The use of PBPK models to inform human health risk assessment: case study on perchlorate and radioiodide human lifestage models.

Physiologically-based pharmacokinetic (PBPK) models are often submitted to or selected by agencies, such as the U.S. Environmental Protection Agency (U.S. EPA) and Agency for Toxic Substances and Disease Registry, for consideration for application in human health risk assessment (HHRA). Recently, U.S. EPA evaluated the human PBPK models for perchlorate and radioiodide for their ability to estimate the relative sensitivity of perchlorate inhibition on thyroidal radioiodide uptake for various population groups and lifestages. The most well-defined mode of action of the environmental contaminant, perchlorate, is competitive inhibition of thyroidal iodide uptake by the sodium-iodide symporter (NIS). In this analysis, a six-step framework for PBPK model evaluation was followed, and with a few modifications, the models were determined to be suitable for use in HHRA to evaluate relative sensitivity among human lifestages. Relative sensitivity to perchlorate was determined by comparing the PBPK model predicted percent inhibition of thyroidal radioactive iodide uptake (RAIU) by perchlorate for different lifestages. A limited sensitivity analysis indicated that model parameters describing urinary excretion of perchlorate and iodide were particularly important in prediction of RAIU inhibition; therefore, a range of biologically plausible values available in the peer-reviewed literature was evaluated. Using the updated PBPK models, the greatest sensitivity to RAIU inhibition was predicted to be the near-term fetus (gestation week 40) compared to the average adult and other lifestages; however, when exposure factors were taken into account, newborns were found to be populations that need further evaluation and consideration in a risk assessment for perchlorate.

Study on the bioaccessibility and bioavailability of perchlorate in different food matrices in vitro.

Perchlorate, a persistent pollutant, interferes with iodine uptake by the thyroid. Perchlorate exposure mainly occurs through ingested food; understanding the bioaccessibility and bioavailability of perchlorate in foods facilitate more accurate human health risk assessments. An in vitro digestion/Caco-2 cell model was used for this research. The bioaccessibility of perchlorate in the control group, lettuce, rice and formula was 93.45%, 70.14%, 70.25%, and 63.68%, respectively. The bioavailability of perchlorate was as follows: control group, 43.45%; rice, 37.17%; lettuce, 35.13%; and formula, 30.72%. The absorptive apparent permeability coefficient (Papp) of the control, lettuce, rice, and formula was 30-101 nm/s, 32-65 nm/s, 54-161 nm/s, and 41-88 nm/s, respectively. The results suggested that the risk from perchlorate was overestimated only when considering the content of perchlorate in foods and that the presence of food matrices reduced perchlorate bioavailability by differing degrees.

Harnessing microbial activities for environmental cleanup.

Human activities have released large amounts of toxic organic and inorganic chemicals into the environment. Toxic waste streams threaten dwindling drinking water supplies and impact terrestrial, estuarine and marine ecosystems. Cleanup is technically challenging and the costs based on traditional technologies are exceeding the economic capabilities of even the richest countries. Recent advances in our understanding of the microbiology contributing to contaminant transformation and detoxification has led to successful field demonstrations. Hence, harnessing the activity of naturally occurring bacteria, particularly the power of anaerobic reductive processes, is a promising approach to restore contaminated subsurface environments, protect drinking water reservoirs and to safeguard ecosystem health.

Perchlorate and radioiodide kinetics across life stages in the human: using PBPK models to predict dosimetry and thyroid inhibition and sensitive subpopulations based on developmental stage.

