Biomarkers in Czech Workers Exposed to 1,3-Butadiene: A Transitional Epidemiologic Study

EPA Grant Number: R828112C116
Subproject: this is subproject number 116 , 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: Biomarkers in Czech Workers Exposed to 1,3-Butadiene: A Transitional Epidemiologic Study
Investigators: Albertini, Richard J
Institution: University of Vermont , Health Effects Institute
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


Butadiene is a four-carbon gaseous chemical synthesized for the manufacture of resins, plastics, and synthetic rubber. It is also produced by combustion; butadiene is present in cigarette smoke and emissions from motor vehicles and some stationary sources. The highest exposures, those that occur in occupational settings, may present a health concern because butadiene is known to be carcinogenic in rats and mice and some epidemiologic studies have implicated it as a human carcinogen by inhalation. Those studies have indicated that workers exposed to butadiene in rubber-producing factories also have an increased incidence of two types of cancer: cancers of the lymphatic system and cancers of the organs and systems of the body that produce blood cells. More recent and comprehensive studies of the same workers have indicated an increased risk of leukemia (but not other types of cancers) in workers with a long duration of employment in the rubber industry. On the basis of these epidemiologic studies, various government and international agencies have conducted risk assessments of butadiene’s carcinogenicity and designated it as “potentially carcinogenic to humans,” “a probable human carcinogen,” and a “known human carcinogen.” 

Epidemiologic studies have encountered two primary difficulties in assessing exposure to carcinogenic agents. First, because the incidence of certain cancers is low, they have needed to study large populations to find an association between exposure and disease. Second, it is often difficult to accurately assess the level or time course of exposure to a possible cancer-causing agent in order to link past exposures to recent disease occurrences. In contrast with this, populations known to have been exposed to certain chemicals (such as groups of workers in a specific industry) show relatively high levels of biomarkers. Therefore, if biomarkers can accurately reflect the level or timing of exposure to a suspected carcinogen, they may be able to enhance exposure assessment in epidemiologic studies. 

Dr Richard Albertini at the University of Vermont in Burlington organized groups of researchers from his own laboratory and laboratories in Galveston, Texas; Chapel Hill, North Carolina; Prague, Czech Republic; Amsterdam and Leiden, The Netherlands; and Sheffield, United Kingdom. Each group had expertise in identifying different biomarkers that appear after butadiene exposure. Dr Radim Šrám of the Laboratory of Genetic Ecotoxicology in Prague provided contact with butadiene-exposed workers in two production units of a factory near Prague.


The researchers proposed to determine whether biomarkers in the blood and urine of the exposed workers correlated with their personal exposure to butadiene. Šrám and coworkers in Prague collected blood and urine from male workers employed either in the butadiene monomer production plant or in the polymerization facility that used butadiene and styrene to produce rubber polymer. They also collected blood and urine from male administrative workers at the plant who had no direct occupational exposure to butadiene and served as control subjects. Each worker’s personal exposure to butadiene in air was measured using a small air sampler attached to his clothes. Samplers were worn on several occasions over a 60-day period preceding and during the three days on which blood or urine samples were acquired. The air samplers were sent to a laboratory in Sheffield where butadiene levels were analyzed. For biomarker analyses, the Prague researchers sent portions of each blood and urine sample to the other research groups and kept a portion for their own use. 

The study was conducted in a blinded fashion. Subject identities were known only to Albertini and the biostatistician for the study in Burlington, where codes were maintained, data were analyzed, and then matched to the three exposure groups. 

The investigators focused their investigation on two types of biomarkers. The first type comprised biomarkers of exposure that were chosen specifically to indicate the level of butadiene in the body that resulted from an exposure. The researchers in Amsterdam and Chapel Hill determined the concentrations of two adducts that form when butadiene metabolites bind to hemoglobin in red blood cells. The Amsterdam researchers also measured levels of other exposure related biomarkers, two metabolites that are excreted in urine when butadiene is detoxified in the body. 

The second type of biomarker comprised biomarkers of effect, including gene mutations and structural changes in chromosomes. The researchers in Leiden and Galveston analyzed mutations in the HPRT gene by different methods and the Prague researchers determined the types and degrees of chromosomal changes. In addition, the Prague and Burlington groups looked at factors that may affect susceptibility to carcinogens, such as changes in the genes that code for enzymes that metabolize butadiene. Such differences can modify an enzyme’s activity and may affect an individual’s response to possible butadiene-induced effects.

Expected Results:

All the biomarkers of exposure were correlated with the measurements of butadiene recorded by the air samplers. Although the correlation between hemoglobin adducts and exposure levels was strongest, urinary metabolites were also found to be very useful measures of butadiene exposure. 

No statistically significant correlations were found between any of the biomarkers of effect and butadiene exposure. Although these biomarkers were investigated, they were evaluated against exposure, not against health outcomes. Thus, no conclusions about health outcomes can be drawn from these results. 

This very important and valuable study established the linkage between exposure to butadiene, as measured by comprehensive conventional sampling techniques, and several biological markers of such exposures. The integration of a comprehensive exposure assessment with a series of logical biomarker analyses was an outstanding feature of this complex international study. Of the many biomarkers analyzed, the biomarkers of exposure (particularly hemoglobin adducts) may prove to be valuable in future epidemiologic studies of the health effects of butadiene exposure.

Supplemental Keywords:

Health Effects, Air Toxics, butadiene, biomarkers, epidemiology, workplace exposure, carcinogenic agents

Relevant Websites: Exit

Progress and Final Reports:

  • 2000
  • 2001
  • 2002
  • 2003
  • Final

  • 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