Working draft
June 11, 2014 Meeting
August 15, 2014
EPA-HSRB-14-02
Robert Kavlock, Ph.D.
Interim EPA Science Advisor
Office of the Science Advisor
1200 Pennsylvania Avenue, NW
Washington, DC 20460
Subject: June 11, 2014 EPA Human Studies Review Board Meeting Report
Dear Dr. Kavlock,
The United States Environmental Protection Agency (EPA or Agency) requested that the
Human Studies Review Board (HSRB) provide scientific and ethics reviews of three pre-Rule
publications relating to oral ingestion of iodine. For each of these reports, the Agency charged
the Board with specific scientific and ethics charges. These questions and the issue of the return
of individual research results to study participants were discussed in the Board's meeting held on
June 11, 2014. The Board's key responses to the charge questions are summarized in this letter
and are detailed in the enclosed final meeting report.
A published report by Paul et al (1988) of an intentional exposure human study measuring
the effects of small increases of dietary iodine on thyroid function
Science
• The Board determined that the study was scientifically sound and does provide reliable
data.
• The Board determined that the study would be relevant for quantitative use in support of
an assessment of the oral risk of exposure to iodine.
Ethics
• The Board concluded that the published report by Paul et al (1988) submitted for
review meets the applicable requirements of 40 CFR part 26 subpart Q.
A published report by Gardner etal (1988) of an intentional exposure human study
measuring the effects of low dose oral iodide supple mentation on thyroid function
Science
The Board concurred that the study is scientifically sound, providing reliable data.
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However, the lack of details in the analytic methods and less than robust statistical
analysis weakened the HSRB's ability to evaluate all aspects of the study's scientific
soundness. Thus, the Board did not find clear and convincing evidence that this study's
data are not reliable.
The HSRB concluded that this study is relevant for quantitative use in support of an
assessment of the oral risk of exposure to iodine. However, the hormone levels and
changes in T4 observed in this study should be viewed as qualitative in nature. In
contrast, the changes in thyroid function are sufficiently reliable to be used in a weight-
of-evidence analysis.
Ethics
• The Board concluded that the published report by Gardner et al (1988) submitted for
review meets the applicable requirements of 40 CFR part 26 subpart Q.
A published report by LeMar etal (1995) of an intentional exposure human study
measuring the effects of chronic tetraglycine hydro periodide water purification tablet use
on thyroid function
Science
Subject to several limitations, the Board concluded that:
• The study is scientifically sound and provides reliable data.
• This study would be relevant in a weight-of-evidence approach for establishing the
reversibility of high dose iodine exposure.
• This study would be relevant in a weight-of-evidence approach for establishing that there
are no sustained adverse effects from high dose iodine exposure.
Ethics
The HSRB concurred that the published report by LeMar et al (1995) submitted for
review meets the applicable requirements of 40 CFR part 26 subpart Q.
Sincerely,
Rebecca T. Parkin, PhD, MPH
Chair
EPA Human Studies Review Board
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NOTICE
This report has been written as part of the activities of the EPA Human Studies Review Board, a
Federal advisory committee providing advice, information and recommendations on issues
related to scientific and ethical aspects of human subjects research. This report has not been
reviewed for approval by the Agency and, hence, the contents of this report do not necessarily
represent the view and policies of the Environmental Protection Agency, nor of other agencies in
the Executive Branch of the Federal government, nor does the mention of trade names or
commercial products constitute a recommendation for use. You may obtain further information
about the EPA Human Studies Review Board from its website at http://www.epa.gov/osa/hsrb.
You may also contact the HSRB Designated Federal Officer, via e-mail at ord-osa-
hsrb@epa.gov
In preparing this document, the Board carefully considered all information provided and
presented by the Agency presenters, as well as information presented by public commenters.
This document addresses the information provided and presented within the structure of the
charge by the Agency.
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US ENVIRONMENTAL PROTECTION AGENCY
HUMAN STUDIES REVIEW BOARD
Chair
Rebecca Parkin, PhD, MPH, Professorial Lecturer (EOH), Milken Institute School of Public
Health, The George Washington University, Washington, DC
Vice Chair
Jewell H. Halanych, M.D., Assistant Professor, Internal Medicine Residency Program,
Montgomery Campus of the University of Alabama School of Medicine, Montgomery, AL
Members
Liza Dawson, Ph.D., Bioethicist, Fogarty International Center, National Institutes of Allergy &
Infectious Diseases, Bethesda, MD
*George Fernandez, PhD, Professor of Applied Statistics, Director of the University of Nevada-
Reno Center for Research Design and Analysis, University of Nevada-Reno, Reno, NV
Kyle L. Galbraith, Ph.D.,Manager, Human Subjects Protection, Carle Foundation Hospital,
Urbana, IL
Edward Gbur, Jr., Ph.D., Professor, Agricultural Statistics Laboratory, University of Arkansas,
Fayetteville, AR
Sidney Green, Jr., PhD, Fellow of the ATS, Professor (Retired), Department of Pharmacology,
Howard University College of Medicine, Washington, DC
Elizabeth Heitman, Ph.D., Associate Professor of Medical Ethics, Center for Biomedical
Bioethics and Society, Vanderbilt University Medical Center, Nashville, TN
*John C. Kissel, PhD, Professor, Department of Environmental and Occupational Health, School
of Public Health, University of Washington, Seattle, WA
*Randy Maddalena, Ph.D., Physical Research Scientist, Indoor Environment, Lawrence
Berkeley National Laboratory, Berkeley, CA
*William Popendorf, PhD, MPH, Professor Emeritus, Department of Biology, Utah State
University, Logan, UT
*Kenneth Ramos, M.D., Ph.D., PharmB, Professor, Department of Biochemistry and Molecular
Biology, University of Louisville, Louisville, KY
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*Leonard Ritter, Ph.D., ATS, Professor Emeritus (Toxicology), School of Environmental
Sciences, University of Guelph, Guelph, ON, Canada
Linda J. Young, PhD, Professor, Department of Statistics, Institute of Food and Agricultural
Sciences, University of Florida, Gainesville, FL
Human Studies Review Board Staff
Jim Downing, Executive Director, Human Studies Review Board Staff, Office of the Science
Advisor, United States Environmental Protection Agency, Washington, DC
*Participated via Adobe Connect.
