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OVERVIEW OF THE NATIONAL TOXICOLOGY PROGRAM

MISSION AND GOALS

ORGANIZATIONAL STRUCTURE AND OVERSIGHT

TOXICOLOGICAL EVALUATIONS

HERBAL MEDICINES

SAFE DRINKING WATER

EMERGING RESEARCH STRATEGIES

MECHANISM-BASED TOXICOLOGY AND RISK ASSESSMENT METHODOLOGIES

Transgenic Animals

Risk Assessment Methodology

HUMAN EXPOSURE ASSESSMENT

Assessment of Endocrine Disruptors

Human Exposure Assessment and Environmental Disease Workshop

REPORT ON CARCINOGENS

NEW NTP CENTERS

THE CENTER FOR THE EVALUATION OF ALTERNATIVE TOXICOLOGICAL METHODS

THE CENTER FOR THE EVALUATION OF RISKS TO HUMAN REPRODUCTION

COMMUNICATION AND PUBLIC OUTREACH

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Overview of the National Toxicology Program

Mission and Goals

Today more than 80,000 chemicals are used in the United States and an estimated 2,000 new ones are introduced annually to be used in products we

encounter in our daily lives such as foods, personal care products, prescription drugs, household cleaners, and lawn care products. The effects of many of

these chemicals on human health are unknown, yet people and our environment may be exposed to them during their manufacture, distribution, use, and

disposal or as pollutants in our air, water, or soil. While relatively few such chemicals are thought to pose a significant risk to human health, the safeguarding

of public health depends upon identifying the effects of these chemicals and the levels of exposure at which they may become potentially hazardous to

humans.

The National Toxicology Program (NTP) was established by the Department of Health and Human Services (DHHS) in 1978 and charged with coordinating

toxicological testing programs within the Public Health Service of the Department; strengthening the science base in toxicology; and providing information

about potentially toxic chemicals to health regulatory and research agencies, scientific and medical communities, and the public. The NTP is an interagency

program whose mission is to evaluate agents of public health concern by developing and applying the tools of modern toxicology and molecular biology. In

carrying out its mission, the NTP has several goals:

to provide toxicological evaluations of substances of public health concern,

to develop and validate improved (sensitive, specific, rapid) testing methods,

to develop approaches and generate data to strengthen the science base for risk assessment, and

to communicate with all stakeholders including government, industry, academia, the environmental community, and the public.

The Program uses these goals to set priorities as it moves forward to improve the nations ability to evaluate human health effects from chemical exposures.

Its vision, leadership, and commitment to the concept of good science for good decisions have created an atmosphere that allows the NTP to be flexible and

innovative in its approach toward addressing public health concerns related to chemical exposures at home and work and in our environment. Nationally, the

NTP rodent bioassay is recognized as the standard for identification of carcinogenic agents. However, the NTP has expanded its scope beyond cancer to

include examining the impact of chemicals on non-cancer toxicities such as those affecting reproduction and development, inhalation, and the immune,

respiratory, and nervous systems. In this effort, The Center for Evaluation of Risks to Human Reproduction was created (see page 18). The NTP has also

worked to reduce the use of experimental animals and to develop and validate alternative testing methods leading to creation of The Center for the Evaluation

of Alternative Toxicological Methods (see page 16).

The strengthening of existing partnerships and the forging of new ones are important to the NTPs achievement of its goals. Partnerships with sister Federal

agencies are increasing and the NTP continues to seek ones with the private sector. Examples include co-sponsorship of numerous workshops, an interagency

initiative in exposure assessment, and establishment of an interagency committee to oversee validation of alternative testing methods. The NTP recognizes

that initiatives, which address critical knowledge gaps in toxicological evaluation, offer the best opportunities for preventing environmentally mediated

diseases. Therefore, the Programs testing of chemicals is evolving to include more mechanism-based toxicology studies (see page 11) that focus on

understanding the mechanistic actions of chemical agents. The NTP also recognizes that the use of human data in toxicological evaluations is imperative in

order to be at the forefront in studying and developing risk assessment methodologies for quantifying the sequence of events that starts with chemical

exposure and ends with toxicity. A new initiative in human exposure assessment (see page 13) contributes to this effort. During the next year, the NTP is

embarking on a process aimed at defining how the NTP can best meet critical issues in public health as we begin the new millennium. This process will

involve our partners in the scientific community, industry, and the public sector and will lead to a White Paper on NTP priorities and initiatives. Looking

forward, the NTP is evolving to remain at the cutting edge of science as a means to meet its commitment to good science for good decisions.

Organizational Structure and Oversight

Three agencies, the National Institute of Environmental Health Sciences of the National Institutes of Health (NIEHS/NIH), the National Institute for

Occupational Safety and Health of the Centers for Disease Control and Prevention (NIOSH/CDC), and the National Center for Toxicological Research of the

Food and Drug Administration (NCTR/FDA) form the core for this program (Figure 1). The NTP is located administratively at the NIEHS/NIH and the

Director of the NIEHS/NIH, Dr. Kenneth Olden, serves as Director of the NTP and as such reports to the Secretary, DHHS. The National Cancer Institute of

the National Institutes of Health (NCI/NIH) was a charter agency and continues to serve on the NTP Executive Committee.

The NTP Executive Committee provides oversight to the NTP for policy issues. This committee is composed of the heads of participating DHHS agencies

including the Agency for Toxic Substances and Disease Registry (ATSDR), the Food and Drug Administration (FDA), National Center for Environmental

Health of the CDC (NCEH/CDC), NCI/NIH, NIEHS/NIH, NIH, and NIOSH/CDC as well as the heads of several non-DHHS agencies that are concerned

with human health including the Consumer Product Safety Commission (CPCS), the Environmental Protection Agency (EPA), and the Occupational Safety

and Health Administration of the Department of Labor (OSHA).

