* Geo-Centers, Inc., Wright-Patterson AFB, Ohio 45433; ManTech Environmental Technology, Inc., Dayton, OH 45437;
National Center for Environmental Assessment (NCEA), U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711;
Operational Technologies Corp., Dayton, Ohio 45432; and ¶ AFRL/HEST, Wright-Patterson AFB, Ohio 45433
1 To whom all correspondence should be addressed at GeoCenters, Inc., 2729 St., Bldg. 837, Wright-Patterson AFB, OH 45433. Fax: (937) 904-9610. E-mail: Elaine.Merrill{at}wpafb.af.mil.
Received April 29, 2004; accepted September 17, 2004
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ABSTRACT |
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Key Words: pharmacokinetics; human; perchlorate; radioactive iodide; inhibition; thyroid.
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INTRODUCTION |
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Perchlorate is not metabolized in the body (Anbar et al., 1959; Yu et al., 2002
). However, because
has a similar hydrated ionic radius and carries the same charge as iodide (I), it is able to affect biological systems by inhibiting I uptake into the thyroid by the sodium-iodide symporter (NIS) (Anbar et al., 1959
; Brown-Grant and Pethes, 1959
). While it is known that
competes with I for NIS binding sites, whether
is actually translocated into thyrocytes is the subject of debate (Eskandari et al., 1997
; Riedel et al., 2001
). The weight of evidence at this time, however, suggests
is a competitive inhibitor of thyroid I uptake, replacing I as a substrate of NIS and crossing the basolateral membrane (Clewell et al., 2004
, Van Sande et al., 2003
). Reduced I uptake may lead to a disturbance in the first stage of normal thyroid hormone genesis. Hence, there is reasonable concern that chronic exposure to low levels of
in drinking water could induce thyroid hormone deficiencies and subsequent thyroid disorders.
NIS resides in the basolateral membrane of thyroid epithelial cells and simultaneously transports two Na+ and one I ion from extracellular fluid (plasma) into the thyroid epithelial cell (Spitzweg et al., 2000). NIS is expressed in the thyroid and other tissues including the GI tract, skin, mammary tissue, and placenta. However, only in the thyroid is I organified to form thyroid hormones and iodinated proteins (Ajjan et al., 1998
; Spitzweg et al., 1998
). Thyroid hormone homeostasis is maintained through a complex feedback mechanism. A drop in circulating serum thyroid hormone levels signals the pituitary to produce more thyroid stimulating hormone (TSH), which in turn stimulates NIS expression.
In rats, a decrease in free thyroxine (fT4) and subsequent increase in TSH occur quickly (within one day) after acute exposures (Wyngaarden et al., 1952
; Yu et al., 2002
). In humans, thyroid hormone conservation is more efficient, although thyroid hormone status is very dependant on the iodine status and life stage under consideration. Little or no significant change in T4, fT4, and TSH was seen in adults after 2 weeks of controlled exposure to
via drinking water at 0.007 to 0.05 mg/kg/day (Greer et al., 2002
) and 0.14 mg/kg/day (Lawrence et al., 2000
), despite significant levels of thyroid I uptake inhibition. However, significant drops in fT4, intrathyroidal iodine, as well as an increase in serum thyroglobulin (Tg) have been reported in humans after high levels of exposure (900 mg/day) for 4 weeks (Brabant et al., 1992
). The dynamics of thyroid hormone homeostasis is very different for a late gestation fetus or neonate. Empirical measurement of intrathyroidal stores of thyroid hormone in human fetuses and neonates have shown that the amount of thyroid hormone stored in the colloid is less than that required for a single day (van den Hove et al., 1999
). The extent of chronic low-level
exposure required to cause significant hormone deficiencies in humans is not yet known. Thus, the question facing risk assessors and regulatory agencies is: what concentrations of perchlorate could be considered problematic? It is known that I deficiency during the fetal and neonatal period affects physical and mental development (Laurberg et al., 2000
; Porterfield, 1994
). In the adult, effects of I deficiency are less dramatic. Clinical and subclinical hypothyroidism is often overlooked due to the vague symptoms associated with the condition. Yet, hypothyroidism occurs in over 10% of older women and is associated with cognitive impairment (Volpato et al., 2002
). The development of hyperthyroidism, especially in multinodular goiters with autonomous nodules, is also associated with long-term mild to moderate I deficiency in adults. Hyperthyroidism is also often overlooked in the elderly and, if left untreated, may lead to cardiac arrhythmias, impaired cardiovascular reserves, osteoporosis, and other abnormalities (Laurberg et al., 2000
). Therefore, perchlorate-induced I deficiency may represent a public health concern not only during perinatal development, but also in the elderly and subpopulations with already compromised thyroid function.
