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The New Revolution in Toxicology: The Good, Bad and Ugly

The New Revolution in Toxicology: The Good, Bad and Ugly

Tuesday, October 4, 2011

The New York Academy of Sciences

Presented By


Protection of human safety is a primary objective of toxicology research and risk management. It is critical that the strategy and tools used to accomplish this are maximally capable to evaluate human risk. The toxicity testing strategy outlined in the 2007 US National Academy of Sciences report Toxicity Testing in the 21st Century: A Vision and a Strategy, involves four main components: chemical characterization, toxicity pathways and targeted testing, dose response and extrapolation modeling, and human exposure data. During this workshop we will discuss the magnitude of the challenge in achieving this vision as it may apply to pharmaceutical discovery and development. We will also review what has been achieved and the relevance of these achievements to safety assessment of new chemical entities intended for pharmaceutical use. Finally, we will discuss current applications of the strategy from the perspective of those in various sectors. A summary discussion will provide critical analysis that may serve as a roadmap for tailoring this highly visible strategy to a pharmaceutical environment.

Networking reception to follow.

Registration Pricing

Student / Postdoc / Fellow Member:$10
Student / Postdoc / Fellow Nonmember:$40
Nonmember Academic / Non-profit:$60
Nonmember Corporate:$80



* Presentation times are subject to change.

Tuesday, October 4, 2011

8:15 AM

Registration & Continental Breakfast

8:45 AM

Welcome & Opening Remarks
Jennifer S. Henry, PhD, The New York Academy of Sciences
Myrtle Davis Millin, DVM, PhD, The National Cancer Institute, NIH

Session 1: Reflections on the National Academy of Sciences Report of 2007

9:00 AM

Background to, and Writing of, the Original Report
Dan Krewski, MHA, MSc, University of Ottawa

9:30 AM

Implementing of the NAS Vision
Thomas Hartung, MD, PhD, Johns Hopkins Bloomberg School of Public Health

9:55 AM

The "Vision" for Toxicity Testing in the 21st Century (Tox21C): Promises, Challenges, and Progress
Michael P. Holsapple, PhD, Battelle Memorial Institute

10:20 AM

Mapping the Pathway to Legal Acceptance of Pathway-based Toxicological Data: How to Climb Mt. Krewski
E. Donald Elliott, JD, Yale Law School

10:45 AM

Coffee Break

Session 2: Key Differences and Challenges Between Safety and Risk Assessment, and the Impact on Use of in vitro Assays

11:15 AM

Predictive Toxicology at Abbott in Early Discovery: A Critical Review of Successes and Failures over an 8-year period
Eric Blomme, DVM, PhD, Abbott Laboratories

11:35 AM

Key Differences and Challenges between Safety Assessment and Risk Assessment and the Impact on the Use of in vitro Assays: Applications in Toxicology Support for Drug Development
Thomas W. Jones, PhD, Eli Lilly and Company

12:00 PM

Tox21 and ToxCast Chemical Landscapes: Laying the Foundation for 21st Century Toxicology
Ann M. Richard, PhD, US Environmental Protection Agency

12:20 PM

The Future of Toxicology in Drug Development
David Jacobson-Kram, PhD, DABT, Food and Drug Administration

12:40 PM

Summary of the Morning Presentations: Where to Next?
Moderator: Marla Weetall, PhD, PTC Therapeutics

1:00 PM


Session 3: Application of the Strategy and Development of the Tools

1:45 PM

Toxicity Testing in the 21st Century: A Toxicologic Pathology Perspective Using Testis Toxicity as an Example
Kim Boekelheide, MD, PhD, Brown University

2:10 PM

Approaches to Evaluate Injection Site Tolerability of Intravenous Formulations Prior to Testing in Humans
Gary Eichenbaum, PhD, Johnson & Johnson Pharmaceutical R&D, LLC

2:35 PM

Integrated Cell Signaling in Toxicology and Chemoprevention
Brad L. Upham, PhD, Michigan State University

3:00 PM

Idiosyncratic Hepatotoxicity: From Man to Mouse to Computer
Paul B. Watkins, MD, The Hamner Institutes for Health Sciences

3:25 PM

The Use of Stem Cell-Derived Tissues to Improve Drug Safety Assessment
Kyle L. Kolaja, PhD, Roche

3:45 PM

Application of Toxicogenomics and in vitro Assays for the Assessment of Chemical Sensitization Potential
Darrell R. Boverhof, PhD, The Dow Chemical Company

4:00 PM

Coffee Break

4:30 PM

Panel Discussion: "Are We Getting There?"
All speakers; Moderator: Raymond A. Kemper, PhD, DABT, Hoffman La Roche

5:00 PM

Networking Reception

6:00 PM




Raymond A. Kemper, PhD, DABT

Hoffmann La Roche

Dr. Ray Kemper received his bachelor's degree in Chemistry from the University of Louisville in 1991 and his Ph.D. in Toxicology from the same institution in 1995. He then went on to do postdoctoral training in the Dept. of Comparative Biosciences at the University of Wisconsin in Madison from 1995–1999. In 1999, Ray joined the Biochemical Toxicology group at DuPont Haskell Laboratory in Newark DE, where his work focused on comparative ADME and investigative toxicology. In 2003 joined the Discovery Toxicology group at DuPont and became involved in development of predictive models to support early ADME and toxicity screening. In 2005, Ray moved to Boehringer Ingelheim Pharmaceuticals in Ridgefield CT and established an Exploratory Toxicology group within Nonclinical Drug Safety to provide on early toxicology support for small molecule discovery programs. In 2011, Ray joined the Early and Investigative Safety section at Hoffman La Roche in Nutley, NJ as head of Mechanistic Safety–US. Ray is a Diplomate of the American Board of Toxicology and an active member of SOT, ISSX and ACS.

