1
Introduction

OVER 11 million people have perchlorate in their public drinking-water supplies at concentrations of 4 ppb (4 µg/L) or higher (EPA 2004a).1 There is no federal drinking-water standard for perchlorate, and the concentration at which a standard should be set to protect public health is being debated. EPA has the responsibility to protect the nation’s drinking water and has issued draft risk assessments that provide reference doses (RfDs) that could be used to set a federal drinking-water standard. However, EPA has been criticized that it did not appropriately consider all the relevant data for its assessments and that it based its conclusions on flawed scientific studies.

Because of the controversy surrounding the concentration at which perchlorate should be regulated, EPA, the Department of Defense (DOD), the Department of Energy (DOE), and the National Aeronautics and Space Administration (NASA) asked the National Research Council (NRC) to assess the adverse health effects of perchlorate ingestion from clinical, toxicologic, medical, and public-health perspectives. They also asked the NRC to evaluate the scientific literature, including human and animal data, and to assess the key studies underlying EPA’s 2002 draft risk assessment, Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization, with respect to quality, reliability, and relevance for drawing conclusions about the health implications of exposure to low concentrations of perchlorate in drinking water. In response to the request,

1  

The estimate of 11 million people is based on sampling data collected as of May 2004 by the U.S. Environmental Protection Agency (EPA) as required by the Unregulated Contaminant Monitoring Rule. The minimum reporting level for data collection under the Unregulated Contaminant Monitoring Rule is 4 parts per billion (ppb) (4 micrograms per liter [µg/L]).



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Health Implications of Perchlorate Ingestion 1 Introduction OVER 11 million people have perchlorate in their public drinking-water supplies at concentrations of 4 ppb (4 µg/L) or higher (EPA 2004a).1 There is no federal drinking-water standard for perchlorate, and the concentration at which a standard should be set to protect public health is being debated. EPA has the responsibility to protect the nation’s drinking water and has issued draft risk assessments that provide reference doses (RfDs) that could be used to set a federal drinking-water standard. However, EPA has been criticized that it did not appropriately consider all the relevant data for its assessments and that it based its conclusions on flawed scientific studies. Because of the controversy surrounding the concentration at which perchlorate should be regulated, EPA, the Department of Defense (DOD), the Department of Energy (DOE), and the National Aeronautics and Space Administration (NASA) asked the National Research Council (NRC) to assess the adverse health effects of perchlorate ingestion from clinical, toxicologic, medical, and public-health perspectives. They also asked the NRC to evaluate the scientific literature, including human and animal data, and to assess the key studies underlying EPA’s 2002 draft risk assessment, Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization, with respect to quality, reliability, and relevance for drawing conclusions about the health implications of exposure to low concentrations of perchlorate in drinking water. In response to the request, 1   The estimate of 11 million people is based on sampling data collected as of May 2004 by the U.S. Environmental Protection Agency (EPA) as required by the Unregulated Contaminant Monitoring Rule. The minimum reporting level for data collection under the Unregulated Contaminant Monitoring Rule is 4 parts per billion (ppb) (4 micrograms per liter [µg/L]).

