Final Report: Benzene Metabolism in Rodents at Doses Relevant to Human Exposure from Urban Air

EPA Grant Number: R828112C113
Subproject: this is subproject number 113 , 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: Benzene Metabolism in Rodents at Doses Relevant to Human Exposure from Urban Air
Investigators: Turteltaub, Kenneth W
Institution: Lawrence Livermore National Laboratory
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: Health Effects , Air Quality and Air Toxics , Air


Human exposure to benzene is widespread because it is a component of gasoline and also is used extensively as an industrial solvent. Exposure to high levels of benzene is associated with development of leukemia and other blood disorders, but the risks of exposure to low levels of benzene are not well understood. In the 1990s, the Health Effects Institute (HEI) initiated a research program designed to study the effects of exposure to toxic air pollutants at ambient levels. As one part of this research program, HEI’s Request for Applications (RFA) 93-1 supported studies to develop reliable and sensitive assays for biomarkers of benzene exposure—both recent and longer-term—and of benzene effect. The biomarkers of recent exposure were urinary metabolites (measuring responses up to hours after exposure) and adducts of blood proteins (days to weeks after exposure). The biomarkers of longer-term exposure were chromosomal changes, integrating exposure over months to years. Because chromosomal changes may be determinants of subsequent health effects, they also may be considered early biomarkers of benzene effect. Chromosomal changes also may be due to causes other than exposure to benzene.

Summary/Accomplishments (Outputs/Outcomes):

Investigators, led by Dr. Kenneth Turteltaub, researched benzene metabolism in rodents over a hundred million–fold dose range. This range encompassed concentrations close to those of human ambient exposure, generally 1 to 10 parts per billion. Turteltaub and his colleague, Chitra Mani, administered radioactive benzene to mice and rats and subsequently analyzed bone marrow, liver, urine, and plasma from these animals. In most experiments, the investigators injected animals intraperitoneally with  14 C-labeled benzene, but in some experiments they exposed animals to radioactive benzene via inhalation. After exposure, the investigators coupled high-performance liquid chromatography (HPLC; to separate benzene metabolites) with the novel and sensitive technique accelerator mass spectrometry (to measure  14 C) in order to measure low levels of metabolites. Accelerator mass spectrometry was developed by nuclear physicists to measure low levels (10-15 to 10-18 molar) of long-lived isotopes such as 14C.


In this innovative study of benzene metabolism, Turteltaub and Mani detected dose-dependent formation of benzene metabolites in plasma, bone marrow, and liver of mice over a wide range of doses (5 ng/kg to 500 mg/kg). Benzene metabolites, including DNA and protein adducts, were detected at levels 100 times lower than had been found in previous studies.

Even at low benzene exposure concentrations, the investigators detected higher levels of benzene metabolites in mouse and rat bone marrow and liver than in plasma. This finding indicates that benzene reaches tissues and is metabolized there, even at levels close to those to which humans are exposed in ambient air. In addition, Turteltaub and Mani found that the levels of DNA and protein adducts detected in bone marrow and liver in different rodents generally correlated well with the ability of benzene to induce tumors in that species or strain. This result suggests that the formation of adducts may be an early marker of benzene carcinogenicity.

All doses of benzene produced a similar pattern of metabolites in mouse urine, suggesting that the pattern of benzene metabolism is similar at widely disparate concentrations. This finding is of interest because other studies have suggested that the pattern of benzene metabolites differs depending on the benzene concentration to which animals are exposed. Such differences in metabolism of benzene could affect the shape of the exposure-response curve. However, Turteltaub and Mani’s results are difficult to compare with previous studies. Although the current study has greater intrinsic analytic sensitivity than previous studies, it did not detect a metabolite previously found in the urine of rodents exposed to benzene.

Although results of the current study show the potential of accelerator mass spectrometry coupled with HPLC, they also illustrate the drawbacks. First, in the current study, urine from mice exposed to radioactive benzene contained a large peak of radioactivity that could not be identified by HPLC. The investigators did not look for this material in plasma or bone marrow; thus, the peak also might have been present in samples from these tissues, with an uncertain impact on the results. This unidentified radioactive material may be a contaminant of the radioactive material used in the assays, a previously unidentified metabolite, or the decomposition product of a known benzene metabolite.

Second, the technique requires administering radiolabeled benzene to the study animals. Although the method uses extremely low levels of radioactive benzene, such an approach is not broadly applicable for controlled exposure studies with humans because benzene is classified as a known human carcinogen. Third, this study indicates the potential influence on results of varying methods of biomarker collection, storage, and processing. In the current study, glucuronidase inhibitors were not added to urine samples, which possibly resulted in the degradation of a major metabolite, hydroquinone glucuronide, that was detected in other studies of benzene metabolism.

Even given these challenges, Turteltaub and Mani provided important information about benzene metabolism at the lowest end (5–500 ng/kg body weight) of the range of benzene doses tested: the dose-response curve for metabolite formation was flatter than that of higher benzene doses but was above zero. This result indicates that metabolism of benzene to activated metabolites occurs even at very low doses. It further suggests, but does not show conclusively, that the dose-response curve for benzene in mice lacks an obvious threshold at the lowest exposure levels evaluated. This finding may have important ramifications for understanding the human response to low-level benzene exposures. Further studies are required to resolve the shape of the dose-response curve for humans at these low benzene levels.


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Type Citation Sub Project Document Sources
Journal Article Creek MR, Mani C, Vogel JS, Turteltaub KW. Tissue distribution and macromolecular binding of extremely low doses of [14C]-benzene in B6C3F1 mice. Carcinogenesis 1997;18(12):2421-2427. R828112C113 (Final)
  • Abstract from PubMed
  • Full-text: Oxford Journals-PDF
  • Abstract: Oxford Journals-Abstract
  • Journal Article Mani C, Freeman S, Nelson DO, Vogel JS, Turteltaub KW. Species and strain comparisons in the macromolecular binding of extremely low doses of [14C]benzene in rodents, using accelerator mass spectrometry. Toxicology and Applied Pharmacology 1999;159(2):83-90. R828112C113 (Final)
  • Abstract from PubMed
  • Abstract: ScienceDirect-Abstract
  • Supplemental Keywords:

    particulate matter, air toxics, epidemiology, health effects, ambient air quality, ozone, particulate matter, exposure and effects, ambient air quality, immune response, inhalation toxicology, aerosol particles, human health risk, air pollutants, particulates, respiratory, neurotoxic, exposure, human health, neurotoxicity

    Relevant Websites: Exit

    Progress and Final Reports:

    Original Abstract
  • 2000
  • 2001
  • 2002
  • 2003

  • 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