5
Risk Characterization of Perchlorate

THE committee was charged with reviewing the relevant data on the health effects of perchlorate and the findings in the 2002 U.S. Environmental Protection Agency (EPA) report Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization. Chapters 2, 3, and 4 of the present report contain the committee’s review of the key studies, including those discussed in EPA’s draft risk assessment, and the committee’s findings will not be repeated here. This chapter provides the committee’s assessment of the mode-of-action model of perchlorate toxicity, the definition of adverse effect, the point of departure, and the use of uncertainty factors to derive a reference dose (RfD) for daily oral exposures to perchlorate.

MODE-OF-ACTION MODEL

EPA’s proposed mode-of-action model of perchlorate toxicity is provided in Chapter 1 (see Figure 1-2). EPA’s model represents a continuum of possible health effects of perchlorate exposure and predicts that perchlorate exposure leads to inhibition of iodide uptake by the thyroid, which causes decreases in thyroxine (T4) and triiodothyronine (T3) production and then increases in thyrotropin (thyroid-stimulating hormone, TSH) secretion. At that point, EPA’s model diverges into two pathways, one labeled as children’s health risk and the other labeled as human health risk. EPA’s model predicts that the changes in thyroid hormone production and increases in TSH production could lead to altered development and ultimately birth defects in children and to thyroid hyperplasia and ultimately thyroid tumors in adults.



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Health Implications of Perchlorate Ingestion 5 Risk Characterization of Perchlorate THE committee was charged with reviewing the relevant data on the health effects of perchlorate and the findings in the 2002 U.S. Environmental Protection Agency (EPA) report Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization. Chapters 2, 3, and 4 of the present report contain the committee’s review of the key studies, including those discussed in EPA’s draft risk assessment, and the committee’s findings will not be repeated here. This chapter provides the committee’s assessment of the mode-of-action model of perchlorate toxicity, the definition of adverse effect, the point of departure, and the use of uncertainty factors to derive a reference dose (RfD) for daily oral exposures to perchlorate. MODE-OF-ACTION MODEL EPA’s proposed mode-of-action model of perchlorate toxicity is provided in Chapter 1 (see Figure 1-2). EPA’s model represents a continuum of possible health effects of perchlorate exposure and predicts that perchlorate exposure leads to inhibition of iodide uptake by the thyroid, which causes decreases in thyroxine (T4) and triiodothyronine (T3) production and then increases in thyrotropin (thyroid-stimulating hormone, TSH) secretion. At that point, EPA’s model diverges into two pathways, one labeled as children’s health risk and the other labeled as human health risk. EPA’s model predicts that the changes in thyroid hormone production and increases in TSH production could lead to altered development and ultimately birth defects in children and to thyroid hyperplasia and ultimately thyroid tumors in adults.

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Health Implications of Perchlorate Ingestion The committee thinks that EPA’s mode-of-action model adequately represents the possible early sequence of events after perchlorate exposure, but it does not think that the model provides an accurate representation of events that follow changes in thyroid hormone and TSH production. Specifically, the development of thyroid tumors as an ultimate result of perchlorate exposure is an unlikely outcome in humans. As discussed in Chapter 4, the committee is not surprised that rats treated with moderate or high doses of perchlorate would develop thyroid follicular-cell tumors. Rats are sensitive to the development of thyroid tumors because their thyroid function is easily disrupted. Humans are much less susceptible than rats to disruption of thyroid function and therefore are not likely to develop thyroid tumors as a result of perchlorate exposure. The committee concludes that the most reasonable pathway of events after changes in thyroid hormone and TSH secretion would be thyroid hypertrophy or hyperplasia, possibly leading to hypothyroidism. At that point, the pathway would diverge to two potential outcomes: (1) metabolic sequelae, such as decreased metabolic rate and slowing of the function of many organ systems, occurring at any age, and (2) abnormal growth and development in fetuses and children. The committee’s suggested mode-of-action model is provided in Figure 5-1. The committee emphasizes that inhibition of iodide uptake by the thyroid has been the only consistently documented effect of perchlorate exposure in humans. The continuum of possible effects of iodide-uptake inhibition caused by perchlorate exposure is only proposed and has not been demonstrated in humans exposed to perchlorate (with the exception that in patients with hyperthyroidism doses of 200 mg daily or higher may reduce thyroid secretion). More important, the outcomes at the end of the continuum are not inevitable consequences of perchlorate exposure. As discussed in Chapter 2, the body can compensate for decreases in T4 and T3 production unless there is a severe pre-existing thyroid disease. Specifically, the resulting increase in TSH secretion can return T4 and T3 production to normal without causing adverse effects on human health. ADVERSE EFFECT AND KEY EVENT EPA defines changes in serum thyroid hormone and TSH concentrations as adverse effects. The effects that would be downstream of those changes in its mode-of-action model would also be considered adverse effects. EPA states that the neurodevelopmental and neoplastic outcomes “confirm that the perturbation of the thyroid hormone economy should be