The NTP Board of Scientific Counselors, which is composed of scientists from the public and private sectors, provides primary scientific oversight. The

Boards Technical Reports Review Subcommittee provides peer review of NTP long-term toxicity, carcinogenesis, and short-term toxicity study reports. The

Report on Carcinogens Subcommittee provides external scientific evaluation of substances nominated for listing in or delisting from the Report on

Carcinogens. The Advisory Committee on Alternative Toxicological Methods provides oversight to The Center for the Evaluation of Alternative

Toxicological Methods.

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Role in Shaping Public Health Policy

Scientific information from multiple sources forms a core upon which regulatory agencies make decisions regarding public health (Figure 2). Over the past

20 years the NTP has maintained an interactive relationship with regulatory agencies and indirectly played a role in setting public health policy. The Program

maintains an objective, science-based approach for dealing with critical issues in toxicology that has had a profound impact on building a strong link between

use of scientific data and establishment of regulatory guidelines and public health decisions. The overarching motivation of the Program is to use the best

science possible in setting priorities, designing and conducting studies, and reporting results in an objective way that best meets the needs of the public and

regulatory agencies. Effective and timely communication with regulatory agencies, the scientific community, and the public is also an integral part of these

efforts.

The American people and government agencies at the State and Federal levels rely on the science base provided by the NTP in making credible decisions that

will protect public health without necessarily increasing the regulatory burden on American industry. The NTP contributes to this process through the

generation of scientific data from the conduct of toxicological studies and through its interactive role with regulatory agencies in interpretation of those data.

A significant contribution to public health policy is publication of the Report on Carcinogens (see page 14), a hazard identification document that lists

potentially carcinogenic substances to which the public is exposed.

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Selected reading

1. Lucier, GW, Barrett JC. Public health policy and the National Toxicology Program (editorial). Environmental Health Perspectives 106(10):A470-471 (1998).

2. Fisher BE. Twenty years of toxicology. Environmental Health Perspectives 106(10):A480-487 (1998).

Toxicological Evaluations

In keeping with its goal of providing up-to-date information about chemicals and potential toxicities, the NTP can initiate chronic bioassays (approximately

10 per year) on only a small fraction of the thousands of chemicals for which there is little or no toxicological information. The cancer studies are lengthy,

can cost approximately $2-4 million each, and may take up to five years from initiation through completion and review. Many more chemicals are also

studied to assess a variety of health-related effects, including but not limited to reproduction and development, immunotoxicity, neurotoxicity, genotoxicity,

metabolism, toxicity to various organs, and carcinogenesis. The possible public health consequences of exposure remain the overriding factor in the decision

to study a particular chemical or agent.

The NTP strives to balance the selection of chemicals for study (e.g. occupational, environmental, food additives, agricultural chemicals, pharmaceuticals). In

selecting chemicals for study, the NTP Executive Committee operates under the principle that industry will evaluate chemicals or other agents for health and

environmental impacts as intended and mandated by Congress under legislative authorities. Chemicals are selected based upon two broad criteria: 1) those

chemicals of greatest concern for public or occupational health and 2) chemicals for which toxicologic data is needed to fill major knowledge gaps, address

mechanisms of toxicity, and reduce uncertainty in risk assessment. The specific categories for which the NTP solicits nominations are given in Table 1.

Nominations are sought from academia, Federal and State regulatory agencies, industry, unions, environmental groups, and the public. Toxic release

inventories and exposure surveys (e.g. National Health and Nutrition Examination Surveys (NHANES) and National Human Exposure Assessment Survey

(NHEXAS) are also reviewed to identify chemicals of concern based upon the opportunity for identifying human exposure and body burden data.

Table 1

Categories for NTP Solicitations

Chemicals found in the environment not closely associated with a single commercial organization

Biological or physical agents that may not be adequately evaluated without Federal involvement

Orphan drugs or chemicals with significant exposure that generate too little revenue to support further evaluations

Chemical agents first marketed prior to current testing requirements (e.g. 1977 Toxic Substances Control Act)

Substances that occur as mixtures for which evaluations cannot be required of industry

Chemicals or agents that will aid the understanding of chemical toxicities or an understanding of the use of test systems to evaluate

potential toxicities

Emergencies or other events that warrant immediate government evaluation of a chemical or agent

A schematic of the chemical nomination process is given in Figure 3. An interagency working group drawn from the NTP Executive Committee member

agencies reviews the chemical nominations. Public comment is solicited on the list of nominees throughout the process. At a public meeting, the NTP Board

of Scientific Counselors reviews the recommendations from the working group and accepts public comments. The NTP Executive Committee then reviews

and and votes on the chemicals recommended for study, deferral, or withdrawal. The selection of a chemical or agent by the Executive Committee does not

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automatically commit the NTP to its evaluation. The priority of the chemicals and the proposed studies are assessed during the nomination process and

reassessed during the study design process. During any of these stages, a chemical or study may be withdrawn if applicable research data is identified, higher

priority studies are identified, or if a study proves impractical.

For all selected chemicals, studies are initiated as time and resources permit. Prechronic, short-term studies generally are performed for two or 13 weeks.

Long-term, chronic bioassays last up to two years. The NIEHS/NTP staff reviews the toxicology literature for each chemical and designs a comprehensive

testing strategy. Project plans are reviewed by a NIEHS/NTP project review committee that evaluates the project plan (e.g. design, methods, hypothesis, etc.)

and proposed the vehicle for execution (e.g. grant, contract, etc). The NIEHS/NIH toxicokinetics faculty examines all chemicals under study and delineates

any areas of chemical metabolism and kinetics for which sufficient data are lacking; studies are designed to address these deficiencies. The results of

toxicological studies undergo rigorous peer review. These findings are published in NTP Technical Reports and may also be published in peer reviewed

scientific journals. The NTP Technical Reports Review Subcommittee, a standing subcommittee of the NTP Board of Scientific Counselors, evaluates the

technical reports from carcinogenicity and toxicity studies. Studies peer reviewed in fiscal year 1999 are listed in Table 2.

