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Below are summaries of recent NICEATM-ICCVAM activities.
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Experts Review Revisions to Local Lymph Node Assay Method
On October 20-22, scientists from NIEHS, the Environmental Protection Agency, the Food and Drug
Administration (FDA), and the Consumer Product Safety Commission (CPSC) participated in an
international expert consultation to evaluate modifications of the murine local lymph node assay
(LLNA), a test method for detecting potential skin-sensitizing substances.
This meeting, which also included experts from industry and other stakeholder
organizations, was convened by the Organisation for Economic Co-operation and Development (OECD) and
took place at CPSC headquarters in Bethesda, Md. The meeting was co-hosted by CPSC, NICEATM, and ICCVAM.
The group of 20 scientists from five countries reviewed proposed revisions to the OECD Test Guideline
(TG) for the LLNA, TG 429. The proposed revisions provide multiple mechanisms for reducing the
number of animals in each test by up to 40 percent. They also provide a standardized approach and
improved guidance for establishing the highest test dose, as well as performance standards that can
be used to expedite the validation of modified versions of the LLNA. All of the proposed revisions
are based on the recommendations recently forwarded to U.S. Federal agencies by ICCVAM (see below,
"ICCVAM Recommends Performance Standards and New Versions
of the Murine Local Lymph Node Assay to U.S. Federal Agencies").
The expert group also reviewed drafts of two new proposed test guidelines for nonradioisotopic
versions of the LLNA. These test methods — the LLNA: DA, which measures adenosine triphosphate (ATP)
content, and LLNA: BrdU-ELISA, which measures bromodeoxyuridine (BrdU) incorporation — do not
require radioisotopes to measure lymphocyte proliferation, which is a requirement in the traditional
LLNA. The availability of OECD test guidelines for these test methods will allow more widespread use
of the LLNA by enabling it to be used where use of radioisotopes is not permitted. The draft test
guidelines are also based on an ICCVAM evaluation of LLNA: DA and LLNA: BrdU-ELISA. Final ICCVAM
recommendations on the usefulness and limitations of these test methods in the U.S. are currently
being finalized and will likely be forwarded to U.S. federal agencies by the end of the year.
The expert group will meet again later this year to consider revised versions of the test
guidelines based on discussions and recommendations at the October meeting. The revised draft TGs
will then be sent out for review and comment by OECD member countries.
View full article in NIEHS Environmental Factor newsletter
ICCVAM-recommended In Vitro Ocular Safety Testing Methods Accepted as OECD Test Guidelines
In September, the OECD
officially adopted two new international test guidelines that can be used to identify ocular
corrosives and severe irritants without the use of live animals. NICEATM and ICCVAM developed the guidelines
for the bovine corneal opacity and permeability (BCOP) and isolated chicken eye (ICE) test methods
following their acceptance by U.S. Federal regulatory agencies in 2008. Substances that may cause
severe irritation or permanent damage to eyes can now be identified using these methods without the
use of live animals in the 30 OECD member countries.
After the BCOP and ICE test methods were accepted last year by U.S. Federal agencies (see NIEHS press release,
“Newly Approved Ocular Safety Methods Reduce Animal Testing,” June 23, 2008), NICEATM and ICCVAM drafted test guidelines in collaboration with validation organizations in
Europe and Japan for submission to OECD. The new test guidelines are designated Test Guidelines 437 (BCOP) and 438
(ICE). This represents the most rapid adoption of new test guidelines by the OECD. The prompt acceptance was due in
large part to the comprehensive ICCVAM evaluation of the validation status of the test methods and the involvement
of international validation partners in the development of the test guidelines.
Final versions of Test Guidelines 437 and 438 are now available on the
NICEATM-ICCVAM website
along with information about the
NICEATM-ICCVAM evaluation of the BCOP and ICE test methods. Information about the OECD Test
Guidelines Program can be found on the OECD website.
ICCVAM Recommends Performance Standards and New Versions
of the Murine Local Lymph Node Assay to U.S. Federal Agencies
In September 2009, ICCVAM recommendations for the reduced murine local lymph node assay (rLLNA), an updated LLNA
test method protocol, and LLNA performance standards were communicated to the heads of Federal agency heads for
their consideration. Links to these letters are available on the NICEATM-ICCVAM website.
Reponses from agencies are required within 180 days and will be posted on the
NICEATM-ICCVAM website as they are received.
