Swenberg, JA, Xi, L, Wiencke, J, Bechtold, WE, Yao, M, Rothman, N, Haas, R, O’Neill, JP, Zhang, D, Wiemels, J, Dosemeci, M, Li, G, Smith, MT (2000) Genotoxic markers among butadiene polymer workers in China. Carcinogenesis (OXF) 21:55–62.Google Scholar
  67. Henderson, RF (2001) Species differences in the metabolism of olefins: implications for risk assessment. Chem-Biol Interact 135–136:53–64.Google Scholar
  68. Henderson, RF, Barr, EB, Belinsky, SA, Benson, JM, Hahn, FF, Menache, MG (2000) 1,3-Butadiene: cancer, mutations, and adducts. Part I: Carcinogenicity of 1,2,3,4-diepoxybutane. Res Rep Health Eff Inst 92. Health Effects Institute, Boston, MA, pp 11–43.Google Scholar
  69. Himmelstein, MW, Turner, MJ, Asgharian, B, Bond, JA (1994) Comparison of blood concentrations of 1,3-butadiene and butadiene epoxides in mice and rats exposed to 1,3-butadiene by inhalation. Carcinogenesis (Oxf) 15:1479–1486.Google Scholar
  70. Himmelstein, MW, Asgharian, B, Bond, JA (1995) High concentrations of butadiene epoxides in livers and lungs of mice compared to rats exposed to 1,3-butadiene. Toxicol Appl Pharmacol 132:281–288.Google Scholar
  71. Himmelstein, MW, Turner, MJ, Asgharian, B, Bond, JA (1996) Metabolism of 1,3-butadiene: inhalation pharmacokinetics and tissue dosimetry of butadiene epoxides in rats and mice. Toxicology 113:306–309.Google Scholar
  72. Himmelstein, MW, Acquavella, JF, Recio, L, Medinsky, MA, Bond, JA (1997) Toxicology and epidemiology of 1,3-butadiene. Crit Rev Toxicol 27:1–108.Google Scholar
  73. Himmelstein, MW, Carpenter, SC, Hinderliter, PM, Snow, TA, Valentine, R (2001a) The metabolism of beta-chloroprene: preliminary in-vitro studies using liver microsomes. Chem-Biol Interact 135–136:267–284.Google Scholar
  74. Himmelstein, MW, Gladnick, NL, Donner, EM, Snyder, RD, Valentine, R (2001b) In vitro genotoxicity testing of (1-chloroethenyl)oxirane, a metabolite of beta-chloroprene. Chem-Biol Interact 135–136:703–713.Google Scholar
  75. Himmelstein, MW, Carpenter, SC, Evans, MV, Hinderliter, PM, Kenyon, EM (2004a) Kinetic modeling of beta-chloroprene metabolism: II. the application of physiologically based modeling for cancer dose response analysis. Toxicol Sci 79(1):28–37.Google Scholar
  76. Himmelstein, MW, Carpenter, SC, Hinderliter, PM (2004b) Kinetic Modeling of beta-chloroprene metabolism: I. In vitro rates in liver and lung tissue fractions from mice, rats, hamsters, and humans. Toxicol Sci 79(1):18–27.Google Scholar
  77. Hirabayashi, Y (2005) p53-dependent gene profiling for reactive oxygen species after benzene inhalation: special reference to genes associated with cell cycle regulation. Chem-Biol Interact 153–154:165–170.Google Scholar
  78. Hong, HL, Devereux, TR, Melnick, RL, Eldridge, SR, Greenwell, A, Haseman, J, Boorman, GA, Sills, RC (1997) Both K-ras and H-ras protooncogene mutations are associated with Harderian gland tumorigenesis in B6C3F1 mice exposed to isoprene for 26 weeks. Carcinogenesis (Oxf) 18:783–789.Google Scholar
  79. Hong, HL, Devereux, TR, Melnick, RL, Moomaw, CR, Boorman, GA, Sills, RC (2000) Mutations of ras protooncogenes and p53 tumor suppressor gene in cardiac hemangiosarcomas from B6C3F1 mice exposed to 1,3-butadiene for 2 years. Toxicol Pathol 28:529–534.Google Scholar
  80. Howard, P, Boethling, R, Jarvis, W, Meylan, W, Michalenko, E (1991) Handbook of Environmental Degradation Rates. Lewis, Chelsea, MI.Google Scholar
  81. 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.Google Scholar
  82. Hughes, K, Meek, ME, Walker, M, Beauchamp, R (2001) 1,3-Butadiene: Human Health Aspects. Concise International Chemical Assessment Doc 30. Health Canada, Ottawa, Ontario, pp 1–73.Google Scholar
  83. Hughes, K, Meek, ME, Walker, M, Beauchamp, R (2003) 1,3-Butadiene: exposure estimation, hazard characterization, and exposure-response analysis. J Toxicol Environ Health B Crit Rev 6:55–83.Google Scholar
  84. Hurst, HE, Ali, MY (2006) Analyses of (1-chloroethenyl)oxirane headspace and hemoglobin N-valine adducts in erythrocytes indicate selective detoxification of (1-chloroethenyl)oxirane enantiomers. Chem-Biol Interact (in press).Google Scholar
