Welcome to the 2017 Annual Report

"The NTP serves a critical role for our nation. It provides a unique, consolidated venue for toxicology 

research, testing, and analysis to occur." – Dr. Linda Birnbaum, NTP Director

Read the 2017 Letter from the NIEHS and NTP Director.

FY 2017 at a Glance

 Completed NTP Reports

 Fifty Years of NIEHS Captured 

in History and Science 

Collections 

 14th Report on Carcinogens 

Released

More

Learn About Us

 Mission and Goals

 Organizational Structure and 

Oversight

 Funding

 Program Contact Information

More

Scientific and Public Input 

Opportunities

 Nominations

 NTP Board of Scientific 

Counselors

 SACATM

More
Research and Testing

 Tox21

 Testing and Toxicology 

Studies

 NICEATM

 ICCVAM

More

Literature Analysis

 Noncancer Research

 Report on Carcinogens

Partner Agency Research

 About NTP at NIEHS

 NTP at NCTR

 NTP at NIOSH

The NTP Annual Report is produced by the NTP Office of Liaison, Policy, and Review. The text is not copyrighted and can be

reprinted without permission. If you use parts of the Annual Report in a publication, please provide us a copy for our records. We

welcome your comments and suggestions. 

Official Citation: National Toxicology Program. Annual Report for Fiscal Year 2017. Research Triangle 

Park, NC: National Toxicology Program; 2018. Available from https://ntp.niehs.nih.gov/annualreport/2017

Director of Office of Liaison, Policy, and Review and Editor-in-Chief: Mary Wolfe | Managing Editor: Joshua Cleland (ICF)
2017 Annual Report – Letter from Director

3

Letter from the NIEHS and NTP Director

In fiscal year (FY) 2017, NTP continued to advance toxicology 

and inform public health policy by providing information to 

decision makers and the public about substances in our 

environment. Numerous studies were published on substances 

of public health concern, such as flame retardants, metals, and 

widely used industrial chemicals. Among these is the first study 

to investigate occupational exposure to bisphenol A by 

manufacturing workers in the United States. 

NTP engaged in several activities to advance alternatives to 

animal testing. The NTP Interagency Center for the Evaluation of 

Alternative Toxicological Methods sponsored several venues to 

receive stakeholder input on a draft Strategic Roadmap toward 

new approaches to safety evaluation of chemicals and medical 

products. In addition, the “Tox21” initiative worked to develop 

high-throughput 3D tissue culture models that mimic the 

functionality of specific organ tissues to predict responses to 

environmental exposures.

The NTP Office of the Report on Carcinogens held a workshop 

to obtain external scientific input on topics important for informing 

their literature-based cancer hazard assessments for shift work 

at night, light at night, and circadian disruption. 

The NTP Office of Health Assessment and Translation published 

the NTP Monograph on Immunotoxicity Associated with 

Exposure to Perfluorooctanoic Acid or Perfluorooctane Sulfonate. 

This evaluation was the first to reach hazard conclusions using the 

new systematic-review approach for study assessment and 

evidence integration.

I invite you to read this report to learn about what we accomplished 

in FY 2017 to safeguard public health by informing policy with the 

best science.

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

Dr. Birnbaum has served as the Director 

of the National Institute of Environmental 

Health Sciences (NIEHS) and the 

National Toxicology Program (NTP) 

since 2009

(Photo courtesy of Steve McCaw)
2017 Annual Report – FY 2017 Glance 

4 

FY 2017 at a Glance

Completed NTP Reports

NTP studies are published in an NTP report series after undergoing peer review. NTP 

reports published in FY 2017 or expected for peer review in FY 2018 are listed.

Timeline of Events

Highlighted NTP activities in FY 2017.

Fifty Years of NIEHS Captured in History and Science Collections

NIEHS catalogs hundreds of mementos and artifacts to commemorate its golden 

anniversary.

14th Report on Carcinogens Released

NTP released the 14th Report on Carcinogens in FY 2017.

Kleinstreuer Receives Lush Prize Young Researcher Award

NTP computational toxicologist Nicole Kleinstreuer, Ph.D., was recognized for her 

work toward eliminating animal use for chemical safety testing.

NTP Supports First Study of BPA Levels in U.S. Factory Workers

NIOSH researchers found elevated BPA levels in workers’ urine.

New Cell Models for Toxicology Better Mimic Human Tissue

For use in high-throughput toxicity testing, the new models can quickly and reliably 

identify environmental toxins linked to human disease.
2017 Annual Report – FY 2017 Glance 

5 

ICCVAM Adds a New Member Agency

The National Institute of Standards and Technology brings expertise in process 

controls, measurement artifacts, and interlaboratory testing.

NTP Archives Supports Global Cancer Research Initiatives

NTP is contributing rodent tumor and normal samples to a new $24.4 million study of 

the links between human cancers and specific environmental factors.

Public Forum on Alternatives to Animal Testing Highlights Next Steps

Attendees learned about and discussed new approaches into safety testing of 

chemicals and medical products in the United States.

New NTP Website Getting Rave Reviews

The visually appealing new site offers many new tools to facilitate navigation and 

usability.

At 10 Years, Tox21 Continues to Drive Toxicity Testing Forward

The Tox21 program has a 10-year track record of developing cutting-edge technology 

to better assess chemical toxicity in humans.

NTP Public Health Impact on Regulatory Agencies

Federal and state regulatory agencies use NTP study data and recommendations 

when considering the need to test and regulate specific chemicals to protect human 

health.

Additional Activities

Additional meetings with stakeholders and the scientific community in which NTP

participated.
2017 Annual Report – FY 2017 Glance 

6 

Publications

Full citations for NTP reports, journal publications, and book chapters published during 

FY 2017.
2017 Annual Report – FY 2017 Glance – NTP Reports 

7 

Completed NTP Reports 

The findings of NTP studies and research projects are published in three types of NTP reports.

• NTP Technical Reports document long-term toxicology and carcinogenicity studies, generally 

of 2 years’ duration.

• Toxicity Reports document shorter-term studies, generally up to 13 weeks’ duration.

• NTP Research Reports provide the results of research studies, rapid communications, and 

literature surveys that do not fall under the scope of the first two report series. 

All published NTP reports are peer reviewed by experts who are screened for conflicts of interest 

prior to their service. NTP reports completed in FY 2017, and in prior years, are available on the NTP 

website and catalogued in PubMed.

Technical Reports Published During FY 2017 Reporting Levels of Evidence 

of Carcinogenic Activity 

NTP Technical Reports published in FY 2017 are listed below. NTP used established criteria to 

evaluate the findings and determine the strength of evidence for conclusions regarding the 

carcinogenic activity of each substance. The conclusions for level-of-evidence of carcinogenic activity 

are included. 

Chemical

Technical 

Report Number 

(CASRN*)

Use

Evidence of Carcinogenic 

Activity

Male

Rats

Female

Rats

Male

Mice

Female

Mice

Indole-3-

Carbinol

TR-584

(700-06-1)

Natural component of brassica 

vegetables; marketed as a dietary 

supplement and cancer preventive 

agent

No

evidence

Some

evidence

Clear

evidence

No

evidence

TRIM® VX

TR-591

(NA)

Metalworking fluid used as a lubricant 

and coolant liquid and for cleaning tools 

and parts during cutting, drilling, milling, 

and grinding

Equivocal

evidence

Equivocal

evidence

Clear

evidence

Clear

evidence

*CASRN = Chemical Abstracts Service Registry Number
2017 Annual Report – FY 2017 Glance – NTP Reports 

8 

Technical Reports that Underwent Peer Review in FY 2017 

Three draft technical reports, listed below, underwent peer review in FY 2017. The NTP website 

provides further information about these and other past technical reports peer review meetings. 

Chemical

Technical 

Report

Number 

(CASRN*)

Use Report Conclusions as 

Written and Panel Vote

2,3-Butanedione TR-593 

(431-03-8)

Used in artificial flavor formulations, 

such as microwave popcorn, cake 

mixes, flour, beer, wine, margarine, 

cheese, candy, crackers, cookies, ice 

cream, and many others food and 

beverage products.

“Exposure to 2,3-butanedione resulted 

in increased incidences of 

nonneoplastic lesions of the nose, 

larynx, trachea, lung, and eye in male 

and female rats and mice.” 

4 yes, 2 no, 0 abstentions 

Panelists who voted “no” 

recommended clear evidence of 

carcinogenic activity for male rats and 

some evidence of carcinogenic 

activity for female mice.

p-Chloroα,α,α-trifluorotolueneTR-594 

(98-56-6)

Solvent used in paints and coatings 

and as an industrial intermediate in 

the production of other chemicals 

(e.g., herbicides, dyes, 

pharmaceuticals).

“Exposure to p-chloro-α,α,αtrifluorotoluene caused increased 

incidences of nonneoplastic lesions in 

the lung and liver of male and female 

rats and mice, in the nose of male 

rats, in the adrenal medulla and 

uterus of female rats, in the 

forestomach of male and female mice, 

and in the larynx in male mice. 

Exposure to p-chloro-α,α,αtrifluorotoluene caused increased 

severity of nonneoplastic lesions in 

the kidney of male rats.” 

6 yes, 0 no, 0 abstentions

Zinc, dietary TR-592 

(5263-02-5)

Used in a wide range of industries 

including rubber production, animal 

feed supplement, fertilizer additive, 

cosmetics, drugs, paint pigment, 

dental cements, wood preservatives, 

batteries, galvanizing and metal work, 

textile production, television screens, 

watches, and smoke bombs.

“Exposure to diets containing excess 

zinc resulted in increased incidences 

of nonneoplastic lesions of the 

pancreas in male and female rats. 

Exposure to diets deficient in zinc 

resulted in increased incidences of 

nonneoplastic lesions of the testes in 

male rats.” 

6 yes, 0 no, 0 abstentions

*CASRN = Chemical Abstracts Service Registry Number
2017 Annual Report – FY 2017 Glance – NTP Reports 

9 

Toxicity Reports Published During FY 2017

NTP Toxicity Reports evaluate and characterize the toxicological potential of a substance under study 

conditions. NTP Toxicity Reports published in FY 2017 are listed below.

Chemical Toxicity Report

Number (CASRN*) Use

o-Chloropyridine TOX-83 

(109-09-1)

Intermediate in synthetic organic, pharmaceutical, and 

agricultural chemical (fungicides, herbicides) 

manufacture. Also used as a catalyst for phase transfer 

and is a key intermediate in the manufacture of 

pyrithione-based biocides for use in cosmetics and 

various pharmaceutical products.

Tetrabromobisphenol A-bis(2,3-

dibromopropyl ether)

TOX-85 

(21850-44-2)

Flame retardant in electronics, building and construction 

materials, and automotive materials.

*CASRN = Chemical Abstracts Service Registry Number

Research Reports Published During FY 2017

The NTP Research Report series was launched in FY 2016 to promote transparency and 

reproducibility. The series strengthens the science base and provides information useful for public 

health decision-makers. NTP Research Reports published in FY 2017 are listed below.

Report Title Research Report Number

Absence of Formaldehyde-Induced Neoplasia in Trp53 

Haploinsufficient Mice Exposed by Inhalation

RR-03
2017 Annual Report – FY 2017 Glance – Timeline of Events 

10

FY 2017 Timeline

November 2016

14th Report on Carcinogens Released

The newly updated Report on Carcinogens released November 

3 includes listings for seven substances: five viruses, 

trichloroethylene, and cobalt and cobalt compounds.

December 2016

NTP Board of Scientific Counselors Meeting

The December 14–15 Board of Scientific Counselors meeting

featured ongoing research collaborations between NTP partner 

agencies. From exploring the organisms in our gut to 

documenting chemical exposures in the workplace, the 

partnerships are proving to be productive scientific 

collaborations.

January 2017

NICEATM Communities of Practice Webinar

On January 24, NICEATM presented a webinar on 

cheminformatics techniques for 21st Century Toxicity Testing. 

February–March 

2017

NICEATM Webinar Series

NICEATM hosted a series of three webinars in February through 

March on the use of informatics to improve data analysis of 

chemical screening assays conducted in zebrafish.

May 2017

ICCVAM Public Forum

The lead topic of an ICCVAM Public Forum on May 23 was A 

Strategic Roadmap for Establishing New Approaches to 

Evaluate the Safety of Chemicals and Medical Products in the 

United States. 

June 2017

BioMed21 – A Human Pathway-based Approach to Disease 

and Medicine Workshop

This workshop, co-organized by NICEATM and the Human 

Toxicology Project Consortium, assembled experts to identify 

barriers and opportunities and to recommend the needs for 

achieving implementation of a human systems-biology platform 

to understand disease and improve interventions.
2017 Annual Report – FY 2017 Glance – Timeline of Events 

11

June 2017

NTP Board of Scientific Counselors Meeting

At its June 29 meeting, the NTP Board of Scientific Counselors

reviewed and enthusiastically supported NTP’s progress in 

researching human exposure to chemical mixtures.

July 2017

Report on Carcinogens Peer Review Panel 

A panel convened by NTP on July 24 recommended listing in 

the Report on Carcinogens six compounds known as haloacetic 

acids as reasonably anticipated to be carcinogens. The 

compounds are byproducts created when chlorine, chloramine, 

or chlorine dioxide are used to disinfect drinking water.

July 2017

NTP Technical Report Peer-Review Panel

The NTP scientific panel convened on July 13 and reviewed and 

accepted draft technical reports on the carcinogenicity and 

toxicity of three substances: 2,3-butanedione (used to flavor 

microwave popcorn and other foods), dietary zinc, and PCTFT 

(p-chloro-α,α,α-trifluorotoluene, an industrial solvent).

August 2017

Symposium on Systematic Review

On August 24–25, NTP hosted the 4th International Symposium 

on Systematic Review and Meta-analysis of Laboratory Animal 

Studies. Experts from Europe, Egypt, India, Australia, North 

America, and South America participated.

September 2017

SACATM Meeting

At its September 18–19 meeting, SACATM provided advice on A 

Strategic Roadmap for Establishing New Approaches to 

Evaluate the Safety of Chemicals and Medical Products in the 

United States then in development by ICCVAM.
2017 Annual Report – FY 2017 Glance – NIEHS 50th Anniversary 

12

Fifty Years of NIEHS Captured in History and Science Collections

To commemorate its golden anniversary year, NIEHS staff 

searched, collected, sorted, identified, and cataloged hundreds of 

mementos and artifacts to record and preserve the institute’s 

history. The NIEHS Office of Communications and Public Liaison 

assembled the material into multimedia collections now available 

on the NIEHS 50th Anniversary webpages.

Photographs, an interactive timeline of scientific milestones, oral 

histories, and testimonial reflections on the institute’s impact have 

been restored, digitized, and organized for easy viewing. Other

keepsakes that could not be digitized for the online collections have 

been stored in a time capsule at the NIEHS facility in Research 

Triangle Park, North Carolina.

The NIEHS Reflections page has news clips, oral histories, and 

early issues of the institute’s newsletter, Environmental Factor. The 

page features a personal tribute to NIEHS, written by environmental 

toxicologist, Bernard Goldstein, M.D., professor emeritus and 

former dean of the University of Pittsburgh Graduate School of 

Public Health.

Audio files of oral histories from scientists and institute leaders 

have been posted on the page, and 50 years of institute history and 

scientific progress, including the following, can be explored:

• Highlights of environmental health science research, such as 

discovery of the link between asbestos and mesothelioma. 

• New programs, including the autism research network. 

• Institutional developments, from creation of the National 

Toxicology Program to information on institute directors. 

The NIEHS communications team collected photos from retirees, 

current employees, archives, and long-forgotten boxes and file 

folders. Most are available to the public on the Photo Gallery page 

of the anniversary website. Posed or informal, artistic or candid, the 

snapshots provide glimpses of institute researchers, facilities, and 

team-building activities across the years.
2017 Annual Report – FY 2017 Glance – Report on Carcinogens 

13

14th Report on Carcinogens Released

The U.S. Department of Health and Human Services released the 

14th Report on Carcinogens November 3, 2016. The 

congressionally mandated report, which NTP prepares, included 

seven newly reviewed substances, bringing the total to 248 listings. 

The Report on Carcinogens lists a variety of environmental factors, 

collectively called substances and grouped into two categories: 

known to be a human carcinogen and reasonably anticipated to be 

a human carcinogen. The listings can include chemicals; mixtures 

of chemicals; infectious agents, such as viruses; and physical 

agents, such as X-rays and ultraviolet radiation.

The seven newly reviewed substances added to the 2016 Report 

are listed below.

Substance Listing Status Description

Trichloroethylene (TCE) Known to be a human 

carcinogen

Industrial 

solvent

Cobalt and cobalt compounds that 

release cobalt ions in vivo

Reasonably 

anticipated to be a 

human carcinogen

Metal and its 

compounds

Human immunodeficiency virus type 

1 (HIV-1)

Known to be a human 

carcinogen

Virus

Human T-cell lymphotropic virus type 

1 (HTLV-1)

Known to be a human 

carcinogen

Virus

Epstein-Barr virus (EBV) Known to be a human 

carcinogen

Virus

Kaposi sarcoma-associated 

herpesvirus (KSHV)

Known to be a human 

carcinogen

Virus

Merkel cell polyomavirus (MCV) Known to be a human 

carcinogen

Virus
2017 Annual Report – FY 2017 Glance – Lush Prize 

14

Kleinstreuer Receives Lush Prize Young Researcher Award

NTP computational toxicologist Nicole Kleinstreuer, Ph.D., was 

recognized for her work toward eliminating animal use for chemical 

safety testing. The Lush Cosmetics Young Researcher—Americas 

Prize, one of the annual Lush Prizes honoring such progress, was 

presented during a November 2, 2016, ceremony at the Lush 

Cosmetics North American headquarters in Vancouver, British 

Columbia.

Kleinstreuer, deputy director of the NTP Interagency Center for the 

Evaluation of Alternative Toxicological Methods, was awarded the 

prize for developing computational toxicity models for predicting 

outcomes such as developmental toxicity, endocrine disruption, and 

skin sensitization. Kleinstreuer said she hopes that some of the 

company’s data from human testing could be used in the models to 

predict skin sensitization. Using human data could improve the 

accuracy of model predictions.

The Lush Young Researcher Prize is only the latest honor for 

Kleinstreuer and the center, as they apply modern methods and 

technologies to chemical safety testing. Kleinstreuer hopes this 

award brings attention and support to the center’s current focus, 

working with U.S. and international regulatory agencies to replace 

animal use worldwide in testing for skin and eye irritation, acute 

toxicity, and skin sensitization.
2017 Annual Report – FY 2017 Glance – BPA in Factory Workers 

15

NTP Supports First Study of BPA Levels in U.S. Factory Workers

A new study supported by NTP was the first to investigate

occupational exposure to BPA (bisphenol A) among 

manufacturing workers in the United States. Researchers at 

NIOSH led the study, which appeared January 1, 2017, in the 

journal “Annals of Work Exposures and Health.” NIOSH is a 

member agency of NTP, and the study was conducted as part of 

an ongoing collaboration between the two agencies.

The NIOSH study included six U.S. companies that make BPA or 

manufacture or use resins and waxes containing BPA. Of the 78 

workers participating in the study, most were white males. Over two 

days, participants provided seven urine samples. The participants 

also answered questions about food and beverage products they 

consumed in the previous 24 hours.

Researchers at the Centers for Disease Control and Prevention 

(CDC) have found BPA in the urine of nearly all people tested, 

indicating widespread exposure in the U.S. population. Diet is 

thought to be the main nonoccupational source of BPA exposure. 

Workers who participated in the new study handled raw BPA, often 

in large quantities, and—unlike the general population—were 

exposed to BPA mainly by inhalation and absorption through the 

skin. 

NIOSH researchers found that BPA levels in the urine of workers 

were, on average, about 70 times higher than that of most adults in 

the United States. Certain job categories were associated with 

average urine levels more than 300 times greater than in the 

general population. Workers who handled sacks of BPA and carried 

process or bulk samples containing BPA for quality control testing, 

for example, had increased urinary BPA levels. Among the highest 

exposed workers were those who worked with molten casting wax 

that contained BPA. The lowest urinary BPA levels (trace amounts) 

were found in workers who handled a resin product. The study did 

not evaluate the health of the participating workers. 

The NIOSH Science Blog provides more information about this 

study and ways to reduce exposure.
2017 Annual Report – FY 2017 Glance – New Cell Models 

16

New Cell Models for Toxicology Better Mimic Human Tissue

NTP researchers are developing cell models that better mimic the

structure and function of human tissue for use in high-throughput 

toxicological testing. The effort is part of the Tox21 initiative to 

move away from animal testing. Advanced tissue culture models 

can quickly and reliably identify environmental toxins linked to 

human disease.

Sreenivasa Ramaiahgari, Ph.D., an NTP postdoctoral fellow, 

described his work on refining cell models during a January 13, 

2017 talk at the Duke University Integrated Toxicology and 

Environmental Health Program seminar series. Ramaiahgari works 

in the NTP Biomolecular Screening Branch, the NTP lead for 

Tox21. His talk, “Organotypic In Vitro Models for Studying 

Chemical-induced Effects,” described his research involving threedimensional organotypic models—models that behave like living 

tissue—of liver, kidney, and cancer cells.

Ramaiahgari developed a liver model using progenitor cells, a type 

of stem cell that can be induced to differentiate into other cell types, 

including liver cells. Ramaiahgari also developed organotypic tissue 

models for breast and prostate cell types. These models display 

tissue-specific functionalities not observed with conventional tissue 

culture models.

Ramaiahgari’s goal at NTP is to develop organotypic tissue culture 

models for all tissue types—liver, kidney, lung, heart, breast, 

neuronal, intestinal, and others—for application in predictive 

toxicology using high-throughput testing.
2017 Annual Report – FY 2017 Glance – NIST 

17

ICCVAM Adds a New Member Agency

In early 2017, the National Institute of Standards and Technology 

(NIST) joined the Interagency Coordinating Committee on the 

Validation of Alternative Methods (ICCVAM). NIST participation 

brings experience to the committee in the study of process 

controls, measurement artifacts, and interlaboratory testing.

Supported by the NTP Interagency Center for the Evaluation of 

Alternative Toxicological Methods, the committee was established 

to facilitate and promote development and regulatory acceptance 

of new toxicological tests that could replace, reduce, or refine 

animal use. The expertise within NIST benefits the committee, 

especially in developing validation studies to assess the 

appropriateness of new test methods for specific purposes. In 

particular, NIST has experience with cell-based and small model 

organism assays, which are becoming increasingly important as 

alternatives for traditional animal tests. NIST also brings expertise 

in experimental design and statistical analysis.

This event represents the first time the committee has expanded its 

membership since its inception in 2000. NIST, part of the U.S. 

Department of Commerce, has been interacting with the committee 

since 2015. The agency submitted an official request to join in 

January 2017, which NIEHS Director Linda Birnbaum approved in 

February 2017.
2017 Annual Report – FY 2017 Glance – NTP Archives 

18

NTP Archives Supports Global Cancer Research Initiatives

The NTP Archives is contributing rodent tumor and normal samples 

to a new $24.4 million study to investigate the links between 

human cancers and specific environmental factors. The project is 

one of four winners of the Cancer Research United Kingdom Grand 

Challenge, announced February 10, 2017. This research examines 

human and animal cancers for unique patterns of genetic 

mutations that might result from chemical exposures. The 

characteristic patterns are called mutational fingerprints or 

mutational signatures. The samples are from carefully documented 

studies of rats and mice exposed to more than 100 chemical 

carcinogens. The study involved exposures of male and female 

rats and mice for 13-week and 2-year durations. The researchers 

will compare mutational fingerprints from the rodent tumors with 

those from human cancer tissues.

The study builds on initial evidence that certain environmental 

factors, such as ultraviolet radiation and tobacco, leave a distinct 

mutational fingerprint when they damage the DNA in human cells. 

At least 50 mutational fingerprints have been identified, but only 

about half have been linked to specific environmental factors.

The NTP Archives also is contributing to a project, “Identifying 

Preventable Causes of Cancer,” led by Professor Sir Mike Stratton, 

M.D., Ph.D., and director of the Wellcome Trust Sanger Institute. 

Collaborators include scientists from the United States, United 

Kingdom, and France. Stratton presented the concept for the 

project in a January 12, 2017 lecture at NIEHS. Stratton’s team 

plans to study mutational fingerprints from 5,000 pancreatic, kidney, 

esophageal, and colorectal cancer samples from around the world, 

comparing them with mutational fingerprints from samples in the 

NTP Archives and other data. This is the most comprehensive 

attempt ever made to compare animal and human cancer mutation 

signatures in relation to chemical exposures.

Arun Pandiri, Ph.D., head of the NTP Molecular Pathology Group at 

NIEHS, is coordinating the pathology evaluation and sample 

selection from the NTP Archives. 

Ron Herbert, D.V.M., Ph.D., oversees the archives. The archives 

are an unmatched collection of publicly available research 

specimens, detailed documentation from chemical exposures, and 

pathology assessments, all of which make the NTP Archives 

especially useful for toxicological research.
2017 Annual Report – FY 2017 Glance – Animal Testing Alternatives 

19

Public Forum on Alternatives to Animal Testing Highlights Next 

Steps

A plan for moving closer to the goal of replacing animals in U.S. 

safety testing and collaborations that have made possible the 

progress to date was highlighted at the May 23, 2017 public 

forum of the Interagency Coordinating Committee on the Validation 

of Alternative Methods (ICCVAM). Many of the presentations at the 

annual public forum, held at NIH in Bethesda, Maryland, involved 

collaborations among federal agencies, between federal agencies 

and stakeholder groups, and among countries. Some of these 

efforts have already reduced the need to use animals for chemical 

safety testing. Other outcomes include technological advances that 

could improve hazard prediction and further reduce animal testing.

The forum was an opportunity for representatives from industry, 

animal welfare organizations, and other interested parties to 

discuss topics for inclusion in the Strategic Roadmap (to be 

published in 2018) on incorporating new approaches into safety 

testing of chemicals and medical products in the United States. The 

strategic roadmap document guides ICCVAM future activity.

The NTP Interagency Center for the Evaluation of Alternative 

Toxicological Methods organized the meeting on behalf of the 

ICCVAM and posted a video of the meeting and the presenters’ 

slides on the NTP website. 
2017 Annual Report – FY 2017 Glance – New NTP Website 

20

New NTP Website Getting Rave Reviews

Since March 2017, Beth Bowden, an information technology 

specialist in the NTP Program Operations Branch at NIEHS, has 

overseen the work of Signature Consulting Group, a contractor, to 

build a versatile, user-friendly new NTP website. 

The NTP Information Technology Resources Advisory Committee, 

which includes members of the NIEHS Division of the NTP, has 

provided guidance and direction for each step in the website 

redesign process.

The new NTP website is current, visually appealing, and designed 

to engage both scientists and citizens. The site offers many new 

tools, including a feature—progressive disclosure—that facilitates 

navigation and improves usability. By displaying less clutter, the 

website allows users to focus on the main content of a page. 

Visitors can delve into the site’s information without becoming lost. 

The site has been updated to be compatible with mobile 

technologies, favored by younger audiences.

In addition to providing easier navigation and a more appealing 

look, the redesign restructured the content to be more 

understandable. Headers and footers were improved to better tell 

NTP’s story. The website includes some 11,000 pages, with 

information about meetings, articles, abstracts, and major NTP 

projects.
2017 Annual Report – FY 2017 Glance – Tox21 at 10 Years 

21

At 10 Years, Tox21 Continues to Drive Toxicity Testing Forward

The Tox21 program has a 10-year track record of developing 

cutting-edge technology to better assess chemical toxicity in 

humans. In August 2017, the 10th World Congress on Alternatives 

and Animal Use dedicated a panel discussion to this milestone. 

In his address to the World Congress meeting, Rick Paules, Ph.D., 

looked ahead to the next 5 years. Paules is the acting head of the 

NTP Biomolecular Screening Branch and serves as the NTP lead 

for the multiagency Tox21 program. Over the next 5 years, Tox21 

scientists will concentrate on new and emerging alternatives, 

including computational models and 3D, organ-like model systems. 

Such alternatives could help address challenges for highthroughput screening, which include processing volatile chemicals 

and predicting dose-response relationships. Other priorities include 

incorporating individual variability, dose-response characteristics, 

and pharmacokinetics. 

A new fact sheet captures milestones from the first decade of 

Tox21, including the more than 200 peer-reviewed articles 

published by the Tox21 researchers. Many of those papers shared 

results of robotic high-throughput screening assays of nearly 

10,000 chemicals, performed at the National Center for Advancing 

Translational Science. These chemicals, referred to as the Tox21 

library, are used in consumer products, industrial processes, 

agriculture, and drug development. Managing this library is a key 

Tox21 priority for the coming years.

Four federal agencies share the achievements of Tox21: 

1. National Toxicology Program headquartered at NIEHS

2. Environmental Protection Agency

3. National Center for Advancing Translational Sciences

4. U.S. Food and Drug Administration
2017 Annual Report – FY 2017 Glance – Regulatory Impact 

22

NTP Public Health Impact on Regulatory Agencies

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

need to regulate and test specific chemicals for the protection of human health. The NTP data and 

recommendations used by other agencies in FY 2017 are listed below. A full listing is available on the 

NTP website.

Use of NTP Study Data or Recommendations by Federal and State 

Regulatory Agencies in FY 2017

Notice Summary of Notice NTP Information Cited

Chemical Listed as Known to 

the State of California to 

Cause Cancer: 

Pentabromodiphenyl Ether 

Mixture [DE-71 (technical 

grade)]

[Effective Date: July 7, 2017]

The California Office of Environmental Health 

Hazard Assessment (OEHHA) added 

pentabromodiphenyl ether mixture [DE-71 

(technical grade)] to the list of chemicals known 

to cause cancer under the “authoritative 

bodies” mechanism. 

July 7, 2017 -- Proposition 65

The listing of pentabromodiphenyl ether 

mixture [DE-71 (technical grade)] is 

based on formal ident(ification by the 

NTP, an authoritative body, that the 

chemical causes cancer. (see NTP 

Technical Report 589).

Notice of Amendment to 

Section 25705, No 

Significant Risk Level for 

Styrene

[Effective Date: July 1, 2017]

On May 4, 2017, the Office of Administrative 

Law approved the amendment of Title 27, 

California Code of Regulations, section 25705, 

No Significant Risk Level (NSRL) to establish a 

No Significant Risk Level of 27 micrograms per 

day for the chemical styrene. 

May 11, 2017 -- Proposition 65

NTP (2011). Report on Carcinogens, 

12th Edition, U.S. Department of Health 

and Human Services, Public Health 

Service, NTP, Research Triangle Park, 

North Carolina. NTP is designated an 

authoritative body for identifying 

chemicals that cause cancer.

Amendment to Section 

25805, Maximum Allowable 

Dose Level (Oral) for 

Ethylene Glycol (Ingested)

[Effective Date: July 1, 2017]

On April 4, 2017, the Office of Administrative 

Law approved the amendment of Title 27, 

California Code of Regulations, section 25805, 

Maximum Allowable Dose Level (MADL) to 

establish a MADL of 8,700 (oral) micrograms 

per day for the chemical ethylene glycol 

(ingested). 

April 6, 2017 -- Proposition 65

NTP (2004). NTP-CERHR Monograph 

on the Potential Human Reproductive 

and Developmental Effects of Ethylene 

Glycol. NTP CERHR MON. 2004 Jan;

(11):1-III36. PubMed PMID: 16015391.

Final Rule: Oxytetracycline; 

Pesticide Tolerances for 

Emergency Exemptions

This regulation establishes a time-limited 

tolerance for residues of oxytetracycline in or 

on fruit, citrus, or crop group 10-10. This action, 

in response to the Environmental Protection 

Agency’s (EPA’s) granting of an emergency 

exemption for the use of oxytetracycline in or 

on fruit, citrus, or crop group 10-10 under the 

Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA) authorizing use of the 

pesticide in citrus production, established a 

time-limited maximum permissible level for 

residues of oxytetracycline in or on 

commodities in this crop group. The timelimited tolerance expires on December 31, 

2019.

March 10, 2017 -- 82 FR 13245

Based upon a literature search of toxicity 

in animals and the weight of the 

evidence as a whole, EPA has classified 

oxytetracycline as a “Group D” 

carcinogen (“Not Classifiable as to 

Human Carcinogenicity”). A review of the 

same animal toxicity data by the NTP 

Peer Review Committee was in 

agreement with this classification. 

Therefore, a dietary exposure 

assessment for the purpose of assessing 

cancer risk is unnecessary and was not 

conducted. (see NTP Technical Report 

315).
2017 Annual Report – FY 2017 Glance – Regulatory Impact 

23

Notice Summary of Notice NTP Information Cited

Final Rule: Formaldehyde 

Emission Standards for 

Composite Wood Products

EPA issued a final rule to implement the 

Formaldehyde Standards for Composite Wood 

Products Act, which added Title VI to the Toxic 

Substances Control Act (TSCA). The purpose 

of TSCA Title VI is to reduce formaldehyde 

emissions from composite wood products, 

which will reduce exposures to formaldehyde 

and result in benefits from avoided adverse 

health effects. This final rule also establishes a 

third-party certification program for hardwood 

plywood, medium-density fiberboard, and 

particleboard and includes procedures for the 

accreditation of third-party certifiers and 

general requirements for accreditation bodies 

and third-party certifiers.

December 12, 2016 -- 81 FR 89674

NTP (2014). Report on Carcinogens, 

13th Edition, U.S. Department of Health 

and Human Services, Public Health 

Service, NTP, Research Triangle Park, 

North Carolina. NTP is designated an 

authoritative body for identifying 

chemicals that cause cancer.

Chemical Listed as Known to 

the State of California to 

Cause Cancer: 

Pentachlorophenol and ByProducts of its Synthesis 

(Complex Mixture)

[Effective Date: October 21, 

2016]

Effective October 21, 2016, OEHHA is adding 

pentachlorophenol and by-products of its 

synthesis (complex mixture) to the list of 

chemicals known to the state to cause cancer.

October 21, 2016 -- Proposition 65

NTP (2014). Report on Carcinogens, 

13th Edition, U.S. Department of Health 

and Human Services, Public Health 

Service, NTP, Research Triangle Park, 

North Carolina. NTP is designated an 

authoritative body for identifying 

chemicals that cause cancer.

*CASRN = Chemical Abstracts Service Registry Number
2017 Annual Report – FY 2017 Glance – Additional Activities 

24

Additional Activities

During FY 2017, NTP participated in several meetings with 

stakeholders and the scientific community. At the 2017 annual 

meeting of the Society of Toxicology in Baltimore, Maryland, staff 

from NTP and NIEHS participated in numerous workshops, 

symposia, platform sessions, education and information sessions, 

and poster sessions. The full program, including all NTP and 

NIEHS activities, can be found at the Society of Toxicology

website. NTP Director Linda Birnbaum received the Distinguished 

Toxicology Scholar award at the 2017 meeting. 

NTP regularly hosts symposiums and workshops to discuss the 

state of the science or issues of public health concern. For 

example, NTP held “Pathology Potpourri,” an annual satellite 

symposium, in Montreal, Canada the day before the 2017 Society 

of Toxicologic Pathology meeting. The symposium’s goal is to 

present current diagnostic pathology or nomenclature issues to the 

toxicological pathology community. Proceedings will be published 

in the journal, “Toxicologic Pathology,” including summaries of 

presentations and images of specific pathologies that were used for 

audience voting and discussion on specific diagnostic and 

nomenclature issues.

NTP also hosted three workshop and webinar series in FY 2017 

related to alternative methods development:

Birnbaum said it was especially 

meaningful to accept the Distinguished 

Toxicology Scholar award because it 

represents recognition from her peers in 

toxicology.

(Photo courtesy of SOT)

• BioMed21 – A Human Pathway-based Approach to Disease

and Medicine.

• Using Informatics to Improve Data Analysis of Chemical

Screening Assays Conducted in Zebrafish.

• Incorporating Chemical Information: Resources, Limitations,

and Characterizing the Domain of Applicability for 21st

Century Toxicity Testing.
2017 Annual Report – FY 2017 Glance – Publications 

25

Publications

NTP Reports and Documents

Morgan, DL, Dixon, D, King, DH, Travlos, GS, Herbert, RA, French, JE, Tokar, EJ, Waalkes, MP, 

Jokinen, MP. 2017. NTP Research Report on Absence of Formaldehyde-Induced Neoplasia in Trp53 

Haploinsufficient Mice Exposed by Inhalation. NTP RR 3. Research Triangle Park, NC: National 

Toxicology Program. (3): 1-30. https://ntp.niehs.nih.gov/ntp/results/pubs/rr/reports/rr03_508.pdf.

NTP Technical Report on the Toxicity Studies of o-Chloropyridine Administered Dermally and in 

Drinking Water to F344/N Rats and B6C3F1/N Mice. Research Triangle Park (NC): National 

Toxicology Program. Natl Toxicol Program Tox Rep Ser. 2017 Feb;(83):1-55; 

https://ntp.niehs.nih.gov/ntp/htdocs/st_rpts/tox83_508.pdf.

NTP Technical Report on the Toxicity Studies of Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) 

Administered by Gavage to F344/NTac Rats and B6C3F1/N Mice. Research Triangle Park (NC): 

National Toxicology Program. Natl Toxicol Program Tox Rep Ser. 2017 Aug;(85):1-43; 

https://ntp.niehs.nih.gov/ntp/htdocs/st_rpts/tox085_508.pdf.

