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6 Research Recommendations THE committee was asked to suggest scientific research that could reduce the uncertainty in the understanding of human health effects associated with low-dose perchlorate ingestion, especially research that could clarify âsafeâ exposures of sensitive populations. Rough estimates of timeframe, costs, and potential to reduce uncertainty were also requested for the proposed research. As noted in Chapter 5, the committee found that the data on perchlorateâs mechanism of action and effects in animals and humans are sufficient to derive a reference dose (RfD). However, research that could provide a more complete understanding of the range of effects of perchlo- rate, especially effects of chronic exposure and effects on sensitive popula- tions, was identified. The committee recommends a series of interrelated clinical, chronic toxicity, mechanistic, and epidemiologic studies that have the potential to clarify âsafeâ 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. OVERVIEW Recommendations for additional research fall into several categories. The first is to determine the effects in humans of chronic low-dose exposure to perchlorate with a prospective controlled clinical trial. The proposed study directly addresses the question of the capacity of the human thyroid to compensate for inhibition of thyroid iodide intake during long-term administration of perchlorate. The committee appreciates the controversial aspects of conducting human studies with perchlorate and provides an 182
Research Recommendations 183 alternative approach that uses nonhuman primates if long-term studies in humans are not possible. The effects of perchlorate on sensitive populations (fetuses, infants, and pregnant women) raise a number of fundamental questions, including the role of the sodium-iodide symporter (NIS) in placental iodide transport, the sensitivity of the NIS in the lactating breast to perchlorate inhibition, the influence of iodide status on perchlorate inhibition in placenta and breast, and finally direct effects of perchlorate on fetal development. Several models and methods developed in the mechanistic studies could be used in human investigations. Epidemiologic studies that include analysis of existing data, use of monitoring data, and new studies to determine per- chlorate effects in sensitive populations are also proposed. Finally, further studies of the public-health implications of iodide status of pregnant women are proposed. CHRONIC EXPOSURE The proposed clinical study is designed to provide information on the potential chronic effects of perchlorate exposure on thyroid function focus- ing on the capacity for and mechanisms of thyroid compensation. The short-term human study (Greer et al. 2002) recommended as the point of departure in Chapter 5 reported inhibition of thyroid iodide uptake at perchlorate doses that are consistent with a wide array of human, animal, and in vitro studies. 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 com- pensatory response to perchlorate exposure in humans and strengthen confidence in the RfD. The hypothesis of the proposed clinical study is that administration of perchlorate in doses of 0.04 mg/kg per day or 0.1 mg/kg per day will transiently decrease thyroid iodide uptake but will have no long-term effect on thyroid function in healthy subjects. Those doses are based on the following data. Greer et al. (2002) reported that administration of perchlo- rate in doses of 0.02 and 0.1 mg/kg per day for 14 days to 10 healthy subjects per group reduced 24-hr thyroid iodide uptake by 16.4% and 44.7%, respectively (see Table 2-1 in Chapter 2). Braverman et al. (2004) reported that administration of 0.04 mg/kg per day to four healthy subjects
184 Health Implications of Perchlorate Ingestion had no effect on thyroid iodide uptake, measured at baseline and at 3 and 6 months, or on serum thyroid hormone and TSH concentrations, measured monthly. The small size of the study group in the latter study makes the results somewhat problematic, but the doses used provide a reasonable basis for a more comprehensive study to determine the effects of the dose at 0.04 mg/kg per day and the effects of a larger perchlorate dose, which also would inhibit iodide uptake acutely but for which compensation would be expected in the longer term. The detailed protocol for this study is shown in Table 6-1. Briefly, it should be a double-blind study involving 90 healthy adults (45 men and 45 women). Subjects whose urinary iodide excretion exceeded 500 :g daily, indicative of a high iodide intake, would be excluded because of the antithy- roid effects of a high iodide intake, but those with a low intake would not be excluded unless their urinary iodide excretion was less than 50 :g daily. 