Antimicrobials Division Office of Pesticide Programs US Environmental Protection Agency EPA Science Assessment of Gardner et al 1988 Study Information Conducted at the Department of Medicine Medical College Richmond VA ID: 1001341
Download Presentation The PPT/PDF document "1 1 LT Jonathan Leshin, Ph.D." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
1. 11LT Jonathan Leshin, Ph.D.Antimicrobials DivisionOffice of Pesticide ProgramsU.S. Environmental Protection AgencyEPA Science Assessment ofGardner et al. (1988)
2. Study InformationConducted at the Department of Medicine, Medical College, Richmond VAStudy Objective – Determine a tolerable upper limit for iodine consumptionSubjects – 30 Males, euthyroid, no history of thyroid disease or use of medications known to affect thyroid function or previous reactions to iodine, age 22-40Self control study2
3. Test SubstanceSodium 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 dailyStudy lasted 14 daysThe subjects were randomly sorted into groups dosed with either 500, 1500 or 4500 µg/mlSubjects maintained their normal dietsSome diets may be higher in iodine than others but assumed average was 300 µg/day3
4. Study MethodAll 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 measuredStimulated TSH was measured after stimulation by thyrotropin releasing hormone (TRH) every 15 minutes for an hourOn day 15, the protocol was repeated4
5. EndpointsSerum T4Serum T3T3-charcoal uptakeTSHStimulated TSH5
6. Results - 1Iodide doseSerum T4 (µg/dl)T3 charcoal uptake ratioFTISerum T3 (ng/dl)500 µg/ml (n= 10)Day 19.2 0.51.06 0.049.8 0.8153 8Day 159.2 0.41.09 0.0410.0 0.6158 7p-valueNSNSNSNS1500 µg/ml (n= 10)Day 18.6 0.41.02 0.048.7 0.5162 11Day 157.5 0.9*1.00 0.057.5 0.4*161 7p-value0.005NS0.005NS4500 µg/ml (n= 10)Day 18.9 0.61.12 0.099.9 0.6151 9Day 158.2 0.7*1.11 0.049.0 0.6*155 6p-value0.02NS0.005NS Table 1: Serum thyroid hormone concentrations before and after iodide administrationPaired Student’s t-test p valueMean SEMNS = Not significantDay 15 compared with Day 16
7. Results - 2Iodide doseTSH (µU/ml) min after TRHMaximum TSH increment015304560500 µg/day (n= 10)Day 13.0 0.39.7 1.412.0 1.811.0 1.79.7 1.89.0 1.6Day 153.3 0.511.1 1.515.2 4.813.7 2.312.8 2.312.5 2.2p-valueNS0.050.020.020.0020.031500 µg/day (n= 10)Day 12.5 0.39.6 1.511.6 1.810.7 1.78.7 1.59.4 1.7Day 153.7 0.514.2 2.216.3 2.214.6 1.912.5 1.912.8 2.0p-value0.040.0040.0020.010.0020.0054500 µg/day (n= 10)Day 12.1 0.48.8 1.19.5 1.18.9 1.07.8 0.97.5 1.0Day 153.7 0.612.7 1.815.5 2.014.0 1.412.0 1.612.2 1.6p-value0.0080.0030.0010.0010.0010.001Table 2: Effect of iodide on basal and TRH stimulated serum TSH concentrationPaired Student’s t-testp valueMean SEM.NS = Not significantDay 15 compared with Day 1.7
8. ConclusionsAt 1500 and 4500 µg/day there were decreases in serum and free T4No change in T3 charcoal uptake or serum T3At 500,1500 and 4500 µg/day there were increases in both basal and TRH induced TSH8
9. 99Kelly ShermanOffice of Pesticide ProgramsU.S. Environmental Protection AgencyEPA Ethics Assessment ofGardner et al. (1988)
10. 1010IntroductionResearch was conducted in the 1980s, before promulgation of the 2006 Human Studies RuleConsidered an intentional exposure human toxicity study because it evaluated potential the toxic effects of iodine intake on thyroid function40 CFR §26.1602 requires HSRB review for pre-rule intentional exposure toxicity studies upon which EPA intended to relyStudy was located by EPA, not submitted to the Agency, so 40 CFR §26.1303 does not apply
11. 1111Value to SocietyProvides data about whether small increases in iodine intake affect thyroid functionThe research was important because at the time of the study, dietary changes were resulting in increased iodine intakeThe data are potentially useful in EPA’s human health risk assessments for products containing iodine
12. 1212Subject Selection30 male subjects, ages 22-40The 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 centerInclusion/exclusion criteria:Subjects had to be healthy, euthyroid, not on any medications that affect thyroid function, no history of thyroid disease
13. 1313Risks, Risk Minimization, Benefits& Risk:Benefit BalanceArticle is silent Benefits No benefits to subjects; Societal benefit from knowledge about iodine intakeRisk:Benefit BalanceNot discussed in articleRisks were minimal, so the potential benefits to society outweigh the risks
14. 1414Ethics OversightResearch was reviewed and approved by the Virginia Commonwealth University Committee on the Conduct of Human Research
15. Informed Consent15Article states that each subject provided written informed consentDr. Gardner stated:Subjects were given the opportunity to read the protocol and ask questionsInvestigators confirmed subject’s understandingCopy of the consent form not available
16. Respect for SubjectsDr. Gardner stated that subjects were paid approximately $150-200 to participateSubjects’ privacy protectedWe do not know whether subjects were free to withdraw during the study16
17. 1717Standards for DocumentationThe 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 EPAEPA located the study at its own initiative
18. Standards of ConductConducted prior to 1988, before EPA’s Rule at 40 CFR part 26 took effectFIFRA §12(a)(2)(P) does not applyDid not involve use of a pesticideDeclaration of Helsinki (1983)Research must be scientifically soundClear purpose and protocol, reviewed and approved by an independent ethics committeePrior informed consent18
19. 19Standards for EPA Reliance40 CFR §26.1703Prohibits EPA reliance on data involving intentional exposure of pregnant or nursing women or of children40 CFR §26.1704Prohibits 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.
20. 2020Compliance with Standards for EPA Reliance40 CFR §26.1703The subjects were all males above the age of 1840 CFR §26.1704No clear and convincing evidence that the conduct of the research was fundamentally unethicalNo clear and convincing evidence that the conduct of the research was deficient relative to prevailing ethical standards
21. 2121ConclusionIf 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
22. 22Charge QuestionsIs the Gardner et al. (1988) 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?Does the study meet the applicable requirements of 40 CFR part 26 subpart Q?