Development of thresholds of excess toxicity for environmental species and their application to identification of modes of acute toxic action.

The acute toxicity of organic pollutants to fish, Daphnia magna, Tetrahymena pyriformis, and Vibrio fischeri was investigated. The results indicated that the Toxicity Ratio (TR) threshold of log TR =1, which has been based on the distribution of toxicity data to fish, can also be used to discriminate reactive or specifically acting compounds from baseline narcotics for Daphnia magna and Vibrio fischeri. A log TR=0.84 is proposed for Tetrahymena pyriformis following investigation of the relationships between the species sensitivity and the absolute averaged residuals (AAR) between the predicted baseline toxicity and the experimental toxicity. Less inert compounds exhibit relatively higher toxicity to the lower species (Tetrahymena pyriformis and Vibrio fischeri) than the higher species (fish and Daphnia magna). A greater number of less inert compounds with log TR greater than the thresholds was observed for Tetrahymena pyriformis and Vibrio fischeri. This may be attributed to the hydrophilic compounds which may pass more easily through cell membranes than the skin or exoskeleton of organisms and have higher bioconcentration factors in the lower species, leading to higher toxicity. Most of classes of chemical associated with excess toxicity to one species also exhibited excess toxicity to other species, however, a few classes with excess toxicity to one species exhibiting narcotic toxicity to other species and thus may have different MOAs between species. Some ionizable compounds have log TR much lower than one because of the over-estimated log KOW. The factors that influence the toxicity ratio calculated from baseline level are discussed in this paper.

Discrimination of excess toxicity from baseline level for ionizable compounds: Effect of pH.

The toxic effect can be affected by pH in water through affecting the degree of ionization of ionizable compounds. Wrong classification of mode of action can be made from the apparent toxicities. In this paper, the toxicity data of 61 compounds to Daphnia magna determined at three pH values were used to investigate the effect of pH on the discrimination of excess toxicity. The results show that the apparent toxicities are significantly less than the baseline level. Analysis on the effect of pH on bioconcentration factor (BCF) shows that the log BCF values are significantly over-estimated for the strongly ionizable compounds, leading to the apparent toxicities greatly less than the baseline toxicities and the toxic ratios greatly less than zero. A theoretical equation between the apparent toxicities and pH has been developed basing on the critical body residue (CBR). The apparent toxicities are non-linearly related to pH, but linearly to fraction of unionized form. The determined apparent toxicities are well fitted with the toxicities predicted by the equation. The toxicities in the unionized form calculated from the equation are close to, or greater than the baseline level for almost all the strongly ionizable compounds, which are very different from the apparent toxicities. The studied ionizable compounds can be either classified as baseline, less inert or reactive compounds in D. magna toxicity. Some ionizable compounds do not exhibit excess toxicity at a certain pH, due not to their poor reactivity with target molecules, but because of the ionization in water.

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.

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.