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Health Implications of Perchlorate Ingestion FIGURE 5-1 Committee’s suggested mode-of-action model of perchlorate toxicity in humans. Solid arrows represent outcomes that have been observed in humans during perchlorate exposure. Dashed arrows represent outcomes that have not been clearly demonstrated in humans exposed to perchlorate but that are biologically possible in the absence of adequate compensation. The thyroid response to increased serum TSH and an independent increase in thyroid iodide uptake would raise T3 and T4 production to normal and therefore usually prevent the later steps from occurring. viewed as adverse” (see EPA 2002a, p. 7-10). The committee, however, does not view transient changes in serum thyroid hormone and TSH concentrations as adverse health effects; it considers them to be biochemical changes that could precede adverse effects. Given its mode-of-action model, the committee concludes that hypothyroidism is the first adverse effect in the mode-of-action model (see Figure 5-2). Any effects downstream of hypothyroidism clearly would be adverse. EPA developed its risk assessment by using data on effects that it views as adverse. However, the committee does not think that hypothyroidism—the effect that the committee views as adverse—should be used as the basis of a perchlorate risk assessment. It recommends that the key biochemical event be used as the basis of the perchlorate risk assessment. EPA and the committee agree that the key event in the continuum of possible effects of perchlorate exposure is the inhibition of iodide uptake by the thyroid. It is the obligatory initial step in the continuum of possible effects of perchlorate exposure, and thyroid uptake of iodide (as radioiodide) can be measured easily and reliably. Inhibition of iodide uptake by the thyroid clearly is not an adverse effect; however, if it does not occur, there is no progression to

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Health Implications of Perchlorate Ingestion FIGURE 5-2 Committee’s suggested mode-of-action model for perchlorate toxicity in humans indicating first adverse effect in the continuum. adverse health effects (see Figure 5-2). The committee views its recommendation to use inhibition of iodide uptake by the thyroid as the basis of the perchlorate risk assessment to be the most health-protective and scientifically valid approach. POINT OF DEPARTURE A primary purpose of EPA’s perchlorate risk assessment was to calculate an oral RfD. EPA (2002b) currently defines the RfD as an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without risk of deleterious effects during a lifetime. It can be derived from a NOAEL [no-observed-adverse-effect level], LOAEL [lowest-observed-adverse-effect level], or BMD [benchmark dose], with UFs [uncertainty factors] generally applied to reflect limitations of the data used. The RfD definition uses several terms that should be defined. The NOAEL is the highest dose at which no adverse health effects have been

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Health Implications of Perchlorate Ingestion observed, and the LOAEL is the lowest dose at which adverse health effects have been observed (EPA 2000). The NOAEL is often confused with the no-observed-effect level (NOEL), and a clear distinction should be made between the two terms. The NOEL is the highest dose “at which there are no statistically or biologically significant increases in the frequency or severity of any effect between the exposed population and its appropriate control” (ITER 2004). Thus, a NOAEL is based on an adverse effect, and a NOEL is based on a nonadverse effect. Traditionally, NOAELs and LOAELs have been used to derive RfDs (EPA 2004). More recently, BMDs (or their lower confidence limits) calculated from mathematical modeling of dose-response data have been used to derive RfDs. Use of the BMD method has increased because it is seen as a more quantitative approach that accounts for variability in observed responses over an entire dose range and incorporates uncertainty due to characteristics of study design (EPA 2000). However, the vast majority of RfDs are based on NOAELs and LOAELs from the literature (EPA 2004). The first step in deriving an RfD is a comprehensive review of all relevant human and animal data (EPA 2004). Traditionally, a critical effect and a critical study are then identified that serve as the point of departure for the risk assessment. Human or animal data can be used, but human data are preferred when sufficient data are available (EPA 2002b). Typically, a NOAEL or LOAEL is identified from the critical study on which the RfD can be based. As noted above, mathematical modeling of the dose-response data in the study can also provide a BMD on which the RfD can be based. As a final step in the RfD process, uncertainty factors are applied to the NOAEL, LOAEL, or BMD to extrapolate from the study population to the general human population, which includes sensitive groups. The individual uncertainty factors used to derive an RfD are discussed in the following sections. For the perchlorate risk assessment, EPA based its point of departure on reported changes in brain morphometry, thyroid histopathology, and serum thyroid hormone concentrations after oral administration of perchlorate to rats. For several reasons, the committee does not think that the animal data or the outcomes selected by EPA should be used as the basis of the perchlorate risk assessment. As discussed in Chapter 4, the rat is a good quantitative model for assessing inhibition of iodide uptake by the thyroid caused by perchlorate exposure, but it is only a good qualitative model for the effects of that inhibition. Because rats are more sensitive to the effects of inhibition of iodide uptake, the dose-response relationships observed in

