NATIONAL TOXICOLOGY PROGRAM

ANNUAL REPORT 

FOR 

FISCAL YEAR 2004 

National Institute of Environmental Health Sciences, National Institutes of Health

National Center for Toxicological Research, Food and Drug Administration 

National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention 

June 2006 

Department of Health and Human Services 

National Toxicology Program

NIH Publication No. 06-5990 

 National Toxicology Program 
FREQUENTLY USED ABBREVIATIONS

ATSDR Agency for Toxic Substances and Disease Registry

CDC Centers for Disease Control and Prevention 

CERHR Center for the Evaluation of Risks to Human Reproduction 

CPSC Consumer Product Safety Commission 

DOD Department of Defense 

DOE Department of Energy

EPA Environmental Protection Agency

FDA Food and Drug Administration 

HHS Department of Health and Human Services 

ICCEC Interagency Committee for Chemical Evaluation and Coordination 

ICCVAM Interagency Coordinating Committee for the Validation of Alternative Methods

NCI/NIH National Cancer Institute of the National Institutes of Health 

NCP NTP Center for Phototoxicology

NCTR/FDA National Center for Toxicological Research of the Food and Drug Administration

NCEH/CDC National Center for Environmental Health of the Centers for Disease Control and 

 Prevention 

NICEATM NTP Interagency Center for the Evaluation of Alternative Toxicological Methods 

NHANES National Health and Nutrition Examination Survey

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 

NIST National Instititute of Standards and Technology 

NLM National Library of Medicine of the National Institutes of Health 

NTP National Toxicology Program

OSHA Occupational Safety and Health Administration 

PBPK Physiologically Based Pharmacokinetic 

RoC Report on Carcinogens 

 National Toxicology Program 
TABLE OF CONTENTS

OVERVIEW OF THE NATIONAL TOXICOLOGY PROGRAM ...................................................... 1

Mission and Goals....................................................................................................................................1 

Organizational Structure and Oversight ...................................................................................................1 

Advisory Board and Committees..............................................................................................................2 

NTP Executive Committee.......................................................................................................................5 

Addressing Scientific and Regulatory Needs...........................................................................................5 

Communication and Public Outreach.......................................................................................................6 

RESOURCES AND PLANNING.............................................................................................................. 8

Current and Projected Research Capacity ................................................................................................8 

Program for the 21st Century ..................................................................................................................10 

REPORT ON CARCINOGENS.............................................................................................................. 13

NTP CENTERS......................................................................................................................................... 18

NTP Center for the Evaluation of Risks to Human Reproduction .........................................................18 

NTP Interagency Center for the Evaluation of Alternative Toxicological Methods..............................22 

NTP Center for Phototoxicology............................................................................................................23 

NTP TESTING PROGRAM.................................................................................................................... 25

Nomination, Selection, Evaluation, and Review....................................................................................25 

Highlighted Current NTP Initiatives ......................................................................................................34 

General Toxicology and Subchronic Studies .........................................................................................44 

Chronic Toxicity, Carcinogenesis, and Mutagenesis .............................................................................47 

Immunotoxicology..................................................................................................................................54 

Neurotoxicology .....................................................................................................................................55 

Developmental and Reproductive Toxicology .......................................................................................56 

Respiratory Toxicology ..........................................................................................................................58 

Epidemiology and Exposure Assessment...............................................................................................59 

Chemical Disposition, Toxicokinetics, and Physiologically Based Pharmacokinetic Models...............62 

ALTERNATIVE TEST SYSTEMS ........................................................................................................ 65

Genetically Modified Mouse Models.....................................................................................................66 

Non-Mammalian Models........................................................................................................................68 

Magnetic Resonance Imaging ................................................................................................................68 

ScanScope–2D Imaging Technology for Pathological Evaluations.......................................................68 

APPENDIX 1............................................................................................................................................. 70

Agency Staff and Contact Information...................................................................................................70 

APPENDIX 2............................................................................................................................................. 73

2004 Bibliography ..................................................................................................................................73 

 National Toxicology Program 
 National Toxicology Program 
OVERVIEW OF THE NATIONAL TOXICOLOGY PROGRAM 

MISSION AND GOALS

Currently, the Toxic Substances Control Act Chemical Substance Inventory, first published in 

1979, lists over 80,000 chemicals as being available for sale and use in the United States. 

Approximately 850 active pesticide ingredients are formulated into approximately 17,000 

pesticide products. An estimated 500-600 new industrial chemicals are introduced annually 

into US commerce. The effects of many of these substances 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 

substances are thought to pose a significant risk to human health, safeguarding the public 

depends upon identifying the effects of these agents as well as certain naturally occurring 

chemicals, and determining the levels of exposure at which they may become potentially 

hazardous to humans. 

The Department of Health Education and Welfare (now the Department of Health and Human 

Services, HHS) established the National Toxicology Program (NTP) in 1978. 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 evaluations of substances of public health concern. 

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

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

• communicate with all stakeholders including government, industry, academia, the 

environmental community, and the public. 

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 serves as the NTP Director. The National Cancer Institute of the 

National Institutes of Health (NCI/NIH) was a charter agency of the NTP and continues to 

participate on the NTP Executive Committee. The NCI/NIH carcinogenesis bioassay 

program was transferred to the NIEHS in July 1981. Questions and inquiries about the NTP 

can be directed to the NTP Office of Liaison and Scientific Review (919-541-0530 or 

liaison@starbase.niehs.nih.gov, see Communication and Public Outreach, page 6). 

NTP Management 

Dr. Kenneth Olden, Director of NIEHS/NIH and NTP 

Dr. Christopher J. Portier, NTP Associate Director 

Agency Program Management

NCTR/FDA: Dr. William T. Allaben, Associate Director for Scientific Coordination 

NIEHS/NIH: Dr. Christopher J. Portier, Director, Environmental Toxicology Program 

NIOSH/CDC: Dr. Albert E. Munson, Director, Health Effects Laboratory Division 

1 National Toxicology Program
Staff of the agencies involved with the program and their contact information are provided in 

Appendix 1. 

Advisory Board and Committees 

NTP Board of Scientific Counselors 

The NTP Board of Scientific Counselors (“the NTP Board”) provides scientific oversight to 

the program including its centers. The NTP Board can be composed of up to 35 scientists, 

primarily from the public and private sectors. A list of the current membership (as of October 

2004) is provided in Table 1. The NTP Board's members serve terms of up to four years. 

Members of the NTP Board are distributed among the parent committee and two standing 

subcommittees in order to provide the necessary scientific expertise to the program. The NTP 

Board’s Technical Reports Review Subcommittee meets approximately once a year and 

provides peer review of NTP long-term toxicology and carcinogenesis technical reports. This 

subcommittee also provides peer review by mail of NTP toxicity studies. The Report on 

Carcinogens Subcommittee of the NTP Board provides external scientific evaluation and peer 

review of substances nominated for listing in or delisting (removal) from the Report on 

Carcinogens (see page 13). Additional information about the NTP Board, including minutes 

from its meetings, are accessible on the NTP website (http://ntp.niehs.nih.gov/ select 

“Advisory Board & Committees”) or from Dr. Barbara S. Shane (NIEHS/NIH). 

Contact Information: NTP Liaison and Scientific Review Office, Dr. Barbara S. Shane, Executive 

Secretary, NIEHS/NIH, P.O. Box 12233, MD A3-01, 111 T.W. Alexander Dr., Research Triangle 

Park, NC 27709; T: (919) 541-4253; shane@niehs.nih.gov. 

2 National Toxicology Program
Table 1. NTP Board of Scientific Counselors Membership Roster

Name and Title Affiliation Term Ends Board Service1

Larry S. Andrews, Ph.D. 

Director, Toxicology Department 

Rohm and Haas Company

Spring House, PA

12/31/04 NTP BSC

TRRS 

Diane F. Birt, Ph.D. 

Distinguished Professor & Director, Center for Research 

 on Botanical Dietary Supplements 

Department of Food Science & Human Nutrition 

Iowa State University

Ames, IA 

6/30/06 NTP BSC

TRRS 

Aaron E. Blair, Ph.D., M.P.H.

Occupational & Environemental Epidemiology Branch 

National Cancer Institute, NIH 

Bethesda, MD 

6/30/05 NTP BSC

RoC 

Gail Charnley, Ph.D. 

Principal 

Health Risk Strategies 

Washington, DC 

6/30/05 NTP BSC

RoC 

Harvey Checkoway, Ph.D., M.P.H. 

Professor, Department of Environmental Health & 

 Epidemiology

School of Public Health & Community Medicine

University of Washington 

Seattle, WA 

6/30/05 NTP BSC

RoC 

George P. Daston, Ph.D. 

Research Fellow 

Miami Valley Laboratories 

The Proctor and Gamble Company

Cincinnati, OH 

6/30/06 NTP BSC

Elizabeth Delzell, M.S.P.H., S.D. 

Professor, Department of Epidemiology

School of Public Health 

University of Alabama 

Birmingham, AL 

6/30/06 NTP BSC

RoC 

Michael R. Elwell, D.V.M., Ph.D. 

Research Advisor 

Pathology, Drug Safety Evaluation 

Pfizer Global Research and 

 Development 

Groton, CT 

6/30/05 NTP BSC

TRRS 

Howard Frumkin, M.D., Dr.P.H. 

Professor, Department of Environmental & Occupational 

 Health 

The Rollins School of Public Health 

Emory University

Atlanta, GA 

6/30/05 RoC

Thomas A. Gasiewicz, Ph.D. 

Professor, Department of Environmental Medicine

Environmental Health Sciences Center 

University of Rochester School of

 Medicine

Rochester, NY 

6/30/05 NTP BSC

TRRS 

John P. Giesy, Jr., Ph.D. 

Distinguished Professor, Department of Zoology 

Michigan State University

East Lansing, MI

6/30/06 NTP BSC

TRRS 

Shuk-Mei Ho, Ph.D. 

Professor , Department of Surgery

Division of Urology

University of Massachusetts 

 Medical School 

Worcester, MA

6/30/05 NTP BSC

TRRS 

Charlene A. McQueen, Ph.D. 

Professor, Department of Pharmacology & Toxicology

College of Pharmacy

University of Arizona 

Tucson, AZ 

6/30/06 NTP BSC

TRRS 

Maria T. Morandi, Ph.D., C.I.H.

Assistant Professor, Department of Environmental 

 Sciences 

School of Public Health 

University of Texas 

Houston, TX 

6/30/06 NTP BSC

RoC 

Barbara C. Pence, Ph.D. 

Associate Vice President for Research 

Associate Dean for Research in the Graduate School 

Professor, Department of Pathology

Texas Tech University Health 

 Sciences Center 

Lubbock, TX 

6/30/05 NTP BSC

RoC 

James A. Popp, D.V.M., Ph.D. 

CEO 

Stratoxon LLC 

Lancaster, PA 

6/30/05 NTP BSC

RoC 

Stephen M. Roberts, Ph.D. 

Professor, Center for Environmental & Human 

 Toxicology

University of Florida 

Gainesville, FL 

6/30/05 NTP BSC

TRRS 

Mary Vore, Ph.D.

Professor & Director, Graduate Center for Toxicology

University of Kentucky

Lexington, KY 

6/30/05 NTP BSC

TRRS 

Cheryl Lyn Walker, Ph.D. 

Professor, Department of Carcinogenesis 

M.D. Anderson Cancer Center 

The University of Texas

Smithville, TX 

6/30/05 NTP BSC

TRRS 

3 National Toxicology Program
Name and Title Affiliation Term Ends Board Service1

Bruce S. Weir, Ph.D. 

William Neal Reynolds Professor, Department of 

 Statistics 

North Carolina State University 

Raleigh, NC 

6/30/05 NTP BSC

Scientific Advisory Committee on Alternative Toxicological Methods

The Scientific Advisory Committee on Alternative Toxicological Methods (SACATM) is a 

federally chartered advisory committee established on January 9, 2002, in response to the 

ICCVAM Authorization Act of 2000 (Public Law 106-545). SACATM advises the 

Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM),

the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods 

(NICEATM), and the Director of the NIEHS regarding statutorily mandated duties of 

ICCVAM and activities of NICEATM (see page 22). SACATM provides advice on priorities 

and activities related to the development, validation, scientific review, regulatory acceptance, 

implementation, and national and international harmonization of new, revised, and alternative 

toxicological test methods. Alternative methods are those that reduce, refine (lessen or avoid 

pain and/or distress), or replace the use of animals in testing. SACATM also provides input 

on ways to foster partnerships and communication with interested parties. The NIEHS 

Director appoints 15 voting members to the SACATM and membership as defined in the 

ICCVAM Authorization Act of 2000, includes representatives from academia, state 

government, industry, and animal protection organizations (Table 2). Members serve rotating 

terms of up to four years. The SACATM typically meets once a year. Additional information 

about SACATM, including minutes from its meetings, is available on the NTP website 

(http://ntp.niehs.nih.gov/ select “Advisory Board & Committees”) or from Dr. Kristina 

Thayer (NIEHS/NIH). 

Contact Information: NTP Liaison and Scientific Review Office, Dr. Kristina Thayer, Executive 

Secretary, NIEHS/NIH, P.O. Box 12233, MD A3-01, 111 T.W. Alexander Dr., Research Triangle 

Park, NC 27709; T: (919) 541-5021; thayer@niehs.nih.gov. 

 Table 2. Scientific Advisory Committee on Alternative Toxicological Methods Membership 

Name and Title Affiliation Term Ends

Daniel Acosta, Jr., Ph.D. 

Dean, College of Pharmacy

University of Cincinnati 

Cincinnati, OH 

6/30/06 

Rodger D. Curren, Ph.D. 

President 

Institute for In Vitro Sciences, Inc. 

Gaithersburg, MD

6/30/05 

Jack H. Dean, Ph.D. 

President & Scientific Director 

Sanofi-Synthelabo Research Division 

Sanofi-Synthelabo, Inc. 

Malvern, PA 

12/30/04 

Nancy Flournoy, Ph.D.

Professor, Department of Statistics 

University of Missouri-Columbia 

Columbia, MO 

6/30/06 

Alan M. Goldberg, Ph.D. 

Director, Center for Alternatives to Animal Testing 

Bloomberg School of Public Health 

Johns Hopkins University

Baltimore, MD 

6/30/06 

Sidney Green Jr., Ph.D. 

Professor, Department of Pharmacology

Howard University College of Medicine 

Washington, DC

6/30/05 

A. Wallace Hayes, Ph.D. 

Visiting Scientist 

Harvard School of Public Health

Boston, MA 

6/30/05 

Nancy A. Monteiro-Riviere, Ph.D.

Professor, Department of Clinical Sciences 

College of Veterinary Medicine

Center for Cutaneous Toxicology

North Carolina State University 

Raleigh, NC 

6/30/06 

4 National Toxicology Program
Name and Title Affiliation Term Ends

Stephen H. Safe, Ph.D.

Distinguished Professor, Department of Veterinary Physiology and 

 Pharmacology

College of Veterinary Medicine

Texas A&M University

College Station, TX 

6/30/06 

Jacqueline H. Smith, Ph.D. Chesapeake Consulting Team

Royal Oak, MD

6/30/06 

Carlos Sonnenschein, M.D. 

Professor, Department of Anatomy and Cellular Biology

Tufts University School of Medicine 

Boston, MA 

6/30/05 

Martin L. Stephens, Ph.D. 

Vice President for Animal Research 

The Humane Society of the United States

Washington, DC

6/30/06 

Katherine A. Stitzel, D.V.M West Chester, OH 6/30/05 

Peter Theran, V.M.D. 

Consultant 

Massachusetts Society for the Prevention of

Cruelty to Animals (MSPCA) Boston, MA 

6/30/05 

Calvin C. Willhite, Ph.D. 

Toxicologist, Department of Toxic Substances Control 

California Environmental Protection Agency

Berkeley, CA 

6/30/06 

NTP EXECUTIVE COMMITTEE

The NTP Executive Committee provides programmatic and policy oversight to the NTP 

Director. The Executive Committee meets once or twice a year in closed forum. Members of 

this committee include the heads (or their designees) from the following federal agencies: 

• Agency for Toxic Substances and Disease Registry (ATSDR) 

• Consumer Product Safety Commission (CPSC) 

• Environmental Protection Agency (EPA) 

• Food and Drug Administration (FDA) 

• National Center for Environmental Health (NCEH) of the CDC 

• National Cancer Institute (NCI) of the NIH 

• National Institute of Environmental Health Sciences (NIEHS) of the NIH 

• National Institute for Occupational Safety and Health (NIOSH) of the CDC 

• Occupational Safety and Health Administration (OSHA) 

ADDRESSING SCIENTIFIC AND REGULATORY NEEDS

The NTP is committed to the concept of “good science for good decisions.” This allows the 

program to be flexible and innovative in its approach toward addressing public health 

concerns related to exposures to chemical and physical agents at home, in the workplace, and 

in the environment. The NTP has expanded its scope beyond cancer to include examining the 

impact of substances on non-cancer outcomes such as those affecting reproduction and 

development and the immune, respiratory, and nervous systems. As part of this effort, the 

NTP Center for Evaluation of Risks to Human Reproduction (CERHR) was created in 1998. 

The NTP recognizes that initiatives addressing critical knowledge gaps in toxicological 

evaluations offer the best opportunities for preventing environmentally mediated diseases. 

Therefore, the program’s testing of substances is evolving to include more mechanism-based 

toxicology studies that focus on understanding the modes of action of chemical agents (see 

“Program for the 21st Century”, page 10). In recent years, the NTP has placed a greater 

emphasis on providing human relevance to the interpretation and understanding of 

toxicological information generated using animal or in vitro cell models. This is imperative in 

5 National Toxicology Program
order to be at the forefront in research efforts to improve risk assessment methodologies for 

quantifying the sequence of events that starts with chemical exposure and ends with toxicity. 

Examples of activities it covers include: 

• the increased application of mechanistic information and scientific judgment in the 

deliberations for listings in the Report on Carcinogens. 

• an enhanced effort to examine the merits of alternative testing methods that may provide 

better information than current models using fewer animals, causing less pain or distress, 

and potentially provide improved data to reduce uncertainties in risk assessments. 

• an increased effort to collect information on a broad variety of exposures (either 

environmental or occupational), mixtures of concern, and life stage susceptibility. 

Nationally, the NTP rodent bioassay is recognized as the standard for identification of 

carcinogenic agents; however, the NTP continues to work to reduce the use of experimental 

animals and develop and validate alternative testing methods. This effort led to the creation 

of the NICEATM in 1998. The NTP will continue to work with the ICCVAM through

NICEATM in promoting the development, validation, and regulatory acceptance of new and 

revised alternative toxicological methods. 

Strengthening existing partnerships and forging new ones are important to achieve the goals 

of the NTP. Partnerships with sister federal agencies are increasing and the NTP continues to 

collaborate with the private sector. Examples include co-sponsorship of numerous 

workshops, establishment of the ICCVAM to oversee validation of alternative testing 

methods, and an interagency initiative to characterize occupational exposures. The NTP 

continues to support an effort to evaluate the phototoxicity of various compounds through the 

NTP Center for Phototoxicology (NCP) at NCTR/FDA. In addition, the NTP is contributing 

to toxicological assessments of emerging issues such as nanotechnology, drinking water 

contaminants, radiofrequency radiation emissions from cellular phones, and herbal 

medicines/dietary supplements and will provide this information to other agencies. 

Regulatory agencies make decisions for the protection of public health based on scientific 

information from multiple sources (e.g., toxicology, human studies, and basic research). The 

NTP plays a critical role in providing needed scientific data, interpretation, and guidance 

concerning the appropriate uses of these data to regulatory agencies as well as other groups 

involved in health-related research. The program is committed to using the best science 

available in setting priorities for future studies and in designing, conducting, and interpreting 

the findings of those studies. The American people and government agencies at state and 

federal levels rely on the NTP to provide a strong scientific basis for making credible 

decisions that will protect public health. Over the past two decades, the NTP has developed 

an increasingly interactive relationship with regulatory agencies which plays an important, 

although indirect, role in shaping public health policy. The program maintains an objective, 

science-based approach in dealing with critical issues in toxicology and is recognized by 

many groups for its scientific rigor, objectivity, and open approach in the continuing dialogue 

on the appropriate application of scientific advances to applied toxicology research and 

testing. 

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. NTP advisory groups 

(see page 2) provide regular scientific and public peer review and input. NTP conferences 

and workshops remain a priority and are designed to bring researchers, regulators, policy 

6 National Toxicology Program
makers, and the public together to examine issues and achieve consensus on future directions 

in toxicology and risk assessment. 

Distribution of NTP study results, program plans, initiatives, announcements, press 

advisories, and publications is accomplished in a variety of ways to communicate as much as 

possible with the public. Information is routinely distributed through both regular postal and 

web-based mailings to interested parties and Federal Register announcements. With the everincreasing number of people gaining access, the Internet is a major source for distributing and 

receiving information for the NTP. For example, the NTP established a list-serv several years 

ago to take advantage of this medium and regularly sends news and updates to subscribers. 

To subscribe to this list-serv go to (http://ntp.niehs.nih.gov).

The NTP homepage (http://ntp.niehs.nih.gov) offers access to information about the program

that details and highlights ongoing and future initiatives, announcements, NTP centers, the 

Report on Carcinogens, NTP Technical Reports, and study data. The NTP website was 

established in 1995 when the Internet was just becoming more readily accessible by the 

public. Over time, as new web tools were developed, many new file types and graphics were 

added to the site and it became clear that it was time to completely redesign and organize the 

website. At the end of 2004, the NTP launched its revised website. The information on this 

site is the same as on the previous site, but with a new format and reorganization to improve 

navigation and file retrieval. Some new features include an improved site search capability 

and new applications to view and download individual animal study data from the NTP 

databases. 

The NIEHS/NIH Central Data Management (CDM) Office oversees distribution (upon 

request) of specific, chemical study information, and printed NTP documents – the NTP 

Study Status Reports, final and draft peer reviewed copies of NTP Technical Reports, and 

background documents for substances nominated to the NTP. 

On-line, searchable access is available for the Report on Carcinogens (http://ehponline.org) 

and the NTP Technical, Toxicity, and Genetically Modified Models Reports 

(http://ntp.niehs.nih.gov or http://ehp.niehs.nih.gov/ntp/docs/ntp.html) and printed copies of 

NTP publications are available from the CDM (CDM@niehs.nih.gov or 1-919-541-3419). 

The NTP is interested in and welcomes stakeholder input into its programs and priorities. 

Nominations, inquiries, and comments from the public and other interested parties are 

encouraged at any time. The NTP Liaison and Scientific Review Office at the NIEHS/NIH 

under the direction of Dr. Mary S. Wolfe serves as the focal point for receiving input to the 

program and for overseeing the distribution of information about programs, workshops, 

initiatives, etc. 

NTP Liaison and Scientific Review Office Central Data Management

NIEHS/NIH NIEHS/NIH

P.O. Box 12233, MD A3-01 P.O. Box 12233

111 T.W. Alexander Drive 79 T.W. Alexander Drive 

Phone: (919) 541-0530 Phone: (919) 541-3419

liaison@starbase.niehs.nih.gov cdm@niehs.nih.gov

7 National Toxicology Program
RESOURCES AND PLANNING 

CURRENT AND PROJECTED RESEARCH CAPACITY

The NTP relies on voluntary allocations from the program's three core agencies (NIEHS/NIH, 

NCTR/FDA, and NIOSH/CDC) for supporting its various programs and initiatives. These 

allocations are specified following the determination of yearly appropriations. As shown in 

Figure 2, the actual allocations from the principals toward the NTP have steadily increased 

over the past three years (2002-2004) and are projected to provide a total funding level of 

$198.9M (direct plus indirect) in FY 2005. The NTP primarily conducts its research studies 

in-house at the core agencies or through contract laboratories, but also supports cooperative 

and/or collaborative agreements with other federal agencies. Funds are also used to sponsor 

workshops and conferences and produce and disseminate printed programmatic materials. 

FY 2002 (Actual) FY 2003 (Actual)

FY 2004 (Actual) FY 2005 (Projected)

NIEHS

$175.0

NIEHS

$145.1 NIEHS

$158.7

NIEHS

$169.9

NCTR

$10.4

NCTR

$7.7

NCTR

$4.7 NCTR

$11.1

NIOSH

$14.6

NIOSH

$13.7

NIOSH

$12.0

NIOSH

$13.5

$161.8 Million

Figure 2. Agency Origin And Amounts of Funding (millions)

NATIONAL TOXICOLOGY PROGRAM

$198.9 Million

$183.5 Million

$192.2 Million

8 National Toxicology Program
The NTP maintains an objective, science-based approach in dealing with critical issues in 

toxicology. The program continually sets priorities to improve the nation’s ability to evaluate 

human health effects from environmental exposures and focuses its resources on three major 

program activities: toxicology studies, methods development, and validation. As shown in 

Figure 3, approximately three-fourths (72%) of the NTP's allocations (direct only) in FY 2004 

were directed toward program activities in basic and applied research (toxicology studies) and 

a similar level of effort is projected for FY 2005 (72%). The NTP also has ongoing activities 

for the development and validation of improved research tools for carrying out its research 

studies. Approximately 28% of the NTP allocations are budgeted in FY 2005 for methods 

development and validation. These include NTP initiatives such as transgenic and/or 

alternative models, biomathematical modeling, and genomics. 

Toxicology Studies**

$122.5 Toxicology Studies**

$129.5

Toxicology Studies**

$133.2

Methods Dev.

$37.7

Validation

$13.8 Validation

$12.5 Validation

$13.0

Figure 3. Funding Levels by Program Activities: FY 2003-2005

NATIONAL TOXICOLOGY PROGRAM (millions)

$172.5

 11.0*

$183.5

2003

$179.7

 12.5*

$192.2

 $185.0

 13.9*

 $198.9

*Includes indirect operational support, etc.

**Includes subchronic, chronic, immunotoxicology, chemical disposition, developmental,

 reproduction, and genetic toxicology studies.

Note: Excludes all Superfund and Acquired Immune Deficiency Syndrome activities.

2004 2005 Methods Dev. Projected

$38.8

Methods Dev.

