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.     

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.     

The HEATOX Project

HEATOX is the acronym for a European Union-funded project entitled Heat-Generated Food Toxicants: Identification, Characterization, and Risk Minimization. Acrylamide will be the main experimental focus, but identification of unknown toxicants in heated carbohydrate-rich foods will also be attempted. The project includes research on formation chemistry, food technology, analytical methods, hazard characterization, and exposure assessment. The results will finally be used in risk assessment and risk management advice.     

Quantification methods of Black Carbon: comparison of Rock-Eval analysis with traditional methods

Black Carbon (BC) quantification methods are reviewed, including new Rock-Eval 6 data on BC reference materials. BC has been reported to have major impacts on climate, human health and environmental quality. Especially for risk assessment of persistent organic pollutants (POPs) it is important to account for risk reduction caused by BC, as suggested for POP safety assessment in the framework of the new European Community Regulation on Registration, Evaluation, Authorization and Restriction of Chemicals (REACH). Four major classes of BC quantification methods are reviewed including application to BC reference materials. Methods include chemical oxidation, thermal oxidation, molecular marker, optical methods and Rock-Eval analyses. Residual carbon from Rock-Eval 6 analysis correlated well with BC data from 'gentle' methods like optical and molecular marker methods, which capture a major part of the BC continuum including labile fractions (e.g. char). In contrast, the temperature at which 50% of the organic matter was oxidized (T(50%)) in an oxidation-only Rock-Eval analysis, correlated well with data from chemothermal oxidation (CTO), which captures only refractory BC fractions (e.g. soot). Rock-Eval analysis can further be used for BC characterization through deconvolution of the dominant peaks of the thermogram and appears to be a powerful tool in BC analysis.     

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.     

EU Approach for Environmental Exposure Assessment: Actual Status and Future Needs

Abstract

To estimate the environmental concentration of a chemical substance, as required by the legislation of the European Union in the context of the risk assessment of chemical substances, several mathematical models are proposed. Representative and reliable analytical monitoring data for the different environmental compartments are indeed only seldom available. The proposed models are simple models as for instance multimedia fugacity models. Although the results of these models only provide an imperfect approximation of the concentration in the different compartments, very high uncertainties can lie upon certain input parameters, like the quantities of the substance released during one of its life-stages, its biodegradation rate in the respective compartments or its partition coefficients between those compartments. The improvement of the risk assessment scheme as proposed by the EU-Member States should focus on these input parameters. This might imply further adapting the test methods or even the requested test battery to the physical-chemical properties or even the structure of a substance.     

The role of the European Chemicals Bureau in promoting the regulatory use of (Q)SAR methods†

Under the proposed REACH (Registration, Evaluation and Authorisation of CHemicals) legislation, (Q)SAR models and grouping methods (chemical categories and read across approaches) are expected to play a significant role in prioritising industrial chemicals for further assessment, and for filling information gaps for the purposes of classification and labelling, risk assessment and the assessment of persistent, bioaccumulative and toxic (PBT) chemicals. The European Chemicals Bureau (ECB), which is part of the European Commission's Joint Research Centre (JRC), has a well-established role in providing independent scientific and technical advice to European policy makers. The ECB also promotes consensus and capacity building on scientific and technical matters among stakeholders in the Member State authorities and industry. To promote the availability and use of (Q)SARs and related estimation methods, the ECB is carrying out a range of activities, including applied research in computational toxicology, the assessment of (Q)SAR models and methods, the development of technical guidance documents and computational tools, and the organisation of training courses. This article provides an overview of ECB activities on computational toxicology, which are intended to promote the development, validation, acceptance and use of (Q)SARs and related estimation methods, both at the European and international levels.     

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.     

Evaluation of SARs for the prediction of eye irritation/corrosion potential: structural inclusion rules in the BfR decision support system

The proposed REACH regulation within the European Union (EU) aims to minimise the number of laboratory animals used for human hazard and risk assessment while ensuring adequate protection of human health and the environment. One way to achieve this goal is to develop non-testing methods, such as (quantitative) structure-activity relationships ([Q]SARs), suitable for identifying toxicological hazard from chemical structure and physicochemical properties alone. A database containing data submitted within the EU New Chemicals Notification procedure was compiled by the German Bundesinstitut für Risikobewertung (BfR). On the basis of these data, the BfR built a decision support system (DSS) for the prediction of several toxicological endpoints. For the prediction of eye irritation and corrosion potential, the DSS contains 31 physicochemical exclusion rules evaluated previously by the European Chemicals Bureau (ECB), and 27 inclusion rules that define structural alerts potentially responsible for eye irritation and/or corrosion. This work summarises the results of a study carried out by the ECB to assess the performance of the BfR structural rulebase. The assessment included: (a) evaluation of the structural alerts by using the training set of 1341 substances with experimental data for eye irritation and corrosion; and (b) external validation by using an independent test set of 199 chemicals. Recommendations are made for the further development of the structural rules in order to increase the overall predictivity of the DSS.     

