Cancer, Mutations, and Adducts in Rats and Mice Exposed to Butadiene and Its Metabolites

EPA Grant Number: R828112C092
Subproject: this is subproject number 092 , established and managed by the Center Director under grant R828112
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Health Effects Institute (2000 — 2005)
Center Director: Greenbaum, Daniel S.
Title: Cancer, Mutations, and Adducts in Rats and Mice Exposed to Butadiene and Its Metabolites
Investigators: Henderson, Rogene F. , Blair, Ian A. , Swenberg, James A. , Recio, Leslie , Walker, Vernon
Institution: Lovelace Biomedical & Environmental Research Institute , The Hamner Institutes , New York State Department of Health , University of North Carolina at Chapel Hill , University of Pennsylvania
Current Institution: Lovelace Biomedical & Environmental Research Institute , New York State Department of Health , The Hamner Institutes , University of North Carolina at Chapel Hill , University of Pennsylvania
EPA Project Officer: Chung, Serena
Project Period: April 1, 2000 through March 31, 2005
RFA: Health Effects Institute (1996) RFA Text |  Recipients Lists
Research Category: Human Health , Air


1,3-Butadiene (BD) is an occupational and environmental pollutant that is widely used in the manufacture of resins, plastics, and synthetic rubber; it is also found in combustion emissions from motor vehicles, stationary sources, and cigarette smoke. Ambient exposures to BD (0.3 to 10 parts per billion [ppb]) are orders of magnitude lower than those that occur in occupational settings (10 to 300,000 ppb), but they are a public health concern because BD may be a human carcinogen. In the Clean Air Act Amendments of 1990, BD is listed as a hazardous air pollutant and a mobile-source toxic air pollutant. Moreover, worldwide regulatory interest has evolved in the potential health effects of occupational and ambient exposures to BD. Epidemiologic studies have suggested that workers occupationally exposed to BD have an increased incidence of cancers of the lymphatic system and of those organs and systems in the body that produce blood cells. Interpretation of these studies has been controversial, however, because of inconsistencies among the results and because some workers may have been exposed to other chemicals in addition to BD. In situations of such uncertainty, data from animal studies are often used to fill information gaps about humans by extrapolating findings from laboratory studies in which animals have been exposed to high doses of a chemical to situations in which human subjects have been exposed to low doses. Consequently, researchers have produced a large range of human cancer risk estimates for BD depending on which animal species and which data they used in their extrapolation models.

One question is: Which species is the best model to use for assessing the human risk of cancer from exposure to BD? Butadiene is known to cause tumors in many organs in rats and mice. These two species differ markedly, however, in their carcinogenic response to BD in that mice have been found to be about 100 times more sensitive than rats to BD exposure. Some evidence indicates this difference may relate to how rats and mice metabolize BD and convert it either to reactive (and possibly carcinogenic) intermediates or to inactive forms that are excreted from the body. Whether humans metabolize BD more like mice or more like rats is uncertain, as is where the human response to BD exposure fits in the range of rodent sensitivity to BD's cancer-causing effects.

The Health Effects Institute's air toxics research program to reduce uncertainties in estimating the human health risks associated with exposure to BD includes (1) studies of the reactivity of BD and its metabolites in animals and people and (2) the development of methods to measure biomarkers (indicators of exposure or of early biological effects of exposure) to use in cross-species studies and in studies of human populations. Five independent studies from the initial phase of HEI's BD research program are summarized in this Statement and are presented in detail in this Research Report.


When HEI's program was initiated, scientists knew that BD itself is not carcinogenic. Rather, BD is transformed to reactive metabolites that can bind to DNA (forming adducts), thus causing genetic mutations and possibly initiating the carcinogenic response. The role of individual metabolites in BD-induced carcinogenesis, however, was not known. Furthermore, the metabolites exist in more than one stereochemical (or three-dimensional) form. Because enzymes may react preferentially with a specific form, these stereochemical configurations may be important in species sensitivity. Some of the products from BD reacting with cellular DNA or proteins had been identified and considered for use as biomarkers of exposure or of a biologically effective dose. However, sensitive analytical methods needed to be developed and validated if these biomarkers were to be useful in animal or human studies.

