Page 115 - The Toxicology of Fishes

Toxicokinetics in Fishes 95

equations for E and CL have to be used. In such cases, there are no direct proportionalities; CL int,u , f ,
u
h
and Q all determine E, CL , and F , and a change in any one of the former variables produces a less
fp
h
than proportional change in the latter.
Renal Clearance
The kidney has two processes by which it clears blood of chemicals: filtration and extraction. Filtration
involves the passage of plasma water across the glomerular membrane. Toxicant dissolved in water is
transported across the membrane and ends up in the pre-urine. When protein binding occurs, protein-
bound compounds remain with the protein in plasma. The plasma concentration of unbound toxicant
remains constant during filtration, as both water and toxicant are removed by the filtration process. The
equilibrium between bound and free toxicant is therefore not disturbed; consequently, the maximum
possible clearance via filtration is the volume flow of plasma water across the glomerular membrane
(GFR) multiplied by the fraction of toxicant that is unbound in plasma.
The extraction mechanism only applies when a toxicant is a substrate for an active tubular secretory
pathway. Unbound toxicant contained in postglomerular and renal portal blood is transported across the
proximal tubule into pre-urine. As in the liver, this may be a high E or low E process, depending on the
toxicant. The same extraction model described for the liver can be used for active tubular secretion. In
this case, CL is the activity of the secretory mechanism.
int
Total clearance by the kidney reflects the net result of filtration, active secretion, and passive reabsorption:
CL = filtration clearance + secretion clearance – reabsorption
r
Passive reabsorption is expected to be minimal in freshwater fish because the kidney does not reabsorb
much water from urine and thereby concentrate the toxicant. In marine fish, the kidney conserves water
by reabsorption and a greater potential exists for toxicant reabsorption from urine.

Branchial Clearance
Fish gills are an important site for toxicant uptake and elimination, and both processes can be described
using clearance concepts. Unlike hepatic and renal clearance, however, the mathematical description of
branchial clearance must be bidirectional to reflect the fact that chemical flux occurs in both directions.
Depending on the concentration gradient across the gills, fish may clear chemical from inspired water
or from blood flowing through the gills. The principal limitations on chemical uptake at fish gills were
identified by Hayton and Barron (1990). If the permeability of the gill epithelium to a toxicant is low,
diffusion can limit exchange, and branchial clearance is controlled by the product of gill permeability
(K ) and the surface area for diffusion (A):
d
CL = K A (3.22)
d
b
The permeability coefficient is proportional to chemical diffusivity in the gill epithelium (D) and is
inversely related to the effective thickness of the diffusion barrier (h):
K = D/h (3.23)
d
If diffusive flux is limited by chemical diffusion within nonaqueous portions of the gill epithelium, it is
appropriate to incorporate a membrane–water partition coefficient (P ), which would be expected to
mw
correlate positively with chemical lipophilicity:
K d = DP mw h (3.24)

The resulting permeability coefficient is identical to that given previously in Equation 3.1. Alternatively,
if chemical diffusion in the aqueous phase of the membrane limits flux, Equation 3.23 is appropriate.
Similarly, the value of D applies to the phase that constitutes the principal barrier to diffusive flux.