NTP

CURRENT DIRECTIONS and EVOLVING STRATEGIES

National Toxicology Program
Table of Contents

I 2 Overview of the National Toxicology Program

II 8 Current Directions

III 14 Evolving Strategies

IV 18 Centers

V 22 Report on Carcinogens

VI 24 Communication and Public Outreach

National Toxicology Program 1

U.S. Department of 

Health and Human Services

Public Health Service

National Toxicology Program

NTP

CURRENT DIRECTIONS and EVOLVING STRATEGIES
2 National Toxicology Program

Mission and Goals

More than 80,000 chemicals are registered for use in

commerce in the United States, and an estimated 2,000

new ones are introduced annually for use in everyday

items such as foods, personal care products, prescription

drugs, household cleaners, and lawn care products. The

effects of many of these chemicals on our health are

unknown, yet we and our environment may be exposed

to them during their manufacture, distribution, use,

and disposal or as pollutants in our air, water, or soil.

Although relatively few chemicals are thought to pose a

significant risk to human health, safeguarding public

health depends on identifying the effects of these

chemicals and the levels of exposure at which they may

become hazardous to humans. 

The National Toxicology Program (NTP) was established by the U.S. Department of Health and Human

Services (HHS) in 1978 to coordinate toxicological

testing programs within the Department, strengthen

the science base in toxicology, develop and validate

improved testing methods, and provide 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 tools of modern

toxicology and molecular biology. The program maintains

an objective, science-based approach in dealing with

critical issues in toxicology and is committed to using

the best science available to prioritize, design, conduct,

and interpret its studies. To that end, the NTP is continually evolving to remain at the cutting edge of scientific

research and to develop and apply new technologies.

Focusing on the Future

The NTP provides information that improves the

nation’s ability to evaluate potential human health

effects from chemical and physical exposures. The NTP

maintains a number of complex, interrelated research

and testing programs that provide unique and critical

information needed by health regulatory and research

agencies to protect public health. All of the NTP's

activities are open to public scrutiny, including communications with all interested parties. The NTP has

always drawn strength and direction from the commitment of its scientists to exchanging information openly,

maintaining impartiality, and applying rigorous scientific

peer review. This will remain a central priority of the

program now and in the future.

I

Overview
The NTP seeks to maintain a balanced research and

testing program that provides data on a wide variety of

issues that are important to public health. In particular,

the NTP seeks nominations of studies that enhance the

predictive ability of future NTP studies, address mechanisms of toxicity, or fill significant gaps in the knowledge

of the toxicity of chemicals or classes of chemicals.

Currently, the NTP is focusing on several areas that

have received inadequate attention in the past, including

photoactive chemicals, contaminants of finished drinking

water, endocrine-disrupting agents, and certain complex

occupational exposures. The NTP is addressing potential

safety issues associated with herbal medicines, radiofrequency radiation emissions from cellular telephones,

hexavalent chromium, and DNA-based therapies. In

general, these initiatives are broad-based and investigate

various health-related effects.

The NTP continues to work to develop and validate

alternative testing methods that will help identify 

chemical hazards using fewer test animals. This effort

includes developing more efficient, mechanism-based

testing strategies, such as transgenic models for toxicology

testing, and implementing microchip-based genomic

technologies. Future initiatives in mechanism-based 

toxicology research will integrate information from 

traditional and gene-expression-based studies to develop

new testing strategies for identifying and studying environmental toxicants. These studies hold the promise of

providing a true mechanistic basis for hazard identification

using short-term, practical assays applied over the broad

range of environmental agents to which we are exposed. 

The NTP also evaluates whether human exposures 

to environmental agents cause adverse effects on 

reproduction, development, and the immune, respiratory,

and central nervous systems. The NTP is expanding its

effort to include routine investigations of changes in

the immune system and the nervous system from exposures occurring during fetal development and early life.

Reproductive studies are being refined to address emerging knowledge of the subtle effects caused by low doses

of endocrine-active chemicals. 

The NTP continues to expand activities designed to

place research and testing results from animals into a

more relevant human health perspective. This includes

human exposure assessment, toxicokinetics, mechanismbased pharmacokinetic modeling, and the interpretation

of results in molecular epidemiology for use in human

hazard identification (e.g., Report on Carcinogens and

the NTP Center for the Evaluation of Risks to Human

Reproduction). The NTP is also coordinating an effort to

obtain “real-world” information about worker practices,

complex occupational exposures, and potentially related

adverse health effects. We need such information to

identify areas for research and to design better laboratory

studies on the potential health effects of chemicals,

complex mixtures, and exposures people encounter in

the workplace.

National Toxicology Program 3

Good

Science

for

Good

Decisions

Dr. Kenneth Olden, Director, NTP
Role in Shaping Public Health Policy 

Over the past two decades, the NTP has developed an

increasingly interactive relationship with regulatory

agencies. Through this relationship, the NTP plays an

important, although indirect, role in shaping public

health policy. Federal and state government agencies rely

on the scientific knowledge base provided by the NTP

to make credible decisions that protect public health

without unnecessarily increasing the regulatory burden

on industry. The NTP plays a critical role in providing

needed scientific data, interpretations, and guidance on

the appropriate uses of these data to regulatory agencies

and other groups involved in health-related research.

The NTP also plays an important role in fostering

interagency collaborations in research and exposure

assessment, providing information to regulatory agencies

about alternative methods for toxicity screening, and

exploring new technologies for evaluating how environmental agents cause disease.

Organizational Structure and Oversight 

Three agencies form the core of the NTP: 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) (Figure 1).

Each agency voluntarily provides resources to support

NTP research, testing, centers, and outreach. Program

contacts for each agency are Dr. Christopher J. Portier

(NIEHS/NIH), Dr. Albert E. Munson (NIOSH/CDC),

and Dr. William T. Allaben (NCTR/FDA). The NTP

is administratively located at the NIEHS/NIH. The

Director of the NIEHS/NIH, Dr. Kenneth Olden, serves

as Director of the NTP and reports to the Secretary,

HHS. The National Cancer Institute of the National

Institutes of Health (NCI/NIH) was a charter agency

for the NTP and continues to serve on the NTP

Executive Committee. 

The NTP Executive Committee (Figure 1) provides

oversight to the NTP for policy issues. This committee is

composed of the heads of federal research and regulatory

agencies. External advisory groups provide review 

and advice to the NTP. The NTP Board of Scientific

Counselors (“the Board”), its subcommittees, and the

Scientific Advisory Committee on Alternative Toxicological

Methods (SACATM) assure regular scientific and public

peer review and input about activities and priorities. 