The studies reported here were designed to advance our understanding of the roles of different metabolites in BD-induced carcinogenesis and of the differences in sensitivity among species, and to develop methods for identifying and measuring biomarkers. The investigators focused on two BD metabolites (1,2-epoxy-3-butene [BDO] and 1,2,3,4-diepoxybutane [BDO 2 ]) that researchers had suspected may play a role in BD carcinogenesis; they also developed information on other metabolites that may be important but had not been extensively studied. Dr. Rogene Henderson (Lovelace Respiratory Research Institute) exposed mice and rats to BDO 2 to determine whether these species differ in their carcinogenic response to this metabolite. Dr. Leslie Recio (Chemical Industry Institute of Toxicology) and Dr. Vernon Walker (New York State Department of Health) compared the mutagenicity of BD, BDO, and BDO 2 in mice and rats. Dr. Ian Blair (University of Pennsylvania) developed methods for measuring DNA adducts derived from BD metabolites in the tissues and urine of rats and mice with the goal of comparing the levels of adducts in the two species and identifying possible biomarkers. Dr. James Swenberg (University of North Carolina at Chapel Hill) developed a sensitive method for detecting adducts formed between BD metabolites and a blood protein (hemoglobin) and measured these adducts in animals and humans exposed to BD. The investigators shared tissues from animals that were exposed by inhalation to BD or its metabolites at either the Chemical Industry Institute of Toxicology or Lovelace Respiratory Research Institute and, in some cases, developed collaborative ventures.

Supplemental Keywords:

Air, ambient air quality, air toxics, epidemiology, health effects, particulate matter, human health risk assessment, genetics, occupational exposure, indoor air quality, butadiene, disease, animal studies, biomarkers., RFA, Health, Scientific Discipline, Air, particulate matter, Toxicology, air toxics, Genetics, Environmental Chemistry, Health Risk Assessment, Risk Assessments, mobile sources, Biochemistry, cancer risk, ambient air quality, lung injury, particulates, motor vehicles, air pollutants, biomarkers, human health effects, inhalability, lung, exposure and effects, mutations, cell biology, engines, epithelial cells, animal model, air pollution, automobiles, diesel exhaust, emissions, lung cancer, environmental health effects, carcinogens, human exposure, inhalation, particulate exposure, ambient particle health effects, butadiene, environmental toxicants, inhaled, PM, inhalation toxicology, carcinogen exposure, cancer risk assessment, human health, mutation

Progress and Final Reports:

  • 2000
  • 2001
  • 2002
  • 2003
  • Final Report

  • Main Center Abstract and Reports:

    R828112    Health Effects Institute (2000 — 2005)

