Health Implications of Perchlorate Ingestion (2005) / Chapter Skim
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6 Research Recommendations
6 Research Recommendations
Pages 182-198
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From page 182... ...
The committee recommends a series of interrelated clinical, chronic toxicity, mechanistic, and epidemiologic studies that have the potential to clarify "safe" perchlorate exposures. The general scope and timeframe of the proposed studies are described; however, meaningful cost estimates cannot be generated in this report, because of the many variables that influence such calculations.
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From page 183... ...
Long-term studies of populations that have iodide insufficiency, post-thyroidectomy patients, and workers occupationally exposed to perchlorate have demonstrated the large capacity of the thyroid to compensate for reduced iodide intake or thyroid mass. However, a rigorously designed controlled clinical study of prolonged exposure to perchlorate would clearly provide more specific information on the compensatory response to perchlorate exposure in humans and strengthen confidence in the RfD.
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From page 184... ...
Dietary iodide intake, as measured by urinary iodide excretion, would be monitored during the study but not controlled, given the high cost of the controlling the subjects' diet. After study selection, the participants should be randomly assigned to receive placebo or perchlorate at 0.04 or 0.1 mg/kg per day in drinking water.
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From page 185... ...
, and 0.1 mg/kg per day (15 men and 15 women) ; these doses are predicted to reduce short-term 24-hr thyroid iodide uptake by about 25% and 45%, respectively · Potassium perchlorate and placebo administered in drinking water Clinical Testing · Physical examination and measurements of serum free T4, T3, TSH, antithyroid peroxidase antibodies, and thyroglobulin; thyroid ultrasound at baseline, 1 week, 2 weeks, monthly · 24-hr urine collection for iodide at baseline, and 1, 3, and 6 months · 24-hr urinary and serum perchlorate at baseline, monthly to ensure compliance · 24-hr thyroid 123I uptake at baseline, 2 weeks, 3 months, 6 months · Serum free T4, T3, TSH, antithyroid antibodies, and thyroglobulin; thyroid ultrasound; urinary iodide; urinary and serum perchlorate 1 month after perchlorate discontinuation · Ultrasound studies done without examiner knowledge of treatment group Safety Monitoring · Data safety monitoring board should monitor thyroid function and ultrasound data · Subjects should be withdrawn from study if serum TSH rises to over 10 mU/L or thyroid volume increases by 100% over baseline at any time aDecision is based on physical examination before study with evaluation of complete blood cell count, routine chemistries, thyroid function, antithyroid peroxidase antibody titers, and pregnancy status.
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From page 186... ...
Clinical Test Measures · Comprehensive hematology and clinical chemistry before dosing, periodically during study Pharmacokinetic Measures · Appropriate pharmacokinetic measures Necropsy and Histopathology · Full necropsy, macroscopic examination, histopathologic examination of many tissues, including the thyroid and pituitary glands ment, refinement, and validation be considered. As discussed in Appendix E, if additional studies are conducted in rats to elucidate the mode of action of perchlorate or dose-response relationships in potentially sensitive life stages (pregnant dams, fetuses, or neonates)
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From page 187... ...
(2003) also identified several measures or biochemical processes that affect simulations of perchlorate and iodide disposition and target-tissue dosimetry in sensitive populations, including · Clearance of perchlorate and iodide in urine.
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From page 188... ...
Placental iodide transport and iodide concentration in the lactating breast have been widely studied with animal and in vitro models. Most of the studies, however, have not characterized in detail the specific contribution of the NIS or the influence of perchlorate inhibition.
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From page 189... ...
Role of Placental NIS in Fetal Iodide Supply Iodide availability to the developing fetus is likely to be influenced by a variety of factors, including maternal nutritional status, placental and uterine 5-deiodinase activity, and perhaps placental NIS activity. NIS mRNA and protein expression have been demonstrated in placenta and placenta-derived cells, but the specific role of placental NIS in iodide nutrition of the developing fetus is not known.
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From page 190... ...
The studies proposed should determine the influence of dietary iodide intake on NIS mRNA and protein expressionandoncellularand subcellular localization of NIS in lactating mammary tissue. The iodide content of milk in lactating mice should be measured to reflect functional iodide transport.
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From page 191... ...
Studies should use direct measures of perchlorate exposure in individuals and methods -- such as case-control, cohort, or nested designs -- which are more suitable for examining potentially causal associations. Future epidemiologic research on possible health effects of exposure to perchlorate in drinking water can be organized into additional analyses of existing data, new studies of health effects in selected populations, and monitoring of the frequencies of specific conditions in communities affected by the continuing efforts to reduce perchlorate in drinking water.
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From page 192... ...
Individual measures of perchlorate exposure can be difficult to obtain, but asking questions about the use of bottled water and the amount of tapwater consumed and taking measurements from the homes and schools of individual study participants (or from the workplaces of adults) would provide more direct measures of individual exposure and also account for variations in individual exposures in a given community.
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From page 193... ...
That question could also be addressed in the current study of pregnant women in Chile, and use of larger samples would improve the precision of the estimates. Similar prospective studies done in the United States would be less useful for detecting subtle neurodevelopmental effects because perchlorate exposures are lower and the range of exposures is considerably narrower than those in Chile.
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From page 194... ...
Anotherway toinvestigatewhetherornotinuteroperchlorateexposure increases the risk of adverse outcomes in the newborn (such as perturbations of thyroid hormones or congenital hypothyroidism) and later neurodevelopmental deficits, especially in infants of mothers who have hypothyroidism or dietary iodide deficiency, would be to use a hybrid nested case-control prospective design within birth cohorts.
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From page 195... ...
Studies that examine time trends have limitations similar to those of ecologic studies, but they can provide indirect evidence of whether a particular exposure is related to a specific disease outcome by determining whether changes in exposure magnitude are associated with parallel changes in outcome frequency. PUBLIC-HEALTH IMPLICATIONS OF IODIDE STATUS In its deliberations on the health effects of perchlorate in drinking water, the committee considered pregnant women and fetuses to be particu
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From page 196... ...
2003b. Predicting neonatal perchlorate dose and inhibition of iodide uptake in the rat during lactation using physiologically basedpharmaco kinetic modeling.
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From page 197... ...
2000. Neonatal thyroxine level and perchlorate in drinking water.
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