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Several exposure limits for perchlorate have been developed based on an early key event, inhibition of radioactive iodide uptake (RAIU) by the thyroid. These assessments have used a variety of definitions of the point of departure. The current assessment revisited the modeling for inhibition of RAIU, using state of the science methods. Bayesian hierarchical modeling was used to account for the repeated measures on the same individuals in the key dataset, and the underlying Beta distribution used for the modeling correctly reflected the bounding of RAIU between 0 and 1. We defined the BMR as a point value of 8% RAIU (rather than a change in RAIU), based on descriptions in the medical literature that RAIU below this value is considered abnormal. Because a definition of the BMR based on the mean response would correspond to about 50% of the population with a response below the BMR at the benchmark dose, we used a hybrid definition of the BMR. That is, the BMD was defined as the dose at which it was estimated that there would be a 10% extra risk in the population of having RAIU of 8% or lower. The resulting point of departure based on the BMDL was 0.03 mg/kg-day., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was supported by Specialised Nutrition Europe (SNE), Brussels, Belgium. The sponsor reviewed a much earlier version of this work, in which the average results from Greer et al. (2002) were modeled using a variety of approaches. However, the sponsor did not see any of the results with the modeling of the individual data from the Greer study prior to submittal of the manuscript. LTH and BCA also have had two recent projects supported by organizations with membership lists that overlap with that of SNE. LTH and BCA received support from Grocery Manufacturers Association, the Institute of Shortening and Edible Oils, the EU Vegetable Oil & Proteinmeal Industry, the Infant Nutrition Council of America, FoodDrink Europe, and the International Technical Caramel Association for a review of benchmark dose modeling methods that was published in 2018. LTH and BCA are also currently receiving support from ILSI NA for an unrelated project., (Copyright © 2021. Published by Elsevier B.V.)

Imaging of cardiac sympathetic innervation is only possible by nuclear cardiology techniques and its assessment is key in the evaluation of and decision-making for patients with cardiac sympathetic impairment. This review includes the basis of cardiac sympathetic scintigraphy with 123 I-meta-iodobenzylguanidine ( 123 I-MIBG), recommended protocols, patient preparation, image acquisition and quantification, reproducibility, dosimetry, etc., and also the clinical indications for cardiac patients, mainly with regard to heart failure, arrhythmia, coronary artery disease, cardiotoxicity, including its contribution to establishing the indication for and monitoring the response to implantable cardiac devices, pharmacological treatment, heart transplantation and other., (Copyright © 2019 Sociedad Española de Medicina Nuclear e Imagen Molecular. Publicado por Elsevier España, S.L.U. All rights reserved.)

Perchlorate, as an oxidizer, has many applications such as explosives and pyrotechnics, especially in rocket propellants and missile motors. Because it was found in water including wells and drinking water in the US, its effect on human health was being noted. However, the reproductive toxic effect on perchlorate is still unclear. In present study, the effects of repeated exposure to perchlorate on reproductive toxicity were evaluated in Wistar rats. The rats were treated orally with perchlorate at doses of 0.05, 1.00 or 10.00 mg/kg body weight (b.w.) daily for 8 weeks. The levels of T 3 and T 4 hormones in the rat serum were detected by radioimmunoassay kit. The indexes of reproduction, percentage of organ in body weight (%) and frequency of abnormal sperm cells were also analyzed in this study. DNA damage in testicular cells was evaluated by Comet assay. The levels of MDA, GSH and SOD were examined in testicle tissues of rats by ELISA. The expression of c-fos and fas protein was examined in testicle tissues by immunohistochemistry. The results showed that perchlorate did not affect the body weight of rats. Perchlorate also significantly decreased indexes of live birth and weaning in the groups of 1.00 and 10.00 mg/kg, and viability index only in the 10.00 mg/kg group (P < 0.05). Perchlorate also significantly decreased the serum level of T 3 in male rats of 1.00 and 10.00 mg/kg groups, increased the rate of sperm abnormality (10.00 mg/kg), potentially caused DNA damage in testicular cells and altered the status of oxidative stress in male rats. In addition, because of the increase in the expression of fas and c-fos protein in testicle tissues, perchlorate could induce apoptosis in spermatogenesis. Thus, these findings indicate that perchlorate could cause DNA damage in testicular tissues and reduce testicular spermatogenic ability, resulting in reproductive toxicity., (Copyright © 2019. Published by Elsevier Ltd.)

Perchlorate is frequently found as contaminant in a variety of food. Based on analytical data of perchlorate occurrence in food products from the Austrian market, this study calculated dietary perchlorate exposure of the Austrian population for the three age classes of adults, children and infants. Furthermore, a detailed risk assessment was conducted based on the tolerable daily intake (TDI) of 0.3 µg/kg body weight/day, established by the European Food Safety Authority in 2014. Calculations of a scenario of average food consumption did not indicate elevated health risks by dietary perchlorate uptake. Exposure estimates reached only 12%, 26% and 24% of the TDI for adults, children and infants, respectively. However, in a scenario of high consumption, the TDI was exceeded by all age classes with 132%, 161% and 156%. The major cause for this exceedance is the comparatively high perchlorate contamination of spinach, but also other leaf vegetables, legumes and pineapples, leading to elevated exposure of high consumers. Our calculations reveal that the current provisional intra-Union trade reference level for perchlorate in spinach of 0.2 mg/kg, advocated by the European Commission, is not sufficient to protect high consumers against possible health risks. In order to reduce health risks to a tolerable level for all consumers, lowering of the regulatory maximum perchlorate concentrations is indicated. Moreover, a generally diversified diet can also counteract excessive exposure to perchlorate as well as to other harmful food contaminants.

Objective: To conduct a more robust examination of perchlorate exposure on iodide uptake inhibition (IUI) using pooled data from four clinical studies of perchlorate exposure., Methods: To establish a response threshold for IUI, data were analyzed using segmented linear regression and benchmark dose (BMD) analysis., Results: Segmented linear regression applied to data for 69 subjects representing nine doses identified a breakpoint corresponding to a change in the slope of the dose-response relationship of 3.0 mg/d perchlorate. The estimated BMD for a 20% decrease in iodine uptake was 2.3 mg/d, with a lower 95% confidence interval limit of 1.6 mg/d., Conclusions: A threshold dose for IUI from perchlorate exposure of 1.6 to 3.0 mg/d (0.021 to 0.038 mg/kg d) was estimated using two modeling approaches. These estimates are slightly higher than the lowest observed effect level of 0.02 mg/kg d from the Greer Study.

Background: This study aimed to establish the changes in the incidence and characteristics of iodine-induced hyperthyroidism (II-Hyper) and iodine-induced hypothyroidism (II-Hypo) in the two-year period before and the 10-year period after the increase in mandatory salt iodization from the previous 10 mg/kg of potassium iodide to 25 mg/kg in 1999. Furthermore, the aim was to determine the duration of treatment in II-Hyper patients, since no data regarding severity and treatment of II-Hyper with respect to iodine supply are available., Methods: This retrospective study reviewed medical records of 885 Slovenian patients first diagnosed with II-Hyper or II-Hypo between 1998 and 2009 at the Thyroid Department of the University Medical Centre Ljubljana. II-Hyper and II-Hypo were diagnosed by one out of 10 senior internal medicine specialists. The diagnosis was based on an adequate patient history, and laboratory measurements of thyrotropin, thyroid hormones, and thyroid antibodies. In most cases, thyroid ultrasound and thyroid scintigraphy were performed. Demographic characteristics and the type and the duration of treatment were also reviewed., Results: The incidence of II-Hypo was significantly higher after the increase in iodine supply than it was before (p < 0.001). After the increase in iodine supply, the incidence of II-Hyper was significantly lower than before the increase (p < 0.001). Furthermore, the portion of patients with overt hyperthyroidism decreased, predominantly due to the increased proportion of patients with subclinical hyperthyroidism (p = 0.007 and p = 0.015, respectively). The duration of treatment with antithyroid drugs and perchlorate was significantly shorter after the increase in iodine supply than it was before (p = 0.001 and p = 0.002, respectively). A significantly positive correlation between the year of the occurrence of excessive iodine intake (EII)-induced thyroid disease and the duration of treatment with amiodarone was found (R = 0.132; p = 0.048), suggesting that the longer the patients had an adequate iodine supply, the longer they could take amiodarone before EII-induced thyroid disorder developed., Conclusions: After the increase in iodine supply, a higher incidence of II-Hypo and a lower incidence of II-Hyper were observed than before the increase. Less severe II-Hyper, shorter duration of treatment of II-Hyper, as well as a longer thyroid disease-free period in patients on amiodarone are additional beneficial clinical consequences after the establishment of an adequate iodine supply.

