Gilman D. Veith

QSARs for photoinduced toxicity: I. Acute lethality of polycyclic aromatic hydrocarbons to Daphnia magna

Research with a variety of aquatic species has shown that while polycyclic aromatic hydrocarbons (PAHs) are generally not acutely toxic in conventional laboratory tests, many are extremely toxic in the presence of sunlight. In an effort to develop a model for predicting which PAHs may exhibit photo-induced toxicity, Newsted and Giesy (1987) reported a parabolic relationship between the toxicity and the energy of the triplet state of a variety of PAHs. We have reexamined these data and propose a more mechanistic explanation for the prediction of photo-induced PAH toxicity. Photo-induced toxicity is the result of competing processes such as stability and light absorbance which interact to produce a complex, multilinear relationship between toxicity and chemical structure. We sought a molecular descriptor which could be computed from structure rather than measured empirically. We found that a measure of the energy stabilization of the toxicant in the form of the HOMO-LUMO (Highest Occupied Molecular Orbital - Lowest Unoccupied Molecular Orbital) gap provided a useful index to explain the persistence, light absorption, and photo-induced toxicity of PAHs. The model clearly shows, for example, why phenanthrene and tetracene are not toxic while anthracene is highly phototoxic. Those PAHs exhibiting photo-induced toxicity were consistently within HOMO-LUMO gap “window” of 7.2 ± 0.4 eV.

An evaluation of using partition coefficients and water solubility to estimate bioconcentration factors for organic chemicals in fish

Bioconcentration factors (BCF), water solubilities, and n-octanol-water partition coefficients are presented for 28 organic chemicals. The chemicals studied were of low to moderate lipid solubility, with bioconcentration factors ranging from 2 to 3400. The equation log BCF = 0.76 log P - 0.23 is proposed for estimating the bioconcentration factor from the partition coefficient. The cost-effectiveness of measuring and estimating the partition coefficient and water solubility of organic chemicals is also discussed. The cost of measuring these two parameters was approximately

Structure-Toxicity Relationships for Industrial Chemicals Causing Type (II) Narcosis Syndrome

1000. Partition coefficients calculated from data in the literature at a cost of

An exhaustive steam-distillation and solvent-extraction unit for pesticides and industrial chemicals

2.00 per chemical differed from the measured values by only 7.2 percent. The water solubilities calculated from the partition coefficient differed from the measured solubilities by 17.2 percent for those chemicals with a partition coefficient greater than 100.

A QSAR analysis of substituent effects on the photoinduced acute toxicity of PAHs

Several structure-activity relationships have been published for estimating the lethality of nonpolar nonelectrolytes to fish. The vast majority of non-reactive industrial chemicals produce toxicity symptoms consistent with narcosis. However, we have found that many chemicals which appear to produce narcosis, are substantially more toxic than the published structure-toxicity relationship predicts. We observed that these chemicals are more polar and often have acidic hydrogen bond donor functional groups. The data are consistent with the “polar” narcotic class proposed by Ferguson five decades ago.

A conceptual framework for predicting the toxicity of reactive chemicals: modeling soft electrophilicity

on techniques use an external steam generator that jets steam into the sample and collects the chemicals by condensing the steam and volatile chemicals in a cooled flask. Although steam distillation is commonly used in flavor and drug analysis (NIELSON and KRYGER 1969; SIEK and LINDSAY 1968; TAMSMA et al. 1969), the large surface areas of the glassware and the low collection efficiency of conventional apparatus have prevented the use of steam distillation as a quantitative technique in the analysis of trace amounts of less volatile organic chemicals. Despite the apparent shortcomings of steam distillation, this technique offers unique possibilities in trace analysis. The vapor pressures of many pesticides and industrial chemicals are appreciably greater than those of water-soluble chemicals in wastewaters and sediments (MACKAY and WOLKOFF 1973; STORHERR et al. 1971). Moreover, the vapor pressures of many trace chemicals are greater than those of the high molecular weight triglyceride lipids in fish and warm-blooded animals. Because exhaustive solvent-extracti on technique~ remove lipids, waxes, and related natural products, as well as the trace contaminants, extensive chromatographic separations are necessary before the extracts can be analyzed for the trace chemicals. We have developed a modified Nielsen-Kryger steam-distillati on apparatus that provides exhaustive distillation of pesticides and industrial chemicals from water, sediments, and tissue and the simultaneous extractior of the distillate by a small volume of organic solvent. The extract is generally suitable for direct gas-liquid chromatography (GLC) analysis without the time-consuming concentration and cleanup procedures.

