Welcome to the 2016 Annual Report https://ntp.niehs.nih.gov/go/2016annualreport

"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 2016 Letter from the NTP Director.

FY 2016 at a Glance

• Cell Phone Radiofrequency

Radiation Program

• NIEHS Celebrated 50 Years

of Public Health

• Completed NTP Reports

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

Home Sections Previous Reports Site Map NTP Site Contact Us

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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 NIOSH

• NTP at NCTR

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 2016. Research Triangle Park, NC: National 

Toxicology Program; 2017. Available from http://ntp.niehs.nih.gov/annualreport/2016

Director of Office of Liaison, Policy, and Review and Editor-in-Chief: Mary Wolfe | Managing Editor: Rachel McIntosh-Kastrinsky

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https://ntp.niehs.nih.gov/go/807207

NTP submitted the 14th Report on Carcinogens to the Health and 

Human Services Secretary for review and approval in FY 2016. On 

November 30, 2016, HHS Secretary Sylvia Burwell released the 14th 

Report on Carcinogens. The newly reviewed listings, include 

trichloroethylene, five viruses, all listed as known to be a human 

carcinogen; and the class cobalt and cobalt compounds that release 

cobalt in vivo, listed as reasonably anticipated to be a human 

carcinogen. There are a total of 248 substances listed in the report.

In May 2016, NTP released preliminary study findings on cancer and 

cell phone radiofrequency radiation in rats. Previous human 

observational studies have found limited evidence for an increased risk 

of cancer from cell phone use. In these new studies, NTP scientists 

found low incidences of tumors in the brains and hearts of male rats, 

but not in female rats. These findings have been shared with federal 

regulatory partners to ensure they have the latest information available 

for public health guidance on cellular telephones and other 

radiofrequency radiation emitting devices.

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

FY 2016 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)

2016 Annual Report - Letter from Director

Letter From the NIEHS and NTP Director

In fiscal year (FY) 2016, NTP continued to advance toxicology and 

inform public health policy by providing information about substances

in our environment to decision makers and the public. Numerous 

studies were published on substances of public health concern, such

as viruses, metals, and widely used industrial chemicals. NTP also 

developed more efficient approaches to predict how chemicals may 

affect human health through the Tox21 initiative.

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Cell Phone Radiofrequency Radiation Program

NTP released preliminary findings on cancer and cell phone radiofrequency radiation in rats.

NIEHS Celebrated 50 Years of Public Health

NIEHS celebrated 50 years of public health with commemorative activities throughout the year.

Completed NTP Reports

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

have been published in FY 2016, or are expected for peer review in FY 2017 are listed.

Timeline of Events

Highlighted NTP activities in FY 2016.

NTP Workshop Explores Challenges of Botanical Dietary Supplement Safety

NTP hosted workshop to discuss challenges of testing botanical dietary supplements.

Workshop Held on Health Effects of Light at Night

International panels of experts discuss how disruptions to circadian rhythms may affect health.

2016 Annual Report - FY 2016 Glance

FY 2016 at a Glance

4
NTP and Partners Launch Tox Testing Challenge

NTP in partnership with the NIH National Center for Advancing Translational Sciences and the 

Environmental Protection Agency to launch the “Transform Tox Testing Challenge: Innovating for 

Metabolism.”

NTP Partners with EPA to Reduce Animal Use for Pesticide Testing

Scientists at the U.S. Environmental Protection Agency (EPA) and NTP Interagency Center for 

the Evaluation of Alternative Toxicological Methods (NICEATM) conducted an analysis to 

determine if acute oral toxicity data can be used to reliably assign EPA acute dermal hazard 

classifications.

14th Report on Carcinogens

NTP submitted the 14th Report on Carcinogens to the Health and Human Services Secretary for 

review in FY 2016.

NTP 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 to protect human health.

Additional Activities

Additional meetings with stakeholders and the scientific community in which NTP participated.

Publications

Full citations for NTP reports, journal publications, and book chapters published during FY 2016.

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https://ntp.niehs.nih.gov/go/810740

In May 2016, NTP released preliminary study findings on cancer 

and cell phone radiofrequency radiation in rats. Previous human 

observational studies have found limited evidence for an increased risk 

of concern from cell phone use. In these new studies, NTP scientists 

found low incidences of tumors in the brains and hearts of male rats, 

but not in female rats. Mice studies are ongoing.

The Food and Drug Administration nominated cell phone 

radiofrequency radiation to the NTP for review in 2000. NTP 

conducted these studies in multiple phases to determine the correct 

field strengths that would not raise animal body temperature and to 

study the toxicity and cancerous effects at different time periods. 

Animals were exposed to the two radiofrequency radiation 

technologies and frequencies widely used in the United States – Code 

Division Multiple Access (CDMA) and Global System for Mobile (GSM) 

communications.

These findings have been shared with federal regulatory partners to 

ensure they have the latest information available for public health 

guidance on cellular telephones and other radiofrequency radiation 

emitting devices. The complete results from all the rat and mice 

studies are tentatively scheduled for peer review and public comment 

by the end of 2017.

Cell Phone Radiofrequency Radiation Program

2016 Annual Report - FY 2016 Glance - Cell Phone Study

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https://ntp.niehs.nih.gov/go/810727

NIEHS celebrated 50 years of environmental public health in FY 2016.

Throughout FY 2016, NIEHS hosted events to celebrate and

commemorate the institute’s history and achievements. Linda

Birnbaum, Ph.D., director of NIEHS and NTP, with input and help from

NIEHS staff, created and buried a time capsule with items

representing NIEHS’ work. Several organizations and companies

partnered with NIEHS to host seminars, workshops, and public forums

to honor NIEHS and to share information about environmental health

and the value of NIEHS’ research.

In July 2016, the Society of Toxicology and NIEHS hosted a day-long

symposium, reflecting on the decades of collaboration and new

opportunities to come in the future. During the symposium, Birnbaum

lauded the important toxicology work conducted by the NTP over the

years. Birnbaum highlighted the establishment of NTP in 1978, NTP’s

2004 roadmap for toxicology in the 21st century, and the 2016

publication of the 14th Report on Carcinogens. Speakers commended

and thanked Birnbaum and John Bucher, Ph.D., associate director of

NTP, for their guidance and perseverance in helping to improve

toxicology research applications. The symposium ended with Nigel

Walker, Ph.D., NTP deputy division director for research, leading a

panel discussion on advice for early-career scientists.

NIEHS Celebrated 50 Years of Public Health

2016 Annual Report - FY 2016 Glance - NIEHS 50th Anniversary

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https://ntp.niehs.nih.gov/go/807064

The results of NTP studies undergo peer review and are published in NTP report series. Long-term 

toxicology and carcinogenicity studies, generally two-years in length, are reported in the NTP Technical 

Report series. Toxicity reports are for shorter-term studies, generally up to 13 weeks. NTP Research

Reports provide results of peer-reviewed NTP research and literature-analysis activities that do not fall

under the scope of existing NTP report series, such as research studies, rapid communications, and 

literature surveys. All peer reviewers are screened for conflict of interest prior to confirming their service. 

These reports are available on the NTP website and catalogued in PubMed. 

Technical Reports Published During FY 2016 Reporting Levels of Evidence of

Carcinogenic Activity

NTP technical reports published in FY 2016 are listed in the table below. NTP used established criteria to

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

activity of each substance. The conclusions for level of evidence of carcinogenic activity are included in the 

table. NTP anticipates three draft technical reports will undergo peer review in FY 2017, as listed in the 

second table below.

Chemical

Technical

Report

Number/CASRN*

Use Male

Rats

Female

Rats

Male

Mice

Female

Mice

Bromodichloroacetic

Acid

TR-583

71133-14-7

Forms when drinking 

water supplies 

containing natural 

organic matter are 

disinfected with 

chlorine-containing 

oxidizing compounds 

and when bromide is 

present in the source 

water.

Clear 

evidence

2016 Annual Report - FY 2016 Glance - NTP Reports

Completed NTP Reports

Clear 

evidence

Clear 

evidence

Clear 

evidence

Green Tea Extract TR-585

N/A

Nutraceutical 

supplements and 

medicinal uses 

containing green tea 

extract are commonly

consumed for weight 

loss. Green tea

extracts are popular

ingredients in

sunblocks, cream 

rinses, and other

cosmetics.

No 

evidence

No 

evidence

No 

evidence

No 

evidence

Pentabromodiphenyl 

Ether Mixture [DE-71 

(Technical Grade)]

TR-589 

32534-81-9

Flame retardant in 

furniture materials.

Clear 

evidence

Clear 

evidence

Clear 

evidence

Clear 

evidence

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Technical Reports Expected to Undergo Peer Review in FY 2017

Chemical Technical Report

Number/CASRN* Use

2,3 Butanedione TR-593

431-03-8

Artificial flavor formulations, such as cake mixes,

flour, beer, wine, margarine, cheese, candy,

crackers, cookies, ice cream, and many others food

and beverage products.

p-Chloroa,a,a-trifluorotolueneTR-594

98-56-6

Solvent used in paints and coatings, and as an

industrial intermediate in the productions of other

chemicals (e.g., herbicides, dyes, pharmaceuticals).

Zinc, dietary TR-592

5263-02-5

Used in 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.

Toxicity Reports Published During FY 2016

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

conditions. NTP toxicity reports published in FY 2016 are listed in the table below.

Chemical Toxicity Report

Number/

CASRN*

Use

Octahydro-tetramethylnaphthalenyl-ethanone

TOX-92

54464-57-2 (β-isomer)

68155-67-9 (α-isomer)

68155-66-8 (γ-isomer)

Perfume ingredient in soap, shampoo, cologne,

liquid detergent compounds, and malodor-reducing

compounds

p-Toluenesulfonamide TOX-88

70-55-3

Formed from chloramine-T, an antimicrobial agent 

used by the aquaculture industry to treat fish 

intended for human consumption. Chloramine-T is 

also widely used as a disinfectant in the medical, 

dental, veterinary, food processing, and agricultural 

industries.

alpha-Pinene TOX-81

80-56-8

Main component in turpentine and is used as a

fragrance and flavoring ingredient.

Sodium thioglycolate TOX-80

367-51-1

Antioxidant, depilating agent, hair

waving/straightening agent, and reducing agent

ingredient in cosmetic industry.

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Research Reports Published During FY 2016

The NTP research report series was launched in FY 2016 to promote transparency and reproducibility. The 

series also strengthens the science base and provide information useful for public health decision-makers.

NTP research reports published in FY 2016 are listed in the table below.

Report Title Research Report Number

Systematic Literature Review on the Effects of

Fluoride on Learning and Memory in Animal

Studies

RR-01

Organotin and Total Tin Levels in Danish Women

of Reproductive Age

RR-02

*CASRN = Chemical Abstracts Service Registry Number

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October 2015

NTP Technical Report on Bromodichloroacetic Acid

Bromodichloroacetic acid occurs as a by-product of water 

disinfection. In October 2015, NTP released a technical report

on bromodichloroacetic acid (TR-583). 

December 2015

NTP Board of Scientific Counselors Meeting 

At the December Board of Scientific Counselors meeting, 

members reviewed the NTP Cellular and Molecular Pathology 

Branch, voted on a contract concept, and were updated on NTP 

meetings and draft reports, such as the Report on Carcinogens 

peer-review meeting on cobalt. 

January 2016

Toxicity Testing Challenge Launched 

To spur innovation and advance predictive toxicology, NTP 

partnered with the NIH National Center for Advancing Translational 

Sciences and the U.S. Environmental Protection Agency to launch 

the Transform Tox Testing Challenge: Innovating for Metabolism. 

The goal of the challenge is to improve Tox21 bioassays by 

incorporating metabolism capabilities. 

January 2016

ICCVAM Communities of Practice Webinar: Predictive

Toxicology 

The second ICCVAM Communities of Practice webinar, 

Fundamentals of Using Quantitative Structure-Activity Relationship 

Models and Read-across Techniques in Predictive Toxicology, was 

held on January 26, 2016. 

https://ntp.niehs.nih.gov/go/807054 2016 Annual Report - FY 2016 Glance - Timeline of Events

FY 2016 Timeline

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February 2016

NICEATM Workshop: In Vitro to In Vivo Extrapolation

NICEATM and the U.S. Environmental Protection Agency 

presented a webinar series from October 2015 through January 

2016 that was background for a workshop held on February 17-18, 

2016." 

February 2016

NTP Technical Report on Pentabromodiphenyl Ether

Pentabromodiphenyl ether mixture [DE-71 (technical grade)] was 

used in the past as an additive flame retardant, often in furniture. 

In February 2016, NTP released a technical report on 

pentabromodiphenyl ether mixture [DE-71 (technical grade)]. 

March 2016

Workshop on Health Effects of Light at Night 

In March 2016, NTP hosted a workshop to obtain external 

scientific input on strategies for integrating data, identifying data 

gaps and research needs on the potential health effects of light at 

night.

March 2016

NTP Partners with EPA to Reduce Animal Use for 

Pesticide Testing 

Scientists at the U.S. Environmental Protection Agency and 

NICEATM conducted an analysis to determine if acute oral 

toxicity data can be used to reliably assign EPA acute dermal 

hazard classifications. 

March 2016

NICEATM Workshop: Acute Inhalation Toxicity

NICEATM and the People for the Ethical Treatment of Animals 

International Science Consortium co-hosted a webinar series

on Alternative Approaches for Acute Inhalation Toxicity to 

Address Global Regulatory and Non-regulatory Data 

Requirements. 

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April 2016

NTP Workshop Explores Challenges of Studying Hazards

of Botanicals

In April 2016, NTP hosted a workshop to discuss current 

knowledge about the safety of botanicals and what research gaps 

may exist. 

April 2016

NTP Board of Scientific Counselors Meeting 

At the April 2016 Board of Scientific Counselors meeting, 

members reviewed two draft Report on Carcinogens concepts on 

(1) di- and tri-haloacetic acids found as water disinfection byproducts and 

(2) Helicobacter pylori (chronic infection). 

April 2016

NTP Technical Report on Green Tea Extract 

Green Tea Extract is used in nutraceutical supplements for weight 

loss and as an ingredient in skincare products. In April 2016, NTP 

released a technical report on green tea extract. 

May 2016

Cell Phone Radiofrequency Radiation Program

In May 2016, NTP released preliminary study findings on cancer 

and cell phone radiofrequency radiation in rats. In these new 

studies, NTP scientists found low incidences of tumors in the brains 

and hearts of male rats, but not in female rats. 

May 2016

ICCVAM Public Forum 

ICCVAM held its third public forum on May 25, 2016, at NIH 

in Bethesda, Maryland. The forum highlighted a proposal for a 

roadmap to replace animal use in U.S. safety testing. 

13
June 2016

NTP Board of Scientific Counselors Meeting

At the June 2016 Board of Scientific Counselors meeting, 

members were updated on NTP research activities such as 

glyphosate research scoping, studies of synthetic turf, and other 

topics. 

July 2016

NIEHS Celebrates 50th Anniversary 

NIEHS celebrated 50 years of environmental public health in FY 

2016. Throughout the year, NIEHS hosted events to celebrate and 

commemorate the institute’s history and achievements.

September 2016

14th Report on Carcinogens

NTP submitted the 14th RoC to the Secretary, Department of 

Health and Human Services, for review and approval in FY 2016 

with recommendations for listing seven newly reviewed substances. 

September 2016

SACATM Meeting 

Scientific Advisory Committee on Alternative Toxicological 

Methods (SACATM) met on September 27, 2016, at NIEHS. The 

meeting focused on a strategy for implementing the vision for 

regulatory toxicity testing in the 21st century. 

September 2016

NTP Monograph on Perfluorooctanoic Acid and 

Perfluorooctane Sulfonate 

In FY 2016, NTP published the NTP Monograph on 

Immunotoxicity Associated with Exposure to Perfluorooctanoic 

Acid or Perfluorooctane Sulfonate, the first evaluation using a 

systematic review approach. 

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https://ntp.niehs.nih.gov/go/810732

Botanical dietary supplements, such as green tea extract and black

cohosh, are regularly used by Americans, but recent public concern 

has raised questions about their safety. NTP is working to identify any 

adverse health effects that may occur from taking botanicals.

In April 2016, NTP hosted a workshop to discuss current knowledge 

about the safety of botanicals and what research gaps may exist. The 

workshop brought together representatives of federal agencies, 

industry, and research institutions to examine this issue. One of the 

issues the workshop reviewed was how a well-characterized reference

botanical may relate to its peers in the marketplace. NTP toxicologist 

Cynthia Rider, Ph.D., presented case studies on Ginkgo biloba, black 

cohosh extract, and Echinacea purpurea extract. The case studies

highlighted complex study issues, such as the number of botanical 

supplement constituents, the large fraction of constituents that may 

be unidentified, and the multiple interactions that could occur between 

constituents.

The workshop helped highlight issues and considered paths forward in

research. For more information on this workshop, go to the NTP

workshop website . NTP will continue its work on botanical dietary 

supplements in FY 2017.

NTP Workshop Explores Challenges of Botanical Dietary

Supplement Safety

2016 Annual Report - FY 2016 Glance - Botanicals Workshop

15
https://ntp.niehs.nih.gov/go/810745

Artificial light at night disrupts many people’s circadian rhythm (or 

light-dark cycles due to things like electronic device usage, urban light 

pollution, and working at night (or night shift work. This disruption can 

alter biological processes that may result in adverse health outcomes. 

NTP’s Office of the Report on Carcinogens and Office of Health 

Assessment and Translation plan to conduct health hazard 

assessments to review cancer and noncancer outcomes.

In March 2016, NTP hosted a workshop to obtain external 

scientific input on strategies for integrating data across evidence 

streams and exposure scenarios, data gaps, and research needs. 

The workshop considered circadian disruptions from:

Exposure to light at night, including use of electronic devices at

night and urban light pollution.

The complex scenario of shift work, which can involve

interruptions in light-dark cycles and changes in sleep patterns.

Changes in the timing of exposures to natural light, including jet

lag.

Participants helped define the scope of the literature-based 

evaluations, including defining the topic, identifying the most relevant

types of studies, and selecting approaches to synthesize across 

studies. Participants noted it is important to define circadian rhythm 

before scientists can address circadian disruptions, especially when 

considering seasonality. Participants also remarked on the need to 

address the different study designs in published papers, such as the 

type of light used and a species’ sensitivity to light.

NTP is using the input from the workshop to guide the cancer and 

noncancer health assessments. More information on the health 

assessment can be found on the Report on Carcinogens Substances 

Selected for Evaluation page .

Workshop Held on Health Effects of Light at Night

2016 Annual Report - FY 2016 Glance - Light at Night Workshop

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https://ntp.niehs.nih.gov/go/810749

To spur innovation and advance predictive toxicology, NTP partnered 

with the NIH National Center for Advancing Translational Sciences and 

the U.S. Environmental Protection Agency to launch the “Transform 

Tox Testing Challenge: Innovating for Metabolism.” In many chemicals 

shown to have toxicity, the toxicity mechanism results from the 

chemical breaking down during metabolism into more reactive 

metabolites (similar chemical structures. The goal of the challenge is 

to improve Tox21 bioassays by incorporating metabolism capabilities.

The three-stage challenge issued in January 2016 offered to provide 

up to $1 million in total prizes for modifications to existing high 

throughput screening (HTS assays that allow both chemicals and their 

metabolites to be evaluated. Stage 1 of the challenge asked 

participants to submit concepts on how to integrate metabolism into 

Tox21 assays. The Stage 1 winners were asked to present their 

concepts at a workshop hosted by the challenge partners in July 2016. 

During the workshop, challenge partners and participants discussed 

the concepts and how to turn the concepts into prototypes for Stage 2 

of the Challenge.

In September 2016, challenge partners launched Stage 2 , where 

participants were asked to create a prototype and produce proof-ofconcept data. During Spring 2017, partners will review the Stage 2 data 

and announce the winners that will move on to Stage 3 of the 

challenge. In Stage 3, participants will demonstrate a standardize

method for incorporating metabolism into Tox21 bioassays.

NTP and Partners Launch Tox Testing Challenge

2016 Annual Report - FY 2016 Glance - Tox Testing Challenge

17
https://ntp.niehs.nih.gov/go/810798

Scientists at the U.S. Environmental Protection Agency (EPA) and NTP 

Interagency Center for the Evaluation of Alternative Toxicological 

Methods (NICEATM) conducted an analysis to determine if acute 

oral toxicity data can be used to reliably assign EPA acute dermal 

hazard classifications. The analysis was the basis for a draft guidance 

document issued by EPA in March 2016. The draft guidance provides a 

rationale for waiving all acute dermal toxicity studies for pesticide 

formulations. This waiver is expected to reduce animal use for acute 

toxicity testing by at least 2,500 animals per year.

Acute dermal toxicity tests, which assess the likelihood that a chemical 

will cause illness when absorbed through the skin, are used by the 

EPA to determine labeling and personal protective equipment 

requirements for users of pesticides. The guidance on acute toxicity 

testing will be finalized in FY 2017, and is part of a broader effort by 

EPA to significantly reduce animal use for acute effects testing.

NTP Partners with EPA to Reduce Animal Use for

Pesticide Testing

2016 Annual Report - FY 2016 Glance - NICEATM Pesticide Testing

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https://ntp.niehs.nih.gov/go/807035

Substance Listing Status Description

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 sarcomaassociated herpesvirus

(KSHV)

Known to be a human

carcinogen Virus

Merkel cell

polyomavrius (MCV)

Known to be a human

carcinogen Virus

Trichloroethylene (TCE) Known to be a human

carcinogen

Industrial

solvent

Cobalt and cobalt

compounds that

release cobalt ion in

vivo

Reasonably

anticipated to be a

human carcinogen

A metal and its

compounds

The Report on Carcinogens is a congressionally mandated report 

prepared for the HHS Secretary by NTP. The report identifies many 

different types of environmental factors, collectively called substances,

2016 Annual Report - FY 2016 Glance - 14th RoC

14th Report on Carcinogens

NTP submitted the 14th Report on Carcinogens (RoC) to the Health 

and Human Services (HHS) Secretary for review and approval in FY

2016 and HHS released the 14th RoC on November 3, 2016. This 

cumulative report contains 248 listings, of which seven were newly

reviewed.

The chemical trichloroethylene (TCE), and the metallic element cobalt 

and cobalt compounds that release cobalt ions in vivo, were 

recommended to be added to the list, as well as five viruses that have 

been linked to cancer in humans. The five viruses include human 

immunodeficiency virus type 1, human T-cell lymphotropic virus type 

1, Epstein-Barr virus, Kaposi sarcoma-associated herpesvirus, and 

Merkel cell polyomavirus.

Newly Listed Substances

19
including chemicals; infectious agents, such as viruses; physical

agents, such as X-rays and ultraviolet radiation; mixtures of chemicals;

and exposure scenarios in two categories — known to be a human

carcinogen and reasonably anticipated to be a human carcinogen. The

new report is available at https://ntp.niehs.nih.gov/go/roc14.

It’s important to note that a listing in the report indicates a cancer

hazard, but does not by itself mean that a substance or a virus will

cause cancer. Many factors, including an individual’s susceptibility to a

substance, and the amount and duration of exposure, can affect

whether a person will develop cancer. In the case of viruses, a

weakened immune system may also be a contributing factor. People

should talk to their health care providers about decreasing their cancer

risk from viruses.

The Report on Carcinogens, 14th Edition, is prepared by the National

Toxicology Program (NTP). NTP is a federal, interagency program,

headquartered at the NIEHS, whose goal is to safeguard the public by

identifying substances in the environment that may affect human

health. For more information about NTP and its programs,

visit https://ntp.niehs.nih.gov.

20
https://ntp.niehs.nih.gov/go/807005

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

regulate and test specific chemicals to protect human health. Below is a table highlighting the NTP data and

recommendations used by other agencies in FY 2016. A full listing is also available on the NTP website.

Use of NTP Study Data or Recommendations by Federal and State Regulatory Agencies in FY 2016

Notice Summary of Notice NTP Information Cited

Chemical listed effective

August 5, 2016, as

known to the state of

California to cause

cancer: 1-bromopropane

Effective August 5, 2016, the Office

of Environmental Health Hazard

Assessment is adding 1-

bromopropane (CASRN* 106-94-5)

to the list of chemicals known to the

state to cause cancer for purposes

of Proposition 65.

August 05, 2016 -- Proposition 65

National Toxicology Program (NTP,

2011). National Toxicology Program.

Toxicology and Carcinogenesis

Studies of 1 Bromopropane (CASRN

106-94-5) in F344/N Rats and

B6C3F1 Mice (Inhalation Studies).

Technical Report Series No. 564. NIH

Publication No. 11-5906. U.S.

Department of Health and Human

Services, NTP, Research Triangle

Park, NC.

Chemical listed effective

July 29, 2016 as known

to the state of California

to cause cancer:

bromodichloroacetic acid

Effective July 29, 2016, Office of

Environmental Health Hazard

Assessment is adding

bromodichloroacetic acid (CASRN*

71133-14-7) to the list of chemicals

known to the state to cause cancer

for purposes of Proposition 65.

July 29, 2016 -- Proposition 65

National Toxicology Program (NTP,

2015). Toxicology Studies of

Bromodichloroacetic Acid (CASRN

71133-14-7) in F344/N Rats and

B6C3F1 Mice and Toxicology and

Carcinogenesis Studies of

Bromodichloroacetic Acid in

F344/NTac Rats and B6C3F1/N Mice

(Drinking Water Studies). NTP

Technical Report Series No. 583. US

Department of Health and Human

Services, NTP, Research Triangle

Park, NC.

Chemical listed effective

April 22, 2016 as known

to the state of California

to cause cancer: styrene

Effective April 22, 2016, Office of

Environmental Health Hazard

Assessment is adding styrene

(CASRN* 100-42-5) to the list of

chemicals known to the state to

cause cancer for purposes of the

Safe Drinking Water and Toxic

Enforcement Act of 1986

(Proposition 65). The listing of

styrene is based on formal

identification by the National

Toxicology Program, an authoritative

body, that the chemical causes

National Toxicology Program (NTP,

2011). Report on Carcinogens,

Twelfth Edition, US Department of

Health and Human Services, Public

Health Service, NTP, Research

Triangle Park, North Carolina, page

383-391.

2016 Annual Report - FY 2016 Glance - Regulatory Impact

NTP Impact on Regulatory Agencies

21
cancer. The criteria used by Office of

Environmental Health Hazard

Assessment for the listing of

chemicals under the “authoritative

bodies” mechanism can be found in

Title 27, Cal. Code of Regs., section

25306.

April 22, 2016 -- Proposition 65

Final Rule: diflubenzuron;

pesticide tolerances

Through this regulation the U.S.

Environmental Protection Agency

establishes tolerances for residues

of diflubenzuron in or on multiple

commodities. Interregional Research

Project Number 4 (IR–4) requested

these tolerances under the Federal

Food, Drug, and Cosmetic Act.

February 12, 2016 -- 81 FR 7466

PCA, a plant metabolite of

diflubenzuron, tested positive for

splenic tumors in the male rats and

hepatocellular adenomas/carcinomas

in male mice in a NTP study.

Final Rule: benzyl

acetate; exemption from

the requirement of a

tolerance

Through this regulation the U.S.

Environmental Protection Agency

establishes an exemption from the

requirement of a tolerance for

residues of benzyl acetate (CASRN*

140–11–4), when used as an inert

ingredient (solvent) in pesticide

formulations applied to growing

crops only under 40 CFR 180.920.