$36.2

Within each of the major program activities, the NTP targets multiple program areas broadly 

represented as genetic toxicology, toxicological characterizations (including immunotoxicology, neurotoxicology, epidemiology and exposure assessment, and general 

toxicology), reproduction and development, and carcinogenesis. Figure 4 shows the projected 

FY 2005 NTP allocations for each of these areas within individual program activities. For 

toxicology studies, the primary single focus remains on carcinogenesis although total 

projected funding for research on non-cancer end points (toxicological characterizations plus 

reproduction and development) is projected at 52%. Methods development and validation 

address strategies for both cancer and non-cancer end points. The majority of the funds for 

both methods development and validation ($25.3M or 65% and $6.6M or 51%, respectively) 

are designated for technologies that will improve the NTP's ability to characterize toxicities. 

9 National Toxicology Program
Toxicology Studies

$133.2

Meth Devel

$38.8

Valid

$13.0

Tox Char

$49.4

Tox Char

$6.6

Carc

$63.9

Carc

$9.3

Carc

$5.9

R&D

$17.3

R&D

$1.9

R&D

$0.25

Genet Tox

$2.6

Genet Tox

$2.3

Figure 4. Funding Levels by Program Area

NATIONAL TOXICOLOGY PROGRAM (millions)

Meth Devel = Methods Development

Valid = Validation

Genet Tox = Genetic Toxicology

Tox Char = Toxicologic Characterization

R & D = Reproduction and Development

Carc = Carcinogenesis

2005 Projected

Genet Tox

$0.25

For each program activity (toxicology studies, methods development and validation), the projected allocated funds for FY 2005 are given for each major

program area (genetic toxicology, toxicological charaterizations, reproduction and development, and carcinogenesis).

Tox Char

$25.3

In totality, the NTP is a comprehensive interagency research program whose core agencies are 

committed to providing resources for continuing the program's research efforts and for 

communicating the knowledge learned to all stakeholders, public and private. The program's

efforts in toxicity testing and risk assessment are directed toward obtaining the best 

scientifically valid data that can be used by health, regulatory, and research agencies for 

making appropriate decisions about potential human risk(s) from exposure to environmental 

toxicants. Toward that end, the NTP is continually evolving to remain at the cutting edge of 

scientific research and the development and application of technology. 

PROGRAM FOR THE 21ST CENTURY

In its more than 25 years of existence, the NTP has fulfilled its mandate by becoming a world 

leader in providing scientific information that improves the nation's ability to evaluate 

potential human health effects from chemical and physical exposures. While the NTP has 

studied over 500 compounds in depth, more than 80,000 chemicals are presently registered in 

the United States for use in such items as foods, personal care products, prescription drugs, 

and household cleaners. During the past quarter of a century, the NTP has provided extensive 

and useful data for predicting human health hazards using a battery of toxicology tests and 

cancer bioassays. However, relatively few of the existing and new chemicals brought to 

market can be fully evaluated for their potential to cause toxicity because these traditional 

toxicity testing methods, while of great value in predicting biological responses, are time

consuming and resource-intensive. Thus, in August of 2003, the NTP decided it was time to 

review its activities and consider how to modify its program to address this deficiency. 

10 National Toxicology Program
11 National Toxicology Program

With this in mind, the NTP began a yearlong process to create a vision and subsequent 

roadmap for the NTP (“NTP Roadmap”) available at http://ntp-server.niehs.nih.gov select 

“NTP Vision and Roadmap.” The NTP Vision for the 21st Century is directed to support the 

evolution of toxicology from a predominantly observational science at the level of diseasespecific models to a predominantly predictive science focused upon a broad inclusion of 

target-specific, mechanism-based, biological observations. To assess potential changes in its 

program, the NTP will evaluate its key activities to determine how best to incorporate new 

scientific technological advances into its present research and testing strategies. The NTP 

Roadmap - developed with input from leading researchers in academia, industry, government, 

and advocacy groups - grew in complexity and scope during its development and addresses 

the goals of the NTP Vision. It provides a framework for setting NTP research priorities to 

achieve the most efficient and effective research portfolio possible. The NTP Roadmap 

identifies the challenges and opportunities confronting the program today and discusses the 

directions envisioned for the NTP in the 21st century in three main areas: (1) refining 

traditional toxicology assays, (2) developing rapid, mechanism-based predictive screens for 

environmentally induced diseases, and (3) improving the overall utility of NTP products for 

public health decisions. 

Over the last two decades, scientists have increasingly studied critical cellular and molecular 

events (mechanisms) that lead to adverse responses to toxicants. Mechanistic information 

may be useful in the identification of biomarkers of exposure and effects that facilitate the 

linkage between laboratory research and human risk. Improving the quality, quantity, and 

utility of mechanistic knowledge is a major impetus behind the NTP Vision. Therefore, for 

the future, the NTP plans to identify and incorporate more mechanistic approaches into its 

toxicology assessments and undertake a systematic and continuing evaluation of the data 

derived from these new approaches to determine their value for providing improved 

information for making public health decisions. Mechanistic information enhances 

interpretation of, but does not currently replace, traditional approaches to toxicological 

evaluation that are the basis for most decisions related to product safety, environmental and 

occupational hazard assessments, and priority setting for detailed chemical toxicity testing. 

Thus, the NTP will continue to conduct long-term bioassays. Any changes in the research 

portfolio of the NTP will be consistent with the principle that the research conducted, data 

collected, and analyses performed should have direct relevance to current and future public 

health decisions. As such, it is important to ensure that changes in the NTP testing program 

are acceptable to and developed in concert with NTP-member agencies and the broader 

scientific community. 

The NTP envisions that over the next decade utilization of our rapidly expanding knowledge 

of the physiological, biochemical, and molecular basis of disease will lead to the development 

of, and a gradual transition to vastly improved and higher-throughput methods for predicting 

the toxicological impacts of environmental agents. Through sustained leadership in creating 

and applying these mechanistic toxicology tools, the NTP will generate the scientific 

information and understanding necessary for public health decision-makers to use for risk 

assessment that will reduce the burden of environmental disease. 

The NTP Roadmap places an increased emphasis on the use of alternative assays for targeting 

the key pathways, molecular events, or processes linked to disease or injury and attempts to 

incorporate them into a research and testing framework. These less expensive, higher 

throughput assays will be used to evaluate or “screen” a greater number of substances and 

establish priorities for their placement in the existing research and testing program. The 

generation of mechanistic information in short or medium high-throughput assays (i.e., gene 

and protein expression, DNA damage/repair, disruptions in cell cycle, and use of nonmammalian models such as Caenorhabditis elegans) will create databases of biological 

observations that can be examined for their predictive value and use in priority setting. The 

results of these screening studies could also potentially stimulate the conduct of more 

extensive, agent-specific, mechanistic studies. If implemented successfully, this framework 
12 National Toxicology Program

should allow the NTP to broaden its testing activities to include more exposure scenarios, 

address susceptibility issues related to the variability in human response, and provide better 

and more targeted scientific guidance for making public health decisions aimed at preventing 

or reducing adverse health effects. The consequence of adding these elements to the NTP’s 

research and testing program is that specific substances or mechanistic hypotheses can feed 

into the traditional testing program in new ways, leading to an enhanced public health impact. 

In addition, the NTP plans to incorporate these screening data into publicly accessible 

databases available to the scientific community for addressing questions about the molecular 

basis of environmentally induced disease. The NTP Roadmap offers hope that at some point 

predictive models could be utilized in reaching public health decisions. 

Additional information about the NTP Roadmap is available at http://ntp-server.niehs.nih.gov

select “NTP Vision and Roadmap.” 

Contact Information: NTP Liaison and Scientific Review Office, Dr. Mary S. Wolfe, Director, 

NIEHS/NIH, P.O. Box 12233, MD A3-01, 111 T.W. Alexander Dr., Research Triangle Park, NC 

27709; T: (919) 541-7539; wolfe@niehs.nih.gov. 
13 National Toxicology Program

Contact information: Report on Carcinogens, Dr. C.W. Jameson, Head, NIEHS/NIH, P.O. Box 12233 

EC-14, 79 T.W. Alexander Dr., Research Triangle Park, NC 27709; T: (919) 541-4096; e-mail: 

jameson@niehs.nih.gov. RoC website: http://ntp.niehs.nih.gov/ select “Report on Carcinogens.”

Table 3 lists the nominations completed for review for listing in the 11th RoC. The

preparation and review process for each RoC extends over approximately a three-year period. 

The scientific review of nominations to the 12th RoC is underway. Table 4 lists the

nominations under consideration for the 12th RoC.

The nomination of substances for listing in or removal from the RoC is open to all interested

individuals and groups. As shown in Figure 5 the process for review of nominations to the 

report is a multi-step, formal, and open process. The scientific review of nominations to the 

11th edition involved three separate reviews (NIEHS/NTP Review Group, NTP Executive 

Committee Interagency Working Group, NTP Board of Scientific Counselors RoC 

Subcommittee) followed by review and comment by the NTP Executive Committee. Public

comments were solicited multiple times during the process and provided to each review group 

as available. The NTP Director received the input from all reviews plus the public comments

and made his recommendations on the nominations to the Secretary, HHS, for review and 

approval. Additional information about the RoC is available on the NTP website:

http://ntp.niehs.nih.gov select “Report on Carcinogens.”

The Biennial Report on Carcinogens (RoC) is a Congressionally mandated listing of

substances (i) that 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, HHS, delegated responsibility for its

preparation to the NTP who prepares the draft with assistance from other federal health and 

regulatory agencies. The RoC is an informational, scientific, and public health document that

identifies and discusses agents, substances, mixtures, or exposure circumstances that may 

pose a carcinogenic hazard to human health. It serves as a meaningful and useful compilation 

of data for listed compounds on (1) the carcinogenicity, genotoxicity, and biological 

mechanisms in humans and/or animals, (2) the potential for exposure, and (3) any relevant 

regulations promulgated by federal agencies. Dr. C.W. Jameson, NIEHS/NIH, oversees

preparation of the RoC.

REPORT ON CARCINOGENS 
 Table 3. Summary of New Listings to the Eleventh Edition of the Report on Carcinogens (Released January 31, 2005) 

Nomination CAS Number Primary Uses or Exposures 

1-Amino-2,4-dibromoanthraquinone 81-49-2 1-Amino-2,4-dibromoanthraquinone is an anthraquinone-derived vat 

dye that is used in the textile industry. 

Certain Heterocyclic Amines (three nominations):(1) 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) (2) 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) (3) 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine(PhIP) 

(1) 77094-11-2 (2) 77500-04-0 

(3) 105650-23-5

MeIQ, MeIQx, and PhIP are heterocyclic amines that are formed during heating or cooking and are found in cooked meat and fish. 

Cobalt Sulfate 10124-43-3 Cobalt sulfate is used in electroplating and electrochemical industrie

It is also used as a coloring agent for ceramics, a drying agent in inkspaints, varnishes and linoleum, and has been added to animal feed as mineral supplement. 

Diazoaminobenzene (DAAB) 136-35-6 DAAB is used as an intermediate, complexing agent, polymer additiv

and also to promote adhesion of natural rubber to steel. 

Diethanolamine (DEA) 111-42-2 DEA is used in the preparation of surfactants used in liquid laundry, 

dishwashing detergents, cosmetics, shampoos, and hair conditioners. DEA is also used in metal working fluids, in textile processing, industrial gas purification and as an anticorrosion agent. 

Hepatitis B Virus (HBV) HBV is a small enveloped DNA virus that is transmitted by

percutaneous or permucosal exposure to infectious blood or bodyfluids that contain blood. 

Hepatitis C Virus (HCV) HCV is an enveloped RNA virus that is transmitted mainly by

percutaneous exposure to infectious blood and less efficiently bypermucosal exposure to infectious blood or body fluids that contain blood. 

Human Papillomaviruses (HPVs) The HPVs are small, non-enveloped viruses that infect oral and genit

mucosa. HPV infections are common throughout the world.

X-Radiation and Gamma (γ)-Radiation The major exposures of concern for cancer from X- and γ-radiation a

from the past use of atomic weapons and from medical uses of radiation. 

Neutrons Exposure to neutrons normally occurs from a mixed irradiation field 

which neutrons are a minor component. The exceptions are exposure of patients to neutron radiotherapy beams and exposures of aircraft passengers and crew. 

Lead and Lead Compounds Major occupational exposures are in the lead smelting and refining

industries, battery-manufacturing plants, steel welding or cutting operations, construction, and firing ranges.

Naphthalene 91-20-3 Naphthalene is used as an intermediate in the synthesis of many

industrial chemicals, an ingredient in some moth repellants and toilet bowl deodorants, as an antiseptic for irrigating animal wounds and to control lice on livestock and poultry. 

14 National To
Nomination CAS Number Primary Uses or Exposures 

Nitrobenzene 98-95-3 Nitrobenzene is used mainly in the production of aniline, itself a maj

chemical intermediate in the production of dyes.

Nitromethane 75-52-5 Nitromethane is used in specialized fuels, in explosives and in the 

synthesis of nitromethane derivatives, pharmaceuticals, agricultural soil fumigants and industrial antimicrobials. In the past it was used achemical stabilizer to prevent the decomposition of varioushalogenated hydrocarbons such as metal degreasers and aerosol propellants. 

4,4’-Thiodianiline 139-65-1 4,4’-Thiodianiline has been produced commercially since the early

1940’s as an intermediate of several diazo dyes. 

Table 4. Nominations Being Reviewed for the Twelth Report on Carcinogens (as of December 2005) 

Nomination CAS Number Primary Uses or Exposures Nominator 

Aristolochic Acid 313-67-7 Aristolochic acid, the principle extract from Aristolochia, is a 

mixture of nitrophenanthrene carboxylic acids. 

NIEHS Naturally occ

IARC2 finding 

carcinogenicihumans (IAR

Herbal Remedies Containing Aristolochic Acid1

Several Aristolochia species (notably A. contorta, A. debilis,

A. fangchi and A. manshuriensis) have been used in traditional Chinese medicine as anti-rheumatics, as diuretics, in thetreatment of edema and for other conditions such as hemorrhoids, coughs and asthma. 

NIEHS Herbal remed

Aristolochia: 

of carcinogenVol. 82, 2002

Captafol 2425-06-01 Captafol is a fungicide that has been widely used since 1961

for the control of fungal diseases in fruits, vegetables and some other plants. Use of captafol in the United States was bannedin 1999. 

NIEHS IARC2 finding 

carcinogenicit53, 1991). IAin many gene

for dominant 

Cobalt–Tungsten Carbide Powders and Hard Metals1

Cobalt-tungsten carbide hard-metals are manufactured by a process of powder metallurgy from tungsten and carbon (tungsten carbide), and small amounts of other metallic compounds using cobalt as a binder. They are used to make cutting and grinding tools, dies, and wear products for a broadspectrum of industries including oil and gas drilling, andmining.. 

NIEHS Recent human 

manufacturing between expocarbide) and lu

15 National To
Nomination CAS Number Primary Uses or Exposures Nominator 

Di-(2-ethylhexyl) Phthalate (DEHP) 

117-81-7 DEHP is mainly used as a plasticizer in polyvinyl chloride

(PVC) resins for fabricating flexible vinyl products. PVC resins have been used to manufacture toys, dolls, vinyl upholstery, tablecloths and many other products. 

Aekyung

Petrochemical Co., 

LTD of Seoul, Korea 

(for delisting) 

Currently listeanticipated to 

reclassified as carcinogenicitMonograph Vwas sufficient experimental liver tumor inis not relevan

Etoposide in Combination with Cisplatin and Bleomycin 

Etoposide in combination with cisplatin and bleomycin is used

to treat testicular germ cell cancers. 

NIEHS IARC2 finding 

carcinogenicit76, 2000). 

Etoposide 33419-42-0 Etoposide is a DNA topoisomerase II inhibitor used in

chemotherapy for non-Hodgkin’s lymphoma, small-cell lungcancer, testicular cancer, lymphomas and a variety of childhood malignancies. 

NIEHS IARC2 finding 

carcinogenicit76, 2000). 

Formaldehyde 50-00-0 Formaldehyde is primarily used in the production of resins that 

are used in the production of many different products, including plastics, adhesives and binders for wood products, pulp and paper, synthetic fibers, and in textile finishing. It isalso used as a disinfectant and preservative and as an intermediate for many industrial chemicals. 

NIEHS Formaldehyde 

reasonably an

Nominated foIARC2 review

sufficient evidformaldehyde 88, 2004). 

Certain Glass Wool Fibers1

*NIEHS recommended that the nomination be defined as “certain glass wool fibers” because of the considerabledifferences in the composition of glass wool fibers 

Glass wool fibers, which are a type of synthetic vitreous fibers, 

are an inorganic fibrous material manufactured primarily fromglass and processed inorganic oxides. The composition ofthese fibers may vary substantially because of differences inend-use, manufacturing requirements and biopersistenceconsiderations. The major uses of glass wool are in thermal, electrical, and acoustical insulation, weatherproofing, andfiltration media. Some glass wool fibers (special purpose fibers) are used for high-efficiency air filtration media, and acid battery separators. 

North American

Insulation

Manufacturers 

Association nominated 

glass wool (respirable 

size) for delisting 

Glass wool (rthe RoC as recarcinogen. I

of limited eviand evaluation carcinogenicitMonograph Vfibers: IARC2 

carcinogenicit81, 2002). 

Metal Working Fluids Metal working fluids are complex mixtures that may contain 

mixtures of oil, emulsifiers, anti-weld agents, corrosion inhibitors, extreme pressure additives, buffers biocides and other additives. They are used to cool and lubricate tools andworking surfaces in a variety of industrial machining andgrinding operations. 

NIEHS Recent human 

fluids that shothese material

ortho-Nitrotoluene 88-72-2 ortho-Nitrotoluene is used to synthesize agricultural and 

rubber chemicals, azo and sulfur dyes, and dyes for cotton, wool, silk, leather, and paper.

NIEHS Results of a N

504, 2002)3, w

carcinogenici

Riddelliine 23246-96-0 Riddelliine is found in class of plants growing in western 

United States. Cattle, horses and sheep ingest these toxicplants. Residues have been found in, milk, and honey.

NIEHS Results of a N

508, 2003)3, w

carcinogenici

16 National To
17 National To

Nomination CAS Number Primary Uses or Exposures Nominator 

Styrene 100-42-5 Styrene is used in the production of polystyrene, acrylonitrilebutadiene-styrene resins, styrene-butadiene rubbers and 

latexes, and unsaturated polystyrene resins. 

Private Individual IARC2 finding 

carcinogenicicarcinogenicit82, 2002). 

Teniposide 29767-20-2 Teniposide is a DNA topoisomerase II inhibitors used mainly

in the treatment of adult and childhood leukemia. 

NIEHS IARC2 finding 

carcinogenicit76, 2000). 

1 Nomination has been redefined based on public comments received from earlier Federal Register Notices and/or review of the literature. The review of severa

 deferred until the 13th RoC (asphalt fumes, atrazine, benzofuran, oxazepam, vinyl mono-halides as a class). The nomination of talc (cosmetic and occupationa

 from review. For additional information on the rationales for deferring or withdrawing a nomination see http://ntp.niehs.nih.gov/ see “Federal Register Notice

 70, No. 200) pages 60548-60544]

2 International Agency for Research on Cancer (IARC). IARC Monographs are available from http://monographs.iarc.fr/.3 NTP Technical Reports are available at http://ntp.niehs.nih.gov/ see “NTP Study Reports.” 
18 National Toxicology Program

NTP CENTERS 

NTP CENTER FOR THE EVALUATION OF RISKS TO HUMAN REPRODUCTION 

The NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) was 

established in 1998 to serve as an environmental health resource to the public and regulatory 

and health agencies. The CERHR is located at the NIEHS/NIH and Dr. Michael Shelby 

serves as the Director. The CERHR publishes monographs that assess the potential for 

substances to cause adverse effects on reproduction and development and whether these 

substances are hazardous for humans. The NTP Board (see page 2) advises the CERHR on its 

processes, priorities, and direction. 

The CERHR follows a formal process for nomination, selection, and review of substances that 

includes evaluation by an ad hoc panel of scientists with topic-specific expertise and three 

formal solicitations of public comment. The CERHR selects substances for review based on 

several factors including production volume, extent of human exposures, public concern about 

the chemical hazard, and the extent of published data from reproductive or developmental 

toxicity studies. Expert panel meetings are open to the public. CERHR held three expert 

panel meetings during fiscal years 2003 and 2004. Other substances have been selected for 

evaluation but expert panel meetings are not yet scheduled (see list below). Following 

completion of an expert panel report and receipt of public comments on the report, the 

CERHR prepares an NTP-CERHR Monograph that is transmitted to federal and state 

agencies, interested parties, the public, and are published in MEDLINE. Each CERHR 

Monograph includes the expert panel’s report, the NTP Brief, and any public comments 

received on the expert panel report. The NTP Brief provides in plain language: 

• background information on the chemical 

• the findings of the expert panel report 

• discussion of any relevant data received after the expert panel meeting 

• the NTP’s conclusions on the potential for the chemical to cause adverse reproductive 

and/or developmental effects in exposed humans 

A summary of conclusions on substances evaluated between 1998 and 2004 is presented in 

Table 5. Additional details about the CERHR process, CERHR expert panel evaluations, and 

monographs are available at the CERHR website (http://cerhr.niehs.nih.gov). The CERHR 

website also contains information covering common questions and concerns regarding a 

healthy pregnancy and the potential of various exposures to adversely affect fertility or the 

development of children 

FY 2003 and 2004 CERHR Expert Panel Evaluations: 

• Ethylene Glycol [CAS No. 107-21-1] - February 11-13, 2003 

• Propylene Glycol [CAS No. 57-55-6] - February 11-13, 2003 

• Fluoxetine (Prozac®) [CAS No. 54910-89-3] - March 3-5, 2004 

• Acrylamide [CAS No. 79-06-1] - May 17-19, 2004 

Contact Information: NTP Center for the Evaluation of Risks to Human Reproduction, Dr. Michael 

Shelby, Director, NIEHS/NIH, P.O. Box 12233 EC-32, 79 T.W. Alexander Dr., Research Triangle 

Park, NC 27709; T: (919) 541-3455; shelby@niehs.nih.gov. CERHR website: 

http://cerhr.niehs.nih.gov 
 Table 5. Summary of NTP-CERHR Monographs and/or Expert Panel Evaluations 

Chemical CAS Number Use NTP Conclusions for Effect on

Human Reproduction 

NTP Conc

Hum

Acrylamide 79-06-1 Used in the production of 

polyacrylamide, which is used in water treatment, pulp and paper production, mineral processing, and scientific research; and in the synthesis of dyes, adhesives, contact lenses, soil conditioners, cosmetics and skin creams, food packaging materials,permanent press fabrics. Acrylamide has recently been found to be produced in some starchy foods cooked at high temperatures. 

Negligible concern for adverse reproductive and developmental effects inthe general population. Minimal concernfor acrylamide-induced heritable effects in the general population. Some concernfor adverse reproductive anddevelopmental effects, including heritable effects, for exposures in occupational settings.

Negligible coreproductive ain the general concern for aheritable effecpopulation. S

reproductive including heriexposures in o

1-Bromopropane 106-94-5 Used as a solvent for fats, waxes and 

resins, and as an intermediate in the synthesis of pharmaceuticals,insecticides, flavors, and fragrances.Used as a vehicle in spray adhesivesand as a cold bath degreaser. 

Serious concern for reproductive effects at the upper end of the human occupational exposure range (18-381 ppm). Minimal concern for reproductive effects when humans are exposed at the lower end of the human occupational exposure range (0.04-0.63 ppm). 

Serious conceeffects at the occupation exppm) (concurMinimal conceffects when lower end of texposure rang

2-Bromopropane 75-26-3 Used as an intermediate in the 

synthesis of pharmaceuticals, dyes and other organic chemicals. In Asia, used as a replacement for chlorofluorocarbons and 1,1,1-trichloroethane and as a solvent/cleaner for micro-electronics.In the US, 2-BP is a contaminant (<0.1%) of 1-bromopropane. 

Some concern for adverse reproductive effects when people are exposed to concentrations of 2-bromopropane at the high end of the occupational exposure range. Minimal concern for adverse reproductive effects when people are exposed to 2-bromopropane at the lowerend of the occupational exposure range. 

Insufficient evdevelopmentabromopropan

Butyl BenzylPhthalate [BBP]

85-68-7 Primarily used in the production of 

vinyl tiles. Also used in food conveyorbelts, artificial leather, automotive trimand traffic cones.

Negligible concern for adverse reproductive effects in exposed men; data are insufficient to reach conclusions for exposed women. 

Minimal conceffects in fetu

Di-n-butyl Phthalate [DBP]

84-74-2 Used as a component of latex

adhesives. Used in cosmetics and otherpersonal care products, as a plasticizer in cellulose plastics, and as a solvent for dyes. 

Negligible concern for reproductive toxicity in exposed adults. 

Minimal conceffects on the when pregnanlevels of 2-10 concern when exposed to hi

19 National To
Chemical CAS Number Use NTP Conclusions for Effect on

Human Reproduction 

NTP Conc

Hum

Di(2-ethylhexyl)Phthalate [DEHP]* 

117-81-7 Used in polyvinyl chloride medical 

devices such as blood bags and IVtubing. Used in a wide variety ofproducts, including flooring, vehicle upholstery, raincoats, toys, and food packaging. It is not used in toysintended for mouthing, such as nipples or teething rings. 

Minimal concern for reproductivetoxicity in exposed adults (Concurs with expert panel). [Expert panel conclusions are presented. NTP conclusions have not yet been determined.]

Concern for dthe reproductiand/or toddlerlevels several general populthat certain mcritically ill mDEHP exposumale reproduc[Expert panel presented. NTyet been deter

Di-n-hexyl Phthalate [DHP] 

84-75-3 A component of industrially important 

phthalates such as di-isohexyl phthalate (up to 25%) and C6-10phthalate (up to 1%). It may occur in a variety of commercial products including dip-molded products such as tool handles or dishwasher baskets, flooring, vinyl gloves, flea collars and conveyer belts used in food processing. 

Insufficient data on hazard and/or

exposure. 

Insufficient daexposure. 

Di-isodecyl Phthalate[DIDP]

26761-40-0 68515-49-1 

Used in a wide variety of products, including insulation of wires andcables, artificial leather, toys, carpet backing, and pool liners. Has onlylimited use in food packaging and handling.

Negligible concern for adverse reproductive effects in exposed adults. 