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Health Implications of Perchlorate Ingestion NRC convened the Committee to Assess the Health Implications of Perchlorate Ingestion, which prepared this report. REGULATORY HISTORY In 1985, the Region 9 Office of EPA raised concern about potential perchlorate contamination at Superfund sites in the San Gabriel Valley in California (see Figure 1-1 for timeline of selected perchlorate-related regulatory activities) (Takata 1985). No validated analytic method was available to measure low perchlorate concentrations, and little information on their possible health effects was available (EPA 2002a). As a result, attention was focused on other chemicals at the California sites. In the early 1990s, perchlorate contamination in monitoring wells at a California Superfund site was confirmed at concentrations greater than 1 part per million (ppm) (1 milligram per liter [mg/L]), and a provisional RfD was issued by the EPA Superfund Technical Support Center in 1992 (EPA 2002a). A revised provisional RfD was released in 1995. The RfDs were considered provisional because they had not undergone internal or external peer review. However, they were used to derive guidance levels for groundwater remediation (see Table 1-1). In March 1997, Toxicology Excellence for Risk Assessment (TERA), a nonprofit risk assessment consulting firm, convened an independent peer review to evaluate an RfD that it had derived for perchlorate (EPA 2002a). The peer review concluded that the scientific database was insufficient to conduct a “credible quantitative risk analysis.” As a result, an independent peer-review panel met in May 1997 and developed a testing strategy to address data gaps and reduce uncertainties regarding possible health effects of low-concentration perchlorate ingestion. The panel recommended a subchronic oral bioassay in rats, a developmental-neurotoxicity study in rats, a developmental study in rabbits, a two-generation reproductive toxicity study in rats, pharmacokinetic and mechanistic studies in test animals and humans, and genotoxicity and immunotoxicity assays. In 1998, perchlorate was placed on EPA’s final version of the Contaminant Candidate List (CCL), which names unregulated contaminants that may pose a public-health concern in drinking water (EPA 2004b). Contaminants on the CCL are being considered for regulation; that is, they are not subjects of federal drinking-water standards. To determine the extent of perchlorate contamination of the national drinking-water supply, monitoring of perchlorate in all large public water systems and a representative sample of small systems became mandatory beginning in 2001 (EPA 2004c).

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Health Implications of Perchlorate Ingestion FIGURE 1-1 Timeline of perchlorate-related regulatory activities.

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Health Implications of Perchlorate Ingestion Although all the studies proposed by the 1997 independent peer-review panel had not been completed, EPA released its first formal draft risk assessment of perchlorate in December 1998. An EPA-sponsored peer review of the risk assessment was convened in February 1999. The panel suggested completion of the studies recommended earlier, conduct of a few additional studies to evaluate further the effects of perchlorate on fetal development, and review of the thyroid histopathology data reported in several studies by an independent group (RTI 1999). EPA issued a revised draft risk assessment in 2002 that incorporated revisions suggested by the peer review and new data generated as of fall 2001. It convened a new peer-review panel in March 2002 to review the revised risk assessment. Comments and suggestions made by that panel are being addressed by EPA. Table 1-1 lists the RfDs proposed by EPA and the corresponding drinking-water guidelines that could be derived from them using standard assumptions regarding body weight and water consumption. CHARACTERISTICS OF PERCHLORATE Perchlorate is a negatively charged ion (an anion) that is composed of one chlorine atom and four oxygen atoms (ClO4−). It is a poor complexing agent and forms a weak association with its counterion (a positively charged ion, or cation). Accordingly, perchlorate salts are extremely soluble in aqueous media and polar organic solvents. The order of solubility of the more common perchlorate salts is sodium > lithium > ammonium > potassium (Mendiratta et al. 1996). Because those perchlorate salts are so soluble, the health risks associated with them are considered equivalent to those associated with perchlorate itself, and the terms “perchlorate,” “perchlorate salts,” and “perchlorates” are often used interchangeably in the risk-assessment literature. Perchlorate has excellent oxidizing ability under some conditions (EPA 2002a). However, the activation energy required to initiate the chemical reaction is very high. The high activation energy and solubility of the salts lead to perchlorate’s stability and mobility in the environment. The high activation energy also leads to perchlorate’s nonreactivity in the human body, where it is excreted virtually unchanged as indicated by absorption, distribution, metabolism, and elimination studies. The primary exposure pathway of concern for perchlorate is ingestion because of its rapid uptake from the gastrointestinal tract (EPA 2002a). Dermal uptake is minimal, and the low vapor pressure of the salts leads to negligible inhalation. People might be exposed to perchlorate dust or

