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Discriminating Toxicant Classes by Mode of Action: 2. Physico-Chemical Descriptors

: Nendza, M.; Müller, M.


Quantitative Structure Activity Relationships 19 (2001), No.6, pp.581-598
ISSN: 0931-8771
Journal Article
Fraunhofer IUCT ( IME) ()
QSAR; ecotoxicity profile; discriminant analysis; quantum-chemical descriptor; environmental hazard assessment; risk assessment

Environmental contaminants with common mode of toxic action (MOA) are generally expected to have similar structures and/or physico-chemical properties. Calculated descriptors of lipophilic, electronic and steric properties were used to cluster 115 test chemicals by MOA into nine different toxicant classes (non-polar non-specific toxicants, polar non-specific toxicants, uncouplers of oxidative phosphorylation, inhibitors of photosynthesis, inhibitors of acetylcholinesterase, inhibitors of respiration, thiol-alkylating agents, reactives (irritants), estrogenic compounds). Stepwise discriminant analysis of the test chemicals resulted in 89.6 % correct classifications into the MOA classes. The final model uses 10 significant variables (log K(OW), Epsilon (HOMO), V(+), Q (AV), H(+MAX), MR, MW, D(EFF), SASA, SAVOL). PLS discrimant analysis of the same data set resulted in a three-component model with r=0.89; the variables with the highest discriminatory power are log K(OW), H(+MAX), D(EFF) and Q(AV). Each MOA class reveals a chracteristic profile in physico-chemical properties. Deviations relative to non-specific baseline toxicants are specific for each MOA class and reflect the structural dependences of the rate-limiting interactions that are causing the respective toxicities (functional similarity). By combining physiological and chemical knowledge about underlying processes, it is possible to indicate descriptor-based discrimination criteria by MOA as an essential prerequisite for rational selection and application of process-related QSARs for predictive purposes.