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Below are summaries of recent NICEATM-ICCVAM activities.
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Federal Agencies Respond to ICCVAM Recommendations on Use of the Murine Local Lymph Node Assay for Potency Categorization
An interagency committee administered by NICEATM recommended to Federal agencies that the murine
local lymph node assay, or LLNA, may be used to categorize the potency of chemicals causing allergic
contact dermatitis (ACD) in humans. Specifically, the Interagency Coordinating Committee on the
Validation of Alternative Methods (ICCVAM) recommended that
the LLNA may be used to categorize some
substances as strong sensitizers, thus identifying those substances considered to have a significant
potential for causing skin hypersensitivity resulting in ACD. U.S. Federal agencies have responded
to the ICCVAM recommendations. Regulatory agencies, including FDA, EPA, CPSC, and OSHA, have
indicated that they will take actions in response to the ICCVAM recommendations to encourage use of
the LLNA for this purpose where appropriate.
Skin diseases are the most common type of occupational illness in the United States, according to
the U.S. Bureau of Labor Statistics. Many skin disease cases arise from repeated exposures to
skin-sensitizing substances, which can lead to ACD, an immunologically mediated hypersensitivity
reaction. Studies have shown that ACD has a significant adverse impact on quality of life in
affected individuals.
Since recommended by ICCVAM in 1999,
the LLNA has been accepted worldwide as a valid alternative to
traditionally accepted guinea pig test methods for assessing ACD hazard potential for most testing
applications. The LLNA uses fewer animals than traditional guinea pig test methods, requires less
time to perform, provides dose-response information, and, in most cases, eliminates pain and
distress in the test animal.
The new ICCVAM recommendation provides guidance on how to use the LLNA to categorize some chemicals
and products as strong skin sensitizers. However, since only half of the known strong human skin
sensitizers can be identified as such in the LLNA (52% or 14 out of 27), all remaining substances
require additional testing or information to determine that they are not strong skin sensitizers.
The ICCVAM evaluation is detailed in a report entitled ICCVAM Test Method Evaluation Report:
Usefulness and Limitations of the Murine Local Lymph Node Assay for Potency Categorization of
Chemicals Causing Allergic Contact Dermatitis in Humans (NIH Publication No. 11-7709). In June
2011, ICCVAM forwarded recommendations to Federal agencies and made these recommendations available
to the public (76 FR 18639 - view PDF of FR notice).
In accordance with the ICCVAM Authorization Act of 2000 (42 U.S.C.
285l–3 - view PDF),
agencies have notified ICCVAM in writing of their findings, and ICCVAM has made these
responses available to the public.
NIEHS/NTP Director Linda Birnbaum, PhD, responded to ICCVAM stating that NIEHS agreed with the
recommendations. Noting the animal welfare advantages of the LLNA, she indicated that NIEHS and the
NTP would ensure that the LLNA test method protocol is routinely considered whenever studies are
proposed to assess ACD hazard potential and to categorize the potency of substances identified as
having the potential to cause ACD in humans.
View NIEHS and other Federal agency responses to the ICCVAM recommendations and more
information about the ICCVAM evaluation of the LLNA for potency categorization
View the test method evaluation report
NICEATM and ICCVAM are also currently evaluating several in vitro and in chemico methods for their
potential to further reduce and eventually replace animal use for ACD safety testing.
View an overview of NICEATM and ICCVAM evaluations of methods for ACD safety testing
ICCVAM Recommends Non-animal In Vitro Method to Identify Potential Endocrine-active Substances
ICCVAM recently recommended to Federal agencies a non-animal test method that can be used as a
screening test to identify substances with in vitro estrogen receptor agonist and antagonist
activity. This test method, the
BG1Luc estrogen receptor (ER) transactivation (TA) test method (also
known as the LUMI-CELL® ER test method) uses cultured human cells to identify substances that can
induce or inhibit human ER activity in vitro.
Xenobiotic Detection Systems, Inc. (XDS, Durham, NC, USA) developed the LUMI-CELL® ER test method
with support from an NIEHS Small Business Innovation Research Grant and nominated the method to
ICCVAM for an interlaboratory validation study. ICCVAM and its advisory committee, the Scientific
Advisory Committee on Alternative Toxicological Methods (SACATM)  recommended the study as a high
priority. NICEATM subsequently coordinated an international validation study with counterparts in
Japan (the Japanese Center for the Validation of Alternative Methods ; JaCVAM) and Europe (the
European Centre for the Validation of Alternative Methods ; ECVAM).
