3
Epidemiologic Studies of Occupational and Environmental Exposures to Perchlorate

THIS chapter considers observational epidemiologic studies of perchlorate exposures and measures of thyroid function and thyroid diseases in selected populations. The committee considered published and unpublished epidemiologic data in forming its conclusions regarding the possible effects on thyroid function of exposure to perchlorate and in assessing the relevant exposure limits. More weight was given to published reports, and unpublished data were considered only when sufficient information was made available to the committee to evaluate the methods used. Most of the unpublished data considered were presented to the committee in open meetings. The committee considered one unpublished master’s thesis (Schwartz 2001). In weighing the evidence on perchlorate exposure, the committee emphasized studies with the soundest scientific methods and studies that included biologically sensitive groups, such as pregnant women, fetuses, and neonates. Of the epidemiologic studies, one is an unpublished mortality study of workers at a chemical plant who had simultaneous exposures to many agents, including perchlorate (Rockette and Arena 1983); three are cross-sectional studies of occupational cohorts that had respiratory exposures to perchlorate and for which assessments of thyroid function were obtained (Gibbs et al. 1998; Lamm et al. 1999; Braverman et al. 2004); and the remainder are primarily ecologic investigations that compared measures of thyroid function or disease and neurodevelopmental outcomes in neonates, children, and adults in geographically defined groups with and without detectable perchlorate in community water supplies (Lamm and Doemland 1999; Brechner et al. 2000; Crump et al. 2000; F.X.



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Health Implications of Perchlorate Ingestion 3 Epidemiologic Studies of Occupational and Environmental Exposures to Perchlorate THIS chapter considers observational epidemiologic studies of perchlorate exposures and measures of thyroid function and thyroid diseases in selected populations. The committee considered published and unpublished epidemiologic data in forming its conclusions regarding the possible effects on thyroid function of exposure to perchlorate and in assessing the relevant exposure limits. More weight was given to published reports, and unpublished data were considered only when sufficient information was made available to the committee to evaluate the methods used. Most of the unpublished data considered were presented to the committee in open meetings. The committee considered one unpublished master’s thesis (Schwartz 2001). In weighing the evidence on perchlorate exposure, the committee emphasized studies with the soundest scientific methods and studies that included biologically sensitive groups, such as pregnant women, fetuses, and neonates. Of the epidemiologic studies, one is an unpublished mortality study of workers at a chemical plant who had simultaneous exposures to many agents, including perchlorate (Rockette and Arena 1983); three are cross-sectional studies of occupational cohorts that had respiratory exposures to perchlorate and for which assessments of thyroid function were obtained (Gibbs et al. 1998; Lamm et al. 1999; Braverman et al. 2004); and the remainder are primarily ecologic investigations that compared measures of thyroid function or disease and neurodevelopmental outcomes in neonates, children, and adults in geographically defined groups with and without detectable perchlorate in community water supplies (Lamm and Doemland 1999; Brechner et al. 2000; Crump et al. 2000; F.X.

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Health Implications of Perchlorate Ingestion Li et al. 2000; Z. Li et al. 2000; Li et al. 2001; Schwartz 2001; Chang et al. 2003; Kelsh et al. 2003; Lamm 2003; Buffler et al. 2004; Gibbs 2004a,b). The ecologic study of Morgan and Cassady (2002) assessed cancer incidence in a community exposed to both perchlorate and trichloroethylene in drinking water. No epidemiologic studies, either published or unpublished, have measured both thyroid outcomes and perchlorate exposure from drinking water in the same people. Many of the epidemiologic data related to the effects of perchlorate are derived from ecologic studies. The smallest units on which exposure or outcome data are available are geographically defined units, most commonly counties, states, or countries; exposure data, outcome data, or both are available only at that level, not on individual subjects. Because ecologic studies do not include information about exposure and outcome in individuals, they are considered to be the weakest type of observational studies. In ecologic studies, comparisons are made between exposures and outcomes among large units. An example of an ecologic study would be one that compares the mean serum concentration of thyroid-stimulating hormone (TSH) in infants born in a county in which the drinking-water supply contains perchlorate with the mean serum TSH concentration in infants born in a county in which the drinking water does not contain perchlorate. That design is subject to what is referred to as the ecologic fallacy: associations observed at the ecologic level may not apply at the individual level. For example, an observation that the average serum TSH concentration is higher in newborns in a city in which the water supply contains perchlorate than in newborns in cities in which the drinking water does not contain perchlorate would be compatible with a perchlorate effect on thyroid function. In that example, being compatible with an association assumes that no other important variations between the cities could account for the difference in serum TSH concentrations. However, it is not known from such a study whether infants who have high TSH concentrations were themselves exposed to perchlorate during gestation. How well ecologic studies are able to characterize individual exposure depends, in part, on how much variability of exposure there is in the geographic unit. For example, ecologic studies of the correlation of dietary fat intake and breast-cancer mortality by country would undoubtedly suffer from considerable variation in the average dietary fat intake among the persons in a given country. The use of average community exposures for ecologic studies of perchlorate in municipal drinking water may be less subject to error, depending on the population coverage of the water supply. In many of the exposed communities included in the literature, an entire community’s water supply has

