EPA/600/P-98/001F October 2002 Health Assessment of 1,3-Butadiene National Center for Environmental Assessment–Washington Office Office of Research and Development U.S. Environmental Protection Agency Washington, DC DISCLAIMER This document has been reviewed in accordance with the U.S. Environmental Protection Agency’s peer and administrative review policies and approved for presentation and publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ABSTRACT This assessment was conducted to review the new information that has become available since EPA’s 1985 health assessment of 1,3-butadiene. 1,3-Butadiene is a gas used commercially in the production of styrene-butadiene rubber, plastics, and thermoplastic resins. The major environmental source of 1,3-butadiene is the incomplete combustion of fuels from mobile sources (e.g., automobile exhaust). Tobacco smoke can be a significant source of 1,3-butadiene in indoor air. This assessment concludes that 1,3-butadiene is carcinogenic to humans by inhalation, based on the total weight of evidence. The specific mechanisms of 1,3-butadiene-induced carcinogenesis are unknown, however, it is virtually certain that the carcinogenic effects are mediated by genotoxic metabolites of 1,3-butadiene. Animal data suggest that females may be more sensitive than males for cancer effects; nevertheless, there are insufficient data from which to draw any conclusions on potentially sensitive subpopulations. The human incremental lifetime unit cancer (incidence) risk estimate is based on extrapolation from leukemias observed in an occupational epidemiologic study. A twofold adjustment to the epidemiologic-based unit cancer risk is then applied to reflect evidence from the rodent bioassays suggesting that the epidemiologic-based estimate may underestimate total cancer risk from 1,3-butadiene exposure in the general population. 1,3-Butadiene also causes a variety of reproductive and developmental effects in mice; no human data on these effects are available. The most sensitive effect was ovarian atrophy observed in a lifetime bioassay of female mice. Based on this critical effect and using the benchmark concentration methodology, an RfC (i.e., a chronic exposure level presumed to be “without appreciable risk” for noncancer effects) was calculated. In summary, the EPA’s conclusions about the health effects of 1,3-butadiene are: C 1,3-Butadiene is carcinogenic to humans by inhalation. C The unit cancer risk estimate is 0.08/ppm (based primarily on linear modeling and extrapolation of human data). This incorporates an adjustment factor of 2 to address concerns for sensitive populations. The corresponding estimate of the chronic exposure level of 1,3-butadiene resulting in extra cancer risk of 10-6 (i.e., 1 in a million) is 0.01 ppb. C A chronic RfC (0.9 ppb), an acute reference value (7 ppb), and a subchronic reference value (7 ppb) are presented for noncancer effects. Preferred citation: U.S. Environmental Protection Agency (EPA). (2002) Health assessment of 1,3-butadiene. National Center for Environmental Assessment, Washington, DC: EPA/600/P-98/001F. Available from: National Technical Information Service, Springfield, VA, <http://www.epa.gov/ncea/>. ii CONTENTS LIST OF TABLES ............................................................ ix LIST OF FIGURES .......................................................... xiii PREFACE ................................................................. xiv AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................... xv 1. INTRODUCTION ........................................................ 1-1 1.1. BACKGROUND .................................................... 1-1 1.2. OVERVIEW OF THE SCOPE OF THIS HEALTH ASSESSMENT ............ 1-1 1.3. SUMMARY OF EPA’S CARCINOGEN ASSESSMENT (U.S. EPA, 1985) ...... 1-3 2. OVERVIEW OF EXPOSURE TO 1,3-BUTADIENE ............................ 2-1 2.1. PHYSICAL/CHEMICAL PROPERTIES .................................. 2-1 2.2. PRODUCTION AND USE ............................................. 2-1 2.2.1. SB Latex and Rubber Production .................................. 2-2 2.2.2. Polybutadiene Production ........................................ 2-2 2.2.3. Neoprene Rubber Production ..................................... 2-3 2.2.4. Acrylonitrile-Butadiene Resin Production ........................... 2-3 2.2.5. Nitrile Elastomer Production ..................................... 2-3 2.2.6. Adiponitrile Production ......................................... 2-3 2.3. SOURCES AND EMISSION ........................................... 2-4 2.3.1. Mobile Sources ................................................ 2-4 2.3.1.1. On-Road Mobile Sources ................................. 