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INTRODUCTION
On June 11, 2014, the United States Environmental Protection Agency's (EPA or Agency)
Human Studies Review Board (HSRB or Board) met to address the scientific and ethical charge
questions related to three publications conducted before promulgation of the 2006 Human
Studies Rule (U.S. Environmental Protection Agency (EPA), 2006). To conduct a quantitative
risk assessment of oral exposure to iodine, the Agency must determine the toxic effects and point
of departure for iodine exposure. EPA selected the three publications for HSRB review from
larger sets of studies, examined by the Institute of Medicine (Institute of Medicine (IOM), 2001)
and the Agency for Toxic Substances and Disease Registry (Agency for Toxic Substances and
Disease Registry (ATSDR), 2004), concerning the ingestion of iodine for nutritional purposes.
The Board also discussed its Work Group's report on returning individual research results to
study participants; this report was submitted to the HSRB during their April 8-9, 2014, meeting
and was appended to that meeting's Final Report.
The four agenda items included in this meeting report are:
• A published report by Paul et al (1988) of an intentional exposure human study
measuring the effects of small increases of dietary iodine on thyroid function
• A published report by Gardner e^a/(1988) of an intentional exposure human study
measuring the effects of low dose oral iodide supplementation on thyroid function
• A published report by LeMar etal (1995) of an intentional exposure human study
measuring the effects of chronic tetraglycine hydroperiodide water purification tablet use
on thyroid function
• HSRB Work Group Report on the Return of Individual Research Results
REVIEW PROCESS
The Board conducted a public meeting in Arlington, Virginia, on June 11, 2014; eight members
were present in the meeting room and six members joined the meeting via Adobe Connect.
Advance notice of the meeting was published in the Federal Register as "Human Studies Review
Board; Notification of a Public Meeting" (EPA, 2014, pp. 30135-30137).
Following welcoming remarks from Agency officials, the Board heard presentations from EPA
on each of the first three published reports listed above. The HSRB Chair introduced the
discussion of the fourth report. This Final Report of the meeting describes the discussion,
recommendations and rationale in response to each charge question for the first three reports; it
summarizes the discussion and consensus of the Board regarding the fourth agenda item.
For each published report, Agency staff first presented their review of the science components of
the publication and the Board asked the Agency presenters clarifying questions about the
science. The staff then described their review of the ethical aspects related to the publication and
the Board asked clarifying questions about the ethical issues. The Board solicited public
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comments and next asked Agency staff to read the Charge Questions for the published report
under consideration. The Board discussed the science questions first and then the ethics
question. Upon conclusion of the discussion of each question, the Chair called for a vote to
confirm concurrence on a summary statement in response to that question.
For their evaluation and discussion, the Board considered materials presented at the meeting, oral
comments, a comment from the public, the original published reports, and the Agency's science
and ethics reviews of the publications. A comprehensive list of background documents is
available online at http://www.epa.gov/hsrb/. At the same website, a copy of the Work Group
report is appended to the Final Report of the HSRB's April 8-9, 2104, meeting.
CHARGE TO THE BOARD AND BOARD RESPONSE
A published report by Paul et a/(1988) of an intentional exposure human study measuring
the effects of small increases of dietary iodine on thyroid function
Overview of the Study
Paul et al (1988) conducted a study of euthyroid adults (9 males and 23 females 23-56 years old)
to identify a tolerable upper limit for iodine consumption. While maintaining their usual diets
over a 14-day period, the female participants took sodium iodide dissolved in water at one of
three dosages (250, 500 or 1500 |og/ml per day) along with 5 mg/ml ascorbic acid. In the same
manner the male participants received only the 1500 |jg/ml per day dose. The authors found no
change in weight and no symptoms of thyroid dysfunction in any of the study participants. Using
the Student's paired t-test, they reported small but statistically significant (p<0.01) increases in
serum thyrotropin (TSH) and thyrotropin-releas ing hormone (TRH)-induced TSH. The changes
were within normal ranges for TSH and TRH; the findings were not indicative of adverse effects.
This intentional exposure human toxicity study of iodine impacts on thyroid function was
conducted among adult subjects. There is no information available about the population used to
recruit these individuals. Subjects were told of the possible risks and were given the option to
withdraw at any time. They provided written consent but were not paid for their participation in
the study. Upon further investigation, no record of Institutional Review Board (IRB) review,
approval or oversight was reported or found.
Science
Charge to the Board
• Is this study scientifically sound, providing reliable data?
• If so, is this study relevant for quantitative use in support of an assessment of the oral risk
of exposure to iodine?
Board Response to the Charge
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HSRB Recommendation
• The Board determined that the study was scientifically sound and does provide reliable
data.
• The Board determined that the study would be relevant for quantitative use in support of
an assessment of the oral risk of exposure to iodine.
HSRB Detailed Recommendations and Rationale
Overall, the Board agreed with the Agency's scientific assessment of this study (Leshin, 2014a).
The HSRB noted that its comments were in the context of the Agency's intended use of the study
in a weight-of-evidence (WOE) approach. Most of the Board's discussion focused on limitations
of the statistical analysis.
Is this study scientifically sound, providing re liable data?
1. Second treatment one year later
Questions were raised about the authors' statement that "some of the women treated at two
dose levels were examined one year apart" (Paul et al, 1988, p. 122). Why was this
information included in the study when no rationale was given for this second treatment?
Furthermore, no data were presented indicating the results of such treatment.