Predicting properties of molecules using graph invariants

Photoinduced toxicity of polycyclic aromatic hydrocarbons (PAHs) is a result of competing effects including stability and light absorbance of the molecules as well as irradiation parameters. The energy difference between the Highest Occupied Molecular Orbital and the Lowest Unoccupied Molecular Orbital (HOMO-LUMO gap), which can be computed directly from structure, was found to be the molecular descriptor that best distinguishes phototoxic chemicals from non-phototoxic chemicals. Aromatic chemicals that are phototoxic in sunlight have HOMO-LUMO gap energies that fall in the range of 6.7 to 7.5 eV. This study showed that the effect of most substituents on the HOMO-LUMO gap was negligible, and that phototoxicity in an aromatic chemical is likely only if the parent aromatic structure is phototoxic. Exceptions included substituents that add to delocalization (nitro and alkenyl) which could shift some chemicals with a HOMO-LUMO gap just above 7.5 eV into the domain of photoinduced toxicity.

Predicting bioconcentration factors of highly hydrophobic chemicals. Effects of molecular size

Although the literature is replete with QSAR models developed for many toxic effects caused by reversible chemical interactions, the development of QSARs for the toxic effects of reactive chemicals lacks a consistent approach. While limitations exit, an appropriate starting-point for modeling reactive toxicity is the applicability of the general rules of organic chemical reactions and the association of these reactions to cellular targets of importance in toxicology. The identification of plausible “molecular initiating events” based on covalent reactions with nucleophiles in proteins and DNA provides the unifying concept for a framework for reactive toxicity. This paper outlines the proposed framework for reactive toxicity. Empirical measures of the chemical reactivity of xenobiotics with a model nucleophile (thiol) are used to simulate the relative rates at which a reactive chemical is likely to bind irreversibly to cellular targets. These measures of intrinsic reactivity serve as correlates to a variety of toxic effects; whats more they appear to be more appropriate endpoints for QSAR modeling than the toxicity endpoints themselves.

A systematic approach to simulating metabolism in computational toxicology. I. The TIMES heuristic modelling framework.

Topological indices (TIs) have been used to study structure-activity relationships (SAR) with respect to the physical, chemical, and biological properties of congeneric sets of molecules. Since there are many TIs and many are correlated, it is important that we identify redundancies and extract useful information from TIs into a smaller number of parameters. Moreover, it is important to determine if TIs, or parameters derived from TIs, can be used for global SAR models of diverse sets of chemicals. We calculated seventy-one TIs for three groups of molecules of increasing complexity and diversity: (a) 74 alkanes, (b) 29 alkylbenzenes, and (c) 37 polycyclic aromatic hydrocarbons (PAHs). Principal components analysis (PCA) revealed that a few principal components (PCs) could extract most of the information encoded by the seventy-one TIs. The structural basis of the first few PCs could be derived from their pattern of correlation with individual TIs. For the three sets of molecules, viz. alkanes, alkylbenzenes and PAHs, PCs were able to predict the boiling points reasonably well. Also, for the combined set of 140 chemicals consisting of the alkanes, alkylbenzenes and PAHs, the derived PCs were not as effective in predicting properties as in the case of individual classes of compounds.

Topological indices: their nature, mutual relatedness, and applications

The bioconcentration factor (BCF) is a parameter that describes the ability of chemicals to concentrate in aquatic organisms. Traditionally, it is modeled by the log–log quantitative structure -activity relationship (QSAR) between the BCF and the octanol- water partition coefficient (Kow). A significant scatter in the parabolic log(BCF)/log(Kow) curve has been observed for narcotics with log(Kow) greater than 5.5. This study shows that the scatter in the log(BCF)/log(Kow) relationship for highly hydrophobic chemicals can be explained by the molecular size. The significance of the maximal cross-sectional diameter on bioconcentration was compared with the traditionally accepted effective diameter. A threshold value of about 1.5 nm for this parameter has been found to discriminate chemicals with log(BCF) > 3.3 from those with log(BCF) < 3.3. This critical value for the maximum diameter is comparable with the architecture of the cell membrane. This threshold is half thickness of leaflet constituting the lipid bilayer. The existence of a size threshold governing bioconcentration is an indication of a possible switch in the uptake mechanism from passive diffusion to facilitated diffusion or active transport. The value of the transition point can be used as an additional parameter to hydrophobicity for predicting BCF variation. The effect of molecular size on bioconcentration has been studied by accounting for conformational flexibility of molecules.