Analysis of solvent central nervous system toxicity and ethanol interactions using a human population physiologically based kinetic and dynamic model

Regulatory Toxicology and Pharmacology : RTP
A J MacDonaldD A Linkens

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 r...Continue Reading

Citations

Jun 28, 2008·Journal of Toxicology and Environmental Health. Part B, Critical Reviews·Chad M ThompsonKannan Krishnan
Feb 10, 2009·Expert Opinion on Drug Metabolism & Toxicology·Masoud JameiAmin Rostami-Hodjegan
Apr 13, 2007·Expert Opinion on Drug Metabolism & Toxicology·Ivan Nestorov
Feb 3, 2007·Nature Reviews. Drug Discovery·Amin Rostami-Hodjegan, Geoffrey T Tucker
Jul 21, 2007·Risk Analysis : an Official Publication of the Society for Risk Analysis·Richard R LesterIgor Linkov

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