American College of Toxicology 31st Annual Meeting · Web viewAmerican College of Toxicology 32nd...

AMERICAN COLLEGE OF TOXICOLOGY

32ND ANNUAL MEETING

November 6-9, 2011

Arizona Biltmore Resort & Spa2400 E. MissouriPhoenix, AZ 85016

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TABLE OF CONTENTSTable of Contents iGeneral Information viProgram-at-a-Glance viiiSUNDAY, November 6, 2011 1

Schedule of Events 1

Continuing Education Courses 2Study Director Training........................................................................................................................................2Nonclinical ADME in Safety Assessment..............................................................................................................3Biomarkers in Nonclinical Toxicology..................................................................................................................4The Changing Role of the Toxicologist in Today’s Pharma: In-Licensing, Ad-comms and Trends in the CROs.....5Clinical Pathology For The Toxicologist – Looking Beyond the Asterisks..............................................................6Study Monitoring at CROs. Keeping Your Sanity and Achieving the Best Product (Best Practices, Pitfalls, And Keys to Efficiency)................................................................................................................................................7Cardiovascular Toxicology Continuing Education Tutorial...................................................................................8Opportunities During Change: Advancing Your Toxicology Career in an Uncertain Market................................9Introduction to Translational Imaging in Nonclinical Safety Assessment: A Technology and Applications Perspective........................................................................................................................................................10Interpreting Stress-Related Findings in Pre-Clinical Safety Assessments...........................................................11

WELCOME BUFFET 12MONDAY, November 7, 2011 13


Plenary Lecture: “GLP Modernization: What Does This Mean To You” 14

Morning Symposia 15Evolving Issues and Approaches to Regulatory Biocompatibility Assessment in the Development of Medical Devices..............................................................................................................................................................15Update on Preclinical Oncology Drug Development..........................................................................................16What Animal Model Do You Use For Your Study?.............................................................................................17

ACT Awards Luncheon 18

Afternoon Symposia 19Safety Evaluation of Drug-Device Combination Products With Dual Efficacy and Drug-Drug Combinations Intended for Co-Administration.........................................................................................................................19Potential Utility of Humanized Mouse Models in Drug Development................................................................20Ocular Toxicity From Systemically Administered Xenobiotics: Considerations in Drug Development................21

ACT Member’s Meeting 22

ACT RECEPTION 23TUESDAY, November 8, 2011 24


Plenary Lecture: “Climate Change and Speaking Truth to Power: How Sound Science Can Inform Wise Policy” 25

Morning Symposia 26

AMERICAN COLLEGE OF TOXICOLOGY 32ND ANNUAL MEETING 2011

In Silico Toxicity Predictions: Fact or Fiction26The Use of Imaging Biomarkers in Nonclinical Research and Development and in Clinical Trials......................27The ELSIE Database: Extractables And Leachables Knowledge Sharing.............................................................28Oligonucleotide Therapeutics: Current Issues in Nonclinical Safety Testing and Regulatory Perspectives........29

2012 Program Planning Meeting 30

Afternoon Symposia 31Alternative Approaches For Preclinical Development of Biotherapeutic Products.............................................31Physiological Biomarkers in Toxicology and Safety Pharmacology....................................................................32New Data on The Toxicology of Petroleum Hydrocarbons................................................................................33New Drug Application (NDA): Industry and Regulatory Perspectives on The Make-Up and Evaluation of The Nonclinical Components Supporting Approval..................................................................................................34

POSTER SESSION & SAGE RECEPTION 36Wednesday, November 9, 2011 37


Plenary Lecture: “ FALLOUT FROM FALLOUT: RISKS VERSUS HYPE” 38

Morning Symposia 39Advances in Assessing The Safety of New Food Additives and Food Contaminants..........................................39FDA-Industry Dialogue on The Draft Guidance on Assessment of Abuse Potential of Drugs.............................40Animal Welfare: Where Science Meets Ethics..................................................................................................41

Afternoon Symposium 42Hot Topics!........................................................................................................................................................42

INSTRUCTIONS FOR PREPARING POSTERS 43SYMPOSIA & CONTINUING EDUCATION COURSE CHAIRS AND SPEAKERS 44ABSTRACTS 57ABSTRACT AUTHORS 112THANK YOU TO OUR EXHIBITORS 116AMERICAN COLLEGE OF TOXICOLOGY 2011 COUNCIL 119ACT COMMITTEES – 2011 123ACT PAST PRESIDENTS 12732ND ANNUAL MEETING SPONSORS – 2011 12832nd ANNUAL MEETING CONSULTANT SPONSORSHIP 130ACT CORPORATE MEMBERSHIP - 2011 132UPCOMING MEETINGS 133


Welcome to the 32nd Annual Meetingof the

American College of Toxicology

GENERAL INFORMATION

SOCIAL ACTIVITIES AWARDS

SUNDAYBuffet dinner followed by entertainment by the Native American DancersPre-Registration Required

ACT DISTINGUISHED SCIENTIST AWARD

(FORMERLY THE DISTINGUISHED SERVICE AWARD)

At the ACT Awards Luncheon held on Monday, this award will be presented to a member of the toxicology community who has made “outstanding contributions to toxicology and its relationship to the regulation of chemicals and the improvement of public health”. The recipient of this award will also make a presentation. Selection of the recipient of this award was done by the Awards Committee and endorsed by the Council.

MONDAY ACT Awards LuncheonACT Members MeetingACT Reception

TUESDAY Poster Session & Wine and Cheese Reception

ACT SERVICE AWARD

(FORMERLY LIFETIME ACHIEVEMENT AWARD)

This award is given at the discretion of the ACT Council to recognize an individual for long term dedication to the American College of Toxicology. Criteria for receiving this award include but are not limited to service to the College (e.g. councilor, officer, committee member), frequent participation and contribution to the Annual Meeting (speaker, chairperson, organizing committee) and longstanding support of the College's activities.

PLENARY LECTURE SERIES (8:00 AM)

MONDAY CT ViswanathanCT Viswanathan & Associates INC “GLP Modernization: What Does This Mean to You”

YOUNG PROFESSIONAL AWARD

The criteria for selection is:An ACT member in good standing; No more than 10 years of graduate/postgraduate experience; active and outstanding service to the College, including serving as an officer, councilor, committee member, and/or frequent participation and contribution at the Annual Meeting or any other College activity (i.e., speaker, chairperson, organizing committee, etc.).

TUESDAY

Richard CJ SomervilleDistinguished Professor Emeritus &

MARSHALL STEINBERG MEMORIAL PRIZE

This prize is given at the discretion of the International Pharmaceutical Excipients Council (IPEC) Foundation


Research ProfessorScripps Institution of OceanographyUniversity of California San Diego“Climate Change and Speaking Truth to Power: How Sound Science Can Inform Wise Policy”.

Board of Directors to reward those individuals who have made outstanding contributions in the area of safety and toxicology for excipients. This prize recognizes achievements in the field of pharmaceutical excipients that includes but is not limited to: (1) research that contributes to the safety of excipients; (2) investigations that establish test methods and standards that enhance the safety of excipients; (3) studies that support the development of new excipients or novel uses for existing excipients that provide or assure greater safety in their use in pharmaceuticals; and (4) toxicology research that improves the overall safety of excipients and/or finished pharmaceuticals.

WEDNESDAY Jacqueline P WilliamsResearch ProfessorUniversity of Rochester School of Medicine and DentistryDept. of Radiation Oncology“Fallout From Fallout: Risks Versus Hype”

FURST AWARD

Through a generous contribution from Dr. Arthur Furst, the American College of Toxicology was able to institute the Furst Award, an award of $2000 for the best student paper presented at each Annual Meeting of the College. Students will present their papers to the Committee on Sunday, November 6, 2011.

STUDENT TRAVEL AWARD

This year the College will provide travel awards in the amount of $1000.00 to some students attending and presenting a poster at the Annual Meeting. Any student receiving a travel award is also eligible for the Furst Award.


PROGRAM-AT-A-GLANCE

SundayNovember 6

MondayNovember 7

TuesdayNovember 8

WednesdayNovember 9

7:00 Continental Breakfast Continental Breakfast Continental Breakfast Continental Breakfast

8:00 Course No.1: Study Director TrainingCourse No.2: Nonclinical ADME in Sfty Assess.Course No.3: Biomarkers In Nonclinical Tox.Course No.4: Changing Role of Toxicologist…Course No.5: Clinical Pathology for The Toxicologist

PLENARY LECTURE PLENARY LECTURE PLENARY LECTURE

9:00 Symposium I: Evolving Issues & Approaches to….Symposium II: Unpdate Preclin Oncology Drug DevelopmentSymposium III: What Animal Model Do You Use for Your Study?

Symposium VII: In Silico Toxicity Predications: …..Symposium VIII: The Use of Imaging Biomarkers in…..Symposium IX: The ELSIE Database: ………Symposium X: Oligonucleotide Therapeutics:Current….

Symposium XV: Advances Assessing Sfty in New Food…Symposium XVI: GFA=Industry Dialogue on …..Symposium XVII: Animal Welfare: Where Science Meets Ethics

10:00

11:00

12:00 Lunch on your Own Awards Ceremony & Luncheon

2011 Program ad hoc Planning Meeting- OPEN to ALL –

SIGN UP PLEASE!!

Lunch on your Own

1:00 Course No.6: Study Monitor at CROsCourse No.7: Cardiovascular Toxicology… Course No.8: Opportunities During Change:…Course No.9: Intro to Translational Imaging…Course No.10: Interpreting Stress-Related Findings in Pre-Clinical Safety Assessments

1:30

Symposium XVIII: Hot Topics

2:00 Symposium IV: Safety Evaluation of Drug-Device…..Symposium V: Potential Utility of Humanized MouseSymposium VI: Ocular Toxicity From Systemically….

