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AD-A267 047
EFFECT OF PROLONGED ADMINISTRATION OF IODINE CONTAINING
WATER PURIFICATION TABLETS IN MAN
FINAL REPORT
HOMER J. LEMAR, JR.
WILLIAM J. GEORGITIS
MICHAEL T. MCDERMOTT
APRIL 15, 1993
Supported by
U.S. ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMAND
Fort Detrick, Frederick, Maryland 21702-5012
MIPR 91MM1525
Fitzsimons Army Medical Center
Aurora, Colorado 80045-5001
Approved for public release; distribution unlimited.
The findings in this report are not to be construed as an
official Department of the Army position unless so designated
by other authorized documents
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15 April 199.3 _ Final Rpnnrt- M /I 5/Q1 -1 7/ VI /Q?>
4. TITLE AND SUBTITLE
Effect of Prolonged Administration of Iodine
Containing Water Purification Tablets in Man
S. FUNDING NUMBERS
MI PR No.
91MM1525
62787A
30162787A874 . ZZ . 281
WUDA335759
6. AUTHOR(S)
Homer J. Lemar, Jr., William J. Georgitis
Michael T. McDermott
7. PERFORMING ORGANIZATION NAME(S) AND AOORESS(ES)
Fitzsimons Army Medical Center
Aurora, Colorado 80045-5001
B. PERFORMING ORGANIZATION
REPORT NUMBER
9. SPONSORING /MONITORING AGENCY NAME(S) AND AODRESS(ES)
U.S. Army Medical Research & Development Command
Fort Detrick
Frederick, Maryland 21702-5012
10. SPONSORING /MONITORING
AGENCY REPORT NUMBER
It. SUPPLEMENTARY NOTES
12a DISTRIBUTION /AVAILABILITY STATEMENT
Approved for public release; distribution unlimit
12b DISTRIBUTION CODE
3d
13. ABSTRACT (Maximum 200 words)
Tetraglycine hydroperiodide tablets purify water by liberating 8 milligrams of iodine
per tablet. The effects on thyroid size, function , and iodine uptake resulting from ingestion of
four of these tablets daily for three months were studied in eight healthy volunteers. Thyroid
size was determined by ultrasound. The thyroid-pituitary axis was assessed by bolus
thyrotropin releasing hormone (TRH) tests. Urinary iodide levels increased from 0.276 to 40
mg/d. The mean RAIU fell and remained less than 2%. As thyroxine levels declined, basal
thyroid stimulating hormone (TSH) and TSH response to TRH rose. In all subjects, thyroid
volume increased. No clinical signs of either hyperthyroidism or hypothyroidism occurred. We
conclude that in response to a sustained increment in TSH, the normal thyroid enlarges to
adapt to the iodine from continuous use of tetraglycine hydroperiodide water purification
tablets.
14 SUBJECT TERMS
RA II, Water Quality
15. NUMBER OF PAGES
16 PRICE CODE
17. SECURITY CLASSIFICATION 18 SECURITY CLASSIFICATION 19. SECURITY CLASSIFICATION
OF REPORT OF THIS PAGE OF ABSTRACT
Unclassified Unclassified Unclassified
20 LIMITATION OF ABSTRACT
Unlimited
NSN 7540 0 I 280-5500
'i'tm .'98 -Rev .' 99)
v*»v • t>»0 tl, -i**N tl a /<'*•* H
Tetraglycine Hydroperiodide (TGH) tablets are used by outdoors enthusiasts and the
American military to purify potentially contaminated water sources, and release approximately
8 milligrams of elemental iodine per tablet. They are available over the counter, and are
stockpiled by the American military to be used in field situations for varying lengths of time.
Iodine, in a variety of formulations, affects thyroid function (1-8). This particular iodide has
not been studied and may be used by a variety of people for potentially prolonged periods. We
investigated the effects of ingesting four TGH tablets daily on thyrotropin (TSH), thyroid
hormone levels, thyroid volume by ultrasound, and 24-hour radioactive iodine uptake in
healthy volunteers.
Eight healthy, euthyroid volunteers comprised of six men and two women, completed
the study. None had a history of thyroid disease, other chronic medical disorder or took
medications containing iodine or with known effect on thyroid function . No subject had a
history of adverse reaction to iodine containing preparations. All signed informed consent
before entering the study. The protocol and consent were reviewed and approved by the
Fitzsimons Army Medical Center Institutional Review Committee. United States Army
quartermaster supply provided the Tetraglycine Hydroperiodide water purification tablets .
Baseline twenty-four hour 131 iodine uptake (24° RAIU), thyroxine (T-4), triiodothyronine
(T-3), thyrotropin (TSH), TSH response to thyrotropin releasing hormone (TSH20), thyroid
volume by ultrasound, serum iodine and twenty-four hour urinary iodine excretion were
performed on each volunteer. Subjects were then instructed to take four water purification
tablets per day dissolved in water or juice for ninety days. 24° RAIU was repeated at days 7 and
28, T-4, T-3, TSH and TSH20 at days 7, 28, and 90; ultrasonic thyroid volume at days 35 and
90; and serum and urinary iodines at days 7, 28, and 90.