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R828112C042 Does Inhalation of Methanol Vapor Affect Human Neurobehavior?
    R828112C043 Human Responses to Nitrogen Dioxide
    R828112C044 The Role of Inflammation in Ozone-Induced Lung Injury
    R828112C045 How Does Exercise Affect the Dose of Inhaled Air Pollutants?
    R828112C046 How Do Chemicals in Diesel Engine Exhaust Damage DNA?
    R828112C047 Effect of Nitrogen Dioxide on Bacterial Respiratory infection in Mice
    R828112C048 Effects of Ozone Exposure on Airway Epithelium
    R828112C049 Inhalation of Aldehydes and Effects on Breathing
    R828112C050 Does Ozone Cause Precancerous Changes in Cells?
    R828112C051 Effects of Formaldehyde on Human Airway Epithelial Cells Exposed in a Novel Culture System
    R828112C052 Carbon Monoxide and Cardiac Arrhythmias
    R828112C053 Effects of Formaldehyde and Particle-Bound Formaldehyde on Lung Macrophage Functions
    R828112C054 Mechanisms for Protecting Lung Epithelial Cells Against Oxidant Injury
    R828112C055 Relationship of Nitropyrene-Derived DNA Adducts to Carcinogenesis
    R828112C056 Particle Trap Effects on Heavy-Duty Diesel Engine Emissions
    R828112C057 Carbon Monoxide and Atherosclerosis
    R828112C058 Nitrogen Dioxide and Respiratory Illness in Children
    R828112C059 Noninvasive Methods for Measuring Ventilation in Mobile Subjects
    R828112C060 Oxidant Air Pollutants and Lung Cancer: An Animal Model
    R828112C061 Detection of Carcinogen-DNA Adducts: Development of New Methods
    R828112C062 Effects of Carbon Monoxide on Heart Muscle Cells
    R828112C063 Development of Personal Ozone Samplers: Three Approaches
    R828112C064 Development of Biomarkers to Monitor Carcinogen Exposure
    R828112C065 Effects of Prolonged Ozone Inhalation on Collagen Structure and Content in Rat Lungs
    R828112C065II Prolonged Ozone Exposure and the Contractile Properties of Isolated Rat Airways
    R828112C065III Changes in Complex Carbohydrate Content and Structure in Rat Lungs Caused by Prolonged Ozone Inhalation
    R828112C065IV Genetic Control of Connective Tissue Protein Synthesis After Prolonged Ozone Inhalation
    R828112C065V Pulmonary Function Alterations in Rats After Chronic Ozone Inhalation
    R828112C065VII Prolonged Ozone Exposure Leads to Functional and Structural Changes in the Rat Nose
    R828112C065VIII - IX Studies of Changes in Lung Structure and Enzyme Activitiesin Rats After Prolonged Exposure to Ozone
    R828112C065X An Innovative Approach to Analyzing Multiple Experimental Outcomes: A Case Study of Rats Exposed to Ozone
    R828112C065XI The Consequences of Prolonged Inhalation of Ozone on Rats: An Integrative Summary of the Results of Eight Collaborative Studies
    R828112C066 Interactive Effects of Nitropyrenes in Diesel Exhaust
    R828112C067 Detection of Formaldehyde–DNA Adducts: Development of New Methods
    R828112C068I Comparison of the Carcinogenicity of Diesel Exhaust and Carbon Black in Rat Lungs
    R828112C068II An Investigation of DNA Damage in the Lungs of Rats Exposed to Diesel Exhaust
    R828112C068III No Evidence For Genetic Mutations Found In Lung Tumors From Rats Exposed To Diesel Exhaust or Carbon Black
    R828112C069 Noninvasive Determination of Respiratory Ozone Absorption: The Bolus-Response Method
    R828112C070 The Effects of Inhaled Oxidants and Acid Aerosols on Pulmonary Function
    R828112C071 Biochemical Consequences of Ozone Reacting with Membrane Fatty Acids
    R828112C072 DNA Mutations in Rats Treated with a Carcinogen Present in Diesel Exhaust
    R828112C073 Developmental Neurotoxicity of Inhaled Methanol in Rats
    R828112C074 Methanol Distribution in Non Pregnant and Pregnant Rodents
    R828112C075 Is Increased Mortality Associated with Ozone Exposure in Mexico City?
    R828112C076 Effects of Fuel Modification and Emission Control Devices on Heavy-Duty Diesel Engine Emissions
    R828112C077 Metabolic Studies in Monkeys Exposed to Methanol Vapors
    R828112C078 Effects of Ozone on Pulmonary Function and Airway Inflammation in Normal and Potentially Sensitive Human Subjects
    R828112C079 Improvement of a Respiratory Ozone Analyzer
    R828112C080 Mechanism of Oxidative Stress from Low Levels of Carbon Monoxide
    R828112C081 Long-Term Exposure to Ozone: Development of Methods to Estimate Past Exposures and Health Outcomes