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Health Implications of Perchlorate Ingestion rat studies are not good estimates of the dose-response relationships in humans. The committee considered several of the animal studies on which EPA based its point of departure to be flawed in their design and execution. Conclusions based on those studies, particularly the neurodevelopmental studies, were not supported by the results of the studies (see Chapter 4 for a discussion of the animal studies). The committee also does not think that changes in brain morphometry, thyroid histopathology, and serum thyroid hormone concentrations should be used as the point of departure for the perchlorate risk assessment. Rather, the committee recommends that inhibition of iodide uptake by the thyroid, which is the key biochemical event and not an adverse effect, should be used as the basis of the risk assessment. Inhibition of iodide uptake is a more reliable and valid measure, it has been unequivocally demonstrated in humans exposed to perchlorate, and it is the key event that precedes all thyroid-mediated effects of perchlorate exposure. The committee emphasizes that its recommendations differ from the traditional approach to deriving an RfD. The committee is recommending using a nonadverse effect rather than an adverse effect as the point of departure for the perchlorate risk assessment. Using a nonadverse effect that precedes the adverse effects is a conservative, health-protective approach to the perchlorate risk assessment, and the committee’s recommendations for uncertainty factors reflect the conservatism of the approach. The committee reviewed the human and animal data and found that the human data provided a more reliable point of departure for the risk assessment than the animal data (see Chapters 2, 3, and 4). The committee recommends using clinical data collected in a controlled setting with the relevant route of exposure to derive the RfD. Although the data from epidemiologic studies of the general population provide some information on possible effects of perchlorate exposure, those studies are ecologic and inherently limited with respect to establishing causality and serving as a basis of quantitative risk assessment. Furthermore, those studies typically focused on changes in serum thyroid hormone and TSH concentrations or clinical manifestations of the changes, not on inhibition of iodide uptake by the thyroid. Therefore, the committee is not recommending using the available epidemiologic studies to derive the point of departure for the risk assessment. The committee recommends using the data from Greer et al. (2002) for derivation of the RfD. As discussed in Chapter 2, Greer et al. (2002) administered perchlorate at 0.007-0.5 mg/kg per day for 14 days to groups of healthy men and women. Inhibition of radioiodide uptake by the thyroid