2-4 2.3.1.2. Nonroad Mobile Sources ................................. 2-6 2.3.1.3. Aircraft ............................................... 2-6 2.3.2. Miscellaneous Sources .......................................... 2-7 2.3.2.1. Miscellaneous Chemical Production ........................ 2-7 2.3.2.2. Secondary Lead Smelters ................................. 2-7 2.3.2.3. Petroleum Refining ..................................... 2-7 2.3.2.4. Combustion Sources .................................... 2-8 2.4. AMBIENT CONCENTRATION OF 1,3-BUTADIENE ...................... 2-9 2.4.1. Air .......................................................... 2-9 2.4.1.1. Ambient Monitoring Data ................................ 2-9 2.4.1.2. Ambient Source Apportionment .......................... 2-19 2.4.2. Indoor Exposure to 1,3-Butadiene ................................ 2-24 2.4.3. Inside Automobile ............................................. 2-25 2.4.4. Water ....................................................... 2-25 2.4.5. Food ....................................................... 2-25 2.5. MODELED ON-ROAD MOBILE SOURCE BUTADIENE EXPOSURE ESTIMATES ....................................................... 2-25 2.6. CONCLUSIONS ABOUT PATHWAYS OF EXPOSURE ................... 2-26 iii CONTENTS (continued) 3. PHARMACOKINETICS ................................................... 3-1 3.1. OVERVIEW OF PHARMACOKINETIC STUDIES ........................ 3-1 3.2. ABSORPTION ...................................................... 3-2 3.3. BIOTRANSFORMATION ............................................. 3-4 3.3.1. Pathway Elucidation ............................................ 3-5 3.3.2. Enzyme Identification .......................................... 3-11 3.3.3. Rates of Metabolism ........................................... 3-13 3.3.3.1. In Vitro .............................................. 3-14 3.3.3.2. Enzymatic Activities ................................... 3-14 3.3.3.3. In Vivo .............................................. 3-27 3.4. DISTRIBUTION .................................................... 3-31 3.4.1. Blood and Tissue Concentrations ................................. 3-31 3.4.1.1. Species Differences .................................... 3-31 3.4.1.2. Gender Differences .................................... 3-39 3.4.1.3. Chronic Exposures ..................................... 3-39 3.4.2. Molecular Dosimetry .......................................... 3-43 3.4.2.1. Hemoglobin Adducts ................................... 3-44 3.4.2.2. DNA Adducts ......................................... 3-47 3.5. EXCRETION ...................................................... 3-49 3.5.1. Pathways of Excretion ......................................... 3-50 3.5.2. Identification of Metabolites ..................................... 3-52 3.6. PHARMACOKINETICS OF STRUCTURALLY RELATED COMPOUNDS . 3-56 3.7. DISCUSSION ...................................................... 3-61 4. MUTAGENICITY ........................................................ 4-1 4.1. 1,3-BUTADIENE .................................................... 4-1 4.1.1. Gene Mutations ................................................ 4-1 4.1.2. Cytogenetic Effects ............................................ 4-15 4.1.2.1. Somatic Cells ......................................... 4-15 4.1.2.2. Germ Cells ........................................... 4-17 4.2. METABOLITES .................................................... 4-20 4.2.1. Gene Mutations ............................................... 4-21 4.2.2. Cytogenetic Effects ............................................ 4-22 4.2.2.1. Somatic Cells ......................................... 4-22 4.2.2.2. Germ Cells ........................................... 4-24 4.3. DISCUSSION ...................................................... 4-25 5. REPRODUCTIVE AND DEVELOPMENTAL EFFECTS ........................ 5-1 5.1. REPRODUCTIVE EFFECTS ........................................... 5-1 5.1.1. Carpenter et al. (1944) ........................................... 5-1 5.1.2. Owen et al. (1987); Owen and Glaister (1990) ........................ 5-1 5.1.3. NTP (1984) ................................................... 5-4 5.1.4. NTP (1993) ................................................... 5-4 iv CONTENTS (continued) 5.1.5. Bevan et al. (1996) ............................................. 5-10 5.1.6. Hackett et al. (1988a) ........................................... 5-10 5.1.7. Pacchierotti et al. (1998b) ....................................... 5-11 5.2. DEVELOPMENTAL EFFECTS ....................................... 5-11 5.2.1. IISRP (1982) ................................................. 5-11 5.2.2. Hackett et al. (1987a) ..........................................