Wei C. Qin

Interspecies correlations of toxicity to eight aquatic organisms: Theoretical considerations

Interspecies correlations allow the prediction of toxicity to a number of other species. However, little attention has been paid to the theoretical considerations of the interspecies relationship based on the differences of bio-uptake and toxic mechanism between species. This study examines the interspecies correlations of toxicity between species of Vibrio fischeri, river bacteria, algae, Daphnia magna, carp, Tetrahymena pyriformis, fathead minnow and guppy based on the theoretical background. The results show that there are good interspecies correlations between marine bacterium and fresh water bacteria or fish and fish. It is suggested that compounds share the same bio-uptake and toxic mechanism of action between the species. On the other hand, poor interspecies relationships were found between toxicities to algae and T. pyriformis or D. magna. It is suggested that compounds have different toxic mechanisms of action between these species. Interspecies relationships can be improved by inclusion of the octanol/water partition coefficient or the energy of the lowest unoccupied molecular orbital. They reflect the difference of bio-uptake or toxic mechanism of action between species for organic compounds. Benzoic acids show very different toxicity contributions to the three species, V. fischeri, D. magna and carp. They can be easily absorbed into the unicellular bacteria, V. fischeri. On the contrary, the skin and lipid content of multicellular organisms, such as D. magna and fish, can strongly inhibit the bio-uptake for ionizable compounds, which results in the different toxic effect between V. fischeri and D. magna or carp. Good correlation coefficients were observed between toxicities to V. fischeri and D. magna or fishes by inclusion of hydrophobic and ionization parameters. V. fischeri or D. magna can serve as a surrogate of fish toxicity for hydrophobic and ionizable compounds studied. Toxic mechanisms of action are discussed based on the theoretical background of the interspecies correlation.

Classification of toxicity of phenols to Tetrahymena pyriformis and subsequent derivation of QSARs from hydrophobic, ionization and electronic parameters.

Phenolic compounds were classified into different groups based on the structure and functional groups of the phenol. Quantitative structure-activity relationship (QSAR) analysis was performed between the toxicity and octanol/water partition coefficient (logP) for these groups. The results showed that the toxicity of non-ionisable phenols is dependent on their hydrophobicity. Poor relationships were found between the toxicity and logP for ionisable compounds, and the use of methods based on logP to predict the toxicity of ionisable compounds can result in considerable errors. Ionized and unionized forms have different contributions to toxicity; the unionized form plays a more important role than the ionized form because the toxicity of organic acids and phenols decreases as the pH increases. In order to investigate the effect of ionization, the fraction of ionized and unionized forms of phenols at different pH values were calculated from the pK(a) values, and a corrected distribution partition coefficient (D(T)) was derived from QSAR analysis for ionisable compounds. The prediction of toxicity of non-reactive ionisable compounds was improved remarkably by using the D(T) parameter. Ionization not only affects the bio-uptake of ionisable compounds, but interaction with the receptor micromolecule can also depend on the electronic situation, which is also related to the ionization. Stepwise regression showed that the reactivity of ionisable phenols was strongly correlated with the fraction of negatively charged form (F(-)). Interpretable QSAR equations with good statistical fits were developed from hydrophobic, ionization and electronic parameters for 207 phenols.

Linear and non-linear relationships between soil sorption and hydrophobicity: model, validation and influencing factors.

The hydrophobic parameter represented by the octanol/water partition coefficient (logP) is commonly used to predict the soil sorption coefficient (K(oc)). However, a simple non-linear relationship between logK(oc) and logP has not been reported in the literature. In the present paper, soil sorption data for 701 compounds was investigated. The results show that logK(oc) is linearly related to logP for compounds with logP in the range of 0.5-7.5 and non-linearly related to logP for the compounds in a wide range of logP. A non-linear model has been developed between logK(oc) and logP for a wide range of compounds in the training set. This model was validated in terms of average error (AE), average absolute error (AAE) and root-mean squared error (RMSE) by using an external test set with 107 compounds. Nearly the same predictive capacity was observed in comparison with existing models. However, this non-linear model is simple, and uses only one parameter. The best model developed in this paper is a non-linear model with six correction factors for six specific classes of compounds. This model can well predict logK(oc) for 701 diverse compounds with AAE = 0.37. The reasons for systemic deviations in these groups may be attributed to the difference of sorption mechanism for hydrophilic/polar compounds, low solubility for highly hydrophobic compounds, hydrolysis of esters in solution, volatilization for volatile compounds and highly experimental errors for compounds with extremely high or low sorption coefficients.

Toxicity of organic chemicals to Tetrahymena pyriformis: effect of polarity and ionization on toxicity.

