Advertisement

Archives of Toxicology

, Volume 78, Issue 10, pp 549–564 | Cite as

Animal testing and alternative approaches for the human health risk assessment under the proposed new European chemicals regulation

  • Thomas HöferEmail author
  • Ingrid Gerner
  • Ursula Gundert-Remy
  • Manfred Liebsch
  • Agnes Schulte
  • Horst Spielmann
  • Richard Vogel
  • Klaus Wettig
Regulatory Toxicology

Abstract

During the past 20 years the EU legislation for the notification of chemicals has focussed on new chemicals and at the same time failed to cover the evaluation of existing chemicals in Europe. Therefore, in a new EU chemicals policy (REACH, Registration, Evaluation and Authorisation of Chemicals) the European Commission proposes to evaluate 30,000 chemicals within a period of 15 years. We are providing estimates of the testing requirements based on our personal experiences during the past 20 years. A realistic scenario based on an in-depth discussion of potential toxicological developments and an optimised “tailor-made” testing strategy shows that to meet the goals of the REACH policy, animal numbers may be significantly reduced below 10 million if industry would use in-house data from toxicity testing, which are confidential, if non-animal tests would be used, and if information from quantitative structure activity relationships (QSARs) would be applied in substance-tailored testing schemes. The procedures for evaluating the reproductive toxicity of chemicals have the strongest impact on the total number of animals bred for testing under REACH. We are assuming both an active collaboration with our colleagues in industry and substantial funding of the development and validation of advanced non-animal methods by the EU Commission, specifically in reproductive and developmental toxicity.

Keywords

Animal experiments EU chemicals policy Hazard assessment Regulatory toxicology Risk assessment 

Notes

Acknowledgements

The authors would like to thank Michael Kunde, Stephan Madle, Axel Oberemm and Hans-Bernhard Richter-Reichhelm for their valuable contributions and review of the first draft.