The Board provides primary scientific oversight to the

Director regarding the NTP, the NTP Center for the

Evaluation of Risks to Human Reproduction (CERHR),

and the NTP Center for Phototoxicology (NCP), and it

evaluates the scientific merit of the NTP’s intramural and

collaborative programs. The Technical Reports Review

Subcommittee of the Board provides peer review for the

4 National Toxicology Program

Overview

ATSDR, Agency for Toxic Substances and Disease Registry; CPSC, U.S. Consumer Product Safety Commission; EPA, U.S. Environmental Protection Agency; FDA, Food and

Drug Administration; NCEH/CDC, National Center for Environmental Health of the Centers for Disease Control and Prevention; NCI/NIH, National Cancer Institute of the

National Institutes of Health; NCTR/FDA, National Center for Toxicological Research of the Food and Drug Administration; NIEHS/NIH, National Institute of Environmental

Health Sciences of the National Institutes of Health; NIH, National Institutes of Health; NIOSH/CDC, National Institute for Occupational Safety and Health of the Centers for

Disease Control and Prevention; OSHA, Occupational Safety and Health Administration.

National Toxicology Program

NCTR/FDA

Director

NIEHS/NIH

NTP Board of Scientific

Counselors

• Technical Reports Review

Subcommittee

• Report on Carcinogens

Subcommittee

Scientific Advisory

Committee on Alternative

Toxicological Methods

Policy Oversight

NTP Executive Committee

• ATSDR

• CPSC

• EPA

• FDA

• NCEH/CDC

• NCI/NIH

• NIEHS/NIH

• NIH

• NIOSH/CDC

• OSHA

External Science Oversight

and Peer Review

NIOSH/CDC

Figure 1
NTP long-term toxicology and carcinogenesis studies

and short-term toxicity study reports. The Report on

Carcinogens Subcommittee of the Board provides external

scientific evaluation of substances nominated for listing 

in or delisting from the Report on Carcinogens. These

groups each meet once or twice each year, and all meetings are open to the public.

The SACATM is a new advisory committee that 

was chartered in January 2002 to fulfill requirements

specified in the ICCVAM Authorization Act of 2000

(Public Law 106-545) for providing advice to the

Interagency Coordinating Committee for the

Validation of Alternative Methods (ICCVAM). The

ICCVAM is an NIEHS interagency coordinating 

committee under the NTP Interagency Center for 

the Evaluation of Alternative Toxicological Methods

(see page 19). The SACATM provides advice to the

Director of the NIEHS, the ICCVAM, and the

NICEATM on priorities and directives related to the

development, validation, scientific review, and regulatory

acceptance of new or revised toxicological test methods

and on ways to foster partnerships and communication

with interested parties. The SACATM replaces the

Advisory Committee on Alternative Toxicological

Methods which previously provided external input to

the NTP on these issues. Members of the SACATM are

appointed by the Director of the NIEHS. The SACATM

will meet two to three times each year, and all meetings

will be open to the public.

Toxicology and Carcinogenesis Evaluations

The NTP has a broad mandate to provide toxicological

characterizations for chemicals and other agents of public

health concern. The NTP continually solicits and reviews

nominations for toxicology studies in the specific categories given in Table 1. The nomination process is open

to all interested individuals and groups. Information about

nominating a substance for testing by the NTP is available

on the NTP web site (http://ntp-server.niehs.nih.gov) 

or by contacting Dr. Scott Masten, Office of Chemical

Nomination and Selection (for contact information, see

back flap). 

Nominations undergo several levels of review before

the NTP selects agents for study and designs and implements toxicological studies (Figure 2). Representatives

from federal agencies on the Interagency Committee

for Chemical Evaluation and Coordination (ICCEC)

and the Board participate in the selection process. The

NTP also solicits and considers public comment on

nominations throughout this formal process. As the

final step of selection, the NTP Executive Committee

reviews and evaluates the testing recommendations and

the public comments for each nomination and makes its

own recommendations to test, to not test at this time,

or to defer testing until additional information is received

and considered. These steps help ensure that the NTP’s

testing program addresses toxicological concerns pertinent

to all areas of public health and helps maintain balance

among the types of substances evaluated. 

The Executive Committee’s recommendation of a 

substance for study does not automatically commit the

NTP to its evaluation. The NTP strives to balance its

selection of substances for study (e.g., occupational

exposures, environmental pollutants, food additives,

consumer products, and pharmaceuticals) and initiates

studies as time and resources permit. In reviewing and

selecting nominated substances for study, the NTP also

considers legislative mandates that require responsible

private-sector and commercial organizations to evaluate

their products for human and environmental health

effects. Also, a nomination selected for study may be

deferred at any time if suitable data become available, 

National Toxicology Program 5

Table 1 Nomination Principles for NTP Studies

• 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

• Commercial chemicals with significant exposure that were first marketed prior to current testing requirements

or those that generate too little revenue to support further evaluations

• Potential substitutes for existing chemicals or drugs that might not be developed without federal involvement

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

• Chemicals that should be evaluated to improve the scientific understanding of structure-activity relationships,

and thereby help limit the number of chemicals requiring extensive evaluations

• Emergencies or other events that warrant immediate government evaluation of a chemical or agent
if higher priority studies are identified, or if a study

proves impractical.

The NTP evaluates substances for a variety of

health-related effects, among them, general toxicity,

reproductive and developmental toxicity, genotoxicity,

immunotoxicity, neurotoxicity, metabolism, disposition, and carcinogenicity. The NTP generally uses

rodent models for study, and performs short-term 

studies for up to thirteen weeks and chronic, long-term

studies for up to two years. For each agent studied, a

project leader designs a comprehensive testing strategy

to address the identified research and testing needs. 

A project review committee evaluates the testing strategy

and proposes an appropriate mechanism for performing

the study (grant, contract, etc.). 

The NTP publishes results of short-term rodent 

toxicology studies in the NTP Toxicity Report series,

and results of longer-term studies, generally two-year

rodent toxicology and carcinogenesis studies, as NTP

Technical Reports or in peer-reviewed scientific journals.

The Technical Reports Review Subcommittee of the

Board (Figure 1) formally reviews these reports in open

public meetings. Table 2 lists candidates for peer review

in 2002 and 2003.

6 National Toxicology Program

Overview

2002 2003

• trans-Cinnamaldehyde • 2-Methylimidazole

• Decalin • 3,3',4,4',5-Pentachlorobiphenyl

• Dipropylene glycol • Propylene glycol t-butyl ether

• Elmiron • Stoddard solvent (Type IIc)

• Pentaerythritol triacrylate • 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)

• Trimethylolpropane triacrylate • Triethanolamine

• Urethane + Ethanol

Table 2 Candidate Chemicals for Peer Review

Federal and State Agencies

Industry

Industry Academia Other Organizations

Labor Public International Organizations

Chemical

Nominations

ICCEC Review

Public Review

NTP Board of Scientific Counselors Review (Public Meeting)

NTP Executive Committee Review and Selection

NTP Designs and Initiates Studies Based on Resources, Priorities, and Knowledge Gaps

Figure 2 NTP Toxicology Study Nomination and Selection Process

8 National Toxicology Program

The NTP conducts research on a broad range of

high-priority agents and issues of public health

concern. Below are brief overviews of some current

NTP initiatives.

Radiofrequency Radiation Emissions 

from Cellular Phones

Over 100 million Americans currently use wireless communication devices, with thousands of new users added

daily. Personal (cellular) telecommunications is a rapidly

evolving technology that uses microwave radiation to

communicate between a fixed base station and a mobile

user. Most systems employ a hand-held cellular telephone,

with the radiation antenna held close to the user's head.

