Modeling the tissue solubilities and metabolic rate constant (Vmax) of halogenated methanes, ethanes, and ethylenes

Experimental solvent:air and tissue:air partition coefficients for 25 halogenated methanes, ethanes, and ethylenes in saline solution; olive oil; and rat blood, muscle, liver, and fat tissues have been examined using theoretical molecular modeling techniques. The metabolic rate constant, Vmax, was also investigated by these techniques for 19 chlorinated compounds in this group. Two graph theoretical approaches (the distance method of Wiener and the connectivity index method of Randic, Kier, and Hall) and an approach utilizing ad hoc molecular descriptors were employed. Satisfactory regression models for solubility were obtained with both the Randic-Kier-Hall approach and the ad hoc descriptors approach. Fluorine substituents decrease tissue solubilities, whereas both clorine and bromine substituents increase tissue solubilities, with the relative influence being Cl less than Br. Tissue solubilities can also be represented conveniently in terms of contributions from oil and saline solubilities, a procedure reinforced by factor analysis of the data. Equations derived by these methods adequately estimated the solubilities for eight additional compounds. No approach could successfully model Vmax for all 19 compounds, but a subset of 16 compounds was modeled using the connectivity indices. The equation is limited in its use but indicated future modeling directions for Vmax.