Appendix E
Physiologically Based Pharmacokinetic Modeling

AS discussed in Chapter 4, physiologically based pharmacokinetic (PBPK) modeling is one of the methods of choice for determining human equivalent exposures and adjusting default uncertainty factors associated with the derivation of reference doses (RfDs) and reference concentrations (RfCs) for lifetime human exposures from animal studies (EPA 2002a). Thus, the U.S. Environmental Protection Agency (EPA) relied on a series of PBPK models developed by the Department of Defense (DOD) for perchlorate to facilitate interspecies extrapolations in its draft risk assessment (EPA 2002b,c). The PBPK models were initially developed to describe the disposition (absorption, distribution, metabolism, and elimination) of perchlorate in adult rats (Fisher et al. 2000). As data became available and perchlorate-induced effects observed in animal studies and humans were shown to be mediated by interactions with iodide at the sodium-iodide symporter (NIS) in thyroid tissues, the initial model was expanded to include the disposition of iodide in the body and the inhibition of iodide uptake at the NIS in pregnant rats and fetuses, lactating rats and pups, and adult humans to address dose-response issues associated with potentially sensitive populations (Clewell et al. 2001, 2003a,b; Merrill 2001b, Merrill et al. 2003).

The purpose of the models was to facilitate extrapolation of internal, target-tissue doses from animals to humans, of high to low dose, and across routes of exposure in human health risk assessments. However, the challenges associated with developing quantitative descriptions of the complex interactions and feedback mechanisms within the hypothalamic-pituitary-thyroid (HPT) axis prevented the development of a model that could describe the dynamic interactions between the inhibition of iodide transport



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Health Implications of Perchlorate Ingestion Appendix E Physiologically Based Pharmacokinetic Modeling AS discussed in Chapter 4, physiologically based pharmacokinetic (PBPK) modeling is one of the methods of choice for determining human equivalent exposures and adjusting default uncertainty factors associated with the derivation of reference doses (RfDs) and reference concentrations (RfCs) for lifetime human exposures from animal studies (EPA 2002a). Thus, the U.S. Environmental Protection Agency (EPA) relied on a series of PBPK models developed by the Department of Defense (DOD) for perchlorate to facilitate interspecies extrapolations in its draft risk assessment (EPA 2002b,c). The PBPK models were initially developed to describe the disposition (absorption, distribution, metabolism, and elimination) of perchlorate in adult rats (Fisher et al. 2000). As data became available and perchlorate-induced effects observed in animal studies and humans were shown to be mediated by interactions with iodide at the sodium-iodide symporter (NIS) in thyroid tissues, the initial model was expanded to include the disposition of iodide in the body and the inhibition of iodide uptake at the NIS in pregnant rats and fetuses, lactating rats and pups, and adult humans to address dose-response issues associated with potentially sensitive populations (Clewell et al. 2001, 2003a,b; Merrill 2001b, Merrill et al. 2003). The purpose of the models was to facilitate extrapolation of internal, target-tissue doses from animals to humans, of high to low dose, and across routes of exposure in human health risk assessments. However, the challenges associated with developing quantitative descriptions of the complex interactions and feedback mechanisms within the hypothalamic-pituitary-thyroid (HPT) axis prevented the development of a model that could describe the dynamic interactions between the inhibition of iodide transport