The Federal Communication Commission requires 

cellular phones and other wireless communication devises

to meet its radiofrequency radiation exposure guidelines.

These guidelines are based on protecting the user from

acute injury from thermal effects produced by radiofrequency radiation. Current data are insufficient to determine whether these guidelines are adequate for protecting

against potential adverse effects of long-term exposure.

Studies in laboratory animals are crucial for understanding whether exposure to radiofrequency radiation

may pose a danger to human health. Other research

groups are performing several long-term animal studies

addressing this issue. In addition, the NTP plans to

conduct laboratory research to help clarify any potential

health hazard for the U.S. population. The NTP is 

working with technical experts from the National

Institute of Standards and Technology to test the 

suitability of various radiofequency radiation exposure

systems for these studies.

Hexavalent Chromium

Chromium is a naturally occurring element present in

various valence states. Trivalent chromium is an essential

nutrient, and chromium occurs most commonly in nature

in this state. Hexavalent chromium compounds are the

next most stable form; however, they rarely occur naturally

and are typically associated with industrial sources.

Because of concerns by a number of California legislators, the California Environmental Protection Agency,

and the California Health and Human Services Agency,

the NTP is studying the carcinogenic potential of 

hexavalent chromium administered in drinking water.

Hexavalent chromium is an established human carcinogen in certain occupational settings, presumably as a

result of inhalation exposure. However, we do not 

know the long-term consequences of exposure to 

hexavalent chromium compounds in the water supply.

Data currently available on the chronic toxicity and

carcinogenicity of hexavalent chromium given orally

are not sufficient to establish or characterize any 

hazard. The NTP studies will include both short- and

long-term administration of hexavalent chromium to

IICurrent Directions
laboratory animals as sodium dichromate dihydrate 

in drinking water, as well as studies on hexavalent

chromium’s tissue absorption. Data from the absorption

studies and outlines of the designs of all studies on

hexavalent chromium are accessible on the NTP web

site (http://ntp-server.niehs.nih.gov/).

Children’s Health

The NTP continues to be a leader in issues related to

children’s health through research and the NTP Center

for the Evaluation of Risks to Human Reproduction

(CERHR; see page 18). The NTP has ongoing efforts

to evaluate effects of various agents on developing

immune and nervous systems through laboratory studies

of pesticides, water disinfectant by-products, and

endocrine-disrupting agents. The program is expanding

these efforts by establishing study protocols where 

perinatal animals will be given these agents and then

examined for developmental immunotoxicology, 

neurotoxicology, and reproductive effects. Toxicokinetic

data from mothers, fetuses, and newborns will be used

to develop physiologically based pharmacokinetic models

of risks to humans from environmental toxicants during

perinatal development.

Phototoxicology 

Because of the public’s increasing exposure to ultraviolet

(UV) radiation from sunlight and other sources (e.g.,

tanning booths), the NTP has begun research on whether

any toxic effects might occur from such exposures. The

NTP is coordinating an effort between the NIEHS/NIH

and NCTR/FDA to study the phototoxicology and

photocarcinogenicity of substances nominated to the

NTP, including those of high priority to the FDA. In

general, these studies investigate the effects on gene

expression, toxicity, and carcinogenicity of sunlight

combined with either topically or systemically applied

substances in the SKH-1 hairless mouse. Much of this

research is being carried out at the NTP Center for

Phototoxicology (NCP; see page 19).

Phototoxicology studies are in progress at the NCP

for topically applied alpha-hydroxy and beta-hydroxy

acids (chemoexfoliating acids) and aloe vera. Many 

cosmetics include alpha-hydroxy and beta-hydroxy acids,

in some cases, to correct or improve the appearance of

“sun-aged” skin. The relation of skin cancer to their

continuous use along with exposure to sunlight is not

known. Studies underway at the NCP are using glycolic

and salicylic acids to represent alpha-hydroxy and betahydroxy acids, respectively. The NCP is also studying

possible acute toxicity and photocarcinogenesis of 

topically applied plant fractions of the aloe vera plant

in combination with simulated sunlight. Numerous

products including cosmetics and dietary supplements

include portions of the aloe vera plant. 

The NTP is currently designing studies on the 

phototoxicity and photocarcinogenicity of other cosmetic

ingredients including topically applied retinyl palmitate

(a vitamin A derivative), tattoo ink chemicals, and 

fluorescein-based dyes.

Animal models for testing the role of specific UV wavelengths and chemicals in the development of human

malignant skin melanoma do not yet exist. We therefore

do not yet understand the effects on melanoma development of chemicals combined with exposure to sunlight.

The NCP is studying a transgenic mouse [TP-ras (+)

p16/INK4a (+/–)] as an animal model for studying

melanoma development.

Herbal Medicines

Medicinal herbs are among our oldest medicines, and

their increasing use in recent years is evidence of public

interest in alternatives to conventional medicine.

Approximately one third of the U.S. population is

National Toxicology Program 9
believed to use some form of alternative medicine,

including herbal remedies. The use of herbal medicines

and other dietary supplements has increased substantially since passage of the 1994 Dietary Supplement

Health and Education Act. Although approximately

1,500 botanicals are sold as dietary supplements or ethnic

traditional medicines, herbal formulations are not 

subjected to FDA premarket approval to ensure their

safety or efficacy. 

The NTP is planning or conducting research on several

medicinal herbs and compounds found in herbs (listed in

Table 3) to examine carcinogenicity, reproductive toxicity,

neurotoxicity, immunotoxicity, or toxic effects associated

with exposures to high acute doses and chronic low doses.

Safe Drinking Water Program 

More than 200 million Americans are estimated to use

municipally treated drinking water, so the availability

10 National Toxicology Program

Current Directions

Aloe vera gel

Black cohosh

Black walnut extract

Comfrey

Echinacea purpurea extract

Ginkgo biloba extract

Ginseng and ginsenosides

Goldenseal

Grape seed extract and pine bark extract

Kava kava

Milk thistle extract

Pulegone

Thujone

Table 3 Herbs and Herbal Components under Study by the NTP

Seventh most widely used herb; used as a dietary

supplement, a component of cosmetics, and a

treatment for minor burns.

Used to treat symptoms of pre-menstrual syndrome

(PMS), dysmenhorrea, and menopause.

Found in hair dye formulations and walnut oil stain;

juglone is a major constituent.

Consumed in teas and as fresh leaves for salads;

contains pyrrolizidine alkaloids that are known to 

be toxic; based in part on NTP studies of the alkaloid

components of comfrey, the FDA has recommended

that manufacturers of dietary supplements containing

this herb remove them from the market.

A common medicinal herb in the United States;

used to treat colds, sore throat, and flu.

Among the five or six most frequently used 

medicinal herbs.

Fourth most widely used medicinal herb; 

ginsenosides are thought to be the active 

ingredients in ginseng, which has been 

associated with adverse health effects.