Technology Sciences Group, on

behalf of the Huntsman Corporation,

submitted a petition to EPA under

the Federal Food, Drug, and

Cosmetic Act, requesting

establishment of an exemption from

the requirement of a tolerance. This

regulation eliminates the need to

establish a maximum permissible

level for residues of benzyl acetate.

February 12, 2016 -- 81 FR 7473

Because of the confounding effects of

corn oil on the incidences of

pancreatic neoplasm and because of

the controversy over the use of the

gavage route of administration, the

NTP decided to re-study benzyl

acetate using the dosed feed route of

administration. In 1993, the NTP

conducted a second set of

carcinogenicity studies in rats and

mice using the dose feed route of

administration.

The point of departure for benzyl

acetate is 110 mg/kg/day from the

NTP 2-year carcinogenicity study in

mice (dietary study) based on

decreased in body weights in both

sexes at the LOAEL of 345/375

mg/kg/day. There was no evidence of

carcinogenicity in mice and rats.

Final Rule: addition of 1-

bromopropane;

community right-to-know

toxic chemical release

reporting

The U.S. Environmental Protection

Agency is adding 1-bromopropane

to the list of toxic chemicals subject

to reporting under section 313 of the

Emergency Planning and

Community Right-to-Know Act of

1986 and section 6607 of the

Pollution Prevention Act of 1990. 1-

Bromopropane has been classified

NTP, 2014. National Toxicology

Program. Report on Carcinogens,

Thirteenth Edition. Released October

2, 2015. U.S. Department of Health

and Human Services, Public Health

Service, National Toxicology

Program, Research Triangle Park, NC

27709.

22
by the NTP in their 13th Report on

Carcinogens as ‘‘reasonably

anticipated to be a human

carcinogen.’’ EPA has determined

that 1-bromopropane meets the

EPCRA section 313(d)(2)(B) criteria

because it can reasonably be

anticipated to cause cancer in

humans.

November 23, 2015 -- 80 FR 72906

NTP, 2013. Report on Carcinogens

Monograph on 1-Bromopropane

Office of the Report on Carcinogens,

Division of the National Toxicology

Program, National Institute of

Environmental Health Sciences, U.S.

Department of Health and Human

Services. NIH Publication No. 13-

5982, September 25, 2013

*CASRN = Chemical Abstracts Service Registry Number

23
https://ntp.niehs.nih.gov/go/806989

In Vitro to In Vivo Extrapolation for High Throughput Prioritization

and Decision Making

Fundamentals of Using Quantitative Structure-Activity

Relationship Models and Read-across Techniques in Predictive

Toxicology

Alternative Approaches for Acute Inhalation Toxicity to Address

Global Regulatory and Non-regulatory Data Requirements

NIEHS postdoctoral fellow Erin Quist,

D.V.M., center, showed Sagi Gillera, left,

and Deirdre Tucker, both from the NTP

Reproductive Endocrinology Group,

updates to the NTP Nonneoplastic Lesion

Atlas. (Photo courtesy of Robin Mackar)

2016 Annual Report - FY 2016 Glance - Additional Activities

Additional Activities

NTP participated in a number of meetings with stakeholders and the 

scientific community. At the 2016 annual meeting of the Society of 

Toxicology in New Orleans, staff from NTP and NIEHS participated in 

more than 35 workshops, symposia, platform sessions, education and 

information sessions, and poster sessions. The full program, including 

all NTP and NIEHS activities, can be found at on the Society of 

Toxicology website.

NTP also hosts symposiums and workshops to discuss the state of 

the science, and advances to the field. For example, the 2016 annual 

NTP Satellite Symposium , Pathology Potpourri, was held in San 

Diego and the 2017 symposium will be held in Montreal, Canada on 

June 24. These symposiums are held the day before the Society of 

Toxicologic Pathology annual meeting. The goal of this annual 

symposium is to present current diagnostic pathology or nomenclature 

issues to the toxicologic pathology community, including diagnostically 

difficult, interesting, or rare lesions, or challenging nomenclature 

issues. Proceedings of the symposiums will be published in the journal 

Toxicologic Pathology, along with summaries of presentations on 

diagnostic or nomenclature issues, and specific pathologic images 

that were used for audience voting and discussion. 

NTP also hosted three webinar series in FY 2016 related to alternative 

methods development:

24
https://ntp.niehs.nih.gov/go/807002

Ashley K, O’Connor PF. Purpose, scope and use of the NIOSH manual of analytical methods. In: NIOSH 

manual of analytical methods, fifth edition. Ashley K, O'Connor PF, editors. Cincinnati (OH): U.S. 

Department of Health and Human Services, Public Health Service, Centers for Disease Control and 

Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014-

151, 2016 Apr;PS1-PS9; https://www.cdc.gov/niosh/docs/2014-151/pdfs/chapters/chapter-ps.pdf .

Birch EM. Monitoring diesel exhaust in the workplace. In: NIOSH manual of analytical methods, fifth 

edition. Ashley K, O'Connor PF, editors. Cincinnati (OH): U.S. Department of Health and Human Services, 

Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational 

Safety and Health, DHHS (NIOSH) Publication No. 2014-151, 2016 Apr;DL1-DL41.

https://www.cdc.gov/niosh/docs/2014-151/pdfs/chapters/chapter-dl.pdf .

Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) 2014-2015 

Biennial Progress Report. National Toxicology Program Interagency Center for the Evaluation of Alternative 

Toxicological Methods. Research Triangle Park (NC): National Toxicology Program. 2016.

https://ntp.niehs.nih.gov/go/2015iccvamreport .

NTP Research Report on the Systematic Review of the Effects of Fluoride on Learning and Memory in 

Animal Studies. Research Triangle Park (NC): National Toxicology Program. Natl Toxicol Program Res Rep 

Ser. 2016 Jul;(RR-01):1-132; https://ntp.niehs.nih.gov/ntp/results/pubs/rr/reports/rr01_508.pdf.

NTP Research Report on Organotin and Total Tin Levels in Danish Women on Reproductive Age. Research 

Triangle Park (NC): National Toxicology Program. Natl Toxicol Program Rep Ser. 2016 Jul;(RR-02):1-27; 

https://ntp.niehs.nih.gov/ntp/results/pubs/rr/reports/rr02_508.pdf .

NTP Technical Report on the Toxicity Studies of p-Toluenesulfonamide (CAS No. 70-55-3) Administered in 

Feed to F344/N Rats, F344/NTac Rats, and B6C3F1/N Mice. Research Triangle Park (NC): National 

Toxicology Program. Natl Toxicol Program Tox Rep Ser.2016 Aug;(88):1-48;

https://ntp.niehs.nih.gov/ntp/htdocs/st_rpts/tox88_508.pdf .

NTP Technical Report on the Toxicity Studies of Octahydro-tetramethyl-naphthalenyl-ethanone (OTNE)

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

Toxicology Program. Natl Toxicol Program Tox Rep Ser. 2016 Jun;(92):1-58;

https://ntp.niehs.nih.gov/ntp/htdocs/st_rpts/tox092_508.pdf

NTP Technical Report on the Toxicity Studies of α-Pinene (CAS No. 80-56-8) Administered by Inhalation to 

F344/N Rats and B6C3F1/N Mice. Research Triangle Park (NC): National Toxicology Program. Natl Toxicol 

Program Tox Rep Ser. 2016 May;(81):1-58; https://ntp.niehs.nih.gov/ntp/htdocs/st_rpts/tox081_508.pdf .

NTP Technical Report on the Toxicity Studies of Sodium Thioglycolate (CAS No. 367-51-1) Administered 

Dermally to F344/N Rats and B6C3F1/N Mice. Research Triangle Park (NC): National Toxicology Program. 

Natl Toxicol Program Tox Rep Ser. 2016 May;(80):1-46;

https://ntp.niehs.nih.gov/ntp/htdocs/st_rpts/tox080_508.pdf .

2016 Annual Report - FY 2016 Glance - Publications

Publications

NTP Reports and Documents

25
 

26
Anderson SE, Shane H, Long C, Lukomska E, Meade BJ, Marshall NB. Evaluation of the irritancy and

hypersensitivity potential following topical application of didecyldimethylammonium chloride. J

Immunotoxicol. 2016 Jul;13(4):557-566; http://dx.doi.org/10.3109/1547691x.2016.1140854. [2]

Arciniega J, Wagner L, Prymula R, Sebo P, Isbrucker R, Descampe B, Chapsal JM, Costanzo A, 

Hendriksen C, Hoonaker M, Nelson S, Lidster K, Casey W, Allen D. Alternatives to HIST for acellular 

pertussis vaccines: Progress and challenges in replacement. Pharmeur Bio Sci Notes. 2016;2015:82-96;

http://www.ncbi.nlm.nih.gov/pubmed/27506225. [5]

Auerbach S, Filer D, Reif D, Walker V, Holloway AC, Schlezinger J, Srinivasan S, Svoboda D, Judson R, 

Bucher JR, Thayer KA. Prioritizing environmental chemicals for obesity and diabetes outcomes research: A 

screening approach using ToxCastTM high-throughput data. Environ Health Perspect. 2016

Aug;124(8):1141-1154; http://dx.doi.org/10.1289/ehp.1510456. [5]

Auerbach SS. In vivo signatures of genotoxic and non-genotoxic chemicals In: Thomas RSW, Michael D, 

editors. Toxicogenomics in predictive carcinogenicity. Royal Society of Chemistry; 2016. p. 113-153. [5]

Bailey RL, Cox-Ganser JM, Duling MG, LeBouf RF, Martin SB, Jr., Bledsoe TA, Green BJ, Kreiss K. 

Respiratory morbidity in a coffee processing workplace with sentinel obliterative bronchiolitis cases. Am J 

Ind Med. 2015 Dec;58(12):1235-1245; http://dx.doi.org/10.1002/ajim.22533. [2]

Ball N, Cronin MT, Shen J, Blackburn K, Booth ED, Bouhifd M, Donley E, Egnash L, Hastings C, Juberg 

DR, Kleensang A, Kleinstreuer N, Kroese ED, Lee AC, Luechtefeld T, Maertens A, Marty S, Naciff JM, 

Palmer J, Pamies D, Penman M, Richarz AN, Russo DP, Stuard SB, Patlewicz G, van Ravenzwaay B, Wu 

S, Zhu H, Hartung T. Toward good read-across practice (GRAP) guidance. ALTEX. 2016;33(2):149-166; 

http://dx.doi.org/10.14573/altex.1601251. [5]

Bandrowski A, Brinkman R, Brochhausen M, Brush MH, Bug B, Chibucos MC, Clancy K, Courtot M, Derom

D, Dumontier M, Fan LJ, Fostel J, Fragoso G, Gibson F, Gonzalez-Beltran A, Haendel MA, He YQ, 

Heiskanen M, Hernandez-Boussard T, Jensen M, Lin Y, Lister AL, Lord P, Malone J, Manduchi E, McGee 

M, Morrison N, Overton JA, Parkinson H, Peters B, Rocca-Serra P, Ruttenberg A, Sansone SA, 

Scheuermann RH, Schober D, Smith B, Soldatova LN, Stoeckert CJ, Taylor CF, Torniai C, Turner JA, Vita 

R, Whetzel PL, Zheng J. The ontology for biomedical investigations. PLoS One. 2016 Apr;11(4);

http://dx.doi.org/10.1371/journal.pone.0154556. [5]

Barroso J, Ahn IY, Caldeira C, Carmichael PL, Casey W, Coecke S, Curren R, Desprez B, Eskes C, 

Griesinger C, Guo J, Hill E, Roi AJ, Kojima H, Li J, Lim CH, Moura W, Nishikawa A, Park H, Peng S, 

Presgrave O, Singer T, Sohn SJ, Westmoreland C, Whelan M, Yang X, Yang Y, Zuang V. International 

harmonization and cooperation in the validation of alternative methods. Adv Exp Med Biol. 

2016;856:343-386; http://dx.doi.org/10.1007/978-3-319-33826-2_14. [5]

Behl M, Hsieh JH, Shafer TJ, Mundy WR, Rice JR, Boyd WA, Freedman JH, Hunter ES, III, Jarema KA, 

Padilla S, Tice RR. Use of alternative assays to identify and prioritize organophosphorus flame retardants 

for potential developmental and neurotoxicity. Neurotoxicol Teratol. 2015 Nov-Dec;52:181-193;

http://dx.doi.org/10.1016/j.ntt.2015.09.003. [5]

Behl M, Rice JR, Smith MV, Co CA, Bridge M, Hsieh JH, Freedman JH, Boyd WA. Comparative toxicity 

of organophosphate flame retardants and polybrominated diphenyl ethers to c. Elegans. Toxicol Sci. 

2016 Aug;154(2):241-252; http://dx.doi.org/10.1093/toxsci/kfw162. [5]

27
Bekele AZ, Gokulan K, Williams KM, Khare S. Dose and size-dependent antiviral effects of silver 

nanoparticles on feline calicivirus, a human norovirus surrogate. Foodborne Pathog Dis. 2016

May;13(5):239-244; http://dx.doi.org/10.1089/fpd.2015.2054. [4]

Bennett JS, Marlow DA, Nourian F, Breay J, Hammond D. Hexavalent chromium and isocyanate 

exposures during military aircraft painting under crossflow ventilation. J Occup Environ Hyg. 2016 

May;13(5):356-371; http://dx.doi.org/10.1080/15459624.2015.1117617. [2]

Bennett WD, Ivins S, Alexis NE, Wu JH, Bromberg PA, Brar SS, Travlos G, London SJ. Effect of obesity 

on acute ozone-induced changes in airway function, reactivity, and inflammation in adult females. PLoS 

One. 2016 Aug;11(8): e0160030; [5] http://dx.doi.org/10.1371/journal.pone.0160030.

Bertke SJ, Lehman EJ, Wurzelbacher SJ, Hein MJ. Mortality of lead smelter workers: A follow up study 

with exposure assessment. Am J Ind Med. 2016;59(11):979-986; http://dx.doi.org/10.1002/ajim.22618. [2]

Bertke SJ, Meyers AR, Wurzelbacher SJ, Measure A, Lampl MP, Robins D. Comparison of methods for 

auto-coding causation of injury narratives. Accid Anal Prev. 2016 Mar;88:117-123;

http://dx.doi.org/10.1016/j.aap.2015.12.006. [2]

Boonmuen N, Gong P, Ali Z, Chittiboyina AG, Khan I, Doerge DR, Helferich WG, Carlson KE, Martin T, 

Piyachaturawat P, Katzenellenbogen JA, Katzenellenbogen BS. Licorice root components in dietary 

supplements are selective estrogen receptor modulators with a spectrum of estrogenic and anti-estrogenic 

activities. Steroids. 2016 Jan;105:42-49; http://dx.doi.org/10.1016/j.steroids.2015.11.006. [4]

Boudreau MD, Imam MS, Paredes AM, Bryant MS, Cunningham CK, Felton RP, Jones MY, Davis KJ, 

Olson GR. Differential effects of silver nanoparticles and silver ions on tissue accumulation, distribution, and 

toxicity in the sprague dawley rat following daily oral gavage administration for 13 weeks. Toxicol Sci. 2016 

Mar;150(1):131-160; http://dx.doi.org/10.1093/toxsci/kfv318. [3]

Boyd WA, Smith MV, Co CA, Pirone JR, Rice JR, Shockley KR, Freedman JH. Developmental effects of the 

ToxCastTM phase I and phase II chemicals in caenorhabditis elegans and corresponding responses in

zebrafish, rats, and rabbits. Environ Health Perspect. 2016 May;124(5):586-593;

http://dx.doi.org/10.1289/ehp.1409645. [5]

Boyles AL, Yetley EA, Thayer KA, Coates PM. Safe use of high intakes of folic acid: Research challenges 

and paths forward. Nutr Rev. 2016 Jul;74(7):469-474; http://dx.doi.org/10.1093/nutrit/nuw015. [5]

Broadwater K, de Perio MA, Roberts J, Burton NC, Lemons AR, Green BJ, Brueck SE. Investigating a 

persistent odor at an aircraft seat manufacturer. J Occup Env Hyg. 2016;13(10):D159-D165;

http://dx.doi.org/10.1080/15459624.2016.1183017. [2]

Brown KK, Shaw PB, Mead KR, Kovein RJ, Voorhees RT, Brandes AR. Development of the chemical 

exposure monitor with indoor positioning (CEMWIP) for workplace VOC surveys. J Occup Environ Hyg. 

2016;13(6):401-412; http://dx.doi.org/10.1080/15459624.2015.1125488. [2]

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

Sciences on the occasion of its 50th anniversary. Environ Health Perspect. 2016;124(1):A192-195.

http://dx.doi.org/10.1289/EHP463. [5]

Bushel PR, Fannin RD, Gerrish K, Watkins PB, Paules RS. Blood gene expression profiling of an early 

acetaminophen response. Pharmacogenomics J. 2016 Mar; http://dx.doi.org/10.1038/tpj.2016.8 . [5] 

Camacho L, Lewis SM, Vanlandingham MM, Juliar BE, Olson GR, Patton RE, da Costa GG, Woodling K,

28
Sepehr E, Bryant MS, Doerge DR, Basavarajappa MS, Felton RR, Delclos KB. Comparison of endpoints

relevant to toxicity assessments in 3 generations of CD-1 mice fed irradiated natural and purified ingredient

diets with varying soy protein and isoflavone contents. Food Chem Toxicol. 2016 Aug;94:39-56;

http://dx.doi.org/10.1016/j.fct.2016.05.014 . [3]

Carbone M, Kanodia S, Chao A, Miller A, Wali A, Weissman D, Adjei A, Baumann F, Boffetta P, Buck B, de

Perrot M, Dogan AU, Gavett S, Gualtieri A, Hassan R, Hesdorffer M, Hirsch FR, Larson D, Mao W, Masten

S, Pass HI, Peto J, Pira E, Steele I, Tsao A, Woodard GA, Yang H, Malik S. Consensus report of the 2015

Weinman International Conference on Mesothelioma. J Thorac Oncol. 2016 Aug;11(8):1246-1262;

http://dx.doi.org/10.1016/j.jtho.2016.04.028 . [5]

Carlin DJ, Naujokas MF, Bradham KD, Cowden J, Heacock M, Henry HF, Lee JS, Thomas DJ, Thompson

C, Tokar EJ, Waalkes MP, Birnbaum LS, Suk WA. Arsenic and environmental health: State of the science

and future research opportunities. Environ Health Perspect. 2016 Jul;124(7):890-899;

http://dx.doi.org/10.1289/ehp.1510209 . [5]

Casey WM. Advances in the development and validation of test methods in the United States. Toxicol Res.

2016 Jan;32(1):9-14; http://dx.doi.org/10.5487/tr.2016.32.1.009 . [5]

Castro L, Gao X, Moore AB, Yu L, Di X, Kissling GE, Dixon D. A high concentration of genistein induces cell

death in human uterine leiomyoma cells by autophagy. Expert Opin Environ Biol. 2016 May;5(Suppl 1);

http://dx.doi.org/10.4172/2325-9655.s1-003 . [5]

Ceballos DM, Whittaker SG, Lee EG, Roberts J, Streicher R, Nourian F, Gong W, Broadwater K.

Occupational exposures to new dry cleaning solvents: High-flashpoint hydrocarbons and butylal. J Occup

Env Hyg. 2016 Oct;13(10):759-769; http://dx.doi.org/10.1080/15459624.2016.1177648 . [2]

Cena L, Chen T, Keane M. Evolution of welding-fume aerosols with time and distance from the source: A 

study was conducted on the spatiotemporal variability in welding-fume concentrations for the

characterization of first- and second-hand exposure to welding fumes. Weld J. 2016 Aug;95(Suppl):280s285s. [2]

Cerniglia CE, Pineiro SA, Kotarski SF. An update discussion on the current assessment of the safety of

veterinary antimicrobial drug residues in food with regard to their impact on the human intestinal

microbiome. Drug Test Anal. 2016 May;8(5-6):539-548; http://dx.doi.org/10.1002/dta.2024 . [4]

Chalbot MCG, Chitranshi P, Gamboa da Costa G, Pollock E, Kavouras IG. Characterization of water-soluble

organic matter in urban aerosol by 1H-NMR spectroscopy. Atmos Environ. 2016 Mar;128:235-245;

http://dx.doi.org/10.1016/j.atmosenv.2015.12.067 . [4]

Chappell G, Pogribny IP, Guyton KZ, Rusyn I. Epigenetic alterations induced by genotoxic occupational and

environmental human chemical carcinogens: A systematic literature review. Mutat Res Rev Mutat Res.

2016 Apr-Jun;768:27-45; http://dx.doi.org/10.1016/j.mrrev.2016.03.004 . [4]

Chappell G, Silva GO, Uehara T, Pogribny IP, Rusyn I. Characterization of copy number alterations in a 

mouse model of fibrosis-associated hepatocellular carcinoma reveals concordance with human disease. 

Cancer Med. 2016 Mar;5(3):574-585; http://dx.doi.org/10.1002/cam4.606 . [4]

Chen S, Zhang Z, Qing T, Ren Z, Yu D, Couch L, Ning B, Mei N, Shi L, Tolleson WH, Guo L. Activation of

the Nrf2 signaling pathway in usnic acid-induced toxicity in HepG2 cells. Arch Toxicol. 2016;

http://dx.doi.org/10.1007/s00204-016-1775-y . [4]

29
Chen T, Schwegler-Berry D, Cumpston A, Cumpston J, Friend S, Stone S, Keane M. Performance of a

scanning mobility particle sizer in measuring diverse types of airborne nanoparticles: Multi-walled carbon

nanotubes, welding fumes, and titanium dioxide spray. J Occup Environ Hyg. 2016 Jul;13(7):501-518;

http://dx.doi.org/10.1080/15459624.2016.1148267 . [2]

Churchill SR, Morgan DL, Kissling GE, Travlos GS, King-Herbert AP. Impact of environmental enrichment

devices on NTP in vivo studies. Toxicol Pathol. 2016 Jan;44(2):233-245;

http://dx.doi.org/10.1177/0192623315625330 . [5]

Cimino AM, Boyles AL, Thayer KA, Perry MJ. Effects of neonicotinoid pesticide exposure on human health:

A systematic review. Environ Health Perspect. 2016 Jul; http://dx.doi.org/10.1289/ehp515 . [5]

Clippinger AJ, Ahluwalia A, Allen D, Bonner JC, Casey W, Castranova V, David RM, Halappanavar S,

Hotchkiss JA, Jarabek AM, Maier M, Polk W, Rothen-Rutishauser B, Sayes CM, Sayre P, Sharma M, Stone 

V. Expert consensus on an in vitro approach to assess pulmonary fibrogenic potential of aerosolized

nanomaterials. Arch Toxicol. 2016 Jul;90(7):1769-1783; http://dx.doi.org/10.1007/s00204-016-1717-8 . [5]

Coelho SG, Patri AK, Wokovich AM, McNeil SE, Howard PC, Miller SA. Repetitive application of sunscreen

containing titanium dioxide nanoparticles on human skin. JAMA Dermatol. 2016 Apr;152(4):470-472;

http://dx.doi.org/10.1001/jamadermatol.2015.5944 . [4]

Cooper GS, Lunn RM, Agerstrand M, Glenn BS, Kraft AD, Luke AM, Ratcliffe JM. Study sensitivity:

Evaluating the ability to detect effects in systematic reviews of chemical exposures. Environ Int. 2016 JulAug;92-93:605-610; http://dx.doi.org/10.1016/j.envint.2016.03.017 . [5]

Cote I, Andersen ME, Ankley GT, Barone S, Birnbaum LS, Boekelheide K, Bois FY, Burgoon LD, Chiu WA, 

Crawford-Brown D, Crofton KM, DeVito M, Devlin RB, Edwards SW, Guyton KZ, Hattis D, Judson RS, 

Knight D, Krewski D, Lambert J, Maull EA, Mendrick D, Paoli GM, Patel CJ, Perkins EJ, Poje G, Portier CJ,

Rusyn I, Schulte PA, Simeonov A, Smith MT, Thayer KA, Thomas RS, Thomas R, Tice RR, Vandenberg JJ, 

Villeneuve DL, Wesselkamper S, Whelan M, Whittaker C, White R, Xia M, Yauk C, Zeise L, Zhao J, 

DeWoskin RS. The next generation of risk assessment multiyear study- highlights of findings, applications 

to risk assessment and future directions. Environ Health Perspect. 2016 Apr;

http://dx.doi.org/10.1289/ehp233 . [5]

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

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

following subchronic inhalation exposure. Clin Exp Allergy. 2016;46(10):1315-1327;

http://dx.doi.org/10.1111/cea.12783 . [1,5]

Cruz-Topete D, Myers PH, Foley JF, Willis MS, Cidlowski JA. Corticosteroids are essential for maintaining

cardiovascular function in male mice. Endocrinology. 2016 Jul;157(7):2759-2771;

http://dx.doi.org/10.1210/en.2015-1604 . [5]

Cummings KJ, Virji MA, Park JY, Stanton ML, Edwards NT, Trapnell BC, Carey B, Stefaniak AB, Kreiss K.

Respirable indium exposures, plasma indium, and respiratory health among indium-tin oxide (ITO) workers.

Am J Ind Med. 2016 Jul;59(7):522-531; http://dx.doi.org/10.1002/ajim.22585 . [2]

Daniels RD, Bertke S, Dahm MM, Yiin JH, Kubale TL, Hales TR, Baris D, Zahm SH, Beaumont JJ, 

Waters KM, Pinkerton LE. Exposure-response relationships for select cancer and non-cancer health 

outcomes in a cohort of U.S. firefighters from San Francisco, Chicago and Philadelphia (1950-2009). 

Occup Environ Med. 2015 Oct;72(10):699-706; http://dx.doi.org/10.1136/oemed-2014-102671 . [2]

30
Davidson D, Derk R, He X, Stueckle T, Cohen J, Pirela S, Demokritou P, Rojanasakul Y, Rojanasakul L. 

Direct stimulation of human fibroblasts by nCeO2 in vitro is attenuated with an amorphous silica coating. 

Part Fibre Toxicol. 2016 May;13(23):1-14; http://dx.doi.org/10.1186/s12989-016-0134-8 . [2]

DeBord DG, Burgoon L, Edwards SW, Haber LT, Kanitz MH, Kuempel E, Thomas RS, Yucesoy B. Systems

biology and biomarkers of early effects for occupational exposure limit setting. J Occup Env Hyg.

2015;Suppl1:12:S41-S54; http://dx.doi.org/10.1080/15459624.2015.1060324 . [2]

DeBord DG, Carreón T, Lentz TJ, Middendorf PJ, Hoover MD, Schulte PA. Use of the "exposome" in the

practice of epidemiology: A primer on -omic technologies. Am J Epidemiol. 2016 Aug;184(4):302-314;

http://dx.doi.org/10.1093/aje/kwv325 . [2]

Dennis KK, Auerbach SS, Balshaw DM, Cui Y, Fallin MD, Smith MT, Spira A, Sumner S, Miller GW. The

importance of the biological impact of exposure to the concept of the exposome. Environ Health Perspect.

2016;124(10):1504-1510. http://dx.doi.org/10.1289/ehp140 . [5]

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Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ,

Lambert PF, Hecht SS, Bucher JR, Stewart BW, Baan RA, Cogliano VJ, Straif K. Key characteristics of

carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect.