Symposium XI: Alternative Approaches for……Symposium XII: Physiological Biomarkers in Tox…..Symposium XIII: New Data Tox Petroleum HydrocarbonsSymposium XIV: NDA: Industry & Reg. Perspectives…

3:00

4:00

5:00

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AMERICAN COLLEGE OF TOXICOLOGY 31ST ANNUAL MEETING 2010

5:30ACT Members Meeting Poster Session &

Reception6:00

6:30

7:00 ACT Social Event ACT Reception

AMERICAN COLLEGE OF TOXICOLOGY 32ND ANNUAL MEETING

0

AMERICAN COLLEGE OF TOXICOLOGY 32ND Annual MEETING 2011

SUNDAY, NOVEMBER 6, 2011SCHEDULE OF EVENTS

7:00 am – 8:00 am Continental Breakfast Frank Lloyd Wright Prefunction Central

7:00 am – 5:00 pm Registration Desk Open Frank Lloyd Wright Registration

8:00 am – 11:30 pm Continuing Education Courses

Course No.1 Grand Canyon

Course No.2 McArthur 3

Course No.3 Frank Lloyd Wright G-H

Course No.4 Frank Lloyd Wright I-J

Course No.5 McArthur 1-2

2:00 pm – 5:00 pm Exhibit Set-Up Frank Lloyd Wright A-F

2:00 pm – 5:00 pm Poster Set-Up Frank Lloyd Wright A-F

1:00 pm – 4:30 pm Continuing Education Courses

Course No.6 Grand Canyon

Course No.7 McArthur 3

Course No.8 Frank Lloyd Wright G-H

Course No.9 Frank Lloyd Wright I-J

Course No.10 McArthur 1-2

7:00 pm – 9:30 pm Buffet & The Native American Dancers(Pre-Registration)

Gold Room

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SUNDAY


CONTINUING EDUCATION COURSES

CONTINUING EDUCATION COURSE NO.1STUDY DIRECTOR TRAINING Grand CanyonThis continuing education course is intended to provide an introduction to a study director’s responsibilities and review both logistical-, regulatory-, and scientific-related aspects of toxicology studies. The course will focus on the practicalities of study director responsibilities for study conduct, oversight, protocols, and final reports. This course will also review the evolution and scope of the GLP regulations and what a study director should do/not do during an FDA inspection, as well as how to manage challenges a study director can encounter in toxicology studies. Scientific aspects of toxicology studies will also be reviewed including animal models and studies used for the assessment of immune function (immunotoxicology). This is an excellent course for newer study directors, as well as an informative review and refresher for the more experienced study directors.

Course Manuals are supported in part by an educational donation provided by:

BATTELLE MEMORIAL INSTITUTE

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8:00 am WELCOME AND INTRODUCTIONBarbara Mounho, Director, Global Regulatory Affairs Biosimilar Policy and Strategy, Amgen, Inc.

8:15 am STUDY DIRECTOR GUIDELINES FOR SUCCESSCarol S. Auletta, Director, Program Management, Huntingdon Life Sciences

8:50 am OVERVIEW AND HISTORY OF GLPs Melissa Reinert, Senior Quality Assurance Auditor, Biotechnical Services, Inc.

9:25 am

TOXICOLOGY STUDY REPORTS – PRINCIPLES AND PRACTICES FOR GENERATING QUALITY DOCUMENTSMark D. Walker, DVM, Vice President of Toxicology, Frontier BioSciences, Inc.

10:00 am REFRESHMENT BREAK

10:20 am ANIMAL MODELS FOR TOXICOLOGY STUDIES Laura Conour, Director, Research Resources, Princeton University

10:55 am IMMUNOTOXICOLOGYThomas Kawabata, Ph.D., Pfizer, Inc.

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CONTINUING EDUCATION COURSE NO.2NONCLINICAL ADME IN SAFETY ASSESSMENT McArthur 3

ADME/PK/TK is integral to the drug discovery and development process at all stages. An understanding of the dispositional characteristics of a new molecular entity (NME) is crucial to the optimal design of safety studies (general tox, DART, safety pharmacology, carcinogenicity) and risk assessment. This course will review the science underpinning each aspect of ADME. Relevant theory, technologies, and methodologies will be presented, but the emphasis will be on practicality and real world utilization of ADME/PK/TK data for decision making and problem solving (candidate selection, dose selection, species selection, etc.). The integration of ADME data with pharmacodynamic and toxicology results for safety assessment will be discussed. This will be supported with case studies of small molecule and large biologic NMEs. This course will be of primary interest to members working within the pharmaceutical industry, however many of the concepts will be of relevance to other industries.


BATTELLE MEMORIAL INSTITUTE & ACLAIRO PDG., INC.

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8:00 am ABSORPTION AND PHARMACOKINETICS Robert J. Guttendorf, Sr. Consultant, DMPK, Aclairo Pharmaceutical Development Group, Inc.

9:00 am DISTRIBUTION AND ELIMINATION Gordon R. Loewen, Sr. Director, Drug Metabolism & Pharmacokinetics, Infinity Pharmaceuticals


10:00 am METABOLISM AND DRUG INTERACTIONS Richard E. Ridgewell, Associate Director, Drug Metabolism, Covance Laboratories Inc.

10:45 am INTEGRATION OF ADME AND TOXICOLOGY DATA FOR SAFETY ASSESSMENT Alan P. Brown, Sr. Toxicology Consultant, Integrated Nonclinical Development Solutions, Inc.

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SUNDAY


CONTINUING EDUCATION COURSE NO.3BIOMARKERS IN NONCLINICAL TOXICOLOGY Frank Lloyd Wright G-HNovel toxicity biomarkers for monitoring drug-induced tissue injury have been useful tools for pharmaceutical candidate development and regulatory applications. This Continuing Education course will provide attendees with an overview of novel toxicity biomarker development, preclinical evaluation and qualification, and translation to clinical settings. Topics include the qualification of transcriptional biomarker sets for safety purposes; the evaluation and qualification of miRNAs as both sensitive and specific biomarkers of tissue toxicity; and a presentation on translational challenges related to liver toxicity biomarkers. The program will close with an update from the FDA on biomarker qualifications (renal and others) and insight on the use of biomarkers in the regulatory setting.



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8:00 am NONCLINICAL BIOMARKERS OF TOXICITY: AN OVERVIEW Richard S. Paules, Acting Chief, Laboratory of Toxicology & Pharmacology Head, Environmental Stress and Cancer Group Director, NIEHS Microarray Core Facility, NIEHS, NIH

8:50 am PLASMA microRNAs AS SENSITIVE AND SPECIFIC BIOMARKERS OF TISSUE INJURY: FROM PRECLINICAL UTILITY TO CLINICAL TRANSLATION Warren E. Glaab, Safety Assessment, Merck and Co.


10:00 am TRANSLATIONAL ASPECTS OF LIVER TOXICITY BIOMARKERS Alison Harrill, Hamner Center for Drug Safety Sciences, The Hamner Institutes for Health Sciences

10:50 am FDA UPDATE ON NONCLINICAL BIOMARKER QUALIFICATIONS Patricia P. Harlow, Pharmacologist, US FDA

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CONTINUING EDUCATION COURSE NO.4THE CHANGING ROLE OF THE TOXICOLOGIST IN TODAY’S PHARMA: IN-LICENSING, AD-COMMS AND TRENDS IN THE CROS

Frank Lloyd Wright I-J

The pharmaceutical industry is in a rapid state of change. Corporate consolidation, restructuring and changing business models have had a major impact on how pre-clinical development is managed. Traditional internal resources such as drug discovery and safety assessment laboratories are now being reduced or replaced with partnerships, in-licensed molecules and out-sourced services. As the business models continue to evolve in an effort to be better, faster and more cost-effective, it can be expected that drug development will become more “virtual” in nature with increased reliance on shared resources amongst partner-companies and the reliance on CRO providers. The nature of such models relies not only on savvy business agreements, but also on in-depth due diligence review of available data. And as cutting edge science and the most current technology in drug discovery continues to identify novel targets, it can be expected that the potential for new drug candidates to be subject to an FDA advisory committee will be even higher. As such, these changes within the pharmaceutical industry will impact the role of the toxicologist and how pre-clinical safety assessment is ultimately managed. This CE course will present how toxicology has been impacted by these changes and address the skills necessary to be successful in the field.

Course Manuals are supported by an educational donation provided by:


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8:00 am WELCOME AND INTRODUCTIONShana Azri-Meehan, Senior Principal Scientist, Forest Research Institute

8:15 am THE CHANGING FACE OF THE PHARMACEUTICAL INDUSTRY: A SWEEPING PERSPECTIVE William J. Brock, President, Brock Scientific Consulting

9:00 am THE ROLE OF THE CRO IN A CHANGING MARKETFred Kirchner, Executive Director, Toxicology, Pathology, Safety Pharmacology, Covance Labs


10:00 am HOW TO CONDUCT DUE DILIGENCE--ASPECTS FOR THE TOXICOLOGIST TO CONSIDER WHEN REVIEWING IN-LICENSING OPPORTUNITIESStephen A. Barat, Director, Forest Research Institute

10:45 am THE CHANGING ROLE OF THE TOXICOLOGIST IN FDA ADVISORY COMMITTEE MEETINGS Shana Azri-Meehan, Senior Principal Scientist, Forest Research Institute

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CONTINUING EDUCATION COURSE NO.5CLINICAL PATHOLOGY FOR THE TOXICOLOGIST – LOOKING BEYOND THE ASTERISKS

McArthur 1-2

Clinical pathology is often one of the key endpoints in safety assessment of drugs and chemicals. Clinical pathology data are screening tools to identify general metabolic or pathologic processes and target organs and may occasionally serve as pharmacodynamic markers. It is important for scientists involved in safety assessment to understand factors that may impact clinical pathology data and their interpretation. This course will describe key study design factors that affect data quality and interpretation and look beyond statistical significance to integrate findings with other findings with other clinical and pathology endpoints; common patterns of change will be highlighted. In addition, the course will discuss the value and appropriate use in safety assessment of several more recently developed clinical pathology biomarkers.



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8:00 am WELCOME AND INTRODUCTIONMingy Trimble, Study Director, Covance Laboratories

8:15 am STUDY DESIGN CONSIDERATIONS (WHAT, WHEN, HOW, WHY) AND DATA INTERPRETATION CONCEPTS (IS IT REAL? IS IT BAD?)Robert Hall, Clinical Pathologist, Covance Laboratories Inc.

9:00 am HEMATOLOGY Nancy Everds, Clinical Pathologist, Amgen Inc.


10:00 am CLINICAL CHEMISTRY, URINALYSIS, AND URINE CHEMISTRY – BASIC CONCEPTS AND SPECIAL CONSIDERATIONS Niraj Tripathi, Clinical Pathologist, Covance Laboratories Inc.

10:45 am COMMONLY USED BIOMARKERS Jacqueline Tarrant, Scientist – Pathologist, Genentech

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CONTINUING EDUCATION COURSE NO.6STUDY MONITORING AT CROS. KEEPING YOUR SANITY AND ACHIEVING THE BEST PRODUCT (BEST PRACTICES, PITFALLS, AND KEYS TO EFFICIENCY)

Grand Canyon

With the increased emphasis on outsourcing toxicology studies to specialty Contract Research Organizations (CRO), toxicologists are being asked to monitor studies being conducted outside of their organizations. In this capacity, they must ensure that the toxicology program is conducted properly and in a cost effective manner. This presents a particular challenge to the toxicologist because many toxicologists have no training in managing these types of programs. This course will provide the participants with the tools they need to succeed in this endeavor. Specifically, this course will discuss what factors the toxicologist needs to consider when selecting a CRO including bid solicitation and bid analysis (cheapest is not always best). It will also discuss the interactions between the Study Monitor and the CRO before, during and after the study. It includes a CRO’s Study Director’s perspective of what makes an effective team between the Study Monitor and the Study Director. It will conclude with a discussion of the legal obligations between you and the CRO. This course is a must for any toxicologist who is responsible for outsourcing toxicology studies, no matter what type of company he/she works for.