2. Statistical issues
Based on the limited and inadequate descriptions regarding statistical design and the results
reported in this study, it is difficult to assess the statistical validity of the findings thoroughly.
However, the reported findings could be considered as statistically valid if we assume that
(1) the duplicate sample values used in the study were treated as subsamples (not as true
replications), and (2) the paired difference means were analyzed in comparing treatments (0
and 15 days on the same subject) and the reportedp-values in Table 1 (Paul etal, 1988, p.
122) were associated with testing the null hypothesis from a paired t-test where the paired
differences between 0 and 15 days means were compared (not based on the reported means
for 0 and 15 days in Table 1).
If so, is this study relevant for quantitative use in support of an assessment of the oral risk of
exposure to iodine?
1. Tolerable upper limit
The Board agreed with the authors' assertion (Paul et al, 1988, p. 123) that there are groups
of individuals who are uniquely susceptible to the adverse effects of iodine, and consequently
thought it is difficult to define an upper limit of normal for the daily iodine intake. This issue
was emphasized because the EPA expressly desired to use this study in establishing a
tolerable upper limit for the oral ingestion of iodine. The Agency explained that this study
would be used as part of a WOE approach to establish such an upper limit. The Board
thought this was a reasonable approach and, if used in this fashion, the study could support
an assessment of the risk of oral exposure to iodine.
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Ethics
Charge to the Board
• Does the study meet the applicable requirements of 40 CFR part 26 subpart Q?
Board Response to the Charge
HSRB Recommendation
• The Board concluded that the published report by Paule/a/(1988) submitted for
review meets the applicable requirements of 40 CFR part 26 subpart Q.
HSRB's Detailed Recommendation and Rationale
The standard outlined in 40 CFR 26 subpart Q (U.S. Environmental Protection Agency (EPA),
2010) requires that EPA must not rely on data from a study that either involves a) intentional
exposure of pregnant or nursing women or children or b) clear and convincing evidence of
unethical conduct, defined specifically as one or more of the following: studies involving
intentional serious harm to study participants; deficiencies in study conduct relative to
prevailing ethical standards; or unethical recruitment such that informed consent is impaired.
The Board concluded that there is no evidence that the published report by Paul etal (1988)
submitted for review involved pregnant or nursing women, nor is there evidence of unethical
conduct as defined above. Therefore, as defined by the regulation 40 CFR part 26 subpart Q,
the study meets the requirements for use by EPA.
The article by Paul et a/, published in February 1988 in Metabolism, is the report of a trial
intended to test the effects of a small increase in dietary iodine on thyroid function in normal
(euthyroid) volunteers. The investigation was not intended as a study of intentional exposure to
a toxin, but rather was identified by the Office of Pesticide Programs (OPP) as a potential source
of data for EPA decision-making.
The Board agreed with the OPP review (Sherman, 2014a) that the article fails to report on a
number of facts relevant to ethical review. At the time that the study was carried out, the 1985
version of 45 CFR 46 (Williams, 2005) * required institutional review board (IRB) approval of
human participant studies funded by the Department of Health and Human Services (DHHS)
which includes the National Institutes of Health (NIH). The authors reported that the study was
funded by NIH, which required documentation of IRB review as part of its grant-making
procedures. However, the article does not mention IRB review and, when interviewed by phone
by EPA's Jonathan Leshin (Sherman, 2014a, p. 7), the study's senior author, L.E. Braverman,
had no memory of whether the study had undergone IRB review. Inquiries by EPA'sKelly
Sherman, found that the IRBs at the three institutions2 where this work might have been
1 For a time line of the regulations re latedto the protection of human subjects in research, see
http ://history .nih.gov/about/time lines_laws_human.html* 1983.
2 University of Massachusetts Medical School, the Medical Co liege of Virginia, and Beth IsraelHospital: These
were the affiliations listed by the authors.
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reviewed have no records from that period. NIH's archived records from the period of the study
do not include information on 1KB review. The applicable regulations at 45 CFR Section
46.116 would also have required informed consent by participants and documentation with a
consent form containing all required elements of consent, unless written documentation was
waived by an 1KB (45 CFR 46.117); however, no records regarding informed consent are
available.
1. The Board concurred with the conclusions of the OPP's Ethics Review (Sherman, 2014a)
that the reported research does not rely on data from intentional exposure of any human
subject who is a pregnant or nursing woman or a child. There is no clear and convincing
evidence that the conduct of the research was fundamentally unethical. There is no evidence
that the re search intentionally placed participants at risk of serious harm (based on the
knowledge available at the time the study was conducted). Because the study most likely
involved only minimal risk, the possibility of unethical conduct is significantly reduced.
Regardless of risk level, it is still essential for study participants to be properly informed and
given opportunity to consent. No information is available on the recruitment processes used
for the study, nor is there any documentation regarding research participants' ability to give
informed consent or the informed consent process itself.
a. Assessment of risks and benefits: The authors stated that the quantity of iodine consumed
by many Americans in their regular diet is greater than that necessary for maintenance of
normal thyroid function, suggesting that knowledge of the effects of small incremental
increases over the daily requirement of iodine would be beneficial for determining a
normal, acceptable, and clearly excessive level of iodine intake, and thus would be of
value to society. The authors did not address additional risks to human participants from
ingesting small additional amounts of iodine, or any potential benefit to participants.
They made no statement about the balance between risk and benefit. However the
amounts of iodine ingested by participants at the maximum dose over a two-week period
were described as being within the range of the average American's normal intake,
suggesting that these amounts thus posed risk equivalent to the risks of everyday life,
which meets the regulatory definition of minimal risk at 45 CFR 46.102(1).
b. Voluntary and informed consent of all participants: No information is available about
recruitment or enrollment of the 37 participants, either from the article or from the
interview with co-investigator Braverman. It is not possible to tell whether participants
from potentially vulnerable populations were recruited or whether the study protocol
included mechanisms designed to minimize coercive recruitment and enrollment.