2016 Jun;124(6):713-721; http://dx.doi.org/10.1289/ehp.1509912 . [5]

Snyder-Talkington BN, Dong C, Porter DW, Ducatman B, Wolfarth MG, Andrew M, Battelli L, Raese R,

Castranova V, Guo NL, Qian Y. Multiwalled carbon nanotube-induced pulmonary inflammatory and fibrotic

responses and genomic changes following aspiration exposure in mice: A 1-year postexposure study. J

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Snyder-Talkington BN, Dong C, Sargent LM, Porter DW, Staska LM, Hubbs AF, Raese R, McKinney W, 

Chen BT, Battelli L, Lowry DT, Reynolds SH, Castranova V, Qian Y, Guo NL. mRNAs and miRNAs in whole 

blood associated with lung hyperplasia, fibrosis, and bronchiolo-alveolar adenoma and adenocarcinoma 

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DeLise AM, de Schaepdrijver L, Dogdas B, French J, Harrouk W, Helfgott J, Henkelman RM, Hesterman J,

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Trbojevich RA, Fernandez A, Watanabe F, Mustafa T, Bryant MS. Comparative study of silver nanoparticle

permeation using side-bi-side and franz diffusion cells. J Nanopart Res. 2016 Mar;18(3):1-12;

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Tryndyak V, de Conti A, Doerge DR, Olson GR, Beland FA, Pogribny IP. Furan-induced transcriptomic and

45
gene-specific DNA methylation changes in the livers of Fischer 344 rats in a 2-year carcinogenicity study. 

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Tryndyak VP, Han T, Fuscoe JC, Ross SA, Beland FA, Pogribny IP. Status of hepatic DNA methylome

predetermines and modulates the severity of non-alcoholic fatty liver injury in mice. BMC Genomics. 2016

Apr;17:298; http://dx.doi.org/10.1186/s12864-016-2617-2 . [4]

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Turkevich LA, Fernback J, Dastidar AG, Osterberg P. Potential explosion hazard of carbonaceous

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Vijay V, Moland CL, Han T, Fuscoe JC, Lee T, Herman EH, Jenkins GR, Lewis SM, Cummings CA, Gao Y,

Cao Z, Yu LR, Desai VG. Early transcriptional changes in cardiac mitochondria during chronic doxorubicin

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Vandenberg LN, Agerstrand M, Beronius A, Beausoleil C, Bergman A, Bero LA, Bornehag CG, Boyer CS,

Cooper GS, Cotgreave I, Gee D, Grandjean P, Guyton KZ, Hass U, Heindel JJ, Jobling S, Kidd KA,

Kortenkamp A, Macleod MR, Martin OV, Norinder U, Scheringer M, Thayer KA, Toppari J, Whaley P,

Woodruff TJ, Ruden C. A proposed framework for the systematic review and integrated assessment

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Newbold RR, Padmanabhan V, Vom Saal FS, Woodruff TJ. Erratum to: A round robin approach to the

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Walters JL, Chelonis JJ, Fogle CM, Orser BA, Paule MG. Single and repeated exposures to the volatile

anesthetic isoflurane do not impair operant performance in aged rats. Neurotoxicology. 2016 Sep;56:159-

169; http://dx.doi.org/10.1016/j.neuro.2016.07.012 . [4]

Wang W, Belosay A, Yang X, Hartman JA, Song H, Iwaniec UT, Turner RT, Churchwell MI, Doerge DR,

Helferich WG. Effects of letrozole on breast cancer micro-metastatic tumor growth in bone and lung in mice

inoculated with murine 4T1 cells. Clin Exp Metastasis. 2016 Jun;33(5):475-485;

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Whaley P, Halsall C, Agerstrand M, Aiassa E, Benford D, Bilotta G, Coggon D, Collins C, Dempsey C,

Duarte-Davidson R, FitzGerald R, Galay-Burgos M, Gee D, Hoffmann S, Lam J, Lasserson T, Levy L,

Lipworth S, Ross SM, Martin O, Meads C, Meyer-Baron M, Miller J, Pease C, Rooney A, Sapiets A, Stewart

G, Taylor D. Implementing systematic review techniques in chemical risk assessment: Challenges,

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Worley RR, Fisher J. Application of physiologically-based pharmacokinetic modeling to explore the role of

kidney transporters in renal reabsorption of perfluorooctanoic acid in the rat. Toxicol Appl Pharmacol. 2015

Dec;289(3):428-441; http://dx.doi.org/10.1016/j.taap.2015.10.017 . [4]

Wu Q, Ning B, Xuan J, Ren Z, Guo L, Bryant MS. The role of CYP 3A4 and 1A1 in amiodarone-induced

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Wu Y, Beland FA, Fang JL. Effect of triclosan, triclocarban, 2,2',4,4'-tetrabromodiphenyl ether, and

bisphenol A on the iodide uptake, thyroid peroxidase activity, and expression of genes involved in thyroid

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Wyde M, Cesta M, Blystone C, Elmore S, Foster P, Hooth M, Kissling G, Malarkey D, Sills R, Stout M,

Walker N, Witt K, Wolfe M, Bucher J. Report of partial findings from the National Toxicology Program

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body exposure). bioRxiv. 2016 Jun; https://doi.org/10.1101/055699 [5]

Xia Q, Zhao Y, Lin G, Beland FA, Cai L, Fu PP. Pyrrolizidine alkaloid-protein adducts: Potential noninvasive biomarkers of pyrrolizidine alkaloid-induced liver toxicity and exposure. Chem Res Toxicol. 2016

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Xie Y, Holmgren S, Andrews DM, Wolfe MS. Evaluating the impact of the U.S. National Toxicology

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Yamashita H, Hoenerhoff MJ, Peddada SD, Sills RC, Pandiri AR. Chemical exacerbation of light-induced

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Yan Y, Cummings CA, Sutton D, Yu L, Castro L, Moore AB, Gao X, Dixon D. Immunogold electron

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Yu LD, Ham K, Gao XH, Castro L, Yan YT, Kissling GE, Tucker CJ, Flagler N, Dong R, Archer TK, Dixon D.

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[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

48
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 2016 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 2016, NIEHS provided support for NTP activities through interagency agreements with 

other federal agencies.

2016 Annual Report - Learn About Us

Learn About Us

49
https://ntp.niehs.nih.gov/go/807219

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, interpretation, and guidance in the 

appropriate uses of these data to regulatory agencies and other 

health-related research groups. The American people and government 

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

scientific basis for making credible decisions that will protect public 

health. In the past 38 years, NTP has studied and shared information 

on the health effects of more than 2,500 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 

communications and dialogue with federal and state agencies, 

industry, nongovernmental organizations, academia, and the public. 

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, and 

notifications through media releases, a calendar of upcoming events, 

and the NTP Update newsletter.

The public and other interested parties can stay abreast of NTP 

activities and events by subscribing to the NTP listserv, an email 

notification system. In addition, requests for information can be 

made through the Central Data Management office via email or 

calling 919- 541-3419, or 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 (919-541-7539 or ntpinfo@niehs.nih.gov).

2016 Annual Report - Learn About Us - Mission

Mission and Goals

NTP was established in 1978 by the U.S. Department of Health, 

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

Human Services, in response to concerns about potential human 

health effects of chemicals in our environment. Specifically, NTP 

goals were to:

50
https://ntp.niehs.nih.gov/go/807224

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., serves as director of both NIEHS and 

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

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

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

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

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

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

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

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

NIOSH’s mission is to generate new knowledge in the field of occupational safety and health, and to transfer 

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

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

Federal Mine Safety and Health Act.

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

Scientific Coordination, manages NTP activities within NCTR, herein referred to as NCTR/NTP. NCTR staff 

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

and industry, provide innovative technology, methods development, vital 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.

2016 Annual Report - Learn About Us - Organization

Organizational Structure and Oversight

51
2016 Annual Report Learn About Us Funding https://ntp.niehs.nih.gov/go/807231

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

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

shown in the figure, the total NTP budget for FY 2016 was $131.0 million.

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

through interagency agreements with other agencies. In FY 2016, NIEHS funded 30 contracts, listed in the

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

advisory meetings for NTP. There may be additional contracts at the other agencies that support some of

their voluntary NTP efforts.

NIEHS Contracts That Supported NTP Activities in FY 2016

Description Contractor

Absorption, Distribution, Metabolism & Excretion Research Triangle Institute

Accelerating Dev/Use of Computational Methods and models U.S. Environmental Protection

Agency

Analytical Chemistry Services Battelle

Battelle Memorial

Midwest Research Institute

Research Triangle Institute

Funding

- -

52
Archives and Specimen Repository Experimental Pathology 

Laboratories

Assessment of Bioavailability following Exposure to 30 Compounds

with potential for Developmental Toxicity in Zebrafish Embryos

BBD Biophenix USA, LLC

Bioinformatics and Computational Support Kelly Scientific

Bioinformatics Methylation Project Laboratory Corp of America

Evaluate Toxicity Following Early Life Exposure Southern Research Institute

Evaluation of Alternative Toxicological Methods Integrated Laboratory Systems

Genetic Toxicity Testing Support Services Integrated Laboratory Systems

Immunotoxicity Potential of Environmental and Therapeutic Agents Burleson Research 

Technologies

In Life Data Collection and Management System INSTEM, LSS

NTP Computer and User Support Vistronix Inc.

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.

Production of Harlan Sprague Rats Envigo

Reproductive Assessments by Continuous Breeding Research Triangle Institute

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

Quality Assessment Support/Audits & Inspections CSS-Dynamac Corporation

Receptor Activation Assays University of California - Irvine

Scientific Information Management and Literature Based Evaluations

for the NTP

ICF

Screening for Cardiotoxicity and Neurotoxicity Combined with 

Heptatotoxicity in Zebrafish

BBD Biophenix USA, LLC

Statistical Support Social and Scientific Systems

 Integrated Laboratory Systems

Support for Toxicological Data Vistronix, LLC.

Toxicological and Carcinogenic Potential of Chemicals Battelle Memorial

53
https://ntp.niehs.nih.gov/go/807234

A Staff Directory is available . 

2016 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

919-541-3419

cdm@niehs.nih.gov (or use our contact form).

54
https://ntp.niehs.nih.gov/go/807227

NIEHS/NTP offers a limited number of postdoctoral training fellowships to prepare trainees for careers in 

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

benefits, and the application process can be found on the NIEHS training website . The training program has six 

focal areas: applied toxicology and carcinogenesis, biomolecular screening and computational toxicology, 

health assessment and translation, laboratory animal medicine, systems and mechanistic toxicology, and 

toxicological pathology. In FY 2016, NIEHS/NTP staff mentored 18 postdoctoral fellows at NIEHS.

NIEHS/NTP Training Program Postdoctoral Fellows in FY 2016

Training Program Fellow

Applied toxicology and carcinogenesis Natasha Catlin

Anika Dzierlenga

Georgia Hinkley

Kristen Ryan

Kelly Shipkowski

Biomolecular screening and computational toxicology Jui-Hua Hsieh

Sreenivasa Ramaiahgari

Health assessment and translation Katie Pelch

Laboratory animal medicine Vivian Chen

Sheba Churchill

Systems and mechanistic toxicology Adam Filgo

Xiaohua Gao

Ngome Makia

Ntube (Olive) Ngalame

Miaofel Xu

Toxicological pathology Gregory Krane

Erin Quist

Eui Jae Sung

2016 Annual Report - Learn About Us - Training Programs

Training Opportunities

55
https://ntp.niehs.nih.gov/go/807215

In FY 2016, NIEHS provided support for NTP activities through interagency agreements with other federal

agencies.

FDA/NCTR

In December 1992, NIEHS and FDA established a formal interagency agreement to conduct toxicology

studies on FDA-regulated agents nominated to NTP and studies at NCTR. 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.

This interagency agreement has supported studies on endocrine active agents, dietary supplements, food

contaminants, AIDS therapeutics, pediatric medicines, electromagnetic radiation, cosmetics, and nanoscale

materials. Studies in these areas have produced 18 published NTP Technical Reports and over 250 peerreviewed journal publications. Some of the data from the interagency agreement-supported studies have led

to an increased understanding of the pharmacokinetics, mechanism of action, or dose-response of

substances. Other data have led to refinement of risk assessment models.

CDC/NIOSH

NIEHS/NTP has two interagency agreements with NIOSH. One interagency agreement was established in

the early 1990s in response to increased efforts by NTP to study noncancer endpoints. NIOSH and

NIEHS/NTP have conducted studies to assess the potential toxicity of exposures to substances such as

fungi, mycotoxins, volatile organics, lead, latex, nickel, isocyanates, nanomaterials, and beryllium in

occupationally exposed populations. Studies have included workers such as miners, farmers, health care

workers, autoworkers, and firefighters exposed to mixtures of chemicals. Several studies examine how

genetic variability in immune-inflammatory-antioxidant responses contributes to the development and

severity of inflammatory and allergic disease in people of different occupations. NIEHS/NTP and NIOSH are 

also leveraging the capability of a unique acoustical generating system located at NIOSH to evaluate the

potential health effects of exposure to airborne molds in short-term toxicology studies.

The second interagency agreement involves multiple projects. NIEHS/NTP and NIOSH have worked to

establish methodologies to assess complex mixtures, such as asphalt fume, welding fume, and tungsten

fibers, and to conduct exposure assessments in occupational settings to identify toxicologically relevant

exposures. During FY 2016, NIEHS/NTP and NIOSH completed a study evaluating occupational exposure

to bisphenol A. Two additional projects are ongoing. The first focuses on an assessment of occupational

exposure to alternative flame retardants used in manufacturing, construction, and service industries. The 

second project assesses exposure to polycyclic aromatic hydrocarbons by applicators of coal tar sealants.

Many studies performed under these interagency agreements are published in the peer-reviewed literature

and have been used for hazard identification, and regulatory and intervention purposes.

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 high throughput and high

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

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

2016 Annual Report - Learn About Us - Interagency Agreements

Interagency Agreements

56
laboratory animals. This collaboration between NIEHS/NTP and NCATS/DPI should produce data for

substances lacking needed toxicological information that can be used to prioritize substances for further

studies, including toxicological evaluation, mechanisms of action investigation, and development of

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

substances tested and decrease the cost of testing.

Additional Agreements

NTP also established several smaller interagency agreements to conduct research, listed in the table below.

Additional Interagency Agreements in FY 2016

Study-Agency Description

Development of Tools for Evaluating NTP's

Effectiveness - U.S. Department of Energy

Research and development of tools, such as web-mining,

that NIEHS can use in its research evaluations of the NTP's

effectiveness.

Accelerating Development and Use of

Computational Methods and Models - U.S.

Environmental Protection Agency

Accelerate development and use of computational methods

and models for quantitative and qualitative assessments of

the risks of environmental chemicals.

57
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.

2016 Annual Report - Scientific and Public Input Opportunities

Scientific and Public Input Opportunities

58
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 via the NTP website. Agencies represented on the

NTP Executive Committee also identify and forward

nominations to NTP.

For new studies or research projects of substantial scope

and complexity, NTP research concepts or project plans are

prepared to facilitate external review as part of a multi-step

process with input from NTP participating federal agencies,

Board of Scientific Counselors, and the public. In addition to

new research programs, NTP also conducts targeted studies to extend or explain findings observed in

previously conducted studies and address nominations that are closely aligned with current research efforts.

In November 2015, the California Office of Environmental Health Hazard Assessment nominated synthetic

turf/recycled tire crumb rubber as part of its Environmental Health Study of Synthetic Turf. In response,

NTP formulated plans to conduct a number of studies to enhance the understanding of potential health

impacts of chemicals released from synthetic turf with an emphasis on the crumb rubber. The NTP

presented the proposed research program to the Board of Scientific Counselors in June 2016 .

Also in FY 2016, in response to a nomination from the Environmental Protection Agency’s Office of Land

and Emergency Management, NTP formulated plans to evaluate the potential for water-soluble thallium

compounds to induce neurological, reproductive, and developmental toxicity following subchronic exposure

in rodents. The NTP Research Concept was released and presented to the Board of Scientific Counselors 

in June 2016

Questions about the nomination, review, and selection process can be sent to Scott Masten, Ph.D.

Research and Testing Projects Initiated in FY 2016

Project

CASRN*

Study Scientist

Nomination Rationale and Project Aims

Synthetic Turf/Recycled Tire Crumb Rubber

N/A

Roberts

In recent years, public health concern for playing

on synthetic turf fields has increased. Crumb

rubber, manufactured from recycled tires and used

in synthetic turf and playground mats, contains

numerous potential carcinogenic and toxic

substances. The NTP research program is

considering potential routes of human contact with

crumb rubber and aims to understand what

exposure conditions in an experimental laboratory

setting have the potential to impact the risk of

developing adverse health outcomes.

2016 Annual Report - Scientific and Public Input Opportunities - Nominations https://ntp.niehs.nih.gov/go/807201

Nominations

59
Thallium and Thallium Salts:

Metallic Thallium (TI); 7440-28-0

Thallium (I) Acetate; 563-68-8

Thallium (I) Carbonate; 6533-73-9

Thallium (I) Chlorate; 13453-30-0

Thallium (I) Chloride; 7791-12-0

Thallium (I) Nitrate; 10102-45-1

Thallium (I) Oxide; 1314-12-1

Thallium (III) Oxide; 1314-32-5

Thallium Selenide; 15123-92-9

Thallium Sulfate; 7446-18-6

Shipkowski

Potential for widespread human exposure to

thallium exists primarily due to its presence as a

contaminant in drinking water near hazardous

waste and industrial sites, and from instances of

accidental or deliberate poisoning. There is a lack

of adequate data to support risk evaluations for

human health following thallium exposure. The goal

of this research program is to evaluate the potential

for water-soluble thallium compounds to induce

neurological, reproductive, and developmental

toxicity following subchronic exposure in rodents.

*CASRN = Chemical Abstracts Service Registry Number

60
2016 Annual Report Scientific and Public Input Opportunities

Board of Scientific Counselors

https://ntp.niehs.nih.gov/go/807189

Reviewed the NTP Cellular and Molecular Pathology Branch and Drs. Robert Sills and David Malarkey.

Voted on a contract concept on Bioinformatics Support.

Heard a report on the RoC peer review meeting on cobalt and certain cobalt compounds held in July

2015.

Reviewed two draft OHAT concepts (1) Mountaintop Removal Mining; Impacts on Health in the

Surrounding Community and (2) Proposed NTP Evaluation on Fluoride Exposure and Potential for

Developmental Neurobehavioral Effects.

Heard a report on a draft NTP Technical Report peer reviewed in June 2015 on pentabromodiphenyl

ether mixture [DE-71 technical grade].

The second BSC meeting was held April 11, 2016. During this meeting, the BSC reviewed two draft RoC

concepts (1) Di- and Tri-Haloacetic Acids Found as Water Disinfection By-Products and (2) Helicobacter

pylori (Chronic Infection).

The third BSC meeting was held on June 16, 2015. During this meeting, the BSC:

Heard an update on new NTP research projects including (1) research problem formulation, (2) a draft

research concept on thallium compounds, (3) the synthetic turf/crumb rubber research program, and (4)

glyphosate research scoping.

Heard a report on draft NTP Technical Reports peer reviewed in February 2016 on antimony trioxide

and TRIM VX.

Heard a report on NTP studies of cell phone radiofrequency radiation.

Heard a report on the RoC peer review meeting on selected viruses held in December 2015.

Received an update on activities at the FDA National Center for Toxicological Research.

Heard a report on NTP projects utilizing the NIEHS Clinical Research Unit and then toured the unit.

Heard reports on three workshops (1) In Vitro to In Vivo Extrapolation for High Throughput Prioritization

and Decision Making, held in February 2016; (2) Shift Work at Night, Artificial Light at Night, and

Circadian Disruption, held in March 2016; and (3) Addressing Challenges in the Assessment of

Botanical Dietary Supplement Safety, held in April 2016.

NTP Board of Scientific Counselors

The NTP Board of Scientific Counselors (BSC), a federally chartered advisory group, provides scientific 

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

to the BSC. The BSC can consist of up to 20 scientists, primarily from the public and private sectors, with 

scientific expertise relevant to NTP activities. The BSC charter and current roster are available on the NTP

webpage. Lori White, Ph.D., served as the designated federal officer and manager of the BSC. Below is the 

roster for FY 2016.

The BSC met three times in FY 2016. During the meeting on December 1-2, 2015 the BSC: 

- -

61
BSC members and NTP staff at the June 2016 BSC meeting.

NTP Board of Scientific Counselors Membership Roster FY 

2016 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.

VP and Global Head

Johnson and Johnson

Spring House, Pennsylvania

6/30/19

Robert E. Chapin, Ph.D.

Laboratory Director

Pfizer

Groton, Connecticut

12/27/15

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

Chair and Professor

Department of Pharmaceutical

Sciences

Eugene Applebaum College of

Pharmacy and Health Sciences

Wayne State University

Detroit, Michigan

12/27/16

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

Professor

College of Veterinary Medicine

North Carolina State University

Raleigh, North Carolina

12/27/15

62
Mary Beth Genter, Ph.D.

Associate Professor

Department of Environmental

Health

  6/30/17

Jack R. Harkema, D.V.M., Ph.D.,

D.A.C.V.P.

Distinguished Professor

Department of Pathobiology and

Diagnostic Investigation

Michigan State University

East Lansing, Michigan

12/27/15

Dale Hattis, Ph.D.

Research Professor

George Perkins Marsh Institute

Clark University

Worcester, Massachusetts

12/27/15

Daniel Kass, M.S.P.H.

Executive VP 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.

Professor

Pharmacology, Toxicology, 

and Neuroscience

Louisiana State University Health Science

Center

Shreveport, Louisiana

6/30/19

Lisa A. Peterson, Ph.D. (BSC

Chair

Professor

Division of Environmental Health

Sciences and Masonic Center

School of Public Health

University of Minnesota

Minneapolis, Minnesota

12/27/16

Kenneth Ramos, M.D., Ph.D.

Associate Vice President

Precision Health Sciences Center

Arizona Health Sciences Center

Tucson, Arizona

6/30/19

Sonya Sobrian, Ph.D.

Associate Professor

Department of Pharmacology

Howard University

Washington, D.C.

12/27/15

James Stevens, Ph.D.

Distinguished Research Fellow

Lilly Research Laboratories

Indianapolis, Indiana

6/30/19

Iris G. Udasin, M.D.

Professor

Department of Environmental and

Occupational Medicine

  6/30/16

Karina Waters, Ph.D. Pacific Northwest National Laboratory 6/30/19

Deputy Director

Biological Sciences Division Richland, Washington

63
https://ntp.niehs.nih.gov/go/807204

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

advisory committee established 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. The table below provides the roster for FY 2016. SACATM typically 

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

designated federal officer and manager of SACATM.

SACATM met once during FY 2016 on September 27, 2016, at NIEHS. At the meeting, ICCVAM and 

NICEATM updated SACATM on the activities since the last meeting. The focus of the meeting was a strategy 

for implementing the vision for regulatory toxicity testing in the 21st century. SACATM was updated on 

ICCVAM’s strategy for the six most commonly used acute animal tests and their roadmap for skin 

sensitization testing. Additional presentations included (1) moving away from animal models for toxicity 

testing, (2) impediments to adoption of alternative approaches, (3) coordinating activities between the federal

government and stakeholders, (4) promoting adoption of alternative testing strategies, and (5) the next steps

toward developing a strategy for implementing the vision for toxicity testing in the 21st century.

Members of SACATM, ICCVAM, and staff from NIEHS and NTP at the September 2016 SACATM meeting

SACATM Membership Roster FY 2016

2016 Annual Report - Scientific and Public Input Opportunities - SACATM

SACATM

64
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

11/30/19

Lauren E. Black, Ph.D.

Senior Scientific Advisor

Navigators Services

Charles River Laboratories

Reno, Nevada

11/30/16

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

Consultant

Eicarte LLC

Gettysburg, Pennsylvania

11/30/15

Joan M. Chapdelaine, Ph.D.

Senior Immunologist and Director, Business

Development

Calvert Laboratories, Inc.

Scott Township, Pennsylvania

11/30/15

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

Research Fellow

La Jolla Laboratories

Pfizer

San Diego, California

11/30/15

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 (Chair)

Executive Director of Lead Discovery

Epizyme, Inc.

Cambridge, Massachusetts

6/30/17

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

11/30/17

Wei Xu, Ph.D.

Associate Professor

Department of Oncology

McArdle Laboratory for Cancer Research

University of Wisconsin at Madison

Madison, Wisconsin

11/30/17

Hao Zhu, Ph.D.

Assistant Professor

Department of Chemistry

Rutgers University at Camden

Camden, New Jersey

11/30/19

65
https://ntp.niehs.nih.gov/go/807186

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

committee meets once or twice a year in closed forum. Members of this committee include the heads, or

their designees, from the following federal agencies:

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

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

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

relevant agency expertise to be brought to bear on NTP issues.

2016 Annual Report - Scientific and Public Input Opportunities - Executive Committee

NTP Executive Committee

66
https://ntp.niehs.nih.gov/go/807192

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 other issues. These panels help ensure transparent, unbiased, and 

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

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

NTP Technical Report Peer Review Panels

NTP Technical Reports are published results of long-term studies, generally two-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 peer reviewing the scientific and technical elements and presentation of the

study, and determining whether the study’s experimental design and conduct support the NTP conclusions 

regarding the carcinogenic activity of the substance tested. There was one technical report meeting in FY 

2016.

NTP convened a meeting on February 16, 2016, to peer review the draft technical report on antimony 

trioxide and the draft technical report on TRIM VX. 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. Yun Xie, Ph.D., 

served as designated federal officer for the meeting.

The meeting was open to the public with time scheduled for oral public comment. The charge to the panel 

was to (1) review and evaluate the scientific and technical elements of the study and its presentation; and 

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

regarding the carcinogenic activity and toxicity of the substance tested. The panel agreed with the NTP 

conclusions in the draft technical reports. Additional information about NTP Technical Report peer review 

meetings can be found on the NTP Technical Reports Peer Review Panels Web page.

NTP Monograph Peer Review Panels

Monographs are publications on a single, detailed specific topic. NTP convened a meeting on July 19, 2016, 

to peer review the draft NTP Monograph on Immunotoxicity Associated with Exposure to Perfluorooctanoic 

Acid (PFOA) or Perfluorooctane Sulfonate (PFOS). The peer review panel included individuals with 

expertise in immunotoxicology, molecular biology, statistics, pharmacokinetics, neurodevelopment, 

endocrine disrupting chemicals, epidemiology, and toxicology. Yun Xie, Ph.D., served as designated federal 

officer for the meeting.

The meeting was open to the public with time scheduled for oral public comment. The charge to the panel 

was to (1) review and evaluate the scientific and technical elements of the study and its presentation; and 

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

regarding whether immunotoxicity is associated with exposure to PFOA or PFOS. The panel agreed with the 

NTP conclusions in the draft monograph. Additional information about NTP monograph peer review 

meetings can be found on the Peer Reviews of Draft Monographs Web page.

2016 Annual Report - Scientific and Public Input Opportunities 

- Special Emphasis Panels

Special Emphasis Panels

67
Report on Carcinogens Peer Review Panels

NTP follows an established, four-part process for preparation of the Report on Carcinogens (RoC). RoC 

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 RoC monographs. These meetings 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 RoC listing status.

On December 17, 2015, NTP convened a panel at NIEHS to peer review the draft RoC monograph on 

selected viruses. The panel voted on the draft level of evidence for carcinogenicity determination, based 

on the available scientific evidence in experimental animals and human cancer studies, and whether the 

information cited in the draft substance profile supported the NTP preliminary listing recommendation in 

the RoC. The review covered the 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. Lori White, Ph.D., served as designated federal 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 and other RoC monograph peer review meetings can be found 

on the Peer Reviews of Report on Carcinogens Monographs Web page.