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Health Implications of Perchlorate Ingestion by the NIS and thyroid function. Thus, the PBPK models that were developed by DOD focused on improving the ability to predict the kinetics of perchlorate and iodide with respect to their interaction at the NIS as the key event identified by EPA over a range of perchlorate exposure that encompasses toxicity studies in animals, therapeutic uses in humans, and relevant environmental exposures. EPA used that approach in the derivation of an RfD for perchlorate, following established guidelines for the selection of key events, points of departure, and derivation of appropriate uncertainty factors (EPA 2002a,b,c). Although the committee has chosen a different point of departure based on human data (see Chapter 5), it agrees with EPA that PBPK modeling constitutes the best approach to determining the human equivalent exposures and adjustments to default uncertainty factors when RfDs are based on data collected in animals. If future studies with perchlorate are conducted in laboratory animals, the PBPK models developed to date may be important tools for integrating the new data into the existing database on the exposure-dose-response relationships for perchlorate in rats and humans. EPA provided a thorough description of the PBPK models in its analysis of the health risks associated with potential perchlorate exposures (EPA 2002b). The models were later reviewed by an external peer-review panel (EPA 2002c). In this appendix, the committee reviews only the general properties of the PBPK models developed by DOD, their underlying assumptions, and their general applicability in animal-to-human extrapolations. GENERAL APPROACHES TO PERCHLORATE PBPK MODEL DEVELOPMENT Perchlorate does not appear to be metabolized in the body. Once absorbed, it is rapidly distributed into all tissues except fat, with preferential uptake by tissues that contain the NIS, and ultimately cleared unchanged in urine. Thus, the development of the PBPK models for adult rats and humans and potentially sensitive life stages (developing fetus and neonate) followed a logical progression of increasing complexity that linked exposure with key biochemical events as the toxicity and mode of action of perchlorate in animals and humans became better defined and methods of analyzing perchlorate in biologic fluids and tissues improved.

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Health Implications of Perchlorate Ingestion In deriving the RfD, EPA relied on the initial published models and a series of memoranda from DOD describing the continued updating of the suite of PBPK models (Clewell 2001a,b; Merrill 2000; Merrill 2001a,b). The final PBPK models were published shortly after the EPA review (Clewell et al. 2003a,b; Merrill et al. 2003) and reflected comments received by EPA’s peer review (EPA 2002c) and journal peer reviewers. The models have similar base structures and sources for model parameter values and additional features where necessary to address specific life stages, such as growth and development and additional compartments associated with pregnancy and lactation in the rat. The first PBPK model of Fisher et al. (2000) was developed to describe the disposition of perchlorate in the adult male rat; it was based on rather sparse kinetic data that were available in the late 1990s. Tissues that were specifically included in the initial framework included lungs, kidneys, thyroid, and gastrointestinal (GI) tract; the remaining tissues were lumped into either poorly perfused or richly perfused compartments (Figure E-1). Each of those compartments consisted of mass-balance equations describing the rates of transfer of perchlorate into and out of each tissue on the basis of their known volumes, blood perfusion rates, partition coefficients, the presence (or absence) of any transport processes (such as that of the NIS in thyroid and GI tract), or the clearance of perchlorate into urine. Only sparse data on perchlorate after intravenous (IV) administration were available for model development. On the basis of the the preliminary analysis, it was observed that perchlorate clearance into urine after IV dosing at 0.01-3 mg/kg followed linear, first-order kinetics, whereas substantial nonlinearities were observed in systemic (serum and tissue) kinetics. Thus, the preliminary model was used as an initial framework for identifying critical data gaps for later model development and definitions of relevant internal-dose surrogates (as opposed to administered doses or external exposures) that could be used to enhance human health risk assessments that were based on toxicity studies in rats. Clewell et al. (2001) later proposed a suite of initial PBPK models that incorporated important steps in the mode of action of perchlorate (NIS iodide uptake inhibition) and key life stages for perchlorate toxicity (fetus and neonate) in addition to the adult male. To accomplish that, initial PBPK models were developed for perchlorate and iodide with interactions between them occurring at the NIS. The purpose of the preliminary PBPK models was to lay the groundwork for extrapolating the internal doses of perchlorate (such as blood concentrations and interactions with iodide in thyroid NIS) from rats to humans as a function of life stage (fetus, neonate,

