A Spreadsheet Program for Modeling Quantitative Structure-Pharmacokinetic Relationships for Inhaled Volatile Organics in Humans*

Abstract

The extent and profile of target tissue exposure to toxicants depend upon the pharmacokinetic processes, namely, absorption, distribution, metabolism and excretion. The present study developed a spreadsheet program to simulate the pharmacokinetics of inhaled volatile organic chemicals (VOCs) in humans based on information from molecular structure. The approach involved the construction of a human physiologically-based pharmacokinetic (PBPK) model, and the estimation of its parameters based on quantitative structure-property relationships (QSPRs) in an Excel® spreadsheet. The compartments of the PBPK model consisted of liver, adipose tissue, poorly perfused tissues and richly perfused tissues connected by circulating blood. The parameters required were: human physiological parameters such as cardiac output, breathing rate, tissue volumes and tissue blood flow rates (obtained from the biomedical literature), tissue/air partition coefficients (obtained using QSPRs developed with rat data), blood/air partition coefficients (Pb) and hepatic clearance (CL). Using literature data on human Pb and CL for several VOCs (alkanes, alkenes, haloalkanes and aromatic hydrocarbons), multi-linear additive QSPR models were developed. The numerical contributions to human Pb and CL were obtained for eleven structural fragments (CH3, CH2, CH, C, C=C, H, Cl, Br, F, benzene ring, and H in the benzene ring structure). Using these data as input, the PBPK model written in an Excel® spreadsheet simulated the inhalation pharmacokinetics of ethylbenzene (33 ppm, 7 h) and dichloromethane (100 ppm, 6 h) in humans exposed to these chemicals. The QSPRs developed in this study should be useful for predicting the inhalation pharmacokinetics of VOCs in humans, prior to testing and experimentation.