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. There were no NTP Expert Panel meetings in FY 

2016. Additional information about NTP Expert Panel meetings can be found on the NTP Expert Panels

Web page.

68
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.

2016 Annual Report - Research and Testing

Research and Testing

69
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 2016.

2016 Annual Report - Research and Testing - Tox21

Tox21

70
https://ntp.niehs.nih.gov/go/807110

Prioritize substances for further in-depth toxicological evaluation.

Identify mechanisms of action for further investigation, such as disease-associated pathways.

Develop models that better predict how chemicals will affect biological responses.

Tox21 research is being conducted in three phases. In Phase I, from 2005 to 

2010, the partners at NCGC performed qHTS testing on 2,870 compounds in 140 

assays, representing 77 predominately cell-based qHTS assays. Phase II started 

in 2011 and is ongoing. In this phase, the partners expanded the chemical library 

from Phase I to greater than 10,000 compounds, and are testing these 

compounds at NCATS using a HTS robotics system sponsored by NIEHS/NTP. 

More than 200 databases of chemicals and drugs in the U.S. and abroad were 

analyzed to select the compounds for testing. This chemical library includes 

industrial and consumer products, food additives, drugs, and mixtures.

Tox21 Phase III was initiated in FY 2013 to increase biological diversity and 

relevance of screening activity by (1) focusing on more physiologically relevant in 

vitro cell systems, such as human stem cell-derived differentiated cell populations; 

(2) incorporating cell types, such as HepaRG, in 2-D and 3-D in vitro models that 

incorporate xenobiotic metabolism and allow for longer-term exposures; (3) 

increasing the characterization and use of computational models to predict 

metabolism and toxicity; (4) increasing the testing of compounds in alternative 

animal models such as zebrafish; (5) increasing the use of models that provide 

information concerning the genetic diversity in population responses to exposures; 

and (6) developing and implementing a high throughput transcriptomics platform 

for human, rat, mouse, and zebrafish.

Related Links

▶ Tox21 Projects in 2016

2016 Annual Report - Research and Testing - Tox21 - About Tox21

About Tox21

The Toxicology in the 21st Century (Tox21) program is a federal collaboration 

that uses automated high throughput screening methods to quickly and efficiently 

test chemicals for activity across a battery of assays that target cellular 

processes. These assays are useful for rapidly evaluating large numbers of 

chemicals to provide insight on potential human health effects.

In June 2015, the Memorandum of Understanding for High Throughput 

Screening, Toxicity Pathway Profiling, and Biological Interpretation of Findings

was renewed to support continuation of the Tox21 program.

Through this memorandum, NIEHS/NTP partnered with the NIH Chemical 

Genomics Center (NCGC) part of National Center for Advancing Translational 

Sciences (NCATS), the EPA National Center for Computational Toxicology, and 

FDA, to foster the advancement of toxicology to a more predictive science, based 

on development and implementation of the most relevant and meaningful tools of 

modern molecular biology and chemistry. This partnership makes it possible to 

pool resources and overcome the resource limitations of a single agency, build on 

existing expertise, and avoid the need to create a new administrative and support 

structure.

A central component of the Tox21 memorandum is to explore the use

of quantitative high throughput screening and quantitative high content screening

(qHTS/qHCS) assays; assays using phylogenetically loweranimal species, such 

as fish and worms; as well as high throughput, gene expression, and analytical 

methods to evaluate mechanisms of toxicity. Through Tox21, the partners hope to 

develop, validate, and translate innovative test methods that will better predict how 

chemicals may affect humans and the environment with the intent to use results 

from these methods to:

71
https://ntp.niehs.nih.gov/go/807098

Project & Study Scientist

Developing a stable cell line to screen

compounds that affect the estrogen-related

receptor/peroxisome proliferator-activated

receptor coactivator pathway

Study Scientist: Merrick, Teng

To develop an assay that will 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

LOPAC library were completed and a manuscript is in

press. Quantitative high throughput screening of the 10K

library was completed in FY 2016 and data analysis is

ongoing for a manuscript in preparation.

High content screening with HepaRG cells

Study Scientist: Ferguson, Ramaiahgari

To establish metabolically functional human HepaRG liver

cells in 96-well or 384-well format for carrying out

multiplex, high-content screening assays in collaboration

with the NIH Chemical Genomics Center. In FY 2015, the

focus was on establishing metabolically competent

HepaRG cells grown in 2-D and 3-D formats. Studies to

characterize the metabolism of xenobiotic compounds in

these cells began in FY 2016.

This table describes the NTP Tox21 projects in FY 2016 that are being carried out by NIEHS/NTP staff.

Click the project title for a brief summary.

Assay Development

Project Summary

2016 Annual Report - Research and Testing - Tox21 - Tox21 Projects

Tox21 Projects

Also see:

Tox21 Background

View Research Areas in

Assay Development

Data Analysis

Testing Projects

NTP WormTox Laboratory Projects

Show All

Search Projects

72
Use of high throughput assays and

computational models to replace current EPA

Endocrine Disruptor Screening Program Tier 1

tests

Study Scientist: Casey (NICEATM)

Testing for gene signatures and profiles in NTP

archival tissues project

Study Scientist: Merrick

Stem cell projects

Study Scientist: Ferguson, Parham, Hsieh,

Behl

To determine if RNA can be extracted from fixed tissue 

blocks there were produced from NTP studies and are 

located in the NTP Archives and used to measure gene 

signatures and develop chemically induced 

transcriptomics profiles. The goal is to measure molecular 

changes caused by chemical exposures in different 

organs of the rat and mouse. An effort to establish a 

relational database to allow identification and linkage of all 

tissues in the NTP Archives is underway.

To screen for chemical toxicity in human or mouse stem 

cell lines (undifferentiated or differentiated) by quantitative 

high throughput screening at National Chemical Genomics 

Center, or by using lower throughput assays at NIEHS. 

Initially, the project focuses on fostering collaborations with 

stem cell technology providers and assessing control 

compounds and subsets of NTP chemicals using various 

assay approaches. Stem cell technology platforms and 

model systems shown to be useful for in vitro toxicology 

screening will be employed with larger sets of chemicals 

for hazard identification and chemical prioritization for 

toxicity testing. Data have been generated on a library of 

80 predominantly developmental neurotoxicants evaluated 

for effects on neurite outgrowth in a human stem cellderived 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 analysis has been carried 

out on the data from these assays. Two manuscripts were 

published in February and August 2016.

To develop 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. 

A description of the method has been published.

Project & Study Scientist

Modeling mixtures of androgen receptor-active 

and estrogen receptor-active compounds 

screened in Tox21 quantitative high throughput 

screening (qHTS) assays 

Study Scientist: Parham

To determine (1) which mathematical models can best 

describe the toxicity of mixtures of these compounds; and 

(2) whether the behavior of the mixtures can be predicted

from the behavior of individual components.

Data Analysis

Project Summary

73
Prioritization of Tox21 compounds for

genotoxicity

Study Scientist: Hsieh, Witt, Smith-Roe

Design of Tox21 data exploration graphical

user interface

Study Scientist: Hsieh

Low-dose extrapolation for Tox21 Phase I

quantitative high throughput screening data

Study Scientist: Parham

Unsupervised, data-driven analysis of Tox21

assay data project

Study Scientist: Auerbach

Next generation sequencing in toxicology

project

Study Scientist: Merrick

To develop 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 takes into account compound

potency, efficacy, and data reproducibility. A manuscript

describing this pipeline was published.

To develop a prioritization approach that includes

compounds showing clear evidence of activity in the

quantitative high throughput screening genotoxic assays

and compounds that are weakly active based on chemical

structure-activity relationship analysis. A manuscript is in

preparation using this data.

To develop two graphical user interfaces for viewing

Tox21 data. One graphical user interface is to explore the

concentration-response data in a line chart, and the

second graphical user interface is to explore compound

similarity relationships in terms of their activities in Tox21

quantitative high throughput screening assays and their

chemical structures. Prototype graphical user interfaces

were developed during FY 2013 and made public in FY

2015.

To determine points of departure for low-dose

extrapolation by using signal-to-noise ratios and a

benchmark-dose method. Data generated by this

approach will be used to help prioritize compounds for

more extensive toxicological testing.

To employ unsupervised data analysis methods (data

organization based on patterns and performed by

software) to identify chemicals that exhibit biological

properties similar to those of well-characterized 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.

To develop 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.

Analysis of Tox21 quantitative high 

throughput screening assay data

Study Scientist: Hsieh

74
Development of a reference database for

estrogenic activity

Study Scientist: Casey-NICEATM

In vitro to in vivo extrapolation using Tox21

data

Study Scientist: Casey-NICEATM

Evaluation of Tox21 data for predicting acute

oral toxicity

Study Scientist: Casey-NICEATM

In silico prediction of metabolism project

Study Scientist: Ferguson

To support 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 over 2,660 

different combinations of chemicals, studies, and 

protocols. These data have potential utility for leading to 

development of 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 was published in FY 

2016.

To quantitatively correlate 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 quantitatively correlate in vitro 

and in vivo dosimetry 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.

To determine 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 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.

To evaluate various in silico methods for predicting the 

extent of xenobiotic metabolism, identity metabolites, and 

prioritize chemicals in the Tox21 10K library. 

Computational methods will be used to partition the 10K 

library and develop subsets of chemicals that are likely to 

be appreciably metabolized in humans. The results of 

these predictions are being summarized in a manuscript 

for submission in FY 2016.

75
Selection of a target set of genes for use in a

high throughput transcriptomics screen

Study Scientist: Paules

To identify patterns of exposure-induced biological

responses, in order to characterize toxicity and disease

pathways and facilitate extrapolation of findings from

model species to humans. An effort has been initiated 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, which were 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, mouse, zebrafish, and Caenorhabditis

elegans.

Development of domain-specific quantitative

structure-activity relationship models to predict

estrogen receptor binding and activity

Study Scientist: Casey-NICEATM

To explore whether domain-specific, quantitative,

structure–activity relationship (QSAR) models might

provide improved predictions of activity and potency of

estrogenic activity. Using data from Tox21 and ToxCast

assays, NICEATM is working with scientists at EPA and

the University of North Carolina at Chapel Hill to develop

QSAR models to predict specific activity and relative

potency of phenolic compounds. The domain-specific

models consistently yield higher balanced accuracies,

sensitivity, and specificity than global models. A

manuscript was submitted in FY 2016.

Development of a computational model for

androgen receptor pathway activity

Study Scientist: Casey-NICEATM

To integrate data from nine Tox21 and ToxCast assays

into a computational model that predicts agonist and

antagonist activity against the androgen receptor

pathway. A manuscript is in preparation.

Development of quantitative structure-activity

relationship (QSAR) models to predict

androgen receptor binding and activity

Study Scientist: Casey-NICEATM

To develop quantitative structure-activity relationship

(QSAR) models to predict androgen receptor (AR) binding

and activity. Using the computational model of the AR

pathway, NICEATM developed QSAR models to predict

AR binding and activity. These QSAR models are

currently being refined, with a goal of using them to

predict AR pathway activity of chemicals in the EPA

Endocrine Disruptor Screening Program. A manuscript

was submitted in FY 2016.

Development of a reference database for

androgen receptor activity

Study Scientist: Casey-NICEATM

To develop 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

76
Development of a bioactivity-based readacross approach

Study Scientist: Casey-NICEATM

To use bioactivity data from ToxCast to characterize

untested environmental chemicals based on their

similarities to chemicals with known toxicological effects.

NICEATM used computational 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.

androgen-inactive chemicals. The final database will be

made available to the public on the NTP website. A

parallel EPA data curation effort is focusing 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.

Project & Study Scientist

Analysis of 52 compounds in the EPA ToxCast

Phase II program

Study Scientist: Casey-NICEATM

To screen 52 compounds nominated by NTP, identified

based largely on immunological relevance, in the EPA

ToxCast program. NICEATM used in vitro chemical

profiling data to examine activity profiles in primary human

cell systems and identify predictive signatures anchored

to in vivo endpoints and toxicity pathways. These

analyses will be used (1) to develop adverse outcome

pathways and (2) to enable chemical prioritization and

hazard predictions.

Epigenetic changes in chemical toxicity project

Study Scientist: Merrick

To determine 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, by MBD2 capture

following bisulfite reduction and sequencing, has been

developed, and a manuscript describing the findings was

submitted for publication.

Polycyclic aromatic hydrocarbon (PAH)

Study Scientist: Ferguson

To evaluate approximately 20 PAHs considered relevant

to human exposure in metabolism-competent HepaRG

cells (derived from a human hepatic progenitor cell line),

using multiplexed high content screening assays and

gene expression platforms. Studies are in progress.

Testing Projects

Project Summary

77
Project & Study Scientist

Mitochondrial toxicants project

Study Scientist: Boyd

To determine 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 is in

preparation for publication.

Project Summary

NTP WormTox Laboratory Projects

78
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

A list of substances tested for genetic toxicity.

Organ System Toxicity

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 2016.

Toxicology and Carcinogenicity Studies

A list of prechronic and chronic toxicity and carcinogenicity studies that were initiated, ongoing, 

or completed during FY 2016.

2016 Annual Report - Research and Testing - Testing and Toxicology Studies

Testing and Toxicology Studies

79
Toxicogenomic Studies

A list of planned or ongoing toxicogenomic studies in FY 2016.

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, but were not started during FY 2016.

80
2016 Annual Report Research and Testing https://ntp.niehs.nih.gov/go/807106

Related Links

• Disposition, Metabolism, and

Toxicokinetic Studies

• Genetic Toxicity

• Organ System Toxicity

• Modified One-Generation

Reproduction Studies

• Toxicology and

Carcinogenicity Studies

• Toxicogenomic Studies

• Project Review Committee

Approved

- -

Testing and Toxicology Studies - About Testing and Toxicology

About Testing and Toxicology Studies

The NTP testing program evaluates substances for a variety of healthrelated 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 2016 are listed in this

section. Of note are the multiple study types initiated, scheduled, or

approved for bisphenol S, phenolic benzotriazoles, sodium 

metavanadate, triclocarban, and trimethylsilyldiazomethane.

81
https://ntp.niehs.nih.gov/go/807102

Test Article CASRN* Species Route Status Study

Scientist

Bisphenol S 80-09-1 Mice,

rats Gavage, intravenous Ongoing Sutherland

NButylbenzenesulfonamide 3622-84-2 Mice,

rats Gavage, intravenous Ongoing Rider

Ethylene glycol 2-

ethylhexyl ether 1559-35-9 Mice,rats Gavage Completed Blystone

2-Ethylhexyl pmethoxycinnamate 5466-77-3 Mice,

rats

Dermal, gavage,

intravenous Ongoing McIntyre

Hydroquinone 123-31-9 Mice,

rats

Gavage, intravenous,

topical application Ongoing Sutherland

Nanoscale silver 7440-22-4 Rats Gavage Ongoing Walker

Silver acetate 563-63-3 Rats Gavage Ongoing Walker

Sulfolane 126-33-0 Mice,

rats Gavage, intravenous Ongoing Blystone

Triclocarban 101-20-2 Mice,

rats Dermal, gavage Initiated Sutherland

Triclosan 3380-34-5 Mice Topical application Ongoing Sutherland

Tris(4-

chlorophenyl)methane

27575-78-

6

Mice,

rats Gavage, intravenous Completed Surh

Tris(4-

chlorophenyl)methanol 3010-80-8 Mice,rats Gavage, intravenous Completed Catlin

*CASRN = Chemical Abstracts Service Registry Number

Disposition, Metabolism, and Toxicokinetic Studies

Complete dosimetry of a chemical or physical agent describes its absorption, distribution, metabolism, and

excretion in the body in both humans and test animals at differing levels of exposure, over all ages, via

several routes of exposure, and under varying genetic backgrounds. Substances evaluated during FY 2016

are listed in the table below.

Disposition, Metabolism, and Toxicokinetics Studies During FY 2016

2016 Annual Report - Research and Testing - Testing and Toxicology Studies - ADME

82
2016 Annual Report Research and Testing

Testing and Toxicology Studies Genetic Toxicity

https://ntp.niehs.nih.gov/go/807136

Genetic toxicity test results are used to help interpret general toxicity, carcinogenicity, or other in vivo test

results, and provide a database for use in structure-activity relationship analysis. Substances tested for

genetic toxicity during FY 2016 are listed in the table below.

Genetic Toxicity Studies During FY 2016

Test Article CASRN* Species Testing Battery Status

Aspergillus fumigatus mold N/A Mice Micronucleus Completed

Black cohosh 84776-26- 1 Salmonella Salmonella Completed

N-Butyl glycidyl ether 2426-08-6 Mice Micronucleus Ongoing

N-Butyl glycidyl ether 2426-08-6 Rats Micronucleus Ongoing

N-Butylpyridinium chloride 1124-64-7 Rats Micronucleus Completed

Corn oil 8001-30-7 Rats Micronucleus Completed

2,2'-Dimorpholinodiethyl

ether 6425-39-4 Salmonella Salmonella Ongoing

Echinacea purpurea extract 90028-20-9 Salmonella Salmonella Completed

Echinacea purpurea extract 90028-20-9 Salmonella Salmonella Completed

Echinacea purpurea extract 90028-20-9 Salmonella Salmonella Completed

Echinacea purpurea extract 90028-20-9 Salmonella Salmonella Completed

Echinacea purpurea extract 90028-20-9 Salmonella Salmonella Completed

Echinacea purpurea extract 90028-20-9 Salmonella Salmonella Completed

Echinacea purpurea extract 90028-20-9 Salmonella Salmonella Completed

Echinacea purpurea extract 90028-20-9 Salmonella Salmonella Completed

Genetic Toxicity

- -

-

83
2-Nitro-2-ethyl-1,3-propanediol 597-09-1 Salmonella Salmonella Completed

Perfluorodecanoic acid 335-76-2 Rats Micronucleus Completed

Sulfolane 126-33-0 Rats Micronucleus Ongoing

Sulfolane 126-33-0 Mice Micronucleus Ongoing

Vinpocetine 42971-09-5 Mice Micronucleus Ongoing

Vinpocetine 42971-09-5 Mice Micronucleus Ongoing

Zinc carbonate, basic 5263-02-5 Rats Micronucleus Completed

Zinc carbonate, basic 5263-02-5 Rats Micronucleus Completed

Zinc carbonate, basic 5263-02-5 Rats Micronucleus Completed

Zinc carbonate, basic 5263-02-5 Rats Micronucleus Completed

*CASRN = Chemical Abstracts Service Registry Number

84
2016 Annual Report Research and Testing Testing and Toxicology Studies

Organ System Tox

https://ntp.niehs.nih.gov/go/807130

NTP studies toxicity of environmental substances on organ systems for development, reproduction, and the 

immune system. NTP immunotoxicity studies address adverse effects on the immune system that may result from

exposure to environmental chemicals, biological materials, or therapeutic agents. Identifying substances with the

potential to alter immune system function is critical to the public health field as these substances may lead to

increased incidence of hypersensitivity disorders, autoimmune disease, infectious disease, or neoplasia. The table

below lists organ systems toxicity studies during FY 2016.

Neurotoxicity, Developmental Toxicity, and Reproductive Toxicity Studies During FY 2016

Test Article CASRN* Species Testing Battery Length Route Status Study

Scientist

Acrylamide 79-06-1 Rats Neurotoxicology

assessment

Phase 1: 3 

and 6 months;

phase 2:12

and 24 months

Gavage Ongoing Beland

Autumn sunset true color

concentrate N/A Mice Immunotoxicity 6 days Subcutaneousinjection Ongoing Howard

Benzo(a)pyrene 50-32-8 Mice Immunotoxicity 28 days Gavage Ongoing Rider

Bisphenol AF 1478-61-1 Rats Immunotoxicity GD 6 - PND 96 Dosed-feed Initiated Sutherland

Dibenz(a,h)anthracene 53-70-3 Mice Immunotoxicity 8 GD - PND 42 Subcutaneous

injection Ongoing Germolec

Diethylene glycol dimethyl

ether

111-96-6 Mice Conventional

teratology

11 GD

(PLUG=GD0) Gavage Ongoing Hardin

Dimethylethanolamine 108-01-0 Rats Conventional

teratology GD 6 to GD 20 Gavage Completed McIntyre

Double dark fudge true color

concentrate N/A Mice Immunotoxicity 7 days Subcutaneousinjection Ongoing Howard

Double fudge concentrate N/A Mice Immunotoxicity 8 days Subcutaneous

injection Ongoing Howard

Efavirenz 154598-52-4 Mice Teratology pilot

studies GD 5 - PND 21 Gavage Ongoing McIntyre

Ethylene oxide 75-21-8 Rabbit Conventional

teratology

7 to 19 GD or

1 to 19 GD Inhalation Ongoing Hardin

2-Hydroxy-4-

methoxybenzophenone

131-57-7 Rats Developmental

toxicity GD 6 to GD 15 Dosed-feed Ongoing Hansen

2-Hydroxy-4-

methoxybenzophenone

131-57-7 Rats Developmental

toxicity GD 6 to GD 15 Dosed-feed Ongoing Hansen

2-Hydroxy-4-

methoxybenzophenone

131-57-7 Rats Developmental

toxicity GD 6 to PND 21 Dosed-feed Ongoing Hansen

4-Methylcyclohexanemethanol 34885-03-5 Mice Immunotoxicity 7 days Topical

application Completed Auerbach

Organ System Toxicity

- - -

85
4-Methylcyclohexanemethanol,

crude

N/A Mice Immunotoxicity 7 days Topical 

application

Completed Auerbach

4-Methylcyclohexanemethanol,

crude N/A Mice Immunotoxicity 7 days Topical 

application Completed Auerbach

Nonylphenol 84852-15-3 Rats Multigenerational

screen 20 weeks Dosed-feed Ongoing Newbold,Delclos

Phenanthrene 85-01-8 Mice Immunotoxicity 28 days Gavage Ongoing Rider

Pyrene 129-00-0 Mice Immunotoxicity 28 days Gavage Initiated Germolec

Rosewood true color

concentrate N/A Mice Immunotoxicity 6 days Subcutaneous 

injection Ongoing Howard

Sodium metavanadate 13718-26-8 Mice Immunotoxicity 28 days Dosed-water Initiated Roberts

Sulfolane 126-33-0 Mice Immunotoxicity 13 weeks Gavage Ongoing Blystone

Sulfolane 126-33-0 Rats Immunotoxicity 13 weeks Gavage Ongoing Blystone

Tenofovir disoproxil 

Fumarate 202138-50-9 Mice Teratology pilot

studies GD 5 - PND 21 Gavage Initiated McIntyre

Tricombination

FTC:TDF:EFV (1:1.5:3) N/A Mice Maternal transfer GD 5-15 Gavage Initiated McIntyre

Tricombination

FTC:TDF:EFV (1:1.5:3) N/A Mice Teratology pilotstudies GD 5 - GD18 Gavage Initiated McIntyre

Vinpocetine 42971-09-5 Rats Conventional 

teratology GD 6 to GD 20 Gavage Completed Catlin

Vinpocetine 42971-09-5 Rabbit Conventional

teratology GD 7 to GD 28 Gavage Completed Catlin

Vinyl toluene 2501315-4 Rats Dominant lethal 5 consecutive 

days

Intraperitoneal 

injection Ongoing Boorman

*CASRN = Chemical Abstracts Service Registry Number

**GD = gestational day

***PND = postnatal day

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2016 Annual Report Research and Testing Testing and Toxicology Studies

Modified One-Generation

https://ntp.niehs.nih.gov/go/807088

NTP modified one-generation study design emphasizes a full evaluation of the first generation offspring 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. The table below

lists planned or ongoing modified one-generation studies.

Modified One-Generation Studies in FY 2016

Test Article CASRN* Species Planned

Cohorts Route Status StudyScientist

2,2'-Dimorpholinodiethyl ether 6425-39-4 Rats Repeated dose Gavage Initiated Roberts

Ethylene glycol 2-ethylhexyl ether 1559-35-9 Rats Dose range finding Gavage Initiated Blystone

Isopropylated phenol phosphate 68937-41-7 Rats Dosedfeed Ongoing Behl

Resveratrol 501-36-0 Rats F0 generation Gavage Ongoing Germolec

Simvastatin 79902-63-9 Rats Gavage Ongoing McIntyre

Triphenyl phosphate 115-86-6 Rats Dosedfeed Ongoing Behl

Valerian (Valeriana officinalis L.)

root extract 8057-49-6 Rats Gavage Ongoing Roberts

*CASRN = Chemical Abstracts Service Registry Number

[1] Dose range-finding: to find the ideal dose for toxicological studies.

Modified One-Generation Reproduction Studies

- - -

Dose range finding

Dose range finding

Dose range finding

Dose range finding

87
https://ntp.niehs.nih.gov/go/807079

NTP performs toxicity studies to provide dose-setting information for chronic studies and address specific deficiencies in the toxicology 

database for the chemical. Toxicology and carcinogenicity studies fall into two categories: prechronic toxicity studies and chronic twoyear 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 Toxic and Carcinogenic Potential of Chemical, Biological, and Physical 

Agents in Laboratory Animals for the National Toxicology Program (January 2011). The tables below list prechronic and chronic toxicity 

studies and carcinogenicity studies, that were initiated, ongoing, or completed during FY 2016.

