Page 137 - The Toxicology of Fishes

Toxicokinetics in Fishes 117

dt = Q gt( C art − Cv gt) + ( C fec − C P fgt)
dA gt k gt gt (3.109)

Chemical concentration in venous blood draining the gut was then determined from that of the gut tissues
by assuming that chemical exchange between blood and tissues was flow limited.
The value of k was determined by Nichols et al. (1998) by fitting model simulations to measured
gt
whole-body TCDD concentrations and calculated assimilation efficiencies. The model was then used to
simulate TCDD kinetics in various tissues and organs, resulting in good correspondence between
predicted and observed values. The disadvantage of this approach is that k is difficult to interpret. The
gt
fitted value of k (which has units of flow) was found to be about 5% of the estimated blood flow rate
gt
to the lower intestine. It could not be determined, however, whether this reduction in uptake was due to
a limitation on diffusion, chemical binding in feces, or some other kinetic constraint.
Recently, Nichols et al. (2004a) developed a more detailed description of the fish GIT to describe
14
dietary uptake of [ C]-2,2′,5,5′-tetrachlorobiphenyl (TCB) by rainbow trout. The GIT was modeled
using four compartments corresponding to the stomach, pyloric ceca, upper intestine, and lower intestine,
and the luminal volume of each compartment was allowed to change in time as a function of bulk flow
of ingesta and nutrient uptake. The model was developed using data from rainbow trout that were fed
a meal of 60-day-old fathead minnows contaminated with TCB. Chemical partitioning coefficients were
adjusted to account for changes in chemical affinity associated with the uptake of dietary lipid. Perme-
ability coefficients for the absorbing gut segments were then fitted by modeling to measured TCB
concentrations in gut contents and tissues.
As expected, most of the TCB was taken up within the upper intestine during the period of peak
lipid absorption. It was concluded, however, that a kinetic limitation on chemical uptake acting along
the entire length of the GIT resulted in a chemical disequilibrium between feces and tissues of the
lower intestine. The mechanistic basis for this kinetic limitation remains unknown; however, a com-
parison of fitted gut permeability coefficients with the permeability coefficient for branchial uptake of
TCB suggests that dietary uptake is unlikely to be limited by the rate of diffusion across the gastrointes-
tinal epithelium.
The gut model was then used to simulate chronic exposures to TCB and a series of hypothetical high
log K compounds (Nichols et al., 2004b). Predicted steady-state biomagnification factors for TCB
ow
were very close to values measured in both laboratory and field studies; however, the incorporation of
a log K -dependent decrease in gut permeability was required to reproduce observed trends in biom-
ow
agnification and dietary assimilation efficiency. Although not constituting proof as such, this finding
suggests that dietary absorption of hydrophobic organic compounds by fish is controlled in part by
factors that vary with chemical log K .
ow

Hepatic and Renal Elimination
The foregoing descriptions of chemical exposure routes in fish are bidirectional with respect to chemical
flux and can function, therefore, as routes of elimination when activity gradients favor the movement of
chemical out of the organism. Thus, blood and water flow limitations that define maximum rates of
chemical uptake at the gills will also act to limit maximal rates of branchial elimination. Depending,
however, on the way that a particular compound is handled, a complete PBTK model may also have to
incorporate other routes of elimination, potentially including urinary and biliary elimination, as well as
biotransformation.
The physiological and biochemical factors that dictate hepatic and renal handling of xenobiotic
compounds were reviewed earlier in this chapter. Although limited, studies in fish suggest that hepatic
and renal clearance contribute substantially to the elimination of many compounds, particularly if they
are substrates for active systems that secrete chemicals to urine and bile. Currently, guidance on the
kinetics of elimination by urinary and biliary routes comes largely from mammalian studies. For most
compounds, the kinetics of renal clearance by glomerular filtration are first order with respect to the
free chemical concentration in plasma. In contrast, clearance pathways involving active secretion to urine
or bile often exhibit saturable, nonlinear kinetics. Biotransformation pathways in both mammals and
fish may also exhibit nonlinear kinetics.