Effects of oral erythrosine (2',4',5',7'-tetraiodofluorescein) on thyroid function in normal men

Erythrosine (Er), a tetraiodinated derivative of fluorescein, is a coloring agent widely used in foods, cosmetics, and pharmaceutical products. Because of its high iodine content and previous reports demonstrating an inhibitory effect of erythrosine on hepatic 5'-monodeiodination, we studied the effects of this compound on thyroid function and serum and urinary iodide concentrations in normal subjects. Thirty normal men, equally divided into three treatment groups, each received a 14-day course of oral Er in doses of 20, 60, or 200 mg/day. Serum thyroxine (T4), triiodothyronine (T3), reverse T3 (rT3), thyroid stimulating hormone (TSH), protein-bound iodide (PBI), and total iodide concentrations, serum T3-charcoal uptake, and 24-hour urinary iodide excretion were measured on Days 1, 8, and 15. Thyrotropin-releasing hormone (TRH) tests were performed on Days 1 and 15. There were no significant changes in serum T4, T3, rT3, and T3-charcoal uptake values at any dose. In men receiving 200 mg Er/day, the mean basal serum TSH concentration increased significantly from 1.7 +/- 0.1 (SE) on Day 1 to 2.2 +/- 0.1 microU/ml on Day 15 (p less than 0.05), and the mean peak TSH increment after TRH increased from 6.3 +/- 0.5 to 10.5 +/- 1.0 microU/ml (p less than 0.05). There were no significant changes in basal or peak TSH responses in the men receiving 20 or 60 mg Er/day. Significant dose-related increases in serum total iodide and PBI concentrations occurred during all three doses, and significant dose-related increases in urinary iodide excretion occurred during the 60 and 200 mg/day Er doses. These data suggest that the increase in TSH secretion induced by Er was related to the antithyroid effect of increased serum iodide concentrations, rather than a direct effect of Er on thyroid hormone secretion or peripheral metabolism.     

Goitre and thyroid dysfunction during chronic amiodarone treatment

We measured thyroid function in a cross-sectional survey of 37 unselected patients receiving chronic amiodarone treatment. Palpable goitre was presented in 17 patients and was a new finding in ten. Despite frequent elevations of serum free T4 (67%) or free T4 index (43%), all 37 patients were clinically euthyroid with a normal or decreased serum free T3 or free T3 index. Mean urine iodide/creatinine excretion was increased 13-fold. Three patterns of thyroid function were seen; in 21 patients with normal TRH responses, the mean basal serum TSH was significantly elevated. Five patients had biochemical hypothyroidism which did not require treatment. Eleven patients had evidence of thyroid autonomy and the three patients with absent TRH responses each gave a past history of goitre or thyrotoxicosis; a trial of carbimazole treatment in these three was without clinical benefit. The observed spectrum of subclinical goitre and thyroid dysfunction may result from an unpredictable thyroid response to excessive free iodide combined with a weak goitrogenic effect of amiodarone mediated by increased TSH secretion.     

Inhibition of thyroid iodine uptake and organification in rats treated with kojic acid.

In order to elucidate the mechanisms of reduction of serum thyroid hormones caused by continuous administration of kojic acid (KA) and its thyroid tumor-promotion effects, male F344 rats were given pulverized basal diet containing 0.008%, 0.03%, 0.125%, 0.5%, or 2% KA for 4 weeks. As an untreated control group, additional rats were given basal diet alone for the same period. The thyroid 125I uptake was significantly decreased in the groups receiving 0.03% or more. In addition, significant reduction of organic formation of iodine and serum T3 and T4 levels were observed in the 2% KA group along with pronounced elevation of serum (TSH). Both absolute and relative thyroid weights were significantly increased in the groups receiving 0.5% of KA or more. Histopathologically, decreased colloid in the thyroid follicles and follicular cell hypertrophy in the thyroid were apparent at high incidences in the groups given 0.03% or more. In addition, thyroid capsular fibrosis was evident in all rats of the 2% KA group. In quantitative morphometrical analysis, the ratio of the area of follicular epithelial cells to the area of colloids was significantly increased in the groups given 0.03% KA or more. The results suggest that KA alteration of thyroid-related hormone levels in the 2% KA group are due to inhibition of iodide uptake and iodine organification in the thyroid, with tumor-promoting effects on development of thyroid proliferative lesions, probably secondary to prolonged serum TSH stimulation resulting from negative feedback through the pituitary-thyroid axis.     