Mary McBride, PhD

Agilent Technologies

Dr. Mary McBride is the Director of Government Relations for Life Sciences and Chemical Analysis at Agilent Technologies. Her primary responsibilities are to identify and develop opportunities for Agilent to expand its business with government agencies, directly and through adoption of next-generation regulatory science. Before assuming her current role at Agilent, she led a strategic program within Agilent Laboratories to leverage and extend Agilent's capabilities into biological food testing. Before joining Agilent in 2007, Dr. McBride served as an Associate Division Leader for the Chemical and Biological National Security Program (CBNP) at Lawrence Livermore National Laboratory. There, she directed and managed the research and development activities of the Detection and Surveillance group within CBNP. Her teams developed and fielded advanced strategies to prepare for, detect and respond to biological terrorism. These technologies have been transitioned from basic research and proof of concept projects to demonstration and pilots, to operational systems with successful commercialization of multiple diagnostic and detection products. Dr. McBride earned a BS in Biochemistry in 1994, and a PhD. in Analytical Chemistry in 1998, both from the University of California, Davis. She has published more than 40 peer-reviewed papers and holds 5 patents related to biodetection instrumentation/assays. She has received an R&D 100 award and LLNL's highest scientific achievement award, the Laboratory S&T award. She lives in Virginia and enjoys hiking, cycling, golf, and yoga.

Myrtle Davis Millin, DVM, PhD

The National Cancer Institute, NIH

Myrtle Davis, DVM, PhD is the currently the Branch Chief for Toxicology and Pharmacology in the Developmental Therapeutics Program of the Division of Cancer Diagnostics and Treatment of the NCI. Her current responsibilities include serving as the Toxicology expert for project and program teams in drug discovery through first human dose, providing mechanistic toxicology expertise to teams, creating and leading major research initiatives within DTP and managing the daily operations of the Toxicology and Pharmacology Branch. Dr. Davis came to NIH from Lilly Research Labs, Eli Lilly and company where she held the position of Research Advisor in the Investigative Toxicology Group. At Lilly, she established cross-functional partnerships to achieve an early, data-driven focus on safety in development of kinase inhibitors as therapeutic agents. She also established a signal transduction laboratory and implemented strategies for pathway analysis and target evaluation resulting in elucidation of complex toxicology issues. Prior to taking the position at Eli Lilly, Dr. Davis was an Associate Professor in the Department of Pathology at the University of Maryland, School of Medicine where she had an active research program exploring mechanisms of toxicant-induced apoptosis and the role of protein phosphorylation. Dr. Davis earned a PhD in Toxicology from the University of Illinois Champaign-Urbana in and completed a post-doctoral fellowship in Toxicologic Pathology at the University of Maryland. She completed Undergraduate work in Chemistry and obtained her Doctor of Veterinary Medicine degree from Tuskegee University School of Veterinary Medicine.

Marla Weetall, PhD

PTC Therapeutics

Dr. Weetall has over 16 years of drug discovery and development experience in industry including extensive experience in designing, overseeing and analyzing experiments. Since joining PTC Therapeutics in 2002, Dr. Weetall has established and directs the pharmacology and pharmaceutical profiling group. The Pharmacology group is responsible for studies to verify the efficacy, non-GLP exploratory safety and DMPK studies for PTC’s discovery and development compounds in genetic disorders, oncology and infectious diseases. Prior to joining PTC, Dr. Weetall was at Novartis, where she participated from early discovery through development in multiple programs that led to the selection of development candidates. Dr. Weetall received her B.S. from Cornell University in biochemistry, her Ph.D. from Cornell University in biophysical chemistry and completed her post-doc at Roche Institute of Molecular Biology in Pharmacology. Dr. Weetall was the co-chair of NY Academy of Sciences Biochemical and Pharmacology Discussion Group Organizing Committee (2003-2008).

Jennifer Henry, PhD

The New York Academy of Sciences


Eric Blomme, DVM, PhD

Abbott Laboratories

Eric Blomme received his D.V.M. from The University of Lyon (France), studied Management at McGill University, and completed a residency in Veterinary Pathology at Cornell University and a PhD at Ohio State University. His areas of expertise include the development of new technologies, in particular genomics, for predictive toxicology and the preclinical safety assessment of new molecular entities using molecular toxicology, genetic toxicology and pathology. Eric joined Abbott in 2003. He is currently head of Investigative Toxicology and Pathology in Preclinical Safety and also oversees Cellular, Molecular and Exploratory Toxicology in Discovery. The role of these 2 groups is to provide predictive, mechanistic and regulatory toxicology data for compounds in discovery and development. In his prior positions at Monsanto/Searle and Pharmacia, Eric worked on various drug discovery and development projects. His publication record includes over 65 peer-reviewed manuscripts, several book chapters and a book (Genomics in Drug Discovery and Development, Wiley). Eric is editor or on the editorial board of several scientific journals.

Kim Boekelheide, MD, PhD

Brown University

Kim Boekelheide, MD, PhD, is Professor of Medical Sciences in the Department of Pathology and Laboratory Medicine at Brown University. He is Board Certified in Anatomic and Clinical Pathology, a past Councilor of the Society of Toxicology, a past member of the Board of Scientific Councilors of the National Toxicology Program, and currently a member of the NIEHS Board of Scientific Councilors. He was a member of the National Academy of Sciences committee that produced the 2007 report "Toxicity Testing in the 21st Century: A Vision and A Strategy." His research examines the biological effects of endocrine disrupting chemicals and mixtures of chemicals affecting the developing and adult male reproductive tract. He directs both the Brown University Superfund Research Program and the Brown University Center for the Evaluation of Environmental Impacts on Fetal Development.

