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Effects of Six Months of Daily Low-Dose Perchlorate Exposure on Thyroid Function in Healthy Volunteers

Section of Endocrinology, Diabetes, and Nutrition (L.E.B., E.N.P., X.H., S.P.), Boston University Medical Center, and Department of Laboratory Medicine (B.M.), Boston Medical Center, Boston, Massachusetts 02118; Gradient Corp. (M.S., B.B.), Cambridge, Massachusetts 02138; Division of Laboratory Sciences (B.C.B.), National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia 30333; and Jerry L. Pettis Memorial Veterans Administration Medical Center (A.F.), Loma Linda, California 92357

Address all correspondence and requests for reprints to: Lewis E. Braverman, M.D., Boston University Medical Center, 88 East Newton Street, Evans 201, Boston, Massachusetts 02118. E-mail: lewis.braverman{at}bmc.org.

	Abstract

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Context: Perchlorate has been detected in U.S. drinking water supplies at levels ranging from 4 to 200 µg/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 µg per 24 h or 248.5 ± 64.5 µg/g creatinine and mean values for the four subjects who received 3 mg perchlorate daily were 2079.5 ± 430.0 µg per 24 h or 1941.7 ± 138.5 µg/g creatinine. There was no significant change in the thyroid ¹²³I uptakes during perchlorate administration. There were no significant changes in serum T₃, free T₄ 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.

	Introduction

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PERCHLORATE SALTS HAVE been used as pharma- ceuticals and oxidizers in solid propellants for rockets and missiles and in explosives, fireworks, and road flares and air bag inflation systems (1). Since 1997, perchlorate has been found in drinking water throughout the United States at levels ranging from 4 to 200 µg/liter and in lettuce and milk (2). Environmental perchlorate contamination has been attributed to industries that manufacture and use perchlorate. However, detection of low perchlorate levels at locations far from such sources suggests that perchlorate may come from natural processes and Chilean nitrate fertilizers (3).

Perchlorate is a competitive inhibitor of thyroid iodine uptake through the sodium-iodide symporter (4). Prolonged major inhibition of iodide uptake can result in decreased synthesis of thyroid hormones. The ability of perchlorate to inhibit iodine uptake was the basis for its use in the 1950s and 1960s to treat hyperthyroidism (5), but after a few reported cases of fatal aplastic anemia in patients treated with high doses (600–1600 mg/d), use of perchlorate essentially ceased. However, more recent experience using perchlorate to treat Graves’ disease and iodine-induced hyperthyroidism demonstrated no serious side effects at doses less than 1000 mg/d for up to 1 yr (6, 7).

In view of the reported environmental perchlorate contamination (2, 3), the potential health effects from this relatively low-level perchlorate ingestion are a matter of public health interest. There have been several recent human studies regarding the health effects of perchlorate. U.S. studies have not shown any thyroid effects at drinking water perchlorate concentrations of 4–16 µg/liter (8, 9). Observational studies in the Atacama region of Chile, where drinking water perchlorate concentrations are up to 100–120 µg/liter, have also not shown any effect of perchlorate on the thyroid in newborns, school-aged children, or pregnant women (10). In a recent study from an area in Israel where well water perchlorate contamination is more than 300 µg/liter, newborn serum T₄ values were normal (11).

Only one ecological drinking water study in the United States has reported thyroidal effects. TSH levels were elevated in newborns in Yuma City, Arizona, where the drinking water perchlorate concentration was 6 µg/liter, compared with newborns in Flagstaff, Arizona, where perchlorate is undetectable in the water supply (12). However, the demographics and altitudes of the two towns are different. When newborns from Yuma City were compared with those from an adjacent town in which perchlorate is not found in the drinking water, serum TSH values were normal and similar (13).

Studies in perchlorate production workers exposed to perchlorate via inhalation at doses up to 34 mg/d for a mean of 3 yr have not indicated any adverse effects on thyroid structure or serum TSH, thyroid hormones, or thyroglobulin (Tg) concentrations (14, 15) even though 14-h thyroid ¹²³I uptakes (RAIU) were decreased by an average of 38% after three consecutive 12-h shifts as compared with preshift RAIU.

Several controlled studies in normal volunteers have evaluated thyroid effects of 14-d exposures to perchlorate in drinking water (16, 17, 18). The thyroid RAIUs significantly decreased by 38% in healthy volunteers consuming 10 mg perchlorate daily. There were no significant changes in serum thyroid hormone or TSH concentrations during perchlorate administration. Administration of 3 mg perchlorate daily for 14 d resulted in an insignificant 10% decrease in the 24-h RAIU (17). A perchlorate pharmacokinetic study was reported in which volunteers drank water for 14 d containing perchlorate (0.5, 1.4, 7, and 35 mg/d for a 70-kg individual) (18). On d 14, 24-h RAIUs for the 0.5 mg/d exposure group were not significantly different from baseline, whereas 24-h RAIUs at the other three doses had decreased significantly by 16, 45, and 67% from baseline, respectively.

