Welcome to the 2018 Annual Report 

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

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

Read the 2018 Letter from the NIEHS and NTP Director. 

FY 2018 at a Glance Learn About Us Scientific and Public Input 

Opportunities 

 

  NTP Board of Scientific 

Counselors 

 SACATM 

 Scientific Panels 

More 

 Completed NTP Reports and 

Publications 

 NTP Public Health Impact 

 Brian Berridge Takes the Helm 

at the National Toxicology 

Program 

More 

 About NTP 

 Organizational Structure and 

Oversight 

 Interagency Agreements 

 Funding 

More 
 

 

- -

Research and Testing Literature Analysis Partner Agency Research 

 NTP at NIEHS 

 NTP at NCTR 

 NTP at NIOSH 

 Noncancer Research 

 Report on Carcinogens 

 Tox21 

 Testing and Toxicology 

Studies 

 NICEATM 

 ICCVAM 

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 2018. Research Triangle Park, NC: National 

Toxicology Program; 2019. Available from https://ntp.niehs.nih.gov/annualreport/2018 

Director of Office of Liaison, Policy, and Review and Editor in Chief: Mary Wolfe | Managing Editor: Joshua Cleland (ICF) 
 

 

 

 

 

2018 Annual Report – Contents 

Contents 

Contents ..............................................................................................................................................3 

Letter from the NIEHS and NTP Director...........................................................................................6 

FY 2018 at a Glance ............................................................................................................................7 

FY 2018 Timeline...............................................................................................................................9 

Completed NTP Reports and Publications ......................................................................................12 

Publications during FY 2018 ........................................................................................................................ 12 

NTP Public Health Impact................................................................................................................13 

Use of NTP Study Data or Recommendations by Federal and State Health Regulatory and Research 

Agencies in FY 2018.................................................................................................................................... 13 

Brian Berridge Takes the Helm at the National Toxicology Program ...............................................17 

Tox Challenge – Stage Two Winners Announced ...........................................................................18 

New Roadmap Guides Progress toward Replacing Animal Use .....................................................19 

NTP Releases Findings from Two CLARITY-BPA Study Components ...........................................20 

NTP Cell Phone Studies – Experts Recommend Elevated Conclusions .........................................21 

Federal Partners Put Tox21 Plan into Action...................................................................................22 

NTP Framework for Innovation Rolled Out at Board Meeting..........................................................23 

ICCVAM Publishes 2016–2017 Biennial Report..............................................................................24 

PFAS in the Spotlight across the Globe...........................................................................................25 

Additional Activities..........................................................................................................................26 

Learn About Us .................................................................................................................................27 

About NTP .......................................................................................................................................28 

Organizational Structure and Oversight...........................................................................................29 

Interagency Agreements..................................................................................................................30 

FDA/NCTR................................................................................................................................................... 30 

CDC/NIOSH................................................................................................................................................. 30 

NIH/NCATS/DPI........................................................................................................................................... 30 

DOE/ORNL .................................................................................................................................................. 31 

EPA/NCCT................................................................................................................................................... 31 

EPA/NCEA................................................................................................................................................... 31 

NIST ............................................................................................................................................................ 31 

Funding............................................................................................................................................32 

NIEHS Contracts That Supported NTP Activities in FY 2018 ....................................................................... 32 

Program Contact Information...........................................................................................................34 

Scientific and Public Input Opportunities.......................................................................................35 

NTP Board of Scientific Counselors.................................................................................................36 

NTP Board of Scientific Counselors Membership Roster FY 2018 ............................................................... 37 

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2018 Annual Report – Contents 

SACATM..........................................................................................................................................38 

SACATM Membership Roster FY 2018........................................................................................................ 39 

Scientific Panels ..............................................................................................................................40 

NTP Technical Reports Peer Reviewed in FY 2018 ..................................................................................... 40 

NTP Research Reports Peer Reviewed in FY 2018 ..................................................................................... 40 

NTP Report on Carcinogens Monographs Peer-Reviewed in FY 2018 ........................................................ 41 

Training Opportunities .....................................................................................................................42 

NIEHS/NTP Training Program Postdoctoral Fellows in FY 2018.................................................................. 42 

Research and Testing.......................................................................................................................43 

Tox21...............................................................................................................................................44 

Testing and Toxicology Studies.......................................................................................................52 

About Testing and Toxicology Studies ......................................................................................................... 53 

Disposition, Metabolism, and Toxicokinetic Studies ..................................................................................... 54 

Genetic Toxicity Studies............................................................................................................................... 56 

Organ System Toxicity Studies .................................................................................................................... 61 

Modified One-Generation Reproduction Studies .......................................................................................... 65 

Toxicology and Carcinogenicity Studies....................................................................................................... 67 

Toxicogenomic Studies................................................................................................................................ 73 

NICEATM ........................................................................................................................................77 

About NICEATM .......................................................................................................................................... 78 

NICEATM Webinars and Workshops ........................................................................................................... 79 

NICEATM Support of Tox21.......................................................................................................................... 81 

Additional NICEATM Activities ...................................................................................................................... 82 

ICCVAM...........................................................................................................................................86 

About ICCVAM............................................................................................................................................. 87 

A Strategic Roadmap for Establishing New Approaches to Evaluate the Safety of Chemicals and Medical 

Products in the United States....................................................................................................................... 88 

ICCVAM Meetings ........................................................................................................................................ 89 

ICCVAM Test Method Evaluation Activities.................................................................................................. 90 

ICCVAM International Validation Activities ................................................................................................... 92 

Literature Analysis............................................................................................................................94 

Noncancer Research .......................................................................................................................95 

Ongoing Noncancer Health Effects Projects ................................................................................................ 95 

Report on Carcinogens....................................................................................................................99 

About the Report on Carcinogens .............................................................................................................. 100 

Report Activities ......................................................................................................................................... 101 

Report Substances Selected for Evaluation ............................................................................................... 102 

Partner Agency Research...............................................................................................................103 

NTP at NIEHS................................................................................................................................104 

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2018 Annual Report – Contents 

Biomolecular Screening ............................................................................................................................. 105 

NTP Laboratory.......................................................................................................................................... 107 

NTP at NCTR.................................................................................................................................110 

About NTP at NCTR................................................................................................................................... 111 

NTP at NCTR: Interagency Agreement Projects......................................................................................... 123 

NTP at NIOSH ...............................................................................................................................126 

About NTP at NIOSH ................................................................................................................................. 127 

NTP at NIOSH: Immunotoxicology Research ............................................................................................. 135 

NTP at NIOSH: Occupationally Relevant Exposures.................................................................................. 137 

Appendix: Publications during FY 2018........................................................................................140 

NTP Reports and Documents........................................................................................................140 

Research Reports ...................................................................................................................................... 140 

Toxicity Reports ......................................................................................................................................... 140 

Technical Reports ...................................................................................................................................... 140 

RoC Monograph......................................................................................................................................... 141 

Journal Articles and Book Chapters...............................................................................................141 

5 
 

 

 

 

 

 

2018 Annual Report – Letter from Director 

Letter from the NIEHS and NTP Director 

In fiscal year (FY) 2018, NTP continued to advance toxicology 

and inform public health policy by providing information to 

decision makers and the public about substances in our 

environment. Numerous studies were published on substances 

of public health concern, such as flame retardants, cell phone 

radiofrequency radiation, and widely used industrial chemicals. 

Among these is the final report from the CLARITY-BPA core 

study and data sets from CLARITY-BPA grantee studies to 

evaluate the range of potential health effects from BPA in rats. 

In addition, NTP engaged in several activities to advance 

alternatives to animal testing. Particularly noteworthy was 

publication of the Strategic Roadmap for Establishing New 

Approaches to Evaluate the Safety of Chemicals and Medical 

Products in the United States, a consensus perspective 

developed with input from many groups. The “Tox21” consortium 

met to discuss the new Toxicology in the 21st Century (Tox21) 

strategic plan that will continue to refine prediction of chemical 

toxicity to humans. 

NTP continued its systemic review literature activities to identify 

potential hazards for human health. In partnership with the NIH 

Countermeasures Against Chemical Threats (CounterACT) 

Program, NTP conducted a systematic review to assess longterm neurological effects following acute exposure to the 

organophosphorus nerve agent sarin. Antimony trioxide and 

Helicobacter pylori were evaluated for possible listing in the 

congressionally mandated Report on Carcinogens. 

I invite you to read this report to learn about our work and what we 

accomplished in FY 2018 toward advancing toxicology and 

safeguarding public health by generating and communicating 

trusted scientific information. 

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.) 

6 
 

 

 

 

 

 

 

 

2018 Annual Report – FY 2018 Glance 

FY 2018 at a Glance 

FY 2018 Timeline 

Highlighted NTP activities in FY 2018. 

Completed NTP Reports and Publications 

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

NTP reports published in FY 2018 or expected for peer review in FY 2019 are listed. 

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

FY 2018 are provided as an appendix to this section. 

NTP Public Health Impact 

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

need to test and regulate specific chemicals to protect human health. 

Brian Berridge takes the Helm at the NTP 

As NTP’s new Associate Director, Brian Berridge, D.V.M., Ph.D., hopes to help NTP 

integrate cutting-edge toxicology methods, including animal studies, cell-based toxicity 

testing, and data intensive computer modeling. 

Tox Challenge – Stage Two Winners Announced 

NTP names five winners of stage two of the Transform Toxicity Testing Challenge for 

producing practical new rapid chemical testing technologies. 

Roadmap to Guide Progress Toward Replacing Animal Use 

The newly published Strategic Roadmap for Establishing New Approaches to Evaluate 

the Safety of Chemicals and Medical Products in the United States will guide progress 

toward replacing use of animals for safety testing of drugs and chemicals in the 

United States. 

7 
 

 

 

 

2018 Annual Report – FY 2018 Glance 

NTP Releases Findings from Two CLARITY-BPA Study Components 

The newly released draft CLARITY-BPA report presents research from an initiative to 

studying the full range of potential health effects in rats from exposure to 

bisphenol A (BPA). 

NTP Cell Phone Studies — Experts Recommend Elevated 

Conclusions 

A panel of external scientific experts convened by NTP recommended that some 

conclusions be changed to indicate stronger evidence that cell phone radiofrequency 

radiation (RFR) caused tumors in rats. 

Federal Partners Put Tox21 Plan into Action 

The new Toxicology in the 21st Century (Tox21) strategic plan promotes an 

automated, high-throughput approach to rapidly measure the toxicity of chemicals. 

NTP Framework for Innovation 

Speaking to the Board of Scientific Counselors, NTP Associate Director Brian 

Berridge, D.V.M., Ph.D., introduced the NTP Translational Toxicology Pipeline Plan for 

strategic realignment. 

ICCVAM Publishes 2016–2017 Biennial Report 

The Interagency Coordinating Committee on the Validation of Alternative Methods 

(ICCVAM) Biennial Report summarizes activities of 16-member agencies that require, 

use, generate, or disseminate toxicological and safety testing information. 

PFAS in the Spotlight across the Globe 

NIEHS and NTP Director Linda Birnbaum, Ph.D., testifies at the U.S. Senate 

September 26 hearing titled “The Federal Role in the Toxic PFAS Chemical Crisis.”

Additional Activities 

An overview of additional meetings with stakeholders and the scientific community in 

which NTP participated. 

8 
 

 

 

2018 Annual Report – FY 2018 Glance – Timeline of Events 

FY 2018 Timeline 

October 2017 

November 2017 

December 2017 

January 2018 

January 2018 

Peer Review of Draft NTP Approach to Genomic DoseResponse Modeling 

An expert panel was convened October 23–25 to review and 

provide NTP scientific input on the elements of its proposed 

approach. 

Alternative Test Methods to Reduce Vertebrate Animal 

Testing Under TSCA 

On November 2, EPA and NICEATM cosponsored a public 

meeting to obtain input toward development of an EPA strategic 

plan that promotes the development and implementation of 

alternative test methods and strategies. 

NTP Board of Scientific Counselors Meeting 

At the December 7–8 meeting, the BSC heard about the U.S. 

Strategic Roadmap for establishing new approach 

methodologies and various programmatic NTP activities. 

ICCVAM Communities of Practice Webinar: Machine 

Learning in Toxicology 

This January 23 webinar explored the fundamentals of machinelearning approaches and precautions that should be taken when 

evaluating their output. 

Peer Review of the Draft Report on Carcinogens Monograph 

on Antimony Trioxide 

On January 24, an external panel peer reviewed the draft 

monograph and concurred with NTP’s listing recommendation

for antimony trioxide in the Report on Carcinogens. 

9 
 

 

 

 

2018 Annual Report – FY 2018 Glance – Timeline of Events 

Publication of the Strategic Roadmap Guide. 

The roadmap is a resource to guide U.S. federal agencies and January 2018 stakeholders seeking to adopt new approaches that improve 

human relevance and replace or reduce the use of animals. 

March 2018 

April 2018 

April 2018 

May 2018 

Peer Review of Draft NTP Reports on Cell Phone 

Radiofrequency Radiation 

An external panel was convened on March 26–28 to peer review 

two draft reports. The panel voted to accept most conclusions as 

written and recommended changes to some conclusions. 

Predictive Models for Acute Oral Systemic Toxicity 

Workshop 

Scientists were invited to a workshop on April 11–12 to present 

their in silico models of acute oral systemic toxicity for five 

endpoints, which were developed in response to an ICCVAMsponsored project. 

Peer Review of the Draft NTP Research Report on CLARITYBPA Core Study 

On April 26, an external panel was convened to review and 

evaluate the scientific and technical elements of the core study 

and its presentation. 

ICCVAM Public Forum 

On May 24 in-person meeting attendees and webcast viewers 

heard presentations by ICCVAM members on current activities 

related to the development and validation of alternative test 

methods and approaches. 

10 
2018 Annual Report – FY 2018 Glance – Timeline of Events 

NTP Board of Scientific Counselors Meeting 

At its June 20 meeting, the board heard about a strategic 

realignment of NTP’s research and current projects as examples June 2018 of translational toxicology at NTP. 

September 2018 

September 2018 

Scientific Advisory Committee on Alternative Toxicological 

Methods Meeting 

At the September 5-6 meeting, the committee heard 

presentations on the goals of the U.S. Strategic Roadmap for 

new approaches to safety and risk assessment. 

The Monocyte Activation Test for Pyrogen Testing of 

Medical Device Workshop 

NICEATM and PETA International Science Consortium coorganized the September 18 workshop to foster discussion on in 

vitro approaches for medical device pyrogen testing. 

11 
 

 

 

2018 Annual Report – FY 2018 Glance – NTP Reports and Publications 

Completed NTP Reports and Publications 

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

• NTP technical reports document long-term toxicology and carcinogenicity studies, generally of 

2 years’ duration.

• NTP toxicity reports document shorter-term studies, generally up to 13 weeks’ duration.

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

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

• NTP Report on Carcinogens monographs are prepared for candidate substances selected for 

review. Each monograph consists of a cancer evaluation and substance profile to support 

NTP’s policy decision to list the substance in the Report on Carcinogens. 

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

prior to their service. In 2018, NTP completed three technical reports, three toxicity reports, four 

research reports, and one Report on Carcinogens monograph. Full citations for these reports are 

provided in an Appendix, and all NTP reports completed in FY 2018, and in prior years, are available 

on the NTP website. 

Publications during FY 2018 

NTP scientists published more than 250 journal articles and book chapters during FY 2018. Citations 

for these publications are provided in an Appendix. 

12 
 

 

 

 

 

 

 

 

 

 

2018 Annual Report – FY 2018 Glance – Public Health Impact 

NTP Public Health Impact 

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

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

recommendations used by other agencies in FY 2018 are listed below. A full listing is available on the 

NTP website. 

Use of NTP Study Data or Recommendations by Federal and State Health 

Regulatory and Research Agencies in FY 2018 

Notice Summary of Notice NTP Information Cited 

Prohibition of Children’s Toys

and Child Care Articles 

Containing Specified 

Phthalates, Final Rule 

October 27, 2017 

82 FR 49938 

The U.S. Consumer Product Safety 

Commission issued a final rule prohibiting 

children’s toys and child care articles that

contain concentrations of more than 0.1% 

of diisononyl phthalate (DINP), diisobutyl 

phthalate (DIBP), di-n-pentyl phthalate 

(DPENP), di-n-hexyl phthalate (DHEXP), 

and dicyclohexyl phthalate (DCHP). 

NTP (2015). Handbook for Conducting a 

Literature-Based Health Assessment 

Using OHAT Approach for Systematic 

Review and Evidence Integration. 

NTP (2016). 14th Report on Carcinogens. 

NIOSH List of Antineoplastic 

and Other Hazardous Drugs in 

Healthcare Settings: Proposed 

Additions to the NIOSH 

Hazardous Drug List 2018, 

Notice of Draft Document 

Available for Public Comment 

January 14, 2018 

83 FR 6563 

The National Institute for Occupational 

Safety and Health (NIOSH) of the Centers 

for Disease Control and Prevention 

announced the availability for public 

comment of proposed additions to the list of 

antineoplastic and other hazardous drugs 

in healthcare settings, as well as NIOSH 

Policy and Procedures for Developing the 

NIOSH List of Antineoplastic and Other 

Hazardous Drugs in Healthcare Settings. 

NTP (2016). 14th Report on Carcinogens. 

Notice of Proposed 

Rulemaking Title 27, California 

Code of Regulations 

Amendment to Section 25705 

Specific Regulatory Levels 

Posing No Significant Risk: 

Bromodichloroacetic Acid 

January 26, 2018 

Proposition 65 

The California Environmental Protection 

Agency’s Office of Environmental Health 

Hazard Assessment (OEHHA) proposed to 

adopt a Proposition 65 No Significant Risk 

Level of 0.95 micrograms per day for 

bromodichloroacetic acid by amending Title 

27, California Code of Regulations, section 

25705(b). 

NTP (2015). Toxicology Studies of 

Bromodichloroacetic Acid (CAS No. 

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

B6C3F1/N Mice and Toxicology and 

Carcinogenesis Studies of 

Bromodichloroacetic Acid in F344/NTac 

Rats and B6C3F1/N Mice (Drinking Water 

Studies). TR 583. 

Notice of Intent to List: TRIM 

VX 

January 26, 2018 

Proposition 65 

The California Environmental Protection 

Agency’s OEHHA proposed to list TRIM VX 

as known to the state to cause cancer 

under the Safe Drinking Water and Toxic 

Enforcement Act of 1986. 

NTP (2016). NTP Technical Report on 

the Toxicology and Carcinogenesis 

Studies of TRIM VX in Wistar Han [Crl:WI 

(Han)] Rats and B6C3F1/N Mice 

(Inhalation Studies). TR 591. 

Announcement of Second 

Public Comment Period for the 

Draft Technical Support 

Document on the Proposed 

Updates of the Public Health 

The California Environmental Protection 

Agency’s OEHHA announced the 

availability of the revised draft technical 

support document for the proposed 

updates of the Public Health Goals for 

nitrate and nitrite in drinking water. 

NTP (2001). NTP Technical Report on the 

Toxicology and Carcinogenesis Studies of 

Sodium Nitrite (CAS No. 7632-00-0) in 

F344/N Rats and B6C3F1 Mice. TR 495. 

NTP (2014). 13th Report on Carcinogens. 

13 
 

 

2018 Annual Report – FY 2018 Glance – Public Health Impact 

Notice Summary of Notice NTP Information Cited 

Goals for Nitrate and Nitrite in 

Drinking Water 

February 09, 2018 

Proposition 65 

Amendment to Section 25705 

No Significant Risk Level –

Glyphosate 

April 10, 2018 

Proposition 65 

On April 6, 2018, the California Office of 

Administrative Law approved an 

amendment of Title 27, California Code of 

Regulations, section 25705, that 

establishes a No Significant Risk Level of 

1100 micrograms per day for glyphosate. 

NTP (2015). Handbook for Preparing 

Report on Carcinogens Monographs. 

Current Proposition 65 No 

Significant Risk Levels 

(NSRLs) Maximum Allowable 

Dose Levels (MADLs) 

April 17, 2018 

Proposition 65 

Under Proposition 65, California has 

established Safe Harbor levels, which 

include NSRLs for cancer-causing 

chemicals and MADLs for chemicals 

causing reproductive toxicity, for many 

listed chemicals. Exposure levels and 

discharges to drinking water sources that 

are below the safe harbor levels are 

exempt from the requirements of 

Proposition 65. In some instances, 

enforcement actions might have resulted in 

negotiated exposure levels relative to 

specific settlement agreements. 

NTP (1987). Toxicology and 

Carcinogenesis Studies of Chlorendic 

Acid in F344 Rats and B6C3F1 Mice 

(Feed Studies). TR 304. 

NTP (1991). Chemical Status Report. 

NTP (1986). Toxicology and 

Carcinogenesis Studies of C.l. Basic Red 

9 Monohydrochloride in F344/N Rats and 

B6C3F1 Mice (Feed Studies). TR 285. 

NTP (1982). Toxicology and 

Carcinogenesis Studies of D & C Red 9 in 

F344/N Rats and B6C3F1 Mice (Feed 

Study). TR 225. 

National Cancer Institute (NCI) 

(1980). Bioassay of 4,4'-Oxydianiline for 

Possible Carcinogenicity. TR 205. 

NTP (1986). Toxicology and 

Carcinogenesis Studies of Diglycidyl 

Resorcinol Ether in F344/N Rats and 

B6C3F1 Mice (Gavage Studies). TR 257. 

NTP (1986). Toxicology and 

Carcinogenesis Studies of Dimethylvinyl 

Chloride (1-chloro-2-methyl-propene) in 

F344/N Rats and B6C3F1 Mice (Gavage 

Studies). TR 316. 

NTP (1985). Toxicology and 

Carcinogenesis Studies of HC Blue 1 in 

F344/N Rats and B6C3F1 Mice (Feed 

Studies). TR 271. 

NTP (1989). Toxicology and 

Carcinogenesis Studies of 

Hexachloroethane in F344/N Rats 

(Gavage Studies). TR 361. 

Notice of Amendment to On May 9, 2018, the California NTP (2015). Toxicology and 

Section 25705 No Significant Environmental Protection Agency’s Office Carcinogenesis Studies of Vinylidene 

Risk Level (NSRL) for of Administrative Law approved an Chloride (CAS No. 75-35-4) in F344/N 

Vinylidene Chloride amendment of Title 27, California Code of 

Regulations, section 25705, which 

Rats and B6C3F1 Mice (Inhalation 

Studies). TR 582. 

14 
 

 

 

 

 

 

 

2018 Annual Report – FY 2018 Glance – Public Health Impact 

Notice Summary of Notice NTP Information Cited 

May 17, 2018 

Proposition 65 

establishes an NSRL for vinylidene chloride 

of 0.88 micrograms per day. 

Acrylamide 

Notice 

May 21, 2018 

Proposition 65 

The California OEHHA published a notice 

providing information on the existing 

Proposition 65 listing of Acrylamide. 

NTP (2016). 14th Report on Carcinogens. 

Chemical Listed Effective May 

25, 2018 as Known to the 

State of California to Cause 

Cancer: TRIM® VX 

May 25, 2018 

Proposition 65 

The California Environmental Protection 

Agency’s OEHHA added TRIM® VX to the 

list of chemicals known to the State of 

California to cause cancer for purposes of 

Proposition 65. The listing of TRIM® VX 

was based on formal identification by NTP 

that the chemical causes cancer. 

NTP (2016). NTP Technical Report on the 

Toxicology and Carcinogenesis Studies of 

TRIM® VX in Wistar Han [Crl:WI (Han)] 

Rats and B6C3F1/N Mice (Inhalation 

Studies). TR 591. 

Revised Draft Technical 

Support Document on the 

Proposed Updates of the 

Public Health Goals for Cisand Trans-1,2-

Dichloroethylene in Drinking 

Water 

June 01, 2018 

Proposition 65 

The California Environmental Protection 

Agency’s OEHHA announced the 

availability for public comment of the (1) 

revised draft technical support document 

for the proposed updates of the Public 

Health Goals for cis- and trans-1,2-

dichloroethylene in drinking water. 

NTP (2002) NTP Technical Report on the 

Toxicity Studies of Trans-1,2-

dichloroethylene (CAS No. 156-60-5) 

Administered in Microcapsules in Feed to 

F344/N Rats and B6C3F1 Mice. TOX 55. 

Asbestos; Significant New Use 

Rule, Proposed Rule 

June 11, 2018 

40 CFR Part 721 

Under the Toxic Substances Control Act 

(TSCA), EPA proposed a significant new 

use rule for asbestos as defined under the 

Asbestos Hazard Emergency Response 

Act. The proposed significant new use of 

asbestos (including as part of an article) in 

manufacturing (including importing) or 

processing for certain uses identified by 

EPA as no longer ongoing. 

NTP (2016). 14th Report on Carcinogens. 

Authoritative Bodies Tracking 

Table, Notice 

June 13, 2018 

Proposition 65 

The California Environmental Protection 

Agency’s OEHHA revised the table of 

chemicals considered for addition to the 

Proposition 65 list. 

NTP (2014). Toxicology Studies of Cobalt 

Metal (CAS No. 7440-48-4) in F344/N 

Rats and B6C3F1/N Mice and Toxicology 

and Carcinogenesis Studies of Cobalt 

Metal in F344/NTac Rats and B6C3F1/N 

Mice (Inhalation Studies). TR 581. 

NTP (2016). NTP Technical Report on the 

Toxicology and Carcinogenesis Studies of 

Trim VX in Wistar Han [Crl:WI (Han)] Rats 

and B6C3F1/N Mice (Inhalation Studies) 

TR 591. 

Review of the Dust-Lead As part of efforts to reduce childhood lead NTP (2012). Health Effects of Low-Level 

Hazard Standards and the exposure, EPA evaluated the current dustlead hazard standards (DLHS) and the 

definition of lead-based paint (LBP). Based 

Lead. NTP Monograph. 

15 
 

 

2018 Annual Report – FY 2018 Glance – Public Health Impact 

Notice Summary of Notice NTP Information Cited 

Definition of Lead-Based Paint, 

Proposed Rule 

July 02, 2018 

83 FR 30889 

on this evaluation, EPA proposed to lower 

the DLHS from 40 μg/ft2 and 250 μg/ft2 to 

10 μg/ft2 and 100 μg/ft2 on floors and 

window sills, respectively. EPA proposed 

no changes to the current definition of LBP 

due to insufficient information to support 

such a change. 

NTP (2012). NTP Monograph: Health 

Effects of Low-Level Lead. 

The Safer Affordable FuelEfficient (SAFE) Vehicles Rule 

for Model Years 2021-2026 

Passenger Cars and Light 

Trucks, Notice of Proposed 

Rulemaking 

August 24, 2018 

83 FR 42986 

The National Highway Traffic Safety 

Administration and EPA proposed the 

“Safer Affordable Fuel-Efficient Vehicles 

Rule for Model Years 2021-2026 

Passenger Cars and Light Trucks” (SAFE

Vehicles Rule). If finalized, the rule would 

amend certain existing vehicle emissions 

standards and establish new standards, all 

covering model years 2021 through 2026. 

NTP (2014). 13th Report on Carcinogens. 

*CASRN = Chemical Abstracts Service Registry Number 

16 
 

 

 

 

2018 Annual Report – FY 2018 Glance – Berridge Takes Helm at NTP 

Brian Berridge Takes the Helm at the National Toxicology Program 

NTP welcomed Brian Berridge, D.V.M., Ph.D., as its new associate 

director on January 7, 2018. He hopes to help NTP integrate 

cutting-edge toxicology methods, including animal studies, cellbased toxicity testing, and data intensive computer modeling. 

As the former director of Worldwide Animal Research Strategy at 

GlaxoSmithKline (GSK), he led efforts to improve animal and nonanimal methods for testing pharmaceuticals. He has contributed 

this expertise to the federal Scientific Advisory Committee on 

Alternative Toxicological Methods since 2015. 

One part of Berridge’s role at GSK was decreasing dependence on 

animal studies by exploring alternative ways to test drugs under 

development, such as by using cells or computer modeling. These 

alternative toxicological methods are a priority for NTP. 

Berridge worked as a safety assessment pathologist at Eli Lilly and 

Company before moving to GSK, where he served first as a 

regulatory toxicologic pathologist. He is now looking forward to 

applying this experience to the NTP mission. 

Berridge said that it has been satisfying to work in the 

pharmaceutical industry, developing drugs that help people live 

longer and feel better. “I’m interested in a bigger picture, particularly 

now that I have two granddaughters,” he added. “The

environmental public health mission of NTP is really appealing.”

Berridge acknowledged that when environmental pollutants have 

long-term implications, for example, on aging or brain development, 

toxicology can become really challenging. “But it’s a mission worth 

doing,” he said. “It’s not easy, but even incremental progress can

have real impact on people.”

NTP’s mission is not just environmental, it 

includes pharmaceuticals, and part of what 

I’m interested in is how to leverage this full

breadth of resources for toxicology,” 

Berridge said. (Photo courtesy of Steve 

McCaw.) 

17 
 

 

 

 

 

 

2018 Annual Report – FY 2018 Glance – Tox Challenge Stage Two Winners 

Tox Challenge – Stage Two Winners Announced 

Scientists are using high-speed, automated screening 

technologies, called high-throughput screening (HTS) assays, to 

expose living cells or isolated proteins to chemicals. Current HTS 

assays measure toxicity of the chemicals themselves, but do not 

test for metabolites, which are altered forms of chemicals produced 

as the body breaks down the original compound and are 

sometimes more toxic than the original chemical. 

To help capture that missing information, NTP and partners 

launched the Transform Toxicity Testing Challenge in January 

2016. The “Tox Test Challenge” asked teams of scientists to

develop techniques to retrofit existing HTS assays to incorporate 

processes that reflect how the body metabolizes chemicals. After 

selecting semi-finalists in May 2017, the partners named the five 

stage two winners on November 1, 2017. 

The winners produced practical designs for new technologies that 

can rapidly test whether some of the thousands of chemicals in use 

can harm human health: 

• Brian Johnson, Ph.D., Onexio Biosystems, LLC. Johnson created a system that uses the

natural metabolic activity of human liver cells to generate chemical metabolites and then

deliver these metabolites to existing assays. This Metabolism Integrated Cell RepOrter

MicroTiter plate (MICRO MT) system is technically simple and requires little additional

equipment.

• Moo-Yeal Lee, Ph.D., Cleveland State University and Rayton Gerald, Solidus Biosciences. Lee

and Gerald developed a 384-well plate that supports three-dimensional cell cultures. It

includes an array of human liver cells for both gene expression and high-content toxicity

screening.

• Albert Li, Ph.D., In Vitro ADMET Laboratories (IVAL), LLC. Li developed the MetMax Human

Hepatocytes system to serve as an external liver metabolism system. The test chemical is

added to allow metabolism by liver cells. Both the parent chemical and its metabolites then

migrate across a semi-permeable membrane to interact with the target cells.

• Lawrence Vernetti, Ph.D., University of Pittsburgh Drug Discovery Institute. Vernetti developed

a system to supply rodent or human liver cells for co-culture with a second cell or cell-free

assay. It allows both test agents and metabolites to be transferred directly to the test plates.

• Hongbing Wang, Ph.D., University of Maryland School of Pharmacy. Wang developed a cell

culture model that uses a type of cell called human primary hepatocyte. The platform can be

scaled up to an HTS format that allows current cell culture-based assays to produce

physiologically relevant metabolites.

18 
 

 

 

 

 

 

2018 Annual Report – FY 2018 Glance – Strategic Roadmap 

New Roadmap Guides Progress toward Replacing Animal Use 

The Interagency Coordinating Committee on the Validation of 

Alternative Methods (ICCVAM), which includes representatives of 

16 federal government agencies, published the Strategic Roadmap 

for Establishing New Approaches to Evaluate the Safety of 

Chemicals and Medical Products in the United States on January 

30, 2018. The roadmap will guide the replacement of animal use in 

safety testing of drugs and chemicals in the United States. 

Many accepted methods for chemical safety testing rely on 

laboratory animals. It has been demonstrated that non-animal 

testing approaches based on toxicity pathways could better predict 

effects in humans. However, acceptance of such approaches to 

date has been limited by a lack of communication and coordination 

among regulatory agencies, test method developers, and regulated 

industries. 

The roadmap was developed to guide the application of new 

technologies to toxicity testing of chemicals and medical products. 

The roadmap provides a conceptual 

framework for development, evaluation, 

and use of new approach methodologies. 

(Photo courtesy of NTP.) 

The roadmap describes three strategic goals required for progress. 

(1) Connect new test method developers with end users.

(2) Promote flexible approaches for establishing confidence in

new methods.

(3) Ensure that new methods will be used by federal agencies

and regulated industries once validated.

The roadmap describes activities to achieve these goals that 

should be undertaken by regulatory agencies, test method 

developers, regulated industries, funding agencies, and other 

stakeholders. 

The roadmap has been translated into Spanish Chinese, Japanese, 

Korean, and Portuguese. These are available on the NICEATM 

website. 

At its September 5–6, 2018 meeting, members of the Scientific 

Advisory Committee on Alternative Toxicological Methods 

(SACATM) and other experts discussed these actions outlined in 

the roadmap and advised U.S. government scientists on issues that 

should be addressed to replace animal use for safety testing. This 

panel of experts was drawn from industry, academia, and animal 

welfare organizations and meets annually to advise ICCVAM, NTP 

Interagency Center for the Evaluation of Alternative Toxicological 

Methods (NICEATM), and the NIEHS director on activities related 

to ICCVAM’s mission.

