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TOXIC CHEMICALS AND XENOBIOTICS

Eduardo Gaitan., M.D. and Robert C. Cooksey, M.S. University of Mississippi School of Medicine and VA Medical Center, Jackson, MS 39216

SIMPLE GOITER AND AUTOIMMUNE THYROIDITIS (AT): ENVIRONMENTAL AND GENETICS FACTORS.

The incidence of AT has steadily increased in the United States during the past five decades and it has been attributed to excessive iodine intake. Prior to iodine prophylaxis in 1924, the Appalachian was one of three areas with highest goiter prevalence in the U.S. At present, Goiter, AT and Subclinical Hypothyroidism are prevalent in the coal-rich Appalachian area, while these conditions are absent in the nearby Inner Bluegrass region of central Kentucky. Thus, the question is raised as to whether the same region-specific environmental factors that cause goiter (i.e., organic and microbial water pollutants) operate in genetically predisposed individuals (i.e., HLA-DR5 antigens) to trigger the pathogenic mechanism leading to AT. Recent findings in western Colombia reinforce the hypothesis that endemic goiter and AT are intimately related and that dietary iodine and genetic composition determine their clinical, histological and autoimmune presentations. Furthermore, AT develops after administration of polycyclic aromatic hydrocarbons (PAH) and carbon tetrachloride to the BUF rat and of thyroglobulin with bacterial lipopolysaccharide to "good responder" mice, which differ from "poor responders" in their H-2 haplotype. Besides, organic goitrogens (resorcinol, thiocyanates, disulfides) and potential "triggers" of the autoimmune response (PAH and halogenated hydrocarbons) have been isolated from coal and water supplies of endemic areas.
 
Thyroid 1995 Jun;5(3):177-83

Nongoitrous (type I) amiodarone-associated thyrotoxicosis: evidence of follicular disruption in vitro and in vivo.

Brennan MD, Erickson DZ, Carney JA, Bahn RS

Department of Laboratory Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

Treatment with the antiarrhythmic agent amiodarone results in alterations in thyroid hormone metabolism, and can induce either hypothyroidism or hyperthyroidism (amiodarone-associated thyrotoxicosis, AAT). AAT occurs in patients both with and without preexisting goiter. In our study of the nongoitrous variety, the effect in vitro of amiodarone treatment and of concurrent treatment with potential inhibitors on thyroid cells (FRTL-5) was assessed by measuring the release of radiolabeled chromium (51Cr). In addition, thyroid histopathology was evaluated in autopsy specimens from six amiodarone-treated patients who had no pretreatment evidence of thyroid disease. Histopathologic examination revealed minimal or no evidence of thyroid follicular damage in specimens from amiodarone-treated euthyroid patients (n = 4). In contrast, moderate to severe follicular damage and disruption were present in glands from patients with AAT (n = 2). Studies in vitro showed amiodarone to be cytotoxic to thyroid cells; this effect was inhibited by treatment with dexamethasone (10(-3) mmol) or perchlorate (2.5 micrograms/mL). In summary, we demonstrate evidence in vitro and in vivo of amiodarone-induced thyroid follicular damage and disruption in specimens from patients with nongoitrous AAT and in cultured normal thyroid cells. In addition, we demonstrate inhibition of this effect following treatment in vitro with dexamethasone or perchlorate. Our findings support the concept that nongoitrous (type I) AAT results from direct drug toxicity with disruption of thyroid follicles and subsequent release of preformed thyroid hormone.
 
Endocrinology 1994 May;134(5):2277-82

Studies on the in vitro cytotoxic effect of amiodarone.

Chiovato L, Martino E, Tonacchera M, Santini F, Lapi P, Mammoli C, Braverman LE, Pinchera A

Istituto di Endocrinologia, University of Pisa, Italy.

Amiodarone, a potent antiarrhythmic drug, contains 37.2% iodine by weight and may induce either hypo- or hyperthyroidism. The high iodine content of amiodarone may be responsible for both complications, but a cytotoxic effect of the drug on the thyroid resulting in thyroiditis has been reported. In the present study the cytotoxic effect of amiodarone was evaluated in three culture systems with different biological properties: 1) a strain of rat thyroid cells (FRTL-5 cells) that maintains most differentiated functions of normal thyroid cells, including an active iodide pump, but an inability to organify iodide; 2) a line of Chinese hamster ovary (CHO) fibroblasts; and 3) freshly prepared primary cultures of human thyroid follicles (hTF) that trap and organify iodide. Cells were radiolabeled with 51Cr and incubated for 24 h with medium alone, medium plus amiodarone (3.75-200 microM), medium plus an iodinated radiographic contrast agent (sodium diatrizoate; 7.5-200 microM), or medium plus potassium iodide (7.5-300 microM). At concentrations ranging from 75-200 microM, amiodarone induced a significant and dose-dependent release of 51Cr in FRTL-5 cells. In contrast, diatrizoate or KI had no cytotoxic effect on FRTL-5 cells. In the same molar concentrations, amiodarone was also cytotoxic in CHO cells. In hTF, the release of 51Cr produced by amiodarone occurred at a lower concentration (37.5 vs. 75 microM) and was significantly greater than that in FRTL-5 cells. The cytotoxic effect of amiodarone in hTF was partially, but significantly, reduced by methimazole, an inhibitor of iodide organification. In the FRTL-5 cell culture system, amiodarone also produced a dramatic inhibition of TSH-stimulated cell growth. This growth-inhibiting effect of amiodarone was evident at low concentrations (3.75-7.5 mumol/liter) of the drug, which did not produce significant cytotoxicity. In conclusion, 1) amiodarone had a cytotoxic effect in CHO fibroblasts, a nonthyroid cell line; 2) this cytotoxic effect occurred in thyroid cells independent of their ability to organify iodide; 3) however, the toxic effect of amiodarone was greater and occurred at a lower molar concentration in freshly prepared human thyroid follicles that trap and organify iodide; and 4) in the latter culture system, methimazole, an inhibitor of iodide organification, partially, but significantly, reduced the cytotoxic effect of amiodarone. These data suggest that thyroid cytotoxicity produced by amiodarone is mainly due to a direct effect of the drug on thyroid cells, but excess iodide released from the drug may contribute to its toxic action.