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Health Implications of Perchlorate Ingestion FIGURE E-1 Diagram of preliminary PBPK model for perchlorate in adult male rat. Abbreviations: GI, gastrointestinal; IV, intravenous; Kg, rate constant for loss of perchlorate from GI tract; Kmg, rate constant for uptake of perchlorate in GI tract; Kmt, rate constant for uptake of perchlorate in thyroid; Kt, rate constant for loss of perchlorate in thyroid; Ku, rate constant for urinary excretion of perchlorate; Vmaxg, maximal capacity for NIS transport in GI tract; Vmaxt, maximum capacity for NIS transport in thyroid. Source: Adapted from Fisher et al. 2000. and adult), dose, and route of exposure with the parallelogram approach discussed in Chapter 4. The structures of the PBPK models across life stages shared physiologic compartments and biologic and chemical-specific sources of parameter

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Health Implications of Perchlorate Ingestion values. Each model contained specific descriptions of tissues involved in the uptake, distribution, and elimination of perchlorate and iodide and specific descriptions of the interactions between perchlorate and iodide via the NIS. Basic model structures thus included NIS-containing tissues, such as the thyroid, GI tract, and skin. The thyroid was divided into three-subcompartments representing the tissue capillary bed (referred to as the stroma in the perchlorate PBPK literature), follicle, and lumen (colloid), as described in more detail below. The GI tract was similarly divided into three subcompartments: the capillary bed, GI tissue, and GI contents; perchlorate and iodide are transported by the NIS from the tissue into the contents against a concentration gradient and diffuse between subcompartments on the basis of partition coefficients and electrochemical gradients. The skin was divided into two subcompartments: skin blood and skin tissue; perchlorate and iodide are transported from blood to tissue by the NIS and diffuse back and forth between the subcompartments. To model pregnancy and lactation, NIS-containing tissues, such as the placenta and mammary glands, were included. Those tissues were also divided into subcompartments as described below for each model. Other NIS-containing tissues—such as ovaries, choroids plexus, and salivary glands—were considered too small to affect the concentrations of perchlorate and iodide in plasma or the thyroid and were therefore not specifically segregated from the poorly or richly perfused tissue groups. Remaining tissues in each model included the kidneys for clearance of perchlorate and iodide in urine, the liver for possible future modeling of hormone metabolism, a separate plasma and red-cell compartment for the distribution of perchlorate (plasma-protein-binding) and iodide, and fat because it is an exclusionary compartment (owing to the poor solubility of perchlorate and iodide anions) that is highly variable and changes during pregnancy and lactation. The lung compartment used in the preliminary model of Fisher et al. (2000) was combined with the richly perfused compartment because neither perchlorate nor iodide is volatile; vapor inhalation was considered to be an irrelevant route of exposure, and neither anion is eliminated to any important degree in breath. Remaining tissues were grouped together on the basis of their similar kinetic properties and blood perfusion rates (as poorly vs richly perfused tissues). As the authors of the PBPK models discussed, it is important to note that the iodide PBPK models used for each life stage (adult, pregnant, lactating, fetus, or neonate) were rudimentary in that they described key physiologic and biochemical processes only in enough detail to reproduce the sparse radiolabeled-iodide kinetic data in animals and humans and the interactions with perchlorate at the NIS. With one exception, discussed