The effects of delta 9-tetrahydrocannabinol on serum thyrotropin levels in the rat

The effects of acute treatment with delta 9-tetrahydrocannabinol (delta 9-THC) on serum levels of thyrotropin (TSH) and the thyroid hormones triiodothyronine (T3) and thyroxine (T4) were determined in the rat. Intraperitoneal doses of delta 9-THC greater than 3 mg/kg reduced serum TSH levels to less than 10% of control. The ED50 for delta 9-THC was approximately 0.3 mg/kg. After a 10 mg/kg dose of delta 9-THC, the maximum decrease in serum TSH occurred at one hour. Both serum T3 and serum T4 levels were decreased by a single 10 mg/kg delta 9-THC injection with maximal decreases at 6 hr post-injection. The effects of delta 9-THC on the ability of thyrotropin releasing hormone (TRH) to increase serum TSH and T3 were determined. TRH produced a 10-fold increase in serum TSH levels and this increase was unaffected by delta 9-THC pretreatment. Serum T3 levels were slightly increased by TRH and this increase was also unaffected by delta 9-THC. These findings indicate that acute treatment with delta 9-THC results in a decrease in circulating TSH, T3 and T4 levels but has no effect on the pituitary or thyroid response to exogenous TRH.     

Response of the pituitary and thyroid to tropic hormones in Sprague-Dawley versus Fischer 344 male rats.

Modulation of endocrine function is frequently a confounding factor in the interpretation of chronic rodent toxicology studies. Of particular interest are agents that cause deviation of thyroid hormone homeostasis and result in thyroid cancer for rodents. An endocrine challenge test (ECT), commonly used to study endocrine organ health in human and veterinary medicine, quantifies the response of the thyroid to tropic hormones. This study compared the response of Fischer (F344) and Sprague-Dawley (SD) rats to a thyrotropin-releasing hormone (TRH) ECT and a thyroid-stimulating hormone (TSH) ECT and characterized the dose-response curve. TSH, thyroxine (T4), triiodothyronine (T3), and prolactin responses were characterized for several doses of TRH over a 4-h time period. Animals were equipped with intra-atrial cannulae and were free moving at all times during blood sampling. Both strains of rats responded to intravenous TRH by releasing TSH into their blood in a dose-responsive fashion. At doses of > or = 100 ng, TSH concentrations were increased by more than 2-fold at 2 min. Concentrations reached a maximum at 15 min for doses of 100 ng/100 g body weight (bw) to 5000 ng/100g bw. The effective dose 50 (ED50) of TRH (that dose causing release of half maximal TSH concentrations) was 61 ng in F344 rats and 78 ng in SD rats. The ED75 was 173 ng and 217 ng/100 g bw, respectively. The response of T4 and T3 after TRH ECT and TSH ECT was highly variable. F344 rats responded with an increase in levels of both hormones, starting at 60 min and continuing through 240 min. In SD rats, the presence of a thyroid hormone response (T4) was present, although that of T3 was not clear. These data provide essential information for design of toxicology studies focused on the effects of toxicants and drugs on the pituitary-thyroid axis.     

The effects of chronic ingestion of spironolactone on serum thyrotropin and thyroid hormones in the male rat

Male rats were fed spironolactone admixed with feed at doses of 6, 50, and 200 mg/kg/day for up to 13 weeks. After 13 weeks of treatment, there were dose-related increases in thyroid weight and follicular hypertrophy. Serum thyrotropin (TSH) concentrations were significantly increased throughout the treatment period. Serum thyroxine (T4) and triiodothyronine (T3) were significantly decreased at Weeks 2 and 4, but returned to control concentrations by Week 13. The TSH increase and transient T4 decrease suggested that the thyroid hypertrophy was a compensatory reaction to lowered thyroid hormone levels. To determine the effect of spironolactone ingestion on T4 synthesis and metabolism, male rats were fed spironolactone admixed with feed at 200 mg/kg for 2 weeks. The decrease in T4 was not due to decreased synthesis, since iodide uptake and organification were significantly increased by spironolactone treatment. Since uridine diphosphate glucuronosyl transferase activity was significantly increased by spironolactone treatment, it appears that, by increasing hepatic clearance of T4, spironolactone causes a decrease in the serum concentration of this hormone. The lower T4 level causes a release of feedback inhibition and an increase in TSH resulting in the increase in thyroid gland size and activity.     