ICCVAM recommended that the rLLNA should be routinely considered before conducting the traditional multi-dose LLNA,
and used where appropriate to determine the potential of chemicals and products to cause allergic contact dermatitis.
Using the rLLNA will reduce animal use by 40% compared to the traditional multi-dose LLNA. ICCVAM also recommended
performance standards that can be used to efficiently evaluate the validity of improved and modified versions of the
LLNA that are mechanistically and functionally similar to the traditional LLNA. The updated LLNA test method protocol
reduces animal use by 20% compared to the original LLNA.The ICCVAM recommendations are provided in the
ICCVAM rLLNA Test Method Evaluation Report (TMER). More information about the NICEATM-ICCVAM
evaluation of the rLLNA and a link to the TMER are on the NICEATM-ICCVAM website.
The ICCVAM-recommended performance standards for the LLNA specify essential test method components,
a minimum list of reference substances to evaluate the accuracy and reliability of a modified LLNA,
and accuracy and reliability values that must be achieved in order for a modified LLNA to be considered
equal to or better than the traditional LLNA. More information about the ICCVAM LLNA performance standards
and the LLNA performance standards report are available on the
NICEATM-ICCVAM website.
NICEATM and ICCVAM Scientists Participate at the Seventh World Congress on Alternatives and Animal Use in the Life Sciences
NICEATM and ICCVAM scientists played a prominent role in the recent international meeting dedicated to
advancements in the reduction, refinement, and replacement of the use of animals for safety testing.
The Seventh World Congress on Alternatives and Animal Use in the Life Sciences was attended by
representatives from industry, regulatory agencies, and animal welfare organizations. (For a related
article, see page 4 of the October 2009 NTP Update
on the main NTP website.) The meeting, cosponsored by NIEHS, was held in Rome, Italy from August 31 to
September 3 and emphasized progress made since the last 2007 Congress (Tokyo, Japan) in the
development of alternatives for toxicity testing. Four plenary sessions featured updates on recent
progress and new initiatives by NICEATM and ICCVAM: (1) a session on the recently signed
International Cooperation on Alternative Test Methods agreement, (2) a session on recent progress
and future directions of the national validation centers in the U.S. (NICEATM-ICCVAM), Europe
(ECVAM), and Japan (JaCVAM), (3) a session on evolving concepts, opportunities, and challenges in
validation, and (4) a session providing an update on the recent acceptance of in vitro pyrogen tests
in the United States and Europe.
NICEATM and ICCVAM scientists also presented eight scientific posters highlighting recent
progress in the validation and evaluation of alternative test method activities. The poster
presentations, available on the NICEATM-ICCVAM website, summarized test method evaluation
activities relevant to skin and eye corrosivity and irritation, skin sensitization, pyrogenicity,
and endocrine disruptors. They also highlighted NICEATM and ICCVAM’s international cooperative
activities including the development of internationally harmonized test method performance
standards, international validation studies, and efforts toward international regulatory acceptance
of in vitro alternatives.
September 14-16, 2010: International Scientific Workshop on Alternative Methods
in Vaccine Potency and Safety Testing
NICEATM and ICCVAM are planning an International Scientific Workshop on Alternative Methods
to Reduce, Refine, or Replace the Use of Animals in Vaccine Potency and Safety Testing, which will be held on
September 14-16, 2010, at the William H. Natcher Conference Center at the National Institutes of Health in
Bethesda, MD. This workshop will bring together international scientific experts representing relevant stakeholder
organizations to review the current status and use of such methods and to prioritize future activities related to research,
development, and validation of new alternative methods.
The goals of the workshop will be to: (1) review the state of the science and current use of
alternative methods that can reduce, refine, and/or replace the use of animals in vaccine potency
and safety testing and (2) identify priorities for research, development, and validation efforts
needed to advance the use of alternative methods for vaccine potency and safety testing while
ensuring the protection of human and animal health. Interested stakeholders and members of the
public are encouraged to attend. More information about the workshop will be posted on the
NICEATM-ICCVAM website as it becomes
available.
ICCVAM has contributed to the approval or endorsement of 27
alternative safety-testing methods by Federal regulatory agencies
since its establishment in 1997. Appropriate use of these test
methods can significantly reduce animal use and improve animal
welfare. ICCVAM has also identified critical research, development, and
validation efforts needed to further advance numerous other alternative methods.
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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