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Health Implications of Perchlorate Ingestion was measured 1 day before perchlorate administration, on days 2 and 14 of perchlorate administration, and 15 days after cessation of perchlorate administration, except that uptake was not measured on day 2 in the lowest-dose group. Serum thyroid hormones and TSH were measured before, during, and after perchlorate administration. The investigators found that inhibition of 24-hour radioiodide uptake by the thyroid ranged from 1.8% in the lowest-dose group to 67.1% in the highest-dose group. The inhibition was not significantly different from baseline in the lowest-dose group (0.007 mg/kg per day) but was significantly different from baseline in all other dose groups (0.02, 0.1, and 0.5 mg/kg per day). As discussed in Chapter 2, the very small decrease (1.8%) in thyroid radioiodide uptake in the lowest dose group was well within the variation of repeated measurements in normal subjects. Serum thyroid hormone concentrations did not change significantly in any group. Serum TSH concentrations decreased slightly and transiently in the highest-dose group—a change in the direction opposite what would be expected had thyroid hormone secretion decreased. The study identified a NOEL for inhibition of iodide uptake by the thyroid at 0.007 mg/kg per day, which is consistent with findings of similar studies in humans (Lawrence et al. 2000, 2001; Braverman et al. 2004), as described in Chapter 2. The committee notes that the NOEL identified by Greer et al. (2002) (0.007 mg/kg per day) is lower than all the LOAELs and almost all the NOAELs identified by EPA in studies using rats, the most sensitive species studied (see Figure 5-3). Human equivalent values based on the animal data were all above 0.007 mg/kg per day (EPA 2003). As part of its deliberations on the point of departure, the committee reviewed the BMD analyses conducted by EPA (2003), the California Environmental Protection Agency (CalEPA 2004), and Crump and Goodman (2003) on the data from Greer et al. (2002). Overall, those analyses used different models, approaches, parameters, response levels, and input data, so comparison of the results of the analyses is difficult. Although the committee recognizes that BMD modeling can be an improvement over the use of the NOAEL or LOAEL as a point of departure, there appears to be no consensus on the criteria for choosing one BMD approach over another. Because no clear justifications were provided with the individual analyses of the Greer et al. (2002) data that allowed selection of one set of results over another, the committee concluded that using the NOEL (0.007 mg/kg per day) for iodide uptake inhibition from Greer et al. (2002) as the point of departure provides a reasonable and transparent approach to the perchlorate risk assessment. As noted above, the NOEL value from Greer et al. (2002) is consistent with other clinical studies that have investigated iodide

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Health Implications of Perchlorate Ingestion FIGURE 5-3 EPA's summary of NOAELs and LOAELs for various health effects in rat studies. Numbers indicate the following sources: 1, Argus Research Laboratories (2001), Consultants in Veterinary Pathology (2003); 2, Springborn Research Laboratories (1998); 3, Springborn Research Laboratories (1998); 4, Argus Research Laboratories (1998); 5, Argus Research Laboratories (1999); 6, Bekkedal et al. (2000); 7, Argus Research Laboratories (2000); 8, BRT-Burleson Research Technologies (2000a,b,c). Adapted from EPA 2003, p. 7-30. uptake inhibition by perchlorate (Lawrence et al. 2000, 2001; Braverman et al. 2004). That the NOEL value from Greer et al. (2002) is a health-protective and conservative point of departure is supported by the results of a 4-week study of higher doses in normal subjects (Brabant et al. 1992; see Chapter 2) and extensive human and animal data that demonstrate that there will be no progression to adverse effects if no inhibition of iodide uptake occurs (see Figure 5-2). As discussed in Chapter 2, a sustained exposure at more than 0.4 mg/kg per day would most likely be required to cause a

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Health Implications of Perchlorate Ingestion sufficient decline in iodide uptake and thyroid hormone production to result in adverse health effects in normal adults. That estimate is based on clinical studies and studies of long-term treatment of patients who had hyperthyroidism. Finally, the occupational and environmental studies described in Chapter 3 do not provide any evidence that would raise concerns about using the NOEL from Greer et al. (2002) as the point of departure for the perchlorate risk assessment. UNCERTAINTY FACTORS Five uncertainty factors are typically considered in calculating an RfD. Those factors account for interspecies differences, intraspecies differences, failure to establish a NOAEL, lack of chronic data, and other database gaps. In its draft risk assessment, EPA proposed a composite uncertainty factor of 300 to apply to its point of departure of 0.01 mg/kg per day, which was based on changes reported in brain morphometry, thyroid histopathology, and serum thyroid hormone concentrations in rats given perchlorate orally. Factors for intraspecies variability, use of a LOAEL, lack of chronic data, and other database gaps contributed to EPA’s composite factor. The committee cannot comment on the uncertainty factors that EPA selected for its primary analysis based on animal data, because the factors are related to the point of departure, and the committee is recommending a point of departure based on human data. As an ancillary analysis, EPA did derive an RfD based on data from the Greer et al. (2002) study in its draft risk assessment (EPA 2002a). In the following subsections, the committee provides its recommendations regarding the five uncertainty factors on the basis of its recommended point of departure (the NOEL from Greer et al. [2002] for inhibition of iodide uptake by the thyroid) and provides comments on EPA’s selection of uncertainty factors used in its ancillary analysis. The committee recognizes that EPA did derive an RfD based on BMD modeling of the Greer et al. (2002) data in its comment-response document (EPA 2003), but using that approach would affect the selection of uncertainty factors. Therefore, the most appropriate comparisons are with the original analysis presented in EPA’s draft risk assessment (EPA 2002a). Interspecies Factor When animal data are used as the basis of the point of departure, an adjustment is typically made for the possibility that humans are more

