QSAR-based toxicity classification and prediction for single and mixed aromatic compounds

Quantitative structure-activity relationships (QSARs) based on the octanol/water partition coefficient were employed to predict acute toxicities of 36 substituted aromatic compounds and their mixtures. In this study, the model developed by Verhaar et al. was modified and used to calculate octano/water partition coefficients of chemical mixtures. To validate the model, acute toxicities of these chemicals were measured to Vibrio fischeri in terms of EC50. The results indicated that the obtained QSAR models could be used to predict toxicities of samples consi sting of these substituted aromatic compounds, individually or in combinations. The obtained equations were proved to be robust enough by using the leave-one-out test method. By classifying these chemicals into two groups, polar and non-polar, the toxicities of chemical mixtures within each group can be predicted accurately from their calculated partition coefficients.     

Nonlinear Dependence of Fish Bioconcentration on n-Octanol/Water Partition Coefficient

Abstract

The log-log relationship between the bioconcentration tendency of organic chemicals in fish and the n?octanol/water partition coefficients breaks down for very hydrophobic compounds. The use of parabolic and bilinear models allows this problem to be overcome. The QSAR equation log BCF = 0.910 log P - 1.975 log (6.8 10^?7 P + 1) - 0.786 (n = 154; r = 0.950; s = 0.347; F = 463.51) was found to be a good predictor of bioconcentration in fish.     

Molecular Lipophilicity Calculations of Chemically Heterogeneous Chemicals and Drugs on the Basis of Structural Similarity and Physicochemical Parameters

Abstract

QSARs based on molecular polarizability (α) and H-bond acceptor factors (∑C_a) as independent variables provided good predictability of octanol/water partition coefficients (P) for chemicals and drugs. However, for some molecules containing few functional groups, the calculated values deviated significantly from those observed. This approach gave good results when applied to a set of 138 chemicals and drugs previously studied by Mannhold and Dross who compared other methods to calculate log P values.

At the same time, three variations on a molecular similarity approach were pursued. In this study, a large training set with experimentally determined octanol/water partition coefficients (P) was searched for structures closely related to the compound-of-interest. The most successful of these variations took the mean log P value of few most closely related compounds after each was adjusted for differences between their and the compound-of-interest's polarizabilities (α) and H-bond acceptor capacities (∑C_a).     

Qsar Models for Predicting the Acute Toxicity of Selected Organic Chemicals with Diverse Structures to Aquatic Non-Vertebrates and Humans

Abstract

The linear and non-linear relationships of acute toxicity (as determined on five aquatic non-vertebrates and humans) to molecular structure have been investigated on 38 structurally-diverse chemicals. The compounds selected are the organic chemicals from the 50 priority chemicals prescribed by the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme. The models used for the evaluations are the best combination of physico-chemical properties that could be obtained so far for each organism, using the partial least squares projection to latent structures (PLS) regression method and backpropagated neural networks (BPN). Non-linear models, whether derived from PLS regression or backpropagated neural networks, appear to be better than linear models for describing the relationship between acute toxicity and molecular structure. BPN models, in turn, outperform non-linear models obtained from PLS regression. The predictive power of BPN models for the crustacean test species are better than the model for humans (based on human lethal concentration). The physico-chemical properties found to be important to predict both human acute toxicity and the toxicity to aquatic non-vertebrates are the n?octanol water partition coefficient (Pow) and heat of formation (HF). Aside from the two former properties, the contribution of parameters that reflect size and electronic properties of the molecule to the model is also high, but the type of physico-chemical properties differs from one model to another. In all of the best BPN models, some of the principal component analysis (PCA) scores of the ¹³C-NMR spectrum, with electron withdrawing/accepting capacity (LUMO, HOMO and IP) are molecular size/volume (VDW or MS1) parameters are relevant. The chemical deviating from the QSAR models include non-pesticides as well as some of the pesticides tested. The latter type of chemical fits in a number of the QSAR models. Outliers for one species may be different from those of other test organisms.     

