One-step sample processing method for the determination of perchlorate in human urine, whole blood and breast milk using liquid chromatography tandem mass spectrometry.

A one-step sample processing was developed to determine the levels of perchlorate in human urine, whole blood and breast milk by using liquid chromatography tandem mass spectrometry (LC-MS/MS). Athena C18-WP column was used to separate and analyze perchlorate. Perchlorate and isotope-labeled perchlorate (Cl18O4-) internal standards were spiked in the sample matrix through vortex mixing, centrifugation, and filtration. The filtrate was collected and subjected to LC analysis. The developed method was validated for its reproducibility, linearity, trueness, and recovery. Satisfactory recovery of perchlorate ranged from 81% to 117% with intraday relative standard deviations (RSDs) (n = 3) and inter-day RSDs (n = 9) of 5-18% and of 5-16%, respectively. Good linearity (R2 ≥ 0.99) was observed. Limits of detection and quantification for perchlorate ranged from 0.06 µg/L to 0.3 µg/L and from 0.2 µg/L to 1 µg/L, respectively. Perchlorate concentrations were found in human urine (n = 38) and whole blood (n = 8) samples with the range of 6.5-288.6 µg/L and 0.3-2.8 µg/L, respectively. These results indicate the applicability of our developed method in determining perchlorate level in real samples. Moreover, this method is also highly reliable, sensitive and selective in detecting perchlorate in human urine, whole blood and breast milk samples and may be applicable to other matrixes i.e. saliva, serum, plasma, milk powder and dairy milk.

Exposure of the US Population to Nitrate, Thiocyanate, Perchlorate, and Iodine Based on NHANES 2005-2014.

Perchlorate, thiocyanate, nitrate, and iodide all have the same action of iodide uptake inhibition. Urinary samples were available for the US population through the National Health and Nutrition Examination Survey (NHANES) database for these compounds and were evaluated for the 2005 through 2014 time period. We were interested in whether exposures to the US population had changed since the mid-2000s. Given that these exposures were largely naturally derived and exposure was from food, we hypothesized that the levels of nitrate, thiocyanate, and perchlorate remained relatively stable over this time period. Additionally, we evaluated mean perchlorate equivalent concentrations (PEC) of all three goitrogens together. There was a significant decrease in urinary perchlorate from 2005 to 2014 (p < 0.01). Thiocyanate and iodide also decreased significantly (p < 0.01), but not nitrate (p = 0.35). PEC decreased since 2005 with contribution from perchlorate at less than 1%, while nitrate increased in contribution.

Evaluation of the risk of perchlorate exposure in a population of late-gestation pregnant women in the United States: Application of probabilistic biologically-based dose response modeling.

The risk of ubiquitous perchlorate exposure and the dose-response on thyroid hormone levels in pregnant women in the United States (U.S.) have yet to be characterized. In the current work, we integrated a previously developed perchlorate submodel into a recently developed population-based pregnancy model to predict reductions in maternal serum free thyroxine (fT4) levels for late-gestation pregnant women in the U.S. Our findings indicated no significant difference in geometric mean estimates of fT4 when perchlorate exposure from food only was compared to no perchlorate exposure. The reduction in maternal fT4 levels reached statistical significance when an added contribution from drinking water (i.e., 15µg/L, 20µg/L, or 24.5µg/L) was assumed in addition to the 90th percentile of food intake for pregnant women (0.198µg/kg/day). We determined that a daily intake of 0.45 to 0.50µg/kg/day of perchlorate was necessary to produce results that were significantly different than those obtained from no perchlorate exposure. Adjusting for this food intake dose, the relative source contribution of perchlorate from drinking water (or other non-dietary sources) was estimated to range from 0.25-0.3µg/kg/day. Assuming a drinking water intake rate of 0.033L/kg/day, the drinking water concentration allowance for perchlorate equates to 7.6-9.2µg/L. In summary, we have demonstrated the utility of a probabilistic biologically-based dose-response model for perchlorate risk assessment in a sensitive life-stage at a population level; however, there is a need for continued monitoring in regions of the U.S. where perchlorate exposure may be higher.

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.

Occurrence of perchlorate and thiocyanate in human serum from e-waste recycling and reference sites in Vietnam: association with thyroid hormone and iodide levels.

