1

LT Jonathan Leshin, Ph.D.

Antimicrobials Division

Office of Pesticide Programs

U.S. Environmental Protection Agency

EPA Science Assessment of

Gardner et al. (1988)
Study Information

 Conducted at the Department of Medicine, Medical 

College, Richmond VA

 Study Objective – Determine a tolerable upper limit 

for iodine consumption

 Subjects – 30 Males, euthyroid, no history of 

thyroid disease or use of medications known to 

affect thyroid function or previous reactions to 

iodine, age 22-40

 Self control study

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Test Substance

 Sodium Iodide dissolved in water (500, 1500 or 4500 

μg/ml per day), co-administered with 1 mg/ml of ascorbic 

acid.

 Administered as two 0.5 ml solutions twice daily

 Study lasted 14 days

 The subjects were randomly sorted into groups dosed 

with either 500, 1500 or 4500 μg/ml

 Subjects maintained their normal diets

 Some diets may be higher in iodine than others but assumed 

average was 300 μg/day

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Study Method

 All subjects had initial evaluations for the study 

 After an eight hour fast, baseline levels of T4, 

T3, T3-charcoal uptake, and thyroid stimulating 

hormone (TSH) were measured

 Stimulated TSH was measured after stimulation 

by thyrotropin releasing hormone (TRH) every 

15 minutes for an hour

 On day 15, the protocol was repeated

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Endpoints

 Serum T4

 Serum T3

 T3-charcoal uptake

 TSH

 Stimulated TSH

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Results - 1

Iodide 

dose

Serum T4

(μg/dl)

T3 charcoal 

uptake ratio FTI Serum T3(ng/dl)

500 μg/ml (n= 10)

Day 1 9.2  0.5 1.06  0.04 9.8  0.8 153  8

Day 15 9.2  0.4 1.09  0.04 10.0  0.6 158  7

p-value NS NS NS NS

1500 μg/ml (n= 10)

Day 1 8.6  0.4 1.02  0.04 8.7  0.5 162  11

Day 15 7.5  0.9* 1.00  0.05 7.5  0.4* 161  7

p-value 0.005 NS 0.005 NS

4500 μg/ml (n= 10)

Day 1 8.9  0.6 1.12  0.09 9.9  0.6 151  9

Day 15 8.2  0.7* 1.11  0.04 9.0  0.6* 155  6

p-value 0.02 NS 0.005 NS

Table 1: Serum thyroid hormone concentrations before and 

after iodide administration

Paired Student’s 

t-test p value

Mean  SEM

NS = Not significant

Day 15 compared 

with Day 1

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Results - 2

Iodide 

dose

TSH (μU/ml) min after TRH Maximum 

TSH 

increment 0 15 30 45 60

500 μg/day (n= 10)

Day 1 3.0  0.3 9.7  1.4 12.0  1.8 11.0  1.7 9.7  1.8 9.0  1.6

Day 15 3.3  0.5 11.1  1.5 15.2  4.8 13.7  2.3 12.8  2.3 12.5  2.2

p-value NS 0.05 0.02 0.02 0.002 0.03

1500 μg/day (n= 10)

Day 1 2.5  0.3 9.6  1.5 11.6  1.8 10.7  1.7 8.7  1.5 9.4  1.7

Day 15 3.7  0.5 14.2  2.2 16.3  2.2 14.6  1.9 12.5  1.9 12.8  2.0

p-value 0.04 0.004 0.002 0.01 0.002 0.005

4500 μg/day (n= 10)

Day 1 2.1  0.4 8.8  1.1 9.5  1.1 8.9  1.0 7.8  0.9 7.5  1.0

Day 15 3.7  0.6 12.7  1.8 15.5  2.0 14.0  1.4 12.0  1.6 12.2  1.6

p-value 0.008 0.003 0.001 0.001 0.001 0.001

Table 2: Effect of iodide on basal and TRH stimulated serum TSH concentration

Paired Student’s t-test

p value

Mean  SEM.

NS = Not significant

Day 15 compared with 

Day 1.