Identification of Phototoxic Polycyclic Aromatic Hydrocarbons in Sediments Through Sample Fractionation and QSAR Analysis

Abstract

The toxicity of certain polycyclic aromatic hydrocarbons (PAHs) can be greatly increased by simultaneous exposure of test organisms to ultraviolet (UV) wavelengths present in sunlight. This phenomenon, commonly termed photoinduced toxicity, had been evaluated extensively in laboratory settings where only one chemical of concern was present. However, more recent studies have demonstrated that complex mixtures of PAHs present, for example in sediments, also can cause phototoxicity to a variety of aquatic species when the samples are tested in simulated sunlight. Unfortunately, because these types of samples can contain thousands of substituted and unsubstituted PAHs it is difficult, if not impossible, to use conventional analytical techniques to identify those responsible for photoinduced toxicity. The objective of the present study was to link two powerful ecotoxicology tools, toxicity-based fractionation techniques and QSAR models, to identify phototoxic chemicals in a sediment contaminated with PAHs emanating from an oil refinery. Extensive chromatographic fractionation of pore water from the sediment, in conjunction with toxicity testing, yielded a simplified set of sample fractions containing 12 PAHs that were identified via mass spectroscopy. Evaluation of these compounds using a recently developed QSAR model revealed that, based upon their HOMO-LUMO gap energies, about half were capable of producing photoinduced toxicity. We further evaluated the phototoxic potential of the reduced set of PAHs by determining their propensity to bioaccumulate in test organisms, through calculation of octanol-water partition coefficients for the chemicals. These studies represent a novel linkage of sample fractionation methods with QSAR models for conducting an ecological risk assessment.     

Prediction of extraction efficiency in supported liquid membrane with a stagnant acceptor phase by means of artificial neural network

An artificial neural network model of supported liquid membrane extraction process with a stagnant acceptor phase is proposed. Triazine herbicides and phenolic compounds were used as model compounds. The model is able to predict the compound extraction efficiency within the same family based on the octanol–water partition coefficient, water solubility, molecular mass and ionisation constant of the compound. The network uses the back‐propagation algorithm for evaluating the connection strengths representing the correlations between inputs (octanol–water partition coefficients logP, acid dissociation constant pK_a, water solubility and molecular weight) and outputs (extraction efficiency in dihexyl ether and undecane as organic solvents). The model predicted results in good agreement with the experimental data and the average deviations for all the cases are found to be smaller than ±3%. Moreover, standard statistical methods were applied for exploration of relationships between studied parameters.     

Evaluation of the lipophilicity of selected sunscreens—A chemometric analysis of thin‐layer chromatographic retention data

The lipophilicities of 22 selected sunscreens, preservatives, and vitamins used in topical skin products were measured by thin‐layer chromatography. Lipophilicity was calculated in silico from the sunscreen molecular structures and compared to the experimental octanol/water partition coefficients found in the literature. The retention of the compounds was investigated on an RP‐18 stationary phase with mobile phases consisting of water and one of six organic modifiers (dioxane, tetrahydrofuran, acetone, acetonitrile, methanol, and dimethylformamide) at different concentrations. The theoretical lipophilicities were calculated by several computational algorithms and the results of these calculations were compared using cluster analysis. The results showed that two out of the six investigated organic modifiers (dioxane and acetone) may be used to estimate the octanol/water partition coefficients of highly lipophilic compounds having lipophilicities that cannot be measured directly by the shake‐flask method.     

Determination of octanol/water partition coefficients by flow injection analysis

Determination of octanol/water partition coefficients by batch-extraction methods is currently the only acceptable procedure for application to structure/activity relationships. Work on the development of flow-injection systems to determine these partition coefficients is reported. It is shown that it is not necessary to know the concentration of the analytic in either phase; the partition coefficient should be equal to the differences in the octanol and water peak widths divided. by the system residence time. For a limited number of compounds, this is shown to be valid. Several systems were developed, including a flow-through dialyzer which was 5 times more efficient than the best commercial unit.     

Water solubility and octanol/water-partitioning of hydrophobic chlorinated organic substances determined by using SPME/GC

The critical step in the determination of water solubilitiy (S _w) and octanol-water partition coefficient (K _ow) of hydrophobic organic chemicals by using the generator-column technique and the slow-stirring procedure, respectively, is the exact quantification of the low water-phase concentrations of the substances under investigation. We have tested the applicability of solid-phase microextraction (SPME) and gas chromatography with seven chlorinated organic compounds. The substances cover a S _w range from 500 mg/L to 7 ng/L and a log K _ow range from 3 to 8. The results show that SPME can be a valuable alternative to common preconcentration techniques in the quantification of hydrophobic organics in pure and octanol-saturated water. The apparent SPME distribution constants K _SPME (obtained with the 100 μm-PDMS fiber for analyte’s partitioning between fiber coating and aqueous sample) do not correlate directly with octanol/water partition coefficients and thus cannot be recommended as a surrogate parameter for K _ow. Received: 15 January 1997 / Revised: 2 May 1997 / Accepted: 8 May 1997     