Evaluation of possible goitrogenic and anti-thyroidal effect of nitrate, a potential environmental pollutant

Nitrate is a wide spread contaminant of ground and surface water. The source of nitrate in the ground water may be from run off or seepage from fertilized soil, municipal or industrial waste water, land fills, septic system, urban drainage or decaying plants. Human and animal systems are affected severely on nitrate exposure. The study was to investigate the effect of dietary nitrate exposure on the thyroid status along with the state of iodine nutrition. Rats were fed diet containing 3% potassium nitrate (KNO3) for 4 weeks and then thyroid status was evaluated by thyroid gland weight, urinary iodine excretion pattern, thyroid peroxidase (TPO) activity, serum levels of total thyroxine (T4), triiodothyronine (T3) and thyroid stimulating hormone (TSH) concentrations. In nitrate treated animals, the weight of thyroid gland was increased significantly (P<0.001) while thyroid peroxidase activity (P<0.01), serum T4 (P<0.01) and serum T3 levels (P<0.001) were reduced; but serum TSH level was increased (P<0.001) along with slightly elevated iodine excretion level (P<0.001) in comparison to control animals. The overall results indicated the development of a relative state of functional hypothyroidism with enlarged thyroid after nitrate exposure. This study can explain a part for the persistence of residual goitre in the post-salt iodization phase.     

Ophthalmic Graves's disease: natural history and detailed thyroid function studies

Of 27 patients with ophthalmic Graves's disease (OGD) who had been clinically euthyroid three years previously, one became clinically hyperthyroid and seven overtly hypothyroid. Improvement in eye signs was associated with a return to normal of thyroidal suppression by triiodothyronine (T3) and of the response of thyroid-stimulating hormone (TSH) to thyrotrophin-releasing hormone (TRH). Of a further 30 patients with OGD who had not been studied previously, three were overtly hypothyroid. Of the combined series, 46 patients were euthyroid, 18 (40%) of whom had an impaired or absent TSH response to TRH, and 3(6-7%) an exaggerated response. Eleven out of 37 patients (29-7%) had abnormal results in the T3 suppression test. There was a significant correlation between thyroidal suppression by T3 and the TSH response to TRH. Total serum concentrations of both T3 and thyroxine (T4) were closely correlated with T3 suppressibility and TRH responsiveness. Free T4 and T3 (fT3) concentrations were normal in all but three patients, in whom raised fT3 was accompanied by abnormal TSH responses and thyroidal suppression. The presence of normal free thyroid hormone concentrations in patients with impaired or absent TSH responses to TRH is interesting and challenges the concept that free thyroid hormones are the major controlling factors in the feedback control of TSH.     

Influence of oral administration of sulfamethazine on thyroid hormone levels in Fischer 344 rats

Fischer 344 rats (810 of each sex) were divided into treatment groups and fed diets containing 0, 10, 40, 600, 1200, or 2400 ppm sulfamethazine. Serum samples were analyzed for levels of thyroid-stimulating hormone (TSH), total thyroxine (T4), total triiodothyronine (T3), and T3 uptake after 12, 18, or 24 mo of continuous dosing. There were no statistically significant differences in T3 levels or percent T3 uptake for either sex after any of the exposure periods. The serum T4 levels were lower (p less than 0.05) for females dosed at 1200 and 2400 ppm for 18 mo and for males dosed at 600, 1200, or 2400 ppm sulfamethazine for 24 mo than for those dosed at levels of 40 ppm or less. Serum TSH levels showed a general increasing trend (but not statistically significant) among animals receiving 600 ppm or more sulfamethazine. There was a significant dose-related reduction in (T3 + T4)/TSH ratio for both sexes (p less than 0.05) after 18 and 24 mo of exposure at dose levels of 600 ppm or more. A lack of response at 12 mo may have been due to the shorter treatment time. At each sacrifice period both sexes of rats fed sulfamethazine at 1200 and 2400 ppm had significantly heavier (p less than 0.05) thyroid weights than animals fed control diet. The heavier thyroid weights in the dosed animals may have resulted from increased TSH levels. The cause of reduction in serum T4 was not clearly evident. Therefore, the thyroid hormone to pituitary feedback mechanism apparently compensated for sulfamethazine effects in most animals. This would suggest that the thyroid gland was not irreversibly affected.     