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1:00 pm WELCOME AND INTRODUCTIONPaul L. Roney, Senior Consultant Toxicology, INC Research

1:05 pm OUTSOURCING NONCLINICAL SAFETY STUDIES: BEST PRACTICES FOR SELECTING A CROJon Daniels, Executive Vice President & Senior Toxicologist, Intrinsik Health Sciences, Inc.

1:35 pm AN INDUSTRY VETERAN’S GUIDE TO EFFECTIVE STUDY MONITORINGSteve Snyder, President, Outsourcing Support Services, Inc.

2:05 pm THE SPONSOR/CRO RELATIONSHIP IN NON-CLINICAL SAFETY TESTINGSusan McPherson, Manager Toxicology, Charles River Laboratories, Inc.

2:35 pm REFRESHMENT BREAK

2:50 pm QA ASSESSMENTWilliam T. Reinholt, Manager, Quality Assurance, MPI Research

3:20 pm LEGAL AND FINANCIAL ARRANGEMENTS (BALANCING ACT BETWEEN YOU, THE ATTORNEYS AND SARBANES-OXLEY)Clynn Wilker, Senior Director, Toxicology, Ardea Biosciences

3:50 pm Q & A

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CONTINUING EDUCATION COURSE NO.7CARDIOVASCULAR TOXICOLOGY CONTINUING EDUCATION TUTORIAL McArthur 3This tutorial is intended to approach cardiovascular toxicology by presentations from a group of scientists with extensive experience with cardiovascular assessments. It includes an overview of commonly used methods and explores the issues relative to the proper use and evaluation of the data. Further, relatively new and advanced techniques will be described as will the impact of pre-clinical data upon clinical design and decision making. The final lecture will suggest a path forward for cardiovascular toxicology including the utilization of approaches that facilitate the choice of the safest and/or most predictable drug candidates.



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1:00 pm BASIC FUNCTIONS AND MEASUREMENT OF THE CARDIOVASCULAR SYSTEM FOR TOXICOLOGICAL STUDIES Brian Roche, Associate Manager Safety Pharmacology Battelle Memorial Institute

1:40 pm WHAT PROPERTIES AND WHAT MAGNITUDE CHANGE WILL LEAD TO CARDIAC MORBIDITY AND MORTALITY Robert L. Hamlin, The Ohio State University College of Veterinary Medicine. QTest Labs

2:20 pm ADVANCED TECHNIQUES AND THEIR APPLICATION TO THE ASSESSMENT OF CARDIOVASCULAR TOXICOLOGY Periannan Kupasami, The Ohio State University College of Medicine


3:15 pm THE USE OF PRECLINICAL QT DATA TO IMPACT EARLY CLINICAL STUDY DESIGNS AND DECISION MAKING Philip Sager, Chair, Scientific Program Committee, Cardiac Safety Research Consortium and Pharmaceutical/Device Consultant

3:55 pm THE TRANSITION OF ANIMAL BASED CARDIOVASCULAR DATA TO CLINICAL TRIALS/SUMMARY OF THE CE SYMPOSIUM Gary A. Gintant, Research Fellow, Chairman, Abbott QT Working Group, Abbott

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CONTINUING EDUCATION COURSE NO.8OPPORTUNITIES DURING CHANGE: ADVANCING YOUR TOXICOLOGY CAREER IN AN UNCERTAIN MARKET

Frank Lloyd Wright G-H

The severity in the economic markets has created uncertainty in many jobs in toxicology, and many toxicologists are considering transitioning earlier in their career to secure continued employment. The goal of this workshop is to educate toxicologists on the various options for their career path before migrating to another career choice. The workshop speakers will include scientists who have made career transitions and have succeeded in their new position in the pharmaceutical industry, consulting, and CRO industry as well as in the legal profession. The various speakers will give a brief overview of their day-to-day workload as well as share their career transition experiences and the lessons learned along the way.



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1:00 pm WELCOME AND INTRODUCTIONL. Peyton Myers, Pharmacology/Toxicology Drug Reviewer, US FDA

1:15 pm WHAT CAN TOXICOLOGY CERTIFICATIONS DO FOR YOU (E.G., DABT, FATS, ERT)?Hanan Ghantous, Supervisory Toxicologist, US FDA, CDER, OND, OAP

1:45 pm LIFE AS A TOXICOLOGIST IN SMALL, MID-SIZE AND LARGE COMPANIES Drew A. Badger, Director, Regulatory Affairs, Amgen Inc.

2:15 pm EXPECTATIONS AND CHALLENGES OF STARTING A CRO Gary R. Burleson, and Florence G. Burleson, President and Executive Vice President, BRT – Burleson Research Technologies, Inc.


3:00 pm TRANSITIONING FROM AN 8-5 JOB TO CONSULTING Hilary Sheevers, President, CEO, Aclairo PDG., Inc.

3:30 pm SCIENTISTS OUTSIDE THE BOX: INFORMATION, INTELLECTUAL PROPERTY AND LEGISLATION Kathy McGown, Director, Knowledge Resources, FoxKiser

4:00 pm Q&A DISCUSSION

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CONTINUING EDUCATION COURSE NO.9INTRODUCTION TO TRANSLATIONAL IMAGING IN NONCLINICAL SAFETY ASSESSMENT: A TECHNOLOGY AND APPLICATIONS PERSPECTIVE


Clinical imaging is a staple in contemporary clinical medicine with continuing advances improving early recognition of disease as well as facilitating monitoring of disease progression or regression. Accordingly, clinical imaging is growing in popularity with drug developers as a means for assessing drug distribution or monitoring efficacious response to a novel therapeutic in living patients. Historically, imaging applications in nonclinical animal species have been limited by the ability to scale the technology to the smaller size of the animals typically used in nonclinical safety studies. These limitations are largely a thing of the past. A great opportunity exists to leverage the advances in clinical imaging to improve the translatability of nonclinical safety assessments. The goal of this session is to introduce nonclinical safety scientists to the array of available imaging technologies, potential applications of those technologies, and future opportunities for improving on contemporary safety assessment paradigms.



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1:00 pm AN INTRODUCTION TO INTEGRATION OF CLINICAL IMAGING TO NONCLINICAL SAFETY ASSESSMENT Brian R. Berridge, Director, Regulatory & Discovery Pathology, GlaxoSmithKline Safety Assessment

1:40 pm MOLECULAR IMAGING FOR TOXICOLOGICAL RESEARCH Serguei Liachenko, Director, Bio-Imaging, US FDA, NCTR

2:20 pm ULTRASOUND IMAGING IN DRUG DISCOVERY AND SAFETY SCIENCES Robert W. Coatney, Director, Comparative Biology and Medicine, GlaxoSmithKline


3:10 pm MAGNETIC RESONANCE MICROSCOPYG. Allan Johnson, Charles E. Putman Professor of Radiology, Physics, and Biomedical Engineering, Duke University Medical School, Center for In Vivo Microscopy

3:50 pm DIGITAL SUBTRACTION ANGIOGRAPHY AND MICROCT FOR SMALL ANIMAL TOXICOLOGY Cristian Tudorel Badea, Associate Professor, Radiology, Duke University Medical School, Center for In Vivo Microscopy

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CONTINUING EDUCATION COURSE NO.10INTERPRETING STRESS-RELATED FINDINGS IN PRE-CLINICAL SAFETY ASSESSMENTS

McArthur 1-2

Stress can confound the interpretation of clinical and anatomical findings in pre-clinical safety assessments. Stress can be the result of physiological responses to perturbations of homeostasis, including those effects caused by changes in either neural or endocrine responses. With regards to pre-clinical safety assessments, the issue of stress becomes distinguishing primary test-article effects from secondary effects. Not only is the stress response highly variable (acute vs. chronic), but the complexity and bidirectional nature of the various organ systems and the hypothalamic-pituitary-adrenal axis can make interpretation of some stress-related findings difficult. This session will provide a basic understanding of the potential sources of stress in toxicology studies and the common stress-associated organ system findings. By focusing on the major organ systems impacted by stress such as the nervous, endocrine, and immune system, the presentations will describe the pathophysiological pathways involved and include some case-based examples of the types of parameters in toxicology studies that are influenced by stress. Because no single parameter can indicate that the animal was stressed, investigators are often reliant on a weight-of-evidence approach to interpreting a set of findings as stress-related. The aim of the topics covered is to provide the toxicologist with an understanding of the stress response and the findings commonly associated with a stress response that can be used in a weight-of evidence approach to facilitate the interpretation of the findings in the correct context of the study objectives.



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1:00 pm WELCOME AND INTRODUCTIONPaul Snyder, Professor Comparative Pathology, Purdue University

1:10 pm STRESS AND THE NERVOUS SYSTEM Brad Bolon, Associate Professor, The Ohio State University

2:00 pm STRESS AND THE ENDOCRINE SYSTEM Tom Rosol, Ohio State University


3:00 pm CLINICAL PATHOLOGY ASPECTS OF STRESS Nancy Everds, Clinical Pathologist, Amgen Inc.

3:50 pm STRESS AND THE IMMUNE SYSTEM Paul W. Snyder, Professor of Pathology, Purdue University

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SUNDAY


(CT SOCIAL EVENT

WELCOME BUFFET

WELCOME BUFFETAnd the

NATIVE AMERICAN DANCERS

SUNDAY EVENING, NOVEMBER 6, 2011

7:00 pm - 9:30 pm

GOLD ROOM & PATIO

PRE-REGISTRATION ONLY

MONDAY, NOVEMBER 7, 2011

12


SCHEDULE OF EVENTS

7:00 am – 8:00 am Continental Breakfast FLW- Exhibit Hall

7:00 am – 5:00 pm Registration Desk Open FLW Registration

8:00 am - 8:45 am Plenary Lecture McArthur 4-7

9:00 am – 12:00 pm Symposia

Symposium I Frank Lloyd Wright G-H

Symposium II Frank Lloyd Wright I-J

Symposium III McArthur 1-2

9:30 am – 5:00 pm Exhibits Open Frank Lloyd Wright A-F

9:00 am – 5:00 pm Posters Open Frank Lloyd Wright A-D

12:00 pm – 2:00 pm ACT Awards Luncheon McArthur 4-7

2:00 pm – 5:00 pm Symposia

Symposium IV Frank Lloyd Wright G-H

Symposium V Frank Lloyd Wright I-J

Symposium VI McArthur 1-2

5:30 pm – 7:00 pm ACT Members Meeting McArthur 1-2

7:00 pm – 8:30 pm ACT Reception Gold Room

13

MONDAY


PLENARY LECTURE: “GLP MODERNIZATION: WHAT DOES THIS MEAN TO YOU”

PLENARY LECTURE8:00 am – 8:45 am McArthur 4 - 7

CT Viswanathan, Ph.D.CT Viswanathan & Associates Inc.