In order to better understand the effect of occupational and environmental exposure to perchlorate on the hypothalamus-pituitary-thyroid (HPT) axis, a few studies have been performed that directly correlate hormone changes to quantitative perchlorate doses. In two occupational health studies at U.S. production facilities, workers were exposed to ammonium perchlorate (NH4ClO4) dust in the air. Perchlorate exposure levels were estimated from monitoring breathing zone air over full work shifts (Gibbs et al., 1998
; Lamm et al., 1999
). Gibbs and coauthors categorized exposure groups based on job tasks and air monitoring results. Controls, selected from an associated plant, were not exposure free, but had exposures estimated to be several orders of magnitude below any of the exposed groups. The researchers found no elevation in pre- and post-shift serum TSH, and no drop in serum free thyroxine (fT4) among any of the exposed workers. In the study by Lamm et al. (1999)
, control or comparison group subjects worked at the same facility but at unrelated processes and were believed to have very low exposure to perchlorate-contaminated particulates. Daily perchlorate doses were estimated from breathing zone air monitoring of respirable particulates over full work shifts and by urinary measurements. No significant differences in triiodothyronine (T3) and T4 were reported between the exposure and comparison groups. However, the mean pre- and post-shift urine perchlorate measurements from the comparison group averaged, respectively, 64% and 22% of those from the lowest exposed group.
Ecological epidemiological studies on neonatal screening data from California, Nevada, and Arizona health departments have resulted in conflicting data. Studies by Lamm and Doemland (1999) and Li et al. (2000)
showed no increase in incidence of congenital hypothyroidism or decrease in neonatal T4 associated with
in drinking water up to 15 µg/l. In contrast, the studies of Schwartz (2001)
and Brechner et al. (2000)
both found effects on newborn thyroid hormones from exposures at similar environmental levels (1 to 15 µg/l). A retrospective study of school-age children and newborns in three Chilean cities with drinking water concentrations of <4, 57, and 100120 µg
revealed significantly higher fT4 but normal TSH in the two cities with highest
concentrations (Crump et al., 2000
), a result opposite to what might be expected. While dietary I levels of the three Chilean populations were within normal range, their urinary excretion levels were increased. Hence, the increase in fT4 may represent an adaptive effect.
These human epidemiological studies, while informative as to the specific populations in which they were performed, have been of limited utility in aiding the extrapolation across species, populations, or exposure scenarios. Furthermore, differences in route of exposure and lack of adequate adjustment for particle dosimetry (Gibbs et al., 1998; Lamm et al., 1999
), ambiguities in level of exposure and exposure misclassification (Crump et al., 2000
; Gibbs et al., 1998
; Lamm et al., 1999
) make these data sets of questionable use for predictive purposes (U.S. Environmental Protection Agency, 2003
). Laboratory animal data, however, have indicated effects on developmental neurotoxicity, thyroid hormones, and thyroid histopathology that have raised concern for human health at various life stages (U.S. Environmental Protection Agency, 2003
). Unfortunately, measurements of critical neuropsychological effects, such as IQ or physical development in children exposed to
in drinking water, are not available. Therefore, to assist in evaluating the potential effects of
in humans, a human PBPK model corresponding to those developed for the male, pregnant, and fetal rat (Clewell et al., 2003a
,b
; Merrill et al., 2003
) is proposed. When used together, these models allow the entire body of
literature (both animal and human) to be used to more effectively predict perchlorate-induced changes in thyroid I uptake across species, life-stage, and exposure doses.
The focus of this and ongoing modeling efforts with is to integrate animal and human data and to evaluate quantitatively the impact of chronic exposure to perchlorate-contaminated drinking water. This physiological model focuses on the first step in the process, perchlorate-induced inhibition of I uptake in the thyroid. The model describes the kinetics and distribution of both radioactive I and
in healthy adult humans and simulates the subsequent inhibition of thyroid uptake of radioactive I by
. Distinct thyroid hormones and their regulatory feedback are not yet incorporated into the model structure, although free and organified I (representing combined thyroid hormones and nonhormonal iodoproteins) in plasma and thyroid secretions are described separately. Hence, in addition to predicting perchlorate's ability to inhibit thyroid uptake of radioactive I, the model represents significant work toward establishing a basis for quantifying the effect of
on the total amount of circulating thyroid hormones.