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Health Implications of Perchlorate Ingestion measurable perchlorate. Thus, it is likely that everyone has some exposure to perchlorate, depending on how much of their water intake comes from the community’s water supply. Individual variation in water exposure undoubtedly still occurs, however, because of the use of wellwater or bottled water or because of nonuniform distributions of contaminants in a geographic area. Some degree of individual variability undoubtedly exists, but it may not be as great as for other types of exposures that are not part of a communitywide, common-source exposure. Another limitation of ecologic studies is that their design cannot control for many confounding factors, because such data are not usually available at the population level. Results of ecologic studies can be useful in providing supporting data on a possible causal relation, but they cannot themselves provide direct evidence of causation. The available pertinent occupational and epidemiologic studies are summarized in Table 3-1 and discussed in the following sections. STUDIES IN OCCUPATIONAL COHORTS AND ADULTS An early study of an occupational cohort by Rockette and Arena (1983) reported mortality patterns for 59 selected causes of death among workers at the Niagara Plant of Hooker Chemical. It included people with at least 1 year of employment from January 1, 1949, to December 31, 1978. The cohort consisted of 3,963 workers (3,715 men and 248 women) at the plant in Niagara Falls, New York. Only 13 deaths were recorded among women, and detailed analyses of the female data were not conducted because the sample was so small. The following results are related to men. Results showed statistically significant excess mortality from stomach cancer (standardized mortality ratio [SMR], 178.9; p < 0.05) and respiratory cancers (SMR, 145.9; p < 0.01). In the respiratory-cancer category, the SMR was significantly increased for cancer of the lung (SMR, 142.4; p < 0.01). A review of work areas and production indicated that exposure to magnesium perchlorate occurred in 1970-1976 with simultaneous exposure to dozens of other chemicals at the plant. Of the work areas in the plant, 12 departments were identified as having exposure to “groups of chemicals.” The department referred to as “area 4” included exposure to magnesium perchlorate and 23 other chemicals. Job titles in the department were not provided, so specific jobs were not assessed with regard to exposure to magnesium perchlorate. A comparison of department-specific

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Health Implications of Perchlorate Ingestion TABLE 3-1 Summary of Epidemiologic Studiesa Reference Study Design Population Exposure Adjustment Factors Outcomes Major Findings Comments Studies of Occupational Groups and Adult Cohorts Rockette and Arena 1983 SMR study, 1970-1978 3,963 chemical workers, 94% male Magnesium perchlorate, unknown amount, in combination with 23 other chemicals Age, calendar time Cause-specific mortality For males 1970-1978, all cancer SMR = 143.7, p < 0.01; respiratory cancer SMR = 169.6, p < 0.01; stomach cancer SMR = 236.7, p < 0.05 Very few deaths recorded in females, so only data on males analyzed in detail; multiple chemical exposures; no adjustment for cigarette-smoking or potential confounders other than age Gibbs et al. 1998 Repeated cross-sectional (preshift and postshift) 18 workers exposed to ammonium perchlorate and 83 nonexposed workers Respiratory exposure at 0.2-436 µg/kg, depending on work area Duration of shift Compared preshift and postshift serum free T4 index, total T4, and TSH No significant relation of perchlorate dose to change in thyroid hormone and TSH measures across shift Respiratory exposure; small number of exposed workers; subject to potential bias of affected workers who left employ ment before study Gibbs et al. 1998 Historical cohort 53 high dose, 44 low dose, 192 nonexposed Lifetime cumulative exposure to perchlorate; mean in “low-dose” group, 3,500 µg/kg; mean “high-dose,” 38,000 µg/kg None Compared medical records on thyroid hormone and TSH measures and disease; medical surveillance data from cohort Neither estimated cumulative lifetime exposure nor exposure category significantly associated with abnormalities of thyroid hormone measures and TSH Respiratory exposure; subject to potential bias of affected workers who left employment before study; no statistical adjustment for BMI or activity level

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Health Implications of Perchlorate Ingestion Lamm et al. 1999 Cross-sectional 31 ammonium perchlorate workers and 21 azide workers at the same site; ages 20-56 yr Absorbed perchlorate categorized as none, low, medium, and high (mean, 1, 4, 11, 34 mg/shift) None Serum TSH, T4, and T3 ; free T4 index; thyroid hormone binding ratio; thyroid peroxidase antibodies; urinary iodide and creatinine; clinical examination No significant differences in any outcome measure between perchlorate-exposed and azide-exposed workers; no clinical evidence of thyroid abnormalities in perchlorate-exposed workers Respiratory exposure; subject to potential bias of affected workers who left employment before study; small number in study groups reduces ability to detect differences Li et al. 2001 Ecologic Medicaid enrollees in Nevada by county of residence, 1997-1998 Residence in Clark County (drinking-water mean=8.9 ppb), Washoe County, or remaining counties combined (nonexposed) None Medicaid payment diagnosis of one of nine thyroid diseases or thyroid cancer Prevalence of thyroid diseases or thyroid cancer not significantly higher in Clark County than in either Washoe or all other nonexposed counties combined Most thyroid diseases were uncommon, so numbers were small in county comparisons; no adjustment for differences among three county groups in age, sex, race or other potential confounders Morgan and Cassady 2002 Ecologic Residents of 13 contiguous census tracts in Redlands, CA (San Bernardino County), 1988-1998 Drinking-water exposure to TCE (0.09-97 ppb) measured since 1980 and ammonium perchlorate (5-98 ppb) since 1997 Age, sex, race, or ethnicity and calendar time O/E numbers of cancer cases; total and site- specific and separately for children < 15 yr old SIR for thyroid cancer = 1.0 (95% CI = 0.63-1.47); cancers of colon or rectum and lung or bronchus had significantly lower SIRs and melanoma and uterine cancer had significantly higher SIRs; no cancers were observed more often than expected in children Timing and duration of exposure to perchlorate unclear; exposure to TCE also present; no adjustment for other potentially confounding variables; expected numbers were based on surrounding four counties and included study county data