“GLP MODERNIZATION: WHAT DOES THIS MEAN TO YOU”

Co-Sponsored by Calvert Laboratories, Inc.

14


MORNING SYMPOSIA

SYMPOSIUM IEVOLVING ISSUES AND APPROACHES TO REGULATORY BIOCOMPATIBILITY ASSESSMENT IN THE DEVELOPMENT OF MEDICAL DEVICES


Evolving Issues and Approaches to Regulatory Biocompatibility and Safety Assessment in the Development of Medical Devices: The development of modern medical devices toxicology is playing an ever increasing role in the treatment and diagnosis of health conditions that impact virtually every sector of our population. Advancements in medical device technology involve significant decisions and considerations for safety evaluation from the design stage through approval and even after market. The increasing use of advanced technologies such as nanotechnology as well as inclusion of antimicrobial agents and the delivery of active pharmaceutical agents incorporated with various types of medical devices makes for a device industry that is constantly evolving. This requires innovative and novel approaches to toxicologic evaluation in addition to traditional biocompatibility tests. This symposium will provide an overview and update of the current medical device safety assessment picture for ISO tests and U.S. FDA requirements for a variety of different types of devices as well as present novel technologies, such as nanotechnology-enabled devices and approaches to medical device biocompatibility and safety evaluation.

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9:00 amINTRODUCTIONShayne C. Gad, Principal, Gad Consulting Services

9:10 am BASIC TESTING REQUIREMENTS: ISO AND FDA Joseph W. Carraway, Director, Toxicology, NAMSA

9:40 amANALYTICAL APPROACHES FOR DEGRADATION PRODUCTS, EXTRACTABLES AND LEACHABLES FROM MEDICAL DEVICESMichael Shelton, Technical Director, Exova Inc.


10:30 am NANOTECHNOLOGY ENABLED DEVICE DESIGN AND SAFETY ASSESSMENT David W. Hobson, President, LoneStar Pharm Tox, LLC

11:00 am BIOCOMPATABILITY ASSESSMENT OF ANTIMICROBIAL DEVICES Shayne C. Gad, Principal, Gad Consulting Services

11:30 am BIOCOMPATABILITY TESTING OF INJECTABLE MEDICAL DEVICES Jeff A. Handler, President, JAH Associates, LLC

15

MONDAY


SYMPOSIUM II

UPDATE ON PRECLINICAL ONCOLOGY DRUG DEVELOPMENT Frank Lloyd Wright I-J

Preclinical testing for oncology drugs has become more streamlined with the finalization of the ICH guidance (S9) on oncology drug development. A successful new oncology drug typically enters patients with limited life expectancy, and the regulatory path of a small number of preclinical studies is sensible. Over time however, some drugs or biologics offer good safety and efficacy in much less serious oncology settings, and the needed preclinical safety and efficacy studies suddenly increase. This symposium is designed to bring people up to date with drug development requirements for oncology drugs and biologics. The presentations will then focus on advancing drug and biologic candidates to less serious indications. Both toxicology (including application of ICH M3 (R2)) and pharmacology animal models will be presented.

This activity is supported by an educational donation provided by:

Ricerca Biosciences

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9:00 am WELCOME AND INTRODUCTIONHillary V. Sheevers, President, CEO, Aclairo PDG, Inc., Vienna, VA

9:15 amONCOLOGY PHARMACOLOGY MODELS: VALUABLE PREDICTIVE TOOLS? Patrice Lee, Senior Director of Pharmacology and Toxicology, Array BioPharma, Inc.

10:00 am

INTRODUCTION TO THE TOXICOLOGY SIDE OF ONCOLOGY DRUG DEVELOPMENT Hilary V. Sheevers, President, CEO, Aclairo PDG, Inc., Vienna, VA and Vincent A. Murphy, Principal Research Investigator, Array BioPharma, Inc.


10:50 amOPTIMIZING LARGE AND SMALL MOLECULE ONCOLOGY DRUG DEVELOPMENT Ron Steigerwalt, Preclinical, Director, Amgen Inc.

11:25 amWHEN TO CHOOSE ICH M3 (R2) FOR THE DEVELOPMENT OF ONCOLOGY PRODUCTS Todd Palmby, Pharmacology/Toxicology Reviewer, US FDA, CDER

16


SYMPOSIUM IIIWHAT ANIMAL MODEL DO YOU USE FOR YOUR STUDY? McArthur 1-2It is often a difficult question to determine the correct animal model for your toxicology study. The most appropriate model may vary depending on the purpose of the toxicology study and the type of test article being evaluated. This symposium will discuss the selection of animal models for various types of toxicology studies. We will present the advantages and disadvantages of different species, strains, and stocks of commonly used laboratory animal models. These would include rat models, mouse models, dog models, and nonhuman primate models. Each speaker will discuss the available models and present an overview of the most appropriate model for specific toxicology studies.


EPL, Inc. & Harlan Laboratories, Inc.

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9:00 am WELCOME AND INTRODUCTIONRobin Guy, Robin Guy Consulting, LLC

9:10 amMOUSE MODELS IN TOXICOLOGY STUDIES Peter C. Mann, Manager, EPL NorthWest, EPL, Inc.

9:40 amRAT MODELS IN TOXICOLOGY STUDIES Prof. Dr. Paul-Georg Germann, Nycomed GmbH


10:50 am DOG MODELS IN TOXICOLOGY STUDIES Klaus Weber, Toxicologic Pathologist, Harlan Laboratories, Inc.

11:20 amNON-HUMAN PRIMATE MODELS IN TOXICOLOGY STUDIES Kevin S. McDorman, General Manager, Charles River Pathology Associates

17

MONDAY


ACT AWARDS LUNCHEON

12:00 – 2:00 PM McArthur 4-7

ACT AWARDS LUNCHEON

ACT

AWAR

DS

WELCOMERussette Lyons, President ACT

STUDENT TRAVEL AWARDS

FURST AWARDBest Student Poster 2011

MARSHALL STEINBERG MEMORIAL PRIZEIPEC Foundation Award

ACT PRESIDENT’S AWARDBest Paper in the International Journal of Toxicology 2011

YOUNG PROFESSIONAL AWARDMelissa Rhodes, Ph.D., DABTSr. Manager, Safety Assessment Project DevelopmentGlaxoSmithKline

ACT SERVICE AWARDDavid W. Hobson, Ph.D., DABTPrincipalLoneStar PharmTox LLC

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ACT DISTINGUISHED SCIENTIST AWARDGlenn Sipes, Ph.D. Fellow ATS and AAASProfessor Emeritus, Department of PharmacologyCollege of Medicine, University of Arizona

“RECOLLECTION OF 40+ YEARS AS A TOXICOLOGIST: PEOPLE, PROJECTS, PROGRAMS AND PROFESSIONALISM”

18


AFTERNOON SYMPOSIA

SYMPOSIUM IVSAFETY EVALUATION OF DRUG-DEVICE COMBINATION PRODUCTS WITH DUAL EFFICACY AND DRUG-DRUG COMBINATIONS INTENDED FOR CO-ADMINISTRATION


Previously, medical products could be readily defined as drugs, biologics or devices, and thereby regulated as such. However, with the advent of new medical technologies, it has become necessary to define a fourth type of medical product: combination products. As this name suggests, these are products that consist of a combination of at least two medical products. Combination products may constitute the use of a device for drug delivery, the use of a drug or biologic to enhance the efficacy of a medical device, drug-drug combinations. Combination products are regulated by the US FDA Center or Division determined to have lead regulatory jurisdiction, based on the primary mode of action or efficacy, but receive consultative input from Center(s) or Division(s) assigned the secondary regulatory jurisdiction. This symposium will focus on nonclinical safety evaluation of those combination products in which the device and the drug/biologic components both contribute towards efficacy of the product and on drug-drug combinations which are intended for co-administration. Examples include drug-eluting vascular stents, orthopedic devices containing growth factors, and wound healing devices containing antimicrobials.

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2:00 pmINTRODUCTION TO SYMPOSIUM Alan P. Brown, Senior Toxicology Consultant, Integrated Nonclinical Development Solutions Inc.

2:30 pmCDER/CDRH REGULATORY PERSPECTIVE ON COMBINATION PRODUCT DEVELOPMENT Kathy Lee, Lead Interdisciplinary Scientist, US FDA-CDER

3:05 pm

PRECLINICAL TESTING REQUIREMENTS FOR STENTS: A CHANGED REGULATORY LANDSCAPE John Dooley, Senior Research Fellow, Preclinical R&D, Codman & Shurtleff (Division of Johnson & Johnson)


3:50 pmREGULATION AND NONCLINICAL ASSESSMENT STRATEGIES FOR DRUG-DRUG COMBINATIONS INTENDED FOR CO-ADMINISTRATION Timothy Hummer, Pharmacology/Toxicology Reviewer, US FDA, CDER

4:25 pm ROUNDTABLE DISCUSSION

19


SYMPOSIUM VPOTENTIAL UTILITY OF HUMANIZED MOUSE MODELS IN DRUG DEVELOPMENT


Laboratory animals are used in drug development as models of clinical disease, PK/ADME, and toxicology. Although the goal of non-clinical studies is to provide insight into clinical outcome, species differences can sometimes result in generation of data with questionable human relevance. To improve the predictive nature of non-clinical evaluations, more clinically relevant models are needed. Humanized mouse models may potentially help meet this need. Promising models include mice that express single or multiple human genes involved in drug metabolism as well as mice with partial to complete human tissues (e.g., liver, immune system, etc.). This symposium is designed to provide updates concerning recent developments in humanized mouse models. The target audience includes scientists involved in commercial drug development (e.g., drug metabolism scientists, toxicologists, etc.) as well as regulators responsible for evaluating data generated during safety testing. Because these models also have potential applications for toxicology testing in general, the symposium will be of interest to scientists in the chemical and consumer healthcare industries.

