Baseline Toxicity Narcosis

However, any compound, even if it is chemically inert, if present at high enough concentrations in biological membranes can change those membranes properties and disrupt their functions. Consequently, membrane-associated processes like photosynthesis, energy transduction, transport in or out of the cell, enzyme activities, transmission of nerve impulses, and so on may deteriorate (see van Wezel and Opperhuizen, 1995 and literature cited therein). Since these effects seem to be primarily dependent on the space that contaminating molecules occupy in the 

Quantitative Structure-Activity Relationships (QSARs) for Baseline Toxicity 

Let us now evaluate how we can assess the baseline toxicity of organic chemicals in a quantitative way. We have already mentioned that certain membrane functions may be disrupted if a chemical occupies a certain volume fraction of that membrane. This means that for two compounds of the same size, we would anticipate that when they are present at equal concentrations in the membrane they would exert the same effect. Furthermore, since the majority of chemicals of interest to us do not differ in size by more than a factor of 3 to 4 (compare molar volumes in Chapter 5, e.g., Fig. 5.2), the membrane concentration required for any compound to cause a narcotic effect will be in the same order of magnitude. Therefore, we may expect that the concentration of a compound required in an environmental medium (e.g., water, air) to cause a narcotic effect in an organism should be inversely proportional to the tendency of the compound to accumulate from that medium into biological membranes. 

For example, such a relationship can be seen to apply to the data of Hutchinson et al. (1978), who reported the concentrations of numerous apolar and slightly monopolar compounds to inhibit microalgal photosynthesis by a factor of 2. When the effective concentrations (in mol L-1) are examined versus each compound s octanol-water partition coefficients, one finds the following relations  

These trends clearly reveal that chemicals with greater tendencies to partition into membranes require lower concentrations in the culture media to cause 

---

What is meant by the terms baseline toxicity or narcosis Why is this type of toxicity relevant in the environment ... 

R.L. Lipnick (1990). Narcosis Fundamental and Baseline Toxicity Mechanism for Nonelectrolyte Organic Chemicals. In W. Karcher and J. Devillers (eds.) Practical Applications of Quantitative Structure-Activity Relationships (QSAR) in Environmental Chemistry and Toxicology, Kluwer Academic Publishers, Dordrecht, The Netherlands, pp. 129-144... 

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... 

Lipnick RL. Narcosis Fundamental and baseline toxicity mechanism for nonelectrolyte organic chemicals. In Karcher W, Devillers J, editors, Practical applications of quantitative structure-activity relationships (QSAR) in environmental chemistry and toxicology. Dordrecht Kluwer Academic, 1990. p. 281-93. 

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. 

Narcosis represents the most fundamental mechanism of the toxicity of nonelectrolyte organic compounds, and corresponds to minimum or baseline toxicity. Quantitative structure-activity relationships for chemicals acting by this mechanism for various organisms and routes of exposure provide a valuable probe for determining whether or not a candidate chemical acts via narcosis or by an electrophile, proelectrophile, cyanogenic, or other more specific molecular mechanism. 

Linear QSAR Models for Narcosis Baseline Toxicity... 

QSAR models can be a valuable means of predicting the toxicity of untested nonelectrolyte organic chemicals. The models need to be derived from a series of chemicals acting by a common molecular mechanism and encompass an adequate domain of spanned substituent space in their physical and chemical properties. The acute toxicity of many classes of nonelectrolytes is consistent with a narcosis or baseline toxicity mechanism. The ability to apply such models for predictive purposes also requires information to suggest that the candidate chemical acts by the same mechanism. 

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. 

All organic chemicals have the potential to cause narcosis. Their ability to do so is mainly governed by their concentration and their ability to cause more serious toxic effects, which would mask any narcotic effect the chemical may cause (van Wezel Opperhuizen, 1995). The toxicity is not observed to be related to hydrophobicity and is in excess of baseline toxicity for the more compoxmds (Fig. 1 and Table 3). 

Figure 2. Baseline narcosis aquatic toxicity QSAR model. For nonelectrolytes acting by a narcosis mechanism, no toxicity is observed if the predicted toxic concentration exceeds the water solubility. With decreasing test duration, pseudo-steady-state partitioning is not achieved for very hydrophobic chemicals, and the location of the water solubility cutoff shifts to chemicals having a lower partition coefficient. Compounds acting by more specific mechanisms produce toxicity at lower aqueous concentrations than predicted by narcosis, and fall within the domain of excess toxicity.

The toxicity of many phenols and anilines is underestimated by the baseline narcosis QSAR presented by Veith et al. (1983). Adopting the convention of this QSAR being the narcosis (I) syndrome, we proposed that these polar chemicals produce narcosis through a different mode of action which we call narcosis (I I) syndrome. We determined that phenol and aniline are not additive in their joint toxic response with octanol, our reference narcosis (I) chemical. These results clearly suggest a second mechanism. We tested 17 phenols and 3 anilines for strict additivity with phenol. The results of the joint action tests with the phenol reference are presented in TABLE 1, together with the toxicity of the chemicals. 

Bradbury said that a mode of action domain must be clearly defined in terms of the biological model, endpoint, and exposure contour (Bradbury, 1995). The use of mode of action-based QSARs requires recognition of both toxic mechanisms and the critical structural characteristics and properties of a chemical that mle its activity by a specific mechanism. The problem is that many chemical QSAR classes that historically were associated with a baseline narcosis include chemicals that act via a baseline narcosis mode of action, as well as chemicals lhat act through an electrophilic-based mode of action. 

---