National Toxicology Program

Risk Assessment Research

A lack of knowledge in certain areas continues to hinder our ability to address important public health issues. Several areas of uncertainty in evaluations of human risk include: (1) the adequacy of animal models to detect all toxicologically-induced disease endpoints; (2) the adequacy of animal models to accurately reflect human risk (is human sensitivity similar to or different from that of experimental animals?); (3) the adequacy of mathematical models used to extrapolate high dose effects to environmental or occupational exposure levels; (4) human exposures to environmental toxicants; and (5) the extent of our understanding of the factors responsible for interindividual variability and the existence of sensitive subpopulations. Developing information in these areas, especially with greater use of the tools available in functional toxicology and the application of mechanistic knowledge, should strengthen the scientific basis for estimating health risks in human populations and thereby improve the decision-making process.

Recent legislative and government acts and authorities have called for improvements in risk assessment and prevention strategies. Because only a small percentage of the approximately 70,000 chemicals presently in commerce have been evaluated by traditional toxicity tests, such as the two-year rodent bioassay, large data gaps exist in evaluating human risk to many environmental agents. While good epidemiology studies provide direct information on adverse effects in humans, such studies are relatively insensitive and tend to detect an effect that has already occurred. A major challenge in environmental health sciences is the development of adequate toxicological information on more chemicals of public health importance while at the same time providing data that reduce uncertainty and strengthen the scientific foundation for estimating human risk. Toxicology, mechanistic studies, structure-activity relationships, and predictive toxicology can provide major sources of information for disease prevention strategies.

In the NTP there has been increasing emphasis on mechanism-based studies. The studies are designed for the following uses: (1) to more rapidly screen chemicals and set priorities for further studies (e.g., based on interactions with critical target genes); (2) to strengthen the scientific basis for evaluating potential hazards; (3) to characterize quantitative relationships between exposure, target organ dosimetry of parent compound or metabolites, and adverse effects; and (4) to understand and evaluate species, strain, and individual differences in susceptibility.

Continuing efforts include molecular epidemiologic studies of damage to critical target genes, such as DNA polymerase b gene (Pol b), which may be mutated in bladder and lung cancers. An upcoming collaborative study will look at the expression and activity of Pol b in one bladder cancer cell line for environmentally associated bladder cancer. Biomarkers have been gaining increasing importance in human exposure characterization. Beginning and ongoing efforts are to develop biomarkers of exposure to glycol ethers and perchloroethylene (a dry cleaning solvent). Another biomarker proposed is to develop an assay to assess DNA damage as a biomarker of effect of exposure, initially with workers exposed to asphalt fumes and/or pesticides. Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variations in susceptibility to cancer and other diseases. Studies continue to be focused on the cytochrome P450 (CYP) monooygenase, glutathione transferase, and 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 physiologic models for two toxicologically important chemicals, 1,3-butadiene and mercury (elemental) continues, and a series of models are being constructed to identify possible causes of renal accumulation of the protein, alpha-2 -microglobulin (a-2m) in male rats exposed to a-2m ligands.

Alternative Methods to Reduce, Refine, and Replace the Use of Animals

Program scientists consider alternative methods and models that may refine animal use to minimize pain and distress and improve animal well-being, that may reduce the number of animals required for toxicity studies, and that may replace traditional animal models with non-animal methods or with phylogenetically lower species. Nearly every new proposed testing method incorporates some aspect of animal use refinement, replacement, or reduction.

An integrated approach that includes computer modelling, in vitro methods, and laboratory animal models is used to assess the potential health effects of chemicals. While many of these established tests provide valuable information useful for human health risk assessment, improved alternative 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 our understanding of the molecular and cellular mechanisms of toxicity into new mechanistically-based testing methodologies. Such methods are expected to provide improved hazard identification and dose-response information. Many new alternative methods in some stage of development or validation by the NTP are described in this and other chapters of the Annual Plan.

New and revised test methods are developed and validated for different purposes, including: 1) as screening tests to provide information for preliminary decision-making and to set priorities for more definitive tests; 2) as adjunct tests to provide mechanistic information to assist in determining the relevance of the results from definitive tests; 3) as substitute tests to replace an existing definitive test method; and 4) as new definitive tests for toxicities for which there was no previous test methodology. The NTP continues to conduct validation studies on promising new methods to determine their usefulness in toxicological testing. Validation studies are conducted to evaluate usefulness of a new test method for a specified use. The utility of any such assay is predicated on confidence that the assay is measuring what it is intended to measure, and on the repeatability and reproducibility of the assay in and among laboratories. Scientific validation is a prerequisite for the eventual regulatory acceptance of new test methods.

The long-standing commitment of the NTP to alternative methods was recently strengthened by Public Law 103-43¹, which directed the NIEHS to 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 goal of the newly established NTP Interagency Center for The Evaluation of Alternative Toxicological Methods (the Center) working with the permanent Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) is to promote the scientific validation and regulatory acceptance of new test methods that are more predictive of human and ecological effects than currently available methods.

To achieve this goal, the Center will work with the ICCVAM to facilitate scientific peer review and interagency consideration of new test methods of multi-agency interest, and to facilitate communication with stakeholders. Emphasis is on toxicological test methods that will enhance agencies’ ability to assess risks and make decisions, and that will refine, reduce, and replace animal use whenever possible. Peer review panels will be convened to develop scientific consensus on the usefulness of test methods to generate information for specific human health and/or ecological risk assessment purposes, and will address how and when the new test method can partially or fully replace existing methods or approaches. In FY 1998, peer review will be carried out on the Mouse Local Lymph Node Assay, a method for assessing skin sensitivity potential of chemicals. A Federal Advisory Committee on Alternative Toxicological Methods was established to provide advice on the activities and priorities of the Center and the ICCVAM, and to provide advice on ways to foster partnership activities and productive interactions among all stakeholders. The first meeting of the Advisory Committee was held in September 1998.

SPECIAL ACTIVITIES

AIDS Program

In FY 1997, the NTP continued to collaborate 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. Planned studies include: 1) reproductive, developmental, and general toxicity of combination therapies in the B6C3F₁ mouse model; 2) toxicity of combination therapies in immunodeficient mouse models; 3) mechanisms involved in enhancement of toxicity of combination therapies; and 4) refinement of procedures for use of the monkey model for evaluation of neurotoxicity of antiretroviral and opportunistic infection therapies.

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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