UNITED STATES ENVIRONMEN TAL 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 In creases 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 co nclude that if the study is determined to be scientifically valid a nd 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 eu thyroid females self-administered a 0.5 ml solution of sodium iodide every twelve hours fo r 14 days. The males received 750 μg of iodine twice daily and the females received either 125, 2 50, 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 wei ght, symptoms of thyroi d dysfunction, and other

toxic effects.

The article contains very little information that would be releva nt to an ethics review, so EPA contacted Lewis Braverman, M.D., one of the investigators, to ask him questions about the2 ethical conduct of the study. Attach ments 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 determ ine whether small increases in iodine intake affect thyroid functi on. 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 functi on in subjects without underlying thyroid disease is unclear. S econd, 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 exce ss of the norm. Finally, we have recently reported that the ingestion of huge quantitie s (200 mg/d for 14 days) of the iodinerich food colorant, 2’,4’,5’,7’ -tetraiodofluorescein (eryth rosine) resulted in small

increases in both basal and TRH-simulate d serum TSH concentrations similar to those that follow ingestion of pharmacologic quantities of iodine. This resulted in an increase in daily urinary iodine excr etion 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 phys iologic supplements would affect thyroid function.” (Paul et al., p. 121)

The study was conducted at the University of Massachusetts Medica l School in 1985 or sometime prior to 1985 (the results were pr esented at a meeting in September 1985). The study was funded by grants from the National In stitutes of Health (NIH), the Center for Environmental Health and Human Toxicology, and the Joseph and Dorothy Benotti Iodine

Research Fund. The resu lts were published in Metabolism in 1988. EPA is proposing to use the study in its risk assessment for i odine 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 participa ting in the study, the 32 subjects provided a medical history and underwent a physical ex amination. All subjects were deemed to be euthyroid, with no evidence of thyroid di sease and no detectab le quantities of antithyroid antibodies. (Paul et al., p. 121-2)

In addition to the 32 subjects who received i odine doses, five male subjects served as controls and were given placebo doses. The artic le notes that the five controls were agematched to the treated subjects, but no further information about them is provided. (Paul et al., p. 122)3 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 st udy, 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 subj ect recruitment, and Dr. Braverman

indicated that he has no r ecollection about recruitment or subject selection. (Attachment 1, p. 7)

3. Risks and Benefits :

a. Risks. The article is silent about risks to subjects. Dr. Brav erman indicated that it was the investigators’ view that th e iodine dose levels were comp arable to levels of iodine received in the diet, and therefore that no risk minimization measures related to the dosing regimen were necessary. Dr. Braverma n 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, a nd 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 consid ered the risk-benefit balance, or whether

it was described in the consent material s or discussed with the subjects.

4. Independent Ethics Review : The article does not indicate, and Dr. Braverman does recall, whether the research underwent indepe ndent ethics review. (Attachment 1, p. 7)

5. Informed Consent : Dr. Braverman stated that the s ubjects provided informed consent before participating in the resear ch, but he said that it is not possible to obtain a copy of the consent form. (Attachment 1, p. 7) Dr. Braverma n indicated that the st udy 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. (Att achment 1, p. 7) Subjects were free to withdraw at any time from the study. (Attachment 2, p. 8) Th e subjects’ identifies were not revealed in the study report.4 Applicable Standards

Standards Applicable to th e Conduct of the Research

This research was conducted in the 1980s, be fore EPA’s Rule for Protection of Human Subjects of Research became ef fective 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 w ith 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 pa rtially 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 pr evailing 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 s ound and conducted by qualified personnel

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

committee

 The interests of science and society should neve r take precedence over c onsiderations related to the well-being of the subject

 Participants should give prio r, informed, voluntary consent

Key principles of the Nuremberg code are: partic ipation must be voluntary, research must avoid unnecessary physical and mental suffering, and benefits must outweigh risks. Three key principles from the Belmont Re port are: respect for persons, beneficence, and justice.