To participate in the study, subjects needed to be healthy, non-pregnant, euthyroid adults.
Women underwent pregnancy testing. Per Braverman (Sherman, 2014a, p. 7), any
woman whose pregnancy test was positive would have been excluded, and no women
participants were nursing (Sherman, 2014a, p. 8).
As stated above, no authoritative information was available about the study's informed
consent materials or process, although senior investigator Braverman reported that
participants gave informed consent and signed documents (Sherman, 2014a, p. 7).
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c. Equitable selection of study participants: It is not possible to determine whether members
of vulnerable populations were recruited or enrolled in the study. PerBraverman
(Sherman, 2014a, p. 7), participants were not compensated for taking part in the study.
2. The Board recommended that the data within this article be considered acceptable for EPA
reliance, contingent upon the determination of its scientific validity.
A published report by Gardner etal (1988) of an intentional exposure human study
measuring the effects of low dose oral iodide supple mentation on thyroid function
Overview of the Study
As in Paul et al (1988), this study was conducted to determine a tolerable upper limit for iodine
consumption. Gardner etal (1988) examined 30 euthyroid males (ages 22-40) who had no
history of thyroid disease, had not been on medications that affected thyroid function, or had a
prior reaction to iodine. Each individual served as his own control. Over a 14-day period while
maintaining his normal diet, each individual was randomly assigned to consume sodium iodide
dissolved in water at 500, 1500 or 4500 |og/ml. The assigned dose was administered, along with
1 mg/ml ascorbic acid, twice a day in 0.5 ml solutions. Compared to baseline measures, post-
administration measures of thyroid function revealed that at 1500 and 4500 |og/ml statistically
significant (p<0.02) decreases in serum and free thyroxine (T4) occurred. At all three dosages,
basal and TRH-induced TSH were found to be significantly (p<0.05 or less) increased.
The study subjects were medical students or employees of the Medical College of Virginia, or
were selected from a list of interested research candidates. The study protocol was reviewed and
approved by the Virginia Commonwealth University (VCU) Committee on the Conduct of
Human Research. Although each subject provided written consent and was compensated for their
participation, there is no information about whether subjects were told they could withdraw at
anytime.
Science
Charge to the Board
• Is this study scientifically sound, providing reliable data?
• If so, is this study relevant for quantitative use in support of an assessment of the oral risk
of exposure to iodine?
Board Response to the Charge
HSRB Recommendations
• The Board concurred that the study is scientifically sound, providing reliable data.
However, the lack of details in the analytic methods and less than robust statistical
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analysis weakened the HSRB's ability to evaluate all aspects of the study's scientific
soundness. Thus, the Board did not find clear and convincing evidence that this study's
data are not reliable.
• The HSRB concluded that this study is relevant for quantitative use in support of an
assessment of the oral risk of exposure to iodine. However, the hormone levels and
changes in T4 observed in this study should be viewed as qualitative in nature. In
contrast, the changes in thyroid function are sufficiently reliable to be used in a weight-
of-evidence analysis.
HSRB Detailed Recommendations and Rationale
While the authors are experienced researchers in this field and designed a reasonable study, the
Board expressed some concern that this particular publication did not provide sufficient details in
their analytic methodologies and in their rationale for the grouping of samples during analysis.
Two additional limitations were the lack of statistical use of duplicate measurements and the
finding that most of the mean thyroid response data did not correlate with the doses of iodine
tested.
Is this study scientifically sound, providing reliable data?
1. Grouping
The Board discussed the dose groups and the grouping of samples for analysis.
a. The first of the uncertainties of the publication is the actual distribution of the subjects
within the three dose groups. On p. 284, Gardner et al (1988) stated that "Thirty normal
men between the ages of 22 and 40 years (mean age 27) were randomly assigned to
receive 500, 1500 or 4500 jog iodide/day." However, the authors did not say in any text
or table that these subjects were distributed evenly at 10 people per dose. This
distribution is reasonable, but it is an assumption made in this review due to its omission
within the text.
b. It is unusual for an article to mention how the samples were grouped during their
analysis, suggesting that batch-to-batch variability within one or more analytical methods
might be an issue. No information was provided regarding the various analytic methods'
variability. The methods used to measure serum hormone levels were cited but not
provided for review; the methods used to measure serum iodide levels were not
mentioned (only that the samples were analyzed by a commercial lab).
In contrast to the grouping of samples by Paul et aim which "all serum samples for a
given test were assayed in the same assay" (Paul etal, 1988, p. 122), in Gardner etal:
"All samples from an individual man were analyzed in the same assay" (Gardner et a/,
1988, p. 285). Analyzing all samples in the same assay has the advantage of eliminating
the effect of any batch-to-batch variability within the analytical method. By grouping all
samples from a given individual together, batch-to-batch variability in the measurements
by Gardner et al (1988) would not affect a given individual's change in hormone level,
but it still could leave the values of the group means vulnerable to batch-to-batch
variability.
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2. Duplicate measurements
The HSRB considered the use of the duplicate measurements, noting that the use of duplicate
samples is very important, especially for finding small differences in a method with intrinsic
variability. As above for Paul etal (1988), the authors of Gardner et al (1988) stated on p.
284 that serum hormone and T3-charcoal uptake ratios "were measured in duplicate," but no
paired data or information regarding the methods' precision or typical intra-personal
variability was provided. Furthermore, the Student's paired t-test did not allow the duplicate
data to be used. For statistical purposes, the duplicate data should have been considered as
repeated measures.
If so, is this study relevant for quantitative use in support of an assessment of the oral risk of
exposure to iodine?