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Health Implications of Perchlorate Ingestion TABLE 1-1 EPA Provisional or Proposed Reference Doses (RfDs) and Corresponding Drinking-Water Concentrationsa Provisional or Proposed RfD (mg/kg per day) Corresponding Drinking-Water Concentration (ppb)b Publication Date 0.0001 4c 1992 0.0001-0.0005 4-18 1995 0.0009 32 1998 0.00003 1 2002 aDrinking-water concentrations derived from standard assumptions about body weight (70 kg) and water consumption (2 L/day). b1 ppb = 1 µg/L. cExample calculation: [(0.0001 mg/kg per day × 70 kg) / 2 L per day] × 1,000 µg/mg = 4 µg/L (4 ppb). particles primarily in an occupational setting. The risk posed by that exposure would depend on the particle size distribution, which determines whether a particle is inhalable and, if it is inhalable, where in the respiratory tract it is deposited, which might affect solubility and absorption. Thus, the major route of concern is ingestion. USE AND OCCURRENCE OF PERCHLORATE The outstanding oxidizing ability of perchlorate led to its early use as a propellant and an explosive (Mendiratta et al. 1996). France, Germany, Switzerland, and the United States began production in the 1890s. Before the 1940s, annual global production of perchlorate was estimated to be 1,800 tons. In the middle 1940s, annual perchlorate production increased dramatically to 18,000 tons because of demand by the military and aerospace industry. Current production values are difficult to estimate because ammonium perchlorate is classified as a strategic compound. Perchlorate is used primarily as an oxidizer in solid rocket fuels and propellants (Mendiratta et al. 1996). Ammonium perchlorate is the perchlorate salt most commonly used for that purpose. Perchlorate is also used in explosives, pyrotechnics, and blasting formulations. Magnesium perchlorate and lithium perchlorate are used in dry batteries. Other uses have been reported (EPA 2002a; Mendiratta et al. 1996). Over the past 50 years, perchlorate has been used to diagnose and treat

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Health Implications of Perchlorate Ingestion thyroid disease. It was used in the 1950s and 1960s to treat hyperthyroidism associated with Graves disease (EPA 2002a). The extent of its use was rather limited, and its use was curtailed when severe hematologic side effects (aplastic anemia and agranulocytosis) were reported and better antithyroid drugs became available. Today, perchlorate is used diagnostically to detect defects in the synthesis of thyroid hormones (Meier and Burger 2000). It is also used as a treatment for patients who have developed hyperthyroidism after exposure to the antiarrythmic drug amiodarone (Martino et al. 2001). However, the Food and Drug Administration (FDA) does not recognize perchlorate as a pharmaceutical to treat endocrine or metabolic disorders (D. Orloff, Division of Metabolic and Endocrine Drug Products, FDA, personal commun., January 2004), and it is rarely used to treat any type of hyperthyroidism in the United States. As of September 2004, environmental perchlorate releases have been confirmed in 35 states (EPA 2004d). The presence of perchlorate in the environment is reported to be associated primarily with the manufacture or use of perchlorates in solid rocket fuels and propellants (EPA 2002a). Environmental releases have also been associated with explosives and fireworks manufacture and disposal. There has been some debate about fertilizers as potential sources of perchlorate contamination (TRC 1998; Susarla et al. 1999, 2000). However, EPA (2001) conducted a survey of fertilizer composition and detected perchlorate only in products derived from Chilean caliche, an ore containing nitrates. EPA concluded that fertilizer use would probably not be a major source of perchlorate contamination and would be possible only where fertilizers derived from Chilean caliche were used. Monitoring of perchlorate in all large public water systems and a representative sample of small systems began in 2001 (EPA 2004a,c). Data as of May 2004 indicate that perchlorate in public drinking-water supplies ranges from less than 4 ppb (minimum reporting level) to 200 ppb, with 6.4 ppb as the median concentration of values above the minimum reporting level (see Table 1-2). The highest concentration reported in the survey thus far is 420 ppb in a water facility in Puerto Rico. Data on California indicate that perchlorate ranges from less than 4 to 67 ppb, with 6.7 ppb as the median concentration of values above the minimum reporting level. The data do not represent perchlorate concentrations in all water sources. Higher perchlorate concentrations have been noted in monitoring wells associated with Superfund sites and other groundwater and surface water not directly associated with drinking-water supplies (EPA 2002a). As noted previously, the data include only a representative sample of small water facilities.