References

  1. Balls M, Botham PA, Bruner LH, Spielmann H (1995) The EC/HO international validation study on alternatives to the Draize eye irritation test. Toxicol In Vitro 9(6):871–929CrossRefGoogle Scholar
  2. Balls M, Berg N, Bruner LH, Curren R, de Silva O, Earl LK, Esdaile DJ, Fentem JH, Liebsch M, Ohno Y, Prinsen MK, Spielmann H, Worth AP (1999) Eye irritation testing: the way forward. Report and recommendations of ECVAM workshop 24. ATLA 27:53–77Google Scholar
  3. Bandara LR, Kennedy S (2002) Toxicoproteomics—a new preclinical tool. Drug Discov Today 7:411–418CrossRefPubMedGoogle Scholar
  4. Bradlaw J, Gupta K, Green S, Hill R, Wilcox N (1997) Practical application of non-whole animal alternatives: summary IRAG workshop on eye irritation. Food Chem Toxicol 35:175–178PubMedGoogle Scholar
  5. Brantom PG, Bruner LH, Chamberlain M, de Silva O, Dupuis J, Earl LK, Lovell DP, Pape WJW, Uttley M, Bagley DM, Baker FW, Brachter M, Courtellemont P, et al (1997) A summary report of the COLIPA international validation study on alternatives to the Draize rabbit eye irritation test. Toxicology In Vitro 11:141–179CrossRefGoogle Scholar
  6. Brown NA, Spielmann H, Bechter R, Flint OP, Freeman SJ, Jelinek RJ, Koch E, Nau H, Newall DR, Palmer AK, Renault JY, Repetto MF, Vogel R, Wiger R (1995) Screening chemicals for reproductive toxicity: the current alternatives (ECVAM Workshop 12). ATLA 23:868–882Google Scholar
  7. Combes R, Barratt M, Balls M (2003) An overall strategy for the testing of chemicals for human hazard and risk assessment under the EU REACH system. ATLA 31:7–19Google Scholar
  8. Corton JC, Andersen SP, Stauber AJ, Janszen DB, Kimbell JS, Conolly RB (1999) Entering the era of toxicogenomics with DNA microarrays. CIIT Activities 19Google Scholar
  9. Cortvrindt R, Daston G, Mantovani A, Maranghi F, Pelkonen O, Ruhdel I, Spielmann H, Bremer S (2003) Reproductive and developmental toxicity; Prepared for the European Commission and the stakeholders for the phasing out of animal experimentation in the field of cosmetics. Unpublished, BrusselsGoogle Scholar
  10. Creasy DM (1997) Evaluation of testicular toxicity in safety evaluation studies: the appropriate use of spermatogenic staging. Toxicol Pathol 25:119–131PubMedGoogle Scholar
  11. Cronin MTD, Jaworska JS, Walker JD, Comber MHI, Watts CD, Worth AP (2003) Use of QSARs in international decision-making frameworks to predict health effects of chemical substances. Environ Health Perspect 111:1391–1401PubMedGoogle Scholar
  12. Danish EPA, Danish Environmental Protection Agency (Danish Ministry of Environment and Energy) (2001) Report on the Advisory list for self classification of dangerous substances. Environmental project No 636. http://www.mst.dk/udgiv/publications/2001/87-7944-694/htmlGoogle Scholar
  13. Draize JH, Woodward G, Calvery HO (1944) Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther 82:377–390Google Scholar
  14. EC TGD (2003) Technical guidance document on risk assessment in support of commission directive 93/67/EEC on risk assessment for new notified substances, Commission Regulation (EC) No 1488/94 on Risk Assessment for existing substances, and Directive 98/8/EC of the European Parliament and of the Council concerning the placing of biocidal products on the market. Part I–IV, European Chemicals Bureau (ECB), JRC-Ispra (VA), Italy, April 2003. http://ecb.jrc.it/tgdocGoogle Scholar
  15. ECETOC (2003) (Q)SARs: evaluation of the commercially available software for human health and environmental endpoints with respect to chemical management applications. ECETOC Technical Report No. 89, Brussels, Belgium, pp 164Google Scholar
  16. ECVAM, European Centre for the validation of Alternative Methods (2003) Development of a novel approach in hazard and risk assessment of reproductive toxicity by combination and application of in vitro, tissue and sensor technologies. Proposal for a research project (unpublished). JRC, Ispra, ItalyGoogle Scholar
  17. Enslein K, Gombar VK, Blake BW (1994) Use of SAR in computer-assisted prediction of carcinogenicity and mutagenicity of chemicals by the TOPKAT program. Mutation Research 305:47–61CrossRefPubMedGoogle Scholar
  18. Eriksson L, Jaworska JS, Worth AP, Cronin MTD, McDowell RM, Gramatica P (2003) Methods for reliability and uncertainty assessment and for applicability evaluations of classification- and regression-based QSARs. Environ Health Perspect 111:1361–1375PubMedGoogle Scholar
