1,3-Butadiene: Cancer, Mutations, and Adducts Part I: Carcinogenicity of 1,2,3,4-Diepoxybutane 955 Massachusetts Avenue Number 92 Cambridge MA 02139 USA Rogene F
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RESEARCH REPORT 1,3-Butadiene: Cancer, Mutations, and Adducts Part I: Carcinogenicity of 1,2,3,4-Diepoxybutane 955 Massachusetts Avenue Number 92 Cambridge MA 02139 USA Rogene F. Henderson et al March 2000 +1-617-876-6700 Part II: Roles of Two Metabolites of 1,3-Butadiene www.healtheffects.org in Mediating Its in Vivo Genotoxicity RESEARCH Leslie Recio et al REPORT Part III: In Vivo Mutation of the Endogenous hprt Genes of Mice and Rats by 1,3-Butadiene Number 92 March 2000 and Its Metabolites Vernon E. Walker and Quanxin Meng Part IV: Molecular Dosimetry of 1,3-Butadiene Ian A. Blair et al Part V: Hemoglobin Adducts as Biomarkers of 1,3-Butadiene Exposure and Metabolism James A. Swenberg et al Includes Commentaries by the Institute’s Health Review Committee BOARD OF DIRECTORS Archibald Cox Chair Alice Huang Carl M Loeb University Professor (Emeritus), Harvard Law School Senior Councilor for External Relations, California Institute of Technology Donald Kennedy Vice Chair Susan B King The Health Effects Institute, established HEALTH Editor-in-Chief, Science; President (Emeritus) and Bing Professor of Fellow, Sanford Institute of Public Policy, Duke University EFFECTS in 1980, is an independent and unbiased Biological Sciences, Stanford University Richard B Stewart INSTITUTE source of information on the health Douglas Costle Professor, New York University School of Law effects of motor vehicle emissions. HEI Chairman of the Board and Distinguished Senior Fellow, Institute Robert M White for Sustainable Communities President (Emeritus), National Academy of Engineering, and Senior studies all major pollutants, including Fellow, University Corporation for Atmospheric Research regulated pollutants (such as carbon HEALTH RESEARCH COMMITTEE monoxide, ozone, nitrogen dioxide, and Bernard D Goldstein Chair Jonathan M Samet particulate matter) and unregulated Director, Environmental and Occupational Health Sciences Institute Professor and Chairman, Department of Epidemiology, School of pollutants (such as diesel engine exhaust, Glen R Cass Hygiene and Public Health, Johns Hopkins University Professor and Chairman, School of Earth and Atmospheric Sciences, methanol, and aldehydes). To date, HEI Robert F Sawyer Georgia Institute of Technology Class of 1935 Professor of Energy (Emeritus), Professor of the Graduate has supported more than 200 projects at Seymour J Garte School, University of California, Berkeley institutions in North America and Europe Professor of Environmental and Community Medicine, Environmental Frank E Speizer and Occupational Health Sciences Institute and has published over 100 research Edward H Kass Professor of Medicine, Channing Laboratory, Harvard Rogene Henderson Medical School, Department of Medicine, Brigham and Women’s Hospital reports. Senior Scientist, Lovelace Respiratory Research Institute Gerald van Belle Typically, HEI receives half its funds Stephen I Rennard Professor, Departments of Environmental Health and Statistics, from the US Environmental Protection Larson Professor, Pulmonary and Critical Care Medicine Section, University of Washington Department of Internal Medicine, University of Nebraska Medical Agency and half from 28 manufacturers Center and marketers of motor vehicles and HEALTH REVIEW COMMITTEE engines in the US. 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The Institute’s Health Research and University School of Medicine Health Review Committees serve complementary scientific purposes and OFFICERS & STAFF draw distinguished scientists as Daniel S Greenbaum President Gail V Allosso Office and Contracts Manager Richard M Cooper Corporate Secretary Thomas Atwood Manager of Publications and Information members. The results of HEI-funded Howard E Garsh Director of Finance and Administration Julia F Campeti Scientific Copy Editor studies are made available as Research Robert M O’Keefe Vice President John R DeRosa Desktop Publishing Specialist Jane Warren Director of Science Reports, which contain both the Sally Edwards Managing Editor Aaron J Cohen Senior Scientist