19 
 

 

 

 

 

 

 

2018 Annual Report – FY 2018 Glance – CLARITY-BPA Findings 

NTP Releases Findings from Two CLARITY-BPA Study Components 

NIEHS and the U.S. Food and Drug Administration (FDA) 

convened the Consortium Linking Academic and Regulatory 

Insights on BPA Toxicity (CLARITY-BPA) to study the range of 

potential health effects from exposure to bisphenol A (BPA) in rats 

and provide data that can be used for regulatory decisions. 

CLARITY-BPA united standard research practices used by 

regulators, called federal guideline studies, with innovative research 

conducted at universities through grants from NIEHS. One purpose 

of CLARITY-BPA was to assess whether these federal guideline 

studies are sensitive enough to detect health effects from low-dose, 

endocrine-disrupting chemicals. 

CLARITY-BPA has two complementary components: 

(1) Core Study: A two-year guideline-compliant study of potential 

BPA toxicity in rats conducted by FDA’s National Center for 

Toxicological Research (NCTR) with guidance from a CLARITYBPA steering committee. This portion of the project examined 

health endpoints typical of so-called guideline studies, such as 

animal weights, tissue changes, and developmental outcomes. 

(2) Grantee Studies: Studies conducted by 14 university 

researchers that tested a range of additional endpoints, 

including genetic effects, cardiovascular disease, obesity, 

and behavior. These studies used control animals, BPAexposed animals, and BPA-exposed tissues from animals 

handled identically to those in the core study, ensuring that 

animals used in both parts of the study were raised in the 

same conditions and exposed to the same doses of BPA. 

NTP released for public comment a draft report of the core study on 

February 23, 2018. It was reviewed by a panel of external scientific 

experts at NIEHS on April 26, 2018, which agreed with NTP 

conclusions that there were minimal toxic effects of BPA exposure 

in rats for the range of doses studied in the core report. The panel, 

however, recommended revisions to several specific interpretations 

of the study findings, which were considered by NTP and FDA staff 

when they finalized the core study report. 

On September 28, 2018, the CLARITY-BPA program released the 

final report from the CLARITY-BPA core study and the data sets 

from the CLARITY-BPA grantee studies. 

A final integrated report from this collaboration between NIEHS, 

NTP, FDA, and academic researchers is expected in 2019. 

BPA is a chemical produced in large 

quantities and is primarily used in the 

production of polycarbonate plastics, 

including water bottles and epoxy resins. 

BPA is also used in some dental 

sealants and composites. 

20 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2018 Annual Report – FY 2018 Glance – Cell Phone Studies 

NTP Cell Phone Studies – Experts Recommend Elevated Conclusions 

A panel of external scientific experts met at NIEHS March 26–28, 

2018, to review the conclusions of two draft NTP technical reports. 

The goal of the NTP studies was to establish the potential health 

hazard of exposure to cell phone radiofrequency radiation (RFR). 

The $30 million studies took more than 10 years to complete and 

are the most comprehensive assessment to date of health effects 

in animals exposed to RFR with modulations used in 2G and 3G 

cell phones; 2G and 3G networks were standard when the studies 

were designed and are still used for calls and texting. 

The expert panel agreed with NTP conclusions that there was little 

indication of RFR-related health problems in mice, but the panel 

recommended that some findings be changed to indicate stronger 

levels of evidence that RFR caused tumors in rats. Working with 

To detect a potential effect in the studies, the NTP scale of clear evidence, some evidence, equivocal the rodents’ whole bodies were exposed to evidence, and no evidence, the panel made several levels equal to and higher than the highest 

recommendations: level permitted for local tissue exposure in 

cell phone emissions today. More recent 

• Tumors in tissues surrounding nerves in the hearts of male 4G, 4G-LTE, and 5G networks for 

streaming video and downloading rats, called malignant schwannomas, should be reclassified attachments use different cell phone signal from some evidence to clear evidence of carcinogenic frequencies and modulations than NTP 

activity. used in these studies. 

• Malignant schwannomas in female rats should be 

reclassified from no evidence to equivocal evidence of 

carcinogenic activity. 

• A type of brain tumor called malignant glioma and a tumor in 

the adrenal gland called pheochromocytoma should be 

reclassified as some evidence of carcinogenic activity in 

male rats. 

The panel agreed there were unusual patterns of cardiomyopathy, 

or damage to heart tissue, in exposed male and female rats and 

that there were increases in damage to brain tissue in exposed 

male and female rats, which further supported the classifications of 

cancerous effects in the brain. For several other tissues, including 

the prostate and pituitary glands, the panel agreed that tissue 

changes were equivocal, meaning it was unclear if any of these 

tumor increases were related to RFR. 

In the final reports, prepared for release in November 2018, NTP 

concluded there is clear evidence that male rats exposed to high 

levels of RFR developed cancerous heart tumors and that there is 

also some evidence of tumors in the brain and adrenal gland of 

exposed male rats. For female rats, and male and female mice, the 

evidence was equivocal as to whether cancers observed were 

associated with exposure to RFR. 

The final reports represent the consensus of NTP and the panel of 

external scientific experts who reviewed the studies in March 2018. 

21 
 

 

 

 

2018 Annual Report – FY 2018 Glance – Tox21 Plan into Action 

Federal Partners Put Tox21 Plan into Action 

Federal partners gathered at NIEHS May 15–16, 2018, to discuss 

the implementation of the new Toxicology in the 21st Century 

(Tox21) strategic plan. 

For more than a decade, Tox21 has used automation and cellbased tests to rapidly measure the toxicity of chemicals with a 

mechanized, high-throughput approach. 

Under the new strategic plan, NTP Tox21 activities will continue to 

refine prediction of chemical toxicity to humans: 

• Enhanced methods for testing genetic toxicity will assess 

whether chemicals are toxic to thousands of genes in 

specific types of cells. 

• Increased use of stem cells will support study of the effects 

of chemicals on developmental processes. 

• New computational models will help to better predict the 

relationship between external chemical doses and resulting 

chemical concentrations in tissues. 

• The Tox21 consortium will test toxicity in biological systems 

more complex than single cell types. 

• Some testing will be done in alternative species like zebrafish. 

Tox21 is exploring the use of 3-D cellular models or tissue chip 

systems that model the structure and function of different organs, or 

even how these organs interact. Such approaches will not be as 

fast as current Tox21 assays, so testing thousands of compounds 

will have to be carefully strategized. 

The Tox21 consortium will continue to refine its high-throughput 

methods and is also developing performance standards to establish 

confidence in novel approaches. 

22 
 

 

 

 

 

2018 Annual Report – FY 2018 Glance – Framework for Innovation 

NTP Framework for Innovation Rolled Out at Board Meeting 

NTP Associate Director Brian Berridge, D.V.M., Ph.D., introduced 

an updated approach to the organization’s mission at the June

20, 2018, Board of Scientific Counselors (BSC) meeting. 

Berridge described the NTP Translational Toxicology Pipeline 

Plan as a strategic realignment and said the new approach aims 

to inform the present and innovate the future, using 

contemporary tools such as literature analysis, animal studies, in 

vitro systems, and in silico or computational analytics. 

These tools and strategies will be used to advance public health 

and the discipline of toxicology in ways that are translatable, 

predictive, and timely. 

“Our proposal is to innovate at a robust pace and for good 

cause,” said Berridge. “By doing that, we’re linking the

innovations to real problems. So, we’re building tools that we need

to answer the problems we have today.” Berridge aims to

accelerate and improve how NTP processes inform public health 

decisions about chemicals. 

The concepts driving the strategic realignment arose from the 

comprehensive review of NTP operations that Berridge undertook 

upon his arrival. He emphasized the complexity of NTP research 

and the breadth of the organization’s scientific endeavors. 

Much of the remainder of the BSC meeting was devoted to updates 

about NTP research on cell phone RFR, BPA and related 

chemicals, crumb rubber, and more. The scientists presenting the 

updates provided examples of the strategic realignment in action 

and NTP’s long-standing willingness to tackle tough scientific 

problems. 

23 
 

 

 

 

 

 

2018 Annual Report – FY 2018 Glance – 2016–2017 Biennial Report 

ICCVAM Publishes 2016–2017 Biennial Report 

ICCVAM published its 2016–2017 ICCVAM Biennial Report 

summarizing activities of member agencies in August 2018. 

ICCVAM is composed of representatives from 16 regulatory and 

research agencies, including NIEHS, that require, use, generate, or 

disseminate toxicological and safety testing information. 

The report highlights member agency activities in 2016 and 2017 

that supported toxicology innovation as well as regulatory agency 

initiatives to promote the 3Rs (replace, reduce, or refine animal 

use) and to provide information about the use of in vitro methods. 

Compiled by NICEATM, the biennial report summarizes U.S. 

government activities to reduce and replace animal use for 

chemical safety testing. Key ICCVAM and NICEATM 

accomplishments summarized in the report include: 

• Publication of the Strategic Roadmap for Establishing New Approaches to Evaluate the Safety 

of Chemicals and Medical Products in the United States 

• Publication of guidance documents by EPA describing approaches to reduce animal use in the 

testing required for pesticide registration 

• Publication of notices by the U.S. Department of Agriculture describing approaches to reduce 

animal use for vaccine testing 

• Publication of the “Predictive Toxicology Roadmap” by FDA

• Development of a non-animal defined approach by NICEATM and EPA that can identify 

substances that might interact with the androgen receptor 

• Development of a non-animal defined approach by NICEATM and ICCVAM to predict skin 

sensitization risk 

• Development of a proposed method in collaboration with international partners to evaluate 

non-animal approaches to identify skin sensitizers 

• Launch of the NICEATM Integrated Chemical Environment (ICE), an online e-resource that 

provides high-quality curated data and computational workflows for chemical safety 

assessment 

24 
 

 

 

 

2018 Annual Report – FY 2018 Glance – PFAS in the Spotlight 

PFAS in the Spotlight across the Globe 

From the halls of the U.S. Congress to an international gathering in 

Zurich, policymakers, scientists, regulators, and others are 

responding to health concerns about a class of chemicals known 

by the acronym PFAS. 

Per- and polyfluoroalkyl substances, or PFAS, possess a variety of 

useful qualities for industry and commerce. At the same time, they 

are highly persistent in the environment and are linked to effects on 

the immune system, hormone levels, neurodevelopment, 

pregnancy outcomes, cancer, and other health concerns, 

according to the U.S. Agency for Toxic Substances and Disease 

Registry. 

After years of use as firefighting foam and in industrial processes, 

PFAS have been found in both surface and groundwater drinking 

sources, from which they can cause exposures through ingestion, 

inhalation during showering, and absorption through the skin. 

NIEHS-supported research is contributing new insights into the 

ways PFAS might affect the health of individuals and communities. 

NIEHS representatives had opportunities to speak at various 

worldwide venues in 2018 at which they conveyed an urgency that 

we learn more about how these chemicals affect the body, and how 

contaminated water can best be treated: 

NIEHS and NTP Director Linda Birnbaum, Ph.D., along with others 

from EPA, Department of Defense, and Government Accountability 

Office, testified at a hearing of the Senate Subcommittee on 

Federal Spending Oversight and Emergency Management titled 

“The Federal Role in the Toxic PFAS Chemical Crisis” on

September 26, 2018. 

25 
 

 

 

 

 

2018 Annual Report – FY 2018 Glance – Additional Activities 

Additional Activities 

During FY 2018, NTP attended several meetings with stakeholders 

and the scientific community. At the 2018 annual meeting of the 

Society of Toxicology in San Antonio, Texas, staff from NTP and 

NIEHS participated in numerous workshops, symposia, platform 

sessions, education and information sessions, and poster sessions. 

The full program, including all NTP and NIEHS activities, can be 

found at the Society of Toxicology website. At this meeting, NTP 

Director Linda Birnbaum received the annual Arnold J. Lehman 

Award for exemplary scientific contributions to risk assessment and 

the regulation of chemical agents. 

NTP regularly hosts symposia and workshops to discuss the state 

of the science or issues of public health concern. For example, NTP 

held “Pathology Potpourri,” an annual satellite symposium, in

Indianapolis, Indiana, the day before the 2018 Society of 

Toxicologic Pathology meeting. The symposium’s goal was to 

present current diagnostic pathology or nomenclature issues to the 

toxicological pathology community. Proceedings were published in 

the journal, Toxicologic Pathology, including summaries of 

presentations and images of specific pathologies that were used for 

audience voting and discussion on specific diagnostic and 

nomenclature issues. 

NTP also hosted two workshops in FY 2018 related to alternative 

methods development: 

• Using the Monocyte Activation Test as a Standalone Release 

Test for Medical Devices 

• Predictive Models for Acute Oral Systemic Toxicity 

Birnbaum accepted the Arnold J. Lehman 

Award from SOT Vice President Leigh 

Ann Burns Naas, Ph.D. 

(Photo courtesy of SOT.) 

26 
 

 

 

2018 Annual Report – Learn About Us 

Learn About Us 

About NTP 

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: NIEHS, NIOSH, and FDA/NCTR. 

Interagency Agreements 

In FY 2018, NIEHS provided support for NTP activities through interagency 

agreements with other federal agencies. 

Funding 

NTP budget for FY 2018 and contracts that support NTP research. 

Program Contact Information 

General inquiries, websites, and staff directory information. 

27 
 

 

 

 

 

 

 

 

 

2018 Annual Report – Learn About Us – About NTP 

About NTP 

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

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

NTP in 1978 in response to concerns about the potential human 

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

• Coordinate toxicology testing programs within the federal 

government. 

• Strengthen the science base in toxicology. 

• Develop and validate improved testing methods. 

• Provide information about potentially toxic chemicals to 

health agencies, regulatory agencies, research agencies, 

scientific communities, medical communities, and the 

public. 

NTP provides scientific data to regulatory agencies and other 

health-related research groups and interpretation and guidance 

in their appropriate use. The American people and government 

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

strong scientific basis for decisions aimed at protecting public 

health. In the past 40 years, NTP has studied and shared 

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

including dietary supplements, industrial chemicals, consumer 

products, and complex mixtures. 

In following government-wide efforts to increase access to the 

results of federally funded scientific research, NTP maintains open 

communication and dialogue with the public, federal and state 

agencies, industry, nongovernmental organizations, and academic 

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

information, including Federal Register notices, status of and data 

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

notifications through media releases, a calendar of upcoming 

events, and a newsletter, the NTP Update. 

The public and other interested parties can stay abreast of NTP 

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

addition, requests for information can be made through the Central 

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

and an online contact form. 

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

be submitted in response to formal requests for public comment in 

Federal Register notices or informal submissions to the Office of 

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

contact form). 

28 
 

 

 

 

 

2018 Annual Report – Learn About Us – Organization 

Organizational Structure and Oversight 

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

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

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

Sciences of the National Institutes of Health. 

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

NTP. Beginning January 7, 2018, Brian Berridge, D.V.M., Ph.D., serves as NTP Associate Director and 

director of the NTP Division at NIEHS, herein referred to as NIEHS/NTP, which is a focal point for 

many NTP activities. NIEHS and NTP espouse best research practices and embrace developments 

in technology to discover how the environment affects people, maintaining leadership in the field of 

environmental health sciences by applying innovative research to address public health issues. 

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

Elizabeth Whelan, Ph.D., chief of the Industry-wide Studies Branch, and Cheryl Estill, Ph.D., 

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

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

“Immunotoxicity of Workplace Xenobiotics” project through a NIOSH-NIEHS interagency agreement. 

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

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

William Slikker Jr., Ph.D., director of FDA/NCTR, provides management oversight and coordination of 

NTP activities within NCTR. Their scientists partner with other researchers in FDA, other government 

agencies, academia, and industry to provide innovative technology, methods development, vital 

scientific training, and technical expertise. NCTR conducts an array of studies that reflect the NTP 

mission and are critical in supporting FDA product centers and their regulatory roles. 

29 
 

 

 

 

 

 

 

2018 Annual Report – Learn About Us – Interagency Agreements 

Interagency Agreements 

In FY 2018, NIEHS provided support for NTP activities through interagency agreements with other 

federal agencies. 

FDA/NCTR 

Under an interagency agreement, NIEHS provided resources to FDA to conduct toxicology studies on 

FDA-regulated agents and on issues of mutual interest to NIEHS and FDA at the National Center for 

Toxicological Research. Gonçalo Gamboa da Costa, Ph.D., Division of Biochemical Toxicology, is 

FDA project officer of the NCTR-NIEHS interagency agreement and provides oversight and 

coordination of NCTR activities funded under the interagency agreement with NIEHS. These studies 

are designed to provide FDA and other regulatory agencies with hazard identification and doseresponse data to support risk assessment and risk management decisions that could affect public 

health. The interagency agreement supports studies on endocrine-active agents, dietary 

supplements, food additives and contaminants, therapeutics and medicines, cosmetic ingredients, 

nanoscale materials and development of novel toxicological approaches. Studies in these areas have 

produced 18 published NTP technical reports and more than 250 peer-reviewed journal publications. 

The studies have led to an increased understanding of the pharmacokinetics, mode-of-action, and 

dose-response relationships of the substances and to refinements of risk assessment models. 

Further information about NTP at the National Center for Toxicological Research and current 

research can be found in the Partner Agency Research section of this annual report. 

CDC/NIOSH 

NIEHS/NTP provides support to the National Institute for Occupational Safety and Health (NIOSH) of 

the Centers for Disease Control and Prevention (CDC) through two interagency agreements. Studies 

under the interagency agreement on “Immunotoxicity of Workplace Xenobiotics” have assessed the 

potential toxicity of exposures to substances such as fungi, mycotoxins, volatile organic compounds, 

lead, latex, nickel, isocyanates, nanomaterials, and beryllium in occupationally exposed populations 

such as miners, farmers, health care workers, autoworkers, and firefighters. The second interagency 

agreement supports the development of methods to assess complex mixtures, such as asphalt 

fumes, welding fumes, and tungsten fibers, and to conduct occupational exposure assessments to 

identify toxicologically relevant exposures. Research under these agreements in FY 2018 evaluated 

occupational exposure to bisphenol A, alternative flame retardants, and polycyclic aromatic 

hydrocarbons in coal tar sealants. For more information, see the Partner Agency Research section of 

the Annual Report. 

NIH/NCATS/DPI 

This interagency agreement supports ongoing and anticipated studies conducted at the National 

Center for Advancing Translational Sciences/Division of Pre-Clinical Innovation to evaluate highthroughput and high-content screening assays in support of Tox21. Tox21 is a collaboration among 

federal agencies to characterize the potential toxicity of chemicals by using cells and isolated 

molecular targets instead of laboratory animals. This interagency agreement between NIEHS/NTP 

and the division produces data for information-poor substances to help prioritize them for further 

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

predictive modeling for biological response. 

30 
 

 

 

 

 

 

2018 Annual Report – Learn About Us – Interagency Agreements 

DOE/ORNL 

Under this interagency agreement, NTP is working with DOE’s Oak Ridge National Laboratory to

develop tools important to evaluating the use and impact of its work. For example, publication mining 

tools help to evaluate NTP’s impact across the agencies and with stakeholders to whom the work is 

disseminated and to extract and organize data (e.g., potential outcomes and impacts) from NTP’s 

large inventory of documents (e.g., publications and progress reports). 

EPA/NCCT 

With projects under this interagency agreement, EPA’s National Center for Computational Toxicology 

works to accelerate the development and use of advanced methods and models for quantitative and 

qualitative risk assessments of environmental chemicals. Specifically, research in FY 2018 used nontargeted approaches to characterize chemicals present in feminine hygiene products. 

EPA/NCEA 

This IAA between NTP and EPA’ National Center for Environmental Assessment facilitates 

communication and coordination to foster common practices in human health assessments and to 

minimize the differences in hazard assessment methodologies. Through exchange of scientific 

expertise and peer review of work products, the agencies increase the quality and integrity of 

toxicological assessments while ensuring efficient use of federal resources and avoiding duplicative 

effort. 

NIST 

Through an IAA to support the experimental study of cell phone radiofrequency radiation exposure, 

NIEHS/NTP and the National Institute of Standards and Technology collaborated under this 

interagency agreement to develop a new exposure system that addresses the limitation in existing 

systems. In a separate agreement, the NIST Text Analysis Conference, NIST assisted NTP with 

development of automated systematic review methods. 

31 
 

 

 

2018 Annual Report – Learn About Us – Funding 

Funding 

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

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

have been determined. The total NTP budget for FY 2018 was $136.7 million. 

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

laboratories or interagency agreements with other agencies. In FY 2018, NIEHS funded 30 contracts, 

listed below, held two workshops, three peer-review meetings, two Board of Scientific Counselors 

meetings, and one scientific advisory meeting. CDC and FDA could have additional contracts that 

support some of their voluntary NTP efforts. 

NIEHS Contracts That Supported NTP Activities in FY 2018 

Description Contractor 

Analytical Chemistry Services Battelle Memorial 

Midwest Research Institute 

Research Triangle Institute 

Archives and Specimen Repository Experimental Pathology Laboratories 

Bioinformatics Methylation Project Laboratory Corp of America 

32 
 

 

 

 

 

2018 Annual Report – Learn About Us – Funding 

Description Contractor 

Bioinformatics Support SCIOME, LLC. 

Collaborative Work with Ramazzini DOE/ORISE 

Evaluation of Alternative Toxicological Methods Integrated Laboratory Systems 

Evaluation of Toxicity Following Early Life Exposure Southern Research Institute 

Evaluation of the Toxicity of Selected Chemicals Battelle Memorial 

Genetic Toxicity Testing Support Services Integrated Laboratory Systems 

Immunotoxicity Burleson Research Technologies 

In-Life Data Collection and Management System INSTEM, LSS 

Kelly Scientific Government Services Kelly Scientific 

NTP Information Systems Support Signature Consulting Group, LLC 

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. 

Provision for Animals and Specialized Services Charles River Laboratories 

The Jackson Labs 

Taconic Biosciences 

Quality Assessment Support/Audits & Inspections CSS-Dynamac Corporation 

Reproductive Assessments by Continuous Breeding Research Triangle Institute 

Scientific Information Management and Literature-Based 

Evaluations for the NTP 

ICF 

Statistical Support Social and Scientific Systems 

Support for Toxicological Data Vistronix, LLC 

Support Services for Clinical Research Studies Social and Scientific Systems 

Toxicological and Carcinogenic Potential of Chemicals Battelle Memorial 

33 
2018 Annual Report – Learn About Us – Contact Information 

Program Contact Information 

For general inquiries, contact: 

Central Data Management 

P.O. Box 12233, MD K2-05 

Research Triangle Park, NC 27709 

984-287-3211 

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

A Staff Directory is available. 

34 
 

 

 

2018 Annual Report – Scientific and Public Input Opportunities 

Scientific and Public Input Opportunities 

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. 

Scientific Advisory Committee on Alternative Toxicological Methods 

The Scientific Advisory Committee on Alternative Toxicological Methods (SACATM) 

provides advice on priorities and activities related to alternative toxicological test 

methods. 

Scientific 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. 

Training Opportunities 

NTP offers postdoctoral training fellowships designed to prepare trainees for careers in 

science. 

35 
 

 

 

2018 Annual Report – Scientific and Public Input Opportunities – BSC 

NTP Board of Scientific Counselors 

The NTP Board of Scientific Counselors (BSC), a federally chartered advisory group whose members 

are appointed by the Secretary of Health and Human Services, oversees the scientific merit of NTP 

programs and activities. The BSC includes scientists, primarily from the public and private sectors, 

with expertise relevant to NTP activities. The current roster and meeting minutes are available on the 

NTP website. In FY 2018, Mary Wolfe, Ph.D., served as the designated federal officer for the BSC. A 

list of FY 2018 members follows. 

The Board met twice in FY 2018: December 7–8, 2017 and June 20, 2018. Materials and highlights 

from each meeting can be accessed on the Past NTP Board of Scientific Counselors Meetings web 

page. The June meeting was Dr. Brian Berridge’s first meeting as new NTP Associate Director. At 

that meeting, Dr. Berridge introduced an updated approach to the organization’s mission and also 

described the NTP Translational Toxicology Pipeline Plan as a strategic realignment aimed to inform 

the present and innovate the future using contemporary tools such as literature analysis, animal 

studies, in vitro systems, and in silico or computations analytics. These tools and strategies would 

yield fit-for-purpose products that advance public health and the discipline of toxicology in ways that 

are translatable, predictive, and timely. 

NTP Board of Scientific Counselors members and NTP staff at the June 2017 BSC meeting 

36 
 

 

 

 

2018 Annual Report – Scientific and Public Input Opportunities – BSC 

NTP Board of Scientific Counselors Membership Roster FY 2018 

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. 

Head of Nonclinical Sciences 

Seatte Genetics 

Bothell, Washington 

6/30/19 

Paul Brandt-Rauf, Dr.P.H., M.D., Sc.D. 

Office of the Dean 

Drexel University 

Philadelphia, Pennsylvania 

6/30/20 

Myrtle Davis, D.V.M., Ph.D. 

Executive Director, Discovery Toxicology, 

Pharmaceutical Candidate Optimization 

Bristol-Myers Squibb 

Princeton, New Jersey 

6/30/20 

Daniel Kass, M.S.P.H. 

Senior Vice President, Environmental 

Health 

Vital Strategies 

New York, New York 

6/30/19 

Kenneth McMartin, Ph.D. 

Board Chair 

Professor, Pharmacology, Toxicology, and 

Neuroscience 

Louisiana State University Health 

Science Center 

Shreveport, Louisiana 

6/30/19 

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

Associate Vice President, Precision Health 

Sciences Center 

Arizona Health Sciences Center 

Tucson, Arizona 

6/30/19 

Jennifer Sass, Ph.D. 

Senior Scientist 

Natural Resources Defense Council 

Washington, District of Columbia 

6/30/20 

James Stevens, Ph.D. 

President 

Paradox Found Consulting Services, 

LLC 

Apex, North Carolina 

6/30/19 

Donald G. Stump, Ph.D., D.A.B.T. 

Vice President, Nonclinical Safety Science 

WIL Research 

Ashland, Ohio 

6/30/20 

Katrina Waters, Ph.D. 

Deputy Director, Biological Sciences 

Division 

Pacific Northwest National Laboratory 

Richland, Washington 

6/30/19 

37 
 

 

 

2018 Annual Report – Scientific and Public Input Opportunities – SACATM 

SACATM 

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

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

Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Authorization Act of 

2000 (42 U.S.C. 285l-3[d]). SACATM advises ICCVAM, the NTP Interagency Center for the 

Evaluation of Alternative Toxicological Methods (NICEATM), and the director of NIEHS and NTP 

regarding statutorily mandated duties of ICCVAM and activities of NICEATM. SACATM provides 

advice on priorities and activities related to the development, validation, scientific review, regulatory 

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

alternative toxicological test methods. The SACATM charter and current roster are available on the 

NTP website, and the roster for FY 2018 is listed below. SACATM typically meets once a year and 

members serve rotating terms of up to 4 years. Elizabeth Maull, Ph.D., served as the FY 2018 

designated federal officer and manager of SACATM. 

SACATM met on September 5–6, 2018, at the NIEHS Rodbell Auditorium in Research Triangle Park, 

North Carolina. In January 2018, ICCVAM published the Strategic Roadmap for Establishing New 

Approaches to Evaluate the Safety of Chemicals and Medical Products in the United States. The 

SACATM meeting focused on implementation efforts for the three strategic goals required for its 

progress: 

• Connect new test method developers with end users. 

• Promote flexible approaches for establishing confidence in new methods. 

• Ensure that new methods will be used by federal agencies and regulated industries once 

validated. 

Members of SACATM and ICCVAM and staff from NIEHS and NTP at the September 2018 SACATM meeting 

38 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2018 Annual Report – Scientific and Public Input Opportunities – SACATM 

SACATM Membership Roster FY 2018 

Name and Title Affiliation Term End Date 

Michael B. Bolger, Ph.D. 

Chief Scientist 

Simulations Plus, Inc. 

Lancaster, California 

11/30/20 

Kelly P. Coleman, Ph.D., D.A.B.T., 

R.A.C. 

Distinguished Scientist and Technical 

Fellow 

Medtronic PLC 

Minneapolis, Minnesota 

11/30/20 

Hisham K. 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 

Executive Director of Lead Discovery 

Epizyme, Inc. 

Cambridge, Massachusetts 

11/20/18 

Lawrence M. 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. 

Committee Chair 

Director of Regulatory and Product 

Stewardship 

ANGUS Chemical Company 

Buffalo Grove, Illinois 

11/30/19 

ClarLynda Williams-Devane, Ph.D. 

Director, Bioinformatics, Genomics, 

and Computational Chemistry 

Biotechnology Biomedical Research 

Institute 

North Carolina Central University 

Durham, North Carolina 

11/30/20 

Wei Xu, Ph.D. 

Associate Professor, Department of 

Oncology 

McArdle Laboratory for Cancer 

Research 

University of Wisconsin at Madison 

Madison, Wisconsin 

11/30/18 

Hao Zhu, Ph.D. 

Assistant Professor, Department of 

Chemistry 

Rutgers University 

Camden, New Jersey 

11/30/19 

39 
 

 

 

-

2018 Annual Report – Scientific and Public Input Opportunities – Scientific Panels 

Scientific Panels 

NTP convenes ad hoc scientific panels, referred to as special emphasis panels, to provide 

independent scientific peer review and advice on targeted issues, such as agents of public health 

concern, new and revised toxicological test methods, and others. All panel reviews provide the 

opportunity for public comment. These panels help ensure that NTP receives transparent, unbiased, 

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

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

NTP Technical Reports Peer Reviewed in FY 2018 

NTP technical reports are published results of long-term studies, generally 2-year rodent toxicology 

and carcinogenesis studies. For each technical report, the panel is charged with reviewing the 

scientific and technical elements and presentation of the study and determining whether the study’s 

experimental design and conduct support NTP conclusions regarding the carcinogenic activity of the 

substance tested. 

The draft technical reports, listed below, underwent peer review in FY 2018. Additional information 

about past technical reports’ peer-review meetings can be found on the NTP Technical Reports PeerReview Panels web page. 

Topic Technical Report 

Number Use Peer Review Information 

Studies in Rats Exposed 

to Whole-body Radio 

Frequency Radiation at 

a Frequency (900 MHz) 

Used by Cell Phones 

TR-595 Utilized in cell 

phones to 

transmit between 

the devices and 

the network. 

Actions 

Peer-Review Report 

Studies in Mice Exposed 

to Whole-body Radio 

Frequency Radiation at 

a Frequency (1,900 

MHz) Used by Cell 

Phones 

TR-596 Utilized in cell 

phones to 

transmit between 

the devices and 

the network. 

Actions 

Peer-Review Report 

NTP Research Reports Peer Reviewed in FY 2018 

Research report peer-review panels are technical, scientific advisory bodies established on an asneeded basis to review drafts reports. 

The draft research reports, listed below, underwent peer review in FY 2018. Additional information 

about past research reports’ peer-review meetings can be found on the NTP Research Reports PeerReview Panels web page. 

40 
 

 

 

 

 

 

-

-

2018 Annual Report – Scientific and Public Input Opportunities – Scientific Panels 

Topic 

Research 

Report 

Number 

Aim Peer Review 

Information 

National Toxicology Program 

Approach to Genomic DoseResponse Modeling 

RR-05 With expert input, outline NTP’s approach

for in vivo and in vitro genomic doseresponse studies. 

Actions 

Peer-Review 

Report 

The CLARITY-BPA Core Study: A 

Perinatal and Chronic ExtendedDose-Range Study of Bisphenol A in 

Rats 

RR-09 Characterize the toxicological potential of 

bisphenol A (BPA) following perinatal-only or 

a chronic exposure in rats exposed to BPA. 

Peer-Review 

Report 

NTP Report on Carcinogens Monographs Peer-Reviewed in FY 2018 

The Report on Carcinogens monographs are prepared for each candidate substance selected for 

review and consist of a cancer evaluation component and a substance profile. For each monograph, 

the panel is 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, the panel is charged with commenting on whether the scientific justification 

presented supports the preliminary NTP policy decision on the Report on Carcinogens listing status. 

The draft Report on Carcinogens monographs, listed below, underwent peer review in FY 2018. 

Additional information about past Report on Carcinogens monographs’ peer-review meetings can be 

found on the NTP Report on Carcinogens Monographs Peer-Review Panels web page. 

Chemical/Topic CASRN* Use/Aim Peer Review 

Information 

Antimony Trioxide 1309-64-4 Used as a flame retardant in canvas, textiles, paper, and 

plastics; also used in batteries, enamels, paint pigment, 

ceramics, and fiberglass. 

Actions 

Peer-Review Report 

Night Shift Work and 

Light at Night 

— Evaluate potential carcinogenic hazard from working night 

shifts and being exposed to aberrant lighting conditions at 

night. 

Actions 

Peer-Review Report 

*CASRN = Chemical Abstracts Service Registry Number 

41 
 

 

 

 

2018 Annual Report – Scientific and Public Input Opportunities – Training Opportunities 

Training Opportunities 

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

careers in pharmaceutical and chemical industries, regulatory agencies, and academia. In FY 2018, 

NIEHS/NTP staff mentored 20 postdoctoral fellows at NIEHS in six focal areas (below). Full details on 

opportunities, benefits, and the application process can be found on the NIEHS training website. The 

training program has six focal areas: 

(1) Applied Toxicology and Carcinogenesis 

(2) Biomolecular Screening and Computational Toxicology; Alternative Methods 

(3) Health Assessment and Translation 

(4) Laboratory Animal Medicine 

(5) Systems and Mechanistic Toxicology 

(6) Toxicological Pathology 

NIEHS/NTP Training Program Postdoctoral Fellows in FY 2018 

Training Program Fellow 

Applied Toxicology and Carcinogenesis Anika Dzierlenga 

Kelly Shipkowski 

Madelyn (Mimi) Huang 

Troy Hubbart 

AtLee Watson 

Biomolecular Screening and Computational Toxicology Sreenivasa Ramaiahgari 

Katelyn Lavrich 

Alex Borrel 

Health Assessment and Translation none 

Laboratory Animal Medicine Manushree Bharadwaj 

David Crizer 

Jingli Liu 

Tony Luz 

Xian Wu 

Systems and Mechanistic Toxicology Gopi Gadupudi 

Miaofel Xu 

Janice Harvey 

Donna Webb-Wright 

Toxicological Pathology Daven Jackson-Humbles 

Gregory Krane 

Eui Jae Sung 

42 
 

 

2018 Annual Report – Research and Testing 

Research and Testing 

Tox21 

Toxicology in the 21st Century (Tox21) 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) 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 at NIEHS. 

