Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater in the southwestern United States, typically at 0.005-0.020 mg/L (5-20 ppb). Perchlorate is a competitive inhibitor of the process by which iodide is actively transported from the bloodstream into the thyroid. This inhibitory action of perchlorate is the basis of its pharmaceutical use (in the treatment of hyperthyroidism) as well as its potential toxicity. To establish the dose response in humans for perchlorate inhibition of thyroidal iodide uptake and any short-term effects on thyroid hormones, we gave perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day to 37 male and female volunteers for 14 days. In 24 subjects we performed 8- and 24-hr measurements of thyroidal (123)I uptake (RAIU) before exposure, on exposure days 2 (E2) and 14 (E14), and 15 days postexposure (P15). In another 13 subjects we omitted both E2 studies and the 8-hr P15 study. We observed a strong correlation between the 8- and 24-hr RAIU over all dose groups and measurement days. We found no difference between E2 and E14 in the inhibition of RAIU produced by a given perchlorate dose. We also found no sex difference. On both E2 and E14, the dose response was a negative linear function of the logarithm of dose. Based on the dose response for inhibition of the 8- and 24-hr RAIU on E14 in all subjects, we derived estimates of the true no-effect level: 5.2 and 6.4 micro g/kg-day, respectively. Given default body weight and exposure assumptions, these doses would be ingested by an adult if the drinking-water supply contained perchlorate at concentrations of approximately 180 and 220 micro g/L (ppb), respectively. On P15, RAIU was not significantly different from baseline. In 24 subjects we measured serum levels of thyroxine (total and free), triiodothyronine, and thyrotropin in blood sampled 16 times throughout the study. Only the 0.5 mg/kg-day dose group showed any effect on serum hormones: a slight downward trend in thyrotropin levels in morning blood draws during perchlorate exposure, with recovery by P15.
TSH, T4, and T3 were measured by radioimmunoassay in plasma samples obtained from 77 young adult male and 114 female rats fed a Purina high-iodine diet and maintained in an isolated room, 2-4/cage, at 24 +/- 1 C with light from 0600-1800 h. In one experiment, 7 male and 7 female rats were decapitated every 3 h for 30 consecutive h and trunk blood was collected. There was a clear nyctohemeral rhythm of plasma TSH in both sexes characterized by a zenith at 1200 h and a nadir between 1800 and 2100 h. The plasma TSH cycle was approximately 180 degrees out of phase and negatively correlated (P less than .05) with that of plasma corticosterone (B) in both sexes. Although glucocorticoids have been reported to suppress TSH secretion, there was no causal relationship between plasma B and TSH in our experiments since the TSH cycles were normal in chronically adrenalectomized rats. Normal TSH cyclicity was not observed in severely iodine-deficient rats with extremely high plasma TSH levels although the nyctohemeral B rhythm was normal. Plasma TSH was approximately twice as high in males as in females (overall mean +/- SE: M = 149 +/- 11, F = 81 +/- 7 muU/ml, p less than 0.001). There was no significant difference (P greater than 0.05) in plasma TSH at different stages of the estrous cycle. Plasma T4 was slightly, but significantly, higher in males than females (overall mean +/- SE: M = 6.4 +/- 0.1, F = 6.0 +/- 0.1 mug/100 ml; P less than 0.001), while T3 was higher in females than in males (overall mean +/- SE: M = 69.5 +/- 1.7, F = 80.3 +/- 2.1 ng/100 ml; P less than 0.001). No significant nyctohemeral rhythm was observed in plasma T4 or T3 in either sex. These observations indicate that: 1) There is a nyctohemeral rhythm of plasma TSH which is independent of plasma B fluctuations and not associated with proportional changes in plasma thyroid hormones. 2) A sustained high rate of TSH secretion abolishes the normal nyctohemeral plasma TSH rhythm. 3) There are significant differences in plasma concentrations of TSH, T4, and T3 between male and female rats.
We investigated whether thyrotoxic patients treated with short-term antithyroid therapy would achieve prolonged remissions. Thirty-one previously untreated and nine previously treated patients with thyrotoxic Graves's disease received a single daily dose of methimazole or propylthiouracil. The drug was stopped at, or shortly after, the time they became euthyroid. Twelve of the 31 previously untreated patients remained in remission for 29 +/- 3.5 months (mean +/- S.E.) after treatment for 4.5 +/- 0.3 months. Four of the nine previously treated have remained in remission of 13.0 +/- 2.1 months after treatment for 3.0 +/- 0.3 months. Of various possibilities analyzed, only a small goiter at the onset of therapy and tri-iodothyronine toxicosis were significantly favorable prognostic indicators that a remission would be maintained. The lasting remission rate is as good when antithyroid drugs are stopped as soon as the patient is euthyroid as when they are continued for one year or more.
Progoitrin is a thioglycoside present in high concentration in the seeds of most Brassicaceous plants and in the edible parts of some, particularly rutabaga and turnip. I t is hydrolyzed by enzymes (myrosinases) in these plants to yield goitrin, a potent antithyroid compound ( 1,2,3) (Fig. 1 ).Although it had been assumed for many years that hydrolysis of thioglycosides similar to progoitrin could be accomplished only through the action of myrosinase of plant origin, recent studies have indicated that this view is incorrect. Reese et aZ(4) reported that the fungus Aspergillus s y d m * produced a P-thioglycosidase (termed "sinigrinase") active on the mustard oil thioglycosides sinigrin, sinalbin, and progoitrin; however, the enzyme could not be obtained from other fungal genera or from the bacteria, Bacillus subtilis or Pseudomonas aeruginosa, which also were found to "consume" sinigrin on prolonged (14-day) incubation with this compound. Thioglycosidase activity hydrblyzing several purinyl thioglycosides has been reported by Goodman et aZ(5) to be widespread in mammalian species, and to occur in the microorganisms Tetrahymena pyriformis and Escherichia coli.Because of the possible importance of goitrin derived from commonly ingested vegetables in the production of human non-toxic goiter, studies were undertaken of the metabolic fate of pure crystalline progoitrin in man after oral ingestion. It was found that in such cases goitrin could be demonstrated * Supported by grants from U.S.P.H.S. in blood and urine(6). These results suggested that the conversion of progoitrin to goitrin might have been carried out by thioglycosidase activity of bacteria in the gastrointestinal tract. This hypothesis was reinforced by the finding that incubation of rat or human feces with progoitrin resulted in goitrin formation( 3 ) . This myrosinase activity in feces was destroyed by boiling, filtration, or sonoration, and was markedly reduced by prior oral administration of Amphotericin B and Neomycin(3), a regimen which has been shown to effect a striking decrease in viable fecal bacterial flora (7).The data reported here concern experiments on the isolation and identification of fecal bacteria with myrminase activity, comparison of such organisms with stock strains of various bacterial species, and conditions necessary for formation and activity of bacterial myrosinase.MateriaZs and methods. Progoitrin was prepared from rutabaga seed by the method of Greer (2). Bacterial cell suspensions were obtained by growing the organisms, unless otherwise stated, in nutrient broth containing 1 % glucose for 18 hours a t 37°C without shaking. The cells were harvested by centrifugation, washed once with water, and resuspended in water at a concentration between 1.0 and 2.0 mg bacterial nitrogen per ml. The cell suspensions were incubated with progoitrin and buffer at concentrations noted in the legends, in a total volume of 5.0 ml contained in 50 ml Erlenmeyer flasks which were shaken in a water bath at 37°C. Length
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