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 subjectsâ 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. Thyroid function and general well-being should be monitored throughout the study. Assuming a 50% variance in mean serum TSH and a 20% variance in thyroid volume by ultrasound, a study with 30 subjects in each perchlorate treatment group and 30 subjects in the placebo group has greater than 90% power to detect a 100% increase in serum TSH and greater than 90% power to detect a 50% increase in thyroid volume by ultrasound at a 5% level of significance (Chow and Liu 1998). Given the costs of clinical testing and screening, subject payment, sample storage, and data analysis, the committee predicts that the study would cost at least $1.5 million. If chronic studies in humans are not possible, chronic studies in nonhu- man primates could provide useful information. Initial studies in monkeys could include a dose-range finding study with perchlorate and a 1-year low- dose chronic toxicity and thyroid function study. The chronic study could be designed to determine the effects of perchlorate administered in drinking water on thyroid iodide uptake and on thyroid gland function. Doses should be selected to evaluate effects of low-dose ingestion of perchlorate. Proto- cols for the suggested monkey studies are shown in Tables 6-2 and 6-3. Studies in pregnant monkeys could also provide useful information on the effects of perchlorate on fetal and neonatal development. If additional studies are conducted in laboratory animals, including nonhuman primates, the committee recommends that additional research in support of physiologically based pharmacokinetic (PBPK) model develop-
Research Recommendations 185 TABLE 6-1 Protocol for Controlled Clinical Study General Aspects â¢ Design: Double blind â¢ Number of subjects: 90 healthy adults (45 men and 45 women) Selection of Subjects â¢ Only subjects with normal examination and laboratory results should be includeda â¢ Subjects with 24-hr urinary iodide excretion over 500 :g to be excluded â¢ Only nonpregnant women (confirmed by pregnancy testing before study) should be included; effective contraception must be used during study period â¢ Subjects with high serum antithyroid antibody titers should not be excluded Treatment Groups â¢ Subjects randomly assigned to receive 1 of 2 potassium perchlorate doses or placebo for 6 months â¢ Group size: placebo (15 men and 15 women), 0.04 mg/kg per day (15 men and 15 women), 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 â¢ Potassium perchlorate and placebo administered in drinking water Clinical Testing â¢ Physical examination and measurements of serum free T4, T3, TSH, antithyroid peroxidase antibodies, and thyroglobulin; thyroid ultrasound at baseline, 1 week, 2 weeks, monthly â¢ 24-hr urine collection for iodide at baseline, and 1, 3, and 6 months â¢ 24-hr urinary and serum perchlorate at baseline, monthly to ensure compliance â¢ 24-hr thyroid 123I uptake at baseline, 2 weeks, 3 months, 6 months â¢ Serum free T4, T3, TSH, antithyroid antibodies, and thyroglobulin; thyroid ultrasound; urinary iodide; urinary and serum perchlorate 1 month after perchlorate discontinuation â¢ Ultrasound studies done without examiner knowledge of treatment group Safety Monitoring â¢ Data safety monitoring board should monitor thyroid function and ultrasound data â¢ 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 a Decision is based on physical examination before study with evaluation of com- plete blood cell count, routine chemistries, thyroid function, antithyroid peroxidase antibody titers, and pregnancy status.
186 Health Implications of Perchlorate Ingestion TABLE 6-2 Three-Month Dose-Range Finding Toxicity Study in Cynomolgus Monkeys Dose Groups â¢ Two of each sex in each group at 0 (control), low, middle, upper middle, and high dose â¢ Ammonium perchlorate administered daily in drinking water for 3 months Observations â¢ General observations for morbidity and mortality, body weight, food consumption Thyroid Function Assessment â¢ Serum T3, T4, and TSH should be measured before dosing, on day 1, at weeks 1, 2, 4, 6, 8, 10, 12 â¢ Thyroid 123I uptake should be measured at appropriate times. Clinical Test Measures â¢ Comprehensive hematology and clinical chemistry before dosing, periodically during study Pharmacokinetic Measures â¢ Appropriate pharmacokinetic measures Necropsy and Histopathology â¢ 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), a number of issues identified as potential data gaps with existing PBPK models could be addressed by studies that â¢ Develop a more biologically based description of placental transfer of perchlorate and iodide in rats. â¢ Determine whether perchlorate is transported by thyroid NIS if analytic methods of sufficient sensitivity can be developed or radiolabeled perchlorate with high radiochemical purity can be synthesized. â¢ Modify the adult human model to include the physiology of preg- nancy and lactation to incorporate data from the recommended human clinical studies (if they are conducted).
