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Modelling of intra-individual and inter-individual variability in 1,3-butadiene metabolism

Sandrine MICALLEF, Thomas J. SMITH, Frédéric Y. BOIS

INERIS, Verneuil en Halatte, France

While inter-subject variability is accounted for in population statistical models, less attention has been devoted to intra-subject variability. In this study, we evaluated whether the metabolism of a toxic substance (1,3-butadiene) varies between occasions for a given subject. Two hierarchical models were built. The first one dealt with both inter-subject and inter-occasion variability. The second one dealt only with inter-subject variability. Both models imbedded a common physiologically-based pharmacokinetic model. Physiologically-based modeling brings a framework to include mechanistic knowledge about model structure and parameter values. Eleven human volunteers were exposed twice by inhalation to low levels of 1,3-butadiene (2 parts per million during 20 minutes). For each subject, exhaled air concentration was measured at different times. Posterior distributions of metabolic clearance parameters were studied after Bayesian calibration of both models. Bayes factors indicate that the model including intra-individual variability is clearly superior. Using this model, the intra-individual and inter-individual variability geometric SDs of metabolic butadiene rate constant are close to 1.5. The impact of these findings on the classification of subjects as low / medium / high metabolizers (as often done in biomarker or epidemiological studies) is investigated and discussed.