Although the human drinking water and occupational studies provide some evidence that low-level perchlorate exposure does not adversely affect the thyroid, exposure was for only 2 wk in the short-term studies, and in the worker studies, the exposures were not continuous. The aim of the present study was to determine whether more prolonged exposure (6 months) to low perchlorate levels would perturb thyroid function.

	Subjects and Methods

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Experimental subjects

The protocol was approved by the Institutional Review Boards at Loma Linda University School of Medicine, the Jerry L. Pettis Memorial Veterans Administration Medical Center, and Boston University School of Medicine.

Subjects were recruited by direct mail advertising in the Loma Linda and San Bernardino, California, area. Subjects with a known history of thyroid disease or taking thyroid hormone or antithyroid medications were excluded. During the first year, 94 subjects provided informed consent, with 24 subjects eventually being randomized to study medication. Of the original 94 subjects, 15 declined further screening evaluation, and 55 were excluded due to an abnormal baseline laboratory test or preexisting illness. Of the original 24 randomized subjects, 14 completed the 7-month study. The 10 randomized subjects who did not complete the study withdrew due to personal scheduling conflicts. None of the 24 randomized study subjects developed an abnormal laboratory or clinical finding or a study-related adverse event. Of the 14 subjects (aged 25–65 yr) completing the study, nine were women, 12 were Caucasian, and two were African-American. Further volunteers could not be recruited due to adverse publicity (Environmental Working Group; www.ewg.org/reports/perchlorate/pr.html/).

Preparation of capsules

Longwood Pharmaceutical Research, Inc. at the Massachusetts College of Pharmacy and Allied Sciences (Boston MA), prepared perchlorate (reagent grade potassium perchlorate) and placebo capsules using good manufacturing practices as specified by the U.S. Food and Drug Administration. Capsules were checked every 3 months for stability.

Protocol

The 14 subjects were randomly and blindly assigned to four dose groups: placebo or 0.5, 1.0, or 3.0 mg perchlorate, taking the dose daily between 0700 and 1000 h for 6 months. Assuming an average daily water ingestion of 2 liters, the 3.0-mg dose corresponds to approximately 1500 µg/liter perchlorate and the 0.5-mg dose to 250 µg/liter. Physical examination by one of the investigators (A.F.), including palpation of the thyroid, was done monthly during the 7 months of study. Blood (2 h after capsule ingestion) and 24-h urines were obtained at baseline and monthly during perchlorate or placebo administration and 1 month later. Serum thyroid function tests and perchlorate and urine iodine, perchlorate, and creatinine were measured monthly. Capsule counts were monitored monthly. Twenty-four-hour thyroid RAIU and serum Tg and Tg antibodies were measured at baseline, 3 and 6 months during perchlorate or placebo ingestion, and 1 month after study medication had been discontinued. To be certain that perchlorate was not adversely affecting serum TSH and free T₄ index (FTI) concentrations, complete blood counts, or blood chemistries during the study, these parameters were assessed monthly.

Laboratory tests

Serum perchlorate measurement was carried out using HPLC at Boston Medical Center as described earlier (14). The perchlorate content of the 24-h urine samples was measured at the Centers for Disease Control and Prevention Laboratories (Atlanta, GA) using ion chromatography-mass spectrometry (19). Serum total T₃, T₄, FTI, and TSH concentrations were measured at the end of the study in the same assay at the Boston Medical Center Clinical Chemistry laboratories by chemiluminescence using the Bayer Advia Centaur automated system (Bayer Healthcare, Tarrytown, NY). Serum Tg and Tg antibodies were measured using chemiluminescence on the Nichols Advantage (Nichols Institute Diagnostics, San Juan Capistrano, CA). Urinary iodine was measured using the Sandell-Kolthoff reaction. Complete blood counts and serum chemistries were carried out in the Jerry L. Pettis Memorial Veterans Administration Medical Center assay laboratory. The 24-h thyroid RAIU was measured at the Loma Linda University School of Medicine Department of Nuclear Medicine (Loma Linda, CA). Subjects were given 100 µCi ¹²³I orally approximately 2 h after the morning ingestion of the perchlorate capsule. They returned to the laboratory 24 h later for measurement of the thyroid ¹²³I uptake.

Statistical analysis

Values are reported as the mean ± SD and significant differences as P < 0.05. Statistical analyses were carried out using SAS (version 8; SAS Institute, Cary, NC). Baseline differences in mean values by group were assessed using ANOVA. Changes over time by treatment group were assessed using repeated-measures ANOVA.

	Results

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Because only one subject received 1 mg perchlorate daily, this subject was omitted from the analysis. No subjects developed abnormal serum TSH or FTI values during the study.

