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  1. Science & Research (NCTR)

Robert Heflich Ph.D.

Director, Division of Genetic and Molecular Toxicology

Robert Heflich, Ph.D.

Robert Heflich, Ph.D.
(870) 543-7121

Back to NCTR Principal Investigator page

 About  |  Publications  |  Division Scientists


Dr. Robert H. (Bob) Heflich received a Ph.D. in microbiology from Rutgers, The State University of New Jersey, in 1976, followed by postdoctoral training with Veronica Maher and Justin McCormick at Michigan State University, studying mechanisms of DNA repair and mutagenesis in normal human fibroblasts. Dr. Heflich joined NCTR in 1979, where he is currently the Director of the Division of Genetic and Molecular Toxicology. He maintains an active research program, while managing a division of over 30 scientists and administrative support personnel. Dr. Heflich has published over 250 papers in peer-reviewed journals, has served as Editor-in-Chief of Environmental and Molecular and Mutagenesis, and participates on several FDA and international committees dealing with genetic toxicology regulatory issues.

Dr. Heflich has been a member of the FDA’s Senior Biomedical Research Service since 2001 and received the Environmental Mutagen and Genomics Society Service Award in 2006 and Alexander Hollaender Award in 2018. He was awarded FDA Critical Path funding in 2008 to develop a human PIG-A assay for use during clinical trials. Since 2009 he has been awarded funding from FDA’s Center for Tobacco Products (CTP) to develop 3-D cell culture models and to evaluate existing genetox assays to regulate tobacco products. Additionally, CTP has funded his research on applying Pig-a assays for in vitro to in vivo extrapolation of tobacco product toxicity.

Dr. Heflich has served on the following NCTR committees:

 NCTR Research Scientist Peer Review Committee
   2000, 2009

 Senior Biomedical Research Service Credentialing Committee
   2007 – Present

Research Interests

Over the years, Dr. Heflich has pursued various research interests to modernize the practice of regulatory genetic toxicology, including developing more relevant, human-based in vitro models, and using advanced genetic analysis techniques designed to evaluate sequence changes in genes responsible for human diseases. A particular long-term interest involves the development of approaches to measure and analyze mutations in laboratory animals.  Studies have been conducted to evaluate the transgenic gpt, lacI, cII, and φX174 am3 reporter genes and the endogenous Hprt, Tk, and Pig-a genes in mice and rats. The overall goal of these efforts is the application of sensitive and predictive in vivo mutation assays for regulatory purposes. Some of his other research interests include the development and characterization of relevant in vitro assays for evaluating the risks associated with tobacco product exposure. Descriptions of two recent research activities follow:

One of the more exciting developments over the last 10 years has been the move to evaluate genetic toxicity dose-response data quantitatively to better estimate human risk. Although it has been known for some time that not all genotoxic carcinogens have linear dose responses, dose response data are rarely used to evaluate the safety of regulated products. This changed when European regulators accepted in vivo mutation data to support a threshold for the carcinogenicity of ethylmethane sulfonate, which was found as a contaminant in a batch of the AIDS drug nelfinivir (Viracept) in 2007. Dr. Heflich and colleagues from HESI/ILSI (now HESI) have explored ways of quantitatively evaluating genetic toxicology data and developing Points of Departure (PoDs) that can be used to establish virtually safe doses for human exposure. Dr. Heflich also has used these methods to distinguish between the genotoxicity produced by related tobacco products that claim to have equivalent or reduced toxicity. These efforts have the potential of making better use of genetic toxicology data for making regulatory decisions.

The in vivo Pig-a gene mutation assay is currently being developed as a regulatory test. Dr. Heflich and his colleagues co-invented the test in 2008, and subsequently have made important discoveries as to its sensitivity to various types of genotoxins, the manifestation and persistence of the response, its ability to integrate into general toxicology studies, and in identifying the mutations that are responsible for inducing the mutant phenotype. Dr. Heflich has led International Workshop on Genotoxicity Testing and Health and Environmental Sciences Institute workgroups seeking to gain regulatory acceptance of the assay. Although the test already meets international regulatory guidelines (e.g., International Conference on Harmonization M7), he currently is working on an Organization for Economic Cooperation and Development (OECD)-approved plan to develop a Test Guideline (TG) for the assay. In April 2020, OECD approved a Detailed Review paper and validation document on the assay (see OECD publications listed below), which clears the way for development of a TG. Approval of an OECD TG will ensure that data from the test is widely accepted by regulatory agencies. 

