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National Toxicology ProgramU.S. Department of Health and Human Services

Annual Reportfor Fiscal Year


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National Toxicology Program

ANNUAL REPORT

for

Fiscal Year 2014

National Institute of Environmental Health Sciences

National Institutes of Health

National Center for Toxicological Research

U.S. Food and Drug Administration

National Institute for Occupational Safety and Health

Centers for Disease Control and Prevention

August 2015

U.S. Department of Health and Human Services

National Toxicology Program

NIH Publication No. 15-5970


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Table of ContentsLetter From the NIEHS and NTP Director .............................................................................................. 1

1. National Toxicology Program: Mission and Goals ........................................................................ 3

A. Organizational Structure and Oversight ....................................................................................... 4

B. Training Programs ........................................................................................................................ 6

C. Advisory Boards and Committees ................................................................................................ 6

i. NTP Executive Committee ............. ............... ............. .............. .............. ............. .............. .6

ii. NTP Board of Scientic Counselors ...................................................................................7

iii. Scientic Advisory Committee on Alternative Toxicological Methods .................................9

iv. Special Emphasis Panels ............. .............. .............. .............. ............. .............. .............. .11

2. Funding ........................................................................................................................................... 13

A. Current and Projected Research Capacity ................................................................................. 13

B. Interagency Agreements ............................................................................................................. 15

i. FDA/NCTR .............. .............. ............. .............. .............. ............. .............. .............. .........15

ii. CDC/NIOSH .............. .............. .............. .............. .............. ............. .............. .............. ......15

iii. CDC/DLS ............ .............. .............. ............. .............. .............. ............. .............. ..............15

iv. NIH/NCATS/DPI ............. .............. .............. .............. ............. .............. .............. ............. ..16

3. NTP Highlighted Activities ............................................................................................................. 17

A. West Virginia Chemical Spill ....................................................................................................... 17

B. Systematic Review and Evidence Integration for Literature-Based Environmental

Health Science Assessments ..................................................................................................... 18

C. Lung Tumors in Mice Induced By Whole-Life Inorganic Arsenic Exposure at

Human-Relevant Doses ............................................................................................................. 18

D. National Research Council Reports Endorse the Listings of Formaldehyde and

Styrene in Report on Carcinogens .............................................................................................18

E. Nonneoplastic Lesion Atlas ........................................................................................................ 19

F. Crowdsourcing Human Variability Data ...................................................................................... 20

G. Mouse Methylome Project .......................................................................................................... 20

H. NTP Impact on Regulatory Agencies .......................................................................................... 21

I. Additional Activities ..................................................................................................................... 23

4. Literature Analysis Activities ........................................................................................................ 24

A. Noncancer Health Effects .......................................................................................................... 24

B. Report on Carcinogens ............................................................................................................... 26

5. Testing and Research .................................................................................................................... 29

A. Technical Reports ....................................................................................................................... 30

B. NTP Testing ................................................................................................................................ 32

i. Disposition, Metabolism, and Toxicokinetic Studies .........................................................32

ii. Genetic Toxicity .............. .............. .............. .............. ............. .............. .............. ............. ..33

iii. Organ System Toxicity ............. .............. .............. .............. .............. ............. .............. ......34

iv. Toxicology and Carcinogenicity Studies ............ .............. .............. .............. ............. ........36

v. Toxicogenomic Studies ............ ............... ............. .............. .............. ............. .............. ......40

vi. Project Review Committee Approved .............. .............. .............. ............. .............. ..........43


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6/103 Letter From the NIEHS and NTP Director 1

Letter From the NIEHS and NTP DirectorIn FY 2014, the National Toxicology Program (NTP) made signicant

accomplishments in testing chemicals of public health concern and

in developing and validating improved toxicological methods. NTP

also successfully collaborated with other federal agencies to provideinformation about environmental and public health.

NTP received a nomination from the Centers for Disease Control and

Prevention Agency for Toxic Substances and Disease Registry to conduct

toxicity studies on the predominant chemicals known to be involved in the

West Virginia chemical spill. In response, NTP began a research program

aimed at producing results in a fairly short period of time that could be

used for making decisions about the need for any follow-up studies. The

NTP studies are focused on acute exposures and the potential for long-

term effects, such as genetic toxicity and reproductive and developmental

toxicity, and short-term effects such as skin irritation and hypersensitivity.

The West Virginia research program includes regular communications with

the public about study results through the NTP website.

NTP also developed a framework to address environmental health questions by applying systematic review

approaches developed for clinical medicine to environmental health sciences. The seven-step framework,

published by the NTP Ofce of Health Assessment and Translation, is used to evaluate scientic literature and

reach conclusions in literature-based, noncancer health assessments.

With its partners in the federal government, NTP continued to provide data to the public from the Tox21

initiative through various databases, such as PubChem, ACTor, and CEBS. The Tox21 initiative aims to

develop more efcient approaches to predict how chemicals may affect human health.

The National Research Council’s review of the Report on Carcinogens listings of styrene as reasonably

anticipated to be a human carcinogen, and formaldehyde as known to be a human carcinogen, were

completed. The council supported and reconrmed the listings based on reviews of updated literature.

In addition, NTP published numerous studies on substances of public health concern, including heavy metals,

ame retardants, and widely used industrial chemicals.

I proudly present our FY 2014 accomplishments and ongoing efforts.

Linda S. Birnbaum, Ph.D., D.A.B.T., A.T.S.


7/1032 National Toxicology Program Annual Report FY 2014


8/103 1. National Toxicology Program: Mission and Goals 3

1. National Toxicology Program: Mission and GoalsSafeguarding public health depends upon identifying the effects of

substances that are in contact with people and their environment,

and determining the levels of exposure at which they may become

potentially hazardous. The Toxic Substances Control Act ChemicalSubstance Inventory of January 2015 (www.epa.gov/oppt/

existingchemicals/pubs/tscainventory/basic.html ) lists more than

84,000 chemicals as being available for sale and use in the U.S.

New chemicals are continuously introduced into the U.S. market

each year. While the effects of many of these substances on human

health are unknown, people may be exposed to them during their

manufacture, distribution, use, and disposal, or as pollutants in our

air, water, and soil.

The U.S. Department of Health, Education, and Welfare, now the

U.S. Department of Health and Human Services (HHS), established

NTP in 1978 to coordinate toxicology testing in the federal

government. In carrying out its mission, NTP has several goals.

● Coordinate toxicology testing programs within the federal government.

● Strengthen the science base in toxicology.

● Develop and validate improved testing methods.

● Provide information about potentially toxic chemicals to health agencies, regulatory agencies, research

agencies, scientic communities, medical communities, and the public.

To protect public health, regulatory agencies make decisions based on scientic information. NTP plays a

critical role in providing scientic data, interpretation, and guidance in the appropriate uses of these data

to regulatory agencies and other health-related research groups. The American people and government

agencies, at state and federal levels, rely on NTP to provide a strong scientic basis for making credible

decisions that will protect public health. In the past 37 years, NTP has studied and shared information on

the health effects of more than 2,500 substances, including dietary supplements, industrial chemicals, and

consumer products.

In following government-wide efforts to increase access to the results of federally funded scientic

research, NTP maintains open communications and dialogue with federal and state agencies, industry,

nongovernmental organizations, academia, and the public. The NTP website (http://ntp.niehs.nih.gov )

provides the public with a variety of information, including Federal Register notices, status of and data from

NTP studies, lists of NTP reports and journal publications, media releases, calendar of upcoming events,

and the NTP Update newsletter.

The public and other interested parties can stay abreast of NTP activities and events by subscribing to the NTP

listserv, an email notication system (http://ntp.niehs.nih.gov/go/getnews). In addition, requests for information

can be made through the Central Data Management ofce ([email protected] or 919-541-3419), or the

Freedom of Information Act coordinator (www.niehs.nih.gov/about/od/ocpl/foia/contact ).

NTP welcomes input on its programs and priorities. This input can be through response to formal requests for

public comment in Federal Register notices, or informal submissions to the NTP Ofce of Liaison, Policy, and

Review (919-541-7539 or [email protected] ).

TO EVALUATE

AGENTS OF PUBLIC

HEALTH CONCERN

BY DEVELOPING

AND APPLYING THE

TOOLS OF MODERN

TOXICOLOGY AND

MOLECULAR BIOLOGY

NTP MISSION:

http://www.epa.gov/oppt/existingchemicals/pubs/tscainventory/basic.htmlhttp://www.epa.gov/oppt/existingchemicals/pubs/tscainventory/basic.htmlhttp://ntp.niehs.nih.gov/http://ntp.niehs.nih.gov/go/getnewsmailto:[email protected]://www.niehs.nih.gov/about/od/ocpl/foia/contact/index.cfmmailto:[email protected]:[email protected]://www.niehs.nih.gov/about/od/ocpl/foia/contact/index.cfmmailto:[email protected]://ntp.niehs.nih.gov/go/getnewshttp://ntp.niehs.nih.gov/http://www.epa.gov/oppt/existingchemicals/pubs/tscainventory/basic.htmlhttp://www.epa.gov/oppt/existingchemicals/pubs/tscainventory/basic.html



A. Organizational Structure and Oversight

Three agencies form the core for NTP (Figure 1): the National Institute for Occupational Safety and Health

(NIOSH) of the Centers for Disease Control and Prevention; the U.S. Food and Drug Administration (FDA),

primarily through the National Center for Toxicological Research (NCTR); and the National Institute of

Environmental Health Sciences (NIEHS) of the National Institutes of Health (NIH).