Urine perchlorate (Table 1)

Urine perchlorate was detected at low levels at baseline in all 13 subjects averaging 9.2 ± 5.7 µg per 24 h or 7.3 ± 5.5 µg/g creatinine. It remained low in the four subjects receiving placebo. In the five subjects given 0.5 mg perchlorate daily, perchlorate values over the 6 months rose appropriately (332.7 ± 66.1 µg per 24 h or 248.5 ± 64.5 µg/g creatinine), as did mean values in the four subjects who re- ceived 3 mg perchlorate daily (2079.5 ± 430.0 µg per 24 h or 1941.7 ± 138.5 µg/g creatinine). Thus, about 65–70% of the daily dose was excreted over a 24-h period.

Serum perchlorate (Table 1)

Perchlorate was not detected in baseline samples or in those subjects receiving placebo. Serum perchlorate was detected in subjects receiving perchlorate, averaging over the 6 months 24.5 ± 16 µg/liter in the 0.5-mg perchlorate group and 77.9 ± 18.2 µg/liter in the 3-mg group. Perchlorate was not detected in any sera 1 month after perchlorate was discontinued.

Urine iodine (Table 1)

Because subjects were not on a controlled diet, daily urine iodine values varied throughout the study, ranging from 54 to 840 µg/g creatinine (median 174 µg/g creatinine). Urine iodine values for the 3-mg perchlorate group were higher, but not significantly so, at baseline than during perchlorate exposure (322 ± 357 vs. 214.7 ± 106 µg/g creatinine or 311.5 ± 263.2 vs. 238.2 ± 132.7 µg per 24 h).

Thyroid RAIU (Table 2)

The thyroid RAIU was measured at baseline, 3 and 6 months during perchlorate or placebo ingestion, and 1 month later. There was no significant change in the thyroid RAIU during perchlorate administration.

Thyroid function tests (Table 2)

There were no significant changes in serum total T₃, FTI, TSH, or Tg concentrations during the exposure period, compared with values before and after perchlorate exposure. Tg antibodies were not detected in any subject.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Although urinary iodine levels were variable both among subjects and across time, there was no relationship between urinary iodine levels and perchlorate levels in serum or urine. Iodine levels were comparable with those of the general population, with the median urinary iodine (174 µg/g creatinine) corresponding to approximately the 70th percentile value in the general population (20).

We observed that a 6-month exposure to perchlorate at 0.5 and 3 mg/d had no effect on thyroid function, including inhibition of thyroid ¹²³I uptake and serum levels of thyroid hormones, TSH, and Tg. These results are similar to those of Lawrence et al. (17) in a 14-d study but differ somewhat from those of Greer et al. (18), who observed a significant 16% decrease in RAIU after a 14-d exposure of 1.4 mg perchlorate daily for a 70-kg individual. The difference between our long-term results and those from the short-term studies may be due to the small number of subjects in our study, differences in the dosing regimen (once daily vs. semicontinuous), or up-regulation of the sodium-iodide symporter as an adaptive response in the long-term study (21).

This is the first study to provide information regarding potential thyroid effects of continuous, long-term exposure to defined low levels of perchlorate. Although perchlorate plant workers were exposed to high amounts of perchlorate on a long-term basis, the exposure pattern in those studies involved 3 d of exposure followed by 3 d without exposure. The intermittent exposure pattern may allow the thyroid to recover, at least partially, from any perchlorate-induced inhibition of iodide uptake during the 3 nonexposed days, thus potentially dampening effects that might be observed with continuous exposure.

This study was limited by the small sample size and is obviously underpowered. Unfortunately, further such studies cannot be carried out at present in the United States. In addition, the once-per-day dosing regimen does not reflect how actual exposures via drinking water and food consumption would occur. Nonetheless, the results suggest that healthy, euthyroid individuals, with normal levels of iodine intake, can tolerate chronic exposure to perchlorate at doses up to 3 mg/d without any effects on thyroid function, including inhibition of iodide uptake.

	Footnotes

 
This work was supported by National Institutes of Health Grant 5K23DK464611 and a grant from Lockheed Martin Corp. The Centers for Disease Control’s role in this study dealt exclusively with perchlorate assessment.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention.

First Published Online April 24, 2006

Abbreviations: FTI, Free T₄ index; RAIU, thyroid ¹²³I uptake; Tg, thyroglobulin.

Received January 26, 2006.

