Relationships between Cellular Toxicity, the Maximum Tolerated Dose, Lipophilicity and Electrophilicity

Abstract

Results on cellular toxicity and maximum tolerated dose (MTD) for rats and mice were available for approximately 175 chemicals tested by the US National Toxicology Program. Additionally, the computed log P (log octanol-water partition coefficient) and the lowest unoccupied molecular orbital (LUMO) energy values, a measure of electrophilicity were also available for most of these chemicals. Analysis of the chemicals on the basis of their physical and quantum chemical properties and their toxic effects on cultured cells and rodents showed that: 1) as a group, the more toxic chemicals showed a trend towards higher LUMO energies (i.e. less electrophilic); 2) cytotoxic chemicals exhibited increased lipophilicity; and 3) cytotoxic chemicals were associated with increased systemic toxicity (as measured by the MTD). None of these relationships was expressed in a significant linear fashion as a function of the concentration at which the chemicals exhibited cytotoxicity.