  85. IARC (1979) Chloroprene and polychloroprene. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol 19. World Health Organization, International Agency for Research on Cancer, Lyon, France, pp 131–156.Google Scholar
  86. IARC (1999a) 1,3-Butadiene. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol 71, pt 1. World Health Organization, International Agency for Research on Cancer, Lyon, France, pp 109–225.Google Scholar
  87. IARC (1999b) Chloroprene. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol 71, pt 1. World Health Organization, International Agency for Research on Cancer, Lyon, France, pp 227–250.Google Scholar
  88. IARC (1999c) Isoprene. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol 71, pt 3. World Health Organization, International Agency for Research on Cancer, Lyon, France, pp 1015–1025.Google Scholar
  89. 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.Google Scholar
  90. 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.Google Scholar
  91. Jackson, MA, Stack, HF, Rice, JM, Waters, MD (2000a) A review of the genetic and related effects of 1,3-butadiene in rodents and humans. Mutat Res 463:181–213.Google Scholar
  92. Jackson, TE, Lilly, PD, Recio, L, Schlosser, PM, Medinsky, MA (2000b) Inhibition of cytochrome P450 2E1 decreases, but does not eliminate, genotoxicity mediated by 1,3-butadiene. Toxicol Sci 55:266–273.Google Scholar
  93. Jacobson-Kram, D, Rosenthal, SL (1995) Molecular and genetic toxicology of 1,3-butadiene. Mutat Res 339:121–130.Google Scholar
  94. Johanson, G, Filser, JG (1993) A physiologically based pharmacokinetic model for butadiene and its metabolite butadiene monoxide in rat and mouse and its significance for risk extrapolation. Arch Toxicol 67:151–163.Google Scholar
  95. Johanson, G, Filser, JG (1996) PBPK model for butadiene metabolism to epoxides: quantitative species differences in metabolism. Toxicology 113:40–47.Google Scholar
  96. Karl, T, Prazeller, P, Mayr, D, Jordan, A, Rieder, J, Fall, R, Lindinger, W (2001) Human breath isoprene and its relation to blood cholesterol levels: new measurements and modeling. J Appl Physiol 91:762–770.Google Scholar
  97. Kemper, RA, Elfarra, AA, Myers, SR (1998) Metabolism of 3-butene-1,2-diol in B6C3F1 mice. Evidence for involvement of alcohol dehydrogenase and cytochrome p450. Drug Metab Dispos 26:914–920.Google Scholar
  98. Kemper, RA, Krause, RJ, Elfarra, AA (2001) Metabolism of butadiene monoxide by freshly isolated hepatocytes from mice and rats: different partitioning between oxidative, hydrolytic, and conjugation pathways. Drug Metab Dispos 29:830–836.Google Scholar
  99. Kligerman, AD, DeMarini, DM, Doerr, CL, Hanley, NM, Milholland, VS, Tennant, AH (1999) Comparison of cytogenetic effects of 3,4-epoxy-1-butene and 1,2:3,4-diepoxybutane in mouse, rat and human lymphocytes following in vitro G0 exposures. Mutat Res 439:13–23.Google Scholar
  100. Koc, H, Tretyakova, NY, Walker, VE, Henderson, RF, Swenberg, JA (1999) Molecular dosimetry of N-7 guanine adduct formation in mice and rats exposed to 1,3-butadiene. Chem Res Toxicol 12:566–574.Google Scholar
  101. Kohn, MC (1997) The importance of anatomical realism for validation of physiological models of disposition of inhaled toxicants. Toxicol Appl Pharmacol 147:448–458.Google Scholar
  102. Kohn, MC, Melnick, RL (1993) Species differences in the production and clearance of 1,3-butadiene metabolites: a mechanistic model indicates predominantly physiological, not biochemical, control. Carcinogenesis (Oxf) 14:619–628.Google Scholar
  103. Kohn, MC, Melnick, RL (1996) Effects of the structure of a toxicokinetic model of butadiene inhalation exposure on computed production of carcinogenic intermediates. Toxicology 113:31–39.Google Scholar
  104. Kohn, MC, Melnick, RL (2000) The privileged access model of 1,3-butadiene disposition. Environ Health Perspect 108(suppl 5):911–917.Google Scholar
  105. Koivisto, P, Kilpelainen, I, Rasanen, I, Adler, ID, Pacchierotti, F, Peltonen, K (1999) Butadiene diolepoxide-and diepoxybutane-derived DNA adducts at N7-guanine: a high occurrence of diolepoxide-derived adducts in mouse lung after 1,3-butadiene exposure. Carcinogenesis (Oxf) 20:1253–1259.Google Scholar