Accepted April 17, 2006.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. U.S. Environmental Protection Agency 2002 Perchlorate environmental contamination: toxicological review and risk characterization. Report no. NCEA-1-0503. Washington, DC: Office of Research and Development, National Center for Environmental Assessment
2. U.S. Food and Drug Administration 2004 Exploratory data on perchlorate in food. College Park, MD: Center for Food Safety and Applied Nutrition/Office of Plant, Dairy Foods
3. Dasgupta PK, Martinelango PK, Jackson WA, Anderson TA, Tian K, Tock RW, Rajagopalan S 2005 The origin of naturally occurring perchlorate: the role of atmospheric processes. Environ Sci Technol 39:1569–1575[Medline]
4. Saito K, Yamamoto K, Takai T, Yoshida S 1983 Inhibition of iodide accumulation by perchlorate and thiocyanate in a model of the thyroid iodide transport system. Acta Endocrinologica 104:456–461[Abstract/Free Full Text]
5. Barzilai D, Sheinfeld M 1966 Fatal complications following use of potassium perchlorate in thyrotoxicosis. Isr J Med Sci 2:453–456[Medline]
6. Martino E, Mariotti S, Aghini-Lombardi F, Lenziardi M, Morabito S, Baschieri L, Pinchera A, Braverman L, Safran M 1986 Short term administration of potassium perchlorate restores euthyroidism in amiodarone iodine-induced hypothyroidism. J Clin Endocrinol Metab 63:1233–1236[Abstract/Free Full Text]
7. Wenzel KW, Lente JR 1984 Similar effects of thionamide drugs and perchlorate on thyroid-stimulating immunoglobulins in Graves’ disease: evidence against an immunosuppressive action of thionamide drugs. J Clin Endocrinol Metab 58:62–69[Abstract/Free Full Text]
8. Li Z, Li FX, Byrd D, Deyhle GM, Sesser DE, Skeels MR, Katkowsky SR, Lamm SH 2000 Neonatal thyroid-stimulating hormone level and perchlorate in drinking water. Teratology 62:429–431[CrossRef][Medline]
9. Li FX, Squartsoff L, Lamm SH 2001 Prevalence of thyroid diseases in Nevada counties with respect to perchlorate in drinking water. J Occup Environ Med 43:630–634[CrossRef][Medline]
10. Tellez RT, Chacon PM, Abarca CR, Blount BC, Landingham CB, Crump KS, Gibbs JP 2005 Long-term environmental exposure to perchlorate through drinking water and thyroid function during pregnancy and the neonatal period. Thyroid 15:963–975[CrossRef][Medline]
11. Amitai Y, Sack J, Wasser J, Winston G, Leuis M, High concentrations of perchlorate in drinking water did not affect neonatal thyroxine levels. Proc Annual Meeting of the North American Congress of Clinical Toxicology, Orlando, FL, September 9–14, 2005
12. Brechner RJ, Parkhurst GD, Humble WO, Brown MB, Herman WH 2000 Ammonium perchlorate contamination of Colorado River drinking water is associated with abnormal thyroid function in newborns in Arizona. J Occup Environ Med 42:777–782[CrossRef][Medline]
13. Lamm SH 2003 Perchlorate exposure does not explain differences in neonatal thyroid function between Yuma and Flagstaff. J Occup Environ Med 45:1131–1132[CrossRef][Medline]
14. Braverman LE, He X, Pino S, Cross M, Magnani B, Lamm SH, Kruse MB, Engel A, Crump KS, Gibbs JP 2005 The effect of perchlorate, thiocyanate, and nitrate on thyroid function in workers exposed to perchlorate long-term. J Clin Endocrinol Metab 90:700–706[Abstract/Free Full Text]
15. Gibbs JP, Ahmad R, Crump KS, Houck DP, Leveille TS, Findley JE, Francis M 1998 Evaluation of a population with occupational exposure to airborne ammonium perchlorate for possible acute or chronic effects on thyroid function. J Occup Environ Med 40:1072–1082[CrossRef][Medline]
16. Lawrence JE, Lamm SH, Pino S, Richman K, Braverman LE 2000 The effect of short-term low-dose perchlorate on various aspects of thyroid function. Thyroid 10:659–663[CrossRef][Medline]
17. Lawrence J, Lamm S, Braverman LE 2001 Low dose perchlorate (3 mg daily) and thyroid function. Thyroid 11:295
18. Greer MA, Goodman G, Pleus RC, Greer SE 2002 Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans. Environ Health Perspect 110:927–937[Medline]
19. Valentin-Blasini L, Mauldin JP, Maple D, Blount BC 2005 Analysis of perchlorate in human urine using ion chromatography and electrospray tandem mass spectrometry. Anal Chem 77:2475–2481[Medline]
20. Hollowell JG, Staehling NW, Hannon WH, Flanders DW, Gunter EW, Maberly GF, Braverman LE, Pino S, Miller DT, Garbe PL, DeLozier DM, Jackson RJ 1998 Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from national health and nutrition examination surveys I and III (1971–1974 and 1988–1994). J Clin Endocrinol Metab 83:3401–3408[Abstract/Free Full Text]
21. National Research Council 2005 Health implications of perchlorate ingestion. New York: The National Academies Press; 276

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