Perchlorate (ClO4(-)) is a drinking-water contaminant, known to disrupt thyroid hormone homeostasis in rats. This effect has only been seen in humans at high doses, yet the potential for long term effects from developmental endocrine disruption emphasizes the need for improved understanding of perchlorate's effect during the perinatal period. Physiologically based pharmacokinetic/dynamic (PBPK/PD) models for ClO4(-) and its effect on thyroid iodide uptake were constructed for human gestation and lactation data. Chemical specific parameters were estimated from life-stage and species-specific relationships established in previously published models for various life-stages in the rat and nonpregnant adult human. With the appropriate physiological descriptions, these kinetic models successfully simulate radioiodide data culled from the literature for gestation and lactation, as well as ClO4(-) data from populations exposed to contaminated drinking water. These models provide a framework for extrapolating from chemical exposure in laboratory animals to human response, and support a more quantitative understanding of life-stage-specific susceptibility to ClO4(-). The pregnant and lactating woman, fetus, and nursing infant were predicted to have higher blood ClO4(-) concentrations and greater thyroid iodide uptake inhibition at a given drinking-water concentration than either the nonpregnant adult or the older child. The fetus is predicted to receive the greatest dose (per kilogram body weight) due to several factors, including placental sodium-iodide symporter (NIS) activity and reduced maternal urinary clearance of ClO4(-). The predicted extent of iodide inhibition in the most sensitive population (fetus) is not significant (approximately 1%) at the U.S. Environmental Protection Agency reference dose (0.0007 mg/kg-d).

Effects of six months of daily low-dose perchlorate exposure on thyroid function in healthy volunteers.

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.

Development of a health-protective drinking water level for perchlorate.

We evaluated animal and human toxicity data for perchlorate and identified reduction of thyroidal iodide uptake as the critical end point in the development of a health-protective drinking water level [also known as the public health goal (PHG)] for the chemical. This work was performed under the drinking water program of the Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency. For dose-response characterization, we applied benchmark-dose modeling to human data and determined a point of departure (the 95% lower confidence limit for 5% inhibition of iodide uptake) of 0.0037 mg/kg/day. A PHG of 6 ppb was calculated by using an uncertainty factor of 10, a relative source contribution of 60%, and exposure assumptions specific to pregnant women. The California Department of Health Services will use the PHG, together with other considerations such as economic impact and engineering feasibility, to develop a California maximum contaminant level for perchlorate. We consider the PHG to be adequately protective of sensitive subpopulations, including pregnant women, their fetuses, infants, and people with hypothyroidism.

Tissue distribution, elimination, and metabolism of sodium [36Cl]perchlorate in lactating goats.

Perchlorate has contaminated water sources throughout the United States but particularly in the arid Southwest, an area containing large numbers of people and few water sources. Recent studies have demonstrated that perchlorate is present in alfalfa and that perchlorate is secreted into the milk of cows. Studies in lactating cows have indicated that only a small portion of a perchlorate dose could be accounted for by elimination in milk, feces, or urine. It was hypothesized that the remainder of the perchlorate dose was excreted as chloride ion. The purpose of this study was to determine the fate and disposition of (36)Cl-perchlorate in lactating dairy goats. Two goats (60 kg) were each orally administered 3.5 mg (16.5 muCi) of (36)Cl-perchlorate, a dose selected to approximate environmental perchlorate exposure but that would allow for adequate detection of radioactive residues after a 72 h withdrawal period. Blood, milk, urine, and feces were collected incrementally until slaughter at 72 h. Total radioactive residue (TRR) and perchlorate concentrations were measured using radiochemical techniques and liquid chromatography mass spectrometry (LC-MS-MS). Peak blood levels of TRR occurred at 12 h ( approximately 195 ppb) postdose; peak levels of parent perchlorate, however, occurred after only 2 h, suggesting that perchlorate metabolism occurred rapidly in the rumen. The serum half-life of perchlorate was estimated to be 2.3 h. After 24 h, perchlorate was not detectable in blood serum but TRR remained elevated (160 ppb) through 72 h. Milk perchlorate levels peaked at 12 h (155 ppb) and were no longer detectable by 36 h, even though TRRs were readily detected through 72 h. Perchlorate was not detectable in skeletal muscle or liver at slaughter (72 h). Chlorite and chlorate were not detected in any matrix. The only radioactive residues observed were perchlorate and chloride ion. Bioavailability of perchlorate was poor in lactating goats, but the perchlorate that was absorbed intact was rapidly eliminated in milk and urine.

Uptake and elimination of perchlorate in eastern mosquitofish.

