Global government applications of analogues,SARs and QSARs 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.     

QSARs for identifying and prioritizing substances with persistence and bioconcentration potential

From the 8511 chemicals with 1998 production volumes reported to the U.S. Environmental Protection Agency (U.S. EPA), the TSCA Interagency Testing Committee's (ITC's) Degradation Effects Bioconcentration Information Testing Strategies (DEBITS) was used to identify 56 chemicals. The DEBITS Quantitative Structure-Activity Relationships (QSARs) and the U.S. EPA's PBT profiler QSARs were used to predict the persistence and bioconcentration factors of these 56 chemicals. Partial order ranking was used to prioritise the chemicals based on persistence and bioconcentration potential.     

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.     

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.     

Regulatory use of (Q)SARs in toxicological hazard assessment strategies

In 2001, the European Commission published a policy statement ("White Paper") on future chemicals regulation and risk reduction that proposed the use of non-animal test systems and tailor-made testing approaches, including (Q)SARs, to reduce financial costs and the number of test animals employed. The authors have compiled a database containing data submitted within the EU chemicals notification procedure. From these data, (Q)SARs for the prediction of local irritation/corrosion and/or sensitisation potential were developed and published. These (Q)SARs, together with an expert system supporting their use, will be submitted for official validation and application within regulatory hazard assessment strategies. The main features are: ? two sets of structural alerts for the prediction of skin sensitisation hazard classification as defined by the European risk phrase R43, comprising 15 rules for chemical substructures deemed to be sensitising by direct action with cells or proteins, and three rules for substructures acting indirectly, i.e., requiring biochemical transformation; ? a decision support system (DSS) for the prediction of skin and/or eye lesion potential built from information extracted from our database. This DSS combines SARs defining reactive chemical substructures relevant for local lesions to be classified, and QSARs for the prediction of the absence of such a potential. The role of the BfR database, and (Q)SARs derived from it, in the use of current and future (EU) testing strategies for irritation and sensitisation is discussed.     

Quantitative prediction of biodegradability,metabolite distribution and toxicity of stable metabolites

An evaluation of the capability of organic chemicals to mineralize is an important factor to consider when assessing their fate in the environment. Microbial degradation can convert a toxic chemical into an innocuous one, and vice versa , or alter the toxicity of a chemical. Moreover, primary biodegradation can convert chemicals into stable products that can be difficult to mineralize. In this paper, we present some new results obtained on the basis of a recently developed probabilistic approach to modeling biodegradation based on microbial transformation pathways. The metabolic transformations and their hierarchy were calibrated by making use of the ready biodegradability data from the MITI-I test and expert knowledge for the most probable transformation pathways. A model was developed and integrated into an expert software system named CATABOL that is able to predict the probability of biodegradation of organic chemicals directly from their structure. CATABOL simulates the effects of microbial enzyme systems, generates the most plausible transformation pathways, and quantitatively predicts the persistence and toxicity of the biodegradation products. A subset of 300 organic chemicals were selected from Canada's Domestic Substances List and subjected to CATABOL to compare predicted properties of the parent chemicals with their respective first stable metabolite. The results show that most of the stable metabolites have a lower acute toxicity to fish and a lower bioaccumulation potential compared to the parent chemicals. In contrast, the metabolites appear to be generally more estrogenic than the parent chemicals.     

Evaluation of Critical Body Residue QSARS for Predicting Organic Chemical Toxicity to Aquatic Organisms

Abstract

The critical body residue (CBR) is the concentration of chemical bioaccumulated in an aquatic organism that corresponds to a defined measure of toxicity (e.g., mortality). The CBR can provide an alternative measure of toxicity to traditional waterborne concentration measurements (e.g., concentration in water causing 50% mortality). The CBR has been suggested as a better estimator of dose than the external water concentration and has been postulated to be constant for chemicals with the same mode of action. CBR QSARs have both theoretical and experimental support, developed primarily from studies on the acute toxicity of narcotic chemicals to small fish. CBR QSARs are less well developed for the aquatic toxicity of non-narcotic chemicals. CBRs vary substantially with the mode of action and toxicity endpoint, and may be affected by genetic, hormonal or environmental variation. CBR QSARs may not be applicable to very hydrophobic chemicals, chemicals with specific modes of action, or those with toxicity controlled by kinetic processes such as biotransformation. CBRs models have not been developed or evaluated for sediment and dietary exposure routes. Application of CBR QSARs to contaminated site assessments will require further research and development.     

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.     