Minimal conceffects in fetu

Di-isononyl Phthalate [DINP]

28553-12-0 68515-48-0 

Used in a wide variety of products, including garden hoses, pool liners, flooring tiles, tarps, and toys. Has limited use in food packaging.

Minimal concern for adverse reproductive effects in exposed adults 

Minimal conceffects in fetu

Di-n-octyl Phthalate [DnOP]

117-84-0 No commercial uses. Makes up

approximately 20% of the industriallyimportant C6-10 phthalate mixture used in the manufacture of commercial products. 

Negligible concern for adverse reproductive effects in exposed adults 

Insufficient daexposure. 

Ethylene Glycol 107-21-1 Used as a chemical intermediate in the 

production of polyester compounds. Also found in automotive anti-freeze, industrial coolants, hydraulic anddeicer fluids. 

Negligible concern for adverse reproductive effects in exposed adults 

Negligible codevelopmentaglycol at expobw. 

20 National To
21 National To

Chemical CAS Number Use NTP Conclusions for Effect on

Human Reproduction 

NTP Conc

Hum

Fluoxetine Prozac®; SarafemTM

59333-67-4 A widely prescribed pharmaceutical, 

used in the treatment of depression. Recently approved for use in 7–17 year-olds. SarafemTM, is now being prescribed to treat premenstrualdysphoric disorder, potentiallyincreasing the number of exposures for women of childbearing age. 

Minimal concern for adverse reproductive effects in exposed adults 

Some concern length and potherapeutic doInsufficient evpregnancy losinfant exposuon children on 

Methanol 67-56-1 Used in chemical syntheses and as an 

industrial solvent. In a variety of consumer products such as paints, antifreeze, cleaning solutions, and adhesives. Produced as a by-product offermentation, sewage treatment, and paper production. Used as a racing carfuel with potential for expanded use asa vehicle fuel. 

Negligible concern for adverse male reproductive effects when exposed tomethanol levels that result in a low blood methanol level (<10 mg/L blood). Insufficient evidence to assess the effects of methanol on female reproduction. 

Concern for aeffects in fetuexposed to min high blood Minimal concdevelopmentaexposed to mlow blood me(<10 mg/L bl

Propylene Glycol 57-55-6 Used as a chemical intermediate in the 

production of unsaturated polyester resins. Used in liquid detergents, deicing fluids, antifreeze/engine coolant, paints and coatings. Used in foods, cosmetics, tobacco products and pharmaceuticals.

Negligible concern for adverse reproductive effects in exposed adults 

Negligible codevelopmentaglycol exposu

 * NTP CERHR Monograph not yet available
NTP INTERAGENCY CENTER FOR THE EVALUATION OF ALTERNATIVE 

TOXICOLOGICAL METHODS

The development, validation, acceptance, and harmonization of new, revised, and alternative 

toxicological test methods are coordinated in the federal government through the Interagency 

Coordinating Committee on the Validation of Alternative Methods (ICCVAM). NIEHS 

established ICCVAM in 1997 to implement directives in the 1993 NIH Revitalization Act - to 

develop a process to achieve the regulatory acceptance of scientifically valid alternative 

testing methods. Alternative methods are those that reduce, refine, or replace the use of 

animals. The NTP Interagency Center for the Evaluation of Alternative Toxicological 

Methods (NICEATM) was established in 1998 to administer ICCVAM and provide scientific 

support for ICCVAM activities. Dr. William Stokes (CAPT, USPHS) is the NICEATM 

Director. The ICCVAM Authorization Act of 2000 (Public Law [P.L.] 106-545) established 

ICCVAM as a permanent committee and directed ICCVAM to carry out technical evaluations 

of new, revised, and alternative methods. ICCVAM is composed of designated 

representatives of the heads of 15 federal regulatory and research agencies (ATSDR, CPSC, 

Departments of Agriculture, Defense, Energy, Interior, and Transportation, EPA, FDA, 

NIOSH/CDC, OD/NIH, NCI/NIH, NIEHS/NIH, NLM/NIH and OSHA). These agencies 

generate, use, or provide information from toxicity test methods for risk assessment purposes. 

Dr. Leonard Schechtman, NCTR/FDA, serves as chair of ICCVAM. 

The Scientific Advisory Committee for Alternative Toxicological Methods (SACATM, see 

page 4) was chartered on January 9, 2002, to fulfill mandates specified in the ICCVAM 

Authorization Act of 2000 (P.L. 106-545). The SACATM provides advice to ICCVAM, 

NICEATM, and the Director of the NIEHS and NTP regarding statutorily mandated duties of 

the ICCVAM and activities of the NICEATM. 

ICCVAM and NICEATM work to promote the validation and regulatory acceptance of new, 

revised, and alternative toxicological test methods that are more predictive of human and 

ecological effects than those currently available and that refine, reduce, and replace animal 

use whenever possible. The desired outcomes from these new methods are an improvement 

in agencies’ abilities to assess risk and make regulatory decisions, more humane animal use, 

and the reduction and replacement of animals. Workshops and expert panels may be 

convened for various purposes, such as to evaluate the adequacy of existing methods, identify 

promising test methods for further development and validation, evaluate the interim validation 

status of methods, and evaluate proposed validation studies. On behalf of ICCVAM, 

NICEATM convenes scientific peer review panels to evaluate the validation status of 

proposed alternative testing methods for which there is evidence of scientific validity. 

ICCVAM then develops formal test method recommendations for consideration of acceptance 

by agencies. 

Contact information: NTP Interagency Center for the Evaluation of Alternative Toxicological 

Methods, Dr. William Stokes, Director, NIEHS/NIH, P.O. Box 12233, MD EC-17, 79 T.W. Alexander 

Dr., Research Triangle Park, NC 27709, T: (919) 541-2384, e-mail: iccvam@niehs.nih.gov. 

NICEATM/ICCVAM website: http://iccvam.niehs.nih.gov. 

Current Nomination, Evaluation, and Validation Activities 

NICEATM receives proposed test method nominations or submissions intended for ICCVAM 

consideration and review. Test methods can be nominated for validation studies or technical 

reviews. The ICCVAM evaluation process involves an initial assessment by NICEATM of 

the adequacy and completeness of the proposed test method nomination or submission, and a 

determination by ICCVAM of the priority of the proposed method for technical evaluation or 

22 National Toxicology Program
validation studies. Once a proposed test method is accepted for evaluation or validation, 

ICCVAM assembles an interagency working group of scientists with appropriate scientific 

and regulatory expertise to collaborate with NICEATM on the evaluation process. Depending 

on the validation status of the proposed test method, ICCVAM, in conjunction with 

NICEATM, develops recommendations and priorities for further efforts. Such efforts might 

include an expert workshop, an expert panel meeting, a peer review meeting, an expedited 

peer review process, or a validation study. Information and status for the following 

NICEATM activities, including meeting reports, and background documents, are available on 

the NICEATM/ICCVAM website. Recent NICEATM publications and test methods 

currently under review are presented in Tables 6 and 7 respectively. 

Table 6. Recent NICEATM Publications 

Title Date

Publications 

ICCVAM Guidelines for the Nomination and Submission of New, Revised, and Alternative

Test Methods 

September 2003

ICCVAM Biennial Progress Report December 2003

ICCVAM Mission, Vision, and Strategic Priorities February 2004 

Agency Responses to ICCVAM Test Recommendations for the Revised Up-and-Down 

Procedure for Determining Acute Oral Toxicity and In Vitro Methods for Assessing Acute 

Systemic Toxicity

March 2004 

Recommended Performance Standards for In Vitro Test Methods for Skin Corrosion May 2004 

Updated Standardized In Vitro Cytotoxicity Test Method Protocols for Estimating Acute 

Oral Systemic Toxicity

October 2004 

 Table 7. Summary of Nominations or Submissions Under Review by NICEATM/ICCVAM

Test Method Nomination or Submission Status of Nomination 

Xenobiotic Detection Systems (XDS) LUMI-CELLTM - Stably

transfected recombinant cell-based estrogen receptor 

transcriptional method 

Initializing protocol optimization and validation study 

– expected 2005

Ocular and dermal toxicity test methods/ approaches for 

antimicrobial cleaning products 

Published call for data and nominees to serve on 

scientific expert panel – expected March 2005 

IA, Inc. - Biosensor system that can assess estrogen receptor

binding and transcriptional activation 

Received letter of intent. Awaiting submission. 

Otsuka Pharmaceutical Company, Ltd. – Androgen receptor

transcriptional activation assay 

Received pre-validation data. NICEATM reviewed 

and is awaiting notice of Otsuka’s intent to submit for 

possible validation study

CertiChem, Inc. - MCF-7 cell proliferation assay Received letter of intent. NICEATM currently

reviewing draft submission 

IRAS, The Netherlands - H295R cell line screening assay Received letter of intent. NICEATM currently

reviewing draft submission 

EPA – ER and AR binding assays EPA validation studies in progress; submission 

pending 

International Life Sciences Institute (ILSI)/ Health and 

Environmental Science Institute (HESI) Biomarkers Committee 

– developing validation study plans for inhibin B, serum cardiac 

troponins, and nephrotoxicity biomarkers 

ILSI/HESI studies in progress; ICCVAM providing 

comments on study plans; submissions pending 

NTP CENTER FOR PHOTOTOXICOLOGY

The NTP Center for Phototoxicology (NCP) was established in 2000 at the NCTR/FDA in 

Jefferson, Arkansas, to conduct mechanism-based research on the potential toxic or 

carcinogenic effects of a test substance in combination with electromagnetic radiation from

several light sources. In general, these studies investigate the effects on gene expression, 

toxicity, and carcinogenicity of exposure to sunlight combined with either topically applied or 

systemically applied administered substances to the SKH-1 hairless mouse. Many of the 

23 National Toxicology Program
substances under study are high priority and regulatory interest to the FDA. These studies 

generate critically important scientific data for use in determining potential human health 

risks from the effects of these agents on light-induced skin toxicity and skin cancer. Dr. Paul 

Howard, NCTR/FDA, serves as NCP Director. 

The NCP’s state-of-the-art laboratory is equipped with two six-inch zenon arc lamps that 

operate at 6,500 watts. The visible and UV radiation emitted from each lamp, when filtered 

through glass designed to simulate the earth’s atmosphere, closely mimics the spectrum of 

solar light. About 5,000 mice can be exposed per day to the simulated solar light making this 

facility unique for handling the large number of animals required for carcinogenicity studies. 

The facility also has a portable fluorescent lamp assembly that can be equipped with most of 

the available fluorescent lamps (e.g., UV-B lamps, tanning lamps, and germicidal lamps) for 

use in studying the biological effects of these light sources. 

Substances are nominated to the NTP for testing by FDA centers and offices within the FDA 

Commissioner’s Office. The FDA Phototoxicology Chemical Selection Working Group 

prioritizes the nominations and forwards them to the Interagency Committee for Chemical 

Evaluation and Coordination (ICCEC) for entry into the NTP nomination and selection 

process (see page 25). The Toxicology Study Selection and Review Committee, composed of 

scientists with expertise in this area from FDA, NIEHS/NIH, other federal agencies, and 

academia, meets periodically to review the design of protocols and progress of ongoing 

studies. 

Phototoxicology studies are in progress at the NCP for topically applied chemoexfoliating 

acids (α- and β-hydroxy acid) and aloe vera. These lotions or creams are often used in 

cosmetics to correct or improve the appearance of "sun-aged" skin so that it appears smoother 

and less wrinkled. The impact on skin cancer from their continuous use in combination with 

exposure to sunlight is not known. Studies underway at the NCP are using glycolic acid and 

salicylic acid as representatives of the α- and β-hydroxy acids, respectively. The NCP is also 

investigating the effect on 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. 

Additional chemicals in the phototoxicity program include retinyl palmitate (a vitamin A 

derivative in cosmetics), padamate O (lime oil), D&C 27 and 28 (cosmetics), tattoo ink 

chemicals, and fluorescein-based dyes. The end points of these studies are time-to-tumor and 

pathology of the tumor. 

Animal models for testing the role of specific UV wavelengths and substances in the 

development of human malignant skin melanoma do not exist at this time. As a result, the 

effects of substances combined with exposure to sunlight on melanoma development are not 

understood. The NCP is investigating the suitability of a transgenic mouse [TP-ras (+) 

p16/INK4a (+/-)] as a surrogate animal for studying melanoma. 

Future NCP plans include the development of a digital imaging capability for documentation 

of skin lesions on the mouse. Digital analysis of the lesions will decrease personnel time and 

the tracking of lesions on each mouse should be more accurate. The NCP also plans to use 

multiplex polymerase chain reaction (PCR) to study 20 genes and perform gene array studies 

on skin tumors for development of a database that can be used to predict the type of 

pathological lesion in the skin. 

Contact information: NTP Center for Phototoxicology, Dr. Paul C. Howard, Director, NCTR/FDA, 

HFT-110, 3900 NCTR Road, Jefferson, Arkansas, 72079; T: (870) 543-7137; phoward@nctr.fda.gov. 

NCP website: www.fda.gov/nctr/sciences/phototox.htm

24 National Toxicology Program
NTP TESTING PROGRAM 

NOMINATION, SELECTION, EVALUATION, AND REVIEW

Nominations for Study 

The NTP seeks to maintain a balanced research and testing program that provides data 

addressing a wide variety of issues important to public health. The NTP actively solicits the 

nomination of studies that permit the testing of hypotheses to 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. Nominations considered appropriate for 

NTP study follow the principles listed in Table 8. 

Table 8. Nomination Principles for NTP Studies 

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

2. Biological or physical agents that may not be adequately evaluated without federal involvement 

3. 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 

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

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

6. Chemicals or agents that will aid our understanding of chemical toxicities, or our understanding of the use of

test systems to evaluate potential toxicities 

7. 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 

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

The nomination process is open to the public. The NTP routinely solicits nominations at 

conferences and workshops; through the NTP newsletter, Federal Register notices, and NTP 

homepage (http://ntp.niehs.nih.gov), and from academia, federal and state regulatory and 

health agencies, industry, labor unions, environmental groups, and the general public. In 

addition, standing nomination committees within the NCI/NIH, FDA, NIOSH/CDC, and 

NIEHS/NIH routinely select and forward nominations to the NTP. The NTP also reviews 

environmental occurrence and human exposure databases and scientific literature reports to 

identify substances of potential interest. 

Contact Information: Office of Chemical Nomination and Selection, Dr. Scott Masten, NIEHS/NIH, 

P.O. Box 12233 MD A3-07, 111 T.W. Alexander Dr., Research Triangle Park, NC 27709; T: (919) 

541-5710; masten@niehs.nih.gov. Nomination website: http://ntp.niehs.nih.gov/ select “Nominations 

to the Testing Program.”

Review and Selection Process 

Nominations undergo a multi-step, formal process of review prior to selection for study 

(Figure 6). During the entire process, the NTP works actively with regulatory agencies and 

interested parties to supplement information about nominated substances and ensure that the 

nomination and selection process meets regulatory and public health needs. The ICCEC plays 

a central role in recommending substances for NTP study and coordinating NTP testing 

efforts with other relevant agency activities. 

Public comments are solicited on nominated substances and those received are considered at 

all stages through study selection and design. At the final step of the formal process, the NTP 

Executive Committee reviews the nominations and makes a final recommendation as to 

whether the nominated substances are accepted for study by the NTP. The NTP Executive 

25 National Toxicology Program
Committee reviewed nominations for NTP toxicological studies at its August 2003 meeting 

and its recommendations are summarized in Table 9. 

The selection of a nomination for study by the NTP does not automatically commit the NTP 

to its evaluation. The 

nominations selected for study 

and the toxicology and 

carcinogenicity study designs are 

carefully considered to ensure that 

the resources invested in NTP 

research are wisely spent. 

A chemical or study may be 

withdrawn if applicable research 

data or higher priority studies are 

identified or if a study proves 

impractical.

Table 9. Study Nominations Reviewed by the NTP Executive Committee During FY 2003 – FY 20041

Substance CAS Number Nominator Basis of Nomination Study Recommendations2

Acrylamide and 

Glycidamide 

79-06-1 

5694-00-8 

FDA Inadequate information

available to accurately assess

human health risks from

exposure to acrylamide in 

foodstuffs; a properly designed

well-conducted bioassay with

appropriate ancillary studies is

needed to provide dose 

response information and

account for the food matrix 

through which humans are 

exposed 

Toxicological characterization;

toxicokinetics; mechanistic 

(i.e., hemoglobin adducts); 

carcinogenicity; bioavailability

from food and drinking water 

Antimony Trisulfide 1345-04-6 NCI Significant human exposure in

occupational settings and 

suspicion of carcinogenicity

Chronic toxicity and 

carcinogenicity

Cadmium Telluride 1306-25-8 DOE, 

Brookhaven 

National 

Laboratory,

National 

Renewable 

Energy

Laboratory, First 

Solar, Inc. 

Potential for widespread 

applications in photovoltaic 

energy generation; anticipated 

increase in human exposures; 

further data needed to address

health and safety issues related 

to manufacture and use 

Toxicological characterization;

chemical disposition (oral and 

inhalation) 

Cedarwood Oil, Virginia 8000-27-9 NCI Widespread occupational and 

consumer exposure; lack of

basic toxicology data 

Toxicological characterization;

developmental toxicity

Chondroitin Sulfate 9007-28-7 NCI Widespread long-term use as a 

dietary supplement and 

inadequate data to assess safety

Chronic toxicity/ 

carcinogenicity; 

carcinogenicity of chondroitin

sulfate and glucosamine 

combined 

26 National Toxicology Program
Substance CAS Number Nominator Basis of Nomination Study Recommendations2

Dimethylethanolamine

(DMAE) 

108-01-0 NIEHS Potential for widespread human

exposure to DMAE through its 

use in industrial and consumer 

products; inadequate 

toxicological database; some

ethanolamines can interfere 

with choline uptake and 

utilization and may also 

generate nitrosamines 

Metabolism

Drugs positive for QT 

Interval 

Prolongation/Induction of 

Torsade Proarrhythmia 

FDA QT interval prolongation and

torsade de pointes is a high

priority cause for concern in 

drug development and

regulatory safety evaluation; a 

clear definition of the strengths, 

limitations, and future 

performance characteristics of 

the canine telemetry model for

pre-clinical safety assessment 

is needed 

Initiate a study program to 

develop in vitro and in vivo test

systems for assessing QT 

interval prolongation 

Glucosamine 3416-24-8 NCI Widespread long-term use as a 

dietary supplement and 

inadequate data to assess safety

Chronic toxicity/ 

carcinogenicity; 

carcinogenicity of chondroitin

sulfate and glucosamine 

combined 

Nanoscale Materials Rice University

Center for 

Biological and

Environmental 

Nanotechnology

Intense current and anticipated 

future research and 

development focus; further

studies and development of 

appropriate toxicological 

methods are needed to

adequately assess health effects

Size- and compositiondependent biological 

disposition of nanocrystalline 

fluorescent semiconductor

materials; toxicological 

characterization of high aspect 

ratio carbon nanomaterials; role 

of particle core and surface 

composition in the 

immunotoxicity of the above 

listed materials; phototoxicity

of representative metal oxide

nanoparticles 

4-Phenylcyclohexene 4994-16-5 Private 

Individuals 

Present in indoor environments

primarily from carpet 

emissions; concern that it has 

not been adequately tested for 

potential health effects 

No toxicological studies at this 

time due to low suspicion of 

hazard based on available 

human exposure and toxicity

information 

trans-Resveratrol 501-36-0 NIEHS Widespread human exposure 

from natural dietary sources 

and use of dietary supplements; 

suspicion of toxicity based on 

estrogenic and genotoxic 

activity; insufficient data

available to characterize safety

Toxicological characterization;

carcinogenicity; reproductive 

toxicity

Tetrabromobisphenol A 79-94-7 NIEHS High production volume, 

widespread human exposure 

and suspicion of thyroid 

toxicity/tumorigenicity

Toxicological characterization;

neurodevelopmental toxicity; 

carcinogenicity

Tetrabromobisphenol A 

bis(2,3-dibromopropyl

ether) 

21850-44-2 NIEHS High production volume; little 

toxicity data available;

suspicion of carcinogenic 

potential due to 2,3-dibromo-1-

propanol substructure 

Toxicological characterization;

in vivo genotoxicity;

metabolism; carcinogenicity

27 National Toxicology Program
Substance CAS Number Nominator Basis of Nomination Study Recommendations2

Tungsten 7440-33-7 NCEH/CDC Important industrial materials; 

insufficient data to assess 

human health implications of

elevated urinary tungsten levels 

Toxicological characterization;

carcinogenicity; studies should 

focus on a representative

soluble tungsten compound 1

 Testing status and study results for completed studies can be found at http://ntp.niehs.nih.gov/ select “Testing Status of Agents at 

 NTP” and “Study Results & Research Projects 2

 Study recommendations are developed by the ICCEC and the NTP Board of Scientific Counselors 

Evaluation 

In carrying out its mission, the NTP provides toxicological evaluations on substances of 

public health concern. Unfortunately, the NTP can initiate bioassays to characterize potential 

carcinogenicity of only a small fraction of the thousands of substances for which there is little 

or no information. Many more substances are also studied to assess a variety of non-cancer 

health-related effects including, but not limited to, reproductive and developmental toxicities, 

immunotoxicity, neurotoxicity, and genotoxicity. Other biological parameters are often 

assessed such as quantifying the disposition and excretion of substances, identifying and 

correlating biochemical markers with exposure and metabolism, and examining genetic 

polymorphisms in human drug metabolizing enzymes to understand the susceptibility of 

individuals and populations to xenobiotic-induced toxicity. 

An NIEHS/NTP project review committee reviews and evaluates a study's project plan (e.g.,

design, methods, hypothesis, etc.) and proposes the funding format for execution (e.g., grant, 

contract, etc.). The toxicological evaluation for carcinogenicity is generally conducted 

through repeated administration of a substance to groups of laboratory animals for variable 

periods of time generally one to two years. Many short-term studies are designed to provide 

dose-setting information for chronic exposure studies and address specific deficiencies in the 

toxicology database. The adverse health effects from short- or long-term exposures of

different dose levels of the substance are evaluated clinically, by histopathology, and by a 

variety of toxicology end points through comparison with groups of animals not administered 

the substance. Many substances are also studied using protocols specifically designed to 

address issues pertaining to the mechanism by which a substance causes a particular toxic 

outcome(s). The NTP has specific requirements for the testing laboratories to comply with 

the Laboratory Animal Welfare Act of 1966 and adhere to the principles enunciated in the 

"Guide for the Care and Use of Laboratory Animals" NRC, 1996. General information about 

the objectives and procedures of NTP study protocols is available on the NTP website 

(http://ntp.niehs.nih.gov/ select “Descriptions of NTP Study Types”). Current testing status 

can be found at http://ntp.niehs.nih.gov/ select “Testing Status of Agents at NTP.” 

Support activities and contact staff at the core agencies: 

• Animal production and care (King-Herbert, NIEHS/NIH; Martin, NCTR/FDA) 

• Archives (Maronpot, NIEHS/NIH) 

• Biological monitoring and health assessment (DeBord, NIOSH/CDC) 

• Chemistry/biochemistry (Beland/Siitonen, NCTR/FDA; 

Smith/Collins/Burka/Cunningham, NIEHS/NIH; Snawder, NIOSH/CDC) 

• Chemical disposition contracts (Cunningham, NIEHS/NIH); chemical metabolism (Burka, 

NIEHS/NIH) 

• Clinical pathology (Travlos, NIEHS/NIH) 

• Genetic toxicity testing (Caspary, NIEHS/NIH) 

• Information retrieval and analysis (Tatken, NIOSH/CDC; Wright, NIEHS/NIH) 

28 National Toxicology Program
• Information systems and central files (Eastin, NIEHS/NIH), database management 

(Rowley, NIEHS/NIH), NTP website (Soward, NIEHS/NIH) 

• Mass spectrometry (Tomer, NIEHS/NIH) 

• Microbiology (Cerniglia, NCTR/FDA; King-Herbert, NIEHS/NIH) 

• Pathology (Hailey/Herbert, NIEHS/NIH; Witt, NCTR/FDA; Hubbs, NIOSH/CDC) 

• Quality assurance (Culp, NCTR/FDA; Bristol, NIEHS/NIH; Benson, NIOSH/CDC) 

• Statistical services (Kodell, NCTR/FDA; Kissling/Dunson, NIEHS/NIH; Krieg, 

NIOSH/CDC) 

• Study coordination/oversight (Weis, NCTR/FDA; Bucher, NIEHS/NIH; Toraason, 

NIOSH/CDC) 

• Toxicogenomics: microarray (Walker/Paules, NIEHS/NIH); proteomics (Merrick, 

NIEHS/NIH) 

• Technical report preparation (Alden, NIEHS/NIH; Schulte, NIOSH/CDC) 

• Toxicology and carcinogenicity testing (Roycroft/Orzech, NIEHS/NIH) 

• Toxicity testing (Chhabra/Vallant, NIEHS/NIH) 

• Transgenic mouse colonies (King-Herbert/French, NIEHS/NIH) 

NTP contracts that facilitate support activities: 

• NTP toxicity study report preparation support (Alden, NIEHS/NIH) 

• Animal husbandry support services for the NIEHS (Boyd, NIEHS/NIH) 

• Quality assurance audit and inspection support resource contract (Bristol, NIEHS/NIH) 

• Conducting comprehensive toxicological assessments (Bucher, NIEHS/NIH) 

• Chemistry support for the Environmental Toxicology Program (Collins, NIEHS/NIH) 

• Research development and planning (DeBord, NIOSH/CDC) 

• Carcinogenic potency database (Eastin, NIEHS/NIH) 

• Website design and content management (Eastin, NIEHS/NIH) 

• Inhalation facility for animal exposures (Goldsmith, NIOSH/CDC) 

• Pathology support for the NTP quality assessment (Hailey, NIEHS/NIH, Malarky, 

NIEHS/NIH) 

• NTP database summarization and evaluation (Haseman, NIEHS/NIH) 

• Statistical analysis and computational support for the NIEHS experimental studies 

(Haseman, NIEHS/NIH) 

• Pathology support for the NIEHS (Herbert, NIEHS/NIH) 

• Support for the preparation of the Report on Carcinogens (Jameson, NIEHS/NIH; Lunn, 

NIEHS/NIH) 

• DNA isolation and molecular analysis (Juras, NIEHS/NIH) 

• Genetic analyses for epidemiologic studies of respiratory disease (London, NIEHS/NIH) 

• Rodent production center (Maronpot, NIEHS/NIH) 

• NIEHS/NTP archives and specimen repository (Maronpot, NIEHS/NIH) 

• Genetic monitoring of inbred rodents (Maronpot, NIEHS/NIH) 

• Molecular oncology support (Maronpot, NIEHS/NIH) 

• Rodent disease diagnostic laboratory (Maronpot, NIEHS/NIH) 

• Magnetic resonance imaging and multimodality imaging support for NIEHS and NTP 

research (Maronpot, NIEHS/NIH) 

29 National Toxicology Program
• Literature search and summary support for the Environmental Toxicology Program

(Masten, NIEHS/NIH) 

• Research on the inhalation toxicology of environmental chemicals (Moorman, 

NIEHS/NIH) 

• Genetics adjudication resource project (Newton, NIEHS/NIH) 

• NIEHS-central computing support for the NTP and the Division of Intramural Research 

(Rowley, NIEHS/NIH) 

• NTP CERHR (Shelby, NIEHS/NIH) 

• Developmental toxicity test data (Shelby, NIEHS/NIH) 

• Record creation and maintenance of the developmental and reproductive toxicology (DART) 

database (Shelby, NIEHS/NIH) 

• Chemistry support for the ETP (Smith, NIEHS/NIH) 

• Inhalation facility for animal exposures (Goldsmith, NIOSH/CDC) 

• CDM and information systems contract (Soward, NIEHS/NIH) 

• Breeding and rederivation of transgenic animals (Stasiewicz, NIEHS/NIH) 

• Genotyping of transgenic animals for NIEHS (Stasiewicz, NIEHS/NIH) 

• Support contract for the NICEATM (Stokes, NIEHS/NIH) 

• NTP Coordination: occupational health exposures (Toraason, NIOSH/CDC) 

• Conduct of studies to evaluate the toxicologic potential of selected chemicals for the NTP 

(Vallant, NIEHS/NIH) 

The NTP carries out toxicology and carcinogenesis research through two primary 

mechanisms: laboratory studies conducted in contract laboratories and in-house studies 

conducted at its core agencies: NIEHS/NIH, NCTR/FDA, and NIOSH/CDC. In addition, the 

NTP leverages resources through cooperative and/or collaborative agreements with other 

Federal agencies, academia, and industry. The NIEHS/NIH Division of Extramural Research 

and Training supports research on methods development. 