1. Lack of correlation
Board members raised concerns about the lack of correlation between iodine levels and
effects measured in either thyroid function or hormone levels.
a. The statistically significant changes in hormone levels reported in Table 2 are in the
range of 8 to 14%; all of these endpoints fall within normal limits. The coefficient of
variation in the standard error of the inter-personal mean T4 levels on any day ranged
from about ±5 to ±8%; but both the intra-personal variability and the method variability
are unknown. Prior research trying to measure similarly small changes in cholinesterase
enzyme activity with an imprecise assay has shown that neglecting the effect of method
variability both within a person and from batch-to-batch could yield incorrect conclusions
(Yageretal, 1976; Trundle and Marcial, 1988; Brock and Brock, 1990). It may be
possible to estimate the statistical impact of method variability in this case if some
quantitative information on its magnitude can be obtained.
b. The Board noted a lack of an expected dose-response correlation within most of these
authors' data. A correlation between dose and effect (a change in either hormone level or
thyroid function in this case) is axiomatic in the field of toxicology. Because the authors
did not provide individual data, the Board was restricted to observing the consistency of
trends and testing for correlations among the mean values. The urinary iodine excretion
reported in Table 1 (Gardner et al, 1988, p. 285) increased in relation to dose,3 although
even its correlation r2 value of 0.996 is not statistically significant with only three mean
values. In contrast, the statistically significant changes in mean serum thyroid hormone
levels reported in Table 2 (Gardner etal, 1988, p. 286) (decreases in T4 and free T4
index) were not consonant with dose, either in their magnitude or in their level of
statistical significance; in fact, by both metrics, the changes in hormone levels at 4500
jog/day were less than at 1500 |ig/day. It should be noted that an inverse dose response is
what was expected and was not clearly established; i.e., as the dose of iodine increases,
the levels of thyroxine T4 and triiodothyronine TS should have decreased. Most (4 out of
3 This would be expectedbased onmass-balance considerations and as noted by the authors.
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5) of the changes in the mean TRH-stimulated TSH concentrations reported in Table 34
increased consistently with dose, except at 15 minutes; only the changes at 45 minutes
were significantly correlated with dose at a p < 0.01.
The lack of a correlation between dose and response for either hormone levels or TSH
response to TRH stimulation may be accounted for by fluctuations in baseline values
among study participants. While such fluctuations may be taken into consideration as
part of a different statistical analysis than has been used thus far, questions about the
biological fidelity of the findings remain given that, despite findings of statistical
significance in the dataset, all values reported fall well within the range of normal clinical
values.
There seems to be some disagreement among studies about how typical such mixed
results might be. On p. 287, Gardner et al (1988) state that "previous studies have
demonstrated that pharmacological doses of 10 to 1000 mg/day for 2-11 weeks resulted
in significant decreases in serum T4 and free T4 concentrations, and compensatory
increases in serum TSH concentrations." However, on p. 123, Paul e^a/(1988)5 state
that such doses result "in a small increase in both basal serum TSH concentrations and
the TSH response to TRH, sometimes [emphasis added] in association with decreased
serum concentrations of T4 and T3."
Read in isolation, the statistical significance of changes in mean hormone levels observed
by Gardner etal (1988) indicates that some change is probably occurring, but the lack of
a dose-response correlation in this study weakens the attribution of dose to the significant
differences in reported hormone levels. Despite the weak correlation of changes in mean
thyroid function with dose, the generally coherent trends in these changes are in
agreement with other studies, cited by Paul et al (1988) and Gardner etal (1988), at
higher dose levels.
2. The large number of t-tests resulted in a higher than expected number of significant results.
The statistical test results in this study should not be used quantitatively for supporting an
assessment of the oral risk of exposure to iodine.
Ethics
Charge to the Board
• Does the study meet the applicable requirements of 40 CFR part 26 subpart Q?
Board Response to the Charge
HSRB Recommendations
• The Board concluded that the published report by Gardner et al (1988) submitted for
review meets the applicable requirements of 40 CFR part 26 subpart Q.
4 According to the authors, this indicated "a definite anti-thyroid effect" (Gardner et al, 1988, p. 287). One Board
member statedthatthe acute TSHreactionmay not be an indicator of such an effect.
5 The authors cited two more than the four references noted by Gardner et al (1988) on p. 287.
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HSRB's Detailed Recommendation and Rationale
The requirements in 40 CFR 26 subpart Q (U.S. Environmental Protection Agency (EPA),
2010), which guided this review, are listed above in the HSRB's review of Paul e^a/(1988)
above. The Board concluded that there is no evidence that the study reported in Gardner etal
(1988) submitted for review involved pregnant or nursing women or children, and there is no
evidence of unethical conduct as defined above. The study therefore meets the requirements
of 40 CFR part 26 subpart Q for use by EPA.
The article by Gardner et al, published in 1988 in Clinical Endocrinology, is the report of a trial
intended to test the effects of very low dose iodine supplementation on thyroid function in
normal (euthyroid) adult male volunteers. The investigation was not intended as a study of
intentional exposure to a toxin, but rather was identified by the Office of Pesticide Programs as a
potential source of data for EPA reliance.
In the Materials and Methods section of the article, the authors reported that the study was
approved by VCU's IRB for the protection of human subjects ("The Committee on the Conduct
of Human Research"), which at that time would have been operating under the 1985 version of
45 CFR 46 (Williams, 2005). They also reported that "each man gave informed written consent"
(Gardner etal, 1988, p. 284).
When interviewed by OPP staff in February 2014, the article's first author, DF Gardner, reported
that participants were given an opportunity to read the study protocol and asked if they
understood, and then each man signed a written informed consent document. No additional
information was requested from VCU's IRB, but it may be assumed that the Committee followed
the regulatory requirements in place at the time the study was reviewed.