43 
 

 

 

 

2018 Annual Report – Research and Testing – Tox21 

Tox21 

Toxicology in the 21st Century (Tox21) is a unique federal 

collaboration among the National Institutes of Health (NIH), 

including the National Toxicology Program (NTP) at the 

National Institute of Environmental Health Sciences (NIEHS) 

and the National Center for Advancing Translational Sciences 

(NCATS), Environmental Protection Agency (EPA), and U.S. 

Food and Drug Administration (FDA). Its purpose is to develop 

new methods to rapidly test whether chemicals adversely 

affect human health. Tox21 uses robotic, high-throughput 

screening methods and other testing approaches to evaluate 

large numbers of chemicals quickly and efficiently to provide 

insight into potential human health effects. Bioinformatics and 

computational toxicology support for Tox21 is provided by Tox21 

members, including members of the Biomolecular Screening 

Branch and the NTP Interagency Center for the Evaluation of 

Alternative Toxicological Methods. 

NTP Tox21 projects in FY 2018 were carried out by the NIEHS/NTP staff listed below. 

Assay Development 

Project 

Study Scientist 

Project Summary 

Development of a stable cell line to screen This project focuses on the development of an assay to detect compounds 

compounds that affect the estrogen-related that interfere with a critical pathway for metabolic homeostasis. Stable 

receptor alpha/peroxisome proliferator- human cell lines expressing the appropriate reporter construct were 

activated receptor coactivator pathway successfully generated. Quantitative high-throughput screening efforts, 

including the full Tox21 10K library, were the subject of two peer-reviewed 

Alex Merrick, Tina Teng, Kristine Witt manuscripts published in FY 2017 and FY 2018. Another manuscript, “HighThroughput Screening," which describes the receptor antagonism results, is 

in preparation for submission in early 2019 to a special issue of the journal 

Molecules. 

Use of HepaRG cells for high-content 

screening 

Stephen Ferguson, Sreenivasa 

Ramaiahgari 

This study examines the establishment of metabolically functional human 

HepaRG liver cells (derived from a human hepatic progenitor cell line) for 

completing multiplex, high-content screening assays. Studies to 

characterize the metabolism of xenobiotic compounds in these cells began 

in FY 2016 and research continuing into FY 2018 examined the metabolic 

function of these HepaRG liver cells in response to 24 reference 

compounds with known effects on human liver. High-throughput 

transcriptomics were incorporated in these studies to help characterize 

liver-like responses of these cultures. A manuscript is currently under 

review for publication in 2019. 

Testing of gene signatures and profiles in 

NTP archival tissues 

Alex Merrick, Julie Foley 

This study is determining whether RNA and DNA extracted from fixed tissue 

and frozen tissue blocks can be used to measure gene signatures and 

mutational profiles based on studies of chemical exposure to toxic 

compounds. The goal is to measure molecular changes caused by 

chemical exposures in rat and mouse organs. A study investigating 

mutational signatures utilizing a newly developed rat exome-sequencing 

platform was published in FY 2018. 

44 
 

 

 

 

 

 

 

2018 Annual Report – Research and Testing – Tox21 

Project 

Study Scientist 

Project Summary 

Screening of chemical toxicity in stem cells 

Stephen Ferguson, Fred Parham, Jui-Hua 

Hsieh, Mamta Behl 

This study screened for chemical toxicity in human or mouse stem cell lines 

(undifferentiated or differentiated) by using quantitative high-throughput 

screening or lower throughput assays. Data were generated on a library of 

80+ predominantly developmental neurotoxicants evaluated for (1) effects 

on neurite outgrowth in a human stem cell-derived neural cell population, 

(2) cytotoxicity in different neural populations derived from human stem 

cells, and (3) effects on the beating of human stem cell-derived 

cardiomyocytes. Dose-response analyses have been completed on the 

data from these assays. Two manuscripts were published in FY 2017 and 

two in FY 2018. 

High-throughput assays and computational This project entails developing an approach for using validated ToxCast 

models to replace current EPA Endocrine and Tox21 high-throughput assays and an associated computational model 

Disruptor Screening Program Tier 1 tests to replace three Tier 1 tests currently used to assess estrogenic activity in 

the EPA Endocrine Disruptor Screening Program. The approach was Warren Casey, Nicole Kleinstreuer developed and validated by EPA and NICEATM scientists. The method has 

been described in several publications. In FY 2017, a similar computational 

model was developed for androgenic activity. In FY 2018, the androgen 

computational model was evaluated against the rodent Hershberger and 

other in vivo tests with androgen-responsive endpoints. 

Liquid biopsy: Circulating cell-free DNA as 

a predictor of chemical toxicity 

Julie Foley, Alex Merrick 

Methods were developed for extracting circulating cell-free DNA (ccfDNA) 

from human, rat, and mouse plasma. ccfDNA changes can serve as a liquid 

biopsy and might help predict or better describe toxicity in affected tissues 

during chemical exposure. The amounts and sequence changes of ccfDNA 

are being investigated as new biomarkers for chemical toxicity and disease 

as part of this project. An NIEHS ccfDNA workshop was held in FY 2018. 

NTP studies are underway to assess ccfDNA changes after chemical 

exposure in mice and rats. 

Liquid biopsy: miRNA as a tissue and cellspecific biomarker of underlying organ 

injury 

Alison Harrill 

Prior experiments indicated that kidney injury biomarkers are leaked into 

the urine following kidney injury, including proteins and miRNA derived from 

kidney cells that can serve as sensitive injury biomarkers. This project is 

using RNA-seq to identify cell-type specific miRNA abundance in the kidney 

to identify biomarkers of specific underlying pathology. The project, focused 

on miRNA specific to the glomerulus, proximal tubule, loop of Henle, and 

collecting duct, is a collaboration through the Health and Environment 

Sciences Institute with Bristol-Myers Squibb, Sanofi, Bayer, Abcam, and 

EPA. In a parallel effort, the project team is currently writing a review article 

on technical challenges of miRNA biofluid measurements. 

Tox21 Cross-Partner Project: In vitro 

pipeline to assess population 

toxicodynamic variability for chemicals 

suspected to cause developmental 

neurotoxicity 

Alison Harrill, Richard Paules, Kristine Witt 

This project encompasses the development of a computational and cellular 

testing framework for assessing genetic susceptibility to chemical agents 

suspected of causing developmental neurotoxicity. A Tox21 Cross-Partner 

Project, it is a collaboration with FDA and EPA in which ~200 Diversity 

Outbred mouse neural progenitor cell lines will be exposed to a chemical 

test battery. Cellular effect potency will be assessed using high-content 

imaging techniques. In FY 2018, a Bayesian statistical framework was 

developed and implemented to quantify inter-individual variability and 

cytotoxicity data were analyzed. 

Tox21 Cross-Partner Project: Retrofitting 

existing Tox21 HTS assays with metabolic 

capability 

This project aims to refine existing methods to (1) imbue Tox21 assays with 

metabolic capability, (2) screen the Tox21 10K compound collection using 

these new methods to identify chemicals that are either bioactivated or 

45 
 

 

 

 

 

 

 

 

 

2018 Annual Report – Research and Testing – Tox21 

Project 

Study Scientist 

Project Summary 

Kristine Witt detoxified by liver cytochrome P450s and cofactors, and (3) identify the 

particular CYPs responsible for observable shifts in bioactivity. 

The p53RE-bla assay will be used initially to test this approach. 

Subsequently, metabolism will be incorporated into high-throughput screens 

by running the Real Time Cell Viability assay and the material-mediated 

pyrogens assay, which have a profile of CYP enzymes similar to that of 

primary human hepatocytes. 

Data Analysis 

Project 

Study Scientist 

Project Summary 

Analysis of Tox21 quantitative highthroughput screening assay data 

Jui-Hua Hsieh 

Data analysis pipelines are being developed for Tox21 Phase II quantitative 

high-throughput screening data to determine the activity of compounds in 

assays. 

The developed ranking, or calling procedure, accounts for compound 

potency, efficacy, and data reproducibility. A manuscript describing this 

pipeline was published, and computational tools to analyze Tox21 data 

have been made publicly available through the Tox21 Toolbox on the NTP 

public website. 

Prioritization of Tox21 compounds for 

genotoxicity 

Jui-Hua Hsieh, Kristine Witt, Stephanie 

Smith-Roe, Scott Auerbach, Alex Merrick 

A prioritization approach is being developed that includes compounds 

showing clear evidence of activity in the quantitative high-throughput 

screening genotoxicity assays and compounds that are weakly active based 

on chemical structure-activity relationship analysis. 

A manuscript using this approach as part of the analysis of the Tox21 

quantitative high-throughput screening p53 activation assay was published 

in FY 2017. In FY 2018, a more extensive modeling exercise was 

completed using data from all Tox21 quantitative high-throughput screening 

assays. 

Design of Tox21 data exploration graphical 

user interface 

Jui-Hua Hsieh 

This project entails the development of two graphical user interfaces for 

viewing Tox21 data. One graphical user interface is used to explore the 

concentration-response data in a line chart, and the second is used to 

explore compound similarity relationships in terms of their chemical 

structures and activities in Tox21 quantitative high-throughput screening 

assays. 

Prototype graphical user interfaces were first developed during FY 2013 

and made public in FY 2015. In FY 2018, these computational tools to 

analyze Tox21 data were developed further and expanded and made 

publicly available through the Tox21 Toolbox on the NTP public website. 

Unsupervised, data-driven analysis of 

Tox21 assay data project 

Scott Auerbach, Nicole Kleinstreuer 

This unsupervised data analysis is focusing on 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. An updated web interface for multiple integrated tools 

46 
 

 

 

 

2018 Annual Report – Research and Testing – Tox21 

Project 

Study Scientist 

Project Summary 

was made public in FY 2018, along with a supporting manuscript, and 

further updates were begun for release in FY 2019. 

Basic machine learning workflows using the Tox21 data for model building 

and data exploration are available on ICE. 

High-throughput in vitro-in vivo 

extrapolation (IVIVE) using Tox21 data 

Nisha Sipes, Warren Casey, Nicole 

Kleinstreuer 

This project entails the development and refinement of ways to extrapolate 

all Tox21 chemical-concentration effect data to estimated human equivalent 

exposure doses. The effort builds on previous efforts (outside of NTP) using 

high-throughput toxicokinetics models and combines them with in silicoestimated parameters. 

A publicly available web application based on these methods is available 

through the Tox21 Toolbox on the NTP public website, and refinement and 

use of the models in a research and prioritization context continued 

throughout FY 2018. Additionally, a simple IVIVE workflow allowing users to 

select Tox21 assays and chemicals and extrapolate to estimated exposures 

is available on ICE. 

Cell line selection for Tox21 Phase III 

Nisha Sipes 

This established Tox21 cross-partner project is developing and using a 

data-driven approach to choose cells to maximize biological diversity. A 

content maximization approach, along with programmatic interest, were 

used to pick a diverse set of 30+ cells based on publicly available gene 

expression data. 

Baseline gene expression profiling is planned in these cells using the 

appropriate technology platform, which will allow harmonization across 

projects. In vitro chemical testing will commence subsequently. 

Aggregated hit-call of Tox21 data 

Nisha Sipes 

This project involves the comparison of Tox21 data analysis methods, 

identification of higher-confidence chemical-assay actives, and 

development of a website for public access to the data and visualizations. A 

web interface with the aggregated hit-call function was developed during FY 

2018 for an anticipated in FY 2019. 

Next-generation sequencing in toxicology 

Alex Merrick, Kristine Witt, Stephanie 

Smith-Roe 

Under this project, bioinformatics pipelines are being developed 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. 

The effort was recently expanded to evaluate gene expression changes in 

frozen tissue samples from brain subregions obtained from genetic toxicity 

studies conducted as part of the NTP Cell Phone Radio Frequency 

Radiation study. In addition, new informatic tools have been developed to 

better identify long noncoding RNAs. 

Development of a reference database for 

estrogenic activity 

Warren Casey, Nicole Kleinstreuer 

This project is supporting future validation of high-throughput in vitro test 

methods and in silico models of estrogenic activity. NICEATM created a 

comprehensive database of high-quality in vivo data from over 1,000 

scientific articles describing uterotrophic assay experiments for more than 

2,660 distinct combinations of chemicals, studies, and protocols. 

These data have potential utility for developing adverse outcome pathways 

or models of estrogenic activity, prioritizing chemicals for further testing, or 

evaluating species-specific responses to chemicals. 

47 
 

 

 

 

 

2018 Annual Report – Research and Testing – Tox21 

Project 

Study Scientist 

Project Summary 

The database is described in a manuscript published in FY 2016. This 

activity is complete, but the database is being used as a training set for the 

automation of systematic reviews. 

Optimization of approaches for in vitro-in NICEATM developed and applied one-compartment or physiologically 

vivo extrapolation using Tox21 data based pharmacokinetic models to data from validated in vitro (EPA ToxCast 

estrogen receptor pathway model) and in vivo (uterotrophic) methods to Warren Casey, Nicole Kleinstreuer correlate in vitro and in vivo dosimetry quantitatively for estrogen receptor 

reference chemicals. 

This approach highlighted the importance of pharmacokinetic 

considerations in assessing and ranking endocrine-active chemicals based 

on in vitro, high-throughput screening assays. 

Subsequent work has focused on understanding the effect of various 

parameters, such as using free plasma concentration as a surrogate for 

total plasma concentration and comparing multiple modeling approaches 

and was published in FY 2018. 

Evaluation of Tox21 data for predicting 

acute oral toxicity 

Warren Casey, Nicole Kleinstreuer 

This project is determining 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 to determine which tests or combinations 

of tests best characterize the rat oral toxicity data. 

The analysis suggests that combinations of in vitro assays and data from 

small model organisms, such as zebrafish, offer promise for predicting 

outcomes of rat acute oral toxicity tests. 

A global collaboration to use quantitative structure-activity relationships, 

Tox21, and other alternative sources to predict acute oral toxicity has been 

initiated. Consensus models have been built as a result of the collaboration 

and a manuscript is being drafted. 

Evaluation and qualification of in silico 

methods for predicting metabolism 

Stephen Ferguson 

This evaluation of various in silico methods for predicting the extent of 

xenobiotic metabolism is also identifying metabolites and for prioritizing 

chemicals in the Tox21 10K library. 

Computational methods are used to partition the 10K library and develop 

subsets of chemicals that are likely to be metabolized appreciably in 

humans. 

Selection of a target set of genes for use in This project includes identifying patterns of exposure-induced biological 

a high-throughput transcriptomics screen responses to characterize toxicity and disease pathways and facilitate 

extrapolation of findings from model species to humans. Criteria were Richard Paules, Scott Auerbach, Elizabeth developed for selecting the best target set of genes representing humans, Maull, Alex Merrick, Nisha Sipes rats, mice, and zebrafish. 

A manuscript describing this work was published in FY 2018. A manuscript 

describing the gene selection process for the creation of a zebrafish 

S1500+ gene set is in preparation for submission in early 2019. 

Development of a computational model for This integration of data from nine Tox21 and ToxCast assays into a 

androgen receptor pathway activity computational model will be used to predict agonist and antagonist activity 

against the androgen receptor pathway. Warren Casey, Nicole Kleinstreuer 

A manuscript describing this work was published in FY 2017. A follow-up 

manuscript comparing the results of the computational model against 

48 
 

 

 

 

 

 

 

 

 

 

2018 Annual Report – Research and Testing – Tox21 

Project 

Study Scientist 

Project Summary 

reference chemicals derived from an in vivo database was published in FY 

2018. 

Development of quantitative structure- Using the computational model of the androgen receptor pathway, 

activity relationship (QSAR) models to NICEATM developed QSAR models to predict androgen receptor binding 

predict nuclear receptor-mediated and activity. 

endocrine activity These QSAR models are currently being refined, with a goal of using them 

Warren Casey, Nicole Kleinstreuer to predict androgen receptor pathway activity of chemicals in the EPA 

Endocrine Disruptor Screening Program. A manuscript is expected to be 

submitted in late 2018 or early 2019. 

Development of reference databases for 

androgen receptor activity 

Warren Casey, Nicole Kleinstreuer 

To develop a reference chemical list for in vitro androgen receptor binding 

and transactivation assay activity, NICEATM conducted literature reviews to 

identify information about in vitro androgen receptor binding and 

transactivation assays for 127 putative androgen-active or androgeninactive chemicals. 

The final database was made available to the public on the NTP website 

and manuscript describing this work was published, both in FY 2017. A 

parallel data curation effort with OECD and EPA partners focused on in vivo 

androgen activity data. 

These data will be used for evaluating high-throughput screening 

approaches, testing strategies, and further development of alternative test 

methods. A manuscript describing this work was published in FY 2018. 

Tox21 assay target mapping and Bayesian 

network modeling 

Warren Casey, Nicole Kleinstreuer 

NICEATM is mapping Tox21/ToxCast assay targets to known modes of 

action for developmental toxicity, acute toxicity, and carcinogenicity. 

Carcinogenicity assay target mapping is informed by the key characteristics 

of carcinogens and the hallmarks of cancer. 

Mapped assays are being combined with in silico features to build Bayesian 

network models to provide probabilistic predictions of chemical hazard. A 

manuscript describing this approach is being drafted. 

Curation of high-throughput screening data NICEATM has curated high-throughput screening data from Tox21 and 

EPA ToxCast HTS program to identify and exclude low-confidence activity Warren Casey, Nicole Kleinstreuer calls. Factors considered in the curation include chemical stability and purity 

information, robustness of concentration-response curve fits, and 

contextualization of active concentrations relative to testing range. 

These data are available through the NICEATM ICE database. ICE, 

launched in 2017, provides high-quality, curated data from NICEATM and 

its partners as well as other data resources and tools to support 

development of new approaches for assessing chemical safety. 

Evaluation of FXR-active chemicals 

identified from Tox21 screening 

Elizabeth Maull 

To better characterize chemicals identified in Tox21 quantitative HTS 

assays as having farnesoid X receptor alpha agonist or antagonist activity, 

NICEATM and collaborators evaluated them using four experimental 

approaches. 

Experiments generally confirmed the Tox21 results, provided orthogonal 

data on protein-to-protein interactions and receptor docking, and translated 

those results to an in vivo system (larval medaka assay). 

The study, presented at the 2018 SOT meeting, demonstrated an approach 

to targeted evaluation of putative bioactivity derived from HTS data. 

49 
 

 

 

 

 

 

 

 

2018 Annual Report – Research and Testing – Tox21 

Project 

Study Scientist 

Project Summary 

Development of software and methods for 

performing genomic dose-response 

analysis 

Scott Auerbach 

Methods and software were developed for performing genomic doseresponse analysis to identify sensitive, screening-level potency estimates. 

An expert panel meeting to discuss the proposed method was held and 

software released in FY 2017. 

A manuscript describing NTP’s method and approach, along with a 

manuscript describing the software, were published in FY 2018. 

Evaluation of the in vivo genomic dose- This evaluation focused on determining if dose-response modeling of 

response approach for identifying toxicogenomics data from short-term, in vivo studies can be used to identify 

biological effect points of departure biological effect points of departure that are comparable in potency to those 

derived from long-term toxicity studies. Mike DeVito, Will Gwinn, Scott Auerbach, 

Fred Parham A manuscript describing the findings from these studies will be published in 

FY 2019. 

Tox21 Cross-Partner Project: 

Performance-Based Validation of Tox21 

Assays 

Nicole Kleinstreuer 

The goal of this project was to develop semi-automated approaches to 

identify reference chemicals for Tox21/ToxCast assay targets with EPA. 

A manuscript on “RefChemDB” was submitted in FY 2018. A manuscript is 

being drafted with NCATS and EPA co-authors on the analysis of Tox21 

assays designed to measure luciferase inhibition and autofluorescence to 

identify interference reference chemicals and build structure-based models 

to predict assay interference; publication is expected in FY 2019. 

Testing Projects 

Project 

Study Scientist 

Project Summary 

Epigenetic changes in chemical toxicity 

Alex Merrick 

This project is focused on determining methylation patterns on a genomewide basis and validation of selected CpG sites (regions of DNA where a 

cytosine nucleotide occurs next to a guanine nucleotide) altered by 

chemical exposure. Methylation of CpG sites can turn a gene off, while 

demethylation can cause transcriptional activation. 

A generalized approach for methylated DNA enrichment has been 

developed and a manuscript describing this work is in press for publication 

in FY 2018. 

Polycyclic aromatic hydrocarbons (PAHs) 

Stephen Ferguson 

Studies are in progress evaluating approximately 20 PAHs considered 

relevant to human exposure in metabolism-competent HepaRG cells using 

multiplexed high-content screening assays and gene expression platforms. 

Tox21 Cross-Partner Project: Predictive 

Modeling of Developmental Toxicity with 

Human Pluripotent Stem Cells 

Nicole Kleinstreuer 

In this evaluation of approximately 80 chemicals in a metabolomic 

biomarker-based assay using human pluripotent stem cells, chemicals were 

selected based on ICH guidance, reference NTP in vivo studies, and 

relevance to the program. 

Testing has been completed and data analysis is underway. Data will be 

combined with EPA ToxCast results and IVIVE to build predictive models 

for developmental toxicity. 

Genotoxicity testing projects This evaluation of the genotoxicity of 19 test articles included in NTP’s

glyphosate toxicity study (formulations and neat compounds present as 

50 
 

 

 

 

2018 Annual Report – Research and Testing – Tox21 

Project 

Study Scientist 

Project Summary 

Kristine Witt, Stephanie Smith-Roe active ingredients in the formulations) is using bacterial reverse mutation 

and in vitro mammalian cell micronucleus assays, as well as in vitro comet 

assays and the in vitro MultiFlow DNA Damage Assay to provide 

information on mode of action for compounds shown to have genotoxic 

activity. 

Efforts to further characterize the genotoxicity profile for several members 

of the cohosh family of botanical supplements continue, with in vitro comet 

assays planned. 

Results of the in vitro micronucleus studies conducted on 13 cohosh 

samples were published in 2018. A set of eight flame retardants of interest 

to the NTP is being evaluated for genotoxicity using the bacterial reverse 

mutation, in vitro micronucleus, and in vitro comet assays. Continued 

evaluation of tissue samples obtained from radiofrequency radiationexposed rats to assess gene expression changes. 

Tox21 Cross-Partner Project: Development Reference chemicals with a rich legacy of molecular target interaction 

of a common reference chemical data set knowledge (e.g., IC50, Ki, KD, EC50) are being leveraged to create a 

for interpretation of high-throughput contextualized biological-response space in MCF-7 cells and 3D HepaRG 

transcriptomic screening data spheroid culture models as a framework for the interpretation of future 

transcriptomic screening studies. Stephen Ferguson, Richard Paules, 

Suramya Waidyanatha 

NTP WormTox Laboratory Projects 

Project 

Study Scientist 

Project Summary 

Mitochondrial toxicants 

Windy Boyd, Mamta Behl, Jui-Hua Hsieh 

This project determined 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 two manuscripts reporting the findings were published, the 

first in 2016 and the second in 2018. 

51 
 

 

 

 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies 

Testing and Toxicology Studies 

About Testing and Toxicology Studies 

The NTP testing program evaluates substances for a variety of health-related effects, 

generally using rodent models for study. 

Disposition, Metabolism, and Toxicokinetic Studies 

A list of substances evaluated through disposition, metabolism, and toxicokinetic 

studies. 

Genetic Toxicity Studies 

A list of substances tested for genetic toxicity. 

Organ System Toxicity Studies 

A list of substances tested for toxicity in organ systems. 

Modified One-Generation Reproduction Studies 

A list of planned or ongoing modified one-generation studies in FY 2018. 

Toxicology and Carcinogenicity Studies 

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

ongoing, or completed during FY 2018. 

Toxicogenomic Studies 

A list of planned or ongoing toxicogenomic studies in FY 2018. 

52 
 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies – About Studies 

About Testing and Toxicology Studies 

The NTP testing program evaluates substances for a variety of health-related effects, generally using 

rodent models. For each test article, a study team develops an appropriate testing strategy to address 

the identified research needs, and a project review committee evaluates the strategy. Reports and 

summaries of NTP toxicity studies, including carcinogenicity and effects on development and 

reproduction, are available on the NTP website. 

The following Division of NTP branches at NIEHS are involved in the testing program: Biomolecular 

Screening Branch, led by acting chief Rick Paules, Ph.D.; Cellular and Molecular Pathology Branch, 

led by Robert Sills, D.V.M., Ph.D.; NTP Laboratory, led by acting chief Michael DeVito, Ph.D.; 

Program Operations Branch, led by Michelle Hooth, Ph.D.; and Toxicology Branch, led by Paul 

Foster, Ph.D. 

Studies initiated, ongoing, or completed in 2018 are listed in this section. 

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies 

Genetic Toxicity Studies 

Organ System Toxicity Studies 

Modified One-Generation Reproduction Studies 

Toxicology and Carcinogenicity Studies 

Toxicogenomic Studies 

53 
 

 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies – ADME 

Disposition, Metabolism, and Toxicokinetic Studies 

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

metabolism, and excretion in the body of both humans and test animals at differing levels of 

exposure, of all ages, via several routes of exposure, and under varying genetic backgrounds. 

Substances evaluated during FY 2018 are listed below. 

Disposition, Metabolism, and Toxicokinetics Studies during FY 2018 

Test Article CASRN* Species Route Status Study 

Scientist 

2-Ethylhexyl p-methoxycinnamate 5466-77-3 Rats Dosed-feed, 

gavage, 

intravenous 

Ongoing Barry 

McIntyre 

2-((1-(4-Phenoxyphenoxy)propan-2-

yl)oxy)pyridine 

95737-68-1 Rats, 

Rabbit 

Gavage Ongoing Barry 

McIntyre 

Bisphenol AF 1478-61-1 Mice, Rats Gavage, 

intravenous 

Ongoing Veronica 

Godfrey 

Robinson 

Efavirenz 154598-52-4 Mice Gavage Completed Barry 

McIntyre 

Emtricitabine 143491-57-0 Mice Gavage Completed Barry 

McIntyre 

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

phenylethyl)phenol) 

70321-86-7 Rats Gavage, 

intravenous 

Ongoing Chad 

Blystone 

Phenolic benzotriazoles (2-(2Hbenzotriazol-2-yl)-4-tert-butylphenol) 3147-76-0 Rats Gavage, 

intravenous 

Ongoing Chad 

Blystone 

Phenolic benzotriazoles (2-(2HBenzotriazol-2-yl)phenol) 10096-91-0 Rats Gavage, 

intravenous 

Ongoing Chad 

Blystone 

Phenolic benzotriazoles (2-(5-Chloro2H-benzotriazol-2-yl)-4,6-bis(1,1-

dimethylethyl)phenol) 

3864-99-1 Rats Gavage, 

intravenous 

Ongoing Chad 

Blystone 

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

4-hydroxybenzenepropanoic acid, octyl 

ester) 

84268-23-5 Rats Gavage, 

intravenous 

Ongoing Chad 

Blystone 

Phenolic benzotriazoles (Bumetrizole) 3896-11-5 Rats Gavage, 

intravenous 

Ongoing Chad 

Blystone 

Phenolic benzotriazoles (Drometrizole) 2440-22-4 Rats Gavage, 

intravenous 

Ongoing Chad 

Blystone 

Polyethylene glycol monomethyl ether N/A Rats Subcutaneous 

injection 

Ongoing Nigel Walker 

54 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – ADME 

Test Article CASRN* Species Route Status Study 

Scientist 

Sulfolane 126-33-0 Mice, Rats Gavage, 

intravenous 

Ongoing Chad 

Blystone 

Tenofovir Disoproxil Fumarate (TDF) 202138-50-9 Mice Gavage Completed Barry 

McIntyre 

Tricombination FTC:TDF:EFV (1:1.5:3) N/A Mice Gavage, 

intravenous 

Completed Barry 

McIntyre 

Tris(chloropropyl)phosphate 13674-84-5 Mice, Rats Gavage, 

intravenous 

Completed Kristen Ryan 

Vinpocetine 42971-09-5 Rats Gavage Completed Natasha 

Catlin 

*CASRN = Chemical Abstracts Service Registry Number 

Related Links: 

Genetic Toxicity Studies 

Organ System Toxicity Studies 

Modified One-Generation Reproduction Studies 

Toxicology and Carcinogenicity Studies 

Toxicogenomic Studies 

55 
 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Genetic Toxicity 

Genetic Toxicity Studies 

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

test results and to provide a database for use in structure-activity relationship analysis. Substances 

evaluated during FY 2018 are listed below. 

Genetic Toxicity Studies in FY 2018 

Test Article CASRN* Species/ 

Cell Line 

Testing 

Battery 

Status Study 

Scientist 

1,2,4-Trimethylbenzene 95-63-6 Mice Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

1,2,4-Trimethylbenzene 95-63-6 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

1020 Long multiwalled carbon nanotube N/A Mice Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

1020 Long multiwalled carbon nanotube N/A Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

1H-Isoindole-1,3(2H)-diimine 3468-11-9 TK6 cells Micronucleus in 

vitro 

Planned Kristine 

Witt 

1H-Isoindole-1,3(2H)-diimine 3468-11-9 Salmonella Salmonella Ongoing Kristine 

Witt 

2-(Thiocyanomethylthio)benzothiazole 21564-17-0 TK6 cells Micronucleus in 

vitro 

Planned Kristine 

Witt 

2-(Thiocyanomethylthio)benzothiazole 21564-17-0 Salmonella Salmonella Ongoing Kristine 

Witt 

2,2'-Dimorpholinodiethyl ether 6425-39-4 Salmonella Salmonella Completed Kristine 

Witt 

2,2'-Dimorpholinodiethyl ether 6425-39-4 Mice Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

2,2'-Dimorpholinodiethyl ether 6425-39-4 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

2-Acetylaminofluorene 53-96-3 Rats Comet assay Completed Kristine 

Witt 

2-Chloro-N-(2-methyl-4-

bromophenyl)acetamide 

96686-51-0 Salmonella Salmonella Ongoing Kristine 

Witt 

2-Chloro-N-(2-methyl-4-

bromophenyl)acetamide 

96686-51-0 TK6 cells Micronucleus in 

vitro 

Planned Kristine 

Witt 

2-Hydroxy-4-methoxybenzophenone 131-57-7 Salmonella Salmonella Completed Kristine 

Witt 

4-(Hexyloxy)phenol 18979-55-0 TK6 cells Micronucleus in 

vitro 

Planned Kristine 

Witt 

4-(Hexyloxy)phenol 18979-55-0 Salmonella Salmonella Ongoing Kristine 

Witt 

56 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Genetic Toxicity 

Test Article CASRN* Species/ 

Cell Line 

Testing 

Battery 

Status Study 

Scientist 

Acrylamide 79-06-1 Mice Comet assay Completed Kristine 

Witt 

Bisphenol S 80-09-1 Rats 

(female 

dams) 

Micronucleus in 

vivo 

Planned Kristine 

Witt 

Bisphenol S 80-09-1 Rats 

(PND28 

pups) 

Micronucleus in 

vivo 

Planned Kristine 

Witt 

Black cohosh 84776-26-1 Salmonella Salmonella Completed Kristine 

Witt 

Cell phone radiation: CDMA N/A Mice Comet assay Completed Kristine 

Witt 

Cell phone radiation: CDMA N/A Rats Comet assay Completed Kristine 

Witt 

Cell phone radiation: GSM N/A Mice Comet assay Completed Kristine 

Witt 

Cell phone radiation: GSM N/A Rats Comet assay Completed Kristine 

Witt 

Deoxynivalenol 51481-10-8 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Dipentaerythritol pentaacrylate 60506-81-2 TK6 cells Micronucleus in 

vitro 

Planned Kristine 

Witt 

Dipentaerythritol pentaacrylate 60506-81-2 Salmonella Salmonella Ongoing Kristine 

Witt 

Dipyrithione 3696-28-4 TK6 cells Micronucleus in 

vitro 

Planned Kristine 

Witt 

Dipyrithione 3696-28-4 Salmonella Salmonella Ongoing Kristine 

Witt 

Echinacea purpurea root extract 90028-20-9 Rats 

(female 

dams) 

Micronucleus in 

vivo 

Planned Kristine 

Witt 

Echinacea purpurea root extract 90028-20-9 Rats 

(PND28 

pups) 

Micronucleus in 

vivo 

Planned Kristine 

Witt 

Echinacea purpurea root extract 90028-20-9 Rats (90 

day) 

Micronucleus in 

vivo 

Planned Kristine 

Witt 

Emtricitabine (FTC) 143491-57-0 Mice Comet assay Completed Kristine 

Witt 

Indium trichloride 10025-82-8 TK6 cells Micronucleus in 

vitro 

Completed Kristine 

Witt 

N-Butylbenzenesulfonamide 3622-84-2 Mice Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

57 
 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Genetic Toxicity 

Test Article CASRN* Species/ 

Cell Line 

Testing 

Battery 

Status Study 

Scientist 

N-Butylbenzenesulfonamide 3622-84-2 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

N-Nitrosodimethylamine 62-75-9 Rats Comet assay Planned Kristine 

Witt 

p-Chloro-a,a,a-trifluorotoluene 98-56-6 Salmonella Salmonella Completed Kristine 

Witt 

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

phenylethyl)phenol) 

70321-86-7 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

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

dimethylpropyl)phenol) 

25973-55-1 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Phenolic benzotriazoles (2-(2HBenzotriazol-2-yl)-4-tert-butylphenol) 3147-76-0 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Phenolic benzotriazoles (2-(2HBenzotriazol-2-yl)phenol) 10096-91-0 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

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

dimethylethyl)phenol) 

3864-99-1 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

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

hydroxybenzenepropanoic acid, octyl 

ester) 

84268-23-5 Rats Micronucleus in 

vivo 

Completed Kristine 

Witt 

Phenolic benzotriazoles (Bumetrizole) 3896-11-5 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Phenolic benzotriazoles (Drometrizole) 2440-22-4 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Phenolic benzotriazoles (Octrizole) 3147-75-9 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Potassium dicyanoaurate 13967-50-5 TK6 cells Micronucleus in 

vitro 

Planned Kristine 

Witt 

Potassium dicyanoaurate 13967-50-5 Salmonella Salmonella Ongoing Kristine 

Witt 

Pubertal vinclozolin study 50471-44-8 Mice Comet assay Completed Kristine 

Witt 

Sodium metavanadate 13718-26-8 Mice Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Sodium metavanadate 13718-26-8 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Sodium tungstate dihydrate 10213-10-2 Mice Comet assay Completed Kristine 

Witt 

58 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Genetic Toxicity 

Test Article CASRN* Species/ 

Cell Line 

Testing 

Battery 

Status Study 

Scientist 

Sodium tungstate dihydrate 10213-10-2 Rats Comet assay Completed Kristine 

Witt 

Stachybotrys chartarum 67892-26-6 Mice Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Sulfolane 126-33-0 Mice Micronucleus in 

vivo 

Completed Kristine 

Witt 

Sulfolane 126-33-0 Rats Micronucleus in 

vivo 

Completed Kristine 

Witt 

Triclosan 3380-34-5 Rats 

(female 

dams) 

Micronucleus in 

vivo 

Planned Kristine 

Witt 

Tris(4-chlorophenyl)methane 27575-78-6 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Vanadyl sulfate 27774-13-6 Mice Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Vanadyl sulfate 27774-13-6 Rats Micronucleus in 

vivo 

Ongoing Kristine 

Witt 

Vincristine sulfate salt 2068-78-2 Rats Comet assay Completed Kristine 

Witt 

Vinpocetine 42971-09-5 Mice Micronucleus in 

vivo 

Completed Kristine 

Witt 

Vinpocetine 42971-09-5 TK6 cells Micronucleus in 

vitro 

Completed Kristine 

Witt 

Vinpocetine 42971-09-5 Mice Comet assay Completed Kristine 

Witt 

*CASRN = Chemical Abstracts Service Registry Number 

59 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Genetic Toxicity 

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies 

Organ System Toxicity 

Modified One-Generation Reproduction Studies 

Toxicology and Carcinogenicity Studies 

Toxicogenomic Studies 

60 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Organ System Toxicity 

Organ System Toxicity Studies 

NTP studies toxicity of environmental substances on development, reproduction, and on the nervous 

and immune systems. Organ systems toxicity studies conducted during FY 2018 are listed below. 

