PRINCIPLES OF TOXICOLOGY

50 ABSORPTION, DISTRIBUTION, AND ELIMINATION OF TOXIC AGENTS
the tissue. This equilibrium will vary from tissue to tissue and may also vary from species to species.
Simple partitioning phenomena, such as into body lipid stores, can be described by defining partition
coefficients, whose values can be determined experimentally at steady state in vivo or in vial
equilibration experiments in vitro. More complex partitioning, such as capacity-limited binding of a
metal to specific binding sites in tissues, must be defined appropriately. Estimates of dissociation
constants may be required.
Diffusion-limited kinetics can also be accommodated within the framework of PBK models. In
diffusion-limited kinetics, the process of transfer across the membrane separating tissue from blood is
the rate-limiting step in tissue uptake. The distinction between flow-limited and diffusion-limited
tissue-uptake kinetics is roughly analogous to the distinction between ventilation-limited and flowlimited
absorption in the lung.
The metabolism of the compound must also be known. Metabolic parameters are more likely than
anatomic or physiologic parameters to be species-specific or even tissue-specific. The differences may
be quantitative or qualitative. Capacity-limited metabolism, absorption, and/or excretion can be
incorporated into PBK models as needed.
Figure 2.11 is a schematic diagram of a PBK model that might be designed for a volatile lipophilic
chemical. Arrows designate the direction of blood flow, with arterial blood entering the organs and
tissue groups and mixed venous blood returning to the lung to be reoxygenated. Organs of entry (lung,
liver), excretion (kidney, intestine, lung), and metabolism (liver), and tissue of accumulation (fat) for
this chemical class are explicitly included in the model. Other tissues are lumped into well-perfused
and poorly perfused groups. Note that uptake into the liver is considered to take place both by way of
the portal vein coming from the intestine and by way of the hepatic artery. An enterohepatic recycling
Absorption Excretion
Lung
Fat
Well-perfused Tissues
Poorly-perfused Tissues
Metabolism
Liver
Kidney
Intestine
Excretion
Excretion
Figure 2.11 Schematic diagram of a physiologically-based model of the kinetic behavior of a volatile chemical
compound.