title: Analysis of solvent central nervous system toxicity and ethanol interactions using a human population physiologically based kinetic and dynamic model.
abstract: The effect of acute ethanol-mediated inhibition of m-xylene metabolism on central nervous system (CNS) depression in the human worker population was investigated using physiologically based pharmacokinetic (PBPK) models and probabilistic random (Monte Carlo) sampling. PBPK models of inhaled m-xylene and orally ingested ethanol were developed and combined by a competitive enzyme (CYP2E1) inhibition model. Human interindividual variability was modeled by combining estimated statistical distributions of model parameters with the deterministic PBPK models and multiple random or Monte Carlo simulations. A simple threshold pharmacodynamic model was obtained by simulating m-xylene kinetics in human studies where CNS effects were observed and assigning the peak venous blood m-xylene concentration (C(V,max)) as the dose surrogate of toxicity. Probabilistic estimates of an individual experiencing CNS disturbances given exposure to the current UK occupational exposure standard (100 ppm time-weighted average over 8 h), with and without ethanol ingestion, were obtained. The probability of experiencing CNS effects given this scenario increases markedly and nonlinearly with ethanol dose. As CYP2E1-mediated metabolism of other occupationally relevant organic compounds may be inhibited by ethanol, simulation studies of this type should have an increasingly significant role in the chemical toxicity risk assessment.
authors.affiliation: Section of Molecular Pharmacology and Pharmacogenetics, Clinical Sciences Division, The University of Sheffield, Sheffield S10 2JF, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: MacDonald
authors.forename: A
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.forename: G T
authors.initials: GT
authors.lastname: Tucker
authors.forename: D A
authors.initials: DA
authors.lastname: Linkens
mesh_terms: D000284:Administration, Oral; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors; D000431:Ethanol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D019570:Inhalation Exposure; D008452:Maximum Allowable Concentration; D008954:Models, Biological; D009010:Monte Carlo Method; D016273:Occupational Exposure; D012997:Solvents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D006113:United Kingdom; D014992:Xylenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D004791:Enzyme Inhibitors; D012997:Solvents; D014992:Xylenes; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; C031285:3-xylene