Neurotoxicity, Developmental Toxicity, and Reproductive Toxicity Studies during FY 2018 

Test Article CASRN* Species Testing 

Battery 

Length Route Status Study 

Scientist 

2-((1-(4-

Phenoxyphenoxy)propan-2-

yl)oxy)pyridine 

95737-68-1 Rabbit Teratology pilot GD 7-28 Gavage Initiated Vicki 

Sutherland 

2-((1-(4-

Phenoxyphenoxy)propan-2-

yl)oxy)pyridine 

95737-68-1 Rabbit Conventional 

teratology 

GD 7-28 Gavage Initiated Vicki 

Sutherland 

3,3',4,4'-

Tetrachloroazobenzene 

14047-09-7 Rats Immunotoxicity 28 days Gavage Ongoing Mamta 

Behl 

2,3-Butanedione 431-03-8 Mice Immunotoxicity 28 days Inhalation Ongoing Dan 

Morgan 

Benz(j)aceanthrylene 202-33-5 Mice Immunotoxicity 28 days Gavage Initiated Cynthia 

Rider 

Dibenz(a,h)anthracene 53-70-3 Mice Immunotoxicity 28 days Gavage Ongoing Cynthia 

Rider 

Dibenz(a,h)anthracene 53-70-3 Mice Immunotoxicity 28 days Subcutaneo 

us injection 

Ongoing Cynthia 

Rider 

Dibenzo(a,l)pyrene 191-30-0 Mice Immunotoxicity 28 days Gavage Ongoing Cynthia 

Rider 

Dibenzothiophene 132-65-0 Mice Immunotoxicity 28 days Gavage Ongoing Cynthia 

Rider 

Perfluorodecanoic acid 335-76-2 Rats Immunotoxicity 28 days Gavage Ongoing Chad 

Blystone 

Vinclozolin 50471-44-8 Rats Continuous 

breeding 

9 months Gavage Ongoing Barry 

McIntyre 

Tenofovir disoproxil fumarate 

(TDF) 

202138-50-9 Mice Teratology pilot GD 5 - PND 

21 

Gavage Ongoing Anika 

Dzierlenga 

dibenzo(a,l)pyrene 191-30-0 Mice Immunotoxicity 28 days Gavage Ongoing Cynthia 

Rider 

Dibenzothiophene 132-65-0 Mice Immunotoxicity 28 days Gavage Ongoing Cynthia 

Rider 

Perfluorodecanoic acid 335-76-2 Rats Immunotoxicity 28 days Gavage Ongoing Chad 

Blystone 

61 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Organ System Toxicity 

Test Article CASRN* Species Testing 

Battery 

Length Route Status Study 

Scientist 

1020 Long multiwalled carbon 

nanotube 

N/A Rats Immunotoxicity 30 days Inhalation Ongoing Dan 

Morgan 

1020 Long multiwalled carbon 

nanotube 

N/A Mice Immunotoxicity 30 days Inhalation Ongoing Dan 

Morgan 

1020 Long multiwalled carbon 

nanotube 

N/A Mice Immunotoxicity 90 days Inhalation Ongoing Dan 

Morgan 

2-((1-(4-

Phenoxyphenoxy)propan-2-

yl)oxy)pyridine 

95737-68-1 Rats Conventional 

teratology 

GD 6-21 Gavage Ongoing Vicki 

Sutherland 

2-((1-(4-

Phenoxyphenoxy)propan-2-

yl)oxy)pyridine 

95737-68-1 Rabbit Conventional 

teratology 

GD 7-28 Gavage Ongoing Vicki 

Sutherland 

2-((1-(4-

Phenoxyphenoxy)propan-2-

yl)oxy)pyridine 

95737-68-1 Rats Immunotoxicity 28 days Gavage Ongoing Vicki 

Sutherland, 

Barry 

McIntyre 

2-Hydroxy-4-

methoxybenzophenone 

131-57-7 Rats Developmental 

toxicity 

GD 6 to 

PND 21 

Dosed-feed Ongoing Dr. D. 

Hansen 

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

application 

Ongoing Scott 

Auerbach 

4-Methylimidazole 822-36-6 Rats Continuous 

breeding 

Continuous Dosed-feed Ongoing Mamta 

Behl 

Acenaphthenequinone 82-86-0 Mice Immunotoxicity 28 days Gavage Ongoing Cynthia 

Rider 

Arsenic 7440-38-2 Rats Developmental 

toxicity 

Pregnant 

dams 

through 

PND21 

Gavage & 

dosed-water 

Completed Nigel 

Walker 

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

Rider 

Benzo(b)fluoranthene 205-99-2 Mice Immunotoxicity 28 days Gavage Initiated Cynthia 

Rider 

Benzo(c)fluorene 205-12-9 Mice Immunotoxicity 28 days Gavage Initiated Cynthia 

Rider 

Benzo(k)fluoranthene 207-08-9 Mice Immunotoxicity 28 days Gavage Initiated Cynthia 

Rider 

Bisphenol AF 1478-61-1 Rats Immunotoxicity GD 6 - PND 

96 

Dosed-feed Ongoing Vicki 

Sutherland 

62 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Organ System Toxicity 

Test Article CASRN* Species Testing 

Battery 

Length Route Status Study 

Scientist 

Chrysene 218-01-9 Mice Immunotoxicity 28 days Gavage Ongoing Cynthia 

Rider 

Crude 4-

Methylcyclohexanemethanol 

N/A Mice Immunotoxicity 7 days Topical 

application 

Ongoing Scott 

Auerbach 

Diisobutyl phthalate 84-69-5 Rats Continuous 

breeding 

Continuous Dosed-feed Ongoing Chad 

Blystone 

Echinacea purpurea root 

extract 

90028-20-9 Rats Immunotoxicity 28 days Gavage Planned Kristen 

Ryan 

Gum guggul extract N/A Mice Immunotoxicity 28 days Gavage Ongoing Dori 

Germolec 

Indeno(1,2,3-cd)pyrene 193-39-5 Mice Immunotoxicity 28 days Gavage Initiated Cynthia 

Rider 

Lovastatin 75330-75-5 Mice Immunotoxicity 28 days Gavage Ongoing Dori 

Germolec 

N-Butylbenzenesulfonamide 3622-84-2 Rats Immunotoxicity GD 6 - PND 

42 

Dosed-feed Ongoing Cynthia 

Rider 

Nelfinavir mesylate 159989-65-8 Mice Immunotoxicity 28 days Gavage Ongoing Dori 

Germolec 

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

Rider 

Pyrene 129-00-0 Mice Immunotoxicity 28 days Gavage Ongoing Cynthia 

Rider 

Sodium metavanadate 13718-26-8 Mice Immunotoxicity 28 days Dosedwater Ongoing Georgia 

Roberts 

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

Blystone 

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

Blystone 

Tricombination FTC:TDF:EFV 

(1:1.5:3) 

N/A Mice Teratology pilot GD 5-18, 

GD 5-15 

Gavage Ongoing Barry 

McIntyre 

Tricresyl phosphate 1330-78-5 Rats Immunotoxicity 21 days Dosed-feed Planned Mamta 

Behl 

Tris(Chloropropyl)phosphate 13674-84-5 Rats Immunotoxicity GD 6 - PND 

127 

Dosed-feed Ongoing Kristen 

Ryan 

*CASRN = Chemical Abstracts Service Registry Number 

63 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Organ System Toxicity 

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies 

Genetic Toxicity Studies 

Modified One-Generation Reproduction Studies 

Toxicology and Carcinogenicity Studies 

Toxicogenomic Studies 

64 
 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Modified One-Generation 

Modified One-Generation Reproduction Studies 

NTP modified one-generation study design emphasizes a full evaluation of the first-generation 

offspring of animals and uses fewer animals than the classical multigenerational study design. These 

studies generate information on the effects of substances on prenatal development, postnatal 

development, and reproduction. Planned or ongoing modified one-generation studies are listed 

below. 

Modified One-Generation Studies in FY 2018 

Test Article CASRN* Species Testing Battery Status Study 

Scientist 

Bisphenol AF 1478-61-1 Rats Dose range finding Ongoing Vicki 

Sutherland 

Echinacea purpurea root 

extract 

90028-20-9 Rats Conventional teratology Ongoing Kristen Ryan 

Echinacea purpurea root 

extract 

90028-20-9 Rats Fertility assessment Ongoing Kristen Ryan 

Echinacea purpurea root 

extract 

90028-20-9 Rats Subchronic Ongoing Kristen Ryan 

Resveratrol 501-36-0 Rats Developmental toxicity, F0 generation, 

fertility assessment 

Ongoing Anika 

Dzierlenga 

2,2'-Dimorpholinodiethyl 

ether 

6425-39-4 Rats Repeated dose Ongoing Georgia 

Roberts 

2-Ethylhexyl pmethoxycinnamate 5466-77-3 Rats Subchronic Ongoing Barry McIntyre 

2-Hydroxy-4-

methoxybenzophenone 

131-57-7 Rats Developmental toxicity Ongoing Barry McIntyre 

Bisphenol S 80-09-1 Rats Dose range finding Ongoing Vicki 

Sutherland 

Bisphenol S 80-09-1 Rats F0 Generation Planned Vicki 

Sutherland 

Boric acid 10043-35-3 Rats Dose range finding Ongoing AtLee Watson 

Deoxynivalenol 51481-10-8 Rats Dose range finding Ongoing Dori Germolec 

Echinacea purpurea root 

extract 

90028-20-9 Rats Dose range finding Ongoing Kristen Ryan 

Ethylene glycol 2-

ethylhexyl ether 

1559-35-9 Rats Dose range finding Ongoing Chad Blystone 

Hydroquinone 123-31-9 Rats Dose range finding Planned Vicki 

Sutherland 

65 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Modified One-Generation 

Test Article CASRN* Species Testing Battery Status Study 

Scientist 

NButylbenzenesulfonamide 3622-84-2 Rats F0 generation Ongoing Cynthia Rider 

NButylbenzenesulfonamide 3622-84-2 Rats Maternal transfer Ongoing Cynthia Rider 

NButylbenzenesulfonamide 3622-84-2 Rats Developmental toxicity Ongoing Cynthia Rider 

NButylbenzenesulfonamide 3622-84-2 Rats Neurotoxicology assessment Ongoing Cynthia Rider 

NButylbenzenesulfonamide 3622-84-2 Rats Subchronic Ongoing Cynthia Rider 

Simvastatin 79902-63-9 Rats Dose range finding Ongoing Barry McIntyre 

Triclosan 3380-34-5 Rats Dose range finding Ongoing Vicki 

Sutherland 

Tricombination 

FTC:TDF:EFV (1:1.5:3) 

N/A Mice F0 generation Initiated Anika 

Dzierlenga 

Tricombination 

FTC:TDF:EFV (1:1.5:3) 

N/A Mice Subchronic Planned Anika 

Dzierlenga 

Tricombination 

ABC:DTG:3TC 

N/A Rats Dose range finding Planned Kristen Ryan 

Tris(4-

chlorophenyl)methane 

27575-78-6 Rats Dose range finding Ongoing Troy Hubbard 

Valerian (Valeriana 

officinalis L.) root extract 

8057-49-6 Rats Dose range finding Ongoing Georgia 

Roberts 

*CASRN = Chemical Abstracts Service Registry Number 

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies 

Genetic Toxicity Studies 

Organ System Toxicity Studies 

Toxicology and Carcinogenicity Studies 

Toxicogenomic Studies 

66 
 

 

 

 

 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity 

Studies 

Toxicology and Carcinogenicity Studies 

NTP performs toxicity studies to provide dose-setting information for chronic studies and to address 

specific deficiencies in the toxicology database for the chemical. Toxicology and carcinogenicity 

studies fall into two categories: prechronic toxicity studies and chronic two-year toxicology and 

carcinogenicity studies. Studies are generally conducted in rats and mice. 

Each study type is performed according to the Specifications for the Conduct of Studies to Evaluate 

the Reproductive and Developmental Toxicity of Chemical, Biological and Physical Agents in 

Laboratory Animals for the National Toxicology Program (NTP) (May 2011). Prechronic and chronic 

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

2018, are listed below. 

Prechronic Toxicology and Carcinogenicity Studies FY 2018 

Test Article CASRN* Species Length Route Status Study 

Scientist 

1,2,4-Trimethylbenzene 95-63-6 Mice, rats 13 weeks Inhalation Ongoing Dan Morgan 

1,2-Bis(2,4,6-

tribromophenoxy)ethane 

37853-59-1 Rats 5 days Gavage Ongoing June 

Dunnick 

1,2-bis(pentabromophenyl)ethane 84852-53-9 Rats 5 days Gavage Completed June 

Dunnick 

1,3,5,7,9,11-

Hexabromocyclododecane 

25637-99-4 Rats 5 days Gavage Completed June 

Dunnick 

1020 Long multiwalled carbon 

nanotube 

N/A Mice, rats 30 days Inhalation Ongoing Dan Morgan 

1020 Long multiwalled carbon 

nanotube 

N/A Mice, rats 2 years Inhalation Ongoing Dan Morgan 

2,2',4,4'-Tetrabromodiphenyl ether 5436-43-1 Rats 5 days Gavage Completed June 

Dunnick 

2,2'-Dimorpholinodiethyl ether 6425-39-4 Mice 28 days Gavage Ongoing Troy 

Hubbard 

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

2-ethylhexyl-2,3,4,5-

tetrabromobenzoate 

183658-27-7 Rats 5 days Gavage Completed June 

Dunnick 

2-ethyltoluene 611-14-3 Mice, rats 2 weeks, 90 

days 

Inhalation Initiated Dan Morgan 

2-Hydroxy-4-

methoxybenzophenone 

131-57-7 Mice, rats 2 years Dosed-feed Ongoing Barry 

McIntyre 

3,3',4,4'-Tetrachloroazobenzene 14047-09-7 Rats 5 days Gavage Ongoing Mamta Behl 

Acetaminophen (4-

hydroxyacetanilide) 

103-90-2 Rats 90 days Gavage Initiated Vicki 

Sutherland 

Acrylamide 79-06-1 Rats 5 days Gavage Ongoing William 

Gwinn 

Aging cohort study: 12951/SvlmJ 

mouse 

N/A Mice 2 years Not 

applicable 

Ongoing June 

Dunnick 

67 
 

 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity 

Studies 

Test Article CASRN* Species Length Route Status Study 

Scientist 

Aging cohort study: A/J mouse N/A Mice 2 years Not 

applicable 

Ongoing June 

Dunnick 

Aging cohort study: B6C3F1J 

mouse 

N/A Mice 2 years Not 

applicable 

Ongoing June 

Dunnick 

Aging cohort study: C3H/HeJ 

mouse 

N/A Mice 2 years Not 

applicable 

Ongoing June 

Dunnick 

Aging cohort study: C57/BL/6J 

mouse 

N/A Mice 2 years Not 

applicable 

Ongoing June 

Dunnick 

Aging cohort study: CAST/EiJ 

mouse 

N/A Mice 2 years Not 

applicable 

Ongoing June 

Dunnick 

Aging cohort study: NOD. B10SnH2(b)/J N/A Mice 2 years Not 

applicable 

Ongoing June 

Dunnick 

Aging cohort study: NZO/HiLtJ 

mouse 

N/A Mice 2 years Not 

applicable 

Ongoing June 

Dunnick 

Aging cohort study: PWK/PhJ 

mouse 

N/A Mice 2 years Not 

applicable 

Ongoing June 

Dunnick 

Aging cohort study: WSB/EIJ 

mouse 

N/A Mice 2 years Not 

applicable 

Ongoing June 

Dunnick 

Aloin 1415-73-2 Rats 13 weeks Dosedwater Completed Alex 

Boudreau 

alpha/beta Thujone mixture 76231-76-0 Rats 5 days Gavage Ongoing William 

Gwinn 

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

Rider 

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

Arsenic 7440-38-2 Mice, rats acute Gavage & 

dosed-water 

Ongoing Nigel 

Walker 

Arsenic 7440-38-2 Monkey acute Gavage Ongoing Nigel 

Walker 

Aspergillus fumigatus mold N/A Mice 13 weeks Inhalation Ongoing Dori 

Germolec 

Bis(2-ethylhexyl) 

tetrabromophthalate 

26040-51-7 Rats 5 days Gavage Completed June 

Dunnick 

Bisphenol A 80-05-7 Rats 2 years Gavage Completed Barry 

Delclos 

Bisphenol AF 1478-61-1 Rats 5 days Gavage Ongoing Vicki 

Sutherland 

Bisphenol S 80-09-1 Mice 14 days Dosed-feed Ongoing Vicki 

Sutherland 

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

Blystone 

68 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity 

Studies 

Test Article CASRN* Species Length Route Status Study 

Scientist 

Brominated vegetable oil 8016-94-2 Rats 90 days Dosed-feed Ongoing Nigel 

Walker 

Cell phone radiation: CDMA N/A Mice, rats 2 years Whole body 

exposure 

Completed Michael 

Wyde 

Cell phone radiation: GSM N/A Mice, rats 2 years Whole body 

exposure 

Completed Michael 

Wyde 

Coumarin 91-64-5 Rats 5 days Gavage Ongoing June 

Dunnick 

Crumb rubber various N/A Mice 14 days N/A Completed Georgia 

Roberts 

Damp building mold mixture N/A Mice 90 days Inhalation Planned Dori 

Germolec 

Decabromodiphenyl ether 1163-19-5 Rats 5 days Gavage Completed June 

Dunnick 

Di(2-ethylhexyl) phthalate 117-81-7 Rats 5 days Gavage Ongoing Troy 

Hubbard 

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

years, 2 

years 

Dosed-feed Ongoing Paul Foster 

Dibutyl Phthalate 84-74-2 Mice, rats 2 years Dosed-feed Ongoing Chad 

Blystone 

Dimethylamine borane 74-94-2 Mice 2 weeks Dermal Completed AtLee 

Watson 

Ethinyl estradiol 57-63-6 Rats 5 days Gavage Ongoing William 

Gwinn 

Fenofibrate 49562-28-9 Rats 5 days Gavage Ongoing Barry 

McIntyre 

Furan 110-00-9 Rats 5 days Gavage Ongoing William 

Gwinn 

Garcinia cambogia extract 90045-23-1 Mice, rats 14 days Dosed-feed Ongoing Cynthia 

Rider 

Ginkgo biloba extract 90045-36-6 Rats 5 days Gavage Completed Cynthia 

Rider 

Ginseng 50647-08-0 Rats 5 days Gavage Ongoing Po Chan 

Goldenseal extract 84603-60-1 Rats 5 days Gavage Completed Cynthia 

Rider 

Green tea extract N/A Rats 5 days Gavage Completed Cynthia 

Rider 

Hexachlorobenzene 118-74-1 Rats 5 days Gavage Ongoing Mike Devito 

Hexachlorobenzene 118-74-1 Rats 90 days Gavage Ongoing Mike Devito 

Hexachlorocyclopentadienyldibromocyclooctane 51936-55-1 Rats 5 days Gavage Completed June 

Dunnick 

69 
 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity 

Studies 

Test Article CASRN* Species Length Route Status Study 

Scientist 

Insertional mutagenesis – definitive 

vector study 

N/A Mice 14 months Intravenous Completed Dori 

Germolec 

Ionic liquid: 1-Butyl-1-

methylpyrrolidinium Chloride 

479500-35-1 Mice, rats 90 days Dosedwater Ongoing Kristen 

Ryan 

Ionic liquid: 1-Butyl-3-

methylimidazolium Chloride 

79917-90-1 Mice, rats 90 days Dosedwater Ongoing Kristen 

Ryan 

Ionic liquid: 1-Ethyl-3-

methylimidazolium Chloride 

65039-09-0 Mice, rats 90 days Dosedwater Ongoing Kristen 

Ryan 

Ionic liquid: N-Butylpyridinium 

Chloride 

1124-64-7 Mice, rats 90 days Dosedwater Ongoing Kristen 

Ryan 

Isopropylated phenol phosphate 68937-41-7 Mice 2 weeks Dosed-feed Ongoing Mamta Behl 

Libby amphibole 2007 N/A Rats 30 days Inhalation Planned Matt Stout 

Melamine + cyanuric acid 

combination 

N/A Rats 90 days Gavage Ongoing Gonçalo 

Gamboa da 

Costa 

Melamine + cyanuric acid 

combination 

N/A Not 

Applicable 

N/A Not 

Applicable 

Ongoing Nigel 

Walker 

Melamine + cyanuric acid 

combination 

N/A Rats 90 days + 

recovery 

Gavage Ongoing Gonçalo 

Gamboa da 

Costa 

Methyleugenol 93-15-2 Rats 5 days Gavage Ongoing William 

Gwinn 

Microbiome N/A Not 

Applicable 

N/A Not 

Applicable 

Ongoing Carl 

Cerniglia 

Microcystin LR 101043-37-2 Mice Gestation day 

6 to postnatal 

day 35 

Gavage Planned Vicki 

Sutherland 

Milk thistle extract 84604-20-6 Rats 5 days Gavage Ongoing June 

Dunnick 

Mixed xylenes N/A Mice, rats 30 days Inhalation Planned Dan Morgan 

N-Butylbenzenesulfonamide 3622-84-2 Mice, rats 14 days, 13 

weeks 

Dosed-feed Completed Cynthia 

Rider 

p-Chloro-a,a,a-trifluorotoluene 98-56-6 Mice, rats 90 days Inhalation Completed Matt Stout 

PCN 66/67 comparison study N/A Rats 2 weeks Gavage Ongoing Mike Devito 

PCN 66/67 comparison study N/A Rats 13 weeks Gavage Ongoing Mike Devito 

Pentabromodiphenyl ether mixture 

[DE-71 (technical grade)] 

32534-81-9 Rats 5 days Gavage Ongoing June 

Dunnick 

Perfluorohexanoic acid (PFHXA) 307-24-4 Rats 28 days Gavage Ongoing Chad 

Blystone 

Perfluorooctanoic acid 335-67-1 Rats 2 years Dosed-feed Ongoing Chad 

Blystone 

70 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity 

Studies 

Test Article CASRN* Species Length Route Status Study 

Scientist 

Perfluorooctanoic acid 335-67-1 Rats 5 days, 28 

days 

Gavage Ongoing Chad 

Blystone 

Phenolic benzotriazoles (2-(2Hbenzotriazol-2-yl)-4,6-bis(1-methyl1-phenylethyl)phenol) 70321-86-7 Rats 14 days Gavage Ongoing Chad 

Blystone 

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

dimethylpropyl)phenol) 

25973-55-1 Rats 14 days Gavage Ongoing Chad 

Blystone 

Phenolic benzotriazoles (2-(2HBenzotriazol-2-yl)-4-tertbutylphenol) 3147-76-0 Rats 14 days Gavage Ongoing Chad 

Blystone 

Phenolic benzotriazoles (2-(2HBenzotriazol-2-yl)phenol) 10096-91-0 Rats 14 days Gavage Ongoing Chad 

Blystone 

Phenolic benzotriazoles (2-(5-

Chloro-2H-benzotriazol-2-yl)-4,6-

bis(1,1-dimethylethyl)phenol) 

3864-99-1 Rats 14 days Gavage Ongoing Chad 

Blystone 

Phenolic benzotriazoles (3-(2HBenzotriazol-2-yl)-5-(1,1-

dimethylethyl)-4-

hydroxybenzenepropanoic acid, 

octyl ester) 

84268-23-5 Rats 14 days Gavage Ongoing Chad 

Blystone 

Phenolic benzotriazoles 

(Bumetrizole) 

3896-11-5 Rats 14 days Gavage Ongoing Chad 

Blystone 

Phenolic benzotriazoles 

(Drometrizole) 

2440-22-4 Rats 14 days Gavage Ongoing Chad 

Blystone 

Phenolic benzotriazoles (Octrizole) 3147-75-9 Rats 14 days Gavage Ongoing Chad 

Blystone 

Pulegone 89-82-7 Rats 5 days Gavage Ongoing Scott 

Auerbach 

Resveratrol 501-36-0 Mice, rats 2 years Gavage Ongoing Anika 

Dzierlenga 

Sodium metavanadate 13718-26-8 Mice, rats 90 days Dosedwater Ongoing Georgia 

Roberts 

Sodium tungstate dihydrate 10213-10-2 Mice, rats 2 years Dosedwater Ongoing Mamta Behl 

Stachybotrys chartarum strain 1 

mold (macrocyclic trichothecene 

chemotype) 

N/A Mice 90 days Inhalation Planned Dori 

Germolec 

Stachybotrys chartarum strain 2 

mold (atranone chemotype) 

N/A Mice 90 days Inhalation Planned Dori 

Germolec 

Sulfolane 126-33-0 Guinea 

pigs, mice, 

rats 

28 days Gavage Ongoing Chad 

Blystone 

Sulfolane 126-33-0 Mice, rats 2 years Dosedwater Ongoing Chad 

Blystone 

71 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicology and Carcinogenicity 

Studies 

Test Article CASRN* Species Length Route Status Study 

Scientist 

Tetrabromobisphenol A 79-94-7 Rats 5 days Gavage Ongoing June 

Dunnick 

Tetrabromobisphenol A-bis(2,3-

dibromopropyl ether) 

21850-44-2 Rats 90 days Gavage Completed June 

Dunnick 

Thallium (I) sulfate 7446-18-6 Mice 2 weeks Dosedwater Initiated Troy 

Hubbard 

Thallium (I) sulfate 7446-18-6 Rats Gestation day 

6 to postnatal 

day 28 

Dosedwater Initiated Troy 

Hubbard 

Triclosan 3380-34-5 Rats 5 days Gavage Ongoing Vicki 

Sutherland 

Triclosan 3380-34-5 Mice 2 years Dermal Ongoing Jia-Long 

Fang 

Trimethylsilyldiazomethane (TMSD) 18107-18-1 Mice, rats 10 days Inhalation Ongoing William 

Gwinn 

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

Tris(chloropropyl)phosphate 13674-84-5 Rats 5 days Gavage Ongoing Kristen 

Ryan 

Tris(chloropropyl)phosphate 13674-84-5 Mice, rats 90 days Dosed-feed Ongoing Kristen 

Ryan 

Tris(chloropropyl)phosphate 13674-84-5 Mice, rats 2 years Dosed-feed Ongoing Kristen 

Ryan 

Valerian (Valeriana officinalis L.) 

root extract 

8057-49-6 Mice 90 days Gavage Ongoing Troy 

Hubbard 

Vanadyl sulfate 27774-13-6 Mice, rats 90 days Dosedwater Ongoing Georgia 

Roberts 

Water damaged building mold 

mixture 

N/A Mice, rats 90 days Inhalation Planned Dori 

Germolec 

Water disinfection byproducts 

(Bromodichloroacetic acid) 

71133-14-7 Rats 5 days Gavage Ongoing Mike Devito 

Zinc carbonate, basic 5263-02-5 Rats 2 years Dosed-feed Ongoing Natasha 

Catlin 

*CASRN = Chemical Abstracts Service Registry Number 

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies 

Genetic Toxicity Studies 

Organ System Toxicity Studies 

Modified One-Generation Reproduction Studies 

Toxicogenomic Studies 

72 
 

 

 

 

 

 

 

 

 

 

 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicogenomics 

Toxicogenomic Studies 

NTP is incorporating the latest toxicogenomic technologies into its testing program to gain further 

insights into the toxicity of environmental substances. Toxicogenomics examines how the entire 

genetic structure, or genome, influences an organism’s response to environmental toxicants. 

Microarray, proteomic, metabolomics analyses, and next-generation (NextGen) sequencing are 

among the advanced technologies that NTP is using to study how chemical exposures change the 

expression of genes, proteins, and metabolites in targeted cells and tissues. 

Measuring genome-wide changes in affected tissues could be useful for identifying disease 

biomarkers, detecting exposure to toxic substances, and understanding individual genetic 

susceptibilities. Once validated, biomarkers can be repeatedly sampled during long-term NTP studies 

to determine if chemical exposures can be detected or if developing diseases (e.g., cancer) provide a 

genetic signature. 

NTP is investigating whether pattern analysis of gene expression can provide toxicity indicators at 

(1) earlier time points and (2) lower doses than are possible using traditional toxicological parameters. 

Evaluating patterns of gene expression is expected to provide insight into the pathogenesis of 

disease and how different rodent models respond to toxicants. In addition, metabolomics provides an 

opportunity to elucidate how chemicals affect metabolism within cells relative to changes in gene 

expression. Expression signatures linked to chemical exposures and apical measures are intended to 

contribute to NTP’s efforts in predictive toxicology.

Several FY 2018 toxicogenomic studies used NextGen sequencing technologies, which improves 

gene expression analysis, including base pair-level resolution of accuracy and increased sensitivity 

compared to microarray platforms. Although microarray analysis is a stable and well-understood 

technology for assaying gene expression, NextGen sequencing methods like RNA-seq likely will 

become more common as sequencing costs decline and bioinformatic analyses become standardized 

and integrated with genomic sequencing. 

One promising research area is the application of exome sequencing (Exome-Seq) to either frozen or 

formalin-fixed, paraffin-embedded tissues. DNA can be extracted from either frozen or archival 

tissues. Coding portions of DNA, or exons, are captured by libraries of hybridization-based probes 

targeting over 200,000 exons and transcriptionally active regions. Exon-enriched DNA can be 

sequenced by DNA-Seq and then genomically aligned to find mutation insertions or deletions and 

other genetic abnormalities associated with disease. An additional area of development is the 

isolation of circulating, cell-free DNA (ccfDNA). DNA released from apoptosis or cell turnover normally 

appears in plasma, but chemical exposure can increase levels of ccfDNA due to toxicity, 

inflammation, or tumor development. The NTP is investigating the use and sequencing of ccfDNA in 

toxicology studies to determine its use as a new marker of chemical exposure. 

Several NTP studies are using Exome-Seq for profiling mutations on a genome-wide scale to 

understand differences between spontaneous and chemically induced tumors. Another promising 

NextGen sequencing-related area in toxicogenomics is the S1500+ platform. This platform provides a 

way to use high-throughput transcriptomic screening for thousands of genes per sample and can be 

applied to both in vitro chemical toxicity screening and in vivo screening of RNA extracted from 

animal tissues. 

NTP is evaluating study conditions that could contribute to differential gene expression, such as 

animal and tissue variability, methods for tissue sampling, and standards for conducting 

toxicogenomic studies under laboratory conditions. Efforts are underway to optimize methods for 

DNA and RNA extraction from archival tissues for molecular analysis. Planned or ongoing NTP 

toxicogenomic studies from FY 2018 are listed below. 

