ATLA 28, 2000

/ATLA 28, 2000

A Computer-Based Structure-Activity Relationship Method for Predicting the Toxic Effects of Organic Chemicals from One dimensional Molecular Structures

Stephan Zinke and Ingrid Gerner

A computer-based method is presented for the analysis and interpretation of structural formulae characterising chemical molecules. This method was developed to enable a computer to identify substructures of chemical molecules that are relevant in the context of specific toxicological questions. The new computer-based structure-examination method was used to develop the “structure” parts of several electronic structure-activity relationship models (SAR models) for analysing and interpreting the structural formula of a chemical from its onedimensional representation, by applying recursive principles and identifying partial isomorphic graphs. The structure-examination method is designed as part of an open-endpoint procedure to be used in expert systems, and could be applied in the construction of SAR models for almost all toxicological endpoints. The system was satisfactorily tested by identifying substructures relevant to severely damaging effects on skin and eyes.
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Conference Report

Elizabeth Jenkins

The second Trans-Tech meeting was held in May 2000 at the Karolinska Institute, Stockholm. This year, the duration of the meeting was extended to three days, a poster session was included and the meeting was attended by 19% more delegates than in 1999.
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2017-01-09T06:27:45+00:00 Tags: |

Book Review

Richard Ryder

Moral concern for animals is usually construed in terms of their welfare. The editors of this book argue that, although welfare is relevant, the “intrinsic value” of animals also has to be recognised. The problem, not lost on the contributors, is what is meant by “intrinsic value”. The concept has hardly been at the forefront of the debate over the moral status of animals, at least in the English language.
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2017-01-09T06:27:46+00:00 Tags: |

News & Views

ATLA Staff Writer

Minister Announces Outline Figures for 1999
Official Home Office Statistics for 1999
Potential Replacement for Mouse Local Lymph Assay
Alternatives Research & Development Foundation: 2000 Research Grant Recipients
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2017-01-09T06:27:46+00:00 Tags: |

Drunken Monkeys and Cruel Humans

Michael Balls

Early in September, the customary air traffic control delay meant that I finished the work I had intended to do on the flight from Milan to Birmingham much earlier than I had expected, so I turned to High Life, the British Airways in-flight magazine, as a means of passing the time.
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2017-01-09T06:27:47+00:00 Tags: |

The Isolated Perfused Bovine Udder as a Model of Dermal Eicosanoid Release

Wolfgang Bäumer and Manfred Kietzmann

The aim of this study was to examine whether the isolated perfused bovine udder could be used as a suitable in vitro inflammation model. A common in vivo inflammation model is arachidonic acid-induced inflammation in mouse ears. As an in vitro substitute for this model, arachidonic acid was administered topically to the skin of an isolated perfused bovine udder and the subsequent changes in eicosanoid synthesis were examined. As with the mouse-ear model, there was a significant increase in eicosanoid synthesis (prostaglandins E2 and F2α and leukotrienes B4 and C4/D4/E4) following topical irritation. This effect lasted for 3 hours. In addition, the changes in prostaglandin E2 synthesis in the skin following irritation with arachidonic acid were measured by the microdialysis technique. In conclusion, the in vitro model described seems suitable for studies of pharmacological effects on eicosanoid synthesis.
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Local Irritation/Corrosion Testing Strategies: Extending a Decision Support System by Applying Self-Learning Classifiers

Stephan Zinke and Ingrid Gerner

Procedures have been established and tested for the extension of a decision support system (DSS) for the prediction of the local irritation/corrosion potential of chemicals by using self-learning classifiers. The different approaches (decision trees, distances examinations in a multidimensional space, k-nearest neighbour method) have been implemented, tested and evaluated independently. A combination of all of the established extension approaches was also developed and tested. Self-learning classifiers are constructed “automatically” by a computer, i.e. they are not derived by a human expert, and thus they can be constructed with minimal effort. The classifiers presented here extend the existing DSS in a manner that increased significantly the predictive power of the extended system. However, automatically calculated results of self-learning classifiers are produced by a machine, and a machine is incapable of explaining the toxicological relevance of the results obtained. Thus, these results must be accepted, despite an inability to prove their reliability. Only the mathematical correctness of the method and the prediction rates for suitable test cases can lend some credibility to predictions produced by a computer calculating on a self-learning basis. This may not be adequate for regulatory hazard assessment purposes.
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Development of a Decision Support System for the Introduction of Alternative Methods into Local Irritancy/Corrosivity Testing Strategies. Creation of Fundamental Rules for a Decision Support System

