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

Abstract

Environmental contaminants with common mode of toxic action (MOA) are generally expected to have similar structures andyor 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-speci®c toxicants, polar non-speci®c 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 classi®cations into the MOA classes. The ®nal model uses 10 signi®cant variables (log K OW , e HOMO , V , Q AV , H MAX , MR, MW, D EFF , SASA, SAVOL). PLS discriminant 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 characteristic pro®le in physico-chemical properties. Deviations relative to non-speci®c baseline toxicants are speci®c for each MOA class and re¯ect 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.

Mode of Action Assignment of Chemicals Using Toxicogenomics: A Case Study with Oxidative Uncouplers

“…In contrast, for PCP, the TPP + assay indicated an uncoupling activity at a very low concentration of 0.5 µM, while the TMRM only showed effects at 118 µM with a higher variability between replicates. On the basis of structural descriptors, PCP is classified as uncoupler (Terada, 1981;McKim et al, 1987;Nendza and Müller, 2001;Schüürmann et al, 2003;Spycher, 2005;Spycher et al, 2005Spycher et al, , 2008a. The differences of effect concentrations between our assays agrees well with what has been observed by Schüürmann et al (1997) The authors identified uncoupling by an excess toxicity above the baseline level using 10 different biological test systems.…”

“…In chemical risk assessment, MoA information is critical for proper hazard classification as compounds belonging to the same MoA class should show similar toxicity (Verhaar et al, 2000;Cronin and Livingstone, 2004;Nendza and Wenzel, 2006;Vonk et al, 2009). To date, the assignment of a chemical to a MoA is largely done on the basis of structural rules (Bradbury and Lipnick, 1990;Russom et al, 1997;Schüürmann, 1998).…”

“…The question is how to recognize that two chemicals have a common MoA, and therefore can be grouped together? One possibility is to assign MoA based on molecular interactions between the chemical and the biological system which initiate specific toxicity pathways like binding to the estrogen receptors, or measuring specific cellular reactions that are indicative for specific effects such as chlorophyll interference in tests with algae (Hamadeh et al, 2002;Escher et al, 2005;Nendza and Wenzel, 2006;Woods et al, 2007;Pereira-Fernandes et al, 2014). Another approach is the grouping of chemicals on the basis of structural rules (Schüürmann, 1998;Verhaar et al, 2000;Enoch et al, 2008;Blackburn et al, 2011).…”

Methods for reliability and uncertainty assessment and for applicability evaluations of classification- and regression-based QSARs.

“…This will lead to the determination of biological response profiles of compounds (Nendza and Müller 2000). Measurement of multivariate biological data leads to statistically beneficial properties of the QSAR and improved possibilities of exploring the biological similarity of the studied substances.…”

“…The use of multiple endpoints is becoming increasingly widespread in QSARs, in both drug design and environmental sciences (Deneer et al 1987(Deneer et al , 1989Nendza and Müller 2000;Sjöström et al 1997;Verhaar et al 1994). And, as discussed above, a multitude of chemical descriptors is often favorable and tends to stabilize the description of the chemical properties of the compounds.…”