Health Implications of Perchlorate Ingestion (2005) / Chapter Skim
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Appendix E Physiologically Based Pharmacokinetic Modeling
Appendix E Physiologically Based Pharmacokinetic Modeling
Pages 219-260
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From page 219... ...
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 toaddressdose-responseissuesassociatedwithpotentially sensitivepopulations (Clewell et al. 2001, 2003a,b; Merrill 2001b, Merrill et al.
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From page 220... ...
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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From page 221... ...
(2001) later proposed a suite of initial PBPK models that incorporated important steps in the mode of action of perchlorate (NIS iodide uptake inhibition)
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From page 222... ...
, dose, and route of exposure with the parallelogram approach discussed in Chapter 4. The structures of the PBPK models acrosslife stages shared physiologic compartments and biologic and chemical-specific sources of parameter
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From page 223... ...
. 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)
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From page 224... ...
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.
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From page 225... ...
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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From page 226... ...
(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)
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From page 227... ...
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.
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From page 228... ...
- RupTFP PTFP , (2) partitioning passive diffusion NIS transport with blood follicle to stroma stroma to follicle 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.
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From page 229... ...
, (5) PTLP active passive diffusion transport follicle to colloid follicle to colloid The active transport of perchlorate from the thyroid stroma to the follicle (RupTFP)
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From page 230... ...
Although the committee considers the inclusion of the competitive inhibition of thyroid perchlorate uptake by iodide as being more consistent with the underlying assumption of competitive inhibition, it agrees with the authors that this simplification has little or no effect on the PBPK simulations. Thus, the biochemical parameters controlling the uptake of perchlorate into the thyroid gland and within the three main regions (capillary bed or stroma, follicle, and colloid or lumen)
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From page 231... ...
(2000) to provide a more detailed description of the disposition of perchlorate and its interactions with iodide in adult male rats.
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From page 232... ...
Abbreviations: ClO4 , ! perchlorate ion; GI, gastrointestinal; IV, intravenous; NIS, sodium-iodide symporter; PBPK, physiologically based pharmacokinetic; RBCs, red blood cells.
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From page 233... ...
The basis of those model parameter values has been extensively peer-reviewed, so only selected parameters and simulation issues will be highlighted here. For instance, increases in thyroid perchlorate were observed in 2-week drinking-water exposure studies conducted by Yu et al.
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From page 234... ...
The first-order clearance value, 0.07 L/hr per kilogram of body weight, is about 25% of the glomerular filtration rate for a male Sprague-Dawley rat, which supports the need to include protein binding in the model in that perchlorate should be readily filtered by the glomeruli. Given the importance of urinary clearance for the model to simulate serum perchlorate concentrations, and thus inhibition of thyroid iodide uptake, independent studies should be conducted to improve the estimation of urinary clearanceofperchlorate(and iodide)
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From page 235... ...
injection of drinking-water exposure to perchlorate and oral gavage or IV and IP injection of iodide. To facilitate comparisons among the final PBPK models, the final physiologic and biochemical values for the adult rat PBPK model and the other PBPK models of the pregnant rat and fetus, lactating rat and neonate, and adult human are summarized together in Table E-1.
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From page 236... ...
236 na b b b Adult Hum ~70.0 65.1 12.4 21.0(M)
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From page 237... ...
237 b b b c 15.0 27.6 16.5 13.0 33.0 5.2 17.5 22.0 1.0 5.8 -- -- 1.6 0.31 0.56 0.05 0.99 0.56 1.80 2.30 1.15 .800 - 18.3-32.5 20.3-30.3 14.0 16.9 40.8 .07 14.0 18.0 1.61 0.058 -- -- .61 0.31 0.50 0.05 0.99 0.56 3.21 5.64 1.15 .730 - 45.0 .19 14.0-21.0 .9-1.97 40.8 7.0 14.0 18.0 1.61 .0580 -- .0-15.09 1.6 0.31 0.50 0.05 0.99 0.56 1.80 2.30 1.15 .730 - 18.3 20.3 67.8 24.0 76.0 -- .63 .54 .64 10.4 -- -- .61 terse 0.31 0.56 -- 0.99 0.56 1.80 2.30 1.15 .730 - Param 45.0 .19 14.0 24.0 76.0 7-8.1 14.0 18.0 13.6 .85 .0-12.30 .2-1.20 1.6 0.31 0.56 .050 0.99 0.56 0.50 1.30 1.15 .730 0.56 0 b b b 24.4 15.7 14. 24.0 76.0 .96 14.0 17.0 1.61 5.8 -- -- .61 Perchlorate-Specific 0.31 0.56 .050 0.99 0.56 0.70 .701 1.00 .730 - kg)
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From page 238... ...
