UNITED STATES ENVIRONMEN TAL 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 Wate r 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 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, eight euthyroid subjects (seven males and one female) ranging in age from 35 to 47 years consumed the iodine released by f our water purification tabl ets dissolved in water or juice every day for 90 days. Urine and serum i odine levels were measured and subjects were studied for symptoms of thyroid dys function and other toxic effects.

To supplement the information provided in th e journal article, EPA contacted Michael McDermott, one of the principal investigators, to ask him questions abou t the ethical conduct of the study. The attachment (on page 6 of this revi ew) is a record of that telephone conversation. Subsequent attempts to reach Dr. McDermott to ask follow-up questions were unsuccessful.2 1. Value of the Research to Society:

The stated objective of this study was to inve stigate the eff ects of ingesting tetraglycine hydroperiodide tablets used to pur ify water. The article states:

“Tetraglycine hydroperiodide (TGH) tablet s containing 20 mg of the germicidal ingredient globaline, are marketed for th e purpose of purifying water. Globaline,

C 16 H 42 I 7 N 8 O 16 , is an iodine-rich compound with a solubility in water of approximately 380 g/L. Each tablet effec tively disinfects 1 quart clear water or 0.5 quart tainted water by releasing approximatel y 8 mg free iodine consumption of water purified by this method delivers a daily io dine intake in amounts known to alter thyroid function in man...The present inves tigation studied the effects of consuming the free iodine generated from dissolved TGH water purificati on tablets on thyroid size, thyroid radioiodi ne uptake, serum thyroid horm one 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 Comm and. 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 fe male) 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 fema le subject in this study was nursing.

c. Inclusion/Exclusion Criteria. To participate in the st udy, subjects had to be healthy, euthyroid, not pregnant, not ta king any medications that aff ect thyroid function, with no kidney or liver disease, and no histor y 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 aske d individuals if they were interested in participating. (Attachment) We do not ha ve any additional information about the recruitment process.

3 . Risks and Benefits :

a. Risks. We have no information about what subj ects were told rega rding possible risks of participating in this study, and we also do not know what risk mitigation measures were in place.3 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 study was reviewed a nd approved by the institutional review board for the Fitzsimmons Army Medical Center. (LeM ar et al., p. 220; Attachment)

5. Informed Consent : Dr. McDermott stated that subject s read the study protocol and were asked if they understood it. Each subject pr ovided written informed consent before participating. Dr. McDermott stated that it w ould likely not be possibl e to obtain a copy of the form because the military base closed in 1999. (Attachment)

6. Respect for Subjects. Subjects were not compensated. S ubjects were free to withdraw from the study at any time. (Attachment) The s ubjects’ identifies were not revealed in the study report.

Applicable Standards

Standards Applicable to th e Conduct of the Research

This research was conducted in the early 1990s, before EPA’s Rule for Protection of Human Subjects of Research became effectiv e 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 De fense 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 s ubjects, as prescribed in 40 CFR

46 1 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:b enefit balance, equitable subject selection, and fully informed, fully voluntary participation by subjects.

FIFRA §12(a)(2)(P) was in effect at th e 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 a nd 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 th e 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.4 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 Common Rule, which EPA believes provides the prevailing ethica l standards for this study.

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. McDermott stated that prospective female subject s were tested for pregna ncy 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 §26.1703.5 The subjects provided written informed c onsent, 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 pa rticipants, I conclude that reliance on the research is not prohibited by 40 CFR §26.1704(1).

With regard to the study’s compliance with pr evailing ethical standard s, I considered all

available information in the article and obtai ned from the telephone conversation with Dr. McDermott. Subjects were given the opportunity to read the protocol a nd 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 subor dinate relationship with one or more of the researchers. However, recruiting among employe es 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 prot ocol was reviewed and approved by an IRB and that it complied with th e policies for protection of human subjects as prescribed in the Common Rule and Army Regul ation 40-38. Given that there is no clear and convincing evidence that this study was deficient w ith regard to the prevailing ethical standards, I conclude that reliance on this study is not prohibite d 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 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.6 Attachment

Record: Phone conversation between Jonath an Leshin (EPA) and Michael McDermott Date/Time: February 11, 2014; 4:13 pm Subject: Questions regard ing ethical conduct of LeMar et al. (1995)

Publication: LeMar., H.J, Ge orgitis, W.J. and McDermott, M.T. Thyroid Adaptation to Chronic Tetraglycine Hydroperiodide Water Purification Tablet Use. Journal of Clinical Endocrinolog y 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 we re subjects recr uited /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 co nsent? 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, euthyroi d, not on any medications that affect thyroid function, no history of kidney or liver disease, and w ith no history of thyroid

disease.

Leshin: Were there stoppi ng 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 independe nt 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.