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2:00 pmUSE OF TRANSGENIC MOUSE MODELS FOR PK AND SAFETY PROFILING OF COMPOUNDS Nico Scheer, Head of ADMET R&D, TaconicArtemis GmbH

2:30 pm

MOUSE MODELS WITH HIGHLY HUMANIZED LIVERS: CURRENT APPLICATIONS AND FUTURE DIRECTIONS Markus Grompe, Director, Oregon Stem Cell Center, Founder and Chief Scientific Officer, Yecuris Corporation, Oregon Health & Science University, Yecuris Corporation

3:05 pmA HUMAN IMMUNE SYSTEM IN THE MOUSE: CURRENT STATE OF THE MODEL AND RESEARCH POTENTIAL Kristina Howard, Commissioner’s Fellow, U.S. FDA


3:50 pmHUMANIZED DRUG METABOLIZING ENZYME MOUSE MODELS– POTENTIAL APPLICATION IN SAFETY ASSESSMENT Alema Galijatovic-Idrizbegovic, Associate Director, Merck & Co., Inc.

4:25 pm FDA PERSPECTIVE ON HUMANIZED ADME MODELS Mark W. Powley, Pharmacologist, Division of Anti-Viral Products, US FDA

20

MONDAY


SYMPOSIUM VIOCULAR TOXICITY FROM SYSTEMICALLY ADMINISTERED XENOBIOTICS: CONSIDERATIONS IN DRUG DEVELOPMENT

McArthur 1-2

The eye is a specialized structure for which irritation or systemic toxicity must be evaluated to determine the safety of drugs, industrial chemicals, consumer products, etc. Indeed, important diseases such as glaucoma and macular degeneration are target diseases pharmaceutical companies are devoting resources in order to develop therapies with fewer side effects. However, for other therapies, ocular toxicity following systemic administration often results in abandoning a potentially efficacious therapy because of a perceived poor safety profile. Currently there are several pharmaceuticals on the market that have induced ocular effects in experimental animals although mechanistic studies have revealed limited concern for humans. In contrast, there are several marketed therapies that have shown adverse ocular effects that were not seen in nonclinical studies. This symposium will discuss the design and execution of toxicity studies with the incorporation of current methods for in vivo assessment of ocular toxicity, and how those methods can detect early changes in the eye that can lead to risk decisions for further development. In addition, the process of detecting microscopic findings due to ocular toxicity will be reviewed and include factors such as anatomical differences among laboratory animals, preparation of globes for examination, and iatrogenic and spontaneous ocular findings. Finally, the correlation between nonclinical outcomes and clinical evaluations will be discussed in terms of expected therapeutic uses, indications and the regulatory consequences of ocular effects.


MPI Research

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2:00 pm OVERVIEW OF SESSION William J Brock, Principal, Brock Scientific Consulting

2:15 pmOCULAR TOXICITY IN AN ONCOLOGY THERAPEUTIC: OBSTACLES AND IMPACT TO DEVELOPMENTVince Torti, Pfizer Inc.

2:45 pmDETECTION OF MICROSCOPIC FINDINGS OF OCULAR TOXICITY James A. Render, Veterinary Pathologist, NAMSA


3:30 pmFIRST DO NO HARM: NONINVASIVE MEASURES OF STRUCTURE AND FUNCTION IN OCULAR TOXICOLOGY AND DRUG DISCOVERY Jeff Jamison, Ophthy-DS, Inc., and MPI Research

4:00 pmCLINICAL AND NONCLINICAL CORRELATES OF OCULAR TOXICITY: EVALUATION AND REGULATORY CONSIDERATIONSMaria I. Rivera, Pharmacologist/Toxicologist, US FDA, CDER

4:30 pm ROUNDTABLE DISCUSSION

21

MONDAY


ACT MEMBER’S MEETING

5:30 PM McArthur 1-2

MEMBER’S MEETING(ACT Members Only)

ACT

BUSI

NES

S

CALL TO ORDERRussette Lyons, ACT President, Novartis Institutes of Biomedical Research

MINUTES FROM 2011 ANNUAL MEETINGTracey Spriggs, ACT Secretary, GlaxoSmithKline Consumer Healthcare

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RTS PRESIDENT’S REPORT

Russette Lyons, Novartis Institutes of Biomedical Research

PRESIDENT-ELECT’S REPORTDavid G. Serota, MPI Research

TREASURER’S REPORTNorman Kim, Biogen Idec, Inc.

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MEMBERSHIP COMMITTEE REPORTJames J. Freeman, ExxonMobil Biomedical Sciences, Inc.

NOMINATING COMMITTEE REPORTACT Past-President, Carol Auletta, Huntingdon Life Sciences

PUBLICATIONS COMMITTEE REPORTEditor-in-Chief, Mary Beth Genter, University of Cincinnati

22


ACT RECEPTION

ACT RECEPTION

Music by our own

“JAZZICOLOGY”

CASH BAR

7:00 – 8: 30 pm

GOLD ROOM

23

MONDAY


TUESDAY, NOVEMBER 8, 2011SCHEDULE OF EVENTS

7:00 am – 8:00 am Continental Breakfast Frank Lloyd Wright A-F


8:00 am - 8:45 am Plenary Lecture McArthur 4-7


Symposium VII McArthur 1-2

Symposium VIII Frank Lloyd Wright I-J

Symposium IX Frank Lloyd Wright G-H

Symposium X McArthur 3

9:30 am – 4:00 pm Exhibits Open Frank Lloyd Wright A-F

9:00 am – 7:00 pm Posters Open Frank Lloyd Wright A-D

12:00 pm – 1:30 pm 2011 Program Planning Mtg Grand Ballroom


Symposium XI McArthur 1-2

Symposium XII Frank Lloyd Wright I-J

Symposium XIII Frank Lloyd Wright G-H

Symposium XIV McArthur 3

24


5:30 pm - 7:00 pm Poster Session & Sage Reception

Frank Lloyd Wright A-D

25


PLENARY LECTURE: “CLIMATE CHANGE AND SPEAKING TRUTH TO POWER: HOW SOUND SCIENCE CAN INFORM WISE POLICY”

PLENARY LECTURE8:00 am – 8:45 am McArthur 4-7

Richard C.J. Somerville, Ph.D.Distinguished Professor Emeritus & Research Professor

Scripps Institution of OceanographyUniversity of California San Diego

“CLIMATE CHANGE AND SPEAKING TRUTH TO POWER:

HOW SOUND SCIENCE CAN INFORM WISE POLICY”

26

TUESDAY


CO-SPONSORED BY WIL RESEARCH COMPANY

MORNING SYMPOSIA

SYMPOSIUM VII

IN SILICO TOXICITY PREDICTIONS: FACT OR FICTION McArthur 1-2With the increasing need to deliver new, safer medicines to the market at lower costs for research and development, the pharmaceutical industry is turning towards the use of cheaper and faster alternatives to selecting safer drug candidates. In silico models for toxicology have an added appeal in that they can be used even prior to any chemical synthesis thus avoiding potential known problems from the outset. Along with providing a basic introduction to computational toxicology, the objectives of this symposium are to provide perspectives from both industry scientists and FDA regulators on the use of various predictive computational software programs. Some key topics of discussion will include:

Which and how many in silico software programs are necessary How to use a weight of evidence approach in predictive assessments Use of in silico predictions for evaluation of potential genotoxic impurities Addressing conflicting outputs from in silico predictions Use of computational models for prediction of hepatotoxicity Overview of FDA internal process for evaluating structural alerts Use of in silico predictions in regulatory decision making Limitations of current methodology


Boehringer Ingelheim & Cubist Pharmaceuticals, Inc.

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9:00 am AN INDUSTRIAL PERSPECTIVE ON MUTAGENICITY MODELING Catrin Hasselgren, Principal Scientist, AstraZeneca R&D

9:30 amAPPLICATION OF COMPUTATIONAL MODELS FOR TOXICOLOGY IN PHARMACEUTICAL DEVELOPMENT Nigel Greene, Associate Research Fellow, Pfizer Inc.

10:05 amCOMPUTATIONAL METHODS BASED ON CHEMICAL STRUCTURE – HOW USEFUL ARE THEY?Oliver Flint, Research Fellow, Bristol-Myers Squibb


10:55 amREGULATORY UTILITY OF IN SILICO PREDICTIONS: PERSPECTIVES FROM AN FDA REVIEWER Mark W. Powley, Pharmacologist, U.S. FDA

11:25 amTHE EXPERIENCE OF THE US FDA/CDER (Q) SAR GROUP: CRITERIA FOR USING COMPUTATIONAL TOXICOLOGY FOR CDER REGULATORY DECISIONSR. Daniel Benz, Computational Toxicologist, US FDA, CDER

27


MORNING SYMPOSIA

SYMPOSIUM VIIITHE USE OF IMAGING BIOMARKERS IN NONCLINICAL RESEARCH AND DEVELOPMENT AND IN CLINICAL TRIALS


A biomarker can be defined as any detectable biologic feature that provides information about its source. As a general term, it applies to any and all detection modalities. An imaging biomarker is a biologic feature detectable by imaging modalities. The use of imaging biomarkers in nonclinical research and development and in clinical trials is becoming a valuable tool in drug development. Before imaging biomarkers can be used as a surrogate endpoint in clinical trials, they must first be developed and validated in nonclinical models. They are also useful in the evaluation of efficacy and toxicity in nonclinical animal models. Clinical trials are known to be one of the most valuable sources of data in evidence-based medicine. For a pharmaceutical, device, or procedure to be approved for regular use in the U.S., it must be rigorously tested in clinical trials, and demonstrate sufficient efficacy. Unfortunately clinical trials are also extremely expensive and time consuming. End-points, such as morbidity and mortality, are used as measures to compare groups within a clinical trial. The most basic endpoint used in clinical trials, mortality, requires years and sometimes decades of follow-up to sufficiently assess. Morbidity, although potentially faster to measure than mortality, can also be a very difficult endpoint to measure clinically, as it is often subjective. These are some of the reasons why biomarkers have been increasingly used in clinical trials to detect subtle changes in physiology and pathology before they can be detected clinically. The use of surrogate endpoints (biomarkers) has been shown to significantly decrease the time and resources used in clinical trials. Because surrogate endpoints allow researchers to assess a marker rather than the patient, it allows participants to act as their own control, and in many cases allows for easier blinding. In addition to surrogate endpoints, imaging biomarkers can be used as predictive classifiers, to assist in selecting appropriate candidates for particular treatment. Predictive classifiers are frequently used in molecular imaging in order to ensure enzymatic response to therapy.


