Title
Model studies for evaluating the neurobehavioral effects of complex hydrocarbon solvents. III. PBPK modeling of white spirit constituents as a tool for integrating animal and human test data
Author
Hissink, A.M.
Krüse, J.
Kulig, B.M.
Verwei, M.
Muijser, H.
Salmon, F.
Leenheers, L.H.
Owen, D.E.
Lammers, J.H.C.M.
Freidig, A.P.
McKee, R.H.
TNO Kwaliteit van Leven
Publication year
2007
Abstract
As part of a project designed to develop a framework for extrapolating acute central nervous system (CNS) effects of hydrocarbon solvents in animals to humans, experimental studies were conducted in rats and human volunteers in which acute CNS effects were measured and toxicokinetic data were collected. A complex hydrocarbon solvent, white spirit (WS) was used as a model solvent and two marker compounds for WS, 1,2,4-trimethyl benzene (TMB) and n-decane (NDEC), were analyzed to characterize internal exposure after WS inhalation. Toxicokinetic data on blood and brain concentrations of the two marker compounds in the rat, together with in vitro partition coefficients were used to develop physiologically based pharmacokinetic (PBPK) models for TMB and NDEC. The rat models were then allometrically scaled to obtain models for inhalatory exposure for man. The human models were validated with blood and alveolar air kinetics of TMB and NDEC, measured in human volunteers. Using these models, it was predicted that external exposures to WS in the range of 344-771 mg/m3 would produce brain concentrations similar to those in rats exposed to 600 mg/m3 WS, the no effect level (NOEL) for acute CNS effects. Assuming similar brain concentration-effect relations for humans and rats, the NOEL for acute CNS effects in humans should be in this range. The prediction was consistent with data from a human volunteer study in which the only statistically significant finding was a small change in the simple reaction time test following 4 h exposure to approximately 570 mg/m3 WS. Thus, the data indicated that the results of animal studies could be used to predict a no effect level for acute CNS depression in humans, consistent with the framework described above. © 2007 Elsevier Inc. All rights reserved.
Subject
Biology
Toxicology and Applied Pharmacology
Central nervous system effects
Cross-species extrapolation
n-Decane
Occupational exposure limits
PBPK model
Toxicokinetics
Trimethyl benzene
White spirit
1,2,4 trimethylbenzene
decane
hydrocarbon
organic solvent
stoddard solvent
unclassified drug
adult
animal experiment
article
behavior
blood analysis
brain
central nervous system
cognition
controlled study
exposure
human
human experiment
in vitro study
lung alveolus
male
nonhuman
partition coefficient
priority journal
rat
toxicokinetics
validation study
Adult
Alkanes
Aniline Compounds
Animals
Behavior, Animal
Body Weight
Brain
Dose-Response Relationship, Drug
Humans
Hydrocarbons
Male
Models, Animal
Models, Biological
Rats
Rats, Wistar
Solvents
Time Factors
Tissue Distribution
Animalia
Rattus
To reference this document use:
http://resolver.tudelft.nl/uuid:704432fd-1ea1-4473-88e5-972087ea9642
DOI
https://doi.org/10.1016/j.neuro.2007.03.005
TNO identifier
240056
ISSN
0161-813X
Source
NeuroToxicology, 28 (4), 751-760
Document type
article