  106. Krause, RJ, Elfarra, AA (1997) Oxidation of butadiene monoxide to meso-and (+/−)-diepoxybutane by cDNA-expressed human cytochrome P450s and by mouse, rat, and human liver microsomes: evidence for preferential hydration of meso-diepoxybutane in rat and human liver microsomes. Arch Biochem Biophys 337:176–184.Google Scholar
  107. Krewski, D, Withey, JR, Ku, LF, Andersen, ME (1994) Applications of physiologic pharmacokinetic modeling in carcinogenic risk assessment. Environ Health Perspect 102(suppl 11):37–50.Google Scholar
  108. Krewski, D, Henderson, RF, Bakshi, K (1999) Current trends in toxicological risk assessment: perspectives from the committee on toxicology. Inhal Toxicol 11:459–476.Google Scholar
  109. Kumar, R, Sukumar, S, Barbacid, M (1990) Activation of ras oncogenes preceding the onset of neoplasia. Science 248:1101–1104.Google Scholar
  110. Kuzma, J, Nemecek-Marshall, M, Pollock, WH, Fall, R (1995) Bacteria produce the volatile hydrocarbon isoprene. Curr Microbiol 30:97–103.Google Scholar
  111. Kuzuyama, T, Seto, H (2003) Diversity of the biosynthesis of the isoprene units. Nat Prod Rep 20:171–183.Google Scholar
  112. Landi, S (2000) Mammalian class theta GST and differential susceptibility to carcinogens: a review. Mutat Res 463:247–283.Google Scholar
  113. Lawley, PD, Brookes, P (1967) Interstrand cross-linking of DNA by difunctional alkylating agents. J Mol Biol 25:143–160.Google Scholar
  114. Leavens, TL, Bond, JA (1996) Pharmacokinetic model describing the disposition of butadiene and styrene in mice. Toxicology 113:310–313.Google Scholar
  115. Leiderman, LJ, Stillman, WS, Shah, RS, Steinhagen, WH, Irons, RD (1986) Altered hematopoietic stem cell development in male B6C3F1 mice following exposure to 1,3-butadiene. Exp Mol Pathol 44:50–56.Google Scholar
  116. Leonard, RC, Lineker, GA, Kreckmann, KH, Marsh, GM, Buchanich, JM, Youk, AO (2006) Comparison of standardized mortality ratios (SMRs) obtained from use of a reference population based on a company-wide registry cohort to SMRs calculated against local and national rates. Chem-Biol Interact (in press).Google Scholar
  117. Li, SQ, Dong, QN, Liu, YQ, Liu, YG (1989) Epidemiologic study of cancer mortality among chloroprene workers. Biomed Environ Sci 2:141–149.Google Scholar
  118. Lynch, J (2001a) BD monomer and elastomer production processes. Chem-Biol Interact 135–136:147–153.Google Scholar
  119. Lynch, J (2001b) Occupational exposure to butadiene, isoprene and chloroprene. Chem-Biol Interact 135–136:207–214.Google Scholar
  120. Lynch, M (2001c) Manufacture and use of chloroprene monomer. Chem-Biol Interact 135–136:155–167.Google Scholar
  121. Macaluso, M, Larson, R, Delzell, E, Sathiakumar, N, Hovinga, M, Julian, J, Muir, D, Cole, P (1996) Leukemia and cumulative exposure to butadiene, styrene and benzene among workers in the synthetic rubber industry. Toxicology 113:190–202.Google Scholar
  122. Marsh, GM, Youk, AO, Buchanich, JM, Cunningham, M, Esmen, NA, Hall, TA, Phillips, ML (2006a) Mortality patterns among industrial workers exposed to chloroprene and other substances: I. General mortality patterns. Chem-Biol Interact (in press).Google Scholar
  123. Marsh, GM, Youk, AO, Buchanich, JM, Cunningham, M, Esmen, NA, Hall, TA, Phillips, ML (2006b) Mortality patterns among industrial workers exposed to chloroprene and other substances: II. Mortality in relation to exposure. Chem-Biol Interact (in press).Google Scholar
  124. Maryland Department of the Environment (2006) MDE Air Quality Data Report. (4-10-2006).Google Scholar
  125. Medinsky, MA, Leavens, TL, Csanady, GA, Gargas, ML, Bond, JA (1994) In vivo metabolism of butadiene by mice and rats: a comparison of physiological model predictions and experimental data. Carcinogenesis (Oxf) 15:1329–1340.Google Scholar
  126. Melnick, RL (2002) Carcinogenicity and mechanistic insights on the behavior of epoxides and epoxide-forming chemicals. Ann NY Acad Sci 982:177–189.Google Scholar
  127. Melnick, RL, Huff, J (1992) 1,3-Butadiene: toxicity and carcinogenicity in laboratory animals and in humans. Rev Environ Contam Toxicol 124:111–144.Google Scholar
  128. Melnick, RL, Kohn, MC (2000) Dose-response analyses of experimental cancer data. Drug Metab Rev 32:193–209.Google Scholar