ICCVAM’s Interagency Endocrine Disruptor Working Group (EDWG), composed of scientists from ICCVAM
member agencies, JaCVAM, and ECVAM, worked with NICEATM to carry out relevant evaluation activities
following completion of the international validation study. Members of the EDWG from NIEHS include
Warren Casey, PhD, Jerry Heindel, PhD, Bill Stokes, DVM, and Julius Thigpen, PhD.
A background review document, test method performance standards, and ICCVAM test method
recommendations were reviewed by an independent international peer review panel. ICCVAM considered
the Panel report and comments from the public, the EDWG, and SACATM in preparing the final test
method recommendations.
ICCVAM recommends that the accuracy and reliability of the BG1Luc ER TA test method support its
use as a screening test to identify substances that can induce or inhibit human ER activity in
vitro. ICCVAM concludes that the accuracy of this assay is at least equivalent to the only ER TA
test method currently listed in a U.S. regulatory test guideline, the Environmental Protection
Agency’s “OPPTS 890.1300: Estrogen Receptor Transcriptional Activation (Human Cell Line (HeLa-
9903))”. The BG1Luc ER TA test method was found to offer several advantages over the existing ER TA
method, including (1) validation for use over a wider concentration range of test substances, (2)
potential to detect a wider range of ER-active substances, (3) ability to identify both substances
that induce and inhibit the estrogen receptor, and (4) availability of the cell line used for the
test from more than one source.
The ICCVAM evaluation is detailed in a report entitled ICCVAM Test Method Evaluation Report: The
LUMI-CELL® ER (BG1Luc ER TA) Test Method: An In Vitro Assay for Identifying Human Estrogen Receptor
Agonist and Antagonist Activity of Chemicals (NIH Publication No. 11-7850).
The report also provides (1) performance standards that can be used to
evaluate functionally and mechanistically similar test methods, (2) recommended test method
protocols, (3) a final background review document describing the current validation status of this
test method, and (4) recommendations for future studies.
The ICCVAM report and recommendations have been transmitted to Federal agencies for their review
and response to ICCVAM in accordance with the provisions of the ICCVAM Authorization Act of 2000 (42 U.S.C.
285l–3 - view PDF),
which requires agencies to review the recommendations and respond to ICCVAM within 180 days.
Casey, who is Deputy Director of NICEATM, received a 2011 NIH Individual Merit Award in
recognition of his excellent performance in leading the international validation and interagency
evaluation of new testing methods to support the Federal government's endocrine disruptor chemical
screening program, including the evaluation of the BG1Luc ER TA test method.
The BG1Luc ER TA test method was adapted to a high-throughput format using 1536-well plates by
the NIH Center for Advancing Translational Sciences (NCATS; formerly the NIH Chemical Genomics
Center). Preliminary results are promising, and it is expected that this method will be incorporated
into the Tox21 screening paradigm in 2012.
View more information about the ICCVAM
evaluation of the BG1 test method
Hold the Date: NICEATM and ICCVAM International Workshop on Alternative Methods for Leptospira Vaccine Potency Testing, September 19–21, 2012
NICEATM and ICCVAM will convene an "
International Workshop on Alternative Methods for Leptospira
Vaccine Potency Testing: State of the Science and Planning the Way Forward" on September 19-21,
2012. The workshop will be hosted by the U.S. Department of Agriculture (USDA) Center for Veterinary
Biologics at the National Centers for Animal Health in Ames, Iowa. NICEATM and ICCVAM are organizing
the workshop in collaboration with partner organizations in the
International Cooperation on
Alternative Test Methods.
Leptospirosis is an emerging and widespread bacterial zoonotic disease caused by spirochetes of
the genus Leptospira. More than 500,000 human cases of leptospirosis are reported worldwide each
year with a fatality rate of up to 25% in some regions. Designated as a Neglected Tropical Disease
by the NIH and the WHO, leptospirosis is a global research and public health priority. Leptospirosis
also affects many animal species including livestock, pets, and wildlife. In the United States,
vaccines are used to protect cattle, swine, and dogs. Vaccines for people are available in some
other countries, and NIH is supporting the development of new human vaccines.