Table 2

Chemicals Peer Reviewed by the

NTP Board Technical Reports Review Subcommittee

Peer Reviewed on October 30, 1998 Peer Reviewed on May 21, 1999

Triethanolamine Anthraquinone

Methyleugenol Emodin

Ethylene Glycol Monobutyl Ether Fumonisin B1

Oxymetholone Gallium Arsenide

Glutaraldehyde

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Public input at these meetings is very important as it is at all phases of study design, performance, and review. NTP Technical Reports are available to the

public and other interested parties (see page 20).

The NTP has a broad mandate to provide toxicological characterizations for chemicals and agents of public health concern. The chemicals recommended for

study most recently by the NTP Executive Committee are given in Table 3. The NTP works on a broad range of high priority agents and issues. During the

past six years, the NTP has been involved in the Congressionally-mandated evaluation of possible human health effects resulting from exposure to electric

and magnetic fields that are associated with the generation, distribution, and use of electric power. In 1998, the NTP completed and reviewed the results from

a two-year bioassay of whole body exposure to magnetic fields in rodents (1-2). The NTP has performed or is performing toxicological evaluations of

pharmaceutical agents such as phenolphthalein (the active ingredient in some over-the-counter laxatives) and natural products such as fumonisin and a series

of phytol and fungal estrogens. The NTP is working to determine the relationships between ecological/wildlife effects and human health. Specifically, the

NTP is collaborating with the State of Minnesota and other State and Federal agencies to determine if the high incidence of malformed frogs found in several

states is associated with increases in human disease. Examples of two new initiatives, the characterization of potential adverse health effects from dietary

supplements and herbal medicines and an assessment of the risk of exposure to the major drinking water disinfection by-products, are described below.

Table 3

Chemicals Approved for Study by the NTP Executive Committee

Approved December 16, 1998

Approved February 24, 1999

Annatto Androstenedione

Bixin Bentonite

Diethylamine Bis (2-chloromethoxy) methane

Dihydroxyacetone Chromium picolinate

Fenchone Cumene hydroperoxide

Isopropylamine Echinacea

Pulegone Fluasterone

a-Solanine Ginkgo

Thujone Pyrogallol

Triethylamine

Trigonelline

References

McCormick DL, Ryan BM, Findlay JC, Gauger JR, Johnson TR, Morrissey RL, Boorman GA. Exposure to 60 Hz magnetic fields and risk of lymphoma in PIM transgenic and TSG-p53

(p53 knockout) mice. Carcinogenesis19(9):1649-1653 (1998).

1. 

NTP. Toxicology and Carcinogenesis Studies of 60-Hz Magnetic Fields in F344/N Rats and B6C3F1 Mice (Whole Body Exposure Studies). Technical Report Series No. 488 NIH

Publication No. 98-3978. Research Triangle Park: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Toxicology Program,

1998.

2. 

Herbal Medicines

Medicinal herbs are some of our oldest medicines and their increasing use in recent years is evidence of a public interest in having alternatives to

conventional medicine. Herbal medicines currently account for one of the fastest growing markets in U.S. pharmacies and constitute a multi-billion dollar

industry. Although approximately 1500 botanicals are sold as dietary supplements or ethnic traditional medicines, herbal formulations are not subject to FDA

premarket toxicity testing to assure their safety or efficacy.

In response to concerns regarding the use and efficacy of medicinal herbs and to recent nominations of these products for study by the NTP, a workshop on

herbal medicines was organized to address research needs. This workshop was sponsored by the NTP in conjunction with the NIH Office of Dietary

Supplements, the DHHS Office of Disease Prevention and Health Promotion, the FDA Office of Special Nutrition, and the Society for the Advancement of

Womens Health Research and held 23-24 September 1998 in Raleigh, NC. Its objectives were to discuss the use, safety, and possible health-related problems

of medicinal herbs; identify how other countries evaluate and regulate medicinal herbs; establish the NTPs role in determining their long-term safety; and

recommend areas for research. A broader objective of the meeting was the focus and coordination of U.S./international research efforts. Recommendations

from the workshop include a call for more research, identification and standardization of product ingredients by industry, and increased consumer education

through package inserts (1).

In follow-up to this workshop, the NTP staff is working with the NIH Office of Dietary Supplements, the FDA, the academic community, and others to

further define and implement research that addresses deficiencies in our knowledge about herbal medicines and their potential toxicities. Several herbs and

active or toxic ingredients found in some herbs have been nominated and selected for study by the NTP (Table 4). These studies will focus on

characterization of potential adverse health effects including reproductive toxicity, neurotoxicity, and immunotoxicity as well as those associated with acute

high dose exposure and chronic exposure to lower doses. In addition, special attention will be given to the potential for herb/herb and herb/drug interactions

and the responses of sensitive subpopulations (e.g. pregnant women, the young, the developing fetus, the elderly, etc). Comments from the public and others

regarding NTP research in this area are welcome and should be forwarded to the NTP Liaison and Scientific Review Office (see page 19).

Table 4

Herbs and Active or Toxic Ingredients for Study by the NTP

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Herb or

Ingredient

Information

Golden Seal Second or third most popular medicinal herb used in this country

Comfrey Herb consumed in teas and as fresh leaves for salads; contains pyrrolizidine alkaloids, which are known to be

toxic

Ginkgo Among the five or six most frequently used medicinal herbs

Echinacea Most commonly used medicinal herb in the United States

Berberine An active ingredient in golden seal

Thujone A toxic compound of worm wood

Pulegone A toxic compound found in pennyroyal

Reference

1. Herbal Health. Environmental Health Perspectives 106(12): A590-592 (1998).

Safe Drinking Water

The availability of safe drinking water is a substantive health concern. Chlorination of our water supply is a standard treatment technique and is considered as

one of the major public health advances in this century. Despite almost two decades of research, questions remain about the potential hazards of disinfection

by-products (DBP) that are produced during this treatment process and found in our water supply. The NTPs studies, which include the use of transgenic

animals and mechanistic studies, will determine which of the by-products are safe and which are dangerous. This information will facilitate development of

strategies to maximize the benefits of disinfection and minimize the risks.