FIFRA §12(a)(2)(P) was also in effect at the time of th is 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 a nd mental health consequences which are reasonably foreseeable therefrom, and (ii) freely volunteer to participate in the test.

Since this study was medical resear ch related to iodine dietary in take, 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. Bu t even if we consider FIFRA §12(a)(2)(P) to apply, the outcome of this review is unchanged because the ethica l 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.5 Standards Applicable to the Do cumentation 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 submissi on 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 re search—like this study—involving in tentional exposure of human subjects. The applicable acceptance standard s 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 invol ving intentional expo sure of any human subject who is a pregnant woman (and therefore her fe tus), a nursing woman, or a child.

§26.1704 EPA must not rely on data from any resear ch subject to this section if there is clear and convincing evidence th at: (1) The conduct of the research was fundamentally unethical (e.g., the research was intended to se riously harm participants or failed to obtain informed consent); or (2) The c onduct of the research was defi cient relative to the ethical standards prevailing at the time the res earch 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 HS RB review for pre-2006 studies intended for EPA reliance that were conducted for the purpose of identifying or measuring a toxic ef fect. 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 arti cle 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 relian ce on the research is not prohibited by 40 CFR §26.1703.

There is no clear and convincing evidence that the research was f undamentally unethical. The subjects were volunteers, they provided inform ed consent, and the researchers attempted to protect the subjects’ welfare by testing the females for pregnanc y and following normal medical protections associated with intr avenous catheter use. Based on th is information, and the absence of any information suggesting that the research was fundamentally unethical or intended to harm participants, I conclude that reliance on th e research is not prohi bited 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 pr evailing of the time of this research. There is essentially no information in the article about th e ethics of this study, but EPA was able to speak with Dr. Lewis Braverman, one of the investigators. Dr. Braver man stated that the subjects provided informed consent, they were informed a bout the study procedures and risks, they were permitted to withdraw during the study, and they we re advised to seek medical attention if they became ill during the study; the researchers excl uded 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 pr evailing ethical st andards at that

time.

Independent ethics review is a key principle of the prevailing ethical standards at the time this study was conducted. The publis hed article about this study is silent – and Dr. Braverman does not recall – whether the study underwent inde pendent 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 stud y was deficient with regard to the prevailing ethical standards. Reliance on this study is therefore not prohibit ed 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 fo r a full review of the scientific validity of this study. If it were determined not to have sc ientific validity, it would also not be ethically acceptable.7 Attachment 1

Publication: Paul, T., Meyers, R.J., Witors ch, R.J., Pino, S., Chipkin, S.H., Ingbar, S.H., Braverman, L.E. The Effect of Small In creases 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 regard ing 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 recruite d or selected?

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

Leshin: Were subjects compensated?

Braverman: No.

Leshin: Did the subjects provide informed co nsent? Did they sign an informed consent form? Is it possible to get a copy of the informed consent form? Braverman: Yes, the subjects provided in formed 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, euthyr oid, not pregnant and not on any medications that affect thyroid function and w ith 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 thyr oid 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 stoppi ng rules for the study? Braverman: The doses used in the study were co nsidered comparable to the levels of iodine normally available via the diet, so no speci al rules were in place for stopping the study.

Leshin: Did the protocol undergo independe nt ethics evaluation before the study was initiated (review by an institutional review board or equivalent)?

Braverman: I don’t remember.8 Attachment 2

Publication: Paul, T., Meyers, R.J., Witors ch, R.J., Pino, S., Chipkin, S.H., Ingbar, S.H., Braverman, L.E. The Effect of Small In creases 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 conversati on between Kelly Sherman (EPA) and Lewis

Braverman

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

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

Sherman: Were any of the female subject s 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 subjec ts told during the consent process? Braverman: We walked them through the study pr ocedures 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 subjec ts about potential risks? Braverman: The dose levels in this study were lo w. I am sure we explained to subjects that iodine affects thyroid functi on, 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.