Second or third most popular medicinal herb 

used in this country; used as a laxative, tonic, 

and diuretic.

Widely used herbals; used to promote health of

the cardiovascular system.

Reported to be the fifth most widely used 

medicinal herb; has psychoactive properties and

is sold as a calmative and antidepressant.

Used to treat depression and several liver 

conditions and to increase breast milk production.

A toxic compound found in pennyroyal.

A toxic compound of wormwood; also found in

other herbs, including sage and tansy.
of safe drinking water is of enormous importance 

to public health. Although chlorination is one of 

the major public health advances of the twentieth 

century, by-products of chlorination or other 

disinfection processes (disinfection by-products, 

DBPs) may cause health problems such as cancer. In

addition, some agents found naturally in water or that

contaminate public water systems may pose a threat to

public health.

The EPA is responsible for setting water standards

for DBPs. To provide scientific data for setting sound

standards for water quality, the NTP is collaborating

with the EPA on a research program to assess potential

risks from human exposure to DBPs. This program

includes a systematic, mechanism-based, toxicological

evaluation of DBPs focusing on reproductive toxicity,

immunotoxicity, neurotoxicity, and carcinogenicity.

The program selects DBPs for study based on their 

presence in drinking water, occurrence with different

disinfection processes, chemical structures, and class of

DPB: trihalomethanes, haloacetic acids, and haloacetonitriles. Table 4 lists DBPs currently under study by

the NTP.

Besides DBPs, many agents occur naturally (e.g.,

arsenic, aluminum), or because of contamination 

(e.g., gasoline additives such as methyl t-butyl ether,

pesticides, organic tin compounds), or with environmental changes (e.g., cyanobacterial toxins from algal

blooms in surface waters). The NIEHS/NIH and EPA

are considering toxicology studies on several of these

agents, including aluminum complexes, organic tin 

compounds, and the two most common cyanobacterial

toxins (microcystin-LR and cylindrospermopsin), for

further study by the NTP. 

Occupational Exposures 

The NTP is coordinating an effort between the

NIEHS/NIH and NIOSH/CDC to better understand

worker exposures, educate workers, and identify occupational health research gaps. Current efforts are addressing

worker exposure to asphalt fumes and 1-bromopropane. 

Asphalt fumes generated during road paving have

been linked to acute irritation of mucous membranes

and skin, but to date no cancer risk has been established. Using a system designed to produce asphalt

fumes similar to those found in the field, the NIOSH/

CDC has developed methods for characterizing these

fumes and for monitoring asphalt fume exposure in

inhalation toxicity studies. Laboratory inhalation studies

are evaluating the effects of exposure to asphalt fumes

in animals.

An industry consortium has petitioned the EPA to list

1-bromopropane as an alternative for ozone-depleting

solvents. This could vastly increase the exposure of 

workers and the public to this compound. To obtain

information on exposures to this chemical, the NIOSH/

CDC is conducting an industry-wide study targeting

adhesive users, the metal degreasing and electronics

industry, and chemical, aerosol, and adhesive manufacturers. Study sites will be selected based on quantity and

type of 1-bromopropane use, number of workers exposed,

type of manufacturing process, and how well the site

represents the industry. Exposure will be studied using

inhalation, exhaled breath, and biological measures. 

The NTP Center for the Evaluation of Risks to Human

Reproduction (CERHR; see page 18) recently held an

external scientific peer review to evaluate the evidence for

potential reproductive and developmental toxicity caused

by exposure to 1-bromopropane and 2-bromopropane.

National Toxicology Program 11

• Bromochloroacetic acid

• Bromodichloromethane

• Chloramine

• Chloroform

• Dibromoacetic acid

• Dibromoacetonitrile

• Dichloroacetic acid

• Sodium bromate

• Sodium chlorate

• Sodium chlorite

Table 4 Water Disinfection By-Products under Study
The NIOSH/CDC is planning a National Exposures

at Work Survey (NEWS), conducted in a nationally

representative sample of workplaces across all industries,

starting with the health services industry. This survey

will collect data on chemical, physical, and biological

agents to which workers could be exposed, as well as

data on exposure controls and health and safety practices.

Information from this initiative will be used to educate

workers, identify occupational health knowledge gaps,

and help target areas where research is likely to reduce

workplace illness. 

Endocrine-Disrupting Agents

Endocrine disruptors are naturally occurring or manmade substances that may mimic or interfere with natural

hormones in the body. Endocrine disruptors may turn

on, turn off, or modify signals that hormones carry and

thus affect the normal functions of tissues and organs.

The NTP is involved in several efforts to strengthen the

scientific knowledge base within this field.

The NIEHS/NIH and the National Center for

Environmental Health of the CDC are collaborating to

quantify approximately 70 chemicals found in human

blood or urine that are considered endocrine-disrupting

agents, including phthalates and phytoestrogens. The

biological samples are collected as part of the National

Health and Nutrition Examination Survey (NHANES),

which includes men and women of various age, socioeconomic, and ethnic groups. The first edition of the

CDC's National Report on Human Exposure to

Environmental Chemicals, released in 2001, presents

levels of 27 environmental chemicals measured in

NHANES samples, including phthalate metabolites.

This study complements the recently completed scientific

peer review by the NTP Center for the Evaluation of

Risks to Human Reproduction (CERHR; see page 18)

on the potential reproductive and developmental toxicity

of phthalates.

Endocrine-disrupting chemicals are of interest to the

FDA, and through an interagency agreement the

NIEHS/NIH supports toxicology studies being conducted at the NCTR/FDA. Chemicals under study

include the phytoestrogen genistein, the pesticide 

vinclozolin, the drug ethinyl estradiol, and the industrial

chemical nonylphenol. These studies assess effects on

reproduction, development of hormone-sensitive

organs, and cancer in rodents over several generations,

as well as behavioral and immunological effects.

As required by the 1996 Food Quality Protection

Act, the EPA is in the process of choosing appropriate

assays to screen endocrine-active agents and developing

standardized, validated protocols for those assays. One

concern is the adequacy of current guidelines for assessing

the reproductive and developmental toxicities of chemicals

at environmental levels. On behalf of the EPA, the NTP

organized a scientific peer review in 2000 to evaluate

reported health-related effects and dose-response relationships for endocrine-disrupting chemicals studied

using dosing regimens lower than those normally

recommended under the EPA’s standard toxicity testing

guidelines. The peer review report is posted on the

NTP web site (http://ntp-server.niehs.nih.gov). A limited

number of printed reports are available from the NTP

Liaison and Scientific Review Office (for contact information, see back flap).

The NTP Interagency Center for the Evaluation of

Alternative Toxicological Methods (NICEATM; see page

19) is involved in preparing background documents for

the EPA on current in vitro methods for assessing

androgenic and estrogenic activities of chemicals. A

peer review of these methods is planned for 2002.

