Page 99 - The Toxicology of Fishes

Toxicokinetics in Fishes 79

exercise, and hypoxia related to netting and venipuncture were associated with changes in xenobiotic
kinetics (Kleinow, 1991). It is likely that these changes were due in part to changes in tissue blood flow.
Ambient temperature affects both cardiac output and the pattern of blood flow to tissues. An increase
in temperature was associated with an increase in cardiac output (Barron et al., 1987a). Blood flow as
a percentage of cardiac output decreased in most organs, maintaining perfusion rates at a constant level.
These changes were offset, however, by a redistribution of blood flow to white muscle, substantially
increasing the perfusion rate of this tissue.
Another circulatory feature of fish with unknown but potential significance to xenobiotic distribution
is the secondary circulation. This network of anastomosing vessels arises from the walls of the primary
arteries and parallels the primary circulation of arteries, capillaries, and veins (Olson et al., 1986). The
secondary circulation shares some characteristics with the mammalian lymphatic system, such as struc-
tural attributes of the vessels and restricted access for formed elements, but is more limited in its
distribution. Tissues perfused by the secondary circulation include the gill filaments, skin, peritoneal
lining, and oral mucosa. Limited studies suggest that the secondary circulation has a volume greater
than that of the primary circulation and a turnover time of several hours (Steffensen and Lomholt, 1992).
When the primary and secondary circulations are combined and expressed as a percentage of body
weight, the total circulatory volume places teleost fishes well into the upper range for vertebrates.

Xenobiotic Transport and Binding in Plasma
Several transport modalities contribute to the circulatory distribution of xenobiotics. Although many
compounds are transported in blood as freely dissolved forms, others may be transported in association
with proteins, lipoproteins, or cellular components. Xenobiotics interact with these components by
several mechanisms. Covalent binding usually restricts further distribution of the compound. In contrast,
noncovalent ligand–protein interactions result in reversible binding that follows the law of mass action.
When more than one binding interaction is possible, the distribution of a compound among binding
proteins depends on both the binding affinity of each protein and their relative concentrations. Binding
affinities may change with changes in ionic strength, pH, temperature, and protein conformation. As
long as binding is reversible, however, an equilibrium will tend to be reestablished, providing an efficient
means by which xenobiotics are transported and redistributed. Binding to plasma proteins can have a
large effect on chemical distribution and clearance; for example, in trout, the plasma free fractions of
parathion and paraoxon were determined to be 1.2 and 52.5%, respectively. Clearance rates determined
for each compound were 21.4 and 3020 mL/hr/kg, respectively (Abbas et al., 1996).
Fish and mammals differ somewhat with regard to the total concentration of plasma proteins as well
as qualitative properties of individual protein classes. Total protein concentrations in fish are generally
much lower than those in mammals, possibly resulting in a reduced number of binding sites. In mammals,
plasma albumin plays an important role in binding weak organic acids, and weak organic bases bind to
plasma glycoproteins. It is clear, however, that some fish species either do not possess albumin at all,
such as sharks and rays (Metcalf et al., 1999; Weisiger et al., 1984), or exhibit only very low concen-
trations (De Smet et al., 1998). The plasma albumin of rainbow trout has been described as “para-
albumin” because of significant functional differences from the albumin of mammals (Perrier et al.,
1977). Thus, the characteristic binding of xenobiotics to mammalian albumin and other plasma proteins
may not directly extrapolate to fish; for example, low concentrations of the antibiotic sulfadimethoxine
become highly (>90%) bound when added to rat plasma, but this binding saturates over a concentration
range of 0.2 to 10 mM (Figure 3.11). In contrast, sulfadimethoxine binding in rainbow trout plasma
ranges from 13 to 17% over the same concentration range, suggesting a nonsaturable, nonspecific
interaction. This low degree of protein binding in trout facilitates the elimination of sulfadimethoxine
and may result in a relatively larger apparent volume of distribution when compared with mammals
(Kleinow and Lech, 1988). Similar differences between fish and mammals have been reported for the
antimicrobial ormetroprim (Droy et al., 1990).
For other compounds, plasma binding in fish and mammals appears to be very similar; for example,
the binding of 1-butanol, phenol, nitrobenzene, and pentachlorophenol was shown to correlate positively
with chemical log K in plasma obtained from both the rainbow trout and rat (Schmieder and Henry,
ow