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Health Implications of Perchlorate Ingestion below, the models did not include dietary or endogenous iodide kinetics, which could be important in interpreting human biomonitoring or clinical studies. And the models did not include formal descriptions of the pharmacodynamics of thyroid hormone control and the HPT biofeedback effects of alterations in iodide concentrations resulting from perchlorate exposure (although NIS up-regulation was modeled to fit the iodide kinetic data after multiple dosing kinetic studies with perchlorate, as discussed below). Such a combined PBPK-pharmacodynamic model would eventually be useful in predicting biologic responses (alterations in thyroid hormone homeostasis) to various perchlorate exposures or different life stages, as noted in EPA (2002c), and in providing a more quantitative basis for understanding species differences in potential toxicity. MODELING KEY EVENTS IN NIS-MEDIATED THYROID RESPONSES TO PERCHLORATE As discussed in Chapter 5, the committee considers the inhibition of iodide uptake at the NIS in the thyroid as one of the key biochemical events preceding the development of adverse responses, such as hypothyroidism, which may result in abnormal growth and development of the fetus and child or in metabolic sequelae at any age. It is important to emphasize that the inhibition of thyroid iodide uptake is not in itself an adverse response. However, because the inhibition of iodide uptake is the first definitive biochemical event that must occur before the chain of events leading to altered hormone homeostasis and then an adverse response, it is a critical component in establishing a relationship between exposure and an internal dose-response for perchlorate risk assessments. Thus, the PBPK models used by EPA in the derivation of an RfD for perchlorate focused on adequately describing the interaction between perchlorate, iodide, and the NIS in the thyroid gland even though the internal-dose metric used by EPA in calculating human equivalent exposures was limited to the blood perchlorate concentration. The working hypothesis underlying the development of the PBPK models for perchlorate and iodide across life stages of concern was that perchlorate competitively inhibits the thyroid uptake of iodide via the NIS and reduces the iodide available for the production of thyroid hormones (Figure E-2). The inhibition of iodide uptake results in decreases in the production of triiodothyronine (T3) and thyroxine (T4), which lead to an increase in thyroid-stimulating hormone (TSH) production that then stimu-

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Health Implications of Perchlorate Ingestion FIGURE E-2 Working hypothesis on mode of action of perchlorate on thyroid gland. Abbreviations: ClO4−, perchlorate ion; I−, iodide; NIS, sodium-iodide symporter; T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. lates an increase in the synthesis of NIS proteins and enzymes associated with hormone production. As reviewed in Chapter 4, there are important species differences in the distribution and disposition of thyroid hormones. In particular, the reduced protein binding of T3 and T4 in rat serum (rats lack a thyroxine-binding globulin that is normally present in humans) results in a greater rate of clearance of thyroid hormones from the body than in humans. That causes a compensatory increase in TSH release from the pituitary gland and a corresponding increase in the overall production rate of T3 and T4, making rats particularly sensitive to perchlorate’s disruptions in iodide uptake.

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Health Implications of Perchlorate Ingestion During the first 10-12 weeks of gestation, the fetus depends on the mother for thyroid hormone production, so the fetus is affected by both alterations in the mother’s hormone production and direct inhibition of iodide uptake by perchlorate that has transferred across the placenta. One of the major goals in the development of the PBPK models of Clewell et al. (2003a,b), Merrill (2001), and Merrill et al. (2003) was to simulate interactions between perchlorate and iodide at the NIS in the thyroid of rats and humans at key life stages (adult, pregnancy, lactation, fetus, and neonate) and thereby to facilitate high-to-low dose, route-to-route, and cross-species extrapolations based on an internal dose of perchlorate that is relevant to toxicity in both cancer and noncancer risk assessments. To accomplish that goal, a PBPK model for iodide was also developed that interfaced with the perchlorate PBPK model at the level of the NIS in the thyroid gland, GI tract, and skin. A fundamental component of the assumed competitive interaction between perchlorate and iodide is transport of perchlorate itself by the NIS. There has been some debate regarding that issue (Wolf 1998; Reidel et al. 2001a,b; EPA 2002c), but it has not been possible to measure perchlorate uptake directly in rat and human thyroid follicular cells, because of a lack of commercially available radiolabeled perchlorate or an analytic method that is sensitive enough. Thus, arguments have largely centered on the use and interpretation of indirect estimates of perchlorate transport (such as electrochemical gradient measurements vs measurement of radiolabeled uptake of chemicals similar to perchlorate in cells that contain the NIS). Until data become available to address the question directly, the committee agrees that the use of a competitive-inhibition model and its underlying assumption of perchlorate transport by the NIS, as reviewed by Clewell et al. (2004), is a reasonable approach and provides an adequate description of the available data. To model the interactions between perchlorate and iodide, Clewell et al. (2003a,b), Merrill (2001a,b), and Merrill et al. (2003) reduced the complexity in potential biologic interactions and maintenance of thyroid hormone homeostasis to a series of rate-limiting steps in a physiologically based compartment specific to each species or life stage (adult human, adult male rat, pregnant female rat and fetus, and lactating female rat and neonate). In their simplified models, the thyroid was divided into three compartments representing the capillary bed (stroma), follicle cells, and colloid (lumen) after less complex descriptions (two compartments) failed to simulate the initial rapid phase of thyroid perchlorate uptake and equilibrium and a slower phase of equilibrium and clearance observed in animal studies (Figure E-3).