DNA-Based Products 

DNA-based therapies are being developed to treat a

wide range of human diseases. However, by their very

nature, they pose a risk of interacting with the host

genome or disrupting normal cellular processes in

unexpected, unpredictable, and potentially harmful

ways. Examples of DNA-based products include 

vaccines against viruses and bacteria made of plasmid

DNA encoding one or more antigenic proteins, 

synthetic oligonucleotides to modulate gene expression,

and viral carriers for gene therapy. Presently, the NTP

is collaborating with the FDA and sister NIH institutes

to study the safety of DNA-based products. These

studies address life-long risks presented by their use and

the potentials for reproductive toxicities, for transmission

of altered genetic material to subsequent generations,

and for DNA-based products to cause autoimmune 

disease or immune dysfunction. 

12 National Toxicology Program

Current Directions

Considering the large number of chemicals in 

commercial use, the NTP must continually set

priorities and develop research strategies for toxicological characterization and hazard identification that

make the best use of available resources. Using new

testing strategies that provide additional or better 

information can strengthen the scientific knowledge 

on which regulatory decisions are based. The NTP 

core agencies are developing and validating new testing

methods, and in addition, university-based researchers

are participating in these efforts through NIEHS/NIH

extramural grants.

Many testing strategies focus on more rapid screening

tests, alternative or complementary in vivo tests for

rodent bioassays, and less use of two-year rodent studies

to determine toxicities. Strategies include molecular

screening methods, non-mammalian test species, transgenic animal models, genetically engineered in vitro cell

systems, microchip-based genomic technologies, and

computer-based predictive toxicology models. Such

techniques can provide insight into the molecular and

biological events associated with a chemical’s toxic

effect, as well as mechanistic information for assessing

human risk. They can also help clarify dose-response

relationships, make species comparisons, and identify

sources of variations among individuals. Below are brief

overviews of some current and emerging NTP initiatives

to make better use of these new research tools.

NTP Research Databases 

A primary goal of the NTP is to evaluate agents of public

concern for their potential toxicity or carcinogenicity.

Some studies address general toxic effects in laboratory

animal species, whereas others focus on specific effects

on the immune, neurological, and reproductive and

developmental systems. Data from general toxicology

and carcinogenesis studies are publicly available on the

NTP web site (http://ntp-server.niehs.nih.gov/). The

NTP is expanding public accessibility to NTP data to

include all study types (general toxicology, carcinogenesis,

genetic toxicity, and organ systems). The NTP will make

the data available in a common format and will provide

web-based applications that allow users to query data,

conduct simple statistical manipulations, and export

the information.

Toxicogenomics

New molecular technologies have brought the NTP

into the arena of toxicogenomics, a new scientific field

that examines how the entire genome is involved in

organisms' responses to environmental toxicants.

Toxicogenomics applies genetic knowledge to environmental medicine by studying the effect of toxicants on

gene activity and specific proteins produced by genes.

It combines information from studies of genomic-scale

messenger RNA (mRNA) profiling (by microarray

analysis), cell-wide or tissue-wide protein profiling

14 National Toxicology Program

III Evolving Strategies
(proteomics), genetic susceptibility, and computational

models to illustrate the roles of gene-environment

interactions in disease. This field could have a revolutionary impact on environmental health, drug safety,

and risk assessment. 

To centralize activities in toxicogenomics, the NIEHS/

NIH established the National Center for Toxicogenomics

(NCT) in 2000. Complementary DNA (cDNA) 

microchip-based technology will enable the NCT to

assess the genetic impact of toxicants. Microarrays 

containing genes from common test animals and organisms,

including mice, rats, and yeast, are currently in use at the

NIEHS/NIH, and the NIOSH/CDC has compiled a

hepatic microarray. 

Gene arrays are being evaluated against known toxicants and building a database of expression information

to determine the typical genetic changes or “signature”

profiles produced by these toxicants. Identification of

such changes in gene expression on a genome-wide

basis could provide a global perspective on how an

organism responds to a specific stress, drug, or toxicant.

As this technology continues to improve, it will help

NTP scientists evaluate and compare compounds

under study. Such information could define cellular

networks of response genes, identify target molecules 

of toxicity, provide future biomarkers and alternative

testing procedures, and identify individuals who are

sensitive to drugs or environmental agents. 

Transgenic Animals

For more than three decades, the NTP has conducted

studies in laboratory rodents (bioassays) to identify 

carcinogens thought to pose risks to human health.

New genomic technologies enable transgenic models

that are being evaluated as alternatives or complements

to rodent bioassays. Genetically altered or transgenic

mouse models carry activated oncogenes or inactivated

tumor suppressor genes known to be involved in 

neoplastic (tumor causing) processes in both humans

and rodents. This trait may allow these mice to respond

or show the effects of carcinogens more quickly than 

conventional rodent strains, and within a time frame in

which few, if any, spontaneous tumors would arise. Target

or reporter genes also allow direct molecular and cellular

analysis of a chemical’s effects and can provide additional

mechanistic information about its mode of action. 

The NTP is evaluating the usefulness of a number of

transgenic rodent models for studies of carcinogenesis

[p16INK4a, p53def (p53 +/–), Tg.AC (v-Ha-ras), and

Tg.NK (MMTV/c-neu)] and mutagenesis [C57BL/

6J-TgN (phiX174am3, cs70) 54Hvm]. The p53def and

Tg.AC models appear to be able to identify known

human carcinogens. The p53def has demonstrated

preferential identification of genotoxic/mutagenic 

carcinogens, and the Tg.AC has responded to both

genotoxic and nongenotoxic carcinogens. As understanding progresses of the complex signaling pathways

turned on or off during carcinogenesis, the NTP will be

able to select transgenic animal models that best mimic

human tissue processes, providing a firmer foundation

for applying hazard data from animals to humans. Efforts

are also underway to develop transgenic cell lines and to

evaluate the usefulness of transgenic fish as alternates to

mouse or cultured cell models.

Risk Assessment Methodology 

Risk assessment involves using facts to determine whether

exposure to hazardous agents affects the health of individuals and populations, and if so, how much. Biologically

based mathematical models for estimating human risk

are useful to risk assessment. These models are mathematical representations of physiological and biochemical

processes known to occur in laboratory animals and

humans. These models can provide a scientifically

National Toxicology Program 15
sound basis for evaluating data in animals and then

applying that information across species to determine 

if and how exposure to an agent might cause health

effects in humans. 

Developing biologically based models relies on first

developing a simple model based on available data and

then testing predictions of the model experimentally. As

more data become available from studies in cell cultures,

animals, and humans, the model is continually adjusted

or expanded. Physiologically based pharmacokinetic

(PBPK) models quantify the biological processes of

absorption, distribution, metabolism, and elimination

of an agent resulting from exposure in animals or

humans (Figure 3). The NIEHS/NIH has created or is

developing PBPK models to evaluate exposure-response

relationships for carcinogenicity and developmental and

reproductive toxicities (listed in Table 5). PBPK models

are now often included in NTP Technical Reports. This

information helps regulatory agencies assess the human

risk from exposure to environmental agents.

