UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

May 28, 2014

MEMORANDUM

SUBJECT: Ethics Review of Human Toxicity Study with Iodine 

FROM: Kelly Sherman, Human Studies Ethics Review Officer 

 Office of the Director 

 Office of Pesticide Programs 

TO: Steven Weiss, Chief 

 Risk Assessment Science Support Branch 

 Antimicrobials Division 

 Office of Pesticide Programs 

REF: LeMar, H.J, Georgitis, W.J. and McDermott, M.T. Thyroid Adaptation to Chronic 

Tetraglycine Hydroperiodide Water Purification Tablet Use. Journal of Clinical 

Endocrinology and Metabolism, Vol. 80 (1995): pp. 220-223. (MRID 49318802) 

I have reviewed the referenced human toxicity study with iodine. I conclude that if the 

study is determined to be scientifically valid and relevant, there is no regulatory barrier to EPA 

relying on this research in actions taken under FIFRA or §408 of FFDCA. 

Summary Characteristics of the Research 

In this study, eight euthyroid subjects (seven males and one female) ranging in age from 

35 to 47 years consumed the iodine released by four water purification tablets dissolved in water 

or juice every day for 90 days. Urine and serum iodine levels were measured and subjects were 

studied for symptoms of thyroid dysfunction and other toxic effects. 

To supplement the information provided in the journal article, EPA contacted Michael 

McDermott, one of the principal investigators, to ask him questions about the ethical conduct of 

the study. The attachment (on page 6 of this review) is a record of that telephone conversation. 

Subsequent attempts to reach Dr. McDermott to ask follow-up questions were unsuccessful. 

 
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1. Value of the Research to Society: 

The stated objective of this study was to investigate the effects of ingesting tetraglycine 

hydroperiodide tablets used to purify water. The article states: 

“Tetraglycine hydroperiodide (TGH) tablets containing 20 mg of the germicidal 

ingredient globaline, are marketed for the purpose of purifying water. Globaline, 

C16H42I7N8O16, is an iodine-rich compound with a solubility in water of 

approximately 380 g/L. Each tablet effectively disinfects 1 quart clear water or 0.5 

quart tainted water by releasing approximately 8 mg free iodine consumption of water 

purified by this method delivers a daily iodine intake in amounts known to alter 

thyroid function in man...The present investigation studied the effects of consuming 

the free iodine generated from dissolved TGH water purification tablets on thyroid 

size, thyroid radioiodine uptake, serum thyroid hormone levels, and basal and TRHstimulated TSH levels over 12 weeks.” 

The study was conducted in the early 1990s and was funded in part by the U.S. Army 

Medical Research and Development Command. The results were published in the Journal 

of Clinical Endocrinology and Metabolism in 1995. EPA is proposing to use the study in its 

risk assessment for iodine as an antimicrobial pesticide. 

2. Subject Selection: 

a. Demographics. Eight subjects (7 males and 1 female) aged 35-47 years with normal 

thyroid function participated in the study. (LeMar et al., p. 220)

b. Pregnancy and Nursing Status. Prospective female subjects were tested for pregnancy, 

and any who tested positive were excluded from the study. (Attachment) We have no 

information to suggest that the one female subject in this study was nursing.

c. Inclusion/Exclusion Criteria. To participate in the study, subjects had to be healthy, 

euthyroid, not pregnant, not taking any medications that affect thyroid function, with no 

kidney or liver disease, and no history of thyroid disease. (Attachment)

d. Recruitment. The subjects were recruited from the employees of the hospital (residents, 

fellows, and faculty); some were civilian and some were military personnel. Dr. 

McDermott indicated that the researchers asked individuals if they were interested in 

participating. (Attachment) We do not have any additional information about the 

recruitment process.

3. Risks and Benefits: 

a. Risks. We have no information about what subjects were told regarding possible risks 

of participating in this study, and we also do not know what risk mitigation measures 

were in place. 
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b. Benefits. There are no benefits to the subjects, and the report is silent on this topic. 

EPA does not know if the subjects were told whether or not they would benefit from 

participating in the research. 

c. Risk-Benefit Balance. The report is silent regarding the risk-benefit balance. EPA 

does not know whether the investigators considered the risk-benefit balance, or whether 

it was described in the consent materials or discussed with the subjects. 

