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 vol atile organic chemicals (VOCs), and (ii) to apply this algorithm to pr edict the rat blood:air PCs of several VOCs. The approach consisted in itially of developing an algorithm to predict the blood:air PCs of VOC s solely based on the solubility phenomenon and then of extending the algorithm to include protein binding. The algorithm based on solubilit y phenomenon predicted blood:air PCs by dividing the estimated solubil ity of chemicals in blood by their saturable vapor concentrations at 3 7 degrees C. The rat blood:air PCs predicted using this algorithm were in close agreement with the experimental values for relatively hydrop hilic VOCs such as ketones, alcohols, acetate esters, and diethyl ethe r (with an average ratio of 0.80 between predicted and experimental va lues), whereas there was a marked discrepancy in the case of relativel y lipophilic VOCs such as alkanes, haloalkanes, and aromatic hydrocarb ons (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 (K-a) for the presumed r eversible hemoglobin binding of several alkanes, haloalkanes, and arom atic hydrocarbons were estimated from the difference between chemical concentration in rat erythrocytes predicted by the solubility-based al gorithm and that deduced from the previously published experimental bl ood:air PCs for these chemicals (which presumably included contributio n of hemoglobin binding in addition to ''true'' solubility). The K-a v alues estimated in this manner ranged from 504 to 4725 M(-1) for the c hemicals investigated in the present study. The a priori predictions o f the percentage of several VOCs (diethyl ether, methyl isobutyl keton e, n-hexane, toluene, and chloroform) in rat erythrocytes obtained wit h the algorithm using these K-a estimates corresponded well with previ ously 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 accou nting for the relative contributions of both the true chemical solubil ity and reversible hemoglobin binding. (C) 1996 Academic Press, Inc.