[Iodine/046905] Subchronic (90-day) Oral Toxicity Study (non-rodents) (1995) I Page 1of6 OPPTS 870.3150 Study Profile version 07/04 

### EPA Reviewer: Jonathan Leshin, Ph.D.

## Signatur"·~--z__-- RASSB, Antimicrobials Division (7510P)

# Da~~~~z 1t-/ Secondary Review: Michelle Centra,Pharmacologist Signature:'/Ul\7/ 

# Ad1;t,. RASSB, Antimicrobials Division (7510P) Date:

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PC CODE: 046905 TXR#: 1003329 

# II DataEvaluation Record 

# II
DP BARCODE: 408676
STUDYTYPE: Subchronic Oral Toxicity- capsule- human; OPPTS 870.3150 [§82-1]. TEST MATERIAL (PURITY): Tetraglycine hydroperiodide (releases to iodine in water) SYNONYMS: Iodine CITATION: LeMar, H.J., Georgitis, W.J., McDermott, M.T. (1988) Thryoid adaptation to chronic tetraglycine hydroperiodide waterpurificationtablet use. Madigan Army Medical Center and Fitzsimmons Army Medical Center: Journal ofClinical Endocrinology and Metabolishm 80(1): 220-223. MRID 49318802 SPONSOR: US Army Medical Research and Development Command, Fort Detrick, MD INVESTIGATORS' EXECUTIVE SUMMARY: In a 90-day oral toxicity study (MRID 49318802), iodine in the form oftetraglycine hydroperiodide was selfadministeredbypatients as four waterpurificationtablets dissolved in juice or water every day for ninety days. The test group was made up ofeight, healthy, Caucasian volunteers; seven male and one female. Each tablet released approximately 8mg of free iodine and thus iodine consumption was approximately 32 mg/day in addition to dietary consumption ofiodine from a typical American diet. Serum inorganic iodide increased from a level of2.7

### ± 1.0 Jlg/dL to 101 

### ±21 Jlg/dL after ninety days ofexposure. Protein bound iodide increased from 4.8 

### ±0.5 J.!g/dL to 27.7 

### ± 1.3 Jlg/dL after ninety days ofexposure. Urinary iodide increased from 0.276 

### ± 0.061 mg/day to 35 

### ±4.4 mg/day after ninety days ofexposure, a rise ofapproximately 150 fold. Radioactive iodine uptake dropped from 8-26% to below 2% after day 7 and remained below 2% through day 90. Mean serum T3 and T4 declined after 7 days, with T4remaining belowbaseline and T3 recovering by the end ofthe treatmentperiod. Serum TSH and TSH response to TRH rose after 7 days and remained elevated throughout the study. The average thyroid volume was increased by 37%. Neither hypo- nor hyper-thyroidism was found in any subject. Forthe 7 subjects available for repeat thyroid volume determinations on average 7.1 months afterthe study was concluded, the[Iodine/046905) Subchronic (90-day) Oral Toxicity Study (non-rodents) (1995) I Page 2 of6 OPPTS 870.3150 Study Profile version 07/04 thyroid volume returned to baseline. This indicates that a reversible, TSH dependent thyroid enlargement occurs in response to increased iodine load from daily use ofwaterpurification tablets. This study is labeled qualitative as it is outside the parameters for a normal guideline study. It does provide useful information onthe effects ofexcess iodine in humans, which include a form ofreversible thyroid gland volume increase and decreases in T4levels, along with a adaptive change in T3 levels. I. MATERIALS AND METHODS A. MATERIALS: 

### 1. TestMaterial: Description: CAS# ifTGAI: Tetraglycine hydroperiodide Tablets provided by the US Army quartermaster supply from Van Ben Industries 7097-60-1**o,,,~o**

