Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment

Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk... There are two basic mechanisms whereby chemicals produce thyroid gland neoplasia in rodents. The first involves chemicals that exert a direct carcinogenic effect in the thyroid gland and the other involves chemicals which, through a variety of mechanisms, disrupt thyroid function and produce thyroid gland neoplasia secondary to hormone imbalance. These secondary mechanisms predominantly involve effects on thyroid hormone synthesis or peripheral hormone disposition. There are important species differences in thyroid gland physiology between rodents and humans that may account for a marked species difference in the inherent susceptibility for neoplasia to hormone imbalance. Thyroid gland neoplasia, secondary to chemically induced hormone imbalance, is mediated by thyroid-stimulating hormone (TSH) in response to altered thyroid gland function. The effect of TSH on cell proliferation and other aspects of thyroid gland function is a receptor mediated process and the plasma membrane surface of the follicular cell has receptors for TSH and other growth factors. Small organic molecules are not known to be direct TSH receptor agonists or antagonists; however, various antibodies found in autoimmune disease such as Graves' disease can directly stimulate or inhibit the TSH receptor. Certain chemicals can modulate the TSH response for autoregulation of follicular cell function and thereby increase or decrease the response of the follicular cell to TSH. It is thus important to consider mechanisms for the evaluation of potential cancer risks. There would be little if any risk for non-genotoxic chemicals that act secondary to hormone imbalance at exposure levels that do not disrupt thyroid function. Furthermore, the degree of thyroid dysfunction produced by a chemical would present a significant toxicological problem before such exposure would increase the risk for neoplasia in humans. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis Elsevier

Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment

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Publisher
Elsevier
Copyright
Copyright © 1995 Elsevier Ltd
ISSN
0027-5107
DOI
10.1016/0027-5107(95)00139-5
Publisher site
See Article on Publisher Site

Abstract

There are two basic mechanisms whereby chemicals produce thyroid gland neoplasia in rodents. The first involves chemicals that exert a direct carcinogenic effect in the thyroid gland and the other involves chemicals which, through a variety of mechanisms, disrupt thyroid function and produce thyroid gland neoplasia secondary to hormone imbalance. These secondary mechanisms predominantly involve effects on thyroid hormone synthesis or peripheral hormone disposition. There are important species differences in thyroid gland physiology between rodents and humans that may account for a marked species difference in the inherent susceptibility for neoplasia to hormone imbalance. Thyroid gland neoplasia, secondary to chemically induced hormone imbalance, is mediated by thyroid-stimulating hormone (TSH) in response to altered thyroid gland function. The effect of TSH on cell proliferation and other aspects of thyroid gland function is a receptor mediated process and the plasma membrane surface of the follicular cell has receptors for TSH and other growth factors. Small organic molecules are not known to be direct TSH receptor agonists or antagonists; however, various antibodies found in autoimmune disease such as Graves' disease can directly stimulate or inhibit the TSH receptor. Certain chemicals can modulate the TSH response for autoregulation of follicular cell function and thereby increase or decrease the response of the follicular cell to TSH. It is thus important to consider mechanisms for the evaluation of potential cancer risks. There would be little if any risk for non-genotoxic chemicals that act secondary to hormone imbalance at exposure levels that do not disrupt thyroid function. Furthermore, the degree of thyroid dysfunction produced by a chemical would present a significant toxicological problem before such exposure would increase the risk for neoplasia in humans.

Journal

Mutation Research/Fundamental and Molecular Mechanisms of MutagenesisElsevier

Published: Dec 1, 1995

References

  • Induction of thyroid tumors in rats by a low iodine diet
    Axelrad, A.A.; Leblond, C.P.
  • Estimation and extrapolation of tumor probabilities from a mouse bioassay with survival/sacrifice components
    Farmer, J.H.; Kodell, R.L.; Gaylor, D.W.
  • The thyrotropin receptor
    Kohn, L.D.; Aloj, S.M.; Tombaccini, D.; Rotella, C.M.; Toccafondi, R.; Marcocci, C.; Corda, D.; Gullman, E.F.
  • Induction of thyroid tumors by a low iodine diet
    Leblond, C.P.; Isler, H.; Axelrad, A.
  • A link between liver microsomal enzyme activity and thyroid hormone metabolism in man
    Ohnhaus, E.E.; Studer, H.

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