The effect of indomethacin, ibuprofen and paracetamol on the TRH induced TSH secretion in the rat

1. The response of TSH to TRH and the TRH content of the hypothalamus, following indomethacin, ibuprofen and paracetamol treatment, was measured in male rats. 2. Daily treatment of indomethacin (3 mg/kg)) for 3 days markedly reduced T4 concentration in the serum, the TRH content of the hypothalmus gland and inhibit Pituitary TSH response to the low T4 level in the blood. 3. Ibuprofen (12 mg/kg) and paracetamol (50 mg/kg) did not influence T4 or TSH levels of the serum nor the TRH content of the hypothalmus. 4. TRH-induced TSH secretion was not influenced by indomethacin, ibuprofen or paracetamol treatment.     

TRH testing, T4-thyrotoxicosis and the aging thyroid gland

Secondary thyroid function tests were compared in 41 mildly thyrotoxic and 36 euthyroid patients with an elevated free thyroxine index (FT4I). A serum TSH measurement 20 minutes after intravenous TRH (delta TSH) most reliably separates these two groups. A significant delta TSH response (greater than 0.5 microU/ml) is also helpful in excluding clinical thyrotoxicosis in patients with nodular goitre. The free T3 index was normal in one-third of mildly thyrotoxic patients and in all euthyroid patients with a falsely elevated FT4I. Blunted delta TSH responses to TRH in elderly New Zealand women were associated with nodular goitre or occult thyroid nodularity revealed only by thyroid scan. The reduced TRH responses are more likely due to partial thyroid autonomy than reduced synthetic capacity of thyrotrophs in old age.     

Effects of 3,4,3',4'-tetrachlorobiphenyl on thyroid function and histology in marmoset monkeys

Marmoset monkeys were treated with oral doses of 0.1, 1 or 3 mg 3,4,3',4'-tetrachlorobiphenyl (TCB) per kg body weight 2 times a week for 18-23 weeks. Histological examination of the thyroid gland revealed a dose-dependent follicular cell hyperplasia. The morphological changes were associated with various disturbances of thyroid function. The average serum thyroxine (T4) levels during the treatment period were reduced by more than 99% in monkeys receiving 3 mg TCB/kg, by 81% in marmosets on a dose of 1 mg TCB/kg, and by 35% with 0.1 mg TCB/kg. The reduction in serum T4 levels was established from the earliest time point (2 weeks) throughout the whole dosing period (18-23 weeks). The reduction in serum T4 levels was reflected in decreased free thyroxine (FT4) index in the 1 and 3 mg TCB/kg dose groups. Serum triiodothyronine (T3) levels were lowered in the 3 mg/kg dose group already after 2 weeks. Evidence for decreased binding to carrier proteins is suggested by increased T3 resin uptake in the highest dose group. Levels of thyrotropin (TSH) were increased in the highest dose group as a feedback response to the dramatically reduced serum T4 levels.     

Effects of phenobarbital, pregnenolone-16alpha-carbonitrile, and propylthiouracil on thyroid follicular cell proliferation.

Reduced thyroid hormone concentrations (T4 and/or T3) and increased thyroid-stimulating hormone (TSH) have been proposed to mediate the thyroid tumor promoting effects of hepatic microsomal enzyme inducers (MEI) and antithyroid drugs. TSH is known to stimulate thyroid gland function and growth, as well as neoplasia. Thyroid weight has been used as an indicator of thyroid gland growth in MEI studies, but little is known about the effects of these inducers on thyroid cell proliferation. Therefore, we determined the time-course of thyroid cell proliferation of rats treated with MEI, and with the antithyroid drug propylthiouracil (PTU). Male Sprague-Dawley rats were fed either a basal diet or a diet containing phenobarbitol (PB) (1200 ppm), PCN (500 ppm), or PTU (30 ppm) for 3, 7, 14, 21, 30, 45, 60, or 90 days. PB and PCN treatments did not affect T3, but PTU reduced T3 60%. PB and PCN treatments reduced T4 25%, whereas PTU treatment reduced T4 90%. PB and PCN treatments increased thyroid weight 80%, and PTU increased thyroid weight 500%. TSH was not appreciably altered in PB-treated rats, but was increased 75% and 830% in PCN- and PTU-treated rats, respectively. Thyroid cell proliferation was increased 260, 330, and 850% in rats treated with PB, PCN, or PTU, respectively, for 7 days, but returned to control levels by the 45th treatment day. In conclusion, treatment with MEI that produced mild increases in TSH resulted in dramatic increases in thyroid cell proliferation, which peaked after 7 days of treatment and then returned to control values. This result is similar to that of antithyroid drugs, which produce large increases in TSH. These findings may have important implications for the role thyroid follicular cell proliferation has in mediating the thyroid tumor promoting effects of MEI.     

