Page 140 - The Toxicology of Fishes

120 The Toxicology of Fishes

Chemical partitioning in a vegetable oil/water system has also been used as a basis for predicting
tissue–blood partitioning (Poulin and Krishnan, 1995, 1996a). Alternatively, measured partitioning values
can be used to fit the value of slope and intercept terms that relate the extent of partitioning to chemical
log K and tissue lipid content. Using this approach, tissue-specific equations have been developed for
ow
rats, humans, and fish (Bertelsen et al., 1998; DeJongh et al., 1997). An interesting feature of these
studies is that fitted slope and intercept terms have suggested that nonlipid cellular constituents contribute
substantially to chemical partitioning in lean tissues, including blood.

High-Affinity Binding
High-affinity binding can affect chemical disposition by reducing the fraction of a compound in blood
or tissues that is free to diffuse across cellular membranes. An example of high-affinity binding is
provided by mammalian PBTK models for TCDD. Although differing in detail, all such models feature
some type of specific binding in the liver, generally including an inducible component (Leung et al.,
1990). An important outcome of this binding is that TCDD can induce its own redistribution from fat
to liver. Fish do not appear to possess these hepatic binding proteins in quantities sufficient to influence
TCDD distribution (Nichols et al., 1998). A second example of high-affinity binding is that exhibited
toward many heavy metals. Endogenous metal-binding proteins regulate internal concentrations of free
metal, both as a means of limiting toxicity and because many metals perform vital biological functions
as cofactors and components of enzymes and oxygen transport proteins (Roesijadi and Robinson, 1994).
To date, no PBTK models have been developed for metals in fish, and only a few exist for mammals
(Gray, 1995; O’Flaherty, 1991, 1996). It may be anticipated that knowledge of metal-binding systems
will be required to develop PBTK models for uptake and disposition of most metals.

Urinary and Biliary Elimination
Radiolabeled microspheres have been used to estimate arterial blood flow to the kidneys of arctic grayling
(Cameron, 1975), rainbow trout (Barron et al., 1987a), and channel catfish (Schultz et al., 1999). Arterial
renal blood flow in the grayling was about 6% of cardiac output; in trout, arterial blood flow ranged
from 6 to 10% of cardiac output, depending on the acclimation temperature. Added together, arterial
blood flows to the head and trunk kidneys of channel catfish constituted about 9% of cardiac output.
Renal portal blood flows in fish are poorly known and cannot be determined using the microsphere
method. In most species, however, renal portal blood is supplied largely by the caudal vein, which drains
both the skin and the trunk musculature (Satchell, 1992; Smith and Bell, 1975). An estimate of total
blood flow to the kidney may therefore be determined by summing the arterial flow and the estimated
flow in the caudal vein. In rainbow trout, this results in a total estimated flow equal to about 42% of
cardiac output (Nichols et al., 1990). Reported urine flows in fish were summarized by Hickman and
Trump (1969) and Hunn (1982). Urine flows in freshwater fish generally range from 1.0 to 10.0 mL hr –1
–1
–1
kg , while those in saltwater fish range from 0.1 to 1.0 mL hr kg . Glomerular filtration rates in fish,
–1
summarized by Hickman and Trump (1969), usually exceed urine flow in a given species by a factor of
about 1.5 to 5.0.
–1
–1
Measured bile flow rates in fish are generally quite low, ranging from 30 to 200 µL hr kg (Boyer
et al., 1976a,b,c; Gingerich et al., 1977; Sanz et al., 1993; Schmidt and Weber, 1973); nevertheless,
secretion into bile may represent an important route of elimination for some compounds. Zaharko et al.
(1972) incorporated biliary elimination into a PBTK model for methotrexate in stingrays. Bungay et al.
(1976) described the biliary elimination of phenol red and its glucuronide conjugate in a PBTK model
for the dogfish shark. In both efforts, first-order rate constants were used to represent the sum of metabolic
and secretory processes. The value of each rate constant was determined by modeling to measured
amounts of chemical in gallbladder bile (because the animals were not fed, all of the bile produced was
retained in the bladder). Time constants were incorporated into both models to simulate observed delays
in chemical appearance due to the time required to transit the biliary tree. The model presented by
Bungay et al. (1976) also incorporated a first-order renal clearance constant to describe the appearance
of phenol red and its glucuronide conjugate in urine. Figure 3.29 shows model simulations and measured
chemical concentrations in bile and urine given in this study.