NTP Technical Report on the Toxicology Studies of Indole-3-Carbinol in F344/N Rats and B6C3F1/N 

Mice and Toxicology and Carcinogenesis Studies of Indole-3-Carbinol in Harlan Sprague Dawley 

Rats and B6C3F1/N Mice (Gavage Studies). Research Triangle Park (NC): National Toxicology 

Program. Natl Toxicol Program Tox Rep Ser. 2017 Jul;(584):1-199; 

https://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr584_508.pdf.

NTP Technical Report on the Toxicology and Carcinogenesis Studies of TRIM® VX in Wistar Han 

[Crl:WI (Han)] Rats and B6C3F1/N Mice (Inhalation Studies). Research Triangle Park (NC): National 

Toxicology Program. Natl Toxicol Program Tox Rep Ser. 2016 Nov;(591):1-186; 

https://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr591_508.pdf. 

Journal Articles and Book Chapters

Research funding sources for each publication are indicated as follows:

[1] Funded by the NIEHS/NIOSH Interagency Agreement

[2] Funded by NIOSH voluntary allocations to the NTP

[3] Funded by the NIEHS/NCTR Interagency Agreement

[4] Funded by NCTR voluntary allocations to the NTP

[5] Funded by NIEHS voluntary allocations to the NTP

Alenius H, Shurin MR, Shurin GV, Beezhold D, Shvedova AA. 2017. Respiratory system, part two: 

Allergy and asthma. Adverse Effects of Engineered Nanomaterials: Exposure, Toxicology, and Impact 

on Human Health: Second Edition. p. 243-253. https://doi.org/10.1016/B978-0-12-809199-9.00010-0

[2]

Alves VM, Capuzzi SJ, Muratov EN, Braga RC, Thornton TE, Fourches D, Strickland J, Kleinstreuer 

N, Andrade CH, Tropsha A. 2016. QSAR models of human data can enrich or replace LLNA testing 

for human skin sensitization. Green Chemistry. 18(24):6501-6515. https://doi.org/10.1039/c6gc01836j

[5]

Anderson JL, Apostoaei AI, Yiin JH, Tseng CY. 2017. Exposure to recycled uranium contaminants in 

gaseous diffusion plants. Radiation Protection Dosimetry. 175(4):503-507. 

https://doi.org/10.1093/rpd/ncw379 [2]
2017 Annual Report – FY 2017 Glance – Publications 

26

Aragon MJ, Topper L, Tyler CR, Sanchez B, Zychowski K, Young T, Herbert G, Hall P, Erdely A, Eye 

T, Bishop L, Saunders S, Muldoon P, Ottens A, Campen M. 2017. Serum-borne bioactivity caused 

by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood-brain barrier 

impairment. Proceedings of the National Academy of Sciences of the United States of America. 

114(10):e1968-e1976. https://doi.org/10.1073/pnas.1616070114 [2]

Arnold KM, Capuzzi SJ, Xu Y, Muratov EN, Carrick K, Szajek AY, Tropsha A, Liu J. 2017. 

Modernization of enoxaparin molecular weight determination using homogeneous standards. 

Pharmaceuticals (Basel, Switzerland). 10(3). https://doi.org/10.3390/ph10030066 [5]

Avdoshina V, Caragher SP, Wenzel ED, Taraballi F, Mocchetti I, Harry GJ. 2017. The viral protein 

gp120 decreases the acetylation of neuronal tubulin: Potential mechanism of neurotoxicity. Journal of 

Neurochemistry. 141(4):606-613. https://doi.org/10.1111/jnc.14015 [5]

Azzam KM, Madenspacher JH, Cain DW, Lai L, Gowdy KM, Rai P, Janardhan K, Clayton N, 

Cunningham W, Jensen H et al. 2017. IRGM1 coordinately regulates autoimmunity and host defense 

at select mucosal surfaces. JCI Insight. 2(16). https://doi.org/10.1172/jci.insight.91914 [5]

Bartley D, Slaven J, Harper M. 2017. Confidence intervals for asbestos fiber counts: Approximate 

negative binomial distribution. Annals of Work Exposures and Health. 61(2):237-247. 

https://doi.org/10.1093/annweh/wxw020 [2]

Beard JD, Steege AL, Ju J, Lu J, Luckhaupt SE, Schubauer-Berigan MK. 2017. Mortality from 

amyotrophic lateral sclerosis and Parkinson's disease among different occupation groups - United 

States, 1985-2011. MMWR-Morbidity and Mortality Weekly Report. 66(27):718-722. 

http://dx.doi.org/10.15585/mmwr.mm6627a2 [2]

Behl M, Rice JR, Smith MV, Co CA, Bridge MF, Hsieh JH, Freedman JH, Boyd WA. 2016. Editor's 

highlight: Comparative toxicity of organophosphate flame retardants and polybrominated diphenyl 

ethers to Caenorhabditis elegans. Toxicological Sciences: An Official Journal of the Society of 

Toxicology. 154(2):241-252. https://doi.org/10.1093/toxsci/kfw162 [5]

Bell SM, Phillips J, Sedykh A, Tandon A, Sprankle C, Morefield SQ, Shapiro A, Allen D, Shah R, 

Maull EA et al. 2017. An integrated chemical environment to support 21st-century toxicology. 

Environmental Health Perspectives. 125(5):054501. https://doi.org/10.1289/ehp1759 [5]

Birnbaum LS. 2016. Early life contributions to breast cancer risk. Toxicology Letters. 259:S59-S59. 

https://doi.org/10.1016/j.toxlet.2016.07.144 [5]

Birnbaum LS. 2017. Updating the NIEHS strategic plan. Environmental Health Perspectives. 125(7). 

https://doi.org/10.1289/ehp2502 [5]

Bishop L, Cena L, Orandle M, Yanamala N, Dahm MM, Birch ME, Evans DE, Kodali VK, Eye T, 

Battelli L et al. 2017. In vivo toxicity assessment of occupational components of the carbon nanotube 

life cycle to provide context to potential health effects. ACS Nano. 11(9):8849-8863. 

https://doi.org/10.1021/acsnano.7b03038 [2]

Boobis A, Cerniglia C, Chicoine A, Fattori V, Lipp M, Reuss R, Verger P, Tritscher A. 2017. 

Characterizing chronic and acute health risks of residues of veterinary drugs in food: Latest

methodological developments by the joint FAO/WHO expert committee on food additives. Critical 

Reviews in Toxicology.1-15. https://doi.org/10.1080/10408444.2017.1340259 [4]

Boudreau MD, Beland FA, Felton RP, Fu PP, Howard PC, Mellick PW, Thorn BT, Olson GR. 2017. 

Photo-co-carcinogenesis of topically applied retinyl palmitate in SKH-1 hairless mice. Photochemistry

and photobiology. 93(4):1096-1114. https://doi.org/10.1111/php.12730 [4]

Boudreau MD, Olson GR, Tryndyak VP, Bryant MS, Felton RP, Beland FA. 2017. From the cover: 

Aloin, a component of the Aloe vera plant leaf, induces pathological changes and modulates the 
2017 Annual Report – FY 2017 Glance – Publications 

27

composition of microbiota in the large intestines of F344/N male rats. Toxicological Sciences: An 

Official Journal of the Society of Toxicology. 158(2):302-318. https://doi.org/10.1093/toxsci/kfx105 [3]

Bower JJ, Vance LD, Psioda M, Smith-Roe SL, Simpson DA, Ibrahim JG, Hoadley KA, Perou CM, 

Kaufmann WK. 2017. Patterns of cell cycle checkpoint deregulation associated with intrinsic 

molecular subtypes of human breast cancer cells. NPJ Breast Cancer. 3:9. 

https://doi.org/10.1038/s41523-017-0009-7 [5]

Boyles AL, Blain RB, Rochester JR, Avanasi R, Goldhaber SB, McComb S, Holmgren SD, Masten 

SA, Thayer KA. 2017. Systematic review of community health impacts of mountaintop removal 

mining. Environment International. 107:163-172. https://doi.org/10.1016/j.envint.2017.07.002 [5]

Braga RC, Alves VM, Muratov EN, Strickland J, Kleinstreuer N, Trospsha A, Andrade CH. 2017. 

Pred-skin: A fast and reliable web application to assess skin sensitization effect of chemicals. Journal 

of Chemical Information and Modeling. 57(5):1013-1017. https://doi.org/10.1021/acs.jcim.7b00194 [5]

Brass DM, Gwinn WM, Valente A, Kelly FL, Brinkley C, Nagler A, Moseley A, Morgan DL, Palmer SM, 

Foster MW. 2016. Artificial butter flavoring exposure causes an extracellular matrix reorganizing 

proteomic signature in primary human airway epithelial cells. American Journal of Respiratory and 

Critical Care Medicine. 193. https://www.atsjournals.org/doi/abs/10.1164/ajrccmconference.2016.193.1_MeetingAbstracts.A5901 [5]

Brass DM, Gwinn WM, Valente AM, Kelly FL, Brinkley CD, Nagler AE, Moseley MA, Morgan DL, 

Palmer SM, Foster MW. 2017. The diacetyl-exposed human airway epithelial secretome: New

insights into flavoring-induced airways disease. American Journal of Respiratory Cell and Molecular 

Biology. 56(6):784-795. https://doi.org/10.1165/rcmb.2016-0372OC [5]

Brass DM, Kelly FL, Gwinn WM, Brinkley C, Nagler A, Morgan DL, Foster MW, Palmer SM. 2016. 

Synthesis of a cross-linked hyaluronan matrix by the airway epithelium in experimental bronchiolitis 

obliterans. American Journal of Respiratory and Critical Care Medicine. 193. 

http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2016.193.1_MeetingAbstracts.A4117

[5]

Brenner SA, Neu-Baker NM, Eastlake AC, Beaucham CC, Geraci CL. 2016. NIOSH field studies 

team assessment: Worker exposure to aerosolized metal oxide nanoparticles in a semiconductor 

fabrication facility. Journal of Occupational and Environmental Hygiene. 13(11):871-880. 

https://doi.org/10.1080/15459624.2016.1183015 [2]

Browne P, Noyes PD, Casey WM, Dix DJ. 2017. Application of adverse outcome pathways to U.S. 

EPA's Endocrine Disruptor Screening Program. Environmental Health Perspectives. 125(9):096001. 

https://doi.org/10.1289/ehp1304 [5]

Bryce SM, Bernacki D, Bemis J, Dertinger S, Witt KL, Smith-Roe SL. 2017. Comprehensive in vitro 

genotoxic mode of action determination using a one step multiplexed kit, and a machine learning 

strategy. Environmental and Molecular Mutagenesis. 58:S51-S51. https://doi.org/10.1002/em.22135

[5]

Bucher JR, Birnbaum LS. 2016. Commemorating toxicology at the National Institute of Environmental 

Health Sciences on the occasion of its 50th anniversary. Environmental Health Perspectives. 

124(11):A192-a195. https://doi.org/10.1289/ehp463 [5]

Catlin NR, Herbert R, Janardhan K, Hejtmancik MR, Fomby LM, Vallant M, Kissling GE, DeVito MJ. 

2016. Dose-response assessment of the dermal toxicity of Virginia cedarwood oil in F344/N rats and 

B6C3F1/N mice. Food and Chemical Toxicology: An International Journal Published for the British 

Industrial Biological Research Association. 98(Pt B):159-168. https://doi.org/10.1016/j.fct.2016.10.016

[5]
2017 Annual Report – FY 2017 Glance – Publications 

28

Catlin NR, Willson CJ, Stout M, Kissling GE, Waidyanatha S, Baker GL, Hayden BK, Wyde M. 2017. 

Evaluation of the respiratory tract toxicity of ortho-phthalaldehyde, a proposed alternative for the 

chemical disinfectant glutaraldehyde. Inhalation Toxicology. 29(9):414-427. 

https://doi.org/10.1080/08958378.2017.1390015 [5]

Ceger P, Allen D, Huang RL, Xia MH, Casey W. 2016. Performance of the BG1Luc ER TA method in 

a qHTS format (vol 32, pg 287, 2015). Altex-Alternatives to Animal Experimentation. 33(1):79-79. 

https://doi.org/10.14573/altex.1512041 [5]

Chen VS, Morrison JP, Southwell MF, Foley JF, Bolon B, Elmore SA. 2017. Histology atlas of the 

developing prenatal and postnatal mouse central nervous system, with emphasis on prenatal days 

E7.5 to E18.5. Toxicologic Pathology. 45(6):705-744. https://doi.org/10.1177/0192623317728134 [5]

Chen X, Han T, Fisher JE, Harrouk W, Tassinari MS, Merry GE, Sloper D, Fuscoe JC, Hansen DK, 

Inselman AL. 2017. Transcriptomics analysis of early embryonic stem cell differentiation under 

osteoblast culture conditions: Applications for detection of developmental toxicity. Reproductive 

Toxicology (Elmsford, NY). 69:75-83. https://doi.org/10.1016/j.reprotox.2017.02.001 [4]

Cheng HN, Doemeny LJ, Geraci CL, Schmidt DG. 2016. Nanotechnology overview: Opportunities

and challenges. In: Cheng HN, Doemeny L, Geraci CL, Schmidt DG, editors. Nanotechnology: 

Delivering on the Promise, Vol 1. p. 1-12. https://doi.org/10.1021/bk-2016-1220.ch001 [2]

Chitranshi P, Gamboa da Costa G. 2016. Simple and rapid quantification of brominated vegetable oil 

in commercial soft drinks by LC-MS. Food Chemistry. 213:567-570. 

https://doi.org/10.1016/j.foodchem.2016.06.110 [3]

Cichocki JA, Furuya S, Konganti K, Luo YS, McDonald TJ, Iwata Y, Chiu WA, Threadgill DW, 

Pogribny IP, Rusyn I. 2017. Impact of nonalcoholic fatty liver disease on toxicokinetics of 

tetrachloroethylene in mice. The Journal of Pharmacology and Experimental Therapeutics. 361(1):17-

28. https://doi.org/10.1124/jpet.116.238790 [4]

Cichocki JA, Furuya S, Luo YS, Iwata Y, Konganti K, Chiu WA, Threadgill DW, Pogribny IP, Rusyn I. 

2017. Nonalcoholic fatty liver disease is a susceptibility factor for perchloroethylene-induced liver 

effects in mice. Toxicological Sciences: An Official Journal of the Society of Toxicology. 159(1):102-

113. https://doi.org/10.1093/toxsci/kfx120 [4]

Coombs K, Taft D, Ward DV, Green BJ, Chew GL, Shamsaei B, Meller J, Indugula R, Reponen T. 

2018. Variability of indoor fungal microbiome of green and non-green low-income homes in 

Cincinnati, Ohio. The Science of the Total Environment. 610-611:212-218. 

https://doi.org/10.1016/j.scitotenv.2017.07.274 [2]

Cora MC, Gwinn W, Wilson R, King D, Waidyanatha S, Kissling GE, Brar SS, Olivera D, Blystone C, 

Travlos G. 2017. A black cohosh extract causes hematologic and biochemical changes consistent 

with a functional cobalamin deficiency in female B6C3F1/N mice. Toxicologic Pathology. 45(5):614-

623. https://doi.org/10.1177/0192623317714343 [5]

Cox-Ganser JM, Park JH, Roseman J, Game S. 2017. Asthma and asthma symptoms in teachers in 

50 elementary schools in a large city. American Journal of Respiratory and Critical Care Medicine. 

195. 

http://gateway.isiknowledge.com/gateway/Gateway.cgi?&GWVersion=2&SrcAuth=CustomerName&S

rcApp=CustomerName&DestLinkType=FullRecord&DestApp=WOS&KeyUT=000400372501206 [2]

Crawford NM, Fenton SE, Strynar M, Hines EP, Pritchard DA, Steiner AZ. 2017. Effects of 

perfluorinated chemicals on thyroid function, markers of ovarian reserve, and natural fertility. 

Reproductive Toxicology (Elmsford, NY). 69:53-59. https://doi.org/10.1016/j.reprotox.2017.01.006 [5]
2017 Annual Report – FY 2017 Glance – Publications 

29

Croston TL, Nayak AP, Lemons AR, Goldsmith WT, Germolec DM, Beezhold DH, Green BJ. 2017. 

Pulmonary immune response following subchronic Stachybotrys chartarum exposure. Journal of 

Allergy and Clinical Immunology. 139(2):AB75-AB75. https://doi.org/10.1016/j.jaci.2016.12.291 [5]

Croston TL, Nayak AP, Lemons AR, Goldsmith WT, Germolec DM, Beezhold DH, Green BJ. 2017. 

Pulmonary immune response following subchronic Stachybotrys chartarum exposure. Journal of 

Allergy and Clinical Immunology. 139(2):AB75-AB75. https://doi.org/10.1016/j.jaci.2016.12.291 [1]

Croston TL, Nayak AP, Lemons AR, Goldsmith WT, Gu JK, Germolec DR, Beezhold DH, Green BJ. 

2016. Influence of Aspergillus fumigatus conidia viability on murine pulmonary microRNA and mRNA 

expression following subchronic inhalation exposure. Clinical and Experimental Allergy. 46(10):1315-

1327. https://doi.org/10.1111/cea.12783 [5]

Daniels RD, Bertke SJ, Richardson DB, Cardis E, Gillies M, O'Hagan JA, Haylock R, Laurier D, 

Leuraud K, Moissonnier M et al. 2017. Examining temporal effects on cancer risk in the international 

nuclear workers' study. Int J Cancer. 140(6):1260-1269. https://doi.org/10.1002/ijc.30544 [2]

de Conti A, Beland FA, Pogribny IP. 2017. The role of epigenomic alterations in furan-induced 

hepatobiliary pathologies. Food and Chemical Toxicology: An International Journal Published for the 

British Industrial Biological Research Association. 109(Pt 1):677-682. 

https://doi.org/10.1016/j.fct.2017.07.049 [3]

de Conti A, Dreval K, Tryndyak V, Orisakwe OE, Ross SA, Beland FA, Pogribny IP. 2017. Inhibition of 

the cell death pathway in nonalcoholic steatohepatitis (NASH)-related hepatocarcinogenesis is 

associated with histone H4 lysine 16 deacetylation. Molecular Cancer Research: MCR. 15(9):1163-

1172. https://doi.org/10.1158/1541-7786.mcr-17-0109 [4]

de Conti A, Ortega JF, Tryndyak V, Dreval K, Moreno FS, Rusyn I, Beland FA, Pogribny IP. 2017. 

MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis. Oncotarget. 

8(51):88517-88528. https://doi.org/10.18632/oncotarget.19774 [4]

de Conti A, Tryndyak V, Doerge DR, Beland FA, Pogribny IP. 2016. Irreversible down-regulation of 

miR-375 in the livers of Fischer 344 rats after chronic furan exposure. Food and Chemical Toxicology: 

An International Journal Published for the British Industrial Biological Research Association. 98(Pt 

A):2-10. https://doi.org/10.1016/j.fct.2016.06.027 [3]

Ding M, Barber T, Aldinger J, Bowman L, Meighan T, Zhao JS. 2017. Induction of transformation by 

freshly fractured silica in JB6 and BEAS-2B cells. Faseb Journal. 31. 

http://www.fasebj.org/content/31/1_Supplement/982.1.abstract?sid=66518393-7d0e-4577-881ef03d3d2446ad [2]

Dobrovolsky VN, Revollo J, Petibone DM, Heflich RH. 2017. In vivo rat T-Lymphocyte Pig-a Assay: 

Detection and expansion of cells deficient in the GPI-anchored CD48 surface marker for analysis of 

mutation in the endogenous Pig-a gene. Methods in Molecular Biology (Clifton, NJ). 1641:143-160. 

https://doi.org/10.1007/978-1-4939-7172-5_7 [4]

Dreval K, de Conti A, Furuya S, Beland FA, Rusyn I, Pogribny IP. 2017. miR-1247 blocks SOX9-

mediated regeneration in alcohol- and fibrosis-associated acute kidney injury in mice. Toxicology. 

384:40-49. https://doi.org/10.1016/j.tox.2017.03.004 [4]

Dunnick JK, Morgan DL, Elmore SA, Gerrish K, Pandiri A, Ton TV, Shockley KR, Merrick BA. 2017. 

Tetrabromobisphenol A activates the hepatic interferon pathway in rats. Toxicology Letters. 266:32-

41. https://doi.org/10.1016/j.toxlet.2016.11.019 [5]

Ellis-Hutchings RG, Settivari RS, McCoy AT, Kleinstreuer N, Franzosa J, Knudsen TB, Carney EW. 

2017. Embryonic vascular disruption adverse outcomes: Linking high throughput signaling signatures 

with functional consequences. Reproductive Toxicology (Elmsford, NY). 70:82-96. 

https://doi.org/10.1016/j.reprotox.2017.05.005 [5]
30

2017 Annual Report – FY 2017 Glance – Publications

Elmore SA. 2016. Book review: Atlas of histology of the juvenile rat Toxicologic pathology.

44(8):1170. https://doi.org/10.1177/0192623316677069 [5]

Elmore SA, Aeffner F, Bangari DS, Crabbs TA, Fossey S, Gad SC, Haschek WM, Hoane JS,

Janardhan K, Kovi RC et al. 2017. Proceedings of the 2017 National Toxicology Program satellite 

symposium. Toxicologic Pathology. 45(7):799-833. https://doi.org/10.1177/0192623317733924 [5]

Elmore SA, Chen VS, Hayes-Bouknight S, Hoane JS, Janardhan K, Kooistra LH, Nolte T, Szabo KA,

Willson GA, Wolf JC et al. 2017. Proceedings of the 2016 National Toxicology Program satellite 

symposium. Toxicologic Pathology. 45(1):11-51. https://doi.org/10.1177/0192623316672074 [5]

Estill CF, Rice CH, Morata T, Bhattacharya A. 2017. Noise and neurotoxic chemical exposure 

relationship to workplace traumatic injuries: A review. Journal of Safety Research. 60:35-42. 

https://doi.org/10.1016/j.jsr.2016.11.005. [2] 

Falcone LM, Erdely A, Meighan TG, Battelli LA, Salmen R, McKinney W, Stone S, Cumpston A,

Cumpston J, Andrews RN et al. 2017. Inhalation of gas metal arc-stainless steel welding fume 

promotes lung tumorigenesis in A/J mice. Archives of Toxicology. 91(8):2953-2962.

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Fang T, Zeng L, Gao D, Verma V, Stefaniak AB, Weber RJ. 2017. Ambient size distributions and lung

deposition of aerosol dithiothreitol-measured oxidative potential: Contrast between soluble and 

insoluble particles. Environmental Science & Technology. 51(12):6802-6811.

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Farcas D, Harper M, Januch JW, Jacobs TA, Sarkisian K, Stetler LD, Schwegler-Berry D. 2017.

Evaluation of fluidized bed asbestos segregator to determine erionite in soil. Environmental Earth 

Sciences. 76(3). https://doi.org/10.1007/s12665-017-6438-7 [2]

Farris BY, Antonini JM, Fedan JS, Mercer RR, Roach KA, Chen BT, Schwegler-Berry D, Kashon ML,

Barger MW, Roberts JR. 2017. Pulmonary toxicity following acute coexposures to diesel particulate 

matter and alpha-quartz crystalline silica in the Sprague-Dawley rat. Inhalation Toxicology. 29(7):322-

339. https://doi.org/10.1080/08958378.2017.1361487 [2]

Farris BY, Fedan JS, Mercer RR, Chen BT, Roberts JR. 2016. Repeated co-exposure to diesel

exhaust particulate and crystalline silica in rats. American Journal of Respiratory and Critical Care 

Medicine. 193. https://www.atsjournals.org/doi/abs/10.1164/ajrccmconference.2016.193.1_MeetingAbstracts.A5407 [2]

Farris S, Wang Y, Ward JM, Dudek SM. 2017. Optimized method for robust transcriptome profiling of

minute tissues using laser capture microdissection and Low-Input RNA-Seq. Frontiers in Molecular

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Fedan JS, Thompson JA, Meighan TG, Zeidler-Erdely PC, Antonini JM. 2017. Altered ion transport in 

normal human bronchial epithelial cells following exposure to chemically distinct metal welding fume 

particles. Toxicology and Applied Pharmacology. 326:1-6. https://doi.org/10.1016/j.taap.2017.04.008

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Fedan JS, Thompson JA, Russ KA, Newcomer D, McKinney W, Cumpston AM, Jackson MC,

Reynolds JS. 2017. In vivo and in vitro effects of work site fracking sand dust (FSD) inhalation on rat

lung: Dose- and time-response evaluation. Faseb Journal. 31.

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Felton RP, Juliar BE, Olson GR, Delclos KB. 2017. A comment on the discussion and application of

statistical methods in Mandrup et al. Low-dose effects of bisphenol A on mammary gland 

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31

Ferguson SA, Panos JJ, Sloper D, Varma V. 2017. Neurodegenerative markers are increased in 

postmortem BA21 tissue from African Americans with Alzheimer's disease. Journal of Alzheimer’s 

Disease: JAD. 59(1):57-66. https://doi.org/10.3233/jad-170204 [4]

Ferrucio B, Tiago M, Fannin RD, Liu L, Gerrish K, Maria-Engler SS, Paules RS, Barros SB. 2017. 

Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human 

melanocytes. Toxicology in Vitro: An International Journal Published in Association With BIBRA. 

38:67-76. https://doi.org/10.1016/j.tiv.2016.11.005 [5]

Fessler MB, Carnes MU, Salo PM, Wilkerson J, Cohn RD, King D, Hoppin JA, Sandler DP, Travlos G, 

London SJ et al. 2017. House dust endotoxin and peripheral leukocyte counts: Results from two large 

epidemiologic studies. Environmental Health Perspectives. 125(5):057010. 

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Flake GP, Morgan DL. 2017. Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat 

model of obliterative bronchiolitis. Toxicology. 388:40-47. https://doi.org/10.1016/j.tox.2016.10.013 [5]

Fleck SC, Churchwell MI, Doerge DR. 2017. Metabolism and pharmacokinetics of zearalenone 

following oral and intravenous administration in juvenile female pigs. Food and Chemical Coxicology: 

An International Journal Published for the British Industrial Biological Research Association. 106(Pt 

A):193-201. https://doi.org/10.1016/j.fct.2017.05.048 [4]

Foster MW, Gwinn WM, Kelly FL, Brass DM, Thompson JW, Moseley MA, Morgan DL, Palmer SM. 

2016. Proteomic analysis reveals significant epithelial remodeling after in vitro exposure to diacetyl 

vapor. American Journal of Respiratory and Critical Care Medicine. 193. 

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Foster MW, Gwinn WM, Kelly FL, Brass DM, Valente AM, Moseley MA, Thompson JW, Morgan DL, 

Palmer SM. 2017. Proteomic analysis of primary human airway epithelial cells exposed to the 

respiratory toxicant diacetyl. Journal of Proteome Research. 16(2):538-549. 

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Foster MW, Thompson JW, Brass DM, Moseley MA, Morgan DL, Palmer SM. 2016. Plasma 

metabolomics analysis identifies candidate biomarkers of flavoring-induced bronchiolitis obliterans. 

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Foster PM. 2017. Influence of study design on developmental and reproductive toxicology study 

outcomes. Toxicologic Pathology. 45(1):107-113. https://doi.org/10.1177/0192623316671608 [5]

Fu PP, Xia Q, He X, Barel S, Edery N, Beland FA, Shimshoni JA. 2017. Detection of pyrrolizidine 

alkaloid DNA adducts in livers of cattle poisoned with Heliotropium europaeum. Chemical Research in 

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Funderburk KM, Auerbach SS, Bushel PR. 2017. Crosstalk between receptor and non-receptor 

mediated chemical modes of action in rat livers converges through a dysregulated gene expression 

network at tumor suppressor Tp53. Frontiers in Genetics. 8:157. 

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Ganini D, Leinisch F, Kumar A, Jiang J, Tokar EJ, Malone CC, Petrovich RM, Mason RP. 2017. 

Fluorescent proteins such as eGFP lead to catalytic oxidative stress in cells. Redox Biology. 12:462-

468. https://doi.org/10.1016/j.redox.2017.03.002 [5]

Gao L, Mutlu E, Collins LB, Walker NJ, Hartwell HJ, Olson JR, Sun W, Gold A, Ball LM, Swenberg 

JA. 2017. DNA product formation in female Sprague-Dawley rats following polyhalogenated aromatic 
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hydrocarbon (PHAH) exposure. Chemical Research in Toxicology. 30(3):794-803. 

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Gao Y, Cao Z, Yang X, Abdelmegeed MA, Sun J, Chen S, Beger RD, Davis K, Salminen WF, Song 

BJ et al. 2017. Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of 

heme oxygenase 1 as a potential plasma biomarker of liver injury. Proteomics Clinical Aplications. 

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Garcia A, Eastlake A, Topmiller JL, Sparks C, Martinez K, Geraci CL. 2017. Nano-metal oxides: 

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14(9):727-737. https://doi.org/10.1080/15459624.2017.1326699 [2]

Germolec D, Luebke R, Rooney A, Shipkowski K, Vandebriel R, van Loveren H. 2017. 

Immunotoxicology: A brief history, current status and strategies for future immunotoxicity assessment. 

Current opinion in toxicology. 5:55-59. https://doi.org/10.1016/j.cotox.2017.08.002 [5]

Germolec DR, Nayak AP, Green BJ, Lemons AR, Croston TL, Goldsmith WT, Beezhold DH. 2016. 

Subchronic exposure to fungal spores promotes allergic pulmonary inflammation. Toxicology Letters. 

259:S26-S26. https://doi.org/10.1016/j.toxlet.2016.07.633 [5]

Gillies M, Richardson DB, Cardis E, Daniels RD, O'Hagan JA, Haylock R, Laurier D, Leuraud K, 

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Glazer L, Wells CN, Drastal M, Odamah KA, Galat RE, Behl M, Levin ED. 2017. Developmental 

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Gokulan K, Cerniglia CE, Thomas C, Pineiro SA, Khare S. 2017. Effects of residual levels of 

tetracycline on the barrier functions of human intestinal epithelial cells. Food and Chemical 

Toxicology: An International Journal Published for the British Industrial Biological Research 

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Gokulan K, Williams K, Khare S. 2017. Silver ion-mediated killing of a food pathogen: Melting curve 

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Goulding DR, White SS, McBride SJ, Fenton SE, Harry GJ. 2017. Gestational exposure to 

perfluorooctanoic acid (PFOA): Alterations in motor related behaviors. Neurotoxicology. 58:110-119. 

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Graham UM, Jacobs G, Yokel RA, Davis BH, Dozier AK, Birch ME, Tseng MT, Oberdorster G, Elder 

A, DeLouise L. 2017. From dose to response: In vivo nanoparticle processing and potential toxicity. 

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Grau-Perez M, Kuo CC, Spratlen M, Thayer KA, Mendez MA, Hamman RF, Dabelea D, Adgate JL, 

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Green BJ, Lemons AR, Park Y, Cox-Ganser JM, Park JH. 2017. Assessment of fungal diversity in a 

water-damaged office building. Journal of Occupational and Environmental Hygiene. 14(4):285-293. 

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Grego S, Dougherty ER, Alexander FJ, Auerbach SS, Berridge BR, Bittner ML, Casey W, Cooley PC, 

Dash A, Ferguson SS et al. 2017. Systems biology for organotypic cell cultures. Altex. 34(2):301-310. 

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Guo X, Dumas M, Robinson BL, Ali SF, Paule MG, Gu Q, Kanungo J. 2017. Acetyl L-carnitine targets

adenosine triphosphate synthase in protecting zebrafish embryos from toxicities induced by verapamil

and ketamine: An in vivo assessment. Journal of Applied Toxicology: JAT. 37(2):192-200.

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Guo X, Li Y, Yan J, Ingle T, Jones MY, Mei N, Boudreau MD, Cunningham CK, Abbas M, Paredes

AM et al. 2016. Size- and coating-dependent cytotoxicity and genotoxicity of silver nanoparticles

evaluated using in vitro standard assays. Nanotoxicology. 10(9):1373-1384.

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Gwinn WM, Flake GP, Bousquet RW, Taylor GJ, Morgan DL. 2017. Airway injury in an in vitro human 

epithelium-fibroblast model of diacetyl vapor exposure: diacetyl-induced basal/suprabasal spongiosis. 

Inhalation Toxicology. 29(7):310-321. https://doi.org/10.1080/08958378.2017.1369604 [5]

Hall JA, McElwee MK, Freedman JH. 2017. Identification of ATF-7 and the insulin signaling pathway

in the regulation of metallothionein in C. elegans suggests roles in aging and reactive oxygen 

species. PloS One. 12(6):e0177432. https://doi.org/10.1371/journal.pone.0177432 [5]

Hamilton RF, Jr., Tsuruoka S, Wu N, Wolfarth M, Porter DW, Bunderson-Schelvan M, Holian A. 2017.

Length, but not reactive edges, of cup-stack MWCNT is responsible for toxicity and acute lung

inflammation. Toxicologic Pathology.192623317732303. https://doi.org/10.1177/0192623317732303

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Hamm J, Sullivan K, Clippinger AJ, Strickland J, Bell S, Bhhatarai B, Blaauboer B, Casey W, Dorman 

D, Forsby A et al. 2017. Alternative approaches for identifying acute systemic toxicity: Moving from

research to regulatory testing. Toxicology in Vitro: An International Journal Published in Association

with BIBRA. 41:245-259. https://doi.org/10.1016/j.tiv.2017.01.004 [5]

Hanley KW, Andrews R, Bertke S, Ashley K. 2017. Exploring manganese fractionation using a

sequential extraction method to evaluate welders' gas metal arc welding exposures during heavy

equipment manufacturing. Annals of Work Exposures and Health. 61(1):123-134. 

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Hansen DK, Inselman AL, Yang X. 2016. Effects of culture conditions on maturation of stem cellderived cardiomyocytes. Stem Cells in Toxicology and Medicine. p. 71-84.

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Harper M, Dozier A, Chouinard J, Ray R. 2017. Analysis of erionites from volcaniclastic sedimentary 

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Harper M, Key-Schwartz RJ. 2017. Letter to the editor: Preparation of respirable crystalline silica

samples for subsequent analysis. Regulatory Toxicology and Pharmacology: RTP. 83:100-102.

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Harrill A, Gatti DM, Luo S, Lyn-Cook L, Churchill G. 2017. Identification of pharmacogenetic risk

factors for zileuton-induced liver injury using diversity outbred mice. Faseb Journal. 31.

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Harrill AH, Lin H, Tobacyk J, Seely JC. 2017. Mouse population-based evaluation of urinary protein 

and miRNA biomarker performance associated with cisplatin renal injury. Experimental Biology and 

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Harrill AH, McAllister KA. 2017. New rodent population models may inform human health risk 

assessment and identification of genetic susceptibility to environmental exposures. Environmental 

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Hart-Unger S, Arao Y, Hamilton KJ, Lierz SL, Malarkey DE, Hewitt SC, Freemark M, Korach KS. 

2017. Hormone signaling and fatty liver in females: Analysis of estrogen receptor α mutant mice. 

International Journal of Obesity. 41(6):945-954. https://doi.org/10.1038/ijo.2017.50 [5]

Hayes AW, Dixon D. 2017. Cornerstones of toxicology. Toxicologic Pathology. 45(1):57-63. 

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He X, Xia Q, Woodling K, Lin G, Fu PP. 2017. Pyrrolizidine alkaloid-derived DNA adducts are 

common toxicological biomarkers of pyrrolizidine alkaloid N-oxides. Journal of food and Drug 

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He Z, Cui L, Ferguson SA, Paule MG. 2017. A working module for the neurovascular unit in the 

sexually dimorphic nucleus of the preoptic area. Molecular Neurobiology. 

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Healy MJ, Tong W, Ostroff S, Eichler HG, Patak A, Neuspiel M, Deluyker H, Slikker W, Jr. 2016. 

Regulatory bioinformatics for food and drug safety. Regulatory Toxicology and Pharmacology: RTP. 

80:342-347. https://doi.org/10.1016/j.yrtph.2016.05.021 [4]

Henneberger PK, Humann MJ, Liang X, Stefaniak AB, LeBouf RF, Stanton ML, Virji MA. 2016. An 

evaluation of nonresponse and bias in a study of asthma in healthcare workers. American Journal of 

Respiratory and Critical Care Medicine. 193. https://www.atsjournals.org/doi/abs/10.1164/ajrccmconference.2016.193.1_MeetingAbstracts.A3708 [2]

Hettick JM, Law BF, Lin CC, Wisnewski AV, Siegel PD. 2017. Mass spectrometry-based analysis of 

murine bronchoalveolar lavage fluid following respiratory exposure to 4,4'-methylene diphenyl 

diisocyanate aerosol. Xenobiotica; the fate of foreign compounds in biological systems.1-11. 

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Hines CJ, Jackson MV, Deddens JA, Clark JC, Ye X, Christianson AL, Meadows JW, Calafat AM. 

2017. Urinary Bisphenol A (BPA) concentrations among workers in industries that manufacture and 

use BPA in the USA. Annals of Work Exposures and Health. 61(2):164-182. 

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Hoffmann GR, Shelby MD, Zeiger E. 2016. Remembering Heinrich Malling in memoriam. 

Environmental and Molecular Mutagenesis. 57(8):575-578. https://doi.org/10.1002/em.22056 [5]

Hoopes SL, Gruzdev A, Edin ML, Graves JP, Bradbury JA, Flake GP, Lih FB, DeGraff LM, Zeldin DC. 

2017. Generation and characterization of epoxide hydrolase 3 (EPHX3)-deficient mice. PloS One. 

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Houck KA, Judson RS, Knudsen TB, Martin MT, Richard AM, Crofton KM, Simeonov A, Paules RS, 

Bucher JR, Thomas RS. 2017. Comment on "On the utility of ToxCast (TM) and ToxPi as methods for 

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Howdeshell KL, Hotchkiss AK, Gray LE, Jr. 2017. Cumulative effects of antiandrogenic chemical 

mixtures and their relevance to human health risk assessment. International journal of hygiene and 

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Howdeshell KL, Ornoy A. 2017. Depression and its treatment during pregnancy: Overview and 

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Hsieh JH, Huang R, Lin JA, Sedykh A, Zhao J, Tice RR, Paules RS, Xia M, Auerbach SS. 2017. 

