1

Kelly Sherman

Office of Pesticide Programs

U.S. Environmental Protection Agency

EPA Science Assessment of

LeMar et al. (1995)
Study Information

 Conducted at the Fitzsimmons Army Medical Center

 Study Objective – Determine the effects of 

subchronic ingestion of iodine purification tablets 

(tetraglycine hydroperiodide)

 Subjects – 7 Males and 1 Female, age 35-47, healthy, 

not pregnant, euthyroid, no history of thyroid 

disease, no chronic medical disorders, no use of 

medications known to affect thyroid function or 

previous reactions to iodine

2
Test Substance

 Tetraglycine hydroperiodide dissolved in water or 

juice totaling 32,000 μg/day (4 tablets) 

 Self administered over the course of the day for 

90 days

 Subjects maintained their normal diets.

 Some diets may be higher in iodine than others 

but assumed average was 300 μg/day

3
Study Method

 All subjects had initial evaluations for the study

 On day 0, baseline levels of T4, T3, and TSH were measured

 Stimulated TSH was measured after stimulation by TRH after 

20 minutes (TSH-20)

 A 24 hour radioactive iodine uptake was recorded after 

dosing with 1 μCi of 131I, with 10 minute counting times 

(RAIU)

 Thyroid volume was measured in the recumbent position by 

ultrasound

 Repeat serum iodine, T3, T4, TSH and TSH-20 and urinary 

iodine measurements were collected on days 7, 28 and 90

 RAIU was re-measured on day 7 and 90

 Thyroid volume was reassessed on day 35 and 90

4
Endpoints

 Serum T4

 Serum T3

 TSH

 TSH-20

 RAIU

 Thyroid volume

5
Results 

-1 Figure 1. 

Individual 24-hour 

radioactive iodine 

uptake before and 

during treatment. 

The normal range of 

uptake is indicated by 

the open rectangle. 

RAIU decreased 

markedly at 7 days 

and remained low at 

90 days. The mean 

SEM are displayed in 

inset. ***, P<0.001

6
Results - 2

Table 1: Effect of tetraglycine hydroperiodide treatment

ANOVA followed by

Student-Newman-Kreuls

multiple comparison 

tests

Mean  SEM

* p<0.05

** p<0.01

Tg = Serum thyroglobulin

Dosing – 32,000 μg/day

Comparison Day 0 to 

Day X

Before 

treatment 

(n = 8)

During Treatment (n = 8)

Day 7 Day 28 Day 90

TSH 

(mU/L) 1.69  0.09 2.80  0.32* 3.30  0.33* 2.98  0.50*

TSH-20 9.90  0.77 14.94  2.41* 18.84 

1.72** 16.33  1.69*

T4

(nmol/L) 83.2  2.9 77.6  4.1 77.6  3.8 78.9  3.3

T3

(nmol/L) 2.15  0.12 1.97  0.09 2.39  0.15 2.29  0.10

Tg

(ng/mL)

13.9  5.6 22.2  9.3 31.4  15.7* 23.3  11.3

7
Results 

-3 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 re-measured 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