Flagship Biosciences & sanofi-aventis US

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LLC 9:00 am

USE OF IMAGING BIOMARKERS IN DRUG DISCOVERY AND IN RESEARCH AND DEVELOPMENT PROGRAMS Norman Barlow, Director, Sanofi

9:40 am

USE OF IMAGING BIOMARKERS IN BASIC RESEARCH AND APPLICATION TO THE DEVELOPMENT OF PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODELING FOR RISK ASSESSMENT O. Joseph Trask, Jr., Head, Cellular Imaging Core, The Hamner Institutes for Health Sciences


10:40 am USE OF DIGITAL PATHOLOGY TO PROVIDE AGGREGATE MEASUREMENTS OF EFFICACY AND TOXICITY IN NONCLINICAL AND CLINICAL STUDIES G. David Young, President and Chief Pathologist, Flagship Biosciences, LLC

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TUESDAY


11:20 amANALYZING DISCRETE BIOLOGICAL ENDPOINTS IN SOLID TUMORS UTILIZING NOVEL DIGITAL PATHOLOGY APPROACHES Joseph Krueger, Director of Biology, Flagship Biosciences, LLC

SYMPOSIUM IXTHE ELSIE DATABASE: EXTRACTABLES AND LEACHABLES KNOWLEDGE SHARING


Extractables and leachables (E&L) safety assessments are an essential element of the development process for pharmaceuticals, biologics and medical devices. Such assessments must be included in applications to health regulatory authorities. Although safety data on E&L is publicly available in scientific journals, government reports and databases, this data has never been incorporated into a single database. The Extractables and Leachables Safety Information Exchange (ELSIE) is a consortium of pharmaceutical, biotech, and medical device companies that is developing a database that will hold (i) safety information on E&L; and (ii) controlled extraction information from materials used in container closure systems and devices. The ELSIE database offers many potential benefits including reducing duplicative safety studies, streamlining the search for safety information for extractables and leachables, providing information that can be used early in the development process to facilitate the extractables evaluation process, and reducing the risk of leachables issues arising at the end of development. This symposium will include an introduction to the ELSIE database initiative, approaches to safety and chemical evaluation of E&L on which the database is built, and a demonstration of the database. The symposium will be of interest to toxicologists from the pharmaceutical, biologics and medical device industries; toxicologists from chemical manufacturers, pharmaceutical packaging engineers, chemists, and regulators.

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9:00 am INTRODUCTION AND BACKGROUND TO ELSIE AND THE ELSIE DATABASE Laurie Iciek, Principal Toxicologist, MedImmune

9:40 amSAFETY ASSESSMENT OF EXTRACTABLES AND LEACHABLES: CHALLENGES AND APPROACHES William P. Beierschmitt, Associate Research Fellow, Pfizer Global R&D


10:40 amTHE MATERIAL SELECTION PROCESS FOR DRUG PRODUCT PACKAGING/DEVICES AND THE ELSIE MATERIALS INITIATIVE Andrew Feilden, Principal Consultant, Smithers Rapra

11:20 amDEMONSTRATION OF THE ELSIE DATABASE Steve Beck, Development Manager, Non-clinical Safety Projects, GlaxoSmithKline Research & Development

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SYMPOSIUM XOLIGONUCLEOTIDE THERAPEUTICS: CURRENT ISSUES IN NONCLINICAL SAFETY TESTING AND REGULATORY PERSPECTIVES

McArthur 3

Oligonucleotides represent a growing class of new therapeutics. To date, oligonucleotides are regulated as small molecules. The Oligo Safety Working Group (OSWG), an international association of professionals from industry, academia and regulatory agencies, is evaluating the historical experience with oligonucleotides, with the aim of achieving an appropriate science-based approach to the toxicity testing of this class of drugs. This symposium will provide an overview of the structure, properties and applications the main of oligonucleotide subclasses (antisense, CpG, aptamer, siRNA, microRNA, etc.). The current position of the OSWG with regard to similarities and differences between the nonclinical safety testing strategies for oligos vs. small molecules vs. biologics will be presented, as well as the class effects that need to be taken into consideration during study design and interpretation. As an example, the challenges of advancing inhaled oligonucleotides to the clinic, including the interpretation of potential adverse effects and their relevance for human safety, will be discussed. The perspective of the regulatory agencies with regard to oligos in general, the OSWG recommendations, and future directions will be presented.


ISIS Pharmaceuticals

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9:00 amINTRODUCTION TO OLIGONUCLEOTIDE THERAPEUTICS: STRUCTURE, FUNCTION, AND APPLICATIONS Scott P. Henry, ISIS Pharmaceuticals

9:30 am OLIGOS: AKIN TO SMALL MOLECULES OR BIOLOGICS? Cindy L. Berman, Independent Consultant


10:15 amCLASS EFFECTS AND OTHER SPECIAL CONSIDERATIONS IN SAFETY TESTING OF OLIGOS Doug Kornbrust, President, Preclinsight

11:00 amPRECLINICAL SAFETY ASSESSMENT OF INHALED OLIGONUCLEOTIDES Nicolay Ferrari, Director Pharmacology, Topigen Pharmaceuticals, part of the Pharmaxis Ltd. Group

11:30 amOLIGONUCLEOTIDE THERAPEUTICS: A PHARM/TOX REVIEWER’S PERSPECTIVE Robert T. Dorsam, Pharmacologist, US FDA

30


12:00 – 2:00 PM Grand Ballroom

2012 PROGRAM PLANNING MEETING

WHATThis is a Program Brainstorming Session. It has been a useful mechanism for generating ideas for topics and sponsors that the Program Committee will assess over the coming months.

WHOAnyone interested in contributing ideas for Symposia, Continuting Education Courses or Plenary Lectures

WHY We need and value your input!

HOWJoin the incoming President-Elect and Program Committee Chair, Robin Guy, for a free brown-bag lunch and let the brainstorming begin!

NOTEPlease sign up for this session at the ACT Registration desk to ensure that we have enough food for all participants.

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TUESDAY


AFTERNOON SYMPOSIA

SYMPOSIUM XIALTERNATIVE APPROACHES FOR PRECLINICAL DEVELOPMENT OF BIOTHERAPEUTIC PRODUCTS

McArthur 1-2

As development of biotherapeutics becomes a more advanced science-based challenge, selection of relevant animal models, utility of traditional species and alternatives to traditional safety approaches are becoming more accepted. Assuring safety in humans is the first task of a well designed program but assuring safety and application to specific patient populations is also essential to targeted therapeutic products. The last ten years has seen significant advancement of knowledge in development of biotechnology products for treatment of chronic diseases. As therapies being developed are more sophisticated and generally more specific the need to establish safety in relevant models has become more of a challenge. Alternatives to traditional safety approaches include use of homologous proteins, transgenic animals, animal models of disease as well as state of the art non-invasive, non-terminal technologies such as high resolution imaging and scanning methods. Topics addressed in this symposium will include general issues related to differences between species that might contribute to species selection/interpretation, considerations into the development of a homologous protein, and development and characterization of animal models as relevant species (including KO animals and models of disease). This symposium will appeal to a broad ACT audience as more companies are developing biologic therapies for use.


BASi

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2:00 pmWELCOME AND INTRODUCTIONLaura Andrews, Vice President, Pharmacology/Toxicology Genzyme Corporation

2:05 pmTHE CHALLENGES AND CONSIDERATIONS OF HOMOLOGOUS MOLECULES USED IN BIOPHARMACEUTICAL DEVELOPMENT Donna Lee, Associate Scientist, Safety Assessment, Genentech

2:45 pmANIMAL MODELS OF DISEASE: UNIQUE OPPORTUNITIES AND CHALLENGES Marque Todd, Regulatory Strategy Lead, Pfizer, Inc.


3:40 pmA TRANSGENIC ANIMAL MODEL AS A USEFUL AND RELEVANT TOOL FOR SAFETY STUDIES: A CASE PRESENTATION James Murray, Staff Scientist, Toxicology, Genzyme Corp

4:20 pmA REGULATORY PERSPECTIVE M. Stacey Ricci, Senior Toxicologist, US FDA

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SYMPOSIUM XIIPHYSIOLOGICAL BIOMARKERS IN TOXICOLOGY AND SAFETY PHARMACOLOGY


The development, understanding, and use of biomarkers in drug development and in translational prediction of later outcomes have long been scientific challenges. In recent years the amount of information in this area of biomarker development has exploded. Confident data based decision making in assessing toxicological and pharmacological safety of new compounds in preclinical models is tightly linked to construction of studies and models that yield understanding of complex physiological system changes. Physiological parameter assessment accuracy and predictive parameter utility in making new compound development science based decisions is critical. Experts will share recent pre-clinical physiological biomarker project experience and recent physiological study data from a perspective of predictive understanding. Their history of overcoming obstacles in practical situations will place emphasis on learning where current advanced methods and tools can provide better understanding and better predictive outcomes.


DATA SCIENCES INTERNATIONAL

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2:00 pmWELCOME AND INTRODUCTIONSteven Hachtman, Director of Application Development, Data Sciences International

2:10 pmBIOMARKERS AND TRANSLATION: WHERE ARE PHYSIOLOGICAL BIOMARKERS EFFECTIVE IN TOXICOLOGY AND SAFETY ASSESSMENT? Rob Wallis, Executive Director, Early Candidate Leads, Pfizer UK

2:40 pm

CARDIAC PHYSIOLOGY AND CARDIOVASCULAR TOXICITY… DO WE HAVE MODELS AND MARKERS THAT MAKE SENSE AND WORK Robert Hamlin, Professor Veterinary Med, Prof. Biomed Eng., Ohio State University

3:10 pmIMPROVING CARDIOVASCULAR ASSESSMENT IN CANINE TOXICOLOGY STUDIES Pierre Lainee, Principle Scientist R & D, Astra Zeneca, UK


4:00 pmBLOOD PRESSURE ASSESSMENT AS A MARKER IN REGULAR TOXICOLOGY STUDIES Mark Niehoff, Study Director Toxicology, Covance Laboratories

4:30 pm

FUNCTIONAL BIOMARKERS IN THE INTEGRATED STUDY DESIGN: WHAT MAKES SENSE AND WHEN Ted Baird, Senior Director Safety Pharmacology and Neurobehavioral Sciences, MPI Research

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TUESDAY


SYMPOSIUM XIIINEW DATA ON THE TOXICOLOGY OF PETROLEUM HYDROCARBONS Frank Lloyd Wright G-HPetroleum products are complex chemical substances that have a wide range of uses beyond the familiar motor gasoline. Human or environmental exposure to low levels of petroleum hydrocarbons can occur from various sources. A number of recent and important toxicology programs on petroleum hydrocarbons are nearing completion in 2011, encompassing risk assessment, hazard assessment and prediction models, including

an updated risk assessment for the consumption of mineral hydrocarbons via food completion of two plus decades of research on the possible carcinogenicity of asphalt fumes approach to the hazard assessment of complex petroleum streams using reference chemicals and read-

across for categories of similar compounds development of a statistical analysis of chromatography data to predict toxicity endpoints for PAH-

containing petroleum streams.These topics will be surveyed and summarized in this symposium following a short overview of the nature of petroleum substances and the general approach to their toxicological evaluation.


