Toxicology of Industrial Compounds

N.P.E.VERMEULEN ET AL. 17
processes, namely glomerular filtration and tubular secretion are used by
the kidneys to remove chemicals from the bloodstream into the urine
(Hook and Hewitt 1986). The kidneys are highly vulnerable to potential
toxicants not only because they receive a high bloodflow (25% of the
cardiac output), but also because they have the intrinsic ability to
concentrate compounds. Recently, it has also become clear that xenobiotics
may become nephrotoxic in the kidney itself due to bioactivation processes
in combination with insufficient protection mechanisms (Commandeur and
Vermeulen, 1991).
The elimination of chemicals by the kidney is generally governed by firstorder
processes. During first-order excretion kinetics the urinary
elimination rate of a chemical is directly proportional to the plasma
concentration. This means that the higher the plasma concentration the
more of the chemical will be excreted in urine per unit of time. The urinary
elimination rate (dQ/dt) can be calculated from a semi-logarithmic plot of
the urinary elimination rate versus the time of the intermittently collected
urine samples (dQ/dt (mg h −l )=volume (1)×concentration (mg 1 −1 )/time (h))
(Figure 2.3A).
From the slope of the semi-logarithmic plasma concentration or urinary
excretion rate versus time curve, the elimination rate constant (k el) and the
urinary half-life of elimination (t 1/2) can be calculated. The half-life of
elimination is the time required to decrease the plasma concentration or the
urinary elimination rate by one-half. The volume of distribution of the
chemical normally can not be calculated from the urinary excretion data.
Because the amount of chemical excreted in urine per unit of time (dQ/dt)
is proportional to the plasma concentration (C p), the t 1/2 derived from the
urinary elimination rate constant is identical to the t 1/2 of the chemical in
plasma. It is evident that under these conditions the urinary excretion rate
curve has the same shape as the plasma concentration curve (Figure 2.3B).
In practice, the concentration of a chemical in urine (mg l −1 ) can be
determined and multiplied by the volume (1) of the urine sample in order
to calcu late the amount (mg) of chemical excreted over a period of time. In
a semi-logarithmic plot the amount of chemical excreted is plotted against
the midpoint of the interval of collection (Figure 2.3B). The accuracy of the
method strongly depends on the way and the number of urine samples
collected. As a rule of thumb, urine samples have to be collected during at
least four half-lives of elimination. The complete cumulative urinary
excretion of a chemical can be calculated as the area under the urinary
excretion rate versus time curve including extrapolation time to infinity.
Occupational exposure to chemicals frequently occurs 5 days a week, 8 h
a day, with an exposure free period of 16 h. Intermittent exposure to a
chemical may lead to different accumulation situations in the body
depending on the periods between exposure in relation to t 1/2 (Table 2.1).
No accumulation will occur when the intervals between the exposure