Darrell R. Boverhof, PhD

The Dow Chemical Company

Dr. Boverhof is a Senior Toxicology Specialist with The Dow Chemical Company's Toxicology & Environmental Research and Consulting (TERC) group in Midland, MI. He earned a B.Sc. degree in Biomedical Toxicology from the University of Guelph, Canada, and a PhD in Biochemistry/Toxicology from Michigan State University. Prior to his graduate work, he was employed as a Toxicologist with Health Canada where he was involved the categorization and evaluation of chemicals on the Canadian Domestic Substances List. Dr. Boverhof joined Dow in 2006 and is responsible for testing, research, and consulting in the areas of immunotoxicology, respiratory allergy and sensitization, nanotoxicology and toxicogenomics. Dr. Boverhof also serves as a Councilor for the Michigan Society of Toxicology, on the Medical Committee for the Elsa U. Pardee Foundation, and on the Editorial Board for Toxicological Sciences. He has authored/coauthored over 25 peer reviewed research publications, review articles, and book chapters in the area of toxicology and toxicogenomics in addition to recently co-editing a book on the application of toxicogenomics to risk assessment.

Gary Eichenbaum, PhD

Johnson & Johnson Pharmaceutical R&D, LLC

Dr. Eichenbaum joined Johnson & Johnson Pharmaceutical R&D, LLC (J&J) in 2002. He is a Preclinical Development Leader/Research Fellow in the department of Drug Safety Sciences. He serves on cross-functional compound development teams and is responsible for directing the DMPK and Toxicology research for early and late development programs including the conduct of studies, writing and filing of regulatory submissions and performing due diligence on in-licensing candidates. Previous roles within J&J have included: head of the US toxicokinetics group and head of a research team at ALZA that was focused on the application of controlled-release drug delivery technologies to differentiate, rescue or reposition NME's. Prior to joining J&J, Dr. Eichenbaum co-founded and was on the senior leadership team of a small biotechnology company called ChemCodes Inc. (spin-out from GlaxoWellcome), which applied its high-throughput chemistry platform to the discovery and development of NME candidates. His primary scientific interests include safety assessment, pharmacokinetics, elucidation of mechanisms of toxicity, and drug delivery. Dr. Eichenbaum has authored more than 25 publications/patent applications. He holds a BS in Bioengineering from the University of Pennsylvania, a BS in Technology Management from the Wharton School, and MS and PhD degrees in Biomaterials/Cell and Biosurface Engineering from Duke University.

E. Donald Elliott, JD

Yale Law School

E. Donald Elliott, a lawyer, is a leading academic expert on improving the relationship between law and science, specializing in environmental law and chemical regulation. He has written and spoken widely legal acceptance of pathway-based toxicology, including at the National Academy Symposium, the Environmental Law Institute, ILSI’s Risk21 workshop and the Universities of Chicago and Ottawa. Elliott is currently Professor (Adjunct) of Law, Yale Law School and Georgetown University Law Center, where he teaches a course comparing chemical regulation in the U.S. and EU. He has been on the Yale Law School faculty since 1981, and is the author of over 70 articles and the author or co-author of 7 books. He teaches in the fields of environmental law, administrative law and law and science. From 2003-2009, he was a member of the Board of Environmental Studies and Toxicology, National Research Council, the board of the Academy under whose auspices the Tox21 report was done. Elliott also practices law and heads the Environment, Health and Safety department worldwide of 600- lawyer international law firm, Willkie Farr & Gallagher LLP and is a partner in its DC office. Formerly Elliott was Assistant Administrator and General Counsel, U.S. Environmental Protection Agency, 1989-1991. In 1993, he was named to the first endowed chair in environmental law and policy at any major American law school. the Julien and Virginia Cornell Chair in Environmental Law and Litigation at Yale Law School, Elliott has served as a consultant on improving the relationship of law and science to the Federal Courts Study Committee, which was chartered by Congress to make recommendations for improving the federal courts, and to the Carnegie Commission for Law, Science and Government. He co-chaired the National Environmental Policy Institute’s Committee on improving science at EPA. He serves on the boards of the Environmental Law Institute and the Center for Clean Air Policy. In 1991, the National Law Journal named him as one of the country’s top 25 environmental lawyers and he is listed in Chambers USA: Leading Lawyers for Business, Best Lawyers in America, DC Superlawyers, Who’s Who in American Law, and Who’s Who in the World. Elliott graduated B.A. (1970) summa cum laude and J.D. (first in class; 1974), from Yale University. Following graduation he was a law clerk for Gerhard Gesell in the U.S. District Court for the District of Columbia, and for Chief Judge David Bazelon of the U.S. Court of Appeals for the District of Columbia Circuit.

Thomas Hartung, MD, PhD

Johns Hopkins Bloomberg School of Public Health

Thomas Hartung, MD, PhD, (Toxicology and Biochemical Pharmacology, respectively) has studied Biochemistry, Medicine and Mathematics / Informatics in Germany at the Universities of Cologne, Hagen, Tübingen, Freiburg and Konstanz. In 2002 he became Head of the European Centre for the Validation of Alternative Methods, at the EU Joint Research Center (JRC) in Italy. In 2003 he was appointed full professor of the University of Konstanz, Germany, for Pharmacology and Toxicology. Since 2009, he is endowed chair (Doerenkamp-Zbinden Foundation) for Evidence-based Toxicology, Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, USA, and director of their Center for Alternatives to Animal Testing. In 2010, he received a joint appointment for Molecular Microbiology and Immunology at this institution. He has authored more than 350 publications.

