Regulatory Focus™ > News Articles > With Eye to Regulatory Science, Toxicology Program Seeks Lists of Genes to Bolster Safety

With Eye to Regulatory Science, Toxicology Program Seeks Lists of Genes to Bolster Safety

Posted 29 July 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) is widely recognized as the country's chief federal regulator of healthcare products, including pharmaceuticals, medical devices and biological products. Lesser-known-but still important-is another federal program known as the National Toxicology Program (NTP), which works to help agencies to understand and accept the toxicological profiles of many chemicals. Now the NTP is announcing its intent to identify and prioritize a list of genes that regulators could use to screen against a large number of potentially toxic substances, with the goal of making it easier to test the safety of chemicals.


Several different agencies are involved with the NTP, including FDA and its parent agency, the US Department of Health and Human Services (DHHS). Its broader goal, it explains on its website, is to test as many of the chemicals introduced into the US each year as it can. These chemicals notably include those used in healthcare products.

[Editor's Note: For a list of NTP assessments used by FDA, please see a complete list here.]

For example, in August 2012 the NTP announced it would be working on a draft monograph to cover chemotherapy products administered to pregnant women. Between one in 6,000 and one in 1,000 women will undergo chemotherapy while pregnant, and NTP noted "nearly all" chemotherapy agents are toxic to the development of the fetus.

Another notice released in July 2012 noted NTP was working to study the effects of chemicals used in Leptospira vaccines and how they might affect their respective potencies. "The goal is to promote development of innovative testing methods and approaches that may provide improved accuracy, efficiency and worker safety and that are more humane and use fewer or no animals," NTP explained in a Federal Registernotice.

But in addition to specific problems, NTP is also focused on solving more general regulatory problems. For example, a June 2012 report noted that it is working with more than a dozen other agencies to reduce reliance on animal testing, instead shifting to the use of validated in chemico and in silico models of safety testing.

A subsequent October 2012 announcement indicated that NTP had adopted new classification criteria that it said would require between 50% and 83% fewer animals to be used in testing to determine if a chemical was harmful to a human eye.

A List of Genes

A new announcement, however, seeks to expand NTP's activities even more. The 29 July 2013 Federal Register announcement states that NTP is looking to "identify and prioritize a comprehensive list of environmentally responsive genes that might be targets for screening cells or tissues obtained from humans, rats, mice, zebrafish, and Caenorhabditis elegans against large numbers of substances."

"The goal is to generate a minimum list of 1000 genes for each species that would provide the maximal toxicogenomic information on (1) effects that reflect general cellular responses, independent of cell type or species, and (2) gene expression changes that are specific by organ and/or cell type," NTP added.

Animals like zebrafish are already widely used to conduct rapid screening on the toxicological effects of chemicals, and are particularly useful due to their extremely short maturation period. As NTP explains later in the notice, prioritized genes could be used to improve the usefulness of screening procedures and result in biomarker development and advance basic research across the industry.

The measure is part of a NTP-run program known as Tox21, which includes FDA, the Environmental Protection Agency (EPA) and the National Center for Advancing Translational Sciences (NCATS). The program, NTP explained, serves to research, develop, validate and translate testing methods for use in conducting research on the safety of chemicals.

In addition, "In keeping with the Tox21 goal of facilitating cross-species extrapolation, the NIEHS/NTP is especially interested in the nomination of genes or gene sets specifically relevant for comparisons between humans, rats, mice, zebrafish, and C. elegans and especially those for which complementary functional pathways exist," NTP explained. This research might come to assist life science companies with strengthening preclinical research programs, reducing the chance that a compound would fail for safety reasons once clinical testing began.

Responses are due to NTP by 23 August 2013.

Federal Register Announcement

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