Ensuring adequate iodine intake is important, particularly among women of reproductive age, because iodine is necessary for early life development. Biologically based dose-response modeling of the relationships among iodide status, perchlorate dose, and thyroid hormone production in pregnant women has indicated that iodide intake has a profound effect on the likelihood that exposure to goitrogens will produce hypothyroxinemia. We evaluated the possibility of increasing iodine intake to offset potential risks from perchlorate exposure. We also explored the effect of dietary exposures to nitrate and thiocyanate on iodine uptake and thyroid hormone production. Our modeling indicates that the level of thyroid hormone perturbation associated with perchlorate exposures in the range of current regulatory limits is extremely small and would be overwhelmed by other goitrogen exposures. Our analysis also shows that microgram levels of iodine supplementation would be sufficient to prevent the goitrogenic effects of perchlorate exposure at current regulatory limits among at risk individuals. The human health risks from supplementing drinking water with iodine are negligible; therefore, this approach is worthy of regulatory consideration., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To evaluate the feasibility of urine perchlorate as a biomarker of ammonium perchlorate (AP) exposure and to explore the correlation between the thyroid function indicators and the perchlorate concentrations, a sensitive and selective ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) method was developed to detect perchlorate in urine samples. Rats were orally administrated with different doses of perchlorate. Serum free thyroxine (FT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) were determined by radioimmunoassays. The results showed that a dose of AP up to 520 mg kg(-1) body weight induced a significant increase of TSH, with a decrease of FT4. Particularly, the levels of urine perchlorate increased dose-dependently on AP exposure from drinking water. The findings highlighted that urine perchlorate may be a useful biomarker for AP environmental exposure.

Steroid hormones exert profound effects on the development of brain areas controlling complex cognitive function in adulthood. One class, progestins, may contribute by acting on the progestin receptor (PR), which is transiently expressed in a critical layer of developing cortex: the subplate. PR expression in the subplate coincides with the establishment of ongoing cortical connectivity and may play an important organisational role. Identification of the factor(s) that regulate the precise timing of PR expression within subplate may help elucidate the function of PR. Thyroid hormone may interact with hormone response elements within the PR gene. The present study examined the effects of maternal hypothyroidism on levels of PR immunoreactivity (PR-IR) within the foetal subplate. Pregnant rats were made hypothyroid by the administration of methimazole and potassium perchlorate in drinking water. Maternal hypothyroidism significantly decreased PR-IR within the foetal subplate. Using the incorporation of 5-bromo-2'-deoxyuridine (BrDU) during subplate cell neurogenesis (embryonic day 13.5) to determine subplate cell survival in hypothyroid animals, we found that decreases in PR-IR cannot be attributed to significant subplate cell loss but are more likely the result of altered PR expression. Gestational thyroxine replacement to hypothyroid dams prevented the decrease in PR-IR within the subplate. These results identify thyroid hormone as a potential factor in the regulation of PR expression in the developing brain. These results are consistent with the idea that endocrine cross-talk between progesterone and thyroid hormone may be one mechanism by which maternal hypothyroidism alters normal cortical development., (© 2012 The Authors. Journal of Neuroendocrinology © 2012 Blackwell Publishing Ltd.)

Context: People being exposed to potentially harmful amounts of radioactive iodine need prophylaxis to prevent high radiation-absorbed doses to the thyroid., Objective: Parameters determining the individual protective effect of a pharmacological intervention were investigated., Design and Participants: Biokinetics of (123)I was evaluated in 27 healthy volunteers (aged 22-46 yr, median 25 yr, in total 48 assessments) twice in a baseline measurement of the undisturbed kinetics and in an intervention assessment 48 h later., Interventions: Seven regimens using single doses of potassium iodide (KI) or sodium perchlorate (SP) at different times relative to exposure were compared: 100 mg KI (-24, 2, 8, 24 h), 100 mg SP (2 h), or 1 g SP (2, 8 h)., Main Outcome Measures: Different drugs and dosages and the influence of individual parameters of iodine kinetics should be tested., Results: Mean dose reductions for interventions at -24, 2, 8, and 24 h relative to the activity incorporation were 88.7, 59.7, 25.4, and 2.8%, respectively. One gram SP was equally effective as 100 mg KI; residual uptake was observed after 100 mg SP. The individual dose reduction decreased exponentially with the effective half-life of the activity in the blood. Kinetics in subjects older than 40 yr was as assumed in official guidelines for the prophylaxis after nuclear accidents but was faster in younger participants., Conclusions: Data on the efficacy of thyroid blocking used in the guidelines are adequate for older people but not for young individuals with their typically faster kinetics. SP may be used for thyroid blocking as alternative for individuals with iodine hypersensitivity.

Perchlorate can perturb thyroid hormone (TH) homeostasis by competitive inhibition of iodide uptake by the thyroid gland. Until recently, the effects of perchlorate on TH homeostasis were examined by measuring serum concentrations of THs by immunoassay (IA) methods. IA methods are sensitive, but for TH analysis they are compromised by lack of adequate specificity. In this study, we determined the concentrations of six THs: L-thyroxine (T₄), 3,3',5-triiodo-L-thyronine (T₃), 3,3',5'-triiodo-L-thyronine (rT₃), 3,5-diiodo-L-thyronine, 3,3'-diiodo-L-thyronine, and 3-iodo-L-thyronine in the serum of rats administered perchlorate by isotope (¹³C₆-T₄)-dilution liquid chromatography-tandem mass spectrometry. The method recoveries for THs spiked into a serum matrix were between 97.0% and 115%, with a coefficient of variation of 2.1% to 9.4%. Rats were placed on an iodide-deficient or iodide-sufficient diet for 2.5 months, and for the last 2 weeks of that period they were provided drinking water either without or with perchlorate (10 mg/kg body weight/day). No significant differences in serum concentrations of T₃ and T₄ were observed between rats given iodide-deficient and iodide-sufficient diets for 2 or 2.5 months. After 24 h of perchlorate exposure, significantly lower concentrations of T₃ and T₄ were found in the serum of rats administered the iodide-deficient diet but not in rats administered the iodide-sufficient diet. However, after 2 weeks of perchlorate exposure, TH levels in rats fed the iodide-sufficient diet were also significantly lower than those in control rats. Our results suggest that perchlorate affects TH homeostasis and that such effects are more pronounced under iodide-deficient nutrition.