73 
 

 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicogenomics 

Toxicogenomic Studies Planned or Ongoing in FY 2018 

Chemical (CASRN*) Species/Cell Line Route Duration Test Type (Platform) Study Scientist 

Arsenite (7784-46-5) Human prostate cell 

line 

In vitro 30 weeks NextGen sequencing 

Exome-Seq (Illumina) 

Alex Merrick 

2,3-Butanedione (diacetyl) (431-

03-8) 

2,3-Hexanedione (3848-24-6) 

Human airway 

epithelium cell line 

In vitro 4 days High-throughput 

transcriptomic screening 

William Gwinn 

Bisphenol A and analogues (80-

05-7) 

Human hepatocyte 

cell line 

In vitro 2 days High-throughput 

transcriptomic screening 

Mike DeVito 

Bisphenol AF (1478-61-1) 

Tetrabromobisphenol A (79-94-

7) 

Rat Gavage 5 days S1500+ NextGen 

sequencing 

Sue Fenton 

Bromodichloroacetic acid (5589-

96-8) 

Methyleugenol (93-15-2) 

Mouse Gavage 2 years NextGen sequencing 

Exome-Seq (Illumina) 

Arun Pandiri 

Dieldrin (60-57-1) 

Ethinyl estradiol (57-63-6) 

Methyl mercury (115-09-3) 

Rotenone (83-79-4) 

Phenol (68937-41-7) 

Isopropylated phosphate (3:1) 

(60348-60-9) 

Pentabromodiphenyl ether 

(60348-60-9) 

Mouse In vitro 1 day S1500+, NextGen 

sequencing 

Alison Harrill 

Phosphate flame retardants: 

tert-Butylphenyl diphenyl 

phosphate 

(56803-37-3) 

2-Ethylhexyl diphenyl phosphate 

(1241-94-7) 

Isodecyl diphenyl phosphate 

(29761-21-5) 

Isopropylated phenol phosphate 

(68937-41-7) 

Rat Gavage 5 days Microarray (Affymetrix) 

Metabolomics 

Scott Auerbach 

Ginkgo biloba extract (90045-36-

6) 

Rat Gavage 5 days Microarray (Affymetrix) Cynthia Rider, 

Scott Auerbach 

Induced pluripotent stem cells 

Embryoid bodies 

Embryonic stem cells 

Human stem cell N/A N/A High-throughput 

transcriptomic screening 

Erik Tokar, Mike 

DeVito 

74 
 

 

 

2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicogenomics 

Chemical (CASRN*) Species/Cell Line Route Duration Test Type (Platform) Study Scientist 

PCB-11 (2050-67-1) Rat 

Human hepatocyte 

cell line 

In vitro 1 day S1500+ NextGen 

sequencing 

Mike DeVito 

PBDE-47 (32534-81-9) Rat Gavage 21 days Microarray June Dunnick 

Polycyclic aromatic compounds: 

Acenaphthenequinone (82-86-0) 

Benzo[b]fluoranthene (205-99-2) 

Benzo(a)pyrene (50-32-8) 

Dibenz[a,h]anthracene (53-70-3) 

9-Methylanthracene (779-02-2) 

1-Methylfluorene (1730-37-6) 

Perinaphthenone (548-39-0) 

Phenanthrene (85-01-8) 

Pyrene (129-00-0) 

Human hepatocyte 

cell line 

In vitro 2 days Cytotoxicity and gene 

expression by 

quantitative polymerase 

chain reaction 

Cynthia Rider, 

Erik Tokar 

Tetrabromobisphenol A (79-94-7) 

Pentabromodiphenyl oxidetechnical (DE-71) (32534-81-9) 

Triclosan (3380-34-5) 

alpha, beta-Thujone (76231-76-0) 

Rat Gavage 5 days High-throughput 

transcriptomic screening 

Mike DeVito, 

William Gwinn 

112-chemical compound test set 

(pharmaceuticals and 

environmental compounds) 

Human hepatocyte 

cell line-HepaRG 

In vitro 2 days High-throughput 

transcriptomic screening 

Stephen 

Ferguson, 

Sreenivasa 

Ramaiahgari 

20-chemical compound test set 

(environmental compounds) 

Primary rat 

hepatocytes Human 

HepaRG cells 

In vitro 3 days S1500+ NextGen 

sequencing 

William Gwinn, 

Mike DeVito 

N/A Human mRNA 

Reference Isolation 

In vitro N/A S1500+ NexGen 

Sequencing 

Richard Paules 

Carcinogens (HCC100) Mouse In vivo 2 years HCC RNA-seq, CNV 

array 

Miaofei Xu, 

Arun Pandiri 

*Chemical Abstracts Service Registry Number 

**This study will compare toxicogenomic effects among the chemicals listed together. 

75 
2018 Annual Report – Research and Testing – Testing and Toxicology Studies – Toxicogenomics 

Related Links: 

Disposition, Metabolism, and Toxicokinetic Studies 

Genetic Toxicity Studies 

Organ System Toxicity Studies 

Modified One-Generation Reproduction Studies 

Toxicology and Carcinogenicity Studies 

76 
 

 

 

2018 Annual Report – Research and Testing – NICEATM 

NICEATM 

About NICEATM 

The NTP Interagency Center for the Evaluation of Alternative Toxicological Methods 

(NICEATM) supports the development and evaluation of new, revised, and alternative 

methods to identify potential hazards to human health and the environment, with a 

focus on replacing, reducing, or refining animal use. 

NICEATM Webinars and Workshops 

A summary of webinars and workshops held or supported by NICEATM in FY 2018. 

NICEATM Support of Tox21 

A description of Tox21 projects NICEATM supported in FY 2018. 

Additional NICEATM Activities 

A summary of other activities NICEATM has conducted and participated in during 

FY 2018. 

77 
2018 Annual Report – Research and Testing – NICEATM – About NICEATM 

About NICEATM 

The NTP Interagency Center for the Evaluation of Alternative 

Toxicological Methods (NICEATM) focuses on the development 

and evaluation of alternatives to animal use for chemical safety 

testing. 

NICEATM activities include: 

• Conducting and publishing analyses and evaluations of data 

from new, revised, and alternative testing approaches 

• Providing information to test method developers, regulators, 

and regulated industry through its website and other 

communications and by organizing workshops and symposia 

• Coordinating and providing scientific and operational support for 

the Interagency Coordinating Committee on the Validation of 

Alternative Methods (ICCVAM) meetings, webinars, 

teleconferences, working groups, and public forums 

• Providing bioinformatics and computational toxicology support 

to NIEHS/NTP projects, especially those related to Tox21 

Related Links 

 

 

 

 

Warren Casey, Ph.D., is director of NICEATM. NICEATM receives 

contract support from Integrated Laboratory Systems, Inc. 

Related Annual Report Pages: 

FY 2018 NICEATM Webinars and Workshops 

NICEATM Support of Tox21 

Additional NICEATM Activities 

Activities and Resources 

Publications 

Reports 

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2018 Annual Report – Research and Testing – NICEATM – Webinars and Workshops 

NICEATM Webinars and Workshops 

Workshop: Predictive Models for Acute Oral Systemic Toxicity 

In coordination with the ICCVAM Acute Toxicity Workgroup, 

NICEATM organized a global project to develop in silico 

models of acute oral systemic toxicity that predict five specific 

endpoints identified by ICCVAM regulatory agencies. These 

endpoints included identification of: 

• “Very toxic” chemicals (LD50 less than 50 mg/kg) 

• “Nontoxic” chemicals (LD50 greater than or equal to 2,000 

mg/kg) 

• Point estimates for LD50s 

• Categorization of toxicity hazard using the EPA classification 

scheme 

• Categorization of toxicity hazard using the United Nations 

Globally Harmonized System of Classification and Labelling 

classification scheme 

The project was sponsored by the ICCVAM Acute Toxicity 

Workgroup. 

NICEATM invited scientists to develop and submit in silico models 

that predicted any or all of these endpoints. This workshop, 

convened in April, provided an opportunity for project participants to 

present their submitted models. NICEATM scientists also presented 

an evaluation of the rat acute oral systemic toxicity test 

reproducibility as well as the development of a consensus model 

that integrates submitted models to generate consensus predictions 

for acute oral systemic toxicity. Workshop participants also 

discussed next steps needed to encourage appropriate use of 

predictive models in regulatory contexts. 

Information about the workshop and follow-up project activities is 

available on the NTP website. 

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2018 Annual Report – Research and Testing – NICEATM – Webinars and Workshops 

Workshop on the Monocyte Activation Test for Pyrogen Testing of 

Medical Devices 

Pyrogens are substances that can produce fever when present as 

contaminants in a drug or medical device. Most pyrogens are 

biological substances derived from bacteria, fungi, and viruses; 

material-mediated pyrogens (MMPs), while less common, might 

also be present. Drugs for injection and medical device products for 

implantation or other systemic exposure should meet pyrogen limit 

specifications before they are marketed. Animal-based pyrogen 

tests are often conducted to investigate the presence of pyrogens. 

Non-animal monocyte activation tests (MATs) are widely available 

but infrequently used for pyrogen testing. 

To review the MAT and discuss ongoing challenges to its 

widespread implementation for medical device testing, NICEATM 

and the PETA International Science Consortium (PISC) coorganized a September workshop. Meeting participants explored 

how the FDA Medical Device Development Tools Program could be 

used to qualify the use of the MAT as a standalone pyrogen test for 

specific medical device contexts of use. Participants generally 

agreed that the MAT could be qualified as acceptable for batchrelease testing for microbial-based pyrogens; however, additional 

studies were recommended to demonstrate its ability to detect 

known MMPs. This testing would determine whether the assay can 

be used for both biocompatibility and sterility or if other information 

on MMPs would be needed to address biocompatibility. Participants 

also discussed information gaps on MMPs, potential test controls, 

and other challenges and opportunities for implementing the use of 

the MAT as a comprehensive pyrogen test. 

More information about the workshop is available on the PISC website. 

Related Annual Report Pages: 

About NICEATM 

NICEATM Support of Tox21 

Additional NICEATM Activities 

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2018 Annual Report – Research and Testing – NICEATM – Support of Tox21 

NICEATM Support of Tox21 

The Tox21 research initiative aims to improve regulatory hazard 

assessment of substances potentially harmful to humans and the 

environment. Tox21 uses in vitro high-throughput screening 

assays to evaluate the biological activity of compounds in a 

10,000-compound library and to relate observed activities to 

toxicological endpoints. 

NICEATM provides support to the Tox21 effort primarily through 

its computational toxicology group. Specific NICEATM projects in 

support of Tox21 are included in the Tox21 Projects section. 

Related Annual Report Pages: 

About NICEATM 

FY 2018 NICEATM Webinars and Workshops 

Additional NICEATM Activities 

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2018 Annual Report – Research and Testing – NICEATM – Additional Activities 

Additional NICEATM Activities 

Integrated Chemical Environment 

Successful computational toxicology projects depend on freely available, high-quality data that are 

formatted for use in computational workflows. The NICEATM Integrated Chemical Environment (ICE) 

resource, launched in 2017, provides data from NICEATM and its partners as well as other resources 

and tools in an environment designed to support chemical safety assessment and new method 

development. 

Updates to ICE in FY 2018 included: 

• Adding formulation data and the ability for users to compare labeling categories from EPA “sixpack” studies with the performance of the formulation’s active ingredients in non-animal 

methods 

• Expanding physicochemical property predictions to include over 720,000 chemicals using an 

updated set of predictive models (Mansouri et al. 2018) 

• Improving filtering on assay endpoints to allow more user control 

• Adding androgen and estrogen pathway model predictions and rat acute oral LD50 data from a 

NICEATM predictive modeling project 

• Providing a workflow to enable in vitro-to-in vivo extrapolation (Casey et al. 2018) 

Updates in early FY 2019 will add two more workflows. The Machine Learning Workflow will provide 

five different machine learning algorithms to let users develop simple predictive models for a subset 

of endpoints using ICE data. The Chemical List Characterization Workflow will use physicochemical 

properties to provide property-based comparison of the chemicals. 

ICE 2.0, to be launched later in FY 2019, will include a refresh to the user interface; data selections 

aimed to guide users less familiar with the assay; and more seamless movement between ICE tools, 

the Integrator, and external resources. 

Acute Systemic Toxicity 

Models developed for the acute oral systemic toxicity project (culminating in the April 2018 workshop) 

that met qualitative and quantitative review criteria were used by NICEATM to generate consensus 

predictions for the acute oral toxicity endpoints of interest. The consensus predictions generated for 

the project will be available in ICE, the EPA’s CompTox Dashboard, and OPERA software. The 

consensus models will be made available and described in a manuscript to be submitted for 

publication in FY 2019. 

NICEATM and NCCT are evaluating the potential of using ToxCast and Tox21 assay data for 

predicting acute oral toxicity; preliminary results suggest this approach could distinguish “toxic” from

“nontoxic” chemicals. A manuscript describing the evaluation is planned for submission in early 2019. 

Botulinum Neurotoxin Testing 

Tests to detect and measure botulinum neurotoxin (BoNT) are required by multiple federal agencies 

for regulatory and other decision contexts. Currently, the standard test for these endpoints is a mouse 

lethality assay that can use large numbers of animals. To support evaluation and promotion of 

alternative test methods, NICEATM published a Federal Register notice in June requesting available 

data and information on approaches and/or technologies currently used to detect and measure BoNT. 

Information submitted in response to the request is being used to assess the state of the science and 

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2018 Annual Report – Research and Testing – NICEATM – Additional Activities 

determine technical needs for non-animal test methods used to detect the presence of BoNT and 

measure potency of BoNT preparations. 

Cardiotoxicity 

An initiative is underway to design, build, and test new non-animal approaches to assess 

cardiotoxicity hazard. The goal is to develop human cell- and protein-based assays to more efficiently 

screen drugs and chemicals for their potential to be toxic to the heart or circulatory system. The 

initiative is supported jointly by NTP (NIEHS/NTP Biomolecular Screening Branch and NICEATM), 

the FDA Center for Drug Evaluation and Research, and the Health and Environment Sciences 

Institute (HESI). Two NTP projects within this initiative focus on in silico screening approaches for 

assessing cardiovascular safety. This NICEATM project will mine public data sources to compile a 

structured cardiotoxicity database and human-relevant data will help build and test the capabilities of 

models and integrated testing strategies for cardiovascular hazards. 

Developmental Toxicity 

Developmental toxicity tests evaluate the extent to which exposure to a substance can interfere with 

normal development. This testing is required by multiple regulatory agencies and uses large numbers 

of animals. NICEATM supports efforts to develop, validate, and implement alternative approaches to 

identify potential developmental toxicants. To this end, NICEATM published a Federal Register notice 

in May requesting available data and information on approaches and/or technologies currently used 

to identify potential developmental toxicants. Submitted information will help assess the state of the 

science for these approaches and technologies and determine technical needs for approaches to 

assess developmental toxicity endpoints. 

NICEATM continues to support the NTP Systematic Evaluation of the Application of Zebrafish in 

Toxicology program. A summary of current zebrafish husbandry and toxicology study practices will be 

published in Alternatives to Animal Experimentation in early FY 2019. An interlaboratory study to 

examine effects of key protocol elements will be initiated later in FY 2019. 

Endocrine Disruptors 

NICEATM compiled high-quality data from in vivo testing of chemicals for potential endocrine 

disruptor activity. These data have potential use for developing adverse outcome pathways or models 

of estrogenic activity, prioritizing chemicals for further testing, and evaluating species-specific 

responses to chemicals. Most recently, NICEATM collaborated with Organisation for Economic Cooperation and Development (OECD) and EPA scientists to develop a reference database and 

evaluate an in vitro model to identify chemicals with the potential to interact with the androgen 

receptor (AR). The AR model is potentially a rapid, cost-effective replacement for the in vivo 

Hershberger assay. Two recent papers describe data and methods used for this effort. 

• Browne et al. 2018, describes assembly and curation of a data set of results for the 

Hershberger and other in vivo assays for AR activity. Ultimately, 49 chemicals were identified 

with reproducible AR pathway responses confirmed in at least two in vivo rodent studies. 

These 49 chemicals could be considered reference chemicals useful for validating alternative 

methods. 

• Kleinstreuer et al. 2018, describes use of the reference chemicals identified through the data 

curation effort to interrogate the performance of a ToxCast/Tox21 AR model based on 11 highthroughput assays. The AR model had 100% positive predictive value for the in vivo response, 

where chemicals with conclusive AR model results were consistently positive in vivo. 

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 AR agonist and antagonist 

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2018 Annual Report – Research and Testing – NICEATM – Additional Activities 

activity. Specifically, NICEATM provided guidance on incorporating a cytotoxicity assay into the test 

method protocol. Testing of 67 coded reference chemicals in agonist and antagonist modes to 

characterize method reliability and relevance is complete, and a report summarizing these results is 

being prepared. 

Skin Sensitization 

The DNTP Toxicology Branch is testing over 200 chemicals nominated by ICCVAM agencies using 

three in vitro test methods to expand the applicability domain of a defined approach for identifying 

skin sensitizers. Mouse local lymph node assay data are available for the nominated chemicals, 

which include pesticides, formulations, industrial chemicals, and other chemicals of interest to 

ICCVAM agencies. The three in vitro test methods are the LuSens method, the direct peptide 

reactivity assay, and the human cell line activation test. NICEATM is coordinating the testing, which 

began in 2017 and is scheduled for completion in early 2019. The study data will enable NICEATM 

and ICCVAM to evaluate the appropriateness of a defined approach using these three in vitro 

methods for various regulatory applications. 

NICEATM collaborated with the Cosmetics Europe Skin Tolerance Task Force to evaluate integrated 

testing and assessment approaches for skin sensitization submitted to OECD. NICEATM evaluated 

six defined approaches with a set of previously untested chemicals having in vitro and in silico data 

provided by Cosmetics Europe. Descriptions of the data sets (Hoffman et al. 2018) and the outcome 

of the analyses (Kleinstreuer et al. 2018) were published in 2018 and demonstrated that many of 

these approaches perform as well or better than animal methods to predict human skin sensitization 

hazards. 

Ocular Irritation 

NICEATM, the PETA International Science Consortium, EPA, and CropLife America member 

companies are collaborating to develop an in vitro-defined approach for hazard classification of eye 

irritation potential of agrochemical formulations. 

• NICEATM analyzed data from four in vitro assays paired with in vivo rabbit eye test data to 

determine if a defined approach using a combination of these assays could be used to assess 

eye irritation potential. While the results of this analysis indicated that developing such a 

defined approach was feasible, it was determined that the evaluated data sets were limited in 

size. Therefore, additional prospective testing was proposed. 

• A two-phased prospective evaluation was designed to (1) assess the applicability of seven in 

vitro eye irritation/corrosion methods to agrochemical formulations and (2) develop a defined 

approach for agrochemical formulations testing for prediction of U.S. and international irritancy 

classifications. In Phase 1, completed in FY 2018, six formulations were tested in seven eye 

irritation test methods. All seven methods will be included in Phase 2A, which will evaluate 10 

formulations that represent a range of eye irritancy classifications. Phase 2B will evaluate an 

additional 30 formulations with a range of eye irritancy potential, and methods to be included 

will be based on Phase 2A results. The study is expected to be completed in FY 2019 and will 

suggest assays that can form the basis of a defined approach for agrochemical formulations 

testing for eye irritation/corrosion potential. 

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2018 Annual Report – Research and Testing – NICEATM – Additional Activities 

Related Annual Report Pages: 

About NICEATM 

FY 2018 NICEATM Webinars and Workshops 

NICEATM Support of Tox21 

85 
 

 

 

 

 

2018 Annual Report – Research and Testing – ICCVAM 

ICCVAM 

About ICCVAM 

The Interagency Coordinating Committee on the Validation of Alternative Methods 

(ICCVAM) is a permanent interagency committee of NIEHS. 

A Strategic Roadmap for Establishing New Approaches to Evaluate 

the Safety of Chemicals and Medical Products in the United States 

ICCVAM is coordinating the development of a strategic roadmap to adopt new 

approaches to safety and risk assessment of chemicals and medical products that 

improve human relevance and replace or reduce the use of animals. 

ICCVAM Meetings 

A description of meetings held by ICCVAM in FY 2018. 

ICCVAM Test Method Evaluation Activities 

A list of NICEATM and ICCVAM test method evaluation activities in FY 2018. 

ICCVAM International Validation Activities 

A description and list of NICEATM and ICCVAM international validation activities in FY 

2018. 

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2018 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. 285l-3), its purpose is “to establish, wherever feasible, 

guidelines, recommendations, and regulations that promote the regulatory acceptance of new or 

revised scientifically valid toxicological tests that protect human and animal health and the 

environment while reducing, refining, or replacing animal tests and ensuring human safety and 

product effectiveness.”

ICCVAM is composed of representatives from 16 U.S. federal regulatory and research agencies that 

generate or use toxicological and safety testing information (see below). Warren Casey, Ph.D., serves 

as administrative director of ICCVAM. 

• Agency for Toxic Substances and Disease Registry 

• U.S. Consumer Product Safety Commission 

• U.S. Department of Agriculture 

Related Links 

• U.S. Department of Defense Information on ICCVAM 

Activities • U.S. Department of Energy 

Complete List of Articles • U.S. Department of the Interior on ICCVAM Activities 

Published in Scientific • U.S. Department of Transportation Journals 

• U.S. Environmental Protection Agency 

• U.S. Food and Drug Administration 

• National Cancer Institute 

• National Institute of Environmental Health Sciences 

• National Institutes of Health 

• National Institute for Occupational Safety and Health 

• National Institutes of Standards and Technology 

• National Library of Medicine 

• Occupational Safety and Health Administration 

Related Annual Report Pages: 

Strategic Roadmap for New Approaches to Evaluate the Safety of 

Chemicals and Medical Products 

ICCVAM Meetings 

ICCVAM Test Method Evaluation Activities 

ICCVAM International Validation Activities 

87 
2018 Annual Report – Research and Testing – ICCVAM – Strategic Roadmap 

A Strategic Roadmap for Establishing New Approaches to Evaluate the Safety of 

Chemicals and Medical Products in the United States 

ICCVAM coordinated the development of a strategic roadmap for 

incorporating new approaches into safety testing of chemicals and 

medical products in the United States. Sixteen federal agencies 

and multiple interagency workgroups developed the roadmap with 

input from a broad range of stakeholder groups. The final 

roadmap document was published in January 2018 and is 

available on the NTP website. 

The roadmap creates a framework that guides the development of 

enabling technologies and promotes strategies to establish 

confidence in and ensure utilization of new approaches to toxicity 

testing that improve human health relevance and reduce or 

eliminate the need for testing in animals. The successful 

development and implementation of these new approaches will 

require coordinated efforts that address three strategic goals: 

(1) Connect users with developers of new approach methodologies. 

(1) Foster the use of efficient, flexible, and robust practices to 

establish confidence in new methods. 

(2) Encourage the adoption and use of new methods and 

approaches by federal agencies and regulated industries. 

Related Links 

 

 

 

 

Pages on the NTP website describe activities underway to 

address the roadmap goals in the following areas: 

• Acute systemic toxicity 

• Skin and eye irritation 

• Skin sensitization 

Related Annual Report Pages: 

About ICCVAM 

ICCVAM Meetings 

ICCVAM Test Method Evaluation Activities 

ICCVAM International Validation Activities 

Information on ICCVAM Activities 

Complete List of Articles on 

ICCVAM Activities Published in 

Scientific Journals 

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2018 Annual Report – Research and Testing – ICCVAM – Meetings 

ICCVAM Meetings 

NICEATM supported eight teleconferences and two in-person 

meetings held by ICCVAM in FY 2018. NICEATM also supported 

eight ad hoc ICCVAM workgroups focused on acute systemic 

toxicity, ocular and dermal irritation, developmental and 

reproductive toxicity, skin sensitization, use of read-across in 

toxicity testing applications, in vitro-to-in vivo extrapolation, 

nanomaterials, and ecotoxicology. 

The fourth ICCVAM Communities of Practice webinar was held on 

January 23, 2018. The webinar explored the fundamentals of 

machine learning approaches, including how they work, how they 

are interpreted, and precautions that should be taken when 

evaluating their output. Sean Ekins, Ph.D., Chief Executive Officer 

of Collaborations Pharmaceuticals, Inc., and NICEATM Deputy 

Director Nicole Kleinstreuer, Ph.D., addressed issues specific to 

machine learning approaches used in a regulatory context. Case 

studies were presented to highlight where such techniques have 

been successfully applied both nationally and internationally. 

Presentations from the webinar are available on the NTP website. 

ICCVAM, with NICEATM support, held its fifth public forum on May 

24, 2018, at the National Institutes of Health in Bethesda, Maryland. 

Representatives from eight ICCVAM member agencies were joined 

by attendees representing stakeholder groups and over 100 

webcast viewers. ICCVAM members provided information about 

their agency activities on the development and validation of test 

methods and approaches that could replace, reduce, or refine 

animal use. 

A main focus of this meeting was implementation of the strategic 

roadmap for establishing new approaches to evaluate the safety of 

chemicals and medical products in the United States. Commenters 

offered suggestions on specific actions that should be taken to 

advance the goals of the strategic roadmap and encouraged less 

active ICCVAM partners to take a greater role. The meeting agenda 

and presentations are available on the NTP website. 

Related Annual Report Pages: 

About ICCVAM 

Strategic Roadmap for New Approaches to Evaluate the Safety of 

Chemicals and Medical Products 

ICCVAM Test Method Evaluation Activities 

ICCVAM International Validation Activities 

Related Links 

 

 

 

 

Information on ICCVAM Activities 

Complete List of Articles on 

ICCVAM Activities Published in 

Scientific Journals 

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2018 Annual Report – Research and Testing – ICCVAM – Test Method Evaluation 

ICCVAM Test Method Evaluation Activities 

ICCVAM welcomes submissions of innovative test methods that might be acceptable for specific 

regulatory use and for which adequate validation studies have been completed. To maximize 

effective implementation of new test methods or approaches, however, ICCVAM evaluates and 

recommends only those test methods proposed for regulatory uses that align with ICCVAM member 

agencies’ needs and priorities. More information on ICCVAM test method submissions is available. 

In FY 2018, the Genomic Allergen Rapid Detection (GARDTM) assay was submitted by SenzaGen AB 

to ICCVAM to evaluate its ability to identify potential skin sensitizers. The ICCVAM Skin Sensitization 

Workgroup reviewed and discussed a validation study report provided by SenzaGen and in response 

to SenzaGen note deficiencies in the validation that precluded a recommendation being made on the 

assay. Ongoing ICCVAM test method evaluation activities in FY 2018 are summarized below. 

Test Method Evaluation Activities in FY 2018 

Test Method ICCVAM Recommendations/Agency Status 

Electrophilic allergen screening assay This test method, nominated by the National Institute for Occupational 

Safety and Health (NIOSH), is an in chemico assay intended to identify 

potential skin sensitizers. 

A validation study of the method began in FY 2017 with four ICCVAM 

agencies participating in the study. NICEATM is coordinating the study, 

and members of the ICCVAM Skin Sensitization Workgroup are serving 

on the study management team. 

Phase 1 testing of 10 chemicals during FY 2018 showed that the method 

had sufficiently good reproducibility and accuracy rates to support further 

evaluation. Phase 2 testing will begin after a 96-well format is developed 

to increase throughput and accessibility of the assay. 

OptiSafe NICEATM coordinated a multi-laboratory validation study to determine 

the reliability and relevance of the OptiSafe test method. In this method, 

a test substance is applied to a semi-permeable membrane to assess 

the substance’s potential to cause eye irritation. 

Testing was completed on 95 coded chemicals in three phases during 

FY 2018; a report on the study will be submitted for publication in FY 

2019. 

EpiAirwayTM A cooperative agreement under the NIEHS Phase IIb Small Business 

Innovation Research provides funding to MatTek Corporation to validate 

its EpiAirwayTM in vitro human bronchial tissue model to predict the 

toxicity of inhaled chemicals. 

Several ICCVAM agency representatives are members of the 

cooperative agreement steering committee. Testing is ongoing with 

chemicals selected by steering committee members. 

NICEATM provides scientific oversight of this NIEHS small business 

program supporting validation of alternative test methods. 

The ICCVAM agencies are engaged in additional activities that support replacing, reducing, and 

refining animal use. Summaries of these additional activities are on the NTP website. 

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2018 Annual Report – Research and Testing – ICCVAM – Test Method Evaluation 

Related Annual Report Pages: 

About ICCVAM 

Strategic Roadmap for New Approaches to Evaluate the Safety of 

Chemicals and Medical Products 

ICCVAM Meetings 

ICCVAM International Validation Activities 

91 
 

 

 

 

 

2018 Annual Report – Research and Testing – ICCVAM – International 

ICCVAM International Validation Activities 

NICEATM and ICCVAM participate in international test method validation activities through OECD. 

They also collaborate with countries and regions participating in the International Cooperation on 

Alternative Test Methods (ICATM), including the European Union, Japan, Korea, Canada, Brazil, and 

China. 

Representatives from OECD and ICATM participating organizations in Canada, Brazil, and Korea 

attended the September 2018 meeting of the Scientific Advisory Committee on Alternative 

Toxicological Methods. In a separate meeting, attendees gave updates on their organizations’ 

activities. 

In FY 2018, ICCVAM agencies commented on draft OECD documents through the U.S. National 

Coordinator for the OECD Test Guidelines Programme, an ex officio ICCVAM member. Beginning in 

2018, the U.S. National Coordinator will be joined at the annual meeting of the National Coordinators 

by one or more ICCVAM members who are subject matter experts in topics planned for discussion at 

the meeting. ICCVAM members and/or NICEATM staff supported the Test Guidelines Programme 

during FY 2018 by: 

• Serving on an expert group developing a performance-based test guideline (PBTG) for defined 

approaches for skin sensitization. PBTGs describe acceptable performance standards for a 

general class of test methods that are intended to measure the same biological effect. 

• Attending meetings of the OECD expert groups on eye irritation and skin sensitization, which 

produced six updated test guidelines published in 2018. 

ICATM collaborations address three critical areas of cooperation: test method validation studies, 

independent peer review of validation studies, and development of formal recommendations on 

alternative testing methods. In October 2016, representatives of NICEATM and ICCVAM attended an 

ICATM coordination meeting and ICATM-sponsored workshop to develop criteria for evaluating nonanimal approaches for skin sensitization potential. Products of this workshop included a white paper 

characterizing international regulatory requirements for skin sensitization testing (Daniel et al. 2018), 

a position paper covering workshop outcomes and ICATM recommendations (Casati et al. 2018), and 

a proposal to develop a PBTG for defined approaches to testing and assessment of skin 

sensitization, which was accepted by OECD in April 2017. NICEATM and ICCVAM representatives 

will attend an ICATM workshop in October 2018 on “Validation and Establishing Scientific 

Confidence.”

In fiscal year 2018, NICEATM staff served on the validation management team for an allergic contact 

dermatitis test for an international amino acid derivation reactivity assay led by the Japanese Center 

for the Validation of Alternative Methods. In addition, an ICCVAM member served on the peer-review 

panel. The study is complete. 

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2018 Annual Report – Research and Testing – ICCVAM – International 

Related Annual Report Pages: 

About ICCVAM 

Strategic Roadmap for New Approaches to Evaluate the Safety of 

Chemicals and Medical Products 

ICCVAM Meetings 

ICCVAM Test Method Evaluation Activities 

93 
2018 Annual Report – Literature Analysis 

Literature Analysis 

Noncancer Research 

NTP conducts evaluations to assess the evidence that substances cause adverse 

health effects and provides opinions on whether these substances could be of human 

concern. 

Report on Carcinogens 

The Report on Carcinogens is a congressionally mandated listing of substances that 

either are known to be human carcinogens or might reasonably be anticipated to be 

human carcinogens and to which a significant number of people residing in the United 

States are exposed. 

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2018 Annual Report – Literature Analysis – Noncancer Research 

Noncancer Research 

In addition to conducting analysis activities to identify cancer hazards, NTP also evaluates the 

scientific evidence to determine whether environmental chemicals, physical substances, or 

mixtures—collectively referred to as substances—cause adverse, noncancer, health effects. NTP 

also provides opinions on whether these substances might be of concern given what is known about 

current human exposure levels. The NIEHS/NTP Office of Health Assessment and Translation 

(OHAT) conducts health hazard assessments and other evidence evaluations, including scoping 

reviews, evidence maps, and state-of-the-science evaluations, which are published as NTP 

monographs, NTP research reports, and journal publications, and hosts workshops to address 

important issues in environmental health sciences. Andrew Rooney, Ph.D., served as acting director 

of OHAT in FY 2018. 

In FY 2018, OHAT added evidence mapping as a new interactive data presentation format as an 

output option of its evidence evaluations. Evidence maps categorize or “map” the key concepts for a

particular question or topic. When performed with a systematic literature search and selection 

process, the resulting evidence map allows readers to explore evidence categorized by health effect, 

exposure, evidence stream (e.g., human, experimental animal, or mechanistic data) and study 

design. The State-of-the Science Evaluation of Transgenerational Inheritance of Health Effects 

demonstrates this new interactive data presentation. 

Ongoing Noncancer Health Effects Projects 

Project 

Study Scientist 

Project Summary Status 

Evaluation of long-term 

neurological effects of acute 

exposure to the 

organophosphorus nerve agent 

sarin 

Andrew Rooney 

Sarin is a highly toxic organophosphorus nerve agent 

developed for chemical warfare during World War II that 

continues to be used as a weapon today. 

In partnership with the NIH Countermeasures Against 

Chemical Threats (CounterACT) Program, NTP has 

conducted a systematic review to evaluate the evidence for 

long-term neurological effects in humans following acute 

exposure to sarin. 