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Health Implications of Perchlorate Ingestion sensitive than the selected test species. In the absence of data on the relative sensitivity of humans and animals, a default uncertainty factor of 10 is applied to the point of departure. The factor is often adjusted if data are available. Because the committee’s point of departure is based on the human data presented in Greer et al. (2002), no adjustment for interspecies extrapolation is needed. Therefore, the interspecies uncertainty factor should be 1. Intraspecies Factor There can be variability in responses among humans. The intraspecies uncertainty factor accounts for that variability and is intended to protect populations more sensitive than the population tested. In the absence of data on the range of sensitivity among humans, a default uncertainty factor of 10 is typically applied. The factor could be set at 1 if data indicate that sensitive populations do not vary substantially from those tested. For the perchlorate risk assessment, potentially the most sensitive population is fetuses, particularly those of pregnant women who have hypothyroidism or iodide deficiency. In pregnant women who have undiagnosed hypothyroidism, perchlorate exposure could exacerbate the hypothyroidism by inhibiting iodide uptake by the thyroid. The National Health and Nutrition Examination Survey (NHANES III, 1991-1994; NCHS 1996) found that 4.6% of the U.S. population 12 years old and older had hypothyroidism (0.3% overt hypothyroidism and 4.3% subclinical hypothyroidism), in most cases not previously known (Hollowell et al. 2002). Similarly, in pregnant women who have iodide deficiency, the deficiency could be exacerbated by perchlorate exposure. In the NHANES III cohort, daily iodide intake was less than 50 µg in 15% of women of childbearing age and 7% of pregnant women (Hollowell et al. 1998). However, serum thyroid hormone and TSH concentrations of those who had a daily iodide intake less than 50 µg were similar to those of people who had a higher daily iodide intake (Hollowell et al. 2002; Soldin et al. in press). Thus, the data indicate that iodide deficiency in the U.S. population is mild, if it exists, so perchlorate exposure most likely would not exacerbate it. Nonetheless, the risk assessment should protect pregnant women who might have hypothyroidism or iodide deficiency. Because Greer et al. (2002) studied healthy men and women, an intraspecies uncertainty factor greater than 1 is appropriate to provide protection for sensitive populations. Although EPA recommended a reduction in the default uncertainty factor from 10 to 3 for intrahuman variability in its draft

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Health Implications of Perchlorate Ingestion risk assessment, the committee recommends use of a full factor of 10 to protect the most sensitive population—the fetuses of pregnant women who might have hypothyroidism or iodide deficiency. The committee views its recommendation as conservative and health-protective, especially given that the point of departure is based on a nonadverse effect that precedes the adverse effect in the continuum of possible effects of perchlorate exposure (see Figure 5-2). LOAEL-to-NOAEL Extrapolation Factor The risk assessment is intended to estimate an exposure at which no adverse effect will occur in humans. Historically, the RfD has been extrapolated from a NOAEL in long-term animal studies and, more recently, derived from BMD modeling. However, many studies fail to establish a NOAEL, and BMD modeling is not always possible or appropriate for some datasets. Therefore, a LOAEL must be used in the analysis instead of a NOAEL. The LOAEL-to-NOAEL uncertainty factor is designed to reduce the higher LOAEL to the lower NOAEL and is often 3 or 10. As discussed, the committee is recommending that a NOEL for a nonadverse effect (inhibition of iodide uptake by the thyroid) be used as the basis for the perchlorate risk assessment. That recommendation is considered to be a more conservative and health-protective approach for the perchlorate risk assessment than traditional risk assessments that use a point of departure based on an adverse effect. In its 2002 draft risk assessment (EPA 2002a), EPA indicated that the NOEL identified in the Greer et al. (2002) study was a minimal LOAEL and applied a factor of 3 in its ancillary analysis. The committee disagrees with EPA’s analysis. Again, inhibition of iodide uptake by the thyroid is not an adverse effect, and the small degree of inhibition (1.8%) observed in the subjects given 0.007 mg/kg per day was not statistically different from the baseline value. Accordingly, the lowest dose (0.007 mg/kg per day) was recognized as a NOEL by the committee. Therefore, the LOAEL-to-NOAEL uncertainty factor should be set at 1. Subchronic-to-Chronic Extrapolation Factor The RfD is intended to protect individuals from lifetime exposures. Therefore, the data must address the potential of long-term exposure to cause adverse effects. If only data on short-term exposures are available,

