Genetic toxicity refers to the ability of
substances or physical agents to damage the DNA and/or chromosomes of
cells. Such damage can lead to mutations that increase the likelihood of
certain diseases, such as cancer and birth defects. The U.S.
Environmental Protection Agency, the U.S. Food and Drug Administration,
and the U.S. Consumer Product Safety Commission have testing
requirements and guidelines in place for assessing the genetic toxicity
of regulated products. ICCVAM and its Genetic Toxicity Working Group
(GTWG) review and provide comments to sponsors on proposed validation
studies, provide recommendations on test method nominations and
submissions for alternative test methods related to genetic toxicity,
and evaluate proposed test guidelines and activities relevant to genetic
toxicity from the Organisation for Economic Co-operation and Development
The In Vitro Mammalian Cell Micronucleus Test
The in vitro micronucleus test is a test method that measures a test substance’s potential for causing damage to chromosomes.
In this method, cultured human or rodent cells are treated with a test substance and then examined for the presence of chromosome
fragments known as micronuclei. The test is intended to reduce the number of animals used to identify substances
that can lead to cancer and other adverse health effects.
The ICCVAM Interagency Genetic Toxicity Working Group (GTWG) provided comments on cytotoxicity evaluation procedures
and study design for a draft test guideline for the in vitro
micronucleus test submitted to the Organisation for Economic Co-operation and Development (OECD).
In November 2009 the GTWG recommended approval of the test guideline based on the results of cytotoxicity
study data provided by European Union and U.S. laboratories. Test Guideline 487 for the in vitro
micronucleus test was formally adopted by OECD in 2010.
- GTWG comments (November 2009) [PDF]
- Cover letter to U.S. National Coordinator accompanying GTWG comments [PDF]
GTWG Comments on Previous Drafts of TG 487
- OECD Draft Test Guideline 487: In Vitro Micronucleus Assay (December 2007) [PDF]
- Cover letter to OECD regarding ICCVAM comments on draft revised Test Guideline 487 [PDF]
- ICCVAM comments on draft revised Test Guideline 487 [PDF]
Inclusion of the Micronucleus Test in ICH Safety Guideline for Genotoxicity Studies
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
has included the method described in Test Guideline 487 in their Guidance on Genotoxicity Testing and Data Interpretation for
Pharmaceuticals Intended for Human Use (Guideline S2[R1]). ICH safety guidelines are internationally agreed upon standards
for safety testing. Guideline S2(R1) is intended to apply to products being developed as human pharmaceuticals and
is recommended for adoption to the regulatory bodies of the European Union, Japan, and USA.
View ICH Safety Guidelines on the ICH website
View Guideline S2(R1) on the ICH website [PDF ]
JaCVAM Comet Assay Validation
NICEATM and ICCVAM are participating with the European Centre
for the Validation of Alternative Methods (ECVAM) in a validation study
of the in vivo rodent comet assay. The comet assay test method is a
potential alternative for the in vivo rat hepatocyte unscheduled DNA
synthesis assay, a standard method with limitations for assessing the
genetic toxicity of a substance. The validation study is sponsored by
the Japanese Center for the Validation of Alternative Methods
ECVAM Cell Transformation Assay Validation
NICEATM and ICCVAM are collaborating with ECVAM in the assessment of carcinogenic
xenobiotics using the in vitro cell transformation assay.