Chemistry Reference
In-Depth Information
picture has yet to be elucidated, many toxic endpoints, including porphyria, indices
of hepatotoxicity, and mortality of embryos of birds are correlated with the degree
to which planar polychlorinated compounds bind to the Ah receptor. As described
earlier (Chapter 2, and Section 6.2.2), interaction with the Ah receptor also leads to
induction of P450 1A1/1A2, a response that is closely linked to what has been termed
Ah-receptor-mediated toxicity (Fernandez-Salguero et al. 1996).
The complex formed between coplanar PCBs and the Ah receptor migrates to the
nucleus, where it triggers the induction of the P450s and certain other enzymes, events
associated with the initiation of toxic responses by mechanisms as yet unknown. It
should be added that P4501A1/1A2 is involved in the activation of some mutagens/
carcinogens. Thus, if organisms are exposed to coplanar PCBs in combination with,
for example, mutagenic PAHs, there may be an increased rate of DNA adduct forma-
tion because the former induce P4501A1/2 (see Walker and Johnston 1989).
Ah-receptor-mediated toxicity is particularly associated with the highly toxic
compound 2,3,7,8-tetrachloro-dibenzo-
p
-dioxin (TCDD), commonly referred to
as
dioxin
. TCDD, and the concept of toxicity equivalency factors (TEFs) based on
TCDDs, will be dealt with in Chapter 7. The main point to make at this juncture is
that the toxicity of each individual coplanar congener in a mixture can be expressed
in terms of a toxic equivalent calculated relative to the toxicity of dioxin. Summation
of the toxic equivalents of the individual coplanar PCBs gives a measure of the toxic-
ity of the whole mixture, as expressed through the Ah receptor mechanism.
In experimental mammals and certain other vertebrates, another mechanism
of action shown by certain coplanar PCBs depends on metabolic activation: con-
version of the PCBs to monohydroxy metabolites by cytochrome P4501A1/1A2
(Figure 6.3). 4′OH 3,3′,4,5′-TCB is a metabolite of 3,3′,4,4′ TCB, which is closely
related structurally to thyroxine (T4). 4′OH 3,3′,4,5′ competes very strongly with T4
for binding positions on the protein transthyretin (TTR) (Figure 6.3; Brouwer et al.
1990; Brouwer 1991; Brouwer et al. 1998). Some other hydroxy metabolites of PCBs
do the same, although less strongly (Lans et al. 1993). When the metabolite binds
to TTR, thereby excluding T4, the associated retinol (vitamin A) binding protein
breaks away (Figure 6.5). Thus, the TCB metabolite can reduce the levels of bound
thyroxine and retinol in blood with consequent physiological effects (e.g., vitamin
A deficiency). These changes have provided the basis for the development of bio-
marker assays for the toxic action of PCBs (Brouwer 1991). 3,4,3′,4′-TCB is also an
inducer of P4501A1/1A2, and can enhance the rate of its own activation if the levels
of exposure are high enough (for further discussion of this question, see Walker and
Johnston 1989). In a laboratory study with common tern (
Sterna hirundo)
chicks,
dosing with coplanar 3,3′4,4′5-PCB either alone or in combination with the nonpla-
nar 2,2′4,4′5,5′-HCB caused a reduction in plasma total thyroxine, which was nega-
tively correlated with hepatic TEQ concentrations (Bosveld 2000). Cyto P4501A1
was also induced in these birds.
In mammals, there is evidence that hydroxy PCBs are transferred across the pla-
centa into the fetus, where they accumulate (Morse et al. 1995). In an experiment
with pregnant rats exposed to 3,3′,4,4′-TCB, substantial levels of 4′ OH,3,3′,4,5′-TC B
accumulated in the fetus, with concomitant reduction in levels of T4. This was due
to competitive binding of the PCB metabolite to TTR, thereby excluding T4. Similar
Search WWH ::
Custom Search