Bayesian Calibration of a Physiologically Based Pharmacokinetic/Pharmacodynamic Model of Carbaryl Cholinesterase Inhibition

Abstract

Carbaryl, an N-methyl carbamate (NMC), is a common insecticide that reversibly inhibits neuronal cholinesterase activity. The objective of this work was to use a hierarchical Bayesian approach to estimate the parameters in a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model from experimental measurements of carbaryl in rats. A PBPK/PD model was developed to describe the tissue dosimetry of carbaryl and its metabolites (1-naphthol and "other hydroxylated metabolites") and subsequently to predict the carbaryl-induced inhibition of cholinesterase activity, in particular in the brain and blood. In support of the model parameterization, kinetic tracer studies were undertaken to determine total radioactive tissue levels of carbaryl and metabolites in rats exposed by oral or intravenous routes at doses ranging from 0.8 to 9.2 mg/kg body weight. Inhibition of cholinesterase activity in blood and brain was also measured from the exposed rats. Markov Chain Monte Carlo (MCMC) calibration of the rat model parameters was implemented using prior information from literature for physiological parameter distributions together with kinetic and inhibition data on carbaryl. The posterior estimates of the parameters displayed at most a twofold deviation from the mean. Monte Carlo simulations of the PBPK/PD model with the posterior distribution estimates predicted a 95% credible interval of tissue doses for carbaryl and 1-naphthol within the range of observed data. Similar prediction results were achieved for cholinesterase inhibition by carbaryl. This initial model will be used to determine the experimental studies that may provide the highest added value for model refinement. The Bayesian PBPK/PD modeling approach developed here will serve as a prototype for developing mechanism-based risk models for the other NMCs.

Parameters for Pyrethroid Insecticide QSAR and PBPK/PD Models for Human Risk Assessment

“…The parameters shown in Table 1 (Blancato et al 2000) are needed for developing pyrethroid PBPK/PD models, as is information on the metabolic pathways of specific pyrethroids in laboratory test animals and humans. Parameters may be obtained by fitting the output from models to experimental data gathered from in vivo studies (Zhang et al 2007;Nong et al 2008), in conjunction with using (1) experimental data obtained from in vitro studies, (2) quantitative structure-activity relationships (QSAR) and (3) other mathematical models, such as the mechanistic Poulin-Theil (2000;2002a; algorithms for obtaining blood:tissue partition coefficients.…”

Biomonitoring of Pesticides: Pharmacokinetics of Organophosphorus and Carbamate Insecticides

“…The pharmacokinetics of organophosphorus and carbamate insecticides has been studied in a range of species, including humans (e.g., see Moody and Franklin, 1987;Nolan et al, 1984;Nong et al, 2008;Poet et al, 2004;Timchalk and Poet, 2008;Timchalk et al, 2002Timchalk et al, , 2006Timchalk et al, , 2007aTimchalk et al, , 2007bTomokuni et al, 1985;Tos-Luty et al, 2001;Wu et al, 1996). These insecticides are readily absorbed into the body and, based on the detection of metabolites in human urine, there is good evidence for widespread although low-level exposures (Aprea et al, 1999;Brouwer et al, 1993;Hill et al, 1995;Putnam et al, 2008;Shealy et al, 1997).…”

“…It is also feasible to link dosimetry with biologically based pharmacodynamic (PD) response models based on a common mode of action (i.e., AChE inhibition). In general, pharmacokinetic modeling approaches can be characterized as empirical or physiologically based and both types of models have been applied to understand the toxicological response to some organophosphorus and carbamate chemicals in multiple species (Brimer et al, 1994;Gearhart et al, 1990;Nong et al, 2008;Pena-Egido, 1988;Sultatos, 1990;Sultatos et al, 1990;Tomokuni et al, 1985;Wu et al, 1996).…”

“…The general model structure is based on an understanding of comparative physiology and xenobiotic metabolism, a chemical's physical properties that define tissue partitioning, the rates of biochemical reactions determined from both in vivo and in vitro experimentation, and the physiological characteristics of the species of interest (Krishnan and Andersen, 2001). PBPK models have been developed to describe target tissue dosimetry for a broad range of environmental contaminants, such as solvents, heavy metals, and pesticides, including organophosphate and carbamate insecticides (Andersen et al, 1987;Corley et al, 1990;Gearhart et al, 1990;Nong et al, 2008;Poet et al, 2004;Sultatos, 1990;Timchalk et al, 2002). A number of reviews have been published on the development, validation, application, and limitations of PBPK models in human health risk assessment (Andersen, 1995(Andersen, , 2003Clewell, 1995;Clewell and Andersen, 1996;Frederick, 1995;Krishnan and Andersen, 2001;Leung and Paustenbach, 1995;Mason and Wilson, 1999).…”

A Semiphysiologically Based Pharmacokinetic Modeling Approach to Predict the Dose-Exposure Relationship of an Antiparasitic Prodrug/Active Metabolite Pair

“…Note: The volume of tissue and vascular blood in the liver represents 95 and 5%, respectively, of total liver volume (Nong et al, 2008). P, pafuramidine; F, furamidine; M, other metabolites.…”