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Below are summaries of recent NICEATM-ICCVAM activities as of September 2008.
Back to Home page of NICEATM-ICCVAM website
Test Method Recommendations for Alternative, Non-Animal Ocular Toxicity Test Methods Accepted by Agencies
NIEHS announced on June 23, 2008, that Federal regulatory agencies have accepted ICCVAM
recommendations for two toxicological test methods that can reduce live animal use for
ocular safety testing. The Federal regulatory acceptance of these recommendations was
featured in the Forum section of the September 2008 issue of Environmental Health Perspectives (EHP).
EHP is a peer-reviewed publication of the Public Health Service, U.S. Department of Health
and Human Services, and is a forum for the discussion and dissemination of news, scientific research,
and ideas relating to the effect of the environment on human health.
ICCVAM recommended the two alternative test methods, the bovine corneal opacity and permeability
(BCOP) assay and the isolated chicken eye (ICE) assay, following an extensive evaluation of their
scientific validity. NICEATM provided scientific support for the evaluation, which included
independent scientific peer review by an international expert panel and consideration of public comments.
The BCOP and ICE do not involve the use of live animals, and the tissues used are obtained from animals
intended for food consumption. If a positive response is obtained using either of the two new approved
alternative methods, the product can be labeled as causing irreversible or severe eye damage without animal
testing. These are the first scientifically valid in vitro alternative methods to gain regulatory acceptance for ocular safety testing.
The full text of the EHP Forum article (September 2008) can be found on the
EHP Website. Information
about the NICEATM-ICCVAM evaluation of the eye safety test methods, including the Test Method
Evaluation Report, the ICCVAM recommendations, and the agency responses, can be found on this website in the
Ocular Alternative Test Method Evaluation section.
Test Guidelines for Alternative, Non-Animal Ocular Toxicity Forwarded to OECD
NICEATM, on behalf of ICCVAM, forwarded draft test guidelines for the BCOP and ICE test methods
to the Organisation of Economic Co-operation and Development (OECD), via the U.S. National
Coordinator on August 20, 2008. The test guidelines were developed by NICEATM and the OTWG
in collaboration with the European Centre for the Validation of Alternative Methods (ECVAM),
the Japanese Center for the Validation of Alternative Methods (JaCVAM), and the developers of
BCOP and ICE. The draft test guidelines are based on the ICCVAM recommended test method protocols
that were developed following a comprehensive review of the validation status of BCOP and ICE, which included independent scientific peer review by an international expert panel and consideration of public comments. The approval of these test methods by the OECD will allow the test methods to be used in the other 29 OECD member countries, which include Japan, Canada and most countries in the European Union and will broaden the impact on reducing animal use.
The transmittal letters and agency responses can be found on this website in the Ocular Alternative Test Method Evaluation section. This page also contains links to the final background review documents, the ICCVAM Test Method Evaluation report, and a June 2008 NIH press release announcing the acceptance of the methods by Federal agencies.
Progress of Agency Responses on Alternative, Non-Animal Acute Toxicity Test Method Recommendations
NICEATM, on behalf of ICCVAM, forwarded the ICCVAM Test Method Evaluation Report: In Vitro Cytotoxicity Test Methods for Estimating Starting Doses for Acute Oral Systemic Toxicity Tests (NIH Publication No. 07-4519) to U.S. Federal agencies in February 2008 for regulatory consideration. ICCVAM recommended that the in vitro basal cytotoxicity test methods tested in the joint ICCVAM/ECVAM validation study (i.e., the neutral red uptake assay using rodent (mouse fibroblast [3T3]) and human (normal human epidermal keratinocyte [NHK]) cells) should be considered before using animals for acute oral toxicity testing, and that the methods should be used where determined appropriate. Data from the test methods should be used in a weight-of-evidence approach for determining starting doses for in vivo studies. Using these in vitro methods where appropriate is expected to reduce the number of animals required for each toxicity test. ICCVAM concluded that the in vitro test methods are not sufficiently accurate to replace animals for regulatory hazard classification purposes.
Responses to the ICCVAM recommendations were received from all Federal agencies and are posted on the website. All Federal agencies concur with ICCVAM’s recommendation regarding the two in vitro cytotoxicity test methods. The test methods should be considered and used before using animals for acute oral toxicity testing and the test methods should be used when determined appropriate.
The publication and transmittal were announced in an FR notice published on March 25, 2008. A link to this FR notice, as well as links to the ICCVAM Test Method Evaluation Report and final background review documents, can be found on this website in the Acute Toxicity Alternative Test Method Evaluation section.
Progress on Validation Studies of In Vitro Methods for Identification of Potential Endocrine Disruptors
A NICEATM-sponsored multi-phased international validation study of the LUMI-CELL® test method is in progress in collaboration with ECVAM and JaCVAM. Efforts have recently been made to optimize the protocol in order to demonstrate intra-laboratory repeatability, and intra- and inter-laboratory reproducibility, of assay results. Using an optimized protocol based on a standardization study completed by the lead laboratory (Xenobiotic Detection Systems, Inc. [XDS, Durham, NC], Phase 1 and 2A testing has been completed by all three participating laboratories (i.e., XDS, Hiyoshi Corporation [Japan], and a laboratory at ECVAM). Phase 2B has recently been initiated. More information about the LUMI-CELL® validation study can be found on this website in the Endocrine Disruptors Alternative Test Method Evaluation section.
Progress on Five In Vitro Pyrogen Test Methods
ICCVAM Test Methods Recommendations on the five in vitro pyrogen test methods proposed for assessing potential pyrogenicity of pharmaceuticals and other products have been forwarded to the Secretary of the Department of Health and Human Services. We anticipate them to be forwarded to ICCVAM agencies for consideration in the near future. A complete report will be released for public dissemination upon receipt from the Federal Agencies. More information about the ICCVAM test method recommendations for pyrogenicity can be found on this website in the Pyrogenicity Test Method Evaluation section.
Progress on Review Activities for the Murine Local Lymph Node Assay (LLNA)
Revised ICCVAM LLNA Performance Standards have been drafted and are being considered in conjunction with draft ECVAM LLNA Performance Standards by representatives of ICCVAM, the ICCVAM Immunotoxicity Working Group (IWG), NICEATM, ECVAM, and the ECVAM Task Force on Skin Sensitization. A meeting of representatives from these groups will be convened at ECVAM on September 23-24, 2008 with the goal of reaching agreement on a consensus document that will have international applicability, and that can be included in a revised OECD Test Guideline for the LLNA.
NICEATM and ICCVAM are also in the process of finalizing the background review document and test method evaluation report (TMER) for the reduced (LLNA), a method identical to the traditional LLNA with the exception that the rLLNA uses only a single test substance dose that is the maximum soluble concentration that is not systemically toxic or excessively irritating. The TMER will describe ICCVAM recommendations on the usefulness and limitations of the rLLNA, a standardized protocol, performance standards, and any future studies to further characterize the usefulness and limitations of the rLLNA.
NICEATM received additional data and information for the non-radioactive versions of the LLNA, which will be used to update a review of their validation status as replacements for the traditional (radioactive) LLNA. NICEATM has also received from chemical companies and trade organizations over 70 traditional LLNA studies with mixtures. These data will also be used in an updated evaluation of the usefulness and limitations of the LLNA for testing mixtures. Once these evaluations are complete, the international independent peer review panel will be reconvened via teleconference to consider the updated information and any revisions to the draft ICCVAM test method recommendations.
Questions about NICEATM and ICCVAM activities can be directed to Dr. William S. Stokes, Director, NICEATM: phone 919-541-2384; fax 919-541-0947.
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