Combining PBPK models with models that measure

changes in cells in target tissues under different concentrations of test agents helps define dose-response

relationships and determine the likelihood of adverse

effects from “low-dose” exposure. These models also

help to assess variation among individuals in specific

groups (e.g., same or similar age, gender, genetic 

predisposition, or ethnicity). The NIEHS/NIH has

developed mechanistic models of aryl hydrocarbon

receptor-dependent changes in gene expression for the

carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin

(TCDD). TCDD is the most potent member of the

dioxin class of chemicals. Dioxins are unwanted, but

widely occurring, by-products of chemical processes

that involve reactions of chlorine and hydrocarbons

(e.g., produced by paper and pulp bleaching or

incineration of hospital and municipal wastes). They

are also contaminants in some pesticides, herbicides,

and wood preservatives. The EPA used this model in its

TCDD cancer risk assessment, which serves as its basis

for regulating human exposure to this environmental

hazard. NTP initiatives in human exposure and new

toxicogenomic technologies should provide human and

animal mechanistic data for developing and improving

biologically based models.

16 National Toxicology Program

Evolving Strategies

Chemical Route of Exposure

Table 5 Physiologically Based Toxicokinetic Modeling

Anthraquinone Oral in feed

Butadiene Inhalation

p-p’-Dichlorodiphenylsulfone Oral in feed

Isoprene Inhalation

Melatonin Endogenous

Mercury (pregnate rat) Inhalation

Methyleugenol Oral by gavage

Naphthalene Inhalation

Polychlorinated biphenyls (209 congeners) Multiple routes

Primidone Oral in fed

Sodium nitrite Oral in drinking water

2,3,7,8-Tetrachlorodibenzo-p-dioxin Oral and dermal

This model represents the uptake, distribution, and metabolism of

an environmental agent administered orally.

Physiologically Based 

Pharmacokinetic Model

Figure 3

Oral Dose

Venous Blood

Arterial Blood

GI Lumen

GI Blood

GI tract

Liver Blood

Liver Metabolism

Fat Blood

Fat

Kidney Blood

Kidney

Human Reproduction

The NTP Center for the Evaluation of Risks to Human

Reproduction (CERHR), established in 1998, serves as

an environmental health resource to the public and to

regulatory and health agencies. It provides scientifically

based, uniform assessments of the potential for adverse

effects on reproduction and development caused by

agents to which humans are exposed. The NTP Board of

Scientific Counselors (“the Board”) advises the CERHR

on its processes, priorities, and direction. 

The CERHR follows a formal, open process for

nomination, selection, and review of chemicals; public

input is encouraged. The CERHR selects chemicals for

review based on several factors, including production

volume, extent of human exposures, public concern

about the chemical hazard, and published evidence of

reproductive or developmental toxicities. The CERHR

carries out these assessments through rigorous evaluations

by independent scientific panels in public forums.

These evaluations are intended to

• interpret scientific evidence to the public and provide 

information about the strength of the evidence that a

given exposure or circumstance poses a hazard to

reproduction or the health and welfare of children;

• provide regulatory agencies with objective and 

scientifically sound assessments of data related to the 

reproductive/developmental health effects associated 

with exposure to specific chemicals or classes of 

chemicals, including descriptions of any uncertainties 

associated with these assessments; and 

• identify knowledge gaps to help establish research and 

testing priorities.

The CERHR’s first expert panel evaluated evidence

that seven selected phthalates [butyl benzyl phthalate,

di(2-ethylhexyl) phthalate, di-isodecyl phthalate, 

di-isononyl phthalate, di-n-butyl phthalate, di-n-hexyl

phthalate, and di-n-octyl phthalate] may pose a reproductive and/or developmental risk for people exposed

to these chemicals. Phthalates are widely used as plasticizers in consumer products such as shower curtains,

medical devices, upholstery, raincoats, and soft-squeeze

toys. Other expert panels have addressed potential

reproductive and/or developmental toxicity of methanol

(October 2001) and 1-bromopropane and 2-bromoprane

(December 2001). Methanol is a commercially important,

high-production-volume chemical with potential for

occupational, consumer, and environmental exposure. 

1-Bromopropane has various industrial uses and is

being considered as a replacement for ozone-depleting

chemicals such as hydrochlorofluorocarbons and 

chlorinated solvents. 2-Bromopropane has no industrial 

uses in the United States but is a contaminant in 

1-bromopropane. A future CERHR evaluation is planned

for ethylene glycol, a high-production-volume chemical

used chiefly in antifreeze for heating and cooling systems.

18 National Toxicology Program

IVCenters
Expert panel reports are posted on CERHR's web 

site (http://cerhr.niehs.nih.gov) and are available in hard

copy from the CERHR. As a final step in its review of a

chemical, the NTP prepares an NTP-CERHR Report.

This report gives the NTP's interpretation of the potential

for the chemical to cause adverse reproductive and/or

developmental effects for humans exposed to it. The

NTP-CERHR Reports are transmitted to federal and

state agencies, interested parties, and the public and will

be available on the center's web site. NTP-CERHR

Reports are currently being developed for the seven

phthalates, methanol, and the bromopropanes.

The center’s web site has information on various

environmental exposures and their potential to affect

pregnancy and child development, as well as links to

other resources. The CERHR welcomes nominations of

chemicals for review or scientists for its expert registry.

Information about the CERHR and the nomination

process is available from its web page or by contacting

Dr. Michael Shelby, Director, CERHR (for contact

information, see back flap). 

NTP Center for Phototoxicology 

The NTP Center for Phototoxicology (NCP) was established in 2000 to conduct mechanistic-based research

and phototoxicology and photocarcinogenesis studies 

on substances nominated to the NTP. Many of these 

compounds are of regulatory importance to the FDA.

Research in this area is very important because of the

public’s increasing exposure to ultraviolet (UV) radiation

or sunlight through more frequent use of tanning booths

and more leisure time spent in outdoor activities. 

The NCP’s state-of-the-art laboratory can study the

potential toxic or carcinogenic effects of a test substance

in combination with electromagnetic radiation from

several light sources. The NCP also conducts mechanistic

studies to learn how these effects might occur. The 

laboratory can simulate sunlight using 6.5 kilowatt

xenon-arc lamps that can mimic terrestrial solar light

for most latitudes. Emulating terrestrial light enables

researchers to experimentally duplicate human exposure

conditions, which is critical for such research. The 

facility can also perform studies using light from different

types of fluorescent tubes, such as those used in fluorescent lamps and suntan-bed lamps. 

The NTP Board of Scientific Counselors advises the

NCP on its programs and priorities. Substances selected

for testing are nominated directly from the FDA and

from outside submissions to the NTP. The FDA's

Phototoxicology Chemical Selection Working Group

prioritizes nominations and forwards them to the NTP

for formal consideration in its nomination and selection

process. Current research initiatives are described on

page 9 under “Phototoxicology.” Additional information

about the NCP is available through the NCP web site

(http://www.fda.gov/nctr/science/phototox.htm) or by

contacting Dr. Paul C. Howard, Director, NCP (for 

contact information, see back flap).