Perchlorate (ClO4 (-)) and thiocyanate (SCN(-)) interfere with iodide (I(-)) uptake by the sodium/iodide symporter, and thereby these anions may affect the production of thyroid hormones (THs) in the thyroid gland. Although human exposure to perchlorate and thiocyanate has been studied in the United States and Europe, few investigations have been performed in Asian countries. In this study, we determined concentrations of perchlorate, thiocyanate, and iodide in 131 serum samples collected from 2 locations in Northern Vietnam, Bui Dau (BD; electrical and electronic waste [e-waste] recycling site) and Doung Quang (DQ; rural site) and examined the association between serum levels of these anions with levels of THs. The median concentrations of perchlorate, thiocyanate, and iodide detected in the serum of Vietnamese subjects were 0.104, 2020, and 3.11 ng mL(-1), respectively. Perchlorate levels were significantly greater in serum of the BD population (median 0.116 ng mL(-1)) than those in the DQ population (median 0.086 ng mL(-1)), which indicated greater exposure from e-waste recycling operations by the former. Serum concentrations of thiocyanate were not significantly different between the BD and DQ populations, but increased levels of this anion were observed among smokers. Iodide was a significant positive predictor of serum levels of FT3 and TT3 and a significant negative predictor of thyroid-stimulating hormone in males. When the association between serum levels of perchlorate or thiocyanate and THs was assessed using a stepwise multiple linear regression model, no significant correlations were found. In addition to greater concentrations of perchlorate detected in the e-waste recycling population, however, given that lower concentrations of iodide were observed in the serum of Vietnamese females, detailed risk assessments on TH homeostasis for females inhabiting e-waste recycling sites, especially for pregnant women and their neonates, are required.

Radioactive iodide (131 I-) excretion profiles in response to potassium iodide (KI) and ammonium perchlorate (NH4ClO4) prophylaxis.

Radioactive iodide ((131)I-) protection studies have focused primarily on the thyroid gland and disturbances in the hypothalamic-pituitary-thyroid axis. The objective of the current study was to establish (131)I- urinary excretion profiles for saline, and the thyroid protectants, potassium iodide (KI) and ammonium perchlorate over a 75 hour time-course. Rats were administered (131)I- and 3 hours later dosed with either saline, 30 mg/kg of NH(4)ClO(4) or 30 mg/kg of KI. Urinalysis of the first 36 hours of the time-course revealed that NH(4)ClO(4) treated animals excreted significantly more (131)I- compared with KI and saline treatments. A second study followed the same protocol, but thyroxine (T(4)) was administered daily over a 3 day period. During the first 6-12 hour after (131)I- dosing, rats administered NH(4)ClO(4) excreted significantly more (131)I- than the other treatment groups. T(4) treatment resulted in increased retention of radioiodide in the thyroid gland 75 hour after (131)I- administration. We speculate that the T(4) treatment related reduction in serum TSH caused a decrease synthesis and secretion of thyroid hormones resulting in greater residual radioiodide in the thyroid gland. Our findings suggest that ammonium perchlorate treatment accelerates the elimination rate of radioiodide within the first 24 to 36 hours and thus may be more effective at reducing harmful exposure to (131)I- compared to KI treatment for repeated dosing situations. Repeated dosing studies are needed to compare the effectiveness of these treatments to reduce the radioactive iodide burden of the thyroid gland.

Electrokinetic injection across supported liquid membranes: new sample pretreatment technique for online coupling to capillary electrophoresis. Direct analysis of perchlorate in biological samples.

A simple and sensitive method for quantifying perchlorate in biological samples using CE and capacitively coupled contactless conductivity detection was developed. An online combination of a supported liquid membrane, an inert polypropylene membrane impregnated with 1-hexanol, and electrokinetic injection of perchlorate across the supported liquid membrane directly into the separation capillary reduced the need for laborious sample pretreatment procedures, resulting in a cheap and rapid method with low LODs capability. Baseline separation of perchlorate and other anions in biological samples was achieved in background electrolyte solution consisting of 15 mM nicotinic acid and 1 mM 3-(N,N-dimethylmyristylammonio)propanesulfonate at pH 3.3. The analytical method showed excellent parameters in terms of reproducibility; RSD values for peak areas and corrected migration times at a spiked concentration of 100 µg/L of perchlorate were below 10 and 0.4%, respectively. Linear calibration curves were obtained for perchlorate in the concentration range 10-1000 µg/L (r(2) >0.999) with LODs between 2 and 5 µg/L for human urine, breast milk, serum, cow's milk, and red wine. Recoveries at 25 µg/L of perchlorate were between 97 and 106% for all biological samples. The low LODs rivaling those of presently used analytical methods support the use of this method for quantification of perchlorate in biological samples in the future.

Perchlorate and iodide in whole blood samples from infants, children, and adults in Nanchang, China.