Unlabelled: (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) scanning precedes radioembolization of the liver to detect extrahepatic shunting to the lung or gastrointestinal tract. Despite strict preventive measures in the production of (99m)Tc-MAA and in scanning protocols, the images frequently show a gastric concentration of free (99m)Tc-pertechnetate, hindering accurate evaluation of the gastroduodenal region. Our aim was to evaluate whether oral administration of sodium perchlorate (NaClO(4)) before (99m)Tc-MAA scanning will improve its accuracy by blocking free (99m)Tc-pertechnetate gastric uptake., Methods: In 144 patients, 171 diagnostic hepatic angiograms combined with a (99m)Tc-MAA scan were performed; 86 angiograms were performed after oral administration of NaClO(4), and 85 were performed without this premedication. Clinical follow-up, esophagogastroduodenoscopy, and angiography served as reference standards., Results: (99m)Tc-MAA studies showed tracer uptake in the gastric region of 25 patients who did not receive NaClO(4). The uptake was interpreted as a free (99m)Tc-pertechnetate concentration in 21 studies and as a (99m)Tc-MAA accumulation in 4 studies. In 5 patients with a free (99m)Tc-pertechnetate concentration, aberrant vessels were detected in angiographic reexamination, and 3 patients developed gastrointestinal ulcer. In 7 studies, gastric findings viewed pretherapeutically as free (99m)Tc-pertechnetate were retrospectively classified as equivocal. Of the patients receiving NaClO(4), 2 showed gastric accumulation of (99m)Tc-MAA but no equivocal or free (99m)Tc-pertechnetate. Oral administration of NaClO(4) increased the negative predictive value and accuracy of the test concerning the detection of gastric perfusion from 68% and 69%, respectively, to 93% and 94%, respectively., Conclusion: Oral administration of NaClO(4) before the test angiogram with (99m)Tc-MAA resulted in effective avoidance of free (99m)Tc-pertechnetate concentration and, consequently, of equivocal findings in the gastroduodenal region. This technique increased test accuracy and reporter confidence, saved time in reviewing the angiograms, and can improve treatment planning and reduce therapeutic side effects.

Thyroid status was assessed in adult female rhesus monkey breeders at the California National Primate Research Center at the beginning of the breeding season. The 95% confidence intervals for thyrotropin (TSH), thyroxine (T(4)) and triiodothyronine (T(3)) (n = 66-80) were similar to those previously reported in smaller samples of macaque monkeys. Based on human criteria, 10 of 80 monkeys (12%) were hypothyroid (TSH > 2.0 µIU/mL). Because hypothyroxinaemia can be a risk factor in pregnancy, T(4) status was compared with past breeding history, breeding outcome for that season and general health records in a subset of 42 breeders. Age, weight and parity did not differ between monkeys in the lowest T(4) quartile as compared with those in the upper three quartiles. However, T(4) concentrations were significantly associated with the number of missed menstrual cycles during the previous breeding season. In additional work, three healthy lactating rhesus monkeys were given three different doses of environmental contaminant and thyroid iodine uptake inhibitor, ammonium perchlorate (0.006, 0.34, 12.8 mg/kg/day, respectively) in food for two weeks. Thyroid status variables (TSH, T(4), T(3), thyroid radioactive iodine uptake) were then measured. In the monkey receiving the highest perchlorate dose, iodine uptake was suppressed relative to baseline. The study shows the availability of tools to study thyroid status in rhesus monkeys, the variability of thyroid status in the breeder colony and the potential ability of environmental factors to influence thyroid status.

Introduction: Amiodarone-induced thyrotoxicosis (AIT) is a common clinical disorder that may be life threatening and whose clinical manifestations and response to treatment may vary among patients., Methods: We present three patients treated with amiodarone for atrial fibrillation who developed AIT at least 36 months after beginning the treatment. Thyrotoxicosis worsened the underlying cardiac disorders and was resistant to treatment based on the combination of dexamethasone 8-12 mg/day i.v., thioamides 45 mg/day p.o., beta blockers and potassium perchlorate at doses of 800 to 1000 mg per day p.o. Two of the patients attained sustained euthyroidism after 12 and 32 days of combined treatment, while the third required total thyroidectomy., Conclusion: The combination of thioamides with potassium perchlorate is an appropriate form of therapy for AIT in patients resistant to thioamides. The use of this combination should be evaluated in patients with mixed AIT or AIT of unclear etiology., (Copyright © 2010 SEEN. Published by Elsevier Espana. All rights reserved.)

Amiodarone is a potent antiarrhythmic drug associated with thyroid dysfunction. Its high iodine content causes inhibition of 5'-deiodinase activity. Most patients remain euthyroid. Amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH) may occur depending on the iodine status of individuals and prior thyroid disease. AIT is caused by excess iodine-induced thyroid hormone synthesis (type I AIT) or by destructive thyroiditis (type II AIT). If the medical condition allows it, discontinuation of the drug is recommended in type I AIT. Otherwise, large doses of thioamides are required. Type II AIT is treated with corticosteroids. Mixed cases require a combination of both drugs. Potassium perchlorate has been used to treat resistant cases of type I AIT but use is limited by toxicity. Thyroidectomy, plasmapheresis, lithium, and radioiodine are used in select cases of AIT. AIH is successfully treated with levothyroxine. Screening for thyroid disease before starting amiodarone and periodic monitoring of thyroid function tests are advocated.

Perchlorate exposure may be higher in infants compared with older persons, due to diet (infant formula) and body weight versus intake considerations. Our primary objective was to quantitatively assess perchlorate concentrations in commercially available powdered infant formulas (PIFs). Secondary objectives were: (1) to estimate exposure in infants under different dosing scenarios and compare them with the perchlorate reference dose (RfD); (2) estimate the perchlorate concentration in water used for preparing PIFs that would result in a dose exceeding the RfD; and (3) estimate iodine intakes from PIFs. We quantified perchlorate levels in three samples (different lot numbers) of reconstituted PIF (using perchlorate-free water) from commercial brands of PIF in each of the following categories: bovine milk-based with lactose, soy-based, bovine milk-based but lactose-free, and elemental (typically consisting of synthetic amino acids). Exposure modeling was conducted to determine whether the RfD might be exceeded in 48 dosing scenarios that were dependent on age, centile energy intake per unit of body weight, body weight percentile, and PIF perchlorate concentration. We obtained three different samples in each of the five brands of bovine- and soy-based PIF, three different samples in each of the three brands of lactose-free PIF, and three different samples in two brands of elemental PIF. The results were as follows: bovine milk-based with lactose (1.72 microg/l, range: 0.68-5.05); soy-based (0.21 microg/l, range: 0.10-0.44); lactose-free (0.27 microg/l, range: 0.03-0.93); and elemental (0.18 microg/l, range: 0.08-0.4). Bovine milk-based PIFs with lactose had a significantly higher concentration of perchlorate (P<0.05) compared with all. Perchlorate was a contaminant of all commercially available PIFs tested. Bovine milk-based PIFs with lactose had a significantly higher perchlorate concentration perchlorate than soy, lactose-free, and elemental PIFs. The perchlorate RfD may be exceeded when certain bovine milk-based PIFs are ingested and/or when PIFs are reconstituted with perchlorate-contaminated water.