  19. EU (1986) Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws, regulations and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes. Official Journal of the European Communities L 358:1–28Google Scholar
  20. EU (1998) Council Decision of 23 March 1998 concerning the conclusion by the Community of the European Convention for the protection of vertebrate animals used for experimental and other scientific purposes. Official Journal of the European Communities L 222:29–37Google Scholar
  21. EU COM, Commission of the European Communities (2001) White paper, strategy for a future chemicals policy. COM(2001)88final, BrusselsGoogle Scholar
  22. EU COM, Commission of the European Communities (2003a) Proposal for a regulation of the European parliament and of the council concerning the registration, evaluation, authorisation and restriction of chemicals (REACH)—consultation document, BrusselsGoogle Scholar
  23. EU COM, Commission of the European Communities (2003b) Directorates General Environment and Enterprise Note: proposal for a regulation concerning the Registration, Evaluation, Authorisation and Restrictions of Chemicals (REACH Regulation). D(2003)635170, BrusselsGoogle Scholar
  24. EU COM, Commission of the European Communities (2003c) Report from the Commission to the Council and the European Parliament—Third Report from the Commission to the Council and the European Parliament on the Statistics on the number of animals used for experimental and other scientific purposes in the member states of the European Union. COM/2003/0019 final, BrusselsGoogle Scholar
  25. EU COM, Commission of the European Communities (2003d) Proposal for a regulation of the European parliament and of the council concerning the registration, evaluation, authorisation and restriction of chemicals (REACH), Brussels September 2003 (draft)Google Scholar
  26. EU COM, Commission of the European Communities (2003e) Business impact study. Brussels October 2003Google Scholar
  27. EU Parliament (2001) Report on the Commission White paper on strategy for a future chemicals policy, Rapporteur Inger Schörling. Session Document final A5-0356/2001-PE304.693. Brussels-Strasbourg, pp 36Google Scholar
  28. Federal Register (2001) Episkin™, EpiDerm™ and rat skin transcutaneous electrical resistance methods: in vitro test methods proposed for assessing the dermal corrosivity potential of chemicals. US Federal Register 66:49685–49686Google Scholar
  29. Fentem JH, Archer GEB, Balls M, Botham PA, Curren RD, Earl LK, Esdaile DJ, Holzhütter HG, Liebsch M (1998) The ECVAM International validation study on in vitro tests for skin corrosivity. 2. Results and evaluation by the management team. Toxicol In Vitro 12:483–524CrossRefGoogle Scholar
  30. Fielden MR, Zacharewski TR (2001) Challenges and limitations of gene expression profiling in mechanistic and predictive toxicology. Toxicology Science 60:6–10CrossRefGoogle Scholar
  31. Frawley JP (1967) Scientific evidence and common sense as a basis for food-packaging regulations. Fd Cosmet Toxicol 5:293–308Google Scholar
  32. Gerner I, Schlede E (2002) Introduction of in vitro data into local irritation/corrosion testing strategies by means of SAR considerations: assessment of chemicals. Toxicology Letters 127:169–175CrossRefPubMedGoogle Scholar
  33. Gerner I, Sivapragasam G, Dudda B, Schlede E, Kayser D (1994) Entwicklung einer neuen Teststrategie zur Bestimmung der akuten dermalen Toxizität im Rahmen des Chemikaliengesetzes (Development of a new test strategy for the determination of the acute dermal toxicity under chemical law). Bundesgesundheitsblatt 11:463–467Google Scholar
  34. Gerner I, Zinke S, Graetschel G, Schlede E (2000) 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. ATLA 28:665–698PubMedGoogle Scholar
  35. Gerner I, Barratt MD, Zinke S, Schlegel K, Schlede E (2003) Development and pre-validation of a list of SAR rules to be used in expert systems for the prediction of skin sensitising properties of chemicals. ATLA (in press)Google Scholar
  36. GESAMP, IMO/FAO/UNESCO-IOC/WMO/WHO/IAEA/UN/UNEP Joint Group of experts on the Scientific Aspects of Marine Environmental Protection (2002) Revised GESAMP hazard evaluation procedure for chemical substances carried by ships. GESAMP Reports and Studies No. 64. International Maritime Organization, LondonGoogle Scholar
  37. Gettings SD, Teal JJ, Bagley DM, Demetrulias JL, DiPasquale LC, Hintze KL, Rozen MG, Weise SL, Chudkowski M, Marenus KD, Pape WJW, Roddy M, Schnetzinger R, Silber PM, Glaza SM, Kurtz PJ (1991) The CTFA evaluation of alternatives program: an evaluation of in vitro alternatives to the Draize primary eye irritation test (phase I). In vitro Toxicology 4(4):247–288Google Scholar