A large toxicity data set containing the toxicities of 250 phenols and 252 aliphatic compounds to Tetrahymena pyriformis was classified into different groups based on the structure and substituted functional groups. QSAR analysis was performed between the toxicity and calculated descriptors, expressed as hydrophobicity, polarity and ionization. Through an analysis of these class-based compounds, significant relationships were developed between the toxicity and hydrophobicity for non-polar and polar narcotic compounds. A single model for both non-polar and polar narcotics was developed by inclusion of a polar descriptor as well as the hydrophobic parameter logP. The highly hydrophobic polar narcotics can be treated as non-polar narcotics because their polar functional group(s) makes a relatively small contribution as compared to their hydrophobicity. A cut-off to classify the polar narcotics is difficult because polarity of a chemical not only depends on one or two functional groups (i.e. amino- or hydroxyl-) substituted on the compound, but also on the overall hydrophobicity of the compound. The toxicity increases with increasing the ionization by increasing the interaction between ionisable compounds and macromolecules at the target sites. However, the toxicity decreases with increasing the ionization by decreasing the bio-uptake for extremely ionisable compounds. A significant QSAR equation has been developed between the toxicity to T. pyriformis and the descriptors of hydrophobic, polarity/polarizability and ionization parameters for 457 compounds (R(2)=0.87). These compounds contain non-polar, polar and reactive compounds, and some of them are extremely ionisable. The models developed are simple, interpretable and transparent, using a small number of descriptors.

Toxicity of organic pollutants to seven aquatic organisms: effect of polarity and ionization

The toxicity of organic chemicals to Vibrio fischeri, river bacteria, algae, Daphnia magna and fishes were analysed. The results showed that the toxicity of chemicals to narcotics was dependent on hydrophobicity. A single model for both polar and non-polar narcotics was developed by inclusion of a polarity descriptor as well as the hydrophobic parameter. The highly hydrophobic polar narcotics could be treated as non-polar narcotics because their polar functional group(s) make(s) a relatively small contribution to polarity as compared with their hydrophobicity. In order to investigate the toxic mechanism of action for reactive compounds, the response–surface approach was used to develop models derived from easily calculated descriptors. The stepwise analysis selected the octanol/water partition coefficient and a polarity descriptor to parameterize bio-uptake and reactivity, respectively, for seven species. Benzoic acids can be easily absorbed into the unicellular bacteria, but this is not the case for multicellular D. magna and fish. Their toxicity to V. fischeri is much higher than that to D. magna and carp. Regression analysis was performed based on the model that we developed for ionizable compounds. Good correlations were observed by introducing the correction factor for ionizable compounds. The toxic mechanisms are discussed.

Investigation on the relationship between bioconcentration factor and distribution coefficient based on class-based compounds: The factors that affect bioconcentration.

Bioconcentration factor (BCF) is one of the most important parameters in the assessment of the potential hazard of new compounds in aquatic ecosystems. However, the factors that influence the estimation of BCFs for a large variety of chemicals have not been systemically investigated in the literature. In this paper, a large BCF data set containing 1088 nonionic and ionic organic compounds was used to study the relationship between BCF and molecular descriptors and influencing factors. Step-by-step analysis on the class-based compounds showed that nonlinear Gaussian and Sigmoid equations could well describe relationships between logBCF and distribution coefficient for the compounds over a wide range of structures and chloro or/and bromo substituted aromatics, respectively. The quality of fit from the nonlinear models is better than the BCFBAF method from the Epi Suite program for the class-based compounds. Systemic prediction deviations have been observed for some types of compounds. The reasons for systemic deviations for these compounds can be attributed to the difference in bioconcentration mechanism for hydrophilic compounds, transformation for hydroxyphenols and three-membered rings, physical barrier for long chain and large polycyclic compounds, difference in determining methods of BCF (kinetic and steady-state), bioavailability for highly hydrophobic compounds and accuracy of BCF measurements for compounds with extremely high or low BCFs. These factors are important and should be considered in any reliable bioconcentration prediction.

Discrimination of excess toxicity from narcotic effect: Influence of species sensitivity and bioconcentration on the classification of modes of action

The toxicity data of 2624 chemicals to fish, Daphniamagna, Tetrahymenapyriformis and Vibriofischeri were used to investigate the effects of species sensitivity and bioconcentration on excess toxicity. The results showed that 47 chemical classes were identified as having the same modes of action (MOAs) to all four species, but more than half of the classes were identified as having different MOAs. Difference in chemical MOAs is one of the reasons resulting in the difference in toxic effect to these four species. Other important reasons are the difference in sensitivity and bioconcentration of species. Among the four species, V. fischeri has the most compounds identified as reactive MOA. This may be due to some compounds can be easily absorbed into the bacteria, react with the DNA or proteins, disrupt the normal function of the cell and exhibit significantly greater toxicity to the bacteria. On the other hand, the skin and lipid content of aqueous organisms can strongly inhibit the bio-uptake for some reactive compounds, resulting in a less toxic effect than expected. D. magna is the most sensitive species and T. pyriformis is the least sensitive species of the four species. For a comparison of interspecies toxicity, we need to use the same reference threshold of excess toxicity. However, some reactive compounds may be identified as baseline or less inert compounds for low sensitive species from the threshold developed from high sensitive species. The difference in the discrimination of excess toxicity to different species is not only because of the difference in MOAs for some compounds, but also due to the difference in sensitivity and bioconcentration.