Perchlorate, ClO(4)(-), interferes with iodide (I(-)) uptake by the sodium-iodide symporter (NIS) and thereby affects thyroid hormone production in the body. Studies have reported human exposures to perchlorate based on measurements in urine, but little is known about the levels in blood. In this study, we determined concentrations of perchlorate, iodide, and other anions (e.g., chlorate [ClO(3)(-)], bromate [BrO(3)(-)], bromide [Br(-)]) in 131 whole blood samples collected from Chinese donors aged 0.4 to 90 yr, in Nanchang, China. Perchlorate, iodide, and bromide were detected in all of the samples analyzed, whereas chlorate was found in only 27% of the samples and bromate was found in only 2%. The mean (range) concentrations of perchlorate, iodide, and bromide were 2.68 (0.51-10.5), 42.6 (1.58-812), and 2120 (1050-4850) ng/mL, respectively. Perchlorate levels in blood from Nanchang adults were 10-fold greater than levels that have been previously reported for U.S. adults. The iodide/perchlorate molar ratio ranged from 3.05 to 15.3 for all age groups, and the ratio increased with age (r = 0.732, p < 0.01). Perchlorate and bromide concentrations decreased significantly with age, whereas iodide concentrations increased with age. No significant gender-related differences in blood perchlorate, iodide, or bromide levels were found. A significant negative correlation was found between the concentrations of perchlorate and iodide in blood. Exposure doses of perchlorate were estimated for infants, toddlers, children, adolescents, and adults based on the measured concentrations in blood, using a simple pharmacokinetic model. The mean exposure doses of perchlorate for our age groups ranged from 1.12 (adults) to 2.22 µg/kg bw/day (infants), values higher than the United States Environmental Protection Agency's (USEPA) reference dose (RfD: 0.7 µg/kg bw/day). This is the first study on perchlorate and iodide levels in whole blood from infants, toddlers, children, adolescents, and adults from a city in China with known high perchlorate levels.

Perinatal exposure to perchlorate. thiocyanate, and nitrate in New Jersey mothers and newborns.

Perchlorate is a commonly occurring environmental toxicant that may be transported across the placental barrier by the sodium-iodide symporter (NIS), possibly resulting in both increased perchlorate exposure and decreased iodide uptake by the fetus. Therefore, we measured levels of three physiologically relevant NIS-inhibitors (perchlorate, nitrate, and thiocyanate) and iodide in maternal and fetal fluids collected during cesarean-section surgeries on 150 U.S. women. Geometric means of perchlorate, thiocyanate, and nitrate levels in maternal urine (2.90, 947, and 47900 microg/L, respectively) were similar to previously published results, while urinary iodide levels (1420 microg/L) were significantly higher (p < 0.0001), likely because of prevalent prenatal vitamin use in the study population (74%). Thiocyanate levels were higher in the maternal serum, cord serum, and amniotic fluid of smokers compared to women with environmental tobacco smoke exposure and nonsmokers (p-values of 0.0006, 0.0011, and 0.0026, respectively). Perchlorate was detected in most samples: urine (100%), maternal serum (94%), cord serum (67%), and amniotic fluid (97%). Maternal urinary perchlorate levels were positively correlated with perchlorate levels in amniotic fluid (r = 0.57), indicating that maternal urine perchlorate is an effective biomarker of fetal perchlorate exposure. Maternal serum perchlorate was generally higher than cord serum perchlorate (median ratio 2.4:1 for paired samples), and maternal urine perchlorate was always higher than fetal amniotic fluid perchlorate levels (mean ratio 22:1); conversely, iodide levels were typically higher in fetal fluids compared to maternal fluids. We found no evidence of either disproportionate perchlorate accumulation or lack of iodide in the fetal compartment. In this panel of healthy infants, we found no association between cord blood levels of these anions and newborn weight length, and head circumference.

Perchlorate in human blood serum and plasma: Relationship to concentrations in saliva.

The perchlorate anion (ClO(4)(-),MW=99) is present in food, drinking water, groundwater, and surface waters. Exposure to perchlorate is of concern, due to the ability of the anion to disrupt the function of the thyroid gland, and affect the synthesis of thyroid hormones. In this study, liquid chromatography - tandem mass spectrometry (LC-MS/MS) method has been optimized to analyze for perchlorate in blood sera and plasma samples from 84 US donors. In addition, 15 volunteers provided saliva and serum samples concurrently, to enable assessment of the ratio of perchlorate in these two matrices. Recoveries of perchlorate from fortified blanks and from serum/plasma samples were between 92% and 97%. Replicate analysis of blood-matrix spikes had a relative standard deviation (RSD) of <3%, and the relative percent difference (RPD) of repeat analysis of samples was <4%. Perchlorate concentrations in serum and plasma ranged from below the limit of quantitation (0.05ngmL(-1)) to a maximum of 7.7ngmL(-1). Perchlorate concentrations in serum and plasma were log-normally distributed. The mean and median concentrations of perchlorate in 84 serum and plasma samples were 0.32 and 0.17ngmL(-1), respectively. No significant difference existed in perchlorate concentrations between serum and plasma. Analysis of paired saliva and serum samples showed a significant positive correlation for log-normalized perchlorate concentrations (r(2)=0.60) and perchlorate concentrations themselves (r(2)=0.86). The mean saliva:serum concentration ratio of perchlorate was 14:1 (after exclusion of two pairs of outliers). This is the first report to provide measurement data for perchlorate in blood sera and plasma of populations in the US.