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METHODS |
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Data supporting the development of the portion of the model were obtained from Greer et al. (2002)
. In brief, Greer and colleagues administered 0.5, 0.1, or 0.02 mg/kg-day
in drinking water for 14 days to twenty-four euthyroid subjects (n = 8, four males and four females at each level) in a main study. Four equal portions of the daily dose were ingested approximately every 4 h from 8 A.M. to 8 P.M. Individual baseline serum and urine samples were collected 1 or 2 days prior to beginning the 14 days of
dosing. During
exposure, serum samples were collected at the following approximate times in the main study: day 1 at 12 and 4 P.M., day 2 at 8 A.M., 12 and 5 P.M., day 3 at 9 A.M., day 4 at 8 A.M. and 12 P.M., day 8 between 8 and 9 A.M., day 14 at 8 A.M., 12 and 5 P.M. and on post-exposure days 1, 2, 3 and 14. Twenty-four-h urine collections were taken on exposure days 1, 2, 14, and post-exposure days 1 through 3. Eight- and 24-h thyroid radioactive I uptake (RAIU) measurements were taken on the baseline day, exposure days 2 and 14, and post-exposure day 1, using an oral dose of 100 µCi of 123I.
An additional set of thirteen subjects were later exposed in a more limited uptake study. Six women and one man were tested in this uptake study at a lower dose of (0.007 mg/kg-day), and two additional subjects each were tested at the previous doses. In this uptake study, serum samples were taken on days 8 and 14 and urine collected on day 14. RAIU measurements were also made in these subjects following 123I ingestion on the day prior to perchlorate exposure (baseline measurements) and at 9 A.M. on exposure day 14 and post-exposure day 1 (Greer et al., 2002). The age of the subjects in both the main and uptake studies ranged from 18 to 57 years with a mean of 38 (SD ± 12) years.
The serum and urine samples were shipped to the Air Force Research Lab (AFRL/HEST) at Wright Patterson Air Force Base for analyses. The analytical method for the analyses was similar to that described in Narayanan et al. (2003)
. However, an important distinction between the analytical method used in this study and that of Narayanan and colleagues is the mobile phase concentration used. These concentrations were 80 mM NaOH for serum and from 60 to 120 mM NaOH for urine (depending on the sample). The range in mobile phase concentrations for the urine samples was required to attain proper sensitivity. Eight- and 24-h thyroid RAIU values were provided directly from the measurements of Greer et al.
Model validation studies. Iodide model parameters were validated through predictions of protein-bound iodine (PBI) data from Scott and Reilly (1954). Data used in validating model predictions of serum
were obtained from a recent unpublished drinking water study conducted by Drs. Georg Brabant and Holger Leitolf of the Medizinische Hochschule, Hanover, Germany. Seven healthy males ingested 12.0 mg/kg-day
for 2 weeks. The daily
dose was dissolved in 1 l of drinking water and divided into three equal portions, which were ingested at approximately 7 A.M., 12 P.M., and 7 P.M. each day for 14 days. Serum specimens were collected on exposure days 1, 7, 14, and post-exposure days 1 and 2. The serum samples from Brabant and Leitolf were also analyzed for perchlorate by AFRL/HEST. Data used in validating model predictions of cumulative urinary
were obtained from Durand (1938)
, Eichler (1929)
, and Kamm and Drescher (1973)
. In these studies healthy males received a single oral dose of potassium perchlorate, ranging from 635 to 1400 mg
.
Predictions of ClO4-induced inhibition of thyroid I uptake were validated with the RAIU data of Greer et al. (2002) and
discharge data by Gray et al. (1972)
. Lastly, the model's ability to predict thyroid I uptake and inhibition in hyperthyroid individuals was tested against data from Stanbury and Wyngaarden (1952)
.
Model structure. The described PBPK model (Fig. 1) conforms to the structure of the concurrently developed model for the male rat (Merrill et al., 2003), with the exception of the newly added plasma subcompartment for bound I, included for completeness. For both I and
, tissues containing NIS (thyroid, skin, and stomach) were described as compartments with nonlinear saturable uptake kinetics (Anbar et al., 1959
; Chow et al., 1969
; Kotani et al., 1998
; Perlman et al., 1941
; Slominski et al., 2002
; Wolff, 1998
). Other NIS-containing tissues, such as the salivary glands, choroid plexus, ovaries, mammary glands, and placenta (Brown-Grant, 1961
; Honour et al., 1952
; Spitzweg et al., 1998
) were lumped with the slowly and richly perfused tissues, as either their anion pools are too small to significantly affect plasma levels (Cserr et al., 1980
), or they are not applicable to the nonpregnant human. In development of the model, a quantitative sensitivity analysis showed no significant effect of either the gastric or thyroid uptake parameters on serum levels. Since the organ volumes are small and relative activity of NIS in the choroids plexus and salivary glands, etc. are even lower, we would expect these tissues to also have little to no effect on plasma concentrations.