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Health Implications of Perchlorate Ingestion Reference Study Design Population Exposure Adjustment Factors Outcomes Major Findings Comments Braverman et al. 2004 Repeated cross-sectional (pre- and postshift) 29 workers at ammonium perchlorate production facility and 12 nonworker volunteers Respiratory exposure to ammonium perchlorate; mean absorbed dose per shift 0.3 mg/kg None Serum TSH, T4, T3, free T4 index, 14-hr radioactive iodide uptake (RAIU), urinary iodide excretion, serum perchlorate, thiocyanate and nitrate; thyroid size Decrease in mean RAIU postshift compared to preshift and increase in iodide excretion postshift; serum perchlorate undetectable after 3 days off work but elevated postshift; TSH unchanged, T4, and T3, free T4 index showed small but significant increases postshift Pre- and postshift evaluation allows for comparison within the same individuals; data are preliminary; subject to potential bias of affected workers leaving employment prior to study; small number of nonexposed volunteers Studies of Neonatal and Pediatric Populations Lamm and Doemland 1999 Ecologic SMR Clark County NV; six southern CA counties; 700,000 newborns screened 1996-1997 Drinking water; NV, 4-16 ppb continuous; CA, 5-8 ppb sporadic Hispanic ethnicity Congenital hypothyroidism O/E cases = 1.0 (0. 90-1.16) Exposure only sporadic in CA; questionable comparison rates used; not adjusted for birthweight Brechner et al. 2000 Ecologic Newborns in Yuma, AZ (1,099) and newborns in Flagstaff, AZ (443) 1994-97 ~6 ppb in Yuma drinking water; none in Flagstaff water Race or ethnicity and age at sample collection Mean log TSH and T4 in serum Adjusted mean log TSH significantly higher in Yuma than in Flagstaff; no significant difference in T4 Not adjusted for birthweight or gestational age; 1999 perchlorate used to characterize the study period, 1994-1997

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Health Implications of Perchlorate Ingestion Crump et al. 2000 Ecologic 6- to 8-yr olds in three cities in Chile, 1999; newborns in the three cities, 1996-1999 Drinking water; Antofagasta, no detectable; Chanaral, 5-7 ppb; Taltal, 100-120 ppb Age, sex, urinary iodide Serum TSH, T4, free T4, T3, liver and kidney function, urinary iodide and creatinine; clinical examination for goiter; family history of goiter by questionnaire For life-long residents, no significant differences in TSH; adjusted free T4 significantly higher in Chanaral and Taltal than in Antofagasta; no significant differences in prevalence of goiter in children (~20% in each city); family history goiter ~5 times as high in Taltal; log TSH significantly lower in newborns from Taltal Drinking-water perchlorate measured in sample from faucets used by children studied; newborn TSH not adjusted for birthweight or gestational age Z. Li et al. 2000 Ecologic Newborns in Las Vegas, NV (17,308), newborns in Reno, NV (5,882), 1998-1999 Las Vegas drinking water (9-15 ppb for 7 mo and undetectable for 8 mo; estimated cumulative exposure in pregnancy, 0.9-4.2 mg); Reno (nonexposed) Sex, age at sample collection, birthweight Mean T4 in newborn blood No significant difference in adjusted mean T4 concentrations between newborns in Las Vegas and newborns in Reno; no difference in prevalence of low T4 (≤ 10th percentile of birth-cohort distribution) Excluded birthweights <2,500 g and >4,500 g F.X. Li et al. 2000 Ecologic Newborns in Las Vegas, NV (407) and Reno, NV (133), 1998-1999 Las Vegas drinking water (9-15 ppb for 7 mo and undetectable for 8 mo; estimated cumulative exposure in pregnancy, 0.9-4.2 mg); Reno (nonexposed) Age at sample collection, sex Mean log TSH in newborn blood No significant difference in adjusted mean log TSH concentrations between newborns in two cities Excluded birthweights <2,500 g and >4,500 g; adjustment for age at specimen collection dichotomous

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Health Implications of Perchlorate Ingestion Reference Study Design Population Exposure Adjustment Factors Outcomes Major Findings Comments Schwartz 2001 Ecologic 507,982 CA newborns, 1996 Drinking water; estimates based on averages obtained from 1997 testing of samples from set of state’s water systems; categorized as none, low (1-2 ppb), medium (3-12 ppb), high (> 12 ppb) Sex, ethnicity, multiple birth, birthweight, age at specimen collection Newborn blood screening T4 and TSH, presumptive and confirmed congenital hypothyroidism Adjusted mean T4 significantly lower and mean log TSH significantly higher with increasing perchlorate exposure; odds of presumptive congenital hypothyroidism significantly increased in low and medium exposure categories, but not in high; confirmed congenital hypothyroidism not related to perchlorate exposure Potential misclassification of perchlorate exposure due to incomplete measurements; failure to account for multiple laboratories doing newborn screening tests Chang et al. 2003 Ecologic NV Medicaid recipients, 1996-2000, <18 yr old with diagnosis of ADHD or autism County of residence; Clark County (Las Vegas) (exposed; median 23.8 ppb), Washoe County (Reno) (nonexposed), all remaining counties (nonexposed) None Proportion of Medicaid recipients with diagnosis of ADHD or autism and national percentile rankings for fourth- grade proficiency test scores No significant differences between exposed and nonexposed counties in the proportion of Medicaid recipients <18 yr old with diagnosis of ADHD or autism; no significant differences in fourth-grade performance scores Analysis does not account for changes in residence; validity of diagnoses not established; exposure time may not have been biologically relevant; diagnoses made by multiple health- care providers without use of standard criteria; no statistical adjustment for potential confounding variables

