Page 266 - The Toxicology of Fishes

246 The Toxicology of Fishes

1
0.9 A alone
0.8
A + low B
0.7 A + high B
Response 0.6
0.5
0.4
0.3
0.2
0.1
0
0.001 0.01 0.1 1 10
Dose A
FIGURE 5.7 Effect of a low-efficacy ligand on the dose–response relationship for a high-efficacy ligand. Dose–response
curves are shown for ligand A alone or with ligand B. The amount of ligand B added is the same at all doses of A within
a single curve. At a low concentration of B, B alone evokes no response but antagonizes the action of A. At a higher
concentration of B, B alone produces a small response and further antagonizes the action of A.

Equations 5.8 and 5.9 make clear that response depends on the concentrations of ligand and receptor
as well as the affinity and efficacy constants. This takes us back to the concept expressed in Figure
5.2, that the ability of a compound to produce a response depends both on affinity and efficacy. If
several compounds vary in their EC values for a response mediated by the same receptor, it is
50
impossible to know without further information whether the compounds vary in their affinity or efficacy,
or both.
Ligand-binding experiments are typically more difficult to perform than dose–response studies.
Fortunately, it is possible to determine the relative efficacies of two ligands without knowing their
receptor binding affinities by treating with combinations of the two. If ligand B has significantly lower
efficacy than ligand A, then in combination ligand B would be expected to reduce the effect of ligand
A (because it is occupying receptors without activating them). Sample data from this type of experiment
are shown in Figure 5.7. A low dose of B, insufficient to elicit a response on its own, nevertheless
occupies receptors, thereby requiring more A to produce a response and shifting the dose–response
curve to the right. At a higher dose of B, the compound can cause a response on its own, but it also
produces a greater inhibition of the response to compound A. If A and B had similar efficacies, the
doses would produce additive effects, and adding B would not shift the dose–response curve to the
right.
This example illustrates the importance of understanding efficacy for effective toxicological risk
assessment. Because chemicals usually occur in the environment in complex mixtures, the presence
of low-efficacy ligands can actually reduce the risk associated with high-efficacy ligands. Measuring
the toxicity of these ligands separately and then summing to estimate the toxicity of the mixture will
result in overestimation of the potential toxicity (Walker et al., 1996; Zabel et al., 1995). Thus, mixtures
including low-efficacy ligands will violate the additivity assumption in the toxic equivalency factor
approach (see Chapter 21). An example of the application of these principles concerning ligand affinity
and efficacy and their application in the context of fish toxicology can be found in Hestermann et al.
(2000).
A special case in which the concepts of affinity, efficacy, and potency are relevant to assessing the
risk of mixtures involves the situation in which each of the individual compounds in the mixture is
present at a concentration less than that which causes a significant biological effect on its own. Under
what conditions might one expect to see a response (“something from nothing”) from such a mixture
(Silva et al., 2002)? The concept of concentration addition has been used to predict the effects of such
mixtures (Brian et al., 2005; Thorpe et al., 2006). Clearly, however, the response will be influenced by
differences in the relative intrinsic efficacies of the compounds. Understanding the interactions of
compounds with different intrinsic efficacies remains incomplete; this is an important area of ongoing
research.