Quantitative Relationships of Structure-Activity and Volume Fraction For Selected Nonpolar and Polar Narcotic Chemicals

Abstract

The relative toxicity of selected industrial organic chemicals was secured from the literature for the static 48-h Tetrahymena pyriformis 50% population growth impairment and the flow-through 96-h Pimephales promelas 50% mortality endpoints. Chemicals were selected to represent the nonpolar narcosis (aliphatic alcohols and aliphatic ketones) and polar narcosis (anilines and phenols) mechanisms of toxic action. molar volume (MV) and 1-octanol/water partition coefficient (log K _ow) data were generated for each chemical. High-quality, log K _ow dependent quantitative structure-activity relationships were observed for each chemical class and mechanism of action for both endpoints. The volume fraction (V _t) for each chemical in the target phase was determined from the toxicant concentration in the water (toxicity data), the MV, and the target/water partition coefficient (K _tw) with K _tw considered equal to K _ow ^(1-a). Analyses of target sites, by way of “a” revealed that “a” was constant for a mechanism of action regardless of chemical class, but distinct for a given test system. Mean V _t was constant for each mechanism of action regardless of chemical class or test system. These results suggest, at least for reversible physical mechanisms, that volume fraction analyses are significant in determining the mechanism of toxic action of a chemical.     

Reversed phase liquid chromatography of PCBs as a basis for the calculation of water solubility and log Kow for polychlorobiphenyls

Summary Water solubility (S _w) and log K _ow values have been determined for 154 possible polychlorobiphenyls using the retention indices obtained by RP-HPLC and structurally selected PCB congeners with known log K _ow values for the regression lines. The water solubility data are melting point corrected.

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Umkehrphasen-Flüssig-Chromatographie von PCBs als Grundlage zur Berechnung der Wasserlöslichkeit und des log K _ow für Polychlorbiphenyle

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Dedicated to Prof. Dr. W. Fresenius on the occasion of his 75th birthday     

Structure-Toxicity Relationships for Aminoalkanols: A Comparison with Alkanols and Alkanamines

Abstract

The relative toxicity (logIGC^?1 ₅₀) of 49 selected aliphatic amines and aminoalkanols was evaluated in the static Tetrahymena pyriformis population growth impairment assay. Excess toxicity, indicated by potency greater than predicted for non-polar narcotic alkanols, was associated with both classes of test chemicals. Moreover, the aminoalkanols were found to be more toxic than the corresponding alkanamines. A high quality 1-octanol/water partition coefficient (log K _ow) dependent quantitative structure-activity relationship (QSAR), logIGC^?1 ₅₀ = 0.78 (log K _ow)-1.42; r ² = 0.934, was developed for alkanamines. This QSAR represented the amine narcosis mechanism of toxic action. No quality QSAR was developed for the aminoalkanols. However, several structure-toxicity features were observed for this class of chemicals. Two-amino-1-hydroxy derivatives being more toxic than the corresponding derivatives, where the amino and hydroxy moieties were separated by methylene groups. Hydrocarbon branching next to the amino moiety resulted in decreased toxicity. Aminoalkanol alters lipid metabolism in T. pyriformis.     

A QSAR for Measuring Sublethal Responses in the Marine Macroalga Enteromorpha intestinalis

Abstract

Two methods for measuring the effect of organic toxicants on the marine macroalga Enteromorpha intestinalis were compared. EC₅₀ data for the effect of C₁?C₈ n?alcohols on neutral red dye retention and ion leakage were used to construct QSARs with log K_ow as the only physicochemical parameter. The two QSARs were statistically indistinguishable suggesting that both procedures reflect the same non-specific narcotic effect on membrane integrity. The effect on ion leakage of compounds with more specific modes of action was also investigated. The herbicides diuron and diquat had no effect at concentrations which inhibit photosynthesis, the uncoupler 2,4-dichlorophenol was no more toxic than a narcotic of similar polarity, but the known high toxicity of the antifouling compound tributyltin was clearly reflected by the ion leakage response.     

