Non-animal Methods for Toxicity Testing


Last Updated: March 1, 2012
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  • The US National Toxicology Program (NTP) was established in 1978 in response to increasing Congressional concern about adverse human health effects from chemicals in the environment.

    The mission of the NTP is to:

    • Coordinate toxicology testing programs within the federal government
    • Strengthen the science base in toxicology
    • Develop and validate improved testing methods
    • Provide information about potentially toxic chemicals to health, regulatory, and research agencies; scientific and medical communities; and the public

    The NTP conducts research and toxicological studies used by federal and state regulatory agencies to protect the public from exposure to toxic and carcinogenic substances. For example, the need to regulate a chemical to protect public health could be based upon NTP data. Since its inception, the NTP has conducted testing on more than 2,500 substances. The NTP also issues a biennial Report on Carcinogens that identifies known cancer-causing agents.

    Located at the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina, the NTP is an interagency program that comprises three federal agencies:

    • National Institute of Environmental Health Sciences of the National Institutes of Health (NIEHS/NIH)
    • National Institute for Occupational Safety and Health of the Centers for Disease Control and Prevention (NIOSH/CDC)
    • National Center for Toxicological Research of the Food and Drug Administration (NCTR/FDA)

    Voluntary allocations from these core agencies support the research and testing conducted by the NTP. The three major program activities of the NTP are toxicology studies, methods development, and methods validation, with targeted areas in each program activity, such as general toxicological characterizations, genetic toxicology, reproduction and development, and carcinogenesis.

    Effective October 28, 2007 the NTP was realigned within the NIEHS, creating a new Program Office and five program branches. These changes were intended to facilitate meeting NTP's mission and program goals. The new structure and some associated major activities are as follows:

    Program Office

    • Office of Liaison, Policy, and Review
    • Office of Nomination and Selection
    • Report on Carcinogens
    • NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)
    • Center for the Evaluation of Risks to Human Reproduction (CERHR)

    Toxicology Branch

    • Consolidates all toxicology efforts within NTP
    • Directs interagency agreements with the Food and Drug Administration's National Center for Toxicological Research
    • Directs interagency agreements with the Center for Disease Control and Prevention's National Institute for Occupational Safety and Health

    Cellular and Molecular Pathology Branch

    • Supports pathology and program archives
    • Supports pathology investigations by intramural researchers
    • Compiles an atlas of non-neoplastic lesions in rodents

    Program Operations Branch

    • Oversight of activities that support research and testing, such as: chemistry and ADME studies; quality assurance; and data storage
    • Oversight of the NTP web site

    Host Susceptibility Branch

    • Assessment of chemical toxicity in multiple murine strains
    • Establishment of collaborations among NTP and intramural and extramural investigators
    • Possible establishment of public-private partnerships to examine the genetic basis of environmental exposures and resulting clinical manifestations

    Bio-molecular Screening Branch

    • Development of high- and medium- throughput screening activities
    • Cooperative work with EPA's ToxCast program and the NIH Chemical Genomics Center to identify and evaluate in vitro and cell based high-throughput assays for screening and prioritizing chemicals for toxicity testing
    • Automated screening of C. elegans performed by the WormTox Group

    The NTP uses four types of external groups for peer review and advice:

    • NTP Executive Committee: Provides policy advice; members are representatives from US agencies including: Agency for Toxic Substances and Disease Registry (ATSDR)/CDC, Consumer Product Safety Commission (CPSC), Environmental Protection Agency (EPA), Food and Drug Administration (FDA), National Cancer Institute (NCI)/NIH, National Center for Environmental Health (NCEH)/CDC, National Institute of Environmental Health Sciences (NIEHS)/NIH, National Institutes of Health (NIH), National Institute for Occupational Safety and Health (NIOSH)/CDC, and Occupational Safety and Health Administration (OSHA)
    • NTP Board of Scientific Counselors (BSC): A federally chartered scientific advisory committee for advising the NTP director and evaluating the scientific merit of NTP programs and studies; subcommittees and working groups include: Report on Carcinogens Subcommittee, Technical Reports Review Subcommittee, Nanotechnology Working Group, and High Throughput Screening Working Group
    • Scientific Advisory Committee on Alternative Toxicological Methods (SACATM): A federally chartered advisory committee to advise the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), and the director of the NIEHS on statutory duties and activities regarding the validation and regulatory acceptance of new and revised toxicological test methods
    • Special Emphasis Panels (SEPs): Ad hoc panels of experts formed as needed and used to conduct independent scientific peer reviews and provide advice; SEPs include panels used by the Center for the Evaluation of Risks to Human Reproduction (CERHR) and NICEATM

    Relevant Programs

    Three NTP Centers

    NICEATM was established to provide scientific and administrative support to ICCVAM. The intended goal of NICEATM activities is to facilitate the scientific review, validation, and regulatory acceptance of new and revised toxicological test methods to address the mission of ICCVAM as defined by law. A primary purpose of NICEATM and ICCVAM is to "reduce, refine, or replace the use of animals in testing, where feasible." Test methods can be nominated to NICEATM for scientific review and validation.

    The NTP Center for Phototoxicology is located at the FDA/NCTR. Its mission is to assess the toxic and/or carcinogenic potential of substances when they are exposed to light. Chemicals are nominated for testing by the FDA, other federal agencies, or other NTP stakeholders.