  38. Gettings SD, DiPasquale LC, Bagley DM, Casterton PL, Chudkowski M, Curren RD (1994) The CTFA evaluation of alternatives program: an evaluation of in vitro alternatives to the Draize primary eye irritation test (phase II). Food Chem Toxicol 32(10):943–976CrossRefPubMedGoogle Scholar
  39. Gettings SD, Lordo RA, Hintze KL, Bagley DM, Casterton PL, Chudkowski M, Curren RD, Demetrulias JL, DiPasquale LC, Earl LK, Feder PI, Galli CL, Glaza SM, Gordon VC, Janus J, Kurtz PJ, Marenus KD, Moral J, Pape WJW, Renskers KJ, Rheins LA, Roddy M, Rozen MG, Tedeschi JP, Zyracki J (1996) The CTFA evaluation of alternatives program: an evaluation of in vitro alternatives to the Draize primary eye irritation test (phase III). Food Chem Toxicol 34:79–117CrossRefPubMedGoogle Scholar
  40. Gillesby BE, Zacharewski TR (1998) Exoestrogens: mechanisms of action and strategies for identification and assessment. Environ Toxicol Chem 17:3–14Google Scholar
  41. Halle W (2003) The registry of cytotoxicity: toxicity testing in cell cultures to predict acute toxicity (LD50) and to reduce testing in animals. ATLA 31:89–198Google Scholar
  42. Halle W, Liebsch M, Traue D, Spielmann H (1997) Reduktion der Tierzahlen bei der Einstufung von Stoffen in die EU-Toxizitätsklassen für akute orale Toxizität mit Hilfe von Daten aus dem Register der Zytotoxizität (RC). ALTEX 14:8–15PubMedGoogle Scholar
  43. Hanway RH, Evans PF (2000) Read-across of toxicological data in the notification of new chemicals. Toxicol Lett 1/116:61Google Scholar
  44. Heinrich-Hirsch B, Madle S, Oberemm A, Gundert-Remy U (2001) The use of toxicodynamics in risk assessment. Toxicol Lett 120:131–141CrossRefPubMedGoogle Scholar
  45. Höfer T, Steinhäuser KG (2000) Use of health hazard criteria for estimating the hazard potential of chemicals to water in case of a spill. Regul Toxicol Pharmacol 31:1–12CrossRefPubMedGoogle Scholar
  46. Höfer-Bosse T, Scharmann W (1986) Numbers of animals used in toxicological experiments—with particular reference to the Federal Republic of Germany. ATLA 13:212–219Google Scholar
  47. Holzhütter HG, Genschow E, Diener W, Schlede E (2003) Dermal and inhalation acute toxic class methods: test procedures and biometric evaluations for the Globally Harmonized Classification System. Arch Toxicol 77:243–254PubMedGoogle Scholar
  48. Huggins J (2003) Alternatives to animal testing: research, trends, validation, regulatory acceptance. ALTEX 20 (in press)Google Scholar
  49. Hulzebos EM, Posthumus R (2003) (Q)SARs: gatekeepers against risk on chemicals. SAR QSAR Environ Res 14:285–316CrossRefPubMedGoogle Scholar
  50. Hulzebos EM, Maslankiewicz L, Walker JD (2003) Verification of literature-derived SARs for skin irritation and corrosion. QSAR & Combinatorial Science 22:351–363Google Scholar
  51. ICCVAM, Interagency Coordinating Committee on the Validation of Alternative Methods (2001) Annual progress report. http://iccvam.niehs.nih.gov/about/annrpt/annrpt01.pdfGoogle Scholar
  52. IEH, Institute for Environment and Health (2001a) Testing requirements for proposals under the EC White Paper “strategy for a future chemicals policy”. Web Report W6. www.le.ac.uk/ieh/webpub/webpub.html. University of Leicester, UKGoogle Scholar
  53. IEH, Institute for Environment and Health (2001b) Assessment of the feasibility of replacing current regulatory in vivo tests with in vitro tests within the framework specified in the EC White Paper “strategy for a future chemicals policy”. Web Report W10. University of Leicester, UKGoogle Scholar
  54. IEH, Institute for Environment and Health (2002) Testing requirements for proposals under the EC White Paper “strategy for a future chemicals policy”—an update. University of Leicester, UKGoogle Scholar
  55. Jaworska JS, Comber M, Auer C, van Leeuven CJ (2003) Summary of a workshop on regulatory acceptance of (Q)SAR for Human health and environmental endpoints. Environ Health Perspect 111:1358–1360PubMedGoogle Scholar
  56. Klimisch HJ, Andreae M, Tillmann U (1997) A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data. Regulatory Toxicol Pharmacol 25:1–5CrossRefGoogle Scholar
  57. Klopman G (1985) Predicting toxicity through a computer automated structure evaluation program. Environ Health Perspect 61:269–274PubMedGoogle Scholar
  58. Klopman G, Rosenkranz HS (1994) Prediction of carcinogenicity/mutagenicity using MULTICASE. Mutation Research 305:33–46CrossRefPubMedGoogle Scholar
