Toxicology of Industrial Compounds

C.K.ATTERWILL AND S.P.AYLWARD 257
or exaggerated pharmacological responses, that is Classes 1 and 2.
Furthermore, it appears that endocrine toxicology can be detected reliably
in pre-clinical studies. What is essential is that Class 3 toxic endocrine effects
are classified appropriately. Class 3a effects would be expected to be seen
across species, whereas there are numerous examples where Class 3b
effects appear to be species-specific. There seems to be a paucity of clear-cut
examples for Class 4 effects. There are several examples of compounds
which have idiosyncratic immunotoxicological effects in susceptible humans
which cannot be predicted from pre-clinical studies.
Incidence of thyroid toxicity and tumours of the thyroid
Most information on incidence is derived from pharmaceutical toxicity
databases. Such data from Ribelin (1984) suggest that the endocrine system
of the rats is particularly sensitive to toxicity from xenobiotics. This is also
supported by Heywood (1984) in which he examined the target organ
toxicity for 42 pharmaceutical compounds in the rat and dog. The
endocrine system of the rat was only second to the liver as the most
frequently affected target organ (38 per cent liver, 31 per cent endocrine).
Ribelin (1984) reported that the most frequent endocrine lesion occurs in
the adrenals followed by the testes but this analysis was conducted on
chemicals and pharmaceuticals, and the data indicated that it was the
cortical layers of the adrenal that were being predominantly effected,
suggesting that the adrenal changes may be reflecting general stress
responses rather than direct adrenal gland toxicity.
In another analysis conducted in conjunction with the Centre of
Medicines Research this area was further explored. Toxicology data on
124 compounds (all pharmaceuticals) were analysed. Just under 50 per
cent (61/124) of these compounds have effects on one or more endocrine
glands. Similar to Ribelin (1984) the adrenals were the most frequently
affected, followed by the testes and the thyroid. An extensive survey of the
different types of thyroid toxicity for both pharmaceutical agents and
industrial chemicals was presented by Atterwill et al. (1993).
Perturbation of thyroid function
Thyroid function can be perturbed by agents affecting a number of
processes involved in the regulation of the hypothalamic-pituitary-thyroidliver
(H-P-T-L) axis (Figure 19.2). These agents can affect function directly
by interacting with thyroid cell receptors on their intracellular transduction
mechanisms (see Figure 19.3). Alternatively thyroid function may be
altered indirectly by agents affecting thyroid hormone metabolism and/or
distribution—this event being followed by the release of thyrotrophic
factors, or by xenobiotic-mediated alterations in the release of these factors