Professional Societies/National and International Groups

Environmental Mutagen and Genomics Society (EMGS)
1980 – Present

Editor-in-Chief, Society Journal
2001 – 2006

Member, EMGS Publications Policy Committee
2001 – Present

Chair, EMGS Annual Meeting Workshops on the Pig-a Gene Mutation Assay
2008, 2009, 2012, 2013, 2014, 2016

EMGS Council
2019 – Present

Federation of American Societies for Experimental Biology (FASEB)
Member, FASEB Communications and Publications Committee
2007 – 2010

Member, FASEB Science Policy Committee

Health and Environmental Sciences Institute (HESI)
Member, HESI Workgroup to Develop the Pig-a Assay as an In Vivo Genotoxicity Test
2009 – Present

Chair, HESI Workgroup to Develop the Pig-a Assay as an In Vivo Genotoxicity Test
2012 – Present

International Workgroup on Genotoxicity Testing (IWGT)
Member, Committee Addressing Transgenic Mutation Assays
2002 – 2003 

Member, Committee on In Vivo-Only Genotoxins
2005 – 2007

Member, Committee on Nonrelevant In Vivo Genotoxins
2005 – 2007

Member, Committee on Integrating Genetox Assays into General Tox Protocols
2009 – 2011

Member, Committee on New In Vitro Assays
2016 – 2020

Member, Committee on 3D Tissue Models
2016 – 2020

Leader (rappateur), Committee on the Pig-a In Vivo Gene Mutation Assay
2012 – 2015

Institute for In Vitro Sciences 
Member, Steering Committee for Conference on In Vitro Models to Assess the Toxicity of Tobacco Smoke

Organization for Economic Cooperation and Development (OECD)
Member, OECD Expert Working Group on TG487 (the In Vitro Micronucleus Assay Technical Guidance)

Member, OECD Expert Working Group on Development of an In Vivo Transgenic Assay Guidance (TG488)
2008 – 2013, 2018 – 2020

Member, OECD Expert Working Group Revising Older Genetic Toxicology TGs
2011 – 2015

Member, OECD Expert Working Group on Revising TG476 (the In Vitro Hprt Assay Guideline)
2015 – 2018

Member, OECD Expert Working Group on Revising TG471 (Bacterial Gene Mutation Assays)
2019 – Present

Chair, OECD Expert Working Group on Developing an OECD TG for the Pig-a Assay
2015 – Present

Sigma Xi
1975 – Present

Treasurer, Central Arkansas Chapter
1990 – 1996

Selected Publications

Publication titles are linked to text abstracts on PubMed.

The In Vivo Erythrocyte Pig-a Gene Mutation Assay — Part 1 —Detailed Review Paper and Performance Analysis.
Heflich R.H., Dertinger S.D., Dobrovolsky V.N., Bhalli J.A., Kenyon M.O., Kimoto T., Miura D., Horibata D., MacGregor J.T., Roberts D.J., Igl B-W, Lovell D.P., Mittelstaedt R.A., Shemansky J.M., Wynne R.A., McDaniel L.P., University of Maryland CERSI, and HESI Genetic Toxicology Technical Committee.
OECD (Organisation for Economic Cooperation and Development). 2020, Environment Directorate. 

The In Vivo Erythrocyte Pig-a Gene Mutation Assay — Part 2 — Validation Report.
Heflich R.H., Dertinger S.D., and Kimoto T.
OECD (Organisation for Economic Cooperation and Development). 2020, Environment Directorate.

Use of In Vitro 3D Tissue Models in Genotoxicity Testing: Strategic Fit, Validation Status and Way Forward. Report of the Working Group from the 7th International Workshop on Genotoxicity Testing (IWGT).
Pfuler S., van Benthem J., Curren R., Doak S., Dusinska M., Hayashi M., Heflich R.H., Kidd D., Kirkland D., Luan Y., Ouedraogo G., Reisinger K., Sofuni T., van Acker F., Yang Y., and Corvi R.
Mutat Res. 2020, 850-851:503135.

