Regulatory Research Agencies

NTP

Last Updated: August 3, 2014

The National Toxicology Program (NTP) was established by Congress in 1978 to address concerns about potential adverse human health effects from the growing burden of chemicals in the environment.

The National Toxicology Program Division of the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina, is home to the NTP.

NTP is an interagency program of 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)

The main goals of NTP are: (1) coordinating/conducting toxicology studies at the request of and to meet the needs of various government agencies, (2) toxicological methods development and validation, (3) developing approaches and data for risk assessments, and (4) communicating these results to stakeholders.

A major purpose of the NTP is to conduct research and toxicological studies used by federal and state regulatory agencies to protect the public from exposure to toxic and carcinogenic substances. NTP toxicology studies are primarily animal-based studies, and typically designed to provide agencies with hazard assessment and dose-response data used to develop risk assessments for regulated products. 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.

NTP was realigned within NIEHS in 2007, creating a new Program Office (now the Division Office) and five program branches. These changes were intended to facilitate meeting NTP’s mission and program goals. The current organizational structure is described below.

Division Office

  • Office of Liaison, Policy, and Review
  • Office of Nominations and Selection
  • Office of the Report on Carcinogens
  • NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)
  • Office of Health Assessment and Translation (OHAT)

NTP Program Branches and Laboratories

  • Toxicology Branch
  • Cellular and Molecular Pathology Branch
  • Program Operations Branch
  • NTP Laboratory
  • Biomolecular Screening Branch

The NTP uses four types of advisory boards and committees:

  • 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 Institute of Environmental Health Sciences (NIEHS)/NIH, and others.
  • NTP Board of Scientific Counselors: 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 the Report on Carcinogens Subcommittee and the Technical Reports Review Subcommittee.
  • 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 NICEATM.
Some NTP Centers and Programs

National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM): see section below.

Toxicology Testing in the 21st Century (Tox21) and High Throughput Screening program (HTS): see section below.

NTP Center for Phototoxicology: This program was established through an Interagency Agreement, and 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. As explained in the 2013-14 NCTR Annual Report (see page 8), animal studies in the presence of simulated solar light are used to assess the phototoxic and photocarcinogenic potential of substances.

NTP Office of Health Assessment and Translation (OHAT): OHAT replaced CERHR in early 2011, and was established to assess the evidence that substances “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 Tox21 and HTS.

Literature-based assessments of the existing data and other information on the toxicity of a substance have long been the starting point for a hazard and/or risk assessment by many toxicologists. NTP explains that their use of literature-based evaluations to explore potential human health hazards led to the decision to implement systematic review methodology. NTP “recognized the necessity to extend existing systematic review methods to accommodate [the] need in environmental health to integrate data from multiple evidence streams (human, animal, in vitro), and focus on observational human studies rather than on the randomized clinical trials (Birnbaum et al., 2013). OHAT developed the OHAT Evaluation Process, so that all systematic reviews would follow the same pre-specified approach to identifying, assessing, and interpreting data from existing studies. “The approach includes seven steps that provide a framework for incorporating systematic review and evidence integration into NTP literature-based, non-cancer health assessments.”

Nanotechnology Safety Initiative: This program 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 and animal toxicity studies (including dermal, inhalation, and systemic toxicity). The development of a battery of in vitro models to assess nanoscale material hazards was proposed by the NTP in 2006, but no longer appears to be part of the Nanotechnology Safety Initiative’s agenda [i.e., due to lack of any information on in vitro methods development or use of the website].

NTP Research Programs: Intramural research provides toxicological characterization of chemicals and other substances that are of concern to public health. NTP research programs of particular interest to in vitro toxicologists include: endocrine-disrupting agents, toxicogenomics, and nanotoxicology.

NTP Testing Program: NTP has 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. “The NTP evaluates substances for a variety of health-related effects, generally using rodent models for study and protocols specifically designed to fully characterize the toxic potential.” Even the test method section “Alternative Models in Toxicity Research” focuses on the use of genetically engineered/transgenic mouse strains in testing, and does not describe the use of any animal alternative model.