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Health Implications of Perchlorate Ingestion TABLE 1-2 Perchlorate Drinking-Water Concentrations Based on Monitoring Data from Unregulated Contaminant Monitoring Rule as of May 2004   Perchlorate Samples Location Minimal Concentration (ppb)a Maximal Concentration (ppb) Median Concentration (ppb)b Number above MRL Total Fraction below MRL (%) United States <4 200c 6.4 535 28,179 98.1 Puerto Rico <4 420 NA 1 734 99.9 California <4 67d 6.7 364 8,179 95.5 a1 ppb = 1 µg/L. bMedian perchlorate concentration of values above the minimum reporting level (<4 ppb). cMaximum in United States was measured in Duval County, Florida. dMaximum in California was measured in San Bernardino County. Abbreviations: MRL, minimum reporting level (<4 ppb); NA, not applicable. Source: Data from EPA 2004a.

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Health Implications of Perchlorate Ingestion Information presented in a recent report from the University of California, Irvine, indicates much higher perchlorate concentrations in California drinking water (Bull et al. 2004). However, that report includes data from 1997 to 2004 and, more important, data on inactive, abandoned, and destroyed water sources. The EPA data (2004a) are only on active drinking-water sources, and this could account for the differences in the two sets of data. Perchlorate has also been detected in food sources. For example, the Environmental Working Group, a nonprofit research organization, reported that perchlorate was detected in four of 22 samples of commercial lettuce purchased in January and February 2003 from seven grocery stores in northern California (Sharp and Lunder 2003). Perchlorate concentrations in the four lettuce samples ranged from 30 to 121 ppb (nanograms per gram of lettuce wet weight); the average was 70 ppb. Perchlorate has been detected in commercial milk samples. Kirk et al. (2003) found perchlorate in all seven samples of milk randomly purchased from seven grocery stores in Lubbock, Texas. Concentrations ranged from 1.75 to 6.30 ppb. Perchlorate also was detected in a sample of evaporated milk and a sample of breast milk but not in a sample of powdered milk. More recent surveys of milk have shown perchlorate concentrations ranging from nondetectable to 10.6 ppb (Sharp 2004). Perchlorate concentrations in breast milk have been measured in a current study in Chile (Gibbs 2004); median concentrations of 19.3 and 103.8 ppb were measured in Chanaral and Taltal, where mean perchlorate concentrations in tap water are 5.8 and 113 ppb, respectively. FDA has developed analytic techniques appropriate for measuring perchlorate in various food sources and is conducting a survey of foods to determine the extent of perchlorate contamination in suspect foods (FDA 2004). Preliminary results of sampling by FDA found perchlorate concentrations ranging from 3 to 11 ppb in 20 milk samples. Thus, the contamination of public water supplies and food sources has raised substantial concerns about the effects of low-level perchlorate ingestion and forced the debate over a drinking-water standard into the public spotlight. SENSITIVE POPULATIONS Transfer of iodide from blood into the thyroid gland is essential for the synthesis of the thyroid hormones: thyroxine (T4) and triiodothyronine (T3) (see Chapter 2). Perchlorate blocks the transport of iodide into the thyroid

