Publications
NTP - FY 1997 Annual Plan Summary
Risk Assessment Research
A lack of knowledge in certain
areas continues to hinder our ability to address important public
health issues. Specifically: (1) there are inadequate models
for extrapolation from animals to humans, and from high doses
to low doses; (2) there are inadequate animal models for many
toxicologically-induced disease endpoints; (3) it is necessary
to develop a better understanding of the factors responsible for
the existence of sensitive subpopulations; and (4) it is necessary
to more fully exploit the tools available in functional toxicology.
Developing information in these areas will help in the application
of mechanistic knowledge to improve risk assessment methodology
and to develop more sensitive and specific tests. Taken together
these approaches will improve the ability to provide reliable
toxicologic evaluations.
Recent legislative and government acts and authorities have called for improvements in risk assessment and prevention strategies. The 1992 Advisory Review report of the NTP Board emphasized the need for more mechanism-based studies, and there has been increasing emphasis by NTP scientists over the past few years in incorporating mechanistic considerations in studies. The problem supporting the need is that of the approximately 70,000 chemicals presently in commerce, adequate toxicological data is available for only 10-20%. Although traditional toxicity tests such as the two-year rodent bioassay have been the basis for most regulatory decisions regarding the safety of environmental chemicals, only a limited number of the many thousands unstudied can be evaluated by this approach. Current risk assessment approaches frequently use default positions which reflect an inadequate scientific foundation for assessing risk. While good epidemiology studies are desirable, they are relatively insensitive and tend to detect an effect that has already occurred; toxicology, mechanistic, structure activity, and predictive toxicology studies can be part of a prevention strategy. Thus, the crux of the problem is at least two-fold - how can adequate toxicological information be developed on more chemicals of public health importance while at the same time providing data for strengthening the scientific foundation and reducing the uncertainty in the making of human risk estimates. Increasing knowledge of mechanisms can help in several ways.
An evolving NTP program in mechanism-based toxicology is drawing on the tools of molecular biology, which can characterize interactions of chemicals with critical target genes, to provide viable approaches for the development of more accurate and inexpensive methods to perform not only the first step in risk assessment, i.e., hazard identification, but also contribute to determining quantitative dose-response relationships and establishing biomarkers for estimation of human exposure. Thus, uses of mechanism-based toxicology will include: (1) to more rapidly screen chemicals and set priorities for further studies; (2) as a basis for reasonably assuming hazard (rebuttable presumption); (3) to determine quantitative dose-response relationships; (4) to understand species, strain, and individual differences in susceptibility; and (5) for species extrapolation. It should be stressed that increased uses of mechanistic data does not mean that the use of chronic rodent bioassays will be diminished.
Current efforts include molecular
epidemiologic studies of damage to critical target genes, such
as p53, in environmentally-associated cancers and studies of genetic
susceptibility and gene-environment interactions in disease risk.
Human genetic polymorphisms in metabolic activation and detoxification
pathways are a major source of inter-individual variation in susceptibility
to cancer and other disease endpoints associated with exposure
to drugs and foreign chemicals. Studies continue to be focused
on the cytochrome P450(CYP) mono-oxygenase enzyme systems, and
on the glutathione transferase and n-acetyltransferase enzyme
systems. There is an initiative on toxicokinetic and biochemical
modeling of hazardous agents which is designed to characterize
parameters of dose, distribution, metabolism, and elimination
of xenobiotics. Development of models for two toxicologically
important chemicals, 1,3-butadiene and mercury, are in progress.
This information can aid in the design and interpretation of
toxicology studies and strengthen the scientific basis for low-dose
extrapolation of risk to humans.
Alternative Methods to Reduce, Refine, and Replace the Use of Animals
Currently, assessment of the
potential adverse health effects of chemicals is accomplished
largely by tests utilizing traditional laboratory animal models.
While these established tests provide valuable information useful
for human health risk assessment, improved test methods are sought
that are more predictive of the potential for human toxicity,
that provide information more useful for quantitative risk assessment,
and that can be achieved in a shorter timeframe and with less
expense. Program scientists seek to integrate recent advances
in understanding the molecular and cellular mechanisms of toxicity
into new mechanistically-based alternative testing methodologies
that will provide improved hazard identification and dose-response
relationship information. In designing their scientific investigations,
program scientists also consider alternative methods that reduce
the number of animals required, that replace traditional animal
models with non-animal methods or with phylogenetically lower
species, and that refine procedures to improve animal well-being.
Nearly every new testing method developed or in development incorporates,
whenever scientifically feasible, some aspect of refinement, replacement,
or reduction.
