UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

May 23, 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: Paul, T., Meyers, R.J., Witorsch, R.J., Pino, S., Chipkin, S.H., Ingbar, S.H., 

Braverman, L.E. The Effect of Small Increases in Dietary Iodine on Thyroid 

Function in Euthyroid Subjects. Metabolism, Vol. 37, No. 2 (February) 1988: pp. 

121-124. (MRID 48358603) 

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, 9 euthyroid males and 23 euthyroid females self-administered a 0.5 ml 

solution of sodium iodide every twelve hours for 14 days. The males received 750 μg of iodine 

twice daily and the females received either 125, 250, or 750 μg of iodine twice daily. The female 

subjects were between the ages of 23 and 44 and the male subjects were between the ages of 26 

and 56. Five additional males served as controls. Urine and serum iodine levels were measured 

and subjects were studied for changes in weight, symptoms of thyroid dysfunction, and other 

toxic effects. 

The article contains very little information that would be relevant to an ethics review, so 

EPA contacted Lewis Braverman, M.D., one of the investigators, to ask him questions about the 
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ethical conduct of the study. Attachments 1 and 2 to this memo (pages 7-8) provide records of 

two telephone conversations with Dr. Braverman. 

1. Value of the Research to Society: 

The stated objective of this study was to determine whether small increases in iodine intake 

affect thyroid function. The article states: 

“...iodine intake has increased in recent years in the United States. Whether or not 

such increases in iodine intake may have affected thyroid function in subjects without 

underlying thyroid disease is unclear. Second, many individuals ingest dietary 

supplements, such as kelp or multivitamin preparations; these contain more, 

sometimes much more, than enough iodine to fulfill the minimum daily requirement 

of approximately 150 μg iodine. When added to the usual dietary sources of iodine, 

they result in daily intakes well in excess of the norm. Finally, we have recently 

reported that the ingestion of huge quantities (200 mg/d for 14 days) of the iodinerich food colorant, 2’,4’,5’,7’-tetraiodofluorescein (erythrosine) resulted in small 

increases in both basal and TRH-simulated serum TSH concentrations similar to 

those that follow ingestion of pharmacologic quantities of iodine. This resulted in an 

increase in daily urinary iodine excretion of approximately 1,200 μg. For these 

reasons, we evaluated the effects of small increments in iodine intake (1,500 μg 

daily), thereby determining whether the alterations in TSH secretion induced by 

erythrosine were due to the dye itself or could have been due to the iodide liberated 

thereof. Even smaller doses of iodine (500 and 250 μg) were also given to normal 

subjects to determine whether these physiologic supplements would affect thyroid 

function.” (Paul et al., p. 121) 

The study was conducted at the University of Massachusetts Medical School in 1985 or 

sometime prior to 1985 (the results were presented at a meeting in September 1985). The 

study was funded by grants from the National Institutes of Health (NIH), the Center for 

Environmental Health and Human Toxicology, and the Joseph and Dorothy Benotti Iodine 

Research Fund. The results were published in Metabolism 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-two subjects – 9 males and 23 females – participated in the 

study and received iodine doses. They ranged in age from 23 to 56 and were described 

in the report as volunteers. Before participating in the study, the 32 subjects provided a 

medical history and underwent a physical examination. All subjects were deemed to be 

euthyroid, with no evidence of thyroid disease and no detectable quantities of 

antithyroid antibodies. (Paul et al., p. 121-2)

 In addition to the 32 subjects who received iodine doses, five male subjects served as 

controls and were given placebo doses. The article notes that the five controls were agematched to the treated subjects, but no further information about them is provided. 

(Paul et al., p. 122)
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b. Pregnancy and Nursing Status. Prospective female subjects were tested for 

pregnancy, and any who tested positive for pregnancy were excluded from the study. 

(Attachment 1, p. 7). None of the female subjects were nursing. (Attachment 2, p. 8)

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 1, p. 7)

d. Recruitment. The article is silent about subject recruitment, and Dr. Braverman 

indicated that he has no recollection about recruitment or subject selection. 