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Health Implications of Perchlorate Ingestion gland, which could potentially lead to iodide deficiency and decreased synthesis of T3 and T4. The thyroid hormones are critical determinants of growth and development in fetuses, infants, and young children. Thus, fetuses and preterm newborns constitute the most sensitive populations although infants and developing children are also considered sensitive populations. People who have compromised thyroid function resulting from conditions that reduce thyroid hormone production and people who are iodide-deficient also constitute potentially sensitive populations. SCIENTIFIC CONTROVERSIES Several issues have been repeatedly raised at conferences and in peer reviews concerning EPA’s assessment of potential adverse health effects of perchlorate exposure (EPA 2002b; Schwartz et al. 2004). The adequacy and relevance of available human data for assessing health risks posed by perchlorate exposure have been debated. Clinical, occupational, and epidemiologic data are available, and some argue that they should be used to determine the RfD, the key value used to derive the drinking-water standard. However, others state that the human studies should not be used as the basis of the RfD, because they contain one or more of the following limitations: lack of control of confounding factors, evaluation only of healthy adults, inadequate exposure information, evaluation of effects over short exposure durations, and assessment of a narrow set of toxicity end points. The quality and validity of some animal data have also been debated (EPA 2002b; Schwartz et al. 2004). Specifically, questions have been raised about neurodevelopmental studies in which rats were exposed to perchlorate in utero and postnatally and then examined for changes in specific areas of the brain. Many have challenged the experimental methods, the statistical analysis of the data, the interpretation of the reported findings, and the inconsistencies between the reported findings and the general literature on thyroid hormones and brain development. Others have argued that those data cannot be disregarded in the assessment of potential adverse health effects of perchlorate ingestion. Another point of contention is the definition of the adverse health effect associated with perchlorate ingestion (EPA 2002b; Schwartz et al. 2004). EPA has proposed a mode-of-action model for perchlorate toxicity, which shows a continuum of possible health effects of perchlorate exposure (see Figure 1-2). The effect that is defined as the adverse effect is a matter of

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Health Implications of Perchlorate Ingestion FIGURE 1-2 EPA’s proposed continuum of possible health effects of perchlorate exposure. Source: EPA 2002a.

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Health Implications of Perchlorate Ingestion debate. Some believe that the adverse effect should be defined as inhibition of iodide uptake by the thyroid or as decreases in T3 and T4 production with corresponding increases in thyroid-stimulating hormone (TSH) production. Others contend that those effects are “preadaptive” or “adaptive” effects and that the adverse effect is one or more clinical manifestations of hypothyroidism, such as developmental deficits. Defining the adverse effect is important because it influences how the RfD is derived and ultimately the value of the drinking-water standard. Finally, the application of various uncertainty factors has become a source of controversy. When an RfD is calculated, uncertainty factors are used to extrapolate from the study population to the larger general population. Those factors account for interspecies differences (extrapolation from animal to human populations, if applicable), intraspecies differences (possible variations or sensitivities that might be present in the general population), failure to identify a no-observed-adverse-effect level, absence of chronic toxicity data, and other database gaps. The uncertainty factors typically range from 1 to 10; 1, 3, and 10 are the values most commonly used. No absolute rules exist for application of the factors, and professional judgment is a large component of their use. Regarding derivation of EPA’s RfD for perchlorate, some have questioned the use of specific uncertainty factors, particularly the factor used to account for database uncertainties (see Chapter 5 for further discussion of uncertainty factors). Questions regarding the use of uncertainty factors and the other issues discussed above all played a role in determining the charge provided to this committee. COMMITTEE’S CHARGE AND APPROACH TO CHARGE The members of the NRC committee were selected for their expertise in pediatrics; endocrinology; pediatric endocrinology; thyroid endocrinology, physiology, and carcinogenesis; immunology; veterinary pathology; animal toxicology; neurotoxicology; developmental toxicology; physiologically based pharmacokinetic modeling; epidemiology; biostatistics; and risk assessment. The committee was asked to accomplish the following tasks: Evaluate the current state of the science regarding potential adverse effects of disruption of thyroid function in humans and laboratory animals at various stages of life. Specifically, evaluate whether science supports the model that predicts potential adverse neurodevelopmental and neoplastic effects from changes in thyroid hormone regulation that result from disrup-

