The multiple indicator dilution method and its utility in risk assessment

The multiple-indicator dilution (MID) technique entails the injection of a mixture of labeled indicators into the blood vessel immediately at the entr ance of an organ, e.g., the liver, kidney, heart, or lung, and characteriza tion of outflow dilution profiles from timed venous samples. The mathematic al basis of the method encompasses linear systems of partial differential e quations that are formulated for flow- or barrier-limited transport combine d with intracellular metabolism/excretion. The concept can be generalized t o include metabolites. MID experiments are useful for determining tissue pa rtition coefficients as well as kinetic parameters such as membrane permeab ilities or metabolic/excretory intrinsic clearances, factors that affect th e mean residence times or exposure of solutes to the organ. The main utilit y of the MID method lies in its role in identifying the basic mechanisms of the interaction of organs with vascular components. The concentration depe ndence in transport and removal is revealed by the rate coefficients upon v arying the input concentrations of unlabeled substances into the organ at s teady state. The data obtained with MID experiments can be incorporated int o physiologically based pharmacokinetic (PBPK) models such as those used fo r biological risk assessment. This is especially pertinent in the case wher e diffusional barriers appear within organs. The insight gained from the MI D organ approach may be useful for PBPK models with more realistic represen tation of organ kinetics.