Standardization of the perchlorate discharge assay for thyroid toxicity testing in rats

The perchlorate discharge assay (PDA) is potentially of high diagnostic value to distinguish between direct and indirect thyroid toxicity mechanisms, provided that standard treatment times are established and positive controls yield reproducible results. Therefore the PDA was evaluated after 2 and/or 4 weeks of treatment with positive control compounds in rats. Phenobarbital, Aroclor 1254 and beta-naphthoflavone (indirect toxic mechanism) enhanced thyroidal radioiodide accumulation, and the administration of potassium perchlorate had no effect on thyroid: blood (125)I ratio. Phenobarbital caused follicular cell hypertrophy and hyperplasia in the thyroid and centrilobular hypertrophy in the liver, without effects on serum triiodotyronine (T(3)), thyroxine (T(4)) levels. Thyroid-stimulating hormone (TSH) levels were moderately increased. Propylthiouracil (direct toxic mechanism) caused severe thyroid follicular cell hypertrophy and hyperplasia, reduced serum T(3) and T(4) levels and increased serum TSH levels, and reduced thyroidal radioiodide accumulation; perchlorate administration significantly reduced thyroid: blood (125)I ratio, demonstrating an iodide organification block. Potassium iodide (direct toxic mechanism) virtually blocked thyroidal radioiodide accumulation, without significant effects on serum T(3), T(4), and TSH levels and a microscopic correlate for higher thyroid weights. Thus, positive controls yielded reproducible results and we conclude that both the 2- and 4-week PDA is suitable to distinguish between direct and indirect thyroid toxicity mechanisms.     

Thyroid function and effects on reproduction in ewes exposed to the organochlorine pesticides lindane or pentachlorophenol (PCP) from conception

There is concern over the potential endocrine-modulating effects of long-term exposure to pesticides. In this study, ewe lambs were exposed to lindane and pentachlorophenol (PCP) from conception to necropsy at 67 wk. of age. The ewe lambs (and their mothers) were given untreated feed (n = 6) or feed treated with 1 mg/kg body weight/day of lindane (n = 8) or PCP (n = 13). Estrus was synchronized at 32 wk. of age, and ewe lambs were exposed to vasectomized rams. Ewe lambs were then exposed to intact rams during the following two natural estrous periods and subsequent reproductive performance was monitored. Serum was collected every 2 wk. during development, daily during the synchronized cycle and frequently (every 15-60 min) for 6-18 h either with or without stimulation with thyroid-stimulating hormone (TSH) during the synchronized luteal phase or TSH/thyroid-releasing hormone (TRH) at 65-66 wk of age. Ewe lambs fed a PCP-treated diet had a significantly reduced serum concentration of both T4 and free T4, and a reduction in the magnitude and duration of the T4 and free T4 response to TSH, despite normal endogenous levels of TSH and a normal TSH response to TRH. PCP exposure had a less detrimental influence on unstimulated T3 levels; however, the T3 (but not reverse T3) response to TSH was markedly reduced in PCP-treated ewe lambs. Ewe lambs given lindane also had a significantly reduced serum concentration of T4; however, despite continued exposure to lindane, T4 levels returned to normal by 10 wk. of age. Detrimental effects on reproductive function were only seen following estrous synchronization when both PCP and lindane exposure reduced the number of corpora lutea (CL) and total CL volume and increased luteinizing hormone (LH) pulse frequency. In addition, lindane-treated ewes had shorter estrous cycles and lower luteal progesterone concentrations. No marked effects of pesticides were seen on fertility following mating during natural estrous periods. In conclusion, the pesticides affected reproduction only after estrous synchronization, whereas PCP consistently disrupted thyroid function, most likely through a direct effect on the thyroid gland.     