1. The Board concurred with the conclusions of the OPP's Ethics Review (Sherman, 2014b)
that the reported research does not rely on data from intentional exposure of any human
subject who was a pregnant or nursing woman or a child. There is no clear and convincing
evidence that the conduct of the research was fundamentally unethical. There is no evidence
that the research was conducted in away that placed participants at increased risk of harm
(based on the knowledge available at the time the study was conducted). Because
recruitment processes were directed toward students and employees of the medical school
where the study was conducted, the participants' ability to give informed consent may have
been impaired by coercion.
a. Assessment of risks and benefits: The authors reported that the quantity of iodine
consumed by many Americans in their regular diet is greater than that necessary for
maintenance of normal thyroid function, suggesting that knowledge of the effects of
small incremental increases over the daily requirement of iodine would be beneficial for
determining a normal, acceptable, and clearly excessive level of iodine intake, and thus
would be of value to society. The authors did not address additional risks to human
participants from ingesting small additional amounts of iodine, or any potential benefit to
participants. The Board found no statement of the balance between risk and benefit in the
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article. However, the amounts of iodine ingested by study participants were described as
being within the range of the average American's normal intake, suggesting that the
amounts thus posed minimal risk equivalent to the risks of everyday life.
b. Voluntary and informed consent of all participants: Participants were recruited from
among students and employees of the Medical College of Virginia or a list of potential
volunteers kept by the institution's Clinical Research Center. It is not possible to tell
whether participants from potentially vulnerable populations were recruited, or whether
the study protocol included mechanisms designed to minimize coercive recruitment and
enrollment of students and employees who may have been in a subordinate position to the
researchers.
To participate in the study, subjects were required to be healthy, euthyroid adult men with
no history of thyroid disease and who were not taking medications that affect thyroid
function. No women and no children were enrolled.
No authoritative information was available about the study's informed consent materials
or process, although investigator Gardner reported that participants gave informed
consent and signed consent documents.
c. Equitable selection of study participants: It is not possible to determine whether selection
of study participants was equitable or whether members of vulnerable populations were
recruited or enrolled in the study. According to investigator Gardner's telephone
interview with EPA's Jonathan Leshin (Sherman, 2014b, p. 6), participants were
compensated approximately $150-200 for taking part in the 2-week study that included
multiple blood draws.
2. The Board recommended that the data within this article be considered acceptable for EPA
decision making, contingent upon the determination of its scientific validity.
A published report by LeMar etal (1995) of an intentional exposure human study
measuring the effects of chronic tetraglycine hydro periodide water purification tablet use
on thyroid function
Overview of the Study
As in the above two studies (Paul etal, 1988; and Gardner etal, 1988), LeMar et al(1995)
conducted a study of adults to identify a tolerable upper limit for iodine consumption, with a
focus on effects of subchronic ingestion of iodine in water purification tablets (tetraglycine
hydroperiodide). All seven males and one female (ages 35-47) in the study were euthyroid, had
no prior thyroid disease, had no chronic medical disorders, were not using medications which
affected thyroid function, and had not had previous reactions to iodine. During the 90-day study
period, the subjects maintained their normal diets; daily they self-administered four tablets
(totaling 32,000 jig) dissolved in water or juice. Measures which decreased during the study
period included 24-hour radioactive iodine uptake, mean serum T4 and T3 (triiodothyronine),
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while serum TSH, and TSH-20 (measured after 20 minutes) increased by the seventh day and
remained elevated. Although no hypo- or hyper-thyroidism was found, thyroid volume increased
an average of 37%. Among the 7 subjects for whom repeat measures were made (anywhere from
0.5 to 16.1 months after the study period), all thyroid volumes had returned to baseline levels.
The authors stated that this result suggests that TSH-dependent thyroid enlargement is reversible
following daily use of water purification tablets.
Participants in the study were employees of the hospital where the study was conducted
(Fitzsimmons Army Medical Center). The protocol was reviewed and approved by the hospital's
1KB. All subjects were equitably selected; they signed a written consent form and were advised
that they could withdraw at any time. They were not compensated for their participation.
Science
Charge to the Board
• Is this study scientifically sound, providing reliable data?
• If so, is this study relevant to establish the reversibility of high dose iodine exposure?
• Also, is this study sufficient to establish that there are no sustained adverse effects from
high dose iodine exposure?
Board Response to the Charge
HSRB Recommendations
Subject to the limitations noted below, the Board concluded that:
• The study is scientifically sound and provides reliable data.
• This study would be relevant in a weight-of-evidence approach for establishing the
reversibility of high dose iodine exposure.
• This study would be relevant in a weight-of-evidence approach for establishing that there
are no sustained adverse effects from high dose iodine exposure.
HSRB Detailed Recommendations and Rationale
The HSRB members discussed each charge question individually, carefully considering the
wording of each query and their responses to each question. In particular, the Board disagreed
with the word "sufficient" in the third question; no single study can be considered "sufficient"
for establishing sustained adverse effects. A body of work is needed to evaluate a study in the
context of other findings. Consequently, the HSRB requested permission from the Agency
representatives to modify the wording of the third question; the request to change "sufficient" to
"relevant" was granted.
Is this study scientifically sound, providing reliable data?
Subject to the limitations noted below, the Board concluded that the study is scientifically sound
and provides reliable data.
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If so, is this study relevant to establish the reversibility of high dose iodine exposure ?
The weaknesses noted here decreased the Board's confidence that the LeMar et al(1995) paper
can be used quantitatively. Following a detailed discussion, the HSRB decided that the study is
relevant but not definitive by itself to establish the reversibility of high dose iodine exposure.
Furthermore, the Board limited its response to the Agency's intended use of the data in a weight-
of-evidence (WOE) approach. The HSRB determined that LeMar etal(l995) can be used
qualitatively in a WOE approach, noting that the results are not sufficiently reliable for
estimating reversibility quantitatively.
Board concerns related to the repeated measures study design and small sample size, the
statistical methods used, and the thyroid volume reversibility data.
1. Repeated measures
Based on the study description in LeMar et al (1995), the design of their experiment appears
to have been a repeated measures study with either three or four unequally spaced time
points, depending on whether or not baseline data are included in the analysis. Eight subjects,
seven males and one female, participated in the experiment. It is commonly assumed that
repeated measurements on a subject over time are correlated.
