Experimental Induction Of Thyroid Tumors

The Natural Thyroid Diet

The Natural Thyroid Diet

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Methods for inducing thyroid tumors in animals can be subdivided into two groups according to the mechanism of action. The first group comprises methods based on the application of substances with a direct oncogenic effect on thyroid cells, i.e., proper carcinogenic agents. The methods in the second group aim primarily at establishing a hormonal imbalance that, in turn, will lead to tumor development. Such a division, however, is rather artificial. Some known carcinogenic agents with a direct mechanism of action may also produce profound and irreversible hormonal disturbances that lead to thyroid carcinogenesis. Vice versa, many of the agents used to disturb the hormonal balance may exert a direct carcinogenic effect.

Tumor induction by elevation of TSH

As a result of numerous investigations, a consistent concept of experimental thyroid tumor pathogenesis was established to explain the tumorigenic effect of antithy-roid drugs (Bielschowsky 1955). According to this concept, the first stage in the development of thyroid tumors is inhibition of hormone production by the thyroid tissue under the influence of goitrogens. The second stage is the sustained intensification of synthesis and release of TSH. Continuous excessive secretion of TSH is assumed to be one of the basic pathogenic factors responsible for thyroid tumor development.

Goitrogen-induced tumors

Experimental goitrogen-induced tumorigenesis began with the observation that prolonged feeding of a diet containing plants of the Brassica species produced goiter in rats (Hercus & Purves 1936) leading to a high yield of adenomas (Griesbach et al. 1945). Kennedy (1942) suggested that the active agent in the rape seed was a urea derivative. Numerous investigations have previously revealed that in the thyroid the family of thiourea derivatives is both goitrogenic and carcinogenic. For example, Paschkis et al (1948), Kuzell et al. (1949), Clausen (1953), Wollman (1961), and Grundman & Seidel (1965) used thiouracil; Doniach (1950), Christov (1968), and Jemec (1977) used methylthiouracil (MTU); Van Dyke (1953) and Sellers & Schonbaum (1957) used propylthiouracil (PTU); Ulland et al. (1972), Graham et al. (1975), and Arnold et al. (1983) used ethylenethiourea (ETU); tetramethylthioura (TMTU) was used by Stula et al. (1979). Although there is some variation in the goitrogenic activity of the different thioureas, subsequent development of tumors appears to be a uniform finding for all members of this family of thiourea derivatives. They all inhibit steps in hormone synthesis (coupling of iodotyrosines, iodination of thyrosines and monoiodotyrosines) and some, such as PTU, also inhibit deiodination. Daily intake of 5-l0mg PTU or 10-20mg MTU is considered an optimum dosis for tumor development. Another compound with goitrogenic and carcinogenic activity is the herbicide aminotriazole (ATA). Jukes & Shaffer (1960) and Napalkov (1967) found a similarly high tumor frequency (25% adenomas) in rats ofboth sexes following lifelong 0.01% ATA administration. Tsuda et al. (1976) and Steinhoff et al. (1983) were able to produce carcinomas in Wistar rats. ATA has turned out to be an experimental goitrogen because the level of general toxicity was lower, than that observed in the thiourea group (Gibson & Doniach 1967). In contrast to mice and rats, hamsters appear to be relatively resistant to tumorigenesis caused by goitrogenic agents. Steinhoff et al. (1983) showed that irrespective of the amount of dosage given to hamsters ATA produced no increase in thyroid neoplasia, while PTU produced thyroid hyperplasia but no neoplasia (Kirkman 1972). However, MTU is reported to produce adenomas and carcinomas in hamsters with frequency and latent intervals similar to those in rats and mice (Akimova et al. 1969, Christov & Raichev 1972). In addition, Hellwig & Welch (1963) described the development of thyroid tumors in 15% of guinea pigs after 14 months PTU intake.

Tumor induction by low-iodine intake

Thyroid tumors have been induced in rats by prolonged over-stimulation of the gland with endogenous TSH only. This method involves maintaining the animals in a state of chronic iodine deficiency. The first observations of rats kept in such a state can be traced back to Bircher (1910, 1911). Since then, the method has been perfected by several groups (Hellwig 1935, Bielschowsky 1953, Isler 1959, Al-Saadi 1968 a.o.), but the most detailed examination was performed by Axelrad & Leblond (1955). These authors found that the changes seen in the thyroid gland and pituitary gland with a low-iodine diet are identical to those seen under long-term goitrogen administration. Thyroid adenomas could be induced in almost all experimental rats when maintaining an iodine-restricted diet with daily intake of about for two years. However, the malignancy of the follicular neoplasms that arise in the rat thyroid as a result of chronic iodine deficiency is questionable. In all cases reported so far, the frequency of carcinomas originating from follicular epithelium is clearly lower in rats kept on a low-iodine diet than in animals treated with goitrogens. In rats, iodine deficiency is a much more effective tumor promoter than is a carcinogen, suggesting that a similar relationship may exist in human populations (Ward & Oshima 1986). In C3H/Hey strain-mice, Schaller & Stevenson (1966) used low-iodine diet to induce benign and malignant thyroid tumors; after one year of treatment, carcinomas developed in 14%. In hamsters, Fortner et al. (1959) found well-differentiated, metastatic follicular tumors in 18% of females, but no lesions in males after a 70-week iodine-deficient diet.

Tumor growth after partial thyroidectomy

Although it has been claimed that subtotal thyroidectomy is a potent method that raises the level of trophic stimulus to the thyroid, the yield of tumors in animals treated in this way is lower than in animals given a low-iodine diet or long-term goitrogen (Domach 1970). Doniach & Williams (1962) and Goldberg et al. (1964) induced 14% adenomas and 4% carcinomas in Lister rats 15 months after 85%-excision of thyroid mass. In contrast, Ird (1968) found that subtotal thyroidectomy alone did not increase the incidence of tumors above that seen in control rats, and that surgery reduced the incidence of tumors in rats treated with MTU (25% vs. 74%). The relatively low yield of tumors obtained by this method may be explained by the fact that owing to surgery most part of the target gland responsible for the trophic stimulus is removed. This, of course, reduces the population of cells that might undergo neoplastic change.

Tumor induction by ionizing radiation

Radiation affecting the thyroid gland is possible via two routes: external or internal. External administration of radiation is achieved by using either X- or gamma-emitting radiation sources. Theoretically, this route has the advantage of permitting delivery of a precisely calculable amount of rads (Gray), but suffers from several practical problems. Firstly, given the size of the thyroid of the rat or mice, it is difficult both to localize the target and to avoid damaging the surrounding tissue. Secondly, it is also essential, but difficult, to avoid unirradiated parts of the thyroid, leading to an overestimation of the dose delivered. These problems may be solved by lightly anaesthetizing animals and by carefully placing a lead collar with a small window over the neck region, both to protect the surrounding tissue and to hold the animal in position. Internal irradiation is usually given in form of sodium salts of I131 or I125 by intraperitoneal or intrathyroidal injection. This method is much more convenient than external irradiation, although different problems arise. Accurate calculation of the dose received is difficult, since it is dependent both on percentage uptake and retention of the isotope. The amount of

Table 1. Review of the literature: incidence of thyroid tumors in rats following a single irradiation with radio-iodine (I131)

1 Dosage


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