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Health Implications of Perchlorate Ingestion a subchronic-to-chronic uncertainty factor of 10 is often used in the derivation of an RfD. Long-term animal toxicology studies are often the basis of the risk assessment, in which case an uncertainty factor of 1 is appropriate. The committee recommends that the NOEL for inhibition of iodide uptake by the thyroid from a human study that involved a 14-day administration of perchlorate be used as the point of departure for the risk assessment. If that nonadverse biochemical event (see Figure 5-2) is used to derive the RfD, chronic exposure will have no greater effect than that resulting from short-term exposure. In fact, it may well have less effect because of the capacity of the pituitary-thyroid system to compensate for iodide deficiency by increasing iodide uptake. If some inhibition of iodide uptake by the thyroid did occur at the minimal dose proposed for the point of departure, data from humans indicate that longer exposures are not likely to result in a greater or more severe response. According to preliminary data presented in an abstract, administration of perchlorate to normal subjects for 6 months at 0.007 and 0.04 mg/kg per day had no effect on thyroid function (Braverman et al. 2004). Furthermore, occupational data suggest that long-term exposure of workers to perchlorate at up to 0.5 mg/kg per day does not have adverse effects on thyroid function (see Chapter 3). Perchlorate also does not accumulate in the body but is rapidly cleared via excretion in the urine even during chronic exposure. In its ancillary analysis (EPA 2002a), EPA recommended a factor of 3 for duration of exposure, given that there are no chronic studies in the database. As indicated above, the committee does not agree with EPA’s rationale. First, if inhibition of iodide uptake by the thyroid is duration-dependent, the effect should decrease rather than increase with time, because compensation would increase the activity of the sodium-iodide symporter and therefore increase iodide transport into the thyroid. Second, concerns that the duration of Greer et al. (2002) is not sufficient to observe the effects of changes in thyroid function are not valid, because the point of departure is selected to prevent those changes. If inhibition of iodide uptake by the thyroid does not occur, there will be no changes in thyroid function in the short or long term. Therefore, the committee recommends that a subchronic-to-chronic uncertainty factor of 1 be used in the risk assessment, with the understanding that the committee’s recommended point of departure (inhibition of iodide uptake by the thyroid) is also used. Adequacy-of-Database Factor The adequacy of the database is typically described in terms of a

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Health Implications of Perchlorate Ingestion specific set of animal toxicology studies. For example, chronic toxicity, reproductive toxicity, developmental toxicity, and carcinogenicity studies are typically required to have the highest confidence in a database of studies. However, mode-of-action studies and relevant human studies can eliminate the need for various animal studies. If critical studies have not been conducted, an uncertainty factor is often used to account for this deficiency. In its ancillary analysis, EPA recommended a factor of 3 for database deficiencies. The committee does not agree and concludes that the database is adequate for deriving an RfD on the basis of inhibition of iodide uptake by the thyroid in humans. First, the database contains both human and animal data on that end point. Second, there is no evidence that perchlorate exposure has effects that do not result from inhibition of iodide uptake by the thyroid. Toxicology studies designed to identify the most sensitive effect of perchlorate exposure have indicated that the thyroid is the primary target of perchlorate exposure in rats, which is the most sensitive species studied (see Chapter 4). There is also no evidence that perchlorate administration to animals or humans causes systemic effects that are not mediated by the thyroid, with the exception of the toxic effects of very high doses given to patients with hyperthyroidism many years ago. Those adverse effects have not been described in any of the more recent studies in which lower doses of perchlorate were given to patients with hyperthyroidism for as long as 2 years. Finally, the absence of high-quality animal studies on outcomes that are downstream of iodide uptake inhibition, such as neurodevelopmental studies, is not relevant. Selection of the point of departure is designed to prevent the first step in the mode-of-action continuum, and studies on downstream events are not necessary. Therefore, the committee recommends that the database-adequacy uncertainty factor be set at 1, with the understanding that the committee’s recommended point of departure is used to derive the RfD.1 1   One committee member thought that the factor for database uncertainty should be greater than 1 and provided the following rationale: The RfD is derived from a study in which a group of only seven healthy adults was given 0.007 mg/kg of perchlorate daily for 14 days (Greer et al. 2002). Although two other studies had similar results, the total number of subjects is still small. In addition to the small number of subjects, no chronic exposure studies have been published. An uncertainty factor of 3 could account for the uncertainty surrounding the small number of subjects and the absence of a long-term study.