The NTP has a long-standing record of developing, validating, and using alternative methods in its testing and research efforts. This commitment was strengthened by the 1993 NIH Revitalization Act1 which directed the NIEHS and the NIH to take specific actions to develop alternative methods and approaches to the use of animals in research and testing. The Act established within the NIEHS an Applied Toxicological Research and Testing Program and directed, with regard to alternative methods, that it carry out activities to: (1) develop and validate assays and protocols, including alternative methods that can reduce or eliminate the use of animals in acute or chronic safety testing; and (2) establish criteria for the validation and regulatory acceptance of alternative testing [methods] and to recommend a process through which scientifically validated alternative methods can be accepted for regulatory use. The Act also directed NIH to: (1) conduct or support research into methods that do not require the use of animals, that reduce the number of animals used, that produce less pain and distress in such animals, and that involve the use of marine life; (2) establish the validity and reliability of these methods; (3) encourage the acceptance by the scientific community of such methods that have been found to be valid and reliable; and (4) train scientists in the use of such methods that have been found to be valid and reliable.
The NIEHS has also initiated actions in response to the directive in the NIH Revitalization Act. The NIEHS considered it essential that staff from Federal agencies that generate or use toxicity testing data for regulatory decisions participate in the development of these criteria and recommendations. An ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) was established to establish criteria for the validation and regulatory acceptance of alternative testing methods and to recommend a process through which scientifically validated alternative methods can be accepted for regulatory use. The NIEHS and 14 other Federal regulatory and research agencies participated in this effort resulting in development of a draft report which was reviewed at an open NTP workshop in December 1995. The ICCVAM and workshop issued reports that included among their recommendations one that a permanent interagency coordinating committee be established and an Interagency Center for the Evaluation of Alternative Toxicological Methods also be established to support the activities of the permanent ICCVAM and an external Scientific Advisory Committee. During FY 1997, these recommendations are being carried out.
There have been significant advances in the use of alternative methods by the NTP. Tests using validated in vitro systems generally precede or complement whole-animal studies and provide some very precise and useful information, particularly in determining when additional testing is necessary and in prioritization of chemicals. In some cases, in vitro systems may be preferred, such as for early first-tier screening of chemicals, or later in the testing process as models to elucidate the mechanisms of in vivo carcinogenicity and toxicity. In vitro assays are crucial tools in evaluating the complexity of interactions that take place in a living animal. As in vitro technology improves, the use of these methods in conjunction with laboratory animal models will likely increase. For the toxicological studies that use whole animals, the NTP incorporates as many observations and measurements as possible on individual animals to minimize the number of animals used. Further, through judicious use of various prechronic studies, short-term in vitro assays, and evaluation of structure-activity relationships, decisions can be made that two-year rodent studies may not be necessary.
Agencies ensure the humane care, treatment, and use of laboratory animals during all phases of experimentation and testing. Institutional Animal Care and Use Committees review all proposed and ongoing animal care and use to assure compliance with the Animal Welfare Act and its amendments, as well as the Public Health Service Policy on the Humane Care and Use of Laboratory Animals.
The Program continues to seek methods that further enhance the well-being of animals used for toxicological testing and research. This includes refinement of procedures to eliminate or further minimize pain and/or distress, and methods or biomarkers that detect toxicity prior to the onset of morbidity or mortality. New information is also sought regarding the relevance of current testing models by further characterization of the similarities and differences with the human species. Such efforts are directed at identification and characterization of structural and functional attributes that will enhance the relevance of the test model and contribute to improved risk assessment.
The development and validation of new improved alternative test methods will enhance the Program's ability to predict the toxicity of chemicals and may also be more rapid and cost-effective. Alternative methods and approaches will further minimize the number of animals required for testing, incorporate refinements that will improve animal well-being, and increase the utilization of methodologies that do not require animals. Thus, both human health and animal welfare will benefit from this program.
Special Activities
AIDS ProgramIn FY 1996, the NTP collaborated with other programs of the NIEHS, other NIH institutes, other government agencies, and manufacturers developing antiretroviral drugs and drugs for opportunistic infections, to identify and study toxicities associated with AIDS therapeutics. Special emphasis is given to studying Reproductive and Developmental Toxicity, General Toxicity including Carcinogenesis, Immunotoxicity, and Neurotoxicity of these agents. Many of the ongoing and planned studies are with combination therapeutics. Reproductive and developmental toxicity studies in a pregnant mouse model and placental transfer and fetal disposition studies in a pregnant monkey model emphasize the importance of NIEHS research to women and the developing fetus as more women become infected with HIV and as the effect of AIDS therapies on the developing fetus becomes an increasingly important issue.
Thus, the National Toxicology Program through continuing and improving established applied toxicology programs while initiating new mechanism-based programs which draw on the tools of molecular biology and advances in predictive toxicology is successfully addressing public health problems under its purview, the cruxes of which are at least two-fold -- how can adequate toxicological information be developed on more chemicals of public health importance including better definition of what these chemicals are, while at the same time providing data for strengthening the scientific foundation and reducing the uncertainty in the making of human risk estimates.
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1Public Law 103-43, 42 U.S.C., National Institutes of Health Revitalization Act of 1993.
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