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.
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 344-771mg/m(3) would produce brain concentrations similar to those in rats exposed to 600mg/m(3) 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 4h exposure to approximately 570mg/m(3) 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.
Hissink
A M
AM
TNO Quality of Life, Zeist, The Netherlands.
Krüse
J
J
Kulig
B M
BM
Verwei
M
M
Muijser
H
H
Salmon
F
F
Leenheers
L H
LH
Owen
D E
DE
Lammers
J H C M
JH
Freidig
A P
AP
McKee
R H
RH
D000328:Adult; D000473:Alkanes / Q000008:administration & dosage / Q000493:pharmacokinetics; D000814:Aniline Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006838:Hydrocarbons / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D023421:Models, Animal; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D012997:Solvents / Q000008:administration & dosage / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution
D000473:Alkanes; D000814:Aniline Compounds; D006838:Hydrocarbons; D012997:Solvents; C051091:1,2,4-triaminobenzene; C012867:decane