Estimates of perchlorate intake by the US population can be derived from either urinary excretion data or through simulation of dietary intake. Estimates from surveys of urinary excretion (NHANES) are subject to substantial uncertainty owing to the small numbers of subjects for which data are currently available. In addition, current excretion estimates are derived from "spot" urine samples and include a component of short-term (intra-day) variability that may give biased estimates of the variability in average daily intakes. Previous dietary estimates have generally not included any contribution from drinking water, owing to a lack of data related to perchlorate concentrations in water supplies. In this paper, we derive simulation (Monte Carlo) estimates of dietary perchlorate intake distributions for reproductive-age women, which include explicit contributions from drinking water, and compare them to estimates based on urinary excretion. Perchlorate concentrations in water were estimated based on measurements from the US Environmental Protection Agency's UCMR1 database, and from other regional studies of perchlorate contamination. We find that including the drinking water contributions in the dietary simulations yields increases in the population's geometric mean perchlorate intake of 3-8 percent, with a conservative maximum of about 24 percent, compared to intakes estimated based on food intake alone. The intake distributions estimated from dietary and water consumption were found to be very similar to estimates based on creatinine-adjusted perchlorate excretion data from the NHANES, except for having lower population variability. When the dietary simulation data were adjusted to include a contribution from short-term variability similar to that in the "spot" urine samples, the variability in the NHANES and diet-derived estimates were found to be very similar. Our analyses indicate that a reasonable upper-bound estimate for the 95th percentile perchlorate intake among women of reproductive age in the US is on the order of 1.5 x 10(-4) mg/kg/day.

Aims: Thyroid hormones (TH) play an important role in the development and functional maintenance of the central nervous system. The purpose of this study was to develop a radiotracer method for studying the in vivo efflux transport of iodide liberated by the TH metabolism in the brain. The rationale of our method is as follows: a radioiodinated compound can enter the brain and rapidly release iodide in situ; the iodide efflux rate can be estimated from the clearance of brain radioactivity after disappearance of the iodinated compound., Main Methods: 6-[(125)I]Iodo-9-pentylpurine ([(125)I]9Pe6IP) was designed to enter the brain and release (125)I(-) by the reaction with glutathione and synthesized from the corresponding bromo derivative in a Br/(125)I exchange reaction. The brain kinetics of radioactivity and radioactive metabolites were investigated after intravenous injection of [(125)I]9Pe6IP into mice. The iodide efflux rate was estimated in mice pretreated with perchlorate, an inhibitor of iodide transport from the brain., Key Findings: High brain uptake (5.3% injected dose/g) was observed at 1 min, and almost complete conversion of [(125)I]9Pe6IP to (125)I(-) occurred 10 min after injection. The (125)I(-) uptake from the blood was negligible. (125)I(-) was eliminated from the brain along a single-exponential curve with a half-life of 6.0 min. Furthermore, dose-dependent inhibition of (125)I(-) efflux was observed in mice pretreated with perchlorate., Significance: We conclude that 9Pe6IP labeled with (124)I (positron emitter) or (123)I (single-photon emitter) may be useful for studying the in vivo efflux transport of iodide in the brain using nuclear medicine imaging devices.

The US Food and Drug Administration (FDA) has conducted the Total Diet Study (TDS) since 1961, which designed to monitor the US food supply for chemical contaminants, nutritional elements, and toxic elements. Recently, perchlorate was analyzed in TDS samples. Perchlorate is used as an oxidizing agent in rocket propellant, is found in other items (e.g., explosives, road flares, fireworks, and car airbags), occurs naturally in some fertilizers, and may be generated under certain climatic conditions. It has been detected in surface and groundwater and in food. Perchlorate at high (e.g., pharmacological) doses can interfere with iodide uptake into the thyroid gland, disrupting its function. The National Academy of Sciences (NAS) has identified that "the fetuses of pregnant women who might have hypothyroidism or iodide deficiency as the most sensitive population." This study reports on intake estimates of perchlorate and iodine, a precursor to iodide, using the analytical results from the TDS. Estimated average perchlorate and iodine daily intakes as well as the contribution of specific food groups to total intakes were estimated for 14 age/sex subgroups of the US population. The estimated smallest lower bound to the largest upper bound average perchlorate intakes by the 14 age/sex groups range from 0.08 to 0.39 micrograms per kilogram body weight per day (microg/kg bw/day), compared with the US Environmental Protection Agency (EPA) reference dose (RfD) of 0.7 microg/kg bw/day. Infants and children demonstrated the highest estimated intakes of perchlorate on a body weight basis. The estimated average iodine intakes by the 14 age/sex groups reveal a lower bound (ND=0) and upper bound (ND=LOD) range of average intakes from 138 to 353 microg/person/day. Estimated iodine intakes by infants 6-11 months exceed their adequate intake (AI), and intakes by children and adult age/sex groups exceed their relevant estimated average requirement (EAR).

The objective of this study was to determine the effect of larval-juvenile exposure to perchlorate, a thyroid hormone synthesis inhibitor, on the establishment of gonadal sex ratios in zebrafish. Zebrafish were exposed to untreated water or water containing perchlorate at 100 or 250 ppm for a period of 30 days starting at 3 days postfertilization (dpf). Recovery treatments consisted of a combination of perchlorate and exogenous thyroxine (T4; 10 nM). Thyroid histology was assessed at the end of the treatment period (33 dpf), and gonadal histology and sex ratios were determined in fish that were allowed an additional 10-day period of growth in untreated water. As expected, exposure to perchlorate caused changes in thyroid histology consistent with hypothyroidism and these effects were reversed by co-treatment with exogenous T4. Perchlorate did not affect fish survival but co-treatment with T4 induced higher mortality. However, relative to the corresponding perchlorate concentration, co-treatment with T4 caused increased mortality only at a perchlorate concentration of 100 ppm. Perchlorate alone or in the presence of T4 suppressed body length at 43 dpf relative to control values. Perchlorate exposure skewed the sex ratio toward female in a concentration-dependent manner, and co-treatment with T4 not only blocked the feminizing effect of perchlorate but also overcompensated by skewing the sex ratio towards male. Moreover, co-treatment with T4 advanced the onset of spermatogenesis in males. There was no clear association between sex ratios and larval survival or growth. We conclude that endogenous thyroid hormone plays a role in the establishment of gonadal sex phenotype during early development in zebrafish.

Recent surveys have identified the presence of perchlorate, a natural compound and environmental contaminant, in forages and dairy milk. The ingestion of perchlorate is of concern because of its ability to competitively inhibit iodide uptake by the thyroid and to impair synthesis of thyroid hormones. A recent study established that milk perchlorate concentrations in cattle highly correlate with perchlorate intake. However, there is evidence that up to 80% of dietary perchlorate is metabolized in clinically healthy cows, thereby restricting the available transfer of ingested perchlorate into milk. The influence of mastitis on milk perchlorate levels, where there is an increase in mammary vascular permeability and an influx of blood-derived components into milk, remains unknown. The present study examined the effect of experimentally induced mastitis on milk perchlorate levels in cows receiving normal and perchlorate-supplemented diets. Over a 12-d period, cows were ruminally infused with 1 L/d of water or water containing 8 mg of perchlorate. Five days after the initiation of ruminal infusions, experimental mastitis was induced by the intramammary infusion of 100 microg of bacterial lipopolysaccharide (LPS). Contralateral quarters infused with phosphate-buffered saline served as controls. A significant reduction in milk perchlorate concentration was observed in the LPS-challenged glands of animals ruminally infused with either water or perchlorate. In control glands, milk perchlorate concentrations remained constant throughout the study. A strong negative correlation was identified between mammary vascular permeability and milk perchlorate concentrations in LPS-infused glands. These findings, in the context of a recently published study, suggest that an active transport process is operative in the establishment of a perchlorate concentration gradient across the blood-mammary gland interface, and that increases in mammary epithelial and vascular endothelial permeability lead to a net outflow of milk perchlorate. The overall finding that mastitis results in lower milk perchlorate concentrations suggests that changes in udder health do not necessitate increased screening of milk for perchlorate.

