Thyroid follicular cell tumors arise in rodents from mutations, perturbations of thyroid and pituitary hormone status with increased stimulation of thyroid cell growth by thyroid-stimulating hormone (TSH), or a combination of the two. The only known human thyroid carcinogen is ionizing radiation. It is not known for certain whether chemicals that affect thyroid cell growth lead to human thyroid cancer. The U.S. Environmental Protection Agency applies the following science policy positions: 1) chemically induced rodent thyroid tumors are presumed to be relevant to humans; 2) when interspecies information is lacking, the default is to assume comparable carcinogenic sensitivity in rodents and humans; 3) adverse rodent noncancer thyroid effects due to chemically induced thyroid-pituitary disruption are presumed to be relevant to humans; 4) linear dose-response considerations are applied to thyroid cancer induced by chemical substances that either do not disrupt thyroid functioning or lack mode of action information; 5) nonlinear thyroid cancer dose-response considerations are applied to chemicals that reduce thyroid hormone levels, increase TSH and thyroid cell division, and are judged to lack mutagenic activity; and 6) nonlinear considerations may be applied in thyroid cancer dose-response assessments on a case-by-case basis for chemicals that disrupt thyroid-pituitary functioning and demonstrate some mutagenic activity. Required data for risk assessment purposes is mode of action information on mutagenicity, increases in follicular cell growth (cell size and number) and thyroid gland weight, thyroid-pituitary hormones, site of action, correlations between doses producing thyroid effects and cancer, and reversibility of effects when dosing ceases.ImagesFigure 1Figure 2Figure 3

Thyroid folliclar celi tumor arise in rodents from mutations, perturbations of thyroid and pituitay hormone status with increased sution of thyroid cell growth by thyroid-stimulating hormone (TSH), or a combination of the two. The only kown human thyroid carcinogen is ionizing radiation. It is not known for certain whether chemicals that affect thyroid cell growth lead to human thyroid cancer. The U.S. Environmental Protection Agency applies the following science policy positions: 1) chemical induced rodent thyroid tumors are presumed to be relevnt to humans; 2) when interspecies information is lacking the default is to asme comparble carcinogenic senitivity in rodents and humans; 3) adverse rodent noncancer thyroid effe due to chemically induced thyroid-pituity disruption are presumed to be relevant to humans; 4) linear dose-response considerations are applied to thyroid cancer induced by chemical substaces that either do not disrupt thyroid functioning or lack mode of action information; 5) nonlinear thyroid cancer dose-response considerations are applied to chemicals that reduce thyroid hormone levels, increase TSH and thyroid cell division, and are judged to lack mutanic acivity, and 6) nonlinear conideions may be applied in thyroid cancer dose-response assessments on a caseby-case basis for chemicalls that disrupt thyroid-pituitary functioning and demonstrate some mutagenic activity. Required data for risk asessment purposes is mode of action information on mutgenicity, increases in follicular cell growth (cell size and number) and thyroid gland weight, thyroid-pituitary honrones, site of action, correlations between doses producing thyroid effects and cancer, and reversibility of effet when dosing ceases. Key won iodide pump, microsomal enzyme induction, 5'-monodeiodinase, ris assessment, thyroid follicular cell tumors, thyroid hormone (T4, T3), thyroid p ida, throid-smulating hormone (TSH), UDP glucuronosyl trnsferase.

No abstract

There has been an increasing interest in the sulfate conjugates of estrogens as important metabolites in steroid hormone homeostasis and activity. In women estrogen sulfates have been known as major components of plasma originating from ovarian secretion and hepatic metabolism. However, only recently has the capacity to sulfurylate estrogens been demonstrated in estrogen target tissues. Porcine uterus estrogen sulfotransferase appears only after the first complete estrous cycle. Following puberty, gilt uterine sulfurylation of estrogens is extremely active during diestrus, whereas estrogen sulfotransferase is not present during estrus. This cycling of estrogen sulfurylation in porcine and human uteri can be related directly to plasma progesterone levels. Rodent and human mammary tumors are also highly active in both steroid alcohol and estrogen sulfotransferases. Unlike uterine sulfotransferases, these enzymes are apparently stimulated by factors that appear following ovariectomy. The function of estrogen sulfurylation by target tissues remains obscure. However, recent investigations have indicated that the cyclic variation in endometrial estrogen sulfurylation may control the availability of 17 beta-estradiol to the cytoplasmic receptor. This premise is supported by the continued high estrogen sulfurylation activity and low nuclear receptor levels during implantation in fertilized gilts and sows. Utilizing purified bovine adrenal sulfotransferase, the substrate and inhibitor requirements were determined for this enzymes. It was also possible to design a specific inhibitor that will block estrogen sulfurylation without interfering with the receptor binding and nuclear migration of physiological levels of 17 beta-estradiol. This inhibitor, 3-methoxy-4-nitroestrone, will help in establishing the role of uterine and mammary estrogen sulfurylation.