Toxicology of Industrial Compounds

C.K.ATTERWILL AND S.P.AYLWARD 261
the biliary excretion pathway) is the formation of the glucuronic acid
conjugate, T 4-glucuronide.
Hepatic conjugation, either sulphation (preferring FT 3) or
glucuronidation (preferring FT 4) yields a more water soluble product,
excreted in the bile/ biliary duct is a major pathway in T 4 excretion.
Further deiodination via the deiodinase group of enzymes of T 4 T 3conjugates,
T 4-amines and T 3 to thyromimetically inactive iodothyronines
(rT 3 Triace, Tetrace, T 2 and T 1; see Figures 19.8 and 19.9) plays an
important part in the T 4/T 3 biotransformation cascade and completes the
thyroid hormone metabolic profile.
The key factor in maintaining correct thyroid follicular capability is an
appropriate TSH output to TRH stimulation alongside circulating levels of
FT 4. Perturbation of this homeostatic control results in a classical thyroid
response. The initial thyroid responses to increasing TSH levels are
follicular cell hypertrophy, loss of colloid and vascular dilatation. In
conventional animal toxicology studies performed for regulatory
authorities one of the first indices of thyrotoxicity, therefore, is the
observation of altered thyroid histopathology, primarily as follicular cell
hypertrophy and/or diffuse hyperplasia, often leading to focal hyperplasia,
thyroid adenomas and adenocarcinomas in longer term toxicity studies
after longer term exposure.
Pathobiology of thyroid follicular cell hyperplasia and
neoplasia
Thyroid neoplasia (see Figure 19.5) develops predictably in experimental
species exposed to any procedure inducing prolonged and excessive TSH
secretion (for example, the administration of chemical goitrogens, chronic
iodine deficiency or subtotal thyroidectomy) although humans and mouse
appear to be more resistant to TSH-induced thyroid neoplasia than rat.
The number of cytogenetic abnormalities within the thyroid epithelium
increases with duration of excess TSH exposure, with follicular cell
hyperplasia potentially leading to neoplasia. The histopathological
sequence of events is as follows (see Zbinden, 1987): following
hypertrophy of the follicular epithelial cells focal hyperplasias appear in the
gland which are distinct areas of papillary growth with enlarged epithelia.
As these foci continue to grow they form nodules partly surrounded by
collagenous fibres. These lesions are transition states between focal
hyperplasias and adenomas. Adenomas are larger nodules that compress
the surrounding tissue and have a distinct capsule. Follicular
microcarcinomas (characterised by irregular gland-like structures,
basophilia and nuclear crowding) may appear in some nodules. Larger
carcinomas usually retain a follicular structure but sometimes consist of
solid sheets of polymorphous cells (Zbinden, 1987).