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Development, Implementation and Use of Alternative Test

Methods in Regulatory Hazard Assessment in OECD Member

countries

Herman B.W.M.Koëter,Principal Administrator

Environment, Health and Safety Division OECD

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“Decides that data generated in the testing of chemicals in an OECD Member country in accordance with OECD Test Guidelines and OECD Principles of Good Laboratory Practice shall be accepted in other Member countries for purposes of assessment and other uses relating to the protection of man and the environment.”

1981 OECD Council Decision on the Mutual Acceptance of Data

For Assessment of Chemicals

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The process: Submission of the proposal to develop a

Test Guideline; Completion of the Standard Project

Submission Form (SPSF); Priority setting by National Co-

ordinators; Start of the project;

Procedure for the development of an OECD Test Guideline (1)

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Procedure for the development of an OECD Test Guideline (2)

The process: Establishment of ad hoc Expert Group; Consider details of the method and

validation status; Review of the draft guideline proposal; Analysis of comments; Expert meeting(s);

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Procedure for the development of an OECD Test Guideline (3)

The process: Review of the revised guideline proposal; Approval of the draft Test Guideline by

WNT; Endorsement at policy level; Adoption by Council; Publication as Addendum to Council

Decision C(81)30(Final).

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Implementation of Alternative Methods (1)

The Regulatory Context:

“The welfare of laboratory animals is important; it will continue to be an important factor influencing the work in the OECD Chemicals Programme”.

[High Level Joint Meeting (1982)]

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Implementation of Alternative Methods (2)

The Regulatory Context:“The progress in OECD on the harmonisation of chemicals control, in particular the agreement on mutual acceptance of data by reducing duplicative testing, will do much to reduce the number of animals used in testing”.

[High Level Joint Meeting (1982)]

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Implementation of Alternative Methods (3)

The Regulatory Context:“Testing in animals cannot be eliminated at present, but every effort should be made to discover, develop and validate alternative testing systems”

[High Level Joint Meeting (1982]

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Implementation of Alternative Methods:

Acute Oral Toxicity (1)

History:

May 1981: first adoption of TG 401; April 1986: OECD Expert Meeting (Paris); February 1987: adoption of revised

TG401; September 1989: EC Seminar on acute

toxicity testing (Brussels);

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Implementation of Alternative Methods:

Acute Oral Toxicity (2)

History:

September 1991: OECD Workshop on

acute toxicity (Washington); July 1992: adoption of TG 420; March 1996: adoption of TG 423; April 1998: OECD Expert Meeting

(Rome);

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Implementation of Alternative Methods:

Acute Oral Toxicity (3)

History:

October 1998: adoption of TG 425; February 1999: circulation of

questionnaire on the need for TG 401; March 1999: OECD Expert Meeting

(Arlington); August 2000: OECD Expert Meeting

(Paris);

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Implementation of Alternative Methods:

Acute Oral Toxicity (4)

History:

June 2001: Joint Meeting endorsement of updated TG 420, 423, 425 and declassification of Guidance Document No.24 on Acute Toxicity;

December 2001: adoption of updated TG 420, 423, 425 and deletion of TG 401.

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Implementation of Alternative Methods:

Acute Oral Toxicity (5)

Council Decision on deletion of TG 401 (1):

deletion effective one year after adoption of updated TG 420, 423, 425 (20th December 2002);

TG 401 tests initiated before that date shall continue to be accepted;

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Implementation of Alternative Methods:

Acute Oral Toxicity (6)

Council Decision on deletion of TG 401 (2):

for TG 401 tests carried out after the date of deletion MAD does not apply (need not be accepted);

non-member countries should be informed of the phasing-out of TG 401.

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Implementation of Alternative Methods:

other examples:

Reproduction toxicity: Adoption of TG 422 as an alternative to TG 407 and TG 421;

Skin Corrosion: Acceptance of TG 430 and 431 as replacements of the corrosion part of TG 405;

Skin Sensitisation: Adoption of TG 429 as alternative to TG 406;

Skin and Eye Irritation: Adoption of testing strategies.

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Implementation of Alternative Methods:

Testing Strategies

Hazard-specific assessment:

Preferably, testing strategies are integrated in Test Guidelines;

Alternatively, they are closely linked to Test Guidelines.

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Implementation of Alternative Methods:

Testing Strategies

Hazard-specific assessment: Agreed stepwise decision logic; Mandatory to follow the subsequent steps; Increasingly more complicated tests; From non-animal methods to simple in vivo

approaches to sophisticated animal studies; Consideration of the need for a next level of

assessment after each step.

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Implementation of Alternative Methods:

Testing StrategiesAn example: Reproduction Toxicity (1)

No in vitro methods available

Tests currently available:

– TG 414: Developmental Toxicity– TG 415: One-Generation Reproduction– TG 416: Two-Generation Reproduction– TG 421: Reproduction Toxicity Screening– TG 422: Combined Reproduction Toxicity

Screening + TG 407– TG 426: Developmental Neurotoxicity (Draft)

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Implementation of Alternative Methods:

Testing StrategiesAn example: Reproduction Toxicity (2)

Testing strategy

Weight of evidence(for existing chemicals)

Characterise hazardsufficient

Physical/chemicalcharacteristics & QSARs

sufficientCharacterise hazard

insufficient

insufficient

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Implementation of Alternative Methods:

Testing StrategiesAn example: Reproduction Toxicity (3)

Future in-vitro methodologysufficient

Characterise hazard

insufficient

Acute toxicity testing strategy, if necessary followed by TG 420, 423 or 425

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Implementation of Alternative Methods:

Testing StrategiesAn example: Reproduction Toxicity (4)

TG 422 orTG 421 plus TG 407 Characterise hazard

Definitive reproduction studies(TG 415, TG 416)

insufficient

sufficient

insufficient

Specific focus study (e.g. TG 414, 426, uterotrophic assay, Hershberger assay)

insufficient

sufficientCharacterise hazard

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Implementation of Alternative Methods:

The future of Validation

Food for thought (1): Validation studies are tailor-made and,

thus, very flexible; Validation studies should be totally

transparent; Validation can be limited to endpoints, as

appropriate; Validation studies could be

virtual/simulated, rather than a real study;

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Implementation of Alternative Methods:

The future of Validation

Food for thought (2): Are there more ways to assess “reliability”

than by repeat experiments? Is it always necessary to conduct tests in

order to assess the “relevance” of an endpoint or a test?

Is there a use for non-validated tests? How useful is it to accumulate data from

regulatory submissions as (additional) validation of a method “in use”?

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Implementation of Alternative Methods:

Is the source drying up?A co-ordinated and target aimed cooperation is

needed between: – governmental regulatory experts, – academic scientists, – experts from the regulated community, and– experts from the animal welfare community

in order to provide the breeding ground for new ideas and approaches in hazard assessment as well as in validation, taking into account both animal and non-animal approaches and integration of both.