Research Recommendations 187 TABLE 6-3 One-Year Chronic Toxicity Study in Cynomolgus Monkeys Dose Groups â¢ Six of each sex in each group at 0 (control), low, middle, upper middle, and high dose; dose selection based on findings of 3-month dose-range finding study â¢ Ammonium perchlorate administered daily in drinking water for 12 months Observations â¢ General observations for morbidity and mortality, body weight, food consumption Thyroid Function Assessment â¢ Serum T3, T4, and TSH should be measured before dosing, on day 1, at weeks 1, 2, 4, monthly thereafter through 12 months â¢ Thyroid 123I uptake should be measured at appropriate time points Clinical Test Measures â¢ Comprehensive hematology and clinical chemistry before dosing and periodically during study Pharmacokinetic Measures â¢ Appropriate pharmacokinetic measures Necropsy and Histopathology â¢ Full necropsy, macroscopic examination, histopathologic examination of many tissues, including the thyroid and pituitary glands â¢ Modify models to incorporate dietary iodide measurements from biomonitoring studies in pregnant or lactating women, such as the studies of Soldin et al. (2003) and Hollowell et al. (1998). By conducting a sensitivity analysis of their PBPK models, Clewell et al. (2003a,b), Merrill (2001), and Merrill et al. (2003) also identified sev- eral measures or biochemical processes that affect simulations of perchlo- rate and iodide disposition and target-tissue dosimetry in sensitive popula- tions, including â¢ Clearance of perchlorate and iodide in urine. â¢ Rates of uptake and clearance of perchlorate and iodide in other tissues that contain NIS, such as skin, placenta, and mammary tissue. â¢ Protein binding of perchlorate in rat and human plasma at different life stages (adult, pregnant, neonate, and fetus).
188 Health Implications of Perchlorate Ingestion â¢ Time lag or kinetics for up-regulation of thyroid NIS by perchlorate (not just steady-state concentrations). â¢ Rates of production and secretion of thyroid hormones as related to iodide uptake by the thyroid in late-term fetal rats. If those measures were assessed experimentally, the number of model parameters that need be estimated from animal studies could be reduced, and more data would then be available for model validation. Consideration should therefore be given to independently measuring some or all of the quantities, depending upon the types of simulations that are to be conducted in the future. Many of the studies, such as one to determine protein binding or others to improve models by incorporating data from the literature, can be conducted for under $50,000 and take only a few weeks or months to complete. Othersâsuch as those to evaluate renal clearance, organification of iodide (thyroid hormone production and secretion) in the fetus, or pla- cental transfer of perchlorateâcould cost considerably more, perhaps $50,000-250,000, and involve several months or even a year or more to complete, depending on the study design. If future studies are conducted in nonhuman primates, it will be impor- tant to develop a quantitative understanding of the disposition of perchlorate and iodide in the monkey model because cross-species extrapolations would still be required. In that case, the rat and human PBPK models would provide an initial template for development of a monkey model that would be supplemented by monkey-specific physiologic constants and biochemi- cal constants similar to those already developed for rats and humans and identified through sensitivity analyses. SENSITIVE POPULATIONS Basic Studies The identified sensitive populations are fetuses, infants, and pregnant women. 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 contribu- tion of the NIS or the influence of perchlorate inhibition. Although the NIS is expressed in the placenta, its contribution to iodide transfer from mother to fetus is not known. An especially critical issue in risk assessment has been the influence of iodide status on the sensitivity of placental and breast iodide transport to perchlorate.
