QUANTUM-CHEMICAL DESCRIPTORS FOR ESTIMATING THE ACUTE TOXICITY OF ELECTROPHILES TO THE FATHEAD MINNOW (PIMEPHALES-PROMELAS) - AN ANALYSIS BASED ON MOLECULAR MECHANISMS

Estimating the toxicity of reactive xenobiotics to aquatic organisms r equires physicochemical descriptors of passive transport and chemical reactions with nucleophilic biological ligands. Herein, electrophiles whose toxic action is attributed to nucleophilic substitution (S-N). M ichael-type addition and Schiff-base formation were examined. Training sets for each molecular mechanism were generated through substructure search applied to chemicals in a fathead minnow (Pimephales promelas) database. Based on a delineation of compounds by a presumed molecular mechanism, relationships between modes of toxic action, potency (96-h our LC(50) values) and mechanistically-appropriate quantum-chemical de scriptors were explored. Monohalo-C(sp(3)) function which may give ris e to S-N reactivity was encountered in 35 compounds. The inclusion of E(LUMO), a nonspecific electrophilicity descriptor, to the generic LC( 50) - hydrophobicity relation increased the explained variance from r( 2) = 36% to 69%. Eighteen potential Michael-type accepters, mainly acr ylates, were identified by the presence of a localized CC double bond at an alpha, beta position to a polar group. Due to different modes of action. the toxic potency of these chemicals varies almost independen tly of hydrophobicity (r(2) = 0.12). Two additional electronic descrip tors that are consistent with the likely molecular mechanism provide a multivariate QSAR with r(2) = 0.78. Forty-five aldehydes and 3 formam ides comprised the training set associated with probable Schiff-base m echanism of toxicity. The results suggest a marginal increase of toxic potency from that expected due to narcosis for more electrophilic car bonyl groups. Overall, it was concluded that regressions based on data sets that combine reactive chemicals with narcotics typically require an electronic descriptor in addition to hydrophobicity, even if the c ompounds all contain a common electrophilic moiety related to the puta tive specific reaction mechanism. However, without the generation of a dditional toxicity data from chemical sets that incorporate a broader range of electronic and steric character, it will likely remain extrem ely difficult to develop a quantitative ability to predict the potency of electrophilic compounds.