The Safe Water Drinking Program is of enormous public health significance since it is estimated that more than 200 million Americans use treated drinking

water. The NTP in collaboration with the EPA has established a research program to assess the potential risks from human exposure to the major DBPs. The

research program includes a systematic, mechanistic-based, toxicologic evaluation of DBPs that can help policy makers in setting drinking water standards.

Research efforts are also underway with the Department of Defense (DOD), and the NIEHS/NTP is interested in involving the extramural research

community in this effort through support of hypothesis-based mechanistic studies.

The selection of DBPs for study is based upon their presence in drinking water, their occurrence with different disinfection processes, their chemical

structure, and representation from among the different DPB families. Research will focus on reproductive toxicity, immunotoxicity, and neurotoxicity as well

as carcinogenesis. Many of the reproductive studies include toxicity and cell proliferation end-points. Traditional animal models, such as the F344 rats and

B6C3F1 mice, are being used as well as transgenic strains (Tg.AC and p53def, see page 11). A brief description of the testing strategy is provided.

Studies are underway with DOD to test chloroform, a member of the halomethane family, in the small fish model, Medaka. Information from this

model may help to provide information on health effects at low concentrations in water, an area that is still unresolved despite numerous long-term and

mechanistic study on this chemical. NTP drinking water studies are underway to characterize the intestinal, renal, and liver responses to low

concentrations of bromodichloromethane, a trihalomethane, in male rats and female mice. A transgenic mouse sensitive to colon cancer is also being

used. Studies in collaboration with NIEHS/NIH will also be conducted in transgenic models (Tg.AC and p53def ) and with DOD in Medaka fish.

Another family formed after chlorination is the haloacetic acids. Members of this family are being evaluated by NIEHS/NIH in F344 rats and B6C3F1

mice in short-term toxicity studies. Based upon these results, several haloacetic acids will be selected for long-term bioassays.

Very little toxicity data is available on a third family of DBPs, the haloacetonitriles. Dibromoacetonitrile is selected as representative of this family;

based upon the results, additional members may be evaluated.

Preliminary studies at EPA and NIEHS/NIH show that chlorate, a by-product of chlorine dioxide, causes thyroid follicular cell hyperplasia in rats after

short-term exposure. Mechanistic studies are underway at EPA to determine if chlorate interferes with iodine uptake by the thyroid. A two-year rodent

bioassay is also underway at NIEHS/NIH, and DOD is evaluating chlorate in the Medaka fish model.

Ozone use in water disinfection prevents the production of many DPBs, but a major by-product is bromate. EPAs testing of bromate in drinking water

showed evidence of mesotheliomas in rats and kidney tumors in both rats and mice; potassium bromate feeding studies caused renal cancer in rats.

Sodium bromate in drinking water is being evaluated in transgenic models (Tg.AC and p53def); further mechanistic studies may be considered.

Emerging Research Strategies

A large number of chemicals (>80,000) are currently in use. The NTP continually faces the task of determining which ones should be studied with the limited

resources available for toxicological testing. As a consequence, the NTP must set its priorities and develop strategies that best use its resources in ways that

strengthen the science base used by regulatory agencies in making decisions for public health policy. It is clear that regulatory agencies, such as the EPA, are

committed to using all relevant information in their assessments. Implementing new strategies, which provide additional information and/or are more

accurate, can strengthen the science base on which regulatory decisions are made. The NTP has a strong and continuing commitment to increase the number

of agents entered into toxicology and carcinogenesis studies. New methods, especially those that provide mechanistic data, may also allow for more rapid

screening and decreased dependence on chronic two-year rodent bioassays.

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Scientists at the NIEHS/NIH, NCTR/FDA, and NIOSH/CDC are involved in development and validation of a wide range of testing methods for toxicological

research including transgenic animals for carcinogenicity testing and genetically engineered cell systems to measure endocrine disruptor activity.

University-based researchers are also involved in this effort through the NIEHS/NIH extramural grants program. Model systems under development include

non-mammalian species, transgenic species, genetically engineered in vitro cell systems, microchip array technology, and computer-based predictive

toxicology models.

Mechanism-Based Toxicology and Risk Assessment Methodologies

As a leader in the design, conduct, and evaluation of toxicological data for use in making public health decisions, the NTP's testing program is committed to

the use of mechanism-based toxicology studies as an enhancement to the traditional approaches. This field uses molecular biology tools to characterize

interactions of chemicals with critical target genes. Examples of mechanism-based toxicology include identification of receptor-mediated toxicants, molecular

screening strategies, use of transgenic animal models (see below) and the development of alternative or complementary in vivo tests to use with rodent

bioassays. Inclusion of such strategies can provide insight into the molecular and biological events associated with a chemical's toxic effect and provide

mechanistic information that is useful in assessing human risk. Such information can also lead to the development of more specific and sensitive (and often

less expensive) tests for use in risk assessment. There is a strong linkage between mechanism-based toxicology and the development of more biologically

based risk assessment models. Such models are useful in clarifying dose-response relationships, making species comparisons, and identifying sources of

inter-individual variability (see below).

Transgenic Animals

Genetically altered or "transgenic" mouse models carry activated oncogenes or inactivated tumor suppressor genes known to be involved in the neoplastic

processes both in humans and rodents. This trait may allow them to respond to carcinogens more quickly than conventional rodent strains. The advantage

provided by such an approach over standard rodent models is that in addition to chemicals undergoing metabolism, distribution, and relevant

pharmacokinetics, the neoplastic effects of agents can be observed in the transgenic models within a time frame in which few if any spontaneous tumors

would arise. The high incidences of spontaneous or background tumors, which occur most often late in the two-year rodent cancer studies, are among the

most confounding factors for interpreting the findings of chemical carcinogenesis and their implications for human health. It is proposed that this problem

would be reduced through the use of transgenic models, since the likely genetic targets for the effects of chemicals are highly conserved oncogenes or tumor

suppressor genes as opposed to the many potentially unidentified genes that contribute to the carcinogenic response in conventional rodent lines (1). The use

of target or reporter genes also allows for direct molecular and cellular analysis of a chemicals effects in these models and can provide additional mechanistic

information about mode of action.