Research Recommendations 189 Other tissues contain the NIS, such as the salivary glands, the gastric mucosa, and perhaps the choroid plexus. However, thyroid hormones are not produced in those tissues, and they are not essential even indirectly for thyroid hormone production, for example by their ability to transport iodide. The committee concludes that the highest priority should be given to studies to determine NIS function in the placenta and mammary gland because it is through these two tissues that iodide and possibly perchlorate reaches the thyroid gland in fetuses and infants. The proposed studies suggested here use in vitro and animal models to determine the role of the NIS in placental iodide transport, the susceptibility of breast NIS to perchlorate inhibition, the role of iodide status on these effects, and the effects of perchlorate on development independent of effects on iodide transport. 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. NIS expression in the thyroid and lactating breast concentrates iodide to a gradient of 20:1 to 30:1. In the case of placental iodide transport, the usual condition is iodide moving down a concentration gradient from mother to fetus. Studies of human placenta and several animal models are proposed to study the role of the NIS in fetal iodide supply. Normal human placenta expresses NIS mRNA and protein, but this has not been correlated with maternal iodide or thyroid status. Initial studies should characterize NIS mRNA and protein expression in the placenta, including cellular and subcellular localization, to provide the best correla- tion with iodide transport. A significant focus should be on functional measurement of iodide transport in placental tissue. Although a direct measurement of iodide transport in placenta would be most useful, it will be technically challenging because of the nature of the placenta. Placental tissue is a mixture of several cell types, which may express NIS differently. However, techniques are available to isolate specific cell types and could be used to study NIS activity in relevant cells more specifically. A func- tional assay of iodide transport in placental samples would be valuable for
190 Health Implications of Perchlorate Ingestion the later studies proposed to determine the impact of environmental expo- sure of pregnant women to perchlorate. There are at least two important issues to address with respect to pla- cental NIS in animal models: the physiologic role of placental NIS in supplying iodide to the developing fetus and the influence of perchlorate on this activity. A series of studies could be performed in mice; the potential to modify placental NIS gene expression make this model very useful. The studies should vary maternal dietary iodide intake and determine the influ- ence on placental NIS mRNA and protein expression. The findings should be correlated with serum iodide concentration. The influence of perchlorate exposure could then be used to determine the influence on placental NIS expression and iodide transport. The studies should include measurement of maternal and fetal serum thyroid hormone and TSH. Litter size and neonatal development should be assessed. Expression of thyroid-hormone- dependent genes in the developing brain and behavior should be assessed. Mammary Gland NIS and Perchlorate Before identification and cloning of the NIS, an extensive literature characterized the factors that regulate the concentration of iodide in lactat- ing breast. Lactogenic hormones, such as progesterone and prolactin, stimulate iodide uptake in lactating breast but not in nonlactating breast. Since the NIS has been cloned, the same factors have been shown to regu- late NIS gene expression in the breast. The regulation of NIS expression in breast is different from that in the thyroid gland, which is regulated primar- ily by TSH. Although the same NIS protein is expressed in thyroid and breast, there have not been functional studies to determine the sensitivity of breast NIS to perchlorate inhibition. The studies proposed should determine the influence of dietary iodide intake on NIS mRNA and protein expression and on cellular and subcellular localization of NIS in lactating mammary tissue. The iodide content of milk in lactating mice should be measured to reflect functional iodide transport. Once the function is assessed across a range of dietary iodide intakes, the influence of perchlorate can be tested. The effects of perchlorate are poten- tially on iodide transport and on thyroid function in the pups. Thyroid function in nursing pups should be evaluated, and thyroid-hormone-depend- ent genes in the brain and liver of the nursing pups profiled.