Michael P. Holsapple, PhD, ATS

Battelle Memorial Institute

Dr. Holsapple is a toxicologist with over 30 years of experience. He received his graduate training in Pharmacology and Toxicology from Purdue University, having earned an MS in 1978 and a PhD in 1981. From 1983–1994, he served on the faculty at the Medical College of Virginia/Virginia Commonwealth University in Richmond, VA. During his academic career, he served as the advisor for 8 PhD and MS candidates, and as a member of the doctoral dissertation committees for 21 other students. From 1994–2002, Dr. Holsapple worked in the Toxicology, Environmental Research and Consulting Laboratories at the Dow Chemical Company in Midland, MI. During his industry career, his responsibilities included leading both the Immunotoxicology and the Respiratory Toxicology groups. From 2002 to 2011, Dr. Holsapple served as the Executive Director of the Health and Environmental Sciences Institute (HESI), the global branch of the International Life Sciences Institute (ILSI) in Washington, DC. During his time with HESI, Dr. Holsapple facilitated the organization's emergence as a recognized global leader in advancing the state-of-the-science of safety and risk assessment. Dr. Holsapple joined the Battelle Memorial Institute in Columbus, OH, as a Senior Research Leader in systems toxicology on August 1, 2011. Dr. Holsapple has published over one hundred and fifty manuscripts and chapters. In recognition of his contributions to toxicology, Dr. Holsapple received the Society of Toxicology (SOT) Achievement Award in 1992. In recognition for his contributions to immunotoxicology, he received the Vos Award–Career Achievement in Immunotoxicology in 2009. Dr. Holsapple served on Council for the SOT from 2005–2007, and on Council for the American College of Toxicology (ACT) from 2003–2006. He was elected a 'fellow' in the Academy of Toxicological Sciences (ATS) in 2006. Dr. Holsapple was elected into the Presidential track of the SOT in 2008, presided over the organization's 50th annual meeting in 2011, and is presently serving as the Society's Past President.

David Jacobson-Kram, PhD, DABT

Food and Drug Administration

David Jacobson-Kram received his PhD in embryology from the University of Connecticut. After receiving his degree, Dr. Jacobson-Kram served as a staff fellow and then a senior staff fellow at the National Institute on Aging. After leaving N.I.H., Dr. Jacobson-Kram joined the faculty of George Washington University School of Medicine and then later, Johns Hopkins University Oncology Center. During this same period he served, on a part-time basis, as a geneticist in the Office of Toxic Substances at the Environmental Protection Agency and as Acting Branch Chief in EPA's Office of Research and Development. Dr. Jacobson-Kram served as the VP of the Toxicology and Laboratory Animal Health Division at BioReliance Corporation, a contract testing laboratory from 1988 until 2003. Currently, he serves as the Associate Director of Pharmacology and Toxicology in FDA's Office of New Drugs. Over the past twenty years he has served as principal and co-principal investigator on several NIH. grants and government contracts and published widely in the areas of genetic and molecular toxicology. Dr. Jacobson-Kram has served as council member, treasurer and chairman of the Genetic Toxicology Association, executive council member to the Environmental Mutagen Society, Editor of Cell Biology and Toxicology, and as a member of NIH. special study sections. In 1996 he became a Diplomate of the American Board of Toxicology (DABT).

Thomas W. Jones, PhD

Eli Lilly and Company

Dr. Jones received his PhD in Experimental Pathology from the University of Maryland in 1983 and completed a two year post-doctoral fellowship in the Department of Toxicology at the Karolinska Institute in Stockholm, Sweden. He joined the University of Maryland School of Medicine as Assistant Professor of Pathology in 1985. He rose to the rank of Associate Professor and was one of the founding members of the University of Maryland Toxicology Program. While at the University of Maryland, his laboratory received major funding support from the American Cancer Society and the National Institutes of Health. Dr. Jones joined Eli Lilly and Co. in 1991 as a Research Scientist in the Department of Investigative Toxicology. In addition to his responsibility for the Nephrotoxicology Laboratory, Dr. Jones also served as the toxicologist for several project teams at different stages of development. He entered the management ranks as Head of Investigative and Lead Optimization Toxicology. In this role he was responsible for developing and implementing a strategy by which Toxicology partnered with the Drug Discovery organization. In 2002, Dr. Jones was promoted to Director; Lead Optimization Toxicology. Since then, his administrative roles and responsibilities have expanded to his current assignment as Senior Director, Toxicology and Pathology. Dr. Jones has served on a number of key Lilly Research Laboratories portfolio governance committees.

Kyle L. Kolaja, PhD


Kyle Kolaja is currently the Director and Global Head of Predictive Toxicology Screens and Investigative Toxicology–US within Nonclinical Safety at Roche. In this role, he provides leadership and strategic direction for the several laboratories including those that conduct all early safety screening assays, provide mechanistic/investigative toxicology support for the projects based in the US and the laboratory focused on applications of stem cells and stem cell-derived tissues. In addition, Dr Kolaja and senior scientific staff in this group provide toxicology representation on discovery project teams. Previously, Dr. Kolaja was the Director of Discovery and Investigative Safety in NCS at Roche–Palo Alto. Prior to joining Roche, Dr. Kolaja was Vice President of Chemogenomics and Toxicology at Iconix Pharmaceuticals, a company which developed and commercialized a large in vivo and in vitro toxicogenomic reference database. At Iconix, Dr Kolaja led the group of scientists responsible for the conduct and interpretation of mechanistic collaborative studies with over 20 pharmaceutical companies as well as the EPA and FDA. Prior to Iconix, Kyle was at Pharmacia Corp. (formerly Searle) where he was a project/platform toxicologist supporting discovery and development projects. He also was the leader of the investigative toxicology group at Skokie and the site director for the laboratory responsible for toxicogenomics. Dr. Kolaja was previously the President of the Drug Discovery Toxicology Specialty Section for the Society of Toxicology, recently named Fellow of the Academy of Toxicological Sciences, and is currently on the Board of Directors for the American Boards of Toxicology. Dr. Kolaja has nearly 60 peer-reviewed publications and reviews, received his BS from Michigan State University and his PhD in Toxicology from Indiana University (mentor James Klaunig) and conducted his post-doctoral research at the University of Kansas (mentor Curt Klaassen).

