Toxicology of Industrial Compounds

266 ENDOCRINE TOXICOLOGY OF THE THYROID
attempting to define mechanisms in thyroid carcinogenesis (Thomas and
Williams, 1992).
In summary, there is, therefore, good evidence that sustained TSH drive
to the thyroid gland can lead to a de-regulation of thyroid function. When
investigating xenobiotic or drug-induced thyroid tumour formation, the
mechanisms whereby TSH drive is increased can be understood by
undertaking a series of experimental studies using in vitro and in vivo
techniques. Having delineated the mechanism of the thyrotoxic effect it
may then be possible to determine whether a particular drug or compound
elicits a similar response in different species (including humans) and to
investigate the dose-response relationship for this effect.
Investigative toxicological studies and examples of
xenobiotics causing thyroid toxicity via the H-P-T-L axis
Introduction
Atterwill et al., (1993) give extensive examples of both pharmaceutical and
industrial compounds causing thyroid toxicity via the five main sites along
the H-P-T-L axis as shown in Figure 19.7 and readers should refer to this
for further and more detailed information. In this chapter, three of these
five thyroid toxicity loci are described in relation to the endocrine effects
produced, industrial xenobiotic examples, and investigative in vivo and in
vitro tests to delineate mechanisms and species-specific effects. This
information is further summarised in Figure 19.8.
In terms of industrial compounds the most frequently cited examples
causing thyroid toxicity appear to be in the categories of: (i) those
potentially affecting the plasma protein binding of thyroid hormones—for
example, the nitrile herbicide, ioxynil (Ogilvie and Ramsden, 1988); (ii)
those acting directly on the thyroidal peroxidase enzyme as goitrogens, and
blocking thyroid hormone synthesis and secretion—for example, the coal
derived hydroxyphenol products (Lindsay et al., 1992); and (iii) those
affecting the hepatic metabolism and elimination T 3 and T 4—for example,
compounds such as β-naphthoflavone, PCBs and alachlor (Ogilvie and
Ramsden, 1988). Tables 19.1–19.3 show examples of these three class
effects, compounds producing the effects and some of the range of
investigative tests currently available.
in vivo and in vitro studies of xenobiotics acting on the
hepatic metabolism and clearance of thyroxine
There is a growing list of agents, both pharmaceutical and industrial
xenobiotics, which act in rodents by interfering with thyroid hormone