    The NTP Office of Health Assessment and Translation (OHAT) replaced CERHR in early 2011, and was established to assesses the potential for substances to "cause adverse health effects" and to provide "opinions on whether these substances may be of concern given what is known about current human exposure levels." This broadened the scope of the original program to include all relevant health effects, while taking into consideration the utilization of information from the Toxicity Testing in the 21st Century initiative (such as linkages between "toxicity pathways" and disease outcomes) and two other NTP initiatives (the biomolecular screening program/High Throughput Screening Initiative and the host susceptibility program to study the genetic basis for differences in susceptibility). Chemicals are nominated for state-of-the-science OHAT assessments, which are published as NTP Monographs.

    NTP Toxicological Testing, Research, and Data

    The NTP Testing Program is part of a formal process for soliciting, reviewing, and selecting substances for toxicological studies. The public and private sectors may nominate a chemical for NTP testing, although most substances are nominated by federal agencies. Industry is expected to evaluate the health and environmental hazards of substances they produce, as mandated by Congress. Substances appropriate for NTP studies include those that are: 1) a possible public health hazard based on significant human exposure and/or suspicion of toxicity; and 2) an unknown human risk due to toxicological data gaps. The NTP also accepts nominations for studies to obtain other types of toxicological data such as determining mechanisms of toxicity or filling a gap in knowledge about the toxicity of a class of chemical. A search page and the Management Status Report provide access to the results and testing status for all NTP studies.

    NTP Research Programs provide toxicological characterization of chemicals and other substances that are of concern to public health. The present list of toxicological research programs includes several of particular interest to in vitro toxicologists, such as endocrine-disrupting agents, toxicogenomics, and phototoxicology.

    NTP study reports and toxicological databases provide a resource for scientists and toxicologists needing toxicity test data on substances already evaluated by the NTP; the sources can be used to reduce duplicative testing.

    The biennial Report on Carcinogens lists known human carcinogens and substances reasonably anticipated to be human carcinogens to which significant human exposure occurs in the US.

    The High Throughput Screening (HTS) program was established in 2005 to identify automated processes using in vitro systems that can be used to rapidly evaluate the toxicity of many substances. The NTP identified three purposes for obtaining HTS data: "to identify mechanisms of action for further investigation, develop predictive models about how substances might react in biological systems, and prioritize substances for more extensive toxicological evaluation." After several years of in-house work and informal collaborations, NTP entered into a formal interagency collaboration in February 2008 by signing a memorandum of understanding with the Environmental Protection Agency and National Institutes of Health Chemical Genomics Center outlining a strategy for "the research, development, validation, and translation of new and innovative test methods that characterize key steps in toxicity pathways." This represents the first substantive effort by the US federal government to implement the vision of 21st century toxicology articulated in 2007 by the National Research Council.

    The Nanotechnology Safety Initiative was established to investigate the potential human health hazards of nanoscale materials. Owing to the unique size and properties of nanoscale materials and the anticipated growth in their use, the NTP is interested in their toxicological properties and interaction with biological systems. The NTP's approach involves characterization of physiochemical properties, animal toxicity studies (including dermal, inhalation, and systemic toxicity), and in vitro studies. A battery of in vitro models will be developed "to assess whether in vitro methods can predict which nanoscale materials might be a hazard for animals or people." 

    Alternatives Policies & Actions

    Animal Testing Policy

    The NTP Roadmap (page 4) describes the principles emphasized at NTP regarding the use of animals in toxicity testing: "The NTP currently emphasizes in the design of its studies full incorporation of the three principle concepts of alternatives-replacement, reduction, and refinement. Further, to be consistent with the Animal Welfare Act and the Public Health Service rules on animal use, the NTP requires that all animal studies be designed to eliminate or, at least, minimize any potential pain or distress. The NTP also requires that investigators and/or contractors have training in humane experimental techniques and, as possible, promotes the use of non-invasive approaches in animal studies. The NTP will hold to these principles and practices as it implements the NTP Roadmap."

    The NTP Roadmap (page 9) states that "A central theme in all these activities is to be mindful of the animal resources needed and strive to address the 3Rs effectively - reduce the number of animals used in these research programs, refine the endpoints to derive the maximum amount of information possible with the minimum amount of pain and suffering, and replace species currently used with lower species or in vitro systems."

    Home of NICEATM

    The most important role of the NTP regarding "alternatives policies & actions" is its involvement with NICEATM and ICCVAM. The NTP established NICEATM in 1998 to support the activities of ICCVAM. NICEATM and ICCVAM are the authorized bodies in the US for conducting the scientific review and validation of new and revised toxicological test methods. They also facilitate US regulatory acceptance and coordinate activities with international organizations. Further information can be found here: NICEATM-ICCVAM.

    The NTP Vision and Roadmap for the 21st Century

    "The NTP Vision for the 21st Century is to support the evolution of toxicology from a predominantly observational science at the level of disease-specific models to a predominantly predictive science focused upon a broad inclusion of target-specific, mechanism-based, biological observations." The NTP Roadmap is the plan for implementing this vision by incorporating scientific advancements and mechanistic approaches into NTP toxicology assessments.

    Data Publication and International Collaborations

    The NTP uses several methods to facilitate the reduction of duplicative toxicological testing. NTP study reports and toxicological databases provide a resource for scientists and toxicologists needing test data. Free electronic access to historical, chemical toxicity test data can prevent the unnecessary duplication of testing, and historical animal data could be useful in the validation of non-animal models. The NTP participates in various international programs as another means for reducing duplicative testing.