Genetic and dietary factors affecting human metabolism of 1,3-butadiene

The objective of this project was to determine the factors associated with differences in butadiene (BD) inhalation uptake and the rate of metabolism for BID to epoxy butene by monitoring exhaled breath during and after a bri ef exposure to BID in human volunteers. A total of 133 subjects (equal male s and females; four racial groups) provided final data. Volunteers gave inf ormed consent and completed a questionnaire including diet and alcohol use. A venous blood sample was collected for genotyping CYP2E1. Subjects receiv ed a 20 min exposure to 2.0 ppm of BID, followed by a 40 min washout period . The total administered dose was 0.6 ppm*h. which is in the range of every day exposures. Ten, 1 or 2 min exhaled breath samples (five during and five after exposure) were collected using an optimized strategy. BD was determi ned by GC-FID analysis. Breathing activity (minute ventilation, breath freq uency and tidal volume) was measured to estimate alveolar ventilation. Afte r the washout period, 250 mg of chlorzoxazone were administered and urine s amples collected for 6 h to measure 2E1 phenotype. The total BID uptake dur ing exposure (inhaled BID minus exhaled) was estimated. A three-compartment PBPK model was fitted to each subject's breath measurements to estimate pe rsonal and population model parameters. including in-vivo BD metabolic rate . A hierarchical Bayesian PBPK model was fit by Monte Carlo simulations to estimate model parameters. Regression and ANOVA analyses were performed. Ea rlier data analysis showed wide ranges for both total uptake BD and metabol ic rate. Both varied significantly by sex and age, and showed suggestive di fferences by race, with Asians having the highest rates. The analyses repor ted here found no correlation between total BID uptake and metabolic rate. No significant differences were found for oxidation rates by 2E1 genotype o r phenotype, but the rates showed trends consistent with reported differenc es by genotype and phenotype for chlorzoxazone metabolism. No effects on me tabolic rate were observed for long-term alcohol consumption, or consumptio n in the past 24 h. Overall, neither dietary factors nor genetic difference s explained much of the wide variability in metabolic rates. Population cha racteristics, age, sex, and race, were the most important explanatory varia bles, but a large fraction of the total variability in metabolism remains t o be explained. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.