1

LT Jonathan Leshin, Ph.D.

Antimicrobials Division

Office of Pesticide Programs

U.S. Environmental Protection Agency

EPA Science Assessment of

Paul et al. (1988)
Introduction

 The Agency is conducting a quantitative 

assessment of the risks of iodine exposure via 

the oral route

 These assessments require the determination of 

a toxic effects and point of departure (POD) of 

iodine exposure.

 There are a number of studies conducted on the 

safety of iodine exposure via the oral route in 

humans, due to its ubiquitous nature and medical 

relevance

2
Introduction - 2

 The Agency is proposing the use of the following 

studies in a weight of evidence manner to 

quantitatively determine the toxicity and NOAEL for 

iodine exposure

 Paul et al, 1988

 Gardner et al, 1988

 LeMar et al, 1995

 As these are open literature studies, there is no raw 

data available for analysis

 These studies represent a subset of the studies used 

by the NAS in assessing iodine for nutritional 

purposes

3
NAS Report (2000)

Examined ~100 papers in a report on nutritional 

dietary reference intakes

Table : Existing Iodine Background Exposure Levels

Exposure Scenario Exposure Level

RDA set by the NAS for adult men and women. 150 μg/day or 0.0021 mg/kg/day

Tolerable Upper Intake Level set by the NAS for adult men 

and women 1100 μg/day or 0.016 mg/kg/day.

U.S. Estimated dietary adult intake established by the U.S. 

Department of Agriculture Continuing Survey of Food 

Intakes by Individuals (1994-1996) 

190 to 210 μg/day for women 

240 to 300 μg/day for men

4
NAS Report (2000)

 The National Academy of Sciences report cited 

Paul et al (1988) and Gardner et al (1988) as the 

standard for establishing a tolerable upper limit

 LeMar et al (1995) chosen to show range of 

safety after high dose exposure

 Are these studies scientifically valid and ethically 

acceptable for use in risk assessment for 

systemic iodine toxicity?

5
Study Information

 Conducted at the University of Massachusetts Medical 

School

 Study Objective – Determine a tolerable upper limit for 

iodine consumption

 Subjects – 9 Males and 23 Females, euthyroid, no 

history of thyroid disease or use of medications known 

to affect thyroid function or previous reactions to 

iodine, age 23-56, not pregnant (if Female), no 

antithyroid antibodies detected

 An additional 5 age-matched males were studied but 

not given iodine supplements as controls

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Test Substance

 Sodium Iodide dissolved in water (250, 500 or 1500 μg/ml per 

day), co-administered with 5 mg/ml of ascorbic acid. 

 This was administered as two 0.5 ml solutions for 14 days.

 Men received 1500 μg per day and women received either 250, 

500 or 1500 μg per day (total)

 Some women were studied at two dose levels (14 day dosing 

schedule) at least one year apart. 

 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. 

 On day 0, baseline levels of thyroxine (T4), 

triiodothyronine (T3) and thyroid stimulating hormone 

(TSH) as well resin T3 uptake and free T4index (FT4I) 

were measured. 

 Stimulated TSH was measured after stimulation by 

thyrotropin releasing hormone (TRH) every 15 minutes for 

an hour. 

 On day 15, the initial protocol was repeated.

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Endpoints

 Serum T4

 Serum T3

 Resin T3 uptake

 Free T4index

 TSH

 Stimulated TSH

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Table 1 Serum thyroid hormone concentrations before and after iodide administration

Student’s paired 

t-test

Mean  SEM

*, p<0.02

**, p<0.01

***, p<0.001

NS – not significant

Comparison is 

day 0 to day 15

Results - 1

Iodide 

dose n

Serum T4

(μg/dl) Serum FT4I

Serum T3

(ng/dl)

Serum TSH 

(μU/ml)

Day 0 Day 15 Day 0 Day 15 Day 0 Day 15 Day 0 Day 15

1500 

μg 18 7.3 

0.2

6.7 

0.2***

7.0 

0.2

6.4 

0.2***

181 

4

173 

4*

1.9 

0.2

2.8 

0.4**

500 

μg 9

7.8 

0.4

7.9 

0.6

7.1 

0.3

7.1 

0.3

148 

5

144 

4

2.1 

0.3

2.4 

0.4

250 

μg 9

7.9 

04

7.5 

0.3

7.6 

0.3

6.9 

0.2

134 

3

135 

4

2.3 

0.4

2.7 

0.5

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Results 

-2

Figure 1: The effect of 

iodine administration of 

the maximum increase 

in serum TSH 

concentration following 

the intravenous 

administration of 1500 

μg TRH. The numbers 

in parenthesis represent 

the number of subjects 

in each group. 

Statistical significance 

was determined using a 

Student’s paired t-test

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Results - 3

Table 2: Effect of 500 or 250 μg iodine administered daily to 

euthyroid women on the TSH response to TRH

Student’s paired t-test

Mean  SEM

Comparison is 

day 0

to day 15 Iodide 

dose n

Delta Max Serum TSH 

(μU/ml)

Integrated Serum TSH 

response (μU/ml x min)

Day 0 Day 15 Day 0 Day 15

500 μg 9 18.4  2.8 20.7  2.8 975  151 1088  159

250 μg 9 19.1  3.9 21.6  5.8 1008  196 1170  298

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Conclusions

 No change in weight, symptoms of thyroid dysfunction or 

other adverse affects reported

 At 1500 μg/day there were small but statistically significant 

decreases in T4 and T3

 At 1500 μg/day there were compensatory and statistically 

significant increases in serum TSH and TRH induced TSH

 These biological changes, while statistically significant, 

remained within the normal range and were not considered 

adverse

 No effects were seen at 250 or 500 μg/day

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14

Kelly Sherman

Office of Pesticide Programs

U.S. Environmental Protection Agency

EPA Ethics Assessment of

Paul 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

 32 subjects (9 males, 23 females); ages 23-56

 None of the female subjects were pregnant or 

nursing; pregnancy testing performed

 No information about the population from which 

subjects were recruited

 Inclusion/exclusion criteria:

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

medications that affect thyroid function, no history of 

thyroid disease

 Not pregnant
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Risks and Risk Minimization

 Article is silent about risks and risk minimization

 Dr. Braverman stated:

 Subjects were told about possible risks associated 

with ingesting too much or too little iodine

 Investigators believed that risk minimization 

measures related to iodine doses were not 

necessary because doses were low

 Investigators followed normal medical safety 

precautions for blood draws and i.v.’s
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Benefits & Risk:Benefit Balance

 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

 Article is silent

 Dr. Braverman did not recall if the research 

underwent independent ethics oversight
Informed Consent

21

• Subjects are referred to as volunteers in 

article

• Dr. Braverman stated:

• Subjects provided written informed 

consent

• Study procedures were explained to the 

subjects, and they were told of possible 

effects of iodine ingestion

• Copy of the consent form not available
Respect for Subjects

 Subjects were offered freedom to 

withdraw at any time

 Subjects were not paid for participation

 Subjects’ privacy protected

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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

 1974 DHEW Regulations

 IRB review and approval

 Written, fully informed, voluntary consent

 Declaration of Helsinki (1983)

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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

 All subjects were above the age of 18

 The female subjects were not pregnant or nursing

 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 

Paul et al. (1988) study in actions taken under 

FIFRA or §408 of FFDCA
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Charge Questions

1. Is the Paul 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?