Prechronic Toxicology and Carcinogenicity Studies FY 2016

Test Article CASRN* Species Length Route Status Study

Scientist

1020 Long multiwalled carbon nanotube N/A Mice,rats 30 days Inhalation Initiated Morgan

2-Ethylhexyl diphenyl

phosphate 1241-94-7 Rats 5 days Gavage Ongoing Auerbach

2-Ethyltoluene 611-14-3 14 days Inhalation Initiated Roberts

2,2'-Dimorpholinodiethyl ether 6425-39-4 Mice 28 days Gavage Initiated Roberts

2,2',4,4'-Tetrabromodiphenyl ether 5436-43-1 Rats GD 6 to

PND 21 Gavage Ongoing Dunnick

3-Ethyltoluene 620-14-4 14 days Inhalation Initiated Roberts

3,3,4,4,5-Pentachlorobiphenyl 57465-28-8 Rats GD 6 to

PND 21 Gavage Ongoing Dunnick

4-Ethyltoluene 14 days Inhalation Ongoing Roberts

4-Methylcyclohexanemethanol 34885- 03-5 Rats 5 days Gavage Completed Auerbach

5-Amino-o-cresol 2835-95-2 13 weeks Topical

Application Completed Dunnick

Aloin 1415-73-2 Rats 13 weeks Dosed-Water Ongoing Boudreau

alpha-Pinene 80-56-8 14 days Inhalation Completed Rider

alpha-Pinene 80-56-8 13 weeks Inhalation Completed Rider

Aspergillus versicolor mold N/A Mice 13 weeks Inhalation Completed Germolec

Bis(2-Chloroethoxy)methane 111-91-1 Mice 10 days,

3 days Gavage Ongoing Dunnick

Black cohosh 84776- 26- 1 Mice 90 days Gavage Ongoing Cora

4-Methylcyclohexanemethanol, crude N/A Rats 5 days Gavage Completed Auerbach

Cumene 98-82-8 14 days Inhalation Ongoing Roberts

Dimethylamine borane 74-94-2 2 weeks Dermal Ongoing Germolec

Ephedrine + caffeine 

combination N/A Mice 10 days,

3 days Gavage Ongoing Dunnick

Formaldehyde 50-00-0 Mice 2 weeks Inhalation Ongoing Morgan

Formaldehyde 50-00-0 Mice 8 weeks Inhalation Ongoing Morgan

Fumonisin B1 116355-83-0 13 weeks Dosed-Feed Ongoing Walters

Toxicology and Carcinogenicity Studies

2016 Annual Report - Research and Testing - Testing and Toxicology Studies - 

Toxicology and Carcinogenicity Studies

Mice,rats

Mice,rats

622-96-8 Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

88
Garcinia cambogia extract 90045-23-1 14 days Dosed-Feed Completed Rider

Ginkgo biloba extract 90045-36-6 Rats 5 days Gavage Initiated Rider

Goldenseal extract 84603-60-1 Rats 5 days Gavage Initiated Rider

Green tea extract N/A Rats 5 days Gavage Initiated Rider

Green tea extract N/A 13 weeks Gavage Completed Blystone

Hydroxyurea 127-07-1 14 days,

13 weeks

Intraperitoneal

Injection Ongoing Ryan

Ionic Liquid: 1-butyl-1-

methylpyrrolidinium chloride 479500-35-1 90 days Dosed-Water Ongoing Ryan

Ionic Liquid: 1-butyl-3-

methylimidazolium chloride

79917-90-1 90 days Dosed-Water Ongoing Ryan

Ionic Liquid: 1-ethyl-3-

methylimidazolium chloride 65039-09-0 90 days Dosed-Water Ongoing Ryan

Ionic Liquid: N-butylpyridinium chloride 1124-64-7 90 days Dosed-Water Ongoing Ryan

Isodecyl diphenyl phosphate 29761-21-5 Rats 5 days Gavage Ongoing Auerbach

Isopropylated phenol 

phosphate 68937-41-7 Mice 2 weeks Dosed-Feed Ongoing Behl

Isopropylated phenol 

phosphate

68937-41-7 Rats 5 days Gavage Ongoing Auerbach

Melamine + cyanuric acid 

combination N/A Rats 90 days Gavage Ongoing Gamboa

Melamine + cyanuric acid 

combination N/A Rats 90 days Gavage Ongoing Gamboa

Melamine + cyanuric acid 

combination N/A Rats 90 days +recovery

Gavage Initiated Gamboa

TRIM VX N/A 13 weeks Inhalation Ongoing Ryan

Microbiome N/A N/A 14 days N/A Ongoing Cerniglia

N-Butylbenzenesulfonamide 3622- 84- 2 Mice 14 days Dosed-Feed Ongoing Rider

N,N-Dimethyl-p-toluidine 99-97-8 Rats 5 days Gavage Ongoing Dunnick

Nanoscale silver 7440- 22- 4 Rats 13 weeks Gavage Ongoing Boudreau

p-Toluidine 106-49-0 Rats 5 days Gavage Ongoing Dunnick

Pentabromodiphenyl ether mixture 

[DE-71 (Technical Grade)] 32534-81-9 13 weeks Gavage Completed Dunnick

Pentabromodiphenyl ether mixture 

[DE-71 (Technical Grade)] 32534-81-9 Rats GD 6 to

PND 21 Gavage Ongoing Dunnick

Pentachlorophenol, purified 87-86-5 Mice 4 weeks Dosed-Feed Ongoing Goldstein

Perfluorohexane sulfonate potassium 

salt 3871-99-6 Rats 28 days Gavage Ongoing Blystone

Perfluorohexanoic acid 307-24-4 Rats 28 days Gavage Ongoing Blystone

Perfluorooctanoic acid 335-67-1 Rats 28 days Gavage Ongoing Blystone

Phenolic benzotriazoles (2-(2Hbenzotriazol-2-yl)-4,6-bis(1-methyl-1-

phenylethyl)phenol)

70321-86-7 Rats 14 days Gavage Initiated Blystone

Phenolic benzotriazoles (2-(2Hbenzotriazol-2-yl)-4-tert-butylphenol) 3147-76-0 Rats 14 days Gavage Initiated Blystone

Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

89
Phenolic benzotriazoles (2-(2Hbenzotriazol-2-yl)-4,6-bis(1,1-

dimethylpropyl)phenol)

25973-55-1 Rats 14 days Gavage Initiated Blystone

Phenolic benzotriazoles (2-(2Hbenzotriazol-2-yl)phenol) 10096-91-0 Rats 14 days Gavage Initiated Blystone

Phenolic benzotriazoles (2-(5-chloro-2Hbenzotriazol-2-yl)-4,6-bis(1,1-

dimethylethyl)phenol)

3864-99-1 Rats 14 days Gavage Initiated Blystone

Phenolic benzotriazoles (3-(2Hbenzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-

hydroxybenzenepropanoic acid, octyl ester)

84268-23-5 Rats 14 days Gavage Initiated Blystone

Phenolic benzotriazoles 

(bumetrizole) 3896-11-5 Rats 14 days Gavage Initiated Blystone

Phenolic benzotriazoles 

(drometrizole) 2440-22-4 Rats 14 days Gavage Initiated Blystone

Phenolic benzotriazoles (octrizole) 3147-75-9 Rats 14 days Gavage Initiated Blystone

Propylene glycol phenyl ether 770-35-4 Rats 5 days Gavage Completed Auerbach

Sodium metavanadate 13718-26-8 90 days Dosed-Water Initiated Roberts

Sodium thioglycolate 367-51-1 2 weeks Topical

Application Completed Mercado-Feliciano

Sodium thioglycolate 367-51-1 13 weeks Topical

Application Completed Mercado-Feliciano

tert-Butylphenyl diphenyl phosphate 56803-37-3 Rats 5 days Gavage Ongoing Auerbach

Tetrabromobisphenol A 79-94-7 Rats 13 weeks Gavage Ongoing Dunnick

Triclosan 3380-34-5 Mice 90 days Dermal Ongoing Fang

Tricresyl phosphate 1330-78-5 Rats 5 days Gavage Ongoing Auerbach

Trimethylsilyldiazomethane 18107-18-1 10 days Inhalation Initiated Gwinn

Triphenyl phosphate 115-86-6 Mice 2 weeks Dosed-Feed Ongoing Behl

Usnea lichen N/A 2 weeks Dosed-Feed Ongoing Leakey

(+)-Usnic acid 7562-61-0 2 weeks Dosed-Feed Ongoing Leakey

(+)-Usnic acid 7562-61-0 90 days Dosed-Feed Ongoing Leakey

Valerian (Valeriana officinalis L.) root 

extract 8057-49-6 Mice 90 days Gavage Ongoing Roberts

Vanadyl sulfate 27774-13-6 90 days Dosed-Water Initiated Roberts

Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

Mice,rats

90
alpha-Pinene 80-56-8 Mice, rats 2 years Inhalation Ongoing Rider

Antimony trioxide 1309-64-4 Mice, rats 2 years Inhalation Ongoing Stout

AZT drug combinations,

transplacental/carcinogenesis study N/A Mice 2 years In utero Ongoing Beland

AZT drug combinations, transplacental/neonatal

study N/A Mice 2 years Gavage Ongoing Beland

Bisphenol A 80-05-7 Rats 2-years Gavage Ongoing Delclos

Black cohosh 84776-26-1 Mice, rats 2 years Gavage Ongoing Blystone

1,3-Butadiene 106-99-0 Mice 2 years Inhalation Ongoing Bucher

2,3-Butanedione 5263-02-5 Rats 2 years Dosed-feed Ongoing Catlin

2,3-Butanedione 335-67-1 Rats 2 years Dosed-feed Ongoing Blystone

2,3-Butanedione 431-03-8 Mice, rats 2 years Inhalation Ongoing Morgan

Cell phone radiation: code division multiple

access N/A Mice, rats 2 years Whole bodyexposure Ongoing Wyde

Cell phone radiation: global system for mobile

communication N/A Mice, rats 2 years Whole bodyexposure Ongoing Wyde

Di(2-ethylhexyl) phthalate 117-81-7 Rats Perinatal

+ 2 years Dosed-feed Ongoing Foster

Di(2-ethylhexyl) phthalate 117-81-7 Rats 2 years Dosed-feed Ongoing Foster

Dibutyl phthalate 84-74-2 Mice, rats 2 years Dosed-feed Ongoing Blystone

Furan 110-00-9 Rats 2 years Gavage Ongoing Beland

2-Hydroxy-4-methoxybenzophenone 131-57-7 Mice, rats 2 years Dosed-feed Ongoing McIntyre

Insertional mutagenesis, definitive vector study N/A Mice 14 months Intravenous Ongoing Germolec

1020 Long multiwalled carbon nanotube N/A Mice, rats 2 years Inhalation Initiated Morgan

TRIM VX N/A Mice, rats 2 years Inhalation Ongoing Ryan

Nitrofurazone 59-87-0 Mice 2 years Dosed-feed Ongoing Davis

p-Chloro-a,a,a-trifluorotoluene 98-56-6 Mice, rats 2 years Inhalation Ongoing Stout

Perfluorooctanoic acid 335-67-1 Rats 2 years Dosed-feed Ongoing Blystone

Resveratrol 501-36-0 Mice, rats 2 years Gavage Ongoing Germolec

Sodium fluoride 7681-49-4 Rats 2 years Dosed-water Ongoing Irwin

Sodium tungstate dihydrate 10213-10-2 Mice, rats 2 years Dosed-water Ongoing Behl

Sulfolane 126-33-0 Mice, rats 2 years Dosed-water Ongoing Blystone

Triclosan 3380-34-5 Mice 2 years Dermal Ongoing Fang

Tris(chloropropyl)phosphate 13674-84-5 Mice, rats 2 years Dosed-feed Ongoing Ryan

*CASRN = Chemical Abstracts Service Registry Number

**GD: gestational day

***PND: postnatal day

Chronic Toxicity and Carcinogenicity Studies Ongoing During FY 2016

Test Article CASRN* Species Length Routes Status Study

Scientist

Aging cohort study, mouse strains:

129S1/SvImJ

B6C3F1 (Jackson)

C3H/HeJ

C57BL/6J (Jackson) 

CAST/EiJ (M. m. castaneus) 

NZO/HiLtJ

PWK/PhJ

WSB/EiJ (M. m. domesticus) 

A/J

NOD. B10Sn-H2(b)/J

N/A Mice 2 years N/A Ongoing Dunnick

91
2016 Annual Report Research and Testing Testing and Toxicology Studies

Toxicogenomics

https://ntp.niehs.nih.gov/go/807118

NTP is incorporating the latest toxicogenomic technologies into its testing program to gain further insight regarding

the toxicity of environmental substances. Toxicogenomics examines how the entire genetic structure, or genome,

is involved in an organism's response to environmental toxicants. Microarray, next-generation (NextGen)

sequencing, proteomics, and metabolomics are among the advanced technologies that NTP is using to study the

way chemical exposures change the expression of genes, proteins, and metabolites in critical cells and tissues.

Measuring genome-wide changes in affected tissues may be useful for identifying biomarkers of disease or

exposure to toxic substances, and for understanding individual genetic susceptibilities. Once biomarkers are

validated, they can be repeatedly sampled during long-term NTP studies to determine whether chemical

exposures can be detected, or whether developing cancers provide a genetic signature.

NTP is researching whether gene expression pattern analysis can provide indicators of toxicity (1) at earlier time

points and (2) at lower doses than is possible for traditional toxicology parameters. Evaluating patterns of gene

expression may provide more than just a link between genetics and morphology. It is also expected to provide

insights into the pathogenesis of the disease and how different rodent models respond to toxicants. In addition,

metabolomics represents a promising area of study, as it can elucidate how chemicals affect metabolism within

cells relative to changes in gene expression.

Several FY 2016 toxicogenomic studies used NextGen sequencing technologies, which provided improvements to

gene expression analysis, including base-pair level resolution of accuracy and increased sensitivity compared to

microarray platforms. While microarrays are a stable and well understood technology for assaying gene 

expression, NextGen sequencing methods like RNA-Seq will likely become more common as sequencing costs

drop and bioinformatic pipelines become standardized and integrated with genomic sequencing. A promising area

of research is the use of exome sequencing (Exome-Seq) that can be applied 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 mutations; indels, which are insertions or deletions; and other genetic abnormalities associated with

disease. Three NTP studies are using Exome-Seq as a means for mutation profiling at a genome-wide scale to

understand differences between spontaneous and chemically induced tumors.

NTP is evaluating study conditions that may 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 have been made to optimize methods for DNA and RNA extraction from archival tissues for

molecular analysis. FY 2016 planned or ongoing NTP toxicogenomic studies are listed in the table below.

Toxicogenomic Studies Planned or Ongoing in FY 2016

Chemical CASRN* Species/

Cell Line Route Length Test Type(Platform) Study Scientist

Aging cohort study, mouse strains:

129S1/SvImJ B6C3F1 

(Jackson) C3H/HeJ

C57BL/6J (Jackson) 

CAST/EiJ (M. m.

castaneus)

NZO/HiLtJ

PWK/PhJ

WSB/EiJ (M. m.

domesticus)

A/J

NOD. B10Sn-H2(b)/J

N/A Mice N/A 2 years

NextGen

sequencing

Exome-Seq

(Illumina)

Dunnick

Toxicogenomic Studies

- - -

92
Arsenite 7784-

46-5

Human

prostate

cell lines

In vitro

exposure

30

weeks

NextGen

sequencing

Exome-Seq

(Illumina)

Merrick

2,3-butanedione (diacetyl)

2,3-hexanedione

431-03-8

3848-24-6

Human

airway

epithelium

cell line

In vitro

exposure 4 days High

throughput

transcriptomics

Gwinn

Bisphenol A and BPA

Analogs 80-05-7

Human

hepatocyte

cell line

In vitro

exposure 2 days

High

throughput

transcriptomics

Devito

Bromodichloroacetic acid

Methyleugenol***

5589-96-8

93-15-2 Mice Gavage 2 years

NextGen

sequencing

Exome-Seq

(Illumina)

Pandiri

DE-71

PCB-126

Phenobarbital***

32534-81-9

57465-28-2

50-06-6

Rats Gavage GD** to

PND 22

Microarray

(Affymetrix) Dunnick

Phosphate flame retardants:

tert-Butylphenyl

diphenyl phosphate 

2-Ethylhexyl diphenyl

phosphate

Isodecyl diphenyl

phosphate 

Isopropylated phenol

phosphate

56803-37-3

1241-94-7

29761-21-5

68937-41-7

Rats Gavage 5 days

Microarray

(Affymetrix)

Metabolomics

Auerbach

Ginkgo biloba extract 90045-

36-6 Rats Gavage 5 days Microarray

(Affymetrix) Rider/ Auerbach

induced Pluripotent Stem

Cells

Embryoid bodies

Embryonic stem cells

N/A Human N/A N/A

High

throughput

transcriptomics

Tokar/Devito

Harlan Sprague-Dawley

rats N/A Rats N/A 2 years Targetedresequencing Pandiri/Kovi

2-Hydroxy-4-

methoxybenzophenone

131-57-

7 Rats Feed 90

days

Microarray

(Affymetrix) Auerbach

Methyleugenol extract

Ginkgo biloba extract***

93-15-2

90045-

36-6

Mice Gavage 2 years

NextGen

sequencing

Exome-Seq

RNA-Seq

(Illumina)

Pandiri/Auerbach/Merrick

93
2,3-Pentanedione 600-14-

6 Rats Inhalation

14 and

28

days

microRNA

Microarray

(Affymetrix)

Morgan

Polycyclic aromatic

compounds:

Acenaphthenequinone

Benzo[b]fluoranthene

Benzo(a)pyrene

Dibenz[a,h]anthracene

9-Methylanthracene

1-Methylfluorene

Perinaphthenone

Phenanthrene

Pyrene

82-86-0

205-99-2

50-32-8

53-70-3

779-02-2

1730-37-6

548-39-0

85-01-8

129-00-0

Human

hepatocyte

cell line

In vitro

exposure

48

hours

Cytotoxicity

Gene

expression by

quantitative

polymerase

chain reaction

(qPCR)

Rider/ Tokar

BDE Toxicogenomics

Studies:

2,2’,4,4’,5-

Pentabromodiphenyl 

ethers 

Pentabromodiphenyl

oxide (technical) (DE-71)

3,3,4,4,5-

Pentachlorobiphenyl 

2,2'4,4'-

Tetrabromodiphenyl 

ether (DE-47)

5436-43-1

32534-81- 9

57465-28-8

5436-43-1

Rats, Mice Gavage

GD** 6

through

3 weeks

Microarray

(Affymetrix) Dunnick

Tetrabromobisphenol A 79-94-7 Rats Gavage 90

days

Microarray

(Affymetrix) Dunnick/ Merrick

Tetrabromobisphenol A

BDE-47

Pentabromodiphenyl

oxide-technical (DE-71)

79-94-7

5436-

43-1

32534-

81-9

Rats Gavage

GD** 6

through

3

weeks

Microarray

(Affymetrix) Pandiri/Kovi

Tetrabromobisphenol A

79-94-7

32534-

In vitro 

exposure

Pentabromodiphenyl

oxide-technical (DE-71)

Triclosan

alpha, beta-Thujone

81-9

3380-

34-5

76231-

76-0

Rats Gavage 5 days

High

throughput

transcriptomics

Devito/Gwinn

112-Chemical compound 

test set; pharmaceuticals 

and environmental 

compounds

*

N/A

High 

throughput 

transcriptomics 

* Chemical Abstracts Service Registry Number

**GD: gestational day

*** This study will compare toxicogenomic effects among the chemicals listed together.

Human 

hepatocyte 

cell lineHEPARG

Ferguson/Ramaiahgari

2 days 

94
2016 Annual Report Research and Testing

Testing and Toxicology Studies Project Review Committee

https://ntp.niehs.nih.gov/go/807082

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 2016.

Protocol Title Study Scientist

Developmental immunotoxicology evaluation of bisphenol AF in harlan

sprague dawley rats exposed via dosed feed

Germolec/Sutherland

Three-month toxicity studies of 1,2,4-trimethylbenzene in harlan

sprague dawley rats (after prenatal exposure, including selected

reproductive, developmental, and neurotoxicity endpoints) and

B6C3F1/N mice exposed via whole body inhalation

Roberts

Developmental immunotoxicity evaluation of tris(chloropropyl)

phosphate (TCPP) in harlan sprague dawley rats exposed via dosed

feed

Germolec/Ryan

Subchronic toxicity of sodium metavanadate and vanadyl sulfate in

harlan sprague dawley rats (after perinatal exposure) and B6C3F1/N

mice exposed via dosed drinking water

Roberts

Immunotoxicology screening study of Echinacea purpurea root extract

in female harlan sprague dawley rats exposed via oral gavage

Ryan

Toxicokinetic studies of phenolic benzotriazole class chemicals

(PBTZs) in male harlan sprague dawley rats via gavage and

intravenous administration

Waidyanatha/Blystone

Immunotoxicology screening study of sodium metavanadate in female

B6C3F1/N mice exposed via drinking water

Roberts

Prenatal developmental dose range-finding toxicity study of the fixeddose ratio tri-combination (1:1.5:3) of emtricitabine, tenofovir disoproxil

fumarate, and efavirenz in CD-1 mice exposed via gavage

McIntyre

Preliminary toxicokinetic investigation in pregnant CD-1 mice treated via

gavage with either emtricitabine, tenofovir disoproxil fumarate,

efavirenz; or the fixed-dose ratio tricombination (1:1.5:3)

McIntyre

Immunological evaluation of acenaphthenequinone, dibenzothiophene,

and pyrene in B6C3F1/N mice treated for 28 days via gavage:

polycyclic aromatic hydrocarbon mixtures assessment program (PACMAP) studies

Germolec/Rider

Absorption, distribution, metabolism, and excretion (ADME) of

triclocarban in harlan sprague dawley rats and B6C3F1/N mice

following gavage, intravenous administration, and dermal application of

Waidyanatha/Sutherland

Project Review Committee Approved

- -

-

95
[14C]triclocarban

Toxicokinetic studies of bisphenol S in harlan sprague dawley rats and

B6C3F1/N mice following gavage, intravenous, and feed exposure

Waidyanatha/Sutherland

Prenatal toxicity study of 2-{[1-(4-phenoxyphenoxy)propan-2-

yl]oxy}pyridine in harlan sprague dawley rats exposed via gavage

McIntyre

Immunotoxicity of

2--{[1--(4--phenoxyphenoxy)propan--2--yl]oxy}pyridine in sprague

dawley rats exposed via gavage

Germolec

Perinatal dose range-finding study of thallium sulfate in sprague dawley

rats and 14-day toxicity study of thallium sulfate in B6C3F1/N mice

exposed via dosed drinking water

Shipkowski

Immunotoxicity of N-butylbenzenesulfonamide in B6C3F1/N mice

exposed for 28 days via dosed feed

Frawley/Rider

96
About 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.

NICEATM Workshops

A summary of workshops held or supported by NICEATM in FY 2016.

NICEATM Support of Tox21

A description of Tox21 projects NICEATM supported in FY 2016.

Additional NICEATM Activities

A summary of other activities NICEATM has conducted and participated in during FY 2016.

2016 Annual Report - Research and Testing - NICEATM

NICEATM

97
https://ntp.niehs.nih.gov/go/807072

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 their website and other

communications, and by organizing workshops and symposia on

topics of interest.

Coordinating and providing logistical support for the Interagency

Coordinating Committee on the Validation of Alternative Methods

(ICCVAM) committee 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 2016 NICEATM Workshops

NICEATM Support of Tox21

Additional NICEATM Activities

Related Links

• Activities and Resources

• Publications

• Reports

2016 Annual Report - Research and Testing - NICEATM - NICEATM

About NICEATM

The NTP Interagency Center for the Evaluation of Alternative 

Toxicological Methods, 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. NICEATM 

activities include the following:

98
https://ntp.niehs.nih.gov/go/807092

NICEATM Support of Tox21

Additional NICEATM Activities

About NICEATM

NICEATM Workshops

In Vitro to In Vivo Extrapolation for High Throughput Prioritization

and Decision Making Workshop

NICEATM and the U.S. Environmental Protection Agency (EPA) 

presented a webinar series on In Vitro to In Vivo Extrapolation for High

Throughput Prioritization and Decision Making. The four webinars, 

presented monthly from October 2015 through January 2016, reviewed 

the current science on the use of in vitro data to predict in vivo 

outcomes of chemical safety testing.

The webinars provided background information for a workshop held on 

February 17-18, 2016 at the EPA in Research Triangle Park, NC. 

Workshop participants reviewed the state of the science to form 

recommendations on best practices for using in vitro to in vivo 

extrapolation in chemical screening and risk-based decision-making. 

They also identified areas needing additional data or research, and 

highlighted examples of how best to apply in vitro to in vivo 

extrapolation in risk-based decision-making strategies.

Presentations from the workshop and webinar series are available on 

the NTP website . A report from the workshop will be submitted for 

publication in FY 2017.

Acute Inhalation Toxicity Webinar Series

NICEATM and the People for the Ethical Treatment of Animals 

International Science Consortium co-hosted a webinar series on 

Alternative Approaches for Acute Inhalation Toxicity to Address Global 

Regulatory and Non-regulatory Data Requirements. The six webinars, 

held from March to September 2016, explored alternative approaches

that could replace, reduce, or refine the use of animals for identifying 

chemicals that may cause acute systemic toxicity when inhaled. Slides 

from the webinars are posted on the NTP website.

Related Annual Report Pages:

2016 Annual Report - Research and Testing - NICEATM - NICEATM Workshops

99
https://ntp.niehs.nih.gov/go/807076

NICEATM Support of Tox21

2016 Annual Report - Research and Testing - NICEATM - 

NICEATM Support of Tox21

NICEATM will make curated data from Tox21 and the U.S. Environmental Protection Agency 

ToxCast program available through its Integrated Chemical Environment resource to be 

launched in FY 2017. Future resource development plans include the addition of tools such 

as in vitro to in vivo extrapolation workflows.

The Tox21 and the U.S. Environmental Protection Agency’s (EPA) ToxCast programs are 

investigating the use of the zebrafish model as a screening tool for hazard identification. A 

Collaborative Workshop on Aquatic Models and 21st Century Toxicology identified the lack 

of standardized husbandry and testing protocols as a challenge to broader use. These 

issues will be addressed by the NTP Systematic Evaluation of the Application of Zebrafish in 

Toxicology initiative supported by NICEATM.

Using the collective results of 16 Tox21 and ToxCast estrogen receptor pathway related 

assays, NICEATM developed and applied one-compartment or physiologically based 

pharmacokinetic models to a workflow that quantitatively correlates in vitro and in vivo 

dosimetry for estrogen receptor reference chemicals. The approach highlighted the 

importance of pharmacokinetic considerations in assessing and ranking endocrine-active 

chemicals based on in vitro high throughput screening assays. This work is described in 

several publications. The first version of the workflow was published in December 2014 in 

Applied In Vitro Toxicology. A manuscript describing the application of

an improved approach to a larger chemical set will be submitted to Environmental Health 

Perspectives in FY 2017 and a poster describing

open-source workflows to conduct these analyses will be presented at the 2017 Society of 

Toxicology annual meeting.

Using data from nine Tox21 and ToxCast assays, NICEATM built a model to predict 

androgen receptor pathway activity and evaluated it using a list of reference chemicals 

developed from high-quality in vitro data from androgenic activity assays. The model and 

evaluation are described in a manuscript submitted to Chemical Research in Toxicology.

From these data and the androgen receptor pathway predictions, NICEATM also developed 

predictive quantitative structure-activity relationship models for androgen receptor binding 

and activity. These models were presented in a poster (Zang et al.) at the 2016 Society of 

Toxicology annual meeting 

Related Annual Report Pages:

FY 2016 NICEATM Workshops 

Additional NICEATM Activities 

About NICEATM

100
2016 Annual Report Research and Testing NICEATM

Additional NICEATM Activities

https://ntp.niehs.nih.gov/go/807115

Acute Systemic Toxicity

NICEATM conducted a retrospective analysis to determine if acute oral toxicity data can be used reliably to 

assign EPA acute dermal hazard classifications, potentially reducing the number of animals needed for 

pesticide testing. NICEATM obtained high-quality data for 910 pesticide-active ingredients and formulations 

from EPA toxicity reports, peer reviewed publications, and databases. Oral hazard classifications based on 

rat oral LD50 values were compared to dermal hazard classifications based on rat dermal LD50 values. 

Results suggest that acute oral hazard categories are sufficiently protective for acute dermal hazard 

classification. EPA used these analyses to support guidance for waiving acute dermal toxicity tests required 

for pesticide formulations . The analysis was described in a poster (Paris et al.) presented at the 2016 

Society of Toxicology (SOT) annual meeting , and a manuscript describing this work is in preparation.

Developmental Toxicity

NICEATM is supporting an NTP effort to systematically evaluate the application of zebrafish in NTP 

toxicology studies (SEAZIT). This effort will provide fundamental knowledge on the use of zebrafish in 

toxicology. In FY 2016, NICEATM and other SEAZIT team members conducted a series of interviews with 

researchers considered to be experts in the use of zebrafish in toxicology studies. These interviews 

identified areas key to development of a harmonized testing protocol for embryonic zebrafish studies and 

important sources of variability among laboratories. Information from these interviews and from a literature 

search will be compiled into a manuscript to be submitted for publication in FY 2017. NICEATM will also 

present a webinar series in February and March 2017 on Using Informatics to Improve Data Analysis of 

Chemical Screening Assays Conducted in Zebrafish. Information about the webinars is on the NTP website.