Comparison of three fish bioaccumulation models for ecological and human risk assessment and validation with field data

This article compares two bioconcentration Quantitative Structure Activity Relationships (QSARs) for fish applied in human risk assessments with the mechanistic bioaccumulation model OMEGA and field data. It was found that all models are virtually similar up to a Kow of 10(6). For substances with a Kow higher than 10(6), the fish bioconcentration curve in the risk assessment model EUSES decreases parabolically. In contrast, OMEGA bioaccumulation outcomes approximately show a linear increase, based on mechanistic bioconcentration and biomagnification properties of chemicals. The OMEGA-outcomes are close to the fish bioconcentration outcomes of the risk assessment model CalTOX. For very hydrophobic substances, field accumulation data in freshwater and marine fish species are closer to OMEGA- and CalTOX-outcomes compared to EUSES. The results also show that it is important to include biomagnification in fish and lipid content of fish in human exposure models.     

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.     

Progress and perspectives of quantitative structure-activity relationships used for ecological risk assessment of toxic organic compounds

Structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR), collec- tively referred to as (Q)SARs, play an important role in ecological risk assessment (ERA) of organic chemicals. (Q)SARs can fill the data gap for physical-chemical, environmental behavioral and ecotoxicological parameters of organic compounds; they can decrease experimental expenses and reduce the extent of experimental testing (especially animal testing); they can also be used to assess the uncertainty of the experimental data. With the development for several decades, (Q)SARs in envi- ronmental sciences show three features: application orientation, multidisciplinary integration, and in- telligence. Progress of (Q)SAR technology for ERA of toxic organic compounds, including endpoint selection and mathematic methods for establishing simple, transparent, easily interpretable and portable (Q)SAR models, is reviewed. The recent development on defining application domains and diagnosing outliers is summarized. Model characterization with respect to goodness-of-fit, stability and predictive power is specially presented. The purpose of the review is to promote the development of (Q)SARs orientated to ERA of organic chemicals.     

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.     

Cytokines in terms of QSAR. Review,evaluation and comparative studies

Cytokines represent a class of chemical factors that act as mediators in the complex biological response of inflammation, potentially implicated in various diseases. Therefore, selective inhibition or antagonism of cytokines is a target of anti-inflammatory drug design. The QSAR (Quantitative Structure–Activity Relationships) analysis presented here attempts to identify the structural features and physicochemical properties that are significant for cytokine antagonists or inhibitors and in particular of i) interleukin-5 (IL-5), ii) interleukin-6 (IL-6) and iii) of the chemotactic cytokine (chemokine) interleukin-8 (IL-8). Firstly, a historical aspect of the limited published QSARs is discussed and then a 2D-QSAR analysis was carried out for 26 data sets of compounds using the C-QSAR program of Biobyte. In six cases hydrophobicity appeared to be important. Steric factors in the form of overall molar refractivity (CMR), molar refractivity of the substituent (MR), molar volume (MgVol), Taft’s E_s constant and the sterimol parameters B₁ and B₅ have a significant impact on biological activity in most of the derived equations whereas electronic parameters as σ_p, σ_m or Σ_σ appeared in five cases.     

Modeling the Environmental Fate of Atrazine

Abstract

Mathematical simulation models of fate and transport of chemicals have been identified by researchers and regulators as potentially valuable tools for improving the understanding of the environmental behavior of chemicals which may be released to the environment as a consequence of routine (i.e., normal manufacturing, use, disposal) and non-routine (e.g., accidental spillage) events. In this context, CHEMFRANCE, a regional fugacity model level III, which calculates the environmental distribution of organic chemicals in 12 defined regions of France, or France as a whole, has been designed. The aim of this study is to show that CHEMFRANCE provides valuable simulation results for understanding the environmental fate behavior of atrazine.     

Evaluation of the Use of QSARS for Priority Setting and Risk Assessment

Abstract

Impending changes in EEC legislation have accelerated the need to define the principles and practical considerations of the use of QSARs in priority setting and risk assessment. It is important to delineate the limitations of this approach and to review whether and how this information should be used in the risk assessment. The value and limitations of QSARs for use in priority setting and risk assessment will not be discussed in detail since the European Chemical Industry Ecology and Toxicology Centre (ECETOC) has only recently established a Task Force to tackle this issue. The terms of reference of the Task Force are: (1) compare the predictions obtained with QSARs to measured data using ECETOC databases and other sources of data and comment on the validity and applicability of such QSARs; (2) identify and review software packages which are available for accessing and using appropriate QSARs; (3) identify those aspects of environmental distribution, fate and effects where the further development of QSARs is desirable and feasible; and (4) provide a scientific basis for ECETOC's contribution to the activities of the European Chemicals Bureau (ECB) in this area. In this short paper, only an initial and personal evaluation is made of when and where to use QSARs in the priority setting and risk assessment process within the regulatory framework. Some critical remarks and suggestions are provided to guide future developments and integration of QSARs in the risk assessment process.