Draft monograph 

released December 

2018 

Evaluation of inflammation-based 

atherosclerosis associated with 

environmental exposures 

Brandy Beverly and Andrew 

Rooney 

This evaluation examines whether 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 

that leads to it. 

Evaluation ongoing 

NIEHS-EPA pilot study of 

exposure to chemicals in 

consumer products 

Kyla Taylor 

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

longitudinal pilot study to evaluate the performance of 

existing survey, measurement, and modeling methods for 

assessing exposures to chemicals in several consumer 

product categories, including personal and child care, 

household cleaning, lawn and garden, home improvement, 

and food packaging products. 

The pilot study addresses several research needs related to 

the measurement and modeling of human exposures. 

Pilot study sample 

collection completed 

September 2018. 

Biological samples are 

being analyzed by 

CDC 

95 
 

 

 

 

 

2018 Annual Report – Literature Analysis – Noncancer Research 

Project 

Study Scientist 

Project Summary Status 

Respiratory effects associated 

with exposure to biocides 

Vickie Walker 

Biocides are commercial products used to kill or control the 

spread of harmful microorganisms like bacteria and viruses. 

The EPA Office of Pesticide Programs nominated biocides 

to NTP for evaluation of the evidence for respiratory 

outcomes from occupational exposure to biocides. 

The ongoing study includes developing a scoping review 

and evidence map on potential respiratory health effects of 

10 major antimicrobial biocides commonly used for 

disinfection in hospitals. 

Evaluation ongoing 

State of the science for 

transgenerational inheritance of 

health effects 

Vickie Walker 

Transgenerational inheritance is the phenomenon in which 

an individual’s exposures have far-reaching consequences, 

affecting multiple generations removed from the original 

insult. 

NTP conducted a state-of-the-science or scoping review to 

examine the evidence for transgenerational inheritance of 

health effects associated with exposure to a wide range of 

stressors (e.g., environmental chemicals, drugs of abuse, 

nutrition and diet, pharmaceuticals, infectious agents, stress) 

in humans and animals. 

The evaluation, published in Environment International in 

February 2018, systematically compiled and categorized the 

literature to develop an evidence map for transgenerational 

inheritance by broad health-effect categories, exposures, 

and types of evidence, and identified areas of consistency, 

uncertainty, data gaps, and research needs. 

Evidence mapping illustrated that risk of bias (having 

generally few studies) and heterogeneity in exposures and 

endpoints examined present serious limitations to available 

bodies of evidence for assessing transgenerational effects. 

Evaluation published 

February 2018 

Evaluation of children’s health 

and traffic-related air pollution 

Kembra Howdeshell and Brandy 

Beverly 

Research on traffic-related air pollution and children’s health 

has increased in the past decade, reflecting improvement in 

air monitoring technology and exposure methodology. 

Traffic-related air pollution has been measured in multiple 

ways, including direct traffic measures (such as traffic 

proximity or density) and surrogate measures of trafficrelated air pollution (such as particulate matter, oxides of 

nitrogen, and other products of fossil-fuel combustion 

generated by motor vehicles including benzene, diesel 

exhaust, and PAHs). 

This topic is the subject of this series of evaluations on the 

evidence for an association between traffic-related air 

pollution and health outcomes impacting the fetus and 

children, beginning with hypertensive disorders of pregnancy 

and neurological development and function in children. 

Evaluation ongoing 

96 
 

 

 

 

 

 

2018 Annual Report – Literature Analysis – Noncancer Research 

Project Project Summary Status 

Study Scientist 

Evaluation of adverse health This evaluation examined the evidence that occupational Final monograph 

effects and occupational exposure to cancer chemotherapy agents is associated with completed September 

exposure to cancer adverse health effects, including genetic toxicity, cancer, 2018 

chemotherapy agents reproductive and developmental effects, and acute effects. 

Kembra Howdeshell The draft NTP monograph has been completed and is 

undergoing formatting for final publication. 

Environmental influences on the This evaluation leveraged newly developed text mining and Deferred 

epigenome: a scoping report machine learning tools to carry out scoping activities that will 

explore the evidence linking environmental exposures to Katie Pelch and Vickie Walker health outcomes via genome-wide alterations in DNA 

methylation. 

Chemical factors affecting breast 

cancer risk: a state-of-the-science 

review 

Vickie Walker and Jason Stanko 

This evaluation is examining the evidence that 

environmental substances or factors influence breast cancer 

risk. 

In collaboration with the DNTP NTP Laboratory, OHAT is 

conducting an evidence evaluation of chemicals, 

pharmaceuticals, and dietary components as well as other 

factors that are associated with adverse effects on the 

breast or mammary gland and could potentially influence 

breast cancer risk. 

Evaluation ongoing 

Neonicotinoid pesticides and 

adverse health outcomes 

Windy Boyd 

Neonicotinoid pesticides are a class of chemicals that act as 

insecticides by exerting neurotoxic effects through 

irreversible binding to insect nicotinic acetylcholine 

receptors. 

This scoping review is identifying the extent of evidence 

available to understand human health effects of seven 

neonicotinoid pesticides (acetamiprid, clothianidin, 

dinotefuran, imidacloprid, nitenpyram, thiacloprid, and 

thiamethoxam). 

Evaluation ongoing 

Parkinson’s disease: associations

with environmental exposures 

Windy Boyd 

Although some Parkinson’s disease cases can be attributed 

to genetic factors, the causes of many cases remain 

unknown. 

Many studies report associations between environmental 

exposures and Parkinson’s disease or related symptoms. 

OHAT conducted two scoping reviews on this topic. The first 

systematically mapped the evidence of the associations 

between exposures to environmental chemicals considered 

broadly and Parkinson’s disease. 

During scoping activities, hundreds of studies on the 

associations between exposure to the herbicide paraquat 

and Parkinson’s disease were identified, making paraquat a 

candidate chemical for further systematic review. Therefore, 

a more detailed scoping review was developed to 

characterize reported associations between paraquat 

exposure and Parkinson’s disease.

Evaluation ongoing 

Systematic reviews on potential 

health effects of fluoride 

This systematic review is evaluating potential 

neurobehavioral effects from exposure to fluoride during 

Evaluation ongoing 

97 
 

 

 

 

 

 

 

 

2018 Annual Report – Literature Analysis – Noncancer Research 

Project 

Study Scientist 

Project Summary Status 

Kyla Taylor development that includes consideration of human 

epidemiological studies, experimental animal studies, and 

mechanistic data. 

The project includes an update to NTP’s 2016 systematic

review of published animal literature examining 

neurobehavioral effects of exposure to fluoride during 

development and adulthood in rodents. The 2016 report 

concluded that the level of evidence supporting adverse 

effects on learning and memory in animals exposed to 

fluoride in the diet or drinking water is low to moderate. 

Prenatal exposure to 

progestogens and adverse health 

outcomes 

Kembra Howdeshell 

Progesterone and synthetic progesterone derivatives are 

administered to reproductive age women for a variety of 

health outcomes, including contraception, infertility, and 

treatment or prevention of miscarriage or preterm birth. 

Concern for possible adverse effects on the developing fetus 

stems from alterations in normal steroid hormone exposure 

during development that have been shown to cause adverse 

effects on offspring health and development. 

A scoping review is underway to identify and characterize 

the literature on the possible association between exposure 

to progestogens during pregnancy and adverse health 

outcomes in the offspring. 

Evaluation ongoing 

Evaluation of the findings from 

the consortium linking academic 

and regulatory insights on the 

toxicity of bisphenol A (CLARITYBPA) program 

Kembra Howdeshell, Brandy 

Beverly, Retha Newbold, Andrew 

Rooney, and John Bucher 

Bisphenol A is used in the manufacture of plastics, among 

other products, and has been identified as an endocrine 

disruptor. Its ubiquity in the environment has raised 

concerns about its potential health effects. 

Academic studies have identified several health effects of 

bisphenol A, while guideline compliant studies have failed to 

detect effects, except at high doses. As a result, NTP and 

NIEHS designed the Consortium Linking Academic and 

Regulatory Insights on the Toxicity of Bisphenol A 

(CLARITY-BPA) program to enhance the links between 

academic and guideline-compliant research. 

The findings of the CLARITY-BPA program will be 

summarized in two reports. The first report, authored by the 

CLARITY-BPA participants with background and publication 

summaries written by NTP, is an integrated assessment of 

the published findings from the guideline compliant and 

investigational research activities undertaken within the 

CLARITY-BPA program. 

The second report, authored by NIEHS/NTP, will attempt to 

synthesize and compare the CLARITY-BPA findings with 

prior studies on BPA from CLARITY-BPA participants to 

identify potential reasons for differences and assess whether 

there are additional scientific approaches to consider when 

performing guideline compliant studies of endocrine active 

agents. 

Evaluation ongoing 

98 
 

 

 

2018 Annual Report – Literature Analysis – Report on Carcinogens 

Report on Carcinogens 

About the Report on Carcinogens 

A congressionally mandated listing of substances that either are known to be human 

carcinogens or might reasonably be anticipated to be human carcinogens and to 

which a significant number of people residing in the United States are exposed. 

Report Activities 

A summary of activities the Office of the Report on Carcinogens conducted during 

FY 2018. 

Report Substances Selected for Evaluation 

A list of substances the Office of the Report on Carcinogens selected for evaluation 

during FY 2018. 

99 
 

 

 

 

 

 

2018 Annual Report – Literature Analysis – Report on Carcinogens – About the Report 

About the Report on Carcinogens 

The Report on Carcinogens (RoC) is a congressionally mandated 

listing of substances that either are known to be human 

carcinogens or might reasonably be anticipated to be human 

carcinogens, and to which a significant number of people residing 

in the United States are exposed [Public Health Service Act, 42 

U.S.C. 241(b)(4)]. Preparation of the RoC at NTP is under the 

direction of Ruth Lunn, Dr.P.H., director of the NIEHS/NTP Office of 

Report on Carcinogens (ORoC). 

The RoC is cumulative, consisting of newly reviewed substances in 

addition to those substances listed in previous editions. NTP 

follows an established four-part process when preparing the report. 

(1) NTP selects nominations for evaluation. 

(2) ORoC conducts cancer hazard evaluations on the selected 

substances and prepares draft RoC monographs. 

(3) Draft RoC monographs are released for public comment and 

external peer review is conducted before finalization. 

(4) NTP submits the proposed listing of newly reviewed 

substances to the Secretary of Health and Human Services 

for review and approval, followed by transmittal to Congress 

and publication on the NTP website. 

Each substance listed in the report has a profile, which contains the 

listing status determined by using established listing criteria, a 

summary of the cancer studies supporting the listing status, 

information on human exposure, and federal regulations to reduce 

exposure. 

Additional Links for the Report on Carcinogens: 

Report on Carcinogens 

Report Activities 

Report Substances Selected for Evaluation 

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2018 Annual Report – Literature Analysis – Report on Carcinogens – Report Activities 

Report Activities 

Activities in FY 2018 primarily focused on carrying out cancer hazard evaluations and preparing 

monographs for several substances under consideration for possible listing in the RoC. 

• Antimony trioxide. On January 24, 2017, the draft monograph was peer reviewed by a panel of 

experts. The panel agreed with NTP’s preliminary recommendations to list antimony trioxide in

the RoC as reasonably anticipated to be a human carcinogen based on sufficient evidence 

from studies in experimental animals and supporting mechanistic data. 

• Helicobacter pylori: Chronic infection. Following its release for public comment, the draft 

monograph on H. pylori was reviewed by letter by three substance-specific experts. The 

reviewers agreed with NTP’s preliminary recommendations to list H. pylori in the RoC as 

known to be a human carcinogen based upon sufficient evidence from studies in humans. 

• Shift work at night, light at night, and circadian disruption. On October 5, 2018, NTP convened 

an external panel to peer review the draft monograph on shift work and light at night. The 

panel agreed with NTP’s preliminary recommendation to list persistent night shift work that 

causes circadian disruption as known to be a human carcinogen based on sufficient evidence 

of carcinogenicity from studies in humans. The panel also accepted NTP’s preliminary

recommendation that certain lighting conditions that cause circadian disruption should be listed 

as reasonably anticipated to be a human carcinogen. The panel recommended that the 

supporting evidence should refer to “certain lighting conditions” and not “light at night.”

For a list of ongoing evaluations, see Report Substances Selected for Evaluation. Preparations are 

ongoing for the 15th RoC. In addition, ORoC is conducting scoping activities to identify substances for 

review for future editions of the report. 

Additional Links for the Report on Carcinogens: 

Report on Carcinogens 

About the Report on Carcinogens 

Report Substances Selected for Evaluation 

101 
 

 

 

 

 

 

2018 Annual Report – Literature Analysis – Report on Carcinogens – Report Substances for Evaluation 

Report Substances Selected for Evaluation 

Substances 

NTP Project Primary Uses/Exposures Status 

Leader 

Antimony trioxide This compound is used mainly as a synergist for halogenated flame 

retardants in plastics, rubber, and textiles, which are used in a diversity of 

Peer-review 

meeting January Amy Wang plastics and other products. 

It also can be used as a catalyst in polyethylene terephthalate production, 

as an additive in glass manufacturing and in pigments, or as an additive in 

paints and ceramics. 

2018 

Revised 

monograph 

released 

September 2018 

Goldenseal root This herbal remedy (botanical product) is used to treat gastrointestinal Deferred 

powder (Hydrastis disturbances; urinary disorders; hemorrhage; skin, mouth, and eye 

canadensis) infections; and inflammation. 

ORoC staff 

Haloacetic acids found This includes 13 individual haloacetic acids or a potential class or subclass Final monograph 

as water disinfection of these haloacetic acids. published 

byproducts People are exposed to these haloacetic acids by ingestion of chlorinated March 2018 

Gloria Jahnke drinking water and by inhalation and dermal contact during bathing or 

showering or when using swimming pools and spas that use chlorine for 

disinfection. 

Helicobacter pylori (H. 

pylori): Chronic 

infection 

Ruth Lunn 

A gram-negative, multiflagellated bacterium, it colonizes the stomach and 

causes peptic ulcer. Bacterium is spread by person-to-person contact, 

especially among family members. 

Routes of exposure include oral-oral, fecal-oral, and iatrogenic; exposure 

from contaminated water is also possible. Risk factors for infection include 

age, race, socioeconomic status such as crowded living conditions, and 

poor sanitation/hygiene. 

Draft monograph 

released 

May 2018 

Revised 

monograph 

released 

September 2018 

Shift work at night, light 

at night, and circadian 

disruption 

Ruth Lunn 

Unnatural (e.g., ill-timed) electrical light, especially light at night, might 

disrupt sleep and biological processes controlled by endogenous circadian 

clocks. People, who by virtue of the nature of their work, lifestyle choices, 

or residence, are subjected to exposure to unnatural light. 

Shift workers who work at night can experience an extreme type of 

exposure to light at night and changes in other activities, such as changes 

in daily activities, eating, sleeping, lifestyle factors, and social behavior. 

Draft monograph 

released 

August 2018 

Additional Links for the Report on Carcinogens: 

Report on Carcinogens 

About the Report on Carcinogens 

Report Activities 

102 
 

 

2018 Annual Report – Partner Agency Research 

Partner Agency Research 

NTP at NIEHS 

Research activities in the Division of NTP at NIEHS are conducted through the several 

branches: Biomolecular Screening Branch, Cellular and Molecular Pathology Branch, 

NTP Laboratory, Program Operations Branch, and Toxicology Branch. 

NTP at NCTR 

NCTR provides innovative technology, methods development, vital scientific training, 

and technical expertise to NTP. 

NTP at NIOSH 

NIOSH research projects for NTP assess the effects of exposures to substances, 

following its mandate to protect worker health and safety. 

103 
 

 

 

2018 Annual Report – Partner Agency Research – NTP at NIEHS 

NTP at NIEHS 

Most NTP research testing and analysis activities are carried out at NIEHS. The following Division of 

NTP branches and offices at NIEHS are actively involved in NTP research activities. 

• Biomolecular Screening Branch, Richard S. Paules, Ph.D., Acting Chief 

• Cellular and Molecular Pathology Branch, Robert Sills, D.V.M., Ph.D., Chief 

• NTP Laboratory, Michael DeVito, Ph.D., Acting Chief 

• Program Operations Branch, Michelle Hooth, Ph.D., Chief 

• Toxicology Branch, Nigel Walker, Ph.D., Acting Chief 

• NTP Interagency Center for the Evaluation of Alternative Methods, Warren Casey, Ph.D., Chief 

NIEHS/NTP Staff 

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2018 Annual Report – Partner Agency Research – NTP at NIEHS 

Biomolecular Screening 

The Biomolecular Screening Branch develops and implements programs in medium- and highthroughput screening of environmental substances for rapid detection of biological activities of 

significance to toxicology. Biomolecular Screening projects for FY 2018 are listed below. 

Biomolecular Screening Projects in FY 2018 

Project 

Study Scientists 

Project Summary 

Development of the S1500+ gene set 

Richard Paules, Scott Auerbach, Steve 

Ferguson and Sreenivasa Ramaiahgari 

The development of the S1500+ gene set and its use in targeted 

sequencing approaches provides a new, cost-effective methodology for 

capturing broad biological responses to chemical exposures in a variety of 

in vitro and in vivo model systems, allowing for quantitative dose-response 

measurements and kinetic studies. S1500+ gene sets have been developed 

for use with human, mouse and rat samples, with a zebrafish set currently 

under development. 

Linking this high-throughput transcriptomic approach with novel organotypic 

cell culture model systems (i.e., models that behave like living tissue) allows 

for a more rapid and deeper investigation of biological responses for 

chemicals of concern and a better understanding of potential implications 

for human health. 

A proof-of-concept study utilizing the human liver cell line HepaRG in 

various states of differentiation—which were exposed to 24 reference 

chemicals and investigated utilizing the human S1500+ gene set platform 

for transcriptomics characterization of responses to those chemical 

exposures—has been submitted for publication in FY 2019. 

Development of more sophisticated 

genetic analyses to make better use of 

current animal models 

Alison Harrill 

Genetic and epigenetic differences between individuals in the human 

population have been proposed as major factors for determining individual 

susceptibility to environmental stressors. 

Safety assessments of environmental substances and drugs are currently 

conducted with a few commonly used animal models that have limited 

genetic diversity. Further, many layers of biological regulation can influence 

individual genetic susceptibility to chemical and drug toxicity. Animal 

models have inherent limitations for extrapolating results to human toxicity 

and disease. 

NTP is developing more sophisticated genetic analyses to make better use 

of current animal models while adopting biological systems that are more 

appropriate for modeling human toxicity and disease. 

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2018 Annual Report – Partner Agency Research – NTP at NIEHS 

Project 

Study Scientists 

Project Summary 

Epigenetic study to examine DNA Work continued in FY 2018 on an epigenetic study of mouse strains to 

methylation and its possible role in examine DNA methylation and its possible role in the susceptibility of mice 

development of liver tumors to develop liver tumors. 

Alex Merrick and Paul Wade Progress included computational analysis of genomic methylation sites in 

relation to known genes and transcriptionally active regions in both parental 

strains and first-generation offspring. The relationships between DNA 

methylation, gene expression, and possible heredity in offspring are being 

determined, and the genomic variations in mouse strains, genders, and 

first-generation offspring are being cataloged. 

The results describing the mouse methylome will be publicly released in a 

manuscript accepted for publication in late 2018 or early 2019. Additional 

studies in FY 2018 addressed the effect of sex hormone signaling on DNA 

methylation at a genome-wide level and the impact of DNA methylation at 

distal regulatory regions. 

106 
 

 

2018 Annual Report – Partner Agency Research – NTP at NIEHS 

NTP Laboratory 

NTP Laboratory conducts in-house, agent-specific, targeted research on the development and 

application of modern toxicology and molecular biology tools. These tools are used to: 

• Evaluate specific substances of concern to NTP. 

• Identify issues of central importance to programs within NTP. 

• Develop methods to advance the NTP mission. 

NTP Laboratory also studies the developmental origins of adult diseases. NTP Laboratory projects for 

FY 2018 are listed below. 

NTP Laboratory Projects in FY 2018 

Project 

Study Scientist 

Project Objectives 

Development of in vitro models of metal Use in vitro cell transformation models (stem/progenitor and “mature” cells)

carcinogenesis of target-relevant cells to elucidate carcinogenic mechanisms and modes of 

action of metals (i.e., arsenic and cadmium). Erik Tokar 

In vitro evaluation of crumb rubber toxic 

effects 

Erik Tokar 

Study the modes of action and metabolomics involved in the toxic effects of 

crumb rubber on various prospective human target tissues. 

Role of microRNAs in malignant Study genes involved in the epigenetics of malignant transformation using 

transformation in vitro human model systems of carcinogenesis. MicroRNAs are thought to 

be a key epigenetic or posttranscriptional gene expression control 

Erik Tokar mechanism. 

Stem cells in toxicology: carcinogenesis, 

developmental toxicology, and 

developmental basis of adult disease 

Erik Tokar 

Develop stem cell model systems (pluripotent, multipotent, progenitor) and 

methods for use in examining the role of these cells in carcinogenesis, 

evaluating developmental bases of adult disease, and assessing 

developmental toxicology. 

These studies will be used to help predict or categorize teratogens and 

developmental toxicants. 

Evaluation of polycyclic aromatic Apply in vitro assays to assess and categorize the biological effects of 

hydrocarbon compounds using in vitro polycyclic aromatic hydrocarbon compounds. 

screens 

Erik Tokar 

Evaluation of the role of oxidative stress in Compare the effects of glyphosate to the effects of glyphosate formulations 

the biological effects of glyphosate and its using measures of genotoxicity, oxidative stress, and cell viability. 

formulations Compare the dose-response relationships among oxidative stress, 

Michael DeVito genotoxicity, and cell viability. 

Application of in vitro assays to evaluate 

botanicals 

Michael DeVito 

Determine whether in vitro assays and chemical analysis of botanicals can 

aid in selecting botanicals for in vivo testing. 

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2018 Annual Report – Partner Agency Research – NTP at NIEHS 

Project 

Study Scientist 

Project Objectives 

Chemical-induced transcriptomic and 

metabolomic changes in vitro 

Michael DeVito 

Evaluate the transcriptomic and metabolomic changes in metabolically 

active cell lines with 24 chemicals that have been tested in vitro. 

Incorporation of metabolism into highthroughput screening assays 

Michael DeVito 

Develop in vitro methods that incorporate xenobiotic metabolism. 

REACT PFAS 

Michael DeVito 

Conduct screening efforts to evaluate the NTP library of per and 

polyfluorinated alkyl substances. 

Utility of a five-day transcriptomic study in 

adult rats 

William Gwinn 

Examine the differences in the transcriptomic bone mineral density and 

adverse effect bone mineral density for 20 chemicals that have been tested 

in vitro at NTP. 

PCB 11: Screening for biological and 

toxicological activity 

Michael DeVito 

Compare the biological and toxicological activity of polychlorinated biphenyl 

(PCB) 11 to prototype PCBs in response to a nomination from EPA. 

Metalloestrogens and uterine/breast 

response 

Darlene Dixon, Suzanne Fenton 

Test the ability of reported metalloestrogens such as cadmium and arsenic 

to cause estrogen receptor stimulation in the uterus as a mode of action for 

cancer development. 

The role of ER-alpha36 in endocrine 

disruption and its localization in fibroid cells 

Darlene Dixon 

Evaluate the role of endocrine disrupter alpha36 (ER-alpha36) in fibroid 

cells and the role of ER-alpha36 in the endocrine-disrupting effects of 

environmental and industrial chemicals. 

Techniques for histologic visualization/ 

evaluation of 3D cultures/in vitro 

assessments 

Darlene Dixon 

Develop techniques for taking 3D spheroid or embryoid cultures from 96-

well plate into paraffin blocks for histochemical and immunohistochemical 

staining. 

Literature-based evidence for 

environmental factors affecting the breast 

Suzanne Fenton, Jason Stanko, Vickie 

Walker 

Review and categorize the evidence in the literature on environmental 

influences on breast development, disease, and function. This work should 

lead to development of systematic reviews on related topics. 

Effects of TBBPA on developmental and 

reproductive endpoints in Harlan SD rats 

Suzanne Fenton, Linda Birnbaum 

Evaluate the effects of TBBPA (tetrabromobisphenol A) following prenatal 

and early life exposure and determine the transcriptomic/metabolomic 

pathways involved in low-dose, hormone-driven responses. 

Effects of PFOA and GenX on 

developmental and reproductive endpoints 

in CD-1 mice 

Suzanne Fenton 

Evaluate the role of placental toxicity in the developmental effects of PFOA 

and GenX. 

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2018 Annual Report – Partner Agency Research – NTP at NIEHS 

Project 

Study Scientist 

Project Objectives 

Screening of perfluorinated compounds for 

effects in human and mouse cell-based 

assays 

Suzanne Fenton, Michael DeVito 

Compare the potencies and effect profiles of 40–75 perfluorinated 

compounds for their effects in cells known to be targets of PFOA and PFOS 

(perfluorooctanoic acid and perfluorooctane sulfonate, two perfluorinated 

compounds removed from the market due to reported health effects). 

Toxicants and mammary gland 

development 

Suzanne Fenton 

Determine the effects of different toxicants, including atrazine and 

bisphenols, on mammary gland development in rats or mice. 

Use of in vitro screens to evaluate potential Develop orthogonal assays to evaluate findings from Tox21 that identified 

obesogens potential obesogens. Mechanisms of action for select chemicals are being 

investigated. Suzanne Fenton 

Refinement of developmental Improve methods for assessing differential changes as a function of 

neurotoxicology methods developmental exposures, including in vivo molecular phenotypes, cellular 

phenotypes, maternal/developmental inflammation, and behavioral G. Jean Harry assessments. 

Method development to assess Examine methods (from screening to mechanisms) for assessing in vitro 

neuroinflammation and in vivo induction of inflammation in the nervous system following 

chemical exposures. G. Jean Harry 

Evaluation of the developmental 

neurotoxicity of fluoride 

G. Jean Harry 

Evaluate fluoride developmental neurotoxicity in rats. The study has been 

completed, and a manuscript has been submitted. 

109 
2018 Annual Report – Partner Agency Research – NTP at NCTR 

NTP at NCTR 

About NTP at NCTR 

NCTR provides innovative technology, methods development, vital scientific training, 

and technical expertise to NTP. 

NTP at NCTR: Interagency Agreement Projects 

A list of projects funded by the NIEHS/NTP interagency agreement with FDA and 

conducted in FY 2018. 

110 
 

 

 

 

2018 Annual Report – Partner Agency Research – NTP at NCTR – About NTP at NCTR 

About NTP at NCTR 

Research in Partnership with NCTR 

The National Center for Toxicological Research (NCTR) partners with researchers from elsewhere in 

the U.S. Food and Drug Administration (FDA), other government agencies, academia, and industry to 

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

The unique scientific expertise of NCTR is critical in supporting FDA product centers and their 

regulatory roles. NCTR research for NTP is funded by both voluntary allocations and an interagency 

agreement. 

NCTR/NTP Staff 

111 
 

 

 

 

 

2018 Annual Report – Partner Agency Research – NTP at NCTR – About NTP at NCTR 

NCTR studies funded by voluntary allocations are listed below. 

Biochemical and Molecular Basis of Toxicology 

Project 

Study Scientist 

Project Objectives 

Role of peroxisome proliferator-activated Examine the role of human and mouse PPARa in triclosan-induced liver 

receptor alpha (PPARa) and PPARa- toxicity in vivo. 

mediated species differences in triclosaninduced liver toxicity 

Jia-Long Fang 

Development of a next-generation 

sequencing method for the quantification of 

low frequency somatic mutations in 

oncogenes 

Page Mckinzie 

Develop a next-generation sequencing method for quantifying somatic 

mutations in oncogenes at fractions in the range of 10-5 to 10-2 . 

Detection of rare genomic mutations 

induced by genotoxic carcinogens using 

next-generation sequencing 

Tao Chen 

Establish tagging and duplex sequencing methods to detect rare mutations 

using synthesized DNA fragments containing known mutation fractions and 

types. 

Use the method to sequence genomic DNA from Salmonella strains treated 

with mutagens and compare the results with those from the Ames test 

conducted with the same treated Salmonella. 

Use the method to sequence exons of all expressed genes from the liver of 

rats or mice treated with different types of carcinogens and compare the 

results with those from previously published transgenic mutation assays 

and Sanger sequencing analysis conducted on the same animals. 

Sex differences in drug-induced QT Establish the in vitro model and positive control. 

prolongation and torsade de pointes: Evaluate model sensitivity and specificity and tests of the possibility of high- Establishing an in vitro model for high- throughput screening and ranking of QT-prolonging drugs for the risk of throughput screening and risk assessment torsade de pointes. of torsadogenic drugs 

Li Pang 

Tumor mutational signatures of acrylamide 

and glycidamide 

Fred Beland 

Determine the mutational signatures of tumors induced in experimental 

animals by acrylamide and glycidamide. 

Compare the mutational signatures obtained from acrylamide and 

glycidamide in experimental animals with mutational signatures obtained 

from acrylamide and glycidamide in experimental animals with mutational 

signatures of human tumors in published databases. 

Evaluation of the effects of black cohosh Determine the effects of risedronate and black cohosh (alone or combined) 

on risedronate efficacy in perimenopausal on bone density, bone turnover, and bone histology in a postmenopausal 

rat model rat model. 

Amy Inselman 

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2018 Annual Report – Partner Agency Research – NTP at NCTR – About NTP at NCTR 

Project 

Study Scientist 

Project Objectives 

Development and evaluation of a novel in Determine the dose-dependent, in vitro genetic and epigenetic effects of 

vitro epigenomic screening model system compounds FDA regulates. 

for the hazard identification of FDA- Characterize the specific epigenetic changes induced in vitro by genotoxic regulated products and nongenotoxic compounds. 

Igor Pogribny Characterize the specific genetic and epigenetic effects of compounds FDA 

regulates using an in vitro three-dimensional organotypic liver culture model 

system. 

Identification of mechanistic biomarkers of 

pyrrolizidine alkaloid (PA)-induced 

hepatocarcinogenesis 

William Tolleson 

Use high-throughput profiling approaches to identify microRNAs that 

regulate genes involved in PA carcinogenicity in hepatic cell systems and 

investigation of the functions of microRNAs by bioinformatics tools and in 

vitro functional assays. These results will identify microRNA species for use 

as biomarkers for PA-induced carcinogenicity, with added benefits derived 

from mechanistic knowledge of how these microRNAs might function in the 

biological effects of PAs. 

Benefit food safety and human health by providing simple tools for 

assessing exposure to foodborne toxins. 

Neurotoxicology 

Project 

Study Scientist 

Project Objectives 

Effects of developmental sevoflurane Examine the effects of early developmental sevoflurane exposure on 

exposure and pretreatment with acetyl-l- neurodegeneration and complex operant learning. 

carnitine on complex brain function in rats Determine whether impairments in these measures can be attenuated by 

John Talpos pretreatment with acetyl-L-carnitine. 

Examine the time course of acetyl-L-carnitine pretreatment on sevofluraneinduced neuroapoptosis. 

Developmental neurotoxicity assessment 

of N-methyl-D-aspartate (NMDA) receptor 

antagonists in zebrafish 

Jyotshnabala Kanungo 

Study wild-type zebrafish embryos exposed to NMDA receptor antagonists 

(MK-801, dextromethorphan, ketamine, and sevoflurane) to assess their 

effects on Rohon-Beard sensory neurons. The effects on the primary and 

secondary motor neurons and their axons are being assessed using 

hb9:GFP transgenic embryos. Postexposure washout experiments are 

being pursued to determine the effects of these drugs on the nervous 

system. 

Determine estradiol-17β levels in control and treated embryos and

quantification of changes in gene expression for the two CYP 

aromatases/estrogen synthases (brain aromatase cyp19a1b and gonadal 

aromatase cyp19a1a) using quantitative polymerase chain reaction (qPCR). 

Assess phenotype-based cell signaling mechanisms, such as MAPK 

(mitogen-activated protein kinases) and neuron development-specific gene 

expression. 

Examine reversal of noted adverse effects of these compounds on neurons, 

particularly by treatment with acetyl L-carnitine. 

Toxicity assessment of graphene sheets 

using primary striatal neurons 

Evaluate the toxicity of graphene sheets using in vitro primary cultures of 

embryonic day 14 primary rat striatal neurons. 

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2018 Annual Report – Partner Agency Research – NTP at NCTR – About NTP at NCTR 

Project 

Study Scientist 

Project Objectives 

Syed Ali Determine pathways involved in graphene toxicity using embryonic day 14 

primary rat striatal neurons. 

Rat blood-brain-barrier-on-a-chip model to 

study traumatic brain injury 

Syed Ali 

Use soft lithograph and microfabrication techniques to engineer a 

multilayered blood-brain-barrier-on-a-chip model that can be subjected to 

different magnitudes and durations of mechanical stress that mimic mild 

and repetitive traumatic brain injury. 

Characterize the effects of traumatic brain injury on blood-brain-barrier 

integrity using the chip model. 

High-throughput neurotoxicity screening of 

metallic nanoparticles: In vitro and in vivo 

imaging 

Syed Imam 

Assess the utility of high-throughput neurotoxicity screening of metallic 

nanoparticles for detecting neurochemical and neurophysiological 

alterations in vitro for use in developing reference standards for metallic 

nanoparticles. Once developed and validated, these techniques can be 

optimized for analyzing other FDA-regulated nanomaterials. 

Nanotoxicology 

Project 

Study Scientist 

Project Objectives 

Proteomic assessment of the cytotoxic Use proteomic approaches to quantify alterations in expression and 

effects of nanoparticles on the blood-brain phosphorylation of proteins involved in apoptosis, inflammation, oxidative 

barrier stress, and tumorigenesis signaling pathways in blood-brain barrier cells 

following exposure to nanoparticles. Qiang Gu 

Establish proteomic parameters for toxicity of nanoparticles. 