NTP is located administratively at NIEHS, and Linda Birnbaum, Ph.D., serves as director of both NIEHS and

NTP. John Bucher, Ph.D., is the NTP associate director and director of the NTP Division at NIEHS, herein

referred to as NIEHS/NTP, which is the focal point for NTP activities. NIEHS and NTP utilize best research

practices and embrace developments in technology to discover how the environment affects people, and

seek to lead the eld of environmental health sciences in innovation and the application of research to solve

health problems.

John Howard, M.D., is the director of NIOSH, and Elizabeth Whelan, Ph.D., chief of the Industrywide Studies

Branch of the Division of Surveillance, Hazard Evaluations, and Field Studies, manages the NTP program

within NIOSH, herein referred to as NIOSH/NTP. Staff from three NIOSH divisions participate in NTP activities:

the Division of Surveillance, Hazard Evaluations, and Field Studies, and the Division of Applied Research and

Technology; Education and Information Division; and Health Effects Laboratory Division.

The mission of NIOSH is to generate new knowledge in the eld of occupational safety and health, and to

transfer that knowledge into practice for the betterment of workers. NIOSH’s participation in NTP is consistent

with its mandate to protect workers’ health and safety under the Occupational Safety and Health Act, and the

Federal Mine Safety and Health Act.

William Slikker Jr., Ph.D., is the director of NCTR, and Paul Howard, Ph.D., associate director of the Ofce of

Scientic Coordination, manages the NTP program within NCTR, herein referred to as NCTR/NTP. NCTR staff

scientists, in partnership with researchers from elsewhere in FDA, other government agencies, academia, and

industry, provide innovative technology, methods development, vital scientic training, and technical expertise.

NCTR conducts an array of studies that reect the NTP mission and is critical in supporting FDA productcenters and their regulatory roles.

Figure 1. Organizational Structure of NTP

U.S. Assistant Secretary for Health

External and Science Oversight and ReviewPolicy OversightNTP Core Agencies

NTP Director

• NTP Executive Committee• CDC/NIOSH

• FDA/NCTR

• NIH/NIEHS

• Board of Scientific Counselors

• SACATM

• Special Emphasis Panels



NIEHS/NTP Staff

NIOSH Staff: Division of Applied Research and

Technology and the Division of Surveillance, Hazard

Evaluations, and Field Studies

NCTR/NTP Staff

NIOSH Staff: Health Effects Laboratory Division

NIOSH Staff: Education and Information Division

NCTR/NTP Staff



B. Training Programs

NTP offers a limited number of postdoctoral training fellowships that prepare scientists for careers in

pharmaceutical and chemical industries, regulatory agencies, and academia. Full details on opportunities,

benets, and applications can be found at http://www.niehs.nih.gov/careers/research/postdoc-training .

The training program falls into six areas: applied toxicology and carcinogenesis, biomolecular screening

and computational toxicology, health assessment and translation, laboratory animal medicine, systemsand mechanistic toxicology, and toxicological pathology. In FY 2014, NTP staff mentored 19 postdoctoral

fellows at NIEHS.

Table 1. NTP Training Program Postdoctoral Fellows in FY 2014

Training Program Fellow

Applied toxicology and carcinogenesis

Natasha Catlin

Georgia Hinkley

Kristen Ryan

Brian Sayers

In Ok Surh

Sheetal Thakur

Biomolecular screening and computational toxicology

Rachel Goldsmith

Jui-Hua Hsieh

Sreenivasa Ramaiahgari

Health assessment and translation Katie Pelch

Laboratory animal medicine Sheba Churchill

Systems and mechanistic toxicology

Xiaohua Gao

Ntube Ngalame

Ruben Orihuela Garcia

Rachel Person

Yuanyuan Xu

Toxicological pathology

Sachin Bhusari

Tanasa Osborne

Erin Quist

C. Advisory Boards and Committees

NTP receives policy guidance, science oversight, and peer review from formal external groups includingthe NTP Executive Committee, NTP Board of Scientic Counselors, and Scientic Advisory Committee on

Alternative Toxicological Methods. Ad hoc special emphasis panels also help guide NTP activities.

i. 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:

http://www.niehs.nih.gov/careers/research/postdoc-traininghttp://www.niehs.nih.gov/careers/research/postdoc-training



● U.S. Consumer Product Safety Commission (CPSC)

● U.S. Department of Defense (DOD)

● U.S. Environmental Protection Agency (EPA)

● U.S. Food and Drug Administration (FDA)

● National Cancer Institute (NCI) ● National Center for Environmental Health/Agency for Toxic Substances and Disease Registry (NCEH/

ATSDR)

● National Institute of Environmental Health Sciences (NIEHS)

● National Institute for Occupational Safety and Health (NIOSH)

● Occupational Safety and Health Administration (OSHA)

To enhance agency interactions, NTP uses agency points of contact, in lieu of formal committees, to

streamline communication. Agency points of contact have a dedicated responsibility and time commitment; are

knowledgeable about the NTP mission, programs, and their agency’s resources; and allow the most relevant

agency expertise to be brought to bear on NTP issues.

ii. NTP Board of Scientic Counselors

The NTP Board of Scientic Counselors (BSC), a federally chartered advisory group, provides scientic

oversight to NTP on the scientic merit of its programs and activities. The HHS Secretary appoints members

to the BSC. The BSC can consist of up to 35 scientists, primarily from the public and private sectors, with

scientic expertise relevant to NTP activities. The BSC charter and current roster are available at http://ntp.

niehs.nih.gov/go/164. Lori White, Ph.D., designated federal ofcer, manages the BSC. Table 2 provides the

roster for FY 2014.

BSC members and NTP staff at the June 2014 BSC meeting

http://ntp.niehs.nih.gov/go/164http://ntp.niehs.nih.gov/go/164http://ntp.niehs.nih.gov/go/164http://ntp.niehs.nih.gov/go/164



The BSC met twice in FY 2014 (http://ntp.niehs.nih.gov/go/9741). At the meeting on April 17-18, 2014, which

was rescheduled from December 2013 due to the federal government shutdown, the BSC:

● Reviewed the NTP Laboratory and its chief, Michael Waalkes, Ph.D.

● Reviewed three draft Report on Carcinogens (RoC) concepts: (1) selected viruses: Epstein-Barr virus,

human immunodeciency virus type 1, human T-cell lymphotrophic virus type 1, Kaposi sarcoma-

associated herpes virus, and Merkel cell polyoma virus; (2) goldenseal root powder; and (3) cobalt.

● Heard a report on the RoC peer-review meeting on ortho-toluidine, and pentachlorophenol and by-

products of its synthesis, held in December 2013.

● Reviewed two draft Ofce of Health Assessment and Translation (OHAT) concepts, Adverse Health

Effects Associated With Occupational Exposure to Cancer Chemotherapy Agents, and Pregnancy

Outcomes Associated With Trafc-Related Air Pollution.

● Heard a report on the draft NTP Technical Reports peer review of vinylidene chloride, cobalt metal,

glycidamide, and tetrabromobisphenol A, held in October 2013.

● Was updated by the NIEHS and NTP director, and NTP associate director, on NTP progress since the

June 2013 meeting.

The second BSC meeting was held June 17-18, 2014. During this meeting, the BSC:

● Reviewed four NTP research concepts on biphenol S, triclocarban, alkylbenzenes, and xylenes.

● Reviewed two OHAT concepts, NIEHS-EPA Collaborative Project to Improve Characterization of

Personal Care Product and Home Exposures, and Inammation-Based Atherosclerosis Associated

With Environmental Exposures.

● Heard about the progress on Tox21, and The S1500 Genes High Throughput Transcriptomics Project

from the Biomolecular Screening Branch.

● Was updated on the current work on the adverse outcome pathways by the NTP Interagency Center

for the Evaluation of Alternative Toxicological Methods (NICEATM).

● Heard from the NIEHS and NTP director, and NTP associate director, on NTP progress since the April

2014 meeting.

Table 2. NTP Board of Scientific Counselors Membership Roster FY 2014

Name and Title Afliation Term Ends

Milton L. Brown, M.D., Ph.D.

Director

Drug Discovery Program

Georgetown University

Medical Center

Washington, D.C.

06/30/17

Robert E. Chapin, Ph.D.Laboratory Director

Pzer

Groton, Connecticut06/30/15

George B. Corcoran, Ph.D., A.T.S.

Chair and Professor

Department of Pharmaceutical Sciences

Eugene Applebaum College of Pharmacy and Health Sciences

Wayne State University

Detroit, Michigan06/30/16

David C. Dorman, D.V.M., Ph.D.

Professor

College of Veterinary Medicine

North Carolina State University

Raleigh, North Carolina06/30/15

http://ntp.niehs.nih.gov/go/9741http://ntp.niehs.nih.gov/go/9741




Mary Beth Genter, Ph.D.