  129. Melnick, RL, Sills, RC (2001) Comparative carcinogenicity of 1,3-butadiene, isoprene, and chloroprene in rats and mice. Chem-Biol Interact 135–136:27–42.Google Scholar
  130. Melnick, RL, Huff, J, Chou, BJ, Miller, RA (1990a) Carcinogenicity of 1,3-butadiene in C57BL/6 × C3H F1 mice at low exposure concentrations. Cancer Res 50:6592–6599.Google Scholar
  131. 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 Health Perspect 86:27–36.Google Scholar
  132. Melnick, RL, Sills, RC, Roycroft, JH, Chou, BJ, Ragan, HA, Miller, RA (1994) Isoprene, an endogenous hydrocarbon and industrial chemical, induces multiple organ neoplasia in rodents after 26 weeks of inhalation exposure. Cancer Res 54:5333–5339.Google Scholar
  133. Melnick, RL, Elwell, MR, Roycroft, JH, Chou, BJ, Ragan, HA, Miller, RA (1996) Toxicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344 rats and B6C3F(1) mice. Toxicology 108:79–91.Google Scholar
  134. Melnick, RL, Sills, RC, Portier, CJ, Roycroft, JH, Chou, BJ, Grumbein, SL, Miller, RA (1999a) Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344/N rats and B6C3F1 mice and comparison of dose response with 1,3-butadiene in mice. Carcinogenesis (Oxf) 20:867–878.Google Scholar
  135. Melnick, RL, Sills, RC, Portier, CJ, Roycroft, JH, Chou, BJ, Grumbein, SL, Miller, RA (1999b) Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344/N rats and B6C3F1 mice and comparison of dose-response with 1,3-butadiene in mice. Carcinogenesis (Oxf) 20(5):867–878.Google Scholar
  136. Merck Index (1996) Isoprene. In: Budavari S (ed) The Merck Index. Merck, Whitehouse Station, NJ, p 887.Google Scholar
  137. Merritt, WK, Scholdberg, TA, Nechev, LV, Harris, TM, Harris, CM, Lloyd, RS, Stone, MP (2004) Stereospecific structural perturbations arising from adenine N(6) butadiene triol adducts in duplex DNA. Chem Res Toxicol 17:1007–1019.Google Scholar
  138. Merritt, WK, Nechev, LV, Scholdberg, TA, Dean, SM, Kiehna, SE, Chang, JC, Harris, TM, Harris, CM, Lloyd, RS, Stone, MP (2005) Structure of the 1,4-bis(2′-deoxyadenosin-N6-yl)-2R,3R-butanediol cross-link arising from alkylation of the human N-ras codon 61 by butadiene diepoxide. Biochemistry-US 44:10081–10092.Google Scholar
  139. Moll, TS, Elfarra, AA (1999) Characterization of the reactivity, regioselectivity, and stereoselectivity of the reactions of butadiene monoxide with valinamide and the N-terminal valine of mouse and rat hemoglobin. Chem Res Toxicol 12:679–689.Google Scholar
  140. Moll, TS, Harms, AC, Elfarra, AA (2000) A comprehensive structural analysis of hemoglobin adducts formed after in vitro exposure of erythrocytes to butadiene monoxide. Chem Res Toxicol 13:1103–1113.Google Scholar
  141. Morisseau, C, Hammock, BD (2005) Epoxide hydrolases: mechanisms, inhibitor designs, and biological roles. Annu Rev Pharmacol Toxicol 45:311–333.Google Scholar
  142. 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 Health Perspect 86:79–84.Google Scholar
  143. Morrow, NL (2001) Significance of 1,3-butadiene to the US air toxics regulatory effort. Chem-Biol Interact 135–136:137–143.Google Scholar
  144. Munter, T, Cottrell, L, Hill, S, Kronberg, L, Watson, WP, Golding, BT (2002) Identification of adducts derived from reactions of (1-chloroethenyl)oxirane with nucleosides and calf thymus DNA. Chem Res Toxicol 15:1549–1560.Google Scholar
  145. Munter, T, Cottrell, L, Golding, BT, Watson, WP (2003) Detoxication pathways involving glutathione and epoxide hydrolase in the in vitro metabolism of chloroprene. Chem Res Toxicol 16:1287–1297.Google Scholar
  146. NTP (1998) Toxicology and carcinogenesis studies of chloroprene (CAS No. 126-99-8) in F344/N Rats and B6C3F1 mice (inhalation studies). Tech Rep Ser 467:1–372.Google Scholar
  147. NTP (1999) NTP toxicology and carcinogenesis studies of isoprene (CAS No. 78-79-5) in F344/N rats (inhalation studies). Natl Toxicol Program Tech Rep Ser 486:1–176.Google Scholar
  148. NTP (2005a) 1,3-Butadiene CAS No. 106-99-0. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, Research Triangle Park, NC.Google Scholar
  149. NTP (2005b) Chloroprene CAS No. 126-99-8. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, Research Triangle Park, NC.Google Scholar