  59. Kroes R, Kozianowski G (2002) Threshold of toxicological concern (TTC) in food safety assessment. Toxicol Lett 127:43–46CrossRefPubMedGoogle Scholar
  60. MacGregor JT (2003) The future of regulatory toxicology: impact of the biotechnology revolution. Toxicol Sci 75:236–248CrossRefPubMedGoogle Scholar
  61. Martínez-Alegría R, Ordóñez C, Taboada J (2003) A conceptual model for analyzing the risks involved in the transportation of hazardous goods: implementation in a geographic information system. Human Ecol Risk Assess 9:857–873Google Scholar
  62. Merrick A, Tomer KB (2003) Toxicoproteomics: a parallel approach to identifying biomarkers. Environ Health Perspect 111:A578–A579.PubMedGoogle Scholar
  63. NICEATM, Interagency Center for the Evaluation of Alternative Toxicological Methods (2001) In vitro test methods for assessing the dermal corrosivity potential of chemicals, Episkin™, EpiDerm™, and rat skin transcutaneous electrical resistance (TER). National Institute of Environmental Health Sciences NIEHS, Research Triangle Park, USA NC 27709Google Scholar
  64. NIH/ICCVAM, National Institutes of Health, Interagency Coordinating Committee on the Validation of Alternative Methods (2001a) Report of the International Workshop on In vitro Methods for Assessing Acute Systemic Toxicity. NIH Publication No. 01-4499. NTP Research Triangle Park, NC 27709. http://iccvam.niehs.nih.gov/methods/invidocs/finalall.pdfGoogle Scholar
  65. NIH/ICCVAM, National Institutes of Health, Interagency Coordinating Committee on the Validation of Alternative Methods (2001b) Guidance document on using in vitro data to estimate in vivo starting doses for acute toxicity. NIH Publication No. 01-4500. NTP Research Triangle Park, NC 27709. http://iccvam.niehs.nih.gov/methods/invidocs/guidance/iv_guide.pdfGoogle Scholar
  66. Oberemm A, Querfurt N, Dieterich A, Meckert C, Brandenburger L, Herzig A, Lindner Y, Krause E, Ittrich C, Kopp-Schneider A, Richter-Reichhelm HB, Gundert-Remy U (2003) Proteomic analysis of TCDD-mediated effects in marmoset liver and thymus. Naunyn Schmiedebergs Arch Pharmacol 367:R153(599)Google Scholar
  67. OECD, Organisation for Economic Co-operation and Development (2001) Appraisal of test methods for sex hormone disrupting chemicals. OECD Series on Testing and Assessment No. 21, ParisGoogle Scholar
  68. OECD, Organisation for Economic Co-operation and Development (2003) Guidelines for testing of chemicals. OECD Publication Office, Paris (see http://www.oecd.org/document/55/0,2340,en_2649_34377_2349687_1_1_1_1,00.html)Google Scholar
  69. Ohno Y, Kaneko T, Inoue T, Morikawa Y, Yoshida T, Fuji A, Masuda M, Ohno T, Hayashi M, Momma J, Uchiyama T Chiba K, Ikeda N, Imanashi Y, Itakagaki H (1994) Interlaboratory validation of the in vitro eye irritation tests for cosmetic ingredients. (1) Overview of the validation study and Draize scores for the evaluation of the tests. Toxicol In Vitro 13:73–98CrossRefGoogle Scholar
  70. Pedersen F, de Bruijn J, Munn S, van Leeuwen K (2003) Assesment of additional testing needs under REACH. Effects of (Q)SAR, risk based testing and voluntary industry initiatives. Joint Research Center. http://europa.eu.int/comm/enterprise/chemicals/chempol/bia/testingneeds031029.pdfGoogle Scholar
  71. Ramos KS, Goehl TJ (2003) Toxicogenomics: an EHP section. Environ Health Perspect 111:A328–A328PubMedGoogle Scholar
  72. Rosenkranz HS (2003) SAR modelling of complex phenomena: probing methodological limitations. ATLA 31:393–399Google Scholar
  73. Sanderson DM, Earnshaw CG (1991) Computer prediction of possible toxic action from chemical structure: the DEREK system. Hum Exp Toxicol 10:261–273PubMedGoogle Scholar
  74. SCCNFP, European Commission’s Scientific Committee on Cosmetics and Non-Food Products (2000) The Scientific Committee on Cosmetics and Non-Food Products Intended for Consumers notes of guidance for testing of cosmetic ingredients for their safety evaluation. SCCNFP/0321/00 final, adpt SCCNFT plenary meeting, 24 Oct 2000Google Scholar
  75. SCCNFP, European Commission’s Scientific Committee on Cosmetics and Non-Food Products (2003) The SCCNFP’s notes of guidance for the testing of cosmetic ingredients and their safety evaluation. SCCNFP/0690/03 final, adpt SCCNFT plenary meeting, 20 Oct 2003Google Scholar
  76. Spielmann H, Kalweit S, Liebsch M, Wirnsberger T, Gerner I, Bertram-Neis E, Kreiling R, Krauser K, Miltenburger HG, Pape WJW, Steiling W (1993) Validation study of alternatives to the Draize eye irritation test in Germany: cytotoxicity testing and HET-CAM test with 136 industrial chemicals. Toxicol In Vitro 7:505–510CrossRefGoogle Scholar
