Page 857 - The Toxicology of Fishes

Reproductive Impairment of Great Lakes Lake Trout by Dioxin-Like Chemicals 837

The egg concentrations of the 2,3,7,8-substituted PCDDs, PCDFs, and non-ortho-substituted PCBs are
the AhR agonists that are routinely measured and included in this additive model of toxicity for fish
(van den Berg et al., 1998).

Ecological Risk Assessment with Fish-Specific TEFs

Fish-specific TEFs for planar PCBs (i.e., PCB 77, 81, 126, and 169) and PCDDs and PCDFs that are
AhR agonists in fish were determined for the endpoint of sac fry mortality in rainbow trout (Walker and
Peterson, 1991; Zabel et al., 1995a). In addition, Zabel et al. (1995c) found that the TEF for PCB 126,
based on sac fry mortality in lake trout (0.003), is similar to that for rainbow trout (0.005). These early-
life-stage mortality-specific TEFs determined in rainbow trout following injection of graded doses of
each TCDD-like PCB, PCDF, or PCDD congener into newly fertilized eggs (Walker and Peterson, 1991;
Zabel et al., 1995a) were adopted by the World Health Organization’s expert panel as fish-specific TEFs
(van den Berg et al., 1998). To provide an additional degree of protection for fish early-life-stage toxicity,
the actual TEF values determined for early-life-stage mortality in rainbow trout by Walker and Peterson
(1991) and Zabel et al. (1995a) were rounded higher in half order of magnitude increments. Therefore,
the fish-specific TEFs for the planar PCBs are typically more conservative than the original values of
the specific studies and will generate slightly greater total TEQ values (Walker and Peterson, 1991;
Zabel et al., 1995a).
The potency of AhR agonists has also been determined in fish cell cultures (Zabel et al., 1996). In
fish, comparisons of potency values based on sac fry mortality, induction of ethoxyresorufin-O-deethylase
(EROD) activity, and induction of cytochrome P4501A mRNA suggest that most congener potencies
determined from cell culture endpoints are higher by an order of magnitude than the potencies determined
for the same congeners based on sac fry mortality. In several individual congeners, however, the cell-
culture-derived potencies are greater by more than one order of magnitude. In addition, it is generally
observed that PCDD, PCDF, and PCB congeners are more potent in cell culture assays with regard to
causing EROD induction and P4501A mRNA induction than in producing early-life-stage mortality
(Cook et al., 1997).
The two major assumptions inherent in the TEF approach have both been validated for early-life-stage
toxicity evaluation in salmonines. The first is that congeners interact additively to produce AhR-mediated
toxicity; hence, toxicity may be predicted by summation of the TEQs calculated for each concentration
of TCDD-like AhR agonist present in fish tissue. We designate these AhR agonists as being TCDD-like
to indicate that they are the PCB, PCDD, and PCDF congeners shown in controlled laboratory studies
to produce the same signs of early-life-stage toxicity in rainbow trout as TCDD. All of these congeners
are full AhR agonists based on early-life-stage mortality, and the slopes of their dose–response curves
in eliciting this response are similar (Walker and Peterson, 1991; Zabel et al., 1995a). The additivity
assumption has been validated for predicting salmonine early-life-stage toxicity (Hornung et al., 1996;
Zabel et al., 1995b); for example, when lake trout eggs were injected with a mixture of PCBs, PCDDs,
and PCDFs mimicking that found in the eggs of feral Lake Michigan lake trout, the interaction was
essentially additive (Walker et al., 1996). Additionally, graded doses of an organic extract made from
Lake Michigan lake trout, injected into eggs of hatchery-reared rainbow trout (Wright and Tillitt, 1999)
and lake trout (Tillitt and Wright, 1997), produced symptoms of dioxin-like toxicity (i.e., yolk-sac edema,
craniofacial deformities, and hemorrhaging) in a dose-related fashion in both species. The TEF/TEQ
approach for quantification of the doses suggests additive toxicity in both of these species. Non-additive
effects of AhR agonists have been observed (Janz and Metcalfe, 1991), but those effects are more often
observed for non-lethal endpoints.
The second major assumption of the TEF approach is that the toxicity of PCBs, PCDDs, and PCDFs
is solely related to their TCDD-like toxicity. This assumption generally holds for predicting lethality in
salmonine embryos and larvae (Cook et al., 1997; Zabel et al., 1995a). Validation of this notion has also
been provided through the use of organic extracts of lake trout from the Great Lakes (Tillitt and Wright,
1997; Wright and Tillitt, 1999). Lake trout were collected and extracted with organic solvents to produce