Evaluation of SARs for the prediction of eye irritation/corrosion potential–structural inclusion rules in the BfR decision support system†

The proposed REACH regulation within the European Union (EU) aims to minimise the number of laboratory animals used for human hazard and risk assessment while ensuring adequate protection of human health and the environment. One way to achieve this goal is to develop non-testing methods, such as (quantitative) structure–activity relationships ([Q]SARs), suitable for identifying toxicological hazard from chemical structure and physicochemical properties alone. A database containing data submitted within the EU New Chemicals Notification procedure was compiled by the German Bundesinstitut für Risikobewertung (BfR). On the basis of these data, the BfR built a decision support system (DSS) for the prediction of several toxicological endpoints. For the prediction of eye irritation and corrosion potential, the DSS contains 31 physicochemical exclusion rules evaluated previously by the European Chemicals Bureau (ECB), and 27 inclusion rules that define structural alerts potentially responsible for eye irritation and/or corrosion. This work summarises the results of a study carried out by the ECB to assess the performance of the BfR structural rulebase. The assessment included: (a) evaluation of the structural alerts by using the training set of 1341 substances with experimental data for eye irritation and corrosion; and (b) external validation by using an independent test set of 199 chemicals. Recommendations are made for the further development of the structural rules in order to increase the overall predictivity of the DSS.     

Predictions for existing chemicals-a multilateral QSAR project

Abstract Following a previous collaborative EU/EPA project focussed on QSAR predictions for a selection of new chemicals which had been notified in the EU, a similar exercise was started in 1993 on existing chemicals. In a first phase, the project addresses the High Production Volume (HPV) chemicals which are produced or imported at levels above a 1000t/year in the EU and 454t/year in the US. The relevant EU (Annex 1 of Existing Chemicals Regulation No. 793/93) and US-EPA lists contain 1036 and 2881 organic substances respectively of which HPV 749 chemicals are in common. The joint project aims at an estimation through validated QSAR models of the physical-chemical, ecotoxicity and toxicity endpoints which are included in the regulation and where experimental data will become available in IUCLID (International Unified Chemicals Information Database). Next to EC-JRC (ECB) and US-EPA, various laboratories in the EU are contributing to the project and recently, two institutes in Japan have joined in this project.     

The EC Standards, Measurements and Testing Programme in support of the quality control of waste analysis

Projects funded within the EC Standards, Measurements and Testing Programme (SM&T) of the European Commission aim to contribute to the harmonization and improvement of methods and measurements carried out within the European Union and hence to the comparability of data necessary for e.g. trade activities, monitoring of environment, food and health control, etc. This goal may be achieved by e.g. the organization of interlaboratory studies and certifications of reference materials, the development of new methods and pre-normative research. Examples of projects undertaken in support of the quality of waste analysis are given in this paper, covering different aspects, namely interlaboratory study and certification of extractable trace metals in sewage sludge amended soil reference materials, pre-normative research for the characterisation of stabilized waste (interlaboratory study), and development of field-measurement device for the monitoring of waste water quality; this paper gives also an account of a network aimed at harmonising leaching/extraction tests used for environmental risk assessment. Finally, the main topics of the workshop on Standards, Measurements and Testing for Solid Waste Management are given in the annex, along with a list of participants.     

The role of the European Chemicals Bureau in promoting the regulatory use of (Q)SAR methods

Under the proposed REACH (Registration, Evaluation and Authorisation of CHemicals) legislation, (Q)SAR models and grouping methods (chemical categories and read across approaches) are expected to play a significant role in prioritising industrial chemicals for further assessment, and for filling information gaps for the purposes of classification and labelling, risk assessment and the assessment of persistent, bioaccumulative and toxic (PBT) chemicals. The European Chemicals Bureau (ECB), which is part of the European Commission's Joint Research Centre (JRC), has a well-established role in providing independent scientific and technical advice to European policy makers. The ECB also promotes consensus and capacity building on scientific and technical matters among stakeholders in the Member State authorities and industry. To promote the availability and use of (Q)SARs and related estimation methods, the ECB is carrying out a range of activities, including applied research in computational toxicology, the assessment of (Q)SAR models and methods, the development of technical guidance documents and computational tools, and the organisation of training courses. This article provides an overview of ECB activities on computational toxicology, which are intended to promote the development, validation, acceptance and use of (Q)SARs and related estimation methods, both at the European and international levels.     

How to measure uncertainties in environmental risk assessment

Environmental risk assessment is an essential element in any decision-making process in order to minimize the effects of human activities on the environment. Unfortunately, often environmental data tends to be vague and imprecise, so uncertainty is associated with any study related with these kind of data.

Essentially, uncertainty in risk assessment may have two origins – randomness and incompleteness. There are two main ways to deal with these uncertainties – probability theory and fuzzy logic.

Probability theory is based on a stochastic approach, using probability functions to describe random variability in environmental parameters.

