Characterizing uncertainty and population variability in the toxicokinetics of trichloroethylene and metabolites in mice, rats, and humans using an updated database, physiologically based pharmacokinetic (PBPK) model, and Bayesian approach.

We have developed a comprehensive, Bayesian, PBPK model-based analysis of the population toxicokinetics of trichloroethylene (TCE) and its metabolites in mice, rats, and humans, considering a wider range of physiological, chemical, in vitro, and in vivo data than any previously published analysis of TCE. The toxicokinetics of the "population average," its population variability, and their uncertainties are characterized in an approach that strives to be maximally transparent and objective. Estimates of experimental variability and uncertainty were also included in this analysis.

Reconstructing exposures from small samples using physiologically based pharmacokinetic models and multiple biomarkers.

This study examines the use of physiologically based pharmacokinetic (PBPK) models for inferring exposure when the number of biomarker observations per individual is limited, as commonly occurs in population exposure surveys. The trade-off between sampling multiple biomarkers at a specific time versus fewer biomarkers at multiple time points was investigated, using a simulation-based approach based on a revised and updated chlorpyrifos PBPK model originally published. Two routes of exposure, oral and dermal, were studied as were varying levels of analytic measurement error.

Parameters for Carbamate Pesticide QSAR and PBPK/PD Models for Human Risk Assessment.

Our interest in providing parameters for the development of quantitative structure physiologically based pharmacokinetic/pharmacodynamic (QSPBPK/PD) models for assessing health risks to carbamates (USEPA 2005) comes from earlier work with organophosphorus (OP) insecticides (Knaak et al. 2004). Parameters specific to each carbamate are needed in the construction of PBPK/PD models along with their metabolic pathways.

A physiologically based pharmacokinetic/pharmacodynamic model for carbofuran in Sprague-Dawley rats using the exposure-related dose estimating model.

Carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl-N-methylcarbamate), a broad spectrum N-methyl carbamate insecticide, and its metabolite, 3-hydroxycarbofuran, exert their toxicity by reversibly inhibiting acetylcholinesterase (AChE). To characterize AChE inhibition from carbofuran exposure, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed in the Exposure-Related Dose Estimating Model (ERDEM) platform for the Sprague-Dawley (SD) rat. Experimental estimates of physiological, biochemical, and physicochemical model parameters were obtained or based on data from the open literature.

In vitro metabolism of the fungicide and environmental contaminant trans-bromuconazole and implications for risk assessment.

trans-Bromuconazole is a chiral chemical representative of a class of triazole derivatives known to inhibit specific fungal cytochrome P-450 (CYP) reactions. Kinetic measurements and delineation of metabolic pathways for triazole chemicals within in vitro hepatic microsomes are needed for accurate risk assessment and predictive in vivo physiological modeling. The studies described here were conducted with rat liver microsomes to determine Michaelis-Menten saturation kinetic parameters (Vmax and KM) for trans-bromuconazole using both substrate depletion and product formation reaction velocities.

Issues in the pharmacokinetics of trichloroethylene and its metabolites.

Much progress has been made in understanding the complex pharmacokinetics of trichloroethylene (TCE) . Qualitatively, it is clear that TCE is metabolized to multiple metabolites either locally or into systemic circulation. Many of these metabolites are thought to have toxicologic importance.

Comments on article "Applying mode-of-action and pharmacokinetic considerations in contemporary cancer risk assessments: an example with trichloroethylene" by Clewell and Andersen.

In their 2004 article, Clewell and Andersen provide their perspective on the application of mode-of-action (MOA) and pharmacokinetic considerations in contemporary cancer risk assessment using trichloroethylene (TCE) as a case example. TCE is a complex chemical toxicologically, with multiple metabolites, multiple sites of observed toxicity, and multiple potential MOAs. As scientists who are responsible for revising the U.