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2. Vehicle and/orpositive control: Juice orwater 3. Test animals: Diet: Subject information: Humans Typical American 7 male and I female Caucasians, age 35-47, healthy, not pregnant, euthyroid, no history of thyroid disease, chronic medical disorders, use ofmedications known to affect thyroid function orprevious reactions to iodine. B. STUDYDESIGNAND METHODS: All subjects had initial evaluations for the study. Baseline levels ofblood basal serum iodine, T4 , T3, and TSH were measured. Stimulated TSH was measured twenty minutes after stimulation by TRH (TSH-20). A 24 urine sample was collected to measure baseline urinary iodine. A 24 hour radioactive iodine uptake (RAIU) was recorded after dosing with l11Ci dose of131

### 1, with ten minute countingtimes. Thyroid volume was measured in therecumbent position by ultrasound. Subjects consumed four waterpurificationtablets dissolved injuiceorwater daily for 90 days in addition to their regular daily diet. Repeat serum iodine, T3, T4, TSH and TSH-20 and urinary iodine measurements were collected on days 7, 28 and 90. RAIU was remeasured on days 7 and 90 and thyroid volume was reassessed on days 35 and 90. Results were expressed as mean 

### ± sem, with a level ofp<0.05 considered statistically significant. Datawas analyzed by analysis ofvariance (ANOVA), followed by Student-Newman-Keuls[lodine/046905) multiple comparison tests. II. RESULTS Subchronic (90-day) Oral Toxicity Study (non-rodents) (1995) I Page 3 of6 OPPTS 870.3150 Study Profile version 07/04



### A. Serum inorganic, protein-bound and urinary iodides: Serum inorganic iodide increased from a level of2.7 

### ± 1.0 J..lg/dL to 101 

### ± 21 J..lg/dL after ninety days ofexposure, with saturation occurring after 28 days. Protein bound iodide increased from 4.8 

### ± 0.5 J..lg/dL to 27.7 

### ± 1.3 J..lg/dL after ninety days ofexposure with saturation occurring after seven days. Urinary iodide increased from 0.276 

### ± 0.061 mg/dayto 35 

### ± 4.4 mg/day after ninety days ofexposure, a rise ofapproximately 150 fold. These changes are outlined inTable 1. T bl 1 Ch

a e : 

### t . b anges m serum morgamc, pro em oun 

## I Before treatment 

## I Inorganic (!lg/dL) 

## I 2.7 ± 1.0 Protein bound {jlg/dL) 

### I 4.8 ±0.5 Iodine (mg/day) 

### I 0.276 ±0.061 Data shown are the mean ±sem. 

### ***O.OOI** 

### B. Radioiodine thyroid uptake: 

## I I I Day7 Serum 93 ±24* 32.0 ±5.2* Urine 37.2 ±4.4* d d an . d'd urmary 10 1 es During Treatment 

### I Day28 

### I Day90 

### I 102 ±23* 

## I 101±21* 

## I 29.8 ±4.2* 

## I 27.7 ± 1.3* 

### I 42.5 ±6.5* 

### I 35.0 ±4.4*

Three 24 hour RAIU tests were performed, before and after 7 and 90 days oftreatment. Uptake dropped from 8-26% to approximatelytwo percent after seven days and belowtwo percent after 90 days. This data is showninFigure 1. Figure 1. Individual 24-hourradioactive iodine uptake before and duringtreatment. Thenormal range ofuptake is indicatedbythe openrectangle. RAIU decreased markedly at 7 days and remained low at 90 days. The mean±SEM are displayed in inset.***, P<0.001[lodine/046905)

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C. Serum thyroid hormones: Subchronic (90-day) Oral Toxicity Study (non-rodents) (1995) I Page 4 of6 OPPTS 870.3150 Study Profile version 07/04



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Mean serum T4 concentration fell slightly on day 7 and remained belowpretreatment value through days 28 and 90. Mean T3 concentration was lower than pretreatment value on day 7 but averaged above baseline on days 28 and 90. No changes were significant. Datais shown in Table 2. Table 2: Effect ofTGH treatment

TSH (mU/L) TSH-20 T4 (nmol/L) T3 (nmol/L) Tg (ng/mL) 

