An Updated Study of Mortality Among North American Synthetic Rubber Industry Workers

EPA Grant Number: R828112C132
Subproject: this is subproject number 132 , 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: An Updated Study of Mortality Among North American Synthetic Rubber Industry Workers
Investigators: Delzell, Elizabeth
Institution: The University of Alabama in Huntsville , 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 Quality and Air Toxics , Air


1,3-Butadiene (BD) is a volatile organic compound used in the production of synthetic rubber. Although industrial emissions contribute to its outdoor presence, mobile sources account for the majority of emissions in the United States and for much of human exposure. Outdoor levels are substantially lower than those found in occupational settings.

Concern about BD toxicity was first raised in the 1980s when animal studies showed an association between BD exposure and tumor development at many sites. Epidemiologic studies suggested an increased risk of cancers of the lymphatic and bloodforming systems (lymphohematopoietic cancers; LHCs) in BD-exposed workers and a higher risk of chronic leukemia in workers with long-term exposure in the styrene-butadiene rubber (SBR) industry. However, because of possible effects of concurrent exposure to other chemicals, it was difficult to identify which chemical or combination of chemicals was responsible for the observed effects.

International agencies that have evaluated cancer risk from BD exposure have classified BD variously as “probably carcinogenic to humans”; “toxic” and “highly likely to be carcinogenic in humans”; and a “known human carcinogen”.

Dr Elizabeth Delzell (University of Alabama) and her colleagues updated an earlier study in which they had investigated mortality among the largest occupational group exposed to BD: 18,000 men employed in SBR production between 1944 and 1991. In the current study, these workers were followed for an additional 6 years and the effects of exposure to other compounds were evaluated.

The study aimed to (1) determine if employment in the SBR industry, assessed by factors such as duration of employment or type of job, is associated with mortality from specific causes; and (2) evaluate if exposure to BD, or styrene, or dimethyldithiocarbamate (DMDTC; the agents of interest) is related to death from leukemia, other LHCs, or other selected cancers


The Investigators conducted research to extended an earlier retrospective study. They analyzed mortality among 18,000 men who had worked at least 1 year in any of eight SBR plants between 1944 and 1998, which added 18% more person-years of follow-up to the earlier study. It assessed cancer mortality, specifically from leukemia, non-Hodgkin lymphoma, and other LHCs.

Vital status was updated for all subjects who had been classified earlier as living or as lost to follow-up and was established for 97% of the cohort. Cause-of-death information was obtained for 98% of decedents.

Exposures were estimated using both qualitative and quantitative methods. Qualitative estimates used data obtained from work records and interviews, including such factors as duration of employment and job type. Quantitative estimates were derived using two methods: (1) analysis of sources of exposure associated with tasks in each job classification and during specific time periods; and (2) mathematical modeling to estimate workplace concentrations.

The models for BD exposure estimated several parameters. The estimates for each parameter contained considerable uncertainty about the true numeric values. A mean exposure estimate was calculated for each work area/job group. Cumulative exposure was computed for each worker by multiplying the estimated exposure in each of his work area/job groups by the number of days he worked in each, and by summing the resulting quantities over all of his jobs for his duration of employment. Neither the parameters used in this model nor the estimates that resulted from it were validated with actual measurements of workplace concentrations.

The investigators compared observed mortality rates for the workers with the mortality rates that would be expected for the general male population (external analyses). Ratios of observed-to-expected rates, known as standardized mortality ratios, were calculated by cause of death for all subjects combined and for subgroups defined by various employment factors. These analyses were carried out for specific forms of leukemia and other cancers. The investigators also compared mortality rates for subgroups of exposed workers with those for unexposed workers (internal analyses); in addition to the specified forms of leukemia and cancer, these analyses also included other causes of death.

Cumulative exposure estimates for BD, styrene, and DMDTC derived from mathematical models were used in regression analyses. Mortality relative rates for each of the agents of interest were estimated in models that included possible confounders; in some analyses, these included exposures to the other agents. (A mortality rate for one group is always reported relative to the rate in a comparison group.)

Expected Results:

External analyses for the entire study period found fewer deaths than expected from all causes combined and for all specific forms of cancer, except colorectal, prostate, and certain forms of LHCs, which all showed higher than the expected number of deaths. This may reflect the “healthy worker effect”, often seen in occupational cohorts that by definition include individuals who are healthier than the general population. For the LHCs, leukemia showed the highest ratio of observed-to-expected number of deaths; these were concentrated in hourly workers, in selected work-area subgroups, in workers with 20 to 29 years since hire, and in those with 10 or more years of employment.

Internal analyses revealed associations between mortality rates from leukemia and cumulative exposures to BD, styrene, and DMDTC. When analyses of the effects of one agent did not take into account exposure to the other agents, results suggested that each compound independently affected rates of death from leukemia. Furthermore, the relative rates generally increased as cumulative exposure increased: mortality rates from leukemia in the highest exposure categories increased by 170% to 270% compared with rates for the no-exposure category. When analyses did take into account exposure to the other agents, only BD and DMDTC retained their association with increased leukemia mortality.

Supplemental Keywords:

AIr toxics, Health Effects, 1,3-Butadiene, VOCs, epidemiology, carcinogenic, dimethyldithiocarbamate

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