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Fecal elimination of the anions is minimal and therefore not included in the model. As mentioned earlier, is fully eliminated in the urine unchanged. Yu et al. (2002)
reported 97% of
eliminated in urine within 26 h after dosing with 3.0 mg/kg in rats. Fecal excretion of I comes from the liver breaking down thyroid hormones and its secretion of the metabolic products into the bile, which enters the intestines. Therefore, when Hays (1993)
administered 125I-T4 orally to seven healthy male subjects, she found that the fraction of fecal radioactivity attributed to 125I was 0.55 ± 0.35. But, administration of radioactive thyroid hormones is very different from administering radioactive I. When radioactive I is given orally, nothing is available for the liver to break down; virtually all of the radioactive I is excreted by the kidneys. As reported in Elmer (1938)
, Scheffer (1937) measured 2.89.0% of the total radioactive I excreted in the feces. They noted that this amount was highly variable. For example, after fasting fecal radioactivity may be undetectable. Braverman and Utiger (1991)
stated fecal excretion of dietary iodine is negligible (5 µg/day). Fecal elimination should be included in future expansion of the model, which will include thyroid hormone metabolism and homeostasis.
The rapid urinary clearance of and radioactive I, seen in both rats (Yu et al., 2002
) and humans (Greer et al., 2002
), was described with a kidney compartment. Urinary clearance could have easily been describe from the free anion portion in the blood; however, significant levels of deiodination occur in the kidneys, which would be critical in future model extrapolations to simulate thyroid hormone metabolism and clearance. Similarly, the liver compartment was maintained separately because it is the major site of extrathyroidal deiodination and it may be required in future pharmacodynamic elaborations of the model. At this point, the inclusions of these compartments did not add a great deal of complexity or uncertainty to the model.
Because both anions are highly hydrophilic, fat acts as an exclusionary compartment. Given the large variability in human body fat, it was important to explore the contribution of this compartment to the overall anion kinetics. In addition, rapidly changing fat content during reproduction made the compartment important for extrapolation across life stages (Clewell et al., 2001, 2003a
,b
). The perfusion-limited compartments (e.g., kidney, liver, fat, slowly perfused, and richly perfused) were each described using partition coefficients and blood flows.
The structure of the plasma compartments for and I are similar. Both include passive diffusion between plasma and red blood cells (RBCs); however, reversible binding between plasma proteins and
and I are slightly different. In human serum,
binding to plasma proteins has also been demonstrated (Hays and Green, 1973
; Scatchard and Black, 1949
). Approximately 9598% of endogenous plasma iodine is reported as protein-bound iodide (PBI) in human serum (Rapport and Curtis, 1950
; Underwood, 1977
). However, unlike bound
, the bound I fraction primarily represents nonexchangeable, covalently bound, incorporated I secreted from the thyroid (e.g., hormonal iodine and iodinated proteins, including tri- and diiodothyronine) rather than simply inorganic I bound to carrier proteins. In fact, it has been shown that approximately 90% of endogenous PBI represents T4 and 5% represents T3 (Berkow et al., 1977
). Michaelis-Menten kinetics were used in the model to describe the association of the free
and I fractions to unspecific plasma binding sites, and first-order rates were used for their dissociations. In the case of I, however, dissociation represents both deiodination of hormones and disassociation of I from serum proteins. Hormone deiodination occurs at several sites throughout the body, but in the absence of better data, it was lumped together as one first-order rate. Although unlabelled I is not included in the model, the behavior of tracer doses of radioactive I is expected to follow that of endogenous I. This is because the average levels of plasma inorganic iodine (PII) are expected to be around 0.40 ± 0.23 µg/dl (Elte et al., 1983
), well below the NIS Km value (described below). Therefore, the NIS will not be saturated in the average person.
Model Parameters
Physiological parameters. Tissue volumes and blood flows are presented in Table 1. Considerable variability was reported for some parameters, such as blood flow to the stomach (QG), which can increase 10-fold in response to enhanced functional activity (secretion and digestion) (Granger et al., 1985). The blood flows used represent estimates of resting values. Human data on the volume of the stomach capillary bed (VGBc) were not available. Therefore, a value derived from rat stomach data (Altman and Dittmer, 1971a
) was allometrically scaled as described below. Mean values reported in the literature were used for all other physical parameters.
