Goitrogens and thyroid follicular cell neoplasia: Evidence for a threshold process

Paynter, O.E.; Burin, G.J.; Jaeger, Robert B.; Gregorio, Carlos

doi:10.1016/0273-2300(88)90009-8

Cited by 76 publications

(34 citation statements)

References 40 publications

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“…In dog breeds of European origin, peak uptake of ra- dioiodine normally occurs between 48 and 96 hr after administration of the tracer, and radioiodine is released from the gland with a half-time otabout 8 to 15 days. Peak uptake ranges from about 15% of the dose in dogs whose iodine intake is 500 pg per day to about 40% yhen iodine intake is 140 pg per day (Fig.…”

Section: Thyroidal Uptake Of Radioiodinementioning

confidence: 99%

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The Effects of Xenobiotics on the Structure and Function of Thyroid Follicular and C-Cells

1989

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The mammalian thyroid gland is composed of 2 distinct endocrine cell populations concerned with the synthesis of 2 different classes of hormones. Follicular cells secrete the metabolically active iodothyronines whereas the C-(parafollicular) cells are concerned with the production ofcalcitonin, a hormone that influences blood levels of calcium and phosphorus, and bone cell metabolism. The synthesis of metabolic thyroid hormones is different than in other endocrine glands because the final assembly of hormone occurs within the follicular lumen. This extracellular synthesis of thyroid hormones is made possible by thyroglobulin, a glycoprotein synthesized by follicular cells. The secretion of thyroid hormones under the influence of pituitary thyrotrophin (TSH) from stores in the luminal colloid is initiated by elongation of microvilli and formation of pseudopods. FD&C Red No. 3 is a tetraiodinated derivative of fluorescein which in lifetime studies increases the incidence of thyroid follicular cell adenomas in male Sprague-Dawley rats. The striking changes in circulating levels of thyroid hormones and morphologic evidence of follicular cell stimulation are the result of alterations in the peripheral metabolism of thyroxine. An inhibition by FD&C Red No. 3 of 5'-deiodinase in the liver and kidney would explain the lower serum triiodothyronine (T,) levels. The pituitary, sensing the lowered circulating levels of T,, increased the secretion of thyroid stimulating hormone which resulted in the morphologic evidence of follicular cell stimulation in the long-term studies. Other xenobiotics increase the incidence of thyroid tumors in rodents by a direct effect on the thyroid gland to disrupt 1 of 3 or more possible steps in the biosynthesis of thyroid hormones. Physiologic perturbations alone, such as iodine deficiency or partial thyroidectomy, can disrupt thyroid hormone economy in rodents and, if sustained, increase the development of thyroid tumors. The wide variety of drugs, chemicals, and physiologic perturbations which increase thyroid tumor development appear to act through a secondary (indirect) mechanism to promote tumor development by causing a long-standing hypersecretion of thyroid stimulating hormone. Nodular and/or diffuse hyperplasia of C-cells occurs with advancing age in many strains of laboratory rats and in response to long-term hypercalcemia in certain animal species and human beings. Focal or diffuse hyperplasia often precedes the development of C-cell neoplasms. Radiation and the feeding of diets high in vitamin D resulting in hypercalcemia have been reported to increase the incidence of C-cell tumors in rats.

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Section: Thyroidal Uptake Of Radioiodinementioning

confidence: 99%

“…3 does not appear to be a direct-acting thyroid oncogen but rather, in massive doses, acts through a secondary mechanism to promote the development of benigtl thyroid tumors, similar to a wide variety of other drugs, chemicals, and physiologic perturbations (48). The initiating factor, be …”

Section: Thyroid Hormone By Radioiiiirtitiiioassaymentioning

confidence: 99%

The Effects of Xenobiotics on the Structure and Function of Thyroid Follicular and C-Cells

1989

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“…Continuous reduction in circulating levels of thyroid hormones due to chemical-treatment also results in a compensatory increase of thyroid stimulating hormone (TSH) through the feedback mechanism. Overstimulation of the thyroid gland by TSH induces follicular cell hypertrophy, hyperplasia and finally neoplasia [3,6,8,10,21].However, there are marked species differences in thyroid gland physiology. The most obvious species difference between the rat and humans is the lack of thyroxin binding globulin (TBG) in the rat [13,24].…”

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confidence: 99%

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confidence: 99%

Thyroid Hyperactivity Induced by Methimazole, Spironolactone and Phenobarbital in Marmosets (Callithrix jacchus): Histopathology, Plasma Thyroid Hormone Levels and Hepatic T4 Metabolism.