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Health Implications of Perchlorate Ingestion tion of iodide uptake by the thyroid gland, and indicate the level of confidence in the model. Assess the levels at which chronic inhibition of iodide uptake may lead to adverse (not just adaptive) health effects in humans, especially sensitive populations. Consider the influence of iodide in the diet on the levels at which adverse effects would be observed, especially in sensitive populations, and indicate the degree of confidence in the proposed levels. Assess the levels at which changes in thyroid hormones may lead to adverse (not just adaptive) health effects in humans, especially sensitive populations, and indicate the level of confidence in those values. Evaluate the animal studies used to assess human health effects of ingestion of perchlorate with particular attention to key end points, including changes in brain morphometry, behavior, thyroid hormone concentrations, and thyroid histopathology. Indicate the level of confidence in the relevance of the adverse effects observed in the animal studies to human health, especially sensitive populations, and specifically address the validity of the model that extrapolates changes in brain morphometry in rats to adverse effects in the human population, especially sensitive populations. Indicate whether adverse effects, other than those associated with iodide uptake inhibition, may result from daily ingestion of perchlorate at low concentrations. On the basis of the above review, determine whether EPA's findings in its 2002 draft risk assessment, Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization, are consistent with current scientific evidence. Specifically, determine whether EPA considered all relevant literature (both supporting and nonsupporting), consistently critiqued that literature, and then used appropriate scientific studies to develop its health risk assessment. If deficiencies in EPA’s analysis are found, such as lack of consideration of a key study, provide suggestions as to how EPA might modify its assessment. Provide a range of values consistent with scientific evidence for percentage iodide uptake that would protect persons at various life stages and with varied thyroid status.2 On the basis of the scientific evidence, provide information that can be used to inform the selection of uncertainty factors used in the approximation of a safe lifetime perchlorate exposure for humans, especially sensitive populations. Finally, suggest specific scientific research that could reduce the uncertainty in the current understanding of human health effects associated 2   The committee interpreted this task as referring to iodide intake that would protect people at various life stages and with varied thyroid status.

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Health Implications of Perchlorate Ingestion with low-level perchlorate ingestion. Specifically, suggest research that could clarify safe levels of exposure of sensitive populations, and provide rough estimates of timeframe, costs, and potential to reduce overall uncertainty for the specific research studies suggested. To accomplish its task, the committee held five meetings from October 2003 to July 2004. Public sessions were held during the first, second, and fourth meetings, in which the committee heard presentations from representatives of the Office of Science and Technology Policy, EPA, DOD, DOE, NASA, the Food and Drug Administration, Congress, the Agency for Toxic Substances and Disease Registry, California EPA, and other interested parties, including industry and environmental groups (see Appendix C). In the second meeting, several noted scientists were invited to make presentations to the committee to answer questions raised in the first meeting. The committee reviewed (1) materials submitted by EPA, DOD, DOE, NASA, industry, and private individuals, (2) studies evaluated in EPA’s 2002 draft perchlorate risk assessment, (3) findings in EPA’s 2002 draft perchlorate risk assessment, and (4) information from publicly available scientific literature. Accordingly, the committee evaluated both published and unpublished data; however, it typically gave more weight in its deliberations to published reports. Unpublished data were considered only when the committee had sufficient information to evaluate the methods used to produce them. Overall, emphasis was given to studies with the soundest scientific methods to draw conclusions regarding effects of perchlorate exposure. For each proposed adverse health effect of perchlorate exposure, the committee evaluated all the evidence gathered. Conclusions were based on the following categories: (1) no evidence, (2) evidence is inadequate to accept or reject a causal relationship, (3) evidence favors rejection of a causal relationship, (4) evidence favors acceptance of a causal relationship, and (5) evidence establishes a causal relationship. Using that hierarchy where appropriate, the committee was able to reach conclusions regarding the potential adverse effects of perchlorate exposure. ORGANIZATION OF REPORT This report is divided into six chapters. Chapter 2 provides information on thyroid function in humans and possible effects of disruption of thyroid function in adults, neonates, and fetuses; it also discusses clinical studies in