NTP Interagency Center for the Evaluation of

Alternative Toxicological Methods 

Toxicity testing is absolutely necessary to assess the 

hazards and safety of substances in our food, air, and

water, in the workplace, and at home. Developing, 

validating, accepting, and harmonizing new and revised

toxicological test methods are coordinated throughout

the federal government through the Interagency

Coordinating Committee on the Validation of

Alternative Methods (ICCVAM). The ICCVAM was

established in 2000 (ICCVAM Authorization Act of

2000: Public Law 106-545) as a permanent interagency

coordinating committee of the NIEHS/NIH under 

the NTP Interagency Center for the Evaluation of

Alternative Toxicological Methods (NICEATM). 

National Toxicology Program 19
20 National Toxicology Program

The ICCVAM consists of the heads of 15 federal agencies

or their designees (Table 6).

The NICEATM and the ICCVAM facilitate the development, scientific review, and validation of new and

revised toxicological test methods that may predict human

health risks better than currently used methods, improve

our understanding of toxicity, save time and money, and

even refine, reduce, or replace animal use. The NICEATM

also promotes information sharing and communication

among the agencies and other interested parties. 

The Scientific Advisory Committee on Alternative

Toxicological Methods (SACATM), established in

January 2002, provides advice on the activities of the

ICCVAM and the NICEATM.

The ICCVAM has a formal process for evaluating new

or revised toxicological test methods. The NICEATM

and the ICCVAM convene workshops and expert panel

meetings to evaluate how well current methods work,

to identify areas needing improved or new methods, to

assess the current status of new methods, and to recommend additional research, development, and validation.

These meetings are open to the public and have opportunity for public comment. Meeting reports, public

comments, and ICCVAM recommendations regarding

the scientific validity and potential acceptability of alternative test methods are forwarded to federal agencies

for their consideration. Each agency determines the 

regulatory acceptability of a method according to its

own statutory mandates. 

The Local Lymph Node Assay (LLNA) was the first

method evaluated under the ICCVAM peer review

process. The panel concluded that the LLNA is a valid

substitute for currently accepted guinea pig test methods. The EPA, the Occupational Safety and Health

Administration, and the FDA announced their acceptance

of the LLNA as an alternative method in October 1999.

Compared to the traditional test, the LLNA can be

completed in a shorter timeframe, provides dose-response

information, reduces the number of animals required,

and eliminates animal pain and distress.

The NICEATM and the ICCVAM recently held a

peer review on the Up-and-Down Procedure (UDP) 

for assessing acute oral toxicity. The peer review panel 

recommended the UDP as a substitute for the conventional LD50 test for hazard classification testing. The

UDP will reduce the number of animals used for acute

toxicity testing. The ICCVAM agreed with the panel's

conclusion and will now develop test recommendations

and forward them to the appropriate federal agencies for

their consideration. In October 2000, the NICEATM

and ICCVAM organized an international workshop to

review and evaluate in vitro methods for assessing acute

systemic toxicity. The workshop experts recommended

in vitro cytotoxicity methods as an approach that could

be used to estimate starting doses for in vivo acute 

toxicity studies, which will further reduce numbers 

of animals used. The ICCVAM agreed with this

recommendation and will develop and forward test

recommendations to the appropriate federal agencies

for their consideration. As follow-up to both reviews, a

workshop on the implementation of acute toxicity test

methods was held in February 2002 at the NIH. The

NICEATM will hold an expert panel meeting in May

2002 to assess the validation status of several in vitro

assays proposed for possible use in the EPA’s Endocrine

Disruptor Screening Program.

Additional information about NICEATM and 

ICCVAM, meeting schedules, meeting reports and

minutes, and information on nominating alternative

toxicological methods is available through the ICCVAM/

NICEATM web site (http://iccvam.niehs.nih.gov) or by

contacting Dr. William S. Stokes, Director, NICEATM

(for contact information, see back flap).

Centers

Table 6 ICCVAM

• Agency for Toxic Substances and 

Disease Registry

• Food and Drug Administration

• National Institute for Occupational 

Safety and Health/Centers for Disease 

Control and Prevention

• National Institutes of Health

• National Cancer Institute/National Institutes

of Health

• National Institute of Environmental Health 

Sciences/National Institutes of Health

• National Library of Medicine/National 

Institutes of Health

• Occupational Safety and Health 

Administration

• U.S. Consumer Product Safety Commission

• U.S. Department of Agriculture

• U.S. Department of Defense

• U.S. Department of Energy

• U.S. Department of the Interior

• U.S. Department of Transportation

• U.S. Environmental Protection Agency

22 National Toxicology Program

The Report on Carcinogens (RoC) is prepared

every two years in response to Section 301 of the

Public Health Service Act, as amended. The RoC lists

all substances that either are known to be human 

carcinogens or may reasonably be anticipated to be

human carcinogens, and to which a significant number

of people living in the United States are exposed. The

Secretary, HHS delegated responsibility preparing 

the RoC to the NTP, which prepares the report with

assistance from other federal health and regulatory

agencies and nongovernment institutions. 

The RoC is an informational, scientific and public

health document that identifies and discusses agents,

substances, mixtures, and exposure circumstances that

may pose a carcinogenic hazard to human health. It

compiles meaningful and useful data on the agents 

listed, including carcinogenicity, genotoxicity, and 

biological mechanisms in humans and/or animals; the

potential for exposure to them; and federal regulations

to limit exposures. 

The NTP solicits and encourages broad participation

from groups or individuals interested in nominating

agents, substances, mixtures, or exposure circumstances

for listing in or delisting from the RoC. Anyone may

submit a nomination for consideration by the NTP.

Review of the nominations for listing in or delisting

from the RoC follows a formal process that includes

many phases of scientific peer review and many

opportunities for public comment (Figure 4). The review

groups evaluate each nomination according to specific

RoC criteria. The NTP Director evaluates all review

group recommendations, public comments, and other

information in developing a recommendation to the

Secretary, HHS. 

The 9th RoC was initially released May 15, 2000,

with an addendum published on January 19, 2001, and

is available on the Environmental Health Perspectives

web site (http://ehponline.org; for contact information,

see back flap). The scientific review of nominations to

the 10th RoC is complete and we anticipate publication in 2002 (see list in Table 7). 

The preparation and review process for each RoC

takes approximately three years. Table 8 lists the nominations under consideration for the 11th RoC; review

of these nominations is underway, and publication is

scheduled for 2004.

Additional information about the RoC, including

how to obtain copies of the report and how to submit 

a nomination for listing in or delisting from the 

RoC, is available through the NTP web page

(http://ntp-server.niehs.nih.gov) or by contacting 

Dr. C.W. Jameson, Head, Report on Carcinogens 

(for contact information, see back flap).