NICEATM is working with other NTP scientists at NIEHS to establish a list of developmental toxicants that 

cause subtle effects, as opposed to being potent or multisite teratogens. The toxicants identified will be 

candidates for testing with in vitro assays using primary cells, stem cells, or cell lines, as well as in vivo 

assays using lower order organisms such as zebrafish or Caenorhabditis elegans. Results from this testing 

may 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. NICEATM is also conducting a review of 

data from completed NTP studies and the scientific literature in support of this effort.

In June 2016, NICEATM requested available data and information on approaches and technologies 

currently used for identifying potential developmental toxicants. Three responses were received that 

described assays using stem cells or C. elegans with in vitro assays to screen for potential developmental

toxicants. Submitted information is being used to assess the state of the science and determine technical

needs for alternative methods to evaluate the potential of chemicals to induce adverse effects in offspring.

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. The study will test 67 reference chemicals to characterize the reliability and relevance of the

method, and 30 consumer products to evaluate the utility of the method beyond single chemicals. The study 

is planned to run through summer 2017.

Additional NICEATM Activities

- - -

101
Skin Sensitization 

NICEATM collaborated with ICCVAM scientists to develop integrated testing strategies that use non-animal 

data to predict skin sensitization hazard. Three manuscripts published or accepted for publication in FY 

2016 describe strategies to use 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.

NICEATM collaborated with scientists at the University of North Carolina at Chapel Hill to develop 

quantitative structure-activity relationship (QSAR) models to support identification of potential human skin 

sensitizers without using animals. A manuscript submitted for publication in FY 2017 describes QSAR 

models that predict human skin sensitization test results.

NICEATM collaborated with the Cosmetics Europe Skin Tolerance Task Force to evaluate the integrated 

approaches to testing and assessment of skin sensitization that have been submitted to the Economic Cooperation and Development. NICEATM has evaluated six IATAs against a set of previously untested 

chemicals with in vitro and in silico data provided by Cosmetics Europe. Manuscripts describing the

datasets and the outcome of the IATA analyses are in preparation.

Ocular Irritation 

Optisafe is an in vitro test method that assesses the potential to cause eye irritation by measuring the 

damage induced by application of a test substance to a semipermeable membrane. NICEATM is 

coordinating an ICCVAM-sponsored multi-laboratory validation study to determine the reliability and 

relevance of the OptiSafe test method. Training of participating laboratories is underway with the first phase 

of chemical testing to begin in FY 2017.

Related Annual Report Pages:

FY 2016 NICEATM Workshops

NICEATM Support of Tox21

About NICEATM

102
About ICCVAM

The Interagency Coordinating Committee on the Validation of Alternative Methods

(ICCVAM) is a permanent interagency committee of NIEHS.

ICCVAM Activities

Description of activities NICEATM support in FY 2016.

ICCVAM Test Method Evaluation Activities

A list of NICEATM and ICCVAM test methods evaluation activities in FY 2016.

ICCVAM International Validation Activities

A description and list of international validation activities NICEATM and ICCVAM

participated in during FY 2016.

2016 Annual Report - Research and Testing - ICCVAM

ICCVAM

103
https://ntp.niehs.nih.gov/go/807124

FY 2016 ICCVAM Activities

ICCVAM Test Method Evaluation

International Validation Activities

Related Links

• Information on ICCVAM

Activities

• Complete list of articles on

ICCVAM activities published in

scientific journals

2016 Annual Report - Research and Testing - ICCVAM - About ICCVAM

About ICCVAM

The Interagency Coordinating Committee on the Validation of Alternative 

Methods (ICCVAM) is a permanent interagency committee of NIEHS 

under NICEATM. Established by the ICCVAM Authorization Act of 2000 

(42 U.S.C. 285i-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 15 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:

104
NICEATM provided support for six teleconferences and two in-person 

meetings held by ICCVAM in FY 2016. NICEATM also supported three 

ad hoc ICCVAM working groups focused on acute systemic toxicity, 

skin sensitization, and identification and characterization of reference 

chemicals for validation of in vitro endocrine disruptor assays.

The second ICCVAM Communities of Practice webinar was held on 

January 26, 2016. The webinar focused on applications of methods 

that use chemical structure, properties, and toxicity data to predict

characteristics of untested chemicals. Alex Tropsha, Ph.D., of the 

University of North Carolina at Chapel Hill discussed how quantitative

structure-activity relationship models allow chemical compounds to be

characterized mathematically, enabling statistical predictions about the 

properties of untested chemicals. Louis Scarano, Ph.D., of the U.S.

Environmental Protection Agency explained how quantitative tools and 

models are used to generate predictions about toxic effects of new 

chemicals. These predictions are then used to conduct occupational 

risk assessments and identify where further testing might be needed.

Slide presentations from the webinar are available on the NTP

website . 

ICCVAM with NICEATM support held its third public forum on May 25, 

2016, at NIH in Bethesda, Maryland. Representatives from 12 ICCVAM 

member agencies were joined by attendees representing stakeholder 

groups and over 100 webcast viewers. ICCVAM members provided 

information about their agency’s activities relevant to the development 

and validation of test methods and approaches that may replace, 

reduce, or refine animal use. A proposal for a roadmap to replace 

animal use in U.S. safety testing was highlighted. Representatives 

from stakeholder groups praised recent progress made by ICCVAM 

and its member agencies towards replacing required animal tests with 

non-animal alternatives, and suggested future activities and areas that 

should receive increased focus. The agenda and presentations are 

available on the NTP website .

The 15 member agencies of ICCVAM are engaged in additional 

activities that support replacing, reducing, and refining animal use. 

Summaries of these activities can be found on the NTP website .

Related Annual Report Pages:

FY 2016 ICCVAM Activities 

ICCVAM Test Method Evaluation

International Validation Activities

Related Links

• Information on ICCVAM

Activities

• Complete list of articles on

ICCVAM activities published in

scientific journals

2016 Annual Report - Research and Testing - ICCVAM - ICCVAM Activities https://ntp.niehs.nih.gov/go/807085

ICCVAM Activities

105
2016 Annual Report Research and Testing ICCVAM

ICCVAM Test Methods

https://ntp.niehs.nih.gov/go/807133

ICCVAM received no formal test method nominations or submissions in FY 2016. ICCVAM welcomes 

submissions of innovative test methods, which may be acceptable for specific regulatory use and for which 

adequate validation studies have been completed. However, to maximize the potential for effective 

implementation of new test methods or approaches, ICCVAM only conducts evaluations and prepares 

recommendations on test method submissions proposed for regulatory uses that align with ICCVAM

member agencies needs and priorities. More information on ICCVAM test method submissions is available.

NICEATM and ICCVAM test method evaluation activities in FY 2016 are summarized in the table below.

Test Method Evaluation Activities in FY 2016

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. A manuscript describing strategies to predict animal and 

human skin sensitization of test results was published in FY 2016. Another

manuscript describing a strategy to predict human skin sensitization potency is

in preparation.

Electrophilic allergen

screening assay

This test method, nominated by NIOSH, is an in chemico assay intended to

identify potential skin sensitizers. A validation study of the method is planned

for FY 2017. Laboratories from three ICCVAM agencies will conduct the

testing. NICEATM will coordinate the study and members of the ICCVAM Skin

Sensitization Working Group will serve on the study management team.

OptiSafe ocular irritation

test

NICEATM is coordinating the validation of the in vitro OptiSafe ocular irritation

test method. In this method, a test substance is applied to a semipermeable

membrane and damage to macromolecules in the membrane is measured to

assess the substance’s potential to cause eye irritation. Training of

participating labs is underway, with the first phase of chemical testing to begin

in FY 2017.

Related Annual Report Pages:

FY 2016 ICCVAM Activities

ICCVAM Test Method Evaluation

International Validation Activities

ICCVAM Test Method Evaluation Activities

- - -

106
2016 Annual Report Research and Testing ICCVAM

ICCVAM International

https://ntp.niehs.nih.gov/go/807121

NICEATM and ICCVAM participate in international test method validation activities through the Organisation

for Economic Co-operation and Development (OECD), and collaborate with countries that are members of

the International Cooperation on Alternative Test Methods (ICTAM), including the European Union, Japan,

Korea, and Health Canada.

In FY 2016, ICCVAM agencies commented on draft OECD documents through the U.S. National

Coordinator for the OECD Test Guidelines Programme, an ex officio ICCVAM member. In FY 2016,

NICEATM and ICCVAM collaborated with international colleagues on the following OECD activities:

Drafted a new proposal for a performance based test guideline regarding defined skin sensitization

approaches and test methods to be submitted to OECD in FY 2017.

Revised the acute dermal toxicity test guideline.

Drafted a guidance document on integrated approaches to testing and assessment (IATAs) for eye

irritation hazard potential.

Drafted a guidance document on the reporting of defined approaches to be used within IATAs.

Contributed a case study to a guidance document on IATAs for skin sensitization.

Representatives of NICEATM and ICCVAM will attend meetings of the OECD expert groups on eye irritation

and skin sensitization in FY 2017.

International Cooperation on Alternative Test Methods collaborations address three critical areas of 

cooperation: test method validation studies, independent peer review of validation studies, and the

development of formal recommendations on alternative testing methods. Representatives of NICEATM and 

ICCVAM attended an ICATM coordination meeting in November 2015. A NICEATM scientist served as a

liaison member to a European Union Reference Laboratory for Alternatives to Animal Testing Scientific 

Advisory Committee working group that reviewed the relevance and predictive capacity of two in vitro eye

irritation test methods. Representatives of NICEATM and ICCVAM will attend the FY 2017 workshop 

sponsored by ICATM to develop criteria for evaluating non-animal approaches for skin sensitization 

potential.

The table below lists ongoing international validation studies led by ICATM member organizations that

include NICEATM or ICCVAM participants.

Participation in International Validation Studies

Test Method Type of Test Lead

Organization NICEATM-ICCVAM Involvement

IL-8 in vitro test for

assessing skin

sensitization potential

Allergic

contact

dermatitis

JaCVAM*

NICEATM staff served on the validation

management team and provided comments

on study design, chemical selection, and test

method protocols.

Vitrigel-SST assay for

assessing skin

sensitization potential

Allergic

contact JaCVAM* NICEATM staff served on the validation

management team.

ICCVAM International Validation Activities

- - -

107
dermatitis

Vitrigel-EIT assay for

eye irritation testing

Ocular

irritation JaCVAM* NICEATM staff served on the validation

management team.

Hand1-luc in vitro test

for assessing

reproductive toxicity

potential

Reproductive

toxicity JaCVAM*

NICEATM staff served on the validation

management team.

SIRC-CVS assay for

eye irritation testing

Ocular

irritation JaCVAM* NICEATM staff served on the validationmanagement team.

Amino acid derivation

reactivity assay

Allergic

contact

dermatitis

JaCVAM* NICEATM staff served on the validation

management team.

*Japanese Center for the Validation of Alternative Methods

Related Annual Report Pages:

FY 2016 ICCVAM Activities

ICCVAM Test Method Evaluation

International Validation Activities

108
Noncancer Research

NTP conducts evaluations to assess the evidence that substances cause adverse health effects 

and provides opinions on whether these substances may be of human concern.

Report on Carcinogens

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

are known to be human carcinogens or may reasonably be anticipated to be human carcinogens, 

and to which a significant number of persons residing in the U.S. are exposed.

2016 Annual Report - Literature Analysis

Literature Analysis

109
https://ntp.niehs.nih.gov/go/807174

Project & Study Scientist

Evaluation of inflammation-based

atherosclerosis associated with environmental

exposures

Study Scientist: Rooney

There is growing evidence 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 identify biomarkers of the

inflammation involved. Atherosclerosis was selected for

investigation because of the significant public health

impact of the disease, and the well-established role for

inflammation in the disease process leading to

atherosclerosis. The draft concept was reviewed at the 

December 2014 Board of Scientific Counselors meeting, 

and the evaluation has been initiated.

NTP has made a commitment to studying noncancer health effects, and conducts evaluations to assess 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 may 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. Kristina Thayer,

Ph.D. served as deputy division director for analysis, Division of NTP, NIEHS, and director of OHAT.

In FY 2016, 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 also published several reports

in the new NTP Research Report series, including a pilot study on tin and organotin levels in Danish women

and a systematic review of the effects of fluoride on learning and memory in animal studies.

Ongoing Noncancer Health Effects Projects

Project Summary

2016 Annual Report - Literature Analysis - Noncancer Research

Noncancer Research

View Research Areas in Noncancer

Research

Ongoing Noncancer Health Effects

Projects

Show All

Search Projects

110
Evaluation of immunotoxicity associated with

exposure to perfluorooctanoic acid (PFOA) or

perfluorooctane sulfonate (PFOS)

Study Scientist: Rooney

Exposure to chemicals in consumer products:

an NIEHS and EPA collaborative methods

demonstration and evaluation pilot study

Study Scientist: Taylor

Perfluorooctanoic acid (PFOA) and perfluorooctane

sulfonate (PFOS) are extremely persistent chemicals and

are widely distributed in the environment as a result of

extensive use over the last 60 years. Although exposures

have been dramatically reduced, the persistence and

bioaccumulation of both PFOA and PFOS result in

detectable levels in the U.S. population. Recent

publications have linked PFOA and PFOS exposure in

humans to functional immune changes that are consistent

with evidence of PFOA- and PFOS-related immunotoxicity

reported in animal studies. The NTP conducted a

systematic review to evaluate the evidence for an

association between exposure to PFOA or PFOS and

immunotoxicity or immune-related health effects. The NTP 

Monograph was finalized in September of 2016 following 

the Peer-Review Meeting by an ad hoc expert panel on 

July 19, 2016 in Research Triangle Park, NC. The NTP 

concluded that both PFOA and PFOS are presumed to be 

an immune hazard to humans based on a high level of 

evidence from animal studies that PFOA and PFOS 

suppressed the antibody response and a moderate level of 

evidence from studies in humans.

There is concern about the endocrine-disrupting potential

of some chemicals found in personal care products and

other consumer products. Given the large number of cooccurring chemicals in these products, new strategies and

techniques need to be developed, and existing tools need

to be evaluated for their utility in assessing the extent of

human exposure to tens of thousands of chemicals.

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

longitudinal pilot study to evaluate the performance of

existing survey, measurement, and modeling methods for

assessing exposures to chemicals in a number of

consumer product categories, including personal and child

care, household cleaning, lawn and garden, home

improvement, and food packaging products. The pilot

study addresses a number of research needs related to

the measurement and modeling of human exposures. The

draft 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 evaluation has

been initiated.

Transgenerational inheritance is the phenomenon in which 

an individual’s exposures have far-reaching 

consequences, affecting multiple generations removed 

from the original insult. The traditional belief suggests that

State of the science for transgenerational

inheritance of health effects

Study Scientist: Walker

111
Evaluation of children’s health and trafficrelated air pollution

Study Scientist: Howdeshell

Evaluation of adverse health effects and

occupational exposure to cancer

chemotherapy agents

Study Scientist: Howdeshell

negative effects of exposure to environmental chemicals

are reset in each generation, such that subsequent

generations are unaffected by the exposure history of their 

parents and grandparents. This state-of-the-science

evaluation will examine the robustness of the evidence for

transgenerational inheritance of health effects associated

with exposure to a wide range of stressors, such as

environmental chemicals; drugs of abuse, nutrition, and

diet; pharmaceuticals; infectious agents; and stress in

humans and animals. A Federal Register Notice was

published in May 2013 soliciting public comments. The

evaluation is nearing completion with a draft manuscript in

development.

Research on traffic-related air pollution and children’s

health has increased in the past decade with

improvements in air monitoring technology and exposure

methodology. Traffic-related air pollution has been

measured in many different ways, including direct traffic

measures, such as proximity or density of traffic;

environmental gases, such as ozone and nitrogen dioxide;

particulate matter, including coarse particles (PM10) and

fine particles (PM2.5); and select components of trafficrelated pollution, including benzene, diesel exhaust, and

polycyclic aromatic hydrocarbons (PAHs). This topic is

being addressed in a series of evaluations on the evidence 

for an association between traffic-related air pollution and 

health outcomes impacting fetal outcome and children, 

beginning with hypertensive disorders during pregnancy 

and neurological development and function in children. 

The draft concept was reviewed at the April 2014 Board of 

Scientific Counselors meeting, and the evaluation has 

been initiated.

Cancer chemotherapy agents are cytotoxic drugs, and

many of these agents are known mutagens and

developmental toxicants. Occupational exposure to cancer 

chemotherapy agents may occur in various professions 

including medical, veterinary, and manufacturing. While 

improved handling procedures and engineering controls 

have reduced contamination, surface contamination 

persists in pharmacy and nursing areas of some hospitalbased cancer centers. This evaluation will examine 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 draft 

concept was reviewed at the April 2014 Board of Scientific 

Counselors meeting, and the evaluation has been initiated.

112
Shift work at night, light at night, and circadian

disruption

Study Scientist: Boyd

Biological activity of bisphenol A (BPA)

structural analogues and functional alternatives

Study Scientist: Pelch

Environmental influences on the epigenome: a

scoping report

Study Scientist: 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 evaluation will examine the extent of the

human, animal, and in vitro evidence of biological activity

of BPA analogues of emerging public health concern. It

will be further addressed by additional in vitro laboratory

experiments and external collaborations to evaluate in vivo 

activity in two model organisms, zebrafish and

Caenorhabditis elegans. The concept was announced in

June 2015 to the Board of Scientific Counselors, and the

evaluation and research is nearing completion . Draft

manuscripts are in development.

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 exploring the extent of the evidence

linking environmental exposures to health outcomes via

genome-wide alterations in DNA methylation. The 

concept was announced in June 2015 to the Board of 

Scientific Counselors, and the evaluation is nearing 

completion with a draft manuscript in development.

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

choices, or residence, are subjected to interruptions in the

natural light-dark cycles, leading to the potential for

circadian disruption. This project is being undertaken in

conjunction with an analysis by the Office of the Report on

Carcinogens for cancer hazard evaluation. The draft

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. Activity is 

underway working with the Office of the Report on 

Carcinogens to finalize the protocol and execute the 

cancer hazard evaluation.

113
About the Report on Carcinogens

The RoC is a congressionally mandated listing of substances that either are known to be human 

carcinogens or may reasonably be anticipated to be human carcinogens, and to which a 

significant number of persons residing in the U.S. are exposed.

RoC Activities

A summary of the Office of the Report on Carcinogens activities conducted during FY 2016.

Newly Reviewed Listings for the 14th RoC

A list of newly reviewed substances under consideration for the 14th Report on Carcinogens.

RoC Substances Selected for Evaluation

A list of substances selected for evaluation by the Office of the Report on Carcinogens during FY 

2016.

2016 Annual Report - Literature Analysis - Report on Carcinogens

Report on Carcinogens

114
2016 Annual Report Literature Analysis Report on Carcinogens

About RoC

https://ntp.niehs.nih.gov/go/807177

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 U.S. are exposed

[Section 301(b)(4) of the Public Health Service Act, 42 U.S.C. 241(b)

(4)].

The RoC is a cumulative report and consists of substances newly 

reviewed, in addition to those listed in previous editions. NTP follows 

an established four-part process for preparing the report.

1. NTP selects nominations for RoC evaluation.

2. Office of RoC conducts cancer hazard evaluations on these

substances.

3. Draft RoC monographs are released for public comment and peer

review before finalization.

4. NTP submits the proposed listing of newly reviewed substances,

whose cancer evaluations are completed, to the U.S. Department

of Health and Human Services (HHS) secretary for review,

approval, and release to the public and congressional members.

Each substance listed in the RoC has a profile, which contains the 

listing status determined by using established listing criteria , and a 

summary of the cancer studies supporting the listing status, 

information on human exposure, and federal regulations to reduce 

exposure.

Preparation of the RoC is conducted by the Office of the Report on 

Carcinogens, under the direction of Ruth Lunn, Dr.P.H. Contract 

support for preparation of the RoC in FY 2016 was provided by 

Integrated Laboratory Systems Inc. and ICF.

Additional Links for the RoC

Report on Carcinogens

RoC Activities in 2016

Newly Reviewed Listings

RoC Candidate Substances

About the Report on Carcinogens

- - -

115
2016 Annual Report Literature Analysis Report on Carcinogens

2016 Activities

https://ntp.niehs.nih.gov/go/807171

Report on Carcinogens

RoC Activities in 2016

Newly Reviewed Listings

RoC Candidate Substances

RoC Activities

- - -

NTP submitted the 14th RoC to the U.S. Department of Health and Human Services (HHS) Secretary for 

review and approval in FY 2016 and HHS released the 14th RoC on November 3, 2016. This cumulative 

report contains 248 listings, of which seven were newly reviewed. The newly reviewed listings, include

trichloroethylene, Epstein-Barr virus, human immunodeficiency virus type-1, human T cell lymphotropic 

virus type-1, Kaposi sarcoma-associated herpesvirus, and Merkel cell polyomavirus, all listed as known to 

be a human carcinogen; and the class cobalt and cobalt compounds that release cobalt in vivo, listed as 

reasonably anticipated to be a human carcinogen.

Other RoC activities in FY 2016 were primarily related to conducting the cancer hazard evaluations of 

several substances that were newly reviewed for the 14th RoC. The RoC Monograph on Cobalt and Cobalt 

Compounds that Release Cobalt In Vivo was finalized following the December 2015 NTP Board of 

Scientific Counselors’ meeting. On December 17, 2015, NTP convened a panel of experts to peer review 

five draft RoC monographs on Epstein-Barr Virus, human immunodeficiency virus type-1, human T cell 

lymphotropic virus type-1, Kaposi sarcoma-associated herpes virus, and Merkel cell. The monographs for 

these five viruses were finalized following the June 2016 NTP Board of Scientific Counselors’ meeting.

Literature-based cancer hazard evaluations are being prepared for (1) shift work at night, light at night, and 

circadian disruption , (2) haloacetic acids found as disinfection by-products , and (3) Helicobacter pylori:

Chronic infection . Concepts documents for haloacetic acids and H. pylori were presented to the NTP 

Board of Scientific Counselors at their April 11, 2016 meeting. Goldenseal Root Powder has also 

selected for review for the RoC. For a table listing RoC ongoing evaluations, go to RoC Substances 

Selected for Evaluation.

The Office of the Report on Carcinogens, in partnership with the Office of Health Assessment and 

Translation, convened a workshop titled Shiftwork at Night, Artificial Light at Night and Circadian Disruption

and held on March 10-11, 2016. The purpose of the workshop was to obtain external scientific input on 

topics important for informing the literature-based health hazard assessments, including strategies for 

integrating data across evidence streams and exposure scenarios, data gaps, and research needs.

Additional Links for the RoC

116
2016 Annual Report Literature Analysis Report on Carcinogens

New RoC Listings

https://ntp.niehs.nih.gov/go/807180

Candidate

CASRN*

Study Scientist

Primary Uses/Exposures Listing Status and

Rationale

Trichloroethylene

79-01-6

Lunn

Industrial solvent best known for its use as

a metal degreaser. Today it is mainly used

for the synthesis of hydrofluorocarbon

refrigerant.

Known to be a human

carcinogen

Linked to kidney cancer and

possibly non-Hodgkin

lymphoma

Epstein-Barr virus

N/A

Jahnke

Herpesvirus that causes infectious

mononucleosis. Infects nine of 10 people

worldwide and is transmitted via saliva.

Known to be a human

carcinogen

Linked to six types of

cancer in humans: four

types of lymphoma,

nasopharyngeal and gastric

cancer

Human immunodeficiency 

virus, type-1

N/A

Jahnke

Retrovirus that causes AIDS. Infects 1.2

million people. Transmitted via blood and

body fluids.

Known to be a human

carcinogen

Linked (or potentially linked)

to 12 types of cancers

Human T cell lymphotropic

virus, type-1

N/A

Jahnke

Retrovirus that is usually asymptomatic.

Transmitted via body fluids and blood.

Known to be a human

carcinogen

Linked to adult T-cell

leukemia/lymphoma

Kapoosi sarcoma-associated

virus

N/A

Jahnke

Herpesvirus usually causing

asymptomatic infections. Transmitted via

salvia and from mother to child

Known to be a human

carcinogen

Linked to Kaposi sarcoma

and two types of lymphoma

in humans

Merkel cell polyomavirus

N/A

Jahnke

Polyomavirus whose route of transmission

is not clear, but may be transmitted

through skin shedding.

Known to be a human

carcinogen

Linked to Merkel cell

carcinoma

Cobalt and cobalt compounds Naturally occurring metallic element that Reasonably anticipated to

Newly Reviewed Listings for the 14th RoC

- - -

117
that release cobalt in vivo

7440-48-4

Lunn

exists in different forms. Used to make

alloys for industrial, medical, and military

purposes; cemented carbides; as

pigments; and for electronics and green

energy.

be a human carcinogen

Sufficient evidence of 

carcinogenicity from studies 

in experimental animals and 

supporting mechanistic data

* Chemical Abstracts Service Registry Number

Additional Links for the RoC

Report on Carcinogens

RoC Activities in 2016

Newly Reviewed Listings

RoC Candidate Substances

118
2016 Annual Report Literature Analysis Report on Carcinogens

Ongoing RoC Evaluations

https://ntp.niehs.nih.gov/go/807168

Substances

Study Scientist Primary Uses/Exposures Listing Status

and Rationale

Goldenseal Root Powder

(Hydrastis canadensis)

Office of RoC staff

Herbal remedy (botanical product) used to treat

gastrointestinal disturbances, urinary disorders,

hemorrhage, skin, mouth, and eye infections and

inflammation.

NTP Board of

Scientific

Counselors

review of draft

concept, April

2014.

Haloacetic Acids Found as

Water Disinfection ByProducts

Gloria Jahnke

13 individual haloacetic acids or potential class or

subclass of these haloacetic acids. People are

exposed to these haloacetic acids by ingestion of

chlorinated drinking water and by dermal contact or

breathing compounds during bathing or using

swimming pools and spas that use chlorine for

disinfection.

NTP Board of

Scientific

Counselors

review of draft

concept, April

2016.

Helicobacter pylori (H.

pylori): Chronic Infection

Ruth Lunn

Gram negative, multi-flagellated bacterium that

colonizes the stomach and causes peptic ulcer.

Bacterium is spread by person-to-person contact

especially among family member. Routes of exposure

include oral-oral, fecal-oral, iatrogenic, and possibly

from contaminated water. Risks factors for infection

include age, race, socioeconomic status such as

crowded living conditions, and poor

sanitation/hygiene.

NTP Board of

Scientific

Counselors

review of draft

concept, April

2016.

Shift Work at Night, Light at

Night, and Circadian

Disruption

Ruth Lunn

Unnatural (e.g., such as ill-timed) electrical light,

especially light-at-night (LAN), 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 LAN. Shift workers

who work at night or evenings starting before 6:00

a.m. can experience an extreme type of LAN

exposure, as well as changes in other activities

related to LAN, 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 RoC

Report on Carcinogens RoC 

Activities in 2016

Newly Reviewed Listings RoC

Candidate Substances 

RoC Substances Selected for Evaluation

- - -

119
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 the NTP program.

NTP at NIOSH

NIOSH research projects for NTP to assess the effects of exposures to substances, following its 

mandate to protect workers' health and safety.

2016 Annual Report - Partner Agency Research

Partner Agency Research

120
https://ntp.niehs.nih.gov/go/807147

The majority of 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, 

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.

NIEHS/NTP Staff

Biomolecular Screening

Genetic and epigenetic differences between individuals in the human population are proposed as major

factors for individual susceptibility to environmental stressors. Environmental and drug safety assessments

are currently conducted with a small number of commonly used animal models, which have limited genetic

2016 Annual Report - Partner Agency Research - About NIEHS

About NTP at NIEHS

121
diversity. Further, there are many layers of biological regulation that can influence individual genetic 

susceptibility to chemical and drug toxicity. Animal models have inherent limitations in extrapolating results 

to human toxicity and disease, and this program is working toward development of more sophisticated 

analyses in epigenetics to make better use of current animal models, and adopt 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.