Research Recommendations 191 Tissue-Specific NIS Gene Inactivation A key experiment to test the relative importance of NIS expression in placenta and lactating breast is to use tissue-specific inactivation of NIS gene expression. Methods are available by which NIS can be deleted from individual tissues, such as breast or placental tissue, in mice. Female mice that have NIS gene deletion can be used to characterize placental or lactat- ing breast iodide transport and effects on their offspring. It is important to characterize the mice across a range of dietary iodide intake because the defects may be most apparent at lower iodide intake. Scope of Basic Studies The proposed studies, divided among laboratories with the appropriate expertise, would take 3-5 years to complete. The proposed studies represent four to six separate projects, each of which would require a âstandardâ basic investigation grant of $200,000 per year in direct costs. Thus, study costs range from $2.4 million (four projects for 3 years) to $6 million (six pro- jects for 5 years) in direct costs. Epidemiologic Research The primary sources of uncertainty in estimating an RfD for perchlorate in drinking water arise from the absence of data on possible effects of exposure among populations at greatest risk of the adverse effects of iodide deficiency (pregnant women, their fetuses, and newborns). New epidemio- logic research should focus on assessing possible health effects of perchlor- ate exposure in populations that are most vulnerable to the adverse effects of iodide deficiency. Studies should use direct measures of perchlorate exposure in individuals and methodsâsuch as case-control, cohort, or nested designsâwhich 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 af- fected by the continuing efforts to reduce perchlorate in drinking water. Additional studies of existing data would be relatively inexpensive and
192 Health Implications of Perchlorate Ingestion could be completed in a few months. Because of the need for follow-up to assess developmental outcomes, new epidemiologic studies would take at least about 5-8 years to complete and cost millions of dollars. Analyses of Existing Data Several ecologic studies have examined the relation between birth in a community whose public drinking water contains perchlorate and perturba- tions of thyroid function in the newborn period (Brechner et al. 2000; Crump et al. 2000; F.X. Li et al. 2000; Z. Li et al. 2000; Schwartz 2001; Kelsh et al. 2003; Buffler et al. 2004). No study has specifically investi- gated a possible association of prenatal exposure to perchlorate and thyroid hormone abnormalities among low-birthweight babies (under 2,500 g), although this group of infants is thought to be potentially more vulnerable to the effects of such exposure. Two studies specifically excluded low- birthweight newborns (F.X. Li et al. 2000; Z. Li et al. 2000). It would be useful, where data are available, to compare neonatal thyroid hormone and TSH concentrations in low-birthweight infants in communities that have perchlorate contamination with thyroid hormone and TSH concentrations in low-birthweight babies in nonexposed communities. The data are al- ready available from ecologic studies and could be used as a first step in investigating the relation of perchlorate exposure to perturbations of thyroid hormone secretion in this presumably sensitive group of neonates. Al- though the relation of perchlorate exposure to thyroid hormone secretion in preterm babies is also of interest, data on gestational age are not always available in the studies. In addition, gestational age is typically measured with less accuracy than birthweight. New Studies in Selected Populations Future studies of the health effects of perchlorate exposure should use case-control, cohort, or nested designs, in which data are obtained on exposure and outcome in the same people. Individual measures of perchlo- rate exposure can be difficult to obtain, but asking questions about the use of bottled water and the amount of tapwater consumed and taking measure- ments 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. Urinary perchlorate might be assessed as a more direct mea-