(Attachment 1, p. 7) 

3. Risks and Benefits: 

a. Risks. The article is silent about risks to subjects. Dr. Braverman indicated that it was 

the investigators’ view that the iodine dose levels were comparable to levels of iodine 

received in the diet, and therefore that no risk minimization measures related to the 

dosing regimen were necessary. Dr. Braverman stated that subjects were told that 

ingesting either too much or too little iodine can be harmful. Dr. Braverman indicated 

that the investigators followed normal medical safety precautions associated with the 

use of venous catheters. (Attachments 1 and 2, pp. 7-8) 

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 article does not indicate, and Dr. Braverman does 

recall, whether the research underwent independent ethics review. (Attachment 1, p. 7) 

5. Informed Consent: Dr. Braverman stated that the subjects provided informed consent 

before participating in the research, but he said that it is not possible to obtain a copy of the 

consent form. (Attachment 1, p. 7) Dr. Braverman indicated that the study procedures were 

explained to the subjects, and they were told of possible effects of ingesting too much or 

too little iodine. (Attachment 2, p. 8) 

6. Respect for Subjects. Subjects were not compensated. (Attachment 1, p. 7) Subjects were 

free to withdraw at any time from the study. (Attachment 2, p. 8) The subjects’ identifies 

were not revealed in the study report.

 
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Applicable Standards 

Standards Applicable to the Conduct of the Research 

This research was conducted in the 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. 

Guidelines from the Department of Health, Education and Welfare (1971), codified as 

regulations in 1974 at 45 CFR part 46, were in effect when this study was conducted. The 1974 

DHEW regulations applied to all research with human subjects conducted or supported by the 

DHEW (now the Department of Health and Human Services) or any of its component agencies, 

including NIH. Given that this study was partially funded by NIH, the DHEW regulations 

applied to this study and provide the prevailing ethical standard. The key principles of the 1974 

DHEW guidelines were: 

 Prior Institutional Review Board (IRB) review and approval of research 

 IRB oversight of ongoing research 

 Written, fully informed, voluntary consent of subjects 

Also instructive about the prevailing ethical standards when this study was conducted are 

the Declaration of Helsinki (1975 or 1983), The Nuremberg Code (1947), and the Belmont 

Report (1979). Key principles from the Declaration of Helsinki are: 

 Research must be scientifically sound and conducted by qualified personnel 

 There must be a clear purpose and protocol, reviewed and approved by an independent ethics 

committee 

 The interests of science and society should never take precedence over considerations related 

to the well-being of the subject 

 Participants should give prior, informed, voluntary consent 

Key principles of the Nuremberg code are: participation must be voluntary, research must avoid 

unnecessary physical and mental suffering, and benefits must outweigh risks. Three key 

principles from the Belmont Report are: respect for persons, beneficence, and justice. 

FIFRA §12(a)(2)(P) was also 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 

§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 DHEW regulations, which EPA believes 

did apply to this study. 
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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. 

Braverman stated that female subjects were tested for pregnancy, pregnant women were 

excluded from the study, and none of the female subjects were nursing. (Attachments 1 and 2, 

pp. 7-8) Based on this information, EPA’s reliance on the research is not prohibited by 40 CFR 

§26.1703. 

There is no clear and convincing evidence that the research was fundamentally unethical. 

The subjects were volunteers, they provided informed consent, and the researchers attempted to 

protect the subjects’ welfare by testing the females for pregnancy and following normal medical 

protections associated with intravenous catheter use. Based on this information, 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). 
6

Likewise, there is no clear and convincing evidence that the conduct of the study was 

deficient with regard to the ethical standards prevailing of the time of this research. There is 

essentially no information in the article about the ethics of this study, but EPA was able to speak 

with Dr. Lewis Braverman, one of the investigators. Dr. Braverman stated that the subjects 

provided informed consent, they were informed about the study procedures and risks, they were 

permitted to withdraw during the study, and they were advised to seek medical attention if they 

became ill during the study; the researchers excluded pregnant women and individuals with 

thyroid disease from participating in the study, and used normal medical precautions. These facts 

suggest that the conduct of the study was consistent with the prevailing ethical standards at that 

time. 