Context: Perchlorate has been detected in U.S. drinking water supplies at levels ranging from 4 to 200 microg/liter as well as in agricultural products. Perchlorate is known to be a competitive inhibitor of iodine uptake by the thyroid through the sodium-iodide symporter., Objective: The objective of the study was to determine whether prolonged exposure (6 months) to low levels of perchlorate would perturb thyroid function., Design: This was a prospective, double-blinded, randomized trial., Participants: The study population consisted of 13 healthy volunteers., Intervention: INTERVENTIONs included placebo vs. 0.5 mg or 3.0 mg potassium perchlorate daily., Main Outcome Measures: Serum thyroid function tests, 24-h radioactive iodine uptake, serum thyroglobulin (Tg), urinary iodine and perchlorate, and serum perchlorate were measured., Results: Mean urinary perchlorate value during ingestion of 0.5 mg perchlorate daily was 332.7 +/- 66.1 microg per 24 h or 248.5 +/- 64.5 microg/g creatinine and mean values for the four subjects who received 3 mg perchlorate daily were 2079.5 +/- 430.0 microg per 24 h or 1941.7 +/- 138.5 microg/g creatinine. There was no significant change in the thyroid (123)I uptakes during perchlorate administration. There were no significant changes in serum T(3), free T(4) index, TSH, or Tg concentrations during the exposure period, compared to baseline or postexposure values. Urine iodine values for the 3-mg perchlorate group were higher, but not significantly so, at baseline than during perchlorate exposure., Conclusions: We observed that a 6-month exposure to perchlorate at doses up to 3 mg/d had no effect on thyroid function, including inhibition of thyroid iodide uptake as well as serum levels of thyroid hormones, TSH, and Tg.

The purpose of the present study was to determine if exposure to perchlorate via food items would have effects on mammals similar to those caused by exposure through drinking water at approximately equivalent doses. Prairie voles (Microtus ochrogaster) and deer mice (Peromyscus maniculatus) were used to assess the potential toxicity of perchlorate-contaminated food items. Voles and mice were divided randomly into three treatment groups--perchlorate-contaminated food (PCF), perchlorate-contaminated water (PCW), and control groups--such that each treatment group contained equal numbers of males and females. Rodents in PCF treatment groups were fed chow formulated with soybean plant matter that had been grown with perchlorate-contaminated irrigation water. Individuals in the control and PCF groups were provided distilled/deionized drinking water, whereas the PCW group received drinking water containing sodium perchlorate. Only slight differences among treatment groups were observed in a variety of endpoints, including reproductive success, tissue perchlorate concentrations, thyroid hormone concentrations, and thyroid histology. However, trends observed in the present study suggest that perchlorate exposure via water may result in slightly greater effects than exposure to perchlorate via food. These data and recent reports of perchlorate in a wide variety of food items indicate that exposure via food intake is an important consideration when examining cumulative risk among humans, livestock, and wildlife.

Perchlorate is a goitrogenic anion that competitively inhibits the sodium iodide transporter and has been detected in forages and in commercial milk throughout the U.S. The fate of perchlorate and its effect on animal health were studied in lactating cows, ruminally infused with perchlorate for 5 weeks. Milk perchlorate levels were highly correlated with perchlorate intake, but milk iodine was unaffected, and there were no demonstrable health effects. We provide evidence that up to 80% of dietary perchlorate was metabolized, most likely in the rumen, which would provide cattle with a degree of refractoriness to perchlorate. Data presented are important for assessing the environmental impact on perchlorate concentrations in milk and potential for relevance to human health.

A recent study further investigated the potential effects of maternal thyroid function and morphology on fetal development upon maternal exposure to ammonium perchlorate during gestation and lactation. Female Sprague-Dawley rats (25/group) were given continual access to 0 (carrier), 0.01, 0.1, 1.0, and 30.0 mg/kg-day perchlorate in drinking water beginning 2 weeks prior to cohabitation through lactation day 10. Maternal, fetal, and pup serum thyroid hormone (thyroid-stimulating hormone [TSH], triiodo thyronine [T(3)], thyroxine [T(4)]) levels and thyroid histopathology were evaluated on gestation day 21, and lactation days 5, 10, and 22. No effects of exposure were observed on cesarean-sectioning, litter parameters, or fetal alterations. Reproductive parameters, including gestation length, number of implants, litter size, pup viability, and lactation indices, were comparable among all groups. Thyroid weights of dams sacrificed on gestation day 21, and lactation days 10 and 22 were significantly increased at 30.0 mg/kg-day. Increased thyroid weights were observed in male and female pups as early as postpartum days 5 and 10, respectively. Changes in maternal and neonatal thyroid histopathology were detectable at 1.0 mg/kg-day exposure. The maternal no-observable-effect level (NOEL) was 0.1 mg/kg-day (follicular cell hyperplasia was present at 1.0 and 30.0 mg/kg-day). The developmental NOEL was less than 0.01 mg/kg-day; thyroid weights of postpartum day 10 pups were increased at all exposures. Colloid depletion at 1.0 and 30.0 mg/kg-day exposures and changes of hormone levels at all exposures were considered an adaptive effect and appeared reversible in the rodent.

A developmental neurotoxicity study was conducted to generate additional data on the potential functional and morphological hazard to the central nervous system caused by ammonium perchlorate in offspring from in utero and lactation exposure. Female Sprague-Dawley rats (23 to 25/group) were given continuous access to 0 (carrier), 0.1, 1.0, 3.0, and 10.0 mg/kg-day perchlorate in the drinking water beginning 2 weeks prior to mating and continuing through day 10 of lactation for the behavioral function assessment or given continuous access to 0 (carrier), 0.1, 1.0, 3.0, and 30.0 mg/kg-day beginning on gestation day 0 and continuing through day 10 of lactation for neurodevelopment assessments. Motor activity was conducted on postpartum days 14, 18, and 22 and juvenile brain weights, neurohistopathological examinations, and regional brain morphometry were conducted on postpartum days 10 and 22. This research revealed a sexually dimorphic response, with some brain regions being larger in perchlorate-treated male rats than in comparable controls. Even so, there was no evidence of any obvious exposure-related effects on male rat brain weights or neuropathology. The most consistent exposure-related effect in the male pups was on the thickness of the corpus callosum, with both the right- and left-sided measures of the thickness of this white matter tract being significantly greater for the male pups in the 0.1 and 1.0 mg/kg-day exposure groups. The behavioral testing suggests prenatal exposure to ammonium perchlorate does not affect the development of gross motor movements in the pups.

Purpose: To evaluate the prevalence of latent and manifest hyperthyroidism in a non-selected group of patients admitted for contrast enhanced CT studies blood samples were tested for the levels of thyroid-stimulating hormone (TSH)., Material and Methods: TSH blood levels were obtained in 548 consecutive patients who were scheduled for contrast-enhanced (Iopromide; 300 mg iodine/ml) CT scanning. In case of TSH levels < 0.4 mU/l, blood samples were also tested for triiodothyronine (T3) and tetraiodothyronine (T4) blood levels, and treatment with Irenat (sodium perchlorate) was commenced before scanning. In case of TSH levels < 0.1 mU/l, CT scanning was not performed but further evaluation of the thyroid function was initiated., Results: TSH blood levels ranged from 0.4 to 7.5 mU/l in 512 patients, and 36 patients (6.6%) had TSH blood levels < 0.4 mU/l and 9 patients blood levels < 0.1 mU/l, with 32 of those patients (5.8%) having regular T3 and T4 blood levels consistent with latent hyperthyroidism. In 4 patients (0.8%), T3 or T4 blood levels were increased consistent with manifest hyperthyroidism., Conclusion: In South Germany, the prevalence of latent or manifest hyperthyroidism in a non-selected patient group is high. Therefore TSH blood levels should be obtained prior to contrast-enhanced CT studies.