  150. NTP (2005c) Isoprene CAS No. 78-79-5. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, Research Triangle Park, NC.Google Scholar
  151. Nystrom, AE (1948) Health hazards in the chloroprene rubber industry and their prevention. A clinical and experimental study, with special reference to chloroprene and its oxidation and polymerization products. Acta Med Scand 132:1–125.Google Scholar
  152. Oe, T, Kambouris, SJ, Walker, VE, Meng, Q, Recio, L, Wherli, S, Chaudhary, AK, Blair, IA (1999) Persistence of N7-(2,3,4-trihydroxybutyl)guanine adducts in the livers of mice and rats exposed to 1,3-butadiene. Chem Res Toxicol 12:247–257.Google Scholar
  153. OSHA (1996) Occupational exposure to 1,3-butadiene. Fed Reg 61:56746–56856.Google Scholar
  154. OSHA (2005a) Occupational Exposure to 1,3-Butadiene. (10-19-2005a).Google Scholar
  155. OSHA (2005b) Safety and Health Topics: Vinyl Chloride. (10-19-2005b).Google Scholar
  156. Osterman-Golkar, S, Bond, JA (1996) Biomonitoring of 1,3-butadiene and related compounds. Environ Health Perspect 104(Suppl 5):907–915.Google Scholar
  157. Osterman-Golkar, S, Kautiainen, A, Bergmark, E, Hakansson, K, Maki-Paakkanen, J (1991) Hemoglobin adducts and urinary mercapturic acids in rats as biological indicators of butadiene exposure. Chem-Biol Interact 80:291–302.Google Scholar
  158. Osterman-Golkar, S, Peltonen, K, Anttinen-Klemetti, T, Landin, HH, Zorcec, V, Sorsa, M (1996) Haemoglobin adducts as biomarkers of occupational exposure to 1,3-butadiene. Mutagenesis 11:145–149.Google Scholar
  159. Osterman-Golkar, SM, Moss, O, James, A, Bryant, MS, Turner, M, Bond, JA (1998) Epoxybutene-hemoglobin adducts in rats and mice: dose response for formation and persistence during and following long-term low-level exposure to butadiene. Toxicol Appl Pharmacol 150:166–173.Google Scholar
  160. Owen, PE, Glaister, JR, Gaunt, IF, Pullinger, DH (1987) Inhalation toxicity studies with 1,3-butadiene. 3. Two year toxicity/carcinogenicity study in rats. Am Ind Hyg Assoc J 48:407–413.Google Scholar
  161. Pell, S (1978) Mortality of workers exposed to chloroprene. J Occup Med 20:21–29.Google Scholar
  162. Penn, A, Snyder, CA (1996) 1,3-Butadiene, a vapor phase component of environmental tobacco smoke, accelerates arteriosclerotic plaque development. Circulation 93:552–557.Google Scholar
  163. Perez, HL, Lahdetie, J, Landin, H, Kilpelainen, I, Koivisto, P, Peltonen, K, Osterman-Golkar, S (1997) Haemoglobin adducts of epoxybutanediol from exposure to 1,3-butadiene or butadiene epoxides. Chem-Biol Interact 105:181–198.Google Scholar
  164. Placke, ME, Griffis, L, Bird, M, Bus, J, Persing, RL, Cox, LA Jr (1996) Chronic inhalation oncogenicity study of isoprene in B6C3F1 mice. Toxicology 113:253–262.Google Scholar
  165. Plugge, H, Jaeger, RJ (1979) Acute inhalation toxicity of 2-chloro-1,3-butadiene (chloroprene): effects on liver and lung. Toxicol Appl Pharmacol 50:565–572.Google Scholar
  166. Powley, MW, Jayaraj, K, Gold, A, Ball, LM, Swenberg, JA (2003) 1,N2-propanodeoxyguanosine adducts of the 1,3-butadiene metabolite, hydroxymethylvinyl ketone. Chem Res Toxicol 16:1448–1454.Google Scholar
  167. Powley, MW, Li, Y, Upton, PB, Walker, VE, Swenberg, JA (2005) Quantification of DNA and hemoglobin adducts of 3,4-epoxy-1,2-butanediol in rodents exposed to 3-butene-1,2-diol. Carcinogenesis (Oxf) 26:1573–1580.Google Scholar
  168. Recio, L, Saranko, CJ, Steen, AM (2000) 1,3-Butadiene: cancer, mutations, and adducts. Part II: Roles of two metabolites of 1,3-butadiene in mediating its in vivo genotoxicity. Res Rep Health Eff Inst 92. Health Effects Institute, Boston, MA, pp 49–87.Google Scholar
  169. Reya, T, Clevers, H (2005) Wnt signaling in stem cells and cancer. Nature (Lond) 434:843–850.Google Scholar
  170. Richardson, KA, Megens, HJ, Webb, JD, van Sittert, NJ (1996) Biological monitoring of butadiene exposure by measurement of haemoglobin adducts. Toxicology 113:112–118.Google Scholar
  171. Richardson, KA, Peters, MM, Wong, BA, Megens, RH, van Elburg, PA, Booth, ED, Boogaard, PJ, Bond, JA, Medinsky, MA, Watson, WP, van Sittert, NJ (1999) Quantitative and qualitative differences in the metabolism of 14C-1,3-butadiene in rats and mice: relevance to cancer susceptibility. Toxicol Sci 49:186–201.Google Scholar