Associate Professor

Department of Environmental Health

University of Cincinnati

Goshan, Ohio06/30/17

Jack R. Harkema, D.V.M., Ph.D., D.A.C.V.P.

Distinguished Professor

Department of Pathobiology and Diagnostic Investigation

Michigan State UniversityEast Lansing, Michigan

06/30/15

Dale Hattis, Ph.D.

Research Professor

George Perkins Marsh Institute

Clark University

Worcester, Massachusetts06/30/15

Steven Markowitz, M.D., Dr.P.H.

Professor and Director

Center for the Biology of Natural Systems

Queens College

City University of New York

Flushing, New York

06/30/17

Lisa A. Peterson, Ph.D., Chair of the BSC

Professor

Division of Environmental Health Sciences and Masonic Center

School of Public Health

University of Minnesota

Minneapolis, Minnesota06/30/16

Sonya Sobrian, Ph.D.

Associate Professor

Department of Pharmacology

Howard University

Washington, D.C.06/30/15

Iris G. Udasin, M.D.

Professor

Department of Environmental and Occupational Medicine

Robert Wood Johnson Medical School

University of Medicine and Dentistry

of New Jersey

Piscataway, New Jersey

06/30/16

iii. Scientic Advisory Committee on Alternative Toxicological Methods

The Scientic Advisory Committee on Alternative Toxicological Methods (SACATM) is a federally chartered

advisory committee established January 9, 2002, in response to the Interagency Coordinating Committeeon the Validation of Alternative Methods (ICCVAM) Authorization Act of 2000 (42 U.S.C. 285l-3(d)). SACATM

advises ICCVAM, the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods

(NICEATM), and the director of NIEHS and NTP regarding statutorily mandated duties of ICCVAM and

activities of NICEATM (see pages 69 and 72). SACATM provides advice on priorities and activities related

to the development, validation, scientic review, regulatory acceptance, implementation, and national and

international harmonization of new, revised, and alternative toxicological test methods. The SACATM charter

and current roster are available at http://ntp.niehs.nih.gov/go/167 . Table 3 provides the roster for FY 2014.

SACATM typically meets once a year and members serve rotating terms of up to four years. Lori White, Ph.D.,

designated federal ofcer, manages SACATM.

SACATM met once during FY 2014 on September 16, 2014, at NIEHS (http://ntp.niehs.nih.gov/go/8202 ). At the meeting, ICCVAM and NICEATM updated SACATM on the new goals for ICCVAM and on activities

by NICEATM and the International Cooperation on Alternative Test Methods (ICATM). ICCVAM members

presented an overview of ICCVAM activities related to oral and dermal testing, animal reductions in Leptospira

vaccine testing, and skin sensitization testing. SACATM heard updates on new ICCVAM communication

activities and reports for four meetings: Aquatic Models and 21st Century Toxicology, Murine Histamine

Sensitization Test, Adverse Outcome Pathways, and ICCVAM Public Forum. SACATM provided input on the

reports from four federal agencies, including the U.S. Department of the Interior, FDA, EPA, and NIEHS.

http://ntp.niehs.nih.gov/go/167http://ntp.niehs.nih.gov/go/8202http://ntp.niehs.nih.gov/go/8202http://ntp.niehs.nih.gov/go/167



Table 3. NTP SACATM Membership Roster FY 2014


Lauren E. Black, Ph.D.

Senior Scientic Advisor Navigators Services

Charles River Laboratories

Reno, Nevada 11/30/16

Tracie E. Bunton, D.V.M., Ph.D.

Consultant

Eicarte LLC

Gettysburg, Pennsylvania06/30/15

Joy Cavagnaro, Ph.D., D.A.B.T., R.A.C., A.T.S., R.A.P.S.

President and Founder

Access BIO LC

Boyce, Virginia11/30/14

Joan M. Chapdelaine, Ph.D.

ConsultantScott Township, Pennsylvania 06/30/15

Mark G. Evans, D.V.M., Ph.D., A.C.V.P.

Research Fellow

La Jolla Laboratories

Pzer

San Diego, California06/30/15

Michael D. Kastello, D.V.M., Ph.D.

Vice President and Global Head

Animal Research and Welfare

Disposition, Safety and Animal Research

Sano

Bridgewater, New Jersey11/30/16

Safdar A. Khan, D.V.M., M.S., Ph.D., D.A.B.V.T.

Senior Toxicologist

Senior Director of Toxicology Research

ASPCA Animal Poison Control Center

Urbana, Illinois11/30/16

Steven M. Niemi, D.V.M. (chair)

Director

Center for Comparative Medicine

Massachusetts General Hospital

Charlestown, Massachusetts06/30/13

Members of SACATM, ICCVAM, and ICATM, and staff from NIEHS and NTP at the September

2014 SACATM meeting




Ricardo Ochoa, D.V.M., Ph.D., A.C.V.P.

President and Principal

Pre-Clinical Safety, Inc.

Niantic, Connecticut11/30/14

Catherine E. Willett, Ph.D.

Director

Regulatory Toxicology, Risk Assessment and Alternatives

The Humane Society of the United

States

Gaithersburg, Maryland

11/30/17

Daniel M. Wilson, Ph.D., D.A.B.T.

Mammalian Toxicology Consultant

Toxicology and Environmental Research and Consulting

The Dow Chemical Company

Midland, Michigan11/30/14

Wei Xu, Ph.D.

Associate Professor

Department of Oncology

McArdle Laboratory for Cancer Research

University of Wisconsin at Madison

Madison, Wisconsin11/30/17

iv. Special Emphasis Panels

NTP uses ad hoc scientic panels, referred to as special emphasis panels, to provide independentscientic peer review and advice on targeted issues, such as agents of public health concern, new and

revised toxicological test methods, and other issues. These panels help ensure transparent, unbiased, and

scientically rigorous input to the NTP for its use in making credible decisions about human health hazards,

setting research and testing priorities, and evaluating test methods for toxicity screening.

NTP Technical Report Peer-Review Panels

NTP Technical Reports (TRs) are published results of long-term studies, generally two-year rodent toxicology

and carcinogenesis studies. NTP convenes external scientic panels to peer review draft TRs at public

meetings held at NIEHS. All reviews provide the opportunity for public comment. For each TR, the panel

is charged with peer reviewing the scientic and technical elements and presentation of the study, anddetermining whether the study’s experimental design and conduct support the NTP conclusions regarding the

carcinogenic activity of the substance tested. There were two TR meetings in FY 2014.

NTP convened a meeting on October 29, 2013 to peer review the draft TRs on cobalt metal, glycidamide,

tetrabromobisphenol A, and vinylidene chloride. The peer-review panel included individuals with expertise

in carcinogenesis, neurotoxicology, pathology, inhalation toxicology, reproductive toxicology, and molecular

toxicology. Lori White, Ph.D., served as designated federal ofcer for the peer-review meeting.

NTP convened a second meeting on May 22, 2014, to peer review the draft TRs for bromodichloroacetic

acid, CIMSTAR 3800, green tea extract, and indole-3-carbinol. The panel consisted of experts in

biochemical metabolism, genetic toxicology, molecular mechanisms of toxicity, pathology, drug development,

reproductive toxicology, and preclinical toxicology. Yun Xie, Ph.D., served as designated federal ofcer for

the peer-review meeting.

Both meetings were open to the public with time scheduled for oral public comment. The charge to both panels

were to (1) review and evaluate the scientic and technical elements of the study and its presentation; and

(2) determine whether the study’s experimental design, conduct, and ndings support the NTP’s conclusions

regarding the carcinogenic activity and toxicity of the substance tested. The panels for both meetings agreed

with the NTP conclusions in all draft TRs. Additional information about review panel meetings is available at

http://ntp.niehs.nih.gov/go/36051.

http://ntp.niehs.nih.gov/go/36051http://ntp.niehs.nih.gov/go/36051



NTP Monograph Peer-Review Panels

Monographs are publications on a single, detailed specic topic. There were no monograph review meetings

in FY 2014. Additional information about NTP monograph peer-review meetings is available at http://ntp.niehs.

nih.gov/go/36639.

Report on Carcinogens Peer-Review Panels

Report on Carcinogens (RoC) monographs are prepared for each candidate substance selected for review.

NTP follows an established, four-part process for preparation of the RoC. More information can be found at

http://ntp.niehs.nih.gov/go/rocprocess and on page 26. In FY 2014, NTP convened two external scientic

panels to peer review draft RoC monographs on three candidate substances. The meetings, held at NIEHS,

were open to the public with time scheduled for oral public comment. Draft RoC monographs, consisting of a

cancer evaluation component and a substance prole, were prepared for each substance. For each candidate

substance, the panel was charged with commenting on whether the draft cancer evaluation component was

technically correct and clearly stated, whether NTP objectively presented and assessed the scientic evidence,

and whether the scientic evidence was adequate for applying the listing criteria. For each draft substance

prole, the panel was charged with commenting on whether the scientic justication presented supported theNTP preliminary policy decision on the RoC listing status.