Daniel Krewski, MHA, MSc

University of Ottawa

Dr. Daniel Krewski is currently Scientific Director of the McLaughlin Centre for Population Health Risk Assessment at the University of Ottawa and holds a Natural Sciences and Engineering Research Council (NSERC) of Canada Industrial Research Chair in Risk Science. Since 2008, Dr. Krewski has also served as Associate Scientific Director for PrioNet Canada, a Network of Centres of Excellence involving 15 Canadian universities, investigating the health risks of prion diseases such as bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD).

Dr. Krewski is also President and CEO of Risk Sciences International Inc. since 2007; Director of the Network for Environmental Risk Assessment and Management (NERAM–Ottawa node) since 2000; Director of the Graduate Certificate in Population Health Risk Assessment and Management, Institute of Population Health since 2004; Adjunct Research Professor of Statistics in the Department of Mathematics and Statistics at Carleton University since 1984. While with Health Canada, he also served as Acting Director of the Bureau of Chemical Hazards and as Chief of the Biostatistics Division in the Environmental Health Directorate. Dr. Krewski is also the principal investigator of a multi-centre project involving 5 universities in the National Population Health Study of Neurological Conditions funded by the Public Health Agency of Canada (PHAC).

Dr. Krewski obtained his PhD in statistics from Carleton University and subsequently completed his MHA at the University of Ottawa. He is internationally known for his research on environmental determinants of health, has contributed to 160 peer-reviewed scientific papers, served as principal or co-investigator on 59 externally funded grants/contracts, and mentored 31 trainees (25 pre-doctoral and 6 post-doctoral) in the last five years. Dr. Krewski has published over 600 articles in scientific and technical reviews; he has also authored or directed the publication of six books to date.

Ann M. Richard, PhD

US Environmental Protection Agency

Dr. Richard obtained her PhD from the U NC–Chapel Hill in Theoretical Physical Chemistry in 1983. She has worked within EPA's Office of Research & Development for her entire career, originally in the National Health & Environmental Effects Lab and, since its inception in 2005, in EPA's National Center for Computational Toxicology. Her research activities have ranged from the application of computational chemistry and structure-activity relationship (SAR) methods to problems in environmental toxicology to, more recently, development of cheminformatics capabilities in support of predictive toxicology. Within NCCT, she is lead for the DSSTox project and provides primary chemical library design and information management for the ToxCast and Tox21 projects. Her current research is focused on developing a cheminformatics foundation and new strategies for integrating SAR capabilities with high-throughput screening data in predictive toxicology.

Brad L. Upham, PhD

Michigan State University

Dr. Upham is an associate in the Department of Pediatrics & Human Development, and the Food Safety and Toxicology Center at Michigan State University (MSU). His laboratory conducts basic cell biology experiments determining the underlying signaling mechanisms involved in epigenetic responses of cells to oncogenes, environmental contaminants and food borne toxicants, and how chemopreventive plant products interact with these signaling pathways in blocking the promoting effects of environmental toxicants. He has received federal grants from the National Institute of Environmental Health Sciences (NIEHS) to support his research program at MSU, and has mentored a number of post-doctoral fellows and trained numerous international scholars. He has served in elected positions as President and Councilor for the Michigan Chapter of the Society of Toxicology, Co-chair of the "In Vitro Animal Cell Section" of the Society of In Vitro Biology (SIVB) and is a recent recipient of a "Distinguished Service Award" from SIVB. Other professional activities also include service on the editorial boards for the Journal of Toxicology and the Journal of Biomedicine and Biotechnology and as ad hoc reviewer for several NIEHS study sections for P30 Environmental Health Centers, T32, K99/R00 & K01 training/mentor grants, and center applications for "Children's Environmental Health & Disease Prevention" and "Formative Centers for Children's Environmental Health & Disease Prevention," reviewed grants for New Zealand Health Research Council, and University of New Hampshire Agricultural Experiment Station, and frequently reviews papers for numerous journals in toxicology and human health. He has authored 58 peer-reviewed scientific journal articles, 137 abstracts, and one US patent. Dr. Upham's research is currently using proteomic, lipidomic and transcriptomic approaches to further map out novel signaling pathways involved in controlling cell proliferation, apoptosis and differentiation using in vitro cell systems and has been developing oncogene-specific in vitro / in vivo rodent model systems.

Paul B. Watkins, MD

The Hamner Institutes for Health Sciences

Dr. Paul B. Watkins is the Verne S. Caviness Distinguished Professor of Medicine, and also Professor of Pharmacology and Experimental Therapeutics, and Professor of Toxicology at the University of North Carolina in Chapel Hill (UNC–CH). He attended medical school at Cornell and completed his residency in internal medicine at New York Hospital–Cornell Medical Center. He received subspecialty training in hepatology at the Medical College of Virginia. He was on faculty at the University of Michigan from 1986-1999 when he moved to North Carolina. There he became the Director of the General Clinical Research center and more recently director of the UNC Translational and Clinical Sciences (TraCS) Institute. In June of 2009, he became the director of a new Institute for Drug Safety Sciences which represents a collaboration between UNC–CH and The Hamner Institutes. The Hamner Institutes is a not-for-profit organization based in Research Triangle Park. It was formerly called the Chemical Institute for Industrial Toxicology (CIIT) and has a three decade history of leading research into the health effects of environmental chemicals. Dr. Watkins is an accomplished basic and translational investigator in the fields of drug metabolism and hepatotoxicity. He is one of the most frequently cited authors in the field of pharmacology according to He serves as the chair of both the Steering and Genetics Committees for the national Drug Induced Liver Injury Network (DILIN) (U01DK065201).