Independent ethics review is a key principle of the prevailing ethical standards at the time 

this study was conducted. The published article about this study is silent – and Dr. Braverman 

does not recall – whether the study underwent independent ethics review. Thus we do not have 

affirmative evidence that there was independent ethics oversight, nor do we have clear and 

convincing evidence of the absence of independent ethics oversight. Thus, I conclude that there 

is no clear and convincing evidence that this study was deficient with regard to the prevailing 

ethical standards. Reliance on this study is therefore not prohibited by 40 CFR §26.1704(2). 

Conclusion 

I find no barrier in law or regulation to reliance on MRID 48358603 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. 

 
7

Attachment 1

Publication: Paul, T., Meyers, R.J., Witorsch, R.J., Pino, S., Chipkin, S.H., Ingbar, S.H., 

Braverman, L.E. The Effect of Small Increases in Dietary Iodine on Thyroid 

Function in Euthyroid Subjects. Metabolism, Vol. 37, No. 2 (February) 1988: pp. 

121-124. (MRID 48358603) 

Subject: Record of telephone conversation between Jonathan Leshin (EPA) and Lewis 

Braverman 

Date/Time: February 12, 2014; 11:30 am 

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

Leshin: Were the female subjects tested for pregnancy before participation? 

Braverman: Yes. If a subject tested positive for pregnancy, she was excluded from study. 

None of the subjects in the study were pregnant. 

Leshin: From what population were subjects recruited or selected? 

Braverman: I can’t remember and I don’t believe any documentation exists at this point. 

Leshin: Were subjects compensated? 

Braverman: 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? 

Braverman: Yes, the subjects provided informed consent and signed forms before 

participating. However, it is not possible to locate a copy of the form as too much 

time has passed. 

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

Braverman: Subjects had to be healthy, euthyroid, not pregnant and not on any medications 

that affect thyroid function and with no history of thyroid disease. 

 

Leshin: What measures were taken to minimize risks to subjects? 

Braverman: The subjects had to be euthyroid, without a history of thyroid disease. The doses 

used in the study were comparable to the levels of iodine normally available via 

the diet, so no measures were taken to minimize risks other than those associated 

with normal i.v. use. 

Leshin: Were there stopping rules for the study? 

Braverman: The doses used in the study were considered comparable to the levels of iodine 

normally available via the diet, so no special rules were in place 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)? 

Braverman: I don’t remember. 
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Attachment 2 

Publication: Paul, T., Meyers, R.J., Witorsch, R.J., Pino, S., Chipkin, S.H., Ingbar, S.H., 

Braverman, L.E. The Effect of Small Increases in Dietary Iodine on Thyroid 

Function in Euthyroid Subjects. Metabolism, Vol. 37, No. 2 (February) 1988: pp. 

121-124. (MRID 48358603) 

Subject: Record of telephone conversation between Kelly Sherman (EPA) and Lewis 

Braverman 

Date/Time: May 23, 2014; 9:20 am 

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

Sherman: Were any of the female subjects nursing/breastfeeding a baby during the study? 

Braverman: No. 

Sherman: Were the subjects allowed to drop out in the middle of the study if they no longer 

wished to participate? 

Braverman: Yes. But no one dropped out during this study. 

Sherman: Do you recall what were subjects told during the consent process? 

Braverman: We walked them through the study procedures and explained to them what they 

were agreeing to do. Whatever was normal at the time, I am sure that’s what we 

did. I can’t remember all of the details. 

Sherman: Did you tell subjects about potential risks? 

Braverman: The dose levels in this study were low. I am sure we explained to subjects that 

iodine affects thyroid function, and that either too little or too much iodine can be 

harmful. 

Sherman: Were subjects told that if they felt ill during the study, they should contact one of 

the investigators or a doctor? 

Braverman: Yes, of course. But nothing happened. This was a very benign study.