Research Recommendations 193 sure of exposure. Using such measures in studies with adequate statistical power and close attention to control for confounding variables would address a number of the limitations in the available data. Many of the important questions related to health effects have been addressed only by a single study or have not been adequately examined because inappropriate or insensitive end points have been used. For exam- ple, additional studies are needed to examine the possible relation between exposures to perchlorate during critical periods of neurodevelopment and adverse outcomes that reflect more subtle alterations in cognitive and motor function than are captured by the diagnostic labels âautismâ and âatten- tion-deficit hyperactivity disorder.â Along those lines, the study in Chile should be extended to incorporate more extensive neurodevelopmental assessments of the children beginning in infancy and continuing through school age (TÃ©llez, R.T., P.M. ChacÃ³n, C.R. Abarca, B.C. Blount, C.B. Van, K.S. Crump, J.P. Gibbs, SÃ³tero del Rio Hospital, unpublished mate- rial, 2004). Functional end points that should be assessed in a follow-up of the infants include auditory function, including measures of oto-acoustic emissions; visual attention; cognitive function, including tests for executive function and memory; and tests of motor function, particularly balance, coordination, and rapid finger movements. The study being done in Chile also should be expanded to increase the sample sizes of the birth cohorts in each city. Larger sample sizes will be required for statistical power to be appropriate for detecting possible differences among exposure groups on the developmental assessments. It is also important to control for con- founding variables. Little information is available as to whether or not exposures to perchlorate at concentrations present in municipal drinking water are related to an increased incidence of maternal hypothyroidism during gestation. 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. The cohort design is inherently limited, however, for examining out- comes in infants born to mothers who have gestational hypothyroidism. Such mothers, once identified in the study, would be treated, so their fetuses would no longer be subjected to their state of inadequate thyroid hormone. Potential effects of early gestational exposure of the fetuses to maternal hypothyroidism could still be examined, but those occurring beyond the first trimester probably could not be. In addition, the frequencies of some
194 Health Implications of Perchlorate Ingestion of the outcomes of interest, such as congenital hypothyroidism and pertur- bations of thyroid function in the newborn, are relatively uncommon; thus, cohorts would have to be very large to yield enough newborns with altered thyroid function for follow-up and sufficient power to detect meaningful developmental differences between exposure groups. Control for confound- ing factors also would be important. Another way to investigate whether or not in utero perchlorate exposure increases the risk of adverse outcomes in the newborn (such as perturba- tions 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. That design allows a focus on sets of newborns potentially at greatest risk for develop- mental abnormalities as a result of perchlorate exposure and later iodide deficiency. It also provides the opportunity to examine outcomes that have already occurred among mothers who had hypothyroidism during gestation. Such studies should be done in geographic areas that have different concen- trations of perchlorate in drinking water, at least some of which are rela- tively high, as was done in the investigations in Chile. For the nested case-control study, newborns who have abnormal thyroid hormone screening values (case group 1), those born at low birthweight or preterm (case groups 2 and 3), and a random sample of their birth cohort who have normal thyroid screening values and normal birthweights (con- trols) could be identified as soon as possible after birth from among all births in areas of known potential exposure to perchlorate. Data collection for the case groups and the controls should include interviews with mothers to collect information on sociodemographic variables and personal behav- ior; obstetrical history; usual consumption of drinking water and sources of water during the index pregnancy and after birth for drinking, formula preparation, and cooking; residential history during the index pregnancy; dietary intake of iodide-containing foods during pregnancy; and other relevant variables. Other information should include mothersâ prenatal records for the index pregnancy, with special emphasis on whether there had been a diagnosis or treatment for hypothyroidism or hyperthyroidism or assessment of urinary iodide, and labor and delivery information. Blood samples from mothers and newborns should be obtained for measurement of postnatal serum thyroid hormones, TSH, and perchlorate. Urinary iodide could be measured in the mothers. Samples of water from the homes of cases and controls should be collected for measurement of perchlorate. All case and control infants would then be followed prospectively with