On December 12-13, 2013, NTP convened a panel to peer review the draft RoC monographs for ortho-

toluidine, and pentachlorophenol and by-products of its synthesis. The panel voted on each draft level of

evidence for carcinogenicity determination, based on the available scientic evidence in experimental animals

and human cancer studies, and whether the information cited in each draft substance prole supported

NTP’s preliminary listing recommendation for the substances in the RoC. The ortho-toluidine review covered

the chemical properties and human exposure, cancer studies in experimental animals, metabolism and

mechanistic data, human cancer studies, an overall cancer evaluation, and the draft substance prole. The

pentachlorophenol and by-products of its synthesis review covered the chemical properties and human

exposure, human cancer studies, studies in experimental animals, supporting mechanistic evidence, an overall

cancer evaluation, and the draft substance prole.

On August 12, 2014, NTP convened a panel to peer review the draft RoC monograph on trichloroethylene. The

panel voted on the draft level of evidence for carcinogenicity determination, based on the available scientic

evidence from human cancer studies for kidney cancer, non-Hodgkin lymphoma, and liver cancer, and whether

the information cited in the draft substance prole supported the NTP’s preliminary listing recommendation

for trichloroethylene in the RoC. The review covered human cancer studies; toxicokinetic, toxicological, and

mechanistic studies; an overall cancer evaluation; and the draft substance prole for trichloroethylene.

Lori White, Ph.D., served as designated federal ofcer for both peer-review meetings. After each meeting, input

from the panels was considered in nalizing the monographs. Additional information about these meetings and

other RoC monograph peer-review meetings is available at http://ntp.niehs.nih.gov/go/38854.

http://ntp.niehs.nih.gov/go/36639http://ntp.niehs.nih.gov/go/36639http://ntp.niehs.nih.gov/go/rocprocesshttp://ntp.niehs.nih.gov/go/38854http://ntp.niehs.nih.gov/go/38854http://ntp.niehs.nih.gov/go/rocprocesshttp://ntp.niehs.nih.gov/go/36639http://ntp.niehs.nih.gov/go/36639


18/103 2. Funding 13

2. FundingA. Current and Projected Research Capacity

NTP relies on voluntary allocations from the program’s three core agencies, NIEHS, FDA/NCTR, and NIOSH,

to support its activities. These allocations are specied after annual appropriations have been determined. As

shown in Figure 2, the total NTP budget for FY 2014 was $127.5 million.

Figure 2: Past, Current, and Projected Budget

NTP conducts its research studies through contract laboratories, in-house at the three core agencies, or

through interagency agreements with other agencies (see page 15). In FY 2014, NIEHS funded 35 contracts

(see Table 4), and held three workshops (see page 70), four special emphasis panel peer-review meetings

(see page 11), and three scientic advisory meetings (see pages 7 and 9) for NTP.



Table 4. NIEHS Contracts That Supported NTP Activities in FY 2014

Description Contractor

Absorption, Distribution, Metabolism, and ExcretionLovelace Biomedical

Research Triangle Institute

Analysis of Bisphenol A in Zebrash Oregon State University

Analysis support for SEARCH project Johns Hopkins University

Analytical Chemistry Services

Battelle Memorial

Midwest Research Institute

Research Triangle Institute

Archives and Specimen Repository Experimental Pathology Laboratories

Bioinformatics Methylation Project Murdock Research Institute

Chemical Sample Analysis for SEARCH Project University of North Carolina at Chapel Hill

Evaluate Toxicity Following Early Life Exposure Southern Research Institute

Evaluation of Alternative Toxicological Methods ILS Inc.Evaluation of the Toxicity of Selected Chemicals Battelle Memorial

Genetic Toxicity Testing Support Services Integrated Laboratory Systems

Immunotoxicity Burleson Research Technologies

In Life Data Collection and Management System INSTEM, LSS

NTP Computer and User Support Vistronix Inc.

NTP Information Systems Support Scimetrika

NTP Statistical and Computer Support SRA International

NTP Technical Reports Preparation Support Services Biotechnical Sciences Inc.

OHAT Literature-Based Evaluations ICF Inc.

Pathology Support Charles River Laboratories International Inc.

Integrated Laboratory Systems

Pathology Support and Quality Assessment Experimental Pathology Laboratories

Production of B6C3F1 Mice Taconic Farms

Productive Assessments by Continuous Breeding Research Triangle Institute

Provision for Animals and Specialized Services Charles River, Jax, Taconic

Quality Assessment Oversight of NTP Toxicology Data System Validation Labscience

Quality Assessment Support, Audits and Inspections Dynamac

Research on Inhalation Toxicology of Environmental Chemicals Alion Science & Technology

Support for GeneCo Databases Thomson Reuters

Support for Preparation of the Report on Carcinogens Integrated Laboratory Systems

Toxicologic and Carcinogenic Potential of Test Agents Battelle Memorial

Toxicological and Carcinogenic Potential of Chemicals Battelle Memorial

Zebrash Immune Function and Disease Resistance Assays North Carolina State University


20/103 2. Funding 15

B. Interagency Agreements

In FY 2014, NIEHS provided support for NTP activities through interagency agreements (IAGs) with other

federal agencies.

i.FDA/NCTR

In December 1992, NIEHS and FDA established a formal IAG, where NTP would support toxicology studies

on FDA-regulated agents nominated to NTP, and conduct the studies at NCTR. These studies are designed to

provide FDA and other regulatory agencies with hazard identication and dose-response data to support risk

assessment and risk management decisions that could affect public health.

This IAG has supported studies on endocrine active agents, dietary supplements, food contaminants, AIDS

therapeutics, pediatric medicines, electromagnetic radiation, cosmetics, and nanoscale materials. Studies in

these areas have produced about 16 published NTP Technical Reports and over 200 peer-reviewed journal

publications. Some of the data from the IAG-supported studies have led to an increased understanding of the

pharmacokinetics, mechanism of action, or dose-response of substances. Other data have led to renement of

risk assessment models.

ii. CDC/NIOSH

NIEHS/NTP has two IAGs with NIOSH. One IAG was established in the early 1990s in general response to

increased efforts by NTP to study noncancer endpoints. NIOSH and NTP have conducted studies to assess

the potential toxicity of exposures to substances such as fungi, mycotoxins, volatile organics, lead, latex,

nickel, isocyanates, and beryllium. Studies included workers that are exposed to mixtures of chemicals, such

as miners, farmers, health care workers, autoworkers, and reghters. There have also been a number of

studies examining how genetic variability in immune-inammatory-antioxidant responses contributes to the

development and severity of inammatory and allergic disease in people of different occupations.

The second IAG involves multiple projects. NIEHS/NTP and NIOSH worked to establish methodologies to

assess complex mixtures, such as asphalt fume, welding fume, and tungsten bers. NIOSH and NIEHS/

NTP are jointly supporting two large initiatives that evaluate emerging issues in nanotechnology. One

project focuses on identifying workplaces engaged in the development, production, and use of engineered

nanomaterials, and determining the potential for worker exposure to selected engineered nanoparticles. A

second facet focuses on evaluating potential toxicity from workplace exposures to engineered nanomaterials.

A study with similar purpose and design is evaluating occupational exposure to bisphenol A.

Many studies performed under these IAGs are published in the peer-reviewed literature and have been used

for hazard identication, and regulatory and intervention purposes.

iii. CDC/DLS

NIEHS/NTP and CDC/Division of Laboratory Sciences (DLS) are participating in a pilot study to characterize

exposure proles in a subset of 50 Danish women, who will be enrolled in a larger study of 500 women.

The pilot study is designed to assess whether exposure to several common endocrine-disrupting chemicals

is related to reproductive health problems, such as infertility, risk of miscarriage, and low birth weight, or

childhood obesity and potentially other health outcomes in the children. Endocrine-disrupting chemicals from

the organotins and phthalates classes will be evaluated. Blood and urine samples will be collected three

times from each woman, once prior to pregnancy and twice during pregnancy. This collaboration between



NIEHS/NTP and CDC/DLS facilitates common goals in understanding individual exposure proles for multiple

chemicals in woman of reproductive age.

iv. NIH/NCATS/DPI

This IAG supports ongoing and anticipated studies conducted at the National Center for Advancing

Translational Sciences (NCATS)/Division of Pre-Clinical Innovation (DPI), to evaluate high throughput and

high content screening assays in support of Tox21. Tox21 is an ongoing collaboration among federal agencies

to characterize the potential toxicity of chemicals by using cells and isolated molecular targets instead of

laboratory animals. The collaboration between NIEHS/NTP and NCATS/DPI will produce data for substances

that lack needed toxicological information. Data from these assays can be used to prioritize substances for

further studies, including toxicological evaluation, mechanisms of actions investigation, and development of

predictive modeling for biological response. The use of the assays should greatly increase the number of

substances tested and decrease the cost of testing.


22/103 3. NTP Highlighted Activities 17

3. NTP Highlighted ActivitiesFigure 3 displays the major events for FY 2014. Additional activities of importance from FY 2014 are

noted below.

