UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

May 27, 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: Gardner, D.F., Centor, R.M., Utiger, R.D. Effects of Low Dose Oral 

Supplementation of Thyroid Function in Normal Men. Clinical Endocrinology, 

Vol. 28 (1988): pp. 283-288. (MRID 47358601) 

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, 30 euthyroid male subjects between the ages of 22 and 40 years selfadministered a 0.5 ml solution of either 500, 1500 or 4500 μg/ml iodine with 1 mg/ml ascorbic 

acid twice daily for 14 days. Urine and serum iodine levels were measured and subjects were 

studied for changes in weight, symptoms of thyroid dysfunction, and other toxic effects. 

To supplement the information provided in the journal article, EPA contacted D.F. 

Gardner, 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. Gardner 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 low dose iodide 

supplementation on thyroid function. The article states: 

“Previous studies have demonstrated that short-term oral iodide administration, in 

doses ranging from 1500 μg to 250 mg/day, has an inhibitory effect on thyroid 

hormone secretion in normal men. As iodide intake in the USA may be as high as 800 

μg/d, we investigated the effects of very low dose iodide supplementation on thyroid 

function.” 

The study was conducted at the Clinical Research Center of the Medical College of 

Virginia in 1987 or sometime prior to 1987 (the submission for publication was received in 

June 1987). The study was funded in part by General Clinical Research Grants and the 

A.D. Williams Fund of the Medical College of Virginia. The results were published in 

Clinical Endocrinology in 1988. EPA is proposing to use the study in its risk assessment 

for iodine as an antimicrobial pesticide. 

2. Subject Selection: 

a. Demographics. Thirty male subjects aged 22-40 years with normal thyroid function 

participated in the study and received iodine doses. (Gardner et al., p. 284)

b. Pregnancy and Nursing Status. There were no female subjects in this study.

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, and 

with no history of thyroid disease. (Attachment)

d. Recruitment. The subjects were medical students or employees of the Medical College 

of Virginia, or people whose names appeared on a list of possible research subjects 

maintained by the research center. The students and employees were recruited through 

flyers posted in the medical school. The other individuals received telephone calls 

inquiring about their interest in participating in the study.

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. 

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

Commonwealth University Committee on the Conduct of Human Research. (Gardner et al., 

p. 284)

5. Informed Consent: Dr. Gardner stated that subjects were given an opportunity to read the 

study protocol and the subjects were asked if they understood the protocol before consent 

was sought. (Attachment) Each subject provided written informed consent before 

participating. 

6. Respect for Subjects. Subjects were compensated approximately $150-200. (Attachment) 

The subjects’ identifies were not revealed in the study report. We do not know whether 

subjects were free to withdraw during the study.

Applicable Standards 

Standards Applicable to the Conduct of the Research 

This research was conducted in the mid-1980s, 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. 

The prevailing ethical standards for medical research conducted in the mid-1980s are 

articulated in the 1983 Declaration of Helsinki. Key elements are: 

1. Research must be scientifically sound and conducted by qualified personnel 

2. There must be a clear purpose and protocol, reviewed and approved by an 

independent ethics committee 

3. The interests of science and society should never take precedence over considerations 

related to the well-being of the subject 

4. Participants should give prior, informed, voluntary consent 

The Nuremberg Code (1947) and the Belmont Report (1979) are also instructive 

regarding the prevailing ethical standards. Key principles of the Nuremberg code are: 

participation must be voluntary, research must avoid unnecessary physical and mental suffering, 

and benefits must outweigh risks. Key principles from the Belmont Report are: respect for 

persons, beneficence, and justice. 

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. 

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 
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§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 Declaration of Helsinki, which EPA 

believes provide the prevailing ethical standard 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 

All of the subjects in this study were adult males, and thus this research did not involve 

intentional exposure of any pregnant or nursing female subjects or any children. Based on this 

information, EPA’s reliance on the research is not prohibited by 40 CFR §26.1703. 

The subjects provided written informed consent and the protocol underwent independent 

ethics review and approval. 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). 
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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. 

Gardner. 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. Some of the subjects were employees or students at the medical 

school, 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 and students 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 

research was reviewed and approved by the Virginia Commonwealth University Committee on 

the Conduct of Human Research. 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 47358601in 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 D.F. Gardner, M.D. 

Date/Time: February 14, 2014; 9:00 am 

Subject: Questions regarding ethical conduct of Gardner et al. (1988) 

Publication: Gardner, D.F., Centor, R.M., Utiger, R.D. Effects of Low Dose Oral 

Supplementation of Thyroid Function in Normal Men. Clinical Endocrinology, 

Vol. 28 (1988): pp. 283-288. (MRID 47358601) 

Leshin: From what population were subjects recruited / selected? 

Gardner: Students of the Medical College of Virginia and employees of the hospital were 

recruited. Also, subjects were obtained from a list of study volunteers maintained 

by research center. 

Leshin: What was the recruitment process? 

Gardner: Students and employees were recruited via flyers in the medical school. 

Individuals on the list of volunteers were called and asked if they wanted to 

participate. 

 

Leshin: Were subjects compensated? 

Gardner: Yes, ~$150-200 dollars over course of study. 

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? 

Gardner: Yes, subjects provided informed consent and signed forms. However, it is 

unlikely copies of the forms still exist as this study was conducted in the 1980s. 

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

obtained from the subjects? 

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

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

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

 function and with no history of thyroid disease. 

Leshin: Were there stopping rules for the study? 

Gardner: We had no specific rules for stopping the study. 

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

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

Gardner: Yes, the Virginia Commonwealth University Board on the Conduct of Human 

Research reviewed this study.