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Health Implications of Perchlorate Ingestion which humans were exposed to perchlorate. Chapter 3 reviews the epidemiologic studies of occupational and environmental exposure to perchlorate, including strengths and weaknesses of the studies. Chapter 4 reviews animal toxicity studies with emphasis on studies of the effect of perchlorate on thyroid hormone production, thyroid histopathology, brain morphometry, neurobehavior, and thyroid tumors. Chapter 4 also addresses the possibility of effects of perchlorate exposure that are independent of inhibition of iodide uptake by the thyroid. Chapter 5 reviews the committee’s critique of EPA’s 2002 draft risk assessment, Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization. Research that could reduce uncertainty regarding health effects of perchlorate exposure is presented in Chapter 6. REFERENCES Bull, R.J., A.C. Chang, C.F. Cranor, R.C. Shank, and R. Trussell. 2004. Perchlorate in Drinking Water: A Science and Policy Review. Urban Water Research Center, University of California, Irvine, CA. [Online]. Available: http://www.urbanwater.uci.edu/UCI-UWRC_Perchlorate_wCorrection061404.pdf [accessed August 18, 2004] EPA (U.S. Environmental Protection Agency). 2001. Survey of Fertilizers and Related Materials for Perchlorate (ClO4): Final Report. EPA/600/R-01/049. Office of Research and Development, U.S. Environmental Protection Agency, Cincinnati, OH. [Online]. Available: http://www.epa.gov/ORD/NRMRL/Pubs/600/R01/047.pdf [accessed August 18, 2004]. EPA (U.S. Environmental Protection Agency). 2002a. Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization. External Review Draft. NCEA-1-0503. National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. EPA (U.S. Environmental Protection Agency). 2002b. Report on the Peer Review of the U.S. Environmental Protection Agency’s Draft External Review Document “Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization.” EPA/635/R-02/003. National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. [Online]. Available: http://www.epa.gov/ncea/pdfs/perchlorate/final_rpt.pdf [accessed August 18, 2004]. EPA (U.S. Environmental Protection Agency). 2004a. Unregulated Contaminant Monitoring Rule (UCMR) 1999. UCMR Data.. Office of Ground Water and Drinking Water, U.S. Environmental Protection Agency. [Online]. Available: http://www.epa.gov/safewater/ucmr.html [accessed June 2004]. EPA (U.S. Environmental Protection Agency). 2004b. Drinking Water Contami-