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Chemical-specific parameters. Terminology and values of chemical-specific parameters are provided in Table 2. These parameters were kept as consistent as possible with those used in the male and pregnant rat models (Clewell et al., 2003b; Merrill et al., 2003
). Across the models, partition coefficients were nearly identical, although differences exist in parameters describing maximum capacities for the nonlinear uptake of the anions. The partitions for the thyroid subcompartments were based on electrical potentials measured within the thyroid stroma, follicular membrane, and lumen after
dosing (Chow and Woodbury, 1970
). Electrical potential differences can be interpreted as effective partition coefficients for charged moieties, such as
and I, hindering entrance of negatively charged ions from the stroma into the follicle, while the equal and opposite potential from the follicle to the lumen enhances passage of negatively charged species into the lumen and indicates an effective partition coefficient greater than one. Using Chow and Woodbury's measured electrical potentials at the stroma:follicle and follicle:lumen interfaces, effective partitions were calculated, as described in Merrill et al. (2003)
. These values were also used to describe the uptake of I based on the fact that I and
have the same ionic charge and similar ionic radii and therefore respond similarly to an electrochemical gradient.
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Kosugi et al. (1996) also measured perchlorate's affinity for NIS and reported a Km of 1.5 x 105 ng/l, approximately ten times lower than the that for I, indicating a greater affinity for perchlorate. Several other studies agree that perchlorate's affinity for NIS is approximately ten times greater than that of I (Halmi and Stuelke, 1959
; Harden et al., 1968
; Lazarus et al., 1974
; Wyngaarden et al., 1952
). Based on this information, a KmTFp value was set to 1.6 x 105 ng/l, adjusting the literature value slightly based on the model fits to
data in NIS-containing tissues. This values lies between that measured by Kosugi et al. and that required in the corresponding male rat model (1.8 x 105 ng/l).
The apical membrane of the thyroid follicle also exhibits a selective I channel, believed to be pendrin. Pendrin is a transmembrane glycoprotein, which facilitates both chloride and I efflux across the apical membrane (Mian et al., 2001; Scott et al., 1999
). Golstein et al. (1992)
measured a Km of 4.0 x 109 ng/l, for I transport from the bovine thyroid follicle into the lumen (KmTLi). However, as in the corresponding rat model, a slightly lower KmTLi of 1.0 x 109 ng/l was required to fit thyroid I data at later time points (>8 h). Golstein et al. (1992)
reported that this apical channel also appears sensitive to
inhibition, suggesting a lower Km for
(KmTLp) than for I. A KmTLp value of 1.0 x 108 ng/l was derived from Chow and Woodbury's (1970)
data, as described in Merrill et al. (2003)
.
Maximum velocities, Vmax(s), for anion uptake vary between tissues and species (Bagchi and Fawcett, 1973; Wolff, 1998
). Humans tend to have lower Vmax values than other species (Gluzman and Niepomniszcze, 1983
; Wolff and Maurey, 1961
) when expressed per gram of tissue. The Vmax(s) (ng/h/kg) for I uptake in the thyroid and plasma were estimated by visually optimizing the clearance portion of the curves to respective time-course data of Degroot et al. (1971)
. This was accomplished by keeping all other parameters fixed, while the Vmax value was adjusted so that the model prediction adequately approximated the observed mean. It may be noted that Vmax values for the thyroid follicle and lumen differ by up to an order of magnitude from preliminary values, reported in Clewell et al. (2001)
. This was attributed to the availability of new data sets, which allowed improved parameterization.
For tissues lacking time-course data, the Vmax(s) were estimated to yield kinetics similar to those described by the male rat model (Merrill et al., 2003). For example, for I kinetics in the stomach and skin, VmaxGi and VmaxSki respectively, were visually optimized to resemble tissue:serum concentration ratios seen in the rat, while maintaining the fits to human serum data. Because
data was only available in serum and urine,
Vmax(s) for NIS-containing tissues were scaled from the I Vmax(s), using the ratios between corresponding I and
Vmax(s) established in the male rat model.
Diffusion, concurrent with active uptake in the stomach, thyroid, and skin, was described using permeability area cross products (PA) (l/h-kg) and effective partition coefficients (P). In general, PA values were visually fit to the uptake portion of the curves, prior to setting Vmax(s), with partition coefficients, and all other parameters were set to the values in Table 2 and held fixed. The early time-course data of I in gastric aspirations from Hays and Solomon (1965) were used to estimate PAGJci, representing 131I transfer from the gastric juice into the gastrointestinal plasma (l/h-kg). To simulate the removal of gastric aspirations, the amount of 131I reabsorbed by the stomach wall had to be mathematically eliminated or set to zero. Once parameters were established using the aspiration session data, stomach reabsorption was reintroduced, and the permeability cross product for 131I transfer between gastric blood and tissue (PAGci) was fit to the corresponding increase in 131I in plasma, thyroid, and urine seen in the control session (where gastric juices were not aspirated). The permeability area cross product between the thyroid stroma and follicle, PATFci, was visually optimized to the uptake portion of the thyroid I data.