EXXONMOBIL BIOMEDICAL SCIENCES, INC. & AMERICAN PETROLEUM INSTITUTE & ASPHALT INSTITUTE

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2:00 pmOVERVIEW OF PETROLEUM SUBSTANCE James J. Freeman, Distinguished Toxicology Associate, ExxonMobil Biomedical Sciences, Inc.

2:30 pmASSIGNING AN ADI TO WHITE MINERAL OIL: USE OF PHARMACOKINETIC DATA Peter J. Boogaard, Senior Toxicologist, Shell International bv


3:15 pmRECENT STUDIES ON THE POTENTIAL CARCINOGENICITY OF ASPHALT FUMES Charles R. Clark, Principal Toxicology Consultant, ConocoPhillips Company

3:50 pmHAZARD CHARACTERIZATION OF COMPLEX PETROLEUM SUBSTANCES Richard H. McKee, Distinguished Toxicology Associate, ExxonMobil Biomedical Sciences, Inc.

4:25 pmPREDICTION OF TOXICITY BASED ON A STATISTICAL ANALYSIS OF AROMATIC COMPOUNDS PRESENT IN A PETROLEUM STREAMMark Nicolich, Consultant in Biostatistics, Cogimet

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TUESDAY


SYMPOSIUM XIVNEW DRUG APPLICATION (NDA): INDUSTRY AND REGULATORY PERSPECTIVES ON THE MAKE-UP AND EVALUATION OF THE NONCLINICAL COMPONENTS SUPPORTING APPROVAL

McArthur 3

Since 1938, the regulation and control of new drugs in the United States has been the subject of an approved New Drug Application (NDA). The NDA and Biologics Licence Application (BLA) are the vehicles through which sponsors formally propose that the Food and Drug Administration (FDA) approve a new pharmaceutical drug or biologic for sale and marketing in the U.S. This symposium will concentrate on small molecules. The NDA should provide sufficient information to permit FDA reviewers to reach the following key decisions:- The safety and efficacy of the drug in its proposed use(s), and whether benefits of the drug outweigh the risks. - The appropriate wording of the drug's proposed labeling (package insert).- The adequacy of the methods in the manufacture and the controls used to maintain the drug's identity, strength, quality, and purity.The data gathered from the animal studies and human clinical trials during the lengthy development cycle under an Investigational New Drug (IND) become an integral part of the NDA. The conduct of proper nonclinical and clinical studies to generate adequate data that demonstrate the safety and efficacy of a drug is imperative, as is the manufacture and formulation of drug substance and drug product is equally important. Given the importance of an NDA document, this symposium reviews the current thought process on nonclinical aspects of the NDA from an industry perspective and from within the Office of New Drugs (OND) under the Center for Drug Evaluation and Research (CDER) at the FDA. Various steps during this process (IND packages, pre-NDA meeting, format and content of NDA per electronic Common Technical Document (eCTD), NDA submission process, Refusal to File, review cycles, advisory committees, labeling process and post-approval commitments) will be discussed. The interactions within a company and a reviewing division, consulting divisions if applicable, and the relevant Office of Drug Evaluation (ODE) level will be described and presentations will include examples. Additionally, the session will discuss the history of drug approval process, the impact of the NDA process since the enactment of the Prescription Drug User Fee Act (PDUFA) in 1997, and potential changes in the future. A Q&A session will follow the presentations.

2:00 pmINTRODUCTIONNorman Kim, Director, Pharmacotoxicology, Biogen Idec and Timothy J. McGovern, Consultant, SciLucent LLC

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2:05 pmINDUSTRY VIEW POINT OF NONCLINICAL ISSUES IN DRUG DEVELOPMENT AND NDA Clynn Wilker, Ardea Biosciences

2:40 pmIND AND NDA REVIEW PROCESS – PERSPECTIVES FROM A PRIMARY REVIEWER Amy Ellis, Pharm/Tox Reviewer, US FDA, CDER, OND


3:30 pm NDA PROCEDURES – SECONDARY REVIEW PERSPECTIVES Lynnda Reid, Supervisory Pharmacologist, US FDA, CDER, OND

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4:05 pmNONCLINICAL REGULATORY & SAFETY OVERVIEW FOR NONPRESCRIPTION (OVER THE COUNTER) PRODUCTS AT THE FDA Wafa A. Harrouk, Senior Pharmacology/Toxicology Reviewer, US FDA. CDER, OND, ODEIV

4:40 pm DISCUSSIONS, Q&A

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TUESDAY


POSTER SESSION & SAGE RECEPTION

5:30 – 7:00 Frank Lloyd Wright A-D

POSTER SESSION AND SAGE RECEPTION

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WEDNESDAY, NOVEMBER 9, 2011

SCHEDULE

7:00 am – 8:00 am Continental Breakfast Frank Lloyd Wright Prefunction


8:00 am - 8:45 am Plenary Lecture Frank Lloyd Wright F


Symposium XV Frank Lloyd Wright A-B

Symposium XVI Frank Lloyd Wright I-J

Symposium XVII Frank Lloyd Wright G-H


Symposium XVIII Frank Lloyd Wright F

4:30 pm Close

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PLENARY LECTURE: “ FALLOUT FROM FALLOUT: RISKS VERSUS HYPE”

PLENARY LECTURE8:00 am – 8:45 am Frank Lloyd Wright F

Jacqueline P. Williams, Ph.D.Research Professor

University of Rochester School of Medicine & DentistryDepartment of Radiation Oncology

“FALLOUT FROM FALLOUT: RISKS VERSUS HYPE”

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MORNING SYMPOSIA

SYMPOSIUM XVADVANCES IN ASSESSING THE SAFETY OF NEW FOOD ADDITIVES AND FOOD CONTAMINANTS

Frank Lloyd Wright A-B

The safety evaluation of a new food additive and food contaminants is a complicated, time consuming and expensive process. The aim of this symposium is to explore how progress in our understanding of structure-activity relationships and computational toxicology methods can serve to facilitate food safety evaluations and reduce the need for extensive animal testing. Approaches to evaluating chemical structures and functional groups are continuously evolving. This session will provide updates on refinements to the Cramer et al. (1978) Decision Tree (DT) and application of the tiered Threshold of Toxicological Concern (TTC) approach. In addition, recent advances in the use of computational toxicology tools for the evaluation of quantitative structure-activity relationships (QSAR) of botanically-derived food additives will be discussed. Computational toxicology employing QSAR modeling is an evidence-based predictive method that is currently being used by regulatory agencies for risk assessment and scientific decisions to support toxicological endpoints of interest. The current status of how regulatory agencies (e.g. FDA) use QSAR as a decision support tool, in conjunction with other information for a weight-of-evidence approach, will be addressed. This symposium will provide a thorough overview of both traditional (DT and TTC) and contemporary (computational modeling) approaches to structure-activity assessments and their potential application for safety evaluation of direct food additives and contaminants.


PEPSICO INC.

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9:00 amSTRUCTURE-BASED THRESHOLD OF TOXICOLOGICAL CONCERN IN RISK ASSESSMENT Susan P. Felter, Proctor & Gamble Company

9:35 am

REDEFINING THE CRAMER DECISION TREE FOR SAFETY EVALUATION OF NEW FOOD ADDITIVES Timothy B. Adams, Scientific Director, The Flavor and Extract Manufacturers Association

10:10 am

APPLICATION OF THE MARGIN-OF-EXPOSURE (MOE) APPROACH TO FOOD ADDITIVES Michael J. DiNovi, Chemist, US FDA, Center for Food Safety and Applied Nutrition


11:00 amCHEMOINFORMATICS APPROACHES FOR TOXICOLOGY PREDICTIONS Kevin P. Cross, Vice President of Product Engineering, Leadscope, Inc.

11:30 amREGULATORY USE OF COMPUTATIONAL TOXICOLOGY TOOLS AND DATABASES AT THE FDA, OFFICE OF FOOD ADDITIVE SAFETY Kirk B. Arvidson, US FDA, Center for Food Safety and Applied Nutrition

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WEDNESDAY


SYMPOSIUM XVIFDA-INDUSTRY DIALOGUE ON THE DRAFT GUIDANCE ON ASSESSMENT OF ABUSE POTENTIAL OF DRUGS


Publication in early 2010 of the draft FDA guidance on assessment of abuse potential of drugs has sharpened interest in the complexities of evaluating the abuse liability of new pharmaceuticals. The draft guidance is comprehensive in its scope, covering the chemistry, manufacturing, animal behavior studies, clinical studies and post-marketing experience that comprises assessment of abuse potential of a new drug. Understanding the intricacies of this path has been the topic of discussion in various venues in the scientific community and in November 2010 led to a day-and-a-half dialogue session between representatives of the pharmaceutical industry and members of FDA's Controlled Substances Staff (CSS). This symposium will highlight important discussion points of this scientific communication session and will explore key issues still open for debate. Topics for discussion will include preclinical and clinical study designs, regulatory expectations, and a proposed flow chart that synthesizes the draft guidance's recommendations for preclinical abuse liability assessments. The dialogue session was a unique opportunity for industry and regulators to engage in open exploration of the intersection between science and the regulation of evaluating new drugs for abuse potential.

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SUMMARY OF ISSUES COVERED IN THE FDA-INDUSTRY 2010 DIALOGUE SESSION ON THE DRAFT GUIDANCE ON ASSESSMENT OF ABUSE POTENTIAL OF DRUGS Jennie L. Walgren, Senior Research Scientist, Eli Lilly and Company

9:30 amSTUDY DESIGN OF ANIMAL BEHAVIOR STUDIES Kristin Horn, Research Investigator II, Bristol-Myers Squibb


10:20 amCLINICAL STUDY DESIGN CONSIDERATIONS Marta Sokolowska , Director, Center of Excellence for Abuse Liability, Grünenthal USA, Inc.

10:50 amREGULATORY EXPECTATIONSBeatriz Rocha, Director, Merck & Co., Inc.

11:20 amFLOW CHART HIGHLIGHTING KEY DECISION POINTS IN PRECLINICAL PROGRESSIONMary Jeanne Kallman, Director, Neuroscience, Covance Laboratories, Inc.