  172. Rodriguez, DA, Kowalczyk, A, Ward, JB Jr, Harris, CM, Harris, TM, Lloyd, RS (2001) Point mutations induced by 1,2-epoxy-3-butene N1 deoxyinosine adducts. Environ Mol Mutagen 38:292–296.Google Scholar
  173. Rydberg, P, Magnusson, AL, Zorcec, V, Granath, F, Tornqvist, M (1996) Adducts to N-terminal valines in hemoglobin from butadiene metabolites. Chem-Biol Interact 101:193–205.Google Scholar
  174. Sabourin, PJ, Burka, LT, Bechtold, WE, Dahl, AR, Hoover, MD, Chang, IY, Henderson, RF (1992) Species differences in urinary butadiene metabolites; identification of 1,2-dihydroxy-4-(N-acetylcysteinyl)butane, a novel metabolite of butadiene. Carcinogenesis (Oxf) 13:1633–1638.Google Scholar
  175. Sanotskii, IV (1976) Aspects of the toxicology of chloroprene: immediate and long term effects. Environ Health Perspect 17:85–93.Google Scholar
  176. Sapkota, A, Halden, RU, Dominici, F, Groopman, JD, Buckley, TJ (2006) Urinary biomarkers of 1,3-butadiene in environmental settings using liquid chromatography isotope dilution tandem mass spectrometry. Chem-Biol Interact 160:70–79.Google Scholar
  177. Sathiakumar, N, Delzell, E, Hovinga, M, Macaluso, M, Julian, JA, Larson, R, Cole, P, Muir, DC (1998) Mortality from cancer and other causes of death among synthetic rubber workers. Occup Environ Med 55:230–235.Google Scholar
  178. Satoh, T, Kaziro, Y (1992) Ras in signal transduction. Semin Cancer Biol 3:169–177.Google Scholar
  179. Scholdberg, TA, Nechev, LV, Merritt, WK, Harris, TM, Harris, CM, Lloyd, RS, Stone, MP (2004) Structure of a site-specific major groove (2S,3S)-N6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl DNA adduct of butadiene diol epoxide. Chem Res Toxicol 17:717–730.Google Scholar
  180. Scholdberg, TA, Nechev, LV, Merritt, WK, Harris, TM, Harris, CM, Lloyd, RS, Stone, MP (2005) Mispairing of a site specific major groove (2S,3S)-N6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl DNA adduct of butadiene diol epoxide with deoxyguanosine: formation of a dA(anti):dG(anti) pairing interaction. Chem Res Toxicol 18:145–153.Google Scholar
  181. Sharkey, TD (1996) Isoprene synthesis by plants and animals. Endeavour 20:74–78.Google Scholar
  182. Shugaev, BB (1969) Concentrations of hydrocarbons in tissues as a measure of toxicity. Arch Environ Health 18:878–882.Google Scholar
  183. Shuker, DE (2002) The enemy at the gates? DNA adducts as biomarkers of exposure to exogenous and endogenous genotoxic agents. Toxicol Lett 134:51–56.Google Scholar
  184. Sills, RC, Boorman, GA, Neal, JE, Hong, HL, Devereux, TR (1999a) Mutations in ras genes in experimental tumours of rodents. IARC Sci Publ 146:55–86.Google Scholar
  185. Sills, RC, Hong, HL, Melnick, RL, Boorman, GA, Devereux, TR (1999b) High frequency of codon 61 K-ras A → T transversions in lung and Harderian gland neoplasms of B6C3F1 mice exposed to chloroprene (2-chloro-1,3-butadiene) for 2 years, and comparisons with the structurally related chemicals isoprene and 1,3-butadiene. Carcinogenesis (Oxf) 20:657–662.Google Scholar
  186. Silver, GM, Fall, R (1995) Characterization of aspen isoprene synthase, an enzyme responsible for leaf isoprene emission to the atmosphere. J Biol Chem 270:13010–13016.Google Scholar
  187. Small, RD, Golding, BT, Watson, WP (1997) Species differences in the stereochemistry of the metabolism of isoprene in vitro. Xenobiotica 27:1155–1164.Google Scholar
  188. Sukumar, S (1990) An experimental analysis of cancer: role of ras oncogenes in multistep carcinogenesis. Cancer Cells 2:199–204.Google Scholar
  189. Sun, JD, Dahl, AR, Bond, JA, Birnbaum, LS, Henderson, RF (1989) Characterization of hemoglobin adduct formation in mice and rats after administration of [14C]butadiene or [14C]isoprene. Toxicol Appl Pharmacol 100:86–95.Google Scholar
  190. Sweeney, LM, Himmelstein, MW, Schlosser, PM, Medinsky, MA (1996) Physiologically based pharmacokinetic modeling of blood and tissue epoxide measurements for butadiene. Toxicology 113:318–321.Google Scholar
  191. Sweeney, LM, Schlosser, PM, Medinsky, MA, Bond, JA (1997) Physiologically based pharmacokinetic modeling of 1,3-butadiene, 1,2-epoxy-3-butene, and 1,2:3,4-diepoxybutane toxicokinetics in mice and rats. Carcinogenesis (Oxf) 18:611–625.Google Scholar