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Health Implications of Perchlorate Ingestion SUMMARY The committee concludes that EPA’s mode-of-action model of perchlorate toxicity does not provide an accurate representation of events that follow changes in thyroid hormone and TSH production. The committee finds that a more realistic representation of effects of changes in serum thyroid hormone and TSH concentrations would be hypertrophy or hyperplasia of the thyroid, which might lead eventually to hypothyroidism. If perchlorate exposure did result in hypothyroidism, possible outcomes would be metabolic sequelae at any age and abnormal growth and development in fetuses or children. The committee notes that effects downstream of inhibition of iodide uptake by the thyroid have not been clearly demonstrated in any human population exposed to perchlorate, even at doses as high as 0.5 mg/kg per day. The committee also differs with EPA regarding the definition of adverse effects associated with perchlorate exposure. The committee does not think that transient changes in serum thyroid hormone or TSH concentrations are necessarily adverse effects. The committee concludes that the first adverse health effect that could result from perchlorate exposure in the proposed continuum of effects would be hypothyroidism. However, hypothyroidism should not be used as the basis of the risk assessment. The committee recommends that inhibition of iodide uptake by the     The other committee members provided the following response: Although the committee acknowledges that the low-dose group (0.007 mg/kg per day) in Greer et al. (2002) had only seven subjects, the study examined the effects of four doses in a total of 37 subjects. In addition to the Greer et al. (2002) study, there are four other studies in which healthy adults were given perchlorate. The results of all the studies are remarkably similar (see Chapter 2, pp. 65-67). In addition to those studies, the studies of long-term treatment of hyperthyroidism and the studies of occupational and environmental exposure add confidence to the overall database. The issue concerning the absence of a long-term study is discussed in the section Subchronic-to-Chronic Extrapolation Factor in Chapter 5. Briefly, the key is recognizing that the committee is recommending that the RfD be based on inhibition of iodide uptake by the thyroid, a non-adverse biochemical event that precedes any adverse effects in the mode-of-action model. If that effect is used to derive the RfD, chronic exposure will have no greater effect than that resulting from short-term exposure, and in fact, it may well have less effect because of the capacity of the pituitary-thyroid system to compensate for iodide deficiency by increasing iodide uptake (see Chapter 5, p. 175).

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Health Implications of Perchlorate Ingestion thyroid, a nonadverse effect, be used for the point of departure in the perchlorate risk assessment. Using that biochemical event provides a conservative, health-protective approach to the risk assessment. If that event does not occur, all other proposed effects of perchlorate exposure would be avoided. Greer et al. (2002) provides a human dataset that can be used to derive the RfD, which is consistent with similar clinical studies. The committee recommends that the NOEL for inhibition of iodide uptake in that study, 0.007 mg/kg per day, be used as the point of departure for the risk assessment. If the committee’s recommendation is used as the point of departure, it recommends using a total uncertainty factor of 10. A full factor of 10 should be used for the intraspecies factor to protect the most sensitive population—the fetuses of pregnant women who might have hypothyroidism or iodide deficiency. No additional factors are needed for duration or database uncertainties. The database is sufficient, given the point of departure selected—one based on inhibition of iodide uptake by the thyroid. The committee recognizes that its recommendations would lead to an RfD of 0.0007 mg/kg per day.2 That value is supported by other clinical studies, occupational and environmental epidemiologic studies, and studies of long-term perchlorate administration to patients with hyperthyroidism. The committee concludes that an RfD of 0.0007 mg/kg per day should protect the health of even the most sensitive populations. The committee acknowledges that the RfD may need to be adjusted upward or downward on the basis of future research, such as that suggested in this report (see Chapter 6). REFERENCES Argus Research Laboratories, Inc. 1998. A Neurobehavioral Developmental Study of Ammonium Perchlorate Administered Orally in Drinking Water to Rats. ARGUS 1613-002. Argus Research Laboratories, Inc., Horsham, PA. [See also York, R.G., J. Barnett, W.R. Brown, R.H. Garman, D.R. Mattie, and D. Dodd. 2004. A rat neurodevelopmental evaluation of offspring, including evaluation of adult and neonatal thyroid, from mothers treated with ammonium perchlorate in drinking water. Int. J. Toxicol. 23(3):191-214.] Argus Research Laboratories, Inc. 1999. Oral (Drinking Water) Two-Generation (One Litter Per Generation) Reproduction Study of Ammonium Perchlorate in 2   For comparison, EPA’s draft RfD in its 2002 draft risk assessment was 0.00003 mg/kg per day.