Complement assays for the detection of Establish two complement assays for routine evaluation of immuneimmune-sensitizing activity of sensitizing activity of nanomaterials. 

nanomaterials Validate the assays using nanoparticles with known immunoreactivity. 

Julian Leakey Determine the immune-sensitizing activity of novel nanomaterials. 

Nonclinical modeling and risk assessment 

of FDA-regulated drug nanocrystals 

Kuppan Gokulan 

Investigate various media milling/high pressure homogenization and 

spray/freeze drying process parameters and formulation parameters to 

determine the critical parameters that affect particle size and drug 

polymorphic form. The project includes the development of a predictive 

model of appropriate criteria to prepare stable crystalline solid nanoparticles 

using multiple linear regression analysis; an accelerated study to determine 

crystalline solid nanoparticle stability; and preliminary in vivo studies to 

show proof of principle of enhanced bioavailability of the crystalline 

nanoparticle formulation compared to crystalline macro-particles. 

Evaluate drug-nanocrystal effects on epithelial cell permeability and 

mucoadherence using in vitro and ex vivo culture models and drug 

permeability and stability using in vitro intestinal epithelial cells. 

Determine macrophage cell viability and proliferation during the treatment 

with different sizes of drug nanocrystals; evaluate the immunotoxic effects 

of drug nanocrystals on intestinal tissue by measuring pro-inflammatory 

cytokines; and determine the effect of drug nanocrystals on the intestinal 

commensal microbiota using in vivo model. 

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Project 

Study Scientist 

Project Objectives 

Evaluation of cadmium oxide nanoparticle 

as a nanoparticle-type positive control for 

toxicity assays 

Tao Chen 

Characterize cadmium oxide nanoparticles and determination of their 

toxicity using in vitro toxicity and genotoxicity assays. 

Explore the possible mechanisms of cadmium oxide nanoparticle toxicity. 

Evaluate where cadmium oxide nanoparticles are suitable for use as a 

positive control according to their toxicity and genotoxicity responses. 

In vitro genotoxicity of graphene-family 

nanomaterials using FDA-recommended 

short-term genetic toxicity test battery 

Nan Mei 

Determine the genotoxicity of graphene and derivatives in standard 

regulatory test battery assays. 

Determine whether any mutagenicity in mouse lymphoma cells is due to 

loss of heterozygosity in chromosome 11. 

Investigate whether genotoxic and mutagenic responses are mediated 

through oxidative pathways. 

Establish the genotoxic and mutagenic mode of action using gene 

expression arrays. 

Graphene-induced toxicity on the Evaluate the effects of graphene on gastrointestinal homeostasis by 

population of intestinal microbiota and gut- determining graphene derivative effects on intestinal bacterial cultures, 

associated immune response polarized intestinal epithelial cells, intestinal commensal bacteria in vivo, 

and gastrointestinal immune responses in vivo. 

Sangeeta Khare 

NCTR/Office of Regulatory Affairs 

Nanotechnology Core Facility 

Anil Patri 

Provide the expertise and equipment for characterizing nanomaterials used 

in toxicology studies and for detecting nanomaterials in in vitro and in vivo 

derived samples. 

Serve as a resource for U.S. agencies for the design of toxicology studies 

and generation of standards for analytical methods. 

Determination of cytotoxicity and Develop a set of cell-free and cell-based in vitro tests that can be used to 

genotoxicity of nanomaterials of interest to rapidly identify nanomaterials of interest to the FDA that elicit oxidative 

the FDA and their mechanism of action damage. 

Peter Fu Determine whether, in the presence of nano-metal materials, endogenous 

and dietary antioxidants can display pro-oxidative activity. 

Assessing epigenetic effects of 

nanoparticles in human cells 

George Hammons 

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). 

Determine the effect of these nanoparticles on the pattern of global histone 

modifications and on genome-wide profiles of histone modifications in the 

four types of human cells. The analysis includes comparisons with diseaseassociated histone modifications. 

Correlate the nanoparticle effect on DNA methylation with its effect on DNA 

methyltransferase expression. 

Correlate the nanoparticle effect on global histone modifications with its 

effect on expression of histone-modifying enzymes as potential underlying 

mechanisms of the alteration in DNA methylation or histone modification 

patterns. 

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2018 Annual Report – Partner Agency Research – NTP at NCTR – About NTP at NCTR 

Project 

Study Scientist 

Project Objectives 

Immunotoxicity assessment of 

nanomaterials using human immune cellbased biomarkers of innate immunity 

Wei Ding 

Assess the immunotoxicity of different categories of nanoparticles using 

biomarkers of innate immunity measured in vitro in human immune cells 

(monocytes, human peripheral blood mononuclear cells). 

An assessment of the interactions of 

nanoscale (TiO2 and zinc oxide) materials 

used in sunscreens on the skin microbiome 

Huizhong Chen 

Examine human skin microbiota cell viability in the presence of nanoscale 

materials in cosmetics. 

Determine the effect of nanomaterials in cosmetics on human skin microbial 

ecology. 

Demonstrate the mechanisms of toxicity of nanoscale materials in 

cosmetics to skin microbiota using the human skin tissue model EpiDerm 

and reverse transcription polymerase chain reaction (RT-PCR) and whole 

genome microarray technologies. 

Elucidate the dose-response relationship of nanoscale materials in 

cosmetics on skin bacterial cell toxicity. 

Assess the potential health risk of human skin exposure to nanomaterials in 

cosmetics. 

Evaluation of the migration and toxic 

potential of Ag nanoparticles in feminine 

hygiene products to vaginal tissue: In vivo 

rodent and in vitro 3D mucosal models 

Anil Patri 

Use established qualitative methods to characterize different species of 

nanoscale Ag contained in five types of dry and five types of liquid feminine 

hygiene products. 

Evaluate the migration/uptake and toxicity of Ag nanoparticles and ions 

used in feminine hygiene products using a human cell-based in vitro threedimensional culture model that has many of the structural and functional 

features of the human vaginal mucosal layer. 

Evaluate the effects of Ag nanoparticles and ions contained in feminine 

hygiene products on human vaginal microbiota using culture techniques 

and semiquantitative molecular methods. 

Interaction of nanoparticles with 

gastrointestinal tract 

Sangeeta Khare 

Determine the effect of nanomaterials on the permeability of epithelial cells 

and establishment of immune correlates. 

Delineate the interaction of nanomaterials with gastrointestinal tract and 

gut-associated microbiota using an ex vivo model (intestinal explants). 

Establish the effect of nanoparticles on the developmental stage of the 

intestine and assessment of the biodistribution of nanoparticles using the 

zebrafish model. 

The effect of nanomaterials used in Compare the relative efficacy of FDA-regulated nanomaterials used in 

dentistry on biofilm formation and the oral dentistry for inhibition of bacterial adhesion to surfaces and biofilm 

microbiota formation. 

John Sutherland Evaluate the effect of nanomaterials on growth and antimicrobial 

susceptibility profiles of typical species from the oral microbiota. 

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2018 Annual Report – Partner Agency Research – NTP at NCTR – About NTP at NCTR 

Bioassay and Biomarker Development and Evaluation 

Project 

Study Scientist 

Project Objectives 

Development of cancer-relevant Understand the distribution and range of spontaneous oncogene mutant 

biomarkers for identification of potential frequencies in the major organs of rats and mice. 

carcinogens: Research to understand the Provide important basic information for the validation of these oncogene normal background frequencies in rats mutant frequencies as biomarkers of chemically induced carcinogenesis. 

Page McKinzie 

Cancer mutations as biomarkers of cancer 

risk: human studies with implications for 

personalized medicine 

Barbara Parsons 

Develop the information necessary for the rational use of oncogene 

mutations as quantitative biomarkers of cancer risk; specifically, allelespecific competitive blocker PCR (ACP-PCR) are being used to determine 

normal and pathological levels of relevant oncogene mutations in multiple 

human tissues and tumors. 

Compare the information derived from human tissues with data generated 

in a parallel rodent protocol as an approach for incorporating 

carcinogenesis-relevant data into the rodent-to-human extrapolation 

necessary in cancer risk assessment. 

Validate a streamlined ACP-PCR methodology and development of the 

methodology necessary to measure oncogene mutant fractions in cell-free 

DNA isolated from plasma. 

Through a series of publications, convey to the regulatory risk assessment 

community the regulatory significance of the data regarding tumorassociated mutations which have and will be generated. 

Study of translational biomarkers for drug- Conduct a comprehensive survey of microRNAs using the next-generation 

induced liver injury with next-generation sequencing technology. Findings will elucidate the molecular pathways and 

sequencing processes modulated by RNAs (including messenger RNAs, microRNAs, 

and other noncoding RNAs) and their importance in drug-induced liver 

Baitang Ning injury risk and phenotypes. 

A comprehensive characterization of 

induced pluripotent stem cell-derived 

cardiomyocyte (iPSC-CM) models for druginduced arrhythmia using high-throughput 

screening assays 

Li Pang 

Develop standard baseline criteria for high-throughput readouts of druginduced arrhythmia in human iPSC-CMs from different suppliers. 

Assess individual variance and possible sex differences in drug-induced 

cardiotoxic responses across a panel of nongenetically modified iPSC lines. 

Validating the rat Pig-a assay for regulatory Develop a method that could routinely identify Pig-a mutations in individual 

use: Determining the molecular basis of Pig-a mutant phenotype cells. 

mutants detected in the rat Pig-a gene 

mutation assay 

Vasily Dobrovolsky 

Developing in vitro approaches to assess Develop and use in vitro assays for assessing drug-induced liver toxicity by 

drug-induced liver toxicity evaluating cytotoxicity and quantifying representative endpoints for 

assessing clinical-related outcomes such as apoptosis/necrosis, steatosis, Lei Guo and cholestasis. 

117 
 

 

 

 

2018 Annual Report – Partner Agency Research – NTP at NCTR – About NTP at NCTR 

Project 

Study Scientist 

Project Objectives 

Evaluation of microRNAs in blood and 

urine for detection of chemical-induced 

carcinogenicity 

Tao Chen 

Determine microRNAs in blood and carcinogenic target tissues that 

respond to carcinogen exposures and the best time for sampling of their 

expression after treatments in rats. 

Determine microRNA profiles from the blood and target tissue samples of 

rats treated with different mode-of-action carcinogens, such as alkylating 

agents, aneugens, clastogens, and nongenotoxic carcinogens at the 

appropriate sampling time. 

Determine the functions and pathways of the dysregulated microRNAs by 

the carcinogen treatments and examine whether the microRNA changes 

can be anchored to the carcinogens with the known mode-of-actions and 

whether the changes in blood are related to those in the target tissues. 

Establish specific microRNA biomarkers in blood for assessing different 

types of carcinogens. 

Development and characterization of a Develop a B6C3F1 mouse model of obesity to investigate the effect of 

diet-induced obesity model using B6C3F1 obesity on anthracycline-induced cardiotoxicity and the model’s suitability to

mouse for evaluation of drug toxicity in investigate other potential drug-induced toxicities under conditions of 

obesity obesity. 

Vijayalakshmi Varma 

Development of advanced safety Establish and demonstrate the feasibility of novel high-throughput and highassessments of FDA-regulated products content in vitro genotoxicity assays conducted using human liver cells in 

using high-throughput and high-content conjunction with quantitative dose-response approaches for assessing and 

quantitative approaches in cultured human distinguishing the genotoxicity of FDA-regulated products. 

cells to evaluate genotoxicity 

Carol Guo 

Enhance the prediction of potential 

endocrine activity of chemicals by 

integrating multiple endpoints data 

Huixiao Hong 

Augment different endocrine-related endpoint data and development of 

prediction models for screening chemicals with endocrine activity potential 

by integrating the augmented multiple types of endocrine-related endpoint 

data. 

Build an androgenic activity database and construction of integration-based 

prediction models. 

Evaluation of an in vitro testis organ Evaluate the in vitro testis organ system as an alternative model to assess 

system as an alternative model for male male reproductive toxicology and establishment of a standardized protocol 

reproductive toxicology for the assay. 

Noriko Nakamura 

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Project 

Study Scientist 

Project Objectives 

Using metabolically competent human cell 

lines to perform high-throughput 

genotoxicity testing 

Nan Mei 

Develop HepG2-derived cell lines that simultaneously express 3-5 Phase I 

cytochrome P450s (CYPs). 

Develop HepG2-derived cell lines co-expressing multiple CYPs and Phase 

II UDP-glucuronosyltransferase (UGT) enzymes. 

Develop TK6-derived cell lines that express 14 CYP genes individually and 

TK6-derived cell lines simultaneously expressing 3-5 CYPs. 

Develop TK6 cells that co-express CYPs and Phase II UGT or 

sulfotransferase (SULT) enzymes. 

Assess the utility and feasibility of newly developed cell lines for toxicity 

studies using a small set of chemicals with known or postulated 

metabolism-related toxicity. 

Perform a pilot high-throughput genotoxicity study (HT-micronucleus assay, 

HT-Comet assay, and HT-ƴH2AX detection) using the established cell lines.

Modification of the Comet assay for in vitro Develop methods for in vitro assessment of global and gene-specific 

and in vivo assessment of global and methylation using a modified Comet assay (methods development). 

gene-specific methylation status Upon successful development of the in vitro modified Comet assay, extend 

Mugimane Manjanatha these methods to modify the high-throughput micropatterned Comet assay 

developed by Ge et al (2015) to conduct pathway-focused, high-throughput, 

methylation assays using human cells. 

Predictive clinical biomarkers for 

chemotherapy-induced cardiotoxicity 

Li-Rong Yu 

Discover novel omics predictive biomarkers of cardiotoxicity and diagnostic 

biomarkers of cardiac injury from Dox-treated breast cancer patients. 

Verify and translate predictive and diagnostic preclinical miRNA and 

metabolomics biomarkers of cardiotoxicity in clinical plasma samples. 

Develop mass spectrometry-based multiplex assays and verification of 

proteomic biomarker candidates in plasma. 

MicroRNAs as novel biomarkers for 

radiation-induced heart disease 

Li Pang 

Identify miRNAs with time-dependent expression changes in heart tissue 

and plasma of radiation-treated rats. 

Evaluate the dose-dependencies of miRNA dysregulation in response to 

radiation. 

Identify potential targets of dysregulated miRNAs in the radiation-injured 

heart by combination of in silico miRNA target prediction and gene 

expression analysis. 

Investigate radiation-induced miRNA dysregulation in plasma and heart 

tissue of mast cell-deficient (Ws/Ws) and mast cell competent wild-type 

rats. 

Prediction of tyrosine kinase inhibitor (TKI) Present in vitro mechanistic analysis beyond proarrhythmic toxicity. 

induced cardiotoxicity using induced Identify noninvasive biomarkers that detect and predict the severity of pluripotent stem cell-derived structural cardiotoxicity. cardiomyocytes 

Develop a systems-based database to capture the characteristics of TKI- Li Pang induced cardiotoxicity. 

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2018 Annual Report – Partner Agency Research – NTP at NCTR – About NTP at NCTR 

Project 

Study Scientist 

Project Objectives 

Somatic oncomutations as biomarkers for Identify the most promising human oncomutation biomarkers by nexttranslating preclinical safety data to human generation sequencing (NGS). 

cancer risk Analyze batteries of rat and mouse amplicons for hotspot oncomutations by 

Barbara Parsons NGS. 

Validate rodent oncomutations as biomarkers of carcinogenic effect. 

Genetic and epigenetic mechanisms of sex 

differences in the kidney of a rat model 

system: developing safety biomarkers for 

FDA-regulated products 

James Fuscoe 

Conduct whole genome expression profiling on 10 rat tissues of both sexes 

at nine ages. 

Conduct miRNA profiling of selected tissues, including liver. 

Conduct DNA methylation profiling of selected tissues, including liver. 

Use bioinformatics and statistical approaches to understand the genetic 

machinery operational at each developmental stage in each sex and relate 

the findings to potential susceptibility to adverse drug reactions and 

disease. 

Use bioinformatics approaches to extrapolate these findings of potential 

age- and sex-associated susceptibility in an animal model system to 

humans. 

Development of a simple in vitro approach Characterize FluoroJade-C (FJ-C) labeling in vitro. 

for the rapid detection of neurotoxicity Validate FJ-C labeling in vitro. 

Qiang Gu Develop an FJ-C based in vitro approach for high-throughput assessment 

of neurotoxicity. 

Explore the mechanism underlying FJ-C labeling. 

Validating the rodent Pig-a gene mutation 

assay: development of a human 

reticulocyte Pig-a assay to evaluate the 

ability of the rodent Pig-a assay to predict 

the genotoxicity of FDA-regulated products 

in humans 

Vasily Dobrovolsky 

Develop a sensitive high-throughput protocol for performing the flow 

cytometry and magnetic enrichment-based human RBC PIG-A assay that is 

capable of detecting GPI-anchored marker-deficient mutants among at least 

several million polychromatic RBCs and at least one hundred million 

normochromatic RBCs from human peripheral blood samples. 

Determine some basic properties of the high-throughput PIG-A assay that is 

developed and measurement of background PIG-A mutant frequency in the 

general population using blood samples from self-identified healthy human 

volunteers. 

Test the ability of the high-throughput RBC PIG-A assay that is developed 

to detect PIG-A mutation in human cancer patients receiving Pt-based 

drugs as part of their antineoplastic chemotherapy. 

Perform a comparative study in rats employing a chemotherapeutic 

treatment regimen similar to human cancer patient Pt-based therapy 

protocol using the most sensitive version of the rat PIG-A assay for 

detection of somatic mutation. 

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Project 

Study Scientist 

Project Objectives 

Quantification of in vivo genomic damage 

by whole genome clone analysis and highfidelity next-generation sequencing 

Javier Revollo 

Develop whole genome clone analysis, a method that detects somatic 

mutations in clones derived from individual cells, to quantify basal and 

xenotoxin-induced whole genome somatic mutations. 

Develop an efficient ultra-high-fidelity NGS method capable of detecting 

somatic mutations in genome pools. 

Direct identify and quantify by ultra-high-fidelity the frequency of somatic 

mutations in tissues derived from laboratory animals treated with known 

mutagens. 

Computational Toxicology 

Project 

Study Scientist 

Project Objectives 

Improving methods and algorithms for Test the feasibility and implementation of software code for enhancements 

enhancing 3D-QSDAR to the three-dimensional quantitative spectral data-activity relationship 

(3D-QSDAR) technique and demonstration of the potential beneficial effect Svetoslav Slavov on the performance of 3D-QSDAR models for various data sets and 

endpoints. 

Evaluation of transcriptomics-based Integrate hepatic life cycle basal gene expression data in male and female 

predictions of sex and age-related rats into a toxicogenomics model and enable the prediction of age- and sexsusceptibilities to treatment-induced related differences in drug or chemical disposition and downstream adverse 

adverse effects in F344 rats events in primary rat hepatocytes. 

James Fuscoe 

Defining applicability domains in 3DQSDAR 

Iva Stoyanova-Slavova 

Select three to four data sets having differing degrees of heterogeneity. 

Analysis of data to determine how heterogeneity of the data affects the 

internal predictivity of the models. 

Compare the external predictive power for models based on data sets of 

different heterogeneity and external test sets of equal size. 

Derive and test different hypotheses and determination pf which 

applicability domain definition results in models with maximum predictivity 

for an external test set of compounds. 

Draw conclusions about the applicability domains of 3D-QSDAR models. 

Of text and gene: using text mining 

methods to uncover hidden knowledge in 

toxicogenomics 

Weida Tong 

Investigate the utility of topic modeling in toxicogenomics as an enhanced 

knowledge discovery means to uncover hidden knowledge for which 

otherwise are difficult to discover using the conventional approaches. 

Computational toxicology for safety and 

risk assessment 

Jeffery Fisher 

Assist other FDA Centers and research organizations outside of FDA with 

their requests for support from staff scientists within NCTR and other 

scientists on safety and risk assessment issues of interest to FDA. 

Pilot study to examine a population-based 

computational framework for assessing 

xenobiotic disposition and interaction 

effects in pregnant women 

Demonstrate proof of concept for using emerging computational techniques 

in understanding pregnancy-related alterations in drug pharmacokinetics. 

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Project 

Study Scientist 

Project Objectives 

Annie Lumen Assist in developing recommendations for dose adjustments and drug 

labeling in the pregnant population, thus promoting women’s health during

this crucial period. 

Statistical methods for whole transcriptome 

sequencing data analysis 

Vivian Zhuang 

Develop and evaluate one-sided and two-sided gene set analysis methods 

for RNA-seq data with discrete counts. 

Develop and evaluate methods for combining correlation estimates and 

sequencing depth to determine sample size calculations in RNA-seq 

experimental design. 

Develop and evaluate methods for identifying outlier samples in RNA-seq 

data. 

The design and development of machine Identify trends and potential risks using historical results. 

learning algorithms to assist with Reduce analyst hours spent reviewing data to determine quality and data automated pattern recognition of persistent usability. organic pollutants in foods and feeds 

Expand automated algorithms outside of the POPs field. Huixiao Hong 

Hepatoxicity of herbal/dietary supplements Assemble a comprehensive list of herbal and dietary supplements that have 

potential to cause drug-induced liver injury in humans into a web-based Weida Tong database that can be used for reference in regulatory processes when 

hepatotoxicity issues arise. 

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2018 Annual Report – Partner Agency Research – NTP at NCTR – NCTR Interagency Agreement 

NTP at NCTR: Interagency Agreement Projects 

NCTR research for NTP is funded by voluntary allocations and an interagency agreement. Below are 

FY 2018 projects funded through an NIEHS/NTP interagency agreement with FDA. 

Food Additives and Contaminants 

Project 

Study Scientist 

Project Summary 

Two-year chronic toxicology study of BPA 

in rats 

Barry Delclos 

This study is characterizing the long-term toxicity of orally administered 

BPA (bisphenol A), including developmental exposure, in NCTR Sprague 

Dawley rats over a broad dose range. Animals generated in this study are 

being assigned to separate protocols for assessment of a range of 

molecular, morphological, and functional endpoints to determine if these 

endpoints are predictive of long-term toxic effects or reveal potential effects 

undetected by standard toxicological evaluations. 

Evaluation of molecular, morphological, 

and functional endpoints in rats treated 

with BPA 

Barry Delclos 

This study includes an evaluation of a range of molecular, morphological, 

and functional endpoints in rats dosed orally with a wide range of BPA 

doses in a chronic toxicology study. The endpoints were selected based on 

reports from previous animal toxicology or human epidemiology studies, 

suggesting they are affected by BPA exposure. Assessments are being 

conducted at various ages (postnatal days 1, 21, and 90 and 6 and 12 

months) to determine if any effects observed are predictive of long-term 

effects evaluated in the companion chronic toxicology study, or if they 

reveal potential effects undetected by standard toxicological evaluations. 

Combined nephrotoxicity of melamine and This study of rats orally co-exposed with melamine and cyanuric acid for 90 

cyanuric acid in rats (recovery study) days is assessing the degree of functional and histological recovery after 

30- and 90-day recovery periods. Gonçalo Gamboa da Costa 

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 

Luisa Camacho 

The objectives of this study are 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 a 

subsequent 90-day recovery period. 

Compare the dose-response relationships of the kidney gene expression 

level of biomarkers of nephrotoxicity and kidney histopathology in rats coexposed to melamine and cyanuric acid for 90 days and upon a 90-day 

recovery period. 

Role of perinatal development on The objective of this study is to determine serum pharmacokinetics and 

toxicokinetics of inorganic arsenic metabolism of low-dose inorganic arsenic in adult female CD-1 mice, 

Sprague Dawley rats, and rhesus monkeys. Daniel Doerge 

Evaluation of brominated vegetable oil in 

rats 

Gonçalo Gamboa da Costa 

The objectives of this study are to: 

Assess the dose-response relationships of a 90-day dietary exposure to 

brominated vegetable oil in Sprague Dawley rats. 

Evaluate the bioaccumulation and clearance of inorganic and organic 

bromine in organs and tissues of Sprague Dawley rats upon dietary 

exposure to brominated vegetable oil. 

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2018 Annual Report – Partner Agency Research – NTP at NCTR – NCTR Interagency Agreement 

Project 

Study Scientist 

Project Summary 

Long-term evaluation of cognitive, 

neurochemical, and histopathological 

effects of developmental inorganic arsenic 

(iAs) exposure in Sprague Dawley rats 

Sherry Ferguson 

The objective of this study is to determine the effects of developmental iAs 

exposure on cognitive behaviors, neurochemistry, and histopathology in 

Sprague Dawley rats. 

Dermal Toxicology Program 

Project 

Study Scientist 

Project Summary 

Two-year dermal carcinogenicity of 

triclosan in B6C3F1 mice 

Jia-Long Fang 

The objective of this study is to determine the toxicity and carcinogenicity of 

topically applied triclosan in mice. 

Dietary Supplement Program 

Project 

Study Scientist 

Project Summary 

Thirteen-week dosed-water study to 

determine the potential toxicity of aloin in 

the cecum and large intestine of F344 rats 

Mary Boudreau 

This evaluation seeks to determine whether drinking water administration of 

aloin-A and aloin-B to F344 rats exerts similar effects in the rat large 

intestine when administered at concentrations similar to those in previous 

NCTR studies on Aloe vera whole leaf extract. 

Effects of fibrinolytic enzymes nattokinase 

and lumbrokinase alone or in combination 

with aspirin in blood parameters 

Luisa Camacho 

This study includes an evaluation in an animal model of the effects of 

nattokinase and lumbrokinase on blood parameters and an assessment of 

their effects in combination with pharmacological doses of aspirin. 

Drugs Program 

Project 

Study Scientist 

Project Summary 

Toxicokinetic profile and toxicity of highmolecular-weight polyethylene glycols in 

rats 

Jia-Long Fang 

The objectives of this study are to: 

Evaluate the toxicokinetic profile of high-molecular-weight polyethylene 

glycols in Sprague Dawley rats given a single dose of the substances via 

subcutaneous injection. 

Evaluate the bioaccumulation of high-molecular-weight polyethylene glycols 

in organs/tissues of rats upon repeated subcutaneous injection for 24 

weeks. 

Assess the toxicities resulting from the bioaccumulation of the substances. 

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Enhancing Toxicology Program 

Project 

Study Scientist 

Project Summary 

NTP capability building for microbiome 

assessment on toxicology studies: 

Assessing the role that the microbiome 

might play in the toxicity of xenobiotics 

Carl Cerniglia 

This study is addressing critical knowledge gaps in the microbiome field 

using the latest advances in microbiome analysis through in vitro, in vivo, 

and ex vivo models in toxicity testing risk assessments. 

Developing an in vitro system to evaluate 

the disease-related toxic effects of inhaled 

test agents in human airway tissue models 

Xuefei Cao 

The objectives of this study are to: 

Develop exposure and dosimetry methods for exposing human air-lung 

interface airway cultures to aerosolized test agents. 

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. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH 

NTP at NIOSH 

About NTP at NIOSH 

NIOSH research projects for NTP assess the effects of exposures to substances 

following its mandate to protect worker 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 2018. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – About NTP at NIOSH 

About NTP at NIOSH 

In accordance with its mandate to protect worker health and safety, the National Institute for 

Occupational Safety and Health (NIOSH) carries out research projects with NTP funded through an 

interagency agreement and voluntary allocations. These projects focus on comprehensive 

assessment of occupationally relevant exposures and immunotoxicology research. Setting priorities in 

occupational toxicological research is based on several sources of information NIOSH develops and 

maintains. Sources include health hazard evaluations, industry-wide studies, gaps in knowledge 

identified while developing criteria for recommended standards or criteria documents, current 

intelligence bulletins, hazard reviews and alerts, other technical reports, and information profiles on 

chemical hazards. 

NIOSH Staff: Health Effects Laboratory Division (left) and Division of Surveillance, Hazard Evaluations, and Field Studies 

(right) 

NIOSH/NTP projects in FY 2018 funded through voluntary allocations are listed below. 

Biomonitoring, Biomarker Development, and Health Assessment 

Project 

Study Scientist 

Project Summary 

Exposure assessment research and 

support 

John Snawder 

The support of multiple branch and interdivisional projects includes (1) 

managing and planning field sample collection, (2) developing new classical 

and immunochemical biomonitoring methods, and (3) validating and 

adapting existing methods. 

This project also includes the design of low-cost, rapid immunochemical and 

analytical chemistry biomonitoring methods to identify exposures and 

evaluate potential interventions as well as the identification of and 

development of new multiplex immunochemical methods to evaluate 

biomarkers of occupational illness or subclinical signs of occupational 

illness. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – About NTP at NIOSH 

Project 

Study Scientist 

Project Summary 

Ultraviolet native fluorescence-based 

monitor for workplace exposures 

John Snawder 

This project includes the development and evaluation of a readily adaptable, 

next-generation, direct-reading personal monitor to measure worker 

exposure to a wide variety of chemicals, including naphthalene and 

components of asphalt fume. 

Personal monitors for volatile and semivolatile workplace chemicals will help 

to rapidly assess chemical exposure and result in more realistic occupational 

exposure assessments. These assessments will allow for rapid interventions 

and lead to reduced worker exposures and prevention of occupational 

illness and disease. 

Evaluation of welding fumes as a lung 

carcinogen in mice exposed by inhalation 

Patti Erdely 

This investigation of both carcinogenic metal-containing and noncarcinogenic metal-containing welding fumes as lung carcinogens is using a 

two-stage initiation-promotion mouse model. 

The findings will establish if welding fume inhalation at relevant occupational 

exposure levels increases lung tumorigenesis. 

The project also is generating valuable data regarding the carcinogenic 

potential of fumes from different types of welding processes that do and do 

not contain carcinogenic metals. In addition, the project is providing 

information on which metal oxide components of the welding fume have the 

greatest carcinogenic potency. 

Systematic assessment of cobalt oxide 

(CoO) and lanthanum oxide (La2O3) in 

pulmonary disease 

Yong Qian 

Metal oxide nanoparticles are an important class of engineered 

nanomaterials with broad application in many industrial products. Concerns 

over potential metal oxide nanoparticle-induced toxicity have emerged, 

particularly due to the propensity of these nanoparticles to induce oxygen 

radicals and oxidative stress. 

This assessment of cobalt oxide (CoO) and lanthanum oxide (La2O3) 

nanoparticle-induced pulmonary injury in vivo and cellular toxicity in vitro will 

reveal the toxicological modes of action for CoO and La2O3 nanoparticles. 

Results obtained from this study indicate that a tiered approach is required 

to predict subchronic responses following inhalation of these nanoparticles, 

which will lead to development of methods for early detection and 

interventions of CoO- and La2O3 -induced pulmonary diseases, particularly 

fibrosis, in humans. 

Industry-wide studies of workers exposed 

to carbon nanotubes and nanofibers 

Matt Dahm 

This project includes the collection of exposure data and exposure factors 

from participating pilot-scale or full-scale manufacturers or users of singlewalled carbon nanotubes (SWCNTs) or multiwalled carbon nanotubes and 

carbon nanofibers. 

A study of biomarkers for early pulmonary, cardiovascular, and carcinogenic 

effects was conducted among workers at these facilities. 

The project will result in the creation of a predictive model using the 

collected exposure factors that will allow for the estimation of exposure for 

future registry and cohort studies. 

Mortality, cancer incidence, and biomarker This study is clarifying exposure-outcome associations, especially dosestudies response relationships, for risk assessment; examining relationships 

between biomarkers of exposure, susceptibility, and oncogene expression; James Yiin and determining health effects. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – About NTP at NIOSH 

Environmental Monitoring 

Project 

Study Scientist 

Project Summary 

Analytical research and development 

infrastructure 

Robert Streicher 

This work supports administrative needs and analytical instrumentation 

repair and maintenance for Chemical Exposure and Monitoring Branch 

chemists conducting research on sampling and developing analytical 

methods for workplace chemicals. 

Development, evaluation, validation, and/or use of methods for hazardous 

drugs, peracetic acid, isocyanates, glyphosate, and flame retardants were 

among the FY 2018 activities. 

Also investigated in FY 2018 were thermal desorption technology coupled 

with portable gas chromatography-mass spectrometry and integration of 

volatile organic compound monitoring with time and location determination. 

Direct-reading methods for metalcontaining aerosol 

Pramod Kulkarni 

Globally, exposure to hazardous metal-containing aerosols remains a 

serious health concern, with growing attention on fine, ultrafine, and 

nanosized aerosol particles. 

Emerging technologies, such as nanotechnology and additive 

manufacturing, are rapidly advancing our ability to create nanomaterials—

3D printed products with potential for aerosol exposure. 

A near-real-time, field-portable instrument for measuring hazardous metalcontaining aerosol has been developed as part of this project. The methods 

used in this study have general application to exposure monitoring, rapid 

hazard identification, and evaluation of engineering controls. 

Direct-reading methods for silica 

measurement 

Pramod Kulkarni 

The monitoring of respirable crystalline silica (RCS) concentrations in the 

workplace is essential for a comprehensive assessment of worker 

exposures. 

This project is developing direct-reading methods that allow onsite 

estimation of RCS. These methods allow either short-time (15–30 min) or 

end-of-shift quantification of RCS content onsite. A new field-portable 

instrument that can continuously measure RCS in near real time at 

concentrations well below the new OSHA PEL of 50 μg/m3 is being 

developed. 

These methods are expected to improve worker exposure monitoring and 

guide the implementation of effective engineering controls. 

Exposure Assessment 

Project 

Study Scientist 

Project Summary 

Exposure assessment for toxicologically 

important chemicals 

Brian Curwin 

This assessment is characterizing workplace exposures to chemicals of 

toxicological concern as identified by NTP and NIOSH. Current studies 

evaluate occupational exposure to carbon nanotubes and nanofibers, flame 

retardants, and PAHs in coal tar sealants. 