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Health Implications of Perchlorate Ingestion FIGURE E-3 Diagram of three-compartment working model for perchlorate and iodide uptake in the thyroid. Abbreviations: ClO4−, perchlorate ion; I-, iodide; NIS, sodium-iodide symporter. Source: Adapted from Clewell et al. 2004. In the simplified model, both perchlorate and iodide were allowed to partition from arterial blood into the thyroid capillary bed on the basis of species-specific and life-stage-specific blood flow rates, tissue:blood partition coefficients, and tissue volumes. The physiologic model thus consisted of a series of mass-balance equations that described the overall rate of change in the amount of perchlorate or iodide in each tissue or tissue compartment as a function of the rate of chemical input less the rate of chemical output: (1) For the thyroid capillary bed compartment—designated as “stroma” in Clewell et al. (2003a,b), Merrill (2001a,b), and Merrill et al. (2003) model equations described below—perchlorate and iodide that enter from the arterial blood can either passively diffuse or be actively transported by the NIS into the thyroid follicle and passively diffuse back from the follicle or partition back into venous blood draining the thyroid. Thus, the following mass-balance equation was used by Clewell et al. (2003a,b), Merrill (2001a,b), and Merrill et al. (2003) to represent the rate of change in the amount of perchlorate in the thyroid stroma (RATSP) according to

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Health Implications of Perchlorate Ingestion (2) where QT is the thyroid blood flow, CAP is the concentration of perchlorate in arterial blood, CVTSP is the concentration of perchlorate in venous blood draining the thyroid stroma, PATFP is the permeability:area cross product for the diffusion of perchlorate across the membrane between the stroma and follicle, CTFP is concentration of perchlorate in thyroid follicle, PTFP is the thyroid stroma:follicle partition coefficient for perchlorate, CTSP is concentration of perchlorate in thyroid stroma, and RupTFP is the rate of active transport of perchlorate by the NIS from stroma to follicle. Identical equations were used to describe the rate of change in the concentration of iodide in the thyroid stroma with iodide-specific chemical parameters, such as the concentration of iodide in arterial blood, thyroid stroma, and thyroid follicle; permeability-area cross products for the diffusion of iodide across the thyroid follicle membrane; the thyroid stroma:follicle partition coefficient for iodide; and the rate constants associated with the active transport of iodide by NIS. The rate of uptake of perchlorate into the thyroid follicle (RATFP) was then described by (3) where RupTLP is the rate of active transport of perchlorate from follicle into colloid (lumen), PATLP is the permeability:area cross product for the diffusion of perchlorate across the membrane between follicle and colloid, CTLP is the concentration of perchlorate in thyroid colloid, PTLP is the thyroid follicle:colloid partition coefficient for perchlorate, and CTFP is the concentration of perchlorate in thyroid follicle. For iodide, the same equation (Equation 3) was used with the addition of terms describing the loss of inorganic iodide due to the production of thyroid hormones (see “Bound

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Health Implications of Perchlorate Ingestion Iodide,” Figure E-3) as a simple, first-order reaction lumping total hormone production: (4) where CLProdI is the first-order rate of organification of iodide and CTFI is the concentration of inorganic iodide in the thyroid follicle. The rate of change in the amount of perchlorate in the thyroid colloid (lumen) then becomes (5) The active transport of perchlorate from the thyroid stroma to the follicle (RupTFP) and from the follicle to the lumen (RupTLP) was described by using Michaelis-Menten equations as the basis of saturable transport processes according to (6) and (7) where VmaxTFP and VmaxTLP are the maximal rates of transport from stroma to follicle via the NIS and follicle to lumen via other transporters (such as pendrin or apical iodide channels), respectively, and KmTP and KmTLP are the Michaelis constants for the transport of perchlorate from stroma to follicle and follicle to lumen, respectively. For the integration between the perchlorate and iodide models, the basic Michaelis-Menten equations for NIS transport (stroma to follicle) and active transport in the apical membrane (follicle to colloid) were modified by Clewell et al. (2003a,b), Merrill (2001a,b), and Merrill et al. (2003) to