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Conclusions

 At 1500 and 4500 μg/day there were 

decreases in serum and free T4

 No change in T3 charcoal uptake or 

serum T3

 At 500,1500 and 4500 μg/day there 

were increases in both basal and TRH 

induced TSH

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9

Kelly Sherman

Office of Pesticide Programs

U.S. Environmental Protection Agency

EPA Ethics Assessment of

Gardner et al. (1988)
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Introduction

 Research was conducted in the 1980s, before 

promulgation of the 2006 Human Studies Rule

 Considered an intentional exposure human toxicity 

study because it evaluated potential the toxic effects of 

iodine intake on thyroid function

 40 CFR §26.1602 requires HSRB review for pre-rule 

intentional exposure toxicity studies upon which EPA 

intended to rely

 Study was located by EPA, not submitted to the Agency, 

so 40 CFR §26.1303 does not apply
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Value to Society

 Provides data about whether small increases in 

iodine intake affect thyroid function

 The research was important because at the time 

of the study, dietary changes were resulting in 

increased iodine intake

 The data are potentially useful in EPA’s human 

health risk assessments for products containing 

iodine
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Subject Selection

 30 male subjects, ages 22-40

 The subjects were medical students or employees of 

the Medical College of Virginia, or people whose 

names appeared on a list of interested research 

candidates maintained by the research center

 Inclusion/exclusion criteria:

 Subjects had to be healthy, euthyroid, not on any 

medications that affect thyroid function, no history of 

thyroid disease
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Risks, Risk Minimization, Benefits

& Risk:Benefit Balance

 Article is silent 

 Benefits 

 No benefits to subjects; Societal benefit from 

knowledge about iodine intake

 Risk:Benefit Balance

 Not discussed in article

 Risks were minimal, so the potential benefits to 

society outweigh the risks
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Ethics Oversight

 Research was reviewed and approved by 

the Virginia Commonwealth University 

Committee on the Conduct of Human 

Research
Informed Consent

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• Article states that each subject provided 

written informed consent

• Dr. Gardner stated:

• Subjects were given the opportunity to 

read the protocol and ask questions

• Investigators confirmed subject’s 

understanding

• Copy of the consent form not available
Respect for Subjects

 Dr. Gardner stated that subjects were 

paid approximately $150-200 to 

participate

 Subjects’ privacy protected

 We do not know whether subjects 

were free to withdraw during the study

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Standards for Documentation

 The requirement at 40 CFR §26.1303 to 

document the ethical conduct of research 

submitted to EPA does not apply:

 Study was obtained from the public literature, not 

submitted to EPA

 EPA located the study at its own initiative
Standards of Conduct

 Conducted prior to 1988, before EPA’s Rule at 

40 CFR part 26 took effect

 FIFRA §12(a)(2)(P) does not apply

 Did not involve use of a pesticide

 Declaration of Helsinki (1983)

 Research must be scientifically sound

 Clear purpose and protocol, reviewed and 

approved by an independent ethics committee

 Prior informed consent

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Standards for EPA Reliance

 40 CFR §26.1703

 Prohibits EPA reliance on data involving intentional 

exposure of pregnant or nursing women or of children

 40 CFR §26.1704

 Prohibits EPA reliance on data if there is clear and 

convincing evidence that:

(1) Conduct of the research was fundamentally unethical; or 

(2) Conduct of 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 or impaired their informed consent.
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Compliance with Standards for EPA Reliance

 40 CFR §26.1703

 The subjects were all males above the age of 18

 40 CFR §26.1704

 No clear and convincing evidence that the conduct of the 

research was fundamentally unethical

 No clear and convincing evidence that the conduct of the 

research was deficient relative to prevailing ethical 

standards
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Conclusion

If it is deemed scientifically valid and relevant, 

there are no barriers in FIFRA or in 40 CFR 

§26.1703 or §26.1704 to EPA’s reliance on the 

Gardner et al. (1988) study in actions taken 

under FIFRA or §408 of FFDCA
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Charge Questions

1. Is the Gardner et al. (1988) study scientifically 

sound, providing reliable data?

2. If so, is this study relevant for quantitative 

use in support of an assessment of the oral 

risk of exposure to iodine?

3. Does the study meet the applicable 

requirements of 40 CFR part 26 subpart Q?