Over the past few years, the NIEHS/NTP has conducted an evaluation of transgenic strains in toxicological testing strategies. The response for 38 chemicals

was compared in two genetically altered mouse strains (p53def: p53+/-heterozygous and Tg.AC: v-Ha-ras transgene) with that of wild-type mice tested in

chronic two-year bioassays. Findings from these studies (2) were evaluated by the NTP Board of Scientific Counselors on 5 February 1998 (3) for their

suitability for use in NTP toxicological evaluations. Based upon the NIEHS/NTP review, the transgenic models performed largely according to predictions;

they identified all known human carcinogens and most of the multi-site/multi-species rodent carcinogens, but failed to identify completely rodent carcinogens

that produced tumors in selected organs in two-year studies.

The use of these genetically altered mouse models holds promise in carcinogenesis research and testing and clearly is more rapid and less expensive than

traditional NTP two-year bioassay studies. The challenge still facing the NTP is to design studies that address remaining questions and concerns and to

explore how these models can be used in risk assessment (4). One current NTP project is examining tumor dose-response relationships of 2,3,7,8-

tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and diethylstilbestrol in the Tg.AC mouse. Comparative toxicokinetic studies in transgenic models and parental

wild type strains are also underway; some recent findings are reported (5). The NTP is looking into ways that transgenic mouse assays could be used to

provide information about selection of doses for the two-year bioassays. One example is their use in a current initiative to evaluate the safety of disinfection

by-products found in drinking water (described earlier). The International Life Sciences Institute, a non-profit foundation, is also coordinating a partnership

between Federal agencies and the pharmaceutical industry to study the utility of transgenic models; the NTP is participating in this effort.

References

Tennant RW, French JE, Spalding JW. Identifying chemical carcinogens and assessing potential risk in short-term bioasays using transgenic mouse models. Environmental Health

Perspectives 103:942-950 (1995).

1. 

2. Special issue. Toxicologic Pathology 26(4) (1998).

3. Fisher BE. NTP talks transgenics. Environmental Health Perspectives 106:A177 (1998).

4. Bucher JR. Update on National Toxicology Program (NTP) assays with genetically altered or "transgenic" mice. Environmental Health Perspectives 106(10):619-621 (1998).

Sanders JM, Burka LT, Fossett JE, Matthews HB. Comparative xenobiotic metabolism between Tg.AC and p53-deficient mice and their respective wild types. Toxicologic Science 42:332

(1998).

5. 

Risk Assessment Methodology

Mathematical risk assessment models are used to quantify the sequence of events that start with chemical exposure and end with overt toxicity. Models,

whose designs are biologically based, allow researchers to link a broad array of experimental findings in ways that are both biologically logical and useful in

risk assessment for defining dose-response relationships, making species comparisons, and assessing inter-individual variability. NTP initiatives, such as the

human exposure assessment (see below), are being undertaken to try and improve the availability of human data for use in development of such risk

assessment models.

Several models are now complete and bear noting. EPA is using a model developed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) as part of an

ongoing mechanistically based risk assessment. This model and one developed for 1,3-butadiene include the best characterizations available for the

pharmacological and biochemical effects of these compounds. Mechanistically based models are also being developed and applied to NTP data to provide a

better means for analyzing and interpreting bioassay results. Inclusion of physiologically based pharmacokinetic models (PBPK) in NTP technical reports is

becoming routine, and such information should give guidance to regulatory agencies interested in extrapolation of data across species.

The NIEHS/NIH toxicokinetics faculty evaluates the appropriateness of a biologically based pharmacokinetic model for each chemical selected for NTP

study. If a credible and potentially useful model can be constructed, then a study is designed to collect the appropriate data. The NTP's effort in risk

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assessment is closely tied to its growing initiatives in mechanism-based toxicology (described earlier). This linkage provides opportunities to improve priority

setting, use mechanistic information to establish risk or safety, clarify dose-response relationships in the "low dose" range, select the most appropriate

experimental systems for estimating risk, and develop science-based models for specific subpopulations (e.g. age, gender, genetic predisposition, ethnicity,

etc.). Information about models and projects related to risk assessment is available at http://www.niehs.nih.gov.

Human Exposure Assessment

The NTP increasingly recognizes the need for human data in its science base for decision-making. Information on human exposure to agents and their body

burden is critical for a successful and scientifically sound approach to the evaluation of potential human health risks. However, the availability of human

exposure assessment data is often the weakest component of risk assessment and limits the effective utilization of experimental data for making decisions

about chemical exposures.

Advances in analytical methodologies now enable the detection of environmental and occupational chemicals in small biological samples (e.g. blood, urine,

and hair). Taking advantage of such advances, the NTP is leading a new interagency human exposure assessment initiative in collaboration with NCEH/CDC,

NIOSH/CDC, and EPA to quantify the body burdens of chemicals released into the environment and workplace. Efforts being undertaken in moving forward

with this initiative are described below. This effort will benefit public health and priority setting by:

allowing the prioritizing of chemicals and chemical mixtures to be studied by the NTP based on their occurrence in human tissue,

providing data documenting exposure to children,

identifying potentially "sensitive" subpopulations,

strengthening the interpretation and use of animal toxicity data in quantifying the amount of chemical and/or active metabolite in blood and target

tissues,

allowing for refinement of human risk assessments through construction of physiologically based pharmaco/toxicokinetic models,

examining relationships between health disparities and fiscal disparities,

enhancing future epidemiological studies of exposure/disease relationships,

allowing government agencies to determine the effectiveness of regulatory actions for environmental standards and clean-up sites, and

linking these data with the NIEHS Environmental Genome Project.

The NIEHS Environmental Genome Project is a multi-center effort to identify systematically in the U.S. population the alleles of 200 or more environmental

disease susceptibility genes. Information from this human exposure assessment initiative together with the environmental genome project will provide the

science base essential for future, meaningful studies of gene/environment interactions in disease etiology.

