Multi-compartment model to study the effect of air-blood and blood-tissue partition coefficients on concentration-time-effect relationships.
The influence of the air-blood (lambda) and blood-tissue partition coefficients of substances on the concentration-time-effect relationship E = [aCnT]b was studied by model simulation of uptake and distribution of gases. The model consisted of a lung compartment and four tissue compartments. Rat and human model parameters were obtained from physiological data, and substance-dependent variables. The observable effect E (righting reflex, mortality, etc.) for directly acting systemic agents was supposed to be related to the (arbitrarily chosen) concentration of the substance in the arterial blood or in the liver compartment. We conclude that for a directly acting systemic agent n greater than or equal to 1. If n less than 1 other mechanisms such as metabolism must be incorporated in the model which, however, should not be excluded when n greater than or equal to 1. If the observable effect is related to arterial concentration of the substance, n increases with decreasing lambda. If the liver concentration is related to the observable effect, man and rat may behave quite differently. This has major consequences for the extrapolation of animal results to the human situation in risk assessment.
Zwart
A
A
TNO Toxicology and Nutrition Institute, Zeist, The Netherlands.
Lommen
J G
JG
Feron
V J
VJ
D000388:Air; D000818:Animals; D001769:Blood / Q000378:metabolism*; D003198:Computer Simulation; D006221:Halothane / Q000493:pharmacokinetics; D006801:Humans; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008752:Methylene Chloride / Q000493:pharmacokinetics; D008954:Models, Biological; D010599:Pharmacokinetics; D051381:Rats; D013343:Styrenes / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution
D013343:Styrenes; D008752:Methylene Chloride; D006221:Halothane