The purpose of this study was to investigate the uptake and elimination of perchlorate in eastern mosquitofish (Gambusia holbrooki). Fish were exposed to 0.1-1000 mg/l sodium perchlorate for 12h, 1, 2, 5, 10, and 30 days, and perchlorate was determined in whole body extracts. Perchlorate was not detected in mosquitofish exposed to the low concentrations of perchlorate (0, 0.1, and 1mg/l sodium perchlorate), regardless of the exposure time, whereas it was detected when fish were exposed to 10, 100, and 1000 mg/l. The tissue concentrations were approximately 10 times less than that in the water. There was no difference in the uptake of perchlorate depending upon the exposure time, however, a difference in perchlorate uptake depending upon the concentration of the exposure dose (P<0.001) was observed. Uptake (K(u)) and elimination (K(e)) rate constants were 0.09 l/mg day and 0.70 day(-1), respectively. The half-life (T1/2) of perchlorate was 0.99 day. Thus, it appears that perchlorate is rapidly taken up and eliminated in eastern mosquitofish. These results are critical and may be used to develop models of fate, effects, and transport of perchlorate in natural systems, as well as to assess ecological risk in affected ecosystems.

Uptake, accumulation and depuration of sodium perchlorate and sodium arsenate in zebrafish (Danio rerio).

In toxicokinetics studies, interactions between chemicals in mixtures has been largely neglected. This study examines a mixture of perchlorate and arsenate because (1) they have the potential to co-occur in contaminated aquatic habitats, and (2) a previous study by the authors found possible toxicological interactive effects. In the present study, zebrafish (Danio rerio) were exposed to two concentrations of sodium perchlorate (10 and 100 mg l(-1)), sodium arsenate (1 and 10 mg l(-1)), and the mixture-sodium perchlorate+sodium arsenate (10+1 mg l(-1) and 100+10 mg l(-1) Na(2)HAsO(4)-high mixture) for 90 d. Their uptake and accumulation by zebrafish was evaluated at 10, 30, 60, and 90 d. In addition, depuration was examined at 1, 3, and 5d after cessation of the exposure. The uptake of either chemical was concentration-dependent, with significantly higher uptake at high concentrations at either exposure interval. In contrast, there was no significant difference in whole body residue between single chemicals and the corresponding mixture except for 100 mg l(-1) sodium arsenate at 90 d. However, there was increasing accumulation over time at the high concentration of either chemical alone and their mixture, and this increasing trend was more pronounced in the single chemical exposures than in the mixture. At the concentrations tested in the current study, both chemicals reduced the uptake but enhanced the depuration of the other chemical from the zebrafish. This study represents the first examination of the interaction of two anions-perchlorate and arsenate with respect to toxicokinetics.

Perchlorate in Water Supplies: Sources, Exposures, and Health Effects.

Perchlorate exposure occurs from ingestion of natural or man-made perchlorate in food or water. Perchlorate is used in a variety of industrial products including missile fuel, fireworks, and fertilizers, and industrial contamination of drinking water supplies has occurred in a number of areas. Perchlorate blocks iodide uptake into the thyroid and decreases the production of thyroid hormone, a critical hormone for metabolism, neurodevelopment, and other physiologic functions. Occupational and clinical dosing studies have not identified clear adverse effects, but may be limited by small sample sizes, short study durations, and the inclusion of mostly healthy adults. Expanding evidence suggests that young children, pregnant women, fetuses, and people co-exposed to similarly acting agents may be especially susceptible to perchlorate. Given the ubiquitous nature of perchlorate exposure, and the importance of thyroid hormone for brain development, studying the impact of perchlorate on human health could have far-reaching public health implications.

Placental transfer of and infantile exposure to perchlorate.