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Health Implications of Perchlorate Ingestion Kelsh et al. 2003 Ecologic Newborns in two CA communities, 1983-1997; Redlands and Mentone (15,330), San Bernardino and Riverside (696,530) Drinking water; Redlands and Mentone (exposed, up to 9 ppb; mean 1 ppb), San Bernardino and Riverside (nonexposed) Age at specimen collection, sex, race, or ethnicity, birthweight, multiple births, calendar year Primary congenital hypothyroidism and high serum TSH (mostly >25 µU/mL, sometimes >16 µU/mL) Residence in exposed community not associated with higher prevalence of congenital hypothyroidism (SPR = 0.45, 95% CI = 0.06-1.64) or high serum TSH in newborns (SPR = 0.72, 95% CI = 0.28-1.54) Analyses based on only two cases of congenital hypothyroidism and six of high TSH in exposed community; exposure data from single year used to characterize entire interval Lamm 2003 Ecologic Newborns in Yuma, San Luis, and Somerton (Yuma County), and Flagstaff, AZ September 1994June 1998 Drinking water; Yuma exposed; San Luis, Somerton, Flagstaff nonexposed None Median serum TSH Median serum TSH concentration higher in Yuma (20.8 mU/L) and San Luis and Somerton (21 mU/L) than in Flagstaff (14.5 mU/L); newborns in Yuma have exposure to perchlorate, those in San Luis and Somerton do not Not adjusted for differences in birthweight, gestational age, ethnicity Buffler et al. 2004 Ecologic Newborns in CA, 1998 (342,257) Drinking water, 1997-1998; exposed communities had mean perchlorate >5 ppb; nonexposed communities had perchlorate <5 ppb Age at specimen collection, sex, ethnicity, birthweight Primary congenital hypothyroidism and high serum TSH (generally >25 µU/mL) No statistically significant relation between residence in exposed community and prevalence or odds of primary congenital hypothyroidism or high TSH Study was extension of Kelsh et al. (2003) addressing lack of exposure assessment for complete study period and small number of cases, although still lacking exposure assessment of individuals; in Buffler et al. (2004), exposure assessment corresponded to newborn screening data period; 15 cases of primary congenital

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Health Implications of Perchlorate Ingestion Reference Study Design Population Exposure Adjustment Factors Outcomes Major Findings Comments               hypothyroidism and 147 cases of high serum TSH observed aIncludes published papers and final study reports. Abbreviations: ADHD, attention-deficit-hyperactivity disorder; AZ, Arizona; BMI, body-mass index; CA, California; CI, confidence interval; g, gram; mg,milligram; µg/kg, microgram per kilogram; µU/mL, microunits per milliliter; mU/L, milliunits per liter; mo, month; NV, Nevada; O/E, observed over expected; ppb, parts per billion; SIR, standardized incidence ratio; SMR, standardized mortality ratio; SPR, standardized prevalence ratio; T3, triiodothyronine; T4, thyroxine; TCE, trichloroethylene; TSH, thyroid-stimulating hormone; yr, year.

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Health Implications of Perchlorate Ingestion mortality of workers in the plant with U.S. and local Niagara County mortality by calendar year found no statistically significant excess mortality for 1970-1978; magnesium perchlorate exposure occurred in “area 4” of the Niagara Falls plant in 1970-1976. However, analyses of the entire cohort by calendar period showed a statistically significant excess of deaths from malignant neoplasms as a group (SMR, 143.7; p < 0.01) and for respiratory cancers (SMR, 169.6; p < 0.01) and stomach cancers (SMR, 236.7; p < 0.05) for 1970-1978. Because of the multiple exposures of those workers and the inability to adjust for important confounding variables, such as cigarette smoking, it was not possible to determine whether perchlorate exposure itself was related to any increase in SMRs. In another study of occupational exposure among 254 employees at an ammonium perchlorate production facility in Nevada, those who agreed to participate in the study were investigated for possible acute or chronic effects of perchlorate exposure on thyroid function (Gibbs et al. 1998). Two analyses were conducted: a single-shift study and a working-lifetime study. For the single-shift study, differences in the triiodothyronine (T3) resin uptake assay, the free thyroxine (T4) index, total T4, and TSH in serum obtained before and after a work shift were compared in exposed workers (n = 18) and control workers (n = 83), defined as persons who had not worked in the production areas for the preceding 30 days. Exposures to ammonium perchlorate in this production facility were through the respiratory tract and were estimated by personal breathing-zone sampling and air sampling of work areas in the plant. Full-shift, personal breathing-zone filters in closed-face cassettes were used to characterize the average airborne exposure to ammonium perchlorate in each work area, which was estimated at 0.2-436 µg/kg (mean, 36 µg/kg) per day, depending on work area. Exposure estimates were obtained for the exact shift in which a worker had volunteered for thyroid hormone and TSH measurements to be taken and were adjusted downward by 65% for areas in which workers wore respiratory protection. Workers taking thyroid medications (all of whom were potential controls) were excluded from analyses. Cumulative working-lifetime exposure estimates were also calculated (Gibbs et al. 1998). Estimates of lifetime exposure of individual workers were based on the product of mean exposures for their work areas, the number of years they worked in those areas, and 2,000 (the estimated number of hours worked per year). Work histories used in the calculation of cumulative lifetime exposures were obtained by reviewing personnel records and interviewing workers. In addition to the individual exposure estimates, three exposure categories were arbitrarily created for the