8
Conclusions

 Mean serum T4 and T3 decreased, with T4 remaining 

below baseline throughout study and T3recovering

 RAIU decreased during the study

 Serum TSH and TSH-20 increased by day 7 and remained 

elevated

 The average thyroid volume increase was 37%

 No hypo or hyperthyroidism was found in any subject

 For the seven subjects with repeat volume determinations 

on average after 7.1 months, thyroid level returned to 

baseline

 This indicates a reversible, TSH dependent thyroid 

enlargement occurred in response to increased iodine load 

from daily use of water purification tablets

9
10

Kelly Sherman

Office of Pesticide Programs

U.S. Environmental Protection Agency

EPA Ethics Assessment of

LeMar et al. (1995)
11

Introduction

 Research was conducted in the 1980s, before 

promulgation of the 2006 Human Studies Rule

 Considered an intentional exposure human toxicity 

study because it evaluated potential the toxic effects of 

iodine intake on thyroid function

 40 CFR §26.1602 requires HSRB review for pre-rule 

intentional exposure toxicity studies upon which EPA 

intended to rely

 Study was located by EPA, not submitted to the Agency, 

so 40 CFR §26.1303 does not apply
12

Value to Society

 Provides data about the effects of 12 weeks of 

daily ingestion of iodine in tetraglycine

hydroperiodide tablets for water purification

 The research was important because of the use of 

tetraglycine tablets to purify drinking water

 The data are potentially useful in EPA’s human 

health risk assessments for products containing 

iodine
13

Subject Selection

 7 male subjects, 1 female subject; ages 35-47

 The female subject was not pregnant or nursing; 

pregnancy testing performed

 The subjects were employees of the hospital

 Inclusion/exclusion criteria:

 Subjects had to be healthy, euthyroid, not on any 

medications that affect thyroid function, no history of 

thyroid disease

 Not pregnant
14

Risks, Risk Minimization, Benefits

& Risk:Benefit Balance

 Article is silent 

 Benefits 

 No benefits to subjects; Societal benefit from 

knowledge about iodine intake

 Risk:Benefit Balance

 Not discussed in article

 Risks were minimal, so the potential benefits to 

society outweigh the risks
15

Ethics Oversight

 Research was reviewed and approved by 

the institutional review board for the 

Fitzsimmons Army Medical Center
Informed Consent

16

• Article states that each subject provided 

written informed consent

• Dr. McDermott stated:

• Subjects were given the opportunity to read the 

protocol

• Investigators confirmed subject’s understanding

• Each subject signed the consent form

• Copy of the form is not available
Respect for Subjects

 Subjects were not compensated

 Subjects were told that they could 

withdraw from the study at any time

 Subjects’ privacy protected

17
18

Standards for Documentation

 The requirement at 40 CFR §26.1303 to 

document the ethical conduct of research 

submitted to EPA does not apply:

 Study was obtained from the public literature, not 

submitted to EPA

 EPA located the study at its own initiative
Standards of Conduct

 Conducted prior to 1995, before EPA’s Rule at 

40 CFR part 26 took effect

 FIFRA §12(a)(2)(P) does not apply

 Did not involve use of a pesticide

 Common Rule

 IRB oversight and prior approval

 Fully voluntary, fully informed consent

 Favorable risk:benefit balance

 Equitable subject selection

19
20

Standards for EPA Reliance

 40 CFR §26.1703

 Prohibits EPA reliance on data involving intentional 

exposure of pregnant or nursing women or of children

 40 CFR §26.1704

 Prohibits EPA reliance on data if there is clear and 

convincing evidence that:

(1) Conduct of the research was fundamentally unethical; or 

(2) Conduct of research was deficient relative to the ethical 

standards prevailing at the time the research was 

conducted in a way that placed participants at increased 

risk of harm or impaired their informed consent.
21

Compliance with Standards for EPA Reliance

 40 CFR §26.1703

 All subjects were above the age of 18

 The female subject was not pregnant or nursing

 40 CFR §26.1704

 No clear and convincing evidence that the conduct of the 

research was fundamentally unethical

 No clear and convincing evidence that the conduct of the 

research was deficient relative to prevailing ethical 

standards
22

Conclusion

If it is deemed scientifically valid and relevant, 

there are no barriers in FIFRA or in 40 CFR 

§26.1703 or §26.1704 to EPA’s reliance on the 

LeMar et al. (1995) study in actions taken 

under FIFRA or §408 of FFDCA
23

Charge Questions

1. Is the LeMar et al. (1995) study scientifically 

sound, providing reliable data?

2. If so, is this study relevant to establish the 

reversibility of high dose iodine exposure?

3. Also, is this study sufficient to establish that 

there are no sustained adverse effects from 

high dose iodine exposure? 

4. Does the study meet the applicable 

requirements of 40 CFR part 26 subpart Q?