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Implementing the NAS Vision
Thomas Hartung, MD, PhD, Johns Hopkins Bloomberg School of Public Health

Safety assessment of drugs and chemicals is largely based on 40 to 80 years old animal tests, which do not meet our needs for throughput, cost efficiency and predictivity of humans. The 2007 vision document of the NAS/NRC Toxicity Testing in the 21st Century: a Vision and a Strategy has created an atmosphere of departure in toxicology to embrace novel concepts based on mechanism, the pathways of toxicity (PoT). Omics technologies represent the prime opportunity to identify PoT, ultimately to map the Human Toxome, the entirety of PoT. This requires novel concepts, how to identify, annotate, share and validate PoT. A pilot project “Mapping the Human Toxome by Systems Toxicology” is under way in the NIH Director’s Transformative Research Projects Program, focusing on endocrine disruption. Similar parallel work addresses developmental neurotoxicity. These initiatives could be the start of a Human Toxicology Project, ultimately developing PoT-based assays for high-throughput testing. A critical element for such developments is objective quality control, both of current practices and the novel approaches. Traditional validation of alternative methods has limitations as to duration, costs and also to accommodate change since the traditional animal test usually serves as point of reference. The role model of evidence-based medicine has been proposed, creating an evidence-based toxicology (EBT). The EBT collaboration was formed in 2011 to shape such a process.

The "Vision" for Toxicity Testing in the 21st Century (Tox21C): Promises, Challenges, and Progress
Michael P. Holsapple, PhD, ATS, Battelle Memorial Institute

Many of the methodologies routinely used today in the traditional approach to toxicity testing originated in the 1960s and 1970s and are based on high-dose studies in a variety of animal species. Besides the need for large numbers of animals, the current approach is expensive and time-consuming. Moreover, when the test results are used for human risk assessment, there are formidable challenges associated with dose and species extrapolation and with the application of uncertainty factors. As noted by Dr. Margaret Hamburg, Commissioner of the FDA, "We must bring 21st-century approaches to 21st-century products and problems. Toxicology is a prime example." Something had to change. In June of 2007, the NAS Committee released a report that outlines a new vision and strategy for toxicity testing in the 21st century that would be based primarily on human biology instead of animal biology and would require anywhere between substantially fewer animals and virtually no animals. The vision would be based on measuring perturbations of toxicity pathways as opposed to changes in apical end points and would thus make far greater use of advances in mechanistic studies. Finally, because the vision would be based on high-throughput in vitro and in silico screens, a much broader range of doses could be characterized. There are clear promises and challenges associated with the vision for Tox21C. Among the promises is the recognition that components of this vision are natural extensions of the evolution of toxicology science, including the desire to integrate state-of-the-art mechanistic, modeling, and risk assessment approaches. Among the challenges are components of the long-standing debate associated with a reliance on cell-based systems and in vitro methods, including the role of metabolism, the ability to extrapolate in vitro concentrations to relevant in vivo doses, and the ability to understand organ interactions. While there are many topics and issues of interest to toxicologists, there are only a few that have the potential to have as great an impact on the science of toxicology as the vision for Tox21C. As such, it can be debated as to whether the NAS Report was indeed a skirmish in the "New Revolution in Toxicology." The goal of this presentation is to highlight some of the promises and challenges of Tox21C and to provide a brief overview of some of the progress within the scientific community to implement the vision for Tox21C.

Mapping the Pathway to Legal Acceptance of Pathway-based Toxicological Data: How to Climb Mt. Krewski
E. Donald Elliott, JD, Yale Law School

Our legal system, based in part of judicial precedent by generalist judges, tends to be conservative in allowing new scientific paradigms and techniques to be accepted in court.There is no single legal standard that pathway-based (non-apical) data must satisfy; legal hurdles differ in different contexts. Standards for legal acceptance of emerging scientific information by courts of general jurisdiction with lay juries are higher while administrative agencieshave more discretion. Judges act as “gatekeepers” to keep new scientific information from reaching juries until it has been shown to be “reliable” and “applicable” (the so-called Daubert rule, after the Supreme Court case that created it). Administrative agencies, on the other hand, are considered experts and may consider emerging scientific information along with other information provided that their final decisions are supported by “substantial evidence on the record as a whole.” Non-expert judges in reviewing courts do not rule on the admissibility of individual piece of evidence before administrative agencies. Therefore, agencies have broad discretion to consider pathway-based toxicological information along with other evidence in making weight of the evidence determinations, and have already begun to do so. For example, in approving chemical dispersants for use against the Deep Water Horizon oil spill, EPA relied in part on pathway-based testing. In general, the legal system is more lenient in accepting new information where the costs of a false positive or false negative are relatively low. Broader acceptance of pathway-based toxicology in contexts where the stakes are higher (such a approving a new drug or banning a pesticide) will depend on developing side-by-side comparisons to the predictive value of traditional data.

Predictive Toxicology at Abbott in Early Discovery: A Critical Review of Successes and Failures Over an 8-year Period
Eric Blomme, DVM, PhD, DACVP, Abbott Laboratories

Predicting toxicity and finding development candidates with an appropriate safety profile remains a major challenge in drug discovery and development. Multiple new approaches and technologies have been proposed over the years to improve toxicity prediction and characterization. Some of those have definitely shown utility; others have not. This presentation will review our experience at Abbott over the last eight years, using examples to illustrate the strengths, weaknesses, limitations, and optimal application of these technologies during lead optimization and candidate selection. We will also discuss several recent promising additions to the toxicologist's toolbox and some key challenges facing toxicologists in the pharmaceutical industry in the near future.