  77. Spielmann H, Liebsch M, Kalweit S, Moldenhauer F, Wirnsberger T, Holzhütter HG, Schneider B, Glaser S, Gerner I, Pape WJW, Kreiling R, Krauser K, Miltenburger HG, Steiling W, Lüpke NP, Müller N, Kreuzer H, Mürmann P, Spengler J, Bertram-Neis E, Siegemund B, Wiebel FJ (1996) Results of a validation study in Germany on two in vitro alternatives to the Draize eye irritation test, the HET-CAM test and the 3T3 NRU cytotoxicity test. ATLA 24:741–858Google Scholar
  78. Spielmann H, Genschow E, Liebsch M, Halle W (1999) Determination of the starting dose for acute oral toxicity (LD50) testing in the up and down procedure (UDP) from cytotoxicity data. ATLA 27:957–966Google Scholar
  79. Stallard N, Whitehead A, Ridgway P (2002) Statistical evaluation of the revised fixed-dose procedure. Human Exp Toxicol 21:183–196CrossRefGoogle Scholar
  80. Tennant RW (2002) The national center for toxicogenomics: using new technologies to inform mechanistic toxicology. Environ Health Perspect 110:A8–A10PubMedGoogle Scholar
  81. Tong W, Perkins R, Strelitz R, Collantes ER, Keenan S, Welsh WJ, Branham WS, Sheehan DM (1997) Quantitative structure-activity relationships (QSARs) for estrogen binding to the estrogen receptor: predictions across species. Environ Health Perspect 105:1116–1124PubMedGoogle Scholar
  82. UN TDG, United Nations Committee of Experts on the Transport of Dangerous Goods (2000) Evolution of the model regulations on the transport of dangerous goods (rationalised development of the regulations). ST/SG/AC.10/2000/21, GenevaGoogle Scholar
  83. United Nations (2003) Globally harmonized system of classification and labelling of chemicals. UN ST/SG/AC.10/30, United Nations Publications sales no. E.03.II.E.25. United Nations, New York/GenevaGoogle Scholar
  84. Valli VE, MCGrath JP, Chu I (2002) Hematopoietic system. In: Haschek WM, Rousseaux CG, Wallig MA (ed) Handbook of toxicologic pathology, vol. 2, 2nd edn. Academic Press, pp 647–679Google Scholar
  85. Villeneuve DC, Koeter HBWM (1993) Proceedings of the international workshop on in-vitro methods in reproductive toxicology. Reprod Toxicol 7[Suppl]: 1–175Google Scholar
  86. Walker JD, Carlsen L, Hulzebos E, Simon-Hettich B (2002) 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. SAR QSAR Environ Res 13:607–616CrossRefPubMedGoogle Scholar
  87. Walker JD, Carlsen L, Jaworska J (2003) Improving opportunities for regulatory acceptance of QSARs: the importance of model domain, uncertainty, validity and predictability. Quantitative Structure-Activity Relationships 22:1–5Google Scholar
  88. WHO/IPCS (2002a) Report of the meeting on bridging the gap between clinical and regulatory toxicology, Edinburgh, United Kingdom, September 2001Google Scholar
  89. WHO/IPCS (2002b) WHO/IPCS meeting on the use of clinical data in risk assessment, Perth, Western Australia, November 2002Google Scholar
  90. Worth AP, Balls M (2002) Alternative (non-animal) methods for chemicals testing: current status and future prospects. A report prepared by ECVAM and the ECVAM Working Group on Chemicals. ATLA 30[Suppl 1]: 1–125Google Scholar
  91. Worth AP, Cronin MTD (2001) The use of pH measurements to predict the potential of chemicals to cause acute dermal and ocular toxicity. Toxicology 169:119–131CrossRefPubMedGoogle Scholar
  92. Worth AP, Fentem JH, Balls M, Botham PA, Curren RD, Earl LK, Esdaile DJ, Liebsch M (1998) An evaluation of the proposed OECD testing strategy for skin corrosion. ATLA 26:709–720Google Scholar
  93. Zinke S, Gerner I, Graetschel G, Schlede E (2000) Local irritation/corrosion testing strategies: development of a decision support system for the introduction of alternative methods. ATLA 28:29–40Google Scholar
  94. Zuang V, Balls M, Botham PA, Coquette A, Corsini E, Curren RD, Elliot GR, Fentem JH, Heylings JR, Liebsch M, Medina J, Roquet R van de Sandt H, Wiemann C, Worth AP (2002) Follow-up to the ECVAM prevalidation study on in vitro tests for acute skin irritation. ATLA 30:109–129PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Thomas Höfer
    • 1
    Email author
  • Ingrid Gerner
    • 1
  • Ursula Gundert-Remy
    • 1
  • Manfred Liebsch
    • 1
  • Agnes Schulte
    • 1
  • Horst Spielmann
    • 1
  • Richard Vogel
    • 1
  • Klaus Wettig
    • 1
  1. 1.Bundesinstitut für Risikobewertung (BfR)BerlinGermany

Personalised recommendations