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Application of physiologically based toxicokinetic modelling to study the impact of the exposure scenario on the toxicokinetics and the behavioural effects of toluene in rats

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Author: Asperen, J. van · Rijcken, W.R.P. · Lammers, J.H.C.M.
Type:article
Date:2003
Institution: TNO Voeding
Source:Toxicology Letters, 1-2, 138, 51-62
Identifier: 236968
doi: doi:10.1016/S0378-4274(02)00373-9
Keywords: Toxicology · Toxicology and Applied Pharmacology · Peak exposure · Physiologically based toxicokinetic modelling · Rat · Toluene · toluene · animal experiment · area under the curve · article · behavior · blood level · brain level · concentration response · controlled study · exposure · male · model · nonhuman · prediction · priority journal · rat · reliability · task performance · tissue level · toxicokinetics · visual discrimination · Administration, Inhalation · Animals · Behavior, Animal · Brain · Discrimination Learning · Dose-Response Relationship, Drug · Inhalation Exposure · Models, Biological · Rats · Toluene · Visual Perception

Abstract

The toxicity of inhalatory exposure to organic solvents may not only be related to the total external dose, but also to the pattern of exposure. In this study physiologically based toxicokinetic (PBTK) modelling has been used to study the impact of the exposure scenario on the toxicokinetics and the behavioural effects of the model solvent toluene in rats. After construction of the model with parameters from literature, toxicokinetic data were collected from rats exposed to either a constant concentration or fluctuating concentrations at total external dose levels of 20 000 and 10 000 ppm×h for model validation. At the same exposure conditions the effects on learned performance were evaluated in separate groups of rats using a visual discrimination task. In general, the PBTK model provided reliable predictions of the toxicokinetics of toluene at different exposure scenarios, but it also tended to underestimate the blood and brain concentrations in the descending parts of the tissue concentration-time curves. At these high dose levels the differences in toxicokinetics between the constant and the fluctuating exposure groups were relatively small. The visual discrimination experiments demonstrated a slowing of response speed and disinhibition of responding in all toluene-exposed groups. The results suggest that the brain concentration of toluene is one of the major determinants of its effect on disinhibition of responding. © 2002 Elsevier Science Ireland Ltd. All rights reserved.