A mechanistic algorithm for predicting blood:air partition coefficients of organic chemicals with the consideration of reversible binding in hemoglobin.

The objectives of the present study were (i) to develop a mechanistic algorithm for predicting blood:air partition coefficients (PCs) of volatile organic chemicals (VOCs), and (ii) to apply this algorithm to predict the rat blood:air PCs of several VOCs. The approach consisted initially of developing an algorithm to predict the blood:air PCs of VOCs solely based on the solubility phenomenon and then of extending the algorithm to include protein binding. The algorithm based on solubility phenomenon predicted blood:air PCs by dividing the estimated solubility of chemicals in blood by their saturable vapor concentrations at 37 degrees C. The rat blood:air PCs predicted using this algorithm were in close agreement with the experimental values for relatively hydrophilic VOCs such as ketones, alcohols, acetate esters, and diethyl ether (with an average ratio of 0.80 between predicted and experimental values), whereas there was a marked discrepancy in the case of relatively lipophilic VOCs such as alkanes, haloalkanes, and aromatic hydrocarbons (with an average ratio of 0.21 between predicted and experimental values). This discrepancy was hypothesized to be due to the occurrence of reversible binding of these substances in rat hemoglobin based on literature evidence of the existence of hydrophobic holes (or "xenon-binding" pockets). The association constants (Ka) for the presumed reversible hemoglobin binding of several alkanes, haloalkanes, and aromatic hydrocarbons were estimated from the difference between chemical concentration in rat erythrocytes predicted by the solubility-based algorithm and that deduced from the previously published experimental blood:air PCs for these chemicals (which presumably included contribution of hemoglobin binding in addition to "true" solubility). The Ka values estimated in this manner ranged from 504 to 4725 M-1 for the chemicals investigated in the present study. The a priori predictions of the percentage of several VOCs (diethyl ether, methyl isobutyl ketone, n-hexane, toluene, and chloroform) in rat erythrocytes obtained with the algorithm using these Ka estimates corresponded well with previously published experimental data. The mechanistic algorithm developed in the present study should be useful for predicting the "apparent" blood:air PCs of VOCs regardless of exposure concentrations, by accounting for the relative contributions of both the true chemical solubility and reversible hemoglobin binding.