The NIEHS/NIH has supported an interagency agreement with the Lawrence Livermore 

National Laboratory in collaboration with the University of California at Berkeley to develop, 

maintain, update, and upgrade a comprehensive database of laboratory animal carcinogenicity 

study results taken from the literature, including carcinogenesis studies conducted by the 

NTP. The Carcinogenic Potency Database contains the results of chronic, long-term animal 

cancer tests, both positive and negative. 

In addition to toxicology research of compounds and exposures, the NTP supports the 

development of new techniques and methods for improving the ability to identify and assess 

potential environmental toxicants and the development and validation of novel and alternative 

testing methods that will reduce, replace, or refine animal use. The NTP also supports 

development of improved statistical methods for toxicology studies. 

Review and Dissemination 

The results of toxicology and carcinogenesis studies undergo rigorous peer review and are 

published in several NTP report series: 

• Technical Reports (TR). This series presents the results of long-term, generally 2-

year, toxicology and carcinogenicity studies, typically conduced in two rodent species, 

rats and mice. Results of chemical disposition and physiologically based 

pharmacokinetic (PBPK) studies are often included in TRs. The Technical Reports 

30 National Toxicology Program
31 National Toxicology Program

Review Subcommittee of the NTP Board (see Advisory Boards and Committees, page 

2) evaluates TRs in an open, public meeting. 

• NTP Toxicity Reports (TOX). TOX reports are prepared for studies where the 

substance exposure period is short-term, generally up to 13-weeks. TOX reports are 

typically peer-reviewed through letter review. 

• Genetically Modified Models Reports (GMM). NTP initiated the GMM report series 

in May 2003. This report series presents the results of substances evaluated by NTP in 

transgenic strains (e.g., p53+/-heterozygous and Tg.AC). The Technical Reports 

Review Subcommittee of the NTP Board (see Advisory Boards and Committees, page 

2) evaluates GMM reports in an open, public meeting. 

Abstracts of the TR, TOX, and GMM series are posted on the NTP website and PDF files of 

completed reports are available free-of-charge at the NTP website (http://ntp.niehs.nih.gov/

select “NTP Study Reports”). Hardcopies of NTP reports can by obtained by contacting 

Central Data Management (919-541-3419, cdm@niehs.nih.gov). TR and TOX report series 

are also catalogued in MedLine. Study summaries for other types of studies, such as 

immunotoxicity, developmental, and reproductive studies, are also available at “NTP Study 

Reports.” All types of NTP studies may also be published in peer-reviewed scientific 

journals. 
Table 10. Technical Reports Completed During FY 2003-2004: Rodents 

Chemical CAS Number Technical Levels of Evidence of Carci

Report Number 

Use 

Male Rat Female Rat Male Mic

Conventional Models Anthraquinone 84-65-1 TR 494 Intermediate in dye 

manufacture 

Some Clear Clear 

Leucomalachite Green 129-73-7 TR 527 Dye; antifungal for fish Equivocal Equivocal Not testeMalachite Green Chloride 569-64-2 TR 527 Dye; antifungal for fish Not tested Equivocal Not teste2-Methylimidazole 693-98-1 TR 516 Chemical and

pharmaceutical intermediate 

Some Clear Some 

PCB-126 (3,3',4,4',5- Pentachlorobiphenyl) 

57465-28-8 TR 520 No longer used 

commercially;persistent polyhalogenatedaromatic hydrocarbons present in the environment 

Not tested Clear Not teste

PeCDF (2,3,4,7,8- Pentachlorodibenzofuran) 

57117-31-4 TR 525 No longer used 

commercially;persistent polyhalogenatedaromatic hydrocarbons present in the environment 

Not tested Some Some 

Propylene Glycol Mono-tbutyl Ether 57018-52-7 TR 515 Solvent Equivocal No evidence Clear Stoddard Solvent (Type IIc) 64742-88-7 TR 591 Paint and dry cleaning 

solvent 

Some No evidence No eviden

TCDD (2,3,7,8- Tetrachlorodibenzo-pdioxin) 

1746-01-6 TR 521 No longer used 

commercially;persistent polyhalogenatedaromatic hydrocarbons present in the environment 

Not tested Clear Not teste

32 National To
33 National To

Chemical CAS Number Technical Levels of Evidence of Carci

Report Number 

Use 

Male Rat Female Rat Male Mic

Chemical CAS Number Technical 

Report Number 

Use Response in Rodents Species M

Medaka No e

Nitromethane 75-52-5 TR 528 

Rocket and engine fuel;synthesis intermediate for agricultural fumigants, biocides,and other products; solvent; explosive in mining, oil-well drilling, and seismic exploration 

No evidence in male rats; clear evidence in femalerats and male and femalemice 

Guppy Ina

exp

2,2-bis- Medaka C(Bromomethyl)-1,3-Propanediol

3296-90-0 TR 528

Fire retardant Clear evidence in male

and female rats and mice Guppy C

1,2,3- Medaka CTrichloropropane 96-18-4 TR 528

Paint and varnish remover, solvent, and degreasing agent,and as a crosslinking agent in the

Clear evidence in maleand female rats and mice Guppy C

TCDD, PCB 126, andPeCDF Mixture

1746-01-6; 

57465-28-8; 

57117-31-4 

TR 526 No longer used 

commercially;persistent polyhalogenatedaromatic hydrocarbons present in the environment 

Not tested Clear Not teste

Triethanolamine 102-71-6 TR 518 Large variety of 

industrial andmanufacturingapplications 

Not tested Not tested Equivoc

Genetically-Modified Mouse Models - p53 Haploinsufficient MiceAspartame 22839-47-0 GMM 1 Artificial sweetener N/A N/A No evidenAcesulfame Potassium 55589-62-3 GMM 2 Artificial sweetener N/A N/A Clear 

Table 11. Technical Reports Completed During FY 2003-2004: Fish 
HIGHLIGHTED CURRENT NTP INITIATIVES

The NTP has a broad mandate to provide toxicological characterizations for substances and 

agents of public health concern. This has resulted in a diverse research program, but with 

emphasis on synthetic chemicals, metals and 40 dietary supplements. The following section 

highlights some current NTP initiatives: several areas that have received inadequate attention 

in the past, i.e., cardiovascular toxicity, photoactive chemicals, endocrine disrupting agents, 

and certain occupational exposures; and research addressing potential safety issues associated 

with radiofrequency radiation emissions from cellular telephones, herbal medicines, drinking 

water contaminants, and DNA-based therapies. In addition, the NTP is also addressing the 

emerging issue of nanotechnology. In general, these initiatives are broad-based and include 

various health-related end points. 

Nanotechnology 

Nanotechnology has become an increasing focus of U.S. and global research and 

development efforts. As with many technological advances, new materials are created, and 

as a result, the potential exists for new and unanticipated human exposures for which the 

impact on human health is unknown. The NTP is developing a broad-based research 

program to address potential human health hazards associated with the manufacture and use 

of nanoscale materials. This research program will apply existing toxicology testing 

methods to the study of nanoscale materials and also explore the development of novel 

toxicological methods to assess potential health effects (Walker, NIEHS/NIH, Howard, 

NCTR/FDA, Castranova, NIOSH/CDC). 

Nanoscale materials are a broadly defined set of substances where at least one critical 

dimension is less than 100 nanometers. Ultrafine particulate matter is a well-known example 

of ambient nanoscale particles; however, the NTP’s research program will initially focus on 

manufactured nanoscale materials of current or projected commercial importance. Nanoscale 

materials can exist in many forms including semiconductor nanocrystals, organic dendrimers, 

carbon fullerenes and carbon nanotubes. They are already appearing in commerce as 

industrial and consumer products and as novel drug delivery formulations. 

The intent of the NTP’s research program is to evaluate the toxicological properties of major 

classes of nanoscale materials which represent a cross-section of composition, size, surface 

coatings, and physico-chemical properties. These model systems will be used to investigate 

fundamental questions concerning if and how nanoscale materials can interact with biological 

systems. Some of these fundamental questions include: What are the appropriate methods for 

detection and quantification of nanoscale particles in tissues? How are nanoscale materials 

absorbed, distributed in the body and taken up by cells? Are there novel toxicological 

interactions? As part of this research program, studies have been initiated to evaluate the 

biological disposition of nanoscale crystalline fluorescent semiconductors (“quantum dots”), 

long-term toxicology studies of carbon-based nanoscale materials (e.g., single- or multiwalled nanotubes, fullerenes), and phototoxicology studies of representative nanoscale metal 

oxide particles used in industrial settings and consumer products (e.g., titanium dioxide). 

Persistent Polyhalogenated Compounds 

Dioxin-like compounds. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like 

compounds (DLCs) comprise a large class of structurally related environmental contaminants 

including polychlorinated dibenzodioxins (PCDD), polychlorinated dibenzofurans (PCDF), 

and some polychlorinated biphenyls (PCBs). Because DLCs are persistent, they remain in 

human tissues for extended periods of time. Both the NTP and the International Agency for 

Research on Cancer have concluded that TCDD, the most potent dioxin, is a known human 

carcinogen. Although the manufacture and use of PCBs was halted in the United States in 

34 National Toxicology Program
1977, PCBs continue to be released into the environment through the use and disposal of 

products containing these compounds, as by-products from the manufacture of certain organic 

chemicals, and during combustion of some waste materials.

Because TCDD is a known human carcinogen and other DLCs bind to the same aryl 

hydrocarbon receptor (AhR), public health officials are concerned that PCBs and other 

compounds that bind to this receptor may also be human carcinogens. Human exposure to 

DLCs always occurs as a complex mixture; therefore, a method known as the Toxic 

Equivalency Factor (TEF) was developed as a mathematical tool to assess the health risk 

posed by mixtures of these compounds. The TEF methodology is a relative potency scheme

that ranks the dioxin-like activity of a compound relative to TCDD , the most potent 

congener. This method allows for the estimation of the potential dioxin-like activity of a 

mixture of chemicals, based on a common mechanism of action involving initial binding to 

the AhR. 

The toxic equivalency of DLCs was nominated for evaluation to the NTP because of the 

widespread human exposure to DLCs and the lack of data on the adequacy of the TEF 

methodology for predicting relative potency for cancer risk. To address this request, the NTP 

conducted a series of chronic toxicity and carcinogenicity assays of DLCs and mixtures of 

these compounds in female Harlan Sprague-Dawley rats (Walker, NIEHS/NIH). Three PCB 

congeners were selected for evaluation singly (PCB 118, 126 and 153) and in combination 

with each other, TCDD, and a polychlorinated dibenzofuran. Studies are also in progress to 

examine the chronic toxicity of compounds with weak dioxin-like activity to which humans 

are exposed. These include polychlorinated naphthalenes, tetrachloroazobenzene, 

hexachlorobenzene, and indole-3-carbinol. 

Polybrominated flame retardants. The NTP is studying how exposure to brominated flame 

retardants might effect human health (Dunnick, NIEHS/NIH). One class of brominated flame 

retardants, polybrominated diphenyl ethers (PBDE), is structurally similar to PCBs and there 

is evidence that PBDEs bioaccumulate in human and animal tissues. Presently, the NTP is 

studying the PBDE isomers found in DE-71, the most widely used commercial formulation of 

a PBDE-based flame retardant. Although the manufacturer of DE-71 recently announced 

plans to stop its production, people will still be exposed to PBDE isomers and decomposition 

products of other brominated flame retardants that are still in use, and they will continue to 

accumulate in the environment. Previous NTP studies of brominated chemicals and/or

brominated flame retardants, such as 2,2-bis(bromomethyl)-1,3-propanediol (FR-1138), have 

shown that these chemicals have the potential to cause cancer in model systems. Other flame 

retardants being studied include tetrabromobisphenol A (TBBPA) and tetrabromobisphenol 

A- bis(2,3-dibromopropyl) ether. 

Perfluorinated compounds. Over the past five years, perfluorinated compounds such as 

perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and similar substances 

have been found globally in humans and the environment. Perfluorinated compounds are 

characterized by their persistence, resistance to heat and chemical stress, as well as their 

insolubility in both water and oil. Because of this unusual combination of physical properties, 

these compounds or their chemical precursors have been used since the 1950s as surfactants 

and emulsifiers in commercial products including stain or water protectors for carpets, 

textiles, auto interiors, camping gear and leather, and in food packaging and other paper 

containers. Although a considerable amount of toxicity information exists for PFOS and 

PFOA, this class of perfluorinated compounds is quite large and includes straight chain as 

well as branched chain compounds. For this reason, the NTP is collaborating with the EPA to 

conduct a class study of the perfluorinated sulfonates and carboxylic acids as well as 

fluorotelomeric alcohol derivatives (potential precursors of perfluorinated carboxylic acids) 

(Melnick, NIEHS/NIH). Initial efforts will include studies on reproduction and development, 

pharmacokinetics, and mechanistic studies to better understand the potential for common 

modes of action by this class of compounds. 

35 National Toxicology Program
Cardiovascular Toxicity 

Heart disease is the leading cause of mortality in the United States. and the NTP is working to 

further understand the contribution of environmental exposures to this disease. To achieve 

this goal, the NTP is studying how environmental exposures may contribute to heart disease, 

elucidate mechanisms of heart toxicity, understand gene changes in heart toxicity, and 

translate basic information into prevention strategies. Recent findings from this project show 

that a combination of the herbal supplement ephedrine with caffeine can cause rapid death by 

inducing heart toxicity. Other findings indicate that certain compounds, such as 3’-azidothymidine (AZT) and bis(2-chloroethoxy)methane, can cause heart toxicity via mitochondrial 

damage. Further work is ongoing to understand gene changes induced by heart toxicants 

(Murphy, NIEHS/NIH). 

In a separate initiative, the NTP is investigating QT interval prolongation and an associated 

life-threatening ventricular arrhythmia because it is a high priority concern in drug 

development and regulatory safety evaluation (Hooth, NIEHS/NIH). The QT interval is a 

reflection of the duration of the ventricular action potential and represents the time during 

which the ventricles depolarize and repolarize. One of the most common causes of drugs 

being removed recently from the U.S. market is QT interval-related cardiac toxicity. Given 

the medical and economic consequences of this issue, a recommendation has been made to 

incorporate preclinical models predictive of QT interval prolongation and proarrhythmia into 

drug development. The conscious canine radiotelemetry model is the most common in vivo

model used to determine if a drug causes QT prolongation; however, the sensitivity and 

specificity of this model are unknown. Consequently, the FDA requested that the NTP 

evaluate both QT-prolonging and non-prolonging drugs in the conscious canine telemetry 

model. The objective of these studies will be to better establish the sensitivity and specificity 

of this in vivo model system for evaluating the ability of a test agent to prolong the QT 

interval. 

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 phone where the radiation antenna is 

close to the user's head. Cellular phones and other wireless communication devices are 

required to meet the radiofrequency radiation exposure guidelines of the Federal 

Communication Commission. These guidelines are based on protecting the user from acute 

injury from thermal effects produced by radiofrequency radiation. Current data are 

insufficient to draw definitive conclusions concerning the adequacy of these guidelines for 

protecting against potential adverse health effects from chronic exposure. 

Studies in laboratory animals are considered crucial for understanding whether chronic 

exposure to radiofrequency radiation may pose a danger to human health. Through an 

interagency agreement with the National Institute of Standards and Technology, studies were 

conducted that demonstrated the feasibility of using reverberation exposure chambers to study 

long-term health effects of cellular phone radiofrequency radiation in laboratory animals. 

Subsequently, the NTP developed a research project aimed at evaluating the toxic and 

carcinogenic potential of cellular phone radiofrequency radiation in rats and mice exposed in 

reverberation chambers. By using radiofrequency signals that simulate exposures of cellular 

phone users it is expected that results from these studies will clarify any potential health 

hazard for the U.S. population. This project will begin in FY 2005 (Melnick, NIEHS/NIH). 

36 National Toxicology Program
37 National Toxicology Program

Herbal Medicines and Dietary Supplements1

Medicinal herbs are among the oldest medicines, and their increasing use in recent years is 

evidence of public interest in alternatives to conventional medicine. Approximately onethird of the U.S. population is 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 pre-market approval to ensure their 

safety or efficacy. 

The NTP is planning or conducting research (listed in Table 12) on numerous medicinal 

herbs, compounds found in herbs, and dietary supplements that focus on carcinogenicity, 

reproductive toxicity, neurotoxicity, immunotoxicity, and toxic effects associated with acute 

exposures to high doses and chronic exposures to low doses (Burka, NIEHS/NIH; Boudreau, 

NCTR/FDA). 

 

1 Congress defined the term "dietary supplement" in the Dietary Supplement Health and Education Act (DSHEA) of 1994. A 

dietary supplement is a product taken by mouth that contains a "dietary ingredient" intended to supplement the diet. The "dietary 

ingredients" in these products may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as 

enzymes, organ tissues, glandulars, and metabolites. Dietary supplements can also be extracts or concentrates, and may be found

in many forms such as tablets, capsules, softgels, gelcaps, liquids, or powders. They can also be in other forms, such as a bar, but 

if they are, information on their label must not represent the product as a conventional food or a sole item of a meal or diet.

Whatever their form may be, DSHEA places dietary supplements in a special category under the general umbrella of "foods," not 

drugs, and requires that every supplement be labeled a dietary supplement.
Table 12. Herbal Ingredients and Dietary Supplements1

Compound CAS Number NTP Studies (completed, ongoing or planned) 

S-Adenosylmethionine 29908-03-0 Genetic toxicity (Salmonella) 

 Aloe Vera Charcoal Filtered Whole Leaf Extract 

Chronic toxicity/carcinogenicity (dermal) 

 Aloe Vera Whole Leaf Extract  (Native)

Subchronic (drinking water), chronic toxicity/carcinogenicity (dermal) 

 Aloe Vera Gel 8001-97-6 Chronic toxicity/carcinogenicity (dermal), genetic toxicity (Salmonella)  Androstenedione 63-05-8 Subchronic (gavage and topical studies), chronic toxicity/carcinogenicity (gavage), chemi

mice, rats - gavage, in vitro, intravenous), genetic toxicity (Salmonella and micronucleus)

 Berberine Chloride 633-65-8 Genetic toxicity (Salmonella and micronucleus)  Berberine Chloride Dihydrate 5956-60-5 Teratology (gavage and feed) Bilberry Fruit Extract 84082-34-8 Genetic toxicity (Salmonella)  Bitter Orange Extract Testing planned  Black Cohosh 84776-26-1 Genetic toxicity (Salmonella), other studies planned  Black Walnut Extract/Juglone Chemical disposition (rat - topical), genetic toxicity (Salmonella)  Blue-Green Algae Genetic toxicity (Salmonella), other studies planned  Chitosan 9012-76-4 Subchronic (feed)  Chromium Picolinate  Monohydrate 

27882-76-4 Subchronic (feed), chronic toxicity/carcinogenicity (feed); chemical disposition (rat - gava

intravenous), genetic toxicity (micronucleus) 

 Chondroitin Sulfate 9007-28-7 Testing planned Echinacea Purpurea Extract 90028-20-9 Immunotoxicity, other studies planned  Ephedrine Alkaloid Dietary  Supplements 

Testing planned

 Folic Acid 59-30-3 Genetic toxicity (Salmonella)  Ginkgo Biloba Extract 90045-36-6 Subchronic (gavage), chronic toxicity/carcinogenicity (gavage), chemical disposition (hum

(micronucleus) 

 Ginseng 50647-08-0 Subchronic (gavage), chronic toxicity/carcinogenicity (gavage), genetic toxicity (Salmone Glucosamine 3416-24-8 Testing planned  Goldenseal Root Powder Subchronic (feed), chronic toxicity/carcinogenicity (feed), chemical disposition (human - 

genetic toxicity (micronucleus) 

 Grape Seed Extract Genetic toxicity (Salmonella)  Grape Seed and Pine Bark  Extracts 

Chemical disposition (human - in vitro) 

38 National Tox
39 National Tox

Compound CAS Number NTP Studies (completed, ongoing or planned) 

 Green Tea Extract Testing planned  Hydrastine 118-08-1 Genetic toxicity (Salmonella) 

Indole-3-carbinol 700-06-1 Subchronic (gavage), chronic toxicity/carcinogenicity (gavage), genetic toxicity (Salmone

 Juglone 481-39-0 Chemical disposition (rat - topical), genetic toxicity (Salmonella)  Kava Kava Extract 9000-38-8 Subchronic (gavage), chronic toxicity/carcinogenicity (gavage), chemical disposition (hum

intravenous), genetic toxicity (Salmonella) 

α-Lipoic Acid 1077-28-7 Genetic toxicity (Salmonella) 

 Melatonin 73-31-4 Subchronic (gavage), teratology (gavage)  Milk Thistle Extract 84604-20-6 Subchronic (feed), chronic toxicity/carcinogenicity (feed), chemical disposition (human - 

(Salmonella and micronucleus) 

 Pulegone 89-82-7 Subchronic (gavage), chronic toxicity/carcinogenicity (gavage), chemical disposition (rat - 

toxicity (Salmonella and micronucleus)

 trans-Resveratrol 501-36-0 Testing planned Senna (Powdered) 8013-11-4 Transgenic model, genetic toxicity (Salmonella)  Silymarin 65666-07-1 Genetic toxicity (Salmonella)  Silybin 22888-70-6 Genetic toxicity (Salmonella) 

α-Thujone 546-80-5 Subchronic (gavage), genetic toxicity (Salmonella) 

α/β-Thujone Mixture Subchronic (gavage), chronic toxicity/carcinogenicity (gavage), genetic toxicity (Salmone

 l-Tryptophan 73-22-3 Subchronic (feed), chronic toxicity/carcinogenicity (feed), genetic toxicity (Salmonella, m

aberration, sister chromatid exchange, mouse lymphoma) 

1 Testing status and study results for completed studies can be found at http://ntp.niehs.nih.gov/ select “Testing Status of Agents at NTP” and “Study R
Safe Drinking Water Program 

More than 200 million Americans are estimated to use municipally treated drinking water, so 

the availability of safe drinking water is of enormous importance to public health. NTP 

research under the safe drinking water program is broad in scope with some studies being 

conducted at NIEHS/NIH and others being done through agreements with the U.S. Army and 

EPA. 

Although chlorination is one of the major public health advances of the 20th century, byproducts of chlorination or other disinfection processes (disinfection by-products, DBPs) may 

cause health problems such as adverse reproductive effects or cancer. The EPA is responsible 

for setting water standards for DBPs under the Safe Drinking Water Act. 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 evaluation of DBPs focusing on reproductive 

toxicity, immunotoxicity, neurotoxicity, and carcinogenicity. The program selected DBPs for 

study based on their presence in drinking water, occurrence with different disinfection 

processes, chemical structures, and class: trihalomethanes, haloacetic acids, and 

haloacetonitriles. 

Besides DBPs, many agents occur (1) naturally (e.g., arsenic, aluminum) in water, (2) because 

of contamination (e.g., methyl tert-butyl ether and other gasoline additives, pesticides, organic 

tin compounds), or (3) with environmental changes (e.g., cyanobacterial toxins from algal 

blooms in surface waters). The NTP is designing long-term toxicology and toxicokinetic 

studies on several of these agents including aluminum complexes, organic tin compounds, and 

the two most common cyanobacterial toxins (microcystin-LR and cylindrospermopsin). 

Table 13 lists DBPs and other water-related agents under study by the NTP. 