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Health Implications of Perchlorate Ingestion (Corley et al. 2003). Therefore, Clewell et al. (2003b) relied on the initial framework described by Shelley et al. (1988) and the earliest model that incorporated physiologic changes of the rat dam and neonate by Fisher et al. (1990) as the structural and physiologic basis of the perchlorate and iodide PBPK models. Additional compartments that were necessary to describe perchlorate and iodide kinetics and interactions were either taken from the adult rat and pregnant rat PBPK models described above or modified to specifically describe the data available on lactation transfer of perchlorate and iodide. The latter modifications are described below. During gestation, the NIS in the mammary gland delays the clearance of iodide (and perchlorate) from mammary tissues although these anions typically do not rise above peak serum concentrations. During lactation, however, iodide is concentrated in the milk. Inhibition of iodide uptake by perchlorate not only decreases the iodide available in milk but also transfers perchlorate, which can inhibit the uptake of iodide in the thyroid of the nursing pup (Yu et al. 2001). Thus, the two-compartment model for the mammary gland used in the pregnancy model of Clewell et al. (2003a) was expanded to three compartments: mammary blood, mammary tissue, and milk at parturition (see Figure E-6). Similar to NIS activity in the thyroid, NIS transport of iodide and perchlorate occurs between mammary blood and mammary tissue. A second mechanism reportedly exists to transport iodide against a concentration gradient into milk, so Clewell et al. (2003b) incorporated equations for the competitive transport of perchlorate and iodide (designated by bold arrows in Figure E-6) between compartments with passive diffusion that is driven by concentration gradients between compartments. Perchlorate and iodide are then transferred from the milk to the GI contents of the pup with a first-order rate of transfer, and both anions are returned to the dam (GI contents) via pup urine with a first-order transfer rate to simulate grooming by the dam. The remaining maternal tissue compartments, except plasma, were structured similarly to the way they were in the pregnancy model with changing physiology over postnatal days 0-10 based on the lactation model of Fisher et al. (1990). The neonatal model was similar to the maternal model except for the absence of mammary tissues. In contrast with the developing fetus, a fat compartment was needed because this tissue begins to grow after birth. To simplify the model, all pups from a given litter were combined in the model structure (that is, total body weight was multiplied by the number of pups in each litter). Thyroid secretion of hormones was modeled in a fashion similar to that used in the adult rat and pregnancy models with one major exception. In

