PRINCIPLES OF TOXICOLOGY

2.4 DISPOSITION: DISTRIBUTION AND ELIMINATION 51
between liver and intestine is also included in the model. These features of the model are choices made
by the model developer, and reflect the known physicochemical behavior of the agent whose kinetics
are being modeled. Models for other chemicals will be quite different. A model for a nonvolatile
chemical would not include an explicit lung compartment, while models for bone-seeking elements
like lead and uranium include bone as a distinct tissue.
In a sense, classical and PBK models work in opposite directions. In classical descriptive kinetics,
model compartments having no necessary relationship to actual tissue volumes and clearances having
no necessary relationship to tissue blood flow are inferred from a set of concentration data. In contrast,
the PBK model is constructed from basic anatomic, physiologic, physicochemical, and metabolic
building blocks. It is then used to simulate concentrations under a defined set of conditions, and its
predictions are compared with observations. If the predictions are not accurate, some premise of the
model is at fault. The need for model revision can afford insight into the processes that control the
kinetic behavior of the chemical.
A PBK model for dichloromethane (DCM) forms the basis of a current human health risk
assessment. DCM is metabolized by two pathways, a capacity-limited oxidative pathway and firstorder
conjugation with glutathione (for descriptions of these biotransformation processes, see Chapter
3). Either pathway was thought potentially capable of generating reactive intermediates involved in
the tumorigenicity of DCM in mice. Andersen et al. (1987) demonstrated that tumorigenicity correlated
well with the activity of the glutathione pathway, but not with the activity of the oxidative pathway.
These investigators scaled a PBK model developed for DCM from mouse to human and from high
dose to low dose in order to predict, based on studies carried out at high doses in mice, the risk associated
with human environmental exposure to DCM. The mouse-to-human scaling of metabolism relied on
experimentally-determined human metabolic parameter values.
Their physiologic foundation and the inclusion of species-specific physiologic and metabolic
mechanisms, when these are known, confer on PBK models a flexibility that allows their use for
route-to-route, dose-to-dose, and species-to-species extrapolations such as this one, for which classical
models would be wholly inappropriate.
Biotransformation
Biotransformation is one of the two general elimination mechanisms. Biotransformation reactions in
general can be divided into two classes: phase I and phase II reactions. Phase I reactions are catabolic
or breakdown reactions (oxidation, reduction, and hydrolysis) that generate or free up a polar functional
group. They produce metabolites that may be excreted directly or may become substrates for phase II
reactions. Phase II reactions, which are often coordinated with phase I activity, are synthetic reactions
in which an additional molecule is covalently bound to the parent or the metabolite, which usually
results in a more water-soluble conjugate. Biotransformation reactions, and the factors that influence
them, are discussed in detail in Chapter 3.
Excretion
Excretion takes place simultaneously with biotransformation and, of course, with distribution. The
kidney is probably the single most important excretory organ in terms of the number of compounds
excreted, but the liver and lung are of greater importance for certain classes of compounds. The lung
is active in excretion of volatile compounds and gases. The liver, because it is a key biotransforming
organ as well as an organ of excretion, is in a unique position with regard to the elimination of foreign
chemicals.
Excretion in the Kidney About 20 percent of all dissolved compounds of less than protein size are
filtered by the kidney in the glomerular filtration process. Glomerular filtration is a passive process; it
does not require energy input. Filtered compounds may be either excreted or reabsorbed. Passive
reabsorption in the kidney, as elsewhere, is a diffusion process. It is governed by the usual principles.