2. Statistical analysis
The authors described their statistical analysis as "analysis of variance, followed by Student
Newman Keuls multiple comparisons" (LeMar et al, 1995, p. 221). In general, the reported
numerical estimates of the means do not contradict their statements regarding trends in the
data. The HSRB's concern lies in the effect of the correlation and variance issues on the
estimates of the standard errors and hence on the statistical significance of the results.
The authors did not indicate the design on which their analysis was based nor did they
indicate that any consideration was given to the correlation and unequal variance issues. Any
analysis of their data should take into account the potential repeated measures correlation
structure as well as the potential for unequal variances. Failure to account for either may
impact the significance or non-significance of the reported results.
a. The Board acknowledges that, at the time the study was conducted, explicitly adjusting
for the correlation was not generally part of analysis of variance.
b. The authors' numerical results provide evidence that, for at least some variables, the
variance changed with time. For example, using the serum protein-bound iodine (FBI)
data in Table 1 (LeMar etal, 1995, p. 221), the ratio of the largest to smallest variance is
approximately 16 for the post-baseline data and about 108 if the baseline data are
included.
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In an attempt to judge the effect of the potential unequal variance problem, the worst case
scenario (i.e., most likely to contradict the stated statistical significance of p<0.05; LeMar
et al, 1995, p. 221) would be to compare the reported means using the largest reported
standard error among the treatments as the standard error for all treatments in the multiple
comparison procedure. Using the largest reported standard error generally confirmed the
conclusions reached in the text regarding statistical significance.
The Board noted that the effects and potential corrective actions for unequal variances
had been in the statistics literature since the 1950's. By the 1990's these methods were
likely fairly well known outside the field of statistics and thus available at the time of the
study analysis.
3. Thyroid volume reversibility
Since there was no indication that the post-experiment data on thyroid volume returning to
normal were analyzed statistically, the results should be treated only as an observationally -
and not a statistically - based indication of recovery.
a. Despite otherwise solid methods used by LeMar et al (1995, pp. 220-221), the paper
contains a serious flaw in the thyroid volume data presented. The authors state that "The
precision of the thyroid volume determined by this method was assessed in five [of 8]
study participants, each examined on five separate occasions before the treatment period.
Coefficients of variation for these thyroid volume measurements ranged from 3.6 to
13.2%" (LeMar etal, 1995, p. 221). However, in the next sentence they state: "The
greatest volume for each of these five subjects was subsequently used as the pretreatment
volume for that individual" (LeMar et al, 1995, p. 221). It is axiomatic in statistics that
the most likely value for any single measurement is the mean for each subject. Thus, this
decision to use the greatest volume for those five participants biased the results to
decrease changes in thyroid volume during treatment (because these subjects' baseline
volume appeared to be larger) and increase the likelihood for complete recovery to
pretreatment volumes. The Board commented that the mean pretreatment volumes (both
individually and collectively) were lower than the greatest volumes reported.6
b. Furthermore, the authors did not state that a goal of their study was to support the kinetics
of either thyroid enlargement or recovery. The wide range of their recovery phase (from
0.5 to 16 months) suggests that this part of the re search project was an unanticipated
"add-on" to the study. Given that wide range and an average of 7.1 months for 7 of 8
subjects, the authors' observation that "the increase in thyroid volume was reversible"
(LeMar etal, 1995, p. 222) is all the more remarkable. This bias weakens the usefulness
of this study to "provide information on the effects of excess iodine in humans, which
include a form of reversible thyroid gland volume increase and decreases in T4 levels"
(Leshin, 2014c, p. 5).
Also, is this study sufficient to establish that there are no sustained adverse effects from high
dose iodine exposure?
6 In Figure 2 (LeMar et al, 1995, p. 222), the "recovery" volumes appearto be lowerthanthe "WeekO" volumes.
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It is unlikely, from a scientific perspective, that any one study (i.e., LeMar etal, 1995) could be
"sufficient to establish that there are no sustained adverse effects from high dose iodine
exposure," as the Agency posed to the Board in this question. However, the Board recognizes
and accepts that LeMar et al (1995) contributes significantly to scientific understanding about
the lack of sustained adverse effects from high dose iodine exposure. The Board also recognizes
that LeMar etal (1995) has been a key study on which daily maximum iodine intake levels have
been established (e.g., in ATSDR, 2004). Therefore, the HSRB concluded that the study is
relevant, but not sufficient, in a WOE approach for establishing whether there are sustained
adverse effects for high dose iodine exposure.
Ethics
Charge to the Board
• Does the study meet the applicable requirements of 40 CFR part 26 subpart Q?
Board Response to the Charge
HSRB Recommendation
• The HSRB concurred that the published report by LeMar et al (1995) submitted for
review meets the applicable requirements of 40 CFR part 26 subpart Q.
HSRB Detailed Recommendations and Rationale
The LeMar etal (1995) manuscript published in the Journal of Clinical Endocrinology and
Metabolism describes a study designed to determine the effects of daily subchronic ingestion of
iodine purification tablets (tetraglycine hydroperiodide) on thyroid size, function, and radioactive
iodine uptake in eight healthy volunteers over a three month period. EPA's OPP has identified
this study as a potential data source for EPA's human health risk assessments for products
containing iodine. In addition to this manuscript, OPP also provided the HSRB with the
transcript of a February 2014 interview between EPA representative Jonathan Leshin and a study
co-investigator, Michael McDermott (Sherman, 2014c, p. 6).
The Agency's rules at 40 CFR part 26 subpart Q (U.S. Environmental Protection Agency (EPA),
2010) that are applicable to this review are stated above in the ethics review of the Paul etal
(1988) study.