硝基芳烃对梨形四膜虫毒性的QSAR研究

用30种硝基芳烃化合物DFT-B3LYP/6-311G**全优化计算结构参数: 最高占有和最低未占分子轨道能级(E_HOMO和E_LUMO)、次最高占有和次最低未占分子轨道能级(E_NHOMO和E_NLUMO)、前线轨道能级差(ΔE＝E_LUMO－E_HOMO)、分子的总能量(E_T)、硝基和硝基碳上净电荷(Q_NO2和Q_C-NO2)、与卤素相连碳原子上的净电荷(Q_C-X)、分子偶极矩(μ)和分子体积(V), 结合文献中的疏水性参数(log K_ow), 按取代基类型和数目分类进行其对梨形四膜虫急性毒性(－log IC₅₀)的定量构效关系(QSARs)研究. 结果表明, 前线轨道能级对硝基芳烃毒性作用有重要贡献, 硝基芳烃对梨形四膜虫的毒性作用主要以与生物分子发生电子转移等化学反应为主, 单硝基芳烃的毒性作用还与疏水性有关. 卤素的存在增加了硝基芳烃化合物的毒性, 卤素易被亲核取代. 对30种标题物作多元线性回归, 所得模型(－log IC₅₀＝18.037＋10.446Q_NO2－41.323ΔE－20.471E_NLUMO＋24.989E_NHOMO, n＝30, R＝0.962, SE＝0.185, F＝78.640, Sig.＝0.000)具有较高毒性预测作用.     

Predicting 1-octanol-water partition coefficient by high-performance liquid chromatography gradient elution

The method to predict 1-octanol-water partition coefficients (K _ow) from capacity factors (k) obtained by Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC) has been extended to use gradient elution rather than isocratic elution. The mobile phase has been changed either linearly or exponentially with time. The initial composition of the mobile phase and its rate of change affected the log K _ow versus log k relation. This relation was exponential in linear gradient experiments. For non-linear gradient elution in which the water fraction of the mobile phase decreased exponentially from 100% to approach 0% asymptotically, a physically-based equation describing the dependence of log K _ow on log k has been derived. Without any preliminary estimation, RP-HPLC gradient elution allows a precise prediction of log K _ow over a range of nearly six orders of magnitude.     

Determination of distribution coefficients of polycyclic aromatic nitrogen heterocycles using solid-phase microextraction

The possibility and the efficiency of solid-phase microextraction (SPME) for determination of distribution coefficients of polycyclic aromatic nitrogen heterocycles (PANHs) in aqueous samples are presented in this study. Influence of sample extraction conditions, extraction time, stirring rate, pH, salinity and temperature were tested to optimize extraction efficiency. Three types of fibre sorbent layers, PDMS, PDMS/DVB and PA, were tested and fibre/water distribution coefficients, K_{f s} , were calculated. The extraction efficiency for PANHs increased in the order PDMS?<?PA?<?PDMS/DVB. Values of log?K_fs ranged from 0.2 to 2.7 for PDMS, from 0.4 to 3.6 for PA and from 1.4 to 4.4 for PDMS/DVB. The values of log?K_fs were correlated with octanol/water distribution coefficients log?K_ow . The relationship between log?K_fs and log?K_ow shows linear response with regression coefficient in the range of 0.985 and 0.997.     

Nonlinear Dependence of Bioconcentration Factors on n-Octanol-Water Partition Coefficients of Chlorinated Dibenzofurans and Dibenzo-p-Dioxins

Abstract

A nonlinear thermodynamic model is applied to the prediction of both the bioconcentration factor (K_bw) in the guppy (Poecilia reticulata) and the n-octanol-water partition coefficient (K_ow) of chlorinated dibenzofurans and dibenzo-p-dioxins. To this end molar liquid volumes, heats of vaporization and empirically fitted parameters of the pertinent solute and solvents are used. Calculated log K_bw and log K_ow values are obtained with correlation coefficients (r = 0.85 and 0.992) and mean deviations (< dev > = 0.19 and 0.17), which compare favourably with experimental data.

In addition the model enables an explanation of the well-known nonlinear log-log relationship between the two properties for compounds with high K_ow values on the basis of differences between the properties of biotic lipid and n-octanol. It is suggested that the breakdown of the linear relationship is caused by entropic effects related to the number of chlorine atoms in the solute molecules and to the structures of the lipid and n-octanol.     