Substances appropriate for NTP toxicology studies include those that are: 1) a possible public health hazard based on significant human exposure and/or suspicion of toxicity, or 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 provides access to the results and testing status for all NTP studies. NTP study reports and toxicological databases provide a resource for scientists and toxicologists needing toxicity test data on substances already evaluated by the NTP; such sources can be used to reduce duplicative testing.

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

NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)

NICEATM was established in 1998 to provide administrative, technical, and scientific support to the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM).

The primary purpose of NICEATM and ICCVAM is to “reduce, refine, or replace the use of animals in testing, where feasible.” NICEATM and ICCVAM are the official government 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. Reorganization of NICEATM in 2013 assigned additional NTP activities to NICEATM.

NICEATM’s current mandate is described as: (a) providing ICCVAM scientific and operational support; (b) conducting and publishing analyses and evaluations of data from new testing approaches; and (c) providing information to stakeholders through the ICCVAM website, workshops, and symposia. NICEATM further supports NTP by: (a) conducting independent validation studies of priority alternative testing approaches, and (b) providing bioinformatics and computational toxicology support to the NTP Biomolecular Screening Branch and NIEHS Tox21 projects.

For more on NICEATM and ICCVAM:

Toxicology Testing in the 21st Century (Tox21)

Tox21 is an interagency collaboration involving NIEHS/NTP, the National Institutes of Health/National Chemical Genomics Center (NIH/NCGC), the Environmental Protection Agency (EPA), and the Food and Drug Administration (FDA).

The establishment of this program followed the development of the 2004 NTP strategic plan, A National Toxicology Program for the 21st Century (NTP Roadmap),which explains the NTP vision “to move 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.” A central theme in the NTP Roadmap activities “is to be mindful of the animal resources needed and strive to address the 3Rs effectively….”

The 2007 National Academy of Sciences report, Toxicity Testing in the 21st Century: A Vision and Strategy, from a scientific panel chartered by the US EPA, further supported the NTP Roadmap approach to revolutionizing toxicity testing. They “envisioned a not-so-distant future in which virtually all routine toxicity testing would be conducted in vitro on human cells or cell lines by evaluating perturbations of cellular responses in a suite of toxicity pathway assays using high throughput robotic assisted methodologies.”

The above reports outlined a new vision for 21st century toxicology, and also recognized the need for a large-scale, multi-agency, collaborative effort to achieve such a goal. Tox21 was established in response to this need. In February 2008, NTP entered into a formal interagency collaboration 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 represented the first substantive government effort to implement the vision of 21st century toxicology articulated in 2007.

NTP’s High Throughput Screening (HTS) program in the Biomolecular Screening Branch is part of this strategy. The HTS program uses in vitro biochemical- and cell-based assays and non-mammalian animal models in high-throughput or medium-throughput screening assays for toxicological testing. HTS allows for the screening of thousands of compounds/chemicals in many assays/endpoints in a short period of time. The initial goal of the HTS program has been to prioritize for further toxicological testing the many thousands of chemicals that are already in the marketplace/environment. Additional goals are to identify mechanistic targets and cellular pathways involved in adverse cell responses, and to identify possible links to in vivo adverse health effects such as carcinogenicity, developmental toxicity, and neurotoxicity.

NTP Animal Alternatives Policies & Actions

Animal Testing Policy

In 2004, the NTP defined a new Vision and Roadmap. “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.

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 and Tox21

The most important role of the NTP regarding the development, validation, and adoption of animal alternative test methods and policies is its role in coordinating and supporting NICEATM and ICCVAM. Certain other NTP programs, such as Tox21, have the potential to develop new methods/approaches for reducing animal use in toxicity testing. These programs are described elsewhere on this page.

Data Publication, Systematic Reviews, 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. Systematic reviews conducted by OHAT are another source for non-test, human hazard information developed by integrating existing human, animal, in vitro, and in silico data. The NTP participates in various international programs as another means for reducing duplicative testing.