Kurata

Wako

Tanaka³

et al. 2000

The Journal of Veterinary Medical Science

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ABSTRACT. To determine drug-induced hyperfunction of marmoset thyroids due to inhibition of synthesis or enhancement of metabolic elimination of thyroid hormones, males were orally administered 10 and 30 mg/kg/day methimazole (MMI), 30 and 100 mg/kg/day spironolactone (SPL), or 50 mg/kg/day phenobarbital (PB) for 4 weeks. MMI caused marked hypertrophy of follicular epithelial cells in accordance with a significant decrease in the plasma thyroxin (T 4 ) level. Hypertrophied epithelial cells were filled with dilated rough endoplasmic reticulum and reabsorbed intracellular colloids, and the luminal surface was covered with abundant microvilli. The colloid included vacuoles positive to anti T 4 immuno-staining. SPL and PB also caused similar histomorphological changes, although they were less severe than those due to MMI and were not clearly associated with decrease in the plasma T 4 levels. Hepatic T 4 UDPGT activities tended to increase due to SPL and PB treatment, however, which were not so significant as increases in microsomal cytochrome P-450 contents. Some animals treated with SPL and PB showed marked increases in thyroid weights due to inactive dilated follicles. In conclusion, hyperactivity of thyroid follicles was induced in marmosets not only due to inhibition of T 4 synthesis produced by MMI but also because of enhancement of hepatic T 4 elimination produced by SPL and PB. However, hypertrophic effects of SPL and PB were less severe than MMI, because plasma T 4 levels were maintained at almost pretreatment or control levels after SPL or PB treatment.-KEY WORDS: marmoset, methimazole, phenobarbital, spironolactone, thyroid hyperactivity.Many chemicals cause thyroid proliferative lesions through non-genotoxic mechanisms in the rat. These chemicals disturb the hypothalamus-pituitary-thyroid gland axis by inhibiting thyroid hormone synthesis (i.e. antithyroid drugs) or by enhancing hormone metabolism (i.e. hepatic microsomal enzyme inducers) and cause thyroid proliferative lesions secondary to hormone imbalance. Under normal conditions, circulating levels of thyroid hormones are maintained at constant levels via the feedback mechanism among the hypothalamus, pituitary and thyroid glands. Continuous reduction in circulating levels of thyroid hormones due to chemical-treatment also results in a compensatory increase of thyroid stimulating hormone (TSH) through the feedback mechanism. Overstimulation of the thyroid gland by TSH induces follicular cell hypertrophy, hyperplasia and finally neoplasia [3,6,8,10,21].However, there are marked species differences in thyroid gland physiology. The most obvious species difference between the rat and humans is the lack of thyroxin binding globulin (TBG) in the rat [13,24]. TBG has the highest affinity for thyroxin [4]. Lack of this protein leads to more T 4 free of protein binding and makes it easier to remove from the body in rats than in humans. Therefore, the halflife of serum T 4 is 12 to 24 hrs in the rat versus 6 to 7 days in humans and serum TSH is 20-fold higher i...

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“…The risk will be 0 when a thrshld exists below which neoplastic conversion does not occur. Paynter et al (17) have suggested that a threshold may exist for thyroid tumor induction, although the evidence in dtis regard is not conclusive.…”

Section: Range-of-risk Estimatesmentioning

confidence: 99%

A Model-Free Approach to Low-Dose Extrapolation

Krewski¹,

Gaylor²,

Szyszkowicz³

1991

Environmental Health Perspectives

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Goitrogens and thyroid follicular cell neoplasia: Evidence for a threshold process

Cited by 76 publications

References 40 publications

The Effects of Xenobiotics on the Structure and Function of Thyroid Follicular and C-Cells

The Effects of Xenobiotics on the Structure and Function of Thyroid Follicular and C-Cells

Thyroid Hyperactivity Induced by Methimazole, Spironolactone and Phenobarbital in Marmosets (Callithrix jacchus): Histopathology, Plasma Thyroid Hormone Levels and Hepatic T4 Metabolism.

A Model-Free Approach to Low-Dose Extrapolation

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