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Health Implications of Perchlorate Ingestion the lactation model, Clewell et al. (2003b) added deiodination of thyroid hormones to the plasma compartment as a surrogate of tissue deiodination and included competitive protein binding between iodide and perchlorate in plasma (Figure E-7). It is not clear why that is needed in the lactation model but not in the adult rat, adult human, and pregnant rat models. To develop the lactation-transfer PBPK model, Clewell et al. (2003b) conducted perchlorate drinking-water exposure studies in Sprague-Dawley rats covering the period from gestation day 2 through postnatal day 5 or 10 and radioiodide kinetic and inhibition studies in lactating rats and neonates on postnatal day 10. Kinetic parameter values for the perchlorate model were estimated from the maternal drinking-water study for both dams and neonates. For the iodide model, chemical-specific parameter values were obtained for the dams and neonates that were each dosed independently. Chemical-specific model parameter values (Table E-1) in tissues other than the mammary gland and blood compartment were kept as similar as possible to those of the adult rat and pregnant rat models although some were adjusted to fit the perchlorate and iodide kinetic studies conducted by Clewell et al. (2003b). Up-regulation of thyroid NIS to simulate the drinking-water kinetic studies was performed as described for the adult male rat PBPK model. Model simulations of neonatal exposure via nursing were assumed to be continuous; in gavage experiments, the dose was introduced as a bolus directly into GI contents. Drinking-water exposure for the perchlorate studies was modeled as 12-hr/day exposure to reflect nocturnal feeding behaviors (6 p.m. to 6 a.m.); simulations of dietary iodide studies, which were reported only for lactating rats and their pups, were based on the assumption of 24-hr/day intake. The reasons for the differences in maternal exposure (12 hr/day vs 24 hr/day) were not explained by the authors. Thus, the radioiodide, dietary iodide, and perchlorate models were operated independently with interactions between the three models occurring at the level of the NIS and, although not explicitly stated by the authors, presumably via competitive plasma-protein binding. The resulting models were able to simulate maternal and neonatal perchlorate and iodide kinetics whether only the dams were exposed or the neonates were exposed directly. Validation of the model simulations was based on several datasets from the literature that were not used to estimate model parameter values and on the thyroid iodide uptake inhibition studies. The lactation-transfer model was able to simulate perchlorate and iodide kinetics and inhibition of NIS transport in the thyroid reliably over a nearly complete period of lactation (up to postnatal day 20).

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Health Implications of Perchlorate Ingestion FIGURE E-6 Diagram of PBPK model for perchlorate and iodide in lactating rat and neonate (adapted from Clewell et al. [2003b]). Bold arrows indicate active transport of perchlorate and iodide NIS in thyroid, skin, gastric mucosa, mammary gland, and placenta and by apical iodide channels in thyroid and mammary gland. Model compartments that were altered or added to pregnancy model of Clewell et al. (2003a) are designated by shading. See Figure E-7 for more detailed diagram of thyroid-blood compartments of iodide model outlined in this figure. Abbreviations: ClO4−, perchlorate ion; GI, gastrointestinal; I−, iodide; IV, intravenous; NIS, sodium-iodide symporter; PBPK, physiologically based pharmacokinetic; RBCs, red blood cells.

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Health Implications of Perchlorate Ingestion FIGURE E-7 Diagram of thyroid and blood subcompartments from iodide PBPK model of lactating and neonatal rat (adapted from Clewell et al. 2003b). Bold arrows indicate active transport of iodide. Model subcompartments that were altered or added to pregnancy model of Clewell et al. (2003a) are designated by shading. Thyroid hormones (free and bound) were lumped together and secreted by thyroid follicle into plasma where first-order deiodination reaction (a surrogate of tissue metabolism) releases inorganic iodide, which can compete with perchlorate for binding to plasma proteins. Abbreviations: Alb, albumin; I−, iodide; fT3, free triiodothyronine; fT4, free thyroxine; T3, triiodothyronine; T4, thyroxine.

