ATLA 27.2, March 1999

//ATLA 27.2, March 1999

Book Review

David Clark

The First World Congress having been such a success, it was always going to be difficult for the Second World Congress to match the high standards that had been set. In the event, the standards were not only matched, but often exceeded. This 1200-page volume of the proceedings of the Congress is an outstanding account of an outstanding event, attended by more than 900 participants from 37 countries.
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Seeking Information on The Three Rs — More Than Just a Legal Burden

Krys Bottril

The report of the Focus on Alternatives (FOA) workshop, which appears in this issue of ATLA (ATLA 27, 239–245), is just one manifestation of the heightened interest in access to information on the Three Rs that is currently evident in the UK. The driving force for this interest is, of course, the revision to the Animals (Scientific Procedures) Act 1986, which took effect in September 1998 and which spells out clearly the requirement for the licence applicant to be aware of all practicable possibilities for implementing any of the Three Rs.a The Home Office Inspectorate has let it be known that one way in which applicants will be required to demonstrate this awareness is by documenting the steps they have taken to inform themselves of such possibilities. The documentation can include a description of literature searches that have been conducted, with details of the search terms used and the databases interrogated, as well as details of other routes of enquiry, for example, searches on the Internet, consultation of mailing list archives, or discussions with colleagues.
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The Integrated Use of Alternative Methods in Toxicological Risk Evaluation

Bas J. Blaauboer, Martin D. Barratt and J. Brian Houston

The ECVAM Task Force on Integrated Testing Strategies was established in December 1996, with the remit of assessing the current status of integrated toxicity testing, and of making proposals regarding the design and implementation of integrated testing strategies. The first step in an integrated testing strategy is usually to determine the chemical functionality of a substance, on the basis of its structure and physicochemical properties. The biokinetic and dynamic behaviours of the chemical in various in vitro systems are then assessed. The various elements are then integrated, in either a parallel or a stepwise fashion, to make predictions of the local or systemic toxicity of the chemical of interest. In this report, a generic scheme for local/systemic toxicity, and a specific scheme for target organ toxicity, are proposed. The scope and limitations of the approaches are discussed. The task force hopes that its proposals will stimulate a discussion on the feasibility of this type of approach and it welcomes any feedback. It is planned that the discussion points will be elaborated in a second task force report.
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Accessing Information on the Reduction, Refinement and Replacement of Animal Experiments

Gill Langley, Caren Broadhead, Krys Bottrill, Robert Combes, Roger Ewbank, Penny Hawkins, Robert Hubrecht, Maggy Jennings, Carol Newman, Sally Rowe, Jacqueline Southee, Martin Todd and Les

All scientists who use animals in scientific procedures have an ethical obligation to ensure that the research aims cannot be
achieved in other ways. However, in many countries, including those of the European Union, this responsibility is also a legislative requirement (1, 2).
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The Use of Human Keratinocytes in the EU/COLIPA International In Vitro Phototoxicity Test Validation Study and the ECVAM/COLIPA Study on UV Filter Chemicals

Richard Clothier, Angie Willshaw, Helen Cox, Michael Garle, Helen Bowler and Robert Combes

The EU/COLIPA in vitro phototoxicity study involved the testing of 30 chemicals in Phase II, and the ECVAM/COLIPA study on UV filter chemicals involved the testing of 20 chemicals, for which in vivo human and/or animal data were available. Primary human keratinocytes, from four separate male donors, were not found to be sensitive to the 5J/cm2 UVA produced by the SOL500 lamp when assayed by using the neutral red uptake endpoint, as employed with the 3T3 cells used in these international interlaboratory validation studies. The primary human keratinocytes tested in one laboratory alongside the 3T3 fibroblasts gave consistent indications of phototoxicity with all the phototoxicants tested in the Phase II and UV filter studies. The one exception was bithionol, which was predicted to be non-phototoxic in both studies. None of the non-phototoxic chemicals resulted in a positive reaction with the Photoirritation Factor (PIF) version of the prediction model. However, when the Mean Photo Effect (MPE) prediction model version was applied (with a cut-off point of 0.1), one sunscreen agent, octyl salicylate, was deemed to have phototoxic potential. The entire set of negative rated chemicals included in Phase II and in the UV filter study were also rated as non-phototoxic by the MPE prediction model.
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Selective Induction of Interleukin-12 in Reconstructed Human Epidermis by Chemical Allergens

Emanuela Corsini, Elena Limiroli, Marina Marinovich, Catherine
Cohen, Roland Roguet and Corrado L. Galli

Keratinocytes play an important role in skin inflammatory and immunological reactions through the release of cytokines and response to them. These cells have been shown to direct T-cell priming by producing cytokines such as interleukin (IL)-10 and IL-12. The purpose of this work was to explore the potential use of IL-12 production to discriminate between skin irritants and contact allergens in vitro. Initially, a reconstituted human epidermis was treated with a known human skin irritant, sodium lauryl sulphate (SLS), and a known human contact allergen, 1-chloro-2,4-dinitrobenzene (DNCB). The expression of IL-12p40 was assessed at specific time intervals by the semi-quantitative reverse transcriptase-polymerase chain reaction (rt-PCR). The data obtained indicated that only DNCB induced an up-regulation of IL-12p40. This up-regulation occurred after exposure to DNCB for 3 hours. Importantly, the application of SLS or vehicles did not induce IL-12 mRNA up-regulation. An increase in total IL-12 protein content was detected in supernatants of allergen-stimulated, but not vehicle-stimulated, reconstituted epidermis. To confirm these results, the effects of benzalkonium chloride, oxazolone and eugenol were assessed. At concentrations that resulted in equivalent IL-1α release, only contact allergens increased IL-12 expression, which confirmed the previous results. These data suggest that IL-12, which is crucial for T-helper type 1 cell responses, could be a useful marker for discriminating between contact allergens and irritants.
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Alternative Methods for Assessing Biocompatibility and Function of Implant Materials

Malgorzata Lewandowska-Szumiel

Biocompatibility testing is used to evaluate the host response to implantable materials and to assess their ability to perform in applications in which they are intended to interact with biological systems. In compliance with international and/or national standards, such assessment is based mainly on the results of experimental implantation into animal tissues. However, the development of in vitro experimental techniques creates new opportunities to observe and to understand the interaction of biomaterials with host tissue. The state-of-theart application of alternative methods in biocompatibility testing is presented in this review article. It is discussed with respect to the Three Rs concept (reduction, refinement, replacement) of Russell & Burch. Perspectives on alternative methods in biocompatibility studies are discussed with regard to the possible role of biomaterials in tissue engineering.
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Lack of Effect of Medium Supplementation With Pyruvate and Hormones on Cytochrome P450-mediated Activity of Rat Hepatocytes in Primary Culture

Porntip Wirachwong and Jeffrey R. Fry

The loss of cytochrome P450 (CYP)-dependent activity continues to be a problem in the use of cultured hepatocytes in xenobiotic toxicity studies. It has been reported that the inclusion of pyruvate and various hormones in the culture medium improves the maintenance of various hepatic functions, including that of CYP2C11 mRNA expression. We have studied this further, by investigating the effects of the addition of pyruvate and hormones on various CYP-dependent enzyme activities and on the CYP-dependent toxicity of precocene II in rat hepatocyte cultures. No beneficial effects of this medium supplementation could be demonstrated.
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