The parallel course of the excretion rates of bromide and sodium ions was demonstrated in adult male and female rats administered simultaneously with potassium 82Br-bromide and 24Na-sodium chloride. The animals were exposed to various intakes of sodium ions accompanied with five different anions: Br-, Cl-, HCO3-, ClO4-, and SCN-. Regardless of the anion accompanying the sodium ion, the excretion rates of 82Br- and 24Na+ ions were proportional to the magnitude of sodium intake in the animals. Hence, we have proved our hypothesis that the biological half-life of bromide depends on the magnitude of sodium intake rather than on the intake of chloride.

Ammonium perchlorate (AP) is a powerful oxidizer manufactured almost exclusively for the aerospace industry. AP salts are also used in airbags, flares, fertilizers, enamels and paints. As a result of widespread industrial use, AP has become a persistent environmental contaminant of drinking water in several U.S. states. AP ion disrupts the trapping of iodide as well as facilitates the discharge of unorganified iodide from the thyroid gland. Such disturbances in thyroid hormone concentrations during critical periods of development are then known to cause profound reproductive and developmental defects, since thyroid hormones modulate both follicular development and steroidogenesis and affect estrogen metabolism and receptor. This study was designed (1) to determine whether exposure to a low or high concentration of AP (LAP, HAP) exerts detrimental effects on follicle maturation in the Long-Evans hooded rat and (2) to determine whether the modulatory effects of AP can be ameliorated by levo-thyroxine sodium (T4) supplementation. Animals were treated via deionized drinking water on GD 7-21 with LAP (0.4 mg/kg/day) or HAP (4.0 mg/kg/day). Half of each group was also given T4 supplements via drinking water on GD 7-21. Female pups were sacrificed on postnatal days 24/25, and the ovaries were excised, fixed for histology and analyzed. The analysis included a count, measurement and classification of preantral and antral follicles in the greatest cross-sectional area of the ovary. The results indicated that treatment with the HAP significantly reduced the number of preantral follicles <50,000 microm2 and the total number of antral follicles in the <50,000, 50-100,000 and >100,000 microm2 size classes. In ovaries treated with the LAP, we observed no significant decrease in preantral follicles of any size class and only a significant reduction in the largest antral follicles. T4 only circumvented the effect on the number of small preantral and antral follicles; however, a significant diminution in the antral follicle number persisted in the mid-sized (HAP) and large (LAP, HAP)-sized classes. These data support the hypothesis that AP reduces the number of preantral and antral follicles in certain size classes in rats exposed during a critical period of development, and that T4 can attenuate the effects of AP on small preantral and antral follicles, but not on medium or large antral follicles. (T35ES007292 & ES08342.).

The effects of a wide range of ammonium perchlorate (AP) concentrations in drinking water on thyroid function in bobwhite quail chicks was investigated at 2, 4, and 8 weeks of exposure. We measured plasma thyroid hormones (THs) to evaluate organismal thyroid status, thyroid weights to evaluate hypothalamic-pituitary-thyroid (HPT) axis activation, and thyroidal TH content to assess TH stores. At the highest AP exposures plasma THs were decreased, thyroid glands were hypertrophied, and thyroidal TH content was decreased. As in our previous studies, thyroidal thyroxine (T(4)) content was the most sensitive indicator of decreased thyroid function; plasma T(4) and thyroid weight were much less sensitive. The lack of sensitivity of these variables appears to result from cyclic patterns of thyroid responses involving the HPT axis and intermittent release of stored THs from the thyroid gland. With sustained AP exposure (8 weeks), at the lowest range of AP concentrations used, chicks showed adaptation in thyroid function that fully compensated for the initial (2 week) effects of AP. At the intermediate AP concentrations there was partial compensation for the initial AP effects. At the highest AP exposures used, thyroid function was very low throughout the study, with no indication of compensatory responses. The capability of chicks to increase some aspects of their thyroid function adaptively in response to some levels of sustained AP exposure is contrary to the common generalization that developing animals are most vulnerable to environmental contaminants.

The most relevant data for developing a reference dose (RfD) for perchlorate exposures comes from human epidemiology and clinical studies, supplemented with available and extensive information on experimental animals. Specifically, serum T4 decrease is the critical effect of perchlorate, based on a mode-of-action analysis and the evidence provided by the body of rodent studies on perchlorate. However, no T4 decreases have been observed in human populations following perchlorate exposure at non-therapeutic doses. An RfD of 0.002 mg/kg-day can be derived using an epidemiology study. A freestanding NOAEL of 0.006 mg/kg-day for T4 decrease was identified in children from the epidemiology study. The use of this NOAEL has the advantage of a being identified in a sensitive subgroup, neonates and children. Data are sufficient to estimate an overall uncertainty factor of 3-fold with this NOAEL based on expected differences in toxicokinetics and toxicodynamics between children, and pregnant women and their fetuses, the second identified sensitive subgroup for perchlorate, and concerns about the over-iodination of this population. This RfD is supported by a human clinical study using inhibition of iodine uptake in adults as a measurable surrogate for the critical effect of T4 decrease in humans. However, although this latter study has a well-established dose-response curve for inhibition of iodine uptake, even perchlorate doses that result in a 70% inhibition of iodine uptake have no apparent effect on human T4 levels. Thus, the use of this study as the primary basis of the RfD is problematic. Nevertheless, a benchmark dose of 0.01 mg/kg-day was identified in this clinical study, which supports a threshold value of 0.006 mg/kg-day identified by its authors and the RfD of 0.002 mg/kg-day estimated in this paper.

Thyroid destruction leading to endemic myxoedematous cretinism is highly prevalent in central Africa, where iodine (I) and selenium (SE) deficiencies as well as thiocyanate (SCN) overload are combined. All three factors have been studied experimentally in the etiology of the disease, but they have never been studied in combination. In a model using rats, we have previously shown that combining I and SE deficiencies increases the sensitivity of the thyroid to necrosis after iodide overload, an event unlikely to occur in the African situation. To develop a model that would more closely fit with the epidemiological findings, we have determined whether an SCN overload would also result in thyroid necrosis as does the I overload. The combination of the three factors increased by 3.5 times the amount of necrotic cells, from 5.5 +/- 0.3% in the I-SE+ thyroids to 18.9 +/- 1.6% in the I-SE-SCN-overloaded ones. Methimazole administration prevented the SCN-induced necrosis. SE- thyroids evolved to fibrosis, whereas SE+ thyroids did not. TGFbeta was prominent in macrophages present in SE- glands. Thyroid destruction in central Africa might therefore originate from the interaction of three factors: I and SE deficiencies by increasing H(2)O(2) accumulation, SE deficiency by decreasing cell defense and promoting fibrosis, and SCN overload by triggering follicular cell necrosis.

Objectives: To test the hypothesis that there is no significant difference in the detectability of chemically-induced periapical lesions between a non-compressed image and one subjected to a Joint Photographic Experts Group (JPEG) lossy compression technique at a ratio of 23:1 or less., Method: Chemically-induced periapical lesions were created by placing a solution of 70% perchloric acid at the apex of extracted teeth in 13 human jaw cadaver specimens. Acid was applied in seven incremental time periods from 0-32 h. Extracted teeth were replaced in the socket and images were made using the Schick CDR digital sensor. Using a JPEG lossy compression algorithm, five compression ratios of 2:1, 14:1, 23:1, 28:1 and 47:1 were applied to the images. Images were viewed three times by three observers who ranked the presence or absence of a lesion at three sites, the mesial area, distal area and apex of the tooth, on a 5-point confidence scale. Intraobserver and interobserver agreement and agreement between the compressed and the original images were assessed with intraclass correlation coefficients (ICCs)., Results: Overall ICCs for measuring intraobserver agreement using all images were 0.77, 0.84, and 0.50 for the three observers, respectively. The overall ICC for assessing agreement between observers was 0.57. There was no significant difference (P>0.05) between compressed and original images for any site at compression ratios of 2:1, 23:1 and 28:1. There were significant differences for a compression ratio of 47:1., Conclusion: JPEG compression does not impact detectability of artificial periapical lesions at low and moderate compression ratios up to and including 28:1.