The first-order clearance rates describing the organification of I shortly after it enters the thyroid follicle (Clhormci) and the secretion of organic I into systemic circulation (Clsecrci) were visually optimized to the clearance portion of thyroid 131I data, as well as the later time points of the plasma PBI data from Degroot et al. (1971). The first-order rate, describing the body's overall deiodination rate (Cldeiodci) was also estimated through visual optimization of the later PBI timepoints, while maintaining the model fit to total plasma iodine and keeping all other parameters fixed. Later plasma time points of PBI reflect the contribution of hormone secretion and deiodination rates due to sufficient lapse of time for radioactive I incorporation into thyroid hormones and precursors. Therefore, earlier PBI time points were visually fit to establish parameters for binding of inorganic I to plasma proteins (e.g., KmBi, VmaxBi). Similarly, reversible plasma binding of perchlorate was described using a first-order rate constant (Clunbp), which was visually optimized to available serum
data. Urinary excretion rates for both anions (ClUi and ClUp) were visually fit to available cumulative urine data (Degroot, 1971
; Greer et al., 2002
; Hays and Solomon, 1965
). Because cumulative urinary perchlorate data was available in the Greer et al. study, ClUp was visually fit to each individual's data, and the average value was then used for the model parameter.
Allometric scaling and rate equations. Differential equations used to simulate radioactive I and transport were written and solved in ACSLTM (Advanced Continuous Simulation Language) (AEgis Technologies, Austin, TX). To account for body-weight-dependent variables and species extrapolations, allometric scaling was applied to Vmax(s), PA(s), Cl(s), tissue volumes (V), and blood flows (Q). The variety of dosing regiments and routes were simulated using various pulse function codes in ACSL.
Rate equations describing I transport in ng/h in the thyroid stroma, follicle and lumen (colloid) (RATSi, RATFi, and RATLi, respectively), as well as the rate of change in bound thyroid iodine (RAbndi) are provided below. These equations demonstrate diffusion-limited uptake, using P(s) and PA(s), and saturable uptake and competitive inhibition using M-M parameters. Equations used in the other compartments are expressed similarly.
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Subscripts i and p identify the anion as either I or , QT is thyroid blood flow (l/h), CAi is the arterial blood concentration (ng/l), CVTSi,p is the thyroid stroma concentration (ng/l), CTFi,p is the follicular concentration (ng/l) of I or
, and CTbndi is the concentration of incorporated I in the entire thyroid. PTFi, PTLi, PATFi, and PATLi are the partition coefficients and permeability cross products describing passive diffusion of I across the basal (follicle:stroma) and apical (lumen:follicle) membranes. Michaelis-Menten equations are used to describe the rates of active uptake of I into the follicle by NIS and into the lumen by the apical I channel (RupTFi and RupTLi, respectively), including inhibition by
. VmaxTFi, VmaxTLi, KmTFi,p and KmTLi,p are the maximum velocities (ng/h/kg) and affinity constants (ng/l) for transport of I or
into the follicle and lumen. Clhormi and Clsecri are first-order clearance values (h1) for the organification of I into thyroid hormones and the secretion of organified I into systemic circulation. Transport of
through the thyroid is calculated similarly, except there are no terms for organification of
(Clhormi and Clsecri). In addition, inhibition of
uptake by I is not included. As described earlier, due to the lower affinity of I (10-fold higher Km) than that of
, I does not significantly inhibit
sequestration in NIS-containing tissues. Example equations of other compartments are shown elsewhere (Merrill et al., 2003
).
Sensitivity analysis of parameters. To assess the relative impact of each parameter on model predictions, a sensitivity analysis was performed. After finalizing all model parameters, the model was run at a drinking water dose below NIS saturation (0.1 mg/kg/day) for 240 h (to ensure equilibrium was reached) to determine the average serum concentration [area under the curve (AUC)]. The model was then repeatedly rerun, using a 1% increase in each parameter to determine the resulting change in predicted serum
concentration AUC, and sensitivity coefficients for each parameter were then calculated using the equation below.
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RESULTS |
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Perchlorate kinetics. Because I parameterization, which was based on actual human time-course data, resulted in many values similar to those developed for the male rat, it is reasonable to expect that the proportional difference between the rat's I and parameters would also apply to the human's
parameters. Using these proportionally scaled
parameters for the thyroid, stomach, and skin, cumulative
in urine was visually fit for each individual in the 0.5, 0.1, and 0.02 mg/kg/day dose groups from Greer et al., (2002)
, resulting in an average urinary clearance constant for
(ClUcp) of 0.13 ± 0.05 l/h-kg (Table 3) (Fig. 5).