Figure 3: FY 2014 Highlights

ICCVAM Interagency Coordinating Committee for the Validation of Alternative Methods

NICEATM NTP Interagency Center for the Evaluation of Alternative Toxicological Methods

SACATM Scientic Advisory Committee on Alternative Toxicological Methods

NTP Technical

Reports Peer-review

Panel MeetingSee page 11

Report onCarcinogens

Peer-review

Panel Meeting

See page 12

Launch of theNonneoplastic

Lesion Atlas

See page 19

NTP at Society

of Toxicology

Meeting in

Phonenix, ArizonaSee page 23

Board of Scientic

Counselors Meeting

See page 8

NICEATM Collaborative

Workshop on Aquatic

Models and 21st

Century Toxicology

See page 70

NTP Technical

Reports Peer-review

Panel Meeting

See page 11

NTP Satellite

Symposium

on PathologyPotpourri

See page 23

Board of Scientic

Counselors Meeting

See page 8

ICCVAM

Public ForumSee page 72

National Research

Council ReportEndorses the Listing

of Styrene in the RoC

See page 18

West Virginia Chemical Spill

Nomination by CDC/ATSDR

See page 17

Release of the OHAT

Approach, A Systemat ic Review

and Evidence Integration forLiterature-based Environmental

Health Science Assessments

See page 18

OCT ‘13 NOV ‘13 DEC ‘13 JAN ’14 FEB ’14 MAR ’14 APR ’14 MAY ’14 JUNE ’14 JULY ’14 AUG ’14 SEPT ’14

National Research Council

Report Endorses the Listing

of Formaldehyde in the RoC

See page 18

Report on

CarcinogensPeer-review

Panel Meeting

See page 12

NICEATM Workshop

on AdverseOutcome Pathways:

From Research

to Regulation

See page 70

NICEATM Worksh

on the Murine

Histamine Sensitiza

Test (HIST) forSafety Testing o

Acellular Pertuss

See page 70

SACATM

MeetingSee page 9

A. West Virginia Chemical Spill

In January 2014, about 10,000 gallons of a liquid used for washing coal to remove impurities was spilled

from a leaking tank into the Elk River in West Virginia. The Elk River is a municipal water source that

serves about 300,000 people in the Charleston area. The spilled material was primarily composed of

4-methylcyclohexanemethanol (MCHM). Other chemicals, including dipropylene glycol phenyl ether and

propylene glycol phenyl ether, were present in lower amounts. Limited toxicity data are available for the

constituents of the spilled liquid. In July 2014, the Agency for Toxic Substances and Disease Registry within the

Centers for Disease Control and Prevention nominated chemicals involved in the spill to NTP for toxicological

characterization. Shortly after, NTP planned and began short-term toxicology studies to provide information

relevant to the potential exposures of Charleston residents to the chemicals. More information can be found on

the NTP West Virginia chemical spill Web page http://ntp.niehs.nih.gov/go/wvspill .

http://ntp.niehs.nih.gov/go/wvspillhttp://ntp.niehs.nih.gov/go/wvspill



B. Systematic Review and Evidence Integration for Literature-Based

Environmental Health Science Assessments

The Ofce of Health Assessment and Translation (OHAT)

developed a systematic review framework, the OHAT Approach,

to address environmental health questions by applying review

approaches developed for clinical medicine to the greaterrange of data relevant to environmental health sciences, such

as human, animal, and mechanistic studies. These systematic

review methodologies provide a structure that increases

transparency in the process of collecting and synthesizing

scientic evidence for literature-based evaluations.

The OHAT Approach outlines a seven-step framework for

evaluating the scientic literature and reaching conclusions in

NTP literature-based, noncancer health assessments. In FY

2014, OHAT published the methodology (http://www.ncbi.nlm.nih.

gov/pubmed/24755067 ). OHAT also held a webinar to presentlessons learned in applying the OHAT Approach to case studies

as part of testing the framework during methods development

(http://ntp.niehs.nih.gov/go/41629).

C. Lung Tumors in Mice Induced By Whole-Life Inorganic Arsenic Exposure

at Human-Relevant Doses

Arsenic is a natural element that is widely distributed in the Earth’s crust. People may be exposed to arsenic

through water, air, food, and soil. Arsenic is present in the drinking water of millions of people worldwide, and

exposure to high levels of arsenic is linked to higher cancer risk. NIEHS/NTP scientists studied whole-life

inorganic arsenic exposure from drinking water in mice at concentrations relevant to humans.

Mice were given arsenic at 0, 50, 500, or 5,000 parts per billion in their drinking water three weeks before

breeding, and throughout pregnancy and lactation. Arsenic at these same concentrations was then given to the

offspring after weaning and all through adulthood. The researchers examined the adult offspring for tumors.

Over half of the male offspring developed signicant increases in benign and malignant lung tumors at 50 parts

per billion and 500 parts per billion. Female offspring developed benign tumors at the lower concentrations.

This study provides evidence that there is potential for adverse health effects from very low exposures to

arsenic. The study published in the journal Archives of Toxicology is available at http://www.ncbi.nlm.nih.gov/

pubmed/25005685 .

D. National Research Council Reports Endorse the Listings of Formaldehydeand Styrene in Report on Carcinogens

In FY 2014, reports from the National Research Council (NRC) of the National Academy of Sciences

supported the listing of styrene and formaldehyde in the 12th Report on Carcinogens (RoC), which was

published in 2011. Styrene is an industrial chemical used to make plastics, resins, and rubber. Formaldehyde

is a major industrial chemical used in building materials, chemical manufacturing, household products, and

other industries.

http://www.ncbi.nlm.nih.gov/pubmed/24755067http://www.ncbi.nlm.nih.gov/pubmed/24755067http://ntp.niehs.nih.gov/go/41629http://www.ncbi.nlm.nih.gov/pubmed/25005685http://www.ncbi.nlm.nih.gov/pubmed/25005685http://www.ncbi.nlm.nih.gov/pubmed/25005685http://www.ncbi.nlm.nih.gov/pubmed/25005685http://ntp.niehs.nih.gov/go/41629http://www.ncbi.nlm.nih.gov/pubmed/24755067http://www.ncbi.nlm.nih.gov/pubmed/24755067



Congress directed the U.S. Department of Health and Human Services (HHS) to arrange for the National

Academy of Sciences to independently review the listings and substance proles for formaldehyde

and styrene. The NRC convened expert committees to conduct scientic peer reviews of styrene and

formaldehyde, and to carry out an independent assessment of the scientic literature published on both

chemicals through 2013.

In July 2014, the NRC committee for styrene endorsed the listing of styrene as reasonably anticipated tobe a human carcinogen, and reached a similar conclusion based on their independent assessment. They

also agreed with the NTP scientic justication to support the listing, including (1) limited evidence of the

carcinogenicity of styrene from studies in humans; (2) sufcient evidence of the carcinogenicity of styrene

from studies in experimental animals; and (3) convincing, relevant information that the chemical acts

through mechanisms that would cause cancer in humans. More information can be found at http://www8.

nationalacademies.org/onpinews/newsitem.aspx?RecordID=18725 .

In August 2014, the NRC committee for formaldehyde endorsed the listing of formaldehyde as known to be

a human carcinogen, and reached a similar conclusion based on their independent assessment. Similar to

the NTP assessment, they concluded there was (1) sufcient evidence of carcinogenicity of formaldehyde

from studies in humans based on consistent ndings of increased incidence of nasopharyngeal cancer,sinonasal cancer, and myeloid leukemia for which chance, bias, and confounding factors can be ruled out with

reasonable condence; (2) sufcient evidence of the carcinogenicity from studies from experimental animals;

and (3) convincing, relevant information that formaldehyde induces mechanistic events associated with the

development of cancer in humans. More information can be found at http://www8.nationalacademies.org/

onpinews/newsitem.aspx?RecordID=18948 .

E. Nonneoplastic Lesion Atlas

In FY 2014, NTP continued work on the NTP

Nonneoplastic Lesion Atlas, a Web-based resource that

currently contains hundreds, and will eventually contain

thousands, of high-quality images and guidelines for

nonneoplastic lesions in experimental rodent models.

While nonneoplastic lesions are not cancerous,

nonneoplastic diseases, such as cardiovascular and

pulmonary diseases, are a major cause of illness and

death, and many are thought to have environmental

causes. For example, forms of pulmonary brosis, a

disease that causes lung scarring, have been linked

to exposures to inorganic materials such as asbestos,

vanadium, cobalt, nickel, beryllium, and sulfur dioxide;

and organic materials such as dust from cotton, grain,

and wood.

Diagnosing and recording nonneoplastic lesions can be challenging, and terminology and diagnostic strategies

can vary among pathologists. The purpose of the NTP Nonneoplastic Lesion Atlas is to standardize the

terminology, diagnostic strategy, and recording of nonneoplastic rodent lesions; improve the consistency;

and facilitate database searches, comparisons between studies, and generation of historical control data

for nonneoplastic lesions. The atlas was launched in FY 2014 and will be completed in FY 2015. For more

information, see http://ntp.niehs.nih.gov/nnl .

http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=18725http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=18725http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=18948http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=18948http://ntp.niehs.nih.gov/nnlhttp://ntp.niehs.nih.gov/nnlhttp://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=18948http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=18948http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=18725http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=18725



F. Crowdsourcing Human Variability Data

In FY 2013, NIEHS, NCATS, the University of North Carolina at Chapel Hill (UNC), Sage Bionetworks,

and DREAM teamed up to launch an innovative crowdsourced challenge, the NIEHS-NCATS-UNC

DREAM Toxicogenetics Challenge, that utilized data collected from the Tox21 1000 Genomes Toxicity

Screening Project. The NIEHS-NCATS-UNC team conducted the largest ever, population-based, in vitro

cytotoxicity study to understand how genetic variation affects individual response to common environmentaland pharmaceutical chemicals. The study evaluated the extent of cytotoxicity induced in 1,086 human

lymphoblastoid cell lines by 179 pharmaceutical or environmental chemicals. The 1,086 cell lines represented

nine distinct geographical populations with dened genetic heterogeneity.

