[lodine/046905) Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page I of4 OPPTS 870.3150 Study Profile version 07/04 

### EPAReviewer: Jonathan Leshin, Ph.D. 

### Signature:

## ~ - 

### RASSB, AntimicrobialsDivision (7510P) Date:

### ~ SecondaryReview: Michelle Centra, Pharmacologist 

### Signature:

## ~**~ ~**  RASSB, Antimicrobials Division (7510P) Date·

### ~t/ Template version 

### 02106



# ,, DataEvaluation Record 

# II

STUDYTYPE: Subchronic Oral Toxicity-liquid- human; OPPTS 870.3150 [§82-1]. 

### PC CODE: 046905 

### TXR#: 1003331 

### TESTMATERIAL (PURITY): Iodine 

### SYNONYMS: None 

### DP BARCODE: 408676



### CITATION: Gardner, D.P., Centor, R.M., Utiger, R.D. (1988) Effects ofthelowdose oral**-- ~**  ... - iodide supplementation onthyroid function in normal men. Medical College of Virginia MRID 47358601: Clinical Endocrinology 28:283-288 

### SPONSOR: Department ofMedicine, Medical College ofVirginia, Richmond, VA 23298 

### INVESTIGATORS' EXECUTIVE SUMMARY: In a 14-day oral toxicity study (MRID 47358601), sodium iodide was selfadministered by patients as a 0.5 ml solution twice daily with doses ofeither 500, 1500 or4500 11g/ml with 1mg/ml ascorbic acid. The test group was made up ofthirty male volunteers. This dosing was in addition to theirnormal unadjusted diets. No changes inweight, symptoms ofthyroid dysfunction, or other adverse effects were reported. There were dose related increases in serumtotal and inorganic iodide concentrations as well as urinary iodide excretion. In the 1500 and 4500 11g/ml dose groups there was a decrease in serum T4 and free T4. No change in T3 charcoal uptake or serum T3 in any dose group occurred. The 500 11glmldose group caused a significant increase in serum TSHresponse to TRH. The 1500 and 4500 11g/ml dose groups caused a significant increase in both basal and TRH induced TSH concentrations. This indicates that iodide supplementation can have some effects onthyroid hormone secretion. This study is labeled 

### qualitative as it does notprovide a lower endpointthan an existing study. It does provide useful information onthe effects ofnutritional levels ofiodine in humans and the results are consistent with existing studies.[lodine/046905) Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page 2 of4 OPPTS 870.3150 Study Profile version 07/04

I. 

### MATERIALSAND METHODS A. MATERIALS: 1. 

### TestMaterial: Description: CAS # ifTGAI: Iodine Sodium iodide dissolved in deionized water 74-88-4 

### 2. Vehicle and/orpositive control: Deionized water 

### 3. Test animals: Diet: Humans Typical American Subject information: 30 normal males, age 22-40, healthy, euthyroid, no history ofthyroid disease, use of medications known to affect thyroid function or previous reactions to iodine. 

### B. STUDY DESIGNAND METHODS: All subjects had initial evaluations for the study. After an eighthour fast, baseline levels ofblood basal serum iodine, T4, T3, T3-charcoal uptake, proteinbound iodide (PBI), total iodide andTSH were measured. StimulatedTSH was measured after stimulationby TRH every 15 minutes for an hour. A 24 urine sample was collectedto measure baseline urinary iodine. Subjects maintained their normal diets. Subjects consumed 0.5 ml ofdissolved iodine in deionized watertwice daily. The subjects were randomly sorted into groups dosed with either 500, 1500 or4500 J..Lg/ml. Onday 15, the initial protocol was repeated. Results were expressed as mean 

### ± sem, with a level ofp<0.05 considered statistically significant. Paired Student'st-tests were usedto compare within-group changes before and after iodide administration. 

### II. RESULTS A. Serum inorganic, protein-bound and urinaryiodides: Changes in serum and urinary iodide occurred at all three dose levels. The changes were dose dependent. No iodide dose caused a significant change in mean serumproteinbound iodine. These changes are outlined in Table 1. 

### Table 1: Urinary iodide excretion and serum iodide concentrations before and afteriodide administration

Iodide dose 

### I Urinary iodide (112124 hrs) 

### I Total iodide (u2/dl) 

### I Serum PBI (ue:/dl) 

### I lnore:anic iodide (ug/dl) 500 ug/day Day I 

### I 256 +44 

### I 6.2 +0.3 

### I 5.0 ± 0.3 

### I 1.2 ± 0.1 Day 15 

### I 638 ±58* 

### I 6.7 +0.3 

### I 4.8 ± 0.2 

### I 1.9 ± 0.3* 1500 ul!:lday[Iodine/046905]
Day I Day 15 Day I Day 15 Mean± SEM. * p<O.OOI 

### I 

### I I I 285 ± 49 1498 ± 105*

319 ±51 5035 ± 315*



### B. Serum thyroid hormones: 

### I I I I Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page3 of4 OPPTS 870.3150 Study Profile version 07/04
6.3 ± 0.3 