Fuzzy logic uses membership functions and linguistic parameters to express vagueness in environmental issues.

We discuss the best way to deal with uncertainties in the environmental field and give examples of probabilistic and fuzzy-logic approaches applied to environmental risk assessment.     

Harmonisation of proficiency testing schemes

The harmonisation of proficiency testing (PT) schemes has been under debate for a long time. There are obvious reasons why harmonisation of the practices in PT would be beneficial. In many areas, there is still a belief that further harmonisation of practices in PT would improve the comparability of measurement data. In particular when two laboratories are to be compared that have not participated in a single PT, problems arise which allegedly can be overcome by further harmonisation of PT schemes. In practice, however, parties involved in PT are not always embracing the idea of harmonisation. With the results of two European projects in mind, a discussion is given on harmonisation aspects, and some considerations are given that may help to decide in practice whether harmonisation is likely to solve particular problems. The first project, the European Proficiency Testing Network (EPTN), is concerned with further harmonisation. The second European project (COEPT) aims at providing a basis to assess equivalence across proficiency tests, and explores the conditions under which such an assessment is feasible.     

The effects of short‐term changes in environmental parameters on the release of biocides from antifouling coatings: cuprous oxide and tributyltin

Current and forthcoming UK and European legislation requires environmental risk assessment of antifouling paints. For assessments to be carried out successfully, the leaching rate of biocides from antifouling paints should be determined. Current methods for the measurement of biocide leach rate have been shown to be very susceptible to changes in parameters such as pH, salinity and temperature. Using apparatus designed to simulate environmental conditions the effect of short‐term changes in salinity, pH, temperature, suspended particulate matter and simulated vessel speed on cuprous oxide and tributyltin (TBT) leaching from self‐polishing antifouling paint was investigated. No effect on copper leaching was observed over a wide range of environmentally relevant conditions, whilst vessel speed was the only parameter found to influence TBT release rates significantly. It is suggested that the decrease observed may be due to the formation of a boundary layer which slows down the release of TBT from the paint surface. The environmental authenticity of this observation and its possible implications for the environmental risk assessment of TBT are discussed. Copyright © 1999 Crown Copyright.     

Assessing toxicological data quality: basic principles,existing schemes and current limitations

Existing toxicological data may be used for a variety of purposes such as hazard and risk assessment or toxicity prediction. The potential use of such data is, in part, dependent upon their quality. Consideration of data quality is of key importance with respect to the application of chemicals legislation such as REACH. Whether data are being used to make regulatory decisions or build computational models, the quality of the output is reflected by the quality of the data employed. Therefore, the need to assess data quality is an important requirement for making a decision or prediction with an appropriate level of confidence. This study considers the biological and chemical factors that may impact upon toxicological data quality and discusses the assessment of data quality. Four general quality criteria are introduced and existing data quality assessment schemes are discussed. Two case study datasets of skin sensitization data are assessed for quality providing a comparison of existing assessment methods. This study also discusses the limitations and difficulties encountered during quality assessment, including the use of differing quality schemes and the global versus chemical-specific assessments of quality. Finally, a number of recommendations are made to aid future data quality assessments.     

Assessing toxicological data quality: basic principles, existing schemes and current limitations

Existing toxicological data may be used for a variety of purposes such as hazard and risk assessment or toxicity prediction. The potential use of such data is, in part, dependent upon their quality. Consideration of data quality is of key importance with respect to the application of chemicals legislation such as REACH. Whether data are being used to make regulatory decisions or build computational models, the quality of the output is reflected by the quality of the data employed. Therefore, the need to assess data quality is an important requirement for making a decision or prediction with an appropriate level of confidence. This study considers the biological and chemical factors that may impact upon toxicological data quality and discusses the assessment of data quality. Four general quality criteria are introduced and existing data quality assessment schemes are discussed. Two case study datasets of skin sensitization data are assessed for quality providing a comparison of existing assessment methods. This study also discusses the limitations and difficulties encountered during quality assessment, including the use of differing quality schemes and the global versus chemical-specific assessments of quality. Finally, a number of recommendations are made to aid future data quality assessments.     

Harmonisation of proficiency testing schemes

The harmonisation of proficiency testing (PT) schemes has been under debate for a long time. There are obvious reasons why harmonisation of the practices in PT would be beneficial. In many areas, there is still a belief that further harmonisation of practices in PT would improve the comparability of measurement data. In particular when two laboratories are to be compared that have not participated in a single PT, problems arise which allegedly can be overcome by further harmonisation of PT schemes. In practice, however, parties involved in PT are not always embracing the idea of harmonisation. With the results of two European projects in mind, a discussion is given on harmonisation aspects, and some considerations are given that may help to decide in practice whether harmonisation is likely to solve particular problems. The first project, the European Proficiency Testing Network (EPTN), is concerned with further harmonisation. The second European project (COEPT) aims at providing a basis to assess equivalence across proficiency tests, and explores the conditions under which such an assessment is feasible.