A Novel QSAR Approach for Estimating Toxicity of Phenols

Abstract

Toxicity values (log IGC^?1 ₅₀) for 60 phenols tested in the 2-d static population growth inhibition assay with the ciliate Tetrahymena pyriformis were tabulated. Each chemical was selected so the series formed uniform coverage of the hydrophobicity/ionization surface. A high quality hydrophobicity-dependent (log K _ow) structure-toxicity relationship (log IGC^?1 ₅₀ = 0.741 (log K_ow) ?1.433; n = 17; r² = 0.970; s = 0.134; F = 486.55; Pr > F = 0.0001) was developed for phenols with pK_a values > 9.8. Similarly, separate hydrophobicity-dependent relationships were developed for phenols with pK_a values of 4.0, 5.1, 6.3, 7.5, and 8.7. Comparisons of intercepts and slopes, respectively, revealed phenols with pK_a values of 6.3 to be the most toxic and the least influenced by hydrophobicity. These relationships were reversed for the more acidic and basic phenols. Plots of toxicity versus pK_a for nitro-substituted phenols and phenols with log K_ow values of either 1.75 or 2.50 further demonstrated bilinearity between toxicity and ionization. In an effort to more accurately model the relationship between toxicity and ionization, the absolute value function |6.3-pK_a| was used to model ionization affects for derivatives with pK_a values between 0 and 9.8. For derivatives with pK_a value > 9.8, a value of 3.50 was used to quantitate ionization effects. The use of log K_ow in conjunction with this modified pK_a (ΔpK_a) resulted in the structure-toxicity relationship (log IGC^?1 ₅₀ = 0.567 (log K_ow)-0.226 (ΔpK_a-0.079; n = 54; r² = 0.926; s = 0.215; F = 321.06; Pr > F = 0.0001). Derivatives with a nitro group in the 4-position typically did not model well with the above equation.     

Assessment of Centrifugal Partition Chromatography for Determination of Octanol-Water Partition Coefficients

Abstract

Centrifugal partition chromatography (CPC) has been assessed as a convenient automated method for the determination of octanol-water partition coefficients (K_OW) over the range of -0.5 to 2.5 log units. The stationary (V_s) and mobile phase (V_m) volumes, which are needed for the calculation of K_ow, are determined in situ by injecting four compounds with known K_ow. V3 and V_m were also determined by independent analytical means to demonstrate that this is a direct measurement of K_ow from fundamental chromatographic principles with no unexplained fitted parameters. Propagation of error shows that a single four-component calibration with duplicate injections of each unknown is sufficient to determine log K_ow with a precision of less than 0.1 log units.     

Dependence of the distribution constant in liquid–liquid partition equilibria on the van der Waals molecular surface area

The direct calculation of free energy of interactions between a solute j and two immiscible liquids shows a linear dependence between the (logarithm of) the distribution constant in liquid–liquid partition equilibrium log K_j and the van der Waals surface area of the solute. The study provides a thermodynamic proof for the formula log K_BA,j = c₁ log K_BC,j + c₂ that describes the linear dependence between (the logarithm of) the distribution constant for a solute j in a solvent system (B/A) and (the logarithm of) the distribution constant for the same solute in a different solvent system (B/C). This relation has been well proven by various experimental studies and it is frequently used in liquid chromatographic separations as well as in liquid–liquid extractions, but was not explained previously based on thermodynamic results. The theory was verified using the prediction of octanol/water distribution constants log K_ow for a wide range of molecules, including hydrocarbons and compounds with a variety of functional groups. The results have also been verified for the distribution constants in other solvent systems. The expression for the distribution constant obtained in this study also gives a theoretical base for the additive fragment methodology used for the prediction of log K_ow.     

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     

Hydrophobic nature of sugars as evidenced by their differential affinity for polystyrene gel in aqueous media

Partition coefficients K _av for the partition of sugars between a polystyrene gel and aqueous solvents were determined. The results show that monosaccharides have different affinities for polystyrene. Their K _av values increase markedly in NaCl solution but reduce to nearly the same value in solutions of NaSCN and LiSCN, both highly chaotropic salts. The K _av of maltodextrins increase with their molecular weight. These partition peculiarities are attributed to the hydrophobic nature of sugars presumably due to their CH surface. The order of increasing hydrophobicity based on K _av is: D-galactose < D-glucose < D-mannose < (D-arabinose, D-xylose) < D-ribose. This order is consistent with that based on the free energy change pertaining to the transfer of sugar molecules from water to 1-butanol.