 Table 13. Water Contaminants1 

Chemical CAS Number NTP Studies (Completed, Ongoing or Planned) 

Disinfection by-products, DBPs

Bromochloroacetic 

Acid 

5589-96-8 Subchronic (water), chronic toxicity/carcinogenicity (water), genetic toxicity

(Salmonella and micronucleus), reproductive toxicity (water) 

Bromodichloromethane 75-27-4 Subchronic (water, gavage, topical), chronic toxicity/carcinogenicity (water, gavage), 

transgenic models (water, gavage), genetic toxicity (Salmonella, micronucleus and 

mouse lymphoma), chemical disposition (rat – gavage, intravenous), toxicokinetic 

(mouse – gavage), reproduction/development (water)

Chloramine 10599-90-3 Chronic toxicity/carcinogenicity (water), 

Chloroform 67-66-3 Subchronic (gavage), chronic toxicity/carcinogenicity (gavage), genetic toxicity

(Salmonella, micronucleus, chromosome aberration, sister chromatid exchange, 

mouse lymphoma), chemical disposition (rat – water, intraperioneal injection), 

reproduction/development (gavage) 

Dibromoacetic Acid 631-64-1 Subchronic (water), chronic toxicity/carcinogenicity (water), genetic toxicity

(Salmonella and micronucleus), immunotoxicity (water), neurotoxicity (water), 

spermiation inhibition (rat – gavage), toxicokinetics (mice – gavage) 

Dibromoacetonitrile 3252-43-5 Subchronic (water), chronic toxicity/carcinogenicity (water), genetic toxicity

(Salmonella, micronucleus and Drosphila), chemical disposition (rat – gavage, 

intravenous), neurotoxicity (water), reproduction/development (water) 

Dichloroacetic Acid 79-43-6 Subchronic (water, topical), chronic toxicity/carcinogenicity (water), genetic toxicity

(Salmonella and micronucleus), spermiation inhibition (rat – gavage), 

immunotoxicity (water), transgenic models (water, topical) 

Sodium Bromate 7789-38-0 Subchronic testing completed, genetic toxicity (micronucleus), toxicokinetic (mice –

gavage, topical), reproduction/development (water), immunotoxicity (water),

transgenic models (water, topical) 

Sodium Chlorate 7775-09-9 Subchronic (water), chronic toxicity/carcinogenicity (water), genetic toxicity

(Salmonella and micronucleus), teratology (gavage) 

40 National Toxicology Program
Chemical CAS Number NTP Studies (Completed, Ongoing or Planned) 

Sodium Chlorite 7758-19-2 Immunotoxicity (water) 

Other Water Contaminants 

Microcystin-LR 101043-37-2 Chronic toxicity/carcinogenicity planned 

Cylindrospermopsin 143545-90-8 Chronic toxicity/carcinogenicity planned 1 Testing status and study results for completed studies can be found at http://ntp.niehs.nih.gov/ select “Testing Status of Agents at 

 NTP” and “Study Results & Research Projects 

Endocrine Disrupting Compounds 

Endocrine disrupting compounds (EDCs) are naturally occurring or man-made substances 

that may mimic or interfere with natural hormones in the body. Endocrine disruptors may 

turn on, shut off, or modify hormone signals and thus affect the normal functions of tissues 

and organs. The NTP is involved in several efforts to strengthen the scientific knowledge 

within this field (Table 14). 

The NIEHS/NIH is examining the cellular and molecular mechanisms through which natural 

and synthetic estrogenic compounds might interact with target tissues (e.g., developing 

genital tract, gonads, and mammary gland) and cause permanent alterations that potentially 

could affect sexual differentiation or induction of hormone-sensitive cancers (e.g., cervix, 

uterus, vagina, breast, testis, and prostate). Diethylstilbestrol is being used as the model 

compound to compare its effects with naturally occurring substances (genistein and daidzein 

found in soy), drugs (Tamoxifen), pesticides (methoxychlor) and xenoestrogens (bisphenol 

A). Other studies include identifying stem cells in target tissues, investigating the role of the 

estrogen receptor in induction and/or progression of neoplasms, identifying potentially 

altered growth factor pathways, and defining markers of pre-neoplasia. This group of 

investigators is also interested in developing assays to determine estrogenicity of 

environmental chemicals that can be used as sensitive markers of exposure (Newbold, 

NIEHS/NIH). Another area of study at NIEHS/ NIH is investigating mechanisms through 

which environmental and synthetic antiandrogenic agents interact with the developing male 

reproductive system in experimental animals that could model human testicular dysgenesis 

syndrome (a collection of adverse reproductive responses with an in utero origin including 

decreased sperm parameters and increased incidence of cryptorchidism, hypospadias, and 

testicular cancer). Efforts are primarily focused on the environmental contaminant di-n-butyl 

phthalate and the pharmaceutical androgen receptor antagonist flutamide as model 

compounds (Foster, NIEHS/NIH). 

Several NIEHS/NIH epidemiology studies are examining the potential effects of endocrine 

disrupting agents in human populations. One project is investigating the impact of exposure 

to hormonally active compounds in soy formula on estrogen-responsive tissues in infants and 

sexual differentiation (Rogan, NIEHS/NIH). Another project is focusing on the effects of 

early-life exposure to a DDT degradation product DDE (an antiandrogen) in relation to 

anogenital distance in newborn males among a highly exposed population in Southern 

Mexico (Longnecker, NIEHS/NIH). In utero exposure to bisphenol A, an estrogenic 

compound, is being studied to assess whether it is associated with body weight in children in 

Rotterdam, the Netherlands (Longnecker, NIEHS/NIH. This same population will be used to 

assess early exposure to phthalates in relation to respiratory outcomes and possibly 

anogenital distance. Another NIEHS/NIH epidemiology study will examine in utero

exposure to perfluorinated alkyl compounds (such as perfluorooctanesulfate) in relation to 

thyroid function in neonates in Norway (Longnecker, NIEHS/NIH). 

41 National Toxicology Program
Table 14. Endocrine Disruptors1

Chemical CAS Number Primary use NTP Studies (Completed, Ongoing or Planned) 

Di(2-ethylhexyl)

Phthalate 

117-81-7 Used as a plasticizer, agaracide, 

and ingredient in pesticides, 

cosmetics, detergents

Subchronic (feed), chronic toxicity/carcinogenicity

(feed), genetic toxicity (Salmonella, chromosome

aberration, sister chromatid exchange, mouse lymphoma 

and Drosophila), chemical disposition (rat – topical), 

mechanism (rat – gavage) 

Ethinyl Estradiol 57-63-6 Nonsteroidal semi-synthetic

estrogen used in the treatment of

breast and prostate cancer 

Genetic toxicity (Salmonella and micronucleus),

reproduction/development (gavage), multigenerational 

study with carcinogenicity (feed), immunotoxicity (feed), 

behavioral toxicity (feed), transgenic models (gavage,

topical) 

Flutamide 13311-84-7 Androgen antagonist used as an

antineoplastic therapy for 

prostate cancer 

Reproduction/development (gavage) 

Flutamide and 

Dibutyl Phthalate 

Mixture 

13311-84-7; 

84-74-2 

Used as a plasticizer, solvent and

textile lubricant 

Reproduction/development (gavage) 

Genistein 446-72-0 Antineoplastic agent; growth 

inhibitor; naturally-occurring 

phytoestrogen found in several 

plants including soy products. 

Nutritional and pharmaceutical 

applications 

Subchronic (feed), multigeneration study with

carcinogenicity (feed), immunotoxicity (feed), behavioral 

toxicity (feed) 

Methoxychlor 72-43-5 Insecticide Subchronic (feed), chronic toxicity/carcinogenicity

(feed), genetic toxicity (Salmonella, chromosome

aberration, sister chromatid exchange, mouse 

lymphoma), reproduction/development (gavage), range 

finding (feed), immunotoxicity (feed), behavioral toxicity

(feed) 

Nonylphenol 84852-15-3 Used extensively as non-ionic 

detergent surfactant in industrial 

applications 

Reproduction/development (feed), multigenerational 

study with carcinogenicity (feed), immunotoxicity (feed), 

behavioral toxicity (feed)

Phenobarbital 50-06-6 Pharmaceutical thyroid-active

agent used as a anticonvulsant

and sedative 

Genetic toxicity (Salmonella, chromosome aberration, 

sister chromatid exchange, mouse lymphoma), 

reproduction/development (gavage),

Propylthiouracil 51-52-5 Used since the 1940s as an

antithyroid agent for the 

treatment of hyperthyroidism

Genetic toxicity (Salmonella), reproduction/development 

(water), neurotoxicity (water)

Vinclozolin 50471-44-8 Fungicide, bactericide, wood 

preservative; used on fruits, 

vegetables, ornamental plants

and vines 

Reproduction/development (gavage), range finding 

(feed), immunotoxicity (feed), behavioral toxicity (feed) 

1

 Testing status and study results for completed studies can be found at http://ntp.niehs.nih.gov/ select “Testing Status of Agents at 

 NTP” and “Study Results & Research Projects 

EDCs 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 pesticides vinclozolin and methoxychlor, 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 multiple 

generations (Delclos, NCTR/FDA). The NCTR/FDA scientific staff is also interested in 

evaluating neuroanatomical, neurobehavioral, and immunological end points associated with 

exposure to endocrine disrupting chemicals (Ferguson, NCTR/FDA; Slikker, NCTR/FDA; 

Scallet, NCTR/FDA). These are critical parallel studies to the multigeneration toxicology 

studies. Two of the compounds (genistein and ethinyl estradiol) are also being investigated 

for chronic exposure effects including neoplasia (Newbold, NIEHS/NIH; Delclos, 

NCTR/FDA). 

42 National Toxicology Program
Studies at NIOSH/CDC are exploring how exposure to occupational chemicals impacts 

normal testicular function in vitro at different stages of maturation/development 

(fetal/neonatal, prepubertal, and adult). Primary cultures of rat cells that synthesize 

testosterone (Leydig cells) and help regulating spermatogenesis (Sertoli cells) from animals 

at different ages following exposure are being used. These studies target the testing of 

endocrine - disrupting chemicals (industrial surfactant additive - octylphenol and pesticides - 

methoxychlor and vinclozolin), which are reported to alter normal functioning of endogenous 

estrogens and androgens. Results from initial studies demonstrate age-dependent responses 

to chemical exposures. Future studies will focus on establishing possible mechanism(s) of 

action and comparing in vitro and in vivo responses (Murono, NIOSH/CDC). NIOSH/CDC 

is examining the relationship between female worker exposure to polychlorinated biphenyls 

and breast cancer. These compounds are suspected carcinogens because of their estrogenic 

and lipophilic properties (Whelan, NIOSH/CDC). 

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 develop standardized, validated 

protocols for those assays. NICEATM is currently evaluating several test methods 

nominated to assess endocrine activities of chemicals (see page 22). 

Occupational Mixtures and Exposures 

The NTP is coordinating an effort between NIEHS/NIH and NIOSH/CDC to better 

characterize worker exposures, educate workers, and identify occupational health research 

gaps. Current efforts are assessing worker exposures to 1-bromopropane (1-BP) and tungsten 

fibers. In addition, laboratory studies designed to address specific questions regarding 

workplace exposure to complex mixtures are being conducted or planned with welding fumes, 

abrasive blasting materials, and metal working fluids (Morgan, NIEHS/NIH; Toraason, 

NIOSH/CDC). 

The EPA has approved 1-BP as an alternative to ozone-depleting solvents for metal cleaning, 

electronics cleaning, and precision cleaning. It is also acceptable for use as an aerosol solvent 

and as a carrier solvent for adhesives. This may result in a vast increase in the exposure of 

workers and the public to this compound. To characterize these exposures, NIOSH/CDC is 

conducting an industry-wide exposure assessment. Study sites are being assessed based on 

quantity and manner of 1-BP use, number of workers exposed, type of manufacturing process, 

and how representative the exposure is for the industry as a whole. Exposures are being 

characterized by monitoring breathing zones, exhaled breath, and biological measures. 

Results from this study will be used to (1) evaluate patterns of exposure, (2) develop and 

validate biomonitoring methods, (3) facilitate development of intervention recommendations 

for reducing exposures, and (4) aid establishment of exposure limits (Hanley, NIOSH/CDC). 

Metallurgists create tungsten-trioxide or suboxide (WO) species as products of reduction 

reactions in processing tungsten containing ores to obtain useful chemical forms of tungsten. 

Recent studies in the Swedish hard-metal industry have shown that calcinations of WO, 

ammonium paratungstate, and ‘blue’ oxide result in the formation of asbestos-like WO

whiskers that are thought to be more toxic than WO powder. Investigations into the existence 

of WO fibers in the U.S. hard-metal industry have not been conducted previously. NIOSH is 

embarking on a field study in the hard metal industry to define baseline exposure to WO 

fibers among U.S. hard-metal workers (Hooth, NIEHS/NIH; Mckernan, NIOSH/CDC). 

Epidemiology suggests that pulmonary exposure to welding fumes may cause adverse health 

effects such as lung inflammation, cancer, and neurotoxicity. However, more information is 

required to determine causality, evaluate temporal and dose-response relationships, and 

elucidate mechanisms. NIOSH/CDC has designed and constructed a welding fume

generation and inhalation exposure system that will be used to characterize the physical and 

chemical properties of generated welding fumes. The system will be used to evaluate 

43 National Toxicology Program
exposure conditions, generator parameters, and welding processes and materials that may 

cause acute biological responses in an animal model (Morgan, NIEHS/NIH; Antonini, 

NIOSH/CDC). 

Alternatives to silica sand for abrasive blasting are frequently recommended to reduce

workers’ risk for developing fibrotic lung disease and cancer. Coal slag, garnet, steel grit, 

crushed glass, and specular hematite are frequently recommended as safe alternatives to silica 

sand. These abrasive blasting materials are being assessed to determine their relative 

potential for inducing lung fibrosis in experimental animals. Results will aid risk assessors in 

providing guidance for development of exposure limits (Suarez, NIEHS/NIH; Hubbs, 

NIOSH/CDC). 

Millions of gallons of metal working fluids are used each day in industry for cutting, milling, 

drilling, stamping, and grinding. NIOSH has estimated that over a million workers are 

engaged in these activities and potentially are exposed dermally and via inhalation to a wide 

variety of formulations. Potential hazards of product formulations are typically identified by 

testing of individual constituents. To determine if inhalation exposure to metal working fluid 

formulations poses an unrecognized hazard, several commercial products will be tested in 

sub-chronic, and in some cases, chronic inhalation bioassays (Roycroft, NIEHS/NIH; 

Toraason, NIOSH/CDC). 

DNA-Based Products 

DNA-based therapies are being developed for the treatment of 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 and unpredictable ways with potentially 

adverse consequences. Examples of DNA-based products include plasmid DNA encoding 

one or more antigenic proteins for vaccines against viral and bacterial pathogens, triplex 

forming synthetic oligonucleotides to modulate gene expression, and viral vectors for gene 

therapy. The FDA has only limited authority to require evaluation of non-acute, long-term

safety risk associated with these therapies. In addition, the majority of the manufacturers of 

DNA-based products are small biotechnology companies and academic sponsors that lack the 

resources to perform long-term, large-scale studies on their products. Presently the NTP is 

collaborating with the FDA and sister NIH institutes to study the safety of DNA-based 

products and address life-long risks presented by their use and their potential for reproductive 

toxicities and transmission of altered genetic material to subsequent generations. In addition, 

the potential for DNA-based products to cause autoimmune disease or immune dysfunction 

will be evaluated (Irwin, NIEHS/NIH). 

GENERAL TOXICOLOGY AND SUBCHRONIC STUDIES

Research Initiatives 

In the area of general toxicology assessments, the scope and types of studies performed are 

dictated to a large degree by the data needs for the specific substance nominated for study. 

General toxicology studies usually fall into two categories: subchronic or prechronic studies 

and 2-year chronic toxicity and carcinogenicity studies. These studies are typically carried out 

as contracted studies at several commercial laboratories in the United States. The NTP 

performs subchronic toxicity studies in part to provide dose-setting information for chronic 

studies and also to address specific deficiencies in the toxicology database for the chemical. 

Although designs are flexible, subchronic studies usually involve exposures of rats and mice 

of both sexes to substances for periods of 14 to 90 days. Assessments almost always include 

tissue histopathology, clinical pathology, and sperm motility or measurements of estrous cycle 

length. A determination of the frequency of micronucleated erythrocytes is conducted as an in 

44 National Toxicology Program
vivo measure of genotoxic potential, and, in some cases, a Functional Observational Battery is 

included as a neurotoxicology screen. The study protocol may include more detailed or 

focused studies when findings published in the existing scientific literature or identified in 

initial NTP studies suggest a target organ or system. Also, the study protocol may include 

separate studies of reproductive, genetic, or immunological toxicity based on the outcome of 

the toxicity screens. 

In some cases, the NTP uses alternative models, including genetically modified mouse models 

and non-mammalian models, for subchronic studies. Such studies are presented in the section 

“Alternative Test Systems” (page 65). Table 15 lists the agents tested in subchronic studies 

during FY 2003-2004. 

 Table 15. Ongoing Subchronic Toxicity Studies During FY 2003-20041

Chemical CAS Number Species/ Strain Route Study

Length 

Project 

Leader2

Acetaminophen (4-

Hydroxyacetanilide) 

103-90-2 Rats: Fischer 344 Gavage 2 days Boorman 

Acrolein 107-02-8 Mice: B6C3F1

Rats: Fischer 344 

Gavage 14 days

90 days

Irwin 

Acrylamide 79-06-1 Mice: B6C3F1

Rats: Fischer 344 

Water, Feed 14 days

90 days

Beland 

(NCTR/FDA) 

Adenoviral Vector (AdHgh) Rats: Fischer 344 Intraductal

Cannulation 

28 days Irwin 

Allyl Acetate 591-87-7 Mice: B6C3F1 

Rats: Fischer 344 

Gavage 14 days

90 days

Irwin 

Allyl Alcohol 107-18-6 Mice: B6C3F1 

Rats: Fischer 344 

Gavage 14 days

90 days

Irwin 

1-Bromopropane 106-94-5 Mice: B6C3F1

Rats: Fischer 344 

Inhalation 14 days

90 days

Morgan

o-Chloropyridine 109-09-1 Mice: B6C3F1

Rats: Fischer 344 

Topical 14 days Chhabra

o-Chloropyridine 109-09-1 Mice: B6C3F1

Rats: Fischer 344 

Water 90 days Chhabra

Diethylamine 109-89-7 Mice: B6C3F1

Rats: Fischer 344 

Inhalation 14 days

90 days

Morgan

N,N-Dimethyl-ptoluidine 99-97-8 Mice: B6C3F1

Rats: Fischer 344 

Gavage 90 days Dunnick

Ginkgo Biloba Extract 90045-36-6 Mice: B6C3F1 

Rats: Fischer 344 

Gavage 90 days Chan

Ginseng 50647-08-0 Mice: B6C3F1

Rats: Fischer 344 

Gavage 14 days

90 days

Chan 

Glycidamide 5694-00-8 Mice: B6C3F1/NCTR BR 

Rats: Fischer 344 

Water 14 days

90 days

Weis

(NCTR/FDA) 

Kava Kava Extract 9000-38-8 Mice: B6C3F1 

Rats: Fischer 344 

Gavage 14 days

90 days

Chan 

Melatonin 73-31-4 Rats: Fischer 344 

Rats: Long-Evans 

Gavage 14 days

90 days

Boorman 

Methyl trans-Styryl 

Ketone 

1896-62-4 Mice: B6C3F1

Rats: Fischer 344 

Feed 90 days Cunningham

Milk Thistle Extract 84604-20-6 Mice: B6C3F1 

Rats: Fischer 344 

Feed 90 days Dunnick

Polychlorinated

Naphthalenes (PCN 66 

and PDN67) 

1034426-96-6; 

1034426-97-7 

Rats: Fischer 344 

Rats: Sprague Dawley

Gavage 14 days

90 days

Hooth 

β-Picoline 108-99-6 Mice: B6C3F1

Rats: Fischer 344 

Water 90 days Abdo

Pyrogallol 87-66-1 Mice: B6C3F1

Rats: Fischer 344 

Topical 90 days Wyde

45 National Toxicology Program
Chemical CAS Number Species/ Strain Route Study

Length 

Project 

Leader2

Sodium Thioglycolate 367-51-1 Mice: B6C3F1 

Rats: Fischer 344 

Topical 14 days

90 days

Hooth 

Styrene-Acrylonitrile 

Trimer 

Rats: Fischer 344 Feed 7 weeks 

18 weeks

Chhabra 

α/β Thujone Mixture 546-80-5; 

471-15-8 

Mice: B6C3F1 

Rats: Fischer 344 

Gavage 90 days Hooth

Triethylamine 121-44-8 Mice: B6C3F1

Rats: Fischer 344 

Inhalation 14 days

90 days

Morgan

 1 Protocols for subchronic toxicity studies are described on the NTP website at http://ntp.niehs.nih.gov/ see “Descriptions of NTP 

 Study Types.” Testing status and study results for completed studies can be found at http://ntp.niehs.nih.gov/ select “Testing 

 Status of Agents at NTP” and “Study Results & Research Projects 2 Project Leader - NIEHS/NIH staff scientist (unless otherwise indicated) who oversees each chemical’s evaluation 

Research Projects (General Toxicology) 

• Statistical methods and applications for laboratory animal studies (Dinse, NIEHS/NIH) 

• Statistical methods for human studies (Dunson, NIEHS/NIH) 

• Statistical methods for studying human fertility (Dunson, NIEHS/NIH) 

• Statistical methods in toxicology (Dunson, NIEHS/NIH) 

• Predicting skin penetration: mode and experiments (Frasch, NIOSH/CDC) 

• The role of growth factors and inflammatory mediators in target-organ toxicity 

(Germolec, NIEHS/NIH) 

• Metabolic activity of human recombinant cytochrome P450 enzymes (Ghanayem,

NIEHS/NIH) 

• Drug metabolizing enzymes in humans and animal models (Goldstein, NIEHS/NIH) 

• Physiological effects of bitter orange in rats (Hansen, NCTR/FDA) 

• Identifying and evaluating sources of variability in rodent studies (Haseman, 

NIEHS/NIH) 

• Three dimensional atlas of mouse anatomy pathology (Maronpot, NIEHS/NIH) 

• Nuclear receptors: action, functions, and roles in disease (Jetten, NIEHS/NIH) 

• The roles of the cyclooxygenases (COXs) in normal physiology and pathological 

conditions (Langenbach, NIEHS/NIH) 

• Development of gene single nucleotide polymorphisms (SNPs) as a web-accessible 

highly annotated relational database of human and mouse environmental response genes 

(Maull, NIEHS/NIH) 

• Membrane transporters: critical determinats of AIDS antiviral drugs (Miller, 

NIEHS/NIH) 

• Regulation of renal xenobiotic excretion (Miller, NIEHS/NIH) 

• Biomarkers of cardiotoxicity (Murphy, NIEHS/NIH) 

• NMR studies of the mechanisms of cell injury (Murphy, NIEHS/NIH) 

• Asphalt fume chemical characterization and hazard identification (Olsen, NIOSH/CDC) 

• Evaluation of methods: polycyclic aromatic hydrocarbons (PAH) determination in 

asphalt fumes (Olsen, NIOSH/CDC)

• Mapping tree coverage in Vietnam in the 1960s (Portier, NIEHS/NIH) 

• Statistical models in toxicology and biochemistry (Portier, NIEHS/NIH) 

• Role of membrane transport in the effectiveness and toxicity of AIDS therapeutics 

(Pritchard, NIEHS/NIH) 

46 National Toxicology Program
• Toxicology of AIDS therapeutics (Roycroft, NIEHS/NIH) 

• Mechanisms of toxicity of redox reactive intermediates in skin (Shvedova, NIOSH/CDC) 

• Environmental atherosclerosis studies (Sills, NIEHS/NIH) 

• Developing healthy and dermatitis skin absorption models (Soderholm, NIOSH/CDC) 

• Mass spectrometry and oxidative stress (Tomer, NIEHS/NIH) 

• Statistical methods in human development/clinical studies (Umbach, NIEHS/NIH) 

• Arachidonic acid metabolism by murine CYP2c isoforms (Zeldin, NIEHS/NIH) 

• Characterization and functional significance of P450 arachidonate epoxygenases (Zeldin, 

NIEHS/NIH) 

CHRONIC TOXICITY, CARCINOGENESIS, AND MUTAGENESIS

Research Initiatives 

Two-year studies in rodents remain the primary laboratory method by which chemicals or 

physical agents are identified as having the potential to be hazardous to man. Studies in 

rodents along with studies in human populations (epidemiology studies) are the best means 

currently available for identifying potential human hazards. The chronic toxicology and 

carcinogenicity studies in conventional rodent models generally employ both genders of rats 

(Fisher 344) and mice (B6C3F1 hybrid) with three exposure levels plus untreated controls in 

groups of 50 animals for two years; genetically modified mouse and fish models are used 

occasionally. If adequate data exist in the literature for one rodent species, then typically only 

the remaining species is studied. The NTP interfaces its testing with regulatory agencies and 

the private sector in order to minimize duplication of effort. Table 16 lists the substances in 

the chronic phase of NTP study during FY 2003 and 2004. 