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Health Implications of Perchlorate Ingestion value of 5% in spite of the apparently high iodide intake. Goiter in the children was assessed by palpation, and the presence of goiter was based on the 1960 WHO criteria, which, although more valid than the revised, 1994 WHO criteria, has a specificity of only about 76% in a high-prevalence area (Peterson et al. 2000). Basing the diagnosis of goiter solely on the results of palpation has been shown to have good reproducibility within observers but not between observers and to have poor specificity compared with ultrasonography, resulting in a high number of false positives (Peterson et al. 2000). Therefore, the committee did not consider the higher than expected prevalence of goiter to be grounds for dismissing the results of the Chilean study. It is suggested in EPA’s critiques that the high dietary iodide intake makes this geographic area unsuitable for studies of the thyroid effects of perchlorate exposure. The contention is that the iodide intake is so high that substantial competition with perchlorate cannot be detected. Because EPA did not supply data to support that contention, the committee performed calculations on the effect of basal serum iodide concentrations in humans on the inhibition of iodide uptake by the thyroid sodium (Na+)/iodide (I−) symporter (NIS) in the presence of perchlorate. The Michaelis-Menten competitive-inhibition equation was used for the calculations; the assumptions used in each model are included in Appendix D. A second set of calculations produced a series of curves of perchlorate’s inhibition of iodide uptake across a 105-fold range of basal serum iodide concentrations (Appendix D). On the basis of those models, serum iodide concentrations in humans over a 10-fold range (1.5-15 µg/dL) are not likely to have a profound influence on the ability to detect a perchlorate effect on the thyroid NIS. In addition, a basal serum iodide concentration over 100 µg/dL would be required to shift the dose-response curve for perchlorate’s inhibition of iodide uptake; this suggests that serum iodide concentrations within 0-100 µg/dL would be equally sensitive to perchlorate’s effects. On the basis of the calculations, the committee concludes that iodide intake in the population in question does not interfere with the study’s ability to detect effects of perchlorate exposure at up to 120 ppb (120 µg/L) on iodide uptake, if effects are present. It should also be noted that in spite of the contention that dietary iodide is too high in the population to allow the detection of a perchlorate effect, an effect on serum free T4 concentrations was observed (albeit inverse). The mean serum T4 value was highest in Taltal, the city with the highest exposure to perchlorate. In addition to those calculations, the committee compared serum concentrations of TSH and thyroid hormones reported by Crump et al. (2000)

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Health Implications of Perchlorate Ingestion in children 6-8 years old with those children of similar ages in the United States during a comparable period (Zurakowski et al. 1999) as another approach to assessing whether data from the Chilean study might be useful for evaluating the U.S. experience. With the exception of serum T3, which is known to vary more depending on the assay used, the mean serum thyroid hormone concentrations were not markedly different between U.S. and Chilean children. The mean TSH concentrations were somewhat higher in Chile but were not accompanied by decreases in serum T4 concentrations. Those results suggest that mean serum thyroid hormone concentrations in Chilean children were similar during the period to those in U.S. children of the same age. On the basis of the iodide-inhibition analyses, the additional comparisons, and a review of information on urinary iodide excretion, the committee concluded that the data from Chile could be considered in the evaluation of the U.S. experience with perchlorate in drinking water. Thyroid Hormone and TSH Production in Pregnant Women and Their Newborns A second study among pregnant women and their newborns in each of the three cities in Chile examined the relation between perchlorate exposure during pregnancy, indexes of maternal thyroid function, and thyroid hormone concentrations in the newborns (Gibbs 2003b). Serum T3, free T4, TSH, thyroid peroxidase antibodies, antithyroglobulin antibodies, and thyroglobulin and urinary iodide were measured in mothers during the first and third trimesters and after birth. Maternal blood specimens from the first trimester, maternal urine specimens from the first and third trimesters and after birth, umbilical cord blood, and samples of breast milk were tested for perchlorate. Water samples from the pregnant women’s homes were analyzed for perchlorate to provide individual home-exposure estimates. Preliminary unpublished results on maternal urinary iodide, serum T3, free T4, thyroglobulin, and TSH concentrations at the first and second prenatal visits, cord blood thyroid hormones, and perchlorate in breast milk were presented at a public meeting in May 2004 (Gibbs 2004a). Analyses of accrued data were provided to the committee in a written report in August 2004 (Gibbs 2004b) and are presented here. Mean urinary iodide in mothers at the first prenatal visit was significantly different among the three cities, with mean levels being lowest in Taltal (323 µg/g creatinine in 62 samples compared with 407 µg/g creatinine in 61 samples in Antofagasta, and 363 µg/g creatinine in 39 samples in Chanaral). Maternal mean

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Health Implications of Perchlorate Ingestion serum free T4 and TSH concentrations from the first prenatal visit were similar among the three cities, although mothers in Chanaral had the highest mean TSH values (2.81 µU/mL vs 2.63 µU/mL in Antofagasta and 2.61 µU/mL in Taltal). Mean serum T3 was significantly different in first-trimester samples. Mean T3 was similar in mothers in Antofagasta and Taltal (183 ng/dL and 187 ng/dL, respectively), but it was higher in Chanaral (207 ng/dL). Mothers identified at the first prenatal visit as hypothyroid (serum TSH, at least 4.5 µU/dL) were treated. Five such mothers were identified in each of the three cities. At the second prenatal visit, serum T3 values were significantly different, with the lowest mean in Taltal (173 ng/dL), but they were not adjusted for week of gestation, which was longest at the time of sampling in Taltal (33.2 weeks). Mean serum free T4 was also significantly different among the cities. Serum free T4 values were similar in Chanaral and Taltal (0.82 ng/dL and 0.83 ng/dL, respectively), but higher in Antofagasta (0.86 ng/dL), again, no adjustment was made for differences in length of gestation. Median iodide concentrations in samples of breast milk from mothers were 36.9 µg/dL in Antofagasta (16 samples), 29.5 µg/dL in Chanaral (16 samples), and 38.4 µg/dL in Taltal (25 samples). Median perchlorate concentrations in breast milk were less than 0.5, 19.3, and 103.8 ppb (µg/L) respectively (Gibbs 2004b). Only mean T3 was significantly different in cord blood samples; the value was lowest in Chanaral at 73 ng/dL compared with 79 ng/dL in Antofagasta and 82 ng/dL in Taltal. In data presented in May but not updated in August, perchlorate was detectable in cord blood specimens from infants born in Taltal, but not in Chanaral. It should be noted that no analyses have been adjusted by gestational age or birthweight, so the results presented for newborns are preliminary. The study had not been published at the time of the committee’s deliberations; therefore, it did not use the results in formulating its conclusions. Ecologic Studies of Neurodevelopment in Children There are sparse data concerning the relation between perchlorate exposure and neurodevelopmental disorders in children. One such study is that of attention-deficit-hyperactivity disorder (ADHD) and autism by Chang et al. (2003), which examined the association between residence in Nevada communities with and without detectable perchlorate in the public water supply and diagnoses of either ADHD or autism in children less than 18 years old who were recipients of Medicaid. Scores on tests of 4th grade