These rules identify three ethical issues that were discussed by the HSRB:
1. Subject profiles
a. LeMar et al (1995, p. 220) reported that their study enrolled eight participants (seven men
and one woman) between 35-47 years of age; thus, the study did not involve intentional
exposure of any subjects who were children.
b. The manuscript makes no reference to the pregnancy or nursing status of the one female
participant, but the co-investigator indicated in the interview that female participants
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were tested for pregnancy before study participation and that if a potential participant was
pregnant, she was excluded from the study (Sherman, 2014c, p. 6). There is no indication
that the subject became pregnant or was nursing in the course of the research.
c. In order to minimize risks to subjects enrolled in the study, all subjects were required to
pass a physical exam prior to study activities, including thyroid level tests to verify
euthyroid status. Subjects were also required to have no chronic medical conditions, not
taking any medications affecting thyroid function, and not have had any reactions to
iodine.
2. Introduction of intentional harm
a. The LeMar et al manuscript indicates that all participants provided their written informed
consent prior to study participation and that the study had been approved by the
institutional research committee (1995, p. 220). In his telephone conversation with EPA
representatives, co-investigator McDermott confirmed that the study was reviewed and
approved by the Fitzsimons Army Medical Center IRB. There was no evidence provided
to the HSRB regarding the contents of informed consent processes, but applicable federal
regulations at the time (Williams, 2005) specify required elements of informed consent,
including a description of experimental procedures, potential risks to subjects, any
potential benefits, and a notice that research participation is voluntary. Additionally, there
was no documentation to verify IRB review and approval beyond the statements provided
in the manuscript and by the co-investigator.
b. The authors described the research protocol (administration of water purification tablets)
and the subjects' responses, including their serum and urine iodide levels, radioactive
iodine uptake, and thyroid volume. Based on the data presented in LeMar etal (1995),
the EPA Science Review, and the discussion of scientists during the HSRB meeting, the
risks to subjects posed by this study of intentional exposure to free iodine do not appear
to be unreasonable, unethical, or intentionally designed to seriously harm participants.
c. The HSRB considered whether the use of nuclear tracers in the RAIU procedures posed
serious or unnecessary risks to participants, but after discussion among the group, the
HSRB concluded that the small amount of radiation exposure (1-jiCi) as described in the
LeMar et al manuscript (1995, p. 221) did not pose unreasonable risks to study
participants.
3. Prevalent ethical standards of the time
a. At the time in which this study was conducted (early 1990's), EPA's rules for the
protection of human subjects at 40 CFR part 26 were not yet in effect. However, the
study was supported by the United States Department of Defense, which adopted the
"Common Rule" (45 CFR part 46) in 1991. As a result, the Common Rule provides the
basic ethical regulatory framework for this investigation at the time of its conduct.
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b. Common Rule provisions at the time required that a study such as this one undergo 1KB
review and approval prior to initiation. As noted above, the LeMar etal (1995)
manuscript indicates that the investigation was reviewed and approved by an institutional
review committee, and co-investigator McDermott indicated that the study had been
under the oversight of the Fitzsimons Army Medical Center 1KB. There was no official
documentation provided to verify such 1KB review and approval; the HSKB
recommended that the EPA's OPP make an attempt to locate such records. However,
given that Fitzsimons Army Medical Center is now closed, HSKB recommendations
would not be contingent upon locating those records.
c. The Common Rule requires that participants in studies such as this must provide their
informed consent prior to study participation. The Common Rule specifies elements that
must be present in the consent process. Both the LeMar et al (1995) manuscript and the
interview with co-investigator McDermott indicate that participants provided their
informed consent prior to study participation. However, given the lack of 1KB and
investigator records regarding the conduct of this study, there is no documentation to
indicate that the consent process met Common Rule requirements. As above, since the
study location is now closed, HSRB recommendations are not contingent upon locating
such records.
d. Common Rule regulations also address the issue of participant compensation. In the
interview with EPA, co-investigator McDermott notes that participants were not
compensated for their participation in this study. Lack of compensation in a study such as
this is consistent with Common Rule standards of the time.
e. The manuscript does not describe participant recruitment practices and the interview with
co-investigator McDermott provided little information on this matter. In the interview,
McDermott stated: "We asked if anyone wanted to volunteer to take part in a study about
iodine water purification tablets" (Sherman, 2014c, p. 6). While nothing provided to the
HSRB indicates that participant recruitment was conducted in an ethical manner that was
consistent with standards of the time, the information provided does not indicate that
there were unethical recruitment practices taking place.
As with many of the points above, the HSRB's ability to assess the study was somewhat limited
by the lack of documentation provided to support the use of this study by the EPA.
HSRB Work Group Report on the Return of Individual Re search Re suits
Overview
On several occasions the HSRB has discussed the return of individual research results. The
Board determined that the topic merited in-depth discussion by a smaller group of HSRB
members and representatives of study participants and their medical providers. A Work Group
was formed to deliberate about this issue; the group's workshop was held at EPA in January
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2013. The WorkGroup membership, its process and report are included in Appendix A of the
HSRB's April 8-9, 2014, Final Report.
The return of individual research results has been addressed for clinical studies and some
community-based research but not for the types of laboratory or field studies within the HSRB's
purview. The return of results is a timely, unresolved and evolving issue in the ethics profession.
The Work Group identified key ethical principles as the underpinnings of their deliberations:
research participant's autonomy and right to know, and researchers'responsibilities to ensure
trust and respect. The group also discussed the potential impacts of results on participants and
sponsors, as well as on the HSRB and the Agency.
Discussion
The HSRB emphasized that the community and laboratory contexts in which the HSRB-related
studies are conducted are quite different from the clinical settings that served as the foundations
for the Work Group's report.
The Board decided that this topic should be considered in newer contexts; for example, in light
of the recent report on handling incidental re search findings (Presidential Commission for the
Study of Bioethical Issues, 2013) and current risk communication knowledge.
One member noted that another committee with different expertise would be needed to discuss
the "how" of returning results, whether the findings are aggregate or individual.
Board Consensus
Before deciding whether the HSRB will address this topic at a later meeting, the Board asked the
Agency to determine whether returning results is a priority concern for study sponsors.
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