Butadiene (BD) is a gaseous compound used in the manufacture of synthetic rubber and is an environmental contaminant derived from auto exhaust and tobacco smoke. It is a potent rodent carcinogen and probable human carcinogen. At current levels of occupational exposure it will be very difficult to determine the cancer risks related to workplace BD exposure. The broad objective of this project has been to characterize human sensitivity to BD by using biological markers of exposure, markers of the effects of exposure, and markers of susceptibility to exposure in BD-exposed workers. In the previous project period we found that BD exposure is associated with an increase in the concentration of a butadiene-related metabolite in urine, and a dose-related increase in hprt mutation in lymphocytes with an. increased proportion of deletion and frameshift mutations. Also, the frequency of mutations was increased in BD-exposed individuals with a combination of polymorphisms resulting in low activity of microsomal epoxide hydrolase (mEH).
The aims of the current proposal are to 1) delineate the influence of microsomal epoxide hydrolase polymorphisms on mutant frequency and on the spectrum of different types of mutations in the HPRT gene in individuals occupationally exposed to BD, 2) characterize, in vitro, the functional significance of mEH polymorphisms in butadiene diepoxide- induced genetic damage, and 3) characterize how the stability of the different allelic forms of mEH proteins contributes to the cellular level of mEH activity. Through these aims we expect to better understand how genetic variation in mEH influences human sensitivity to the genotoxic effects of BD, and better understand the role of variants in biotransformation genes in modifying human susceptibility to toxic chemicals

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES006015-06A1
Application #
6543955
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Packenham, Joan P
Project Start
1993-08-01
Project End
2006-07-31
Budget Start
2002-09-06
Budget End
2003-07-31
Support Year
6
Fiscal Year
2002
Total Cost
$357,253
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Abdel-Rahman, S Z; Ammenheuser, M M; Ward Jr, J B (2001) Human sensitivity to 1,3-butadiene: role of microsomal epoxide hydrolase polymorphisms. Carcinogenesis 22:415-23
Ma, H; Wood, T G; Ammenheuser, M M et al. (2000) Molecular analysis of hprt mutant lymphocytes from 1, 3-butadiene-exposed workers. Environ Mol Mutagen 36:59-71
Ma, H; Smith, D H; Hsie, A W et al. (2000) Multiplex polymerase chain reaction-based analysis of T-cell receptor gamma gene rearrangements for the determination of T-lymphocyte clonality. Environ Mol Mutagen 35:8-Jan

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