Robert Heflich, Ph.D.
Dr. Robert 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. 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
Senior Biomedical Research Service Credentialing Committee
2007 – Present
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 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. 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
Federation of American Societies for Experimental Biology (FASEB)
Member, FASEB Communications and Publications Committee
2007 – 2010
Member, FASEB Science Policy Committee
Institute for In Vitro Sciences
Member, Steering Committee for Conference on In Vitro Models to Assess the Toxicity of Tobacco Smoke
International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI)
Member, (2009-presentILSI/HESI Workgroup to develop the Pig-a assay as an in vivo genotoxicity test
Chair (2012-present) ILSI/HESI Workgroup to develop the Pig-a assay as an in vivo genotoxicity test
International Workgroup on Genotoxicity Testing
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 – Present
Leader (rappateur), Committee on the Pig-a In Vivo Gene Mutation Assay
2012 – 2015
Organization for Economic Cooperation and Development (OECD)
Member, OECD Working Group on TG487 (the In Vitro Micronucleus Assay Technical Guidance)
Member, OECD Working Group on Development of an In Vivo Transgenic Assay Guidance (TG488)
2008 – 2013
Member, OECD Working Group Revising Older genetic toxicology TGs
2011 – 2015
Member, OECD Working Group on Revising TG476 (the In Vitro Hprt Assay Guideline)
Chair, OECD Working Group on Developing an OECD TG for the Pig-a Assay
2015 – Present
1975 – Present
Publication titles are linked to text abstracts on PubMed.
The In Vivo Pig-a Assay: A Report of the International Workshop on Genotoxicity Testing (IWGT) Workgroup.
Gollapudi B., Lynch A., Heflich R., Dertinger S., Dobrovolsky V., Froetschl R., Horibata K., Kenyon M., Kimoto T., Lovell D., Stankowski L., White P., Witt K. and Tanir J.
Mutat Res. in press.
Quantitative Analysis of the Relative Mutagenicity of Five Chemical Constituents of Tobacco Smoke in the Mouse Lymphoma Assay.
Guo X., Heflich R., Dial S., Richter P., Moore M. and Mei N.
Mutagenesis. in press, PMID: 26001754.
New Approaches to Advance the Use of Genetic Toxicology Analyses for Human Health Risk Assessment.
Johnson G., Slob W., Doak S., Fellows M., Gollapudi B., Heflich R., Rees B., Soeteman-Hernandez L., Verma J., Wills J., Jenkins G. and White P.
Toxicol. Res. in press.
Derivation of Point of Departure (PoD) Estimates in Genetic Toxicology Studies and Their Potential Applications in Risk Assessment.
Johnson G., Soeteman-Hernandez L., Gollapudi B., Bodger O., Dearfield K., Heflich R., Hixon J., Lovell D., Macgregor J., Pottenger L., Thompson C., Abraham L., Thybaud V., Tanir J., Zeiger E., van Benthem J. and White P.
Environ Mol. Mutagenesis. 2014, 55: 609-623.
Quantitative Dose-Response Analysis of Ethyl Methanesulfonate Genotoxicity in Adult gpt-Delta Transgenic Mice.
Cao X., Mittelstaedt R., Pearce M., Allen B., Soeteman-Hernandez L., Johnson G., Bigger C. and Heflich R.
Environ. Mol. Mutagenesis. 2014, 55: 385-399.
In Vivo Assessment of Pig-a Gene Mutation – Recent Developments and Assay Validation.
Dertinger S. and Heflich R.
Environ. Mol. Mutagenesis. 2011, 52: 681-684.
International Pig-a Gene Mutation Assay Trial: Evaluation of Transferability Across Fourteen Laboratories.
Dertinger S., Phonethepswath S., Weller P., Nicolette J., Murray J., Sonders P., Vohr H., Shi J., Krsmanovic L., Gleason C., Custer L., Henwood A., Sweder K., Stankowski L., Roberts D., Giddings A., Kenny J., Lynch A., Defrain C., Nesslany F., van der Leede B., Van Doninck T., Schuermans A., Tanaka K., Hiwata Y., Tajima O., Wilde E., Elhajouji A., Gunther W., Thiffeault C., Shutsky T., Fiedler R., Kimoto T., Bhalli J., Heflich R. and MacGregor J.
Environ. Mol. Mutagenesis. 2011, 52: 690-698.
Monitoring Humans for Somatic Mutation in the Endogenous Pig-a Gene Using Red Blood Cells.
Dobrovolsky V., Elespuru R., Bigger C., Robinson T. and Heflich R.
Environ. Mol. Mutagenesis. 2011, 52: 784-794.
Manifestation of Pig-a Mutant Bone Marrow Erythroids and Peripheral Blood Erythrocytes in Mice Treated with N-Ethyl-N-Nitrosourea; Direct Sequencing of Pig-a cDNA from Cells. Negative for GPI-Anchored Protein Expression.
Kimoto T., Suzuki K., Kobayashi M., Dobrovolsky V., Heflich R., Miura D. and Kasahara Y.
Mutation Res. 2011, 723: 36-42.
The In Vivo Pig-a Gene Mutation Assay, A Potential Tool for Regulatory Safety Assessment.
Dobrovolsky V., Miura D., Heflich R. and Dertinger S.
Environ. Mol. Mutagenesis. 2010, 51: 825-835.
Accumulation and Persistence of Pig-A Mutant Peripheral Red Blooded Cells Following Treatment of Rats with Single and Split Doses of N-Ethyl-N-Nitrosourea.
Miura D., Dobrovolsky V., Kimoto T., Kasahara Y. and Heflich R.
Mutat. Res. 2009, 677: 86-92.
Development of an In Vivo Gene Mutation Assay Using the Endogenous Pig-A Gene; II. Selection of Pig-A Mutant Rat Spleen T-Cells with Proaerolysin and Sequencing Pig-A cDNA from the Mutants.
Miura D., Dobrovolsky V., Mittelstaedt R., Kasahara Y., Katsuura Y. and Heflich R.
Environ. Mol. Mutagenesis. 2008, 49: 622-630.
Development of an In Vivo Gene Mutation Assay Using the Endogenous Pig-A Gene; I. Flow Cytometric Detection of CD59-Negative Peripheral Red Blood Cells and CD48-egative Spleen T-Cells From the Rat.
Miura D., Dobrovolsky V., Kasahara Y., Katsuura Y. and Heflich R.
Environ. Mol. Mutagenesis. 2008, 49: 614-621.
Analysis of In Vivo Mutation Data Can Inform Cancer Risk Assessment.
Moore M., Heflich R., Haber L., Allen B., Shipp A. and Kodell R.
Reg. Pharmacol. Toxicol. 2008, 51: 151-161.
Contact information for all lab members:
ORISE Postdoctoral Research Associate
Roberta A. Mittelstaedt
- Contact Information
- Robert Heflich
ExpertiseApproachDomainTechnology & DisciplineToxicology