MODELING HUMAN EXPOSURE DOSE RELATIONSHIPS--1,3-BUTADIEN

描述：（改编自研究者摘要）个人的

DESCRIPTION: (Adapted from the Investigator's Abstract) 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. Thus individuals who have sustained high exposure to 1,3-butadiene (BD), and have both high oxidation rates and slow detoxification rates are most likely to have high risk of adverse effects. However, in vivo data on human metabolism of BD are not available. Laboratory exposures are needed to fill this critical gap. Specific Aims: (1) Recruit populations of potential subjects: 400 each from Caucasian, African-American, and Hispanic groups, and 160 from Chinese-Americans; (2) Prescreen all potential subjects to determine their genotypes for EH and GST-theta. Select a set of 60 test subjects (equal numbers of males and females) from each racial subgroup, who meet human subject criteria and are over-represented in subjects with variant EH allele (reduced hydrolase activity) and GST-theta null genotypes. (3) Expose the selected subjects to low levels of BD in the laboratory, and collect timed blood, breath and urine samples before, during and after the exposure. Phenotype subjects for oxidative activity of CYP2E1 with chlorooxazone. Analyze blood and breath samples for BD and urine samples for metabolites. (4) Use lab data to fit parameters of personal PBPK model using SimuSolv program. (5) Characterize variation in BD metabolism by genotype, sex, racial subgroups, diet, and lifestyle factors. Methods: Volunteers will give informed consent, complete a questionnaire including diet and alcohol use and will meet with a physician for an interview and collection of a blood sample for screening. Samples will be genotyped to determine polymorphic types for EH and GST-theta. Subjects selected for testing will be asked to abstain from alcohol for 7 days before they receive a brief, low-level exposure to BD (total dose 0.5 ppm/hr); the exposures are in the range of everyday exposures from cigarette smoke and urban air pollution. An 11-compartment PBPK model developed by Johanson and Filser (1993) will be fitted to the timed measurements of BD in breath and blood, and urinary metabolite data to derive estimates of apparent in vivo metabolic rate constants. Twenty exhaled breath measurements and 5 venous blood measurements during 15-60 min. exposures and 80 min. post exposure. Pilot studies and preliminary computer simulations indicate that reasonable precision (coeff. var. 10-20%) can be achieved for subject-specific BD oxidation rates. Urine samples will be collected before and for 12-hr post exposure. Urine from fast oxidizers (about one-third of the population) will be analyzed by Bechtold, ITRI, for mercapturic acids specific for EH and GST pathways. Data Analysis: A maximum likelihood technique will be used to fit the oxidation rates for butadiene from PBPK fitting are associated with population characteristics such as phenotype for 2E1, race, or sex, while controlling for dietary factors. Similarly, differences in the overall detoxification rates and composition of urinary metabolites for fast oxidizers will be tested for associations with population characteristics, such as genotype for EH or GST, race, and sex, while controlling for dietary and lifestyle factors. The observed oxidation rates and variations in urinary metabolites with genotypes and 2E1 phenotype will be used to formulate personalized PBPK models for major subgroups of the US population. These models will be suitable for US population risk assessment.