Ingrid Gerner, Stephan Zinke, Gabriele Graetschel and Eva Schlede

The notification procedure of the European Union (EU) for new chemicals requires the application of protocols on physicochemical and toxicological tests for the evaluation of physicochemical properties and probable toxic effects of each notified substance. A computerised database was developed from data sets and toxicological test protocols relating to substance properties responsible for skin and eye irritation/corrosion. To develop specific structure-activity relationship (SAR) models and to find rules for a decision support system (DSS) to predict local irritation/corrosion, physical property data, chemical structure data and toxicological data for approximately 1300 chemicals, each having a purity of 95% or more, were evaluated. The evaluation demonstrated that the lipid solubility and aqueous solubility of a chemical are relevant to, or — in some cases — responsible for, the observed local effects of a substance on the skins and eyes of rabbits. The octanol/water partition coefficient and the measured value of the surface tension of a saturated aqueous solution of the substance give additional information that permits the definition of detailed SAR algorithms that use measured solubility values. Data on melting points and vapour pressure can be used to assess the intensity and duration of local contact with a chemical. Considerations relating to the reactivity of a pure chemical can be based on molecular weight and the nature of the heteroatoms present. With respect to local lesions produced following contact with the skin and eyes of rabbits, the data evaluation revealed that no general “local irritation/corrosion potential” of a chemical can be defined. A variety of mechanisms are responsible for the formation of local lesions on the skin or in the eyes: serious lesions are produced by mechanisms different from those that cause moderate irritation in these organs. In order to develop a DSS that uses the information extracted from the database, chemical main groups were categorised on the basis of their empirical formulae, and rules were defined of the type IF (physicochemical property) A, THEN not (toxic) effect B, based on correlations between specific local effects and measured physicochemical values. Other rules of the type IF substructure A, THEN effect B were developed based on correlations between specific local effects and the submitted structural formulae. Reactive chemical substructures relevant to the formation of local lesions and rules for the prediction of the absence of any skin irritation potential were identified. Proposals are made relating to the development of alternatives to eye irritation testing with rabbits.
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The Humoral Immune Response and the Productivity of Laying Hens Kept On the Ground or In Cages

Michael H. Erhard, Haydar Özpinar, Tanay Bilal, Ysmail Abbas, Can Kutay, Hüseyin Eseceli and Manfred Stangassinger

The effects of two different keeping systems on the humoral immune response and productivity were compared for 80 laying hens, divided into four groups. Two groups, each of 20 hens, were kept on the ground and two were kept in cages. All the birds were immunised subcutaneously with human serum immunoglobulin G at a dose of 100μg per injection. The immunisations were performed twice at 4-week intervals. The lipopeptide Pam3Cys-Ser-(Lys)4 was used as an adjuvant at a dose of 0.25mg per injection in one group from each housing system. In the second group from each housing system, the hens were immunised without any adjuvant (antigen control groups). The mean egg yield was significantly higher in both the antigen control group and the adjuvant group, when laying hens were kept in cages. Total egg weight remained constant in both of the housing systems. Keeping hens in cages resulted in higher mean specific antibody titres and mean immunoglobulin Y concentrations in the egg yolk
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An Evaluation of Mechanistic In Vitro Tests for the Discrimination of Photoallergic and Photoirritant Potential

William W. Lovell and Penny A. Jones

Photochemical tests were used to discriminate between photoallergens and photoirritants. UV absorption spectrometry was employed to identify chemicals that absorbed sunlight wavelengths and which required further testing. Photoallergic potential was assessed by studying photobinding of the test chemicals to human serum albumin. Photobinding was determined by increased UV absorbance of the protein fraction after gel filtration chromatography. Photooxidation of histidine was used to screen for a mechanism of photoirritancy. Efficient photooxidisers can be considered to be photoirritant rather than photoallergic. The substances selected for the EU/COLIPA phototoxicity project were tested. There were 14 photoirritants (three tested as both free acid/base and salts, i.e. a total of 17 samples), four photoallergens, three of which were photoirritant and photoallergenic (i.e. 17 photoirritants and seven photoallergens) and six “negatives” (four clearly non-phototoxic and two unclear). UV spectrometry showed that 28 of the 30 substances absorbed sunlight significantly and had the potential for adverse photoreaction. Six of seven photoallergens were identified as such by the photobinding assay. Most photoirritants also caused photomodification of protein, but eleven of these photooxidised histidine efficiently and so were classified as photoirritants. Four photoirritants remained falsely predicted as photoallergens. Two photoirritants were negative for both photomodification of protein and histidine photooxidation. Four chemicals negative in vivo were negative in vitro. The remaining two chemicals could not be classified, because of unclear data both in vivo and in vitro. Therefore, the in vitro test battery was useful for the discrimination of photoallergic and photoirritant potential.
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2017-01-09T06:27:50+00:00 Tags: , |