In FY 2016, work continued on the mouse methylome project by Alex Merrick, Ph.D., and Paul Wade, 

Ph.D. Epigenetics involves the study of modifications to DNA, like methylation, and related cellular 

structures, such as histones, that affect gene expression and an organism’s ability to adapt to the 

environment. NTP designed an epigenetic study to examine DNA methylation and its possible relationship 

with the susceptibility of mouse strains to develop liver tumors. Male and female C57BL/6N mice were 

crossed with C3H/HeN mice. Five tissues — brain, liver, cardiac and skeletal muscle, brown and white fat, 

and epididymal sperm — from the first-generation offspring were collected at the average age NTP starts 

mice in a subchronic toxicity study, and flash frozen for DNA/RNA isolation and liver sequencing. Progress 

in FY 2016 involved computational analysis on sites of genomic methylation in relation to known genes and 

transcriptionally active regions in both parental strains and the resulting first generation offspring. The 

relationship of DNA methylation to gene expression and possible heredity in offspring is being determined, 

and the genomic variation between mouse strains, genders, and F1 offspring is being catalogued. The 

epigenetic landscape is being carefully described in these two mouse strains and offspring to help interpret 

the contribution of differences in DNA methylation to their differential susceptibility to hepatic malignancy. A 

manuscript is in preparation to be followed by public release of the methylome data. Additional studies in 

2016 have been initiated that will address the impact of sex hormone signaling on DNA methylation at a 

genome-wide level and the impact of DNA methylation at distal regulatory regions.

NTP Laboratory

The NTP Laboratory, within the NIEHS Division of NTP, conducts in-house, agent-specific, targeted 

research related to the development and application of modern toxicology and molecular biology tools. 

These tools are used in the (1) evaluation of specific substances of concern to NTP, (2) issues of 

central importance to NTP programs, and (3) methods development to advance the NTP mission. The 

NTP Laboratory also focuses on the study of the developmental origins of adult diseases. The table 

below includes projects in the NTP Laboratory in FY 2016.

NTP Laboratory Projects in FY 2016

View Research Areas in

NTP Laboratory Projects in FY 2016

Show All

Search Projects

Project & Study Scientist Project Summary

To determine if in vitro assays and chemical analysis of

botanicals can aid in selecting botanicals for in vivo

testing. In FY 2016, a workshop on botanical dietary

supplement safety was held.

Application of in vitro assays to evaluate 

botanicals

Study Scientist: DeVito

122
To evaluate the transcriptomic and metabolomic 

changes in metabolically active cell lines with 24 

chemicals that have been tested in vitro.

To develop in vitro cell transformation models with target

relevant cells using arsenic and cadmium. In FY 2016,

this project was completed and resulted in multiple

publications.

To determine if there are differences in the toxicity of

glyphosate and its formulations on oxidative stress and

other carcinogenic characteristics.

To evaluate fluoride developmental neurotoxicity in rats.

To define the role of formaldehyde inhalation in

hematopoietic tumor induction. This study was completed

in FY 2016 and the report is being developed.

To perform a proof of concept study of in vitro

formaldehyde-induced malignant transformation in

hematopoietic stem cells. This is a companion study to

the formaldehyde in p53 mice study. This study was

completed in FY 2016 and the report is being developed.

To develop in vitro methods that incorporate xenobiotic

metabolism. A manuscript is in development.

To retest the ability of reported metalloestrogens, like

cadmium and arsenic, to cause estrogen receptor

stimulation in the uterus as a mode of action towards

cancer development.

(1) To develop an in vitro transwell method with metal

particles and macrophages in one well and cells of

interest, such as lung epithelium, in the other; and (2) to

define the ability of various types of macrophages to

release different metals from different particles. In FY

2016, this project was completed and a manuscript was

published.

Chemical induced transcriptomic and

metabolomic changes in vitro.

Study Scientist: DeVito

Development of in vitro models of metal

carcinogenesis

Study Scientist: Tokar

Effects of glyphosate and its formulations on

the induction of oxidative stress.

Study Scientist: DeVito

Evaluation of the developmental neurotoxicity

of fluoride

Study Scientist: Harry

Formaldehyde in p53 knockout mice

Study Scientist: Morgan

Formaldehyde-induced transformation of

human myeloid progenitor cells

Study Scientist: Morgan

Incorporating metabolism into high 

throughput screening assays

Study Scientist: DeVito

Metalloestrogens and uterine/breast response

Study Scientist: Dixon, Fenton

Method for assessing biological impact of

metal particle dissolution

Study Scientist: Morgan

123
Methods in histopathology of mammary gland

development

Study Scientist: Fenton

Refinement of developmental neurotoxicology

methods

Study Scientist: Harry

Role of microRNAs in malignant 

transformation Study Scientist: Tokar

Stem cells in toxicology and carcinogenesis

Study Scientist: Tokar

Toxicants and mammary gland development

Study Scientist: Fenton

Using Caenorhabditis elegans for screening

mitochondrial toxicants

Study Scientist: Boyd

Using Caenorhabditis elegans as screens for 

toxicity of flame retardants

Study Scientist: Boyd

Using in vitro screens to evaluate potential

obesogens

Study Scientist: Fenton

Using in vitro screens to evaluate polyaromatic

compounds

Study Scientist: DeVito

Utility of a five-day transcriptomic study in 

adult rats.

Study Scientist: Gwinn

To develop standardized methods to quantitatively assess

chemical insult on mammary gland development. This

project was completed in FY 2016 and several

manuscripts were published.

To improve methods for various efforts including genetic

signatures, stem cells, inflammation, behavior, and

conditioning.

To study genes of interest 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.

To perform various in vitro studies on the role of stem 

cells and cancer stem cells in carcinogenesis 

and the developmental basis of adult disease.

To determine the effects of different toxicants, including

atrazine, on mammary gland development in rats and

mice.

To study the effects of mitochondrial toxicants in

Caenorhabditis elegans. This project was completed in 

FY 2016 and a manuscript was published.

To study the effects of flame retardants in Caenorhabditis

elegans. This project was completed in FY 2016, and a

manuscript was published.

To develop orthogonal assays to evaluate findings from

Tox21 that identified potential obesogens.

To apply in vitro assays to assess and categorize the

biological effects of polyaromatic compounds.

To determine the difference in the transcriptomic bone 

mineral density and adverse effect bone mineral density 

by examining 20 chemicals that have been tested in vitro 

at the NTP.

124
About NTP at the National Center for Toxicological Research

NCTR provides innovative technology, methods development, vital scientific training, 

and technical expertise to the NTP program.

NTP at NCTR: Interagency Agreement Projects

A list of projects funded by the NIEHS/NTP interagency agreement with FDA and conducted in FY 

2016.

2016 Annual Report - Partner Agency Research - NTP at NCTR

NTP at NCTR

125
https://ntp.niehs.nih.gov/go/807161

About NTP at the National Center for Toxicological Research

Research in Partnership with NCTR

The National Center for Toxicological Research (NCTR), in partnership with researchers from elsewhere in

FDA, other government agencies, academia, and industry, provides 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 in the table below. Click the project title for a brief

summary.

2016 Annual Report - Partner Agency Research - NTP at NCTR - NCTR

View Research Areas in

Biochemical and Molecular Basis of

Toxicology

Neurotoxicology

Nanotoxicology

Bioassay and Biomarker Development and

Evaluation

Search Projects

126
Project & Study Scientist

Physiologically based pharmacokinetic (PBPK)

models for bisphenol A (BPA)

Study Scientist: Fisher

Biologically based dose-response modeling for

the thyroid axis in the fetus and neonate

Study Scientist: Fisher

Relationship between liver epigenetic

phenotype and susceptibility to nonalcoholic

steatohepatitis-induced (NASH)

hepatocarcinogenesis in mice

Study Scientist: Pogribny

(1) To create physiologically based pharmacokinetic

(PBPK) models for bisphenol A (BPA) in mouse, rat, and 

rhesus monkey for multiple life stages: adult; neonate; 

pregnant, including both mother and fetus; and lactating, 

both 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. (2) 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, and limited information from 

humans 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 humans, and to extrapolate dosimetry from

regions of observation to low levels of exposure to BPA 

for which no experimental data exist. This simulation 

protocol will help reduce the uncertainty in the 

assessment of health risks posed by BPA to human 

populations.

(1) To create biologically based dose-response models for 

the hypothalamic-pituitary-thyroid axis in the developing 

rat and human as a function of iodide status. (2) To 

interface the models with physiologically-based 

pharmacokinetic or toxicokinetic models for thyroid active 

chemicals to predicted conditions, such as iodide status 

and chemical exposure, for which brain thyroid hormone 

homeostasis cannot be maintained in the fetus and 

neonate. (3) To use 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.

(1) To determine the role of epigenetic dysregulation in 

the etiology and pathogenesis of dietary nonalcoholic 

steatohepatitis (NASH)-induced hepatocarcinogenesis in 

mice. (2) To determine whether or not interstrain-specific 

susceptibility of mice to NASH-induced 

hepatocarcinogenesis is associated with differences in

individual hepatic epigenetic phenotypes. (3) To determine 

the role of epigenetic dysregulation in the etiology and 

pathogenesis of NASH-induced hepatocarcinogenesis in 

mice induced by tamoxifen administration. 

Biochemical and Molecular Basis of Toxicology

Project Summary

127
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: Pang

Human biomonitoring for bisphenol A (BPA) 

Study Scientist: Doerge

Role of peroxisome proliferator-activated 

receptor alpha (PPARa) and PPARa-mediated 

species differences in triclosan-induced liver 

toxicity

Study Scientist: Wu

Evaluation of the effects of black cohosh on

risedronate efficacy in peri-menopausal rat

model

Study Scientist: Hansen

(4) To determine whether or not aberrant epigenetic 

markers can be used as targets for prevention of NASHinduced hepatocarcinogenesis in mice.

(1) To establish a model and positive control. (2) To 

evaluate the sensitivity and specificity of the model, and 

test the possibility of high throughput screening and 

ranking of QT-prolonging drugs for the risk of torsade de 

pointes.

(1) To validate the proposed mechanism by which 

pyrrolizidine alkaloids induce tumors in rodents. (2) To 

develop an LC-ES/MS/MS method for detection and 

quantification of dehaloperoxidase-derived DNA adducts 

in rodents. (3) To develop an LC-ES/MS/MS method for 

detection and quantification of genotoxic pyrrolizidine

alkaloids in herbal plants and herbal dietary supplements 

(4) To develop an LC-ES/MS/MS method for detection 

and quantification of dehaloperoxidase-derived 

hemoglobin adducts in rodents.

(1) To develop and implement sensitive and selective 

analytical methodology to measure bisphenol A in the 

blood and urine from humans. (2) To integrate animal

exposure data and human biomonitoring data into a 

physiologically-based pharmacokinetic model for 

bisphenol A.

To examine the role of human and mouse peroxisome

proliferator-activated receptor alpha (PPARa) in triclosaninduced liver toxicity in vivo.

(1) To determine the effect of risedronate or black cohosh 

individually on bone density, bone turnover and bone 

histology in a postmenopausal rat model. (2) To 

determine the effect of the combination of black cohosh 

and risedronate on bone density, bone turnover and bone 

histology in a postmenopausal rat model.

Mechanism of tumorigenic pyrrolizidine

alkaloids and development of liquid

chromatography-electrospray

ionization/multistage mass spectrometry (LCES/MS/MS) methodology for detection and 

quantification of pyrrolizidine alkaloids

Study Scientist: Fu

128
Development and evaluation of a novel in vitro 

epigenomic screening model system for the 

hazard identification of FDA-regulated products 

Study Scientist: Pogribny

Relationship between liver epigenetic 

phenotype and susceptibility to nonalcoholic 

steatohepatitis-induced (NASH) 

hepatocarcinogenesis in mice

Study Scientist: Pogribny

Developing methods for the analysis of 

brominated vegetable oils and derivatives 

Study Scientist: Gamboa da Costa

(1) To determine the dose-dependent in vitro genetic and 

epigenetic effects of compounds regulated by FDA. (2) To 

characterize the specific epigenetic changes induced in 

vitro by genotoxic and non-genotoxic compounds. (3) To 

characterize the specific genetic and epigenetic effects of 

compounds regulated by FDA using an in vitro 3-D 

organotypic liver culture model system.

(1) To determine the role of epigenetic dysregulation in 

the etiology and pathogenesis of dietary nonalcoholic 

steatohepatitis (NASH)-induced hepatocarcinogenesis in 

mice. (2) To determine whether or not interstrain-specific 

susceptibility of mice to NASH-induced 

hepatocarcinogenesis is associated with differences in

individual hepatic epigenetic phenotypes. (3) To 

determine the role of epigenetic dysregulation in the 

etiology and pathogenesis of NASH-induced 

hepatocarcinogenesis in mice induced by tamoxifen 

administration. (4) To determine whether or not aberrant 

epigenetic markers can be used as targets for prevention 

of NASH-induced hepatocarcinogenesis in mice.

To develop methods for the analysis of the food additive 

brominated vegetable oil in rat feed and rat tissues.

Project & Study Scientist

The use of computed tomography (CT)

combined with positron emission tomography

(microPET) to evaluate the neurotoxicity

associated with pediatric exposures to the

anesthetics sevoflurane and propofol

Study Scientist: Wang

(1) To use computed tomography (CT) and positron 

emission tomography (microPET) to study neurotoxicity in 

vivo associated with the pediatric use of gaseous 

anesthetics sevoflurane and propofol. (2) To develop 

procedures to localize in vivo specific brain areas and 

structures to evaluate their response to test compounds.

(3) To determine the utility of fluorine-18-labeled PET 

compounds to identify stem cells and apoptotic cells in 

brain in vivo. (4) To determine cytotoxicity of compounds, 

including gaseous anesthetics, using embryonic 

neuralstem cells in vitro.

Neurotoxicology

Project Summary

129
Identification of protein biomarkers for

neurotoxicity assessments using a high

throughput antibody microarray approach

Study Scientist: Gu

Assessment of gaseous anesthetics in the

developing nonhuman primate

Study Scientist: Wang

Developmental neurotoxicity assessment of Nmethyl-D-aspartate (NMDA) receptor

antagonists in zebrafish

Study Scientist: Kanungo

Toxicity assessment of graphene sheets using

primary striatal neurons

Study Scientist: Ali

(1) To determine the dose-response effects of individual or 

combined gaseous anesthetics nitrous oxide and 

isoflurane on neuronal cell death in the developing 

nonhuman primate, using magnetic resonance imaging 

(MRI) and positron emission tomography (MicroPET). (2) 

To determine the effect of dose and duration of gaseous 

anesthetics on nonhuman primate long-term behavior and 

pathology, using MRI and MicroPET. (3) To evaluate

antioxidants in the amelioration of toxicity of gaseous 

anesthetics.

(1) To study wildtype zebrafish embryos exposed to 

NMDA receptor antagonists (MK-801, dextromethorphan, 

ketamine and sevoflurane), in order to assess their effects 

on Rohon-Beard sensory neurons. The effects on the 

primary and secondary motor neurons and their axons will 

also be assessed using hb9:GFP transgenic embryos. 

Postexposure washout experiments will be pursed to 

determine the effects of these drugs on the nervous 

system. (2) Certain NMDA receptor antagonists, such as 

ketamine, are known to modulate hormone levels in 

mammals and zebrafish. Based on the importance of the 

neuroprotective nature of neurosteroids, the study will 

determine estradiol-17’ levels in control and treated 

embryos. Changes in gene expression for the two CYP 

aromatases/estrogen synthases (brain aromatase 

cyp19a1b and gonadal aromatase cyp19a1a) will be 

quantified using quantitative polymerase chain reaction 

(qPCR). (3) Phenotype-based cell signaling mechanisms, 

such as MAPK and neuron development-specific gene 

expression, will be assessed. (4) Reversal of noted 

adverse effects of these compounds on neurons will be 

attempted, particularly by treatment with acetyl L-carnitine.

(1) To evaluate the toxicity of graphene sheets using in 

vitro primary cultures of embryonic day 14 (E14) primary 

rat striatal neurons. (2) To determine pathways involved in 

graphene toxicity using E14 primary rat striatal neurons.

(1) To examine proteomic changes at both the expression 

and phosphorylation levels using five established in vivo

models of neurotoxicity. (2) To identify common changes 

in protein expression and phosphorylation status in these 

animal model systems. (3) To confirm the observed 

alterations in protein expression and phosphorylation

status by means of other independent methods. (4) To 

apply the proteomic findings to a global ischemic animal 

model to further validate the utility of protein biomarkers 

for use in neurotoxicity assessments.

130
Project & Study Scientist

Proteomic assessment of the cytotoxic effects

of nanoparticles on the blood-brain barrier

Study Scientist: Gu

To use proteomic approaches to quantify alterations in

expression and phosphorylation of proteins involved in

apoptosis, inflammation, oxidative stress, and

tumorigenesis signaling pathways in blood-brain barrier

cells following exposure to nanoparticles. The long-term

goal is to establish proteomic parameters for toxicity of

nanoparticles.

Complement assays for the detection of

immune-sensitizing activity of nanomaterials

Study Scientist: Leakey

(1) To establish two complement assays for routine

evaluation of immune-sensitizing activity of nanomaterials.

(2) To validate the assays using nanoparticles with known

immunoreactivity. (3) To determine the immunesensitizing activity of novel nanomaterials.

Physiologically based pharmacokinetic (PBPK)

modeling of nanomedicine; building clinically

relevant standards for FDA-regulated

nanoparticulate drug products

Study Scientist: Leakey

(1) To determine in vivo liposomal doxorubicin release

kinetics in individual tissues and blood stream by

physiologically based pharmacokinetic (PBPK) modeling.

(2) To establish quantitative physicochemical property

(liposomal size and content of ammonium sulfate)

biodistribution relationships of liposomal doxorubicin

products by PBPK modeling. (3) To extrapolate the PBPK

model to rats and humans. A whole-body PBPK model will

be developed to describe and simulate the biodistribution

of liposomal vesicles and doxorubicin.

Assessment of size- and shape- dependent

toxicity of silver nanoparticles as measured by

changes in the permeability at the

gastrointestinal surface

Study Scientist: Khare

(1) To investigate 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, by determining the effect of

nanomaterials on the permeability of intestinal epithelial

cells in vitro and ileal mucosa ex vivo. (2) To measure the

toxicity of silver nanoparticles as measured by 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 shortterm genetic toxicity test battery

Study Scientist: Mei

To determine (1) the genotoxicity of graphene and

derivatives in standard regulatory test battery assays; (2)

if any mutagenicity in mouse lymphoma cells is due to

loss of heterozygosity in chromosome 11; (3) if genotoxic

and mutagenic response is mediated through oxidative

pathways; and (4) the genotoxic and mutagenic mode of

action using gene expression arrays.

Nanotoxicology

Project Summary

131
Graphene induced toxicity on the population of 

intestinal microbiota and gut-associated 

immune response

Study Scientist: Khare

NCTR/Office of Regulatory Affairs (ORA) 

Nanotechnology Core Facility

Study Scientist: Patri

Assessment of whether engineered silver 

nanomaterials (AG-ENMs) varying by size and 

coatings behave differently than bulk silver in 

their ability to induce genetic damage

Study Scientist: Chen

Determination of cytotoxicity and genotoxicity 

of nanomaterials of interest to the FDA and 

mechanism of action

Study Scientist: Fu

Assessing epigenetic effects of nanoparticles 

in human cells

Study Scientist: Hammons

To evaluate 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.

The goals of the Nanotechnology Core Facility are to (1) 

provide the expertise and equipment for characterization 

of nanomaterials used in toxicology studies, (2) provide 

the expertise and equipment to detect nanomaterials in in 

vitro and in vivo derived samples, and (3) serve as a 

resource for U.S. agencies for the design of toxicology 

studies and generation of standards for analytical 

methods.

(1) To evaluate whether or not the Ames test and mouse 

lymphoma assay, in addition to the in vitro micronucleus 

assay, are suitable for detecting the genetoxicity of 

titanium dioxide nanoparticles, a known rodent carcinogen. 

(2) To investigate Ag-ENPs of various sizes and to 

compare the results to those obtained using bulk silver.

(1) To develop 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) To 

determine if in the presence of nano-metal materials, 

endogenous and dietary antioxidants can display prooxidative activity.

(1) To determine 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) To determine the effect of two types of 

nanoparticles, silver and titanium dioxide, at various particle 

sizes, surface coatings, dosages, and durations of exposure 

on the pattern of global histone modifications, examining the 

full spectrum of histone modifications, and on genome-wide 

profiles of histone modifications in four types of human cells 

(liver, lung, skin, and colorectal). The analysis will include 

comparisons with disease-associated histone modifications. 

(3) To correlate the effect on DNA methylation with its effect 

on DNA methyltransferase expression; correlate the 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.

132
Project & Study Scientist

(1) To understand the distribution and range of

spontaneous oncogene mutant frequencies in the major

organs of rats and mice. (2) To provide important basic

information for the validation of these oncogene mutant

frequencies as biomarkers of chemically induced

carcinogenesis.

To develop and validate a 3-D quantitative structureactivity relationship (QSAR) model for estrogen receptor

binding and provide estrogen binding affinity for

chemicals. (2) To identify structural binding elements. (3)

To evaluate the available databases, including EPA EPcat

and EPA Endocrine Disruptor Screening Program data for

estrogen receptor binding activity.

To evaluate a newly developed transgenic, hairless,

albino mouse bearing a gpt-delta reporter construct (THA)

for (1) responsiveness of the construct (gpt and spired/gam genes) to ultraviolet B radiation (UVB); and (2)

examine kinetics of induction of UVB-induced mutations in

a reporter construct in the dermis and epidermis, and

correlate activity with UVB induction of skin tumors.

To conduct a comprehensive survey of miRNA using the

next generation sequencing technology. The resulting

findings will elucidate the molecular pathways and

processes modulated by RNAs (including mRNAs,

miRNAs and other non-coding RNAs) and their

importance in drug-induced liver injury risk and

phenotypes.

(1) To develop standard baseline criteria for high

throughput readouts of drug-induced arrhythmia in human

iPSC-CMs from different suppliers. (2) To assess

individual variance and possible sex differences in druginduced cardiotoxic responses across a panel of nongenetically modified iPSC lines.

Development of cancer-relevant biomarkers for 

identification of potential carcinogens: research 

to understand the normal background 

frequencies in rats

Study Scientist: McKinzie

Development and validation of 3-D quantitative 

structure-activity relationship (QSAR) models 

for prediction of the binding affinity of 

chemicals from the ToxCast database to the 

estrogen receptor (ER)

Study Scientist: Slavov

Validation of a newly developed transgenic, 

hairless, albino mice

Study Scientist: Manjanatha

Study of translational biomarkers for druginduce liver injury with next-generation 

sequencing

Study Scientist: Wang

A comprehensive characterization of iPSCCMs models for drug-induced arrhythmia using 

high throughput screening assays

Study Scientist: Pang

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: Dobrovolsky

To develop a method that could routinely identify Pig-a

mutations in individual Pig-a mutant phenotype cells.

Bioassay and Biomarker Development and Evaluation

Project Summary

133
Evaluation of microRNAs in blood and urine for 

detection of chemical-induced carcinogenicity 

Study Scientist: Chen

To develop and utilize 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.

(1) To determine miRNAs in blood and carcinogenic target

tissues that respond to exposure of carcinogens, and the

best time for sampling of their expression after the

treatments in rats. (2) To determine miRNA profiles from

the blood and target tissue samples of rats treated with

different mode-of-action carcinogens, such as alkylating

agents, aneugens, clastogens, and non-genotoxic

carcinogens at the appropriate sampling time. (3) To

determine the functions and pathways of the dysregulated

miRNAs by the carcinogen treatments and examine

whether the miRNA changes can be anchored to the

carcinogens with the known mode-of-actions and whether

the changes in blood related to those in the target tissues.

(4) To establish specific miRNA biomarkers in blood for

assessing different types of carcinogens.

Developing in vitro approaches to assess 

drug-induced liver toxicity

Study Scientist: Guo

134
2016 Annual Report Partner Agency Research NTP at NCTR

NCTR Interagency Agreement Projects

https://ntp.niehs.nih.gov/go/807143

Project & Study Scientist

To characterize the long-term toxicity of orally

administered bisphenol A (BPA), including developmental

exposure, in NCTR Sprague Dawley rats over a broad

dose range. In addition, animals generated in this study

will be assigned to separate protocols for assessment of a

range of molecular, morphological, and functional

endpoints to determine if these endpoints are predictive of

long-term toxic effects or reveal potential effects

undetected by standard toxicological evaluations.

Two-year chronic toxicology study of bisphenol 

A (BPA) administered by gavage to NCTR 

Sprague Dawley rats from gestational day 6 

until birth and directly to pups from postnatal 

day 1; continuous and stop-dose exposures 

Study Scientist: Delclos

Evaluation of molecular, morphological, and 

functional endpoints in NCTR Sprague Dawley 

rats treated with bisphenol A (BPA) 

administered by gavage from gestational day 6 

until birth and directly to F1 pups from 

postnatal day 1; continuous and stop-dose

(postnatal day 21) exposures

Study Scientist: Delclos

To evaluate a range of molecular, morphological, and

functional endpoints in rats dosed orally with a wide range

of bisphenol A 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 bisphenol A exposure.

Assessments will be conducted at various ages (postnatal

days 1, 21, and 90, as well as 6 and 12 months) to

determine if any effects observed are predictive of longterm effects evaluated in the companion chronic

toxicology study, or if they reveal potential effects

undetected by standard toxicological evaluations.

NTP at NCTR: Interagency Agreement Projects

NCTR research for NTP is funded by both voluntary allocations and an interagency agreement. Below are

FY 2016 projects that were funded through an NIEHS/NTP interagency agreement with FDA. Click the

project title for a brief summary.

Food Contaminants

Project Summary

- - -

View Research Areas in

Food Contaminants

Dermal Toxicology Program

Dietary Supplement Program

Enhancing Toxicology Program

Show All

Search Projects

135
Combined nephrotoxicity of melamine and 

cyanuric acid in rats – recovery study

Study Scientist: Gamboa

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: Camacho

Role of perinatal development on toxicokinetics 

of inorganic arsenic

Study Scientist: Doerge

To assess 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.

(1) To compare 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 

subsequent 90-day recovery period. (2) To compare the 

dose-response 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.

To determine serum pharmacokinetics and metabolism of 

inorganic arsenic at a low dose in adult female CD-1 mice, 

Sprague Dawley rats, and rhesus monkeys.

Project & Study Scientist

Two-year dermal carcinogenicity of triclosan in

B6C3F1 mice

Study Scientist: Fang

To determine the toxicity and carcinogenicity of topically

applied triclosan in mice.

Project & Study Scientist

Thirteen-week dosed water study to determine

the potential toxicity of aloin in the cecum and

large intestine of F344 rats

Study Scientist: Boudreau

To evaluate whether or not 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.

Project & Study Scientist

NTP capability building for microbiome

assessment on toxicology studies: assessing

the role that the microbiome may play in the

toxicity of xenobiotics

Study Scientist: Cerniglia

To address critical knowledge gaps in the microbiome 

field by using the latest advances in microbiome analysis, 

using in vitro, in vivo, and ex vivo models in toxicity testing 

risk assessments. 