Key Differences and Challenges between Safety Assessment and Risk Assessment and the Impact on the Use of in vitro Assays: Applications in Toxicology Support for Drug Development
Thomas W. Jones, PhD, Eli Lilly and Company

The 2007 report from the National Research Council entitled Toxicity Testing in the 21st Century: a Vision and a Strategy was published with the goal of "mobilizing the scientific community and marshalling scientific resources to initiate and sustain new approaches ... to toxicity testing." The report proposes a vision of transforming toxicity-testing through the development and adoption of new approaches which capitalize upon recent advances in our understanding of human biology. The realization of this vision will depend upon defining a series of toxicity pathways (i.e., cytotoxicity, cell proliferation, apoptosis, etc.) that can be monitored using medium- to high-throughput in vitro test systems—preferably based on human cells, cell lines, or tissues—and which will provide a sufficiently comprehensive characterization of human risk to reduce or eliminate the use of the apical endpoints currently collected through in vivo animal testing. It is acknowledged that an extraordinary amount of effort will be needed to (1) determine the most informative set of toxicity pathways; (2) develop, validate, and implement the appropriate test systems; (3) create the necessary data management and computational tools; and (4) define how regulatory decision making will be adjusted to utilize these new data. While the report, sponsored by the U.S. Environmental Protection Agency, primarily focuses on the challenges of identifying, assessing, and managing the risks associated with human exposure to chemical agents found in the environment, there is passing reference to the potential of applying this revolutionary approach to toxicity testing in other applications, including pharmaceutical research and development. While the report stops short of recommending expanding the testing requirements for pharmaceuticals, interest in extending the Tox21 testing principles in that direction has clearly grown over the last several years. However, there has been limited discussion regarding the inherent differences in how toxicity testing is applied to enable human pharmaceutical development compared with that used to support environmental decision making. It would seem that further consideration of how these differences might affect choices of appropriate test systems and how those systems would be applied in practice is warranted. The purpose of this presentation will be to provide a brief overview of the current testing paradigm used to support global drug development activities, to highlight the role that in vitro test systems currently play, as well as discuss the opportunities and challenges associated with the development and implementation of in vitro human cell-based alternatives to current in vivo animal testing models.

Tox21 and ToxCast Chemical Landscapes: Laying the Foundation for 21st Century Toxicology
Ann M. Richard, PhD, U.S. Environmental Protection Agency

The U.S. Environmental Protection Agency's ToxCast project and the related, multi-Agency Tox21 project are employing high-throughput technologies to screen hundreds to thousands of chemicals in hundreds of assays, probing a wide diversity of biological targets, pathways and mechanisms for use in predicting in vivo toxicity. The ToxCast chemical library consists of 960 unique chemicals (including Phase I and II) and was constructed to span a diverse range of chemical structures and use categories. This library is fully incorporated into EPA's approximately 4000 chemical contribution to the larger, more diverse Tox21 chemical library (totaling 10K). These chemical libraries represent central pillars of the ToxCast and Tox21 projects and are unprecedented in their scope, structural diversity, multiple use-scenarios (pesticides, industrial, food-use, drugs, etc.), and chemical feature characteristics in relation to toxicology. Chemical databases built to support these efforts consist of high quality DSSTox chemical structures and generic substance descriptions linked to curated test sample information (supplier, lot, batch, water content, analytical QC). Cheminformatics, feature and property profiling, and a priori and interactive categorization of these libraries in relation to biological activity will serve as essential components of toxicity prediction strategies.
Abstract does not represent EPA policy.

The Future of Toxicology in Drug Development
David Jacobson-Kram, PhD, DABT, U.S. Food and Drug Administration

Toxicology testing serves several important needs in drug development. In the earliest stages, toxicology data are used to determine the maximum recommended doses for first-in-man phase 1 studies. This information can also help to identify potential toxicities and can also specify maximum stopping doses. Toxicology studies can also identify certain risks that cannot be studied in clinical trials: potential for genetic damage (genotoxicity), carcinogenicity, teratogenicity, and risks from long term exposures. In vitro studies have been useful in identifying hazards; for example, the Ames assay provides information on whether a drug candidate can induce gene mutations, and the hERG assay is useful in determining if a candidate pharmaceutical has potential for QT-interval prolongation. While hazard assessment is an important aspect in drug development, ultimately hazards must be linked to exposures in order to quantify risks. Use of in vitro assays in risk assessment is challenging primarily because of the difficulty in modeling adsorption, distribution, metabolism, and excretion (ADME). While not insurmountable, use of in vitro assays for all aspects of drug development will require new methods and better understanding of ADME processes.

Toxicity Testing in the 21st Century: A Toxicologic Pathology Perspective Using Testis Toxicity as an Example
Kim Boekelheide, MD, PhD, Brown University

There is a growing international movement to take advantage of the ongoing revolution in biology to revise longstanding approaches to toxicity testing and risk assessment of environmental chemicals, pharmaceuticals, and consumer products. At its core, this new approach will measure changes in human cells in vitro to develop a mechanistic understanding of chemically-induced alterations in the function of biological pathways. Computational systems biology models fitted to dose-response data will be used to extrapolate from in vitro effects to in vivo responses during the risk assessment process.
The European Union has been a leader in advancing alternative testing strategies through legislative action and by funding the development of new testing paradigms. Two examples of European-based initiatives will be reviewed. In the first example, a group from Unilever in the United Kingdom in 2004 conceptualized a new testing approach entitled Assuring Safety without Animal Testing (ASAT). The ASAT Initiative sought to tie together how human disease processes are identified in the clinic and the development of human relevant in vitro mechanistic data, bypassing the current need for toxicity testing in animals. In the second example, a consortium of European investigators developed an in vitro based testing system for reproduction and development call ReProtect. The strengths and weaknesses of the ASAT Initiative and ReProtect will be discussed.
The remainder of the presentation will be focused on the current limitations and possible paths forward for detecting toxicant-induced effects in the testis. Current approaches to understanding the etiology of human male infertility are limited by reliance on traditional measures of effect, including hormones and semen parameters, which are insensitive, highly variable, and lack diagnostic specificity. Animal models of interactions of xenobiotics with testicular function are limited by uncertainties about their relevance to humans. In vitro approaches to evaluating testicular function have so far been limited by the inability to recapitulate spermatogenesis, a complex process unique to the testis. The results of a recent 2-day workshop focused on revolutionizing testis testing approaches will be reviewed, including the main recommendation to design a functioning "testis in a petri dish" capable of spermatogenesis.
The presentation will end with a broad view of approaches to developing the in vitro tests of the future. A combination of unbiased testing with pathway-specific expert-driven testing is likely to yield the most complete toxicity assessment capability.