A developmental toxicity study was conducted with ammonium perchlorate (AP) in the drinking water at doses of 0.0, 0.01, 0.1, 1.0, and 30.0 mg/kg-day beginning 14 days before cohabitation and continuing through sacrifice. Twenty-four rats/group were cesarean-sectioned on day of gestation (DG) 21 and fetuses examined for visceral and skeletal alterations. An additional 16 litters/group were sacrificed on DG 21 for maternal and fetal serum TSH, T(3), and T(4) (thyroid-stimulating hormone, triiodothyronine, and thyroxine) levels and thyroid histopathology. Clinical and necropsy observations, body weights, feed and water consumption, and cesarean-sectioning parameters were comparable among the groups with only delays in ossification observed in the 30 mg/kg-day group. Maternal thyroid weights were increased in the 30.0 mg/kg-day group. Decreased colloid was present in male and female fetal thyroids in the 1.0 and 30.0 mg/kg-day groups. Maternal TSH was increased and T(4) was decreased at all levels, and T(3) was reduced at 30.0 mg/kg-day. Fetal TSH was increased at 1.0 and 30.0 mg/kg-day, T(4) was reduced at 30.0 mg/kg-day, and T(3) was decreased at all levels. The maternal no-observable-adverse-effect level (NOAEL) was 1.0 mg/kg-day; exposures of 30.0 mg/kg-day increased absolute and relative maternal thyroid weights and histopathology findings. The developmental NOAEL was 1.0 mg/kg-day; developmental delays in ossification occurred in the 30.0 mg/kg-day group. The colloid depletion in the thyroids and increased TSH and decreased T(3) and T(4) levels at lower exposures were considered adaptive and not adverse. No adverse effects on development at occurred levels that did not cause maternal toxicity. AP is not a selective developmental toxicant.

Perchlorate (ClO4-), a contaminant in drinking water, competitively inhibits active uptake of iodide (I-) into various tissues, including mammary tissue. During postnatal development, inhibition of I- uptake in the mammary gland and neonatal thyroid and the active concentration ClO4- in milk indicate a potentially increased susceptibility of neonates to endocrine disruption. A physiologically based pharmacokinetic (PBPK) model was developed to reproduce measured ClO4- distribution in the lactating and neonatal rat and predict resulting effects on I- kinetics from competitive inhibition at the sodium iodide symporter (NIS). Kinetic I- and ClO4- behavior in tissues with NIS (thyroid, stomach, mammary gland, and skin) was simulated with multiple subcompartments, Michaelis-Menten (M-M) kinetics and competitive inhibition. Physiological and kinetic parameters were obtained from literature and experiment. Systemic clearance and M-M parameters were estimated by fitting simulations to tissue and serum data. The model successfully describes maternal and neonatal thyroid, stomach, skin, and plasma, as well as maternal mammary gland and milk data after ClO4- exposure (from 0.01 to 10 mg/kg-day ClO4-) and acute radioiodide (2.1 to 33,000 ng/kg I-) dosing. The model also predicts I- uptake inhibition in the maternal thyroid, mammary gland, and milk. Model simulations predict a significant transfer of ClO4- through milk after maternal exposure; approximately 50% to 6% of the daily maternal dose at doses ranging from 0.01 to 10.0 mg ClO4-/kg-day, respectively. Comparison of predicted dosimetrics across life-stages in the rat indicates that neonatal thyroid I- uptake inhibition is similar to the adult and approximately tenfold less than the fetus.

Perchlorate (ClO4-) disrupts endocrine homeostasis by competitively inhibiting the transport of iodide (I-) into the thyroid. The potential for health effects from human exposure to ClO4- in drinking water is not known, but experimental animal studies are suggestive of developmental effects from ClO4- induced iodide deficiency during gestation. Normal hormone-dependent development relies, in part, on synthesis of hormones in the fetal thyroid from maternally supplied iodide. Although ClO4- crosses the placenta, the extent of inhibition in the fetal thyroid is unknown. A physiologically-based pharmacokinetic (PBPK) model was developed to simulate ClO4- exposure and the resulting effect on iodide kinetics in rat gestation. Similar to concurrent model development for the adult male rat, this model includes compartments for thyroid, stomach, skin, kidney, liver, and plasma in both mother and fetus, with additional compartments for the maternal mammary gland, fat, and placenta. Tissues with active uptake are described with multiple compartments and Michaelis-Menten (M-M) kinetics. Physiological and kinetic parameters were obtained from literature and experiment. Systemic clearance, placental-fetal transport, and M-M uptake parameters were estimated by fitting model simulations to experimental data. The PBPK model is able to reproduce maternal and fetal iodide data over five orders of magnitude (0.36 to 33,000 ng/kg 131I-), ClO4- distribution over three orders of magnitude (0.01 to 10 mg/kg-day ClO4-) and inhibition of maternal thyroid and total fetal I- uptake. The model suggests a significant fetal ClO4- dose in late gestation (up to 82% of maternal dose). A comparison of model-predicted internal dosimetrics in the adult male, pregnant, and fetal rat indicates that the fetal thyroid is more sensitive to inhibition than that of the adult.

Due to perchlorate's (ClO4-) ability to competitively inhibit thyroid iodide (I-) uptake through the sodium-iodide symporter (NIS), potential human health risks exist from chronic exposure via drinking water. Such risks may include hypothyroidism, goiter, and mental retardation (if exposure occurs during critical periods in neurodevelopment). To aid in predicting perchlorate's effect on normal I- kinetics, we developed a physiologically-based pharmacokinetic (PBPK) model for the adult male rat. The model structure describes simultaneous kinetics for both anions together with their interaction at the NIS, in particular, the inhibition of I- uptake by ClO4-. Subcompartments and Michaelis-Menten (M-M) kinetics were used to describe active uptake of both anions in the thyroid, stomach, and skin. Separate compartments for kidney, liver, plasma, and fat were described by passive diffusion. The model successfully predicts both 36ClO4- and 125I- kinetics after iv doses of 3.3 mg/kg and 33 mg/kg, respectively, as well as inhibition of thyroid 125I- uptake by ClO4- after iv doses of ClO4- (0.01 to 3.0 mg/kg). The model also predicts serum and thyroid ClO4- concentrations from 14-day drinking water exposures (0.01 to 30.0 mg ClO4-/kg/day) and compensation of perchlorate-induced inhibition of radioiodide uptake due to upregulation of the thyroid. The model can be used to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other species and life stages, such as rat gestation (Clewell et al., 2003). Because the model successfully predicts perchlorate's interaction with iodide, it provides a sound basis for future incorporation of the complex hypothalamic-pituitary-thyroid feedback system.