The crowdsourced challenge asked participants to use data from the toxicogenetics project to meet two

subchallenges: (1) use the biological data to develop a model that accurately predicts individual responses to

chemical exposure, and (2) use the data on chemical properties to develop a model that accurately predicts

how a particular population will respond to certain types of chemicals.

The challenge launched in June 2013 and closed in September 2013. There were 99 submissions from 34

teams for subchallenge 1, and 85 submissions from 24 teams for subchallenge 2. The top-scoring teams were

announced at the November 2013 DREAM Conference in Toronto. The winning teams for both challenges

were from the Quantitative Biomedical Research Center at the University of Texas Southwestern Medical

Center in Dallas. The results of the challenge will be published in Nature Biotechnology.

G. Mouse Methylome Project

The methylome, a component of the epigenome, is one of the factors that may affect susceptibility to cancer

and other chemical exposure-related diseases. The methylome is an individual’s genome-wide pattern of

cytosine methylation, which is the addition of a methyl group to cytosine, one of the four major bases of DNA.

Presently, there is no central mouse reference database for the methylome, which signicantly handicaps an

understanding of the mouse model in toxicology and environmentally related diseases, and the designing andconducting of research to understand associated mechanisms.

The Mouse Methylome Project is creating a high-resolution map of the mouse liver methylome from three

different mouse strains — two parental strains C57BL/6N and C3H/HeN, and their rst generation hybrid

offspring B6C3F1/N. These strains show dramatically different incidences of spontaneous liver tumors, which

often confound two-year toxicology and carcinogenesis studies. This variable incidence of liver cancer may

be due, in part, to differences in the epigenetic machinery, and also in the sites and amounts of cytosine

methylation in critical tumor suppressor genes and other regulatory regions of the genome that affect liver

cancer susceptibility and its heritability across generations.

NIEHS scientists collected liver samples, as well as samples of four other tissues, including brain, cardiac

and skeletal muscle, brown and white fat, and epididymal sperm, from all mice, at the same age, to minimize

age as a confounding factor for gene expression and epigenetics. They prepared sequencing libraries of

the liver samples and banked samples of the other four tissue types for future use. In FY 2014, scientists

completed characterization of the liver methylome by genomic sequencing and bisulte treatment of DNA,

to map all methylated sites in the mouse genome. Ongoing bioinformatics analyses found relationships with

gene expression, and differentially methylated regions related to gender, strain, and heritability. Analyses

will continue in FY 2015, methylome and genomic data will be made publicly available, and a manuscript is

currently in the works.



H. NTP Impact on Regulatory Agencies

Federal and state regulatory agencies use NTP study data and recommendations in considering the need to

regulate and test specic chemicals to protect human health. Table 5 lists NTP data and recommendations

used by other agencies in FY 2014.

Table 5. Use of NTP Study Data or Recommendations by Federal and State Regulatory Agencies in FY 2014

Notice Summary of Notice NTP Information Cited

California Ofce of Environmental Health Hazard Assessment

Chemical Listed

Effective May 2, 2014

as Known to the State

of California to Cause

Cancer: N,N -dimethyl-

p-toluidine

Effective May 2, 2014, the Ofce of

Environmental Health Hazard Assessment is

adding N,N -dimethyl- p-toluidine to the list of

chemicals known to the state to cause cancer

for purposes of Proposition 65.

May 02, 2014 -- Proposition 65

http://oehha.ca.gov/prop65/prop65_

list/050214list.html

NTP. 2012. National Toxicology Program

Technical Report on the Toxicology and

Carcinogenesis Studies of N,N -Dimethyl- p-

Toluidine (CAS No. 99-97-8) in F344/N Rats and

B6C3F1/N Mice (Gavage Studies). NTP TR 579,

NIH Publication No. 12-5921. Research Triangle

Park, North Carolina. http://ntp.niehs.nih.gov/ go/37162 .

Notice of Adoption of

Reference Exposure

Levels for Benzene

The Ofce of Environmental Health Hazard

Assessment is adopting new and revised

Reference Exposure Levels for benzene.

June 27, 2014 -- Proposition 65

http://www.oehha.ca.gov/air/chronic_rels/

BenzeneJune2014.html

NTP conducted a chronic two-year toxicity

bioassay in F344 rats and B6C3F1 mice of

benzene by gavage in corn oil. Doses were 0, 25,

50, and 100 mg/kg-day for females and 0, 50,

100, and 200 mg/kg-day for males. Dose-related

lymphocytopenia and leukocytopenia were

observed in both species in all dosed groups.

Mice exhibited lymphoid depletion of the thymus

and spleen and hyperplasia of the bone marrow.


Technical Report on the Toxicology andCarcinogenesis Studies of Benzene (CAS No.

71-43-2) in F344/N Rats and B6C3F1 Mice

(Gavage Studies). NTP TR 289, NIH Publication

No. 86-2545. Research Triangle Park, NC. http://

ntp.niehs.nih.gov/go/7460 .

http://oehha.ca.gov/prop65/prop65_list/050214list.htmlhttp://oehha.ca.gov/prop65/prop65_list/050214list.htmlhttp://ntp.niehs.nih.gov/go/37162http://ntp.niehs.nih.gov/go/37162http://www.oehha.ca.gov/air/chronic_rels/BenzeneJune2014.htmlhttp://www.oehha.ca.gov/air/chronic_rels/BenzeneJune2014.htmlhttp://ntp.niehs.nih.gov/go/7460http://ntp.niehs.nih.gov/go/7460http://ntp.niehs.nih.gov/go/7460http://ntp.niehs.nih.gov/go/7460http://www.oehha.ca.gov/air/chronic_rels/BenzeneJune2014.htmlhttp://www.oehha.ca.gov/air/chronic_rels/BenzeneJune2014.htmlhttp://ntp.niehs.nih.gov/go/37162http://ntp.niehs.nih.gov/go/37162http://oehha.ca.gov/prop65/prop65_list/050214list.htmlhttp://oehha.ca.gov/prop65/prop65_list/050214list.html



Notice Summary of Notice NTP Information Cited

Environmental Protection Agency

Final Rule: Control

of Air Pollution from

Motor Vehicles: Tier3 Motor Vehicle

Emission and Fuel

Standards

This action establishes more str ingent vehicle

emissions standards and will reduce the sulfur

content of gasoline beginning in 2017, as part ofa systems approach to addressing the impacts

of motor vehicles and fuels on air quality and

public health. The gasoline sulfur standard will

make emission control systems more effective

for both existing and new vehicles, and enable

more stringent vehicle emissions standards.

The vehicle standards will reduce both tailpipe

and evaporative emissions from vehicles,

resulting in signicant reductions in pollutants

and help state and local agencies in their efforts

to attain and maintain health-based National

Ambient Air Quality Standards. These vehicle

standards are intended to harmonize withCalifornia’s Low Emission Vehicle program, thus

creating a federal vehicle emissions program

that will allow automakers to sell the same

vehicles in all 50 states. The vehicle standards

will be implemented over the same timeframe

as the greenhouse gas/fuel efciency standards

for light-duty vehicles (promulgated by EPA and

the National Highway Safety Administration in

2012), as part of a comprehensive approach

toward regulating emissions from motor

vehicles.

April 28, 2014 -- 79 FR 23414

http://www.gpo.gov/fdsys/pkg/FR-2014-04-28/ pdf/2014-06954.pdf

In the NTP Report on Carcinogens the following

compounds have been listed as: (1) known

carcinogens to humans: benzene, 1,3-butadiene,formaldehyde; (2) possibly carcinogenic to

humans: acetaldehyde; or (3) reasonably

anticipated to be a human carcinogen:

naphthalene.

http://ntp.niehs.nih.gov/go/roc13

Final Rule:

Diubenzuron;

Pesticide Tolerances

This regulation establishes tolerances for

residues of diubenzuron (N-[(4-chlorophenyl)

amino]carbonyl]-2,6-diuorobenzimide) in

or on fruit, citrus, group 10-10 and citrus,

oil. Chemtura Corporation requested these

tolerances under the Federal Food, Drug, and

Cosmetic Act.

January 31, 2014 -- 79 FR 5294

http://www.gpo.gov/fdsys/pkg/FR-2014-01-31/

html/2014-02064.htm

Para-chloroaniline hydrochloride, a plant

metabolite of diubenzuron, tested positive for

splenic tumors in male rats and hepatocellular

adenomas/carcinomas in male mice.


Technical Report on the Toxicology and

Carcinogenesis Studies of para-Chloroaniline

Hydrochloride (CAS No. 20265-96-7) in F344/N

Rats and B6C3F1 Mice (Gavage Studies). NTP

TR 351, NIH Publication No. 89-2806. Research

Triangle Park, North Carolina. http://ntp.niehs.nih.gov/go/6963.