利用气相色谱相对比保留体积估算芳烃的正辛醇/水分配系数

采用气相色谱法在９种常见的固定液上分别测定了１３种芳烃的相对比保留体积,同时对经典的摇瓶法测定了相同化合物的正辛醇／水分配系数,并以此建立了（Ｖｇ〈Ｒ〉－Ｋｖｗ回归方程。利用所建立的回归方程和１３种芳烃化合物的Ｖｇ〈Ｒ〉值对其Ｋｖｗ进行估算的结果表明,选用９种固定液中的任何一种,其Ｋｖｗ估算值的相对误差均在允许的范围内,其中以选用固定液ＤＣ－２００,ＳＥ－３０和ＰＥＧ－２０Ｍ误差较小。     

Predicting octanol/water partition coefficients using molecular simulation for the SAMPL7 challenge: comparing the use of neat and water saturated 1-octanol

Journal of Computer-Aided Molecular Design - Blind predictions of octanol/water partition coefficients at 298.15 K for 22 drug-like compounds were made for the SAMPL7 challenge. The octanol/water...     

Microemulsion electrokinetic chromatography as a suitable tool for lipophilicity determination of acidic,neutral, and basic compounds

In the present work, several MEEKC systems are studied to assess their suitability for lipophilicity determination of acidic, neutral, and basic compounds. Thus, several microemulsion compositions over a wide range of pH values (from 2.0 to 12.0), containing heptane, 1?butanol and different types and amounts of surfactant (SDS or sodium cholate: from 1.3 to 3.3%) are characterized using Abraham's solvation model. The addition of acetonitrile (up to 10%) is also studied, since it increases the resolution of the technique for the most lipophilic compounds. The system coefficients obtained are very similar to those of the 1?octanol/water, used as the reference lipophilicity index, allowing simple and linear correlations between the 1?octanol/water partition values (log P_o/w) and MEEKC mass distribution ratios (log k_MEEKC). Variations in the microemulsion composition (aqueous buffer, surfactant, concentration of ACN) did not significantly affect the similarity of the MEEKC systems to log P_o/w partition.     

Some observations regarding different retention properties of HPLC stationary phases

Summary The retention of 32 monocyclic aromatic compounds and 14 polynuclear aromatic hydrocarbons (PAHs) has been studied on four different bonded phases in each of two mobile phases. An additional data set of 21 monocyclic aromatics judiciously chosen for their well-established solvatochromic parameters, 12 PAHs and 12 polychlorinated biphenyls (containing up to 10 chlorines), were studied on a single column. The results indicate that despite the accuracy of the solvatochromic linear solvation energy method for predicting and correlating the octanol/water partition coefficients and water solubilities of these environmentally important materials, the methodology is limited to only certain types of bonded phases. As a corollary to this observation, we caution others that the common practice of estimating log K_ow (K_ow=octanol-water partition coefficient) based on measurement of the reversed-phase capacity factors should be limited to specific types of columns. Part 5 of Solute-Solvent Interactions in Chemistry and Biology.     

Comparison of two simulation methods to compute solvation free energies and partition coefficients

The thermodynamic integration (TI) and expanded ensemble (EE) methods are used here to calculate the hydration free energy in water, the solvation free energy in 1‐octanol, and the octanol‐water partition coefficient for a six compounds of varying functionality using the optimized potentials for liquid simulations (OPLS) all‐atom (AA) force field parameters and atomic charges. Both methods use the molecular dynamics algorithm as a primary component of the simulation protocol, and both have found wide applications in fields such as the calculation of activity coefficients, phase behavior, and partition coefficients. Both methods result in solvation free energies and 1‐octanol/water partition coefficients with average absolute deviations (AAD) from experimental data to within 4 kJ/mol and 0.5 log units, respectively. Here, we find that in simulations the OPLS‐AA force field parameters (with fixed charges) can reproduce solvation free energies of solutes in 1‐octanol with AAD of about half that for the solute hydration free energies using a extended simple point charge (SPC/E) model of water. The computational efficiency of the two simulation methods are compared based on the time (in nanoseconds) required to obtain similar standard deviations in the solvation free energies and 1‐octanol/water partition coefficients. By this analysis, the EE method is found to be a factor of nine more efficient than the TI algorithm. For both methods, solvation free energy calculations in 1‐octanol consume roughly an order of magnitude more CPU hours than the hydration free energy calculations. © 2012 Wiley Periodicals, Inc.