Ammonium perchlorate is used as an oxidizer in rocket fuel. It has become a groundwater contaminant, dissociating to ammonium cation and perchlorate anion. The perchlorate ion competes with iodide for uptake into the thyroid, reducing thyroid hormone production. Pregnant Sprague-Dawley rats were given either untreated or perchlorate (1 mg/kg-day) treated drinking water beginning on gestation day 2. One set of control and exposed dams was sacrificed on gestation day 20. The litters from the second set of control and exposed dams were crossed immediately after parturition and were sacrificed at postnatal day 10. Dam serum and thyroid, pooled fetal sera, and male and female pup sera were collected and analyzed for perchlorate, thyroid-stimulating hormone (TSH), triiodothyronine (T(3)), and thyroxine (T(4)). Control pups receiving perchlorate through lactation had serum levels at postnatal day 10 of 0.54 microg/ml and 0.56 microg/ml for male and female pups, respectively, whereas exposed fetuses had serum perchlorate levels of 0.38 +/- 0.04 microg/ml. Female pups receiving perchlorate lactationally had significantly lower levels of serum T(4) than control pups and prenatally exposed pups. Serum T(4) levels in male pups were not affected by perchlorate. Serum thyroid hormone levels from gestational perchlorate exposure were restored to control values by postnatal day 10. In utero perchlorate-exposure decreased serum T(4) levels in the fetus. Gestational studies in conjunction with a cross-fostering study design helped discern thyroid hormonal changes caused by perchlorate exposure during the perinatal period.

Thyroid gland hormone levels and histology and sex hormone levels in developing deer mice (Peromyscus maniculatus) were measured following in utero and lactational exposure to ammonium perchlorate (AP), a component of rocket fuel and a thyroid toxicant. Breeding pairs were dosed continuously with 0, 1 nM, 1 micro M, or 1 mM concentrations of AP in drinking water from the time of cohabitation until pups from the third litter were weaned. Pups from the second litter were used for evaluation in this study. The active (colloid-containing) thyroid follicle number per unit area was significantly different between treatment groups. The 1-nM and 1-mM treatment groups had significantly fewer active follicles per unit area than did controls. The 1-mM treatment group also had significantly fewer active follicles than the 1- micro M and the 1-nM treatment groups. Total T(4) concentrations were significantly increased in the 1-nM and 1- micro M groups compared to the controls. No significant difference was observed in total T(3) concentrations. None of the 1-mM plasma had concentrations of total testosterone above the detection limit, and only one of the 1- micro M samples was above the detection limit of the assay. All estradiol concentrations were below the detection limits of the assay. In contrast to the situation in adult rodents, it appears that AP increases thyroid hormone production in developing deer mice and produces variable effects with increasing concentrations.

The cellular expression of the sodium iodide symporter (NIS) has been shown to confer iodide-concentrating capacity in non-thyroid cell types. We examined the role of NIS in the uptake of the alpha-particle emitting radiohalide [(211)At]astatide in the UVW human glioma cell line transfected to express NIS. [(211)At]Astatide uptake is shown to be NIS-dependent, with characteristics similar to [(131)I]iodide uptake. These studies suggest [(211)At]astatide as a possible alternative radionuclide to [(131)I]iodide for NIS-based endoradiotherapy, and provide a model for the study of [(211)At]astatide behavior at a cellular level.

The perchlorate (ClO4(-))-respiring organism, strain perclace, can grow using nitrate (NO3(-)) as a terminal electron acceptor. In resting cell suspensions, NO(-) grown cells reduced ClO4(-), and ClO4(-) grown cells reduced NO3(-). Activity assays showed that nitrate reductase (NR) activity was 1.31 micromol min(-1) (mg protein)-1 in (ClO4)- grown cells, and perchlorate reductase (PR) activity was 4.24 micromol min(-1) (mg protein)(-1) in NO3(-) grown cells. PR activity was detected within the periplasmic space, with activities as high as 14 pmol min(-1) (mg protein)(-1). The NR had a pH optimum of 9.0 while the PR had an optimum of 8.0. This study suggests that separate terminal reductases are present in strain perclace to reduce NO3(-) and ClO4(-).

A 52-year-old woman was hospitalized because of dyspnea and dysphagia. Thoracic computed tomography revealed a retrotracheal mass. Tc-99m pertechnetate scintigraphy showed intense accumulation of radioactivity corresponding to the mediastinal mass detected by computed tomography. Repeated Tc-99m pertechnetate scintigraphy performed after oral administration of potassium perchlorate (KCLO4) revealed complete disappearance of the radioactive accumulation in the mediastinum, suggesting that the retrotracheal mass was a retrosternal goiter. Subsequent surgical removal and analysis of the mass showed it was indeed a retrosternal goiter. This case highlights the importance of Tc-99m pertechnetate thyroid scintigraphy with and without KCLO4 administration as a simple, accurate, and cost-effective imaging method to diagnose retrosternal goiter.

Radioactive wires and other linear sources are currently being used in clinical trials as endovascular brachytherapy to prevent restenosis after percutaneous transluminal coronary angioplasty. A new concept is the use of a liquid-filled balloon containing a beta-emitting radioisotope. A major advantage is optimal delivery of the radioactivity to the vessel wall. Rhenium-188 (188Re) is a high-energy beta-emitter that is routinely available from a 188W/188Re generator in liquid form. Since 188Re-perrhenate could be released in the unlikely event of balloon rupture, we investigated whether, in analogy to pertechnetate, subsequent use of perchlorate can reduce the uptake of perrhenate in the thyroid. We performed static (n = 9) and dynamic (n = 11) thyroid scintigraphy with 99Tcm-pertechnetate to estimate the overall reduction in activity within 30 min and the washout from the thyroid after oral administration of 600 mg perchlorate (T1/2). In two patients, 188Re was injected to estimate the whole-body distribution and the discharge of thyroid activity after perchlorate use. Based on MIRD Dose Estimate Report No. 8 (valid for 99Tcm-pertechnetate), the radiation burden was calculated for intravenous administration of 188Re and competitive blocking with perchlorate. In 20 patients, 99Tcm uptake by the thyroid was reduced by 85% within 30 min by perchlorate. The mean (+/- S.D.) washout rate (T1/2) was 8 +/- 2 min in 11 patients. Perrhenate showed a whole-body distribution similar to that of pertechnetate and the thyroid activity could be displaced (T1/2 = 6.3 and 9.3 min, respectively) by oral administration of perchlorate, with reductions in uptake of 83% and 75% within 30 min, respectively. Whole-body scanning demonstrated no regional accumulation of 188Re-perrhenate with excretion by urine. Dose estimates gave an effective dose equivalent of 0.42 mSv MBq-1, which decreased to 0.16 mSv MBq-1 after perchlorate blocking. 188Re has favourable properties for endovascular brachytherapy via a balloon catheter and, in the unlikely event of balloon rupture, whole-body radiation can be reduced to 38% by subsequent oral administration of perchlorate.

To better understand the altered skeletal muscle excitation-contraction (E-C) coupling that occurs in malignant hyperthermia, we have examined the potentiating actions of perchlorate in intact muscle fiber bundles, isolated sarcoplasmic reticulum (SR) vesicles, and the purified ryanodine receptor/Ca2+ release channel (RyR) isolated from malignant-hyperthermia-susceptible (MHS) and normal porcine muscle. The concentration of perchlorate that half-maximally potentiated twitch tension (2.5-3.5 mM) was not significantly different for MHS and normal muscles. The effect of perchlorate on fractional twitch force was significantly greater for normal than for MHS muscle, although the absolute twitch potentiation was similar for both muscle types. The K-contracture threshold of MHS muscle bundles is significantly lower than that of normal bundles; perchlorate shifted the K-contraction activation curves of both MHS and normal muscle bundles to lower K+ concentrations. Perchlorate both increased ryanodine binding to MHS and normal SR vesicles and increased single-channel open probability of the purified MHS and normal RyR. In both cases, the percentage increase was greater for normal than for MHS preparations; however, the absolute increase in activity was not different for MHS and normal RyR indicating that there is no difference in the perchlorate sensitivity of MHS and normal SR Ca2+ release channels. Thus, the greater absolute responses of the MHS Ca2+ release channel in the presence of perchlorate is likely to be due to the greater basal activity of the MHS release channel and does not reflect an underlying defect in the site of action of perchlorate on the MHS skeletal muscle Ca2+ release channel.