Manufacturers perform potency testing prior to release of each production lot of Leptospira
vaccine to ensure that it will be effective. However, current methods for this testing require large
numbers of laboratory animals. Many of the animals experience significant unrelieved and distress
without the benefit of pain-relieving drugs, accounting for over one-third of the animals reported
to the USDA in this pain category. While in vitro potency assays are now approved by the USDA and
available for four Leptospira serovars, these new assays have not yet been widely implemented.
Accordingly, NICEATM, ICCVAM, and their international partners recently identified Leptospira
vaccines as one of its top three vaccine priorities for development, validation, and implementation
of improved test method alternatives.
This workshop, the second in a series of specialized vaccine workshops organized by NICEATM and
ICCVAM, will review recent advances and innovations in science and technology that can be translated
to methods that are more humane, use fewer or no animals, and provide improved accuracy, efficiency,
and worker safety. The workshop will also address global acceptance and implementation of
scientifically valid alternative methods.
View information about the workshop
NICEATM and ICCVAM also invite the submission of abstracts for scientific posters to be displayed
during this workshop; abstracts should be submitted by August 13, 2012. If you have questions about
the workshop or would like more information, please contact NICEATM.
NICEATM and ICCVAM Presentations at the 51st Annual Meeting of the Society of Toxicology
NICEATM and ICCVAM presented seven scientific posters describing recent accomplishments at the
51st Annual Meeting of the Society of Toxicology, which took place on March 11–15, 2012 in San
Francisco, CA, USA.
View NICEATM-ICCVAM presentations at SOT
Two posters focused on the
ICCVAM evaluation of the BG1Luc ER TA test method. This test method
uses human cells to identify substances with in vitro estrogen agonist and antagonist activity (see
article above). One poster summarized the ICCVAM recommendations on the BG1Luc ER TA test method,
and the second described performance standards that have been developed for the test method.
Three posters described NICEATM evaluations of methods to identify substances with the potential
to cause allergic contact dermatitis (ACD). One poster described an updated evaluation of the
reduced LLNA, and another presented an evaluation of the use of two nonradiolabeled LLNA methods for
potency categorization of substances causing ACD in humans. A third poster described a NICEATM
analysis comparing use of the direct peptide reactivity assay with a three-test battery for in vitro
identification of potential skin sensitizers, and proposes an integrated testing strategy that can
significantly reduce animal testing.
A sixth NICEATM–ICCVAM poster presented the results of a NICEATM analysis to determine if acute
oral systemic toxicity data can be used to estimate and avoid acute dermal systemic toxicity
testing. The final poster presented a summary of conclusions and recommendations from the October
2011
International Workshop on Alternative Methods for Human and Veterinary Rabies Vaccine
Testing.
Former ICCVAM Advisory Committee Member Receives SOT Award
Donald Fox, PhD, of the University of Houston College of Optometry has received a Career
Achievement Award from the SOT Ocular Toxicity Specialty Section. The award recognizes lifetime
achievement or contribution of a particularly influential body of work to the field of ocular
toxicology.
Fox served on the Scientific Advisory Committee for Alternative Toxicological Methods (SACATM)
from June 2005 to June 2009. SACATM, which is one of the formal advisory committees to the NTP,
advises the NIEHS Director, ICCVAM, and NICEATM on ICCVAM functions and activities.
In addition to his service on SACATM, Fox participated on the NICEATM-ICCVAM Expert Panel
convened in January 2005 to evaluate the validation status of in vitro test methods for identifying
ocular corrosives and severe irritants. In that capacity, he reviewed and commented on ICCVAM
recommendations on in vitro test methods that were subsequently adopted by U.S. agencies and
internationally through the Organisation for Economic Co-operation and Development.
Fox is Professor of Vision Sciences, Biology & Biochemistry, Pharmacology, and Health & Human
Performance at the University of Houston College of Optometry. His research interests are in the
areas of mammalian retinal cell biology/biochemistry, molecular biology, and neurotoxicology. Some
of his recent research has focused on the effects of prenatal lead exposure on retinal development
(see article in Environmental Health Perspectives).
ICCVAM has contributed to the approval or endorsement of over 40
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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