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In October 2007, ICCVAM forwarded its first recommendations for the use of in vitro methods for ocular safety testing to Federal agencies.
ICCVAM recommended that two methods, the Bovine Corneal Opacity and Permeability (BCOP) test method and the Isolated Chicken Eye (ICE) test method,
can be used in a tiered testing strategy to determine ocular hazards, with specific limitations
for certain chemical classes and/or physical properties. Substances
that test positive in these assays can be classified as ocular corrosives or severe irritants without further testing in animals. The report also recommends
that these in vitro test methods should be considered before using animals for ocular testing and used when determined appropriate. These recommendations,
once accepted by Federal agencies, will result in a reduction of the number of animals used for safety testing to determine corrosive or severely irritating damage to the eye.
ICCVAM evaluated two other in vitro test methods, the Isolated Rabbit Eye (IRE) test method
and the Hen's Egg Test - Chorioallantoic Membrane (HET-CAM) test method. Before these two methods
can be recommended for use as screening tests for the identification of ocular corrosives and severe
irritants, the protocol and decision criteria for the identification of ocular corrosives and severe
irritants need to be optimized and undergo further validation.
Nomination History and Evaluation
In October 2003, the U.S. Environmental Protection Agency (EPA) submitted several nominations to ICCVAM to reduce, replace, and refine the use of rabbits
for ocular irritation testing. Such safety testing is required by Federal agencies to determine whether consumer products or other substances may cause temporary
or permanent damage to the eye.
In response to the nominations, ICCVAM initiated evaluation of four in vitro ocular toxicity test methods as
potential screening methods for eye corrosion or severe irritation: the BCOP test method, the ICE test method, the IRE test method, and the
HET-CAM test method. NICEATM compiled data and information on each test method into four draft
Background Review Documents (BRDs).
ICCVAM, in collaboration with NICEATM, convened an independent Expert
Panel in January 2005 to determine the validation status of these
methods. The
Expert Panel Report: Evaluation of the Current Validation
Status of In Vitro Test Methods for Identifying Ocular Corrosives and
Severe Irritants, was made available in March 2005. Submission of additional data after the Expert Panel Meeting led to release of addenda to the BRDs.
The Expert Panel was subsequently reconvened in September 2005 to reconsider their evaluation.
An
Addendum to the Expert Panel Report, incorporating additional data and analyses, was made available in November 2005.
ICCVAM considered the expert panel report and its addendum, public comments, the comments of the Scientific Advisory Committee on Alternative Toxicological Methods,
and the draft BRDs and
their addenda in finalizing its recommendations on the validation status of these four test methods. These are contained in the ICCVAM
Test Method Evaluation Report: In Vitro Ocular Toxicity Test
Methods for Identifying Severe Irritants and Corrosives.
In October 2007, the ICCVAM Test Method Evaluation Report, as well as the
supporting final BRDs, were forwarded to
Federal agencies for their consideration of regulatory acceptance as required by the ICCVAM Authorization Act of 2000 (42 U.S.C. 285l-3).
These are the first alternative nonanimal test methods for ocular safety testing reviewed by ICCVAM and transmitted to agencies.
Agencies' response to the test method recommendations, which are due in April 2008, will be posted on the NICEATM-ICCVAM website as they are received.
In addition to the evaluation discussed above, the October 2003 EPA nomination recommended the review of
the validation status of the in vitro methods for identifying
nonsevere ocular irritants (i.e., those that induce reversible ocular damage) and non-irritants. In June 2007, NICEATM requested the submission of
data from substances tested for ocular irritancy in humans, rabbits, and/or
in vitro. NICEATM welcomes the submission of all relevant data, which will be compiled and added to the database maintained by NICEATM and utilized where appropriate in the evaluation of in vitro ocular
irritation test methods. Data received will also be considered and used where applicable for future evaluation activities.
In January 2008, NICEATM received an EPA-sponsored submission of a nonanimal approach using in vitro test methods to assess the eye irritation
potential of antimicrobial cleaning products. This proposed testing strategy will utilize the BCOP, the Cytosensor Microphysiometer, and the EpiOcular
in vitro test methods to determine the EPA toxicity category and labeling requirements for these substances. NICEATM and ICCVAM are conducting a preliminary
evaluation of the submission to determine its completeness and adherence to ICCVAM guidelines.
In May 2007, NICEATM requested the submission of data from completed studies on the use of topical anesthetics and/or systemic analgesics for in vivo ocular
irritancy testing. These data will be used to evaluate the validation status of the use of topical anesthetics and/or analgesics to reduce pain and distress for in vivo
testing situations. ICCVAM and NICEATM also requested the submission of information and data from in vivo methods, procedures, and/or strategies that may reduce or
eliminate the pain and suffering associated with current in vivo eye irritation methods.
In vivo tests used to evaluate the risk of substances to cause irritation or corrosion to the eyes present the potential for pain and distress in rabbits after application of a severely
irritating or corrosive substance. In October 2003, the EPA requested that ICCVAM review ways to alleviate
pain and suffering that might arise during current in vivo tests. ICCVAM has recommended with high priority that NICEATM review the data
currently available on the use of topical anesthetics and/or
systemic analgesics to reduce animal pain and distress.
Two Scientific Symposia on ocular toxicity topics were held in May 2005. Both symposia were sponsored by ICCVAM, NICEATM, the European Centre for the Validation
of Alternative Methods (ECVAM), and the European Cosmetic, Toiletry and Perfumery Association, and were organized by ICCVAM, NICEATM and ECVAM.
Symposium I: Mechanisms of Chemically-Induced Ocular Injury and
Recovery identified research needed to address current knowledge
gaps and to advance the development and validation of ocular toxicity
test methods for regulatory testing that provide for protection of
human health while reducing, refining (less pain and distress), and/or
replacing the use of animals. The participants in Symposium I made the following recommendations:
- Data collected from objective, quantitative endpoints and biomarkers should be used to assess the severity of
chemically-induced ocular injuries in animal safety studies and human accidental exposures.
- The routine collection of this data can be expected to:
- Provide insights into chemical-specific mechanisms of ocular injury and recovery
- Support the development and validation of more predictive mechanism-based in vitro test models
- Improve the accuracy and reliability of ocular hazard assessments
- Aid in identifying predictive, mechanism-based earlier humane endpoints
Symposium II:
Minimizing Pain and Distress in Ocular Toxicity Testing, reviewed current understanding of the sources and mechanisms
of pain and distress in ocular toxicity testing; identified current best practices for preventing, recognizing,
and alleviating ocular pain and distress; and identified additional research, development, and validation
studies necessary to support scientifically valid ocular toxicity
testing procedures that avoid pain and distress. The participants in Symposium II made the following recommendations:
- Pre-treatment with topical or general anaesthesia should be used routinely to avoid pain from topical application
of test substances
- Systemic analgesics should be administered prior to test article application and continued until injuries resolve
or the study is terminated
- Ocular injuries predictive of severe or irreversible ocular damage should be used as earlier humane endpoints
- Objective, quantitative measurements should be collected during ocular studies to assist in identifying earlier,
more humane endpoints. Data from these measurements are also critical to the development and validation of more predictive
in vitro methods.
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