Goals of these studies include: (1) identifying industries, workplaces, uses, 

and users; (2) determining occupational health relevance; (3) estimating the 

number of workers exposed; and (4) conducting exposure sampling. 

Industry-wide studies, branch research, 

development, and planning 

This project supports strategic planning and feasibility studies of highpriority issues and emerging problems in occupational health. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – About NTP at NIOSH 

Project 

Study Scientist 

Project Summary 

Elizabeth Whelan 

Nanotechnology field evaluations 

Charles Geraci 

This project entails the collection of information from as many different 

facilities in the field as possible regarding the (1) nature of engineered 

nanomaterials, (2) processes involved in the manufacture and use of 

nanomaterials, (3) potential worker exposures to nanomaterials, and (4) 

practices and control procedures in the workplace where nanomaterials are 

produced or used. 

As toxicology studies identify the biological hazards of nanomaterials, 

gaining a better understanding of actual workplace exposures is essential. 

Immunotoxicity and Immunology 

Project 

Study Scientist 

Project Summary 

Immunotoxicological evaluation of 

occupational chemicals 

Stacey Anderson 

This study includes the identification of occupational and environmental 

chemical hazards and evaluation of immune function and mechanisms 

associated with exposure. 

This research is contributing to better risk assessment and increased 

identification of immunological hazards encountered in the workplace, 

which ultimately will establish occupational exposure limits. 

Identification of occupational allergens 

John Noti 

The objectives of this project are 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. 

Develop improved techniques for detecting such immune reactions before 

adverse clinical outcomes occur. 

Develop improved techniques for detecting and identifying inciting 

occupational agents. 

This project is analyzing clinical samples, environmental bulk samples, and 

environmental aerosol samples. Successful completion of these 

investigations should lead to the development of effective prevention 

strategies for occupational allergies and asthma. 

Characterization of in vivo protein This study is determining the molecular targets of inhaled diisocyanate 

haptenation following exposure to particulates and increase comprehension of the pathogenic mechanism of 

aerosolized 4,4’-methylene diphenyl isocyanate-induced allergic disease. 

diisocyanate The project will clarify the fate of diisocyanate in vivo following occupational 

Justin Hettick exposure by increasing understanding of disease and identifying potential 

biomarkers of exposure. 

Exosomes as biomarkers and immune 

modulators of diisocyanate asthma 

Justin Hettick 

This study is defining mechanisms of occupational asthma associated with 

exposure to methylene diphenyldiisocyanate (MDI) by identifying 

biomarkers of MDI exposure and immune regulatory factors that influence 

the progression and severity of MDI-associated occupational asthma. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – About NTP at NIOSH 

Project 

Study Scientist 

Project Summary 

This project is identifying response and legacy biomarkers found in 

exosomes secreted into the bloodstream that would indicate isocyanate 

exposure and sensitization. 

These biomarkers can be incorporated into a human exosome database 

and be used in future studies to distinguish MDI-associated occupational 

asthma from general environmental asthmas. 

The study is also attempting to determine how exosome genetic content 

can influence asthma progression. 

Genetics 

Project 

Study Scientist 

Project Summary 

Immunotoxicity of subchronic fungal 

exposures 

Brett Green 

This study is determining the pulmonary immunopathological outcomes of 

subchronic exposures to certain fungi nominated to NTP. Subchronic 

exposure studies with mycotoxin-producing strains of Stachybotrys 

chartarum and Aspergillus versicolor have been completed. 

Future subchronic exposure studies will focus on an atranone-producing 

strain of S. chartarum, A. versicolor, A. alternata, and fungi identified in 

NIOSH Health Hazard Evaluations and collaborative exposure assessment 

studies. Proposed studies will provide further insight into the mechanisms of 

pulmonary toxicity to fungi encountered in the workplace. 

Immunomodulatory effects of triclosan on 

effector CD4 T-cell development 

Hillary Shane 

This study is identifying the cellular and molecular mechanisms behind the 

immune-modulating effects of the antibacterial chemical, triclosan. This 

information is providing the basis for evaluating other nonsensitizing 

antimicrobial chemicals and helping to identify potentially conserved 

mechanisms that contribute to allergic disease. 

Results of this project will help assess the need to evaluate these types of 

workplace chemicals, leading to better risk assessment and establishment 

of occupational exposure limits. 

Highly sensitive and practical biomarkers 

for nanotoxicity 

Pius Joseph 

This project includes the development, validation, and testing (using a rat 

model) of highly sensitive and minimally invasive biomarkers for early 

detection of pulmonary toxicity that is potentially associated with exposure 

to toxic nanomaterials. 

The study is also conducting bioinformatic analysis of the global 

transcriptomics data to gain insights into the molecular mechanisms 

underlying the pulmonary toxicity of nanomaterials. 

Determining the molecular mechanisms of pulmonary toxicity and 

developing highly sensitive and minimally invasive biomarkers for 

nanotoxicity have implications in monitoring workers for their risk of 

developing adverse health effects potentially associated with exposure to 

toxic nanomaterials. 

Results obtained from preliminary studies have demonstrated that rats 

exposed to multiwalled carbon nanotubes can be distinguished from those 

exposed to crystalline nanocellulose using blood gene expression profiles. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – About NTP at NIOSH 

Project 

Study Scientist 

Project Summary 

Toxicological investigations of nitrogendoped multiwalled carbon nanotubes 

Dale Porter 

These studies are examining the potential effect of altering the chemical 

composition of multiwalled carbon nanotubes (MWCNTs) on their bioactivity 

in vivo by comparing two with different chemical compositions: MWCNTs 

and nitrogen-doped MWCNTs. 

Knowledge of doping modification could allow for the development and use 

of MWCNTs with reduced bioactivity, which might help reduce the hazard 

from workplace exposures. Such information might enable material 

scientists to incorporate a prevention-through-design philosophy into new 

nanoparticle-based technologies using nanomaterials that pose lower risks 

to human health. 

These studies should increase our understanding of the toxicological 

mechanisms responsible for MWCNT-induced pathologies and could help 

identify extrapulmonary sites of toxicity resulting from systemic transport of 

MWCNTs after pulmonary exposure. 

Neurological risks associated with 

workplace chemicals and nanomaterials 

Krishnan Sriram 

This is an evaluation of potential neurotoxicological effects associated with 

exposure to chemical agents, incidental nanoparticles, and engineered 

nanomaterials in experimental models. 

This study includes identifying hazards, evaluating molecular mechanisms 

of neurotoxicity, and identifying potential biomarkers of neurotoxicity. 

Findings from this study will contribute to the development of novel 

biomarkers for monitoring exposures and health effects, pre-job planning 

protocols, hazard and risk assessment paradigms, and occupational safety 

standards for neurotoxic exposures. 

Occupational heat stress, toxicant 

exposure, and neurological health risks 

Krishnan Sriram 

High environmental temperature is a natural stressor that can influence 

physiological and behavioral functions. Emerging evidence suggests that 

the central nervous system is particularly vulnerable to protracted or 

excessive hyperthermia. 

Although the physiological effects of hyperthermia are well known, limited 

information exists on how high-temperature environments influence the 

neurotoxicological outcome of workplace toxicants. In this project, 

laboratory-based studies will model relevant worker exposures to mild or 

moderate heat as well as co-exposure to select chemical and particulate 

agents. 

Neurochemical, molecular, and neuropathological assessments will be 

conducted. High-throughput analysis of the brain genome and proteome will 

help determine the underlying mechanisms and identify biomarkers that 

might serve as reliable predictors of neural injury. 

Mechanism of carbon nanotube-induced 

carcinogenesis and aneuploidy 

Linda Sargent 

In vitro exposure of human cells to 1- to 4-nm-diameter single-walled 

carbon nanotubes disrupts the mitotic apparatus, resulting in errors of 

chromosome number. Data comparisons with 10- to 20-nm-diameter 

multiwall carbon nanotubes (MWCNTs) suggest the diameter of the 

nanotube is important in the genotoxic response and that carbon nanotubes 

are potentially carcinogenic. This study is exploring the relationship 

between carbon nanotube diameter and mechanism of carcinogenesis and 

aneuploidy. Ongoing research is investigating the dose-response 

relationship of lung tumor promotion in a mouse model. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – About NTP at NIOSH 

Project 

Study Scientist 

Project Summary 

Nano-metal oxide property affecting 

fibrogenesis or carcinogenesis 

Liying Rojanasakul 

Metal oxide nanoparticles are increasingly used in a variety of applications 

having the potential to release particles into the workplace air. Limited 

published studies using animal models have shown lung inflammation and 

fibrosis with pulmonary exposure to metal oxide nanoparticles at human 

exposure-relevant doses. 

This project is determining the effects of physicochemical properties (size 

and coating) on metal oxide nanoparticles toxicity and the underlying 

mechanisms. 

Results thus far have shown that cerium oxide nanoparticles in mice cause 

lung inflammation that is particle-size dependent. In addition, consistent 

fibrogenic effects from cerium oxide nanoparticles are observed in vitro and 

in an animal model. 

These results support the development of an economical in vitro tool for 

predicting the potential toxicity of metal oxide nanoparticles in vivo. 

Hydraulic fracturing: toxicological effects of 

silica and diesel exhaust exposure 

Jeffrey Fedan 

This study of the toxicities of inhaled hydraulic fracturing sand dust (silica)—

alone and in combination with inhaled diesel exhaust to mimic worker 

exposures during hydraulic fracturing operations—is using a battery of in 

vivo and in vitro experiments to examine the effects of exposure on the 

lungs, cardiovascular system, immune system, brain, skin, and blood. The 

initial exposures to silica, using two exposure doses, are complete. 

Exposures to a low dose of diesel exhaust from a type II diesel engine are 

underway and exposures to a high dose are complete. 

The assessment of inhalation exposures to silica in combination with diesel 

exhaust will be the next phase of this study. 

Pulmonary function and nanoparticle 

inhalation: in vivo and in vitro effects 

Jeffrey Fedan 

In vivo experiments have demonstrated changes in pulmonary function and 

airway reactivity in animals exposed to multiwall carbon nanotubes 

(MWCNTs). A comparison of the relative pulmonary toxicities of pristine and 

nitrogen-doped MWCNTs indicates that doping of MWCNTs with nitrogen 

might decrease its relative toxicity in comparison to MWCNTs with regard to 

its effects on pulmonary function. 

This study is characterizing MWCNT effects on critical aspects of lung 

function in vivo and airway function in vitro and provide metrics to enable 

risk assessment strategies. 

Health effects of inhaled crude oil 

Jeffrey Fedan 

This project includes the design and building of an inhalation exposure 

system that delivers crude oil vapor to rats to study the effects of its 

inhalation on the lungs, cardiovascular system, immune system, brain, skin, 

and blood. Acute and subchronic inhalation exposures have been 

completed. 

Toxicity assessment of carbon nanotubes 

and carbon nanofibers from U.S. facilities 

Aaron Erdely 

This study is assessing general pulmonary and systemic toxicity, pathology, 

biodistribution, and genotoxicity 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. 

Toxicity associated with the life cycle of 

carbon nanotubes 

In vivo and in vitro data suggest that exposure to carbon nanotubes has 

significant adverse health effects. Few data are available to define the 

toxicity of carbon nanotubes at each stage of the production life cycle (as 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – About NTP at NIOSH 

Project 

Study Scientist 

Project Summary 

Aaron Erdely produced, modified post-production, and incorporated into composites), 

although the numbers of potentially exposed workers increase with each 

stage. 

This project is evaluating the pulmonary response and genotoxicity of 

carbon nanotubes at different stages of production. 

A translational in vitro approach to assess 

cardiovascular risk 

Aaron Erdely 

Respiratory exposure to particulates has been associated with increased 

mortality from cardiovascular diseases. 

This project is developing and testing methods to assess cardiovascular 

risk following pulmonary exposure to engineered nanomaterials and other 

occupational exposures. 

It will establish a translational model using ex vivo and in vitro techniques to 

assess cardiovascular risk from particulate exposures. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – NIOSH Immunotoxicology 

NTP at NIOSH: Immunotoxicology Research 

Interagency Agreement on Immunotoxicology Research 

The NIEHS and NIOSH interagency agreement provides for support of NTP hazard identification 

activities aimed at preventing diseases or adverse effects caused by environmental exposure to 

chemical or physical agents. These cooperative studies continue to improve risk assessment by 

measuring what constitutes an adverse health effect on the immune system in humans. The FY 2018 

studies listed below evaluate unique cohorts of individuals from professions associated with immunemediated occupational diseases. 

Immunotoxicology Studies 

Project 

Study Scientist 

Project Summary 

Identification and characterization of cross- Monoclonal and polyclonal antibodies to recombinant fungal biomarker 

reactive fungal biomarkers antigens are being developed in this project. 

Brett Green The utility of these antibodies is important for quantifying occupationally 

relevant fungal biomarkers, particularly to those fungi nominated to NTP. 

Toxicity of subchronic fungal exposures 

Brett Green 

A model that replicates human exposure is being used to characterize the 

toxicological and pulmonary immune responses associated with subchronic 

fungal exposures. This model uses an acoustical generator system and 

nose-only exposure chamber to characterize toxicological endpoints 

following subchronic exposures to spores derived from fungi nominated to 

NTP. 

Subchronic exposure studies with Aspergillus fumigatus, two mycotoxinproducing strains of Stachybotrys chartarum, and A. versicolor have been 

completed. 

Future subchronic exposure studies will focus on an atranone-producing 

strain of S. chartarum, A. versicolor, Alternaria alternata, mixed fungal 

exposures, and other occupationally relevant fungi identified in concurrent 

NTP-funded fungal diversity studies. 

These toxicological studies will provide novel data sets that will be used to 

characterize the hazards that fungal exposure might present to human and 

occupational health. 

Identification and characterization of fungal 

exposures 

Brett Green 

These studies are investigating and characterizing the diversity of fungi in 

indoor and occupational environments using internal transcribed spacer 

region sequencing. 

In collaboration with intramural and external stakeholders, results from 

these studies have provided new insight into the complex diversity of mold 

present in these environments. 

This methodological approach has been used to support NIOSH Health 

Hazard Evaluations to characterize microbial hazards in the workplace. 

Analysis of mycotoxins in dust samples 

from a water-damaged building 

Ju-Hyeong Park 

This examination of effects of exposure to fungal secondary metabolites, 

including mycotoxins, is focused on occupant health in water-damaged 

buildings. 

Cost-effective and robust methods have been developed using 

ultraperformance liquid chromatography-tandem mass spectrometry for 

simultaneous analysis of 31 fungal secondary metabolites in environmental 

samples. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – NIOSH Immunotoxicology 

Project 

Study Scientist 

Project Summary 

The accuracy of the method has been improved by using eight isotopically 

labeled (13carbon) mycotoxin internal standards to compensate for 

extraction loss and matrix effects. 

The developed method has been applied to (1) examine stability of 

secondary metabolites in spiked dust samples stored in different 

temperature conditions at seven different points of time for 2 years, and (2) 

analyze 500 dust samples collected from our Philadelphia School Study. 

The project team is currently examining stability of standard materials of 

fungal metabolites stored at -200C and 40C for a year. We will examine the 

effect of exposure to fungal secondary metabolites on occupants’ health 

using statistical models adjusted for exposures to other microbial agents 

that were quantified in the epidemiological studies. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – NIOSH Occupationally Relevant 

NTP at NIOSH: Occupationally Relevant Exposures 

Comprehensive Assessment of Occupationally Relevant Exposures 

NIEHS is coordinating an NTP effort with NIOSH to better understand worker exposures, identify 

occupational health research gaps, and educate workers. The NIEHS and NIOSH interagency 

agreement supports these projects. The FY 2018 efforts listed below address worker exposures to 

welding fumes, nanosized materials, food flavorings, and other industrial chemicals. 

NIOSH mobile lab for field studies 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – NIOSH Occupationally Relevant 

Occupationally Relevant Exposures 

Project 

Study Scientist 

Project Summary 

Administrative support Under this project, support is being provided to NIOSH scientists for (1) 

participating in review and oversight of NTP activities and (2) attending Elizabeth Whelan NTP-related meetings at NIEHS in Research Triangle Park, NC, and 

Washington, DC. 

Occupational exposure assessment of 

welding fumes with emphasis on 

manganese compounds 

Kevin Hanley 

In this characterization of welding fume exposures, with a focus on 

manganese, welders’ exposures to total and respirable manganese were 

evaluated using a novel sequential chemical extraction method to (1) 

identify industries, such as construction, shipbuilding, manufacturing 

companies, and unions, involved in welding operations for which the 

potential for substantial manganese exposure exists; (2) develop methods 

to identify manganese compounds and different oxidation states based on 

selective solubility with various welding fume matrices; and (3) characterize 

welding fume exposures based on welding-associated jobs, tasks, and 

processes. 

To date, three manuscripts have been published (and a fourth has been 

submitted to a journal) that demonstrated excessive manganese exposures 

associated with welding fumes, often exceeding Threshold Limit Values of 

the American Conference of Governmental Industrial Hygienists (ACGIH 

TLVs) by an order of magnitude. 

Exposure assessment of engineered 

nanoparticles 

Charles Geraci 

This identification of workplaces engaged in the synthesis, manufacture, 

and use of engineered nanomaterials is characterizing workplace 

exposures to selected engineered nanoparticles. 

Durability of nanoscale cellulose fibers in This project is investigating the in vitro durability of nanocellulose materials 

artificial human lung fluids in artificial lung fluids. Data generated from this study will be used to inform 

larger in vivo inhalation studies. Aleksandr Stefaniak 

Assessment of occupational exposures to 

flame retardants 

Cheryl Estill 

This study is comparing exposures among industries, processes, and tasks; 

determining the routes of exposure; and making recommendations to 

reduce exposures. 

These data will be used to determine exposure levels of workers in different 

occupations and how they relate to the general population by comparison to 

the National Health and Nutrition Examination Survey data. The results will 

aid in the design, understanding, and use of toxicological studies and risk 

assessment. 

Exposure has been assessed at 19 facilities involved in the manufacture, 

installation, or use of goods containing these flame retardants. Worksite 

categories included are manufacture of products that use flexible 

polyurethane foams; fabrication and manufacture of rigid polystyrene foam; 

cutting, installing, or spraying polyurethane foam insulation at construction 

sites; gymnasiums; nail salons; and the fire service industry. 

Assessment of occupational exposure to 

polycyclic aromatic hydrocarbons (PAHs) 

in coal tar sealant applications 

Kevin Hanley 

This study focuses on the assessment of occupational exposure to PAHs 

among coal tar sealant workers. Currently, no data are available in the 

scientific literature on exposure to PAHs and their metabolites for workers 

applying coal tar sealant-based coatings on pavements. 

The study is providing data regarding levels of exposure to airborne 

chemicals for comparison to current NIOSH recommended exposure limits, 

if available. 

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2018 Annual Report – Partner Agency Research – NTP at NIOSH – NIOSH Occupationally Relevant 

Project 

Study Scientist 

Project Summary 

Results for specific PAH chemicals using NIOSH analytical methods will be 

reported. PAHs were measured in skin wipe samples, and PAH metabolites 

were measured in biological samples collected from workers to characterize 

levels present in this workforce. 

In FY 2018, construction surveys increased the database by 264 PAH 

measurements for air exposure time-weighted-average calculations; 396 

skin wipe PAH measurements; and 252 PAH metabolite analyses in urine 

specimens. 

139 
 

 

 

 

 

2018 Annual Report – Appendix – Publications 

Appendix: Publications during FY 2018 

NTP Reports and Documents 

Research Reports 

National Toxicology Program. 2017. NTP Research Report on Biological Activity of Bisphenol A 

(BPA) Structural Analogues and Functional Alternatives. NTP Research Report 4. Research Triangle 

Park, NC: National Toxicology Program (RR-04):1-80. 

https://ntp.niehs.nih.gov/results/pubs/rr/reports/abstracts/rr04/index.html 

National Toxicology Program. 2018. NTP Research Report on National Toxicology Program 

Approach to Genomic Dose-Response Modeling. NTP Research Report 5. Research Triangle Park, 

NC: National Toxicology Program (RR-05): 1-42. 

https://ntp.niehs.nih.gov/results/pubs/rr/reports/abstracts/rr05/index.html 

Harrill, AH, Borghoff, S, Zorrilla, L, Blystone, C, Kissling, GE, Malarkey, DE, Shockley, K, Travlos, G, 

DeVito, MJ. 2017. NTP Research Report on Baseline Characteristics of Diversity Outbred (J:DO) 

Mice Relevant to Toxicology Studies. NTP Research Report 6. Research Triangle Park, NC: National 

Toxicology Program (RR-06): 1-32. 

https://ntp.niehs.nih.gov/results/pubs/rr/reports/abstracts/rr06/index.html 

National Toxicology Program. 2018. NTP Research Report on the CLARITY-BPA Core Study: A 

Perinatal and Chronic Extended-Dose-Range Study of Bisphenol A in Rats. NTP Research Report 9. 

Research Triangle Park, NC: National Toxicology Program (RR-09): 1-221. 

https://ntp.niehs.nih.gov/results/pubs/rr/reports/abstracts/rr09/index.html 

Toxicity Reports 

National Toxicology Program. 2018. NTP Technical Report on the Toxicity Studies of Triethylamine 

(CASRN 121-44-8) Administered by Inhalation to F344/N Rats and B6C3F1/N Mice. NTP Toxicity 

Report 78. Research Triangle Park, NC: National Toxicology Program (TOX-78): 1-118. 

https://ntp.niehs.nih.gov/results/pubs/shortterm/reports/abstracts/tox078/index.html 

National Toxicology Program. 2018. NTP Technical Report on the Toxicity Studies of oPhthalaldehyde (CASRN 643-79-8) Administered by Inhalation to Sprague Dawley (Hsd:Sprague 

Dawley SD) Rats and B6C3F1/N Mice. NTP Toxicity Report 84. Research Triangle Park, NC: 

National Toxicology Program (TOX-84): 1-142. 

https://ntp.niehs.nih.gov/results/pubs/shortterm/reports/abstracts/tox084/index.html 

National Toxicology Program. 2017. NTP Technical Report on the Toxicity Study of Chitosan 

(CASRN 9012-76-4) Administered in Feed to Sprague Dawley [Crl:CD(SD)] Rats. NTP Toxicity 

Report 93. Research Triangle Park, NC: National Toxicology Program (TOX-93): 1-93. 

https://ntp.niehs.nih.gov/results/pubs/shortterm/reports/abstracts/tox093/index.html 

Technical Reports 

National Toxicology Program. 2017. NTP Technical Report on the Toxicology and Carcinogenesis 

Studies of Antimony Trioxide (CASRN 1309-64-4) in Wistar Han [Crl:WI (Han)] Rats and B6C3F1/N 

Mice (Inhalation Studies). NTP Technical Report 590. Research Triangle Park, NC: National 

Toxicology Program (TR-590): 1-250. 

https://ntp.niehs.nih.gov/results/pubs/longterm/reports/longterm/tr500580/listedreports/tr590/index.html 

National Toxicology Program. 2018. NTP Technical Report on the Toxicology and Carcinogenesis 

Studies of 2,3-Butanedione (CASRN 431-03-8) in Wistar Han [Crl:WI (Han)] Rats and B6C3F1/N 

140 
 

 

 

 

 

2018 Annual Report – Appendix – Publications 

Mice (Inhalation Studies). NTP Technical Report 593. Research Triangle Park, NC: National 

Toxicology Program (TR-593): 1-198. 

https://ntp.niehs.nih.gov/results/pubs/longterm/reports/longterm/tr500580/listedreports/tr593/index.html 

National Toxicology Program. 2018. NTP Technical Report on the Toxicology and Carcinogenesis 

Studies of p-Chloro-α,α,α-Trifluorotoluene (CASRN 98-56-6) in Sprague Dawley Rats (Hsd:Sprague 

Dawley SD) and B6C3F1/N Mice (Inhalation Studies). NTP Technical Report 594. Research Triangle 

Park, NC: National Toxicology Program (TR-594): 1-199. 

https://ntp.niehs.nih.gov/results/pubs/longterm/reports/longterm/tr500580/listedreports/tr594/index.html 

RoC Monograph 

National Toxicology Program. 2018. Report on Carcinogens Monograph on Antimony Trioxide. RoC 

Monograph. Research Triangle Park, NC. National Toxicology Program: 1-169. 

https://ntp.niehs.nih.gov/pubhealth/roc/listings/antimonyt/index.html 

Journal Articles and Book Chapters 

Research funding sources for each publication are indicated as follows: 

[1] Funded by the NIEHS/NIOSH Interagency Agreement 

[2] Funded by NIOSH voluntary allocations to the NTP 

[3] Funded by the NIEHS/NCTR Interagency Agreement 

[4] Funded by NCTR voluntary allocations to the NTP 

[5] Funded by NIEHS voluntary allocations to the NTP 

Ahn Y, Jung JY, Veach BT, Khare S, Gokulan K, Pineiro SA and Cerniglia CE. In vitro test systems to 

determine tetracycline residue binding to human feces. Regul Toxicol Pharmacol. 2018 Nov;99:105-

115. Epub 2018 Sep15. https://doi.org/10.1016/j.yrtph.2018.09.013 [4] 

Ahrenholz SH, Brueck SE, Rule AM, Noti JD, Noorbakhsh B, Blachere FM, de Perio MA, Lindsley 

WG, Shaffer RE and Fisher EM. Assessment of environmental and surgical mask contamination at a 

student health center - 2012-2013 influenza season. J Occup Environ Hyg. 2018 Sep;15(9):664-675. 

https://doi.org/10.1080/15459624.2018.1486509 [2] 

Anderson SE and Meade BJ. Occupational Immunotoxicology. Comprehensive Toxicology: Third 

Edition. 2018;11-15:542-558. https://doi.org/10.1016/B978-0-12-801238-3.64239-3 [2] 

Anderson SE and Shane HL. Investigative immunotoxicology. Methods Mol Biol. 2018;1803:27-46. 

https://doi.org/10.1007/978-1-4939-8549-4_3 [2] 

Auerbach SS, Xu M, Merrick BA, Hoenerhoff MJ, Phadke D, Taxman DJ, Shah R, Hong HL, Ton TV, 

Kovi RC et al. Exome sequencing of fresh-frozen or formalin-fixed paraffin-embedded B6C3F1/N 

mouse hepatocellular carcinomas arising either spontaneously or due to chronic chemical exposure. 

Toxicol Pathol. 2018 Aug;46(6):706-718. http://dx.doi.org/10.1177/0192623318789398 [5] 

Beard JD, Erdely A, Dahm MM, de Perio MA, Birch ME, Evans DE, Fernback JE, Eye T, Kodali V, 

Mercer RR et al. Carbon nanotube and nanofiber exposure and sputum and blood biomarkers of 

early effect among U.S. workers. Environ Int. 2018 Jul;116:214-228. 

https://doi.org/10.1016/j.envint.2018.04.004 [2] 

Beaucham C, King B, Feldmann K, Harper M and Dozier A. Assessing occupational erionite and 

respirable crystalline silica exposure among outdoor workers in Wyoming, South Dakota, and 

Montana. J Occup Environ Hyg. 2018 Jun;15(6):455-465. 

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2018 Annual Report – Appendix – Publications 

https://doi.org/10.1080/15459624.2018.1447116 [2] 

Bell SM, Chang X, Wambaugh JF, Allen DG, Bartels M, Brouwer KLR, Casey WM, Choksi N, 

Ferguson SS, Fraczkiewicz G et al. In vitro to in vivo extrapolation for high throughput prioritization 

and decision making. Toxicol In Vitro. 2018 Mar;47:213-227. 

http://dx.doi.org/10.1016/j.tiv.2017.11.016 [5] 

Bennett J, Marlow D, Nourian F, Breay J, Feng A and Methner M. Effect of ventilation velocity on 

hexavalent chromium and isocyanate exposures in aircraft paint spraying. J Occup Environ Hyg. 

2018 Mar;15(3):167-181. https://doi.org/10.1080/15459624.2017.1401710 [2] 

Bertke SJ, Yiin JH and Daniels RD. Cancer mortality update with an exposure response analysis 

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perfluoroalkyl substance (PFAS) levels and measures of thyroid hormone, kidney function, and body 

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Bryce SM, Bernacki DT, Smith-Roe SL, Witt KL, Bemis JC, Dertinger SD. Investigating the 

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Catlin N, Waidyanatha S, Black SR, Mathews J, Snyder RW, Patel P, Watson S, Fennell TR. 

Disposition of tris(4-chlorophenyl)methanol and tris(4-chlorophenyl)methane in male and female 

Harlan Sprague Dawley rats and B6C3F1/N mice following oral and intravenous administration. 

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Catlin N, Waidyanatha S, Mylchreest E, Miller-Pinsler L, Cunny H, Foster P, Sutherland V, McIntyre 

B. Embryo-fetal development studies with the dietary supplement vinpocetine in the rat and rabbit. 

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released from laser printers using nano-enabled toners: potential health implications from exposures 

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Cheong A, Johnson SA, Howald EC, Ellersieck MR, Camacho L, Lewis SM, Vanlandingham MM, 

Ying J, Ho SM and Rosenfeld CS. Gene expression and DNA methylation changes in the 

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and Rusyn I. Modulation of tetrachloroethylene-associated kidney effects by nonalcoholic fatty liver or 

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and validation of an analytical method to quantitate tris(chloroisopropyl)phosphate in rat and mouse 

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Croston TL, Lemons AR, Beezhold DH and Green BJ. MicroRNA Regulation of host immune 

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JE, Mercer RR and Grinshpun SA. Exposure assessments for a cross-sectional epidemiologic study 

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Dere E, Anderson LM, Huse SM, Spade DJ, McDonnell-Clark E, Madnick SJ, Hall SJ, Camacho L, 

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on 90 day old rat testes function and sperm molecular profiles: A CLARITY-BPA consortium study. 

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AA, Rudel R et al. Systematic reviews and meta-analyses of human and animal evidence of prenatal 

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Dreval K, Tryndyak V, Kindrat I, Twaddle NC, Orisakwe OE, Mudalige TK, Beland FA, Doerge DR 

and Pogribny IP. Cellular and molecular effects of prolonged low-level sodium arsenite exposure on 

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Elmore SA. Enhanced histopathology evaluation of lymphoid organs. Methods Mol Biol. 

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Falcone LM, Erdely A, Kodali V, Salmen R, Battelli LA, Dodd T, McKinney W, Stone S, Donlin M, 

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PC. Inhalation of iron-abundant gas metal arc welding-mild steel fume promotes lung tumors in mice. 

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Falcone LM, Erdely A, Salmen R, Keane M, Battelli L, Kodali V, Bowers L, Stefaniak AB, Kashon ML, 

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Fang JL, Loukotkova L, Chitranshi P, Gamboa da Costa G and Beland FA. Effects of human 

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Metabolism and disposition of 2-ethylhexyl-p-methoxycinnamate following oral gavage and dermal 

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Gokulan K, Arnold MG, Jensen J, Vanlandingham M, Twaddle NC, Doerge DR, Cerniglia CE and 

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Green BJ. Emerging insights into the occupational mycobiome. Curr Allergy Asthma Rep . 

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Hur J, Danes L, Hsieh JH, McGregor B, Krout D, Auerbach S. Tox21 Enricher: web-based 

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Kleinstreuer NC, Browne P, Chang X, Judson R, Casey W, Ceger P, Deisenroth C, Baker N, Markey 

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H, Walker NJ, Welch C, Rider CV. Naturally complex: perspectives and challenges associated with 

botanical dietary supplement safety assessment. Food Chem Toxicol. 2018 Aug;118:963-971. 

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Shoeb M, Joseph P, Kodali V, Mustafa G, Farris BY, Umbright C, Roberts JR, Erdely A and Antonini 

JM. Silica inhalation altered telomere length and gene expression of telomere regulatory proteins in 

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Sisler JD, Qi C, McKinney W, Shaffer J, Andrew M, Lee T, Thomas T, Castranova V, Mercer RR and 

Qian Y. Physical chemical properties and cell toxicity of sanding copper-treated lumber. J Occup 

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Slikker W and Wang C. The developing nervous system. Comprehensive Toxicology: Third Edition. 

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Auerbach SS, Witt KL. Black cohosh extracts and powders induce micronuclei, a biomarker of genetic 

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Sun Q, Yang Q, Xu H, Xue J, Chen C, Yang X, Gao X, Liu Q. miR-149 negative regulation of mafA is 

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Sung EJ, Ryuda M, Matsumoto H, Uryu O, Ochiai M, Cook ME, Yi NY, Wang H, Putney JW, Bird GS, 

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Sutherland C, Wang Y, Brown RV, Foley J, Mahler B, Janardhan KS, Kovi RC, Jetten AM. Laser 

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Thomas RS, Paules RS, Simeonov A, Fitzpatrick SC, Crofton KM, Casey WM and Mendrick DL. The 

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Waidyanatha S, Ryan K, Roe AL, Jia W, Paine MF, Ferguson S, Gurley BJ, Welch K, Chow MSS, 

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Waidyanatha S, Toy H, South N, Gibbs S, Mutlu E, Burback B, McIntyre BS, Catlin N. Systemic 

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Wang C, Han X, Liu F, Patterson TA, Hanig JP, Paule MG and Slikker W, Jr. Lipid profiling as an 

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Yan Y, Yu L, Castro L, Dixon D. ERalpha36, a variant of estrogen receptor alpha, is predominantly 

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Yu D, Wu L, Gill P, Tolleson WH, Chen S, Sun J, Knox B, Jin Y, Xiao W, Hong H et al. Multiple 

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