4. Independent Ethics Review: The study was reviewed and approved by the institutional 

review board for the Fitzsimmons Army Medical Center. (LeMar et al., p. 220; 

Attachment)

5. Informed Consent: Dr. McDermott stated that subjects read the study protocol and were 

asked if they understood it. Each subject provided written informed consent before 

participating. Dr. McDermott stated that it would likely not be possible to obtain a copy of 

the form because the military base closed in 1999. (Attachment) 

6. Respect for Subjects. Subjects were not compensated. Subjects were free to withdraw 

from the study at any time. (Attachment) The subjects’ identifies were not revealed in the 

study report. 

Applicable Standards 

Standards Applicable to the Conduct of the Research 

This research was conducted in the early 1990s, before EPA’s Rule for Protection of 

Human Subjects of Research became effective in 2006. Thus, 40 CFR part 26 did not apply 

when this research was conducted. 

This study was funded by the U.S. Army and conducted at the Fitzsimmons Army 

Medical Center. The U.S. Department of Defense adopted the Common Rule in January 1991, 

and thus the Common Rule provides the ethical standards for this research. The article states that 

“[t]he protocol adhered to the policies for protection of human subjects, as prescribed in 40 CFR 

461 in accordance with AR [Army Regulation] 40-38.” Key elements of the Common Rule and 

AR 40-38 are IRB oversight and prior approval, an acceptable informed consent process and 

consent form, risk minimization, a favorable risk:benefit balance, equitable subject selection, and 

fully informed, fully voluntary participation by subjects. 

FIFRA §12(a)(2)(P) was in effect at the time of this study. The provision reads: 

In general, [i]t shall be unlawful for any person...to use any pesticide in tests on human 

beings unless such human beings (i) are fully informed of the nature and purposes of the 

test and of any physical and mental health consequences which are reasonably 

foreseeable therefrom, and (ii) freely volunteer to participate in the test. 

 

1 LeMar et al. cites to 40 CFR 46, although it seems that the intended citation was 45 CFR 46, which is HHS’ 

codification of the Common Rule. 40 CFR 46 is unrelated - it sets forth requirements for EPA fellowship awards. 
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Since this study was medical research related to iodine dietary intake, not research designed to 

study the toxicity of iodine as an antimicrobial pesticide, EPA does not consider FIFRA 

§12(a)(2)(P) to be applicable. But even if we consider FIFRA §12(a)(2)(P) to apply, the outcome 

of this review is unchanged because the ethical principles of fully informed, fully voluntary 

consent articulated in §12(a)(2)(P) are contained in the Common Rule, which EPA believes 

provides the prevailing ethical standards for this study. 

Standards Applicable to the Documentation of the Research 

EPA identified this study through a review of the public literature. No person has 

independently submitted the published article or any results of this research to EPA. 

Consequently, the requirements for the submission of information concerning the ethical conduct 

of completed human research contained in EPA regulations at 40 CFR part 26, subpart M do not 

apply. 

Standards Applicable to EPA’s Reliance on the Research 

The Agency’s rule (40 CFR part 26 subpart Q) defines standards for EPA to apply in 

deciding whether to rely on research—like this study—involving intentional exposure of human 

subjects. The applicable acceptance standards from 40 CFR part 26 subpart Q are these: 

§26.1703. Except as provided in §26.1706, EPA must not rely on data from any research 

subject to this subpart involving intentional exposure of any human subject who is a 

pregnant woman (and therefore her fetus), a nursing woman, or a child. 

§26.1704 EPA must not rely on data from any research subject to this section if there is 

clear and convincing evidence that: (1) The conduct of the research was fundamentally 

unethical (e.g., the research was intended to seriously harm participants or failed to obtain 

informed consent); or (2) The conduct of the 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 (based on knowledge available at the time the study 

was conducted) or impaired their informed consent. 

EPA has submitted this study for review by the Human Studies Review Board (HSRB) 

because 40 CFR §26.1602 requires HSRB review for pre-2006 studies intended for EPA reliance 

that were conducted for the purpose of identifying or measuring a toxic effect. This study meets 

those criteria. 