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Hsu CW, Hsieh JH, Huang R, Pijnenburg D, Khuc T, Hamm J, Zhao J, Lynch C, van Beuningen R, 

Chang X et al. 2016. Differential modulation of FXR activity by chlorophacinone and ivermectin 

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Hur J, Danes L, Krout D, Hsieh JH, Auerbach S. 2017. Tox21 Enricher: Web-based chemical and 

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Iavicoli I, Leso V, Beezhold DH, Shvedova AA. 2017. Nanotechnology in agriculture: Opportunities, 

toxicological implications, and occupational risks. Toxicology and Applied Pharmacology. 329:96-111. 

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Imam SZ, He Z, Cuevas E, Rosas-Hernandez H, Lantz SM, Sarkar S, Raymick J, Robinson B, Hanig 

JP, Herr D et al. 2017. Changes in the metabolome and microRNA levels in biological fluids might 

represent biomarkers of neurotoxicity: A trimethyltin study. Experimental Biology and Medicine 

(Maywood, NJ). 243(3):228-236. https://doi.org/10.1177/1535370217739859 [4]

Irizarry AR, Gropp KE, Dixon D. 2017. A brief overview of the STP 35th annual symposium on the 

basis and relevance of variation in toxicologic responses. Toxicologic Pathology. 45(1):52-56. 

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Jackson MA, Yang L, Lea I, Rashid A, Kuo B, Williams A, Lyn Yauk C, Fostel J. 2017. The TGx-28.65 

biomarker online application for analysis of transcriptomics data to identify DNA damage-inducing 

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Jenkins GR, Lee T, Moland CL, Vijay V, Herman EH, Lewis SM, Davis KJ, Muskhelishvili L, Kerr S, 

Fuscoe JC et al. 2016. Sex-related differential susceptibility to doxorubicin-induced cardiotoxicity in 

B6C3F1 mice. Toxicology and Applied Pharmacology. 310:159-174. 

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Jevtovic-Todorovic V, Bushnell PJ, Paule MG. 2017. Introduction to the special issue "Developmental 

neurotoxicity associated with pediatric general anesthesia: Preclinical findings". Neurotoxicology and 

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Johnson VJ, Auerbach SS, Luster MI, Waidyanatha S, Masten SA, Wolfe MS, Burleson FG, Burleson 

GR, Germolec DR. 2017. Evaluation of 4-methylcyclohexanemethanol (MCHM) in a combined 

irritancy and Local Lymph Node Assay (LLNA) in mice. Food and Chemical Toxicology: An 

International Journal Published for the British Industrial Biological Research Association. 105:99-105. 

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Johnson-Weaver BT, McRitchie S, Mercier KA, Pathmasiri W, Sumner SJ, Chan C, Germolec D, 

Kulis M, Burks AW, Staats HF. 2017. Effect of endotoxin and alum adjuvant vaccine on peanut 

allergy. The Journal of Allergy and Clinical Imunology. https://doi.org/10.1016/j.jaci.2017.07.043 [5]

Jokinen MP, Morgan DL, Price HC, Herbert RA, Saddler T, Dixon D. 2017. Immunohistochemical 

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Joseph P. 2017. Transcriptomics in toxicology. Food and Chemical Toxicology: An International 

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Juberg DR, Knudsen TB, Sander M, Beck NB, Faustman EM, Mendrick DL, Fowle JR, 3rd, Hartung 

T, Tice RR, Lemazurier E et al. 2017. FutureTox III: Bridges for translation. Toxicological Sciences: 

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Kang J, Erdely A, Afshari A, Casuccio G, Bunker K, Lersch T, Dahm MM, Farcas D, Cena L. 2017. 

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Karystianis G, Thayer K, Wolfe M, Tsafnat G. 2017. Evaluation of a rule-based method for 

epidemiological document classification towards the automation of systematic reviews. Journal of 

biomedical informatics. 70:27-34. https://doi.org/10.1016/j.jbi.2017.04.004 [5]

Khajanchi BK, Han J, Gokulan K, Zhao S, Gies A, Foley SL. 2016. Draft genome sequences of four 

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Khajanchi BK, Hasan NA, Choi SY, Han J, Zhao S, Colwell RR, Cerniglia CE, Foley SL. 2017. 

Comparative genomic analysis and characterization of incompatibility group FIB plasmid encoded 

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Khaliullin T, Fatkhutdinova L, Vasilyeva O, Zalyalov R, Mustafin I, Kisin E, Birch ME, Yanamala N, 

Shvedova A. 2017. Biomarkers of fibrosis in workers exposed to multi-walled carbon nanotubes. 

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43

Ruder AM, Bertke SJ. 2017. Cancer incidence among boat-building workers exposed to styrene. 

American Journal of Industrial Medicine. 60(7):651-657. https://doi.org/10.1002/ajim.22735 [2]

Ruder AM, Hein MJ, Hopf NB, Waters MA. 2017. Cancer incidence among capacitor manufacturing 

workers exposed to polychlorinated biphenyls. American Journal of Industrial Medicine. 60(2):198-

207. https://doi.org/10.1002/ajim.22657 [2]

Sager TM, Wolfarth M, Leonard SS, Morris AM, Porter DW, Castranova V, Holian A. 2016. Role of 

engineered metal oxide nanoparticle agglomeration in reactive oxygen species generation and 

cathepsin B release in NLRP3 inflammasome activation and pulmonary toxicity. Inhalation 

Toxicology. 28(14):686-697. https://doi.org/10.1080/08958378.2016.1257664 [2]

Sakamachi Y, Morioka S, Mihaly SR, Takaesu G, Foley JF, Fessler MB, Ninomiya-Tsuji J. 2017. 

TAK1 regulates resident macrophages by protecting lysosomal integrity. Cell Death & Disease. 

8(2):e2598. https://doi.org/10.1038/cddis.2017.23 [5]

Sarkar S, Liachenko S, Paule MG, Bowyer J, Hanig JP. 2016. Brain endothelial dysfunction following 

pyrithiamine induced thiamine deficiency in the rat. Neurotoxicology. 57:298-309. 

https://doi.org/10.1016/j.neuro.2016.10.014 [4]

Saylor DM, Adidharma L, Fisher JW, Brown RP. 2016. A biokinetic model for nickel released from 

cardiovascular devices. Regulatory Toxicology and Pharmacology: RTP. 80:1-8. 

https://doi.org/10.1016/j.yrtph.2016.05.019 [4]

Schubauer-Berigan MK, Couch JR, Deddens JA. 2017. Is beryllium-induced lung cancer caused only 

by soluble forms and high exposure levels? Occupational and Environmental Mdicine. 74(8):601-603. 

https://doi.org/10.1136/oemed-2016-104064 [2]

Seehra MS, Narang V, Geddam UK, Stefaniak AB. 2017. Correlation between X-ray diffraction and 

Raman spectra of 16 commercial graphene-based materials and their resulting classification. Carbon. 

111:380-385. https://doi.org/10.1016/j.carbon.2016.10.010 [2]

Sellamuthu R, Umbright C, Roberts JR, Young SH, Richardson D, McKinney W, Chen BT, Li S, 

Kashon M, Joseph P. 2017. Molecular mechanisms of pulmonary response progression in crystalline 

silica exposed rats. Inhalation Toxicology. 29(2):53-64. 

https://doi.org/10.1080/08958378.2017.1282064 [2]

Shimbo T, Dunnick JK, Brix A, Mav D, Shah R, Roberts JD, Wade PA. 2017. DNA methylation 

changes in Tbx3 in a mouse model exposed to polybrominated diphenyl ethers. International Journal 

of Toxicology. 36(3):229-238. https://doi.org/10.1177/1091581817706676 [5]

Shoeb M, Kodali V, Farris B, Bishop LM, Meighan T, Salmen R, Eye T, Roberts JR, Zeidler-Erdely P, 

Erdely A et al. 2017. Evaluation of the molecular mechanisms associated with cytotoxicity and 

inflammation after pulmonary exposure to different metal-rich welding particles. Nanotoxicology. 

11(6):725-736. https://doi.org/10.1080/17435390.2017.1349200 [2]

Shoeb M, Kodali VK, Farris BY, Bishop LM, Meighan TG, Salmen R, Eye T, Friend S, SchweglerBerry D, Roberts JR et al. 2017. Oxidative stress, DNA methylation, and telomere length changes in 

peripheral blood mononuclear cells after pulmonary exposure to metal-rich welding nanoparticles. 

Nanoimpact. 5:61-69. https://doi.org/10.1016/j.impact.2017.01.001 [2]

Shpyleva S, Dreval K, de Conti A, Kindrat I, Melnyk S, Yan J, Chen T, Beland FA, Pogribny IP. 2017. 

Editor's highlight: Organ-specific epigenetic changes induced by the nongenotoxic liver carcinogen 

methapyrilene in Fischer 344 rats. Toxicological Sciences: An Official Journal of the Society of 

Toxicology. 156(1):190-198. https://doi.org/10.1093/toxsci/kfw242 [4]
44

2017 Annual Report – FY 2017 Glance – Publications

Shpyleva S, Melnyk S, Pavliv O, Pogribny I, Jill James S. 2017. Overexpression of LINE-1 

retrotransposons in autism brain. Molecular Neurobiology. https://doi.org/10.1007/s12035-017-0421-x

[4]

Sills R, Brix A, Cesta M, Churchill SR, Cora MC, Dixon D, Dykstra M, Flake G, Herbert R, Kovi R et

al. 2017. NTP/NIEHS global contributions to Toxicologic Pathology. Toxicologic

Pathology.192623317740326. https://doi.org/10.1177/0192623317740326 [5]

Singh AP, Foley J, Tandon A, Phadke D, Karimi Kinyamu H, Archer TK. 2017. A role for BRG1 in the 

regulation of genes required for development of the lymphatic system. Oncotarget. 8(33):54925-

54938. https://doi.org/10.18632/oncotarget.18976 [5]

Sipes NS. 2017. Databases and analysis tools supporting toxicology in the 21st century. In Vitro

Cellular & Developmental Biology-Animal. 53:S7-S7. https://doi.org/10.1007/s11626-017-0153-2 [5]

Sipes NS, Wambaugh JF, Pearce R, Auerbach SS, Wetmore BA, Hsieh JH, Shapiro AJ, Svoboda D,

DeVito MJ, Ferguson SS. 2017. An intuitive approach for predicting potential human health risk with 

the Tox21 10k library. Environmental Science & Technology. 51(18):10786-10796.

https://doi.org/10.1021/acs.est.7b00650 [5]

Sirenko O, Grimm FA, Ryan KR, Iwata Y, Chiu WA, Parham F, Wignall JA, Anson B, Cromwell EF,

Behl M et al. 2017. In vitro cardiotoxicity assessment of environmental chemicals using an

organotypic human induced pluripotent stem cell-derived model. Toxicology and Applied 

Pharmacology. 322:60-74. https://doi.org/10.1016/j.taap.2017.02.020 [5]

Slikker W, Jr. 2017. Biomarkers and their impact on precision medicine. Experimental Biology and

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Smani D, Sarkar S, Raymick J, Kanungo J, Paule MG, Gu Q. 2017. Downregulation of 14-3-3 

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Smith-Roe SL, Wyde ME, Stout MD, Winters JW, Hobbs CA, Shepard KG, Green AS, Kissling GA,

Tice RR, Bucher JR et al. 2017. Evaluation of the genotoxicity of cell phone radiofrequency radiation

in male and female rats and mice following subchronic exposure. Environmental and Molecular

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Stacey P, Thorpe A, Mogridge R, Lee T, Harper M. 2016. A new miniature respirable sampler for inmask sampling: Part 1-Particle size selection performance. The Annals of Ocupational Hygiene. 

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Stanko JP, Fenton SE. 2017. Quantifying branching density in rat mammary gland whole-mounts

using the sholl analysis method. Jove-Journal of Visualized Experiments. (125).

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Stefaniak AB, LeBouf RF, Duling MG, Yi J, Abukabda AB, McBride CR, Nurkiewicz TR. 2017.

Inhalation exposure to three-dimensional printer emissions stimulates acute hypertension and 

microvascular dysfunction. Toxicology and Applied Pharmacology. 335:1-5.

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Stefaniak AB, LeBouf RF, Yi J, Ham J, Nurkewicz T, Schwegler-Berry DE, Chen BT, Wells JR, Duling

MG, Lawrence RB et al. 2017. Characterization of chemical contaminants generated by a desktop

fused deposition modeling 3-dimensional Printer. Journal of Occupational and Environmental

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Stefaniak AB, Virji MA, Badding MA, Cummings KJ. 2017. Application of the ICRP respiratory tract

model to estimate pulmonary retention of industrially sampled indium-containing dusts. Inhalation 

Toxicology. 29(4):169-178. https://doi.org/10.1080/08958378.2017.1333548 [2] 
45

2017 Annual Report – FY 2017 Glance – Publications

Strickland J, Zang QD, Paris M, Lehmann DM, Allen D, Choksi N, Matheson J, Jacobs A, Casey W,

Kleinstreuer N. 2017. Multivariate models for prediction of human skin sensitization hazard. Journal of

Applied Toxicology. 37(3):347-360. https://doi.org/10.1002/jat.3366 [5]

Su H, Wang Y, Gu Y, Bowman L, Zhao J, Ding M. 2018. Potential applications and human biosafety

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Sumner ET, Chawla AT, Cororaton AD, Koblinski JE, Kovi RC, Love IM, Szomju BB, Korwar S, Ellis

KC, Grossman SR. 2017. Transforming activity and therapeutic targeting of C-terminal-binding

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Sun J, Jin J, Beger RD, Cerniglia CE, Chen H. 2017. Evaluation of metabolism of azo dyes and their

effects on Staphylococcus aureus metabolome. Journal of Industrial Microbiology & Biotechnology. 

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Szabo DT, Pathmasiri W, Sumner S, Birnbaum LS. 2017. Serum metabolomic profiles in neonatal

mice following oral brominated flame retardant exposures to hexabromocyclododecane (HBCD)

alpha, gamma, and commercial mixture. Environmental Health Perspectives. 125(4):651-659.

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Tal T, Kilty C, Smith A, LaLone C, Kennedy B, Tennant A, McCollum CW, Bondesson M, Knudsen T,

Padilla S et al. 2017. Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model

for developmental vascular toxicity. Reproductive Toxicology. 70:70-81.

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Taylor KW, Baird DD, Herring AH, Engel LS, Nichols HB, Sandler DP, Troester MA. 2017.

Associations among personal care product use patterns and exogenous hormone use in the NIEHS

Sister Study. Journal of Exposure Science & Environmental Epidemiology. 27(5):458-464.

https://doi.org/10.1038/jes.2016.82 [5]

Taylor KW, Joubert BR, Braun JM, Dilworth C, Gennings C, Hauser R, Heindel JJ, Rider CV, Webster

TF, Carlin DJ. 2016. Statistical approaches for assessing health effects of environmental chemical

mixtures in epidemiology: Lessons from an innovative workshop. Environmental Health Perspectives. 

124(12):a227-a229. https://doi.org/10.1289/ehp547 [5]

Teng CT, Hsieh JH, Zhao J, Huang R, Xia M, Martin N, Gao X, Dixon D, Auerbach SS, Witt KL et al.

2017. Development of novel cell lines for high-throughput screening to detect estrogen-related 

receptor alpha modulators. SLAS Discovery: Advancing Life Sciences R & D. 22(6):720-731.

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Tokar EJ. 2016. MicroRNAs: Small molecules with big effects. Toxicology and Applied Pharmacology. 

312:1-2. https://doi.org/10.1016/j.taap.2016.11.004 [5]

Tokar EJ, Xu YY, Waalkes MP. 2016. Cancer induced by exposure to arsenicals in animals.

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Townsend TA, Parrish MC, Engelward BP, Manjanatha MG. 2017. The development and validation of

EpiComet-Chip, a modified high-throughput comet assay for the assessment of DNA methylation 

status. Environmental and Molecular Mutagenesis. 58(7):508-521. https://doi.org/10.1002/em.22101

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Tucker DK, Foley JF, Bouknight SA, Fenton SE. 2017. Sectioning mammary gland whole mounts for

lesion identification. Journal of Visualized Experiments: JoVE. (125). https://doi.org/10.3791/55796 [5]

Umbright C, Sellamuthu R, Roberts JR, Young SH, Richardson D, Schwegler-Berry D, McKinney W,

Chen B, Gu JK, Kashon M et al. 2017. Pulmonary toxicity and global gene expression changes in 

response to sub-chronic inhalation exposure to crystalline silica in rats. Journal of Toxicology and
2017 Annual Report – FY 2017 Glance – Publications 

46

Environmental Health Part A. 80(23-24):1349-1368. https://doi.org/10.1080/15287394.2017.1384773

[2]

VanSteenhouse H, Babic M, Shepard P, Auerbach S, Merrick A, Mav D, Shah R, Paules RS, Yeakley 

J, Seligmann B. 2016. TempO-Seq surrogate whole transcriptome targeted gene expression profiling 

of archived rat FFPE. Toxicology Letters. 258:S279-S279. 

http://dx.doi.org/10.1016/j.toxlet.2016.06.1975 [5]

Vicetti Miguel RD, Quispe Calla NE, Dixon D, Foster RA, Gambotto A, Pavelko SD, Hall-Stoodley L, 

Cherpes TL. 2017. IL-4–secreting eosinophils promote endometrial stromal cell proliferation and 

prevent Chlamydia-induced upper genital tract damage. Proceedings of the National Academy of 

Sciences of the United States of America. 114(33):E6892-E6901. 

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Vo E, Zhuang ZQ, Birch E, Birch Q. 2016. Application of direct-reading and elemental carbon analysis 

methods to measure mass-based penetration of carbon nanotubes through elastomeric half-face and 

filtering facepiece respirators. Aerosol Science and Technology. 50(10):1044-1054. 

https://doi.org/10.1080/02786826.2016.1216519 [2]

Von Tungeln LS, Walker NJ, Olson GR, Mendoza MC, Felton RP, Thorn BT, Marques MM, Pogribny 

IP, Doerge DR, Beland FA. 2017. Low dose assessment of the carcinogenicity of furan in male 

F344/N Nctr rats in a 2-year gavage study. Food and Chemical Toxicology: An International Journal 

Published for the British Industrial Biological Research Association. 99:170-181. 

https://doi.org/10.1016/j.fct.2016.11.015 [5]

Voronkova MA, Luanpitpong S, Rojanasakul LW, Castranova V, Dinu CZ, Riedel H, Rojanasakul Y. 

2017. SOX9 regulates cancer stem-like properties and metastatic potential of single-walled carbon 

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[2]

Wagner L, Isbrucker R, Locht C, Arciniega J, Costanzo A, McFarland R, Oh H, Hoonakker M, 

Descamps J, Andersen SR et al. 2016. In search of acceptable alternatives to the murine histamine 

sensitisation test (HIST): What is possible and practical? Pharmeuropa Bio & Scientific Notes. 

2016:151-170. http://www.ncbi.nlm.nih.gov/pubmed/28279256 [5]

Walters JL, Paule MG. 2017. Review of preclinical studies on pediatric general anesthesia-induced 

developmental neurotoxicity. Neurotoxicology and Teratology. 60:2-23. 

https://doi.org/10.1016/j.ntt.2016.11.005 [4]

Wang C, Liu F, Patterson TA, Paule MG, Slikker W, Jr. 2017. Relationship between ketamineinduced developmental neurotoxicity and NMDA receptor-mediated calcium influx in neural stem cellderived neurons. Neurotoxicology. 60:254-259. https://doi.org/10.1016/j.neuro.2016.04.015 [4]

Weaver JL, Tobin GA, Ingle T, Bancos S, Stevens D, Rouse R, Howard KE, Goodwin D, Knapton A, 

Li X et al. 2017. Evaluating the potential of gold, silver, and silica nanoparticles to saturate 

mononuclear phagocytic system tissues under repeat dosing conditions. Particle and Fibre 

Toxicology. 14(1):25. https://doi.org/10.1186/s12989-017-0206-4 [4]

Weston EH, Mantooth SN, Knight EN, Klein CB, Ward JB, Banda M, Nicolette JJ, Smith-Roe SL. 

2017. Looking at the environmental mutagenesis and genomics society through the lens of 

bibliometric data analysis: Identifying relationships and areas for growth. Environmental and 

Molecular Mutagenesis. 58:S73-S74. https://doi.org/10.1002/em.22135 [5]

Whitehead GS, Thomas SY, Shalaby KH, Nakano K, Moran TP, Ward JM, Flake GP, Nakano H, 

Cook DN. 2017. TNF is required for TLR ligand-mediated but not protease-mediated allergic airway 

inflammation. The Journal of Clinical Investigation. 127(9):3313-3326. 

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2017 Annual Report – FY 2017 Glance – Publications 

47

Williams K, Valencia L, Gokulan K, Trbojevich R, Khare S. 2017. Assessment of antimicrobial effects 

of food contact materials containing silver on growth of Salmonella Typhimurium. Food and Chemical 

Toxicology: An International Journal Published for the British Industrial Biological Research 

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Witt KL, Hsieh JH, Smith-Roe SL, Xia M, Huang R, Zhao J, Auerbach SS, Hur J, Tice RR. 2017. 

Assessment of the DNA damaging potential of environmental chemicals using a quantitative highthroughput screening approach to measure p53 activation. Environmental and Molecular 

Mutagenesis. 58(7):494-507. https://doi.org/10.1002/em.22112 [5]

Woodall GM, Hoover MD, Williams R, Benedict K, Harper M, Soo JC, Jarabek AM, Stewart MJ, 

Brown JS, Hulla JE et al. 2017. Interpreting mobile and handheld air sensor readings in relation to air 

quality standards and health effect reference values: Tackling the hallenges. Atmosphere. 8(10):182. 

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Worley RR, Moore SM, Tierney BC, Ye X, Calafat AM, Campbell S, Woudneh MB, Fisher J. 2017. 

Per- and polyfluoroalkyl substances in human serum and urine samples from a residentially exposed 

community. Environment International. 106:135-143. https://doi.org/10.1016/j.envint.2017.06.007 [4]

Worley RR, Yang X, Fisher J. 2017. Physiologically based pharmacokinetic modeling of human 

exposure to perfluorooctanoic acid suggests historical non drinking-water exposures are important for 

predicting current serum concentrations. Toxicology and Applied Pharmacology. 330:9-21. 

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Wu L, Liu Z, Auerbach S, Huang R, Chen M, McEuen K, Xu J, Fang H, Tong W. 2017. Integrating 

drug's mode of action into quantitative structure-activity relationships for improved prediction of druginduced liver injury. Journal of Chemical Information and Modeling. 57(4):1000-1006. 

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Wu Y, Chitranshi P, Loukotkova L, Gamboa da Costa G, Beland FA, Zhang J, Fang JL. 2017. 

Cytochrome P450-mediated metabolism of triclosan attenuates its cytotoxicity in hepatic cells. 

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factors influencing CYP1A2 expression as potential determinants of interindividual variation. 

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Yanamala N, Orandle MS, Kodali VK, Bishop L, Zeidler-Erdely PC, Roberts JR, Castranova V, Erdely 

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Yiin JH, Anderson JL, Daniels RD, Bertke SJ, Fleming DA, Tollerud DJ, Tseng CY, Chen PH, Waters 

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2017 Annual Report – Learn About Us 

49

Learn About Us

Mission and Goals

NTP was established in 1978 in response to concerns about potential human health 

effects of chemicals in our environment.

Organizational Structure and Oversight

Three agencies form the core for NTP: NIOSH, NCTR, and NIEHS.

Funding

The total NTP budget for FY 2017 and contracts that support NTP research.

Program Contact Information

General inquiries, websites, and staff directory information.

Training Opportunities

NTP offers postdoctoral training fellowships designed to prepare trainees for careers 

in science.

Interagency Agreements

In FY 2017, NIEHS provided support for NTP activities through interagency 

agreements with other federal agencies.
2017 Annual Report – Learn About Us – Mission 

50

Mission and Goals

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

U.S. Department of Health and Human Services, established NTP 

in 1978 in response to concerns about the potential human health 

effects of chemicals in our environment. NTP goals are to:

• 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, 

scientific communities, medical communities, and the public. 

NTP provides scientific data to regulatory agencies and other 

health-related research groups and interpretation and guidance in 

their appropriate use. The American people and government 

agencies, at state and federal levels, rely on NTP to provide a 

strong scientific basis for decisions aimed at protecting public 

health. In the past 39 years, NTP has studied and shared 

information on the health effects of more than 2,800 substances, 

including dietary supplements, industrial chemicals, consumer 

products, and complex mixtures.

In following government-wide efforts to increase access to the 

results of federally funded scientific research, NTP maintains open 

communication and dialogue with the public, federal, and state 

agencies, industry, nongovernmental organizations, and academic 

institutions. The NTP website provides the public with a variety of 

information, including Federal Register notices, status of and data 

from NTP studies, access to NTP reports and journal publications, 

notifications through media releases, a calendar of upcoming 

events, and a newsletter, the NTP Update. 

The public and other interested parties can stay abreast of NTP 

activities and events by subscribing to receive email of news. In 

addition, requests for information can be made through the Central 

Data Management office (984-287-3211or cdm@niehs.nih.gov), an 

online contact form, or the Freedom of Information Act coordinator. 

NTP welcomes input on its programs and priorities. This input can 

be submitted in response to formal requests for public comment in 

Federal Register notices or informal submissions to the Office of 

Liaison, Policy, and Review (984-287-3209 or the online contact 

form).
2017 Annual Report – Learn About Us – Organization 

51

Organizational Structure and Oversight

Three agencies form the core for NTP: National Institute for Occupational Safety and Health of the 

Centers for Disease Control and Prevention; U.S. Food and Drug Administration, primarily through 

the National Center for Toxicological Research; and National Institute of Environmental Health 

Sciences of the National Institutes of Health.

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

NTP. In FY 2017, John Bucher, Ph.D., served as 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 espouse best research practices and embrace developments in technology to discover how 

the environment affects people, maintaining leadership in the field of environmental health sciences 

by applying innovative research to address public health issues.

John Howard, M.D., is director of NIOSH. Staff from two NIOSH divisions participate in NTP activities. 

Elizabeth Whelan, Ph.D., chief of the Industrywide Studies Branch, and Cheryl Estill, Ph.D., 

supervisor of Industrial Hygiene, manage NTP activities within the Division of Surveillance, Hazard 

Evaluations, and Field Studies. Donald Beezhold, Ph.D., is the principal investigator for the 

“Immunotoxicity of Workplace Xenobiotics” project through an NCTR-NIEHS interagency agreement.

NIOSH’s participation in NTP is consistent with its mandate to protect worker health and safety under 

the Occupational Safety and Health Act and the Federal Mine Safety and Health Act.

William Slikker Jr., Ph.D., (director of FDA/NCTR) and Goncalo Gamboa Da Costa, Ph.D., (project 

officer of the NCTR-NIEHS interagency agreement, Division of Biochemical Toxicology) provide 

management oversight and coordination of NTP activities within NCTR. 

NCTR staff scientists partner with other researchers in FDA, other government agencies, academia, 

and industry to provide innovative technology, methods development, vital scientific training, and 

technical expertise. NCTR conducts an array of studies that reflect the NTP mission and are critical in

supporting FDA product centers and their regulatory roles.
2017 Annual Report – Learn About Us – Funding 

52

Funding

NTP relies on voluntary allocations from the three core agencies—NIEHS, FDA/NCTR, and 

CDC/NIOSH—to support its activities. These allocations are specified after annual appropriations 

have been determined. The total NTP budget for FY 2017 was $133.5 million. 

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

laboratories or interagency agreements with other agencies. In FY 2017, NIEHS funded 39 contracts, 

listed below, held three workshops, three special emphasis panel peer-review meetings, and one 

scientific advisory meeting for NTP. CDC and FDA could have additional contracts that support some 

of their voluntary NTP efforts.

NIEHS Contracts That Supported NTP Activities in FY 2017

Description Contractor

Analytical Chemistry Services Battelle Memorial

Midwest Research Institute

Research Triangle Institute

Archives and Specimen Repository Experimental Pathology Laboratories

Assessment of Exposure to Coal Tar Pitch Volatiles Containing PAHs 

in Coal Tar Sealant Applicators

Interagency Agreement (IAA) with NIOSH
2017 Annual Report – Learn About Us – Funding 

53

Description Contractor

Assessment of Occupational Exposure to Flame Retardants IAA with NIOSH

Assessment of Occupationally Relevant Exposures IAA with NIOSH

Bioinformatics Methylation Project Laboratory Corp of America

Bioinformatics Support SCIOME, LLC.

Collaborative Work with Ramazzini DOE/ORISE

Conducting Comprehensive Toxicological Assessments IAA with NCTR – FDA

Development of Tools for Evaluating NTP’s Effectiveness DOE Oakridge National Laboratory

Evaluation of Toxicity Following Early Life Exposure Southern Research Institute

Evaluation of Alternative Toxicological Methods Integrated Laboratory Systems

Evaluation of the Toxicity of Selected Chemicals Battelle Memorial

Genetic Toxicity Testing Support Services Integrated Laboratory Systems

Hepatocytes Bioreclamation, LLC

Immunotoxicity Burleson Research Technologies

Immunotoxicity of Workplace Xenobiotics IAA with NIOSH

In-Life Data Collection and Management System INSTEM, LSS

NTP Information Systems Support Signature Consulting Group, LLC

NTP Statistical and Computer Support SRA International

NTP Technical Reports Preparation Support Services Biotechnical Sciences, Inc.

Pathology Support Experimental Pathology Laboratories

Integrated Laboratory Systems

PAI/Charles River Laboratories

Production of B6C3F1 Mice Taconic Biosciences, Inc.

Quality Assessment Support/Audits & Inspections CSS-Dynamac Corporation

Reproductive Assessments by Continuous Breeding Research Triangle Institute

Scientific Information Management and Literature-Based Evaluations 

for the NTP

ICF

Scientific Positions Kelly Scientific

SECAS - Search for Environmental Contaminants Ancillary Study IAA with CDC

Statistical Support Social and Scientific Systems
2017 Annual Report – Learn About Us – Funding 

54

Description Contractor

Support for Toxicological Data Vistronix, LLC

Toxicity Profiling Using HTS – TOX 21 IAA with NHGRI/NCATS

Toxicological and Carcinogenic Potential of Chemicals Battelle Memorial
55

2017 Annual Report – Learn About Us – Contact Information 

Program Contact Information

For general inquiries, contact:

Central Data Management

P.O. Box 12233, MD K2-05 

Research Triangle Park, NC 27709 

984-287-3211

Email cdm@niehs.nih.gov or use our contact form.

A Staff Directory is available.
2017 Annual Report – Learn About Us – Interagency Agreements 

56

Interagency Agreements

In FY 2017, NIEHS provided support for NTP activities through interagency agreements with other

federal agencies.

FDA/NCTR

Under an interagency agreement, NIEHS and FDA conduct toxicology studies on FDA-regulated 

agents nominated to NTP at the National Center for Toxicological Research. These studies are 

designed to provide FDA and other regulatory agencies with hazard identification and dose-response 

data to support risk assessment and risk management decisions that could affect public health. The 

interagency agreement supports 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 18 published NTP Technical Reports and 

over 250 peer-reviewed journal publications. The studies have led to an increased understanding of 

the pharmacokinetics, mode of action, and dose-response relationships of the substances and to 

refinements of risk assessment models. Further information about NTP at the National Center for 

Toxicological Research and current research can be found in the Partner Agency Research section of 

this annual report.

CDC/NIOSH

NIEHS/NTP has two interagency agreements with the National Institute for Occupational Safety and 

Health (NIOSH). Studies under the interagency agreement on “Immunotoxicity of Workplace 

Xenobiotics” assess the potential toxicity of exposures to substances such as fungi, mycotoxins, 

volatile organic compounds, lead, latex, nickel, isocyanates, nanomaterials, and beryllium in 

occupationally exposed populations such as miners, farmers, health care workers, autoworkers, and 

firefighters. A second interagency agreement between NIEHS and NIOSH supports development of 

methods to assess complex mixtures, such as asphalt fumes, welding fumes, and tungsten fibers, 

and to conduct occupational exposure assessments to identify toxicologically relevant exposures. 

Research under these agreements in FY 2017 evaluated occupational exposure to bisphenol A, 

alternative flame retardants, and polycyclic aromatic hydrocarbons in coal tar sealants. For more 

information, see the Partner Agency Research section of the Annual Report.

NIH/NCATS/DPI

This interagency agreement supports ongoing and anticipated studies conducted at the National 

Center for Advancing Translational Sciences/Division of Pre-Clinical Innovation to evaluate highthroughput and high-content screening assays in support of Tox21. Tox21 is a collaboration among 

federal agencies to characterize the potential toxicity of chemicals by using cells and isolated 

molecular targets instead of laboratory animals. This interagency agreement between NIEHS/NTP 

and the division produces data for information-poor substances to help prioritize them for further 

studies, including toxicological evaluation, mechanisms of action investigation, and development of 

predictive modeling for biological response. 

Additional Agreements
2017 Annual Report – Learn About Us – Interagency Agreements 

57

NTP also established several smaller interagency agreements to conduct research, listed below.

Additional Interagency Agreements in FY 2017

Study—Agency Description

Development of Tools for Evaluating NTP’s 

Effectiveness—U.S. Department of Energy

Research and develop tools, such as publication mining tools, that 

NTP can use to evaluate the use and impact of its work across the 

agencies and stakeholders to whom the work is disseminated and

extract and organize data (e.g., potential outcomes and impacts) from 

NTP’s large inventory of documents (e.g., publications and progress 

reports). 

Accelerating Development and Use of 

Computational Methods and Models— 

Environmental Protection Agency

Accelerate development and use of methods/models for quantitative 

and qualitative risk assessments of environmental chemicals. 
2017 Annual Report – Learn About Us – Training Programs

58

Training Opportunities

NIEHS/NTP offers a limited number of postdoctoral training fellowships to prepare trainees for 

careers in pharmaceutical and chemical industries, regulatory agencies, and academia. In FY 2017, 

NIEHS/NTP staff mentored 15 postdoctoral fellows at NIEHS. Full details on opportunities, benefits,

and the application process can be found on the NIEHS training website. The training program has six 

focal areas: 

1. Applied toxicology and carcinogenesis

2. Biomolecular screening and computational toxicology

3. Health assessment and translation

4. Laboratory animal medicine

5. Systems and mechanistic toxicology

6. Toxicological pathology

NIEHS/NTP Training Program Postdoctoral Fellows in FY 2017

Training Program Fellow

Applied toxicology and carcinogenesis Natasha Catlin

Anika Dzierlenga

Kelly Shipkowski

Biomolecular screening and computational toxicology Sreenivasa Ramaiahgari

Health assessment and translation Katie Pelch

Laboratory animal medicine Manushree Bharadwaj 

David Crizer

Jingli Liu

Tony Luz

Systems and mechanistic toxicology Sheba Churchill 

Gopi Gadupudi

Miaofel Xu

Toxicological pathology Daven Jackson-Humbles

Gregory Krane

Eui Jae Sung
2017 Annual Report – Scientific and Public Input Opportunities

59

Scientific and Public Input Opportunities

Nominations

NTP nominations are open to the public, and continually accepted through the NTP

website.

NTP Board of Scientific Counselors

The NTP Board of Scientific Counselors (BSC) provides scientific oversight to NTP on 

the scientific merit of its programs and activities.

SACATM

Scientific Advisory Committee on Alternative Toxicological Methods (SACATM)

provides advice on priorities and activities related to alternative toxicological test 

methods.

NTP Executive Committee

The NTP Executive Committee provides programmatic and policy oversight to the 

NTP director.

Special Emphasis Panels

NTP uses ad hoc scientific panels to provide independent scientific peer review and

advice on targeted issues including the review of NTP technical reports and

monographs.
2017 Annual Report – Scientific and Public Input Opportunities – Nominations

60

Nominations

NTP continually accepts and reviews nominations for studies in 

its research and testing program. The NTP nomination process 

is open to the public, and nominations can be submitted 

through the NTP website. Agencies represented on the NTP 

Executive Committee also identify and forward nominations to

NTP. 

For new research projects or studies of substantial scope and 

complexity, NTP research concepts or project plans are 

prepared to facilitate external review as part of a multistep

process with input from NTP participating federal agencies, the 

Board of Scientific Counselors, and the public. In addition to new 

research projects, NTP conducts targeted studies to extend or 

explain findings observed in previous studies and to address 

nominations closely aligned with current research efforts.

A 2016 nomination from the Environmental Working Group

requested that NTP evaluate the hypothesis that mixtures of 

unrelated substances with specific reported biological activity 

corresponding to cancer “hallmarks” could jointly contribute to 

cancer development. Plans and progress toward addressing this 

nomination were presented at the NTP Board of Scientific 

Counselors meeting in June 2017.

New projects were initiated in FY 2017 to address nominations for 

adverse reproductive outcomes of certain analgesics and to explore 

the possibility of using Tox21 approaches to query biological 

activities of concern associated with exposure to consumer 

products intended for children.

Questions about the nomination, review, and selection process can 

be sent to Scott Masten, Ph.D. 