Fetuses and infants are vulnerable to perchlorate toxicity. We assessed fetal and infantile exposure to perchlorate in two Chinese cities (Nanchang and Tianjin). Perchlorate was widely found (82%-100%) in breast milk, dissolved infant formula, infants' urine, maternal and cord blood samples. Perchlorate levels in infants' urine (mean ± standard deviation: 22.4 ± 35.6 ng mL(-1)), breast milk (36.6 ± 48.1 ng mL(-1)), and cord blood (3.18 ± 3.83 ng mL(-1)) samples collected from Nanchang and Tianjin were approximately an order of magnitude higher than those reported for the U.S. Perchlorate concentrations in cord blood were comparable to that in maternal blood, indicating that perchlorate is transferred from mother to fetus through placenta. Among all infants providing urine samples, the average daily intake of perchlorate (DOSEU) was estimated to be 1.17 ± 1.57 µg kg(-1) bw d(-1), and 40% of these infants had DOSEU exceeding the RfD (0.7 µg kg(-1) bw d(-1)) recommended by U.S. EPA. However, approximately 70% of exclusively breast-fed infants had perchlorate exposure dose via breast milk exceeding the RfD. For breast-fed infants, breast milk was the overwhelmingly predominant exposure pathway; while infant formula and indoor dust ingestion were major perchlorate exposure sources for formula-fed infants. To our knowledge, this is the first report to assess the fetal and infantile exposure to perchlorate in China.

Benchmark calculations for perchlorate from three human cohorts.

The presence of low concentrations of perchlorate in some drinking water sources has led to concern regarding potential effects on the thyroid. In a recently published report, the National Academy of Sciences indicated that the perchlorate dose required to cause hypothyroidism in adults would probably be > 0.40 mg/kg-day for months or longer. In this study, we calculated benchmark doses for perchlorate from thyroid-stimulating hormone (TSH) and free thyroxine (T4) serum indicators from two occupational cohorts with long-term exposure to perchlorate, and from a clinical study of volunteers exposed to perchlorate for 2 weeks. The benchmark dose for a particular serum indicator was defined as the dose predicted to cause an additional 5 or 10% of persons to have a serum measurement outside of the normal range. Using the data from the clinical study, we estimated the half-life of perchlorate in serum at 7.5 hr and the volume of distribution at 0.34 L/kg. Using these estimates and measurements of perchlorate in serum or urine, doses in the occupational cohorts were estimated and used in benchmark calculations. Because none of the three studies found a significant effect of perchlorate on TSH or free T4, all of the benchmark dose estimates were indistinguishable from infinity. The lower 95% statistical confidence limits on benchmark doses estimated from a combined analysis of the two occupational studies ranged from 0.21 to 0.56 mg/kg-day for free T4 index and from 0.36 to 0.92 mg/kg-day for TSH. Corresponding estimates from the short-term clinical study were within these ranges.

PBPK model for radioactive iodide and perchlorate kinetics and perchlorate-induced inhibition of iodide uptake in humans.

Detection of perchlorate (ClO4-) in several drinking water sources across the U.S. has lead to public concern over health effects from chronic low-level exposures. Perchlorate inhibits thyroid iodide (I-) uptake at the sodium (Na+)-iodide (I-) symporter (NIS), thereby disrupting the initial stage of thyroid hormone synthesis. A physiologically based pharmacokinetic (PBPK) model was developed to describe the kinetics and distribution of both radioactive I- and cold ClO4- in healthy adult humans and simulates the subsequent inhibition of thyroid uptake of radioactive I- by ClO4-. The model successfully predicts the measured levels of serum and urinary ClO4- from drinking water exposures, ranging from 0.007 to 12 mg ClO4-/kg/day, as well as the subsequent inhibition of thyroid 131I- uptake. Thyroid iodine, as well as total, free, and protein-bound radioactive I- in serum from various tracer studies, are also successfully simulated. This model's parameters, in conjunction with corresponding model parameters established for the male, gestational, and lactating rat, can be used to estimate parameters in a pregnant or lactating human, that have not been or cannot be easily measured to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other human life stages. For example, by applying the adult male rat:adult human ratios of model parameters to those parameters established for the gestational and lactating rat, we can derive a reasonable estimate of corresponding parameters for a gestating or lactating human female. Although thyroid hormones and their regulatory feedback are not incorporated in the model structure, the model's successful prediction of free and bound radioactive I- and perchlorate's interaction with free radioactive I- provide a basis for extending the structure to address the complex hypothalamic-pituitary-thyroid feedback system. In this paper, bound radioactive I- refers to I- incorporated into thyroid hormones or iodinated proteins, which may or may not be bound to plasma proteins.

