Toxicology of Industrial Compounds

322 ANTIOXIDANTS AND LIGHT STABILISERS: TOXIC EFFECT
metabolism has been observed with various deiodinase inhibitors (Hill et
al., Liang et al., 1993) and hepatic enzyme inducers (McClain, 1989;
Curran and DeGroot, 1991; Barter and Klaassen, 1992; Visser et al.,
1993).
Induction of thyroid neoplasia
In a long-term feeding study, administration of Compound B to rats at a
dose level of 1000 ppm was associated with an increased incidence of
thyroid gland follicular adenoma and carcinoma (Muakkassah-Kelly et al.,
1991). Compound B was shown to be devoid of mutagenic and clastogenic
activity (Muakkassah-Kelly et al., 1991). Therefore, it is likely that thyroid
tumour induction by Compound B was not the result of a direct, genotoxic
effect on this organ, but rather a consequence of the hormonal imbalance
induced by this antioxidant in the rat.
An intact hypothalamic-pituitary-thyroid axis is able to respond to a
chemically induced alteration in peripheral hormone metabolism with
increased hormone production by the hypertrophic gland. However, it is
known that chronic, excessive stimulation of the gland can lead to
follicular hyperplasia and ultimately progress to thyroid neoplasia (Paynter
et al., 1988; McClain, 1989; Curran and DeGroot, 1991; Johnson et al.,
1993). For Compound B, this hypothesis is in agreement with the doseresponse
characteristics obtained in the long-term study, where thyroid
tumours were induced exclusively at a dose-level sufficiently high to cause
hormonal imbalance (Muakkassah-Kelly et al., 1991).
Implications for human risk assessment
For human risk assessment, it is of critical importance to identify the
mechanism by which Compound B caused thyroid neoplasia in the rat, a
species most often used for carcinogenic hazard identification. Hyperplastic
changes in the thyroid are frequently observed in rat carcinogenicity
studies, and this species appears to be very sensitive to compounds which
interfere with thyroid hormone synthesis and/or catabolism. They evoke an
immediate stimulation of the gland upon short-term treatment as a
consequence of an increased pituitary TSH secretion (Zbinden, 1987;
Paynter et al., 1988; McClain, 1989).
However, the effects of xenobiotics on the pituitary-thyroid axis in
rodents cannot necessarily be extrapolated to man since rodents and man
are distinguished by many important physiological and biochemical
differences (Gopinath, 1991): e.g. the amount of thyroxin-binding
globulin, the half-life of T 4 and its biliary excretion as well as plasma THSlevels
and their response to thyrotropin releasing hormone. These
differences render the rat very sensitive to small changes in the plasma T 4