Research and Testing Projects Initiated in FY 2017

Project & Study Scientist Project Description

Reproductive Outcomes Following Developmental 

Exposure to Acetaminophen

Study Scientist: Vicki Sutherland

Recent studies suggest that maternal consumption of mild 

analgesics during pregnancy has detrimental effects on male 

reproductive tract development (e.g., cryptorchidism). This rat study 

evaluates reproductive and endocrine endpoints in offspring 

exposed to acetaminophen during the period of male androgendependent development.

Screening for Biological Activities of Concern in 

Consumer Products

Study Scientist: Scott Masten

Targeted screening approaches and methods are being explored to 

evaluate the bioactivity of physiologically relevant extracts of 

selected consumer products used by children.

Cancer Network and Environmental Exposure 

Research Agenda (CNVERGE)

Study Scientist: Cynthia Rider

CNVERGE applies a systems-based approach to use adverse 

outcome pathways as a framework for identifying environmental 

exposures that might converge at the pathway or tissue level to 

contribute cumulatively to disease development. 
2017 Annual Report – Scientific and Public Input Opportunities – BSC

61

NTP Board of Scientific Counselors

The NTP Board of Scientific Counselors, a federally chartered advisory group whose members are 

appointed by HHS, oversees the scientific merit of NTP programs and activities. The Board includes 

scientists, primarily from the public and private sectors, with expertise relevant to NTP activities. The 

Board’s charter and current roster are available on the NTP webpage. In FY 2017, Mary Wolfe, Ph.D., 

served as the designated federal officer and manager of the Board. FY 2017 members are listed 

below. 

The Board met twice in FY 2017: December 14–15, 2016 and June 29, 2017. In December, the Board 

heard reports by:

• Carl Cernigila, Ph.D., director of the FDA National Center for Toxicological Research Division

of Microbiology, on center efforts to discover how exposures to hazardous chemicals affect the

microbial ecosystem in the human gastrointestinal tract.

• Elizabeth Whelan, Ph.D., chief of the Industrywide Studies Branch of the Division of

Surveillance, Hazard Evaluations, and Field Studies, on seven research projects led by the

National Institute for Occupational Safety and Health in collaboration with NTP.

• Ruth Lunn, Ph.D., of NIEHS/NTP on the recently released 14th Report on Carcinogens.

• Warren Casey, Ph.D., on efforts by the NTP Interagency Center for the Evaluation of

Alternative Toxicological Methods to spearhead development of a new framework for the

safety testing of drugs and chemicals, which aims to provide more human-relevant toxicology

data while reducing the use of animals.

The Board also discussed:

• An initiative to consider antimony trioxide for possible listing in the Report on Carcinogens.

• The peer-review of the “Draft NTP Monograph on Immunotoxicity Associated with Exposure to

Perfluorooctanoic Acid (PFOA) or Perfluorooctane Sulfonate (PFOS).”

The second meeting focused on NTP’s research investigating how exposures to multiple chemicals 

affect human health. Cynthia Rider, Ph.D., of NTP briefed the Board on the challenges of evaluating 

the toxicity of chemical mixtures and the substantial progress NTP has made in this area. Rider also 

briefed the Board on the NTP crumb rubber research program and discussed a potential project to 

examine chemical mixtures in children’s products. 
2017 Annual Report – Scientific and Public Input Opportunities – BSC

62

NTP Board of Scientific Counselors members and NTP staff at the June 2017 BSC meeting

NTP Board of Scientific Counselors Membership Roster FY 2017

Name and Title Affiliation Term End 

Date

Cynthia Afshari, Ph.D. 

Scientific Executive Director

Amgen, Inc.

Thousand Oaks, California

6/30/19

Norman J. Barlow, D.V.M., Ph.D. 

Vice President and Global Head

Johnson and Johnson 

Spring House, Pennsylvania

6/30/19

Paul Brandt-Rauf, Dr.P.H., M.D., Sc.D. 

Office of the Dean

Drexel University

Philadelphia, Pennsylvania

6/30/20

Myrtle Davis, D.V.M., Ph.D. 

Executive Director, Discovery Toxicology, Pharmaceutical 

Candidate Optimization

Bristol-Myers Squibb

New York, New York

6/30/20

Mary Beth Genter, Ph.D. 

Associate Professor, Department of Environmental Health

University of Cincinnati 

Goshan, Ohio

6/30/17

Daniel Kass, M.S.P.H. 

Executive Vice President, Environmental Health

Vital Strategies

New York, New York

6/30/19

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

6/30/17

Kenneth McMartin, Ph.D. 

Board Chair

Professor, Pharmacology, Toxicology, and Neuroscience

Louisiana State University Health 

Science Center

Shreveport, Louisiana

6/30/19

Kenneth Ramos, M.D., Ph.D. 

Associate Vice President, Precision Health Sciences Center

Arizona Health Sciences Center

Tucson, Arizona

6/30/19

Jennifer Sass, Ph.D.

Senior Scientist

Natural Resources Defense Council

Washington, District of Columbia

6/30/20

James Stevens, Ph.D. 

Distinguished Research Fellow

Lilly Research Laboratories

Indianapolis, Indiana

6/30/19
2017 Annual Report – Scientific and Public Input Opportunities – BSC

63

Name and Title Affiliation Term End 

Date

Donald G. Stump, Ph.D., D.A.B.T. 

Vice President, Nonclinical Safety Science

WIL Research

Ashland, Ohio

6/30/20

Katrina Waters, Ph.D. 

Deputy Director, Biological Sciences Division

Pacific Northwest National Laboratory

Richland, Washington

6/30/19
2017 Annual Report – Scientific and Public Input Opportunities – SACATM

64

SACATM

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

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

Coordinating Committee on 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. 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. The SACATM charter and current roster are available on the 

NTP website, and the roster for FY 2017 is listed below. SACATM typically meets once a year and 

members serve rotating terms of up to 4 years. Mary Wolfe, Ph.D., served as the FY 2017 designated 

federal officer and manager of SACATM.

SACATM met on September 18–19, 2017, at the NIH Natcher Conference Center in Bethesda, 

Maryland. At the meeting, Warren Casey, Ph.D., director of NICEATM, updated SACATM on the 

efforts to construct a strategic roadmap that would guide development of new approaches for 

evaluating the safety of chemicals and medical products in the United States. SACATM members 

expressed a generally positive response to the roadmap and provided feedback on topics related to 

its implementation. The topics included encouraging federal agencies and regulated industries to 

adopt new toxicological methods, connecting users with new tools, and establishing greater 

confidence in new methods. 

Members of SACATM and ICCVAM and staff from NIEHS and NTP at the September 2016 SACATM meeting 

SACATM Membership Roster FY 2017 
2017 Annual Report – Scientific and Public Input Opportunities – SACATM

65

Name and Title Affiliation Term End

Date

Brian Berridge, D.V.M., Ph.D., D.A.C.V.P.

Director, WW Animal Research Strategy

GlaxoSmithKline

King of Prussia, Pennsylvania

12/31/17

Michael B. Bolger, Ph.D.

Chief Scientist

Simulations Plus, Inc.

Lancaster, California

11/30/20

Kelly P. Coleman, Ph.D., D.A.B.T., R.A.C.

Distinguished Scientist and Technical Fellow

Medtronic PLC

Minneapolis, Minnesota

11/30/20

Hisham Hamadeh, Ph.D., D.A.B.T., M.B.A. Director, 

Comparative Biology and Safety Sciences

Amgen, Inc.

Thousand Oaks, California

11/30/19

William P. Janzen

Committee Chair

Executive Director of Lead Discovery

Epizyme, Inc.

Cambridge, Massachusetts

11/20/18

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

Associate Director, Global Pharmacovigilance

Zoetis

Kalamazoo, Michigan

11/30/16

Lawrence Milchak, Ph.D., D.A.B.T.

Senior Manager, Toxicology and Strategic Services

3M

St. Paul, Minnesota

11/30/19

Pamela J. Spencer, Ph.D., D.A.B.T.

Director of Regulatory and Product Stewardship

ANGUS Chemical Company

Buffalo Grove, Illinois

11/30/19

Catherine E. Willett, Ph.D.

Director, Regulatory Toxicology, Risk Assessment and 

Alternatives

The Humane Society of the United 

States

Gaithersburg, Maryland

11/30/18

ClarLynda Williams-Devane, Ph.D.

Director, Bioinformatics, Genomics, and Computational 

Chemistry 

Biotechnology Biomedical Research Institute

North Carolina Central University

Durham, North Carolina

11/30/20

Wei Xu, Ph.D.

Associate Professor, Department of Oncology

McArdle Laboratory for Cancer Research

University of Wisconsin at Madison

Madison, Wisconsin

11/30/18

Hao Zhu, Ph.D.

Assistant Professor, Department of Chemistry

Rutgers University

Camden, New Jersey

11/30/19
2017 Annual Report – Scientific and Public Input Opportunities – Executive Committee 

66

NTP Executive Committee

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

director. The committee meets once or twice a year in a closed forum. Members include the heads, or 

their designees, from the following federal agencies. 

• U.S. Consumer Product Safety Commission.

• U.S. Department of Defense.

• U.S. Environmental Protection Agency.

• U.S. Food and Drug Administration.

• National Cancer Institute.

• National Center for Environmental Health/Agency for Toxic Substances and Disease Registry.

• National Institute of Environmental Health Sciences.

• National Institute for Occupational Safety and Health.

• Occupational Safety and Health Administration.

To enhance agency interactions by streamlining communication, NTP uses agency points of contact, 

rather than formal committees. Agency points of contact have a dedicated responsibility and time 

commitment, are knowledgeable about the NTP mission and programs and their agency’s resources, 

and bring the most relevant agency expertise to bear on NTP issues. 
2017 Annual Report – Scientific and Public Input Opportunities – Special Emphasis Panels

67

Special Emphasis Panels

NTP uses ad hoc scientific panels, referred to as special emphasis panels, to provide independent 

scientific peer review and advice on targeted issues, such as agents of public health concern, new 

and revised toxicological test methods, and others. These panels help ensure that NTP receives 

transparent, unbiased, and scientifically rigorous input 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 are published results of long-term studies, generally 2-year rodent toxicology 

and carcinogenesis studies. NTP convenes external scientific panels to peer review draft technical 

reports at public meetings held at NIEHS. All reviews provide the opportunity for public comment. For 

each technical report, the panel is charged with reviewing the scientific and technical elements and 

presentation of the study and determining whether the study’s experimental design and conduct 

support NTP conclusions regarding the carcinogenic activity of the substance tested. One technical 

report meeting was held in FY 2017, on July 13.

Three draft technical reports were peer reviewed at the July meeting: dietary zinc; 2,3 butanedione; 

and p-chloro-α,α,α-trifluorotoluene. The peer-review panel included individuals with expertise in 

molecular carcinogenesis, physiology, pharmacology, inhalation pathology, statistics, inhalation 

toxicology, genetic toxicology, occupational health, and general toxicology and pathology. Mary 

Wolfe, Ph.D., served as designated federal officer for the meeting. The panel agreed that elements 

and presentation of each study were appropriate and NTP’s conclusions in the draft technical reports 

were sound. Additional information about this meeting can be found on the NTP Technical Reports 

Peer Review Panels webpage.

Report on Carcinogens Peer Review Panels

NTP follows an established, four-part process in preparing the Report on Carcinogens. The Report 

monographs are prepared for each candidate substance selected for review and consist of a cancer 

evaluation component and a substance profile. NTP convenes external scientific panels to peer 

review draft Report monographs at meetings that are open to the public with time scheduled for oral 

public comment. The panels are charged with commenting on whether the draft cancer evaluation 

component is technically correct and clearly stated, whether NTP objectively presents and assesses 

the scientific evidence, and whether the scientific evidence is adequate for applying the listing criteria. 

For the draft substance profile, panels are charged with commenting on whether the scientific 

justification presented supports the preliminary NTP policy decision on the Report listing status.

On July 24, 2017, NTP convened a panel at NIEHS to peer review the draft Report monograph on 

haloacetic acids, which are found in the environment as byproducts of water disinfection. The panel

was charged to: 

1. Comment on whether the draft monograph was technically correct, clearly stated, and

objectively presented.

2. Provide opinion on whether significant human exposure to haloacetic acids as water

disinfection byproducts has been found.

The panel voted unanimously to accept NTP’s conclusions on the draft level of evidence for 

carcinogenicity determination, based on the available scientific evidence in experimental animal and 

human cancer studies. They also agreed unanimously with NTP’s preliminary listing 

recommendations in the Report. The review covered viral properties and human exposure, cancer 

studies in experimental animals, metabolism and mechanistic data, human cancer studies, an overall 

cancer evaluation, and the draft substance profile. Mary Wolfe, Ph.D., served as designated federal 
2017 Annual Report – Scientific and Public Input Opportunities – Special Emphasis Panels

68

officer for the peer-review meeting. After the meeting, the input from the panel was considered in 

finalizing the monograph. Additional information about this meeting can be found on the Peer 

Reviews of Report on Carcinogens Monographs webpage.

NTP Expert Panels

NTP expert panels provide independent advice to NTP on agents of public health concern, new and 

revised toxicological test methods, or other topics. In August and September 2017, NTP hosted a 

series of four webinars to provide background information to an expert panel that is planned to 

convene in FY 2018 on the Draft NTP Approach to Genomic Dose-Response Modeling. The webinar 

speakers and subjects are listed below.

Webinar 1: The NTP Proposed Approach to Genomic Dose-Response Modeling, August 30 

Scott Auerbach, Ph.D., of the National Toxicology Program presented the NTP proposed approach to 

genomic dose-response modeling. This approach is consistent with the modeling approach the EPA 

recommends for continuous non-genomic endpoints, which is implemented in its Benchmark Dose 

Software.

Webinar 2: Overview of the U.S. Army Approach to Genomic Dose-Response Modeling, 

September 1

Lyle Burgoon, Ph.D., U.S. Army Engineer Research and Development Center, discussed the Good 

Risk Assessment Value for Environmental Exposures approach. This approach is used in estimating 

points of departure from dose-response data.

Webinar 3: Overview of the NC State Approach to Genomic Dose-Response Modeling, 

September 13

Fred Wright, Ph.D., North Carolina State University, gave an overview of the NC State approach to 

handling genomic dose-response data for cell lines treated with chemicals at varying concentrations.

Webinar 4: An Automated Method to Identify Dose-Responsive Genes and Quantitate Points of 

Departure (PODs) from Transcriptomic Data, September 25

David Gerhold, Ph.D., National Center for Advancing Translational Sciences, presented an 

automated method to identify dose-responsive genes and quantitate points of departure from 

transcriptomic data.

Additional information about the webinar series is available online. General information about NTP 

expert panel meetings can be found on the NTP Expert Panels webpage.
2017 Annual Report – Research and Testing

69

Research and Testing

Tox21

The Toxicology in the 21st Century (Tox21) program is a federal collaboration that 

uses automated high-throughput screening methods to quickly test chemicals across a 

battery of assays. 

Testing and Toxicology Studies

The NTP testing program evaluates substances for a variety of health-related effects, 

generally using rodent models for study.

NICEATM

The NTP Interagency Center for the Evaluation of Alternative Toxicological Methods 

(NICEATM), an office within NIEHS/NTP, supports the development and evaluation of 

new, revised, and alternative methods to identify potential hazards to human health 

and the environment, with a focus on replacing, reducing, or refining animal use.

ICCVAM

The Interagency Coordinating Committee on the Validation of Alternative Methods 

(ICCVAM) is a permanent interagency committee of NIEHS.
2017 Annual Report – Research and Testing – Tox21

70

Tox21

About Tox21

The Toxicology in the 21st Century (Tox21) program is a federal collaboration that 

uses automated high-throughput screening methods to quickly test chemicals across a 

battery of assays.

Tox21 Projects

A list of NTP Tox21 projects conducted in FY 2017.
2017 Annual Report – Research and Testing – Tox21 – About Tox21

71

About Tox21

Toxicology in the 21st Century (Tox21) is a unique federal 

collaboration among the National Institutes of Health (NIH), 

including the National Toxicology Program (NTP) at the National 

Institute of Environmental Health Sciences (NIEHS) and 

the National Center for Advancing Translational Sciences

(NCATS), Environmental Protection Agency (EPA), and U.S. Food 

and Drug Administration (FDA). Its purpose is to develop new 

methods to rapidly test whether chemicals adversely affect human 

health. Tox21 uses robotic, high-throughput screening methods 

and other testing approaches to evaluate large numbers of 

chemicals quickly and efficiently to provide insight into potential 

human health effects. Bioinformatics and computational toxicology 

support for Tox21 is provided by the NTP Interagency Center for 

the Evaluation of Alternative Toxicological Methods. 

Related Links

Tox21 Projects in 2017
2017 Annual Report – Research and Testing – Tox21 – Tox21 Projects

72

Tox21 Projects 

Also see: 

Tox21 Background

NTP Tox21 projects in FY 2017 were carried out by the NIEHS/NTP staff listed below. 

Assay Development

Project & Study Scientist Project Summary

Development of a stable cell line to screen 

compounds that affect the estrogen-related 

receptor/peroxisome proliferator-activated receptor 

coactivator pathway

Study Scientists: Alex Merrick, Tina Teng

Development of an assay to detect compounds that interfere with 

the estrogen-related receptor/peroxisome proliferator-activated 

receptor gamma coactivator pathway, a critical pathway for 

metabolic homeostasis. Stable human cell lines expressing the 

appropriate reporter construct were successfully generated.

Quantitative high-throughput screening efforts with the Library of 

Pharmacologically Active Compounds (LOPAC) were completed 

and a manuscript is in press. Quantitative high-throughput 

screening of the 10K library was completed, in FY 2016, and two 

peer-reviewed manuscripts describing the results were published in 

FY 2017.

Use of HepaRG cells for high-content screening

Study Scientists: Stephen Ferguson, Sreenivasa 

Ramaiahgari

Establishment of metabolically functional human HepaRG liver cells

(derived from a human hepatic progenitor cell line) in 96-well or 

384-well format for completing multiplex, high-content screening

assays in collaboration with the NCATS Chemical Genomics

Center. Studies to characterize the metabolism of xenobiotic

compounds in these cells began in FY 2016 and were published in

FY 2017.

Testing of gene signatures and profiles in NTP 

archival tissues 

Study Scientist: Alex Merrick

Determination of whether RNA extracted from fixed tissue block can 

be used to measure gene signatures and develop chemically 

induced transcriptiomic profiles. The goal is to measure molecular 

changes caused by chemical exposures in rat and mouse organs. 

An effort to establish a relational database to allow identification 

and linkage of all tissues in the NTP Archives is underway. The 

tissue blocks, stored at the NTP Archives, were derived from NTP 

studies. 

Screening of chemical toxicity in stem cells

Study Scientists: Stephen Ferguson, Fred Parham, 

Jui-Hua Hsieh, Mamta Behl

Screening for chemical toxicity in human or mouse stem cell lines 

(undifferentiated or differentiated) by quantitative high-throughput 

screening at the NCATS Chemical Genomics Center or by using 

lower throughput assays at NIEHS. Stem cell technology platforms 

and model systems shown to be useful for in vitro toxicology 

screening were employed with larger sets of chemicals for hazard 

identification and chemical prioritization for toxicity testing. Data 

were generated on a library of 80+ predominantly developmental 

neurotoxicants evaluated for effects on neurite outgrowth in a 

human stem cell-derived neural cell population, cytotoxicity in 

different neural populations derived from human stem cells, and 

effects on the beating of human stem cell-derived cardiomyocytes. 

Dose-response analyses have been completed on the data from 

these assays. Two manuscripts were published in FY 2017. 
2017 Annual Report – Research and Testing – Tox21 – Tox21 Projects

73

High-throughput assays and computational models 

to replace current EPA Endocrine Disruptor 

Screening Program Tier 1 tests 

Study Scientists: Warren Casey, Nicole 

Kleinstreuer

Development of an approach using validated ToxCast and Tox21 

high-throughput assays and an associated computational model to 

replace three Tier 1 tests currently used to assess estrogenic 

activity in the EPA Endocrine Disruptor Screening Program. The 

approach was developed and validated by EPA and NICEATM 

scientists. EPA solicited public comments on the plan in June 2015. 

The method has been described in several publications. In FY 

2017, a similar computational model was developed for androgenic 

activity. 

Data Analysis

Project & Study Scientist Project Summary

Analysis of Tox21 quantitative high-throughput 

screening assay data 

Study Scientist: Jui-Hua Hsieh

Development of data analysis pipelines for Tox21 Phase II 

quantitative high-throughput screening data to determine the activity 

of compounds in assays. The developed ranking, or calling 

procedure, accounts for compound potency, efficacy, and data 

reproducibility. A manuscript describing this pipeline was published, 

and computational tools to analyze Tox21 data have been made 

publicly available through the Tox21 Toolbox on the NTP public 

website.

Prioritization of Tox21 compounds for genotoxicity

Study Scientists: Jui-Hua Hsieh, Kristine Witt, 

Stephanie Smith-Roe

Development of a prioritization approach that includes compounds 

showing clear evidence of activity in the quantitative highthroughput screening genotoxic assays and compounds that are 

weakly active based on chemical structure-activity relationship 

analysis. A manuscript using this approach as part of the analysis of 

the Tox21 quantitative high-throughput screening p53 activation 

assay was published in FY 2017. In addition, a more extensive 

modeling exercise has been completed using data from all Tox21 

quantitative high-throughput screening assays. A second 

manuscript describing the outcome of this modeling approach for 

identifying genotoxicants is in preparation.

Design of Tox21 data exploration graphical user 

interface

Study Scientist: Jui-Hua Hsieh

Development of two graphical user interfaces for viewing Tox21 

data. One graphical user interface is used to explore the 

concentration-response data in a line chart, and the second is used 

to explore compound similarity relationships in terms of their 

chemical structures and activities in Tox21 quantitative highthroughput screening assays. Prototype graphical user interfaces 

were first developed during FY 2013 and made public in FY 2015.

These computational tools to analyze Tox21 data have since been 

developed further and expanded and made publicly available 

through the Tox21 Toolbox on the NTP public website.

Unsupervised, data-driven analysis of Tox21 assay 

data project

Study Scientist: Scott Auerbach

Use of unsupervised data analysis methods (data organization 

based on patterns and performed by software) to identify chemicals 

that exhibit biological properties similar to those of wellcharacterized toxicants from the quantitative high-throughput 

screening assays used to screen the 10K library. The results are 

being used to help prioritize compounds for more extensive 

toxicological testing. Updated web interfaces for multiple integrated 

tools will be made public in FY 2018 along with supporting 

manuscripts.

High-throughput in vitro-in vivo extrapolation 

(IVIVE) using Tox21 data

Development and refinement of ways to extrapolate all Tox21 

chemical-concentration effect data to estimated human equivalent 

exposure doses. This effort builds on previous efforts (outside of 
2017 Annual Report – Research and Testing – Tox21 – Tox21 Projects

74

Study Scientist: Nisha Sipes NTP) using high-throughput toxicokinetics models and combines it 

with in silico-estimated parameters. The development of this 

method is described in a manuscript published in FY 2017, and a 

publicly available web application is available through the Tox21 

Toolbox on the NTP public website. Refinement of the model is 

ongoing.

Cell-line selection for Tox21 Phase III

Study Scientist: Nisha Sipes

Development and use of a data-driven approach for choosing cells 

to maximize biological diversity. This project is an established 

Tox21 Cross-Partner Project. Gene expression data from existing 

resources such as transcriptomics databases are used, and in vitro 

chemical testing is anticipated. 

Aggregated hit-call of Tox21 data

Study Scientist: Nisha Sipes

Comparison of Tox21 data analysis methods, identification of 

higher-confidence chemical-assay actives, and development of a 

website for public access to the data and visualizations. A web 

interface with the aggregated hit-call function is anticipated in FY 

2018.

Next-generation sequencing in toxicology

Study Scientists: Alex Merrick, Kristine Witt

Development of bioinformatics pipelines for genomic and 

transcriptomic gene expression and mutational analysis on a 

genome-wide level using next-generation sequencing technologies 

to build signatures of toxicity and chemical exposure. This effort 

was recently expanded to evaluate gene expression changes in 

frozen tissue samples obtained from genetic toxicity studies 

conducted at the NTP Genetic Toxicity Testing laboratory. In 

addition, new informatic tools have been developed to better identify 

long non-coding RNAs (lncRNAs).

Development of a reference database for 

estrogenic activity

Study Scientists: Warren Casey, Nicole 

Kleinstreuer

Support for future validation of high-throughput in vitro test methods 

and in silico models of estrogenic activity. NICEATM created a 

comprehensive database of high-quality in vivo data from over 

1,000 scientific articles describing uterotrophic assay experiments 

for more than 2,660 distinct combinations of chemicals, studies, and 

protocols. These data have potential utility for developing adverse

outcome pathways or models of estrogenic activity, prioritizing 

chemicals for further testing, or evaluating species-specific 

responses to chemicals. The database is described in a manuscript

published in FY 2016. This activity is complete, but the database is 

being used as a training set for the automation of systematic 

reviews.

Development of an approach for in vitro-in vivo 

extrapolation using Tox21 data

Study Scientists: Warren Casey, Nicole 

Kleinstreuer

Quantitative correlation of in vitro and in vivo dosimetry for estrogen 

receptor reference chemicals. Using collective results of 16 Tox21 

and ToxCast estrogen receptor pathway related assays, NICEATM

developed and applied one-compartment or physiologically based 

pharmacokinetic models to correlate in vitro and in vivo dosimetry 

quantitatively for estrogen receptor reference chemicals. This 

approach highlights the importance of pharmacokinetic 

considerations in assessing and ranking endocrine-active chemicals 

based on in vitro, high-throughput screening assays. The initial 

approach and results are described in a published manuscript. 

Refinements to the approach are ongoing and are described in a 

manuscript expected to be published in FY 2018. 

Evaluation of Tox21 data for predicting acute oral 

toxicity

Determination of the potential of high-throughput screening data to 

reduce animal use for acute oral toxicity testing. NICEATM 

analyzed high-throughput screening data from Tox21 and ToxCast 

for correlation and model fitting to rat oral LD50 data. The goal of 
2017 Annual Report – Research and Testing – Tox21 – Tox21 Projects

75

Study Scientists: Warren Casey, Nicole 

Kleinstreuer

the analysis is to determine which tests or combinations of tests 

best characterize the rat oral toxicity data. The analysis suggests 

that combinations of in vitro assays and data from small model 

organisms, such as zebrafish, offer promise for predicting outcomes 

of rat acute oral toxicity tests. A global collaboration to use 

quantitative structure-activity relationships, Tox21, and other 

alternative sources to predict acute oral toxicity has been initiated. 

Development of in silico methods for predicting 

metabolism

Study Scientist: Stephen Ferguson

Evaluation of various in silico methods for predicting the extent of 

xenobiotic metabolism and identifying metabolites and for 

prioritizing chemicals in the Tox21 10K library. Computational 

methods are used to partition the 10K library and develop subsets 

of chemicals that are likely to be metabolized appreciably in 

humans. 

Selection of a target set of genes for use in a highthroughput transcriptomics screen

Study Scientists: Rick Paules, Scott Auerbach, 

Elizabeth Maull, Alex Merrick, Nisha Sipes

Identification of patterns of exposure-induced biological responses 

to characterize toxicity and disease pathways and facilitate 

extrapolation of findings from model species to humans. An effort 

has begun to select a set of 1,500 sentinel genes, or the S1500 set 

of genes, that best captures and represents the full biological 

response to exposures and disease for use in a high-throughput 

transcriptomics screening assay. Additional genes, identified as 

being particularly informative to toxicological processes, were 

added to the S1500 set, giving rise to the S1500+ set of 

approximately 2,750 genes. Criteria were developed for selecting 

the best target set of genes representing humans, rats, mice, and 

zebrafish. A manuscript describing this selection process was 

submitted in FY 2017 and is currently under revision.

Development of a computational model for 

androgen receptor pathway activity

Study Scientists: Warren Casey, Nicole 

Kleinstreuer

Integration of data from nine Tox21 and ToxCast assays into a 

computational model that predicts agonist and antagonist activity 

against the androgen receptor pathway. A manuscript describing 

this work was published in FY 2017. 

Development of quantitative structure-activity 

relationship (QSAR) models to predict androgen 

receptor binding and activity

Study Scientists: Warren Casey, Nicole 

Kleinstreuer

Development of QSAR models to predict androgen receptor binding 

and activity. Using the computational model of the androgen 

receptor pathway, NICEATM developed QSAR models to predict 

androgen receptor binding and activity. These QSAR models are 

currently being refined, with a goal of using them to predict 

androgen receptor pathway activity of chemicals in the EPA 

Endocrine Disruptor Screening Program. A manuscript is expected 

to be published in FY 2018. 

Development of a reference database for 

androgen receptor activity

Study Scientists: Warren Casey, Nicole 

Kleinstreuer

Development of a reference chemical list for in vitro androgen 

receptor binding and transactivation assay activity. NICEATM is 

conducting literature reviews to identify information about in vitro 

androgen receptor binding and transactivation assays for 127 

putative androgen-active or androgen-inactive chemicals. The final 

database will be made available to the public on the NTP website. A 

parallel EPA data curation effort focuses on in vivo androgen 

activity data. These data will be used for evaluating high-throughput 

screening approaches, testing strategies, and further development 

of alternative test methods. A manuscript describing this work was 

published in FY 2017.

Development of a bioactivity-based, read-across 

approach

Use of bioactivity data from ToxCast to characterize untested 

environmental chemicals based on their similarities to chemicals 

with known toxicological effects. NICEATM used computational 
2017 Annual Report – Research and Testing – Tox21 – Tox21 Projects

76

Study Scientists: Warren Casey, Nicole 

Kleinstreuer

methods to create clusters of tested chemicals based on their 

activity in ToxCast assays. Clusters containing known toxicants 

were examined to identify similar in vitro bioactivity patterns in 

environmental chemicals lacking in vivo data. A new ICCVAM 

working group on the read-across approach was formed in FY 

2017.

Development of software and methods for 

performing genomic dose-response analysis

Study Scientist: Scott Auerbach

Development of methods and software for performing genomic 

dose-response analysis to identify sensitive, screening-level 

potency estimates. An expert panel meeting to discuss the 

proposed method was held and software released in FY 2017. 

Testing Projects

Project & Study Scientist Project Summary

Epigenetic changes in chemical toxicity 

Study Scientist: Alex Merrick

Determination of methylation patterns on a genome-wide basis and 

validate selected CpG sites (regions of DNA where a cytosine 

nucleotide occurs next to a guanine nucleotide) altered by chemical 

exposure. Methylation of CpG sites can turn a gene off, while 

demethylation can cause transcriptional activation. A generalized 

approach for methylated DNA enrichment has been developed, and 

a manuscript describing the findings was submitted for publication.

Polycyclic aromatic hydrocarbons (PAHs) 

Study Scientist: Stephen Ferguson

Evaluation of approximately 20 PAHs considered relevant to human 

exposure in metabolism-competent HepaRG cells using multiplexed 

high-content screening assays and gene expression platforms. 

Studies are in progress.

NTP WormTox Laboratory Projects

Project & Study Scientist Project Summary

Mitochondrial toxicants 

Study Scientists: Windy Boyd, Mamta Behl, Jui-Hua 

Hsieh

Determination of the effects of the mitochondrial toxicant subset 

from the Tox21 10K library on Caenorhabditis elegans growth and 

in vivo adenosine-5’-triphosphate levels and membrane potential. 

Compounds for testing were received in late FY 2014. Testing 

occurred in FY 2015, and a manuscript reporting the findings was 

published in FY 2017. 
2017 Annual Report – Research and Testing – Testing and Toxicology Studies

77

Testing and Toxicology Studies

About Testing and Toxicology Studies

The NTP testing program evaluates substances for a variety of health-related effects, 

generally using rodent models for study.

Disposition, Metabolism, and Toxicokinetic Studies

A list of substances evaluated through disposition, metabolism, and toxicokinetic 

studies.

Genetic Toxicity Studies

A list of substances tested for genetic toxicity.

Organ System Toxicity Studies

A list of substances tested for toxicity in organ systems.

Modified One-Generation Reproduction Studies

A list of planned or ongoing modified one-generation studies in FY 2017. 

Toxicology and Carcinogenicity Studies

A list of prechronic and chronic toxicity and carcinogenicity studies that were initiated, 

ongoing, or completed during FY 2017. 

Toxicogenomic Studies

A list of planned or ongoing toxicogenomic studies in FY 2017. 
2017 Annual Report – Research and Testing – Testing and Toxicology Studies

78

Project Review Committee Approved

A list of studies approved by either the internal NIEHS/NTP protocol approval 

committee or the internal NIEHS/NTP project review committee that were not started 

during FY 2017. 
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – About Studies

79

About Testing and Toxicology Studies

The NTP testing program evaluates substances for a variety of 

health-related effects, generally using rodent models. For each test 

article, a study team develops an appropriate testing strategy to 

address the identified research needs, and a project review 

committee evaluates the strategy. Reports and summaries of NTP 

toxicity studies, including carcinogenicity and effects on 

development and reproduction, are available on the NTP website.

The following Division of NTP branches at NIEHS are involved in 

the testing program: Biomolecular Screening Branch, led by acting 

chief Rick Paules, Ph.D.; Cellular and Molecular Pathology Branch, 

led by Robert Sills, D.V.M., Ph.D.; NTP Laboratory, led by acting 

chief Michael DeVito, Ph.D.; Program Operations Branch, led by 

Michelle Hooth, Ph.D.; and Toxicology Branch, led by Paul Foster, 

Ph.D.

Studies initiated, ongoing, or completed in 2017 are listed in this 

section. 

Related Links

Disposition, Metabolism, and 

Toxicokinetic Studies

Genetic Toxicity Studies

Organ System Toxicity Studies

Modified One-Generation 

Reproduction Studies

Toxicology and Carcinogenicity 

Studies

Toxicogenomic Studies

Project Review Committee 

Approved
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – ADME

80

Disposition, Metabolism, and Toxicokinetic Studies

Complete dosimetry of a chemical or physical agent describes its absorption, distribution, 

metabolism, and excretion in the body of both humans and test animals at differing levels of 

exposure, of all ages, via several routes of exposure, and under varying genetic backgrounds. 

Substances evaluated during FY 2017 are listed below.

Disposition, Metabolism, and Toxicokinetics Studies During FY 2017 

Test Article CASRN* Species Route Status Study Scientist

2-((1-(4-

Phenoxyphenoxy)propan-2-

yl)oxy)pyridine

95737-68-1 Rabbit Gavage Initiated Vicki Sutherland

2-((1-(4-

Phenoxyphenoxy)propan-2-

yl)oxy)pyridine

95737-68-1 Rats Gavage Initiated Vicki Sutherland

2-Ethylhexyl pMethoxycinnamate5466-77-3 Mice, Rats Dermal, Gavage, 

Intravenous

Completed Barry McIntyre

2-Ethylhexyl pMethoxycinnamate5466-77-3 Rats Dosed-Feed, Gavage, 

Intravenous

Ongoing Barry McIntyre

Bisphenol AF 1478-61-1 Mice, Rats Gavage, Intravenous Ongoing Vicki Sutherland

Bisphenol S 80-09-1 Mice, Rats Gavage, Intravenous Completed Vicki Sutherland

Efavirenz (EFV) 154598-52-4 Mice Gavage Ongoing Barry McIntyre

Emtricitabine (FTC) 143491-57-0 Mice Gavage Ongoing Barry McIntyre

Hydroquinone 123-31-9 Mice, Rats Gavage, Intravenous, 

Topical Application

Completed Vicki Sutherland

Nanoscale Silver 7440-22-4 Rats Gavage Ongoing Nigel Walker

Nanoscale Silver 7440-22-4 Rats Intravenous Ongoing Nigel Walker

N-Butylbenzenesulfonamide 3622-84-2 Mice, Rats Gavage, Intravenous Completed Cynthia Rider

Resveratrol 501-36-0 Mice, Rats Gavage, Intravenous Ongoing Dori Germolec

Sodium arsenite 7784-46-5 Mice, 

Monkey, 

Rats

Dosed-Feed, DosedWater, GavageOngoing Daniel Doerge

Sulfolane 126-33-0 Mice, Rats Gavage, Intravenous Completed Chad Blystone

Tenofovir Disoproxil 

Fumarate (TDF)

202138-50-9 Mice Gavage Ongoing Barry McIntyre

Triclocarban 101-20-2 Mice, Rats Dermal, Gavage Completed Vicki Sutherland

Triclosan 3380-34-5 Mice Topical Application Ongoing Vicki Sutherland

Triclosan 3380-34-5 Mice Topical Application Ongoing Jia-Long Fang
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – ADME

81

Test Article CASRN* Species Route Status Study Scientist

Tris(4-chlorophenyl)methane 27575-78-6 Mice, Rats Gavage, Intravenous Completed Natasha Catlin

Tris(4-

chlorophenyl)methanol

3010-80-8 Mice, Rats Gavage, Intravenous Completed Natasha Catlin

Tris(Chloropropyl)phosphate 13674-84-5 Mice, Rats Gavage, Intravenous Ongoing Kristen Ryan

Vinpocetine 42971-09-5 Rats Gavage Ongoing Natasha Catlin

Related Links: 

Genetic Toxicity Studies 

Organ System Toxicity Studies 

Modified One-Generation Reproduction Studies

Toxicology and Carcinogenicity Studies 

Toxicogenomic Studies 

Project Review Committee Approved 
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Genetic Toxicity

82

Genetic Toxicity Studies

Genetic toxicity test results are used to help interpret general toxicity, carcinogenicity, or other in vivo 

test results and to provide a database for use in structure-activity relationship analysis. During FY 

2017, NTP completed genetic toxicity testing for one substance, 2,2'-Dimorpholinodiethyl Ether

(CASRN 6425-39-4). 