238 na -4 5 4 8 10 10 10 10 b b × × × × Adult Hum -- -- -- .130 7.00 0.60 0.80 .001 1.00 -- -- -- 1.0 0.01 1.8 5.0 1.0 0-18) -5 5 3 8 10 10 10 10 × × × × PND Neonate -- -- -- .130 7.00 1.00 1.00 .001 1.00 -- -- -- 4.0 0.01 1.5 1.5 1.0 (Rat, -5 5 3 8 10 10 10 10 × × × × Lactation amD -- .660 .392 .130 7.00 1.00 1.00 .500 1.00 0.01 .100 -- 4.0 0.01 1.5 1.5 1.0 a 3 10 -5 5 0-21)
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From page 239... ...
239 5 b5 b5 5 6 4 2 10 10 10 10 10 10 10 × × × × × × × 2.5 .02 1.0 2.0 1.0 -- -- -- -- 1.8 5.0 0.025 0.1265 4 6 5 5 4 3 10 10 10 10 10 10 × × × × × × 1.0 -- 1.0 1.5 8.0 -- -- -- -- -- -- -- -- -- -- -- -- 1.0 2.0 0.01 .00750 4 5 6 5 5 5 4 6 4 4 3 10 10 10 10 10 10 10 10 10 10 10 × × × × × × × × × × × 1.0 1.5 1.0 1.5 8.0 .51 .02 .01 .02 -- -- 1.0 9.0 0.034 .070 4 5 5 5 5 4 3 10 10 10 10 10 10 10 × × × terse × × × × 1.0 1.0 1.0 1.0 4.0 -- -- -- -- -- -- -- -- -- -- 1.5 1.5 0.01 - Param 4 5 5 5 5 5 4 5 4 4 3 10 10 10 10 10 10 10 10 10 10 10 × × × × × × × × × × × 1.0 1.0 8.0 1.0 6.0 .01 .22 -- -- .01 .06 .0650 .120 1.0 4.0 0.034 0.07 4 b5 b4 5 5 4 3 10 10 10 10 10 10 10 × × × × × × × 2.0 1.7 2.0 Perchlorate-Specific 1.8 5.0 -- -- -- -- -- -- -- -- 1.1 3.4 0.032 0.07 kg)
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From page 240... ...
240 na b b b b Adult Hum -- 0.21 0.40 0.05 1.09 0.44 0.50 3.50 0.70 .001 -- -- -- -- .150 7.00 0.20 2.00 0-18) PND Neonate -- 0.21 0.40 0.05 1.09 0.44 1.20 1.00 1.00 .001 -- -- -- -- .150 7.00 0.04 0.09 (Rat, Lactation amD 0.80 0.21 0.40 0.05 1.09 0.44 1.00 1.00 0.70 .001 -- -- 08.0 .001 .150 7.00 0.80 0.60 a 0-21)
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From page 241... ...
241 -4 -4 6 5 9 8 b6 b5 6 5 10 10 10 10 10 10 10 10 10 10 × × × × × × × × × × .060 1.00 -- -- -- 1.0 1.0 4.0 1.5 1.0 1.0 -- -- -- .04 9.0 4.0 7.0 -4 -4 6 4 9 7 -6 6 6 5 10 10 10 10 10 10 10 10 10 10 × × × × × × × × × × .020 1.00 -- -- -- 1.0 1.0 4.0 1.3 1.0 6.0 .060 1.0 .0250 -- 2.0 4.0 2.5 -- -- -- - -4 -4 6 4 9 7 -7 b6 6 6 5 6 5 10 10 10 10 10 10 10 10 10 10 10 10 10 × × × × × × × × × × × × × .200 1.00 -- .020 .020 1.0 1.0 4.0 5.0 1.0 6.0 0.1 .07 .020 4.0 2.0 4.0 4.0 .04 .08 4 -4 -4 6 10 9 6 b6 6 6 5 10 10 10 × 10 10 10 10 10 10 × × × × × × × × × .020 1.00 -- -- -- 1.0 4.0 4.0 0-5.0 1.0 4.0 -- -- -- 4.0 2.0 4.0 7.0 -- - -4 -7 6 4 9 6 -6 b6 6 6 4 6 4 10 10 10 10 10 10 10 10 10 10 10 10 10 × × × × × × × × × × × × × .100 1.00 0.005 0.01 -- 1.0 4.0 4.0 4.4 1.0 4.0 .030 1.0 -- 4.0 1.0 4.0 6.0 .04 .04 -4 -7 6 6 9 6 6 b6 b6 6 5 10 10 10 10 10 10 10 10 10 10 10 × × × × × × × × × × × .100 1.00 -- -- -- .01 4.0 4.0 5.4 1.0 4.0 0.1 1.2 -- 4.0 2.0 4.0 5.0 -- - kg)
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From page 242... ...