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DISCUSSION |
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Data available for calibrating and validating serum I were limited to tracer dose levels. However, the kinetic behavior of I is expected to be linear over a wide range of doses. Although the mechanism of transfer into the tissues with NIS is saturable, the value of Km (4.0 x 106 ng/l) indicates that very high doses would be required to saturate this mechanism. Additionally, similar parameter values and identical model structures in the corresponding rat models of various life stages have yielded validated serum predictions at dose levels ranging three or more orders of magnitude for both anions.
Aspects of the model, which were supported in the literature or laboratory studies but could not be directly observed in humans, were incorporated if necessary to improve the fit of the model to available data. For example, active uptake of I and into human skin and the relatively slow diffusion of both anions from skin back into systemic circulation were incorporated in spite of a lack of human time-course data. The literature supports this behavior, as NIS has been identified in human skin (Slominski et al., 2002
), and slow diffusion has been noted with similar anions, such as pertechnetate. Hays and Green (1973)
performed dialysis studies on intact human tissues with pertechnetate. They found skin had a relatively slow uptake of pertechnetate peaking at 18 h and, in fact, more retention after leaching dialysis than seen in brain, muscle, and serum.
It is possible that the reason elevated I in human skin has not been reported in clinical radioactive I scans is the difficulty in differentiating skin radioactivity from background radioactivity. The large volume of the skin allows radioactive I to be diffused over a large surface. However, this same property allows the skin to be an important pool for the storage and slow turnover of I. Simulations with this model demonstrated that inclusion of active uptake in human skin was required to simulate serum data. Sensitivity analysis on the corresponding male rat model indicated that serum levels were highly sensitive to parameters of the skin and plasma binding and urinary excretion (Merrill et al., 2003
).
Kinetic data for establishing parameters for the gastric compartment were limited to the early I data (3 h post-dosing) by Hays and Solomon (1965). Their gastric juice 131I data indicated rapid transport of I into the gastric mucosa (Fig. 2C). It is expected that
uptake in the stomach would behave likewise, due to the similarity of the anions in size and charge. The time-course behavior of radioactive iodine in stomach contents of any species is complicated by the fact that it reflects more than sequestration of radioactive I by NIS. Its appearance also reflects the accumulation of salivary radioactive I that is swallowed involuntarily throughout the study. Several studies that examined sequestration of these anions in digestive juices have all shown high variability in the concentrations measured over time (Hays and Solomon, 1965
; Honour et al., 1952
). There is a tendency for the gastric juice:plasma ratio to be low when the rate of secretion of gastric juice and saliva is high (Honour et al., 1952
). This is because the increase in secretions does not correspond with upregulation of NIS; therefore, the gastric juice concentration becomes diluted. Fluctuations in the secretion rate are probably the most important factor in determining the pattern of the concentration ratios in individuals. Therefore, variability in stomach or GI tract parameters between models is expected. However, the early rise in the gastric juice:plasma ratio mentioned earlier is a constant feature across these data sets, whether or not an attempt was made to eliminate contamination of gastric juices by dietary contents or saliva. Animal data that show both the anion uptake and clearance in the stomach (Yu et al., 2002
), unlike the data in Figure 2C which only show uptake, indicate that the clearance portion is less rapid. This model, and the series of different life-stage rat models (Clewell et al., 2003a
,b
; Merrill et al., 2003
;) consistently predict this same trend.
Average urinary clearance values were found to be 0.11 l/h-kg for I and 0.13 l/h-kg for . However, these values are not expected to be successfully applied to every euthyroid individual studied, though the use of these average values should provide a reasonable prediction of the euthyroid population. Individual differences in urinary I are expected with variation in thyroid function and protein-bound I in plasma. Iodide is ultimately removed or eliminated by two competing mechanisms, thyroidal uptake and urinary excretion. Thus, a higher amount of excreted I in urine is indicative of reduced thyroid uptake. Historically, this relationship has been used to estimate thyroid function. A cumulative 24-h urinary clearance of less than 30% of a tracer dose is indicative of hyperthyroidism, whereas clearances exceeding 40% are often associated with normal or decreased thyroid function. However, a high degree of variability exists between human subjects. Such a significant degree of overlap exists in thyroid test results for normal, hyperthyroid, and hypothyroid patients, that it is often necessary to run several different additional screens in order to identify subclinical conditions (NRC, 1996
).