Twenty-four hour RAIU was performed in the standard fashion, but using one
microcurie of 131I and longer counting times. T-4 measurement was by T4 Plus TDX system
(Abbott Diagnostics, Inc., North Chicago, Illinois). This Fluorescent Polarization immunoassay
method has a specific intraassay coefficient of variation (CV) of 4.5%. Serum T-3 was measured
by radioimmunoassay (Autopack T-3 RIA Kit, Horsham, Pennsylvania) with an intraassay CV of
4.7%. TSH20 was performed by drawing blood for serum TSH before and twenty minutes after
intravenous injection of 500 micrograms of thyrotropin releasing hormone (Thypinone,
Abbott, North Chicago, Illinois). TSH was measured by IMx Ultrasensitive hTSH Assay based
on the microparticle enzyme immunoassay (MEIA) technology (Abbott Laboratories Abbott
Park, Illinois) with an intraassay CV of 3.3-5.2%.
Thyroid volume was determined by ultrasound as described by Rasmussen (9) using a
Picker Echoview system model 80L, Echoview system 80C ultrasound machine with a Rohe
7.5 megahertz/6mm 2 OM focus transducer. Briefly, longitudinal images were recorded to
determine right and left lobe lengths. Serial transverse images were then made through each
lobe at one half to one centimeter intervals based on length. Images were recorded on
radiographic film and traced for digitization and volume calculation utilizing Sigma Scan and
Sigma Plot computer software programs.
Serum and urine iodines were performed by autoanalyzer utilizing ion exchange and
catalytic reduction methods (S.K. Bioscience Labs, 6330 Variel Ave., Woodland Hills,
California). Serum iodine measurements included protein bound, inorganic, and total iodine.
Data was analyzed for statistical significance by ANOVA and Student Newman Kewls.
Results
The results are summarized in table 1 as group means with standard errors. RAIU was
virtually completely suppressed at day 7 and remained so on day 28. The mean T-4 fell slightly
but not significantly on day 7 compared to baseline, and stayed slightly below the pre¬
treatment value on days 28 and 90. Mean T-3 was also lower than the initial value on day 7, but
rose to levels slightly above baseline on days 28 and 90. These changes also failed to reach
statistical significance.
Significant and parallel increases were seen in TSH, TSH20, and thyroid volume during
the study. The TSH rose and remained significantly above baseline on days 28 and 90. The
TSH20 was also significantly higher than baseline on days 7, 28, and on day 90. Thyroid
volume increased significantly by day 35, and slightly more by day 90. The increase from day
35 to day 90 was not significant on statistical analysis.
Mean baseline serum and urine iodines were 8.5 ug/dl and 275.7 ug/24° respectively.
Serum iodine rose significantly tol04 ug/dl and urine iodine to 37,210 ug/24° on day 7. These
values remained elevated on day 28 (serum 140 ug/dl, urine 41,808 ug/24°) and day 90
(seruml53 ug/dl, urine 30,585 ug/24°).
The water purification tablets were well tolerated by all participants. No subject
developed signs or symptoms of thyroid dysfunction.
Discussion
This study shows significant increases in TSH, (TSH20), thyroid volume, a small
decrement in T-4, and suppressed 24° RAIU, with intake of 32 mg. of iodine per day in the
form of TGH tablets. These changes persisted for the three months of therapy, but were not
associated with any clinically evident thyroid dysfunction.
Several studies have shown that healthy volunteers administered 1.5-250 mg of stable
iodide per day for shorter durations of up to 2 weeks develop statistically significant decreases
in serum levels of thyroid hormones (T4 and T3) and elevated serum thyroid stimulating
hormone (TSH) levels (1-7). Administering 30 mg or more as a single dose or 15 mg cr more
for 12 days also completely suppresses thyroid radio-iodine uptake (4).
Far fewer studies have examined the effects on these variables of more prolonged iodide
administration in normal individuals. Euthyroid subjects receiving 72-360 mg per day for 30
days (1) or massive doses of 1080 mg per day for 11 weeks (11) developed persistent alterations
of thyroid hormone and TSH levels that were similar in magnitude to those seen in short term
studies (1-10) and which appeared to be reversible upon discontinuation of the medication
(ID.
Three points can be considered from these findings. First, since cold iodine ingestion
blocks RAIU, it is recommended as a prophylactic measure to prevent thyroidal accumulation
of radioisotopes of iodine in nuclear environments. Potassium iodide has been used for this
purpose but may be less readily available to the general public than TGH tablets. TGH tablets,
if found to block RAIU with a single dose as well as with prolonged administration, may
represent a readily available, convenient and well-tolerated alternative to potassium iodide.
Second, this study shows a significant increase in thyroid volume associated with a
mild but significant TSH elevation due to iodine intake. Only one other study has examined
the effect of iodine consumption on thyroid volume in normal subjects. Very recently Namba
and colleagues reported increases in thyroid volume and thyroglobulin, a slight decline in T-4,
and a TSH increase within the normal range in subjects given 27 milligrams of iodine daily for
four weeks (8). They speculated the TSH elevation "within the normal range may control
thyroid volume and function", and commented that thyroid autoregulation must be
reconsidered .
