Toxicological & Environmental Chemistry Estimation

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Toxicological & Environmental Chemistry

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Estimation of exposure and ecotoxicity related parameters by computer based structure-property and structure-activity relationships

Monika Nendzaab; Hannelore Jäckela; Martin Müllera; Andreas Gies-Reuschelac; Werner Kleina a Fraunhofer-Institut für Umweltchemie und Okotoxikologie, Schmallenberg b Fraunhofer-Institut für Umweltchemie und Ökotoxikologie, Schmallenberg c Umweltbundesamt, Berlin 33

To cite this Article Nendza, Monika , Jäckel, Hannelore , Müller, Martin , Gies-Reuschel, Andreas and Klein, Werner(1993)

'Estimation of exposure and ecotoxicity related parameters by computer based structure-property and structure-activity relationships', Toxicological & Environmental Chemistry, 40: 1, 57 — 69 To link to this Article: DOI: 10.1080/02772249309357931 URL: http://dx.doi.org/10.1080/02772249309357931

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Toxicologicai and Environmental Chemistry, Vol. 40, pp. 57-69 Reprints available directly from the publisher Photocopying permitted by license only

© 1993 Gordon and Breach Science Publishers S.A. Printed in the United States of America

ESTIMATION OF EXPOSURE AND ECOTOXICITY RELATED PARAMETERS BY COMPUTER BASED STRUCTURE-PROPERTY AND STRUCTUREACTIVITY RELATIONSHIPS* MONIKA NENDZA1+, HANNELORE JÄCKEL1, MARTIN MÜLLER*1, ANDREAS GIES-REUSCHEL2, WERNER KLEIN1 1

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Fraunhofer-Institut für Umweltchemie und Okotoxikologie, Aberg 1, D-57392 Schmallenberg, 2Umweltbundesamt, Bismarckplatz 1, D-14193 Berlin 33

The risk assessment of chemicals requires comprehensive data material, which often is not available. In order to provide substitutes for the lacking experimental ecotoxico-logical and physico-chemical data, a software-system (SAR-Programme) has been developed comprising more than 90 estimation models for endpoints considered relevant in environmental assessment. The approach is based on quantitative structureactivity relationships (QSARs). Two major aspects were emphasized when developing the SARProgramme: (1) The implemented models were tested for their validity and application range. (2) The QSARs are accessible by a user-friendly, exclusively menudriven programme package. The following endpoints are included: Physico-Chemical Data: log POW, vapour pressure, water solubility, pKa-values, boiling point: Biological Endpoints: toxicity towards fish, daphnia, tetrahymena, algae, bacteria and rodents, mutagenicity; Distribution: soil Sorption, bioconcentration, Henry-Constant, Mackay (Level I); Degradation: photodegradation, biodegradability. KEY WORDS:

1.

QSAR, computer, ecotoxicity, physico-chemical properties, estimation methods.

INTRODUCTION

Risk assessment of chemicals requires comprehensive data material about ecotoxicological and exposure related parameters, which are often not available. For preliminary screening purposes quantitative structure-activity relationships (QSARs) may be used to provide substitutes for lacking experimental data. The QSAR approach is based on the assumption that quantitative relationships exist between the structure of a compound and its interactions with the environment. QSARs represent mathematical models relating the observed properties of chemicals to descriptors of their structure1.

† This paper presents the English transcription of the publication H. Jäckel, M. Müller, M. Nendza, W. Klein, A. Gies-Reuschel "Abschätzung des umweltchemischen und ökotoxikologischen Verhaltens von Stoffen durch computergestützte Struktur-Verhaltens- und Struktur-Wirkungs- Analyse", Umweltwissens, Schaften und Schadstoff-Forschung, 11-18, (1993), as it was presented at the Ecoinforma '92 in Bayreuth. + Current Address: Dr. M. Nendza, Wühren 48, D-24794 Bünsdorf, Germany. * Correspondence: Dr. Martin Müller, Fraunhofer-Institut für Umweltchemie und Ökotoxikologie, Aberg 1, D-57392 Schmallenberg. 57

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The molecular structure may be quantified by various description such as 1-octanol/ water partition coefficient or molar volume. The derived QSARs may then be used to estimate various parameters for analogous compounds, which were not yet tested. There are methods available to calculate various missing data with sufficient accuracy23. The crucial point to the application of these predictive techniques is the selection of the appropriate model, since reliable predictions based on QSARs demand that the limitations and application range of each model, e.g. with respect to chemical classes, are considered.

