National Toxicology Program

National Toxicology Program
http://ntp.niehs.nih.gov/go/iccvam-genetox

ICCVAM Participation in International Evaluations of Genetic Toxicity Test Methods

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 member agency scientists 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 (OECD).


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. A proposal for updating Test Guideline 487 was made in 2012 and can be viewed on the OECD website.

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 Exiting the NTP website


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 (JaCVAM). An OECD test guideline for the in vivo comet assay is currently under development; a draft test guideline was made available for comment in May 2013 on the OECD website.


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. An OECD test guideline for the in vivo cell transformation assay is currently under development; a draft test guideline was made available in February 2013 on the OECD website.

The NTP is located at the National Institute of Environmental Health Sciences, part of the National Institutes of Health.