Differential effects of microsomal enzyme inducers on in vitro thyroxine (T(4)) and triiodothyronine (T(3)) glucuronidation.

Microsomal enzyme inducers that increase UDP-glucuronosyltransferase (UDP-GT) activity are suspected to affect the thyroid gland by increasing the glucuronidation of T(4), which reduces serum thyroxine (T(4)). In response to reduced serum T(4), serum thyroid-stimulating hormone (TSH) increases. However, not all microsomal enzyme inducers that reduce serum T(4) produce an increase in serum TSH. We have shown that serum TSH is increased the most in rats treated with the microsomal enzyme inducers phenobarbital (PB) or pregnenolone-16alpha-carbonitrile (PCN), whereas TSH is affected less in rats treated with 3-methylcholanthrene (3MC) and Aroclor 1254 (PCB). It is unclear why serum TSH is differentially affected by various microsomal enzyme inducers. We propose that the glucuronidation of T(3) might be the reason serum TSH is increased by some microsomal enzyme inducers but not by others. Male Sprague-Dawley rats were fed either a basal diet or a diet containing PB (at 300, 600, 1200, or 2400 ppm), PCN (at 200, 400, 800, or 1600 ppm), 3MC (at 50, 100, 200, or 400 ppm), or PCB (at 25, 50, 100, or 200 ppm) for 7 days; and T(4) and T(3) UDP-GT activities were then determined. T(4) UDP-GT activity was increased in rats treated with PB (120%), PCN (250 to 400%), 3MC (400 to 600%), or PCB (300 to 430%). In contrast, T(3) UDP-GT activity was increased in rats treated with PB (90%) or PCN (120 to 200%), whereas 3MC and PCB treatments did not have an appreciable effect. In conclusion, differential effects on T(3) glucuronosyltransferase activity were found in rats treated with microsomal enzyme inducers.     

Serotonergic and catecholaminergic influence on thyroid function in the vervet monkey

Vervet monkeys were pharmacologically treated acutely and with repeated dose loading to alter serotonergic systems to assess the role of serotonin in the regulation of the hypothalamus-pituitary-thyroid axis. Acute L-tryptophan administration failed to alter basal levels of thyroid hormones but did decrease the TRH-induced TSH response. Repeated dose loading of tryptophan or 5-hydroxytryptophan increased blood serotonin and plasma T3 and decreased plasma TSH. The tryptophan hydroxylase inhibitor p-chlorophenylalanine yielded decreased blood serotonin, but did not affect plasma TSH, T4 or T3. The monoamine oxidase inhibitor chlorgyline also resulted in increased blood serotonin, but increased plasma TSH and T4 and decreased T3. These data may be explained by a unitary hypothesis involving central catecholaminergic, rather than serotonergic, control of TRH release. Chlorgyline may produce its effects predominantly by facilitating catecholaminergic stimulation of TRH release resulting in increased TSH and a consequent increase in T4. It is suggested that the effects of tryptophan and 5-hydroxytryptophan result from increases in serotonin levels in the thyroid gland to produce an increase in T3 with a compensatory decrease in TSH via negative feedback. The differences observed between the acute and repeated dose loading studies stress the need for both types of studies before drawing conclusions about the effects of pharmacological manipulations on hormonal levels.     

Effects of diethofencarb on thyroid function and hepatic UDP-glucuronyltransferase activity in rats.