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Health Implications of Perchlorate Ingestion Rats. ARGUS 1416-001. Argus Research Laboratories, Inc., Horsham, PA. Argus Research Laboratories, Inc. 2000. Oral (Drinking Water) Developmental Toxicity Study of Ammonium Perchlorate in Rats. ARGUS 1416-003D. Argus Research Laboratories, Inc., Horsham, PA. Argus Research Laboratories, Inc. 2001. Hormone, Thyroid and Neurohistological Effects of Oral (Drinking Water) Exposure to Ammonium Perchlorate in Pregnant and Lactating Rats and in Fetuses and Nursing Pups Exposed to Ammonium Perchlorate During Gestation or Via Maternal Milk. ARGUS 1416-003. Argus Research Laboratories, Inc., Horsham, PA. Bekkedal, M.Y.V., T. Carpenter, J. Smith, C. Ademujohn, D. Maken, and D.R. Mattie. 2000. A Neurodevelopmental Study of Oral Ammonium Perchlorate Exposure on the Motor Activity of Pre-Weanling Rat Pups. Report No. TOXDET-00-03. Neurobehavioral Effects Laboratory, Naval Health Research Center Detachment (Toxicology), Wright-Patterson Air Force Base, OH. Brabant, G., P. Bergmann, C.M. Kirsch, J. Kohrle, R.D. Hesch, and von zur Muhlen. 1992. Early adaptation of thyrotropin and thyroglobulin secretion to experimentally decreased iodide supply in man. Metabolism 41(10):1093-1096. 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. BRT-Burleson Research Technologies, Inc. 2000a. Ammonium Perchlorate: Effect on Immune Function. Quality Assurance Audit: Study No. BRT 19990524—Plaque-Forming Cell (PFC) Assay; Study No. BRT 19990525—Local Lymph Node Assay (LLNA) in Mice. BRT-Burleson Research Technologies, Inc., Raleigh, NC. June 30, 2000. BRT-Burleson Research Technologies, Inc. 2000b. Addendum to Study Report: Ammonium Perchlorate: Effect on Immune Function. BRT 19990524 Study Protocol Plaque-Forming Cell (PFC) Assay; BRT 19990525 Study Protocol Local Lymph Node Assay (LLNA) in Mice. BRT-Burleson Research Technologies, Inc., Raleigh, NC. August 31, 2000 BRT-Burleson Research Technologies, Inc. 2000c. Ammonium Perchlorate: Effect on Immune Function. Study Report. BRT 19990524 Study Protocol Plaque-Forming Cell (PFC) Assay; BRT 19990525 Study Protocol Local Lymph Node Assay (LLNA) in Mice. BRT-Burleson Research Technologies, Inc., Raleigh, NC. CalEPA (California Environmental Protection Agency). 2004. Public Health Goal for Chemicals in Drinking Water, Perchlorate. Office of Environmental Health Hazard Assessment, California Environmental Protection Agency. [Online]. Available: http://www.oehha.ca.gov/water/phg/pdf/finalperchlorate31204.pdf [accessed August 25, 2004]. Consultants in Veterinary Pathology, Inc. 2003. Hormone, Thyroid and Neurohistological Effects of Oral (Drinking Water) Exposure to Ammonium Perchlorate in Pregnant and Lactating Rats and in Fetuses and Nursing Pups Exposed to Ammonium Perchlorate During Gestation or Via Maternal Milk. Task One—

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