 Table 16. Ongoing Chronic Toxicity/Carcinogenicity Studies During FY 2003-20041

Chemical Name CAS Number Species/ Strain Route Study

Length 

Project 

Leader2

Aloe-Emodin 481-72-1 Mice:SKH-1 Hairless Topical 62 weeks Boudreau

(NCTR/FDA) 

Aloe Vera Charcoal 

Filtered Whole Leaf

Extract 

Mice:SKH-1 Hairless Topical 62 weeks Boudreau 

(NCTR/FDA) 

Aloe Vera Gel 8001-97-6 Mice:SKH-1 Hairless Topical 62 weeks Boudreau 

(NCTR/FDA) 

Aloe Vera Whole Leaf

Extract (Native)

Mice:SKH-1 Hairless Topical 62 weeks Boudreau 

(NCTR/FDA) 

Androstenedione 63-05-8 Mice:B6C3F1

Rats:Fischer 344

Gavage 2 years Eastin

Anthraquinone 84-65-1 Mice:B6C3F1

Rats:Fischer 344

Feed 2 years Irwin

AZT (3'-Azido-3'-

Deoxythymidine) 

30516-87-1 Mice:B6C3F1

Mice:B6C3F1/NCTR BR 

Gavage 2 year Beland

(NCTR/FDA) 

AZT+ 3TC (2', 3'-Dideoxy3'-thiacytidine) 30516-87-1; 

134678-17-4 

Mice:B6C3F1 

Mice:B6C3F1/NCTR BR 

Gavage 2 year Beland

(NCTR/FDA) 

AZT + 3TC + NLFT

(Nelfinavir Mesylate ) 

30516-87-1; 

134678-17-4; 

159989-65-8

Mice:B6C3F1 

Mice:B6C3F1/NCTR BR 

Gavage 2 year Beland

(NCTR/FDA) 

AZT + 3TC + NVP 

(Nevirapine) 

30516-87-1; 

134678-17-4; 

129618-40-2 

Mice:B6C3F1 

Mice:B6C3F1/NCTR BR 

Gavage 2 year Beland

(NCTR/FDA) 

47 National Toxicology Program
Chemical Name CAS Number Species/ Strain Route Study

Length 

Project 

Leader2

AZT Transplacental

Carcinogenesis Study

30516-87-1 Mice:Swiss CD-1 In utero 19 months Dunnick 

Benzophenone 119-61-9 Mice:B6C3F1

Rats:Fischer 344

Feed 2 years Chhabra

Bromochloroacetic Acid 5589-96-8 Mice:B6C3F1 

Rats:Fischer 344

Water 2 years Melnick 

Bromodichloromethane 75-27-4 Mice:B6C3F1

Rats:Fischer 344

Water 2 years Melnick 

1-Bromopropane 106-94-5 Mice:B6C3F1

Rats:Fischer 344

Inhalation 2 years Morgan

bis (2-Chloroethoxy)

Methane 

111-91-1 Mice:B6C3F1

Rats:Fischer 344

Topical 2 years Dunnick 

Chromium Picolinate 

Monohydrate 

27882-76-4 Mice:B6C3F1

Rats:Fischer 344

Feed 2 years Abdo 

Cresols 1319-77-3 Mice:B6C3F1

Rats:Fischer 344

Feed 2 years Chhabra 

Cumene 98-82-8 Mice:B6C3F1

Rats:Fischer 344

Inhalation 2 years Chan 

Dibromoacetic Acid 631-64-1 Mice:B6C3F1 

Rats:Fischer 344

Water 2 years Melnick 

Dibromoacetonitrile 3252-43-5 Mice:B6C3F1

Rats:Fischer 344

Water 2 years Melnick 

1,2-Dibromo-2,4-

dicyanobutane 

35691-65-7 Mice:B6C3F1

Rats:Fischer 344

Topical 2 years Dunnick 

Diethylamine 109-89-7 Mice:B6C3F1

Rats:Fischer 344

Inhalation 2 years Morgan

Diisopropylcarbodiimide 693-13-0 Mice:B6C3F1

Rats:Fischer 344

Topical 2 years Chhabra 

N,N-Dimethyl-p-toluidine 99-97-8 Mice:B6C3F1

Rats:Fischer 344

Gavage 2 years Dunnick 

Divinylbenzene 1321-74-0 Mice:B6C3F1

Rats:Fischer 344

Inhalation 2 years Morgan

Formamide 75-12-7 Mice:B6C3F1

Rats:Fischer 344

Gavage 2 years Irwin 

Ginseng 50647-08-0 Mice:B6C3F1

Rats:Fischer 344

Gavage 2 years Chan 

Goldenseal Root Powder Mice:B6C3F1 

Rats:Fischer 344

Feed 2 years Dunnick 

β-Hydroxy Acids (Salicylic

Acid) 

69-72-7 Mice:SKH-1 Hairless Topical 1 year Howard 

(NCTR/FDA) 

α-Hydroxy Acid (Glycolic 

Acid) 

79-14-1 Mice:SKH-1 Hairless Topical 1 year Howard 

(NCTR/FDA) 

5-(Hydroxymethyl)-2-

Furfural 

67-47-0 Mice:B6C3F1

Rats:Fischer 344

Gavage 2 years Irwin 

Isoeugenol 97-54-1 Mice:B6C3F1

Rats:Fischer 344

Gavage 2 years Abdo 

Leucomalachite Green 129-73-7 Mice:B6C3F1/NCTR BR 

Rats:Fischer 344

Feed 2 year Culp 

(NCTR/FDA) 

Malachite Green 569-64-2 Mice:B6C3F1/NCTR BR 

Rats:Fischer 344

Feed 2 year Culp 

(NCTR/FDA) 

Methylene Blue Trihydrate 7220-79-3 Mice:B6C3F1 

Rats:Fischer 344

Gavage 2 years Chhabra 

2-Methylimidazole 693-98-1 Mice:B6C3F1

Rats:Fischer 344

Feed 2 years Chan 

4-Methylimidazole 822-36-6 Mice:B6C3F1

Rats:Fischer 344

Feed 2 years Chan 

Methyl Isobutyl Ketone 108-10-1 Mice:B6C3F1 

Rats:Fischer 344

Inhalation 2 years Suarez 

48 National Toxicology Program
Chemical Name CAS Number Species/ Strain Route Study

Length 

Project 

Leader2

α-Methylstyrene 98-83-9 Mice:B6C3F1

Rats:Fischer 344

Inhalation 2 years Morgan

Methyl trans-Styryl Ketone 1896-62-4 Mice:B6C3F1 

Rats:Fischer 344

Topical 2 years Cunningham 

Milk Thistle Extract 84604-20-6 Mice:B6C3F1 

Rats:Fischer 344

Feed 2 years Dunnick 

β-Myrcene 123-35-3 Mice:B6C3F1

Rats:Fischer 344

Gavage 2 years Chan 

β-Picoline 108-99-6 Mice:B6C3F1

Rats:Fischer 344

Water 2 years Abdo 

Propargyl Alcohol 107-19-7 Mice:B6C3F1 

Rats:Fischer 344

Inhalation 2 years Hooth 

Propylene Glycol Mono-tbutyl Ether 57018-52-7 Mice:B6C3F1

Rats:Fischer 344

Inhalation 2 years Chhabra 

Pulegone 89-82-7 Mice:B6C3F1

Rats:Fischer 344

Gavage 2 years Chan 

All-trans-Retinyl Palmitate 79-81-2 Mice:SKH-1 Hairless Topical 1 year Fu 

(NCTR/FDA) 

Sodium Chlorate 7775-09-9 Mice:B6C3F1 

Rats:Fischer 344

Water 2 years Hooth

Sodium Dichromate 

Dihydrate (VI) 

7789-12-0 Mice:B6C3F1

Rats:Fischer 344

Water 2 years Abdo 

Stoddard Solvent (Type 

IIC) 

64742-88-7 Mice:B6C3F1

Rats:Fischer 344

Inhalation 2 years Chhabra 

Toxic Equivalency Factor 

TEF) Evaluation (Dioxin 

Mixture) 

Rats:Sprague Dawley Gavage 2 years Walker

TEF Evaluation (Binary 

Mixture; PCB 126/ PCB 

153 

57465-28-8 

35065-27-1 

Rats:Sprague Dawley Gavage 2 years Walker

TEF Evaluation (PCB 118) 31508-00-6 Rats:Sprague Dawley Gavage 2 years Walker

TEF Evaluation (PCB 

Mixture; PCB 126/PCB 

118) 

57465-28-8 

31508-00-6

Rats:Sprague Dawley Gavage 2 years Walker

TEF Evaluation (PCB 126) 57465-28-8 Rats:Sprague Dawley Gavage 2 years Walker

TEF Evaluation (TCDD) 1746-01-6 Rats:Sprague Dawley Gavage 2 years Walker

TEF Evaluation

(Pentachlorodibenzofuran) 

57117-31-4 Rats:Sprague Dawley Gavage 2 years Walker

3,3',4,4'-

Tetrachloroazobenzene 

14047-09-7 Mice:B6C3F1

Rats:Sprague Dawley

Gavage 2 years Hooth 

Tetralin 119-64-2 Mice:B6C3F1

Rats:Fischer 344

Inhalation 2 years Chan 

α/β-Thujone Mixture Mice:B6C3F1 

Rats:Fischer 344

Gavage 2 years Hooth 

TEF Evaluation (PCB 153- 

2,2'-4,4',5,5'-

Hexachlorobiphenyl) 

35065-27-1 Rats:Sprague Dawley Gavage 2 years Wyde

Triethanolamine 102-71-6 Mice:B6C3F1 Topical 2 years Suarez 

Trimethylolpropane 

Triacrylate 

15625-89-5 Mice:B6C3F1

Rats:Fischer 344

Topical 2 years Chhabra 

1

 Protocols for chronic toxicity and carcinogenicity studies are described on the NTP website at http://ntp.niehs.nih.gov/ see 

 “Descriptions of NTP Study Types.” Testing status and study results for completed studies can be found at 

 http://ntp.niehs.nih.gov/ select “Testing Status of Agents at NTP” and “Study Results & Research Projects 2

 Project Leader - NIEHS/NIH staff scientist (unless otherwise indicated) who oversees each chemical’s evaluation 

49 National Toxicology Program
Mutagenesis and Genetic Toxicity

Genetic toxicity test results are used to make decisions about whether a substance should be 

tested for carcinogenicity in rodents; to aid in the interpretation of toxicity, carcinogenicity, or 

other in vivo test results; and to provide a database for use in structure-activity analyses. 

Testing is conducted at contract laboratories. 

Analysis of the early, multi-test database showed that positive results for a chemical in the 

Salmonella gene mutation assay were highly correlated with carcinogenicity in multiple 

species/sexes of rodents and at multiple tissue sites; data from additional tests did not improve 

the correlation. Subsequently, studies of the correlation between mutagenicity test data and 

rodent carcinogenicity showed a strong association between clearly positive results in longterm mouse peripheral blood micronucleus tests and rodent carcinogenicity. The importance 

of genetic toxicity test data in assessing exposure hazard for NTP chemicals is underscored by 

the fact that most organic chemicals (other than hormones) identified by the International 

Agency for Research on Cancer as human carcinogens are genotoxic, and the vast majority of 

them are detected by both the Salmonella assay and rodent micronucleus tests. Additional 

assays may be conducted with certain chemicals to gain further insight into the types of DNA 

and chromosomal damage induced by a chemical. 

Gene mutations and DNA damage are examined in most tissues; cytogenetic effects, 

measured as the induction of micronuclei, are generally examined in bone marrow cells or in 

peripheral erythrocytes. The erythrocyte studies are integrated with other toxicity evaluations 

to minimize the use of animals and to expand the toxicology information for the chemical in 

the same animals. Compounds tested for genetic toxicity during FY 2003 and 2004 are listed 

in Table 17. 

50 National Toxicology Program
 Table 17. Ongoing and Completed Genetic Toxicity Studies During FY 2003-20041

Chemical CAS Number Testing Battery

Abscisic Acid 14375-45-2 Salmonella 

N-2-Acetylaminofluorene 53-96-3 Sister Chromatid Exchange 

2-Acetylthiazole 24295-03-2 Salmonella

Acid Red 14 (C.I. 14720) 3567-69-9 Chromosome Aberrations

Acrylamide 79-06-1 Micronucleus

Acrylonitrile 107-13-1 Micronucleus

S-Adenosylmethionine 29908-03-0 Salmonella

β-Alanine 107-95-9 Salmonella

DL-Alanine 302-72-7 Salmonella

All-trans-Retinyl Palmitate 79-81-2 Salmonella

Aluminum Citrate 31142-56-0 Salmonella

Aluminum Fluoride 7784-18-1 Salmonella

2-Aminoanthracene 613-13-8 Salmonella

4-Androstene-3,17-dione 63-05-8 Micronucleus

Anthraquinone 84-65-1 Salmonella

Apigenin 520-36-5 Salmonella

Aspartame 22839-47-0 Micronucleus

AZT (3'-Azido-3'-deoxythymidine) 30516-87-1 Micronucleus

AZT + 2',3'-Dideoxyinosine 30516-87-1; 

69655-05-6 

Micronucleus 

AZT + 3TC (2', 3'-Dideoxy-3'-thiacytidine) 30516-87-1; 

134678-17-4 

Micronucleus 

Benzene 71-43-2 Micronucleus, Chromosome Aberrations

Benzo(a)pyrene 50-32-8 Chromosome Aberrations

Bisphenol A 80-05-7 Chromosome Aberrations

Bixin 6983-79-5 Salmonella

Black Cohosh 84776-26-1 Salmonella

Blackberry Extract 84787-69-9 Salmonella 

1-Bromopropane 106-94-5 Micronucleus

Bupivacaine 38396-39-3 Salmonella

1,3-Butadiene 106-99-0 Chromosome Aberrations

2-Butanol 78-92-2 Salmonella

Cedarwood Oil 8000-27-9 Salmonella 

Cefuroxime 55268-75-2 Salmonella

Cimperial 1070 Salmonella 

Cimstar 3733 Salmonella 

Cimtech 310 Salmonella 

2-Chloro-l,3-butadiene (Chloroprene) 126-99-8 Chromosome Aberrations

Chlorodibromomethane 124-48-1 Chromosome Aberrations

2-(Chloromethyl)pyridine HC1 6959-47-3 Chromosome Aberrations

4-Chloronitrobenzene 100-00-5 Micronucleus

4-Chloro-o-phenylenediamine 95-83-0 Chromosome Aberrations

2-Chloropyridine 109-09-1 Salmonella, Micronucleus 

Chromium Picolinate Monohydrate 27882-76-4 Micronucleus

Clearedge 6584 Salmonella 

Colchicine 64-86-8 Micronucleus

Cumene Hydroperoxide 80-15-9 Micronucleus 

Cyclophosphamide 50-18-0 Micronucleus

D&C Red 27 13473-26-2 Salmonella

D&C Red 28 18472-87-2 Salmonella

2,4-Decadienal 25152-84-5 Micronucleus

1,2-Dichlorobenzene 95-50-1 Micronucleus, Sister Chromatid Exchange

cis-l,2-Dichloroethylene 156-59-2 Chromosome Aberrations

2',3'-Dideoxyinosine (DDI) 69655-05-6 Micronucleus

2', 3'-Dideoxy-3'-thiacytidine (3TC) 134678-17-4 Micronucleus 

51 National Toxicology Program
Chemical CAS Number Testing Battery

Diethylamine 109-89-7 Micronucleus

Diethylformamide 617-84-5 Salmonella

Dimepranol (1-(dimethylamino)-2-propanol) 108-16-7 Salmonella

Dimethyl Hydrogenphosphite 868-85-9 Sister Chromatid Exchange

N,N-Dimethyl-p-toluidine 99-97-8 Salmonella, Micronucleus

Diphenolic Acid 126-00-1 Salmonella

Dodecyl Alcohol, Ethoxylated 9002-92-0 Sister Chromatid Exchange

Dong Quai Salmonella 

Drinking Water Contaminants Mixture Numerous CAS 

Numbers 

Chromosome Aberrations, Sister Chromatid

Exchange

L-Ephedrine 299-42-3 Salmonella

1,2-Epoxypropane 75-56-9 Sister Chromatid Exchange

Ethyl Methanesulfonate 62-50-0 Micronucleus 

2-Ethylhexyl-p-dimethylaminobenzoic Acid 21245-02-3 Salmonella 

α-Fenchone 1195-79-5 Micronucleus

Ginseng and Ginsenosides 50647-08-0 Micronucleus

Glucono Delta Lactone 90-80-2 Salmonella

Glycidamide 5694-00-8 Salmonella

Glycidol 556-52-5 Micronucleus

Goldenseal Root Powder Micronucleus

Grape Seed Extract Salmonella

2,2',4,4',5,5'-Hexabromodiphenyl Ether 68631-49-2 Salmonella 

2,4-Hexadienal 142-83-6 Micronucleus

Hydergine 8067-24-1 Salmonella

1-Hydroxyanthraquinone 129-43-1 Salmonella

2-Hydroxyanthraquinone 605-32-3 Salmonella

Indole-3-carbinol 700-06-1 Salmonella, Micronucleus

Iso-E Super 54464-57-2 Salmonella 

Kava Kava Extract 9000-38-8 Micronucleus 

Lime oil 8008-26-2 Salmonella

D-Mannitol 69-65-8 Sister Chromatid Exchange

2-Methyl-2-ethoxypropane (t-Butyl Ethyl Ether) 637-92-3 Micronucleus

Methyl Soyate 67784-80-9 Salmonella

2-Methyl Tetrahydrofuran 96-47-9 Salmonella

Milk Thistle Extract 84604-20-6 Micronucleus

Mitomycin C 50-07-7 Chromosome Aberrations

Monobutyltin Trichloride 1118-46-3 Salmonella

Monomethyltin Trichloride 993-16-8 Salmonella

1-Nitroanthracene 54738-93-1 Salmonella

2-Nitroanthracene 3586-69-4 Salmonella

9-Nitroanthracene 602-60-8 Salmonella

Nitrogen Trifluoride 7783-54-2 Salmonella 

Norbixin 542-40-5 Salmonella

Oleid Acid Diethanolamine Condensate 93-83-4 Micronucleus

4,4'-Oxydianiline 101-80-4 Chromosome Aberrations

2,2',4,4',5-Pentabromodiphenyl Ether 60348-60-9 Salmonella

Pentabromodiphenyl Oxide 32534-81-9 Salmonella

Pentachloroethane 76-01-7 Sister Chromatid Exchange

Phenolphthalein 77-09-8 Micronucleus

3-Picoline 108-99-6 Micronucleus

Pimenta Oil 8006-77-7 Salmonella 

Pine Bark Extract Salmonella

Polybrominated Biphenyl Mixture (Firemaster FF1) 67774-32-7 Sister Chromatid Exchange

Prilocaine 721-50-6 Salmonella

Primaclone 125-33-7 Micronucleus

Pyrogallol 87-66-1 Micronucleus

Resveratrol 501-36-0 Salmonella

52 National Toxicology Program
Chemical CAS Number Testing Battery

Scutellaria Salmonella

Senna, Powdered 8013-11-4 Salmonella

Sodium Azide 26628-22-8 Salmonella 

Sodium Dichromate Dihydrate (VI) 7789-12-0 Micronucleus

Sodium (2-Ethylhexyl)alcohol Sulfate 126-92-1 Sister Chromatid Exchange

Styrene 100-42-5 Micronucleus

Sulfisoxazole 127-69-5 Sister Chromatid Exchange

Superedge 6768 Salmonella 

Syntilo 1023 Salmonella 

Tetrabromobisphenol A-bis(2,3-dibromopropyl

ether) 

21850-44-2 Salmonella

2,2'4,4'-Tetrabromodiphenyl Ether 5436-43-1 Salmonella

1,1,1,2-Tetrachloroethane 630-20-6 Sister Chromatid Exchange

Tetrahydrofuran 109-99-9 Sister Chromatid Exchange

Thioglycolic Acid, Na+ Salt 367-51-1 Micronucleus

α, β- Thujone Mixture 546-80-5; 

471-15-8 

Salmonella, Micronucleus

p-Toluenesulfonamide 70-55-3 Salmonella

Triethylamine 121-44-8 Micronucleus

Trim 229 Salmonella 

Trim SC210 Salmonella 

Trim VX Salmonella 

Turpentine 8006-64-2 Salmonella

Urethane (Ethyl Carbamate) 51-79-6 Micronucleus

Valerian 8008-88-6 Salmonella

Vincristine Sulfate 57-22-7 Micronucleus 1

 Protocols for genetic toxicity studies are described on the NTP website at http://ntp.niehs.nih.gov/ see “Descriptions of 

 NTP Study Types.” Testing status and study results for completed studies can be found at http://ntp.niehs.nih.gov/ select 

 “Testing Status of Agents at NTP” and “Study Results & Research Projects 

Research Projects 

• Genetic susceptibility to carcinogens (Bell, NIEHS/NIH)

• Mechanism of carcinogens—genetic alterations in rodent and human tumors (Devereux, 

NIEHS/NIH) 

• Biochemical mechanisms related to risk factors of mammary carcinogenesis 

(DiAugustine, NIEHS/NIH) 

• Molecular mechanisms of UV-induced carcinogenesis (Ding, NIOSH/CDC)

• Genotoxicity, mutagenicity, and exposure biomarkers of acrylamide and its metabolite, 

glycidamide, in rodents (Doerge, NCTR/FDA) 

• Anti-carcinogenic activity of nonsteroidal anti-inflammatory drugs (NSAID) mediated by 

a new TGF-β superfamily gene (Eling, NIEHS/NIH)

• Effect of topically applied skin creams containing retinyl palmitate on the 

photocarcinogenicity of simulated solar light in SKH-1 mice (Fu, NCTR/FDA) 

• Molecular mechanisms of cadmium carcinogenesis (Joseph, NIOSH/CDC) 

• Role of cytochrome P450-mediated oxidation in chemical-induced 

toxicity/carcinogenicity (Ghanayem, NIEHS/NIH)

• Effect of COX-1 or COX-2 deficiency on epidermal differentiation (Langenback, 

NIEHS/NIH)

• In vivo mammalian mutagenesis (Malling, NIEHS/NIH)

53 National Toxicology Program
• Identification of single nucleotide polymorphisms (SNPS) in disease susceptibility genes 

(Maull, NIEHS/NIH)

• Recombination and DNA divergence (Resnick, NIEHS/NIH)

• Mechanisms of genome instability (Resnick, NIEHS/NIH) 

• Regulation of human carcinoma cell adhesion (Roberts, NIEHS/NIH) 

• Genetic alterations in rodent cancer—prospective and retrospective studies (Sills, 

NIEHS/NIH) 

• Mechanisms of carcinogenesis caused by occupational exposure to metals (Shi, 

NIOSH/CDC) 

• Silica carcinogenicity: use of susceptible mouse models (Vallyathan, NIOSH/CDC) 

• Studies of breast cancer incidence in occupational cohorts exposed to PCB and ethylene 

oxide (ETO) (Whelan, NIOSH/CDC) 

IMMUNOTOXICOLOGY

Research Initiatives 

NTP immunotoxicity studies address adverse effects on the immune system that may result 

from exposure to environmental chemicals, biological materials, or therapeutic agents. The 

identification of substances that have potential to cause injury to the immune system is of

considerable public health significance as alterations in immune function can lead to 

increased incidence of hypersensitivity disorders, autoimmune or infectious disease, or 

neoplasia. Immunotoxicity can be divided into two broad research areas: (1) studies of altered 

hematopoietic (blood cell development) or immunologic events associated with exposure of 

humans and animals to chemicals and (2) studies of immune-mediated hypersensitivity 

(allergy and autoimmunity) resulting from exposure to environmental chemicals or 

therapeutics. In the former case, the immune system acts as a passive target (nonspecific) for 

the xenobiotic, and the result may be an increased incidence or severity of infectious disease 

or neoplasia because of the inability to respond adequately to the invading agent. In 

hypersensitivity (i.e., allergy), the immune system responds to small molecular weight 

compounds that bind to host tissue, recognizing the complex as foreign antigen. This immune 

response to the chemical-host tissue complex may lead to a disease, such as respiratory tract 

allergies (e.g., asthma, rhinitis) or allergic contact (skin) dermatitis. Autoimmunity, another 

form of immune-mediated disease, is characterized by an immune response against 

constituents of the body's own tissues (autoantigens). Table 18 lists the substances in 

undergoing immunotoxicity assessment during FY 2003 and 2004. The NCTR/FDA is 

evaluating the effects of endocrine disrupting chemicals on the immune system in 

multigenerational studies (see page 41). 

 Table 18. Ongoing Immunotoxicity Studies During FY 2003-20041

Chemical Name CAS Number Species/ Strain Route 

Testing 

Battery2

5-Amino-o-cresol 2835-95-2 Mice: B6C3F1 Topical HY

Annatto 1393-63-1 Mice: BALB/C Topical HY

AZT (3'-Azido-3'-

deoxythymidine) 

30516-87-1 Mice: B6C3F1 Gavage IM, MG 

Cadmium Chloride 10108-64-2 Rats: Brown-Norway Gavage/Water AI

Chloroform 67-66-3 Mice: B6C3F1 Water IM

Dibromoacetic Acid 631-64-1 Mice: B6C3F1 Water IM

1,3-Dichloropropene (Telone II) 542-75-6 Mice: B6C3F1 Water IM

Echinacea Purpurea, Extract 90028-20-9 Mice: B6C3F1 Gavage IM, AI

54 National Toxicology Program
Chemical Name CAS Number Species/ Strain Route 

Testing 

Battery2

Elmiron (Sodium

Pentosanpolysulfate) 

37319-17-8 Mice: B6C3F1 Gavage IM

Itraconazole 84625-61-6 Mice: B6C3F1 Gavage IM

Nevirapine 129618-40-2 Mice: B6C3F1 Gavage IM, MG

Phenol 108-95-2 Mice: B6C3F1

Rats: Fisher 344

Water IM

Pyrogallol 87-66-1 Mice: BALB/C Topical HY

Rifamycin 6998-60-3 Mice: BALB/C Topical HY

Saquinavir Mesylate 149845-06-7 Mice: B6C3F1 Gavage IM 

Sodium Dichromate Dihydrate 

(VI) 

7789-12-0 Mice: B6C3F1

Rats: Fischer 344/ Sprague Dawley

Water IM

Trichloroethylene 79-01-6 Rats: Brown-Norway Gavage AI

Urethane 51-79-6 Mice: B6C3F1 Subcutaneous 

Injection 

AI 

 1 Protocols for immunotoxicity studies are described on the NTP website at http://ntp.niehs.nih.gov/ see “Descriptions of NTP 

 Study Types.” Testing status can be found at http://ntp.niehs.nih.gov/ select “Testing Status of Agents at NTP.” Project Leader - 

 Dr. Germolec (NIEHS/NIH) serves as the staff scientist who oversees each chemical’s evaluation. 

