The Use of PBPK Models to Inform Human Health Risk Assessment: Case Study on Perchlorate and Radioiodide Human Lifestage Models

Abstract

Physiologically-based pharmacokinetic (PBPK) models are often submitted to or selected by agencies, such as the U.S. Environmental Protection Agency (U.S. EPA) and Agency for Toxic Substances and Disease Registry, for consideration for application in human health risk assessment (HHRA). Recently, U.S. EPA evaluated the human PBPK models for perchlorate and radioiodide for their ability to estimate the relative sensitivity of perchlorate inhibition on thyroidal radioiodide uptake for various population groups and lifestages. The most well-defined mode of action of the environmental contaminant, perchlorate, is competitive inhibition of thyroidal iodide uptake by the sodium-iodide symporter (NIS). In this analysis, a six-step framework for PBPK model evaluation was followed, and with a few modifications, the models were determined to be suitable for use in HHRA to evaluate relative sensitivity among human lifestages. Relative sensitivity to perchlorate was determined by comparing the PBPK model predicted percent inhibition of thyroidal radioactive iodide uptake (RAIU) by perchlorate for different lifestages. A limited sensitivity analysis indicated that model parameters describing urinary excretion of perchlorate and iodide were particularly important in prediction of RAIU inhibition; therefore, a range of biologically plausible values available in the peer-reviewed literature was evaluated. Using the updated PBPK models, the greatest sensitivity to RAIU inhibition was predicted to be the near-term fetus (gestation week 40) compared to the average adult and other lifestages; however, when exposure factors were taken into account, newborns were found to be populations that need further evaluation and consideration in a risk assessment for perchlorate.

Scientific Opinion on the risks to public health related to the presence of perchlorate in food, in particular fruits and vegetables

“…For breast-fed infants, the thyroid iodine uptake inhibition almost doubled was predicted by the corrected models in comparison to those developed by Clewell and coworkers (e.g. The CONTAM Panel concluded that in view of the limited information available on the changes in thyroid hormone levels under conditions of mild to moderate iodine deficiency and on the thyroid hormone kinetic parameters for pregnant women, and the limitations of the PBK model predictability for iodine-deficient individuals identified by Clewell et al (2007) and McLanahan et al (2014), the results of the BBDR model at low iodine intake should be interpreted with caution. per day, thyroid iodine uptake inhibitions of 17 % and 8 % were predicted by the revised PBK model and the model from Clewell and coworkers, respectively.…”

“…The corrected models were applied to estimate the thyroid iodine uptake inhibition under a steady state perchlorate concentration. The predictions of the corrected models developed by McLanahan et al (2014) were compared to those of the models developed by Clewell and coworkers, showing a good correlation for all life stages, with the exception of the breast-fed infants and lactating women. For breast-fed infants, the thyroid iodine uptake inhibition almost doubled was predicted by the corrected models in comparison to those developed by Clewell and coworkers (e.g.…”

“…The human PBK models developed by Clewell and coworkers were evaluated and reviewed by McLanahan et al (2014). Several errors were reported in the mathematical description of the models, most of them considered to have a little impact on the model output.…”

“…This is particularly important for the transfer of iodine into breast milk, which was decreased by about 3 % (for a perchlorate maternal dose of 7 µg/kg b.w.) McLanahan et al (2014) also evaluated uncertainties and limitations associated with the PBK models and identified data that need to be considered for model refinement. The corrected models were applied to estimate the thyroid iodine uptake inhibition under a steady state perchlorate concentration.…”

Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods

“…We should keep in mind that it is not necessarily the concentration (as peak concentration or area under the curve) that matters, but that some lipophilic (see example in Fig. 4) to predict the internal dose that will be distributed to target organs, and they are increasingly being used in risk assessment across industries (McLanahan et al, 2014). They can be used for in vitro to in vivo, route to route, and animal to human extrapolations (Basketter et al, 2012;Espié et al, 2009;Rietjens et al, 2011).…”