Quantitative studies of the inhibitory effect of perchlorate on the concentration of 36ClO4−125I− and 99mTcO4− in salivary glands of male and female mice

Lazarus, John H.; Harden, R. McG.; Robertson, James Louis

doi:10.1016/0003-9969(74)90063-6

Cited by 7 publications

(3 citation statements)

References 13 publications

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“…¡ is approximately a factor of 10 lower than that of iodide (Halmi and Stuelke, 1959;Harden et al, 1968;Chow et al, 1969;Lazarus et al, 1974).…”

Section: Model Developmentmentioning

confidence: 84%

“…In the model, a slightly lower value of 1.0£10 9 ng/l was used for K m TL i , based on the ability of the model to better fit the later (>8 h) time points. The binding of ClO 4 ¡ to NIS was assigned a value ranging from 1.0£10 5 to 1.8£10 5 ng/l, based on the work of Wolff and Maurey (1963) as well as several other studies, suggesting that the K m of ClO 4 ¡ is approximately a factor of 10 lower than that of iodide (Halmi and Stuelke, 1959;Harden et al, 1968;Chow et al, 1969;Lazarus et al, 1974).…”

Section: Model Developmentmentioning

confidence: 99%

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The use of physiologically based models to integrate diverse data sets and reduce uncertainty in the prediction of perchlorate and iodide kinetics across life stages and species

Clewell¹,

Merrill²,

Robinson

2001

Toxicol Ind Health

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The effects of perchlorate on the incorporation of iodide into thyroid hormones have been studied for more than 40 years in many species and under varying exposure conditions. Nevertheless, the database for this drinking water contaminant is still incomplete, particularly with regard to human developmental risk. A method for integrating the available data and forming meaningful conclusions for risk assessment is needed. To this end, an initial suite of physiologically based pharmacokinetic (PBPK) models has been developed, which incorporates physiological data for the relevant species and life stages and kinetic data for perchlorate and iodide, as well as the interaction between the two anions. The validated models successfully describe perchlorate-induced inhibition of thyroid iodide uptake and perchlorate and iodide kinetics in the male, pregnant, lactating, fetal, and neonatal rats and the adult humans. The relationships of model-predicted internal dose metrics and kinetic parameters allow a direct comparison of internal dose metrics across life stages in rats and humans. By incorporating all the available data, these models provide a framework for species and life stage extrapolation where the lack of specific data sets would otherwise limit predictive capability. This paper demonstrates two approaches for calculating life stage-specific equivalent doses in a risk assessment for perchlorate: the direct combination of validated model predictions, and the development of preliminary PBPK models for the human-sensitive populations based on the relationship of the parameters in the validated rat and human models. Either approach can be used to perform the needed dosimetry. However, the second approach provides the advantage of a preliminary human life stage-specific PBPK model that can be used for identification of key data gaps and estimation of uncertainty.

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“…¡ is approximately a factor of 10 lower than that of iodide (Halmi and Stuelke, 1959;Harden et al, 1968;Chow et al, 1969;Lazarus et al, 1974).…”

Section: Model Developmentmentioning

confidence: 84%

Section: Model Developmentmentioning

confidence: 99%

The use of physiologically based models to integrate diverse data sets and reduce uncertainty in the prediction of perchlorate and iodide kinetics across life stages and species

Clewell¹,

Merrill²,

Robinson

2001

Toxicol Ind Health

View full text Add to dashboard Cite

show abstract

“…Thus the K m value for binding of ClO 4 to NIS (KmTF p ) was set between these two values (1.0 ϫ 10 5 ng/l) in the model. This value is further supported by various literature sources suggesting that ClO 4 actually has as much as an order of magnitude greater affinity for NIS than Iitself (Chow et al, 1969;Halmi and Stuelke, 1959;Harden et al, 1968;Lazarus et al, 1974). The K m for the second transport mechanism in the thyroid colloid (KmTL p ) was set to 1.0 ϫ 10 8 ng/l, approximately a factor of 10 lower than the K m values used for iodide.…”

Section: Dosing Proceduresmentioning

confidence: 63%

Predicting Fetal Perchlorate Dose and Inhibition of Iodide Kinetics during Gestation: A Physiologically-Based Pharmacokinetic Analysis of Perchlorate and Iodide Kinetics in the Rat

Clewell¹

2003

Toxicological Sciences

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Perchlorate (ClO4-) disrupts endocrine homeostasis by competitively inhibiting the transport of iodide (I-) into the thyroid. The potential for health effects from human exposure to ClO4- in drinking water is not known, but experimental animal studies are suggestive of developmental effects from ClO4- induced iodide deficiency during gestation. Normal hormone-dependent development relies, in part, on synthesis of hormones in the fetal thyroid from maternally supplied iodide. Although ClO4- crosses the placenta, the extent of inhibition in the fetal thyroid is unknown. A physiologically-based pharmacokinetic (PBPK) model was developed to simulate ClO4- exposure and the resulting effect on iodide kinetics in rat gestation. Similar to concurrent model development for the adult male rat, this model includes compartments for thyroid, stomach, skin, kidney, liver, and plasma in both mother and fetus, with additional compartments for the maternal mammary gland, fat, and placenta. Tissues with active uptake are described with multiple compartments and Michaelis-Menten (M-M) kinetics. Physiological and kinetic parameters were obtained from literature and experiment. Systemic clearance, placental-fetal transport, and M-M uptake parameters were estimated by fitting model simulations to experimental data. The PBPK model is able to reproduce maternal and fetal iodide data over five orders of magnitude (0.36 to 33,000 ng/kg 131I-), ClO4- distribution over three orders of magnitude (0.01 to 10 mg/kg-day ClO4-) and inhibition of maternal thyroid and total fetal I- uptake. The model suggests a significant fetal ClO4- dose in late gestation (up to 82% of maternal dose). A comparison of model-predicted internal dosimetrics in the adult male, pregnant, and fetal rat indicates that the fetal thyroid is more sensitive to inhibition than that of the adult.

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Quantitative histochemistry of sex differences of periodic acid-schiff reaction in mouse submandibular gland

Sato¹,

Maruyama²,

Chen³

1977

Archives of Oral Biology

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Quantitative studies of the inhibitory effect of perchlorate on the concentration of 36ClO4−125I− and 99mTcO4− in salivary glands of male and female mice

Cited by 7 publications

References 13 publications

The use of physiologically based models to integrate diverse data sets and reduce uncertainty in the prediction of perchlorate and iodide kinetics across life stages and species

The use of physiologically based models to integrate diverse data sets and reduce uncertainty in the prediction of perchlorate and iodide kinetics across life stages and species

Predicting Fetal Perchlorate Dose and Inhibition of Iodide Kinetics during Gestation: A Physiologically-Based Pharmacokinetic Analysis of Perchlorate and Iodide Kinetics in the Rat

Quantitative histochemistry of sex differences of periodic acid-schiff reaction in mouse submandibular gland

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