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2. THE SAR-PROGRAMME The SAR-Programme has been developed at the Fraunhofer-Institute for Environmental Chemistry and Ecotoxicology (IUCT) for the German Federal Environmental Agency, Berlin. The software-system comprises more than 90 estimation models for endpoints considered relevant in environmental assessment. The SAR-Programme is to provide a tool to predict ecotoxicologically and exposure relevant parameters based solely on the chemical structure. The SAR-Programme was developed with respect to several criteria, which can also be considered the basic philosophy of the system: Transparency and comprehensibility of the calculations and predictions, validity of the models, modular construction to allow further extension and improvement. Since the task was to provide structure-activity relationships for the application in existing chemicals' assessment in those cases when no experimental data are available, two major aspects had to be emphasized: To allow a sufficiently reliable application, the considered QSARs were examined with respect to their validity, i.e. the exactness of the calculated predictions was tested. For this purpose, each of the QSARs was applied to a wide variety of chemicals, which were not considered when developing the model, but for which experimental data are available. The calculated predictions were then compared to the experimental data. Only if agreement between the calculated and the experimental values was observed, sufficient validity of the respective QSAR was assumed. As a result of the validity assessment, the application range of the model as well as its limitations were determined, e.g. with respect to compound classes or parameter ranges. According to the outlined procedure, the QSARs to be implemented were selected: 96 of > 260 tested models were sufficiently valid. For a broader coverage, the QSARs available from the literature were supplemented with further models which were derived concerning endpoints or chemical classes not yet sufficiently considered. The second important aspect was the implementation of the validated QSARs into a user-friendly, exclusively menu-driven programme-package. For calculations, the user is solely required to draw the respective chemical structure on the screen with a mouse, select the desired option by clicking the respective buttons in the menus, and then all consecutive operations are executed automatically. The operation of the SARProgramme's functions and calculation modules were designed to be comprehensible and transparent to the user. With the results of a calculation, simultaneously the results of the validity

ESTIMATION OF EXPOSURE AND ECOTOXICITY RELATED PARAMETERS

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assessment are provided (e.g. confidence intervals); if application criteria are not fulfilled, warnings are given (e.g. warnings concerning extrapolations outside the parameter-range spanned, warnings concerning the occurrence of reactive substructures). The outcome of the validity assessment is incorporated in the results in order to avoid misuse of the QSARs. Irrespective of all these application criteria, the selection of the appropriate QSAR-model for a given compound and endpoint exclusively remains with the user as well as the evaluation of the predictions. The information required therefore is assembled in the SAR-Programme manual4. The SAR-Programme is based on commercial and in-house developed software, which is installed on a VAX computer. MACCS-II5 constitutes the backbone of the system by serving as database as well as graphical user-surface. Additionally, further commercial software (Table 1) was implemented. The structure of the SARProgramme (Figure 1) corresponds to the classification of the implemented models with respect to the endpoints. The comprehensible structure and an always uniform menu-design provide the user with easy access to the various calculation modules, without the need to become familiar with each of the employed software programmes.

Table 1

Software implemented into the SAR-Programme

Software

Application

Reference

MedChem

calculation of logP ow , molar refraction, database for experimental distribution coefficients, pKa-values

Daylight Chemical Information System Inc. (1989)

AOP

estimation of atmospheric half-life time

Syracuse Research Corp. (1990)

ADAPT

geometric descriptor calculation

Molecular Design Ltd. (1989)

PRXBLD

geometry optimisation

Molecular Design Ltd. (1986)

AMPAC

quantum-chemical calculations

QCPENr. 506(1986)

Additionally to the QSAR-models, several databases are integrated in the SARProgramme: The experimental data used in the validation process of the models were assembled in the database QBASE. It contains molecular structures and compound names, CASnumbers, physico-chemical and biological data for > 3000 compounds and it is available to the user for the input of further structures and data (Figure 2). This database can be searched for structures as well as for data. The structure searches are possible for defined compounds as well as for substructures, isomers or chemical classes. Various search criteria may be combined; e.g. all substituted phenols with LC50-values (Pimephales promelas) < 10 mg/1 can be retrieved by first conducting a substructure search for the phenol skeleton and consecutively a search for LC50-values in the range of 0-10 mg/1 in this sublist.

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g

SARProgramme

Descriptors — Pow Topological Indices Quant.-chem, Data Geometrical Data

Phys.-Chen. Data — Pow Watersolubility — Vapour Press. — Henry-Const. — Sorption — pKa — Boiling Pt.

Biological Endpoints

Distribution

Fish LC50, NOEC Daphnia EC50, NOEC Algae EC50, NOEC — Bacteria EC50

— Pow Henry-Const. — Sorption — BCF Mackay Level I

Tetrahymena FC Mammals LD50, LD100 — Mutagenicity — BCF Figure 1

SAR-Programme Structure.

Degradation Atmospher. Degradation Biological Degradation

Databases — Qbase: Tox/PC-Data Data Input Data Retrieval Search for - Substructures - Compound Classes _

THOR log Pow, pKa Structure/CASNr.

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Listen-Elemente: Element-Nr.: Suche

3171 1 Gesamtliste

Vergroessern

Prev-Curr Regno:

286

PC-Daten

Deskriptoren

Datenbank-M.

Abbau

Tox. Daten

Substanzk 1.

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