Dermal Toxicology Program

Project Summary

Dietary Supplement Program

Project Summary

Enhancing Toxicology Program

Project Summary

136
Evaluation of genotoxicity and epigenetic 

modification of black cohosh extract (BCE) 

using the modified comet assay

Study Scientist: Manjanatha

(1) To develop exposure and dosimetry methods for

exposing human air-lung interface airway cultures to

aerosolized test agents. (2) To use previously developed

disease-related endpoints and air-lung interface culture

exposure methods to evaluate the respiratory toxicity of

two known airway toxicants, two presumed nontoxicants,

and one compound of current interest.

(1) To perform alkaline single cell gel electrophoresis

(Comet) assays to detect both DNA single and double

strand breaks using several human cell lines. (2) To

perform modified Comet assays using the addition of

uracil-DNA glycosylase (UDG) to evaluate the potential

underlying mechanism(s) of BCE-associated genotoxicity.

(3) To perform 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.

Developing an in vitro system to evaluate the

disease-related toxic effects of inhaled test

agents in human airway tissue models

Study Scientist: Cao

137
About NTP at the National Institute for Occupational Safety and Health

NIOSH research projects for NTP to 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 2016.

2016 Annual Report - Partner Agency Research - NTP at NIOSH

NTP at NIOSH

138
2016 Annual Report Partner Agency Research NTP at NIOSH

About NIOSH

https://ntp.niehs.nih.gov/go/807154

Project & Study Scientist

Exposure assessment research and support

Study Scientist: Striley

To support multiple branch and interdivisional projects

through (1) the management and planning of field sample

About NTP at the National Institute for Occupational

Safety and Health

In following its mandate to protect workers’ health and safety, the National Institute for Occupational Safety

and Health (NIOSH) carries out research projects for NTP to assess the effects of exposure to substances,

through an interagency agreement with NIEHS. Setting priorities in occupational toxicological research is

based upon several sources of information that NIOSH develops and maintains. These 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 for NTP is funded by

both voluntary allocations and an interagency agreement focusing 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 the Division of Surveillance, Hazard Evaluations, and Field Studies

The table below lists NIOSH/NTP projects in FY 2016 funded through voluntary allocations. Click the project

title for a brief summary.

Biomonitoring, Biomarker Dev. & Health Assessment

Project Summary

- - -

View Research Areas in

Biomonitoring, Biomarker Dev. & Health 

Assessment

Environmental Monitoring

Exposure Assessment 

Immunotoxicity and Immunology 

Genetics

Show All

Search Projects

139
collection, (2) the development of new classical and

immunochemical biomonitoring methods, and (3) the

validation and adaptation of existing methods. Biological

monitoring can assess exposure by analyzing acute and

latent metabolites in various biological media. The goal of

this project is to develop low-cost, rapid immunochemical

and analytical chemistry biomonitoring methods that will

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: Snawder

To develop and evaluate 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 result

in more realistic occupational exposure assessments that

allow for rapid interventions leading to reduced worker

exposures and aiding prevention of occupational illness

and disease.

Evaluation of welding fumes as a lung

carcinogen in mice exposed by inhalation

Study Scientist: Erdely

To investigate both carcinogenic-metal 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 will also

generate valuable data regarding the carcinogenic

potential of fumes from different types of welding activities

that may or may not contain carcinogenic metals. In

addition, the project will establish knowledge on which

subcomponents of the total welding fume have the

greatest carcinogenic potency. The results will be

important for the potential reevaluation of welding fume by

the International Agency for Research on Cancer.

Systematic assessment of cobalt oxide (CoO)

and lanthanum oxide (La2O3) in pulmonary

disease

Study Scientist: Qian

To investigate cobalt oxide and lanthanum oxide

nanoparticle–induced pulmonary injury in vivo and cellular

toxicity in vitro. This project will reveal the toxicological

mode of actions for cobalt oxide and lanthanum oxide

nanoparticles. Metal oxide nanoparticles are an important

class of engineered nanomaterials with a broad

application in many industrials. Concerns over potential

metal oxide nanoparticle-induced toxicity have emerged,

140
Mortality, cancer incidence, and biomarker

studies

Study Scientist: Ruder

To elucidate exposure-outcome associations, especially

dose-response relationships, for risk assessment and to

examine relationships between biomarkers of exposure,

susceptibility, and oncogene expression and determine

health effects.

particularly due to their ability 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: Schubauer-Berigan

To collect exposure data from participating pilot-scale or

full-scale manufacturers or users of single-walled or

multiwalled carbon nanotubes and carbon nanofibers. A

study of biomarkers for early pulmonary, cardiovascular,

and carcinogenic effect will be carried out among workers

at these facilities.

Project & Study Scientist

Analytical research and development

infrastructure

Study Scientist: Streicher

To provide for administrative needs and analytical

instrumentation repair and maintenance in support of

Chemical Exposure and Monitoring Branch chemists

conducting research on sampling, and analytical methods

development for workplace chemicals. Development,

evaluation, validation, and use of methods for chemicals

such as bisphenol A, manganese speciation, and flame

retardants are part of the NIOSH/NTP exposure

assessment interagency agreement. In FY 2015, a

method developed for bisphenol A was used to analyze

field samples. The manganese speciation method used to

evaluate field samples has undergone review for formal

inclusion in the NIOSH Manual of Analytical Methods.

Additionally, sampling and analysis methods for flame

retardants were investigated in support of field surveys.

Diacetyl exposure assessment

Study Scientist: Streicher

To develop and evaluate sampling and analytical methods

for diacetyl and other higher molecular weight alpha

dicarbonyl flavoring compounds and enable accurate

exposure assessment and evaluation of the effectiveness

of control technology. Two sampling and analytical

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 and the other

measures these compounds in airborne particles and bulk

powders.

Environmental Monitoring

Project Summary

141
Nanoaerosol monitoring methods

Study Scientist: Birch

To develop and apply measurement methods for

hazardous aerosols. Globally, exposure to hazardous

aerosols remains a serious health concern, with growing

attention on fine, ultrafine, and nanomaterial aerosols.

New nanomaterials are being developed and used in

multiple commercial products, but there is relatively little

knowledge regarding their health and environmental

impacts. Multiple analytical tools are being utilized,

because the properties most responsible for nanoaerosol

toxicity are unclear and exposures are often to complex

mixtures. This research is providing critical exposure data

and information on the widely differing physical and

chemical properties of nanoscale aerosols and materials.

These properties may have influence on particle toxicity.

These methods have general application to exposure

monitoring and control studies. Metal contents were

determined by inductively coupled plasma atomic

emission spectroscopy after microwave digestion in

concentrated nitric acid. In addition, 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. High iron

content was found in most of the samples, and the

residual ash contents of the materials ranged from about

1-10%. In FY 2016, polycyclic aromatic hydrocarbons and

transmission electron microscopy analyses will be

completed.

Project & Study Scientist

Exposure assessment for toxicologically

important chemicals

Study Scientist: Curwin

Industry-Wide Studies Branch research, 

development, and planning

Study Scientist: Whelan

To characterize workplace exposures to chemicals of 

toxicological concern as identified by NTP and NIOSH. 

Current studies include welding fumes with emphasis on 

manganese, occupational exposure to bisphenol A, 

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.

To support strategic planning and feasibility studies of 

high priority and emerging problems in occupational 

health.

Exposure Assessment

Project Summary

142
Dermal permeation of benzene from gasoline

and crude oil: current and historical issues

Study Scientist: Frasch

Nanotechnology field evaluations

Study Scientist: Geraci

To obtain information from as many different facilities in 

the field as possible, regarding (1) the nature of 

engineered nanomaterials, (2) the processes involved in 

their manufacture and use, (3) the potential worker 

exposures, and (4) the work practices and control 

procedures where nanomaterials are produced or used. 

As toxicology studies identify the biologic hazards of 

nanomaterials, it is important to gain a better 

understanding of actual workplace exposures.

To generate and interpret data on the dermal absorption 

potential of benzene from gasoline. Specifically, (1) to 

quantify benzene in a sample of gasoline to be used for 

dermal absorption rate testing; (2) to quantify the dermal 

absorption rate of benzene in gasoline, both steady state 

fluxes from “infinite” dose application and non-steady 

state absorption profiles from finite dose applications; (3) 

to repeat dermal absorption rates using gasoline fortified 

with benzene to mimic historically high levels, and 

undiluted or neat benzene; and (4) to measure the 

thermodynamic activity of benzene in gasoline. This 

research will be used in the dermal risk assessment of 

current and historical benzene exposures.

Project & Study Scientist

Immunotoxicological evaluation of occupational

chemicals

Study Scientist: Anderson

To identify occupational and environmental chemical

hazards and evaluate immune function and mechanisms

associated with exposure. This research will contribute to

better risk assessment and increased identification of

immunological hazards encountered in the workplace,

which will ultimately establish occupational exposure

limits.

Identification of occupational allergens

Study Scientist: Noti (1) To identify 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) To develop improved techniques for the

detection of such immune reactions before adverse

clinical outcomes occur. (3) To develop improved

techniques for the detection and identification of inciting

occupational agents. This project will involve the analyses

of 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.

Immunotoxicity and Immunology

Project Summary

143
Exosomes as biomarkers and immune

modulators of diisocyanate asthma

Study Scientist: Hettick

To define mechanisms underlying methylene

diphenyldiisocyantate (MDI) associated occupational

asthma by identifying biomarkers of MDI exposure and

immune regulatory factors that influence the progression

and severity of MDI associated occupational asthma.

Exposure to MDI, which is used in the manufacturing of

glues and polyurethanes, results in occupational asthma

in approximately five to 15 percent 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 will identify response and

legacy biomarkers found in exosomes secreted into the

bloodstream that would indicate isocyanate exposure and

sensitization. Attempts will be made to distinguish

chemical induced biomarkers from high molecular weight

allergen induced markers, 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 used in future studies

to distinguish MDI associated occupational asthma from

general environmental asthmas.

Characterization of in vivo protein haptenation

following exposure to aerosolized 4,4’-

methylene diphenyl diisocyanate

Study Scientist: Hettick

To determine the molecular targets of inhaled

diisocyanate particulates and better understand the

pathogenic mechanism of isocyanate-induced allergic

disease. The project will enhance 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.

Project & Study Scientist

Immunotoxicity of subchronic fungal exposures

Study Scientist: Nayak

To determine the pulmonary immunopathological 

outcomes of subchronic exposures to fungi nominated to 

the NTP. In FY 2016, subchronic exposure studies with a 

mycotoxin producing strain of Stachybotrys chartarum

were completed and a manuscript was published. 

Future subchronic exposure studies will focus on a low 

tricothescene producing strain of S. chartarum, as well as 

Aspergillus versicolor. Proposed studies will provide

further insight into the mechanisms of pulmonary toxicity 

to fungi encountered in the workplace.

Genetics

Project Summary

144
Immunomodulatory effects of triclosan on 

effector CD4 T cell development

Study Scientist: Marshall

Highly sensitive and practical biomarkers for

nanotoxicity

Study Scientist: Joseph

Toxicological investigations of nitrogen-doped

multiwalled carbon nanotubes

Study Scientist: Porter

To identify the cellular and molecular mechanisms behind 

the immune-modulating effects of the antibacterial 

chemical triclosan. This information will provide the basis 

for evaluating other nonsensitizing antimicrobial chemicals 

and help identify potentially conserved mechanisms that 

contribute to allergic disease. This will help determine the 

need for evaluating these types of workplace chemicals, 

leading to better risk assessment and establishment of 

occupational exposure limits.

To develop, validate, and test in a rat model highly 

sensitive and minimally invasive biomarkers for early 

detection of pulmonary toxicity, potentially associated with 

exposure to toxic nanomaterials. Techniques will be 

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 

will be 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.

To examine the potential effect of altering the chemical 

composition of multiwalled carbon nanotubes on their 

bioactivity in vivo. Knowledge of doping modification may 

allow for the development and use of less bioactive 

multiwalled carbon nanotubes. This may reduce the hazard 

from workplace exposures. Such information may allow 

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 will also 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 will compare two multiwalled carbon nanotubes with 

different chemical compositions, such as multiwalled carbon 

nanotubes and nitrogen-doped multiwalled carbon nanotubes. 

These studies should increase our understanding of the 

toxicological mechanisms responsible for multiwalled carbon 

nanotube-induced pathologies, and may also identify extrapulmonary sites of toxicity resulting from systemic transport of 

multiwalled carbon nanotubes after pulmonary exposure.

145
Toxicological evaluation of pulmonary

exposure to graphenes

Study Scientist: Roberts

Neurological risks associated with workplace

chemicals and nanomaterials

Study Scientist: Sriram

Mechanism of carbon nanotube-induced

carcinogenesis and aneuploidy

Study Scientist: Sargent

Epigenetic changes in response to

nanoparticle exposure

Study Scientist: Ding

(1) To characterize the pulmonary, cardiovascular, and

neurological toxicity that may be associated with

respiratory exposure to graphenes, using an in vivo, tiered

toxicity testing approach that incorporates a doseresponse, time-course model with aspiration of

nanomaterials as the route of exposure. This will be

followed by an inhalation study with a specific particle and

dose identified in the first tier of studies. (2) To determine

potential mechanisms of pathology, when applicable, and

address whether respiratory exposure to graphene

nanomaterials, which differ in size and oxidative form,

pose a risk for work-related illness. This project is from the

Nanotechnology Research Center at NIOSH.

To evaluate potential neurotoxicological effects associated 

with exposure to chemical agents, incidental 

nanoparticles, and engineered nanomaterials experimental 

models. This includes hazard identification, evaluating 

molecular mechanisms of neurotoxicity, and identifying 

potential biomarkers of neurotoxicity. Findings from this 

study may contribute toward developing (1) novel 

biomarkers for monitoring exposures and health effects; 

(2) pre-job planning protocols, hazard and risk assessment

paradigms; and (3) occupational safety standards for

neurotoxic exposures.

In vitro exposure of human cells to one to four nanometer 

diameter single-walled carbon nanotubes disrupts the 

mitotic apparatus, resulting in errors of chromosome 

number. Data comparison with 10-20 nanometer diameter 

multiwalled carbon nanotubes suggests that the diameter 

of the nanotube is important in the genotoxic response, 

and that carbon nanotubes are potentially carcinogenic. A 

study where multiwalled carbon nanotube were inhaled 

utilizing a two-stage initiation and promotion mouse model 

demonstrated that multiwalled carbon nanotube are strong 

promoters of lung adenocarcinoma.

To investigate 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 will be conducted to explain the events 

of WC-Co-induced tumor initiation, promotion, and 

progression. Determining the mechanisms involved in WCCo-induced carcinogenesis and elucidating target146
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: Rojanasakul

Metal oxide nanoparticles (nMOs), including cerium oxide

(nCeO2) and ferric oxide (nFe2O3), are increasingly used

in a variety of industrial and commercial applications with

the potential of releasing particles into the workplace air.

Limited published studies show that pulmonary exposure

to nMOs in animal models causes lung inflammation and

fibrosis at the human exposure relevant dose. The overall

strategy of this project is to determine the effects of

physicochemical properties (size and coating) of nMOs

and their toxicities using a panel of well characterized

nMOs. In vitro study data showed consistent fibrogenic

effect of nCeO2 as observed in animal study. This

supported the project goal to develop an economic in vitro

tool to predict in vivo toxic potential of nMOs. Sub-chronic

exposure of nFe2O3 induced neoplastic transformation of

primary human small airway epithelial cells. The

mechanism of this effect is under investigation. By utilizing

such in vitro/in vivo models, key physicochemical

properties of nMOs affecting their toxic responses were

identified, which may support potential safe-by-design

strategies.

Hydraulic Fracturing: toxicological effects of

silica and diesel exhaust exposure

Study Scientist: Fedan

The toxicities of inhaled hydraulic fracturing sand dust,

alone and in combination with inhaled diesel exhaust that

mimic worker exposures during hydraulic fracturing

operations, are being studied. Effects on several organ

systems are being investigated using a battery of in vivo

and in vitro animal model tests. The initial exposures to

hydraulic fracturing sand dust, using two exposure doses,

is nearly finished. Effects of exposure on the lung,

cardiovascular system, immune systems, brain, skin, and

blood have been examined. The next set of exposures will

be to diesel exhaust, where organ effects will be

investigated.

Pulmonary function and nanoparticle

inhalation: in vivo and in vitro effects

Study Scientist: Fedan

To characterize multiwalled carbon nanotube effects on

critical aspects of lung function in vivo and airway function

in vitro, and provide metrics to enable risk assessment

strategies. In vivo experiments have demonstrated

changes in pulmonary function in animals exposed to

multiwalled carbon nanotubes.

Health effects of inhaled crude oil

Study Scientist: Fedan

To design and build an inhalation exposure system that

delivers crude oil vapor to rats. This system will be used

to study the effects of crude oil vapor inhalation on the

147
A translational in vitro approach to assess

cardiovascular risk

Study Scientist: Erdely

Respiratory exposure to particulates has been associated

to increased mortality from cardiovascular diseases. This

project will develop and test an in vitro model to assess

cardiovascular risk following a pulmonary exposure to

engineered nanomaterials. If successful, these studies will

have direct impacts on future toxicological assessment

methods, as the cardiovascular system appears more

sensitive than typical pulmonary toxicity measurements.

lung, cardiovascular system, immune system, brain, skin,

and blood. Surrogate oil from the Gulf of Mexico, and oil

from the Macondo well, has been obtained. The exposure

system for delivering oil vapor to rats is completed and

awaits calibration gases before the exposures can begin.

Toxicity assessment of carbon nanotubes and

carbon nanofibers from U.S. facilities

Study Scientist: Erdely

To evaluate 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 will

assess general pulmonary and systemic toxicity,

pathology, biodistribution, and genotoxicity.

Toxicity associated with the life cycle of carbon

nanotubes

Study Scientist: Erdely

In vivo and in vitro data suggests exposure to carbon

nanotubes has significant adverse health effects. There is

little data defining the toxicity of carbon nanotubes at each

stage of their production life-cycle (as produced, postproduction modification, and incorporation into

composites), although the numbers of potential exposed

workers increases with each stage. This project will

evaluate the pulmonary response and genotoxicity of

carbon nanotubes at different stages of production.

148
2016 Annual Report Partner Agency Research NTP at NIOSH

NIOSH Immunotoxicology

https://ntp.niehs.nih.gov/go/807158

Project & Study Scientist

To develop monoclonal species-specific antibodies to

recombinant fungal biomarker antigens. The utility of

these antibodies will be important for the quantification of

occupationally-relevant fungal biomarkers, particularly to

those fungi that have been nominated to the NTP.

Identification and characterization of 

cross-reactive fungal biomarkers

Study Scientist: Green

Toxicity of subchronic fungal exposures 

Study Scientist: Green

To characterize the toxicological and pulmonary immune

responses associated with subchronic fungal exposures

using a model that replicates human exposure. This

model utilizes an acoustical generator system, and noseonly exposure chamber to characterize toxicological

endpoints following subchronic exposures to spores

derived from fungi nominated to the NTP. In FY 2016,

subchronic exposure studies with a mycotoxin producing

strain of Stachybotrys chartarum were completed and two

NTP at NIOSH: Immunotoxicology Research

Interagency Agreement on Immunotoxicology Research

The NIEHS and NIOSH interagency agreement provides 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 studies listed in the table below evaluate

unique cohorts of individuals from professions associated with immune-mediated occupational diseases.

The table below lists NIEHS and NIOSH Interagency Agreement on Immunotoxicology Studies in FY 2016.

Click the project title for a brief summary.

Immunotoxicology Studies

Project Summary

- - -

View Research Areas in

Immunotoxicology Studies

Show All

Search Projects

149
Analysis of mycotoxins in dust samples from a

water-damaged building

Study Scientist: Park

To examine potential roles of exposure to fungal toxins on

occupants’ health in water-damaged buildings. Costeffective and robust methods have been developed using

ultra-performance liquid chromatography-tandem mass

spectrometry for simultaneous analysis of 30 fungal

secondary metabolites, including mycotoxins in

environmental samples. The accuracy of the method was

increased by using isotopically labeled (C13) mycotoxin

internal standards to compensate for extraction loss and

matrix effects. Methods to examine stability of mycotoxins

in floor dust stored in different temperature conditions by

analyzing them at different points of time for two years are

being used. Next steps include: (1) quantifying fungal

secondary metabolites including mycotoxins in floor dust

samples collected from a school study conducted in FY

2015 and previous epidemiologic studies of waterdamaged buildings; (2) continuing to collaborate with a

research group in Austria to screen more than 550

microbial metabolites in the dust samples from the school

study; and (3) examining the effect of exposure to fungal

secondary metabolites including mycotoxins on

occupants’ health using statistical models adjusted for

exposures to other microbial agents that were also

measured in the epidemiologic studies.

manuscripts are in preparation. Future subchronic

exposure studies will focus on a low tricothescene

producing strain of S. chartarum, as well as Aspergillus

versicolor. Proposed studies will provide further insight

into the mechanisms of pulmonary toxicity to fungi

encountered in the workplace. Alternaria alternata, mixed

fungal exposures, and other occupationally relevant fungi

identified in concurrent NTP funded diversity studies will

be evaluated in the future. These toxicological studies will

provide novel datasets that will be used to characterize

the hazards that fungal exposure may represent to human

and occupational health.

Identification and characterization of fungal

exposures

Study Scientist: Green

To investigate and characterize the diversity of mold in

indoor and occupational environments using ribosomal

RNA 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. These methodological

approaches have been used to support NIOSH Health

Hazard Evaluations to characterize microbial hazards in

the workplace.

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2016 Annual Report Partner Agency Research NTP at NIOSH

NIOSH Occupationally Relevant

https://ntp.niehs.nih.gov/go/807151

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. FY 2016 efforts listed in the table below address worker exposures 

to welding fumes, nanosized materials, food flavorings, bisphenol A, indium compounds, and other 

industrial chemicals.

NIOSH mobile lab for field studies

The table below lists NIEHS and NIOSH Interagency Agreement Projects on Occupationally Relevant 

Exposures in FY 2016. Click the project title for a brief summary.

- - -

151
Project & Study Scientist

To enable NIOSH scientists to (1) participate in review

and oversight of NTP activities, and (2) attend NTPrelated meetings in Research Triangle Park, North

Carolina and Washington, D.C.

(1) To identify industries, such as construction,

shipbuilding, railroad, manufacturing companies, and

unions involved in welding operations for exposure

assessments where the potential for substantial

manganese exposure exists; (2) develop methods to

identify manganese compounds and different valence

states, based on selective solubility with various welding

fumes matrices; and (3) characterize welding fume

exposures based on welding-associated jobs, tasks, and

processes.

(1) To identify workplaces engaged in the synthesis,

manufacture, and use of engineered nanomaterials; and

(2) characterize workplace exposure to selected

engineered nanoparticles.

Administrative support

Study Scientist: Whelan

Occupational exposure assessment of welding 

fume with emphasis on manganese 

compounds

Study Scientist: Hanley

Exposure assessment of engineered 

nanoparticles

Study Scientist: Geraci

Durability of nanoscale cellulose fibers in 

artificial human lung fluids

Study Scientist: Stefaniak

Occupational exposure to bisphenol A (BPA) in 

the U.S.

Study Scientist: Hines

To investigate 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.

(1) To understand bisphenol A (BPA) use in industry, 

including processes, jobs, and tasks with potential BPA 

exposure; (2) develop air, hand wipe, and surface wipe 

sampling, and analytical methods for BPA, using liquid 

chromatography-tandem mass spectrometry and liquid 

chromatography with ultraviolet detection; and (3) assess 

exposure to BPA among workers through air, hand wipe, 

and urine sample collection.

Occupationally Relevant Exposures

Project Summary

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View Research Areas in

Occupationally Relevant Exposures

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152
Assessment of occupational exposure to 

polycyclic aromatic hydrocarbons (PAHs) in 

coal tar sealant applications

Study Scientist: Hanley

Assessment of occupational exposures to 

flame retardants.

Study Scientist: Estill

To assess exposure to nine alternative flame retardants 

plus a panel of polybrominated diphenyl ethers. Exposure 

will be assessed among workers involved in the 

manufacture, installation, or use of goods containing these 

nine alternative flame retardants. Worksite categories 

included in the study are manufacture of products that use 

flexible polyurethane foams, plastics, or resins; fabrication 

and manufacture of rigid polystyrene foam; cutting, 

installing, or spraying polyurethane foam insulation at 

construction sites; using gymnasiums; manufacture of wire 

harnesses or printed circuit boards; and the fire service 

industry. This study will compare exposures among 

industries, processes, and tasks; determine the route of 

exposure; and make 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 of toxicological studies, 

understanding and use of toxicological studies, and risk 

assessment.

To evaluate 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 percent of the formulation in some 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. These coal tar pitch volatiles contain 

several chemicals known as polycyclic aromatic 

hydrocarbons (PAHs). The focus of this study is on the 

assessment of occupational exposure to PAHs among 

coal tar sealant workers. This study will provide data 

regarding levels of exposure to airborne chemicals that will 

be compared to current NIOSH recommended exposure 

limits for coal tar pitch volatiles, and will report results for 

specific PAH chemicals using NIOSH analytical methods. 

PAHs will be measured in dermal wipe samples, and PAH 

metabolites will be measured in biological samples 

collected from workers to characterize levels present in 

this workforce.

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https://ntp.niehs.nih.gov/go/806981

2016 Annual Report

Letter from Director

FY 2016 at a Glance

Cell Phone Radiofrequency Radiation Program

NIEHS Celebrated 50 Years of Public Health

Completed NTP Reports

Timeline of Events

NTP Workshop Explores Challenges of Botanical Dietary Supplement Safety

Workshop Held on Health Effects of Light at Night

NTP and Partners Launch Tox Testing Challenge

NTP Partners with EPA to Reduce Animal Use for Pesticide Testing

14th Report on Carcinogens

NTP Impact on Regulatory Agencies

Additional Activities

Publications

Learn About Us

Mission and Goals

Organizational Structure and Oversight

Funding

Program Contact Information

Training Opportunities

Interagency Agreements

Scientific and Public Input Opportunities

Nominations

Board of Scientific Counselors

SACATM

Executive Committee

Special Emphasis Panels

Research and Testing

Tox21

About Tox21

Tox21 Projects

Testing and Toxicology Studies

About Testing and Toxicology

Disposition, Metabolism, and Toxicokinetic Studies

Genetic Toxicity

Organ System Toxicity

Modified One-Generation Reproduction Studies

Toxicology and Carcinogenicity Studies

Toxicogenomic Studies

Project Review Committee Approved

NICEATM

About NICEATM

2016 Annual Report - 2016 Annual Report Sitemap

2016 Annual Report Sitemap

154
NICEATM Workshops

NICEATM Support of Tox21

Additional NICEATM Activities

ICCVAM

About ICCVAM

ICCVAM Activities

ICCVAM Test Method Evaluation Activities

ICCVAM International Validation Activities

Literature Analysis

Noncancer Research

Report on Carcinogens

About Report on Carcinogens

RoC Activities

Newly Reviewed Listings for the 14th RoC

RoC Substances Selected for Evaluation

Partner Agency Research

About NTP at NIEHS

NTP at NCTR

About NTP at the National Center for Toxicological Research

NTP at NCTR: Interagency Agreement Projects

NTP at NIOSH

About NTP at the National Institute for Occupational Safety and Health

NTP at NIOSH: Immunotoxicology Research

NTP at NIOSH: Occupationally-Relevant Exposures

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