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Health Implications of Perchlorate Ingestion A rudimentary dietary and drinking-water exposure iodide PBPK model was developed to simulate “endogenous” iodide from the radioidide studies in the lactating rat and nursing pups, so the authors conducted additional simulations to determine the effect of changing dietary iodide on predicted acute radioiodide kinetics and perchlorate-induced inhibition of dietary uptake. Their simulations were consistent with the committee’s calculations for humans discussed in Chapter 3 and Appendix D. Changes in dietary iodide, even at concentrations over at least 100 times those used in standard laboratory diets, should have no effect on the sensitivity of the thyroid to the inhibition of iodide uptake by perchlorate in the lactating rat. As with the other PBPK models, Clewell et al. (2003b) also conducted a sensitivity analysis to determine which model parameters had the greatest effects on the predictions of serum perchlorate and thyroid iodide uptake inhibition. The results were similar to those of previous model sensitivity analyses and included parameters associated with plasma-protein binding, renal clearance, and rates of transfer between dams and nursing pups. COMPARISONS OF INTERNAL-DOSE SURROGATES ACROSS SPECIES AND LIFE STAGE Clewell et al. (2003b) compared the results of simulating the serum concentrations of perchlorate measured as area under the curve after drinking-water exposure with results of simulating the inhibition of thyroid iodide uptake after acute exposure to perchlorate in each of the PBPK models described above for the rat. The results of area under the curve simulations for serum perchlorate are shown in Figure E-8, and those of simulated inhibition of thyroid iodide uptake in Figure E-9. Clewell et al. (2003b) did not report whether up-regulated NIS parameter values were used in the simulations. Regardless, on the basis solely of the two internal-dose metrics, the lactating dam may be at greatest risk from perchlorate exposure if serum perchlorate area under the curve is used as the internal-dose surrogate, whereas the fetus appears to be the most sensitive if inhibition of thyroid iodide uptake is used as the surrogate. Clewell et al. (2003b) attributed the increased sensitivity of the lactating dam to the increase in protein binding of perchlorate in plasma (see Table E-1); fetal sensitivity to iodide uptake inhibition is multifactorial and is influenced by maternal transfer of perchlorate, inhibition of iodide transfer at the placenta, and other factors. EPA (2002b) used such simulations to calculate human equivalent exposures that corresponded to the internal-dose surrogates.

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Health Implications of Perchlorate Ingestion FIGURE E-8 Dose-response simulations of area under the curve for concentrations of perchlorate in serum of adult male, pregnant, fetal, lactating, and neonatal rats after drinking-water exposure as described in Clewell et al. (2003b). Abbreviations: AUC, area under the curve; kg, kilogram; mg, milligram; mg/L, milligrams per liter; mg/kg/day, milligrams per kilogram of body weight per day. FIGURE E-9 Dose-response simulations of inhibition of thyroid iodide uptake in adult male, pregnant, fetal, lactating, and neonatal rats after acute perchlorate exposure as described in Clewell et al. (2003b). Abbreviation: mg/kg/day, milligram per kilogram of body weight per day.

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Health Implications of Perchlorate Ingestion SUMMARY AND CONCLUSIONS Although the PBPK models simplified the interactions between perchlorate and iodide to a series of rate-limiting steps, their underlying biologic basis effectively reduced the uncertainties associated with extrapolating blood concentrations of perchlorate and inhibition of thyroid iodide uptake across species, dose, and routes of exposure for adult animals. Furthermore, the parallelogram approach discussed in Chapter 4, applied where models have been validated in the adult, pregnant, and lactating rat, and adult humans, serves as a useful tool for constraining extrapolations to adult human females during pregnancy or lactation. However, given the important species differences in developmental biology and the current inability to validate extrapolation to human fetuses and neonates, such an approach should be used with caution for these potentially sensitive populations. The committee concludes that it was appropriate for both DOD and EPA to limit animal-to-human extrapolations for pregnancy and lactation to maternal serum perchlorate concentrations or interactions with iodide in maternal thyroid NIS. The suite of PBPK models developed by DOD for the adult rat, adult human, pregnant rat and fetus, and lactating rat and neonate represent the current state-of-the-science approach for integrating available animal (rat) and human data on the disposition of perchlorate and iodide and their interactions at the level of the thyroid NIS. Although many of the PBPK model parameter values had to be estimated from a limited set of in vivo pharmacokinetic studies rather than independently measured, enough studies were available for validation of model simulations over a broad range of perchlorate doses and iodide concentrations to lend confidence to the application of the models for extrapolating internal-dose surrogates from animals to adult humans. If future studies are conducted to elucidate further the toxicity or mode of action of perchlorate in animal models, consideration should be given to updating the PBPK models because they provide a convenient framework to assemble current knowledge on the disposition of perchlorate in the body and on how it may interact with iodide at various stages of development. REFERENCES Brown, R.P., M.D. Delp, S.L. Lindstedt, L.R. Rhomberg, and R.P. Beliles. 1997. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol. Ind. Health 13(4):407-484.

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