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies

Organ System Toxicity 

Modified One-Generation Reproduction Studies 

Toxicology and Carcinogenicity Studies 

Toxicogenomic Studies 

Project Review Committee Approved 
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Organ System Toxicity

83

Organ System Toxicity Studies

NTP studies toxicity of environmental substances on development, reproduction, and on the nervous 

and immune systems. Organ systems toxicity studies conducted during FY 2017 are listed below. 

Neurotoxicity, Developmental Toxicity, and Reproductive Toxicity Studies During FY 2017 

Test Article CASRN* Species Testing

Battery Length Route Status Study Scientist

2-((1-(4-

Phenoxyphenoxy)propa

n-2-yl)oxy)pyridine

95737-68-1 Rabbit Conventional 

Teratology

3 weeks Gavage Scheduled Vicki 

Sutherland

2-((1-(4-

Phenoxyphenoxy)propa

n-2-yl)oxy)pyridine

95737-68-1 Rabbit Conventional 

Teratology

GD 7-28 Gavage Initiated Vicki 

Sutherland

2-((1-(4-

Phenoxyphenoxy)propa

n-2-yl)oxy)pyridine

95737-68-1 Rabbit Teratology Pilot 

Studies

-- Gavage Scheduled Vicki 

Sutherland

2-((1-(4-

Phenoxyphenoxy)propa

n-2-yl)oxy)pyridine

95737-68-1 Rats Conventional 

Teratology

GD 6-21 Gavage Initiated Vicki 

Sutherland

2-((1-(4-

Phenoxyphenoxy)propa

n-2-yl)oxy)pyridine

95737-68-1 Rats Immunotoxicity 28 days Gavage Initiated Vicki 

Sutherland

2-Hydroxy-4-

methoxybenzophenone

131-57-7 Rats Developmental 

Toxicity

35 days DosedFeedCompleted Deborah 

Hansen

2-Hydroxy-4-

methoxybenzophenone

131-57-7 Rats Developmental 

Toxicity

GD 6 to 

PND 21

DosedFeedOngoing Deborah 

Hansen

2-Hydroxy-4-

methoxybenzophenone

131-57-7 Rats Developmental 

Toxicity

GD 6 to GD 

15

DosedFeedOngoing Deborah 

Hansen

Acenaphthenequinone 82-86-0 Mice Immunotoxicity 28 days Gavage Initiated Cynthia 

Rider

Arsenic 7440-38-2 Rats Developmental 

Toxicity

Pregnant 

dams 

through 

PND21

Gavage & 

DosedWater

Initiated Sherry 

Ferguson

Benz(j)aceanthrylene 202-33-5 Mice Immunotoxicity 28 days Gavage Scheduled Cynthia 

Rider

Benzo(a)pyrene 50-32-8 Mice Immunotoxicity 28 days Gavage Ongoing Cynthia 

Rider

Benzo(b)fluoranthene 205-99-2 Mice Immunotoxicity 28 days Gavage Scheduled Dori 

Germolec

Benzo(c)fluorene 205-12-9 Mice Immunotoxicity 28 days Gavage Scheduled Dori 

Germolec
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Organ System Toxicity 

84

Test Article CASRN* Species Testing 

Battery Length Route Status Study Scientist

Benzo(k)fluoranthene 207-08-9 Mice Immunotoxicity 28 days Gavage Scheduled Dori

Germolec

Bisphenol AF 1478-61-1 Rats Immunotoxicity GD 6 -

PND 96

DosedFeedOngoing Vicki 

Sutherland

Chrysene 218-01-9 Mice Immunotoxicity 28 days Gavage Initiated Cynthia 

Rider

Dibenz(a,h)anthracene 53-70-3 Mice Immunotoxicity 28 days Gavage Initiated Cynthia 

Rider

Dibenz(a,h)anthracene 53-70-3 Mice Immunotoxicity 8 GD -

PND 42

Subcutane

ous 

Injection

Ongoing Cynthia 

Rider

Dibenzo(a,l)pyrene 191-30-0 Mice Immunotoxicity 28 days Gavage Initiated Cynthia 

Rider

Dibenzothiophene 132-65-0 Mice Immunotoxicity 28 days Gavage Initiated Cynthia 

Rider

Efavirenz (EFV) 154598-52-4 Mice Teratology Pilot 

Studies

GD 5 -

PND 21

Gavage Ongoing Anika 

Anika 

Dzierlenga

Indeno(1,2,3-cd)pyrene 193-39-5 Mice Immunotoxicity 28 days Gavage Scheduled Cynthia 

Rider

NButylbenzenesulfonamid

e 

3622-84-2 Mice Immunotoxicity 28 days DosedFeedInitiated Cynthia 

Rider

NButylbenzenesulfonamid

e 

3622-84-2 Rats Immunotoxicity GD 6 -

PND 42

DosedFeedInitiated Cynthia 

Rider

Phenanthrene 85-01-8 Mice Immunotoxicity 28 days Gavage Ongoing Cynthia 

Rider

Pyrene 129-00-0 Mice Immunotoxicity 28 days Gavage Ongoing Cynthia 

Rider

Sodium Metavanadate 13718-26-8 Mice Immunotoxicity 28 days DosedWaterOngoing Georgia 

Roberts

Sulfolane 126-33-0 Mice Immunotoxicity 13 weeks Gavage Ongoing Chad 

Blystone

Sulfolane 126-33-0 Rats Immunotoxicity 13 weeks Gavage Ongoing Chad 

Blystone

Tenofovir Disoproxil 

Fumarate (TDF)

202138-50-9 Mice Teratology Pilot 

Studies

GD 5 -

PND 21

Gavage Ongoing Anika 

Dzierlenga
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Organ System Toxicity 

85

Test Article CASRN* Species Testing 

Battery Length Route Status Study Scientist

Tricombination 

FTC:TDF:EFV (1:1.5:3)

N/A Mice Maternal 

Transfer

GD 5-15 Gavage Completed Barry 

McIntyre

Tricombination 

FTC:TDF:EFV (1:1.5:3)

N/A Mice Teratology Pilot 

Studies

GD 5 - GD 

18

Gavage Completed Barry 

McIntyre

Tricombination 

FTC:TDF:EFV (1:1.5:3)

N/A Mice Teratology Pilot 

Studies

-- Gavage Scheduled Anika 

Dzierlenga

Tris(Chloropropyl)phosp

hate

13674-84-5 Rats Immunotoxicity GD 6 -

PND 127

DosedFeedInitiated Kristen 

Ryan

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies 

Genetic Toxicity Studies 

Modified One-Generation Reproduction Studies 

Toxicology and Carcinogenicity Studies 

Toxicogenomic Studies 

Project Review Committee Approved 
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Modified One-Generation

86

Modified One-Generation Reproduction Studies

NTP modified one-generation study design emphasizes a full evaluation of the first generation 

offspring of animals and uses fewer animals than the classical multigenerational study design. These 

studies generate information on the effects of substances on prenatal development, postnatal 

development, and reproduction. Planned or ongoing modified one-generation studies are listed 

below. 

Modified One-Generation Studies in FY 2017 

Test Article CASRN* Species Testing Battery Status Study 

Scientist

2,2'-Dimorpholinodiethyl Ether 6425-39-4 Rats Repeated Dose Gavage Georgia 

Roberts

Bisphenol S 80-09-1 Rats Dose Range Finding Dosed-Feed Vicki 

Sutherland

Echinacea purpurea root extract 90028-20-9 Rats Dose Range Finding Gavage Kristen Ryan

Ethylene glycol 2-ethylhexyl ether 1559-35-9 Rats Dose Range Finding Gavage Chad 

Blystone

Isopropylated Phenol Phosphate 68937-41-7 Rats Dose Range Finding Dosed-Feed Mamta Behl

N-Butylbenzenesulfonamide 3622-84-2 Rats Developmental Toxicity Dosed-Feed Cynthia Rider

N-Butylbenzenesulfonamide 3622-84-2 Rats F0 Generation Dosed-Feed Cynthia Rider

N-Butylbenzenesulfonamide 3622-84-2 Rats Maternal Transfer Dosed-Feed Cynthia Rider

Resveratrol 501-36-0 Rats F0 Generation Gavage Anika 

Dzierlenga

Simvastatin 79902-63-9 Rats Dose Range Finding Gavage Barry 

McIntyre

Triclosan 3380-34-5 Rats Dose Range Finding Gavage Vicki 

Sutherland

Tricombination FTC:TDF:EFV 

(1:1.5:3)

N/A Mice F0 Generation Gavage Anika 

Dzierlenga

Triphenyl Phosphate 115-86-6 Rats Dose Range Finding Dosed-Feed Mamta Behl

Tris(4-chlorophenyl)methane 27575-78-6 Rats Dose Range Finding Dosed-Feed Natasha 

Catlin

Valerian (Valeriana officinalis L.) 

root extract

8057-49-6 Rats Dose Range Finding Gavage Georgia 

Roberts

Wyeth 14,643 (WY) 50892-23-4 Mice, Rats Dose Range Finding Gavage Chad 

Blystone
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Modified One-Generation

87

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies

Genetic Toxicity Studies 

Organ System Toxicity Studies 

Toxicology and Carcinogenicity Studies 

Toxicogenomic Studies 

Project Review Committee Approved
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity

[ 

88

Toxicology and Carcinogenicity Studies

NTP performs toxicity studies to provide dose-setting information for chronic studies and to address 

specific deficiencies in the toxicology database for the chemical. Toxicology and carcinogenicity 

studies fall into two categories: prechronic toxicity studies and chronic two-year toxicology and 

carcinogenicity studies. Studies are generally conducted in rats and mice. 

Each study type is performed according to the Specifications for the Conduct of Studies to Evaluate 

the Reproductive and Developmental Toxicity of Chemical, Biological and Physical Agents in 

Laboratory Animals for the National Toxicology Program (NTP) (May 2011). Prechronic and chronic 

toxicity studies and carcinogenicity studies, that were initiated, ongoing, or completed during FY 

2017, are listed below. 

Prechronic Toxicology and Carcinogenicity Studies FY 2017 

Test Article CASRN* Species Length Route Status Study 

Scientist

(+)-Usnic Acid 7562-61-0 Mice, Rats 2 weeks Dosed-Feed Ongoing Julian 

Leakey

(+)-Usnic Acid 7562-61-0 Mice, Rats 90 days Dosed-Feed Ongoing Julian 

Leakey

1,2,4-trimethylbenzene 95-63-6 Mice, Rats 13 weeks Inhalation Initiated Dan Morgan

1,2-Bis(2,4,6-

tribromophenoxy)ethane

37853-59-1 Rats 5 days Gavage Initiated June Dunnick

1,2-

bis(pentabromophenyl)ethane

84852-53-9 Rats 5 days Gavage Initiated June Dunnick

1,3,5,7,9,11-

Hexabromocyclododecane

25637-99-4 Rats 5 days Gavage Initiated June Dunnick

1020 Long Multiwalled 

Carbon Nanotube

N/A Mice, Rats 2 years Inhalation Ongoing Dan Morgan

1020 Long Multiwalled 

Carbon Nanotube

N/A Mice, Rats 30 days Inhalation Ongoing Dan Morgan

2,2',4,4'-Tetrabromodiphenyl 

Ether

5436-43-1 Rats 5 days Gavage Initiated June Dunnick

2,2'-Dimorpholinodiethyl Ether 6425-39-4 Mice 28 days Gavage Ongoing Troy 

Hubbard

2-Ethylhexyl Diphenyl

Phosphate

1241-94-7 Rats 5 days Gavage Ongoing Scott 

Auerbach

2-ethylhexyl-2,3,4,5-

tetrabromobenzoate

183658-27-7 Rats 5 days Gavage Initiated June Dunnick

3,3',4,4'-

Tetrachloroazobenzene

14047-09-7 Rats 5 days Gavage Initiated Mamta Behl

Acrylamide 79-06-1 Rats 5 days Gavage Initiated Frederick 

Beland
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity

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Test Article CASRN* Species Length Route Status Study 

Scientist

Aging Cohort Study: 

12951/SvlmJ mouse

N/A Mice 2 years N/A Ongoing June Dunnick

Aging Cohort Study: A/J 

mouse

N/A Mice 2 years N/A Ongoing June Dunnick

Aging Cohort Study: 

B6C3F1J mouse

N/A Mice 2 years N/A Ongoing June Dunnick

Aging Cohort Study: C3H/HeJ 

mouse

N/A Mice 2 years N/A Ongoing June Dunnick

Aging Cohort Study: 

C57/BL/6J mouse

N/A Mice 2 years N/A Ongoing June Dunnick

Aging Cohort Study: 

CAST/EiJ mouse

N/A Mice 2 years N/A Ongoing June Dunnick

Aging Cohort Study: NOD. 

B10Sn-H2(b)/J

N/A Mice 2 years N/A Ongoing June Dunnick

Aging Cohort Study: 

NZO/HiLtJ mouse

N/A Mice 2 years N/A Ongoing June Dunnick

Aging Cohort Study: 

PWK/PhJ mouse

N/A Mice 2 years N/A Ongoing June Dunnick

Aging Cohort Study: WSB/EIJ 

mouse

N/A Mice 2 years N/A Ongoing June Dunnick

Aloin 1415-73-2 Rats 13 weeks Dosed-Water Ongoing Mary 

Boudreau

alpha/beta Thujone mixture 76231-76-0 Rats 5 days Gavage Initiated William 

Gwinn

alpha-Pinene 80-56-8 Mice, Rats 2 years Inhalation Ongoing Cynthia Rider

Antimony Trioxide 1309-64-4 Mice, Rats 2 weeks Inhalation Ongoing Matt Stout

Antimony Trioxide 1309-64-4 Mice, Rats 2 years Inhalation Ongoing Matt Stout

AZT/Drug Combinations 

Transplacental/Neonatal 

Study

N/A Mice 2 years Gavage Ongoing Frederick 

Beland

Bis(2-chloroethoxy)methane 111-91-1 Mice 10 days, 3 

days

Gavage Completed June Dunnick

Bis(2-ethylhexyl) 

tetrabromophthalate

26040-51-7 Rats 5 days Gavage Initiated June Dunnick

Bisphenol AF 1478-61-1 Rats 5 days Gavage Initiated Vicki 

Sutherland
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90

Test Article CASRN* Species Length Route Status Study 

Scientist

Bisphenol S 80-09-1 Mice 14 days Dosed-Feed Initiated Vicki 

Sutherland

Black Cohosh 84776-26-1 Mice 90 days Gavage Ongoing Michelle 

Cora

Black Cohosh 84776-26-1 Mice, Rats 2 years Gavage Ongoing Chad 

Blystone

Brominated Vegetable Oil 8016-94-2 Rats 90 days -- Initiated Gamboa da 

Costa

Cell Phone Radiation: CDMA N/A Mice, Rats 2 years Whole Body 

Exposure

Ongoing Michael 

Wyde

Cell Phone Radiation: GSM N/A Mice, Rats 2 years Whole Body 

Exposure

Ongoing Michael 

Wyde

Coumarin 91-64-5 Rats 5 days Gavage Initiated June Dunnick

Crumbrubber various N/A Mice 14 days N/A Initiated Georgia 

Roberts

Cumene 98-82-8 Mice, Rats 14 days Inhalation Ongoing Georgia 

Roberts

Decabromodiphenyl Ether 1163-19-5 Rats 5 days Gavage Initiated June Dunnick

Di(2-ethylhexyl) Phthalate 117-81-7 Rats 2 years Dosed-Feed Ongoing Troy 

Hubbard

Di(2-ethylhexyl) Phthalate 117-81-7 Rats 5 days Gavage Initiated Troy 

Hubbard

Di(2-ethylhexyl) Phthalate 117-81-7 Rats Perinatal + 2 

years

Dosed-Feed Ongoing Troy 

Hubbard

Dibutyl Phthalate 84-74-2 Mice, Rats 2 years Dosed-Feed Ongoing Chad 

Blystone

Dimethylamine Borane 74-94-2 Mice, Rats 2 weeks Dermal Ongoing Dori 

Germolec

Ephedrine + caffeine 

combination

N/A Mice 10 days, 3 

days

Gavage Completed June Dunnick

Ethinyl estradiol 57-63-6 Rats 2 weeks Subcutaneou

s Injection

Ongoing Todd Auman

Ethinyl estradiol 57-63-6 Rats 5 days Gavage Initiated Todd Auman

Fenofibrate 49562-28-9 Rats 5 days Gavage Initiated Barry 

McIntyre

Formaldehyde 50-00-0 Mice 2 weeks Inhalation Ongoing Dan Morgan
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity 

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91

Test Article CASRN* Species Length Route Status Study 

Scientist

Formaldehyde 50-00-0 Mice 8 weeks Inhalation Ongoing Dan Morgan

Furan 110-00-9 Rats 5 days Gavage Initiated Frederick 

Beland

Ginkgo biloba extract 90045-36-6 Rats 5 days Gavage Ongoing Cynthia Rider

Goldenseal extract 84603-60-1 Rats 5 days Gavage Ongoing Cynthia Rider

Green Tea Extract N/A Rats 5 days Gavage Ongoing Cynthia Rider

Hexachlorobenzene 118-74-1 Rats 5 days Gavage Initiated Michael 

DeVito

Hexachlorocyclopentadienyldibromocyclooctane

51936-55-1 Rats 5 days Gavage Initiated June Dunnick

Indole-3-carbinol 700-06-1 Mice, Rats 2 years Gavage Completed Michael 

Wyde

Insertional Mutagenesis - 

Definitive Vector Study

N/A Mice 14 months Intravenous Ongoing Dori 

Germolec

Ionic Liquid: 1-Butyl-1-

methylpyrrolidinium Chloride

479500-35-1 Mice, Rats 90 days Dosed-Water Ongoing Kristen Ryan

Ionic Liquid: 1-Butyl-3-

methylimidazolium Chloride

79917-90-1 Mice, Rats 90 days Dosed-Water Completed Kristen Ryan

Ionic Liquid: 1-Ethyl-3-

methylimidazolium Chloride

65039-09-0 Mice, Rats 90 days Dosed-Water Ongoing Kristen Ryan

Ionic Liquid: NButylpyridinium Chloride1124-64-7 Mice, Rats 90 days Dosed-Water Ongoing Kristen Ryan

Isodecyl Diphenyl Phosphate 29761-21-5 Rats 5 days Gavage Ongoing Scott 

Auerbach

Isopropylated Phenol 

Phosphate

68937-41-7 Mice 2 weeks Dosed-Feed Ongoing Mamta Behl

Isopropylated Phenol 

Phosphate

68937-41-7 Rats 5 days Gavage Ongoing Scott 

Auerbach

Melamine + Cyanuric Acid 

combination

N/A Rats 90 days Gavage Ongoing Gamboa da 

Costa

Melamine + Cyanuric Acid 

combination

N/A Rats 90 days + 

recovery

Gavage Ongoing Gamboa da 

Costa

Metal Working Fluids: TRIM® 

VX

N/A Mice, Rats 13 weeks Inhalation Completed Kristen Ryan

Metal Working Fluids: TRIM® 

VX

N/A Mice, Rats 2 years Inhalation Completed Kristen Ryan
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity

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92

Test Article CASRN* Species Length Route Status Study 

Scientist

Methyleugenol 93-15-2 Rats 5 days Gavage Initiated Michael 

DeVito

Microbiome N/A -- -- N/A Ongoing Carl Cerniglia

Milk thistle extract 84604-20-6 Rats 5 days Gavage Initiated June Dunnick

Nanoscale Silver 7440-22-4 Rats 13 weeks Gavage Completed Mary 

Boudreau

N-Butylbenzenesulfonamide 3622-84-2 Mice 14 days Dosed-Feed Ongoing Cynthia Rider

ortho-Phthalaldehyde 643-79-8 Mice, Rats 90 days Inhalation Ongoing Michael 

Wyde

Pentabromodiphenyl Ether 

Mixture [DE-71 (Technical 

Grade)]

32534-81-9 Rats 5 days Gavage Initiated June Dunnick

Perfluorohexane sulfonate 

potassium salt (PFHSKslt)

3871-99-6 Rats 28 days Gavage Completed Chad 

Blystone

Perfluorohexanoic acid

(PFHXA)

307-24-4 Rats 28 days Gavage Completed Chad 

Blystone

Perfluorooctanoic Acid 335-67-1 Rats 2 years Dosed-Feed Ongoing Chad 

Blystone

Perfluorooctanoic Acid 335-67-1 Rats 28 days Gavage Completed Chad 

Blystone

Perfluorooctanoic Acid 335-67-1 Rats 5 days Gavage Initiated Chad 

Blystone

Phenolic Benzotriazoles (2-

(2H-benzotriazol-2-yl)-4,6-

bis(1-methyl-1-

phenylethyl)phenol)

70321-86-7 Rats 14 days Gavage Ongoing Chad 

Blystone

Phenolic Benzotriazoles (2-

(2H-benzotriazol-2-yl)-4,6-

bis(1,1-

dimethylpropyl)phenol)

25973-55-1 Rats 14 days Gavage Ongoing Chad 

Blystone

Phenolic Benzotriazoles (2-

(2H-Benzotriazol-2-yl)-4-tertbutylphenol)

3147-76-0 Rats 14 days Gavage Ongoing Chad 

Blystone

Phenolic Benzotriazoles (2-

(2H-Benzotriazol-2-yl)phenol)

10096-91-0 Rats 14 days Gavage Ongoing Chad 

Blystone

Phenolic Benzotriazoles (2-

(5-Chloro-2H-benzotriazol-2-

yl)-4,6-bis(1,1-

dimethylethyl)phenol)

3864-99-1 Rats 14 days Gavage Ongoing Chad 

Blystone
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity 

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93

Test Article CASRN* Species Length Route Status Study 

Scientist

Phenolic Benzotriazoles (3-

(2H-Benzotriazol-2-yl)-5-(1,1-

dimethylethyl)-4-

hydroxybenzenepropanoic 

acid, octyl ester)

84268-23-5 Rats 14 days Gavage Ongoing Chad 

Blystone

Phenolic Benzotriazoles 

(Bumetrizole)

3896-11-5 Rats 14 days Gavage Ongoing Chad 

Blystone

Phenolic Benzotriazoles 

(Drometrizole)

2440-22-4 Rats 14 days Gavage Ongoing Chad 

Blystone

Phenolic Benzotriazoles 

(Octrizole)

3147-75-9 Rats 14 days Gavage Ongoing Chad 

Blystone

p-Toluidine 106-49-0 Rats 5 days Gavage Ongoing June Dunnick

Pulegone 89-82-7 Rats 5 days Gavage Initiated Scott 

Auerbach

Resveratrol 501-36-0 Mice, Rats 13 weeks Gavage Ongoing Anika 

Dzierlenga

Resveratrol 501-36-0 Mice, Rats 2 weeks Gavage Ongoing Anika 

Dzierlenga

Resveratrol 501-36-0 Mice, Rats 2 years Gavage Ongoing Anika 

Dzierlenga

Sodium Tungstate Dihydrate 10213-10-2 Mice, Rats 2 years Dosed-Water Ongoing Mamta Behl

Sulfolane 126-33-0 Mice, Rats 2 years Dosed-Water Ongoing Chad 

Blystone

tert-Butylphenyl Diphenyl 

Phosphate

56803-37-3 Rats 5 days Gavage Ongoing Scott 

Auerbach

Tetrabromobisphenol A 79-94-7 Rats 13 weeks Gavage Ongoing June Dunnick

Tetrabromobisphenol A 79-94-7 Rats 5 days Gavage Initiated June Dunnick

Triclosan 3380-34-5 Mice 2 years Dermal Ongoing Jia-Long 

Fang

Triclosan 3380-34-5 Rats 5 days Gavage Initiated Vicki 

Sutherland

Tricresyl Phosphate 1330-78-5 Rats 5 days Gavage Ongoing Scott 

Auerbach

Trimethylsilyldiazomethane 

(TMSD)

18107-18-1 Mice, Rats 10 days Inhalation Ongoing William 

Gwinn

Triphenyl Phosphate 115-86-6 Mice 2 weeks Dosed-Feed Ongoing Mamta Behl
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity

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Test Article CASRN* Species Length Route Status Study 

Scientist

Triphenyl Phosphate 115-86-6 Rats 5 days Gavage Ongoing Scott 

Auerbach

Tris(Chloropropyl)phosphate 13674-84-5 Mice, Rats 2 years Dosed-Feed Ongoing Kristen Ryan

Tris(Chloropropyl)phosphate 13674-84-5 Mice, Rats 90 days Dosed-Feed Ongoing Kristen Ryan

Tris(Chloropropyl)phosphate 13674-84-5 Rats 5 days Gavage Initiated Kristen Ryan

Usnea Lichen N/A Mice, Rats 2 weeks Dosed-Feed Ongoing Julian 

Leakey

Valerian (Valeriana officinalis 

L.) root extract

8057-49-6 Mice 90 days Gavage Ongoing Troy 

Hubbard

Water disinfection byproducts 

(Bromodichloroacetic Acid)

71133-14-7 Rats 5 days Gavage Initiated Michael 

DeVito

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies

Genetic Toxicity Studies 

Organ System Toxicity Studies 

Modified One-Generation Reproduction Studies 

Toxicogenomic Studies 

Project Review Committee Approved 
95

2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicogenomics

Toxicogenomic Studies 

NTP is incorporating the latest toxicogenomic technologies into its testing program to gain further 

insights into the toxicity of environmental substances. Toxicogenomics examines how the entire 

genetic structure, or genome, influences an organism’s response to environmental toxicants.

Microarray, proteomic, metabolomics analyses, and next-generation (NextGen) sequencing are 

among the advanced technologies that NTP is using to study how chemical exposures change the

expression of genes, proteins, and metabolites in targeted cells and tissues. 

Measuring genome-wide changes in affected tissues could be useful for identifying disease

biomarkers, detecting exposure to toxic substances, and understanding individual genetic

susceptibilities. Once validated, biomarkers can be repeatedly sampled during long-term NTP studies

to determine if chemical exposures can be detected or if developing diseases (e.g., cancer) provide a 

genetic signature.

NTP is investigating whether pattern analysis of gene expression can provide toxicity indicators at 

(1) earlier time points and (2) lower doses than are possible using traditional toxicological parameters.

Evaluating patterns of gene expression is expected to provide insight into the pathogenesis of

disease and how different rodent models respond to toxicants. In addition, metabolomics provide an

opportunity to elucidate how chemicals affect metabolism within cells relative to changes in gene

expression.

Several FY 2017 toxicogenomic studies used NextGen sequencing technologies, which improves 

gene expression analysis, including base pair-level resolution of accuracy and increased sensitivity 

compared to microarray platforms. Although microarray analysis is a stable and well-understood 

technology for assaying gene expression, NextGen sequencing methods like RNA-Seq likely will 

become more common as sequencing costs decline and bioinformatic analyses become standardized 

and integrated with genomic sequencing. 

One promising research area is the application of exome sequencing (Exome-Seq) to either frozen or

formalin-fixed, paraffin-embedded tissues. DNA can be extracted from either frozen or archival 

tissues. Coding portions of DNA, or exons, are captured by libraries of hybridization-based probes

targeting over 200,000 exons and transcriptionally active regions. Exon-enriched DNA can be 

sequenced by DNA-Seq and then genomically aligned to find mutation insertions or deletions and 

other genetic abnormalities associated with disease.

Several NTP studies are using Exome-Seq for profiling mutations on a genome-wide scale to 

understand differences between spontaneous and chemically induced tumors. Another promising

NextGen sequencing-related area in toxicogenomics is the S1500+ platform. This platform provides a

way to use high-throughput transcriptomic (HTT) screening for thousands of genes per sample and 

can be applied to both in vitro chemical toxicity screening and in vivo screening of RNA extracted

from animal tissues.

NTP is evaluating study conditions that could contribute to differential gene expression, such as

animal and tissue variability, methods for tissue sampling, and standards for conducting

toxicogenomic studies under laboratory conditions. Efforts are underway to optimize methods for

DNA and RNA extraction from archival tissues for molecular analysis. Planned or ongoing NTP

toxicogenomic studies from FY 2017 are listed below.
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicogenomics

96

Toxicogenomic Studies Planned or Ongoing in FY 2017 

Chemical (CASRN*) Species/

Cell Line Route Duration Test Type(Platform)

Study 

Scientist

Anthraquinone (84-65-1)

Oxazepam (604-75-1)

DE-71 (32534-81-9)

Dibutyl phthalate (84-74-2)

PCTFT (98-56-6)

TCPP (115-96-8)

Bromodichloroacetic acid (5589-96-8)

Ginkgo biloba extract (90045-36-6)

Primaclone (125-33-7)

Bromochloroacetic acid (5589-96-8)

Mouse Gavage 2 years Infinium DNA 

methylation bead 

array

Arun Pandiri

Arsenite (7784-46-5) Human 

prostate 

cell line

In vitro 30 weeks NextGen 

sequencing 

Exome-Seq 

(Illumina)

Alex Merrick

2,3-Butanedione (diacetyl) (431-03-8)

2,3-Hexanedione (3848-24-6)

Human 

airway 

epithelium 

cell line

In vitro 4 days High-throughput 

transcriptomic 

screening

William Gwinn

Bisphenol A and analogs (80-05-7) Human 

hepatocyte 

cell line

In vitro 2 days High-throughput 

transcriptomic 

screening

Mike DeVito

BPAF (1478-61-1)

TBBPA (79-94-7)

Rat Gavage 5 days S1500+ 

NextGen 

sequencing

Sue Fenton

Bromodichloroacetic acid (5589-96-8)

Methyleugenol (93-15-2)***

Mouse Gavage 2 years NextGen 

sequencing 

Exome-Seq 

(Illumina)

Arun Pandiri

Dieldrin (60-57-1)

Ethinyl estradiol (57-63-6)

Methyl mercury (115-09-3)

Rotenone (83-79-4)

Phenol (68937-41-7)

Isopropylated phosphate (3:1) (60348-60-9)

Pentabromodiphenyl ether (60348-60-9)

Mouse In vitro 1 day S1500+, 

NextGen 

sequencing

Alison Harrill

DE-71 (32534-81-9)

PCB-126 (57465-28-2)

Phenobarbital (50-06-6)***

Rat Gavage GD** to 

PND 22

Microarray 

(Affymetrix)

June Dunnick
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicogenomics

97

Chemical (CASRN*) Species/

Cell Line Route Duration Test Type(Platform)

Study 

Scientist

Phosphate flame retardants:

tert-Butylphenyl diphenyl phosphate

(56803-37-3)

2-Ethylhexyl diphenyl phosphate (1241-94-7)

Isodecyl diphenyl phosphate (29761-21-5)

Isopropylated phenol phosphate (68937-41-7)

Rat Gavage 5 days Microarray 

(Affymetrix) 

Metabolomics

Scott Auerbach

Ginkgo biloba extract (90045-36-6) Rat Gavage 5 days Microarray 

(Affymetrix)

Cynthia Rider, 

Scott Auerbach

Induced Pluripotent Stem Cells

Embryoid bodies

Embryonic stem cells

Human 

stem cell

N/A N/A High-throughput 

transcriptomic 

screening

Erik Tokar, 

Mike DeVito

N/A Rat N/A 2 years Targeted 

resequencing

Arun Pandiri, 

Ramesh Kovi

2-Hydroxy-4- methoxybenzophenone (131-57-

7)

Rat Oral (food) 90 days Microarray 

(Affymetrix)

Scott Auerbach

Methyleugenol extract (93-15-2)

Ginkgo biloba extract (90045-36-6)***

Mouse Gavage 2 years NextGen 

sequencing 

Exome-Seq 

RNA-Seq 

(Illumina)

Arun Pandiri, 

Scott Auerbach, 

Alex Merrick

PCB-11 (2050-67-1) Rat 

Human 

hepatocyte 

cell line

In vitro 1 day S1500+ 

NextGen 

sequencing

Mike DeVito

2,3-Pentanedione (600-14-6) Rat Inhalation 14 and 28 

days

microRNA 

Microarray 

(Affymetrix)

Dan Morgan

PBDE-47 (32534-81-9) Rat Gavage 21 days Microarray June Dunnick

Polycyclic aromatic compounds:

Acenaphthenequinone (82-86-0)

Benzo[b]fluoranthene (205-99-2)

Benzo(a)pyrene (50-32-8)

Dibenz[a,h]anthracene (53-70-3)

9-Methylanthracene (779-02-2)

1-Methylfluorene (1730-37-6)

Perinaphthenone (548-39-0)

Phenanthrene (85-01-8)

Pyrene (129-00-0)

Human 

hepatocyte 

cell line

In vitro 2 days Cytotoxicity 

Gene expression 

by quantitative 

polymerase 

chain reaction

Cynthia Rider, 

Erik Tokar
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicogenomics

98

Chemical (CASRN*) Species/

Cell Line Route Duration Test Type(Platform)

Study 

Scientist

2,2’,4,4’,5-Pentabromodiphenyl ethers (5436-

43-1)

Pentabromodiphenyl oxide (technical) (DE-71) 

(32534-81-9)

3,3,4,4,5- Pentachlorobiphenyl (57465-28-8)

2,2'4,4'- Tetrabromodiphenyl ether (DE-47) 

(5436-43-1)

Rat

Mouse

Gavage GD** 6 

through 3 

weeks

Microarray 

(Affymetrix)

June Dunnick

Tetrabromobisphenol A (79-94-7)

BDE-47 (5436-43-1)

Pentabromodiphenyl oxide-technical (DE-71) 

(32534-81-9)

Rat Gavage GD** 6 

through 3 

weeks

Microarray 

(Affymetrix)

Arun Pandiri, 

Ramesh Kovi

Tetrabromobisphenol A (79-94-7)

Pentabromodiphenyl oxide-technical (DE-71) 

(32534-81-9)

Triclosan (3380-34-5)

alpha, beta-Thujone (76231-76-0)

Rat Gavage 5 days High-throughput 

transcriptomic 

screening

Mike DeVito, 

William Gwinn

112-chemical compound test set

(pharmaceuticals and environmental

compounds)

Human 

hepatocyte 

cell lineHepaRG

In vitro 2 days High-throughput 

transcriptomic 

screening

Stephen 

Ferguson, 

Sreenivasa 

Ramaiahgari

20-chemical compound test set (environmental

compounds)

Primary rat 

hepatocyte

s Human 

HepaRG 

cells

In vitro 3 days S1500+ 

NextGen 

sequencing

William Gwinn, 

Mike DeVito

Time-restricted feeding

Shift work-surrogate study

Rat In vivo 4 months Microarray Gopi Gadupudi, 

Arun Pandiri

*Chemical Abstracts Service Registry Number

**GD: gestational day

***This study will compare toxicogenomic effects among the chemicals listed together.

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies

Genetic Toxicity Studies 

Organ System Toxicity Studies 

Modified One-Generation Reproduction Studies 

Toxicology and Carcinogenicity Studies 

Project Review Committee Approved 
2017 Annual Report – Research and Testing – Testing and Toxicology Studies – Project Review Committee

99

Project Review Committee Approved

The table below lists studies that were approved by either the internal NIEHS/NTP protocol approval 

committee or the internal NIEHS/NTP project review committee, but were not started during FY 2017. 

Protocol Title Study Scientists 

Prenatal Toxicity Study of 2-{[1-(4-Phenoxyphenoxy)propan-2-

yl]oxy}pyridine in New Zealand White Rabbits Exposed Via Gavage

Vicki Sutherland/ Barry McIntyre

Toxicokinetic Studies (K03014) of α-Pinene (CAS 80-56-8, Test 

Article M030014) in Hsd:Sprague Dawley SD Rats and B6C3F1/N 

Mice Exposed Via Whole Body Inhalation

Cynthia Rider

Investigative Mammary and Reproductive Endpoint Studies of αPinene in Hsd:Sprague Dawley SD Rats Exposed Via Whole Body 

Inhalation

Cynthia Rider

Modified One-Generation (MOG) Dose Range-Finding Study 

(MOG00056) of Microcystin LR (CAS# 101043-37-2, M000056) in 

CD1 Mice Exposed Via Oral Gavage

Vicki Sutherland/ Barry McIntyre

Developmental Immunotoxicity Evaluation (# I10482B) of NButylbenzenesulfonamide (NBBS, CAS #3622-84-2, Test Article 

#10057) in Sprague Dawley (HSD: Harlan Sprague Dawley SD) Rats 

Exposed Via Dosed Feed

Kelly Shipkowski/ Cynthia Rider

Modified One-generationStudy (MOG 16001B) of Echinacea 

Purpurea Root Extract (CAS #90028-20-9,Test Article #16001) in 

Sprague Dawley (Hsd:Harlan Sprague Dawley SD) Rats Exposed 

via Gavage

Kristen Ryan

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies

Genetic Toxicity Studies 

Organ System Toxicity Studies 

Modified One-Generation Reproduction Studies 

Toxicology and Carcinogenicity Studies 

Toxicogenomic Studies 
2017 Annual Report – Research and Testing – NICEATM

100

NICEATM

About NICEATM

The NTP Interagency Center for the Evaluation of Alternative Toxicological Methods

(NICEATM) supports the development and evaluation of new, revised, and alternative 

methods to identify potential hazards to human health and the environment, with a 

focus on replacing, reducing, or refining animal use.

NICEATM Webinars and Workshops

A summary of webinars and workshops held or supported by NICEATM in FY 2017.

NICEATM Support of Tox21

A description of Tox21 projects NICEATM supported in FY 2017.

Additional NICEATM Activities

A summary of other activities NICEATM has conducted and participated in during 

FY 2017. 
2017 Annual Report – Research and Testing – NICEATM – About NICEATM

101

About NICEATM

The NTP Interagency Center for the Evaluation of Alternative 

Toxicological Methods (NICEATM) supports the development and 

evaluation of methods for identifying potential hazards to human 

health and the environment that could replace, reduce, or refine 

animal use.

