Grantee Research Project Results
Final Report: Biological Markers of Exposure to Benzene
EPA Grant Number: R826249Title: Biological Markers of Exposure to Benzene
Investigators:
Institution: Lovelace Biomedical & Environmental Research Institute
EPA Project Officer: Chung, Serena
Project Period: March 20, 1998 through March 19, 2001
Project Amount: $471,696
RFA: Ambient Air Quality (1997) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Air
Objective:
The objective of this research project was to develop a panel of biological markers of exposure to benzene that can be used to relate the level of markers in the body in a quantitative manner to both recent and earlier exposures. The hypothesis is that by using a battery of benzene-specific biomarkers of varying half-lives in the body, one can more readily describe the type of exposure to benzene that has occurred in the past than with a single biomarker. For example, one should be able to distinguish between a person who has had a continuous, low-level exposure to benzene (as in someone exposed to environmental tobacco smoke) from someone who has had a single, high-level exposure to benzene (such as an exposure from a hobby project). In the former case, one would expect to find a buildup of longer, half-life markers and only a low level of shorter, half-life markers, while in the latter case, one would detect high levels of shorter half-life markers and very little of the longer, half-life markers. An empirically based mathematical model was used to relate the current levels of biomarkers of varying half-lives to prior exposures to benzene. A variety of exposure regimens were conducted in mice to determine if the markers can distinguish between the different regimens. Lastly, if time permits, limited studies in petroleum workers will explore the usefulness of the battery of markers in assessing exposures in an occupational setting.
Summary/Accomplishments (Outputs/Outcomes):
We chose to use benzene as a model compound to test the hypothesis that a battery of biomarkers of differing half-lives would be useful in describing prior chemical exposures. The following benzene-specific markers of exposure were chosen: urinary phenyl mercapturic acid and t,t-muconic acid (relatively short half-lives) in addition to blood S-phenylcysteine adducts on albumin and hemoglobin (relatively long half-lives). Sensitive assays were developed for all of the metabolites.
A study to determine the half-lives of the four biomarkers was completed in male B6C3F1 mice exposed to 20, 200, or 600 ppm benzene for 4 hours. The half-lives determined in the study were used to develop an empirical mathematical model to be used to predict prior exposure based on multiple biomarkers of varying half-lives. The logic of the model is that equations describing the concentration-time relationships for multiple markers can be used to solve for the concentration and the time since exposure to benzene. A generalized negative exponential function has been fit to the data. The results suggest that the proposed empirical model will be capable of distinguishing between different time-concentration patterns of benzene exposure. Furthermore, because of the empirical basis of the underlying model structure, it may easily be extended to model different compounds.
A "mystery" exposure of mice to different levels of benzene was completed, and blood and urine samples were analyzed for the biomarkers of interest. These data were given blind (as to benzene exposure level and time since exposure) to Dr. Ménache, who developed the model. The model predicted the time since exposure well; however, the concentration of the exposures was off by four- to five-fold. Analysis of the data indicated that the standard curves for the biomarker analytes differed substantially from those used in the analyses to set up the model.
Conclusions:
A battery of biomarkers of differing half-lives appears to be useful in defining prior exposures to a chemical. In this study, the chemical analytical assays for the biomarkers varied greatly between the assays performed to develop the model and the assays performed in the mystery (blind) exposure. This caused the model to under-predict the exposure concentration; however, the model correctly predicted the time since exposure. Future studies should include development of more robust assays for the metabolites. It also would be best to develop a physiologically based pharmacokinetic model for the biomarkers to be able to extrapolate from the mouse model to the human conditions.
Journal Articles:
No journal articles submitted with this report: View all 7 publications for this projectSupplemental Keywords:
ambient air, exposure, toxics, mathematics, measurement methods, petroleum, benzene, toxicokinetics., Scientific Discipline, Health, Air, Toxics, air toxics, Environmental Chemistry, Health Risk Assessment, HAPS, Epidemiology, Risk Assessments, Biochemistry, Atmospheric Sciences, risk assessment, ambient air quality, monitoring, blood samples, animal model, air sampling, ambient monitoring, benzene, inhalation, human exposure, urine and blood samples, biocontaminants, half-life markers, biological markers, human health, Volatile Organic Compounds (VOCs), Benzene (including benzene from gasoline)Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.