    R828112C082 Effects of Ambient Ozone on Healthy, Wheezy, and Asthmatic Children
    R828112C083 Daily Changes in Oxygen Saturation and Pulse Rate Associated with Particulate Air Pollution and Barometric Pressure
    R828112C084 Evaluation of The Potential Health Effects of the Atmospheric Reaction Products of Polycyclic Aromatic Hydrocarbons
    R828112C085 Mechanisms of Response to Ozone Exposure: The Role of Mast Cells in Mice
    R828112C086 Statistical Methods for Epidemiologic Studies of the Health Effects of Air Pollution
    R828112C087 Development of New Methods to Measure Benzene Biomarkers
    R828112C088 Alveolar Changes in Rat Lungs After Long-Term Exposure to Nitric Oxide
    R828112C089 Effects of Prenatal Exposure to Inhaled Methanol on Nonhuman Primates and Their Infant Offspring
    R828112C090 A Pilot Study of Potential Biomarkers of Ozone Exposure
    R828112C091 Effects of Concentrated Ambient Particles on the Cardiac and Pulmonary Systems of Dogs
    R828112C092 Cancer, Mutations, and Adducts in Rats and Mice Exposed to Butadiene and Its Metabolites
    R828112C093 Effects of Concentrated Ambient Particles in Rats and Hamsters: An Exploratory Study
    R828112C094I The National Morbidity, Mortality, and Air Pollution Study: Methods and Methodologic Issues
    R828112C094II The National Morbidity, Mortality, and Air Pollution Study: Morbidity and Mortality from Air Pollution in the United States
    R828112C095 Association of Particulate Matter Components with Daily Mortality and Morbidity in Urban Populations
    R828112C096 Acute Pulmonary Effects of Ultrafine Particles in Rats and Mice
    R828112C097 Identifying Subgroups of the General Population That May Be Susceptible to Short-Term Increases in Particulate Air Pollution
    R828112C098 Daily Mortality and Fine and Ultrafine Particles in Erfurt, Germany
    R828112C099 A Case-Crossover Analysis of Fine Particulate Matter Air Pollution and Out-of-Hospital Sudden Cardiac Arrest
    R828112C100 Effects of Mexico City Air on Rat Nose
    R828112C101 Penetration of Lung Lining and Clearance of Particles Containing Benzo[a]pyrene
    R828112C102 Metabolism of Ether Oxygenates Added to Gasoline
    R828112C103 Characterization and Mechanisms of Chromosomal Alterations Induced by Benzene in Mice and Humans
    R828112C104 Acute Cardiovascular Effects in Rats from Exposure to Urban Ambient Particles
    R828112C105 Genetic Differences in Induction of Acute Lung Injury and Inflammation in Mice
    R828112C106 Effects on Mice of Exposure to Ozone and Ambient Particle Pollution
    R828112C107 Emissions from Diesel and Gasoline Engines Measured in Highway Tunnels
    R828112C108 Case-Cohort Study of Styrene Exposure and Ischemic Heart Disease Investigators
    R828112C110 Effects of Metals Bound to Particulate Matter on Human Lung Epithelial Cells
    R828112C111 Effect of Concentrated Ambient Particulate Matter on Blood Coagulation Parameters in Rats
    R828112C112 Health Effects of Acute Exposure to Air Pollution
    R828112C113 Benzene Metabolism in Rodents at Doses Relevant to Human Exposure from Urban Air
    R828112C114 A Personal Particle Speciation Sampler
    R828112C115 Validation and Evaluation of Biomarkers in Workers Exposed to Benzene in China
    R828112C116 Biomarkers in Czech Workers Exposed to 1,3-Butadiene: A Transitional Epidemiologic Study
    R828112C117 Peroxides and Macrophages in the Toxicity of Fine Particulate Matter in Rats
    R828112C118 Controlled Exposures of Healthy and Asthmatic Volunteers to Concentrated Ambient Particles in Metropolitan Los Angeles
    R828112C119 Manganese Toxicokinetics at the Blood-Brain Barrier
    R828112C120 Effects of Exposure to Concentrated Ambient Particles from Detroit Air on Healthy Rats and Rats with Features of Asthma or Mild Bronchitis
    R828112C121 Field Evaluation of Nanofilm Detectors for Measuring Acidic Particles in Indoor and Outdoor Air
    R828112C123 Time-Series Analysis of Air Pollution and Mortality: A Statistical Review
    R828112C126 Effects of Exposure to Ultrafine Carbon Particles in Healthy Subjects and Subjects with Asthma
    R828112C128 Neurogenic Responses of Rat Lung to Diesel Exhaust
    R828112C130-I Relationships of Indoor, Outdoor, and Personal Air (RIOPA). Part I. Collection Methods and Descriptive Analyses
    R828112C132 An Updated Study of Mortality Among North American Synthetic Rubber Industry Workers