You are here:
Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-throughput In Vitro Data, High-throughput Exposure Modeling, and Physiologically-Based Pharmacokinetic/Pharmacodynamic Modeling
Citation:
Leonard, J., C. Tan, M. Gilbert, K. Isaacs, AND H. El-Masri. Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-throughput In Vitro Data, High-throughput Exposure Modeling, and Physiologically-Based Pharmacokinetic/Pharmacodynamic Modeling. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 151(1):57-70, (2016).
Impact/Purpose:
In this study, a physiologically based pharmacokinetic (PBPK) model was linked with a pharmacodynamic (PD) model to establish internal doses capable of modulating thyroid hormone serum levels in an adult female. Using exposure modeling in combination with the PBPK/PD models, a set of chemicals were investigated for their potential impact on thyroid hormone serum levels. This overall approach provides a mechanism for integrating in vitro data (such as that derived from TPO inhibition assays), pharmacokinetic properties, and exposure levels predicted through high-throughput means when interpreting adverse outcome pathways (AOPs). The utility of this integrated framework is demonstrated using chemicals with varying degrees of TPO inhibitory activity, varying distributions of exposure levels, and varying ADME properties. Impact of the applicability for this integrated framework include 1) the integration of hazard data from high throughput in vitro tests, high throughput exposure predictions, and ADME-related considerations to screen for chemicals of concern and 2) the allowance of chemicals that are considered of low importance in one AOP to be disregarded and for focus to be placed on their effects in other AOPs of interest. There is clear evidence that simply assessing the health risk of a chemical by its potency, as determined solely through in vitro testing, may be misleading and that both exposure and ADME-related properties need to be considered to make better-informed decisions for human health risk assessors in program offices and ORD.
Description:
Some pharmaceuticals and environmental chemicals bind the thyroid peroxidase (TPO) enzyme and disrupt thyroid hormone production. The potential for TPO inhibition is a function of both the binding affinity and concentration of the chemical within the thyroid gland. The former can be determined through in vitro assays, and the latter is influenced by pharmacokinetic properties, along with environmental exposure levels. In this study, a physiologically based pharmacokinetic (PBPK) model was linked with a pharmacodynamic (PD) model to establish internal doses capable of inhibiting TPO in relation to external exposure levels predicted through exposure modeling. The PBPK/PD model was evaluated using published serum or thyroid gland chemical concentrations or circulating thyroxine (T4) and triiodothyronine (T3) hormone levels measured in rats and humans. After evaluation, the model was used to estimate human equivalent intake doses resulting in reduction of T4 and T3 levels by 10% (ED10) for six chemicals of varying TPO-inhibiting potencies. These chemicals were methimazole, 6-propylthiouracil, resorcinol, benzophenone-2, 2-mercaptobenzothiazole, and triclosan. Margin of exposure (MOE) values were estimated for these chemicals using the human equivalent intake doses and predicted population exposure levels for females of child-bearing age. The modeling approach presented here revealed that examining hazard or exposure alone when prioritizing chemicals for risk assessment may be insufficient, and that consideration of pharmacokinetic properties is warranted. This approach also provides a mechanism for integrating in vitro data, pharmacokinetic properties, and exposure levels predicted through high-throughput means when interpreting adverse outcome pathways (AOPs) based on biological responses.