Terésa Fasulo Senior Administrative Assistant Maria G Costantini Senior Scientist Investigators’ Report and the Review L Virgi Hepner Senior Scientific Editor Alison Geyh Staff Scientist Committee’s evaluation of the work’s Darlene Jones Senior Administrative Assistant Bernard Jacobson Staff Scientist Judith Lopez Receptionist scientific quality and regulatory Debra A Kaden Senior Scientist Francine Marmenout Senior Executive Assistant relevance. Diane J Mundt Staff Scientist Martha E Richmond Staff Scientist Teresina McGuire Accounting Assistant Geoffrey H Sunshine Staff Scientist Beverly Morse Administrative Assistant JoAnn Ten Brinke Staff Scientist Jacqueline C Rutledge Controller Annemoon van Erp Staff Scientist STATEMENT Synopsis of Research Report 92 Cancer, Mutations, and Adducts in Rats and Mice Exposed to Butadiene and Its Metabolites BACKGROUND indicates this difference may relate to how rats and 1,3-Butadiene (BD) is an occupational and environ- mice metabolize BD and convert it either to reactive mental pollutant that is widely used in the manufac- (and possibly carcinogenic) intermediates or to inac- ture of resins, plastics, and synthetic rubber; it is also tive forms that are excreted from the body. Whether found in combustion emissions from motor vehicles, humans metabolize BD more like mice or more like stationary sources, and cigarette smoke. Ambient rats is uncertain, as is where the human response to exposures to BD (0.3 to 10 parts per billion [ppb]) are BD exposure fits in the range of rodent sensitivity to orders of magnitude lower than those that occur in BD’s cancer-causing effects. occupational settings (10 to 300,000 ppb), but they are a public health concern because BD may be a human The Health Effects Institute’s air toxics research pro- carcinogen. In the Clean Air Act Amendments of 1990, gram to reduce uncertainties in estimating the human BD is listed as a hazardous air pollutant and a mobile- health risks associated with exposure to BD includes source toxic air pollutant. Moreover, worldwide regula- (1) studies of the reactivity of BD and its metabolites in tory interest has evolved in the potential health effects animals and people and (2) the development of of occupational and ambient exposures to BD. methods to measure biomarkers (indicators of expo- sure or of early biological effects of exposure) to use in Epidemiologic studies have suggested that workers cross-species studies and in studies of human popula- occupationally exposed to BD have an increased inci- tions. Five independent studies from the initial phase dence of cancers of the lymphatic system and of those of HEI’s BD research program are summarized in this organs and systems in the body that produce blood Statement and are presented in detail in this Research cells. Interpretation of these studies has been contro- Report. versial, however, because of inconsistencies among the results and because some workers may have been APPROACH exposed to other chemicals in addition to BD. In situa- When HEI’s program was initiated, scientists knew that tions of such uncertainty, data from animal studies are BD itself is not carcinogenic. Rather, BD is transformed often used to fill information gaps about humans by to reactive metabolites that can bind to DNA (forming extrapolating findings from laboratory studies in adducts), thus causing genetic mutations and possibly which animals have been exposed to high doses of a initiating the carcinogenic response. The role of indi- chemical to situations in which human subjects have vidual metabolites in BD-induced carcinogenesis, been exposed to low doses. Consequently, researchers however, was not known. Furthermore, the metabo- have produced a large range of human cancer risk esti- lites exist in more than one stereochemical (or three- mates for BD depending on which animal species and dimensional) form. Because enzymes may react pref- which data they used in their extrapolation models. erentially with a specific form, these stereochemical One question is: Which species is the best model to use configurations may be important in species sensitivity. for assessing the human risk of cancer from exposure Some of the products from BD reacting with cellular to BD? Butadiene is known to cause