Citation:

Mallick, P., M. Moreau, G. Song, A. Efremenko, S. Pendse, M. Creek, T. Osimitz, R. Hines, P. Hinderliter, H. Clewell, B. Lake, AND M. Yoon. Development and Application of a Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 173(1):86-99, (2020). https://doi.org/10.1093/toxsci/kfz211

Impact/Purpose:

The purpose of this study was to develop an in vitro to in vivo extrapolation informed life-stage physiologically-based pharmacokinetic model to address concerns regarding age-related sensitivity to pyrethroid pesticides. The study demonstrated efficient metabolic clearances across the ages of concern resulted in comparable, or even lower internal exposures in target tissues in children than in adults in response to the same levels of exposure. This is inconsistent that what is observed in rodent animal models and is largely due to significant species differences in metabolic pathways. These results will directly inform Agency decision-making regarding the safety of this class of chemicals.

Description:

To address concerns around age-related sensitivity to pyrethroids, a life-stage physiologically based pharmacokinetic (PBPK) model, supported by in vitro to in vivo extrapolation (IVIVE) was developed. The model was used to predict age-dependent changes in target tissue exposure of eight pyrethroids, deltamethrin (DLM), cis-permethrin (CPM), trans-permethrin (TPM), esfenvalerate, cyphenothrin, cyhalothrin, cyfluthrin and bifenthrin. A single model structure was used based on previous work in the rat. Intrinsic clearance (Clint) of each individual cytochrome P450 (CYP) or carboxylesterase (CES) enzyme that are active for a given pyrethroid were measured in vitro, then biologically scaled to obtain in vivo age-specific total hepatic CLint. These IVIVE results indicate that, except for bifenthrin, CES enzymes are largely responsible for human hepatic metabolism (>50% contribution). Given the high efficiency and rapid maturation of CESs, clearance of the pyrethroids is very efficient across ages, leading to a blood flow-limited metabolism. Together with age-specific physiological parameters, in particular liver blood flow, the efficient metabolic clearance of pyrethroids across ages results in comparable to or even lower internal exposure in the target tissue (i.e., brain) in children than that in adults in response to the same level of exposure to a given pyrethroid (Cmax ratio in brain between 1 and 25 year old = 0.69, 0.93 and 0.94 for DLM, bifenthrin and CPM, respectively). Our study demonstrated that a life-stage PBPK modeling approach, coupled with IVIVE, provides a robust framework for evaluating age-related differences in pharmacokinetics and internal target tissue exposure in humans for the pyrethroid class of chemicals.

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