Approaches to Evaluate Injection Site Tolerability of Intravenous Formulations Prior to Testing in Humans
Gary Eichenbaum, PhD, Johnson & Johnson Pharmaceutical R&D, LLC

Prior to administering an intravenous drug formulation in humans for the first time, it is necessary to evaluate its vascular irritation potential in nonclinical models so that the potential for clinical infusion site reactions can be identified and prevented. If an intravenous formulation causes severe injection site reactions, these adverse effects may pose significant challenges for both the nonclinical safety assessment of systemic toxicity as well as the clinical development and use of the compound. The extent to which infusion site reactions may limit further development depends in part on the severity and root cause of the adverse effects, as well as the dose/concentration response and the margin of safety. This talk will focus on in vitro and in vivo nonclinical strategies/models for developing, evaluating and optimizing intravenous formulations of compounds that have the potential to cause local toxicity following injection.

Integrated Cell Signaling in Toxicology and Chemoprevention
Brad L. Upham, PhD, Michigan State University

Many human diseases, such as cancer, is a consequence of aberrant development of tissues in which the transition of adult stem cells into their appropriate differentiated cell type lineages and designated niches within a tissue has been interrupted by either genetic or epigenetic events. These molecular events often result in dysfunctional tissues or as in the case of cancer, the development of tumors that bypass all normal cybernetic control mechanisms. These control mechanisms require homeostatic-regulated gene expression through highly coordinated networks of extracellular, intercellular and intracellular signaling events within and between the cells of a tissue. We propose a hypothesis that gap junction intercellular channels are critical in modulating the levels of low molecular weight second messengers needed in the transduction of an external signal to the nucleus in the expression of genes needed for the normal maintenance of a tissue. Thus, any comprehensive-systems biology approach to understanding the role of signaling in toxicology must also include gap junctions, in which aberrant gap junctions have been clearly implicated in many human diseases.

Idiosyncratic Hepatotoxicity: From Man to Mouse to Computer
Paul B. Watkins, MD, Hamner University of North Carolina Institute for Drug Safety Sciences

Drug Induced Liver Injury (DILI) remains the major adverse drug event that leads to termination of clinical development programs and regulatory actions including failure to approve for marketing, restricted indications, and withdrawal from the marketplace. The type of DILI that is most problematic is "idiosyncratic," meaning that only a very small fraction of treated patients are susceptible to the DILI. Current preclinical models, even "humanized" ones, do not reliably identify molecules that have this liability and, conversely, predict liabilities in molecule that are, in fact, quite safe for the liver. Reliable preclinical testing will probably not be developed until there is greater understanding of the mechanisms underlying idiosyncratic DILI. Based on the belief that the best models to study DILI are the people who have actually experienced it, there are two major efforts underway to create registries and tissue banks from these rare individuals: the Severe Adverse Events Consortium supported by industry and the Drug Induced Liver Injury Network supported by the National Institutes of Health. Genome wide association analyses and whole exome/whole genome sequencing of certain DILI cases is well underway and appear promising. However, it has become clear that preclinical experimental approaches are also needed to both provide biological plausibility for associations observed and to generate specific hypotheses that can be tested with the genetic data. Approaches underway include chemoinformatic analysis of implicated drugs, identification of pathways perturbed by these drugs in primary human hepatocytes and more organotypic cultures, and use of panels of inbred mice. DILIsim is a new public–private initiative to create a MATLAB-based computer model to synthesize the rapidly accumulating data to ultiimately predict DILI liability in drug candidates. This collaboration involves the Food and Drug Administration, pharmaceutical companies, and our institute. The model has already organized a large amount of data and clarified important gaps in knowledge to additional experimentation.

The Use of Stem Cell-Derived Tissues to Improve Drug Safety Assessment
Kyle Kolaja, PhD, DABT, ATS, Roche

Safety-related attrition is a major concern for pharmaceutical companies, yet organ toxicities are often not assessed until later in development. One possible means to bridge this gap is through the use of human pluripotent stem cell-derived tissues, which afford improved cellular systems that replicate the critical functional aspects of intact tissues. The combination of stem cell-derived tissues with small-scale assays can ensure these models are amenable to high-throughput, low compound usage assays, and thus have utility in drug discovery toxicology. Our work has focused on stem cell-derived cardiomyocytes, characterizing these cells genomically and functionally as a novel model of pro-arrhythmia prediction.

Application of Toxicogenomics and in vitro Assays for the Assessment of Chemical Sensitization Potential
Darrell R. Boverhof, PhD, The Dow Chemical Company

Advances in molecular and cellar biology are expected to provide tools to modernize our approaches for chemical hazard assessment. We have been researching the application of toxicogenomics and in vitro assays for assessing the sensitization potential of chemicals. Determination of the skin sensitization potential of industrial chemicals, agrochemicals and cosmetics is crucial for defining their safe handling and use. The mouse local lymph node assay (LLNA) has emerged as the preferred assay for this evaluation; however, the assay has certain limitations including the use of radioactivity, poor specificity with certain chemistries (false positives) and the inability to distinguish between different classes of sensitizers, namely skin and respiratory sensitizers. To address these limitations, we have researched the application of toxicogenomics to the LLNA to provide enhanced endpoints for the assessment of chemical sensitization potential. In addition, extensive research efforts have been applied to develop in vitro assays for predicting skin sensitization potential. These assays have built upon our current understanding of the molecular and cellular events involved in the acquisition of sensitization and are showing promise for providing non-animal alternatives for characterization of skin sensitizing chemicals. This presentation will discuss both the promises and challenges of applying toxicogenomics and in vitro technologies for the assessment chemical sensitization potential.

* Additional abstracts forthcoming.

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