A complete listing of NTP studies used by federal and state regulatory agencies can be found at http://ntp.

niehs.nih.gov/go/regact .

http://www.gpo.gov/fdsys/pkg/FR-2014-04-28/pdf/2014-06954.pdfhttp://www.gpo.gov/fdsys/pkg/FR-2014-04-28/pdf/2014-06954.pdfhttp://ntp.niehs.nih.gov/go/roc13http://www.gpo.gov/fdsys/pkg/FR-2014-01-31/html/2014-02064.htmhttp://www.gpo.gov/fdsys/pkg/FR-2014-01-31/html/2014-02064.htmhttp://ntp.niehs.nih.gov/go/6963http://ntp.niehs.nih.gov/go/6963http://ntp.niehs.nih.gov/go/regacthttp://ntp.niehs.nih.gov/go/regacthttp://ntp.niehs.nih.gov/go/regacthttp://ntp.niehs.nih.gov/go/regacthttp://ntp.niehs.nih.gov/go/6963http://ntp.niehs.nih.gov/go/6963http://www.gpo.gov/fdsys/pkg/FR-2014-01-31/html/2014-02064.htmhttp://www.gpo.gov/fdsys/pkg/FR-2014-01-31/html/2014-02064.htmhttp://ntp.niehs.nih.gov/go/roc13http://www.gpo.gov/fdsys/pkg/FR-2014-04-28/pdf/2014-06954.pdfhttp://www.gpo.gov/fdsys/pkg/FR-2014-04-28/pdf/2014-06954.pdf



I. Additional Activities

NTP participates in a number of meetings with stakeholders and the scientic community. At the 2014 annual

meeting of the Society of Toxicology (SOT) in Phoenix, staff from NTP and NIEHS participated in more than 30

workshops, symposia, and platform sessions; education and information sessions; and poster sessions. The

full program, including all NTP and NIEHS activities, can be found at http://www.toxicology.org /.

NTP also hosts symposiums and workshops, to discuss the state of the science and advance the eld. For

example, the 2014 annual NTP Satellite Symposium, Pathology Potpourri, was held in Washington, D.C., June

21, in advance of the 33rd annual meeting of the Society of Toxicologic Pathology. The goal of the annual NTP

symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology

community. The Proceedings of the 2014 National Toxicology Program Satellite Symposium was published in

the journal Toxicologic Pathology, along with summaries of presentations, including diagnostic or nomenclature

issues that were presented, and select images that were used for audience voting and discussion.

NTP also hosted three workshops in FY 2014 related to alternative methods development (see page 70).

http://www.toxicology.org/http://www.toxicology.org/



4. Literature Analysis ActivitiesNTP conducts literature analysis and review to examine the state of the science and assess if a substance has

adverse health effects.

A. Noncancer Health Effects

NTP has made a commitment to studying noncancer health effects. The Ofce of Health Assessment and

Translation (OHAT) within NIEHS/NTP conducts evaluations to assess the evidence that environmental

chemicals, physical substances, or mixtures, collectively referred to as substances, cause adverse health

effects. OHAT also provides opinions on whether these substances may be of concern, given what is known

about current human exposure levels. Assessments of potential adverse effects of environmental substances

on reproduction or development, carried out by the Center for the Evaluation of Risks to Human Reproduction

from 1998 to 2010, are now undertaken by OHAT, as are workshops and state-of-the-science evaluations

to address issues of importance in the environmental health sciences. Assessments are published as NTP

monographs. The OHAT evaluation process can be found at http://ntp.niehs.nih.gov/go/38138 . Kristina Thayer,

Ph.D., is director of OHAT.

As highlighted on page 18, in FY 2014, OHAT published the Systematic Review and Evidence Integration for

Literature-Based Environmental Health Science Assessments, methodologies that provide a structure that

increases transparency in the process of collecting and synthesizing scientic evidence for literature-based

evaluations (http://ntp.niehs.nih.gov/go/38673). Table 6 lists literature analysis projects that were initiated,

ongoing, or completed in FY 2014.

Table 6. NTP Noncancer Health Effects Ongoing Projects in FY 2014

NTP Project

[Study Scientist]Objective and/or Summary

Identifying research needs for assessing

safe use of high intakes of folic acid; state

of the science evaluation (http://ntp.niehs.

nih.gov/go/38144)

[Boyles]

NTP, in conjunction with the NIH Ofce of Dietary Supplements, is convening

an expert panel to identify research needs, based on consideration of the

state of the science related to the safe use of high intakes of folic acid. The

benet of supplemental folic acid for pregnant women to prevent neural tube

defects in their children is well established. At the same time, there is interest

in understanding potential adverse health effects from high intakes of folic

acid. The expert panel will discuss the areas of consistency and inconsistency

in the literature at a public meeting at NIH on May 11-12, 2015, in Bethesda,

Maryland. The NTP literature review and expert panel report will be published.

More information about the meeting can be found at http://ntp.niehs.nih.gov/

about/org/ntpexpertpanel/past/index.html . This project aims to identify research

needs and inform the development of a research agenda for evaluating the safe

use of high intakes of folic acid.

http://ntp.niehs.nih.gov/go/38138http://ntp.niehs.nih.gov/go/38673http://ntp.niehs.nih.gov/go/38144http://ntp.niehs.nih.gov/go/38144http://ntp.niehs.nih.gov/about/org/ntpexpertpanel/past/index.htmlhttp://ntp.niehs.nih.gov/about/org/ntpexpertpanel/past/index.htmlhttp://ntp.niehs.nih.gov/about/org/ntpexpertpanel/past/index.htmlhttp://ntp.niehs.nih.gov/about/org/ntpexpertpanel/past/index.htmlhttp://ntp.niehs.nih.gov/go/38144http://ntp.niehs.nih.gov/go/38144http://ntp.niehs.nih.gov/go/38673http://ntp.niehs.nih.gov/go/38138


30/103 4. Literature Analysis Activities 25

NTP Project


Evaluation of inammation-based

atherosclerosis associated withenvironmental exposures (http://ntp.niehs.

nih.gov/go/721549)

[Rooney]

There is growing evidence that the environment plays a role in a wide range

of diseases that involve inammation. The extent to which environmental

exposures ultimately lead to these adverse health effects through an

inammatory pathway remains unclear. This evaluation will examine the

evidence that environmental substances contribute to inammation, which

ultimately leads to atherosclerosis, and identify biomarkers of the inammation

involved. Atherosclerosis was selected for investigation because of the

signicant public health impact of the disease, and the well-established role for

inammation in the disease process leading to atherosclerosis.

Draft case-study protocols to assess the

systematic review and evidence integration

framework (http://ntp.niehs.nih.gov/

pubhealth/hat/noms/index-2.html )

[Rooney]

Case studies are being undertaken to determine if additional renement or

revision to the OHAT Approach, a systematic review framework for evaluating

scientic literature, might be needed. Two case studies are underway to

evaluate the evidence regarding the association of (1) bisphenol A (BPA)

exposure with obesity; and (2) peruorooctanoic acid or peruorooctane

sulfonate exposure with immunotoxicity.

Exposure to chemicals in consumer

products: an NIEHS and EPA collaborative

methods demonstration and evaluation pilot

study (http://ntp.niehs. nih.gov/go/ 721548 )

[Taylor]

There is concern about the endocrine-disrupting potential of some chemicalsfound in personal care products and other consumer products. Given the

large number of co-occurring chemicals in these products, new strategies and

techniques need to be developed, and existing tools need to be evaluated, for

their utility in assessing the extent of human exposure to tens of thousands

of chemicals. NIEHS is collaborating with EPA to perform a small-scale,

longitudinal pilot study, to evaluate the performance of existing survey,

measurement, and modeling methods for assessing exposures to chemicals in

a number of consumer product categories, including personal and child care,

household cleaning, lawn and garden, home improvement, and food packaging

products. The pilot study addresses a number of research needs related to the

measurement and modeling of human exposures.

State of the science for transgenerational

inheritance of health effects (http://ntp.

niehs.nih.gov/go/38159 )

[Walker]

Transgenerational inheritance is the phenomenon in which an individual’s

exposures have far-reaching consequences, affecting multiple generations

removed from the original insult. The traditional belief suggests that negative

effects of exposure to environmental chemicals are reset in each generation,

such that subsequent generations are unaffected by the exposure history

of their parents and grandparents. This state of the science evaluation will

examine the robustness of the evidence for transgenerational inheritance of

health effects associated with exposure to a wide range of stressors, such as

environmental chemicals, drugs of abuse, nutrition and diet, pharmaceuticals,

infectious agents, and stress in humans and animals.