NICEATM activities include:

• Conducting and publishing analyses and evaluations of data

from new, revised, and alternative testing approaches.

• Providing information to test method developers, regulators,

and regulated industry through its website and other

communications and by organizing workshops and

symposia.

• Coordinating and providing logistical support for the

Interagency Coordinating Committee on the Validation of

Alternative Methods (ICCVAM) meetings, webinars,

teleconferences, working groups, and public forums.

• Providing bioinformatics and computational toxicology

support to NIEHS/NTP projects, especially those related to

Tox21.

Warren Casey, Ph.D., is director of NICEATM. NICEATM receives 

contract support from Integrated Laboratory Systems, Inc.

Related Annual Report Pages:

FY 2017 NICEATM Webinars and Workshops

NICEATM Support of Tox21

Additional NICEATM Activities

Related Links

Activities and Resources

Publications

Reports
2017 Annual Report – Research and Testing – NICEATM – Webinars and Workshops

102

NICEATM Webinars and Workshops

Webinar Series: Using Informatics to Improve Data Analysis of Chemical 

Screening Assays Conducted in Zebrafish

NICEATM presented a webinar series in February and March 

2017 as part of the NTP Systematic Evaluation of the Application 

of Zebrafish in Toxicology initiative. Zebrafish is a useful 

vertebrate model for toxicological screening studies because of its

small size and rapid development, but a lack of harmonization in 

several key protocol components hinders the model’s broader 

adoption. This webinar series examined how variability in 

protocols for toxicological screening studies using zebrafish might 

be addressed by implementing standardized nomenclature 

systems or ontologies.

The webinar series was open to the public and viewed by over 

100 participants. The webinars also provided information on an 

April 2017 meeting at NIEHS where expert investigators and data 

scientists discussed how to improve zebrafish screening data 

analysis by implementing ontologies. A report from the meeting 

describing recommendations on best practices and identifying 

technology development and other needs is planned for publication 

in FY 2018.

Presentations from the webinar series are available on the NTP 

website. 

BioMed 21 Workshop

NICEATM and the Human Toxicology Project Consortium 

organized a June 2017 workshop, BioMed21 – A Human 

Pathway-based Approach to Disease and Medicine.

Recognition is growing for the need for greater focus on humanrelevant data to increase the success rate of drug development. 

Such data will support implementation of methods to assess

chemical toxicity that are based on human biological pathways. 

Several international projects are underway to mine literature, 

collect data, and organize data into adverse outcome pathways. 

This workshop assembled representatives from several of these 

projects to identify barriers and opportunities for improvement and 

to recommend support for implementation of a human systems 

biology platform to understand disease and improve interventions.

More information about the workshop is available on the NTP 

website. 

Related Annual Report Pages:

About NICEATM

NICEATM Support of Tox21

Additional NICEATM Activities
2017 Annual Report – Research and Testing – NICEATM – Support of Tox21

103

NICEATM Support of Tox21

The Tox21 research initiative aims to improve regulatory hazard 

assessment of substances potentially harmful to humans and the 

environment. Tox21 uses in vitro high-throughput screening 

assays to evaluate the biological activity of compounds in a 

10,000 compound library and to map the observed activities to 

toxicity pathways. 

One goal of Tox21 is to incorporate in vitro assay data into 

models that can be used to predict toxic (or adverse) effects in 

humans resulting from chemical exposures. NICEATM provides 

support to the Tox21 effort primarily through its computational 

toxicology group. Specific NICEATM projects in support of Tox21 

are included in the Tox21 Projects section.

Related Annual Report Pages:

About NICEATM

FY 2017 NICEATM Webinars and Workshops

Additional NICEATM Activities
2017 Annual Report – Research and Testing – NICEATM – Additional Activities 

104

Additional NICEATM Activities

Acute Systemic Toxicity

Alternative models developed for estimating acute systemic toxicity generally are evaluated using in 

vivo LD50 values, but variability in the values makes such assessments challenging. To characterize 

this variability more fully, NICEATM and collaborators at the Environmental Protection Agency (EPA) 

National Center for Computational Toxicology compiled a large data set of acute oral LD50 values 

from several curated databases. 

Some chemicals having multiple LD50 values exhibited high variability, with some values ranging 

across multiple orders of magnitude. Such variability, which confounds hazard categorization, 

underscores the importance of considering an appropriate margin of uncertainty when using in vivo

oral acute toxicity data to assess the performance of alternative methods. The analysis of the full data 

set will be presented at the 2018 Society of Toxicology meeting, and a manuscript describing the 

analysis is in preparation for publication in 2018.

Developmental Toxicity

NICEATM is working with other National Toxicology Program (NTP) scientists at NIEHS to compile a 

list of developmental toxicants that cover developmental outcomes ranging from subtle effects such 

as fetal weight changes through post-implantation loss. Toxicants are selected based on the 

availability of “high-quality” studies, those appropriately designed and powered with relevant 

endpoints that cover likely different modes of action. 

After further evaluation and assessment, the studies are used to identify and extract data. Identified 

toxicants are candidates for testing with in vitro assays using primary cells, stem cells, or cell lines 

and for conducting in vivo assays using lower-order organisms such as zebrafish or roundworm 

(Caenorhabditis elegans). Test results will be compared to available in vivo mammalian data from 

rodents, rabbits, and humans. The toxicant list is being constructed with input from experts in 

industry, academia, and government and is expected to include agrochemicals, pharmaceuticals, and 

other chemicals.

Endocrine Disruptors

NICEATM is collaborating with test method developer CertiChem, Inc., to validate an in vitro test

method that uses MDA-Kb2 human breast cancer cells to measure androgen receptor agonist and 

antagonist activity. Testing of 67 coded reference chemicals in agonist and antagonist modes to 

characterize method reliability and relevance is anticipated to be completed in early FY 2018. Then, 

30 additional consumer products will be tested to evaluate the method’s applicability for more than 

single chemicals. 

Skin Sensitization

NICEATM and ICCVAM scientists developed integrated testing strategies that use non-animal data to 

predict skin sensitization hazard. Three manuscripts published in FY 2016 and FY 2017 describe 

strategies for using non-animal data to predict outcomes of animal skin sensitization tests, human 

skin sensitization tests, and human or animal tests for skin sensitization potency classification. 

The NTP Toxicology Branch is testing over 200 chemicals nominated by ICCVAM agencies using 

three in vitro test methods to expand the applicability of a defined approach for identifying skin 

sensitizers. Mouse local lymph node assay data are available for the nominated chemicals, which 

include pesticides, formulations, industrial chemicals, and other chemicals of interest to ICCVAM 

agencies. The three in vitro test methods are the LuSens method, the direct peptide reactivity assay, 

and the human cell line activation test. NICEATM is coordinating the testing, which began in 2016 

and is scheduled for completion in early 2019. The study data will enable NICEATM and ICCVAM to 
2017 Annual Report – Research and Testing – NICEATM – Additional Activities 

105

evaluate the appropriateness of a defined approach using these three in vitro methods for various 

regulatory applications.

NICEATM collaborated with the Cosmetics Europe Skin Tolerance Task Force to evaluate integrated

testing and assessment approaches for skin sensitization submitted to the Organisation for Economic 

Co-operation and Development. NICEATM evaluated six defined approaches with a set of previously 

untested chemicals having in vitro and in silico data provided by Cosmetics Europe. Manuscripts 

describing the data sets and the outcome of the analyses have been submitted for publication.

Ocular Irritation

NICEATM and the PETA International Science Consortium are proposing a joint study to evaluate the 

utility and limitations of a group of in vitro test methods to identify the ocular irritation and corrosion 

potential of agrochemicals. Coded pesticide formulations donated by agrochemical companies will be 

tested to describe each method’s performance characteristics and determine which methods could be 

combined with in vitro defined approaches to assign hazard classification and labeling for eye 

irritation potential. Although the focus of this study will be on EPA hazard classification, study results 

also will be evaluated for classification and labeling under the United Nations Globally Harmonized 

System of Classification and Labelling of Chemicals. Testing will begin in 2018.

Integrated Chemical Environment

Successful computational toxicology projects depend on freely available, high-quality data that are 

formatted for use in computational workflows. The NICEATM Integrated Chemical Environment (ICE)

resource, launched in March 2017, provides high-quality, curated data from NICEATM, its partners, 

and other resources and tools to facilitate chemical safety assessment. 

At the end of FY 2017, ICE included data from animal and non-animal tests that assessed regulatory 

endpoints such as acute oral toxicity, skin and eye irritation, skin sensitization, and endocrine activity. 

It also included curated high-throughput screening data from Tox21 and physicochemical property 

data on chemicals such as solubility, melting point, and molecular weight. The site offers

downloadable workflows for predicting physicochemical properties, skin sensitization potency, and 

adverse outcome pathway mapping. ICE is open to all users, with no registration needed.

Updates to ICE in FY 2018 will add formulation data and allow users to compare labeling categories 

from EPA “six-pack” studies with the performance of the formulation’s active ingredients in nonanimal methods. Additional updates will expand the offered in silico prediction models and 

computational workflows to include in vitro-to-in vivo extrapolation and characterization of chemicals 

from the ICE website and through downloadable workflows.

Related Annual Report Pages:

About NICEATM

FY 2017 NICEATM Webinars and Workshops

NICEATM Support of Tox21
2017 Annual Report – Research and Testing – ICCVAM

106

ICCVAM

About ICCVAM

The Interagency Coordinating Committee on the Validation of Alternative Methods 

(ICCVAM) is a permanent interagency committee of NIEHS.

A Strategic Roadmap for Establishing New Approaches to Evaluate 

the Safety of Chemicals and Medical Products in the United States

ICCVAM is coordinating the development of a strategic roadmap to adopt new 

approaches to safety and risk assessment of chemicals and medical products that 

improve human relevance and replace or reduce the use of animals. 

ICCVAM Meetings

A description of meetings held by ICCVAM in FY 2017.

ICCVAM Test Method Evaluation Activities

A list of NICEATM and ICCVAM test method evaluation activities in FY 2017.

ICCVAM International Validation Activities

A description and list of NICEATM and ICCVAM international validation activities in FY

2017.
2017 Annual Report – Research and Testing – ICCVAM – About ICCVAM

107

About ICCVAM

The Interagency Coordinating Committee on the Validation of 

Alternative Methods (ICCVAM) is a permanent interagency 

committee of NIEHS under NTP Interagency Center for the 

Evaluation of Alternative Toxicological Methods (NICEATM). 

Established by the ICCVAM Authorization Act of 2000 (42 

U.S.C. 285l-3), its purpose is “to establish, wherever feasible, 

guidelines, recommendations, and regulations that promote

the regulatory acceptance of new or revised scientifically valid

toxicological tests that protect human and animal health and 

the environment while reducing, refining, or replacing animal 

tests and ensuring human safety and product effectiveness.” 

ICCVAM is composed of representatives from 16 U.S. federal

regulatory and research agencies that generate or use 

toxicological and safety testing information. Warren Casey, 

Ph.D., serves as administrative director of ICCVAM.

Related Annual Report Pages:

Strategic Roadmap for New Approaches to Evaluate the 

Safety of Chemicals and Medical Products

ICCVAM Meetings

ICCVAM Test Method Evaluation Activities

ICCVAM International Validation Activities

Related Links

Information on ICCVAM Activities

Complete list of articles on 

ICCVAM activities published in 

scientific journals
2017 Annual Report – Research and Testing – ICCVAM – Strategic Roadmap

108

A Strategic Roadmap for Establishing New Approaches to 

Evaluate the Safety of Chemicals and Medical Products in the 

United States

During FY 2017, ICCVAM coordinated the development of a 

strategic roadmap for incorporating new approaches into safety 

testing of chemicals and medical products in the United States. 

Sixteen federal agencies and multiple interagency workgroups, 

with input from a broad range of stakeholder groups, developed the 

roadmap.

The roadmap creates a framework that guides the development of 

enabling technologies and promotes strategies to establish 

confidence in and ensure utilization of new approaches to toxicity 

testing that improve human health relevance and reduce or 

eliminate the need for testing in animals. The successful 

development and implementation of these new approaches will 

require coordinated efforts that address three strategic goals: 

1. Connect users with developers of new approach 

methodologies. 

2. Foster the use of efficient, flexible, and robust practices to 

establish confidence in new methods. 

3. Encourage the adoption and use of new methods and 

approaches by federal agencies and regulated industries. 

The roadmap was first proposed to the Scientific Advisory 

Committee on Alternative Toxicological Methods (SACATM) in 

2015. SACATM expressed support for the development of the 

roadmap as an ICCVAM activity at its September 2016 meeting. A 

meeting of ICCVAM members and other federal employees in 

February 2017 established an outline for the roadmap. 

Opportunities for public comment during development of the 

roadmap occurred during the annual meeting of the Society of 

Toxicology in March, ICCVAM Public Forum in May, NTP Board of 

Scientific Counselors meeting in June, and SACATM meeting in 

September.

The final roadmap document was published in January 2018 and is 

available on the NTP website. 

Activities are underway to address the roadmap goals. 

Presentations at the September 2017 SACATM meeting described 

implementation of the roadmap for skin sensitization and acute 

systemic toxicity testing. Reviews of U.S. agency information 

requirements for these areas are being prepared and are planned 

for publication in FY 2018. 

Related Links

Information on ICCVAM Activities

Complete list of articles on 

ICCVAM activities published in 

scientific journals
2017 Annual Report – Research and Testing – ICCVAM – Strategic Roadmap

109

Related Annual Report Pages:

About ICCVAM

ICCVAM Meetings

ICCVAM Test Method Evaluation Activities

ICCVAM International Validation Activities
2017 Annual Report – Research and Testing – ICCVAM – Meetings

110

ICCVAM Meetings

NICEATM supported six teleconferences and three in-person 

meetings held by ICCVAM in FY 2017. These included one inperson meeting and three teleconferences of ICCVAM 

representatives developing “A Strategic Roadmap for Establishing 

New Approaches to Evaluate the Safety of Chemicals and Medical 

Products in the United States.” 

NICEATM also supported seven ad hoc ICCVAM workgroups 

focused on acute systemic toxicity, ocular and dermal irritation, 

developmental and reproductive toxicity, skin sensitization, use of 

read-across in toxicity testing applications, in vitro-to-in vivo 

extrapolation, and identification and characterization of reference 

chemicals for validation of in vitro endocrine disruptor assays.

The third ICCVAM Communities of Practice webinar was held on 

January 24, 2017. The webinar emphasized the importance of 

understanding the structural and functional diversity of chemical 

sets used in developing and validating alternative approaches to 

traditional in vivo toxicology test methods. Denis Fourches, Ph.D., 

of North Carolina State University described chemoinformatics 

methods for predicting toxicity. Kamel Mansouri, Ph.D., of the 

Environmental Protection Agency (EPA) presented case studies on 

how such methods have been successfully applied. Slide 

presentations from the webinar are available on the NTP website.

ICCVAM, with NICEATM support, held its fourth public forum on 

May 23, 2017, at the National Institutes of Health (NIH) in 

Bethesda, Maryland. Representatives from 10 ICCVAM member 

agencies were joined by attendees representing stakeholder 

groups and over 100 webcast viewers. ICCVAM members provided 

information about their agency activities on the development and 

validation of test methods and approaches that could replace, 

reduce, or refine animal use. Stakeholder groups suggested areas 

to be addressed and encouraged development of the strategic 

roadmap. The agenda and presentations are available on the NTP 

website. 

Related Annual Report Pages:

About ICCVAM

Strategic Roadmap for New Approaches to Evaluate the Safety of 

Chemicals and Medical Products 

ICCVAM Test Method Evaluation Activities 

ICCVAM International Validation Activities 

Related Links

Information on ICCVAM Activities

Complete list of articles on 

ICCVAM activities published in 

scientific journals
2017 Annual Report – Research and Testing – ICCVAM – Test Method Evaluation 

111

ICCVAM Test Method Evaluation Activities

ICCVAM received no formal test method nominations or submissions in FY 2017. ICCVAM welcomes 

submissions of innovative test methods that might be acceptable for specific regulatory use and for 

which adequate validation studies have been completed. To maximize effective implementation of 

new test methods or approaches, however, ICCVAM evaluates and recommends only those test 

methods proposed for regulatory uses that align with ICCVAM member agencies’ needs and 

priorities. More information on ICCVAM test method submissions is available. ICCVAM test method 

evaluation activities in FY 2017 are summarized below.

Test Method Evaluation Activities in FY 2017

Test Method ICCVAM Recommendations/Agency Status

ICCVAM integrated 

decision strategy for skin 

sensitization

ICCVAM developed integrated decision strategies using in vitro, in chemico, and in silico 

information based on an established skin sensitization adverse outcome pathway. Following 

publication in FY 2016 of two manuscripts describing strategies to predict animal and 

human skin sensitization of test results, a third manuscript describing a strategy to predict 

animal and human skin sensitization potency was published in FY 2017. 

Electrophilic allergen 

screening assay

This test method, nominated by the National Institue for Occupational Safety and Health 

(NIOSH), is an in chemico assay intended to identify potential skin sensitizers. A validation 

study of the method began in FY 2017 with four ICCVAM agencies participating in the 

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

(NICEATM) coordinates the study, and members of the ICCVAM Skin Sensitization 

Workgroup serve on the study management team. Current efforts focus on testing a small 

group of blinded chemicals for a preliminary assessment of accuracy and reproducibility. 

The study is expected to continue through the end of FY 2018.

OptiSafe NICEATM is coordinating a multilaboratory validation study to determine the reliability and 

relevance of the OptiSafe test method. In this method, a test substance is applied to a 

semipermeable membrane to assess the substance’s potential to cause eye irritation. Three 

participating laboratories completed testing of 30 chemicals in FY 2017. In FY 2018, the 

nominating laboratory will complete testing on 60 additional coded chemicals to expand the 

applicability of the method. 

EpiAirway A cooperative agreement under the NIEHS Phase IIb Small Business Innovation Research

is providing funding to MatTek Corporation to validate its EpiAirwayTM in vitro human 

bronchial tissue model to predict the toxicity of inhaled chemicals. Several ICCVAM agency 

representatives are members of the cooperative agreement steering committee. In FY 2017, 

the steering committee recommended test chemicals to expand the domain of applicability, 

making EpiAirwayTM more relevant to their respective agencies, and test chemicals are 

being procured. NICEATM provides scientific oversight of this NIEHS small business 

program supporting validation of alternative test methods. 

The 16 member agencies of ICCVAM are engaged in additional activities that support replacing, 

reducing, and refining animal use. Summaries of these additional activities can be found on the NTP 

website. 
2017 Annual Report – Research and Testing – ICCVAM – Test Method Evaluation 

112

Related Annual Report Pages:

About ICCVAM

Strategic Roadmap for New Approaches to Evaluate the Safety of 

Chemicals and Medical Products

ICCVAM Meetings

ICCVAM International Validation Activities
2017 Annual Report – Research and Testing – ICCVAM – International

113

ICCVAM International Validation Activities

The NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) and 

ICCVAM participate in international test method validation activities through the Organisation for 

Economic Co-operation and Development (OECD) and collaborate with member countries of the 

International Cooperation on Alternative Test Methods (ICATM), including the European Union, Japan, 

Korea, and Canada.

In FY 2017, ICCVAM agencies commented on draft OECD documents through the U.S. National 

Coordinator for the OECD Test Guidelines Programme, an ex officio ICCVAM member. NICEATM 

and ICCVAM collaborated with international colleagues on a revision of the acute dermal toxicity test 

guideline (Test Guideline 402), adopted by OECD in 2017. A NICEATM scientist also served on a 

peer-review panel updating Test Guideline 442B for non-radiolabeled murine local lymph node assay 

methods.

Representatives of NICEATM and ICCVAM attended meetings of the OECD expert groups on eye

irritation and skin sensitization in FY 2017.

ICATM collaborations address three critical areas of cooperation: test method validation studies, 

independent peer review of validation studies, and development of formal recommendations on 

alternative testing methods. Representatives of NICEATM and ICCVAM attended an ICATM 

coordination meeting and ICATM-sponsored workshop to develop criteria for evaluating non-animal 

approaches for skin sensitization potential in October 2016. 

Representatives of NICEATM and ICCVAM also attended an October 2016 workshop sponsored by 

ICATM. Products of this workshop include a white paper characterizing international regulatory 

requirements for skin sensitization testing (to be submitted for publication in FY 2018), a position 

paper covering workshop outcomes and ICATM recommendations (accepted for publication in FY 

2018), and a proposal to develop a performance-based test guideline for defined approaches to 

testing and assessment of skin sensitization, which was accepted by OECD in April 2017.

Ongoing international validation studies led by ICATM member organizations that include NICEATM 

or ICCVAM participants are listed below.

Participation in International Validation Studies

Test Method Test Type Lead 

Organization* NICEATM-ICCVAM Involvement

IL-8 in vitro test for 

assessing skin sensitization 

potential

Allergic contact 

dermatitis

JaCVAM Study is complete; an ICCVAM member 

served on a peer-review panel. 

Vitrigel-SST assay for 

assessing skin sensitization 

potential

Allergic contact 

dermatitis

JaCVAM NICEATM staff are serving on the 

validation management team; study is 

currently on hold.

Vitrigel-EIT assay for eye 

irritation testing

Ocular irritation JaCVAM Study is complete; an ICCVAM member 

served on a peer-review panel. 

Hand1-luc in vitro test for 

assessing reproductive 

toxicity potential

Reproductive 

toxicity

JaCVAM Study is complete, and ICCVAM members 

served on a peer-review panel.

SIRC-CVS assay for eye 

irritation testing

Ocular irritation JaCVAM Study is complete; an ICCVAM member 

served on a peer-review panel. 
2017 Annual Report – Research and Testing – ICCVAM – International

114

Test Method Test Type Lead 

Organization* NICEATM-ICCVAM Involvement

Amino acid derivation 

reactivity assay

Allergic contact 

dermatitis

JaCVAM NICEATM staff served on the validation 

management team; a peer review of the 

study is scheduled for spring 2018.

*Japanese Center for the Validation of AlternativeMethods

Related Annual Report Pages:

About ICCVAM

Strategic Roadmap for New Approaches to Evaluate the Safety of 

Chemicals and Medical Products

ICCVAM Meetings

ICCVAM Test Method Evaluation Activities
2017 Annual Report – Literature Analysis

115

Literature Analysis 

Noncancer Research

NTP conducts evaluations to assess the evidence that substances cause adverse 

health effects and provides opinions on whether these substances could be of human 

concern.

Report on Carcinogens

The Report on Carcinogens 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 significant number of persons residing in the 

United States are exposed.
2017 Annual Report – Literature Analysis – Noncancer Research

116

Noncancer Research

NTP has made a commitment to studying noncancer health effects. As part of that commitment, NTP 

assesses the evidence that environmental chemicals, physical substances, or mixtures—collectively 

referred to as substances—cause adverse health effects. NTP also provides opinions on whether 

these substances might be of concern, given what is known about current human exposure levels. 

The Office of Health Assessment and Translation (OHAT) conducts health hazard assessments and 

scoping reviews or state-of-the-science evaluations, which are published as NTP monographs, NTP 

research reports, and journal publications. OHAT also hosts workshops to address important issues 

in environmental health sciences. Andrew Rooney, Ph.D., served as acting director of OHAT in FY 

2017.

In FY 2017, NTP published the NTP Monograph on Immunotoxicity Associated with Exposure to

Perfluorooctanoic Acid or Perfluorooctane Sulfonate, the first evaluation reaching hazard conclusions 

using the OHAT Approach to Systematic Review and Evidence Integration. OHAT began using a new 

data visualization format—an interactive systematic evidence map—that allows readers to search and 

explore evidence categorized by health effect, exposure, and type such as the literature collected in 

the state-of-the-science evaluation of transgenerational inheritance. 

As part of efforts to promote harmonization in development of systematic review methods, OHAT 

hosted the 4th International Symposium on Systematic Review and Meta-Analysis of Laboratory 

Studies in April 2017. OHAT also published several reports in the new NTP research report series, 

including a pilot study on tin and organotin levels in Danish women, a systematic review of biological 

activity of bisphenol A structural analogues, and a systematic review of the effects of fluoride on 

learning and memory in animal studies.

Ongoing Noncancer Health Effects Projects

Project & Study Scientist Project Summary

Evaluation of long-term neurological 

effects of acute exposure to the 

organophosphorus nerve agent sarin 

Study Scientist: Andrew Rooney

Sarin is a highly toxic organophosphorus nerve agent developed for chemical 

warfare during World War II that continues to be used as a weapon today. 

The immediate, or acute, effects of sarin exposure are serious and well 

known, including constriction of the pupils, muscle paralysis, seizures, 

cardiorespiratory depression, and death due to respiratory failure. Although 

there are reports of potential long-term neurological effects from sarin 

exposure, the evidence has not been evaluated with the increased objectivity, 

rigor, and transparent process of a systematic review methodology. In 

partnership with the NIH Countermeasures Against Chemical Threats 

(CounterACT) Program, NTP is conducting a systematic review to evaluate 

the evidence for long-term neurological effects in humans following acute 

exposure to sarin. The protocol was posted in April 2017, and this evaluation 

is ongoing.

Evaluation of inflammation-based 

atherosclerosis associated with 

environmental exposures 

Study Scientists: Andrew Rooney and 

Brandy Beverly

Evidence is growing that the environment plays a role in a wide range of 

diseases that involve inflammation. The extent to which environmental 

exposures ultimately lead to these adverse health effects through an 

inflammatory pathway remains unclear. This evaluation will examine the 

evidence that environmental substances contribute to inflammation, which 

ultimately leads to atherosclerosis, and will identify biomarkers of the 

inflammation involved. Atherosclerosis was selected for investigation 

because of the significant public health impact of the disease, and the wellestablished role for inflammation in the disease process that leads to it. The 

concept was reviewed at the December 2014 Board of Scientific Counselors 

meeting, and the evaluation has been initiated.
2017 Annual Report – Literature Analysis – Noncancer Research

117

NIEHS-EPA pilot study of exposure to 

chemicals in consumer products 

Study Scientist: Kyla Taylor

Concern has been raised about the endocrine-disrupting potential of some 

chemicals found in personal care and other consumer products. Given the 

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

and techniques need to be developed. 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 several consumer product categories, including 

personal and child care, household cleaning, lawn and garden, home 

improvement, and food packaging products. The pilot study addresses 

several research needs related to the measurement and modeling of human 

exposures. The concept was reviewed at the June 2015 Board of Scientific 

Counselors meeting, and the NIEHS Institutional Review Board (IRB) for the 

Protection of Human Subjects in Research has approved the project. This

study is currently open for enrollment.

State of the science for transgenerational 

inheritance of health effects 

Study Scientist: Vickie Walker

Transgenerational inheritance is the phenomenon in which an individual’s 

exposures have far-reaching consequences, affecting multiple generations 

removed from the original insult. NTP conducted a state-of-the-science or 

scoping review to examine the evidence for transgenerational inheritance of 

health effects associated with exposure to a wide range of stressors (e.g., 

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

infectious agents, stress) in humans and animals. The report systematically 

compiled and categorized the literature to develop an evidence map for 

transgenerational inheritance by broad health-effect categories, exposures, 

and types of evidence, and identified areas of consistency, uncertainty, data 

gaps, and research needs. Evidence mapping illustrated that risk of bias, 

having generally few studies, and heterogeneity in exposures and endpoints 

examined present serious limitations to available bodies of evidence for 

assessing transgenerational effects. This report was accepted for publication 

in Environment International in December 2017.

Evaluation of children’s health and trafficrelated air pollution 

Study Scientists: Kembra Howdeshell and 

Brandy Beverly

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

the past decade, reflecting improvement in air monitoring technology and 

exposure methodology. Traffic-related air pollution has been measured in 

multiple ways, including direct traffic measures (such as traffic proximity or 

density) and surrogate measures of traffic-related air pollution (such as 

particulate matter, oxides of nitrogen, and other products of fossil-fuel 

combustion generated by motor vehicles including benzene, diesel exhaust, 

and polycyclic aromatic hydrocarbons). This topic is the subject of a series of 

evaluations on the evidence for an association between traffic-related air 

pollution and health outcomes impacting the fetus and children, beginning 

with hypertensive disorders of pregnancy and neurological development and 

function in children. The concept was reviewed at the April 2014 Board of 

Scientific Counselors meeting. The protocol was posted in June 2016, and 

the evaluation is ongoing.

Evaluation of adverse health effects and 

occupational exposure to cancer 

chemotherapy agents 

Study Scientist: Kembra Howdeshell

Cancer chemotherapy agents are cytotoxic drugs, many of which are known 

mutagens and developmental toxicants. Occupational exposure to cancer 

chemotherapy agents can occur in various professions including medical, 

veterinary, and manufacturing. Although 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 examined the evidence that occupational exposure 

to cancer chemotherapy agents is associated with adverse health effects,

including genetic toxicity, cancer, reproductive and developmental effects, 

and acute effects. The concept was reviewed at the April 2014 Board of 

Scientific Counselors meeting and the protocol posted in October 2015. The 

draft NTP monograph has been completed and is undergoing peer review.
2017 Annual Report – Literature Analysis – Noncancer Research

118

Biological activity of bisphenol A (BPA) 

structural analogues and functional 

alternatives 

Study Scientist: Katie Pelch

Bisphenol A (BPA) is a high production volume chemical used in the 

manufacture of polycarbonate plastic, thermal paper, dental resins, and other 

composite materials used in consumer products. Recent studies report 

widespread use and exposure to a variety of chemicals with structural or 

functional similarity to BPA, referred to as BPA analogues. This study reviews

human, animal, and in vitro evidence that the biological activity of BPA 

analogues is an emerging public health concern. The topic will be addressed 

further through in vitro laboratory experiments and external collaborations to 

evaluate in vivo activity in two model organisms, zebrafish and 

Caenorhabditis elegans. The concept was reviewed at the June 2015 Board 

of Scientific Counselors meeting. The protocol was finalized in August 2015, 

and the NTP research report was published in October 2017.

Environmental influences on the 

epigenome: a scoping report 

Study Scientists: Katie Pelch and Vickie 

Walker

NIEHS is interested in understanding the effects of the environment on 

epigenetic regulation of biological and pathological processes. Of the various 

epigenetic modifications, the alteration of DNA methylation patterns has been 

the most widely studied and highly funded modification to date. This 

evaluation will leverage newly developed text mining and machine learning 

tools to carry out scoping activities that will explore the evidence linking 

environmental exposures to health outcomes via genome-wide alterations in 

DNA methylation. The concept was reviewed at the June 2015 Board of 

Scientific Counselors meeting, and the evaluation is ongoing.

Shift work at night, light at night, and 

circadian disruption 

Study Scientist: Windy Boyd

Circadian disruption occurs when endogenous circadian rhythms, which are 

daily and predictable variations in biological, physiological, and behavioral 

processes, are out of phase with the external environment or with each other. 

Through their work, lifestyle choices, or residences, people are subjected to 

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

circadian disruption. This project is being undertaken in conjunction with an 

analysis by the Office of the Report on Carcinogens for cancer hazard 

evaluation. The concept was reviewed at the April 2014 Board of Scientific 

Counselors meeting, and a public workshop/webinar was held at NIEHS in 

March 2016 to obtain expert opinion to inform potential health hazard 

assessments. The workshop report was published in Science of the Total 

Environment in December 2017. With the Office of the Report on 

Carcinogens, activity is underway to finalize the protocol and execute the 

cancer hazard evaluation.

Neonicotinoid pesticides and adverse 

health outcomes 

Study Scientist: Windy Boyd

Neonicotinoid pesticides are a class of chemicals that act as insecticides by 

exerting neurotoxic effects through irreversible binding to insect nicotinic 

acetylcholine receptors. Nicotinic acetylcholine receptors are also present in 

the nervous systems of mammals, raising concern that neonicotinoids might

affect animals other than their insect targets, including humans. In Spring 

2015, neonicotinoid pesticides were nominated to NTP for possible 

evaluation of noncancer health outcomes. In response, OHAT is conducting a 

scoping review to identify the extent of evidence available to understand 

human health effects of seven neonicotinoid pesticides (acetamiprid, 

clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and 

thiamethoxam). The protocol was posted in November 2017, and the 

evaluation is ongoing.
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Parkinson’s disease: associations with 

environmental exposures 

Study Scientist: Windy Boyd

Parkinson’s disease is a group of motor system disorders including tremor of 

the extremities, rigidity of the limbs and body, slowness of movement, and 

postural instability. Although some Parkinson’s disease cases can be 

attributed to genetic factors, the causes of many cases remain unknown. 

Many studies report associations between environmental exposures and 

Parkinson’s disease or related symptoms. OHAT is conducting two scoping 

reviews on this topic. The first project is a scoping review to systematically 

map the evidence of the associations between exposures to environmental 

chemicals considered broadly and Parkinson’s disease. During scoping 

activities, hundreds of studies on the associations between exposure to the 

herbicide paraquat and Parkinson’s disease were identified, making paraquat 

a candidate chemical for further systematic review. Therefore, a more 

detailed scoping review is being developed to characterize reported 

associations between paraquat exposure and Parkinson’s disease. Both 

evaluations are ongoing. 

Systematic reviews on potential health 

effects of fluoride 

Study Scientist: Kyla Taylor

NTP is currently conducting a systematic review to evaluate potential 

neurobehavioral effects from exposure to fluoride during development that 

includes consideration of human epidemiology, additional experimental 

animal studies, and mechanistic data. This update to NTP’s 2016 systematic 

review of published animal literature is examining neurobehavioral effects of 

exposure to fluoride during development and adulthood in rodents. The 2016 

report concluded the evidence supporting adverse effects on learning and 

memory in animals exposed to fluoride in the diet or drinking water is low to 

moderate. The concept was approved at the December 2015 Board of 

Scientific Counselors meeting. The protocol was posted in July 2017, and the 

systematic review is ongoing.
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Report on Carcinogens

About the Report on Carcinogens

The Report on Carcinogens 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 significant number of persons residing in the 

United States are exposed.

Report Activities

A summary of activities the Office of the Report on Carcinogens conducted during 

FY 2017. 

Report Substances Selected for Evaluation

A list of substances the Office of the Report on Carcinogens selected for evaluation 

during FY 2017.
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About the Report on Carcinogens

The Report on Carcinogens 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 significant number of persons residing in the United States 

are exposed [Section 301(b)(4) of the Public Health Service Act, 42 

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

The Report is cumulative, consisting of newly reviewed substances 

in addition to those substances listed in previous editions. NTP

follows an established four-part process when preparing the 

Report.

1. NTP selects nominations for Report evaluation.

2. The Office of Report on Carcinogens conducts cancer

hazard evaluations on the nominated substances.

3. Draft Report monographs are released for public comment

and peer review before finalization.

4. NTP submits the proposed listing of newly reviewed

substances to the U.S. Department of Health and Human

Services secretary for review, approval, and release to the

public and congressional members.

Each substance listed in the Report has a profile, which contains 

the listing status determined by using established listing criteria, a 

summary of the cancer studies supporting the listing status, 

information on human exposure, and federal regulations to reduce 

exposure.

The Report is prepared by the Office of the Report on Carcinogens,

under the direction of Ruth Lunn, Dr.P.H. Contract support for

preparation of the Report in FY 2016 was provided by Integrated 

Laboratory Systems Inc. and ICF.

Additional Links for the Report

Report on Carcinogens

Report Activities in 2017

Report Candidate Substances
122

2017 Annual Report – Literature Analysis – Report on Carcinogens – Report Activities

Report Activities 

The U.S. Department of Health and Human Services released the 14th Report on Carcinogens on 

November 3, 2016. This cumulative report contains 248 listings, of which 7 were newly reviewed.

Report activities in FY 2017 primarily were related to identifying substances for review and preparing

cancer hazard evaluations of several substances for review for future reports. The Office of the 

Report on Carcinogens at NIEHS prepared and released the draft monograph, Haloacetic Acids 

Found as Water Disinfection By-Products, for public comment. On July 24, 2017, an external panel 

of experts peer reviewed the draft monograph and agreed with NTP’s preliminary recommendations 

to list six haloacetic acids in the next edition of the Report. The Office also developed a concept 

document proposing review of antimony trioxide for the Report. The concept was presented to the

NTP Board of Scientific Counselors at their December 14–15, 2016 meeting.

Literature-based cancer hazard evaluations were initiated for: 

• Antimony trioxide.

• Shift work at night, light at night, and circadian

disruption.

• Helicobacter pylori: chronic infection.

For a list of ongoing evaluations, see Report Substances Selected for Evaluation. 

Office of Report on Carcinogens Staff Publications on Agents 

Recently Listed or Under Review

• Tumour virus epidemiology.

• Health consequences of electric lighting practices in the modern world: A report on the

National Toxicology Program’s workshop on shift work at night, artificial light at night, and

circadian disruption.

Additional Links for the Report on Carcinogens 

Report on Carcinogens

About Report on Carcinogens

Report Candidate Substances
2017 Annual Report – Literature Analysis – Report on Carcinogens – Report Substances for Evaluation

123

Report Substances Selected for Evaluation

Substances 

NTP Project Leader Primary Uses/Exposures Status

Antimony Trioxide

Amy Wang Compound used mainly as a synergist for halogenated 

flame-retardants in plastics, rubber, and textiles, which 

are used in a diversity of plastics and other products. It 

also can be used as a catalyst in polyethylene 

terephthalate production, as an additive in glass 

manufacturing and in pigments, or as an additive in 

paints and ceramics. 