  192. Sweeney, LM, Himmelstein, MW, Gargas, ML (2001) Development of a preliminary physiologically based toxicokinetic (PBTK) model for 1,3-butadiene risk assessment. Chem-Biol Interact 135–136:303–322.Google Scholar
  193. Swenberg, JA, Christova-Gueorguieva, NI, Upton, PB, Ranasinghe, A, Scheller, N, Wu, KY, Yen, TY, Hayes, R (2000) 1,3-Butadiene: cancer, mutations, and adducts. Part V: Hemoglobin adducts as biomarkers of 1,3-butadiene exposure and metabolism. Res Rep Health Eff Inst 92. Health Effects Institute, Boston, MA, pp 191–210.Google Scholar
  194. Swenberg, JA, Koc, H, Upton, PB, Georguieva, N, Ranasinghe, A, Walker, VE, Henderson, R (2001) Using DNA and hemoglobin adducts to improve the risk assessment of butadiene. Chem-Biol Interact 135–136:387–403.Google Scholar
  195. Taalman, RD (1996) Isoprene: background and issues. Toxicology 113:242–246.Google Scholar
  196. Tareke, E, Golding, BT, Small, RD, Tornqvist, M (1998) Haemoglobin adducts from isoprene and isoprene monoepoxides. Xenobiotica 28:663–672.Google Scholar
  197. Thornton-Manning, JR, Dahl, AR, Bechtold, WE, Griffith, WC Jr, Henderson, RF (1995) Disposition of butadiene monoepoxide and butadiene diepoxide in various tissues of rats and mice following a low-level inhalation exposure to 1,3-butadiene. Carcinogenesis (Oxf) 16:1723–1731.Google Scholar
  198. Thornton-Manning, JR, Dahl, AR, Bechtold, WE, Henderson, RF (1996) Gender and species differences in the metabolism of 1,3-butadiene to butadiene monoepoxide and butadiene diepoxide in rodents following low-level inhalation exposures. Toxicology 113:322–325.Google Scholar
  199. 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 Mutagen 9:235–250.Google Scholar
  200. Tice, RR, Boucher, R, Luke, CA, Paquette, DE, Melnick, RL, Shelby, MD (1988) Chloroprene and isoprene: cytogenetic studies in mice. Mutagenesis 3:141–146.Google Scholar
  201. Tornqvist, M, Landin, HH (1995) Hemoglobin adducts for in vivo dose monitoring and cancer risk estimation. J Occup Environ Med 37:1077–1085.Google Scholar
  202. Tornqvist, M, Mowrer, J, Jensen, S, Ehrenberg, L (1986) Monitoring of environmental cancer initiators through hemoglobin adducts by a modified Edman degradation method. Anal Biochem 154:255–266.Google Scholar
  203. Tornqvist, M, Fred, C, Haglund, J, Helleberg, H, Paulsson, B, Rydberg, P (2002) Protein adducts: quantitative and qualitative aspects of their formation, analysis and applications. J Chromatogr B Analyt Technol Biomed Life Sci 778:279–308.Google Scholar
  204. Tretyakova, NY, Chiang, SY, Walker, VE, Swenberg, JA (1998) Quantitative analysis of 1,3-butadiene-induced DNA adducts in vivo and in vitro using liquid chromatography electrospray ionization tandem mass spectrometry. J Mass Spectrom 33:363–376.Google Scholar
  205. Trochimowicz, HJ, Loser, E, Feron, VJ, Clary, JJ, Valentine, R (1998) Chronic inhalation toxicity and carcinogenicity studies on b-chloroprene in rats and hamsters. Inha Toxicol 10:443–472.Google Scholar
  206. USEPA (1999) Draft Revised Guidelines for Carcinogen Risk Assessment. (3-14-2006).Google Scholar
  207. USEPA (2000) Compendium of methods for the determination of toxic organic compounds in ambient air; Compendium Method TO-15. (12-5-2000).Google Scholar
  208. USEPA (2002) Health Assessment of 1,3-Butadiene. EPA/600/P-98/001F.U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Washington Office, Washington, DC.Google Scholar
  209. USEPA and IRIS (2002) 1,3-Butadiene. (12-6-2005).Google Scholar
  210. USEPA (2005a) Guidelines for Carcinogen Risk Assessment and Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens. (12-6-2005a).Google Scholar
  211. USEPA (2005b) Memorandum: Application of New Cancer Guidelines. (12-6-2005b).Google Scholar
  212. USEPA (2005c) TRI Explorer-Releases: Chemical Report-1,3-Butadiene. (10-11-2005c).Google Scholar
  213. USEPA (2005d) TRI Explorer-Releases: Chemical Report-Chloroprene. (10-11-2005d).Google Scholar
  214. Valentine, R, Himmelstein, MW (2001) Overview of the acute, subchronic, reproductive, developmental and genetic toxicology of beta-chloroprene. Chem-Biol Interact 135–136:81–100.Google Scholar