### I 5.0 ± 0.3 

### I 1.3 ± 0.2 7.7 ± 0.2* 

### I 4.7 ± 0.2 

### I 3.0± 0.2* 4500 J.Lg/day 6.0 ± 0.3 

### I 4.7 ± 0.3 

### I 1.3 ± 0.2 12.7 ± 1.2* 

### I 4.8 ± 0.3 

### I 7.9 ± 0.9*

There were no significant changes in the 500 1-1-g/ml dose group. The 1500 and4500 1-1-g/ml dose groups resulted in decreases in the mean serum T4 concentration and free T4index. Free T4 (serum free thyroxine, FTI) was calculatedbymultiplying serumT4 concentrationbythe T3 charcoal uptake ratio. SerumT3 concentrations and T3 charcoal uptake ratio did not change for any dosing group. These results are shown in Table 2. 

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### e a miDIS ra IOD Iodide dose Serum**T~** (JJ.g/dl) Day I 9.2 ± 0.5 Day 15 9.2 ± 0.4 p-value NS Day I 8.6 ± 0.4 Day 15 7.5 ± 0.9 p-value 0.005 Day I 8.9 ± 0.6 Day 15 8.2 ± 0.7 p-value 0.02 p value, day 15 compared w1th day I. Mean± SEM. NS- not significant T3 charcoal uptake ratio 500 J.Lg/ml 1.06 ± 0.04 1.09 ± 0.04 NS

1500 J.Lg/ml 1.02 ± 0.04 1.00 ± 0.05 NS 4500 Jlg/ml 1.12 ± 0.09 1.11 ± 0.04 NS



### C. TSH, stimulated and unstimulated: FTI Serum**_(~/dl)** 9.8 ± 0.8 153 ± 8 10.0 ± 0.6 158 ± 7 NS NS 8.7 ± 0.5 162± II 7.5 ± 0.4 161 ± 7

0.005 NS 9.9 ± 0.6 151 ± 9 9.0 ± 0.6 155 ± 6

0.005 NS

There was an increase in basal serum TSH from the 1500 and 4500 1-1-g/ml dose groups, butnot the 500 1-1-g/ml group. There was a significant increase in TRH induced TSH in all three dosing groups. Datais shown in Table 

### 3. Table3: Effect ofiodide on basal andTRH stimulated serumTSHconcentration TSH (J.I.U/ml) min afterTRH Maximum Iod

.ide dose 0 15 30 45 60 TSH increment 500 J.Lg/day Day I 3.0 ± 0.3 9.7 ± 1.4 12.0 ± 1.8 11.0± 1.7 9.7 + 1.8 9.0 ± 1.6 Day 15 3.3 ± 0.5 11.1±1.5 15.2 ± 4.8 13.7 ± 2.3 12.8 ± 2.3 12.5 ± 2.2 p-value NS 0.05 0.02 0.02 0.002 0.03 1500 J.Lg/day Day I 2.5 ± 0.3 9.6 ± 1.5 11.6 ± 1.8 10.7 ± 1.7 8.7 ± 1.5 9.4 ± 1.7 Day 15 3.7 ± 0.5 14.2 ± 2.2 16.3 ± 2.2 14.6 ± 1.9 12.5 ± 1.9 12.8 ± 2.0[Iodine/046905)
p-value 0.04 Day I 2.1 ± 0.4 Day 15 3.7±0.6 p-value 0.008 p value, day 15 compared With day I. Mean± SEM. NS =Not significant 0.004 Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page 4 of4 OPPTS 870.3150 Study Profile version 07/04
0.002 0.01 0.002 0.005 4500 Jlg/day 8.8 ± 1.1 9.5 ± 1.1 8.9 ± 1.0 7.8 ± 0.9 7.5 ± 1.0 12.7 ± 1.8 15.5 ± 2.0 14.0 ± 1.4 12.0 ± 1.6 12.2 ± 1.6

0.003 0.001 0.001 0.001 0.001



### III. INVESTIGATORS' DISCUSSIONAND CONCLUSIONS: There were dose related increases in serum total and inorganic iodide concentrations as well as urinary iodide excretion. Inthe 1500 and 4500 J..l.g/ml dose groups, there was a decrease in serum T4 and free T4. No change in T3 charcoal uptake or serum T3 in any dose group occurred. The 500 J..l.g/ml dose group caused a significant increase in serum TSH response to TRH. The 1500 and 4500 J..l.g/ml dose groups caused a significant increase inbothbasal and TRH induced TSH concentrations. This indicates that iodide supplementation canhave some effects onthyroid hormone secretion. This study is labeled qualitative as it does notprovide a lower endpointthan an existing study. It does provide useful informationonthe effects ofnutritional levels ofiodine inhumans andthe results are consistent with existing studies.