The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.

 

Johns Hopkins School of Public Health

Abstract for TestSmart--A Humane and Efficient Approach to Screening Information Data Sets (SIDS) Data

Manfred Liebsch
ZEBET

This talk is given on behalf of Professor Michael Balls, Head of ECVAM

Basis for European Centers

DIRECTIVE 86/609/EEC

European Centers for Alternatives to Animal Testing
Figure 1

Stakeholders in ECVAM's Woi

Figure 2

ECVAM's Mission

To coordinate the independent evaluation of the relevance and reliability of tests for specific purposes, and in particular through prevalidation and validation studies, so that chemicals and products of various kinds, including medicines, vaccines, other biologicals, medical devices, cosmetics, household products and agricultural products, can be manufactured, transported and used more economically and more safely, whilst the current reliance on animal test procedures is progressively reduced.

The Duties of ECVAM

(Commission Communication to Council and the Parliament, 29 October 1991)

ECVAM Scientific Advisory Committee (ESCA)

Member state representatives

Organisation representatives

EC/JRC representatives

Definition of "Alternative Method" According to: the Three Rs of Russell & Burch

Reduction: any decrease in the numbers of animals used to obtain infor-mation of a given amount and precision.

Refinement: any decrease in the incidence or severity of procedures applied to animals necessarily used.

Replacement: the substitution of conscious living higher animals by non-sentient material.

Validation of Alternative Methods--AMDEN I

"The process by which the reliability and relevance of a procedure are established for a particular purpose"

This definition stems from the 1990 Amden CAAT/ERGATT workshop and Frazier's 1990 report to the OECD.

What is Meant by Relevance, Reliability, and Purpose?

Relevance: scientific value and practical usefulness in relation to a clearly defined and specific purpose.

Reliability: reproducibility of results within and between laboratories and over time.

Purpose: relevance and reliability in relation to a specific aspect of in vivo toxicity (according to type of toxicity, target species, degree of toxicity, and spectrum of test materials and products).

AMDEN II

Practical Aspects of the Validation of Toxicty Test Procedures: The Report and Recommendations of ECVAM Workshop 5

Michael Balls, Bas J. Blaauboer, Julia H. Fentem, Leon Bruner, Robert D. Combes, Björn Ekwall, Robin J. Fielder, Andre Guillouzo, Richard W. Lewis, David P. Lovell, Christoph A. Reinhardt, Guillermo Repetto, Dariusz Sladowski, Horst Spielmann and Flavia Zucco

ATLA 23: 129-147, 1995

AMDEN II: Validation Study Management

Figure 3

ECVAM Guideline for Prevalidation

The Role of Prevalidation in the Development, Validation and Acceptance of Alternative Methods
Rodger D. Curren, Jacqeline A. Southee, Horst Spielmann, Manfred Liebsch, Julia H. Fentem and Michael Balls

ATLA 23: 211-217, 1995

Harmonization of Validation and Acceptance Criteria

ECVAM

ICCVAM

OECD

Key points:

Up Front a Prevalidation Study Info Must Be Provided

  1. Description of the basis of the method
  2. Definition of scientific purpose and practical application
  3. Test protocol / Standard Operating Procedures
    • specification of endpoint
    • derivation and expression of results
    • their interpretation & application, via Pred. Model
    • appropriate controls & historical data
  4. Limitations of the method
  5. Data supporting
    • intralaboratory reproducubility
    • if available, interlab. transferability

ECVAM Procedures

Figure 4

ECVAM's Criteria for Acceptibility of a Validation Study

Example 1: Validation of the 3T3NRU-PT in vitro phototoxicity test (1992-1998)

EU-COLIPA Project

Goals

  1. Validate one new in vitro phototoxicity test: 3T3 NRU-PT
  2. Evaluate "in house tests" used in industry
    • photohaemolysis in red blood cells (RBC)
    • primary human keratinocytes
    • skin models (LSE & Skin2)
    • histidine oxidation
    • photobinding to proteins
    • photoactivation of complement

Participants

ZEBET-BgVV, Beiersdorf AG, Unilever, ESL, Novartis, Hoffmann-La Roche, Henkel KGaA, Procter & Gamble, FRAME, University of Warsaw

Time Frame

Sponsors

EU DG XI, ECVAM, ZEBET-BgVV, COLIPA

Design of 3T3NRU-PT

3T3 monolayer => 24 hours => chemical => 1 hour => UVA-vis/dark => 24 hour => viability test (NR Uptake)

Prediction model: comparison of "dose-responses" obtained in concurrent (+UVA) and (-UVA) exp.

Chemicals Tested

  1. Prevalidation Study: 11 PT, 9 NPT, not blind
  2. Validation Study: 25 PT, 5 NPT, blind trial
  3. UV Filter Study: 10 PT, 10 PT blind trial

Outcome

  1. sensitivity: 84%
    specificity: 93%
  2. sensitivity: 100%
    specificity: 98%

Independent Experts Involved

Example 2: ECVAM Skin Corrosivity Validation Study (1994-1998)

Tests

Participants

Chemicals

60 selected by independent CSSC Outcome

Independent Experts Involved

ECVAM is Validating Test Strategies

An Evaluation of the Proposed OECD Testing Strategy for Skin Corrosion

Andrew P. Worth, Julia H. Fentem, Michael Balls, Philip A. Botham, Rodger D. Curren, Lesley K. Earl David J. Esdaile and Manfred Liebsch

ATLA 26: 709-720, 1998

Example 3: Planning of the ECVAM Skin Irritation Prevalidation Study (1998-1999)

Alternative Methods for Skin Irritation Testing: the Current Status

ECVAM Skin Irritation Task Force Report 1

Philip A. Botham, Lesley K. Earl, Julia Fentem, Roland Roguet and Johannes J.M. van de Sandt

ATLA 26: 195-211, 1998

Recommendations

Preparation of a New Study

Conclusions

So far, ECVAM has sucessfully promoted three tests to regulatory acceptance by sponsoring and managing Prevalidation Studies, followed by formal Validation Studies and additional Special Studies.

The duration of the processes was four years in case of Skin Corrosivity Tests, and seven years in case of the 3T3NRU Phototoxicity Test.

Apart from the peer review of the publication mauscripts, during these processes, both, the methods and results obtained had undergone scientific reviews by various expert groups, finalizing in the respective ESAC statements.

In contrast, the ESAC statement "on the scientific acceptability and practical availability of in vitro methods for the production of monoclonal antibodies" (31 March 1998) was based on conclusions of an ECVAM Workshop a peer review report produced for ESAC.