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Health Implications of Perchlorate Ingestion nant Candidate List. Office of Ground Water and Drinking Water, U.S. Environmental Protection Agency. [Online]. Available: http://www.epa.gov/safewater/ccl/cclfs.htm [accessed March 2004]. EPA (U.S. Environmental Protection Agency). 2004c. Revisions to the Unregulated Contaminant Monitoring Rule Fact Sheet. EPA 815-F-01-008. Office of Water, U.S. Environmental Protection Agency. [Online]. Available: http://www.epa.gov/safewater/standard/ucmr/ucmrfact.html [accessed March 2004]. EPA (U.S. Environmental Protection Agency). 2004d. Known Perchlorate Releases in the U.S. - September 23, 2004. Perchlorate Occurrences. Federal Facilities Restoration and Reuse Office, Office of Solid Waste and Emergency Response, U.S. Environmental Protection Agency [Online]. Available: http://www.epa.gov/fedfac/detection_with_dates09_23_04.xls [accessed Nov. 15, 2004]. FDA (Food and Drug Administration). 2004. Perchlorate: Questions and Answers. Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration. September 20, 2003. [Online]. Available: http://www.cfsan.fda.gov/~dms/clo4qa.html [accessed June 2004]. Gibbs, J.P. 2004. Chronic Environmental Exposure to Perchlorate in Drinking Water and Thyroid Function during Pregnancy and the Neonatal Period. Presentation at the Fourth Meeting on Assess the Health Implications of Perchlorate Ingestion, May 24, 2004, Woods Hole, MA. Kirk, A.B., E.E. Smith, K. Tain, T.A. Anderson, and P.K. Dasgupta. 2003. Perchlorate in milk. Environ. Sci. Technol. 37(21):4979-4981. Martino, E., L. Bartalena, F. Bogazzi, and L.E. Braverman. 2001. The effects of amiodarone on the thyroid. Endocr. Rev. 22(2):240-254. Meier, C.A., and A.G. Burger. 2000. Effects of drugs and other substances on thyroid hormone synthesis and metabolism. Pp. 265-280 in Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 8th Ed., L.E. Braverman, and R.D. Utiger, eds. New York: Lippincott Williams and Wilkins. Mendiratta, S.K., R.L. Dotson, and R.T. Brooker. 1996. Perchloric acid and perchlorates. Pp. 157-170 in Kirk-Othmer Encyclopedia of Chemical Technology, 4th Ed., Vol. 18, J.I. Kroschwitz, and M. Howe-Grant, eds. New York: John Wiley and Sons. RTI (Research Triangle Institute). 1999. Perchlorate Peer Review Workshop Report. EPA Contract Number 68-W98-085. Prepared for Office of Solid Waste, U.S. Environmental Protection Agency, Washington, DC, by Center for Environmental Analysis, Research Triangle Institute, Research Triangle Park, NC. Schwartz, H.L., M. Aschner, A.J. Elberger, J.C. Lind, F.R. Brush, M.K. Cowles, A.J. DeRoos, K.C. Donnelly, J.M. Hershman, R. Wilson, J.T. Lane, D.B. Bylund, D.W. Cragin, S.C. Lewis, J.D. Wilson, and R. Wilson. 2004. Perchlorate State of the Science Symposium 2003: Report of the Planning Committee and Reports of the Expert Review Panels. Reports compiled from the

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Health Implications of Perchlorate Ingestion Perchlorate State of the Science Symposium, September 29-October 1, 2003, Omaha, NE. Sharp, R. 2004. Rocket Fuel Contamination in California Milk. Environmental Working Group. [Online]. Available: http://www.ewg.org/reports/rocketmilk/ [accessed August 31, 2004]. Sharp, R., and S. Lunder. 2003. Suspect Salads: Toxic Rocket Fuel Found in Samples of Winter Lettuce, Part 1. Environmental Working Group, Washington, DC. [Online]. Available: http://www.ewg.org/reports/suspectsalads/part1.php [accessed August 18, 2004]. Susarla, S., T.W. Collette, A.W. Garrison, N.L. Wolfe, and S.C. McCutcheon. 1999. Perchlorate identification in fertilizers. Environ. Sci. Technol. 33(19): 3469-3472. Susarla, S., T.W. Collette, A.W. Garrison, N.L. Wolfe, and S.C. McCutcheon. 2000. Perchlorate identification in fertilizers. Environ. Sci. Technol. 34(1):224. Takata, K. 1985. Request for CDC Assistance Regarding Potential Health Effects of Perchlorate Contamination at the San Gabriel Valley Superfund Sites. Memorandum to Don Hawkins, CDC Regional Representative (T-1), from Keith Tanaka, Chief, Superfund Programs Branch (T-4), U.S. Environmental Protection Agency, Francisco, CA. December 23, 1985. TRC (TRC Environmental Corporation). 1998. Chemical Fertilizer as a Potential Source of Perchlorate. Prepared for Lockheed Martin Corp., Burbank, CA, by TRC, Irvine, CA. November 1998.