In addition to the expected variability in thyroid uptake parameters (VmaxcTFi values ranging from 5.0 x 104 to 5.0 x 105 ng/h-kg) between individuals, variability across data sets was also noted. However, the difference seen in the average VmaxcTFi obtained from the Greer et al. (2002) subjects (1.5 x 105 ng/h-kg) and those from Hays and Solomon (1965)
(2.5 x 105 ng/h-kg) is easily explained by the difference in experimental conditions between the two studies. Hays and Solomon's subjects fasted 12 h prior to the administration of the 131I, whereas Greer and coauthors' subjects had no dietary restrictions prior to 125I administration. As a result, intrathyroidal I levels would have been lower in the fasted individuals, and as anticipated, the average VmaxcTFi from Hays and Solomon (1965)
would be increased.
Dietary iodine and endogenous inorganic I levels are clearly important in modeling I and kinetics, because excessive I levels cause the ion to inhibit its own uptake (Wolff and Chaikoff, 1948
). The ability of the model to describe the bound and free I fractions in the thyroid and serum provides the basis for subsequent modeling of hormone synthesis and regulation in humans. Measurements of tracer radioactive I can be fitted to predict transfer rates. However, the use of these acute parameters is limited when attempting to describe long-term thyroid kinetics, unless the existing endogenous I and the relationships between the regulating hormones are taken into consideration. Ultimately, such factors as preexisting thyroid conditions and regional dietary iodine might be addressed in a more comprehensive hormone feedback model. In its present state, our model is useful in predicting perchlorate's effect on thyroid I uptake in what is considered the normal population: euthyroid individuals with adequate dietary I.
That the model is capable of predicting I uptake in hyperthyroid subjects by increasing the VmaxTFi supports the usefulness of the current model structure. TSH increases the total amount of NIS in a membrane, thereby increasing VmaxTFi. Gluzman and Niepomniszcze (1983) reported elevated Vmax(s) in thyroid specimens from subjects with Graves' disease, toxic adenoma, and dishormonogenetic goiter. In future versions of the model, the increase of TSH and subsequent effect on this parameter can be described mathematically in order to predict the dose- and time-dependent response of the thyroid activity to various disease states. In specimens from nontoxic nodular goiter, Hashimoto's thyroid, or extranodular tissue from toxic adenoma, Vmax(s) were decreased. However, in all subjects there was little variation in the KmTi. Therefore, one would not expect the underprediction of thyroid inhibition in the subject with Graves' disease to be due to disease-induced lowering of Km, but rather the increased inhibition is mostly likely due to simple interindividual differences. Sensitivity analyses performed on the model for the rat indicates that model-predicted values of inhibition are highly sensitive to even small changes in Km for
. Thus, it is quite possible that changing Km within the range of normal values would account for this apparent discrepancy in the model fit.
The PBPK models developed for perchlorate-induced inhibition have been useful to the ongoing risk assessment of , and helped integrate the data from diverse data sets to evaluate the dose response of adverse effects from low levels of
exposure (U.S. Environmental Protection Agency, 2003
). The resulting parameters may be used in conjunction with those established for the male (Merrill et al., 2003
) and perinatal rat models (Clewell et al., 2003a
,b
) to extrapolate to human gestational and lactational models (Clewell et al., 2001
). In order to further assess model performance and to facilitate the use of these models in risk assessment, a more comprehensive statistical evaluation of model parameters may prove additionally useful. Sensitivity analysis provided insight into the relative importance of model parameters with respect to specific measures of dose. Comparing the highest sensitivity coefficients between the male rat and human models indicated that, at low doses, human serum
levels are most sensitive to urinary clearance, whereas the rat's serum levels are more sensitive to plasma binding parameters (Fig. 15) (Merrill et al., 2003
). The fact that data was available across multiple doses for establishing parameter values for urinary clearance and plasma binding adds confidence to the model's predictive ability. More useful to the application of the models, for human dosimetry predictions, is variability analysis that is performed with known distributions for model parameters. This tool can be applied to the model to allow the prediction of likely ranges of the dosimetrics within a human population.
Modeled effects on hormone regulation are yet to be developed. Perturbations in hormones levels after exposure demonstrate complex differences in the hormone regulatory mechanisms between rats and humans, which are difficult to describe (Clewell et al., 2001
; Merrill et al., 2001
). However, the current model structures may provide a basis for evaluating thyroid effects from other environmental contaminants. For example, excessive exposure to other similarly behaving anions, such as sodium chlorate, thiocyanate, or nitrate, all found to also contaminate ground and surface waters, may contribute to environmental anti-thyroid effects in humans (Hooth et al., 2001
; Wolff and Maurey, 1963
). Further, the possibility of additive anti-thyroid effects to those of perchlorate from these cocontaminants may need to be considered (Kahn et al., 2004
).
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NOTES |
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2 Current address: CIIT Centers for Health Research, Research Triangle Park, NC 12137.
3 Current address: Environmental Health Science, University of Georgia, Athens, GA 30602.
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ACKNOWLEDGMENTS |
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