[lodine/046905) 

Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page I of 4 

OPPTS 870.3150 

Study Profile version 07/04 

EPA Reviewer: Jonathan Leshin, Ph.D. Signature: ~ -

RASSB, 

RASSB, 

Secondary 

Antimicrobials 

Antimicrobials 

Review: Michelle 

Division 

Division 

Centra, 

(7510P) 

(7510P) 

Pharmacologist Signature: 

Date· 

Date: 

~ ~ ~ ~t/ ~ 

Template version 02106 

,, Data Evaluation Record II 

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

PC CODE: 046905 

TXR#: 1003331 

TEST MATERIAL (PURITY): Iodine 

SYNONYMS: None 

DP BARCODE: 408676 

CITATION: Gardner, D.P., Centor, R.M., Utiger, R.D. (1988) Effects ofthe low dose oral 

--~ ... -

iodide supplementation on thyroid 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 4 73 5 8601 ), sodium iodide was self administered by 

patients as a 0.5 ml solution twice daily with doses of either 500, 1500 or 4500 11g/ml with 

1mg/ml ascorbic acid. The test group was made up of thirty male volunteers. This dosing was in 

addition to their normal unadjusted diets. No changes in weight, symptoms of thyroid 

dysfunction, or other adverse effects were reported. 

There were dose related increases in serum total 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 11glml dose group caused a significant increase in serum TSH response 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 on thyroid 

hormone secretion. 

This study is labeled qualitative as it does not provide a lower endpoint than an existing study. It 

does provide useful information on the effects of nutritional levels of iodine in humans and the 

results are consistent with existing studies. 
[lodine/046905) 

Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page 2 of 4 

OPPTS 870.3150 

Study Profile version 07/04 

I. MATERIALS AND METHODS 

A. MATERIALS: 

1. Test Material: 

Description: 

CAS # if TGAI: 

Iodine 

Sodium iodide dissolved in deionized water 

74-88-4 

2. Vehicle and/or positive control: Deionized water 

3. Test animals: 

Diet: 

Humans 

Typical American 

Subject information: 30 normal males, age 22-40, healthy, euthyroid, no history of thyroid disease, use of 

medications known to affect thyroid function or previous reactions to iodine. 

B. STUDY DESIGN AND METHODS: 

All subjects had initial evaluations for the study. After an eight hour fast, baseline levels of blood 

basal serum iodine, T4, T3, T3-charcoal uptake, protein bound iodide (PBI), total iodide and TSH 

were measured. Stimulated TSH was measured after stimulation by TRH every 15 minutes for an 

hour. A 24 urine sample was collected to measure baseline urinary iodine. Subjects maintained 

their normal diets. 

Subjects consumed 0.5 ml of dissolved iodine in deionized water twice daily. The subjects were 

randomly sorted into groups dosed with either 500, 1500 or 4500 J..Lg/ml. On day 15, the initial 

protocol was repeated. 

Results were expressed as mean ± sem, with a level of p<0.05 considered statistically significant. 

Paired Student's t-tests were used to 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 serum protein bound iodine. 

These changes are outlined in Table 1. 

Table 1: Urinary iodide excretion and serum iodide concentrations before and after iodide 

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 Page 3 of 4 

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 and 4500 1-1-g/ml dose 

groups resulted in decreases in the mean serum T 4 concentration and free T 4 index. Free T 4 

(serum free thyroxine, FTI) was calculated by multiplying serum T4 concentration by the T3 

charcoal uptake ratio. Serum T3 concentrations and T3 charcoal uptake ratio did not change for 

any dosing group. These results are shown in Table 2. 

T a e bl 2 : S erum th 1yr01 "d h ormone concen t ra f wns b e ~ ore an d a ft er 10 . d"d 1 e a d miDIS .. t ra f 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, but not 

the 500 1-1-g/ml group. There was a significant increase in TRH induced TSH in all three dosing 

groups. Data is shown in Table 3. 

Table 3: Effect of iodide on basal and TRH stimulated serum TSH concentration 

TSH (J.I.U/ml) min after TRH 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 of 4 

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' DISCUSSION AND CONCLUSIONS: 

There were dose related increases in serum total and inorganic iodide concentrations as well as 

urinary iodide excretion. In the 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 in both basal and TRH induced TSH 

concentrations. This indicates that iodide supplementation can have some effects on thyroid 

hormone secretion. 

This study is labeled qualitative as it does not provide a lower endpoint than an existing study. It 

does provide useful information on the effects of nutritional levels of iodine in humans and the 

results are consistent with existing studies.