A spreadsheet program for modeling quantitative structure-pharmacokinetic relationships for inhaled volatile organics in humans

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 (R) 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 (R) 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.