Use of a simple pharmacokinetic model to characterize exposure to perchlorate.

A simple two-compartment first-order pharmacokinetic model that predicts concentrations of perchlorate in blood and urine was constructed and validated. The model was validated using data from a high-dose experiment in humans where doses and resulting concentrations of perchlorate in blood and urine were well documented. Specifically, data were available for individuals who had been dosed at 0.5, 0.1, and 0.02 mg/kg/day for 14 consecutive days, significantly higher than the average background dose, which is estimated to be less than 0.0001 mg/kg/day. The average measured urine concentration in the high-dose regime during the experiment was 15.4 mg/l compared with an average prediction of 17.3 mg/l. In the medium-dose regime, the average measured was 3.0 mg/l compared with 4.1 mg/l predicted, and in the low-dose regime, the average measured was 0.53 mg/l compared with 0.68 mg/l predicted. For blood, the analogous results include 0.51 mg/l measured compared with 0.54 mg/l predicted in the high-dose regime and 0.12 mg/l measured versus 0.11 mg/l predicted in the medium-dose regime. The model was then used to study background exposures to perchlorate. A national sampling of perchlorate in urine showed a median concentration of 0.0035 mg/l, and this was used to back-calculate a dose of 0.000064 mg/kg/day. This finding was independently verified with the modeling structure of this study, as use of that back-calculated dose of 0.000064 mg/kg/day resulted in predictions of urine concentration with an average virtually identical at 0.0033 mg/l. An examination of literature data on the possible pathways of exposure suggests that the consumption of foods, rather than ingestion of water, dominates background exposures. Daily variation in urine concentration was studied with the model, and it was found that concentrations in the morning hours were lower than concentrations in the afternoon and evening hours, corresponding to the time when most exposure was assumed to occur.

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.

Effect of mastitis on milk perchlorate concentrations in dairy cows.

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.

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.

Monitoring perchlorate exposure and thyroid hormone status among raccoons inhabiting a perchlorate-contaminated site.

Perchlorate is a water soluble anion that is readily accumulated in vegetation. It inhibits uptake of iodide into thyroid gland tissue, thereby reducing production of thyroid hormones. Potential raccoon food items including berries, fish, and vegetation collected at a contaminated site contained quantifiable concentrations of perchlorate as determined by ion chromatography. Therefore, we monitored resident raccoons for exposure to perchlorate by examining plasma perchlorate and thyroid hormone concentrations. Resulting analytical data failed to demonstrate perchlorate exposure among raccoons that likely consumed food items collected along perchlorate-contaminated water bodies. There were no correlations between triiodothyronine or thyroxine and thyroid stimulating hormone concentrations, but triiodothyronine concentrations in raccoon plasma were significantly higher in 2000 than in 2001 (p = 0.0081). These data suggest that natural attenuation and remedial efforts initiated in January of 2001 may have reduced perchlorate exposure among raccoons inhabiting this site from 2000 to 2001. Temporal, spatial, and analytical factors limited our ability to quantify exposure among raccoons, however, our data do not indicate that raccoons currently inhabiting this site are at risk for significant exposure to perchlorate and subsequent effects.

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.

Evidence for competitive inhibition of iodide uptake by perchlorate and translocation of perchlorate into the thyroid.

Various published data sets that investigate the potential effect of exogenous perchlorate (ClO4-) on the uptake of iodide in the thyroid and subsequent changes in thyroid hormone levels are available. In order to best use the data towards the prediction of human health effects resulting from ClO4- exposure, the available literature data must be integrated into a self-consistent, coherent, and parsimonious quantitative model based on the most likely mode of action of perchlorate effect on thyroid function. We submit that the simplest mode of action for ClO4- in the thyroid that remains consistent with all available data involves competitive inhibition of iodide transport into the thyroid follicle, transport of perchlorate into the thyroid follicle against a concentration gradient, further transport into the thyroid lumen (where it may again interfere with iodide transport), and, finally, passive diffusion back into the blood. We believe this description of perchlorate's kinetic behavior should serve as the foundation for predictive physiologically based pharmacokinetic (PBPK) models and as a working hypothesis for further experimental exploration.

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.