VRoC
National Toxicology Program 23

Table 7 Summary of the Agents, Substances, Mixtures, or Exposure Circumstances 

for Possible Listing in or Delisting from the 10th Report on Carcinogens

Reviewed in January 2000 Reviewed in December 2000

• 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) 

• Beryllium and beryllium compounds

• 2,2-bis-(Bromomethyl)-1,3-propanediol

• 2,3-Dibromo-1-propanol

• Dyes metabolized to 3,3 ́-dimethoxybenzidine

(dimethoxybenzidine dyes as a class)

• Dyes metabolized to 3,3 ́-dimethylbenzidine

(dimethylbenzidine dyes as a class)

• Styrene-7,8-oxide

• Vinyl bromide

• Vinyl fluoride

• Broad-spectrum UV radiation, UVA, UVB, and UVC

• Chloramphenicol

• Estrogens, steriodal

• Nickel and nickel compounds

• Methyleugenol

• Trichloroethylene

• Wood dust

• 1-Amino-2,4-dibromo-anthraquinone • Naphthalene

• 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) • Neutrons

• 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) • Nitrobenzene

• Cobalt sulfate heptahydrate • Nitromethane

• Diazoaminobenzene • Occupational exposure to lead or lead compounds

• Diethanolamine • Phenylimidazopyridine (PhIP)

• Hepatitis B virus • 4,4'-Thiodianiline

• Hepatitis C virus • X-radiation and gamma (γ)-radiation

• High-risk human papillomaviruses

Table 8 Summary of Nominations under Consideration for the 11th Report on Carcinogens

ATSDR, Agency for Toxic Substances and Disease Registry; CPSC, U.S. Consumer Product Safety Commission; EPA, U.S. Environmental Protection Agency; FDA, Food and

Drug Administration; NCEH/CDC, National Center for Environmental Health of the Centers for Disease Control and Prevention; NCI/NIH, National Cancer Institute of the

National Institutes of Health; NCTR/FDA, National Center for Toxicological Research of the Food and Drug Administration; NIEHS/NIH, National Institute of Environmental

Health Sciences of the National Institutes of Health; NIH, National Institutes of Health; NIOSH/CDC, National Institute for Occupational Safety and Health of the Centers for

Disease Control and Prevention; OSHA, Occupational Safety and Health Administration.

Figure 4 Report on Carcinogens Review Process

Nominations from Federal and State Agencies,

Industry, Public, Labor, and Academia

Solicit Public Comment

NIEHS Review Group

NTP Executive Committee Interagency Work Group

(NCI/NIH, NIEHS/NIH, NCTR/FDA, NCEH/CDC, NIOSH/CDC, ATSDR, CPSC, EPA, OSHA)

Solicit Public Comment

NTP Board of Scientific Counselors 

RoC Subcommittee

(External Peer Review, Public Meeting)

Solicit Public Comment

NTP Executive Committee

(NCI/NIH, NIEHS/NIH, NIH, NCEH/CDC, FDA,

NIOSH/CDC, ASTDR, CPSC, EPA, OSHA)

Director NTP

Secretary HHS
Communication and Public Outreach

Open communication with federal and state agencies,

industry, academia, and the public is crucial for the

success of NTP activities. Partnerships with sister 

federal agencies are increasing, and the NTP continues

to collaborate with the private sector. NTP conferences

and workshops give researchers, regulators, policy 

makers, and the public the chance to examine issues

together, exchange information, and reach agreement

on future directions for toxicology and risk assessment.

The NTP is interested in input from the public and

all interested parties on its programs and priorities.

Nominations, inquiries, and comments are welcome at

any time. The NTP Liaison and Scientific Review Office

collects input, represents the program through exhibits at

national and international meetings, and oversees the

distribution of information about programs, workshops,

initiatives, and other projects. General inquiries and

requests for information can be directed to this office. 

The NTP web site (http://ntp-server.niehs.nih.gov)

offers access to information about the NTP, with links

that detail and highlight ongoing and future initiatives

and the NTP centers. The NTP distributes testing and

research results, program plans, and other publications

through mailings, Federal Register announcements,

and the NTP web site. In addition, individuals can

subscribe free-of-charge to the NTP listserve by 

registering online through the web site or by sending 

e-mail to ntpmail-request@list.niehs.nih.gov with

“subscribe” as the message.

The Central Data Management (CDM) oversees 

distribution (on request) of specific chemical study

information and NTP documents, including the NTP

Annual Plan, NTP Study Status Reports, pre-peer

review copies of draft NTP Technical Reports, background documents for chemicals nominated to the

NTP for study, and minutes from meetings of the NTP

Board of Scientific Counselors and its subcommittees.

To request any of these documents, contact the CDM. 

The Environmental Health Perspectives (EHP) web

site (http://ehponline.org) provides searchable access

and printed copies of NTP publications, including the

Report on Carcinogens, NTP Technical Reports, and

NTP Toxicity Reports. EHP subscription packages

include access to NTP publications, Environmental

Health Perspectives journal, the Rodent Historical

Controls Database, and the Chemical Health and Safety

Database. For additional information, contact EHP.

24 National Toxicology Program

VI Outreach
Primary Contact:

NTP Liaison and Scientific Review Office

P.O. Box 12233, MD A3-01

Research Triangle Park, NC 27709

Telephone: (919) 541-0530

E-mail: liaison@starbase.niehs.nih.gov

Program Contacts:

NTP Center for the Evaluation of Risks 

to Human Reproduction (CERHR)

P.O. Box 12233, MD EC-32

Research Triangle Park, NC 27709

Telephone: (919) 541-3455

E-mail: cerhr@niehs.nih.gov

Web site: http://cerhr.niehs.nih.gov

NTP Center for Phototoxicology (NCP)

NCTR/FDA, HFT-110

3900 NCTR Road

Jefferson, AR 72079

Telephone: (870) 543-7672

E-mail: phoward@nctr.fda.gov

Web site: http://www.fda.gov/nctr/science/phototox.htm

NTP Interagency Center for the Evaluation of 

Alternative Toxicological Methods (NICEATM)

P.O. Box 12233, MD EC-17

Research Triangle Park, NC 27709

Telephone: (919) 541-2384

E-mail: niceatm@niehs.nih.gov

Web site: http://iccvam.niehs.nih.gov

Office of Chemical Nomination and Selection

P.O. Box 12233, MD A3-01

Research Triangle Park, NC 27709

Telephone: (919) 541-5710

E-mail: ntpnomin@niehs.nih.gov

Report on Carcinogens (RoC)

P.O. Box 12233, MD EC-14

Research Triangle Park, NC 27709

Telephone: (919) 541-4096

E-mail: jameson@niehs.nih.gov

Central Data Management (CDM)

P.O. Box 12233, MD E1-02

Research Triangle Park, NC 27709

Telephone: (919) 541-3419

E-mail: cdm@niehs.nih.gov

Environmental Health Perspectives (EHP)

P.O. Box 12510, MD EC-15

Research Triangle Park, NC 27709

Telephone: (800) 315-3010

E-mail: ehis@niehs.nih.gov 

Web site: http://ehponline.org

Contact Information

NTP

National Toxicology Program

U.S. Department of Health and Human Services

headquartered at the

National Institutes of Health

National Institute of Environmental Health Sciences

P.O. Box 12233

Research Triangle Park, NC 27709

Web site: http://ntp-server.niehs.nih.gov

U.S. Department of 

Health and Human Services

Public Health Service

National Toxicology Program

Printed in 2002 on recycled paper