The overall objective of this study is to develop quantitative, predictive models that account for person-specific factors that influence ETBE toxicokinetics, leading to better assessment of biological levels following human exposures. Occupational and environmental exposure to oxygenated fuel additives is an important concern due to the increasingly widespread use of these substances and the diversity of associated toxicities. The relationships among human exposures, time-varying levels of toxicants or metabolites in body tissues or fluids, and short or long-term biological responses are greatly influenced by factors that are specific to the person exposed or even to the actual exposure event. Important tools for the investigation of these intricate relationships that the applicant and his associates have developed in prior studies include: controlled exposures to stable isotope-labeled and unlabeled compounds; accurate measurements of these compounds and metabolites in blood, breath, and urine; and implementation of physiologically based models. A person-specific physiologically-based toxicokinetic (PBTK) modeling approach developed previously uses stable isotope tracers for styrene, toluene and xylene exposures, administered to male volunteers via inhalation. The role of person-specific parameters including body weight, per cent adipose tissue, pulmonary ventilation rate, cardiac output, and blood/air partition coefficient are determined for each subject, while other personal parameters (extra-hepatic metabolic rate and adipose perfusion) are obtained by fitting to experimental data. Person-specific input parameters used to fit 33 controlled exposures to 50 ppm 2H8-toluene explained 91 5% (mean 75-96%) of data variability; averaged values of input parameters from the same subjects gave model fits accounting for 81 9% (range 50-94%) of variability, and use of literature values permitted only 53 36% (range 1.3-94%) of variability to be explained. This proposal has the specific aim of extending this technique to evaluate ETBE kinetics in men and women subjects in order to validate the modeling framework across gender, to examine the role of gender-specific differences in PBTK parameters for women, and to provide a basis for assessing gender-specific responses to ETBE exposures
| Pierce, Crispin; Chen, Yili; Hurtle, William et al. (2004) Exponential modeling, washout curve reconstruction, and estimation of half-life of toluene and its metabolites. J Toxicol Environ Health A 67:1131-58 |