242 na so from 11,y usted protein Adult Hum adj -- -- -- -- -- -- -- 0.1 -- only da but were ]
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From page 243... ...
243 M, liter;,L; yticapac m muix ma, skin. kilogram x ma ofe kg, V hour; tract; volum hr, VSk, weight; constant; gastrointestinal ofe body by volum scaled VGI, Michaelis-Menten, K m day; transport or day; postnatal binding gestation PND,; for GD, le;a capacity nanogram fem mu ng, F, ximam porter; C, weight; x sym ma V body, -iodide BW transport; sodium or NIS, Abbreviations: le;am binding for
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From page 244... ...
In addition to potential differences in NIS protein expression between subjects, there are potential environmental influences on the variability of the kinetic data, including differences in endogenous iodide concentrations resulting from differences in diets, the timing of blood collections relative to meals, the presence of other potential inhibitors of NIS, and other factors that were not controlled for. As discussed in Chapter 3 and Appendix D, the differences in absolute capacities of the NIS or differences in basal iodide concentrations between humans by themselves should not have an important effect on intersubject sensitivity to the rates of perchlorate inhibition of iodide uptake.
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From page 245... ...
Regardless, including a skin compartment was critical to the human model simulations of serum perchlorate concentrations, so the paucity of human data on the disposition of perchlorate and iodide in skin remains a concern for future research. Although no formal sensitivity analysis was performed on the human PBPK model, it is likely that, in addition to the skin compartment, urinary clearance of both anions and the plasma-protein binding of perchlorate may be important for additional future research.
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From page 246... ...
In the PBPK models just described for adult rats and humans, the volume of each tissue and its corresponding blood flow were treated as constants. However, during pregnancy, some tissue volumes and blood flow rates change in the mother and the embryo and fetus and must be treated as variables rather than constants in the PBPK model.
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From page 247... ...
Appendix E 247 Pregnant Female Fetus IV Bound ClO4- Bound ClO4 Plasma Plasma Free ClO4 - Free ClO4 RBCs RBCs Oral GI Contents GI Contents GI Tissue GI Tissue Capillary Bed Capillary Bed Liver Liver Richly Richly Perfused Perfused Kidney Kidney Colloid Urine Colloid Bound Thyroid Thyroid Iodide Follicle Follicle Capillary Bed Capillary Bed Skin Skin Capillary Capillary Bed Bed Fat Poorly Perfused Poorly Perfused Mammary Gland Capillary Bed Capillary Bed Placenta
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From page 248... ...
Those studies were used to develop and refine estimates of NIS transport parameter values, thyroid apical membrane transport parameter values,partitioncoefficients,permeability-areacrossproductsfordiffusion, plasma-protein binding (perchlorate only) , and urinary clearance.
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From page 249... ...
(2003a) also performed a sensitivity analysis to determine which model parameters had the greatest effect on simulations of serum perchlorate concentrations and thyroid iodide uptake.
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From page 250... ...
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.
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From page 251... ...
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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From page 252... ...
. 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.
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From page 253... ...
Thyroid Follicle Capillary Bed FIGURE E-7 Diagram of thyroid and blood subcompartments from iodide PBPK model of lactating and neonatal rat (adapted from Clewell et al.
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From page 254... ...
(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.
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From page 255... ...
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.
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From page 256... ...
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 theapplicationofthemodelsforextrapolatinginternal-dosesurrogatesfrom 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.
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From page 257... ...
2003b. Predicting neonatal perchlorate dose and inhibition of iodide uptake in the rat during lactation using physiologically based pharmacokinetic modeling.
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From page 258... ...
2000. Preliminary development of a physiological model for perchlorate in the adult male rat: a framework for further studies.
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From page 259... ...
Human PBPK Model for Perchlorate Inhibition of Iodide Uptake in the Thyroid. MemorandumwithattachmentstoAnnieM.Jarabek,NCEA,U.S.Environ mental Protection Agency, Research Triangle Park, NC, from Elaine Merrill, Air Force Research Laboratory/HEST, Department of the Air Force, Wright-Patterson Air Force Base, OH.
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From page 260... ...
2001. Tissue distribution and inhibition of iodide uptake by perchlorate in pregnant and lactating rats in drinking water studies.
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