Concept review: NTP 

Board of Scientific 

Counselors Meeting 

December 2016

Goldenseal Root Powder

(Hydrastis canadensis)

Office of Report on 

Carcinogens staff

Herbal remedy (botanical product) used to treat 

gastrointestinal disturbances; urinary disorders; 

hemorrhage; skin, mouth, and eye infections; and 

inflammation.

Concept review: NTP 

Board of Scientific 

Counselors Meeting 

April 2014

Haloacetic Acids Found as

Water Disinfection ByProducts

Gloria Jahnke

Includes 13 individual haloacetic acids or a potential 

class or subclass of these haloacetic acids. People are 

exposed to these haloacetic acids by ingestion of 

chlorinated drinking water and by inhalation and dermal 

contact during bathing or showering or when using 

swimming pools and spas that use chlorine for 

disinfection.

Peer review of draft 

monograph:

July 2017

Helicobacter pylori (H.

pylori): Chronic Infection

Ruth Lunn

Gram-negative, multiflagellated bacterium that colonizes 

the stomach and causes peptic ulcer. Bacterium is 

spread by person-to-person contact, especially among 

family members. Routes of exposure include oral-oral, 

fecal-oral, and iatrogenic; exposure from contaminated 

water is also possible. Risks factors for infection include 

age, race, socioeconomic status such as crowded living 

conditions, and poor sanitation/hygiene.

Concept review: NTP 

Board of Scientific 

Counselors Meeting 

April 2016

Shift Work at Night, Light at

Night, and Circadian

Disruption

Ruth Lunn

Unnatural (e.g., ill-timed) electrical light, especially light at 

night, may disrupt sleep and biological processes 

controlled by endogenous circadian clocks. People, who 

by virtue of the nature of their work, lifestyle choices, or 

residence, are subjected to exposure to unnatural light. 

Shift workers who work at night can experience an 

extreme type of exposure to light at night and changes in 

other activities, such as changes in daily activities, 

eating, sleeping, lifestyle factors, and social behavior.

Workshop: Shift Work 

at Night, Artificial 

Light at Night, and 

Circadian Disruption 

workshop

March 2016

Additional Links for the Report on Carcinogens 

Report on Carcinogens

About Report on Carcinogens

Report Activities in 2017
2017 Annual Report – Partner Agency Research 

124

Partner Agency Research 

About NTP at NIEHS

Research activities in the Division of NTP at NIEHS are conducted through the several

branches: Biomolecular Screening Branch, Cellular and Molecular Pathology Branch, 

NTP Laboratory, Program Operations Branch, and Toxicology Branch.

NTP at NCTR

NCTR provides innovative technology, methods development, vital scientific training, 

and technical expertise to NTP.

NTP at NIOSH

NIOSH research projects for NTP assess the effects of exposures to substances, 

following its mandate to protect worker health and safety.
2017 Annual Report – Partner Agency Research – About NIEHS

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About NTP at NIEHS

Most NTP research testing and analysis activities are carried out at NIEHS. The following Division of 

NTP branches at NIEHS are actively involved in NTP research activities. 

• Biomolecular Screening Branch, Richard S. Paules, Ph.D., acting chief.

• Cellular and Molecular Pathology Branch, Robert Sills, D.V.M., Ph.D., 

chief.

• NTP Laboratory, Michael DeVito, Ph.D., acting chief.

• Program Operations Branch, Michelle Hooth, Ph.D., chief.

• Toxicology Branch, Paul Foster, Ph.D., chief. 

NIEHS/NTP Staff 

Biomolecular Screening

The Biomolecular Screening Branch develops and implements programs in medium- and highthroughput screening of environmental substances for rapid detection of biological activities of 

significance to toxicology. A focus is to develop analysis tools and approaches that integrate 

screening assessments with findings from traditional toxicology. The branch also administers the NTP 

High-Throughput Screening Initiative, which includes NTP’s Tox21 activities. Tox21 emphasizes the 
2017 Annual Report – Partner Agency Research – About NIEHS 

126

use of alternative assays for targeting the key pathways, molecular events, or processes linked to 

disease or injury, with the goal of incorporating the assays into a research and testing framework. An 

important priority for moving forward is to expand the biological coverage of the screening program 

and enhance the human relevance of alternative tests’ findings. Key to this effort is the integration of 

high-throughput transcriptomic screening into Tox21 and other NTP studies. The development of the 

S1500+ gene set and its use in targeted sequencing approaches provides a new, cost-effective 

methodology for capturing broad biological responses to chemical exposures in a variety of in vitro 

and in vivo model systems, allowing for quantitative dose-response measurements and kinetic 

studies. Linking this high-throughput transcriptomic approach with novel organotypic cell culture 

model systems (i.e., models that behave like living tissue) allows for a more rapid and deeper 

investigation of biological responses for chemicals of concern and a better understanding of potential 

implications for human health.

Genetic and epigenetic differences between individuals in the human population have been proposed 

as major factors for determining individual susceptibility to environmental stressors. Safety 

assessments of environmental substances and drugs are currently conducted with a few commonly 

used animal models that have limited genetic diversity. Further, many layers of biological regulation 

can influence individual genetic susceptibility to chemical and drug toxicity. Animal models have 

inherent limitations for extrapolating results to human toxicity and disease. NTP is developing more 

sophisticated genetic analyses to make better use of current animal models while adopting biological 

systems that are more appropriate for modeling human toxicity and disease. The NTP Biomolecular 

Screening Branch conducts in-house projects aimed at understanding individual susceptibility.

Epigenetics involves the study of modifications to DNA and related cellular structures that affect gene 

expression and an organism’s ability to adapt to the environment. In FY 2017, work continued on an 

epigenetic study of mouse strains, led by Alex Merrick, Ph.D., and Paul Wade, Ph.D., to examine 

DNA methylation and its possible role in the susceptibility of mice to develop liver tumors. Male and 

female C57BL/6N mice were crossed with C3H/HeN mice. Five tissue types—brain, liver, cardiac and 

skeletal muscle, brown and white fat, and epididymal sperm—from first-generation offspring were 

collected and flash frozen for DNA/RNA isolation and liver sequencing. Progress in FY 2017 included 

computational analysis of genomic methylation sites in relation to known genes and transcriptionally 

active regions in both parental strains and first-generation offspring. The relationships between DNA 

methylation, gene expression, and possible heredity in offspring are being determined, and the 

genomic variations in mouse strains, genders, and first-generation offspring are being catalogued. 

The epigenetic landscape in the two mouse strains and their offspring will be described to help

interpret the contribution of differences in DNA methylation to differential susceptibility to hepatic

malignancy. The data will be publicly released following completion of a manuscript. Additional 

studies in FY 2017 addressed the impact of sex hormone signaling on DNA methylation at a genomewide level and the impact of DNA methylation at distal regulatory regions.

NTP Laboratory

NTP Laboratory conducts in-house, agent-specific, targeted research on the development and 

application of modern toxicology and molecular biology tools. These tools are used to: 

• Evaluate specific substances of concern to NTP. 

• Identify issues of central importance to programs within NTP. 

• Develop methods to advance the NTP mission. 

NTP Laboratory also studies the developmental origins of adult diseases. NTP Laboratory projects for 

FY 2017 are listed below. 
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NTP Laboratory Projects in FY 2017

Project & Study Scientist Project Summary

Development of in vitro models of metal 

carcinogenesis

Study Scientist: Erik Tokar

Use of in vitro cell transformation models (stem/progenitor and “mature” 

cells) of target-relevant cells to elucidate carcinogenic mechanisms and 

modes of action of metals (i.e., arsenic and cadmium). 

In vitro evaluation of crumb rubber toxic effects

Study Scientist: Erik Tokar

Study of the modes of action and metabolomics involved in the toxic 

effects of crumb rubber on various prospective human target tissues.

Role of microRNAs in malignant transformation

Study Scientist: Erik Tokar

Study of genes involved in the epigenetics of malignant transformation 

using in vitro human model systems of carcinogenesis. MicroRNAs are 

thought to be a key epigenetic or posttranscriptional gene expression 

control mechanism.

Stem cells in toxicology: carcinogenesis, 

developmental toxicology, and developmental 

basis of adult disease 

Study Scientist: Erik Tokar

Development of stem cell model systems (pluripotent, multipotent, 

progenitor) and methods for use in examining the role of these cells in 

carcinogenesis, evaluating developmental bases of adult disease, and 

assessing developmental toxicology. These studies will be used to help 

predict or categorize teratogens and developmental toxicants. 

Evaluation of polycyclic aromatic hydrocarbon 

compounds using in vitro screens 

Study Scientist: Erik Tokar

Application of in vitro assays to assess and categorize the biological 

effects of polycyclic aromatic hydrocarbon compounds.

Evaluation of the role of oxidative stress in the 

biological effects of glyphosate and its 

formulations

Study Scientist: Michael DeVito

Comparison of the effects of glyphosate to the effects of glyphosate 

formulations using measures of genotoxicity, oxidative stress, and cell 

viability. Comparison of the dose-response relationships among 

oxidative stress, genotoxicity, and cell viability.

Application of in vitro assays to evaluate 

botanicals

Study Scientist: Michael DeVito

Determination of whether in vitro assays and chemical analysis of 

botanicals can aid in selecting botanicals for in vivo testing. 

Chemical-induced transcriptomic and 

metabolomic changes in vitro

Study Scientist: Michael DeVito

Evaluation of the transcriptomic and metabolomic changes in 

metabolically active cell lines with 24 chemicals that have been tested in 

vitro.

Incorporation of metabolism into high 

throughput screening assays 

Study Scientist: Michael DeVito

Development of in vitro methods that incorporate xenobiotic 

metabolism. A manuscript is in development.

Utility of a five-day transcriptomic study in adult 

rats 

Study Scientist: William Gwinn

Examination of the differences in the transcriptomic bone mineral 

density and adverse effect bone mineral density for 20 chemicals that 

have been tested in vitro at NTP.
2017 Annual Report – Partner Agency Research – About NIEHS 

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Project & Study Scientist Project Summary

PCB 11: Screening for biological and 

toxicological activity

Study Scientist: Michael DeVito

Comparison of the biological and toxicological activity of polychlorinated 

biphenyl (PCB) 11 to prototype PCBs in response to a nomination from 

EPA.

Metalloestrogens and uterine/breast response

Study Scientists: Darlene Dixon, Suzanne 

Fenton

Tests of the ability of reported metalloestrogens such as cadmium and 

arsenic to cause estrogen receptor stimulation in the uterus as a mode 

of action for cancer development.

The role of ER-alpha36 in endocrine disruption 

and its localization in fibroid cells

Study Scientist: Darlene Dixon

Evaluation of the role of endocrine disrupter alpha36 (ER-alpha36) in 

fibroid cells and the role of ER-alpha36 in the endocrine disrupting 

effects of environmental and industrial chemicals. 

Literature-based evidence for environmental 

factors affecting the breast

Study Scientists: Suzanne Fenton, Jason 

Stanko, Vickie Walker

Review and categorization of the evidence in the literature on 

environmental influences on breast development, disease, and function. 

This work should lead to development of systematic reviews on related 

topics. 

Effects of TBBPA on developmental and 

reproductive endpoints in Harlan SD rats

Study Scientists: Suzanne Fenton, Linda 

Birnbaum

Evaluation of the effects of TBBPA (tetrabromobisphenol A) following 

prenatal and early life exposure and determination of 

transcriptomic/metabolomic pathways involved in low-dose, hormonedriven responses.

Screening of perfluorinated compounds for 

effects in human and mouse cell-based assays

Study Scientists: Suzanne Fenton, Michael 

DeVito

Comparison of potencies and effect profiles of 40–75 perfluorinated 

compounds for their effects in cells known to be targets of PFOA and 

PFOS (perfluorooctanoic acid and perfluorooctane sulfonate, two 

perfluorinated compounds removed from the market due to reported 

health effects).

Toxicants and mammary gland development

Study Scientist: Suzanne Fenton

Determination of the effects of different toxicants, including atrazine and 

bisphenols, on mammary gland development in rats or mice.

Use of in vitro screens to evaluate potential 

obesogens 

Study Scientist: Suzanne Fenton

Development of orthogonal assays to evaluate findings from Tox21 that 

identified potential obesogens. Mechanisms of action for select 

chemicals are being investigated.

Refinement of developmental neurotoxicology 

methods

Study Scientist: G. Jean Harry

Improvement of methods for assessing differential changes as a 

function of developmental exposures, including in vivo molecular 

phenotypes, cellular phenotypes, maternal/developmental inflammation, 

and behavioral assessments. 

Method development to assess 

neuroinflammation

Study Scientist: G. Jean Harry

Examination of methods (from screening to mechanisms) for assessing 

in vitro and in vivo induction of inflammation in the nervous system 

following chemical exposures. 

Evaluation of the developmental neurotoxicity 

of fluoride

Study Scientist: G. Jean Harry

Evaluation of fluoride developmental neurotoxicity in rats. The study has 

been completed, and a manuscript has been submitted.
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NTP at NCTR

About NTP at the National Center for Toxicological Research

NCTR provides innovative technology, methods development, vital scientific training, 

and technical expertise to NTP.

NTP at NCTR: Interagency Agreement Projects

A list of projects funded by the NIEHS/NTP interagency agreement with FDA and

conducted in FY 2017.
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130

About NTP at the National Center for Toxicological Research

Research in Partnership with NCTR

The National Center for Toxicological Research (NCTR) partners with researchers from elsewhere in 

FDA, other government agencies, academia, and industry to provide innovative technology, methods 

development, vital scientific training, and technical expertise. The unique scientific expertise of NCTR 

is critical in supporting FDA product centers and their regulatory roles. NCTR research for NTP is 

funded by both voluntary allocations and an interagency agreement. 

NCTR/NTP Staff

NCTR studies funded by voluntary allocations are listed below. 
2017 Annual Report – Partner Agency Research – About NCTR 

131

Biochemical and Molecular Basis of Toxicology

Project & Study Scientist Project Summary

Physiologically based pharmacokinetic (PBPK) 

models for bisphenol A (BPA)

Study Scientist: Jeffrey Fisher

Creation of PBPK models for BPA in mouse, rat, and rhesus 

monkey for multiple life stages: adult; neonate; pregnant, mother 

and fetus; and lactating, mother and neonate. These PBPK models 

will be used to calculate internal measures of dose for both aglycone 

(i.e., active) and conjugated (i.e., inactive) forms of BPA. Human 

PBPK models for BPA (adult, neonate, pregnant mother and fetus, 

and lactating mother and infant) will be created using information 

obtained from the monkey, mouse, and rat models and from the 

limited human information published in the literature. The human 

suite of PBPK models will be used to extrapolate the internal doses 

of BPA associated with toxicity in laboratory animals to human 

doses. They will also be used to better characterize internal 

dosimetry of BPA. This simulation protocol will help reduce the 

uncertainty in assessment of health risks BPA poses to human 

populations.

Biologically based dose-response modeling for the 

thyroid axis in the fetus and neonate

Study Scientist: Jeffrey Fisher

(1) Creation of biologically based dose-response models for the 

hypothalamic-pituitary-thyroid axis in the developing rat and human 

as a function of iodide status.

(2) Interfacing of the models with physiologically based 

pharmacokinetic or toxicokinetic models for thyroid active chemicals 

with predicted conditions, such as iodide status and chemical 

exposure, for which brain thyroid hormone homeostasis cannot be 

maintained in the fetus and neonate. 

(3) Use of the models to evaluate the possible influence of 

population exposures to thyroid active chemicals on fetal and 

neonatal thyroid status as a function of iodide intake.

Relationship between liver epigenetic phenotype 

and susceptibility to nonalcoholic steatohepatitisinduced (NASH) hepatocarcinogenesis in mice

Study Scientist: Igor Pogribny

(1) Determination of the role of epigenetic dysregulation in the 

etiology and pathogenesis of dietary NASH-induced 

hepatocarcinogenesis in mice. 

(2) Determination of whether interstrain-specific susceptibility of 

mice to NASH-induced hepatocarcinogenesis is associated with 

differences in individual hepatic epigenetic phenotypes. 

(3) Determination of the role of epigenetic dysregulation in the 

etiology and pathogenesis of NASH-induced hepatocarcinogenesis 

in mice induced by tamoxifen administration. 

(4) Determination of whether aberrant epigenetic markers can be 

used as targets for preventing NASH- induced 

hepatocarcinogenesis in mice.

Sex differences in drug-induced QT prolongation 

and torsade de pointes: Establishing an in vitro 

model for high throughput screening and risk 

assessment of torsadogenic drugs

Study Scientist: Li Pang

(1) Establishment of the in vitro model and positive control.

(2) Evaluation of model sensitivity and specificity and tests of the 

possibility of high-throughput screening and ranking of QTprolonging drugs for the risk of torsade de pointes.
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Mechanism of tumorigenic pyrrolizidine alkaloids 

and development of liquid chromatographyelectrospray ionization/multistage mass 

spectrometry (LC-ESI/MS/MS) methodology for 

detection and quantification of pyrrolizidine 

alkaloids

Study Scientist: Peter Fu

(1) Validation of the proposed mechanism by which pyrrolizidine 

alkaloids induce tumors in rodents. 

(2) Development of an LC-ES/MS/MS method for detecting and 

quantifying dehaloperoxidase-derived DNA adducts in rodents. 

(3) Development of an LC-ES/MS/MS method for detecting and 

quantifying genotoxic pyrrolizidine alkaloids in herbal plants and 

herbal dietary supplements. 

(4) Development of an LC-ES/MS/MS method for detecting and 

quantifying dehaloperoxidase-derived hemoglobin adducts in 

rodents.

Human biomonitoring for bisphenol A (BPA)

Study Scientist: Daniel Doerge

(1) Development and implementation of a sensitive and selective 

analytical methodology to measure BPA in human blood and urine. 

(2) Integration of animal exposure data and human biomonitoring 

data into a PBPK model for BPA.

Evaluation of the effects of black cohosh on 

risedronate efficacy in perimenopausal rat model

Study Scientist: Amy Inselman

Determination of the effects of risedronate and black cohosh (alone 

or combined) on bone density, bone turnover, and bone histology in 

a postmenopausal rat model.

Development and evaluation of a novel in vitro 

epigenomic screening model system for the hazard 

identification of FDA-regulated products

Study Scientist: Igor Pogribny

(1) Determination of the dose-dependent, in vitro genetic and 

epigenetic effects of compounds FDA regulates.

(2) Characterization of the specific epigenetic changes induced in 

vitro by genotoxic and nongenotoxic compounds. 

(3) Characterization of the specific genetic and epigenetic effects of 

compounds FDA regulates using an in vitro three-dimensional 

organotypic liver culture model system.

Developing methods for the analysis of brominated 

vegetable oils and derivatives

Study Scientist: Gonçalo Gamboa da Costa

Development of methods for analyzing the food additive, brominated 

vegetable oil, in rat feed and rat tissues.

Identification of mechanistic biomarkers of 

pyrrolizidine alkaloid (PA)-induced 

hepatocarcinogenesis

Study Scientist: William Tolleson

Use of high-throughput profiling approaches to identify microRNAs 

that regulate genes involved in PA carcinogenicity in hepatic cell 

systems and investigation of the functions of microRNAs by 

bioinformatics tools and in vitro functional assays. These results will 

identify microRNA species for use as biomarkers for PA-induced 

carcinogenicity, with added benefits derived from mechanistic 

knowledge of how these microRNAs might function in the biological 

effects of PAs. The discovery and characterization of microRNAs 

associated with the hepatocarcinogenic activity of PAs will benefit 

food safety and human health by providing simple tools for 

assessing exposure to foodborne toxins.
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Neurotoxicology

Project & Study Scientist Project Summary

Assessment of gaseous anesthetics in the 

developing nonhuman primate

Study Scientist: John Talpos

(1) Determination of the dose-response effects of gaseous 

anesthetics nitrous oxide and isoflurane (individual or combined) on 

neuronal cell death in the developing nonhuman primate using 

magnetic resonance imaging (MRI) and positron emission 

tomography (MicroPET). 

(2) Determination of the effects of dose and duration of gaseous 

anesthetics on nonhuman primate long-term behavior and pathology 

using MRI and MicroPET. 

(3) Evaluation of antioxidants in the amelioration of toxicity 

associated with gaseous anesthetics.

Developmental neurotoxicity assessment of Nmethyl-D-aspartate (NMDA) receptor antagonists in 

zebrafish

Study Scientist: Jyotshnabala Kanungo

(1) Study of wildtype zebrafish embryos exposed to NMDA receptor 

antagonists (MK-801, dextromethorphan, ketamine, and 

sevoflurane) to assess their effects on Rohon-Beard sensory 

neurons. The effects on the primary and secondary motor neurons 

and their axons are being assessed using hb9:GFP transgenic 

embryos. Postexposure washout experiments are being pursued to 

determine the effects of these drugs on the nervous system. 

(2) Determination of estradiol-17β levels in control and treated 

embryos and quantification of changes in gene expression for the 

two CYP aromatases/estrogen synthases (brain aromatase 

cyp19a1b and gonadal aromatase cyp19a1a) using quantitative 

polymerase chain reaction (qPCR). 

(3) Assessment of phenotype-based cell signaling mechanisms, 

such as MAPK (mitogen-activated protein kinases) and neuron 

development-specific gene expression. 

(4) Examination of reversal of noted adverse effects of these 

compounds on neurons, particularly by treatment with acetyl Lcarnitine.

Toxicity assessment of graphene sheets using 

primary striatal neurons

Study Scientist: Syed Ali

(1) Evaluation of the toxicity of graphene sheets using in vitro 

primary cultures of embryonic day 14 primary rat striatal neurons. 

(2) Determination of pathways involved in graphene toxicity using 

embryonic day 14 primary rat striatal neurons.

Identification of protein biomarkers for neurotoxicity 

assessments using a high-throughput antibody 

microarray approach

Study Scientist: Qiang Gu

(1) Examination of proteomic changes at the expression and 

phosphorylation levels using five established in vivo models of 

neurotoxicity. 

(2) Identification of common changes in protein expression and 

phosphorylation status in these animal model systems. 

(3) Confirmation of the observed alterations in protein expression 

and phosphorylation status by independent methods. 

(4) Application of the proteomic findings to a global ischemic animal 

model to verify the utility of protein biomarkers for use in 

neurotoxicity assessments.
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Effects of developmental sevoflurane exposure and 

pretreatment with acetyl-L-carnitine on complex 

brain function in rats 

Study Scientist: John Chelonis

(1) Examination of the effects of early developmental sevoflurane 

exposure on neurodegeneration and complex operant learning. 

(2) Determination of whether pretreatment with acetyl-L-carnitine 

can attenuate impairments in these measures.

(3) Examination of the time course of acetyl-L-carnitine pretreatment 

on sevoflurane-induced neuroapoptosis.

Rat blood-brain-barrier-on-a-chip model to study 

traumatic brain injury

Study Scientist: Syed Ali

(1) Use of soft lithograph and microfabrication techniques to 

engineer a multilayered blood-brain-barrier-on-a-chip model that can 

be subjected to different magnitudes and durations of mechanical 

stress that mimic mild and repetitive traumatic brain injury. 

(2) Characterization of the effects of traumatic brain injury on bloodbrain-barrier integrity using the chip model.

High-throughput neurotoxicity screening of metallic 

nanoparticles: In vitro and in vivo imaging

Study Scientist: Syed Imam

Assessment of the utility of high-throughput neurotoxicity screening 

of metallic nanoparticles for detecting neurochemical and 

neurophysiological alterations in vitro for use in developing 

reference standards for metallic nanoparticles. Once developed and 

validated, these techniques can be optimized for analyzing other 

FDA-regulated nanomaterials.

Nanotoxicology

Project & Study Scientist Project Summary

Proteomic assessment of the cytotoxic effects of 

nanoparticles on the blood-brain barrier

Study Scientist: Qiang Gu

Use of proteomic approaches to quantify alterations in expression 

and phosphorylation of proteins involved in apoptosis, inflammation, 

oxidative stress, and tumorigenesis signaling pathways in bloodbrain barrier cells following exposure to nanoparticles. The longterm goal is to establish proteomic parameters for toxicity of 

nanoparticles.

Complement assays for the detection of immunesensitizing activity of nanomaterials

Study Scientist: Julian Leakey

(1) Establishment of two complement assays for routine evaluation 

of immune-sensitizing activity of nanomaterials.

(2) Validation of the assays using nanoparticles with known 

immunoreactivity. 

(3) Determination of the immune-sensitizing activity of novel 

nanomaterials.

Physiologically based pharmacokinetic (PBPK) 

modeling of nanomedicine: Building clinically 

relevant standards for FDA-regulated 

nanoparticulate drug products

Study Scientist: Julian Leakey

(1) Determination of in vivo liposomal doxorubicin release kinetics in 

individual tissues and the blood stream using PBPK modeling. 

(2) Establishment of quantitative physicochemical property 

(liposomal size and content of ammonium sulfate) biodistribution 

relationships of liposomal doxorubicin products by PBPK modeling. 

(3) Extrapolation of the PBPK model to rats and humans. A wholebody PBPK model is being developed to describe and simulate the 

biodistribution of liposomal vesicles and doxorubicin.
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Assessment of size- and shape-dependent toxicity 

of silver (Ag) nanoparticles as measured by 

changes in the permeability at the gastrointestinal 

surface

Study Scientist: Sangeeta Khare

(1) Determination of the effect of nanomaterials on the permeability 

of intestinal epithelial cells in vitro and ileal mucosa ex vivo.

(2) Investigation of various cellular components involved in the 

uptake of nanoparticles in intestine, their accumulation in various 

cell types, and the effect of nanoparticles on the intestinal 

microbiome. 

(3) Measurement of the toxicity of silver nanoparticles using 

changes in the expression of genes involved in the epithelial 

integrity of polarized epithelial cells and ileal mucosa.

In vitro genotoxicity of graphene-family 

nanomaterials using FDA-recommended short-term 

genetic toxicity test battery

Study Scientist: Nan Mei

(1) Determination of the genotoxicity of graphene and derivatives in 

standard regulatory test battery assays.

(2) Determination of whether any mutagenicity in mouse lymphoma 

cells is due to loss of heterozygosity in chromosome 11.

(3) Investigation of whether genotoxic and mutagenic responses are 

mediated through oxidative pathways. 

(4) Establishment of the genotoxic and mutagenic mode of action 

using gene expression arrays.

Graphene-induced toxicity on the population of 

intestinal microbiota and gut-associated immune 

response

Study Scientist: Sangeeta Khare

Evaluation of the effects of graphene on gastrointestinal 

homeostasis by determining graphene derivative effects on 

intestinal bacterial cultures, polarized intestinal epithelial cells, 

intestinal commensal bacteria in vivo, and gastrointestinal immune 

responses in vivo.

NCTR/Office of Regulatory Affairs (ORA) 

Nanotechnology Core Facility

Study Scientist: Anil Kumar Patri

(1) Provision of the expertise and equipment for characterizing 

nanomaterials used in toxicology studies and for detecting 

nanomaterials in in vitro and in vivo derived samples.

(2) Serving as a resource for U.S. agencies for the design of 

toxicology studies and generation of standards for analytical 

methods.

Assessment of whether engineered Ag 

nanomaterials (Ag-ENMs) varying by size and 

coatings behave differently from bulk Ag in their 

ability to induce genetic damage

Study Scientist: Tao Chen

(1) Evaluation of whether the Ames test and mouse lymphoma 

assay, in addition to the in vitro micronucleus assay, are suitable for 

detecting the genotoxicity of titanium dioxide (TiO2) nanoparticles, a 

known rodent carcinogen. 

(2) Investigation of Ag-ENPs of various sizes and compare the 

results to those obtained using bulk Ag.

Determination of cytotoxicity and genotoxicity of 

nanomaterials of interest to the FDA and their 

mechanism of action

Study Scientist: Peter Fu

(1) Development of a set of cell-free and cell-based in vitro tests that 

can be used to rapidly identify nanomaterials of interest to the FDA 

that elicit oxidative damage. 

(2) Determination of whether, in the presence of nano-metal 

materials, endogenous and dietary antioxidants can display prooxidative activity.
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Assessing epigenetic effects of nanoparticles in 

human cells

Study Scientist: George Hammons

(1) Determination of the effect of two types of nanoparticles, silver 

and titanium dioxide, at various particle sizes, surface coatings, 

dosages, and durations of exposure on global methylation and 

genome-wide DNA methylation using array profiling in four types of 

human cells (liver, lung, skin, and colorectal). 

(2) Determination of the effect of these nanoparticles on the pattern 

of global histone modifications and on genome-wide profiles of 

histone modifications in the four types of human cells. The analysis 

includes comparisons with disease-associated histone 

modifications. 

(3) Correlation of the nanoparticle effect on DNA methylation with its 

effect on DNA methyltransferase expression.

(4) Correlation of the nanoparticle effect on global histone 

modifications with its effect on expression of histone-modifying 

enzymes as potential underlying mechanisms of the alteration in 

DNA methylation or histone modification patterns.

Immunotoxicity assessment of nanomaterials using 

human immune cell based biomarkers of innate 

immunity

Study Scientist: Wei Ding

Assessment of the immunotoxicity of different categories of 

nanoparticles using biomarkers of innate immunity measured in vitro 

in human immune cells (monocytes, human peripheral blood 

mononuclear cells).

An assessment of the interactions of nanoscale 

(TiO2 and zinc oxide) materials used in sunscreens 

on the skin microbiome

Study Scientist: Tao Chen

(1) Examination of human skin microbiota cell viability in the 

presence of nanoscale materials in cosmetics.

(2) Determination of the effect of nanomaterials in cosmetics on 

human skin microbial ecology.

(3) Demonstration of the mechanisms of toxicity of nanoscale 

materials in cosmetics to skin microbiota using the human skin 

tissue model EpiDerm and reverse transcription polymerase chain 

reaction (RT-PCR) and whole genome microarray technologies.

(4) Elucidation of the dose-response relationship of nanoscale 

materials in cosmetics on skin bacterial cell toxicity. 

(5) Assessment of the potential health risk of human skin exposure 

to nanomaterials in cosmetics.

Evaluation of the migration and toxic potential of Ag 

nanoparticles in feminine hygiene products to 

vaginal tissue: In vivo rodent and in vitro 3D 

mucosal models

Study Scientist: Anil Patri

(1) Use of established qualitative methods to characterize different 

species of nanoscale Ag contained in five types of dry and five types 

of liquid feminine hygiene products.

(2) Evaluation of the migration/uptake and toxicity of Ag 

nanoparticles and ions used in feminine hygiene products using a 

human cell-based in vitro three-dimensional culture model that has 

many of the structural and functional features of the human vaginal 

mucosal layer.

(3) Evaluation of the effects of Ag nanoparticles and ions contained 

in feminine hygiene products on human vaginal microbiota using 

culture techniques and semiquantitative molecular methods.
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Interaction of nanoparticles with gastrointestinal 

tract

Study Scientist: Sangeeta Khare

(1) Determination of the effect of nanomaterials on the permeability 

of epithelial cells and establishment of immune correlates. 

(2) Delineation of the interaction of nanomaterials with 

gastrointestinal tract and gut-associated microbiota using an ex-vivo 

model (intestinal explants).

(3) Establishment of the effect of nanoparticles on the 

developmental stage of the intestine and assessment of the 

biodistribution of nanoparticles using the zebrafish model.

The effect of nanomaterials used in dentistry on 

biofilm formation and the oral microbiota

Study Scientist: John Sutherland

(1) Comparison of the relative efficacy of FDA-regulated 

nanomaterials used in dentistry for inhibition of bacterial adhesion to 

surfaces and biofilm formation. 

(2) Evaluation of the effect of nanomaterials on growth and 

antimicrobial susceptibility profiles of typical species from the oral 

microbiota.

Mechanistic toxicological evaluation of engineered 

nanomaterials using a human stem cell model

Study Scientist: Anil Patri

(1) Establishment of the human stem cell model for nanotoxicity 

testing.

(2) Exploitation of the preliminary observation that titanium dioxide 

inhibits mesenchymal stem cell differentiation into adipocytes while 

other nanomaterials have no effect on the cells.

(3) Establishment of a novel sensitive model for nanotoxicity testing 

and provision of that information to FDA regulators on effects of 

titanium dioxide and other nanomaterials used in food, drugs, 

cosmetics, and medical products.

Bioassay and Biomarker Development and Evaluation

Project & Study Scientist Project Summary

Development of cancer-relevant biomarkers for 

identification of potential carcinogens: Research to 

understand the normal background frequencies in 

rats

Study Scientist: Page McKinzie

(1) Understanding of the distribution and range of spontaneous 

oncogene mutant frequencies in the major organs of rats and mice. 

(2) Provision of important basic information for the validation of 

these oncogene mutant frequencies as biomarkers of chemically 

induced carcinogenesis.

Validation of a newly developed transgenic, 

hairless, albino mouse

Study Scientist: Manju Manjanatha

Evaluation of a newly developed transgenic, hairless, albino mouse 

bearing a gpt-delta reporter construct (THA) for responsiveness of 

the construct (gpt and spi- red/gam genes) to UVB (ultraviolet B 

radiation). The animal will be used to examine kinetics of induction 

of UVB-induced mutations in a reporter construct in the dermis and 

epidermis and to correlate activity with UVB induction of skin 

tumors.

Study of translational biomarkers for drug-induced 

liver injury with next-generation sequencing

Study Scientist: Yuping Wang

Conduct of a comprehensive survey of microRNAs using the next 

generation sequencing technology. Findings will elucidate the 

molecular pathways and processes modulated by RNAs (including 

messenger RNAs, microRNAs, and other noncoding RNAs) and 

their importance in drug-induced liver injury risk and phenotypes.
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Project & Study Scientist Project Summary

A comprehensive characterization of induced 

pluripotent stem cell-derived cardiomyocyte (iPSCCM) models for drug-induced arrhythmia using 

high-throughput screening assays

Study Scientist: Li Pang

(1) Development of standard baseline criteria for high-throughput 

readouts of drug-induced arrhythmia in human iPSC-CMs from 

different suppliers. 

(2) Assessment of individual variance and possible sex differences 

in drug-induced cardiotoxic responses across a panel of 

nongenetically modified iPSC lines.

Validating the rat Pig-a assay for regulatory use: 

Determining the molecular basis of mutants 

detected in the rat Pig-a gene mutation assay

Study Scientist: Vasily Dobrovolsky

Development of a method that could routinely identify Pig-a 

mutations in individual Pig-a mutant phenotype cells.

Developing in vitro approaches to assess druginduced liver toxicity

Study Scientist: Lei Guo

Development and utilization of in vitro assays for assessing druginduced liver toxicity by evaluating cytotoxicity and quantifying 

representative endpoints for assessing clinical-related outcomes 

such as apoptosis/necrosis, steatosis, and cholestasis.

Evaluation of microRNAs in blood and urine for 

detection of chemical-induced carcinogenicity

Study Scientist: Tao Chen

(1) Determination of microRNAs in blood and carcinogenic target 

tissues that respond to carcinogen exposures and the best time for 

sampling of their expression after treatments in rats. 

(2) Determination of microRNA profiles from the blood and target 

tissue samples of rats treated with different mode-of-action 

carcinogens, such as alkylating agents, aneugens, clastogens, and 

nongenotoxic carcinogens at the appropriate sampling time. 

(3) Determination of the functions and pathways of the dysregulated 

microRNAs by the carcinogen treatments and examine whether the 

microRNA changes can be anchored to the carcinogens with the 

known mode-of-actions and whether the changes in blood are 

related to those in the target tissues. 

(4) Establishment of specific microRNA biomarkers in blood for 

assessing different types of carcinogens.

Development and characterization of a dietinduced obesity model using B6C3F1 mouse for 

evaluation of drug toxicity in obesity

Study Scientist: Vijayalakshmi Varma

Development of a B6C3F1 mouse model of obesity to investigate 

the impact of obesity on anthracycline-induced cardiotoxicity and the 

model’s suitability to investigate other potential drug-induced 

toxicities under conditions of obesity.

Development of advanced safety assessments of 

FDA-regulated products using high-throughput and 

high-content quantitative approaches in cultured 

human cells to evaluate genotoxicity

Study Scientist: Carol Guo

Establishment and demonstration of the feasibility of novel highthroughput and high-content in vitro genotoxicity assays conducted 

using human liver cells in conjunction with quantitative doseresponse approaches for assessing and distinguishing the 

genotoxicity of FDA-regulated products.

Enhance the prediction of potential endocrine 

activity of chemicals by integrating multiple 

endpoints data

Study Scientist: Huixiao Hong

(1) Augmentation of different endocrine-related endpoint data and 

development of prediction models for screening chemicals with 

endocrine activity potential by integrating the augmented multiple 

types of endocrine-related endpoint data. 

(2) Building of an androgenic activity database and construction of 

integration-based prediction models.
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Project & Study Scientist Project Summary

Evaluation of an in vitro testis organ system as an 

alternative model for male reproductive toxicology

Study Scientist: Noriko Nakamura

Evaluation of the in vitro testis organ system as an alternative model 

to assess male reproductive toxicology and establishment of a 

standardized protocol for the assay.

Computational Toxicology

Project & Study Scientist Project Summary

Improving methods and algorithms for enhancing 

3D-QSDAR

Study Scientist: Svetoslav Slavov

Testing of the feasibility and implementation of software code for 

enhancements to the three-dimensional quantitative spectral dataactivity relationship (3D-QSDAR) technique and demonstration of 

the potential beneficial effect on the performance of 3D-QSDAR 

models for various data sets and endpoints. 

Computational toxicology for safety and risk 

assessment

Study Scientist: Jeffery Fisher

Assistance to other FDA Centers and research organizations 

outside of FDA with their requests for support from staff scientists 

within NCTR and other scientists on safety and risk assessment 

issues of interest to FDA.