Comparison of Tetrahymena pyriformis toxicity based on hydrophobicity, polarity, ionization and reactivity of class-based compounds

A toxicity data set containing the toxicities of 970 hydrophobic, polar and ionizable, nitro substituted and α,β-unsaturated compounds to Tetrahymena pyriformis was classified into different groups based on the structure and substituted functional groups. Polar, ionizable and reactive compounds exhibit greater toxicity as compared with the non-polar hydrophobic compounds. Step-by-step analysis was carried out between the toxicity and descriptors representing hydrophobicity, polarity/polarizability, ionization and reactivity of compounds. Significant relationships were developed between the toxicity and these descriptors for the compounds. The models developed are simple, interpretable and transparent, using a small number of descriptors that may reflect the interactions of chemicals with the biological macromolecules at the target sites. Hydrophobic parameter log P reflects bio-uptake process compounds. Polarity/polarizability descriptor S reflects the interaction of hydrophilic residues of polar chemicals with biological macromolecules. The fractions of ionized (F i) and neutral (F 0) forms calculated from pK a reflect the interactions of ionizable compounds with the macromolecules and effect of ionization of ionizable compounds on the bio-uptake process, respectively. A successful single model was developed by using the descriptors log P, S, F i and log F 0 for non-polar, polar and ionizable compounds.

Relationship between lethal toxicity in oral administration and injection to mice: Effect of exposure routes

The lethal toxicity (LD₅₀) in oral administration, intravenous, intraperitoneal, intramuscular and subcutaneous injections were used to investigate relationships of log 1/LD₅₀ from different exposure routes. Regression analysis showed that log 1/LD₅₀ in oral route was related to the toxicity in injection route. This relationship in lethality between the two routes is apparently due to the same mechanisms of the compounds to the same species. However, the scatter in the correlation curve indicates that exposure route is an important factor that influences the relationship. Some compounds with low intestinal absorption exhibit much less toxicity in oral administration than that in the injection route. A systemic bias of log 1/LD₅₀ between oral and injection routes indicates that tissue distribution of compounds between blood and target site is a very rapid process, leading to log 1/LD₅₀ in injection greater than those in oral administration. Although compounds can be metabolized in the body both from oral and injection routes, first-pass metabolism occurs in oral route but not in injection route. This will result in decrease of toxicity in oral route for most compounds as compared with injection route. In addition, experimental uncertainty, differences in gender, and species can also affect relationships of log1/LD₅₀ between exposure routes.

Comparison of Toxicities to Vibrio fischeri and Fish Based on Discrimination of Excess Toxicity from Baseline Level

Investigations on the relationship of toxicities between species play an important role in the understanding of toxic mechanisms to environmental organisms. In this paper, the toxicity data of 949 chemicals to fish and 1470 chemicals to V. fischeri were used to investigate the modes of action (MOAs) between species. The results show that although there is a positive interspecies correlation, the relationship is poor. Analysis on the excess toxicity calculated from toxic ratios (TR) shows that many chemicals have close toxicities and share the same MOAs between the two species. Linear relationships between the toxicities and octanol/water partition coefficient (log KOW) for baseline and less inert compounds indicate that the internal critical concentrations (CBRs) approach a constant both to fish and V. fischeri for neutral hydrophobic compounds. These compounds share the same toxic mechanisms and bio-uptake processes between species. On the other hand, some hydrophilic compounds exhibit different toxic effects with greatly different log TR values between V. fischeri and fish species. These hydrophilic compounds were identified as reactive MOAs to V. fischeri, but not to fish. The interspecies correlation is improved by adding a hydrophobic descriptor into the correlation equation. This indicates that the differences in the toxic ratios between fish and V. fischeri for these hydrophilic compounds can be partly attributed to the differences of bioconcentration between the two species, rather than the differences of reactivity with the target macromolecules. These hydrophilic compounds may more easily pass through the cell membrane of V. fischeri than the gill and skin of fish, react with the target macromolecules and exhibit excess toxicity. The compounds with log KOW > 7 exhibiting very low toxicity (log TR < –1) to both species indicate that the bioconcentration potential of a chemical plays a very important role in the identification of excess toxicity and MOAs.