NTP Five-Year Plan Prioritizes Collaboration, Anticipates Tech Innovations

Interagency groups under the U.S. National Toxicology Program release their latest draft Five-Year Plan, which will push for adoption of new alternatives to animal tests and technologies to enhance methods.

Interagency groups under the U.S. National Institutes of Environmental Health Science's National Toxicology Program have released their 2013-2017 draft Five-Year Plan, which seeks to leverage recent momentum in non-animal testing methods to propel the development and adoption of new alternative strategies.

Announced in a June 13 Federal Register notice, the proposed plan is designed to guide the activities of the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) and the NTP's Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM).

The initiative builds on the groups’ 2008-2012 Five-Year Plan, zeroing in on “opportunities to achieve greater long-term progress in the three Rs [refining, reducing and replacing animal tests] by promoting emerging science and harnessing innovative technology,” the groups state in the proposal.

The draft plan has four primary goals:

• Promote the application and translation of innovative science and technology
• Advance alternative test methods and testing strategies
• Facilitate regulatory acceptance and use of alternative methods
• Develop and strengthen partnerships

The advancement of alternative test methods is critical given the EU's Seventh Amendment to the European Cosmetics Directive, which will ban the sale of cosmetic ingredients and finished products tested on animals by 2013.

In their recently released Biennial Progress Report, ICCVAM and NICEATM highlighted their contribution to 14 new and updated animal alternative test methods in 2010-2011 (Also see "NTP Touts 2010-2011 Achievements In Race To End Animal Testing" - HBW Insight, 18 Jun, 2012.).

In the Five-Year Plan, the groups say “substantial work remains to be done.”

Key Endpoints Identified

In the area of acute systemic toxicity testing, the Organization for Economic Cooperation and Development (OECD) has formally adopted a guidance document from ICCVAM and NICEATM for in-vitro methods to estimate starting doses that cut down on the number of animals used per test by up to 50%.

Over the next five years, ICCVAM and NICEATM will work to refine options for that endpoint, reviewing and providing recommendations for developing technologies, with a view toward fully eliminating the use of animals to assess acute dermal systemic toxicity.

Methods that are currently showing promise use two types of cultured liver cells to test for cytotoxicity endpoints. Such an approach would replace in-vivo oral-toxicity tests using rodents.

The replacement of rabbit tests to identify ocular corrosives and irritants is another area in which NTP feels it can make major inroads in coming years.

Under the NTP program's previous Five-Year Goal (2008-2012), the interagency groups made progress in validating and achieving regulatory acceptance for a number of test methods designed to replace rabbit tests, including the Cytosensor Microphysiometer method, which was the “first accepted” in-vitro test method by federal agencies under the NTP program that can be used instead of animals to determine whether a substance requires eye-hazard labeling, according to the groups.

However, “none of these methods, either used alone or in combination with other methods, is able to detect all the substances that can cause corrosive or severe ocular injury, as every evaluation of such approaches has resulted in an unacceptable number of false negative results,” the groups note in the draft.

“Therefore, the next five years will focus on in-vitro methods that fill these gaps in ocular testing,” they say.

ICCVAM and NICEATM also hope to make strides in testing for skin corrosivity and irritation. Although the groups have endorsed three in-vitro assays that use a 3D human skin model based on skin cells – including L'Oreal SA's commercially available EpiSkin – they note the tests do not replace animal tests altogether.

The human skin models reduce animal use insofar as substances they identify as corrosive do not require an animal test; however, some substances not flagged as corrosive still require animal testing.

“ICCVAM's ultimate goal in this area is the replacement of the rabbit skin test for both corrosivity and irritation with alternative methods that meet the requirements of U.S. regulators,” the draft plan states.

Other testing areas identified by ICCVAM and NICEATM as priorities include endocrine disruptors, reproductive and developmental toxicity testing and repeat dose and chronic toxicity/carcinogencity testing.

Communication Improvements Targeted

Another key objective under the new NTP Five-Year Plan is to facilitate the regulatory acceptance and use of alternative methods.

“Over the next five years, NICEATM and ICCVAM will continue to foster the use of alternative test methods by broadly communicating the outcomes of ICCVAM review activities and/or workshops via notices in the Federal Register, at national or international scientific meetings, via peer-reviewed journal publications, and at implementation and best practices workshops,” the interagency groups say in the draft plan.

Communication is vital to regulatory acceptance, they suggest. NICEATM, ICCVAM and the 15 agencies represented by ICCVAM will incorporate new communication strategies that leverage technologies and platforms including social media, webinars and podcasts to provide updated information on training opportunities for alternative test methods, the groups say.

NICEATM/ICCVAM suggest that strengthening partnerships with stakeholders is crucial to fulfilling its other goals outlined in the plan.

The groups aim to connect more effectively with national and international organizations that represent government and non-government sectors, including academia, industry and advocacy groups, among others.

ICCVAM will foster international collaboration, for example, by inviting experts from the international scientific community to serve on advisory panels and in workshops.

Technology's “Profound” Effect On 3Rs

ICCVAM and NICEATM note that innovations in science and technology will “profoundly affect” their mission and activities in coming years.

“Innovation is a powerful driver of progress in improved health and the 3Rs since innovative test methods and strategies potentially provide 'better' information (i.e. information that is potentially more relevant to human health and safety, less likely to miss important toxic effects and less expensive and time-consuming to acquire),” they assert in the plan.

The groups note that several “omics” research fields are converging to provide an integrated network that is “far more comprehensive” and predictive of toxicity than a single pathway or in-vitro method.

Omics is an umbrella term used to cover genomics, the study of gene activity and expression; proteomics, the study of proteins; and metabolomics, the study of how changes in genes and proteins translate to biochemical processes inside cells.

In the cosmetics industry, omics research is being led by companies including Procter & Gamble and L'Oreal, which are exploring the area for potential breakthroughs in skin and hair care (Also see "P&G Omics Research Yielding Breakthrough Skin, Hair Technologies" - HBW Insight, 4 Jul, 2011.).

The interagency entities also believe that progress will be made in the use of in-vitro and in-silico (via computer simulation) technologies to better predict the safety or hazards of uncharacterized chemicals and chemical mixtures through Tox21, an interagency collaboration between NTP, EPA, FDA and NIH, intended to characterize toxicity pathways.

Tox21 is a robotic technology being used to profile approximately 10,000 consumer-product ingredients, food additives and other chemicals through a battery of high-throughput cellular and biochemical assays. The initiative should provide valuable insight into chemicals' potential to affect biological pathways and result in toxicity, the NTP groups say.

Meanwhile, L’Oreal is working alongside EPA to gauge the usefulness of the agency's Chemical Toxicity Forecaster (ToxCast) chemical screening platform in predicting the toxicity of cosmetic substances (Also see "L'Oreal/EPA Partnership Could Expand Non-Animal Test Strategies" - HBW Insight, 19 Mar, 2012.).

ICCVAM and NICEATM state that toxicology databases such as ToxCast will be “essential” for capturing, analyzing and providing access to all of the data generated from new approaches to safety testing.

“The volume and breadth of potentially relevant science and the number of substances being evaluated are too large to be managed without extensive informatics support,” they note.

Public comments on the draft plan will be accepted through Aug. 13, 2012 on the NICEATM-ICCVAM website at iccvam.niehs.nih.gov/docs/5yearplan.htm.