To examine the mechanism and toxicological significance of thyroidal tumor observed slightly in a long-term rat study with diethofencarb (isopropyl 3,4-diethoxycarbanilate), male Sprague-Dawley rats were fed diethofencarb in diets at concentrations of 0, 5,000 or 20,000 ppm for 3 months. Examinations mainly for thyroid functions including thyroid uptake of 125I, serum thyroid hormone and thyroid stimulating hormone (TSH) level, hepatic UDP-glucuronyltransferase (UDP-GT) activity and histopathological examination in thyroid were performed at week 13. Decreases of body weights and food consumptions were observed at and above 5,000 ppm. Under these conditions, decrease of serum free T4 and increase of serum TSH level were observed only at 20,000 ppm, concurrently with liver weight increase at and above 5,000 ppm and increase of hepatic UDP-GT activity at 20,000 ppm. However, no compound related effects were noted in thyroid weight, thyroid uptake of 125I and gross or histopathological examination in thyroid. These results indicate that the administration of diethofencarb leads to an increase in UDP-GT activity and acceleration of thyroid hormone excretion from the liver. The acceleration causes a decrease in serum free T4 level, triggering the feedback mechanism of the pituitary gland, promotion of TSH release and consequently an increase in serum TSH level. Thus, the slightly higher incidence of thyroid follicular cell tumors observed in the chronic and oncogenicity study with non-genotoxic diethofencarb is considered to be caused by these weak pituitary-thyroid hormonal imbalances. The toxicological significance in humans is extremely low according to the well established facts that the chronic TSH stimulating would not induce thyroid tumors in humans and humans may be less sensitive than rats in regard to the response to goitrogenic stimuli.     

A biologically based dose-response model for dietary iodide and the hypothalamic-pituitary-thyroid axis in the adult rat: evaluation of iodide deficiency.

A biologically based dose-response (BBDR) model was developed for dietary iodide and the hypothalamic-pituitary-thyroid (HPT) axis in adult rats. This BBDR-HPT axis model includes submodels for dietary iodide, thyroid-stimulating hormone (TSH), and the thyroid hormones, T(4) and T(3). The submodels are linked together via key biological processes, including (1) the influence of T(4) on TSH production (the HPT axis negative feedback loop), (2) stimulation of thyroidal T(4) and T(3) production by TSH, (3) TSH upregulation of the thyroid sodium (Na(+))/iodide symporter, and (4) recycling of iodide from metabolism of thyroid hormones. The BBDR-HPT axis model was calibrated to predict steady-state concentrations of iodide, T(4), T(3), and TSH for the euthyroid rat whose dietary intake of iodide was 20 mug/day. Then the BBDR-HPT axis model was used to predict perturbations in the HPT axis caused by insufficient dietary iodide intake, and simulation results were compared to experimental findings. The BBDR-HPT axis model was successful in simulating perturbations in serum T(4), TSH, and thyroid iodide stores for low-iodide diets of 0.33-1.14 mug/day. Model predictions of serum T(3) concentrations were inconsistent with observations in some cases. BBDR-HPT axis model simulations show a steep dose-response relationship between dietary intake of iodide and serum T(4) and TSH when dietary iodide intake becomes insufficient (less than 2 mug/day) to sustain the HPT axis. This BBDR-HPT axis model can be linked with physiologically based pharmacokinetic models for thyroid-active chemicals to evaluate and predict dose-dependent HPT axis alterations based on hypothesized modes of action. To support continued development of this model, future studies should include time course data after perturbation of the HPT axis to capture changes in endogenous iodide, serum TSH, T(4), and T(3).     

Interspecies differences in susceptibility to perturbation of thyroid homeostasis: a case study with perchlorate

Despite many physiological similarities, humans and rats exhibit notably different susceptibilities to thyroid perturbation. Considerable research has recently been conducted on the thyroid-active chemical perchlorate, a chemical of emerging environmental and regulatory interest. While the data indicate humans and rats exhibit similar dose-response relationships in terms of acute inhibition of thyroidal iodide uptake, the two species appear to exhibit notable differences in terms of thyroid hormone response, the toxicologically significant consequence of iodide uptake inhibition. We analyzed dose-response data for changes in serum T(3), T(4), and TSH levels from studies in humans, rats, mice, and rabbits. We found that thyroid homeostasis in the rat appears to be strikingly more sensitive to perchlorate than any of the other species. Rats exhibited an increase in serum TSH at 0.1mg/kg-day whereas other species remained unresponsive even at doses of 10mg/kg-day. Less pronounced but consistent effects were seen with serum T(3) and T(4). These cross-species comparisons provide strong evidence that data obtained from rat studies should be critically evaluated for their relevance to humans. If rat data are used to develop toxicity criteria for perchlorate, we propose that this is an instance where an inter-species uncertainty factor less than one is supportable. DISCLOSURE STATEMENT: One of the authors (BDB) has been hired by Lockheed Martin Corporation as an expert in litigation involving perchlorate. A portion of the initial research presented in this paper was conducted in conjunction with her role in that matter.