Evolution of the international workshops on quantitative structure-activity relationships (QSARs) in environmental toxicology

This presentation will review the evolution of the workshops from a scientific and personal perspective. From their modest beginning in 1983, the workshops have developed into larger international meetings, regularly held every two years. Their initial focus on the aquatic sphere soon expanded to include properties and effects on atmospheric and terrestrial species, including man. Concurrent with this broadening of their scientific scope, the workshops have become an important forum for the early dissemination of all aspects of qualitative and quantitative structure-activity research in ecotoxicology and human health effects. Over the last few decades, the field of quantitative structure/activity relationships (QSARs) has quickly emerged as a major scientific method in understanding the properties and effects of chemicals on the environment and human health. From substances that only affect cell membranes to those that bind strongly to a specific enzyme, QSARs provides insight into the biological effects and chemical and physical properties of substances. QSARs are useful for delineating the quantitative changes in biological effects resulting from minor but systematic variations of the structure of a compound with a specific mode of action. In addition, more holistic approaches are being devised that result in our ability to predict the effects of structurally unrelated compounds with (potentially) different modes of action. Research in QSAR environmental toxicology has led to many improvements in the manufacturing, use, and disposal of chemicals. Furthermore, it has led to national policies and international agreements, from use restrictions or outright bans of compounds, such as polychlorinated biphenyls (PCBs), mirex, and highly chlorinated pesticides (e.g. DDT, dieldrin) for the protection of avian predators, to alternatives for ozone-depleting compounds, to better waste treatment systems, to more powerful and specific acting drugs. Most of the recent advances in drug development could not have been achieved without the use of QSARs in one form or another. The pace of such developments is rapid and QSARs are the keystone to that progress. These workshops have contributed to this progress and will continue to do so in the future.     

Evolution of the international workshops on quantitative structure-activity relationships (QSARs) in environmental toxicology†

This presentation will review the evolution of the workshops from a scientific and personal perspective. From their modest beginning in 1983, the workshops have developed into larger international meetings, regularly held every two years. Their initial focus on the aquatic sphere soon expanded to include properties and effects on atmospheric and terrestrial species, including man. Concurrent with this broadening of their scientific scope, the workshops have become an important forum for the early dissemination of all aspects of qualitative and quantitative structure-activity research in ecotoxicology and human health effects. Over the last few decades, the field of quantitative structure/activity relationships (QSARs) has quickly emerged as a major scientific method in understanding the properties and effects of chemicals on the environment and human health. From substances that only affect cell membranes to those that bind strongly to a specific enzyme, QSARs provides insight into the biological effects and chemical and physical properties of substances. QSARs are useful for delineating the quantitative changes in biological effects resulting from minor but systematic variations of the structure of a compound with a specific mode of action. In addition, more holistic approaches are being devised that result in our ability to predict the effects of structurally unrelated compounds with (potentially) different modes of action. Research in QSAR environmental toxicology has led to many improvements in the manufacturing, use, and disposal of chemicals. Furthermore, it has led to national policies and international agreements, from use restrictions or outright bans of compounds, such as polychlorinated biphenyls (PCBs), mirex, and highly chlorinated pesticides (e.g. DDT, dieldrin) for the protection of avian predators, to alternatives for ozone-depleting compounds, to better waste treatment systems, to more powerful and specific acting drugs. Most of the recent advances in drug development could not have been achieved without the use of QSARs in one form or another. The pace of such developments is rapid and QSARs are the keystone to that progress. These workshops have contributed to this progress and will continue to do so in the future.     

QSAR Modeling of Large Heterogeneous Sets of Molecules

Abstract

In aquatic toxicology, QSAR models are generally designed for chemicals presenting the same mode of toxic action. Their proper use provides good simulation results. Problems arise when the mechanism of toxicity of a chemical is not clearly identified. Indeed, in that case, the inappropriate application of a specific QSAR model can lead to a dramatic error in the toxicity estimation. With the advent of powerful computers and easy access to them, and the introduction of soft modeling and artificial intelligence in SAR and QSAR, radically different models, designed from large non-congeneric sets of chemicals have been proposed. Some of these new QSAR models are reviewed and their originality, advantages, and limitations are stressed.     

U.S. EPA Regulatory Perspectives on the Use of QSAR for New and Existing Chemical Evaluations

Abstract

As testing is not required, ecotoxicity or fate data are available for ≈ 5% of the approximately 2,300 new chemicals/year (26,000 + total) submitted to the US-EPA. The EPA's Office of Pollution Prevention and Toxics (OPPT) regulatory program was forced to develop and rely upon QSARs to estimate the ecotoxicity and fate of most of the new chemicals evaluated for hazard and risk assessment. QSAR methods routinely result in ecotoxicity estimations of acute and chronic toxicity to fish, aquatic invertebrates, and algae, and in fate estimations of physical/chemical properties, degradation, and bioconcentration. The EPA's Toxic Substances Control Act (TSCA) Inventory of existing chemicals currently lists over 72,000 chemicals. Most existing chemicals also appear to have little or no ecotoxicity or fate data available and the OPPT new chemical QSAR methods now provide predictions and cross-checks of test data for the regulation of existing chemicals. Examples include the Toxics Release Inventory (TRI), the Design for the Environment (DfE), and the OECD/SIDS/HPV Programs. QSAR screening of the TSCA Inventory has prioritized thousands of existing chemicals for possible regulatory testing of: 1) persistent bioaccumulative chemicals, and 2) the high ecotoxicity of specific discrete organic chemicals.     