Evaluation of children’s health and trafc-

related air pollution (http://ntp.niehs.nih.gov/

go/721550 )

[Howdeshell]

Research on trafc-related air pollution and children’s health has increased in

the past decade with improvements in air monitoring technology and exposure

methodology. Trafc-related air pollution has been measured in many different

ways, including direct trafc measures, such as proximity or density of trafc;environmental gases, such as ozone and nitrogen dioxide; particulate matter,

including coarse particles (PM10) and ne particles (PM2.5); and select

components of trafc-related pollution, including benzene, diesel exhaust,

and polycyclic aromatic hydrocarbons (PAHs). This topic will be addressed in

a series of evaluations that examine the evidence for an association between

trafc-related air pollution and health outcomes impacting fetal outcome and

children, including gestational hypertension and neurological development and

function in children.

http://ntp.niehs.nih.gov/go/721549http://ntp.niehs.nih.gov/go/721549http://ntp.niehs.nih.gov/pubhealth/hat/noms/index-2.htmlhttp://ntp.niehs.nih.gov/pubhealth/hat/noms/index-2.htmlhttp://ntp.niehs.nih.gov/go/721548http://ntp.niehs.nih.gov/go/38159http://ntp.niehs.nih.gov/go/38159http://ntp.niehs.nih.gov/go/721550http://ntp.niehs.nih.gov/go/721550http://ntp.niehs.nih.gov/go/721550http://ntp.niehs.nih.gov/go/721550http://ntp.niehs.nih.gov/go/38159http://ntp.niehs.nih.gov/go/38159http://ntp.niehs.nih.gov/go/721548http://ntp.niehs.nih.gov/pubhealth/hat/noms/index-2.htmlhttp://ntp.niehs.nih.gov/pubhealth/hat/noms/index-2.htmlhttp://ntp.niehs.nih.gov/go/721549http://ntp.niehs.nih.gov/go/721549



NTP Project


Evaluation of adverse health effectsand occupational exposure to cancer

chemotherapy agents (http://ntp.niehs.nih.

gov/go/721547 )

[Howdeshell]

Cancer chemotherapy agents are cytotoxic drugs, and many of these agents

are known mutagens and developmental toxicants. Occupational exposure

to cancer chemotherapy agents may occur in various professions including

medical, veterinary, and manufacturing. While improved handling procedures

and engineering controls have reduced contamination, surface contamination

persists in pharmacy and nursing areas of some hospital-based cancer

centers. This evaluation will examine the evidence that occupational exposure

to cancer chemotherapy is associated with adverse health effects. It will

focus on nonreproductive health, as NIOSH recently published a review of

occupational exposure to anti-neoplastic drugs and reproductive health effects.

B. Report on Carcinogens

The Report on Carcinogens (RoC) is a congressionally mandated listing of substances that either are known to

be human carcinogens or may reasonably be anticipated to be human carcinogens, and to which a signicantnumber of persons residing in the U.S. are exposed [Section 301(b)(4) of the Public Health Service Act, 42

U.S.C. 241(b)(4)].

Each substance listed in the RoC has a prole, which contains the listing status, a summary of the cancer

studies supporting the listing status, information on human exposure, and federal regulations to reduce

exposure. The RoC is a cumulative report that consists of substances reviewed in previous editions, as well

as newly reviewed substances. NTP, with assistance from other federal health and regulatory agencies,

prepares the RoC for the HHS Secretary. Preparation of the RoC is conducted by the Ofce of the RoC, under

the direction of Ruth Lunn, Dr.P.H. Contract support for preparation of the RoC in FY 2014 was provided by

Integrated Laboratory Systems Inc.

NTP follows a four-part process for preparing the RoC (http://ntp.niehs.nih.gov/go/rocprocess), using

established listing criteria (http://ntp.niehs.nih.gov/go/15209) to evaluate substances for possible listing

in the report. The cancer evaluation for each substance is captured in the draft RoC monograph, which

summarizes, assesses, and integrates the scientic information, and applies the RoC listing criteria to the body

of knowledge to reach a preliminary listing decision. NTP selects nominations for RoC evaluation, referred to

as candidate substances, and conducts cancer hazard evaluations on those substances. On a periodic basis,

NTP submits the proposed listings status of substances, whose cancer evaluations are completed, to the HHS

Secretary for review, approval, and release to the public and congressional members.

In FY 2014, the Ofce of the RoC continued efforts towards nalizing the 13th RoC, which is planned for

release in early FY 2015 (http://ntp.niehs.nih.gov/go/roc13). The cumulative report will include the listings of

four newly reviewed substances.

Other RoC activities in FY 2014 were related to completing the cancer hazard evaluations of the listed

substances, continuing ongoing evaluations of previously identied substances, and identifying new

substances for evaluation (see Table 7). In December 2013, NTP convened a panel of experts to peer

review the draft monographs on ortho-toluidine and pentachlorophenol in a public forum (http://ntp.niehs.nih.

gov/go/38854). Following the April Board of Scientic Counselors (BSC) meeting, these monographs were

nalized and posted on the RoC Web page (http://ntp.niehs.nih.gov/go/721814).

http://ntp.niehs.nih.gov/go/721547http://ntp.niehs.nih.gov/go/721547http://ntp.niehs.nih.gov/go/rocprocesshttp://ntp.niehs.nih.gov/go/15209http://ntp.niehs.nih.gov/go/roc13http://ntp.niehs.nih.gov/go/38854http://ntp.niehs.nih.gov/go/38854http://ntp.niehs.nih.gov/go/721814http://ntp.niehs.nih.gov/go/721814http://ntp.niehs.nih.gov/go/38854http://ntp.niehs.nih.gov/go/38854http://ntp.niehs.nih.gov/go/roc13http://ntp.niehs.nih.gov/go/15209http://ntp.niehs.nih.gov/go/rocprocesshttp://ntp.niehs.nih.gov/go/721547http://ntp.niehs.nih.gov/go/721547


32/103 4. Literature Analysis Activities 27

The Ofce of the RoC completed the draft monograph for trichloroethylene, a substance previously

identied for review. The cancer hazard evaluation portion of the monograph was informed by expert

presentations and discussions at a public webinar in March 2014 (http://ntp.niehs.nih.gov/go/tcewebinar ).

The presentations and discussions were focused on assessing the quality of the exposure and outcome

assessments in the human cancer studies. A panel of experts peer reviewed the draft RoC monograph on

August 12, 2014 (http://ntp.niehs.nih.gov/go/38854). The Ofce of the RoC will share information concerning

the peer review, such as the revised draft monograph (available at http://ntp.niehs.nih.gov/go/37899), with

the BSC at their December 2014 meeting.

At the April 2014 BSC meeting, the Ofce of the RoC presented, for review, concept documents for seven

substances, including ve viruses, cobalt, and goldenseal root powder. These were selected as candidate

substances and their cancer hazard evaluations have been initiated (for more information, see http://ntp.niehs.

nih.gov/go/37894).

Table 7. Candidate Substances for the RoC

Candidate SubstanceCASRN

[Study Scientist]

Primary Uses/Exposures RoC Review Status

Cobalt

7440-48-4

[Spencer]

A naturally occurring element that is present in different

forms, such as a metal and salts. Cobalt metal and cobalt

compounds are used in the production of metal alloys

for a variety of commercial applications, as a pigment for

dying pottery and colored glass, and in green energies.

BSC review of draft concept,

April 2014.

Cancer hazard evaluation

initiated.

Goldenseal root powder

[Spencer]

Member of the plant family Ranunculaceae. The root

is used as an alternative medicine to treat a variety of

ailments.

People are exposed to this botanical by ingesting one ofover 150 products, including dietary supplements and

herbal remedies that contain goldenseal root powder.


April 2014.

Shift Work at Night, Light

at Night, and Circadian

Disruption

[Lunn]

Circadian disruption occurs when endogenous circadian

rhythms, daily and predictable variations in biological,

physiological, and behavioral processes, are out of phase

with the external environment or with each other.

People, by virtue of the nature of their work, lifestyle

choices, or residence, are subjected to interruptions in

the natural light-dark cycles, leading to the potential for

circadian disruption.


June 2013.

Cancer hazard evaluation

initiated.

Trichloroethylene*

79-01-6

[Lunn]

Halogenated alkene used primarily for degreasing metals.

Peer-review meeting August 12,

2014.

Revised draft monograph posted

on RoC website.

http://ntp.niehs.nih.gov/go/tcewebinarhttp://ntp.niehs.nih.gov/go/38854http://ntp.niehs.nih.gov/go/37899http://ntp.niehs.nih.gov/go/37894http://ntp.niehs.nih.gov/go/37894http://ntp.niehs.nih.gov/go/37894http://ntp.niehs.nih.gov/go/37894http://ntp.niehs.nih.gov/go/37899http://ntp.niehs.nih.gov/go/38854http://ntp.niehs.nih.gov/go/tcewebinar



Candidate Substance

CASRN

[Study Scientist]

Primary Uses/Exposures RoC Review Status

5 Selected viruses:

Epstein-Barr virus (EBV)

Human immunodeciency

virus type 1 (HIV)

Human T-cell lymphotrophic

virus type 1 (HTLV-1)

Kaposi’s sarcoma-associated

herpes virus (KSHV)

Merkel cell polyoma virus

(MCV)

[Jahnke]

EBV and KSHV: herpes viruses (enveloped; double

stranded DNA genome). Exposure occurs through saliva.

HIV and HTLV-1: retroviruses (enveloped; single stranded

RNA genome). Exposure occurs via breast feeding and

perinatal, parenteral, and sexual transmission.

MCV: polyomavirus (nonenveloped, double stranded DNA

genome). It is not known how people are infected with the

virus.

ntp annual report fy2014 508

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