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Health Implications of Perchlorate Ingestion performance were also compared with national values for 1998-1999 and 2001. The three comparison groups were in Clark County, which includes Las Vegas and in which the public water supply has perchlorate ranging from undetectable to 23.8 ppb (23.8 µg/L) (median, 10.5 ppb [10.5 µg/L]) as measured in 1997-2001; Washoe County, which includes Reno and has no detectable perchlorate in the public water supply; and the remainder of Nevada, was considered a “rural” control for Las Vegas. The rural areas have no detectable perchlorate in public water supplies. Data from the service records of the Nevada Medicaid Program for calendar years 1996-2000 were used to ascertain the total number of Medicaid recipients less than 18 years old for each year and the number of cases with a first, underlying diagnosis of ADHD or autism. The midpoint Medicaid population size for that period and the average number of cases per year in each of the three geographically defined groups were used to calculate the average annual proportion of Medicaid recipients under 18 years old with ADHD or autism. For ADHD, the annual numbers of cases per 1,000 Medicaid recipients under 18 years old were 17, 28, and 29 for Clark, Washoe, and the rest of the state, respectively; for autism, the annual numbers of cases per 1,000 were 1.4, 2.8, and 1.2. Thus, Clark County, the only area exposed to perchlorate in drinking water, did not have a higher proportion of ADHD or autism than nonexposed communities. Similarly, 4th grade proficiency scores, expressed as national percentile ranks, did not differ significantly among the three areas. A comparison of 2001 4th grade achievement scores allowed inclusion only of children who had resided in the same community for at least 3 years. The results also showed no important differences with respect to 4th grade achievement among the three exposure groups. Other than the single analysis of the 2001 4th grade achievement scores, the data cannot account for any changes in children’s residence. They also do not reflect exposures to perchlorate at a time in neurologic development that is considered biologically relevant, at least for autism, namely early gestation. As an ecologic study, the study measured neither exposure nor outcome in individuals. In addition, the specific criteria used to make individual diagnoses of ADHD or autism are unknown; diagnoses were made by multiple health-care providers and without the use of uniform diagnostic criteria. Thus, the validity of the diagnoses cannot be assessed, and geographic differences could reflect diagnostic practices in local communities rather than true differences in risk. Furthermore, no adjustment was made for potentially confounding factors, such as age, sex, race, and ethnicity. Finally, the end points studied are not the most sensitive indicators of the kinds of neuro-

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Health Implications of Perchlorate Ingestion developmental outcomes that might be predicted on the basis of prior studies of the effects of hypothyroidism on the developing nervous system. The indicators include subtle impairments in cognitive and motor function, such as those observed in children who have untreated or inadequately treated congenital hypothyroidism. In addition, neither autism nor autistic-spectrum disorder has been observed previously in association with thyroid hormone deficiencies. SUMMARY Limitations of Existing Data Epidemiologic studies have examined possible associations between environmental exposure to perchlorate in drinking water at about 4-120 ppb (4-120 µg/L) and abnormalities of thyroid hormone and TSH production in newborns, as well as thyroid diseases (such as congenital hypothyroidism and goiter) and cancer in children and adults (Lamm and Doemland 1999; Brechner et al. 2000; Crump et al. 2000; F.X. Li et al. 2000; Z. Li et al. 2000; Schwartz 2001; Morgan and Cassady 2002; Kelsh et al. 2003; Lamm 2003; Buffler et al. 2004). Occupational studies of respiratory exposures up to 0.5 mg/kg perchlorate per day and abnormalities of thyroid hormone and TSH production in adult workers have been conducted (Gibbs et al. 1998; Lamm et al. 1999; Braverman et al. 2004). Only one study has examined a possible relation between perchlorate exposure and adverse neurodevelopmental outcomes (ADHD and autism) in children (Chang et al. 2003). A number of the studies have samples that are too small to detect differences in frequency of outcomes between exposure groups, and adjustment for potentially confounding factors was limited. Nearly all the studies were ecologic, including those in newborns and children, the groups potentially most vulnerable to the effects of perchlorate exposure. Ecologic studies can provide supporting evidence of a possible association but cannot themselves provide definitive evidence regarding cause. Perchlorate exposure of individuals is difficult to measure and was not assessed directly in any of the studies conducted outside the occupational setting. The only study with measures of perchlorate made directly from drinking-water samples taken from faucets potentially used by people who were studied was that done in Chile by Crump et al. (2000). No studies have examined the relation of perchlorate exposure and adverse outcomes, either in thyroid function or in neurodevelopment,