Pilot study to examine a population-based 

computational framework for assessing xenobiotic 

disposition and interaction effects in pregnant 

women 

Study Scientist: Annie Lumen

(1) Demonstration of a proof of concept for using emerging 

computational techniques in understanding pregnancy-related 

alterations in drug pharmacokinetics. 

(2) Assistance in developing recommendations for dose adjustments 

and drug labeling in the pregnant population, thus promoting 

women’s health during this crucial period. 

Hepatoxicity of herbal/dietary supplements 

Study Scientist: Weida Tong

Assembly of a comprehensive list of herbal and dietary supplements 

that have potential to cause drug-induced liver injury in humans into 

a web-based database that can be used for reference in regulatory 

processes when hepatotoxicity issues arise. 
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NTP at NCTR: Interagency Agreement Projects

NCTR research for NTP is funded by voluntary allocations and an interagency agreement. Below are 

FY 2017 projects funded through an NIEHS/NTP interagency agreement with FDA. 

Food Additives and Contaminants

Project & Study Scientist Project Summary

Two-year chronic toxicology study of BPA in rats

Study Scientist: Barry Delclos

Characterization of the long-term toxicity of orally administered 

BPA (bisphenol A), including developmental exposure, in NCTR 

Sprague Dawley rats over a broad dose range. Animals generated 

in this study are being assigned to separate protocols for 

assessment of a range of molecular, morphological, and functional 

endpoints to determine if these endpoints are predictive of longterm toxic effects or reveal potential effects undetected by standard 

toxicological evaluations.

Evaluation of molecular, morphological, and 

functional endpoints in rats treated with BPA

Study Scientist: Barry Delclos

Evaluation of a range of molecular, morphological, and functional 

endpoints in rats dosed orally with a wide range of BPA doses in a 

chronic toxicology study. The endpoints were selected based on 

reports from previous animal toxicology or human epidemiology 

studies, suggesting they are affected by BPA exposure. 

Assessments are being conducted at various ages (postnatal days 

1, 21, and 90 and 6 and 12 months) to determine if any effects 

observed are predictive of long-term effects evaluated in the 

companion chronic toxicology study, or if they reveal potential 

effects undetected by standard toxicological evaluations.

Combined nephrotoxicity of melamine and cyanuric 

acid in rats (recovery study) 

Study Scientist: Gonçalo Gamboa da Costa

Assessment of the degree of functional and histological recovery 

after 30- and 90-day recovery periods in rats orally co-exposed with 

melamine and cyanuric acid for 90 days.

Comparison of the dose-response and temporal 

dynamics of traditional and novel biomarkers of 

nephrotoxicity upon a combined exposure to 

melamine and cyanuric acid in rats 

Study Scientist: Luisa Camacho

(1) Comparison of the dose-response and temporal dynamics of 

circulating microRNAs, blood urea nitrogen, and serum creatinine 

in rats co-exposed to melamine and cyanuric acid over a 90-day 

treatment period and a subsequent 90-day recovery period. 

(2) Comparison of the dose-response relationships of the kidney 

gene expression level of biomarkers of nephrotoxicity and kidney 

histopathology in rats co-exposed to melamine and cyanuric acid 

for 90 days and upon a 90-day recovery period.

Role of perinatal development on toxicokinetics of 

inorganic arsenic

Study Scientist: Daniel Doerge

Determination of serum pharmacokinetics and metabolism of lowdose inorganic arsenic in adult female CD-1 mice, Sprague Dawley 

rats, and rhesus monkeys.

Evaluation of brominated vegetable oil in rats

Study Scientist: Gonçalo Gamboa da Costa

(1) Assessment of the dose-response relationships of a 90-day 

dietary exposure to brominated vegetable oil in Sprague-Dawley 

rats. 

(2) Evaluation of the bioaccumulation and clearance of inorganic 

and organic bromine in organs and tissues of Sprague-Dawley rats 

upon dietary exposure to brominated vegetable oil.

Developmental neurotoxicity evaluation of inorganic 

arsenic exposure in rats

(1) Determination of appropriate doses and survivability for direct 

oral inorganic arsenic exposure in neonatal Sprague-Dawley rats. 
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Project & Study Scientist Project Summary

Study Scientist: Sherry Ferguson (2) Development and refinement of techniques for future, more 

comprehensive studies. 

(3) Determination of the early neurobehavioral toxicology of 

inorganic arsenic exposure on two preweaning behaviors and 

developmental milestones.

Dermal Toxicology Program

Project & Study Scientist Project Summary

Two-year dermal carcinogenicity of triclosan in 

B6C3F1 mice

Study Scientist: Jia-Long Fang

Determination of the toxicity and carcinogenicity of topically applied 

triclosan in mice.

Dietary Supplement Program

Project & Study Scientist Project Summary

Thirteen-week dosed water study to determine the 

potential toxicity of aloin in the cecum and large 

intestine of F344 rats

Study Scientist: Mary Boudreau

Evaluation of whether drinking water administration of aloin-A and 

aloin-B to F344 rats exerts similar effects in the rat large intestine 

when administered at concentrations similar to those in previous 

NCTR studies on Aloe vera whole leaf extract.

Effects of fibrinolytic enzymes nattokinase and 

lumbrokinase alone or in combination with aspirin in 

blood parameters

Study Scientist: Luisa Camacho

Evaluation in an animal model of the effects of nattokinase and 

lumbrokinase on blood parameters and assessment of their effects 

in combination with pharmacological doses of aspirin.

Drugs Program

Project & Study Scientist Project Summary

Toxicokinetic profile and toxicity of high-molecularweight polyethylene glycols in rats

Study Scientist: Jia-Long Fang

(1) Evaluation of the toxicokinetic profile of high-molecular-weight 

polyethylene glycols in Sprague-Dawley rats given a single dose of 

the substances via subcutaneous injection. 

(2) Evaluation of the bioaccumulation of high-molecular-weight 

polyethylene glycols in organs/tissues of rats upon repeated 

subcutaneous injection for 24 weeks.

(3) Assessment of the toxicities resulting from the bioaccumulation 

of the substances.

Enhancing Toxicology Program

Project & Study Scientist Project Summary

NTP capability building for microbiome assessment 

on toxicology studies: Assessing the role that the 

microbiome may play in the toxicity of xenobiotics

Study Scientist: Carl Cerniglia

Addressing critical knowledge gaps in the microbiome field using 

the latest advances in microbiome analysis through in vitro, in vivo, 

and ex vivo models in toxicity testing risk assessments.
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Project & Study Scientist Project Summary

Developing an in vitro system to evaluate the 

disease-related toxic effects of inhaled test agents in 

human airway tissue models

Study Scientist: Xuefei Cao

(1) Development of exposure and dosimetry methods for exposing 

human air-lung interface airway cultures to aerosolized test agents. 

(2) Use of previously developed disease-related endpoints and airlung interface culture exposure methods to evaluate the respiratory 

toxicity of two known airway toxicants, two presumed nontoxicants, 

and one compound of current interest.

Evaluation of genotoxicity and epigenetic 

modification of black cohosh extract (BCE) using the 

modified comet assay

Study Scientist: Manju Manjanatha

(1) Performance of alkaline single-cell gel electrophoresis (Comet) 

assays to detect DNA single- and double-strand breaks using 

several human cell lines. 

(2) Performance of modified Comet assays using the addition of 

uracil-DNA glycosylase to evaluate the potential underlying 

mechanism(s) of BCE-associated genotoxicity.

(3) Performance of recently established modified Comet assays 

using DNA restriction enzyme, McrBC, which specifically 

recognizes DNA sites of the form 5'-R(m)C-3' and cuts DNA at 

methylated Cs for evaluating methylation modification by BCE.
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NTP at NIOSH

About NTP at NIOSH

NIOSH research projects for NTP assess the effects of exposures to substances 

following its mandate to protect workers' health and safety. 

NTP at NIOSH: Immunotoxicology Research

A list of studies to evaluate unique cohorts of individuals from professions associated

with immune-mediated occupational diseases.

NTP at NIOSH: Occupationally Relevant Exposures

A summary and list of projects to identify and assess worker exposures in FY 2017.
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About NTP at NIOSH

In accordance with its mandate to protect worker health and safety, the National Institute for 

Occupational Safety and Health (NIOSH) carries out research projects with NTP through an 

interagency agreement with NIEHS to assess the effects of exposure to substances. Setting priorities 

in occupational toxicological research is based on several sources of information NIOSH develops 

and maintains. Sources include health hazard evaluations, industry-wide studies, gaps in knowledge 

identified while developing criteria for recommended standards or criteria documents, current 

intelligence bulletins, hazard reviews and alerts, other technical reports, and information profiles on 

chemical hazards. NIOSH research projects with NTP are funded by voluntary allocations and an 

interagency agreement focused on comprehensive assessment of occupationally relevant exposures

and immunotoxicology research.

NIOSH Staff: Health Effects Laboratory Division; Education and Information Division; Division of Applied Research and 

Technology and Division of Surveillance, Hazard Evaluations, and Field Studies

NIOSH/NTP projects in FY 2017 funded through voluntary allocations are listed below. 

Biomonitoring, Biomarker Development, and Health Assessment

Project & Study Scientist Project Summary

Exposure assessment research and support

Study Scientist: John Snawder

Support of multiple branch and interdivisional projects through (1) 

managing and planning field sample collection, (2) developing new 

classical and immunochemical biomonitoring methods, and 

(3) validating and adapting existing methods. Biological monitoring 

can assess exposure by analyzing acute and latent metabolites in 

various biological media. This project will develop low-cost, rapid 

immunochemical and analytical chemistry biomonitoring methods to 

be used to identify exposures and evaluate potential interventions. 

Concurrent with development of exposure assessment methods, 

this project will identify and develop new multiplex immunochemical 

methods to evaluate biomarkers of occupational illness or 

subclinical signs of occupational illness.

Ultraviolet native fluorescence-based monitor for 

workplace exposures 

Study Scientist: John Snawder

Development and evaluation of a readily adaptable, next-generation, 

direct-reading personal monitor for use in measuring worker 

exposure to a wide variety of chemicals, including naphthalene and 

components of asphalt fume. The development of personal monitors 

for volatile and semivolatile workplace chemicals will be helpful in 

rapidly assessing chemical exposure and will result in more realistic 

occupational exposure assessments. These assessments will allow 

for rapid interventions leading to reduced worker exposures and 

helping prevent occupational illness and disease.
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Project & Study Scientist Project Summary

Evaluation of welding fumes as a lung carcinogen 

in mice exposed by inhalation 

Study Scientist: Patti Erdely

Investigation of both carcinogenic metal-containing and noncarcinogenic metal-containing welding fumes as lung carcinogens 

using a two-stage initiation-promotion mouse model. The findings 

will establish if welding fume inhalation at relevant occupational 

exposure levels increases lung tumorigenesis. The project also is 

generating valuable data regarding the carcinogenic potential of 

fumes from different types of welding processes that contain or do 

not contain carcinogenic metals. In addition, the project is providing 

information on which metal oxide components of the welding fume 

have the greatest carcinogenic potency. Thus far, the results of this 

project have contributed to the reevaluation of welding fumes by the 

International Agency for Research on Cancer in March 2017.

Systematic assessment of cobalt oxide (CoO) and 

lanthanum oxide (La2O3) in pulmonary disease 

Study Scientist: Yong Qian

Investigation of cobalt oxide and lanthanum oxide nanoparticleinduced pulmonary injury in vivo and cellular toxicity in vitro. This 

project will reveal the toxicological modes of action for cobalt oxide 

and lanthanum oxide nanoparticles. Metal oxide nanoparticles are 

an important class of engineered nanomaterials with broad 

application in many industrial products. Concerns over potential 

metal oxide nanoparticle-induced toxicity have emerged, particularly 

due to the propensity of these nanoparticles to induce oxygen 

radicals and oxidative stress. Results obtained from this study will 

lead to development of methods for early detection and 

interventions of cobalt oxide and lanthanum oxide-induced 

pulmonary diseases, particularly fibrosis, in humans.

Industry-wide studies of workers exposed to carbon 

nanotubes and nanofibers 

Study Scientist: Mary Schubauer-Berigan

Collection of exposure data and exposure factors from participating 

pilot-scale or full-scale manufacturers or users of single-walled 

carbon nanotubes (SWCNTs) or multiwalled carbon nanotubes and 

carbon nanofibers. A study of biomarkers for early pulmonary, 

cardiovascular, and carcinogenic effects was carried out among 

workers at these facilities. The creation of a predictive model using 

the collected exposure factors will allow for the estimation of 

exposure for future registry and cohort studies.

Mortality, cancer incidence, and biomarker studies 

Study Scientist: James Yiin

Elucidation of exposure-outcome associations, especially doseresponse relationships, for risk assessment and to examine 

relationships between biomarkers of exposure, susceptibility, and 

oncogene expression and determine health effects.

Environmental Monitoring

Project & Study Scientist Project Summary

Analytical research and development infrastructure 

Study Scientist: Robert Streicher

Support of administrative needs and analytical instrumentation 

repair and maintenance for Chemical Exposure and Monitoring 

Branch chemists conducting research on sampling and developing 

analytical methods for workplace chemicals. Development, 

evaluation, validation, and use of methods for evaluating 

bisphenol A, manganese speciation, flame retardants, and other 

chemicals are part of the NIOSH/NTP exposure assessment 

interagency agreement. 
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Diacetyl exposure assessment 

Study Scientist: Robert Streicher

Development and evaluation of sampling and analytical methods for 

diacetyl and other higher molecular-weight alpha dicarbonyl 

flavoring compounds to enable accurate exposure assessment and 

evaluation of the effectiveness of control technology. Two sampling 

and analysis methods are being investigated for measurement of 

specific flavoring compounds, most notably diacetyl and 2,3-

pentanedione. One method measures alpha dicarbonyl compounds 

present as vapor; the other measures the compounds in airborne 

particles and bulk powders. A modification to improve a recently 

developed Occupational Safety and Health Administration method 

for flavorings by gas chromatography-mass spectrometry using a 

different extraction solvent has been investigated in FY 2017. In 

addition, a new sampler that can distinguish flavorings present in air 

as vapors, particle-bound flavorings, and vapors off-gassing from 

collected particles has undergone evaluation with diacetyl and has 

performed well.

Nanoaerosol monitoring methods 

Study Scientist: Eileen Birch

Development and application of measurement methods for 

hazardous aerosols. Globally, exposure to hazardous aerosols 

remains a serious health concern, with growing attention on fine, 

ultrafine, and nanosized aerosol particles. New nanomaterials are 

being developed and used in multiple commercial products, but their 

health and environmental impacts are little known. Multiple 

analytical tools are being used because the properties most 

responsible for nanoaerosol toxicity are unclear and exposures to 

complex mixtures often occur. This research is providing critical 

exposure data and information on the widely differing physical and 

chemical properties of nanoscale aerosols and materials, properties 

which might influence particle toxicity. The methods have general 

application to exposure monitoring and control studies. 

Metal content was determined by inductively coupled plasma atomic 

emission spectroscopy after microwave digestion in concentrated 

nitric acid. All materials were analyzed by thermogravimetric 

analysis, which gives the onset of oxidation (a measure related to 

stability) and residual ash content (a measure of purity). Most 

sample contained high concentrations, and the residual ash 

contents of the materials ranged from about 1 to 10%. Previously 

(FY 2016), polycyclic aromatic hydrocarbons and transmission 

electron microscopy analyses were completed.

Exposure Assessment

Project & Study Scientist Project Summary

Exposure assessment for toxicologically important 

chemicals 

Study Scientist: Brian Curwin

Characterization of workplace exposures to chemicals of 

toxicological concern as identified by NTP and NIOSH. Current 

studies evaluate welding fumes with emphasis on manganese, 

occupational exposure to carbon nanotubes and nanofibers, flame 

retardants, and polycyclic aromatic hydrocarbons in coal tar 

sealants. Goals of these studies include: (1) identifying industries, 

workplaces, uses, and users; (2) determining occupational health 

relevance; (3) estimating the number of workers exposed; and (4) 

conducting exposure sampling.

Industry-Wide Studies Branch research, 

development, and planning 

Study Scientist: Elizabeth Whelan

Support of strategic planning and feasibility studies of high-priority 

issues and emerging problems in occupational health.
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Nanotechnology field evaluations 

Study Scientist: Charles Geraci

Collection of information from as many different facilities in the field 

as possible regarding the (1) nature of engineered nanomaterials, 

(2) processes involved in the manufacture and use of 

nanomaterials, (3) potential worker exposures to nanomaterials, and 

(4) practices and control procedures in the workplace where 

nanomaterials are produced or used. As toxicology studies identify 

the biological hazards of nanomaterials, gaining a better 

understanding of actual workplace exposures is essential.

Immunotoxicity and Immunology

Project & Study Scientist Project Summary

Immunotoxicological evaluation of occupational 

chemicals 

Study Scientist: Stacey Anderson

Identification of occupational and environmental chemical hazards 

and evaluation of immune function and mechanisms associated with 

exposure. This research is contributing to better risk assessment 

and increased identification of immunological hazards encountered 

in the workplace, which ultimately will establish occupational 

exposure limits.

Identification of occupational allergens 

Study Scientist: John Noti

(1) Identification of exposures to substances that can cause 

inflammatory or immune reactions in certain work environments. 

These exposures are important causes of occupational lung 

diseases, such as asthma and allergic alveolitis.

(2) Development of improved techniques for detecting such immune 

reactions before adverse clinical outcomes occur.

(3) Development of improved techniques for detecting and 

identifying inciting occupational agents.

This project is analyzing clinical samples, environmental bulk 

samples, and environmental aerosol samples. Successful 

completion of these investigations should lead to the development of 

effective prevention strategies for occupational allergies and 

asthma.

Characterization of in vivo protein haptenation 

following exposure to aerosolized 4,4’-methylene 

diphenyl diisocyanate 

Study Scientist: Justin Hettick

Determination of the molecular targets of inhaled diisocyanate 

particulates and better understanding of the pathogenic mechanism 

of isocyanate-induced allergic disease. The project enhances the 

overall understanding of the fate of diisocyanate in vivo following 

occupational exposure by increasing our understanding of disease 

and identifying potential biomarkers of exposure.
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Exosomes as biomarkers and immune modulators 

of diisocyanate asthma 

Study Scientist: Justin Hettick

Definition of mechanisms of occupational asthma associated with 

exposure to methylene diphenyldiisocyanate (MDI) by identifying 

biomarkers of MDI exposure and immune regulatory factors that 

influence the progression and severity of MDI-associated 

occupational asthma. Exposure to MDI, used in the manufacturing 

of glues and polyurethanes, results in occupational asthma in 

approximately 5–15% of workers. Currently, sensitive and reliable 

markers for MDI exposure and sensitization do not exist, partially 

due to the lack of specificity of markers commonly associated with 

asthma. Furthermore, the factors influencing susceptibility and 

severity of MDI-associated occupational asthma have not been 

elucidated. This project is identifying response and legacy 

biomarkers found in exosomes secreted into the bloodstream that 

would indicate isocyanate exposure and sensitization. Attempts are 

being made to distinguish chemically induced biomarkers from highmolecular-weight allergen-induced biomarkers and determine how 

exosome genetic content can influence asthma progression. The 

biomarkers identified in this study can be incorporated into a human 

exposome database and be used in future studies to distinguish 

MDI-associated occupational asthma from general environmental 

asthmas.

Genetics

Project & Study Scientist Project Summary

Immunotoxicity of subchronic fungal exposures 

Study Scientist: Brett Green

Determination of the pulmonary immunopathological outcomes of 

subchronic exposures to fungi nominated to NTP. Subchronic 

exposure studies with mycotoxin-producing strains of Stachybotrys 

chartarum and Aspergillus versicolor have been completed. Future 

subchronic exposure studies will focus on an atranone-producing 

strain of S. chartarum, A. versicolor, A. alternate, and fungi identified 

in NIOSH Health Hazard Evaluations and collaborative exposure 

assessment studies. Proposed studies will provide further insight 

into the mechanisms of pulmonary toxicity to fungi encountered in 

the workplace.

Immunomodulatory effects of triclosan on effector 

CD4 T cell development 

Study Scientist: Nikki Marshall

Identification of the cellular and molecular mechanisms behind the 

immune-modulating effects of the antibacterial chemical, triclosan. 

This information is providing the basis for evaluating other 

nonsensitizing antimicrobial chemicals and helps identify potentially 

conserved mechanisms that contribute to allergic disease. Results 

of this project will help assess the need to evaluate these types of 

workplace chemicals, leading to better risk assessment and 

establishment of occupational exposure limits.
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Highly sensitive and practical biomarkers for 

nanotoxicity 

Study Scientist: Pius Josephweb

Development, validation, and testing (using a rat model) of highly 

sensitive and minimally invasive biomarkers for early detection of 

pulmonary toxicity potentially associated with exposure to toxic 

nanomaterials. Techniques are being employed to develop 

transcriptomic signatures in blood as surrogate biomarkers for the 

pulmonary toxicity induced by inhalation exposure to specific 

nanomaterials. Bioinformatic analysis of the global transcriptomics 

data is being conducted to gain insights into the molecular 

mechanisms underlying the pulmonary toxicity of nanomaterials. 

Determining the molecular mechanisms of pulmonary toxicity and 

developing highly sensitive and minimally invasive biomarkers for 

nanotoxicity have implications in monitoring workers for their risk of 

developing adverse health effects potentially associated with 

exposure to toxic nanomaterials. 

Results obtained from preliminary studies demonstrated that rats 

exposed to multiwalled carbon nanotubes (MWCNTs) can be 

distinguished from those exposed to crystalline nanocellulose using 

blood gene expression profiles.

Toxicological investigations of nitrogen-doped 

multiwalled carbon nanotubes 

Study Scientist: Dale Porter

Examination of the potential effect of altering the chemical

composition of MWCNTs on their bioactivity in vivo. Knowledge of

doping modification could allow for the development and use of

MWCNTs with reduced bioactivity, which mighthelp reducethe

hazard from workplace exposures. Such information might enable 

material scientists to incorporate a prevention-through-design 

philosophy into the development of new nanoparticle-based 

technologies using nanomaterials that pose lower risks to human 

health. These data contribute to NIOSH’s effort to develop and 

implement an evidence-based strategy for recommending 

occupational exposure limits or occupational exposure bands for 

carbon nanotubes. These studies are comparing two MWCNTs with 

different chemical compositions: MWCNTs and nitrogen-doped 

MWCNTs. These studies should increase our understanding of the 

toxicological mechanisms responsible for MWCNT-induced 

pathologies and could help identify extrapulmonary sites of toxicity 

resulting from systemic transport of MWCNTs after pulmonary 

exposure.

Neurological risks associated with workplace 

chemicals and nanomaterials 

Study Scientist: Krishnan Sriram

Evaluation of potential neurotoxicological effects associated with 

exposure to chemical agents, incidental nanoparticles, and 

engineered nanomaterials in experimental models. This study 

includes identifying hazards, evaluating molecular mechanisms of 

neurotoxicity, and identifying potential biomarkers of neurotoxicity. 

Findings from this study could contribute to the development of 

novel biomarkers for monitoring exposures and health effects, prejob planning protocols, hazard and risk assessment paradigms, and 

occupational safety standards for neurotoxic exposures.
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Mechanism of carbon nanotube-induced 

carcinogenesis and aneuploidy 

Study Scientist: Linda Sargent

Investigation of the relationship between carbon nanotube diameter 

and mechanism of carcinogenesis and aneuploidy. In vitro exposure 

of human cells to 1- to 4-nm-diameter single-walled carbon 

nanotubes disrupts the mitotic apparatus, resulting in errors of 

chromosome number. Data comparisons with 10- to 20-nm-diameter 

MWCNTs suggest the diameter of the nanotube is important in the 

genotoxic response and that carbon nanotubes are potentially 

carcinogenic. In a study in which MWCNTs were inhaled using a 

two-stage initiation and promotion model, 49-nm-diameter MWCNT 

not only disrupted the mitotic spindle pole but also disrupted the 

center of the chromosome. Previous work has demonstrated that 

MWCNTs are strong promoters of mouse lung adenocarcinoma. 

Ongoing research investigates the dose-response relationship of 

lung tumor promotion in a mouse model. 

Epigenetic changes in response to nanoparticle 

exposure 

Study Scientist: Min Ding

Investigation of potential pulmonary carcinogenesis in response to 

tungsten carbide-cobalt (WC-Co) particle exposure using cell culture 

and animal models. Mechanistic investigations, including gene 

mutation, activation of transcription factors, and reactive oxygen 

species generation, are being conducted to explain the events of 

WC-Co-induced tumor initiation, promotion, and progression. 

Determining the mechanisms involved in WC-Co-induced 

carcinogenesis and elucidating target-signaling pathways could 

provide insights for the development of biomarkers and possible 

prevention strategies for WC-Co-induced diseases.

Nano-metal oxide property affecting fibrogenesis or 

carcinogenesis 

Study Scientist: Liying Rojanasakul

Investigation of the properties of nano-metal oxides that affect their 

fibrogenicity or carcinogenicity. Metal oxide nanoparticles are 

increasingly used in a variety of applications having the potential to 

release particles into the workplace air. Limited published studies 

using animal models have shown lung inflammation and fibrosis with 

pulmonary exposure to metal oxide nanoparticles at human

exposure-relevant doses. This project is determining the effects of 

physicochemical properties (size and coating) on metal oxide 

nanoparticles toxicity and the underlying mechanisms. Results thus 

far have shown that cerium oxide nanoparticles in mice cause lung 

inflammation that is particle-size dependent. In addition, consistent 

fibrogenic effects from cerium oxide nanoparticles are observed in 

vitro and in an animal model. These results support the 

development of an economical in vitro tool for predicting the 

potential toxicity of metal oxide nanoparticles in vivo. Lowdose/long-term in vitro exposure models have been continually 

tested using several well-characterized metal oxide nanoparticles 

and human lung cells to determine metal oxide nanoparticle-typedependent neoplastic transformation induction and mechanism, 

including ferric oxide nanoparticle-disrupted iron homeostasis. 

Silicon dioxide coating of the ferric oxide nanoparticle partially 

ablated such effects and could support potential safe-by-design 

strategies.
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Hydraulic fracturing: toxicological effects of silica 

and diesel exhaust exposure 

Study Scientist: Jeffrey Fedan

Study of toxicological effects associated with hydraulic fracturing 

silica exposure and diesel exhaust exposure. The toxicities of 

inhaled hydraulic fracturing sand dust—alone and in combination 

with inhaled diesel exhaust to mimic worker exposures during 

hydraulic fracturing operations—are being studied. Effects of 

exposure on the lung, cardiovascular system, immune system, 

brain, skin, and blood are being examined using a battery of in vivo 

and in vitro experiments. The initial exposures to hydraulic fracturing 

sand dust, using two exposure doses, are completed. Exposures to 

diesel exhaust from a type II diesel engine are underway. Inhalation 

exposures to fracturing sand dust in combination with diesel exhaust 

also will be assessed.

Pulmonary function and nanoparticle inhalation: in 

vivo and in vitro effects 

Study Scientist: Jeffrey Fedan

Characterization of MWCNT effects on critical aspects of lung 

function in vivo and airway function in vitro and provision of metrics 

to enable risk assessment strategies. In vivo experiments have 

demonstrated changes in pulmonary function and airway reactivity 

in animals exposed to MWCNTs. A comparison of the relative 

pulmonary toxicities of pristine and nitrogen-doped MWCNTs is 

underway.

Health effects of inhaled crude oil 

Study Scientist: Jeffrey Fedan

Design and building of an inhalation exposure system that delivers 

crude oil vapor to rats. This system is being used to study the 

effects of crude oil vapor inhalation on the lung, cardiovascular 

system, immune system, brain, skin, and blood. Surrogate oil for the 

Macondo well in the Gulf of Mexico is being used. Acute inhalation 

exposures have been completed, and subchronic exposures are in 

progress.

Toxicity assessment of carbon nanotubes and 

carbon nanofibers from U.S. facilities 

Study Scientist: Aaron Erdely

Evaluation of the toxicity of carbon nanotubes and carbon 

nanofibers obtained from U.S. facilities. To date, few studies have 

examined the toxicity of such a broad range of materials collected 

from manufacturing facilities with direct relevance to U.S. worker 

health. This study is assessing general pulmonary and systemic 

toxicity, pathology, biodistribution, and genotoxicity.

Toxicity associated with the life cycle of carbon 

nanotubes 

Study Scientist: Aaron Erdely

Investigation of carbon nanotube toxicity at different stages of 

production. In vivo and in vitro data suggest that exposure to carbon 

nanotubes has significant adverse health effects. Few data are 

available to define the toxicity of carbon nanotubes at each stage of 

the production life cycle (as produced, post-production modification, 

and incorporation into composites), although the numbers of 

potentially exposed workers increases with each stage. This project 

is evaluating the pulmonary response and genotoxicity of carbon 

nanotubes at different stages of production.

A translational in vitro approach to assess 

cardiovascular risk 

Study Scientist: Aaron Erdely

Development of an in vitro model to assess cardiovascular risk from 

particulates. Respiratory exposure to particulates has been 

associated with increased mortality from cardiovascular diseases. 

This project is developing and testing an in vitro model to assess 

cardiovascular risk following pulmonary exposure to engineered 

nanomaterials. 
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NTP at NIOSH: Immunotoxicology Research 

Interagency Agreement on Immunotoxicology Research

The NIEHS and NIOSH interagency agreement provides for support of NTP hazard identification 

activities aimed at preventing diseases or adverse effects caused by environmental exposure to 

chemical or physical agents. These cooperative studies continue to improve risk assessment by 

measuring what constitutes an adverse health effect on the immune system in humans. The FY 2017 

studies listed below evaluate unique cohorts of individuals from professions associated with immunemediated occupational diseases. 

Immunotoxicology Studies

Project & Study Scientist Project Summary

Identification and characterization of cross-reactive 

fungal biomarkers

Study Scientist: Brett Green

Development of monoclonal and polyclonal antibodies to 

recombinant fungal biomarker antigens. The utility of these 

antibodies is important for quantifying occupationally relevant 

fungal biomarkers, particularly to those fungi nominated to NTP.

Toxicity of subchronic fungal exposures

Study Scientist: Brett Green

Characterization of the toxicological and pulmonary immune 

responses associated with subchronic fungal exposures using a 

model that replicates human exposure. This model uses an 

acoustical generator system and nose-only exposure chamber to 

characterize toxicological endpoints following subchronic 

exposures to spores derived from fungi nominated to NTP. 

Subchronic exposure studies with Aspergillus fumigatus, two 

mycotoxin producing strains of Stachybotrys chartarum, and A. 

versicolor have been completed. Future subchronic exposure 

studies will focus on an atranone-producing strain of S. chartarum, 

A. versicolor, Alternaria alternata, mixed fungal exposures, and 

other occupationally relevant fungi identified in concurrent NTPfunded diversity studies. Proposed studies will provide further 

insight into the mechanisms of pulmonary toxicity due to fungi 

encountered in the workplace. These toxicological studies will 

provide novel data sets that will be used to characterize the 

hazards that fungal exposure might present to human and 

occupational health.

Identification and characterization of fungal 

exposures

Study Scientist: Brett Green

Investigation and characterization of the diversity of mold in indoor 

and occupational environments using internal transcribed spacer 

region sequencing. In collaboration with intramural and external 

stakeholders, results from these studies have provided new insight 

into the complex diversity of mold present in these environments. 

This methodological approach has been used to support NIOSH 

Health Hazard Evaluations to characterize microbial hazards in the 

workplace.
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Analysis of mycotoxins in dust samples from a 

water-damaged building

Study Scientist: Robert Park

Examination of effects of exposure to fungal secondary 

metabolites, including mycotoxins, on occupant health in waterdamaged buildings. Cost-effective and robust methods have been 

developed using ultra-performance liquid chromatography-tandem 

mass spectrometry for simultaneous analysis of 31 fungal 

secondary metabolites in environmental samples. The accuracy of 

the method has been improved by using eight isotopically labeled 

(13carbon) mycotoxin internal standards to compensate for 

extraction loss and matrix effects. The developed method has been 

applied to (1) examine stability of secondary metabolites in spiked 

dust stored at different temperature conditions with 7 different 

points of time over 2 years, (2) analyze 500 dust samples collected 

from our Philadelphia School Study, and (3) quantify 2 mycotoxins 

(macrocyclic trichothecenes and sterigmatocystin) in air and culture 

samples from the subchronic animal exposure studies of S. 

chartarum, and A. versicolor. Future studies will (1) examine 

stability of standard materials of fungal metabolites stored in a 

freezer for over a year; (2) in collaboration with a research group in 

Austria, screen more than 550 microbial metabolites in dust 

samples collected from four water-damaged buildings in different 

areas in the United States; and (3) examine the effect of exposure 

to fungal secondary metabolites on occupant health using 

statistical models adjusted for exposures to other microbial agents 

also measured in the epidemiological studies.
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NTP at NIOSH: Occupationally Relevant Exposures 

Comprehensive Assessment of Occupationally Relevant Exposures

NIEHS is coordinating an NTP effort with NIOSH to better understand worker exposures, identify 

occupational health research gaps, and educate workers. The NIEHS and NIOSH interagency 

agreement supports these projects. The FY 2017 efforts listed below address worker exposures to 

welding fumes, nanosized materials, food flavorings, and other industrial chemicals. 

NIOSH mobile lab for field studies
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Occupationally Relevant Exposures

Project & Study Scientist Project Summary

Administrative support

Study Scientist: Elizabeth Whelan

Support of NIOSH scientists in (1) participating in review and 

oversight of NTP activities and (2) attending NTP-related meetings 

in Research Triangle Park, North Carolina and Washington, D.C.

Occupational exposure assessment of welding 

fumes with emphasis on manganese compounds

Study Scientist: Kevin Hanley

Characterization of welding fume exposures with a focus on 

manganese. Welders’ exposures to total and respirable manganese 

were evaluated using a novel sequential chemical extraction method 

to (1) identify industries, such as construction, shipbuilding, 

manufacturing companies, and unions, involved in welding 

operations for which the potential for substantial manganese 

exposure exists; (2) develop methods to identify manganese 

compounds and different oxidation states based on selective 

solubility with various welding fume matrices; and (3) characterize 

welding fume exposures based on welding-associated jobs, tasks, 

and processes. Three hundred full-shift worker-days were assessed 

during stick electrode welding, gas metal arc welding, flux cored 

welding, and gas tungsten arc welding in construction, refineries, 

heavy equipment, structural steel, shipyard, and appliance 

industries. To date, three manuscripts have been published (and a 

fourth has been submitted to a journal) that demonstrated excessive 

manganese exposures associated with welding fumes, often 

exceeding Threshold Limit Values of the American Conference of 

Governmental Industrial Hygienists (ACGIH TLVs) by an order of 

magnitude.

Exposure assessment of engineered nanoparticles

Study Scientist: Charles Geraci

Identification of workplaces engaged in the synthesis, manufacture, 

and use of engineered nanomaterials and characterization of 

workplace exposures to selected engineered nanoparticles.

Durability of nanoscale cellulose fibers in artificial 

human lung fluids

Study Scientist: Aleksandr Stefaniak

Investigation of the in vitro durability of nanocellulose materials in 

artificial lung fluids. Data generated from this study will be used to 

inform larger in vivo inhalation studies.

Assessment of occupational exposures to flame 

retardants

Study Scientist: Cheryl Estill

Assessment of exposure to nine alternative flame retardants plus a 

panel of polybrominated diphenyl ethers. Exposure has been 

assessed at 19 facilities involved in the manufacture, installation, or 

use of goods containing these flame retardants. Worksite categories 

included are manufacture of products that use flexible polyurethane 

foams; fabrication and manufacture of rigid polystyrene foam; 

cutting, installing, or spraying polyurethane foam insulation at 

construction sites; gymnasiums; nail salons; and the fire service 

industry. This study is comparing exposures among industries, 

processes, and tasks; determining the routes of exposure; and 

making recommendations to reduce exposures. These data will be 

used to determine exposure levels of workers in different 

occupations and how they relate to the general population by 

comparison to the National Health and Nutrition Examination Survey 

data. The results will aid in the design, understanding, and use of 

toxicological studies and risk assessment.

Assessment of occupational exposure to polycyclic 

aromatic hydrocarbons (PAHs) in coal tar sealant 

applications

Evaluation of the levels of occupational chemical exposure among 

workers who are using coal tar-based pavement sealants. Coal tar 

is sometimes used as a base material for blacktop pavement 

sealants, accounting for as much as 35% of the formulation in some 
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Project & Study Scientist Project Summary

Study Scientist: Kevin Hanley of these products. Coal tar is a byproduct of the production of coke, 

which is needed for steel production. Coal tar pitch volatiles are a 

mixture of chemicals that can evaporate into air from products 

containing coal tar, including coal tar pavement sealants. Coal tar 

sealant aerosols and volatiles contain several chemicals known as 

PAHs. This study focuses on the assessment of occupational 

exposure to PAHs among coal tar sealant workers. Currently, no 

data are available in the scientific literature on exposure to PAHs 

and their metabolites for workers applying coal tar sealant-based 

coatings on pavements. This study is providing data regarding levels 

of exposure to airborne chemicals for comparison to current NIOSH 

recommended exposure limits, if available. Results for specific PAH 

chemicals using NIOSH analytical methods will be reported. PAHs 

are measured in dermal wipe samples, and PAH metabolites 

measured in biological samples collected from workers to 

characterize levels present in this workforce. In FY 2017, 

construction surveys increased the database by 968 PAH 

measurements for air exposure time-weighted-average calculations, 

968 skin wipe PAH measurements; and 704 PAH metabolite 

analyses in urine specimens.