Toxicology of Industrial Compounds

19
Endocrine Toxicology of the Thyroid for
Industrial Compounds
CHRISTOPHER K.ATTERWILL and SAMUEL
P.AYLWARD
CellTox Centre, University of Hertfordshire, Hatfield, Herts
General introduction
Classification of endocrine toxicity
Xenobiotic-induced endocrine dysfunction and toxicity is a common
finding in safety studies and an increasingly important consideration in the
riskassessment process. The effective identification of potential endocrine
toxicological effects depends upon xenobiotic effect classification in
relation to normal endocrine function and pathology.
Classifications of different types of endocrine toxicity have been
proposed in previous publications on this subject. Capen and Martin
(1989) proposed a detailed classification based on clinical endocrine
function and pathology. On the other hand, Baylis and Tunbridge (1985)
proposed a simpler classification based on the adverse endocrine reactions
of xenobiotics which are observed clinically. From a toxicological or
preclinical safety testing point of view, Atterwill and Flack (1993) favoured
classifying endocrine toxicology of xenobiotics in a manner which is
similar in concept to that for classifying other toxicological phenomena
(CIOMS, 1983) taking into account the unique nature of the endocrine
system. This is as follows (see also Figure 19.1):
Class 1 Effects which can be predicted from the endocrine pharmacology
of compounds. An example would be the oestrogens and progestogens
which have a plethora of effects on metabolic parameters in addition to their
actions on oestrogen sensitive target sites when administered at
pharmacological doses (the therapeutic dose levels). Further examples are
certain dopamine and 5-HT antagonists acting on hypothalamic and
pituitary receptors which may disrupt ‘downstream’ endocrine functions.
Class 2 Effects which again can be predicted from the endocrine
pharmacology of the compound when administered at doses well in excess
of the therapeutic dose level. An example would be adrenal steroid
suppression and general excessive catabolism observed with high dose and