  215. van Sittert, NJ, Megens, HJ, Watson, WP, Boogaard, PJ (2000) Biomarkers of exposure to 1,3-butadiene as a basis for cancer risk assessment. Toxicol Sci 56:189–202.Google Scholar
  216. van Steeg, H (2001) The role of nucleotide excision repair and loss of p53 in mutagenesis and carcinogenesis. Toxicol Lett 120:209–219.Google Scholar
  217. Waddell, WJ (2002) Thresholds of carcinogenicity of flavors. Toxicol Sci 68:275–279.Google Scholar
  218. Waddell, WJ (2003a) Comparison of human exposures to selected chemicals with thresholds from NTP carcinogenicity studies in rodents. Hum Exp Toxicol 22:501–506.Google Scholar
  219. Waddell, WJ (2003b) Thresholds in chemical carcinogenesis: what are animal experiments telling us? Toxicol Pathol 31:260–262.Google Scholar
  220. Waddell, WJ (2003c) Thresholds of carcinogenicity in the ED01 study. Toxicol Sci 72:158–163.Google Scholar
  221. Waddell, WJ (2005) Comparisons of thresholds for carcinogenicity on linear and logarithmic dosage scales. Hum Exp Toxicol 24:325–332.Google Scholar
  222. Ward, JB Jr, Ammenheuser, MM, Bechtold, WE, Whorton, EB Jr, Legator, MS (1994) hprt mutant lymphocyte frequencies in workers at a 1,3-butadiene production plant. Environ Health Perspect 102(suppl 9):79–85.Google Scholar
  223. Washington Department of Ecology (2006) Annual data summary, 1,3-butadiene.,3-butadiene.shtml (3-10-2006).Google Scholar
  224. Watkinson, R, Somerville, H (1976) The microbial utilization of butadiene. Shell Research Limited, Sittingbourne Research Centre, Kent, UK.Google Scholar
  225. Watson, WP, Cottrell, L, Zhang, D, Golding, BT (2001) Metabolism and molecular toxicology of isoprene. Chem-Biol Interact 135–136:223–238.Google Scholar
  226. Westphal, GA, Blaszkewicz, M, Leutbecher, M, Muller, A, Hallier, E, Bolt, HM (1994) Bacterial mutagenicity of 2-chloro-1,3-butadiene (chloroprene) caused by decomposition products. Arch Toxicol 68:79–84.Google Scholar
  227. Wickliffe, JK, Galbert, LA, Ammenheuser, MM, Herring, SM, Xie, J, Masters, OE III, Friedberg, EC, Lloyd, RS, Ward, JB Jr (2006) 3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice. Environ Mol Mutagen 47:67–70.Google Scholar
  228. Wilson, RH (1944) Health hazards encountered in the manufacture of synthetic rubber. JAMA 124:701.Google Scholar
  229. Wiseman, RW, Cochran, C, Dietrich, W, Lander, ES, Soderkvist, P (1994) Allelotyping of butadiene-induced lung and mammary adenocarcinomas of B6C3F1 mice: frequent losses of heterozygosity in regions homologous to human tumorsuppressor genes. Proc Natl Acad Sci USA 91:3759–3763.Google Scholar
  230. Wistuba, D, Weigand, K, Peter, H (1994) Stereoselectivity of in vitro isoprene metabolism. Chem Res Toxicol 7:336–343.Google Scholar
  231. WJCCTF (2006) West Jefferson County Community Task Force, Air Toxics Monitoring Sites Data. (3-10-2006).Google Scholar
  232. Yaws, CL (1976) Physical and thermodynamic properties. Part 18. Butadiene, isoprene and chloroprene. Chem Eng 83:107–115.Google Scholar
  233. Zeiger, E, Anderson, B, Haworth, S, Lawlor, T, Mortelmans, K, Speck, W (1987) Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. Environ Mutagen 9(suppl 9):1–109.Google Scholar
  234. Zhao, C, Vodicka, P, Sram1, RJ, Hemminki, K (2000) Human DNA adducts of 1,3-butadiene, an important environmental carcinogen. Carcinogenesis (Oxf) 21:107–111.Google Scholar
  235. Zhao, C, Vodicka, P, Sram, RJ, Hemminki, K (2001) DNA adducts of 1,3-butadiene in humans: relationships to exposure, GST genotypes, single-strand breaks, and cytogenetic end points. Environ Mol Mutagen 37:226–230.Google Scholar
  236. Zhuang, SM, Cochran, C, Goodrow, T, Wiseman, RW, Soderkvist, P (1997) Genetic alterations of p53 and ras genes in 1,3-butadiene-and 2′,3′-dideoxycytidineinduced lymphomas. Cancer Res 57:2710–2714.Google Scholar
  237. Zhuang, SM, Wiseman, RW, Soderkvist, P (2002) Frequent mutations of the Trp53, Hras1 and beta-catenin (Catnb) genes in 1,3-butadiene-induced mammary adenocarcinomas in B6C3F1 mice. Oncogene 21:5643–5648.Google Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Harrell E. Hurst
    • 1
  1. 1.Department of Pharmacology and ToxicologyUniversity of Louisville School of MedicineLouisvilleUSA

Personalised recommendations