Page 98 - The Toxicology of Fishes

78 The Toxicology of Fishes

transport proteins. For many compounds, movement out of blood and into tissues occurs by simple
diffusion following a concentration gradient. When a compound diffuses rapidly across biological
membranes, organ blood flow and the maintenance of a concentration gradient are primary determinants
of distribution. In other cases, the rate of membrane diffusion may control chemical flux between blood
and tissues. Chemical affinities for blood and tissue constituents can further influence the distribution
process, both as an impediment to distribution (e.g., plasma protein binding) and as a means of facilitating
uptake by creating a favorable tissue-to-blood concentration gradient. As discussed below, distribution
processes controlled by simple diffusion or blood-flow rate generally exhibit first-order kinetics. Under
these circumstances, the rate of chemical flux between blood and tissue is proportional to the magnitude
of the concentration gradient. In contrast, membrane transport proteins often exhibit nonlinear (saturable)
kinetics.
The distribution of a xenobiotic can also be viewed in terms of the fluid spaces that it occupies. Blood
and extracellular and intracellular fluid spaces may individually or collectively define the distribution
volume of a compound. This distribution is determined by: (1) binding to nondiffusing molecular species,
and (2) the ability of the unbound compound to diffuse across biological membranes. If a xenobiotic is
confined to plasma, low (perhaps unmeasurable) concentrations will be found elsewhere. If the same
quantity of toxicant were distributed to interstitial fluid or total body water, the plasma concentration
would be markedly lower.

Local Distribution
At early time points in an exposure, chemical distribution to tissues may be highly influenced by the
route of administration. High concentrations in the skin following exposure to contaminated sediments,
the gastrointestinal mucosa following dietary exposure, or muscle following an intramuscular injection
are obvious examples. These distribution patterns are generally restricted to the absorption phase of the
exposure.
Anatomical and physiological peculiarities of fish may also result in characteristic distribution patterns;
for example, xenobiotics administered by intramuscular injection in the trunk muscle may be initially
transported to the kidney. Venous blood from the trunk muscle collects in the caudal vein, which is part
of the renal portal circulation in fish (Figure 3.1). Similarly, compounds taken up from the GIT or
intraperitoneal cavity are transported first to the liver by the hepatic portal vein and then to the gills via
the ventral aorta before distributing into the general circulation. The systemic availability of a compound
taken up by this route may be influenced, therefore, by elimination pathways operating in the gut, liver,
and gills. The fish anesthetic tricaine methane sulfonate (MS 222), for example, when given by intrap-
eritoneal injection will not produce anesthesia because of its rapid metabolism in the liver and the ease
with which both metabolites and parent compound diffuse out across the gills (Hunn and Allen, 1974).
Anesthetic concentrations of MS 222 in arterial blood can only be achieved by maintaining high MS 222
concentrations in water.

The Circulation
Blood flow, expressed per unit of tissue mass, is a major determinant of the rate of chemical distribution
to tissues. The tissues with the highest blood perfusion rates in fish are kidney, red muscle, pyloric ceca,
intestine, spleen, and liver (Barron et al., 1987a). Tissues receiving an intermediate level of blood
perfusion include the gonads, skin, and white muscle, while adipose tissue and bone are poorly perfused.
The influence of blood flow on chemical distribution was demonstrated in rainbow trout exposed to
linear alkylbenzene sulfonate (LAS) in water (Tolls et al., 2000). LAS concentrations in the internal
organs (primarily kidney and GIT) and liver exceeded 80% of their steady-state values after 8 hours of
exposure, while concentrations in the muscle and skin continued to increase until 78 hours.
Blood flow to some tissues may change substantially in response to physiological stimuli. An example
of this phenomena is provided by the pre- and post-prandial intestine (Axelsson and Fritsche, 1991;
Axelsson et al., 1989, 2000). Exercise (Neumann et al., 1983) and hypoxia (Cameron, 1975) altered
blood-flow patterns in rainbow trout and arctic grayling (Thymallus arcticus), respectively. Stress,