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Proceedings for Pain Management and Humane Endpoints

Humane Endpoints - An Update on OECD Activities

Dr. Alan Goldberg, Ph.D.
Associate Dean, Corporate Affairs, Professor of Toxicology Director
Center for Alternatives to Animal Testing
Johns Hopkins University School of Hygiene and Public Health
111 Market Place, Suite 840
Baltimore, Maryland 21202-6709

NOTE: Dr. Goldberg is not a member of the OECD staff, nor does he represent them. He was an on-site consultant during a four-month period and continues to be a consultant to the program. This is not an OECD report, but is the individual effort of the author.


The OECD has initiated a program of animal welfare in the test guidelines program. The magnitude of the test guidelines program is extensive and covers considerable testing programs.

Approaches to animal welfare follow the Russell and Burch concept of the 3Rs and thus all aspects of refinement, reduction and replacement are included in the approaches used.

Many protocols have already incorporated the reduction approach Ð such as, acute toxicity and dermal toxicity methods. In the area of refinement, the current program is examining approaches to Humane Endpoints. At an upcoming Nominate Expert Meeting (November 6, 1998), physiological components will be discussed and incorporated into the first OECD Guidance document on Humane Endpoints. Other approaches to humane endpoints will be developed.

Additionally in the area of refinement, protocols of the LLNA as a replacement for the guinea pig assay for hypersensitivity is being submitted for review.

In the area of non-animal tests, two procedures are under consideration. The development of an in vitro protocol for skin penetration and the 3T3 NRU Phototoxicity Assay have just been submitted for consideration.

Although this is not the complete program in process at the OECD for animal welfare, it provides an overview of activities encompassing all 3Rs and represents only the beginning of more extensive activities in this area.


The Organization for Economic Co-operation and Development (OECD) is an assembly of 29 member countries that provides the opportunity for these 29 member country governments to talk with each other about economic and social policy.

The exchanges between the OECD and their member countries flow from information and analysis provided by a Secretariat in Paris. The Secretariat collects data, monitors trends, analyzes and forecasts economic developments and, for the purposes of this paper, has a chemical test guideline program, which provides, once an accepted OECD guideline, legally binding approaches to chemical safety testing.

Developing new test guidelines or updating existing ones is provided by the Test Guidelines Program. Member countries appoint National Coordinators to the program. The National Coordinators set priorities and review proposals for new and updated guidelines.

Scientific input to the Test Guidelines Program is primarily obtained through the National Coordinators with consultations with national experts nominated by member countries.

A number of years ago, the National Coordinators decided to include a focus on animal welfare issues in the Test Guidelines Program.

There have been many successes in this activity, with development of alternatives to acute toxicity testing, to dermal and inhalation irritancy, as well as the development of procedures that would be, by their very design, in vitro approaches to testing. Considerable effort has been devoted to refinement procedures that reduce potential pain and distress and reduction procedures that keep to a minimum the number of animals necessary for a specific test guideline.

Percutaneous Absorption

The OECD test guidelines on percutaneous absorption is a whole-animal procedure. During the last decade, several approaches to the development of in vitro methodologies have developed and, as such, an in vitro approach to percutaneous absorption was submitted to the OECD for consideration. This methodology is currently under review by an expert steering committee to make sure that the in vitro protocols will provide at least the same level of information as the current in vivo method. Both the in vitro and in vivo methods are being evaluated by a peer review committee to establish the validity of the data and quality and predictability of the methodological approaches. As this manuscript is being prepared, the expert committee is developing and fine tuning the guideline for percutaneous absorption, and is evaluating the available data submitted, as well as examining the literature published in the field. Once these tasks are completed, this material will be presented to the entire steering committee and will then be presented as appropriate to the National Coordinators. Once this process is complete, this will be the first guideline that will have both an in vivo and in vitro approach to a specific testing protocol.

Humane Endpoints

An expert committee was identified to develop a guidance document on humane endpoints in toxicology. Specifically, the question this group was asked to address is when should an animal's life be terminated in an experimental protocol so that the maximum amount of data from the protocol can be obtained, at the same time any pain, suffering or distress is kept to an absolute minimum. This document, "Recognition, Assessment and Use of Clinical Signs as Humane Endpoints for Experimental Animals Used in Safety Evaluation Studies," has been distributed to the National Coordinators for their evaluation and for their nomination of experts to discuss at a meeting scheduled in Zeist, The Netherlands in November 6, 1998.

The document examines terminology, euthanasia of moribund animals, recognizing pain and distress, humane endpoints for specific toxicity studies, making an informed decision to humanly euthanize animals, and methods for humane euthanasia in toxicological studies.

Other Procedures

During the last year, several alternative procedures have been validated by member countries. The first is in the area of refinement. The Local Lymph Node Assay (LLNA) has been reviewed by the U.S. Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) and has been determined to be valid as a stand-alone replacement for the guinea pig assay for hypersensitivity. This protocol will be submitted to the OECD for consideration as a test guideline. The extensive review process provided by ICCVAM was very broad based, open, and allowed the evaluation of the data supporting the LLNA as a replacement assay. The peer review that evaluated the data against ICCVAM validation criteria was truly international in scope and without conflict. The findings of that committee were presented to the ICCVAM committee (a U.S. government committee representing 14 U.S. agencies), and as such has undergone and met all criteria for a valid assay.

The second test, one that has been submitted to the OECD for consideration, is the 3T3 Neutral Red Uptake Phototoxicity Assay (3T3 NRU PT). This assay was deemed valid by the ECVAM Scientific Committee and then submitted to the appropriate European Union committees. This assay also will be considered by the OECD for a test guideline.


These are just some examples of the approach being developed at the OECD. There will be an ongoing and continuing effort to incorporate animal welfare concerns into the test guidelines program with continual refinement and expansion of guidance documents on humane endpoints and other topics as identified by member countries.


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