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Studies on an Indirect Mechanism of Rat Thyroid Follicular Cell Neoplasia Initiated by Microsomal Enzyme Inducing Agents.

Rush, Kevin C. (1996) Studies on an Indirect Mechanism of Rat Thyroid Follicular Cell Neoplasia Initiated by Microsomal Enzyme Inducing Agents. Doctoral thesis, University of Surrey (United Kingdom)..

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Both genotoxic and non-genotoxic processes can lead to thyroid follicular cell carcinogenesis. Whereas the latter are threshold mediated and are therefore able to be regulated by a margin of safety approach, the former are not. Discrimination between these two processes is critical in longterm biosassays in animals that are used for the purpose of hazard assessment in the chemical industry. These data are then considered in relation to exposure to enable an evaluation of risk to human health. Mechanistic studies have been performed which show that non-genotoxic thyroid carcinogenesis is the consequence of an increased plasma thyrotropin (TSH). Using phenobarbital as a reference material of known clinical safety and no evidence of human thyroid follicular cell neoplasia, disruptive events have been shown to occur in the hypothalamic-pituitary-thyroid axis of rats. Interestingly, the primary action appears to have occurred in the liver, resulting remotely in an indirect, secondary effect in the thyroid gland. This pattern of perturbation was noted with a number of new candidate plant protection products - liver weight increases, hepatocyte hypertrophy, changes in thyroid gland morphology progressing from reductions in colloid to follicular cell hypertrophy, hyperplasia, adenoma and carcinoma after some 18 months to 2 years. Parallel changes, which began very early (within 24 hours), were seen in biochemical and hormonal markers such as thyroxine (T4) tri-iodothyronine (T3), and TSH. Nevertheless, the evidence of increased thyroid hormone clearance resulting from increased hepatic (peripheral) metabolism became less evident after 2 to 4 weeks. This was assumed to be due to compensation by the thyroid as the result of an increase in glandular activity to regain normal homeostasis. This raised the question whether hypothalamic-pituitary control was activated by hormone level (reductions were uncommon) or by clearance rate possibly mediated by some unclear receptor mechanism. To distinguish primary from secondary thyroid effects, use was made of the perchlorate discharge test. This in-line with other authors was considered a robust method for establishing whether appropriate levels of iodine uptake and organification were taking place. It is proposed that early evidence of liver weight increase, cytochrome P-450 induction and an increase in hepatic microsomal uridine diphosphoglucuronyl transferases (UDPCT) in the first two weeks of xenobiotic administration are likely to lead to increased thyroid hormone metabolism. Concurrent reduction in T4 and/or T3 together with an increase in TSH, in association with morphological evidence of an effect on the thyroid, supports the hypothesis that the hypothalamic-pituitary thyroid axis has been disrupted. This may help explain the mechanism of action for subsequent thyroid tumour formation and will help in the process of new product development and risk assessment for man. A proposed diagnostic algorithm for evaluating such indirect effects on thyroid function is presented.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors : Rush, Kevin C.
Date : 1996
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 1996.
Depositing User : EPrints Services
Date Deposited : 14 May 2020 14:03
Last Modified : 14 May 2020 14:06

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