Polar narcosis

LAS. The toxicity of C12LAS to aquatic organisms has been widely studied and is reported to span a wide concentration range (Table II see ref. 65 for a more extensive review the references we report in this chapter were selected for applicability to the United States and Europe and for data quality). The toxicity mechanism of LAS and other surfactants (AS and AES) is unknown but is suspected to be polar narcosis. Acute toxicity to invertebrate species (48-h hC ) range from 1.7 mg/L for the oligochaete, Dero,... 

Criteria underpinning the acceptability of QSARs Toxicity of nonpolar and polar narcosis to aquatic species — recommended QSARs... 

The TGD provides recommendations for the use of QSARs to predict long term toxicity to fish (no observed effect concentration [NOEC], 28 days) and to Daphnia (NOEC, 21 days). In particular QSARs are provided for chemicals acting by non-polar narcosis and polar narcosis mechanisms of action. No QSARs have been recommended for substances that act by more specific modes of action. For persistence, the TGD recommends two of the SRC BIOWIN models, namely the BIOWIN2 nonlinear model and the BIOWIN3 survey model for ultimate biodegradation. The exact cutoff points for these models have been calibrated on the basis of the model score for 1,2,4-trichlorobenzene — a substance that is known to be relatively persistent under environmental... 

IV. An Imaginary Case Study A QSAR for Non-polar Narcosis in Fish... 

The QSAR was developed for chemicals considered to act by a single mechanism of toxic action, non-polar narcosis, as defined by Verhaar et al. (1992), and therefore has a clear mechanistic basis. Non-polar narcosis has been established experimentally by using the Fish Acute Toxicity Syndrome methodology (McKim et al., 1987). The QSAR is based on a descriptor for hydropho-bicity (log Kow), which is relevant to the mechanism of action (i.e., toxicity results from the accumulation of molecules in biological membranes). There are numerous regression models based on log Kow for this mechanism of action, so the development of such models has enabled interspecies comparisons (Dimitrov et al., 2003). 

Table 20.1 Training Set of Data Used to Develop a QSAR for Non-polar Narcosis ... 

The domain of applicability of the QSAR was well defined by the model developer. The QSAR was stated to be applicable to chemicals having log K,v values in the range from -1.24 to 5.13, and operating by a non-polar narcosis mechanism of action. Such chemicals can be identified on a structural basis (Verhaar et al., 1992), or from physicochemical descriptors (Boxall et al., 1997). 

The domain of the external test set falls within that of the training set. The range of log Kow values for the test set is from -0.43 to 4.50. The chemical structures represented by the test set are consistent with those representing non-polar narcosis (Verhaar et al., 1992), and are similar to those in the training set. The predicted toxicities of the test set chemicals are reported in Table 20.2. There is a statistically significant relationship between predicted and observed toxicity ... 

The QSAR is acceptable for the prediction of the acute toxicity to Pimephales promelas of organic chemicals, considered to act by the non-polar narcosis mechanism of action. The range of acceptable log Kow values for which it can be applied is from -1.24 to 5.13. The coefficient of determination (r2 value) of the model is 0.9, and its expected accuracy (95% prediction interval) is 0.64 log unit... 

Verhaar, H J., Urrestarazu R2unos, E. and Hermens, J.L. (19%). Classifying Environmental Pollutants. 2 Separation of Qass 1 (Baseline Toxicity) and Class 2 ( Polar Narcosis ) Type Com-poimds Based on Chemical Descriptors. J.Chemom., 10,149-162. 

TABLE 23.3 Examples of Baseline Toxicity (BT), Polar Narcosis (PN), and Oxidative Phosphorylation Uncoupling (OPU) QSARs... 

Dearden, J.C., Cronin, M.T.D., Zhao, Y.H. and Raevsky, O.A. (2000) QSAR studies of compounds acting by polar and non-polar narcosis an examination of the... 

Hermens, J.L.M. (1996) Classifying environmental pollutants. 2. Separation of class 1 (baseline toxicity) and class 2 ( polar narcosis ) type compounds based on chemical descriptors. 

The software now uses structurally intrinsic parameters for only one QSAR model (LSER) and the results are used to predict one property (acute toxicity) to four aquatic species by one mechanism (nonreactive, non-polar narcosis) however, we intend to continue to refine our equations as databases grow, incorporate other models, predict other properties, and include other organisms. We will attempt to differentiate between modes of toxic action and improve our estimates accordingly. For the widely divergent classes of chemicals and types of environmental behavior, no one model will best describe every situation and no one species is the optimal organism to monitor. As the software evolves, the expert system should choose the best model based on the contaminant, the species, and the property to be predicted (e.g., toxicity or bioaccumulation). In addition, we envision an interactive screen system for data entry that will bypass the SMILES notation and allow the user to describe the molecule by posing a series of questions about the compound s backbone and functional groups. The responses will translate directly into values of LSER variables. 

Schultz (1987) used the ionization constant values (pKa) for predicting the mechanism of toxicity of phenols. Two mechanisms have been proposed polar narcosis and uncoupling of oxidative phosphorylation, based on which equations have been derived to determine the toxicities of phenols. 

The accordingly rescaled QSARs are listed in Table 2. They were derived from the Kow-based QSAR for nonpolar narcosis because this QSAR is based on a larger data set than the QSAR for polar narcosis. However, if all assumptions are correct, the resulting Dnpw-based QSARs should not be different from the one derived from the Kow-based QSAR for polar narcotics. This is indeed the case for fish but not for Daphnia magna. In fish, the slope is equal for both models and the intercept of the rescaled QSAR derived from the Kow-based... 

Vaes WHM, Urrestarazu-Ramos E, Verhaar H, Hermens JLM (1998) Acute toxicity of nonpolar versus polar narcosis is there a difference Environ Toxicol Chem 17 1380-1384... 

The mechanism of toxic action involved in the algorithm loop of Fig. 4 is associated with the critical biological effect of the toxicant at the molecular or cellular level. The main classes of toxic action mechanisms are as follows nonpolar narcosis, polar narcosis, weak acid respiratory uncoupling, formation of free radicals, electrophilic reactions, and toxic action by specific (receptor-mediated) mechanisms. 

Verhaar, H. J. M., Ramos, E. U. and Mermens, J. L. M. (1995) Classifying environmental pollutants 2. Separation of class 1 (baseline toxicity) and class 2 (polar narcosis) type compounds based on chemical descriptors, in Predictive Methods in Aquatic Toxicology (by H. J. M. Verhaar). Thesis, Utrecht University, Utrecht. 

Zhao, V. H., Cronin, M. T. D., Dearden, J. C. (1998). Quantitative structure-activity relationships of chemicals acting by non-polar narcosis - theoretical considerations. Quant Struct-Act Re lat. 17, 131-138. 

Non-polar narcosis Saturated alkanes with, for example, halogen and/ or alkoxy substituent (aliphatic alcohols, ketones, ether, amines) halogens and alkyl substituted benzenes... 

Polar narcosis Phenols with pK greater than or equal to 6.0 phenols and anQines with three or fewer halogen atoms and/or alkyl substituent... 

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