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Analysis of solvent central nervous system toxicity and ethanol interactions using a human population physiologically based kinetic and dynamic model.
Regul Toxicol Pharmacol. 2002 Apr; 35(2 Pt 1):165-76.RT

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+Show Affiliations

Section of Molecular Pharmacology and Pharmacogenetics, Clinical Sciences Division, The University of Sheffield, Sheffield S10 2JF, UK.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12052002

Citation

MacDonald, A J., et al. "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, vol. 35, no. 2 Pt 1, 2002, pp. 165-76.
MacDonald AJ, Rostami-Hodjegan A, Tucker GT, et al. Analysis of solvent central nervous system toxicity and ethanol interactions using a human population physiologically based kinetic and dynamic model. Regul Toxicol Pharmacol. 2002;35(2 Pt 1):165-76.
MacDonald, A. J., Rostami-Hodjegan, A., Tucker, G. T., & Linkens, D. A. (2002). 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, 35(2 Pt 1), 165-76.
MacDonald AJ, et al. Analysis of Solvent Central Nervous System Toxicity and Ethanol Interactions Using a Human Population Physiologically Based Kinetic and Dynamic Model. Regul Toxicol Pharmacol. 2002;35(2 Pt 1):165-76. PubMed PMID: 12052002.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Analysis of solvent central nervous system toxicity and ethanol interactions using a human population physiologically based kinetic and dynamic model. AU - MacDonald,A J, AU - Rostami-Hodjegan,A, AU - Tucker,G T, AU - Linkens,D A, PY - 2002/6/8/pubmed PY - 2002/11/26/medline PY - 2002/6/8/entrez SP - 165 EP - 76 JF - Regulatory toxicology and pharmacology : RTP JO - Regul Toxicol Pharmacol VL - 35 IS - 2 Pt 1 N2 - 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. SN - 0273-2300 UR - https://www.unboundmedicine.com/medline/citation/12052002/Analysis_of_solvent_central_nervous_system_toxicity_and_ethanol_interactions_using_a_human_population_physiologically_based_kinetic_and_dynamic_model_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0273230001915077 DB - PRIME DP - Unbound Medicine ER -