### *p<0.05 ** p<O.OI Tg=Serum thyroglobulinBefore treatment 1.69 ± 0.09 9.90 ± 0.77 83.2 ± 2.9 2.15±0.12 13.9 ± 5.6

D. Thyroid volume and TSH: Day7 2.80 ± 0.32* 14.94 ± 2.41 * 77.6 ± 4.1 1.97 ± 0.09 22.2 ± 9.3 DuringTreatment Day28 Day 90 3.30 ± 0.33* 2.98 ± 0.50* 18.84 ± 1.72** 16.33 ± 1.69* 77.6 ± 3.8 78.9 ± 3.3 2.39 ± 0.15 2.29 ± 0.10 31.4±15.7* 23.3 ± 11.3

Serum TSH and TSH-20 values rose significantly from baseline by day 7 and remained elevated on days 28 and 90. Unstimulated TSH increased approximately doubled on average and the greatest increase in unstimulated TSH grewbythree fold during the study. This subject also had the greatest change in thyroid volume of 1.8 fold. Thyroid volume increased significantly from baseline by day 35 and remained elevatedthrough day 90. The mean increase in thyroid volume was 37%. Changes in thyroid volume and unstimulated TSH were not correlated. Those subjects available for repeat thyroid volume determinations showed a return to baseline volume during an[lodine/046905) Subchronic (90-day) Oral Toxicity Study (non-rodents) (1995) I Page 5 of6 OPPTS 870.3150 Study Profile version 07/04 average of7.1 months posttreatment. TSH remained persistently above initial baseline values in all subjects, with one exception whose TSH fell below baseline butremained inthe middle ofthe established range oftreatment. Datais shown in Figure 2 and Table 2. Figure 2: Thyroid volumes before, during and after treatment. Thyroid volume increased significantly after day 35 and enlarged slightly more after day 90. Thyroid volumes had returned to pretreatment values when remeasured at variable time intervals in seven subjects (mean 7.1 months; range 0.5-16.1 months. Shown are the mean±SEM, *, p<0.05, ** p<0.01 .;i 25 

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### E. General observations: No subject developed hyperthyroidism, hypothyroidism or symptomatic thyroid enlargement.


### III. INVESTIGATORS' DISCUSSION AND CONCLUSIONS: Serum inorganic iodide increased from a level of2.7 

### ± 1.0 J..Lg/dL to 101 

### ± 21 J..Lg/dL after ninety days ofexposure. Protein bound iodide increased from 4.8 

### ± 0.5 J..Lg/dL to 27.7 

### ± 1.3 J..Lg/dL after ninety days ofexposure. Urinary iodide increased from 0.276 

### ± 0.061 mg/day to 35 

### ±4.4 mg/day after ninety days ofexposure, a rise ofapproximately 150 fold. Radioactive iodine uptake dropped from 8-26% to below 2% after day 7 and remained below 2%through day 90. Mean serum T3 and T4 declined after 7 days, withT4remaining belowbaseline and T3 recovering by the end ofthe treatment period. Serum TSH and TSH response to TRH rose after 7 days and remained elevated throughout the study. The average thyroid volume was increased by 37%. Neitherhypo- nor hyper-thyroidism was found in any subject. Forthe 7 subjects available for repeat thyroid volume determinations on average 7.1 months after the study was concluded, the thyroid volume returned to baseline. This indicates that a reversible, TSH dependent thyroid enlargement occurs in response to increased iodine load from daily use ofwaterpurification tablets. This study is labeled 

### qualitative as it is outside the parameters for a normal guideline study. It does provide useful information on the effects ofexcess iodine in humans, which include a form ofreversible thyroid gland volume increase and decreases inT4levels, along with an adaptive[Iodine/046905] change in T3 levels. Subchronic (90-day) Oral Toxicity Study (non-rodents) (1995) I Page 6 of6 OPPTS 870.3150 Study Profile version 07/04