Non-linear modeling of bioconcentration using partition coefficients for narcotic chemicals

Bioconcentration factors (BCFs) have traditionally been used to describe the tendency of chemicals to concentrate in aquatic organisms. A reexamination of the log-log QSAR between the BCF and K OW for non-congener narcotic chemicals is presented on the basis of recommended data for fish. The model is extended to give a simple correlation between BCF and the toxicity of highly, moderately and weakly hydrophilic chemicals. For the first time, in this study an equation for calculating BCF was applied in a QSAR model for predicting the acute toxicity of chemicals to aquatic organisms.     

A perspective on environmental models and QSARs

A general review is presented of the roles of QSARs and mass balance models as tools for assessing the environmental fate and effects of chemicals of commerce. It is argued that all such chemicals must be assessed using a consistent and transparent methodology that uses chemical property data derived from QSARs, or experimental determinations when possible and applies evaluative or region-specific environmental models. These data and models enable an assessment to be made of the key chemical features of persistence, bioaccumulation, potential for long-range transport and toxicity. The other key feature is quantity used or discharged to the environment. A taxonomy of environmental models is presented in which it is suggested that rather than develop a single comprehensive model, the aim should be to establish a set of coordinated and consistent models treating evaluative and real environmental systems at a variety of scales from local to global and including food web models, organism-specific models and human exposure and pharmacokinetic models. The concentrations derived from these models can then be compared with levels judged to be of toxic significance. A brief account is given of perceived QSAR needs in terms of partitioning, reactivity, transport and toxicity data to support these models.     

Response-surface analyses for toxicity to Tetrahymena pyriformis: reactive carbonyl-containing aliphatic chemicals

A response-plane has been developed with Tetrahymena pyriformis population growth impairment toxicity data [log 1/50% growth inhibitory concentration (IGC50)], the 1-octanol/water partition coefficient (log Kow), and the energy of the lowest unoccupied molecular orbital (Elumo). A statistically robust plane [log 1/IGC50 = 0.530 (log Kow) -0.890 (Elumo) -0.271, n = 50, s = 0.295, r2 = 0.855, F = 145] was found for reactive carbonyl-containing aliphatic chemicals. These compounds had a variety of electrophilic mechanisms of action and included aldehydes acting as Schiff-base formers, alpha,beta-unsaturated aldehydes and alpha,beta-unsaturated ketones acting as Michael-type acceptors, and selected alpha-diones acting as selective binders to arganine residues; gamma-diones acting as selective binders to tubulin; and beta-diones with unknown mechanisms of action. Outliers to this model broadly fell into two groups: small reactive molecules (e.g., acrolein) that were more toxic than predicted and molecules in which the reactive center was sterically hindered by an alkyl group (e.g., 2,4-dimethyl-2,6-heptadienal) that were less toxic than predicted.     

Toxicity testing of chemicals without use of animals

A series of publications on the studies of phytotoxicity of chemicals (pollutants, ecotoxicants), carried out by the author and his research group, have been reviewed. Tests (bioassays) based on experiments with many higher plant species, both terrestrial and aquatic ones (macrophytes), were used in these studies. Among the chemicals tested there were various organic (synthetic detergents, surfactants, and pesticides) and some inorganic (e.g., metal oxide nanoparticles) compounds. New methods for bioassay using plant species never used before have been developed by the author. New facts of phytotoxicity of a synthetic detergent have been discovered and reported. Specifically, an aqueous solution of liquid detergent Frosch (Werner & Mertz, FRG) at a concentration of 0.25 mL/L (and higher concentrations) inhibited the elongation rate of seedlings of Lens culinaris higher plant species. Also, phytotoxicity of synthetic cationic surfactant dodecyltrimethylammonium bromide has been reported for the first time. This surfactant at a concentration of 4 mg/L inhibited the elongation of Lens culinaris plant seedlings. The phytotesting methods contribute to the development of alternative approaches to studying the toxicity of chemicals through non-animal testing.     

Global Government applications of analogues,SAR s and QSAR s to predict aquatic toxicity,chemical or physical properties,environmental fate parameters and health effects of organic chemicals

Faced with the need to predict physical and chemical properties, environmental fate, ecological effects and health effects of organic chemicals in the absence of experimental data, several Government organizations have been applying analogues, Structure Activity Relationships (SARs) and Quantitative Structure Activity Relationships (QSARs) to develop those predictions. To establish some benchmarks for monitoring future increases in applications of analogues, SARs and QSARs by global Government organizations, this paper describes the current applications of analogues, SARs and QSARs by Australian, Canadian, Danish, European, German, Japanese, Netherlands, and United States Government organizations to predict physical and chemical properties, environmental fate, ecological effects and health effects of organic chemicals.     

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.     

Development of classification models for predicting chronic toxicity of chemicals to Daphnia magna and Pseudokirchneriella subcapitata

Both the acute toxicity and chronic toxicity data on aquatic organisms are indispensable parameters in the ecological risk assessment priority chemical screening process (e.g. persistent, bioaccumulative and toxic chemicals). However, most of the present modelling actions are focused on developing predictive models for the acute toxicity of chemicals to aquatic organisms. As regards chronic aquatic toxicity, considerable work is needed. The major objective of the present study was to construct in silico models for predicting chronic toxicity data for Daphnia magna and Pseudokirchneriella subcapitata. In the modelling, a set of chronic toxicity data was collected for D. magna (21 days no observed effect concentration (NOEC)) and P. subcapitata (72 h NOEC), respectively. Then, binary classification models were developed for D. magna and P. subcapitata by employing the k-nearest neighbour method (k-NN). The model assessment results indicated that the obtained optimum models had high accuracy, sensitivity and specificity. The model application domain was characterized by the Euclidean distance-based method. In the future, the data gap for other chemicals within the application domain on their chronic toxicity for D. magna and P. subcapitata could be filled using the models developed here.