Assessment of Endocrine Disruptors

As a part of the interagency human exposure assessment initiative, the NTP and the NCEH/CDC are collaborating on a pilot project for quantifying

approximately 70 chemicals in either human blood or urine that are considered to be endocrine disruptors. The biological samples from the National Health

and Nutrition Examination Surveys (NHANES) are being tested. This data will be used to estimate human exposure to endocrine disrupting agents within the

U.S. population and to identify the ones of greatest public health concern. This information can be used in prioritizing chemicals for study and in developing

biologically based models for estimating human risks.

Human Exposure Assessment and Environmental Disease Workshop

The NIEHS/NIH and NTP are sponsoring a workshop 22-24 September 1999 to bring together scientists and policy-makers from government agencies,

academia, industry, and community groups who have an interest in exposure assessment issues. This workshop should provide information on diseasespecific chemical exposure, highlight approaches for future research, and facilitate development of effective prevention and intervention strategies for

chemical exposures. For additional information about this workshop visit the NTP web-site, http://ntp-server.niehs.nih.gov, or contact:

Dr. Scott Masten, NIEHS/NTP, P.O. Box 12233, Research Triangle Park, NC 27709

T: 919-541-5710, F: 919-541-7666, e-mail: masten@niehs.nih.gov.

Selected reading

1. Lucier GW, Schecter A. Human exposure assessment and the National Toxicology Program. Environmental Health Perspectives 106(10):623-627 (1998).

Report on Carcinogens

The Report on Carcinogens (RoC), previously called the Annual Report on Carcinogens, is prepared in response to Section 301 of the Public Health Service

Act, as amended. This law stipulates that the Secretary of the Department of Health and Human Services (DHHS) shall publish a report which contains a list

of all substances (i) which either are known to be human carcinogens or may reasonably be anticipated to be human carcinogens; and (ii) to which a

significant number of persons residing in the United States are exposed. The Secretary of DHHS has delegated responsibility for preparation of the Report to

the Director of the NTP. The RoC is prepared by the NTP with the assistance of other Federal health research and regulatory agencies and non-government

institutions. The listing of a substance in the RoC is descriptive in nature and represents an initial step in hazard identification, which is generally considered

the first step in the analytical process known as risk assessment. The Report is not intended to constitute a risk assessment; it is a hazard identification

document only.

The NTP solicits and encourages the broadest participation from interested individuals or parties in nominating agents, substances, mixtures, or exposure

circumstances for listing in or delisting from the RoC. Nominations are requested to contain a rationale for listing or delisting. Appropriate supporting

background documents (e.g. journal articles, NTP Technical Reports, International Agency for Research on Cancer listings, exposure surveys, release

inventories, etc.) that support a nomination should be provided or referenced when possible. Anyone may nominate a substance to be considered for listing in

or delisting from the RoC . The nominations should be submitted to Dr. C.W. Jameson, NTP, Report on Carcinogens, NIEHS/NIH, P.O. Box 12233, MD

EC-14, Research Triangle Park, NC 27709, T: 919-541-4096, F: 919-541-0947, e-mail: jameson@niehs.nih.gov.

The review of agents, substances, mixtures, or exposure circumstances for listing in or delisting from the RoC involves a multi-phased, peer review process.

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Public comment on the nominations is solicited several times during the review process. Briefly, two Federal scientific review groups independently evaluate

all available data relevant to the inclusion or exclusion of candidate agents and vote on each agent. A subcommittee of the NTP Board of Scientific

Counselors also evaluates the data independently and votes on classification during an open, public meeting that also provides an opportunity for public

comment. All comments and recommendations are presented to the NTP Executive Committee for review and comment. The NTP Director makes the final

recommendation for listing and/or delisting in the final draft of the RoC and submits it to the Office of Secretary, DHHS for approval.

The criteria used for listing in the RoC are as follows:

Known to be Human Carcinogens:

There is sufficient evidence of carcinogenicity from studies in humans which indicates a causal relationship between exposure to the agent,

substances or mixture and human cancer.

Reasonably Anticipated to Be Human Carcinogens:

There is limited evidence of carcinogenicity from studies in humans which indicates that a causal interpretation is credible but that alternative

explanations such as chance, bias or confounding factors could not be adequately excluded; or

There is sufficient evidence of carcinogenicity from studies in experimental animals which indicates there is an increased incidence of malignant

and/or a combination of malignant and benign tumors: (1) in multiple species or at multiple tissue sites, or (2) by multiple routes of exposure, or (3)

to an unusual degree with regard to incidence, site or type of tumor or age at onset; or

There is less than sufficient evidence of carcinogenicity in humans or laboratory animals; however, the agent, substance or mixture belongs to a well

defined, structurally-related class of substances whose members are listed in a previous Report on Carcinogens as either a known to be human

carcinogen or reasonably anticipated to be human carcinogen or there is convincing relevant information that the agent acts through mechanisms

indicating it would likely cause cancer in humans.

Conclusions regarding carcinogenicity in humans or experimental animals are based on scientific judgement, with consideration given to all relevant

information. Relevant information includes, but is not limited to dose-response, route of exposure, chemical structure, metabolism, pharmacokinetics,

sensitive sub-populations, genetic effects, or other data relating to mechanism of action or factors that may be unique to a given substance. For example,

there may be substances for which there is evidence of carcinogenicity in laboratory animals but there are compelling data indicating that the agent acts

through mechanisms which do not operate in human and would therefore not reasonably be anticipated to cause cancer in humans.

The most recent RoC is the 8th Edition that was published in 1998. The 8th RoC is available on the NTP home page at http://ntp-server.niehs.nih.gov or may

be obtained by contacting the Environmental Health Information Service (EHIS, see page 19). The 9th Report is scheduled for publication in late 1999. A list

of the nominations under consideration for listing in or delisting from the 9th RoC is given in Table 5.

Nominations to be considered in 1999 and 2000 for listing and delisting in the 10th Edition of the RoC will be announced for public comment early in 1999.

Publication of the 10th Edition is anticipated for 2001.