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Health Implications of Perchlorate Ingestion among especially vulnerable groups, such as low-birthweight or preterm infants. In addition, the available studies do not assess the possibility of adverse outcomes associated with perchlorate exposure in infants born to mothers who had inadequate dietary iodide intake. Thus, no direct human data are available regarding a possible interaction between maternal iodide intake and perchlorate exposure. Although the ecologic design is inherently limited with respect to establishing causality, results of such studies can be informative when combined with other data on the biology of the thyroid gland, experimental studies of the effects of acute exposure to perchlorate, and studies of occupational perchlorate exposure. Committee Conclusions Drawn from Epidemiologic Data on Specific Health Outcomes Congenital Hypothyroidism Ecologic data alone are not sufficient to demonstrate whether or not an association is causal, but they do provide evidence that can be used to evaluate possible associations. Acknowledging that ecologic data alone are inherently limited in drawing causal inferences, the committee concludes that the available epidemiologic evidence is not consistent with a causal association between perchlorate exposure and congenital hypothyroidism as defined by the authors of the studies reviewed here. All studies of this association were negative. Perturbation of Thyroid Hormone and TSH Production in Newborns Again given the limitations of ecologic data in inferring causation, the available epidemiologic evidence is not consistent with a causal association between perturbations of thyroid hormone and TSH production in normal newborns (that is, not low-birthweight or preterm) and exposure during gestation to perchlorate in drinking water at up to 120 ppb (120 µg/L). Most studies do not show either significantly lower T4 concentrations or significantly higher TSH concentrations among infants born in geographic areas in which the water supply has measurable perchlorate.

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Health Implications of Perchlorate Ingestion However, no epidemiologic studies are available on the association between perchlorate exposure and thyroid dysfunction among low-birth-weight or preterm newborns, offspring of mothers who had iodide deficiency during gestation, or offspring of hypothyroid mothers. Those are the groups of greatest concern with respect to potential effects of perchlorate exposure. Neurodevelopmental Outcomes The epidemiologic evidence is inadequate to determine whether or not there is an association between perchlorate exposure and adverse neurodevelopmental outcomes in children. The only relevant study used an ecologic design and examined autism and ADHD as end points. Subtler neurodevelopmental outcomes have not been assessed in human populations. Although inclusion of ADHD was considered plausible, the committee questioned the appropriateness of autism as an end point. Autism has not been observed among the spectrum of clinical outcomes in children who had congenital hypothyroidism and were evaluated prospectively (Rovet 1999, 2002, 2003). Thyroid Diseases and Hypothyroidism in Adults On the basis of data from studies of chronic occupational exposures to ammonium perchlorate and ecologic investigations in adults, the committee concludes that the epidemiologic evidence is not consistent with a causal association between exposure to perchlorate at the concentrations studied and thyroid diseases in adults. The thyroid diseases and thyroid measures investigated included simple and nonspecified goiter, nontoxic nodular goiter, thyrotoxicosis with or without goiter, acquired hypothyroidism, thyroiditis, and other disorders of the thyroid, and measures of serum TSH and the two thyroid hormones. In occupational studies, perchlorate exposures as high as 0.5 mg/kg per day have not been associated with adverse effects on thyroid function in workers, but small samples in some studies may have reduced the ability to identify important differences, and studies were limited to workers who remained in the workforce.

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Health Implications of Perchlorate Ingestion Thyroid Cancer in Adults The epidemiologic evidence is insufficient to determine whether there is a causal association between perchlorate exposure and thyroid cancer. Only two studies related to this issue have been done, and both were ecologic. In one study, the number of thyroid-cancer cases was too small to have a reasonable chance of detecting an association if one existed (Li et al. 2001). In the second, larger study (Morgan and Cassady 2002), mixed exposures were present (to perchlorate and TCE). In neither study was it possible to adjust for potential confounding variables. The committee notes, however, that on the basis of its understanding of the biology of human and rodent thyroid tumors, it is unlikely that perchlorate poses a risk of thyroid cancer in humans. REFERENCES Braverman, L.E., X. He, S. Pino, M. Cross, B. Magnani, S.H. Lamm, K. Crump, and J. Gibbs. 2004. The effect of perchlorate, thiocyanate, and nitrate on thyroid function in long-term workers exposed to perchlorate. Presentation at the Fourth Meeting of the Committee to Assess the Health Implications of Perchlorate Ingestion, May 24, 2004, Woods Hole, MA. 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. April 2004, Berkeley, CA. Chang, S., C. Crothers, S. Lai, and S. Lamm. 2003. Pediatric neurobehavioral diseases in Nevada counties with respect to perchlorate in drinking water: An ecological inquiry. Birth Defects Res. Part A Clin. Mol. Teratol. 67(10):886-892. 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. Gibbs, J.P., R. Ahmad, K.S. Crump, D.P. Houck, T.S. Leveille, J.E. Findley, and M. Francis. 1998. Evaluation of a population with occupational exposure to airborne ammonium perchlorate for possible acute or chronic effects on thyroid function. J. Occup. Environ. Med. 40(12):1072-1082.

