Structure-activity relationship (SAR) models established in vitro with the neutral red cytotoxicity assay

The neutral red (NR) cytotoxicity assay has been applied to the determination of structure-activity relationships (SARs). The in vitro cytotoxic potency of a series of alcohols with varying chain lengths, of chlorinated phenolics, of nitro- and methyl-containing phenolics and of chlorinated toluenes could be directly correlated with the lipophilicity of the molecules, expressed in terms of their log octanol/water partition coefficients (log P values). Dinitrotoluenes were outliers, in that their cytotoxicity was not a function of their lipophilicity. The sequence of cytotoxicity for a series of divalent cationic metals was a function of softness: the softer the metal (i.e. the lower its chemical softness parameter, sigma(p)), the greater its cytotoxicity. The SAR models developed with the NR assay were consistent with similar models developed in vivo. The NR assay has been further modified to include, when useful, total protein determinations.