Research Recommendations 195 assessments of thyroid function, physical growth, and neurodevelopmental measures at appropriate ages beginning in infancy. The same measures recommended for follow-up of the cohort of Chilean newborns should be used. Test scores, growth measures, and frequencies of specific abnormal outcomes should then be compared in cases and controls. For example, the proportion of 5-year-olds who have abnormal performance on a test of motor function could be compared between cases (defined either on the basis of newborn thyroid hormone concentrations or birthweight) and controls born in areas of differing perchlorate exposure. Assessments should be done for a possible interaction between magnitude of perchlorate exposure and maternal hypothyroidism or iodide deficiency. The design also allows for identification of neurodevelopmental abnormalities, if any, associated with prenatal exposure to perchlorate in infants who do not have abnormalities of thyroid function or growth identifiable at birth. Monitoring Studies Remediation of perchlorate contamination in the Las Vegas wash is already being done, and average concentrations in the effluent have dropped significantly (Croft 2003). If perchlorate in public drinking water were a contributor to thyroid disease, perturbations in thyroid function, or develop- mental delays in exposed populations, one would expect a decrease in those outcomes after reduction in or cessation of the exposure. Continued moni- toring of thyroid hormone concentrations in newborns and of the prevalence of thyroid diseases in populations that have already been studied for those outcomes would allow comparisons of disease frequencies before and after the remediation efforts were instituted. Such monitoring would be rela- tively inexpensive because it is based on existing, routinely collected data. Studies that examine time trends have limitations similar to those of ecologic studies, but they can provide indirect evidence of whether a partic- ular 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-
196 Health Implications of Perchlorate Ingestion larly sensitive populations. Although iodide deficiency is believed to be rare in the United States, it has been reported in pregnant women, as has subclinical hypothyroidism and overt hypothyroidism (Klein et al. 1991; Hollowell et al. 1998). The committee believes that further research is needed to quantify more precisely the extent of and risk factors for iodide deficiency, particularly in pregnant women. However, while studies are being conducted, the committee emphasizes the importance of ensuring that all pregnant women have adequate iodide intake and, as a first step, recom- mends that consideration be given to adding iodide to all prenatal vitamin. REFERENCES Braverman, L.E., X. He, S. Pino, B. Magnani, and A. Firek. 2004. The effect of low dose perchlorate on thyroid function in normal volunteers [abstract]. Thyroid 14(9):691. Brechner, R.J., G.D. Parkhurst, W.O. Humble, M.B. Brown, and W.H. Herman. 2000. Ammonium perchlorate contamination of Colorado River drinking water is associated with abnormal thyroid function in newborns in Arizona. J. Occup. Environ. Med. 42(8):777-782. Buffler, P.A., M.A. Kelsh, E.C. Lau, C.H. Edinboro, and J.C. Barnard. 2004. Epidemiologic Studies of Primary Congenital Hypothyroidism and Newborn Thyroid Function Among California Residents. Final Report. University of California, Berkeley, CA. April 2004. Chow, S.C., and J.P. Liu. 1998. Design and Analysis of Clinical Trials: Concepts and Methodologies. New York: Wiley and Sons. Clewell, R.A., E.A. Merrill, K.O. Yu, D.A. Mahle, T.R. Sterner, D.R. Mattie, P.J. Robinson, J.W. Fisher, and J.M. Gearhart. 2003a. Predicting fetal perchlorate dose and inhibition of iodide kinetics during gestation: A physiologically based pharmacokinetic analysis of perchlorate and iodide kinetics in the rat. Toxicol. Sci. 73(2):235-255. Clewell, R.A., E.A. Merrill, K.O. Yu, D.A. Mahle, T.R. Sterner, J.W. Fisher, and J.M. Gearhart. 2003b. Predicting neonatal perchlorate dose and inhibition of iodide uptake in the rat during lactation using physiologically based pharmaco- kinetic modeling. Toxicol. Sci. 74(2):416-436. Croft, T. 2003. Overview of Las Vegas Valley Perchlorate Remedial Efforts. Presentation at the Second Meeting on Assess the Health Implications of Perchlorate Ingestion meeting, December 12 13, 2003, Irvine, CA. Crump, C., P. Michaud, R. Tellez, C. Reyes, G. Gonzalez, E.L. Montgomery, K.S. Crump, G. Lobo, C. Becerra, and J.P. Gibbs. 2000. Does perchlorate in drinking water affect thyroid function in newborns or school-age children? J. Occup. Environ. Med. 42(6):603-612.
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