Pharmacokinetics of toxic chemicals in breast milk: use of PBPK models to predict infant exposure.

Factors controlling the transfer of potentially toxic chemicals in the breast milk of nursing mothers include both chemical characteristics, such as lipophilicity, and physiologic changes during lactation. Physiologically based pharmacokinetic (PBPK) models can aid in the prediction of infant exposure via breast milk. Benefits of these quantitative models include the ability to account for changing maternal physiology and transfer kinetics, as well as the chemical-specific characteristics, in order to produce more accurate estimates of neonatal risk. A recently developed PBPK model for perchlorate and iodide kinetics in the lactating and neonatal rat demonstrates the utility of PBPK modeling in predicting maternal and neonatal distribution of these two compounds. This model incorporates time-dependent changes in physiologic characteristics and includes interactions between iodide and perchlorate that alter the distribution and kinetics of iodide.

PBPK predictions of perchlorate distribution and its effect on thyroid uptake of radioiodide in the male rat.

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.

Predicting fetal perchlorate dose and inhibition of iodide kinetics during gestation: a physiologically-based pharmacokinetic analysis of perchlorate and iodide kinetics in the rat.

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.

Predicting neonatal perchlorate dose and inhibition of iodide uptake in the rat during lactation using physiologically-based pharmacokinetic modeling.

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.

The effect of short-term low-dose perchlorate on various aspects of thyroid function.

Perchlorate (ClO4) salts are found in rocket fuel, fireworks, and fertilizer. Because of ground water contamination, ClO4 has recently been detected in large public water supplies in several states in the 4-18 microg/L (parts per billion [ppb]) range. The potential adverse effect of chronic low level ClO4 ingestion on thyroid function is of concern to the Environmental Protection Agency (EPA). The daily ingestion of ClO4 at these levels would be magnitudes below the therapeutic effect level of hundreds of milligrams of ClO4 used in treating hyperthyroidism. Studies were carried out in nine healthy male volunteers who had normal thyroid function and negative thyroid antibodies to determine whether the ingestion of 10 mg of ClO4 daily (approximately 300 times the estimated maximum amount of ClO4 consumed from the affected water supplies) would affect any aspect of thyroid function. They ingested 10 mg of ClO4 dissolved in a liter of spring water during waking hours for 14 days. Baseline serum thyrotropin (TSH), free thyroxine index (FTI), total triiodothyronine (TT3), 4-, 8-, and 24-hour thyroid 123I uptakes (RAIU), serum and 24-hour urine ClO4, 24-hour urine iodine, complete blood count (CBC), and chemistry profile were determined. All blood and urine tests were repeated on days 7 and 14 of ClO4 administration and thyroid RAIU on day 14 of ClO4 administration. All tests were repeated 14 days after ClO4 was discontinued. No effect of ClO4 on serum thyroid hormone or TSH concentrations, urinary iodine excretion, CBC, or blood chemistry was observed. Urine and serum ClO4 levels were appropriately elevated during the course of ClO4 ingestion in all subjects, demonstrating compliance. By day 14 of ClO4 administration, the 4-, 8-, and 24-hour thyroid RAIU values decreased in all nine subjects by a mean value of 38% from baseline and rebounded above baseline values by 25% at 14 days after ClO4 withdrawal (p < 0.01 analysis of variance (ANOVA) and Tukey). It is well known that the major effect of ClO4 on the thyroid is a decrease in the thyroid iodide trap by competitive inhibition of the sodium iodide symporter (NIS). The present study demonstrates the sensitivity of the thyroid iodide trap to ClO4 because a low dose of 10 mg daily significantly decreased the thyroid RAIU without affecting circulating thyroid hormone or TSH concentrations. It is possible, however, that the daily consumption of low levels of ClO4 in drinking water over a prolonged period of time could adversely affect thyroid function but no evidence of hypothyroidism was observed at 10 mg of ClO4 daily in this 2-week study. It is now of interest to determine a no effect level for ClO4 on the inhibition of the thyroid RAIU and to carry out a long-term ClO4 exposure study.