In Vitro Mammalian Cell Assays Based on the Pig-a Gene: A Report of the 7th International Workshop on Genetic Toxicology (IWGT) Workgroup.
Bemis J.C. and Heflich R.H.
Mutat Res. 2019, 850-851:403028.

Celebrating 50 Years of EMGS: A Visionary Idea Continues.
Yauk C.L., Heflich R.H., and DeMarini D.M.
Environ Mol Mutagenesis. 2020, 61:5-6.

Mutation as a Toxicological Endpoint for Regulatory Decision-Making.
Heflich R.H., Johnson G.E., Zeller A., Marchetti F., Douglas G.R., Witt K.L., Gollapudi B.B., and White P.A. 
Environ Mol Mutagenesis. 2020, 61:34-41.

Dr. Daniel Acosta and In Vitro Toxicology at the U.S. Food and Drug Administration’s National Center for Toxicological Research.
Inselman A., Liu F., Wang C., Shi Q., Pang L., Mattes W., White M., Lyn-Cook B., Rosas-Hernandez H., Cuevas E., Lantz S., Imam S., Ali S., Petibone D.M., Shemansky J.M., Xiong R., Wang Y., Tripathi P., Cao X., Heflich R.H., and Slikker W. Jr.
Toxicol in Vitro. 2020, 64:104471.

Pig-a Gene Mutation Database.
Shemansky J.M., McDaniel L.P., Klimas C., Dertinger S.D., Dobrovolsky V.N., Kimoto T., Horibata K., Polli J.E., and Heflich R.H. 
Environ Mol Mutagenesis. 2019, 60:759-762.

Evaluation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) Mutagenicity Using In Vitro and In Vivo Pig-a Assays.
Mittelstaedt R.A., Dobrovolsky V.N., Revollo J.R., Pearce M.G., Wang Y., Dad A., McKinzie P.B., Rosenfeldt H., Yucesoy B., Yeager R., Hu S-C, Tang Y., Min S., Kang H-K, Yang D-J, Basavarajappa M., and Heflich R.H.
Mutat Res. 2019, 837:65-72.

Cigarette Whole Smoke Solutions Disturb Mucin Homeostasis in a Human In Vitro Airway Tissue Model.
Cao X., Wang Y., Xiong R., Muskhelishvili L., Davis K., Richter P.A., and Heflich R.H.
Toxicology. 2018, 409:119-128.

Analysis of Mutation in the Rat Pig-a Assay:  II) Studies with Bone Marrow Granulocytes.
Dad A., Revollo J., Petibone D., Pearce M.G., Heflich R.H., and Dobrovolsky V.N.
Environ Mol Mutagen. 2018, 59:733-741.

Quantitative Differentiation of Whole Smoke Solution-Induced Mutagenicity in the Mouse Lymphoma Assay.
Guo X., Heflich R.H., Dial S.L., De M., Richter P.A., and Mei N.
Environ Mol Mutagen. 2018, 59:103-113.

Division Scientists

Contact information for all lab members:
(870) 543-7121

Michelle Bishop

Xuefei Cao
Research Pharmacologist

Tao Chen
Research Toxicologist

Ying Chen

Stacey Dial

Vasily Dobrovolsky
Research Microbiologist 

Xiaoqing Guo
Research Biologist

Mugimane Manjanatha
Supervisory Research Microbiologist 

Karen McKim

Page McKinzie
Research Microbiologist   

Nan Mei
Research Biologist  

Jaime Miranda-Colon

Roberta A. Mittelstaedt

Meagan Myers
Research Toxicologist  

Barbara Parsons
Research Microbiologist  

Mason Pearce

Dayton Petibone
Research Biologist 

Javier Revollo
Research Biologist

Sharon Shelton

Yiying Wang
Staff Fellow

Rebecca Wynne

Rui Xiong
Visiting Scientist 

Contact Information
Robert Heflich
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