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Health Implications of Perchlorate Ingestion Gibbs, J.P. 2003a. Comments and Some Information About Specific Issues, Rafael Tellez. Letter to R. Johnston, Committee to Assess the Health Implications of Perchlorate Ingestion, from J.P. Gibbs, Kerr-McGee Corp., Oklahoma City, OK. December 16, 2003. Gibbs, J.P. 2003b. Comments Regarding Previous and Ongoing Studies in Northern Chile. Protocol and Preliminary Data from an Ongoing Study Among Pregnant Women and Newborns in the Same Three Cities as Studied by Crump et al (2000). Letter to E.K. Mantus, National Academy of Sciences, from J.P. Gibbs, Kerr-McGee Corp., Oklahoma City, OK. October 27, 2003. Gibbs, J.P. 2004a. Preliminary: Chronic Environmental Exposure to Perchlorate in Drinking Water and Thyroid Function During Pregnancy and the Neonatal Period. Presentation at the Fourth Meeting of the Committee to Assess the Health Implications of Perchlorate Ingestion, May 24, 2004, Woods Hole, MA. Gibbs, J.P. 2004b. Chronic Environmental Exposure to Perchlorate in Drinking Water and Thyroid Function During Pregnancy and the Neonatal Period. August 8, 2004 Update. Letter to R. Johnston, Committee to Assess the Health Implications of Perchlorate Ingestion, from J.P. Gibbs, Kerr-McGee Corp., Oklahoma City, OK. August 7, 2004. Gibbs, J., and K. Crump. 2003. Analysis of Review of Original Statistical Methods and Alternate Analyses for Ecological Epidemiological Study of Crump et al. (2000) by A.H. Marcus, National Center for Environmental Assessment, in memorandum to A.M. Jarabek, National Center for Environmental Assessment, Washington, DC, September 23, 2003. December 11, 2003. International Council for the Control of Iodine Deficiency Disease. 2001. The Western Hemisphere Nears Iodine Sufficiency. IDD Newsletter 17(1):2. [Online]. Available: http://www.people.virginia.edu/%7Ejtd/iccidd/newsletter/feb2001.htm [accessed July 8, 2004]. International Council for the Control of Iodine Deficiency Disease. 2002. Iodine Deficiency Disease (IDD) Prevalence and Control Program Data: Chile. [Online]. Available: http://www.people.virginia.edu/~jtd/iccidd/mi/idd_034.htm [accessed July 8, 2004]. Kelsh, M.A., P.A. Buffler, J.J. Daaboul, G.W. Rutherford, E.C. Lau, J.C. Cahill, A.K. Exuzides, A.K. Madl, L.G. Palmer, and F.W. Lorey. 2003. Primary congenital hypothyroidism, newborn thyroid function, and environmental perchlorate exposure among residents of a southern California community. J. Occup. Environ. Med. 45(10):1116-1127. Lamm, S. H. 2003. Perchlorate exposure does not explain differences in neonatal thyroid function between Yuma and Flagstaff. [Letter]. J. Occup. Environ. Med. 45(11):1131-1132. Lamm, S.H., and M. Doemland. 1999. Has perchlorate in drinking water increased the rate of congenital hypothyroidism? J. Occup. Environ. Med. 41(5):409-411. Lamm, S.H., L.E. Braverman, F.X. Li, K. Richman, S. Pino, and G. Howearth. 1999. Thyroid health status of ammonium perchlorate workers: A cross-sectional occupational health study. J. Occup. Environ. Med. 41(4):248-260.

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Health Implications of Perchlorate Ingestion Li, F.X., D.M. Byrd, G.M. Deyhle, D.E. Sesser, M.R.Skeels, S.R.Katkowsky, and S.H. Lamm. 2000. Neonatal thyroid-stimulating hormone level and perchlorate in drinking water. Teratology 62(6):429-431. Li, Z., F.X. Li, D. Byrd, G.M. Deyhle, D.E. Sesser, M.R. Skeels, and S.H. Lamm. 2000. Neonatal thyroxine level and perchlorate in drinking water. J. Occup. Environ. Med. 42(2):200-205. Li, F.X., L. Squartsoff, and S.H. Lamm. 2001. Prevalence of thyroid diseases in Nevada counties with respect to perchlorate in drinking water. J. Occup. Environ. Med. 43(7):630-634. Marcus, A.H. 2003. Review of Original Statistical Methods and Alternate Analyses for Ecological Epidemiology Study of Crump et al. (2000). Memorandum to A.M. Jarabek, National Center for Environmental Assessment, from A.H. Marcus, National Center for Environmental Assessment, Washington, DC. Sept. 23, 2003. [Online]. Available: http://www.epa.gov/ncea/perchlorate/references/documents/crump_memo.pdf [accessed September 30, 2004]. Mercado, M., V.Y. Yu, I. Francis, W. Szymonowicz, and H. Gold. 1988. Thyroid function in very preterm infants. Early Hum. Dev. 16(2-3):131-141. Morgan, J.W., and R.E. Cassady. 2002. Community cancer assessment in response to long-time exposure to perchlorate and trichloroethylene in drinking water. J. Occup. Environ. Med. 44(7):616-621. Nahum, G.G., and H. Stanislaw. 2004. Hemoglobin, altitude and birth weight: Does maternal anemia during pregnancy influence fetal growth? J. Reprod. Med. 49(4):297-305. Park, R.M. 2001. Perchlorate Health Effects in the Epidemiological Literature. Letter to A. Jarabek, National Center for Environmental Assessment, Office of Research and Development, Washington, DC, from R.M. Park, National Institute for Occupational Safety and Health, Cincinnati, OH. [Online]. Available: http://www.epa.gov/ncea/perchlorate/references2/documents/100842.pdf [accessed September 30, 2004]. Peterson, S., A. Sanga, H. Eklof, B. Bunga, A. Taube, M. Gebre-Medhin, and H. Rosling. 2000. Classification of thyroid size by palpation and ultrasonography in field surveys. Lancet 355(9198):106-110. Rockette, H.E., and V.C. Arena. 1983. Mortality Pattern of Workers in the Niagara Plant. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA. June 1983. Rothman, K.J., and S. Greenland. 1998. Precision and validity in epidemiologic studies. Pp. 115-134 in Modern Epidemiology, 2nd Ed., K.J. Rothman and S. Greenland, eds. Philadelphia: Lippincott-Raven Publishers. Rovet, J.F. 1999. Long-term neuropsychological sequelae of early-treated congenital hypothyroidism: Effects in adolescence. Acta Paediatr. 88(432):88-95. Rovet, J.F. 2002. Congenital hypothyroidism: An analysis of persisting deficits and associated factors. Neuropsychol. Dev. Cogn. Sect. C Child Neuropsychol. 8(3):150-162.

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