Table 5

Summary of the Agents, Substances, Mixtures, or Exposure Circumstances

Reviewed for Possible Listing in or Delisting from the 9th Report on Carcinogen*

Reviewed in 1997

Reviewed in 1998

Benzidine-based dyes as a class

Alcoholic beverage consumption

1,3-Butadiene

Boot and shoe manufacture and repair

Cadmium and Cadmium compounds

Diesel exhaust particulates

Chloroprene

Environmental tobacco smoke

Phenolphthalein

Ethyl Acrylate

Saccharin

Ethylene Oxide

Smokeless tobacco

Isoprene

Solar radiation and exposure to sunlamps and sunbeds

Sulfuric acid mist

Methyl-t-Butyl Ether

Tamoxifen

Nickel compounds

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Tetrafluoroethylene

Silica, crystalline (respirable size)

Tobacco smoking

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCCD)

Trichloroethylene

*These agents were reviewed by three groups, the NIEHS/NIH Review Group for the RoC, NTP Executive Committee Working Group, and NTP Board of Scientific Counselors

Subcommittee for the RoC. Actions by each of the groups can be found at the NTP web-site, http://ntp-server.niehs.nih.gov

New NTP Centers

Two new administrative centers, The Center for the Evaluation of Alternative Toxicological Methods and The Center for the Evaluation of Risks to Human

Reproduction, have been established within the NTP.

The Center for the Evaluation of Alternative Toxicological Methods

The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) was established in 1997 in response to the 1993 NIH

Revitalization Act to reduce, refine, or replace the use of animals in research and testing. ICCVAM has membership from 14 Federal agencies and programs

(ATSDR, CPSC, Departments of Defense, Energy, Interior, and Transportation, EPA, FDA, NCI/NIH, NIEHS/NIH, NIH, NIOSH/CDC, National Library of

Medicine/NIH, and OSHA). The Committee functions to provide cross-agency communication and coordination on issues relating to validation, acceptance,

and national/international harmonization of toxicological testing methods.

The NTP Center for the Evaluation of Alternative Toxicological Methods (NICEATM) was established in 1998 to provide operational support for ICCVAM

and to coordinate committee-related review panels and workshops. ICCVAM and NICEATM work to promote the validation and regulatory acceptance of

toxicological test methods that are more predictive of human and ecological effects than those currently available and to communicate with stakeholders and

the public. The desired outcomes from these new methods are the improvement in agencies abilities to assess risk and make regulatory decisions, and the

refinement, reduction, and replacement of animals in toxicological testing. The Advisory Committee on Alternative Toxicological Methods established by

DHHS meets biannually to provide ICCVAM and NICEATM advice on activities and priorities. It is composed of knowledgeable representatives from

academia, industry, public interest and animal welfare organizations, other agencies, and the international community.

Workshops are held, as needed for evaluation of adequacy of existing methods, identification of areas needing alternative methods, and evaluation of

proposed validation studies. A formal, scientific review process is in place for evaluation of the validation status of proposed alternative testing methods.

Briefly,

ICCVAM considers whether a proposed alternative method should be evaluated.

Peer review panels are convened and charged with development of a scientific consensus on the usefulness, limitations, and validation status of the

proposed test method.

ICCVAM reviews the panels document on scientific validity and potential acceptability of a test method and forwards the report to regulatory agencies.

Each agency decides the regulatory acceptability of a new method according to its own mandates.

Two alternative methods have been brought to ICCVAM and the Center for consideration. The murine Local Lymph Node Assay (LLNA), a method for

assessing allergic contact dermatitis of chemicals, was reviewed in September 1998 and the final report is available. The peer review panel concluded that the

LLNA is a valid alternative to the currently accepted guinea pig test methods and also provides for the refinement and reduction of animal use. Unlike

traditional guinea pig test methods, this mechanistic test quantifies the proliferation of lymphocytes in the regional lymph nodes in response to a chemical and

can be used to evaluate its relative potency. From an operational and economic viewpoint, the LLNA also appears to be more efficient, quicker, cost less, use

fewer animals, and subject the animals to less pain and distress. Individual regulatory agencies will now decide the acceptability of this method according to

their own mandates. An in vitro method, CorrositexR, used for assessing the dermal corrosivity potential of chemicals, was reviewed by a peer review panel

in January 1999. The panel concluded that the method could be used for assessing the corrosivity of certain chemical classes and used in a tiered testing

approach for other classes; the report will be available in June 1999 or accessible from a link on the NTP homepage, htt;://ntp-server.niehs.nih.gov.

Information about ICCVAM and NICEATM is found at http://iccvam.niehs.nih.gov or contact:

NICEATM, NIEHS/NIH, P.O. Box 12233, MD EC-17, Research Triangle Park, NC 27709

T: 919-541-3398, F: 919-541-0947, e-mail: NICEATM@niehs.nih.gov.

For inquiries regarding nominations of alternative testing methods contact:

Dr. William S. Stokes

Director NICEATM and Co-Chair ICCVAM

NTP

NIEHS/NIH

P.O. Box 12233, MD EC-17

Research Triangle Park, NC 27709

T: 919-541-7997

F: 919-541-0947

e-mail: stokes@niehs.nih.gov

Dr. Richard N. Hill

Co-Chair ICCVAM

U.S. EPA

Mail Code 7101

401 M Street SW

Washington, DC 20406

T: 202-260-2894

F: 202-260-1847

e-mail: hill.richard@epamail.gov

Selected reading

1. Clay, R. New tricks for an old assay. Environmental Health Perspectives 106(10):A488-489 (1998).

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2. Twombly R. New NTP centers meet the need to know. Environmental Health Perpectives 106(1):A480-483 (1998).

NTP. Validation and Regulatory Acceptance of Toxicological Test Methods, A Report on the Ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods. NIH

Publication No. 97-3981. Research Triangle Park: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Toxicology Program,

1997.

3. 

Chhabra, R.S., Bucher, J.R., and Stokes, W.S. US National Toxicology Program strategies for use of alternate test systems. van Zutphen, L.F.M. and Balls, M. (eds.) Animal Alternatives,

Welfare and Ethics, Elsevier Science, B.V. pp. 607-615 (1997).