4
Autoregulation is defined as the "regulation of thyroidal iodine metabolism
independent of thyroid-stimulating hormone or other external stimulators" and excess iodine
has been considered the major autoregulatory factor (12). This concept is upheld by the
observation of highly stable thyroid hormone and TSH levels in iodine sufficient areas with
widely varying iodine intake (12). The data from Namba and colleagues and the present study
both show an increase in thyroid volume associated with a significant rise in TSH albeit within
the normal range. These data support a role for TSH in the human thyroid response to excess
iodine.
Third, our subjects , who were all free of known thyroid disease, experienced only
subclinical changes in thyroid function within the normal range. However, patients with
underlying thyroid disease, such as treated or untreated Graves' disease, Hashimoto’s disease,
or multinodular goiter, often previously undiagnosed, were much more susceptible to the
effect of iodine. When such patients consume large amounts of iodine for prolonged periods,
they may develop overt and severe hypothyroidism (13, 14) or paradoxically, and without
explanation, thyrotoxicosis ( 15, 16). Therefore, when administering iodides to large
populations, one must be aware that some members are likely to develop significant thyroid
dysfunction.
In summary we have shown increases in thyroid volume and TSH, decreased T-4 levels
and marked suppression of RAIU by consumption of iodine in the form of tetraglycine
hydroperiodide.
5
BIBLIOGRAPHY:
1. Vagenakis AG. Control of thyroid hormone secretion in normal subjects receiving iodides. J
Clin Invest 52:5 28, 1973.
2. Vagenakis AG. Hyper-response to thyrotropin-releasing hormone accompanying small
decreases in serum thyroid hormone concentrations. J Clin Invest 54:913, 1974.
3. Saberi M. Augmentation of thyrotropin responses to thyrotropin-releasing hormone
following small decreases i n serum thyroid hormone concentrations. Endocrinol Metab
40:435, 1975.
4. Sternthal E. Suppression of thyroid radioiodine uptake by various doses of stable iodide. N
Engl J Med 303: 1083, 1980.
5. Meyers B. A small increase in dietary iodine affects thyroid function in euthyroid subjects.
Clin Res 34:429 A, 1986.
6. Paul T. The effect of small increases in dietary iodine on thyroid function in euthyroid
subjects. Metabolism 38:121, 1988.
7. Gardner D. Effects of low dose oral iodide supplementation on thyroid function in normal
men. Clin Endocrinol 28:283, 1988.
8. Namba H, Yamashita S, Kimura H, et al. Evidence of thyroid volume increase in normal
subjects receiving excess iodide. J Clin Endocrinol Metab 76: 605-608, 1993.
9. Rasmussen SN, Hjorth L. Determination of thyroid volume by ultrasonic scanning. J. Clin
Ultrasound 2:143-147, 1974.
10. Georgitis WJ, McDermott M. Iodide water purification tablets alter thyroid function in
men. 71st Meeting of the Endocrine Society, Seattle, WA. Endocrinology 124 (suppl):480
(1830A), 1989.
11. Jubiz W. Serum thyrotropin and thyroid hormone levels in humans receiving chronic
potassium iodide. J Clin Endocrinol Metab 44:379, 1977.
12. Nagataki S. 1991 Autoregulation: effects of iodide. In: Braverman LE, Utiger RD, eds. The
Thyroid, 6th ed. Philadelphia: Lippincott; pp 306-312.
13. Braverman LD. Enhanced susceptibility to iodide myxedema in patients with
Hashimoto's disease. J Clin Endocrinol 32: 515, 1971.
14 Tajiri J. Studies of hypothyroidism in patients with high iodine intake. J Clin Endocrinol
Metab 63:412, 1986.
15 Vagenakis AG. Iodide-induced thyrotoxicosis in Boston. N Engl J Med 287:523, 1972.
16. Rajatanavin R. Five patients with iodine-induced hyperthyroidism. Am J Med 77:378, 1984.
6
laoie i.
RAIU %
Baseline
15 ± 2.6
T4 ug/dl
6.5 ± 0.2
T3 ng/dl
140 ±8
TSH uU/ml
1.69 ± 0.09
TSH20 uU/ml
9.9 ± 0.77
Size (mLs)
Baseline
14.8 ± 0.9
Dav 7
Pay
1.2 ± 0.3***
0.7± 0.3
6.0 ± 0.3
6.0 ± 0.3
128 ±6
155 ± 10
2.8 * 0.32*
3.3 ± 0.33*
14.94 ± 2.41*
18.84 ± 1.72
Dav 35
19.4 ± 1.2 *
Mean ± SE, * p< 0.05, **p< 0.01, ***p< 0.001, ANOVA and SNK
Pay 90
NA
6.1± 0.3
149 ±7
2.98 ± 0.50*
16.33 ± 1.69*
Dav 90
20.3 ± 1.4*
7