 2

 Testing Battery Abbreviations 

 AI = Automimmunity

 HY = Hypersensitivity

 IM = Immunomodulation 

 MG = Multiple generations, assess effects on immunologic function and cancer end points for multiple generations 

Research Projects

• Improving the sensitivity and predictability of testing strategies for immunotoxicity 

(Germolec, NIEHS/NIH) 

• Immunotoxicity of workplace xenobiotics (Germolec, NIEHS/NIH) 

• The role of cytokines in the developing immune system (Germolec, NIEHS/NIH) 

• Potential for environmental and therapeutic agents to induce immunotoxicity (Germolec, 

NIEHS/NIH) 

• Neuroimmunotoxicology: autoimmunity, viral, infections and environmental agents 

(Harry, NIEHS/NIH) 

• Identification of occupational allergens (Beezhold, NIOSH/CDC) 

• The role of innate immunity genes in viral infection and disease progression (Kleeberger, 

NIEHS/NIH) 

• Investigations of hypersensitivity responses and mechanisms (Meade, NIOSH/CDC) 

• Pathogenesis and genetic/environmental risk factors for autoimmune disease (Miller, 

NIEHS/NIH) 

• Assessment and therapy of autoimmune disease (Miller, NIEHS/NIH) 

• Is the immune system targeted by asphalt fumes? (Munson, NIOSH/CDC) 

NEUROTOXICOLOGY

Research Initiatives 

Behavioral and neurologic alterations in response to deleterious environmental agents often 

represent the earliest observable manifestation of toxicity. Neurotoxicology screening of NTP 

compounds often employs the EPA Neurobehavioral Screening Battery and Functional 

Observational Battery (FOB), with addition of locomotor activity measurements or the 

NIEHS Neurobehavioral Test Battery. The testing batteries examine the various 

55 National Toxicology Program
neurobehavioral systems: sensory, motor, autonomic, and peripheral nervous system. The 

FOB employs observational screening while the NIEHS test battery uses automated test 

systems to evaluate the various nervous system components. Table 19 lists substances being 

evaluated for neurotoxicity during FY 2003 and 2004. 

 Table 19. Completed Neurotoxicity Studies During FY 2003-20041

Chemical Name CAS Number Species/ Strain Route Project Leader

2

Carbonyl Sulfide 463-58-1 Rats: Fisher 344 Inhalation Morgan/Sills 

Molinate 2212-67-1 Rats: Long-Evans Hooded Feed Harry

6-Propyl-2-thiouracil 51-52-5 Rats: Long-Evans Hooded Water Harry

Tellurium 13494-80-9 Rats: Long-Evans Hooded Feed Harry

Trimethyltin Hydroxide 56-24-6 Mice: CD1 Injection Harry 1 Testing status can be found at http://ntp.niehs.nih.gov/ select “Testing Status of Agents at NTP” 2 Project Leader - NIEHS/NIH staff scientist who oversees each chemical’s evaluation, unless otherwise indicated. 

Research Projects 

• Mechanisms of synaptic plasticity in the adult and developing nervous system (Dudek, 

NIEHS/NIH) 

• Environmentally induced alterations in neuron and glia development (Harry, 

NIEHS/NIH) 

• Cellular indicators of neuronal insult (Harry, NIEHS/NIH) 

• Role of arachidonate cyclooxygenanse in inflammation-mediated neuronal death (Hong, 

NIEHS/NIH) 

• Roles of brain neuroimmune system in neurodegeneration (Hong, NIEHS/NIH) 

• Lead and other neurotoxins as risk factors for amyotrophic lateral sclerosis (Kamel, 

NIEHS/NIH) 

• Bioactivity of neuropeptides (Lazarus, NIEHS/NIH) 

• Neurotoxicity of inhaled carbonyl sulfide (Morgan, NIEHS/NIH) 

• Signalling pathways associated with toxicant-induced gliosis (O'Callaghan, 

NIOSH/CDC) 

• Developmental neurotoxicity: Assessment of acrylamide in rats: Long-term studies 

(Paule, NCTR/FDA) 

• Developmental neurotoxicity: Assessment of acrylamide in rats: Range-finding studies 

(Paule, NCTR/FDA) 

• A case-control study of primary intracranial gliomas among rural residents (Ruder, 

NIOSH/CDC) 

• NMDA antagonist/GABA agonist-induced cell death in the developing rat brain (Wang, 

NCTR/FDA) 

• Modulation of neuronal channels and receptors in the brain (Yakel, NIEHS/NIH) 

DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY

Research Initiatives 

As part of its charge to test chemicals of concern for potential toxicity the NTP evaluates 

developmental and reproductive toxicity primarily by using teratology and Reproductive 

Assessment by Continuous Breeding (RACB) study designs. The RACB study design was 

developed by the NTP for use to identify potential hazards to toxic effects on male and/or 

female reproduction, characterize that toxicity, and define the dose-response relationships for 

56 National Toxicology Program
each compound. The study design has evolved over the years; initially the study employed 

predominantly mice as the test species and now almost exclusively uses rats. As our 

improved knowledge and use of sensitive end points has increased, they have been 

incorporated into revisions of the study design. Table 20 list chemicals undergoing 

developmental and reproductive toxicity assessment during FY 2003 and 2004. 

 Table 20. Ongoing Developmental and Reproductive Toxicity Studies During FY 2003-20041

Chemical Name 

CAS

Number Species/ Strain Route

Project 

Leader2 Testing Battery3

Aniline 62-53-3 Mice: B6C3F1 Gavage Bishop Sperm Fish Aneuploidy

AZT (3'-Azido-3'-

deoxythymidine) + 2',3'-

Dideoxyinosine 

30516-87-1; 

69655-05-6 

Mice: Swiss (CD-1) Gavage Bishop RACB 

AZT+ 3TC (2', 3'-

Dideoxy-3'-thiacytidine) 

30516-87-1; 

134678-17-4 

Mice: Swiss (CD-1) Gavage Bishop RACB 

AZT + Dapsone 30516-87-1; 

80-08-0 

Mice: Swiss (CD-1) Gavage Jahnke TER 

Benzene 71-43-2 Mice: B6C3F1 Gavage Bishop Sperm Fish Aneuploidy

1,2,3,4-

Butanetetracarboxylic

Acid 

1703-58-8 Rats: Sprague Dawley Water Bishop RACB 

Cyclophosphamide 

Monohydrate 

6055-19-2 Mice: B6C3F1 Gavage Bishop Sperm Fish Aneuploidy

Dibutyl Phthalate +

Flutamide 

84-74-2; 

13311-84-7 

Rats: Sprague Dawley

& Wistar 

Gavage Bishop RACB

Diazoaminobenzene 136-35-6 Mice: B6C3F1 Gavage Bishop Sperm Fish Aneuploidy

Di(2-ethylhexyl) Phthalate 117-81-7 Rats: Sprague Dawley Feed Bishop RACB 

Hexachlorobenzene 118-74-1 Rats: Sprague Dawley Gavage Bishop RACB 

Sodium Bromate 7789-38-0 Rats: Sprague Dawley Water Bishop RACB 

3,3',4,4'-

Tetrachloroazobenzene 

14047-09-7 Rats: Sprague Dawley Gavage Bishop RACB 

 1 Protocols for developmental and reproductive toxicity studies are described on the NTP website at http://ntp.niehs.nih.gov/ see 

 “Descriptions of NTP Study Types.” Testing status and study results for completed studies can be found at 

 http://ntp.niehs.nih.gov/ select “Testing Status of Agents at NTP” and “Study Results & Research Project 2 Project Leader - NIEHS/NIH staff scientist who oversees each chemical’s evaluation, unless otherwise indicated. 3 Testing Battery Abbreviations 

 RACB = Reproductive Assessment by Continuous Breeding 

 TER = Teratology

Research Projects 

• Molecular detection of chromosome damage in rodent germ cells (Bishop, NIEHS/NIH) 

• Human germ line effects from zidovudine and other dideoxynucleosides (Bishop, 

NIEHS/NIH) 

• Molecular detection of aneuploidy in mouse germ cells (Bishop, NIEHS/NIH) 

• Propylthiouracil (PTU) induced failure of tooth eruption in Sprague Dawley rats (Bishop, 

NIEHS/NIH) 

• Mechanistic studies of female reproductive toxicants and carcinogens (Davis, 

NIEHS/NIH) 

• Pathobiology of uterine leiomyomas (fibroids) (Dixon, NIEHS/NIH) 

• Analysis of mechanisms of testicular toxicity using DNA microarray technology (Eddy, 

NIEHS/NIH) 

• Gene expression in spermatogenic cells (Eddy, NIEHS/NIH) 

57 National Toxicology Program
• Sperm scoring using multi-spectral flow imaging and fluorescence in situ hybridization 

(Heindel, NIEHS/NIH; Small Business Innovation Research contract) 

• Developmental toxicity of bitter orange in rats (Hansen, NCTR/FDA) 

• Reproductive state, xenoestrogens, and work (Huffman, NIOSH/CDC) 

• Methods for assessing reproductive potential in females (Kesner, NIOSH/CDC) 

• Chemical receptor interactions in reproduction and hormonal toxicity (Korach, 

NIEHS/NIH) 

• Evaluation of the toxicity of jet fuel during in utero development (Meade, NIOSH/CDC) 

• Emerging reproductive hazards (Moorman, NIOSH/CDC) 

• Acrylamide workers' reproductive and neurological health (Moorman, NIOSH/CDC) 

• Reproductive toxicity of occupational chemicals (Murono, NIOSH/CDC) 

• Developmental biology/toxicology of estrogenic environmental chemicals (Newbold, 

NIEHS/NIH) 

• Methods assessing toxicity to four sites of male reproductive toxicity (Schrader, 

NIOSH/CDC) 

• The source, concentration, and role of phytoestrogens in rodent diets (Thigpen, 

NIEHS/NIH) 

• Reproductive disorders in female flight attendants: health effects (Whelan, NIOSH/CDC) 

RESPIRATORY TOXICOLOGY

Research Initiatives 

Inhalation exposure to environmental and occupational toxicants is a major contributing factor 

to human health problems. Several agents are also under consideration as causative agents for 

adult or childhood respiratory diseases through epidemiology studies (Tables 21 and 22). 

 Table 21. Ongoing Inhalation Toxicity Studies During FY 2003-20041

Chemical CAS Number Study Design

Carbonyl Sulfide 463-58-1 Neurotoxicity

Cumene 98-82-8 Subchronic, chronic toxicity/carcinogenicity

Diethylamine 109-89-7 Subchronic, chronic toxicity/carcinogenicity

Divinylbenzene 1321-74-0 Subchronic, chronic toxicity/carcinogenicity, 

chemical disposition 

Methyl Isobutyl Ketone 108-10-1 Chronic toxicity/carcinogenicity

α-Methylstyrene 98-83-9 Subchronic, chronic toxicity/carcinogenicity, 

chemical disposition 

α-Pinene 80-56-8 Subchronic

Propargyl Alcohol 107-19-7 Subchronic, chronic toxicity/carcinogenicity, 

chemical disposition 

Propylene Glycol Mono-tButyl Ether 57018-52-7 Chronic toxicity/carcinogenicity, toxicokinetics 

Stoddard Solvent (Type IIC) 64742-88-7 Chronic toxicity/carcinogenicity, mechanism 

Tetralin 119-64-2 Subchronic, chronic toxicity/carcinogenicity

Triethylamine 121-44-8 Subchronic

Vinylidene Chloride 75-35-4 Subchronic, chronic toxicity/carcinogenicity 1 Testing status and study results for completed studies can be found at http://ntp.niehs.nih.gov/ select “Testing Status 

 of Agents at NTP” and “Study Results & Research Project 

58 National Toxicology Program
Research Projects 

• Pulmonary, systemic and dermal effects of welding fume inhalation exposure (Antonini, 

NIOSH/CDC) 

• Particle-induced lung injury in mixed exposures (Hubbs, NIOSH/CDC) 

• Particle surface program: biological interactions (Keane, NIOSH/CDC) 

• Particle-induced cardiopulmonary injury in mice: genetic susceptibility (Kleeberger, 

NIEHS/NIH) 

• Genetic mechanisms of susceptibility to ozone-induced pulmonary inflammation 

(Kleeberger, NIEHS/NIH) 

• Gene-environment interaction and pulmonary disease: translational studies (Kleeberger, 

NIEHS/NIH) 

• Vibration effects on pulmonary responses to toxic agents (Lindsley, NIOSH/CDC) 

• Occupational asthma: Inflammation and workplace disease (Luster, NIOSH/CDC) 

• Pulmonary toxicity of diesel exhaust particles (Ma, NIOSH/CDC) 

• Role of apoptosis in particle induced lung injury (Mercer, NIOSH/CDC) 

• Toxicological evaluation of World Trade Center dust (Morgan, NIEHS/NIH) 

• Mechanisms of indium phosphide pleural and pulmonary toxicity (Morgan, NIEHS/NIH) 

• Uric acid and susceptibility to ozone-induced lung injury (Porter, NIOSH/CDC) 

• Noninvasive measures of small animal response to inhalation exposure (Reynolds, 

NIOSH/CDC) 

• Characterization of experimental trimelletic anhydride late-phase airway response 

(Siegel, NIOSH/CDC)

• Carbonyl sulfide Clean Air Act studies (Sills, NIEHS/NIH) 

• Airways disease induced by low molecular weight agents (Weissman, NIOSH/CDC) 

• Dermal particle exposure and granulomatous lung disease (Weston, NIOSH/CDC) 

• Molecular genetics of granulomatous disease in beryllium workers (Weston, 

NIOSH/CDC) 

EPIDEMIOLOGY AND EXPOSURE ASSESSMENT

Research Initiatives 

The presence of toxicants in the environment is a potential threat to human health and the 

extent of that threat is unclear. Environmental toxicants may produce a variety of health 

effects depending upon the timing of exposure, dose, individual susceptibility, and other, yet 

unidentified, factors. Many of the studies currently underway or planned by the NTP 

investigate occupational or environmental exposure to toxicants as potential risk factors for 

specific health effects. Table 22 lists specific exposures and health effects presently under 

consideration. 

In the past, environmental research often has studied the crudest, most easily measurable 

health effects (cancer or death). More subtle damage (e.g., infertility, neurological function, 

or endocrine imbalance) is often harder to detect although such effects may be more common 

and impact a greater number of individuals. Increasingly, the NTP looks for ways to improve 

its ability to detect potential health effects from environmental exposures. Efforts are 

underway by the NTP to develop sensitive techniques for measuring the phenotypic effects of 

exposure and studying genetic changes associated with disease etiology, identify new genes 

involved in response to environmental toxicants, and identify genetic polymorphisms. Some

59 National Toxicology Program
of the important tools in this effort come from recent advances in biotechnology that include 

more sensitive methods for measuring low dose exposures, detecting early stages of disease, 

determining genetic susceptibility, and evaluating illnesses for which the causes are largely 

unknown, but for which environmental etiology is plausible. 

The NTP recognizes that accurate and complete exposure assessment is critical both to the 

success of epidemiology studies of toxicant exposure and the utility of such studies for risk 

assessment and public health policy. However, the availability of human data is often the 

weakest component of risk assessment and limits the effective utilization of experimental data 

for making decisions about chemical exposures. Increased knowledge about the mechanisms

that are responsible for environmentally induced diseases coupled with both sensitive and 

specific biomarkers and tests of biological effect from exposure are important in detecting and 

monitoring the early insult(s) of environmental toxicants and evaluating those effects under 

low-dose exposure. Advances in analytical methodologies now enable the detection of 

environmental and occupational chemicals in small volumes of biological samples (e.g., blood, urine, and hair). 

In addition, the development of novel statistical tools is aiding epidemiologic investigations. 

Such tools are being applied to evaluations of gene-environment interactions and genetic 

susceptibility. Improvements in study designs and associated techniques for data analysis are 

facilitating the study of interactions between genetic susceptibility factors and environmental 

exposures. 

Table 22. Exposures under Consideration as Risk Factors for Specific Human Health Effects

Exposure Health Effect

Air pollution Childhood respiratory diseases 

Beryllium Chronic beryllium disease 

Diet Nonmalignant respiratory disease in adults, lung cancer 

Ionizing radiation Female reproductive health and outcomes 

Lead Amyotrophic Lateral Sclerosis and reproductive disorders 

Magnetic fields Breast cancer 

Mercury Amyotrophic Lateral Sclerosis 

Nickel Reproductive effects in females 

Organochlorines (DDT, PCBs, 

dioxin, PCDFs) 

Birth term and size, childhood neurologic deficits, child development, Type 2 diabetes, breast 

cancer, thyroid function, and reproductive disorders 

Pesticides (insecticides, 

herbicides, fungicides, and

fumigants) 

Childhood diabetes, systemic lupus erythematosus, macular degeneration, neurobehavioral 

function, Amyotrophic Lateral Sclerosis, adult neurologic deficits, attention deficit hyperactivity

disorder, Parkinson’s disease, primary intracranial gliomas, and reproductive health effects 

Radon Lung cancer and childhood leukemia 

Ionizing radiation Reproductive disorders 

Silica Systemic lupus erythematosis 

Smoking and Environmental 

Tobacco Smoke 

Nonmalignant respiratory disease in adults, asthma, chronic bronchitis, lung cancer 

Soy Child development

Uranium mining Lung and other cancers 

Research Projects 

• Environmental effects on fertility (Baird, NIEHS/NIH) 

• A method for simultaneous analysis of multiple pesticides (Biagini, NIOSH/CDC) 

• Biomonitoring analyses for studies of dermal exposure (Cheever, NIOSH/CDC) 

• Antineoplastic drug exposure: Effectiveness of guidelines (Connor, NIOSH/CDC) 

• Systemic lupus erythmatosus and other autoimmune diseases (Cooper, NIEHS/NIH) 

• Environmental and take-home pesticide exposures - farm families (Curwin, 

NIOSH/CDC) 

60 National Toxicology Program
• Environmental pollution in Eastern and Central Europe (Gladen, NIEHS/NIH) 

• Organochlorines and their human health effects (Gladen, NIEHS/NIH) 

• Bromopropanes: exposure assessment of general industry (Hanley, NIOSH/CDC) 

• Estimation of exposure to oxidized terpene products (Harper, NIOSH/CDC) 

• Agriculture Health Study, pesticide exposure among farmer applicators and their families 

(Hines, NIOSH/CDC) 

• Identification of a cohort for a reproductive health study of phthalates (Hines, 

NIOSH/CDC) 

• The Norwegian mother and child study: environmental specimen collection (Hoppin, 

NIEHS/NIH) 

• Pesticides and Parkinson's disease in the Agricultural Health Study (Kamel, NIEHS/NIH) 

• Pesticide exposure and neurologic function in farmworkers (Kamel, NIEHS/NIH) 

• Genetic and environmental factors in cancer (London, NIEHS/NIH) 

• Genetic and environmental factors in childhood respiratory health (London, NIEHS/NIH) 

• Genetic and environmental factors in adult nonmalignant respiratory disease (London, 

NIEHS/NIH) 

• The Generation R Cohort Study as an NIEHS resource (Longnecker, NIEHS/NIH) 

• Human health effects of exposure to organochlorine compounds (Longnecker, 

NIEHS/NIH) 

• Effect of diet on child development and the occurrence of chronic disease (Longnecker, 

NIEHS/NIH) 

• Study of health effects of DDT in Mexico (Longnecker, NIEHS/NIH) 

• National children's study with National Institute of Child Health and Development 

(Longnecker, NIEHS/NIH) 

• Effect of the antiandrogen on anthropometric measures at birth (Longnecker, 

NIEHS/NIH) 

• Health assessment of workers exposed to bromopropane (Lynch, NIOSH/CDC) 

• Biomarker development exposure assessment (Lynch, NIOSH/CDC) 

• Characterization of adverse effects of complex occupational exposures (Morgan, 

NIEHS/NIH) 

• Characterization of adverse effects of complex occupational exposures (Morgan, 

NIEHS/NIH) 

• US/Vietnamese study on the effects of Agent Orange (Portier, NIEHS/NIH) 

• Implications of dioxin in the food supply (Portier, NIEHS/NIH) 

• Toxicity of lead in children--clinical trial (Rogan, NIEHS/NIH) 

• Human exposure to halogenated aromatic compounds (Rogan, NIEHS/NIH) 

• Estrogenicity of soy formula (Rogan, NIEHS/NIH) 

• Genetic and environmental risk factors for breast cancer: the Sister Study (Sandler, 

NIEHS/NIH) 

• Risk factors for attention deficit hyperactivity disorder (Sandler, NIEHS/NIH) 

• Health effects of exposures in agriculture (Sandler, NIEHS/NIH) 

• Environmental exposures and risk for cancer and chronic diseases in adults (Sandler, 

NIEHS/NIH) 

• Cancer risk in Czech uranium miners (Sandler, NIEHS/NIH) 

61 National Toxicology Program
• Exposure to radon and cancer risk (Sandler, NIEHS/NIH) 

• Improved environmental exposure sampling for bioterrorism research (Schnorr, 

NIOSH/CDC) 

• Biomonitoring methods for agricultural exposures (Striley, NIOSH/CDC)

• Genetic susceptibility and the environment in cancer risk (Taylor, NIEHS/NIH) 

• Exposure specific mutation in critical target genes (Taylor, NIEHS/NIH) 

• Statistical method for gene/environmental interaction and genetic susceptibility (Umbach, 

NIEHS/NIH) 

• Indoor allergens and asthma (Zeldin, NIEHS/NIH) 

CHEMICAL DISPOSITION, TOXICOKINETICS, AND PHYSIOLOGICALLY BASED

PHARMACOKINETIC MODELS

Research Initiatives 

Complete dosimetry of a chemical or physical agent describes its absorption, distribution, 

metabolism, and elimination (ADME) at differing levels of exposure, over all ages, via 

multiple routes of exposure, and under varying genetic backgrounds in humans and test 

animals. Data from NTP chemical disposition, metabolism, and toxicokinetic studies are used 

in these efforts. Those substances evaluated during FY 2004 are listed in Table 23. Most 

studies are conducted in intact laboratory animals; some require incubations of human and 

rodent liver slices with the chemical. This information provides dosimetric data that can be 

integrated with other anatomical, biochemical, and physiological information into 

development of biochemical and Physiologically Based Pharmacokinetic models. Such 

models are used increasingly in risk assessment to extrapolate between species, across dose 

ranges, and across different routes of exposure. 

Risk assessment involves using factual data to determine the plausibility and magnitude of 

health effects for individuals and populations from exposure to hazardous agents. Useful to 

risk assessment is the development of biologically based models for estimating human risk. 

These models are mathematical representations of physiological and biochemical processes 

that occur in laboratory animals and humans. They can provide a scientifically sound basis 

for evaluating data in animals and then extrapolating that information across species to

determine if and how exposure to an agent might cause health effects in humans. The process 

of developing biologically based models is iterative. It relies upon first developing a simple 

model based upon available data, testing predictions of the model experimentally, and then 

making adjustments or expanding the model’s complexity as more data become available 

from studies in cell culture, animals, and humans. 

PBPK models are an improved and realistic description of key physiological processes and 

biochemical activities that affect both ADME of the parent compound and its metabolites. 

Substitution of estimates of human physiological and biochemical parameters into models 

characterized for laboratory animals provides a sound scientific basis for extrapolations of 

tissue dosimetry across species, extrapolation from high exposures to low exposures, and 

extrapolation across different routes of exposure. Because PBPK models use parameters 

measurable in human populations, these models can also be used to evaluate the impact of 

inter-individual variability. PBPK models have been created or are under development at the 

NIEHS/NIH to evaluate exposure-response relationships for carcinogenicity and 

developmental and reproductive toxicities (Table 24). Inclusion of PBPK models in the NTP 

Technical Reports is routine.

62 National Toxicology Program
 Table 23. Ongoing Chemical Disposition, Metabolism and Toxicokinetic Studies During FY 2003-20041

Chemical 

CAS

Number Test Type Species/Strain Route Project Leader

2

Acesulfame Potassium 55589-62-3 Toxicokinetics Mice: C57BL/6 Feed, Gavage, 

Intravenous 

Collins 

5-Amino-o-Cresol 2835-95-2 Chemical

Disposition 

Mice: B6C3F1 (female) 

Rats: Fischer 344 (female) 

Rats: Fischer 344 (female) 

Gavage 

Gavage 

Topical 

Burka 

Androstenedione 63-05-8 Chemical

Disposition 

Mice: B6C3F1 (male) 

Rats: Fischer 344 

Dog: Beagle 

Human: Liver microsomes 

In vitro, Gavage 

Intravenous, In vitro, 

Gavage 

Intravenous, Gavage 

In vitro

Cunningham 

AZT Transplacental

Carcinogenesis Study

30516-87-1 Toxicokinetics Mice: Swiss CD-1 (female) Intravenous, Water Dunnick 

1-Bromopropane 106-94-5 Chemical

Disposition 

Rats: Fischer 344 (male) Inhalation, Topical 

Intravenous

Burka 

Bisphenol A 80-05-7 Metabolism Mice: B6C3F1 

Rats: Fischer 344 

Gavage 

Gavage 

Cunningham 

Di-N-Butyltin Dichloride 683-18-1 Chemical 

Disposition 

Mice: B6C3F1 (male) 

Rats: Fischer 344 (male) 

Gavage 

Gavage 

Burka 

N,N-Dimethyl-p-toluidine 99-97-8 Chemical

Disposition 

Mice: B6C3F1 (male) 

Rats: Fischer 344 (male) 

Intravenous Burka 

Estragole 140-67-0 Chemical

Disposition 

Mice: B6C3F1 

Rats: Fischer 344 

Human: Liver microsomes 

Gavage 

Gavage 

In vitro

Cunningham 

Ethanone, 1-

(1,2,3,4,5,6,7,8-

Octahydro-2,3,8,8-

tetramethyl-2-

naphthalenyl)- 

54464-57-2 Chemical

Disposition 

Mice: B6C3F1 (female) 

Rats: Fischer 344 (male) 

Gavage 

Gavage 

Burka 

Ginkgo Biloba Extract 90045-36-6 Chemical 

Disposition 

Human: Liver microsomes In vitro Burka

Goldenseal Root Powder Chemical

Disposition 

Human: Liver microsomes In vitro Burka

Grape Seed and Pine 

Bark Extracts 

Chemical

Disposition 

Human: Liver microsomes In vitro Burka

Kava Kava Extract 9000-38-8 Chemical 

Disposition 

Rats: Fischer 344 (male) 

Human: Liver microsomes 

Intravenous, Gavage 

In vitro 

Burka 

2-Methyltetrahydrofuran 96-47-9 Chemical

Disposition 

Mice: B6C3F1 (male) 

Rats: Fischer 344 (male) 

Gavage 

Gavage 

Burka 

Milk Thistle Extract 84604-20-6 Chemical 

Disposition 

Human: Liver microsomes In vitro Burka

Myristicin 607-91-0 Metabolism Mice: B6C3F1

Rats: Fischer 344 

Human: Liver microsomes 

In vitro 

In vitro 

In vitro

Cunningham 

Pentabromodiphenyl 

Oxide (Technical) (DE 

71) 

32534-81-9 Chemical

Disposition 

Rats: Fischer 344 (male) Gavage Burka 

Sodium Tungstate 

Dihydrate 

10213-10-2 Chemical

Disposition 

Mice: B6C3F1 (female) 

Rats: Fischer 344 (female) 

Gavage, Water 

Gavage, Water 

Burka 

2,2'4,4'-

Tetrabromodiphenyl 

Ether 

5436-43-1 Chemical

Disposition 

Rats: Fischer 344 (male) Gavage, Intravenous Burka 

1

 Protocols for chemical disposition, metabolism and toxicokinetic studies are described on the NTP website at http://ntp.niehs.nih.gov/ see 

 “Descriptions of NTP Study Types.” Testing status and study results for completed studies can be found at http://ntp.niehs.nih.gov/ select 

 “Testing Status of Agents at NTP” and “Study Results & Research Project.” 2

 Project Leader - NIEHS/NIH staff scientist who oversees each chemical’s evaluation 

63 National Toxicology Program
 Table 24. Completed or Ongoing Physiologically Based Pharmacokinetic Modeling During FY 2003- 

 2004 

Chemical CAS Number NTP Technical Report Number1

Anthraquinone 478-43-3 494

Bromochloroacetic Acid 5589-96-8 

Dibromoacetic Acid 631-64-1 537 

Dichloroacetic Acid 79-43-6 

p,p’-Dichlorodiphenyl Sulfone 80-07-9 501 

Divinylbenzene 1321-74-0 534

Isoprene 78-79-5 486

Melatonin 73-31-4

Mercury (Pregnant Rat) 16056-34-1 

Methyleugenol 93-15-2 491

4-Methylimidazole 822-36-6 535

Naphthalene 91-20-3 500

PCB126 57465-28-8 520

PCB153 35065-27-1 529

PCB Mixtures Multiple 530, 531 

Primidone 125-33-7 476

Sodium Nitrite 7632-00-0 495 

TCDD (2,3,7,8-Tetrachloro-dibenzo-p-dioxin) 1746-01-6 521 1 Results for PBPK models without a Technical Report number will be presented in future NTP Technical Reports and/or in the 

 peer reviewed literature

64 National Toxicology Program
ALTERNATIVE TEST SYSTEMS 

Considering the large number of chemicals in commerce, the NTP must continually set 

priorities and develop research strategies to characterize toxicants and identify hazards that 

make the best use of available resources. Implementing new strategies, which provide 

additional or more accurate information, can strengthen the science base on which regulatory 

decisions are based. Through the NTP, efforts are focused on the development and 

validation of new alternative test systems (sensitive, specific, rapid) for toxicological 

research that will reduce, replace, or refine animal use.