4. 

The Center for the Evaluation of Risks to Human Reproduction

The Center for the Evaluation of Risks to Human Reproduction (CERHR) was established in June 1998 through the NIEHS/NIH and NTP in response to an

increasing awareness of the public and scientific community about possible adverse effects of environmental exposures on fertility and childbearing. The

NTP Board of Scientific Counselors provides oversight for the Center. The CERHRs goal is to provide the public, scientific community, regulatory agencies,

and public health policy makers a compilation of available information for a chemical or mixture and an objective scientific assessment on its reproductive

risk(s) and to identify critical gaps in the science base and special research needs. Two to three chemicals are evaluated per year, and the Center follows a

formal process for their nomination, selection, and review including:

call for nomination of chemicals for evaluation,

compilation of available scientific information on nominated chemicals,

evaluation of whether or not to move forward with formal review of the agent,

review of background documents and information by a Scientific Review Panel with diverse scientific expertise, and

preparation of evaluation documents by the Scientific Review Panel.

Public input is important in this process and can occur through 1) the nomination of chemicals for evaluation, 2) public comments on nominations and the

prioritizing and selecting of chemicals nominated for evaluation, and 3) public comments on the evaluation of a particular chemical at the time of the expert

panel meetings. The public is encouraged to nominate chemicals or chemical mixtures for review through the Center and/or suggest scientists to be added to

an Expert Registry from which reviewers will be appointed to serve on the ad hoc panels that assess the reproductive and developmental toxicity of selected

agents. Nominations of chemicals or chemical mixtures should be accompanied by a justification for the nomination, and whenever possible, include

appropriate background information, data, or literature citations. Scientists names suggested for addition to the Expert Registry should be accompanied by a

description of their expertise and curriculum vitae. All chemical nominations and suggestions for the Expert Registry should be forwarded to:

NTP Center for the Evaluation of Risks to Human Reproduction, Attn: Dr. John A. Moore, 1800 Diagonal Road, Suite 500, Alexandria, VA, 22314

T: 703-838-9440, F: 703-684-2223, e-mail: jmoore@sciences.com, web address: http://cerhr.niehs.nih.gov. The Centers web-site is operational and is

accessible directly or through links with the NIEHS and NTP home pages, http://www.niehs.nih.gov and http://ntp-server.niehs.nih.gov.

Scientific Review Panel reports of evaluated chemicals will be published in Environmental Health Perspectives and will also be available on the Centers

web-site. The first evaluation to be conducted will deal with a selected group of phthalates that are widely used in consumer products. It is anticipated that the

first review will be conducted in the summer 1999.

For additional information about the Center contact:

Dr. Michael D.Shelby, Director CERHR, NIEHS/NTP, P.O. Box 12233, MD B3-09, Research Triangle Park, NC 27709

T: 919-541-3455, F: 919-541-4634, e-mail: shelby@niehs.nih.gov.

Selected reading

1. Twombly R. New NTP centers meet the need to know. Environmental Health Perspectives 106(1):A480-483 (1998).

Communication and Public Outreach

Maintaining open communications and ensuring dialogue with Federal and State agencies, industry, stakeholders, academia, and the public are goals of the

NTP. The NTP Board of Scientific Counselors, its subcommittees for review of Technical Reports and the Report on Carcinogens (RoC), and the newly

established Advisory Committee on Alternative Toxicological Methods assure regular scientific and public peer review and input. NTP conferences and

workshops designed to bring researchers, regulators, policy makers, and the public together to examine issues and to achieve consensus on future directions

in toxicology and risk assessment remain a priority. Emphasis continues on ensuring broad dissemination of the results of NTP research and testing and in

communicating information about its evolving programs and priorities. The distribution of NTP testing and research results and its program plans, initiatives,

announcements, and publications occur through mailings, Federal Register announcements, and the world-wide-web that includes a subscription-based NTP

List-Server. The NTP home page, http://ntp-server.niehs.nih.gov, offers access to information about the NTP, and links are available that detail and highlight

ongoing and future initiatives, NTP centers, NTP documents, Report on Carcinogens, and announcements.

On-line, searchable access, as well as printed copies of NTP publications including the Report on Carcinogens, NTP Technical Reports, NTP Toxicology

Reports, and other NTP documents, is available through the Environmental Health Information Service (EHIS) at http://ehis.niehs.nih.gov. Subscription

packages to the EHIS include access to NTP publications, as well as Environmental Health Perspectives (primary issues and supplements), the Rodent

Historical Controls Database, the Chemical Health and Safety Database, and a variety of other services. To purchase single copies or to subscribe on-line,

visit the EHIS at http://ehis.niehs.nih.gov, e-mail: ehis@niehs.nih.gov, or call 1-800-315-3010.

The Central Data Management Office oversees distribution, upon request, of specific chemical study information and NTP documents including the NTP

Annual Plan and Annual Plan Summary, NTP Study Status Reports, pre-peer review copies of draft NTP Technical Reports, background documents for

chemicals nominated to the NTP, and summaries of minutes from NTP meetings including the Board of Scientific Counselors, and its subcommittees.

Requests for these documents should be directed to:

Central Data Management, NIEHS/NIH, P.O. Box 12233, MD E1-02, Research Triangle Park, NC 27709

T: 919-541-3419, F: 919-541-3687, e-mail: cdm@niehs.nih.gov.

The NTP is interested in stakeholder input into its programs and priorities. Nominations, inquiries, and comments from the public and other interested parties

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are welcome at any time. The NTP Liaison and Scientific Review Office serves as the focal point for receiving input to the Program and for overseeing the

distribution of information about programs, workshops, initiatives, etc. Questions regarding the program, comments, and input can be submitted to:

NTP Liaison and Scientific Review Office, NIEHS/NIH, P.O. Box 12233, Research Triangle Park, NC 27709, T: 919-541-0530, F: 919-541-0295, e-mail:

liaison@starbase.niehs.nih.gov.

Return to Table of Contents Return to NTP Homepage

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