Modeling Human Exposure-Dose Relationships:1,3-Butadiene

描述：个体暴露于代谢激活的

DESCRIPTION: An individual's risk from exposure to a metabolically activated and/or detoxified agent is defined by the interaction of exposure intensity and duration with genetic factors that control metabolic enzyme activity. The first phase of this project measured the uptake and oxidative metabolism of butadiene (BD) in a set of 140 subjects (equal males and females; four racial groups). Total metabolism ranged from 12 percent to 74 percent of BD entering the well perfused tissues, and varied significantly by sex and age, and showed suggestive differences by race. There was clear evidence of extrahepatic metabolism in approximately 15 percent of the subjects. The renewal project proposes to improve methods, and observe epoxide formation and removal via a new tracer method. Specific Aims: (1) To optimize the exposure system and tracer methods; (2) To collect real-time measurements of breath-by-breath alveolar concentrations (-700 obs.) and optimize a physiologically-based pharmacokinetic (PBPK) model for estimating of metabolism rates; (3) To measure the distribution of population metabolism of BD-BDO for 200 subjects selected as a cross-section by sex, race, and age; and (5) To select 40 high uptake and fast metabolizers from the 200 for exposure to C14 labeled BD to perform mass balance studies and time course determinations for epoxides and their metabolites in breath, blood, and urine. Methods: PBPK parameters will be fitted by Monte-Carlo Markov chain (MCMC) simulation analyses to estimate in vivo epoxide formation and removal rates and variation with the population. A real-time mass spectroscopic (MS) breath monitoring system will used to measure breath-by-breath alveolar concentrations during and after exposure. Those data will be used initially to optimize testing protocols and later to study model structure. About 200 adult subjects will be recruited through existing community outreach programs. After giving informed consent, volunteers will complete a questionnaire including diet and alcohol use, and provide a blood sample. They will be exposed for 20 min to 2.0 ppm BD followed by a 40 min wash-out period using our computer controlled exposure system. Genotypes will be determined for CYP2A6, EH, GSTtheta and GSTmu. A group of 40 high uptake, fast metabolizers will be asked to do a second exposure to C14 labeled BD (very low activity, 0.82 microCi/L) in our hospital lab; individual doses will range 6- 55 microCi with a mean of 24 microCi. An extremely sensitive, accelerator mass spectrometer (AMS) will be used to determine relative amounts of C14 to C12 in bulk samples and the metabolite fractions. Approximately 2 x 10-18 mole of C14 can be measured in under 1 minute with a statistical accuracy of 10 percent, whereas detection radioactivity would take over 80 years. Data Analysis: MCMC-PBPK modeling will be used to fit the PBPK model parameters and explore model structure. Generalized likelihood ratio testing will be used to detect any significant differences in individual oxidation rates for butadiene associated with population characteristics, such as genotype, age, race, or sex, while controlling for dietary and life style factors. Similarly differences in the formation and detoxification rates will be tested for associations with subject characteristics, such as genotypes and dietary antioxidants. Findings will be important for US risk assessments.