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, genetically 

engineered 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. Data gleaned from

these tests can help to clarify dose-response relationships, aid in species comparisons, and 

identify sources of variations among individuals. In addition, through the NICEATM a 

concerted and coordinated federal effort is being made to identify, validate, and promote 

regulatory acceptance of alternative test systems. Extramural researchers are also involved in 

alternative methods development and validation through the NIEHS/NIH grants program. Below are brief overviews of some current and emerging NTP initiatives that make use of 

these new research tools. 

TOXICOGENOMICS

New molecular technologies have brought the NTP into the arena of toxicogenomics, a 

scientific field that examines how the entire genetic structure, or genome, is involved in an 

organism’s response to environmental toxicants. Toxicogenomics applies genetic knowledge 

to environmental medicine by studying the effect of toxicants on gene activity and specific 

proteins encoded by genes. It combines information from studies of genomic-scale 

messenger RNA profiling (by microarray analysis), cell-wide or tissue-wide protein profiling 

(proteomics), genetic susceptibility, and computational models. This information aids in our 

understanding of the interactions between genes and the environment in disease etiology. 

This field could revolutionize 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 microchip-based technology 

enables 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. 

The NCT is evaluating gene arrays and building a database of gene 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 the 

toxic effects and molecular changes elicited by compounds under study. Such information 

could define cellular networks of responsive genes, identify target molecules of toxicity, 

provide future biomarkers and alternative testing procedures, and identify individuals who 

are sensitive to drugs or environmental agents. 

Initial efforts by the NTP include profiling a classic liver toxicant, acetaminophen, by 

65 National Toxicology Program
66 National Toxicology Program

studying the variables that affect gene expression in exposed and unexposed animals. In 

addition, the NTP is also collecting gene expression data from unexposed animals to 

establish which genes are expressed at different stages of life and which are expressed 

continuously. 

GENETICALLY MODIFIED MOUSE MODELS

The conventional rodent bioassay has been used for over three decades and is accorded 

credibility in identifying carcinogens thought to pose risks for human health. An ongoing 

goal of the NTP is to seek other model systems for toxicology and carcinogenesis studies, 

especially those that can provide mechanistic information relative to understanding an agent's 

mode of action. The use of transgenic models holds promise for improving both the accuracy 

and efficacy of experimental assessment of the carcinogenic potential of chemicals. 

Genetically altered or “transgenic” mouse models carry activated oncogenes or inactivated 

tumor suppressor genes known to be involved in neoplastic processes both in humans and 

rodents. This trait may allow them to respond to carcinogens more quickly than conventional 

rodent strains. In addition, the neoplastic effects of agents can be observed in 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 

these chemical carcinogenesis studies and their implications for human health. The use of 

target or reporter genes also allows for direct molecular and cellular analysis of a chemical’s 

effects in these models and can provide additional mechanistic information about its mode of 

action. A list of chemicals being evaluated in transgenic animals in subchronic and chronic 

studies during FY 2003 and 2004 are presented in Table 25. 

The NTP has undertaken more than 100 studies with genetically modified mouse models 

(GMM) to assess the carcinogenicity of known human and rodent genotoxic and nongenotoxic agents since 1995. The NTP has sought input from its advisory groups and the 

public about the usefulness of a number of transgenic rodent models for short-term studies 

of carcinogenicity [p53(+/–), Tg.AC, (v-Ha-ras), and RasH2]. Overall there is a 

concordance of 70 to 85% between GMMs and conventional rodent bioassays. In general, 

there is more support for the p53(+/-) and RasH2 models than the Tg.AC model for 

evaluating the carcinogenic potential of chemical or physical agents. While these GMM 

models often detect known or probable human carcinogens, some were missed. In contrast, 

no known or probable human carcinogens were missed using the conventional bioassay. 

These findings have led the NTP to conclude that positive findings in GMM should be taken 

seriously, but chemicals with negative findings should be viewed with caution. The NTP’s 

current approach is to employ GMM models to conduct studies that can not be easily 

addressed in the conventional 2-year bioassay, such as mixture studies or class studies (e.g., 

dioxin-like compounds), when response of the model to an index substance is known to 

develop relative potencies for other members of the class. 
67 National To

Table 25. Ongoing Subchronic and Chronic Toxicity Studies in Genetically Modified Mouse Models During 

Chemical Name CAS Number Species/ Strain Route Study Length P

Acesulfame Potassium 55589-62-3 Mice: p53 +/- (C57BL/6) 

Mice: Tg.AC (FVB/N) hemizygous 

Feed 2 years 

Aspartame 22839-47-0 Mice: p53 +/- (C57BL/6) 

Mice: Tg.AC (FVB/N) hemizygous Mice: P16 (Ink 4A)+/- (C57BL/6)

Feed 2 years 

AZT+3TC (2', 3'-Dideoxy3'-thiacytidine) 30516-87-1; 134678-17-4 Mice:P53 +/- (C57BL/6) Gavage 6 month Bromodichloromethane 75-27-4 Mice: p53 +/- (C57BL/6) 

Mice: Tg.AC (FVB/N) hemizygous 

Gavage, 

Water 

26 weeks 

Dichloroacetic Acid 79-43-6 Mice: p53 +/- (C57BL/6) 

Mice: Tg.AC (FVB/N) hemizygous 

Water, 

Topical 

26 & 39 weeks 

Diisopropylcarbodiimide 693-13-0 Mice: Tg.AC (FVB/N) hemizygous 

Mice: p53 +/- (C57BL/6) 

Topical 20 & 27 weeks 

PCB 126 57465-28-8 Mice:Tg.AC (FVB/N) hemizygous Topical 26 weeks PeCDF (2,3,4,7,8-Pentachlorodibenzofuran) 

57117-31-4 Mice:Tg.AC (FVB/N) hemizygous Topical 26 weeks 

PCB 126 + PeCDF 57465-28-8; 

57117-31-4 

Mice:Tg.AC (FVB/N) hemizygous Topical 26 weeks 

Sodium Bromate 7789-38-0 Mice: p53 +/- (C57BL/6) 

Mice: Tg.AC (FVB/N) hemizygous 

Water, 

Topical 

26 & 39 weeks 

TCDD (2,3,7,8-Tetrachlorobenzo-p-dioxin) 

1746-01-6 Mice: Tg.AC (FVB/N) hemizygous Topical 26 weeks 

1 Protocols for chronic toxicity and carcinogenicity studies are described on the NTP website at http://ntp.niehs.nih.gov/ see “Descriptions o

 Types.” Testing status can be found at http://ntp.niehs.nih.gov/ select “Testing Status of Agents at NTP.” 

2 Project Leader - NIEHS/NIH staff scientist who oversees each chemical’s evaluation 
NON-MAMMALIAN MODELS

The NTP has initiated studies in non-mammalian species to explore the use of 

alternate or additional models for examining chemical toxicity and carcinogenicity. 

For example, the use of small fish species in carcinogenicity testing may offer 

advantages as a bioassay test system including significant savings in cost and time

over rodent studies. Large numbers of small fish can be easily maintained in a limited 

area. Draft technical reports (see Table 11) have been released for three compounds 

[nitromethane, (2,2-bis(bromomethyl)-1,3-propanediol), (1,2,3-trichloropropane)] 

tested in two species of fish, the guppy (Poecilia reticulata) and medaka (Oryzias 

latipes). The guppy and medaka are hardy, easily maintained, and have a low 

occurrence of background lesions 

The NTP is interested in developing rapid, sensitive, and specific tests for screening 

environmental agents. The NTP is investigating the utility of Caenorhabditis elegans

(C. elegans) as a screen for developmental, neurological, and behavioral toxicities. If 

C. elegans is sufficiently sensitive to specific agents with known neurological and 

behavioral toxicities, the NTP will expand this project to address a broader array of

agents. Five compounds are currently planned for testing in C. elegans: cadmium (II) 

chloride hydrate, chlorpyrifos (Dursban), dimethyl sulfoxide, iron citrate, and 

methylcellulose (Freedman, Duke/NIEHS) 

MAGNETIC RESONANCE IMAGING 

Traditionally, in NTP toxicology and carcinogenicity studies, tissues are evaluated 

with conventional optical microscopy for histopathological changes. Representative 

samples are collected because examining numerous samples of each tissue is 

impractical. Because of recent advances in the technology for imaging, magnetic 

resonance imaging (MRI) of the entire body at microscopic resolution is now 

possible. The NTP is investigating MRI for imaging laboratory animals. MRI 

microscopy is three-dimensional, can examine the same specimens at different angles, 

and measures the volume of tissue and organs. MRI of live animals permits 

acquisition of imaging data at different times over an animal’s lifetime. Because the 

images are digital, web-based viewing by pathologists anywhere in the world is 

possible. 

MRI is a noninvasive technique that permits more complete and thorough 

examination of tissues and organs from test animals without destroying the samples 

and may also allow more information to be gathered from NTP studies than before. 

Anticipated uses include monitoring lesions and examining the morphology and 

functionality of genetically engineered mice. The NTP also plans to apply this 

technology in the future to studies of birth defects. This technology is being applied 

to NTP microarray studies of acetaminophen-induced hepatotoxicity. 

SCANSCOPE–2D IMAGING TECHNOLOGY FOR PATHOLOGICAL

EVALUATIONS 

The NTP has now acquired a new technology for evaluation of lesions in tissues of 

animals exposed to potentially toxic substances. ScanScope scans entire 

histopathology slides at high resolution and compresses the large file using 

JPEG2000. The resulting image can be viewed over the Internet and one is able to 

 68 National Toxicology Program
select any area for viewing and magnifing the image to the same degree as that seen 

with a microscope using a 10, 20, or 40X objective. The result is that the computer 

becomes equivalent to a microscope and one can examine any portion of the whole 

image at microscopic resolution. This technology provides the NTP pathologists a 

tool to share treatment-induced lesions with colleagues via the Internet and, as 

needed, obtain their diagnostic opinions. 

Research Projects 

• Discovery and genetics of environmental response genes (Bell, NIEHS/NIH) 

• Environmental genomics (Bell, NIEHS/NIH) 

• Microarray gene expression database (Bushel, NIEHS/NIH) 

• Altered gene expression in response to toxicants (Cunningham, NIEHS/NIH) 

• Carcinogen inactivation of tumor suppressor genes in p53 haploinsufficient mice 

(French, NIEHS/NIH) 

• Mechanism(s) of leukemogenesis in genetically altered mouse models (French, 

NIEHS/NIH)

• Development of a database of genetic alterations from environmental chemicals: 

development of the NIEHS genetic alterations in cancer database (Heindel, 

NIEHS/NIH; Small Business Innovation Research contract) 

• System for high-throughput proteome characterization (Heindel, NIEHS/NIH; 

Small Business Innovation Research contract) 

• Development of microarray profiles for microbial toxicity (Heindel, NIEHS/NIH; 

Small Business Innovation Research contract) 

• Hepatitis C virus: From gene expression profiling to biomarkers (Heindel, 

NIEHS/NIH; small business innovation research contract) 

• Targeted antibody microarrays: A tool for toxicoproteomics (Heindel, 

NIEHS/NIH; small business innovation research contract) 

• Mass spectrometry based high-throughput proteomics approach (Heindel, 

NIEHS/NIH; Small Business Innovation Research contract) 

• The toxicity studies of combination of AIDS drugs in p53 (+/-) transgenic mice 

(Leakey, NCTR/FDA) 

• Microarray technology to study molecular pathways in disease and apoptosis 

(Paules, NIEHS/NIH) 

• NCT proteomics resource - toxicoproteomics expression and microarray resource 

databases (Stasiewicz, NIEHS/NIH) 

• National Center for Toxicogenomics microarray resources - gene expression 

analysis (Stasiewicz, NIEHS/NIH) 

• NCT proteomics resource - proteomics analysis/identification (Stasiewicz,

NIEHS/NIH) 

• A validation study for in vitro basal cytotoxicity testing (Stokes, NIEHS/NIH) 

• Characterization of follicular stem cells in Tg.AC mice (Tennant, NIEHS/NIH) 

• Global analysis of arsenic-induced gene expression profiles in yeast (Van Houten, 

NIEHS/NIH) 

 69 National Toxicology Program
APPENDIX 1 

AGENCY STAFF AND CONTACT INFORMATION

The following listing (alphabetical by agency) includes NTP agency program leaders,

project officers, and other key agency staff listed in this plan. 

Name Telephone Number E-mail Address 

NCTR/FDA 

Allaben, William (870) 543-7211 wallaben@nctr.fda.gov 

Appleget, John (870) 543-7536 jappleget@nctr.fda.gov 

Beland, Fred (870) 543-7216 fbeland@nctr.fda.gov 

Boudreau, Mary (870) 543-7526 mboudreau@nctr.fda.gov 

Carraway, Jeff (870) 543-7347 jcarraway@nctr.fda.gov 

Cerniglia, Carl (870) 543-7341 ccerniglia@nctr.fda.gov 

Chou, Ming (870) 543-7661 mchou@nctr.fda.gov 

Culp, Sandra (870) 543-7941 sculp@nctr.fda.gov 

Delclos, Barry (870) 543-7124 bdelclos@nctr.fda.gov 

Doerge, Daniel (870) 543-7943 ddoerge@nctr.fda.gov 

Ferguson, Sherry (870) 543-7589 sferguson@nctr.fda.gov 

Fu, Peter (870) 543-7207 pfu@nctr.fda.gov

Heflich, Robert (870) 543-7493 rheflich@nctr.fda.gov 

Howard, Paul (870) 543-7137 phoward@nctr.fda.gov 

Kadlubar, Fred (870) 543-7204 fkadlubar@nctr.fda.gov 

Kodell, Ralph (870) 543-7008 rkodell@nctr.fda.gov 

Leakey, Julian (870) 543-7916 jleakey@nctr.fda.gov 

Manjanatha, Mugimane (870) 543-7098 mmanjanatha@nctr.fda.gov

Moore, Martha (870) 543-7050 mmoore@nctr.fda.gov 

Morris, Suzanne (870) 543-7580 smorris@nctr.fda.gov 

Paule, Merle (870) 543-7147 mpaule@nctr.fda.gov 

Scallet, Andy (870) 543-7146 ascallet@nctr.fda.gov 

Slikker Jr., William (870) 543-7203 wslikker@nctr.fda.gov 

Wang, Cheng (870) 543-7259 cwang@nctr.fda.gov 

Weis, Connie (870) 543-7378 cweis@nctr.fda.gov 

Witt, William (870) 543-7949 wwitt@nctr.fda.gov 

NIEHS/NIH 

Abdo, Kamal (919) 541-7819 abdok@niehs.nih.gov 

Afshari, Cynthia (919) 541-1310 afshari@niehs.nih.gov 

Alden, Charles (919) 541-5722 alden@niehs.nih.gov 

Baird, Donna (919) 541-2786 baird@niehs.nih.gov 

Bell, Douglas (919) 541-7686 bell1@niehs.nih.gov 

Bishop, Jack (919) 541-1876 bishop@niehs.nih.gov 

Boorman, Gary (919) 541-4330 boorman@niehs.nih.gov 

Bristol, Douglas (919) 541-2756 bristol@niehs.nih.gov 

Bucher, John (919) 541-4532 bucher@niehs.nih.gov 

Burka, Leo (919) 541-4667 burka@niehs.nih.gov 

Caspary, William (919) 541-2150 caspary@niehs.nih.gov 

Chan, Po-Cheun (919) 541-7581 chanp@niehs.nih.gov 

Chhabra, Rajendra (919) 541-3386 chhabrar@niehs.nih.gov 

Chignell, Colin (919) 541-4575 chignell@niehs.nih.gov 

Cooper, Glinda (919) 541-0799 cooper1@niehs.nih.gov

Cunningham, Michael (919) 541-3799 cunning1@niehs.nih.gov 

Davis, Barbara (919) 541-2764 davis1@niehs.nih.gov 

Devereux, Theodora (919) 541-3241 devereux@niehs.nih.gov 

Dinse, Gregg (919) 541-4931 dinse@niehs.nih.gov 

Dixon, Darlene (919) 541-3814 dixon@niehs.nih.gov 

Dunnick, June (919) 541-4811 dunnickj@niehs.nih.gov 

Dunson, David (919) 541-3033 dunson1@niehs.nih.gov 

 70 National Toxicology Program
Name Telephone Number E-mail Address 

Eastin, William (919) 541-7941 eastin@niehs.nih.gov 

Freedman, Jonathan (919) 541-7899 freedma1@niehs.nih.gov 

French, John (919) 541-2569 french@niehs.nih.gov 

Germolec, Dori (919) 541-3230 germolec@niehs.nih.gov

Ghanayem, Burhan (919) 541-3369 ghanayem@niehs.nih.gov 

Goldstein, Joyce (919) 541-4495 goldste1@niehs.nih.gov 

Hailey, J. Richard (919) 541-0294 hailey@niehs.nih.gov 

Harry, G. Jean (919) 541-0927 harry@niehs.nih.gov 

Haseman, Joseph (919) 541-4996 haseman@niehs.nih.gov

Herbert, Ronald (919) 541-4613 herbert@niehs.nih.gov 

Hoppin, Jane (919) 541-7622 hoppin1@niehs.nih.gov 

Huff, James (919) 541-3780 huff1@niehs.nih.gov 

Irwin, Richard (919) 541-3340 irwin@niehs.nih.gov 

Jameson, C. William (919) 541-4096 jameson@niehs.nih.gov 

Kamel, Freya (919) 541-1581 kamel@niehs.nih.gov

Korach, Kenneth (919) 541-3512 korach@niehs.nih.gov 

Langenbach, Robert (919) 541-7558 langenb1@niehs.nih.gov 

London, Stephanie (919) 541-5772 london2@niehs.nih.gov 

Longnecker, Matthew (919) 541-5118 longnec1@niehs.nih.gov 

Malling, Heinrich (919) 541-3378 malling@niehs.nih.gov 

Maronpot, Robert (919) 541-4861 maronpot@niehs.nih.gov 

Masten, Scott (919) 541-5710 masten@niehs.nih.gov 

Melnick, Ronald (919) 541-4142 melnickr@niehs.nih.gov 

Merrick, B. Alex (919) 541-1531 merrick@niehs.nih.gov 

Miller, David (919) 541-3235 miller@niehs.nih.gov 

Moorman, Michael (919) 541-0598 moorma@niehs.nih.gov 

Morgan, Dan (919) 541-2264 morgand@niehs.nih.gov 

Newbold, Retha (919) 541-0738 newbold1@niehs.nih.gov

Olden, Kenneth (919) 541-3201 olden@niehs.nih.gov 

Orzech, Denise (919) 541-5717 orzech@niehs.nih.gov 

Portier, Christopher (919) 541-4999 portier@niehs.nih.gov 

Pritchard, John (919) 541-4054 pritcha3@niehs.nih.gov 

Rogan, Walter (919) 541-4578 rogan@niehs.nih.gov 

Rowley, Michael (919) 541-3436 rowley@niehs.nih.gov 

Roycroft, Joseph (919) 541-3627 roycroft@niehs.nih.gov 

Sandler, Dale (919) 541-4668 sandler@niehs.nih.gov 

Shelby, Michael (919) 541-3455 shelby@niehs.nih.gov 

Sills, Robert (919) 541-0180 sills@niehs.nih.gov

Smith, Cynthia (919) 541-3473 smith19@niehs.nih.gov 

Soward, Sharon (919) 541-5132 soward@niehs.nih.gov 

Stasiewicz, Stanley (919) 541-7638 stasiew1@niehs.nih.gov

Stokes, William (919) 541-7997 stokes@niehs.nih.gov

Taylor, Jack (919) 541-4631 taylor@niehs.nih.gov 

Tennant, Raymond (919) 541-4141 tennant@niehs.nih.gov 

Tomer, Kenneth (919) 541-1966 tomer@niehs.nih.gov 

Travlos, Greg (919) 541-0653 travlos@niehs.nih.gov 

Umbach, David (919) 541-4939 umbach@niehs.nih.gov 

Walker, Nigel (919) 541-4893 walker3@niehs.nih.gov 

Weinberg, Clarice (919) 541-4927 weinberg@niehs.nih.gov

Wilcox, Allen (919) 541-4660 wilcox@niehs.nih.gov 

Wolfe, Mary (919) 541-7539 wolfe@niehs.nih.gov 

Wright, Larry (919) 541-3426 wright1@niehs.nih.gov 

Zeldin, Darryl (919) 541-1169 zeldin@niehs.nih.gov 

NIOSH/CDC 

Antonini, James (304) 285-6244 jga6@cdc.gov 

Beezhold, Donald (304) 285-5963 dbeezhold@cdc.gov 

Biagini, Raymond (513) 533-8196 reb4@cdc.gov 

Cheever, Kenneth (513) 533-8193 klc1@cdc.gov 

DeBord, D. Gayle (513) 533-8212 ded4@cdc.gov 

 71 National Toxicology Program
Name Telephone Number E-mail Address 

Ding, Min (304) 285-6229 mid5@cdc.gov 

Frasch, H. Frederick (304) 285-5755 hbf9@cdc.gov 

Frazer, David (304) 285-5872 dgf1@cdc.gov 

Hanley, Kevin (513) 841-4113 khanley@cdc.gov

Hubbs, Ann (304) 285-6128 afh0@cdc.gov 

Huffman, Linda (304) 285-6144 ljh3@cdc.gov 

Kesner, James (513) 533-8208 jsk4@cdc.gov 

Kommineni, Choudari (304) 285-6160 cdk2@cdc.gov 

Krieg, Edward (513) 533-8160 erk3@cdc.gov 

Lindsley, William (304) 285-6336 wdl7@cdc.gov 

Luster, Michael (304) 285-5940 mluster@cdc.gov 

Lynch, Dennis (513) 533-8213 dlynch@cdc.gov

Ma, Jane (304) 285-5844 jym1@cdc.gov 

Meade, B. Jean (304) 285-5809 bhm8@cdc.gov

Mercer, Robert (304) 285-6157 rpm7@cdc.gov 

Moorman, William (513) 533-8275 wmoorman@cdc.gov 

Munson, Albert E. (304) 285-6121 akm5@cdc.gov 

Murono, Eisuke (304) 285-6145 eem8@cdc.gov 

Ong, T-M (304) 285-5817 too2@cdc.gov 

Reynolds, Jeff (304) 285-6238 jsr0@cdc.gov 

Ruder, Avima (513) 841-4440 amr2@cdc.gov 

Sanderson, Wayne (513) 841-4476 wts1@cdc.gov 

Savage, Russell (513) 533-8289 ras6@cdc.gov 

Schrader, Steven (513) 533-8210 sms4@cdc.gov 

Schulte, Paul (513) 533-8302 pas4@cdc.gov 

Shi, Xianglin (304) 285-6158 xshi@cdc.gov 

Siegel, Paul (304) 285-5855 pds3@cdc.gov 

Shvedova, Anna (304) 285-6177 ats1@cdc.gov 

Snawder, John (513) 533-8496 jts5@cdc.gov 

Soderholm, Sidney (304) 285-6034 sgs2@cdc.gov 

Striley, Cynthia (513) 533-8123 cstriley@cdc.gov

Toraason, Mark (513) 533-8207 mtoraason@cdc.gov 

Wallace, William (304) 285-6096 wew2@cdc.gov

Weston, Ainsley (304) 285-6221 agw8@cdc.gov 

Whelan, Elizabeth (513) 841-4437 ewhelan@cdc.gov 

 72 National Toxicology Program
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 85 National Toxicology Program
Development of a sensitivity enhanced multiplexed fluorescence covalent microbead immunosorbent assay 

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 87 National Toxicology Program
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of cell-mediated immune responses to Listeria infection by repeated exposure to diesel exhaust particles in

 88 National Toxicology Program
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Zeidler PC, Hubbs A, Battelli L, Castranova V. 2004. Role of inducible nitric oxide synthase-derived nitric 

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149.

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