[The role of scintigraphy with dual tracer and potassium perchlorate (99mTcO4 & KClO4/ MIBI) in primary hyperparathyroidism]. / Ruolo della scintigrafia con doppio indicatore e perclorato di potassion (99mTc04 & KCl04/MIBI) nell'iperparatiroidismo.

BACKGROUND: The diagnostic value of scintigraphy using a dual tracer and high-resolution neck ecotomography in the preoperative localisation of parathyroid enlargements was evaluated in a group of consecutive patients suffering from primary hyperparathyroidism (HPT) who were uniformly studied and subsequently operated by the same surgical team. METHODS: Scintigraphic imaging and high-resolution neck ecotomography were carried out in a single session on 143 patients. Scintigraphic imaging was performed using a dual tracer, 99mTc-pertechnetate/99mTc-MIBI), modified by the addition of potassium perchlorate (KCL04) to achieve a rapid washout of 99mTc04 from the thyroid and, consequently, to achieve good quality and rapid MIBI images. In a limited number of patients (21 cases) SPECT was also performed. Limited surgery was planned in patients with evidence of single parathyroid lesions and with normal thyroid parameters, in the form of either unilateral or with mini-invasive surgery (91 cases). Patients with eco-scintigraphic evidence of multiglandular parathyroid pathology or the coexistence of a nodular thyroid goitre, or in patients suffering from MEN or familial HPT, or lastly those with negative eco-scintigraphic results under-went more extensive surgery with bilateral exploration of the neck (52 cases). A single parathyroid lesion was diagnosed during surgery in 90 out of 91 patients undergoing planned unilateral or mini-invasive exploration of the neck. Therefore, in our experience, the predictive value of preoperative imaging as a mean of identifying single parathyroid lesions was 98.9% with a clear impact on the choice of conservative surgery. After the removal of the parathyroid to which preoperative imaging referred, it was only necessary in one patient to extend surgical exploration to the other side of the neck to remove another enlarged parathyroid owing to persistent high PTH. RESULTS: The sensitivity of scintigraphy and high-resolution neck ecotomography in pa-tients with a single adenoma was 94% and 83.7% respectively, whereas it was 76.9% and 64.5% respectively in the group of patients with multiglandular pathology. It is worth underlining that in all 31 patients with associated nodular thyroid pathology, the evaluation of thyroid scintigraphic imaging using 99mTc04 and high-resolution neck ecotomography enabled the preoperative diagnosis of thyroid pathology, therefore guiding the surgeon towards more extensive surgery. SPECT enabled the parathyroid adenoma to be correctly localised in a deep site in 5 patients, in the neck in 3 cases and at the mediastinum in 2 patients, providing additional data that helped the surgeon to plan surgery. CONCLUSIONS: In conclusion, in our experience: a) an integrated diagnostic approach based on scintigraphy 99mTc04 & KCLO4/MIBI and high-resolution neck ecotomography was an extremely accurate mean of identifying patients with single parathyroid lesions before surgery, enabling them to undergo limited surgery, b) scintigraphy with a dual tracer might be the elective methods for studying patients with HPT because it allows the contemporary diagnosis of possible thyroid diseases. This aspect is extremely important in geographical areas with a high predominance of nodular thyroid pathology, c) SPECT scintigraphic analysis may be useful in some patients with suspected parathyroid adenoma localised in a deep seat, allowing a more precise identification of the latter and better surgical planning.

A study on perchlorate exposure and absorption in beef cattle.

Perchlorate exposure and potential effects were evaluated in large mammals by monitoring heifer calves placed on a site with access to streamwater fed by a perchlorate-contaminated groundwater spring ( approximately 25 ng/mL). Blood was collected from the two calves on the site (and two control calves from an uncontaminated site) approximately every 2 weeks for analysis of perchlorate residues and thyroid hormones. During the 14 week study, perchlorate was detected (detection limit = 13.7 ng/mL) in blood plasma twice (15 ng/mL and 22 ng/mL) in one of the heifer calves drinking perchlorate-contaminated water on consecutive sampling periods 4 and 6 weeks after the beginning of perchlorate exposure. Constant exposure to 25 ppb perchlorate in drinking water had no effect on circulating thyroid hormones (T(3) and T(4)) in the heifer calves.