Compliance with Applicable Standards 

This research did not involve intentional exposure of any pregnant or nursing female 

subjects or any children. The article indicates that all subjects were over the age of 18, and Dr. 

McDermott stated that prospective female subjects were tested for pregnancy and that pregnant 

women were excluded from the study. We have no evidence to suggest that the one female 

subject in this study was nursing. Based on this information, EPA’s reliance on the research is 

not prohibited by 40 CFR §26.1703. 
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The subjects provided written informed consent, the protocol underwent independent 

ethics review and approval, and subjects were allowed to drop out of the study at any time. 

Based on these facts, and the absence of any information suggesting that the research was 

fundamentally unethical or intended to harm participants, I conclude that reliance on the 

research is not prohibited by 40 CFR §26.1704(1). 

With regard to the study’s compliance with prevailing ethical standards, I considered all 

available information in the article and obtained from the telephone conversation with Dr. 

McDermott. Subjects were given the opportunity to read the protocol and researchers confirmed 

the subjects’ understanding of the protocol before seeking their consent. All of the subjects 

provided written informed consent. The subjects were employees of the hospital, so it is possible 

that some of the subjects may have had a subordinate relationship with one or more of the 

researchers. However, recruiting among employees was common practice at the time of this 

study, and there is no clear and convincing evidence to suggest undue influence or lack of fully 

informed, fully voluntary consent. The article indicates that the protocol was reviewed and 

approved by an IRB and that it complied with the policies for protection of human subjects as 

prescribed in the Common Rule and Army Regulation 40-38. Given that there is no clear and 

convincing evidence that this study was deficient with regard to the prevailing ethical standards, 

I conclude that reliance on this study is not prohibited by 40 CFR §26.1704(2). 

Conclusion 

I find no barrier in law or regulation to reliance on MRID 49318802 in EPA actions taken 

under FIFRA or §408 of FFDCA. I defer to others for a full review of the scientific validity of 

this study. If it were determined not to have scientific validity, it would also not be ethically 

acceptable. 

 
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Attachment

Record: Phone conversation between Jonathan Leshin (EPA) and Michael McDermott 

Date/Time: February 11, 2014; 4:13 pm 

Subject: Questions regarding ethical conduct of LeMar et al. (1995) 

Publication: LeMar., H.J, Georgitis, W.J. and McDermott, M.T. Thyroid Adaptation to 

Chronic Tetraglycine Hydroperiodide Water Purification Tablet Use. Journal of 

Clinical Endocrinology and Metabolism, Vol. 80 (1995): pp. 220-223. (MRID 

49318802) 

Leshin: Were female subjects tested for pregnancy before participation? 

McDermott: Yes and if a subject was pregnant, she was excluded from the study. 

Leshin: From what population were subjects recruited /selected? 

McDermott: The subjects were employees of the hospital (residents, fellows, faculty); a mix of 

civilian and military personnel. 

Leshin: What was the recruitment process? 

McDermott: We asked if anyone wanted to volunteer to take part in a study about iodine water 

purification tablets. 

 

Leshin: Were subjects compensated? 

McDermott: No. 

Leshin: Did the subjects provide informed consent? Did they sign an informed consent 

form? Is it possible to get a copy of the informed consent form? 

McDermott: Yes, subjects were provided informed consent forms and they all signed the form 

before participating. It is unlikely copies of the form still exist as this base was 

shut down in the late 1990s. 

Leshin: What were the circumstances and methods by which informed consent was 

obtained from the subjects? 

McDermott: Subjects read the study protocol and were asked if they understood it. 

Leshin: Were there exclusion/inclusion criteria for subject selection? 

McDermott: Subjects had to be healthy, euthyroid, not on any medications that affect thyroid 

function, no history of kidney or liver disease, and with no history of thyroid 

disease. 

Leshin: Were there stopping rules for the study? 

McDermott: Subjects could drop out at any time but otherwise there were no special stopping 

rules. 

Leshin: Did the protocol undergo independent ethics evaluation before the study was 

initiated (review by an institutional review board or equivalent)? 

McDermott: Yes, it was reviewed and approved by the IRB for the Fitzsimmons Army 

Medical Center.