11:50 am Q&A

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SYMPOSIUM XVIIANIMAL WELFARE: WHERE SCIENCE MEETS ETHICS Frank Lloyd Wright G-HThe session is intended to stimulate thinking, awareness, and understanding of the place where animal welfare and changing regulatory guidelines connect to contemporary toxicology and pharmacology. Recent regulatory directives in Europe and new laboratory animal care and use guidances in the USA are increasing the focus on animal welfare considerations in our laboratories and research studies. The speakers bring a variety of perspectives to the forefront of consideration in planning and conducting modern toxicology and safety studies while sharing their successes in achieving both scientific excellence and animal welfare goals.


CHARLES RIVER

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9:00 amWELCOME AND INTRODUCTIONRussette Lyons, Head, Education Office, Novartis Institutes of Biomedical Research

9:15 am

WHAT’S NEW IN ANIMAL WELFARE AND IN THE NEW GUIDE? WHERE DID WE COME FROM, WHY ARE WE HERE AND WHERE ARE WE GOING? Patricia V. Turner, Assoc. Prof. Dept. Pathobiology, Program Leader Graduate Studies in Laboratory Animal Sciences, University of Guelph

9:50 am

SCIENCE, 3R’S AND EXPERIMENTAL DESIGN…. SHIFTING THE BALANCE WITH NEW TECHNOLOGY AND BETTER EXPERIMENTAL DESIGNS TO SUPPORT IMPROVED ANIMAL WELFARE Henry Holzgrefe, Scientific Advisor, Navigator Services, Charles River Laboratories


10:45 am

DIRECTIVE 2010/63/EU: THE RENEWED EUROPEAN FOCUS ON PROTECTION OF ANIMALS USED FOR SCIENTIFIC PURPOSES AND ITS INFLUENCE ON OUR RESEARCH Karen Blumer, Scientific Affairs/Global Animal Welfare Policies, Novartis International AG

11:25 amDEPARTMENTAL COOPERATION FOR BETTER SCIENCE AND BETTER WELFARE: A CASE STUDY Russell Bialecki, Associate Director of Safety Pharmacology, AstraZeneca

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WEDNESDAY


AFTERNOON SYMPOSIUM

SYMPOSIUM XVIIIHOT TOPICS! Frank Lloyd Wright F

The Hot Topics session will provide a variety of topics that include key updates to the International Conference on Harmonization (ICH) Guidelines and FDA regulatory perspectives that serve as a guide to Pharmaceutical Safety Evaluation. Presentations will be provided by members of the ICH working committee and other regulatory professionals that have unique insights into the regulatory process. In addition, multiple late-breaking hot topics will be included in the program as ~10-minute overviews of broad interest topics. Examples from last year include discussion of “Recent FDA Facility Audit Citations – Impact Perspective and Collaborative Industry Responses,” and “FDA Update - Pregnancy and Lactation Labeling Rule.” This session is critical for regulatory toxicologists in the pharmaceutical industry as well as those that are impacted by evolving regulatory requirements which includes a majority of ACT attendees including industry, CRO, and academic scientists.


SCILUCENT, LLC

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1:30 pm INTRODUCTIONDrew Badger, Director of Global Regulatory Affairs, Amgen Inc.

CURRENT STATUS OF BIOSIMILAR LEGISLATION Barbara J. Mounho, Amgen Inc.

PERSPECTIVES OF A PHARM/TOX REVIEWER IN THE PULMONARY, ALLERGY, AND RHEUMATOLOGY PRODUCTS DIVISION Molly (Shea) Topper, Pharmacology/Toxicology Supervisor, US FDA, CDER, Division of Pulmonary, Allergy, and Rheumatology Products


ICH S6 UPDATE Shawn M. Heidel, Director, Toxicology, Eli Lilly and Company

UPDATE ON ICH M7 GUIDANCE WITH EMPHASIS ON QSAR AND GENOTOXIC IMPURITIESKenneth L. Hastings, Associate Vice President, Regulatory Policy, sanofi-aventis

44


INSTRUCTIONS FOR PREPARING POSTERS

FOR THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF TOXICOLOGY

The Poster Session has been scheduled for Tuesday, November 8, 2011 from 5:30 pm until 7:00 pm. You have been assigned a number for the exact location of your poster.

Each presentation is assigned a 4’ x 8’ cork board that includes 2.2. square meters (24 square feet) on which to display data. Please identify your poster with a title and the names of the investigators in 1” (2.5 cm) lettering at the top of the display. It is very helpful to post a copy of your abstract.

Micrographs, photomicrographs, charts, and graphs should be mounted on firm mounting board. Matte finish on photographs gives the best visibility. Matte surface paper may be used, or you can simply dry glossy prints with the emulsion side of the paper facing away from the drying drum surface.

Presenters should provide their own push pins (5/8” long) for attaching posters to the display unit.

The Poster Boards will be available Sunday evening, November 6, 2011. Posters should be set up by Monday morning to be available for as long as possible to attendees.

You are expected to be present at your poster for discussion and to answer questions during the 5:30 pm to 7:00 pm Poster Session, Tuesday, November 8, 2011.

Please remove your posters at the end of the session (7:00 pm) on Tuesday evening . ACT IS NOT RESPONSIBLE FOR REMOVING OR STORING POSTERS.

45

WEDNESDAY


SYMPOSIA AND CONTINUING EDUCATION COURSECHAIRS AND SPEAKERS

46

Timothy B. Adams, Ph.D. Scientific Director The Flavor & Extract Manufacturers Associate 1620 I Street, N.W.Washington, D.C., 20006-4035202.293.5800 [email protected]

Laura Andrews, PhD., DABT, Fellow ATSVice President, Pharmacology and ToxicologyGenzyme5 Mountain RoadFramingham, MA 01701508-271-3713 [email protected]

Kirk B. Arvidson, Ph.D. ChemistUS FDACFSANOffice of Food Additive SafetyHFS-275College Park, MD 20770301.436.1152 [email protected]

Carol S. Auletta, DABT, MBA, RACDirector, Program ManagementHuntingdon Life SciencesP. O. Box 2360Mettlers RoadEast Millstone, NJ 08875-2360732- 873-2550 x2960 [email protected]

Shana Azri-Meehan, Ph.D., DABT Senior Principal Scientist Forest Research Institute Harborside Financial CenterPlaza VJersey City, New Jersey 07311201.437.8451 [email protected]

Cristian Tudorel Badea, Ph.D.Associate Professor, RadiologyDuke University Medical School Center for In Vivo MicroscopyRoom 139, Bryan Research Building for NeurobiologyDurham, NC [email protected]

Drew A. Badger, PhD, DABTDirector, Regulatory AffairsAmgen Inc.One Amgen Center DriveThousand Oaks, CA [email protected]

Ted Baird, Ph.D.Senior Director Safety Pharmacology & Neurobehavioral SciencesMPI Research54943 North Main StreetMattawan, MI 49071269.377.5181 [email protected]

Stephen A. Barat, Ph.D. DirectorForest Research InstituteHarborside Financial CenterPlaza VJersey City, New Jersey 07311201.437.8441 [email protected]

Norman Barlow, DVM, PhD, MBA, MLD, DACVP, DABT Director Sanofi1041 Route 202-206Mail Code: JR2-103ABridgewater, NJ 08807908.231.2733 [email protected]

mailto:[email protected]










Steve BeckDevelopment Mgr., Non-clinical Sfty ProjectsGlaxoSmithKline Research & Development3F69Park RoadWare, Hertfordshire, SG12 0DOEngland, UK [email protected]

William P. Beierschmitt, PhD, DABTAssociate Research FellowPfizer Global R&DDrug Safety Research & DevelopmentEastern Pt Rd., Bldg. 274Groton, CT 06340860.441.5245 [email protected]

Lisa Beilke, PhD.Research Scientist IIGilead Sciences, Inc.Safety Evaluation Department333 Lakeside DriveFoster City, CA650.522.6361 [email protected]

R. Daniel Benz, Ph.D.Computational ToxicologistUS FDA, CDEROffice of Testing and Research2012 W06410903 New Hampshire AvenueSilver Spring, MD 20993301.796.1645 [email protected]

Cindy L. Berman, Ph.D. Independent Consultant15 Campbell RoadWayland, MA 01778508.358.4906 [email protected]

Brian R. Berridge, DVM, Ph.D. Director, Regulatory & Discovery Pathology GlaxoSmithKline Safety Assessment 5 Moore Dr., RD9.3005Research Triangle Park, NC [email protected] m

Russell Bialecki, PhDAssociate Director of Safety Pharmacology

Astra ZenecaP. O. Box 15431800 Concord PikeWilmington, DE 19850-5437302.886.5356 [email protected]

Karen Blumer, Ph.D.Scientific Affairs/Global Animal Welfare PoliciesNovartis International AGForum 1Novartis CampusCH-4056 BaselSwitzerland+41.61.3242675 [email protected]

Brad BolonAssociate Professor – ClinicalDepartment of Veterinary BiosciencesThe Ohio State University1900 Coffey Road – 350 VMABColumbus, OH 43210614.292.0676 [email protected]

Peter J. BoogaardSenior ToxicologistShell International bvPO Box 1622501 AN The Hague, The Netherlands+31 70 37 72 123 +31 70 37 72 [email protected]

William J Brock, Ph.D., DABT, ATS PrincipalBrock Scientific Consulting19909 Hamil CircleMontgomery Village, MD 20886301.519.3666 [email protected]

Alan P. Brown, Ph.D., DABTSenior Toxicology ConsultantIntegrated Nonclinical Development Solutions Inc.3005 Miller AvenueAnn Arbor, MI 48103734.929.5392 [email protected]

SPEAKERS













Florence G. Burleson, Ph.D. Executive Vice PresidentBRT – Burleson Research Technologies, Inc.120 First Flight LaneMorrisville, NC 27560919.719.2500 [email protected]

Gary R. Burleson, Ph.D. President BRT – Burleson Research Technologies, Inc.120 First Flight LaneMorrisville, NC 27560919.719.2500 [email protected]

Joseph W. Carraway, DVM, M.S.Director, ToxicologyNAMSA6750 Wales RoadNorthwood OH 43619-1012419.662.4440 419.666.2954

Charles R. ClarkPrincipal Toxicology ConsultantConocoPhillips Company1204 Phillips BuildingBartlesville, OK [email protected]

Robert W. Coatney, DVM, Ph.D. Director, Comparative Biology and Medicine GlaxoSmithKline P.O. Box 1539, UW2630King Of Prussia, PA 19406 610.270.4523 [email protected]

David Compton, PhD, DABT Principal Research Investigator sanofi-aventis 1041 Route 202-206, PO Box 6800Mail code: JR2-103ABridgewater NJ 08807-0800908.541.5328 [email protected]

Laura A Conour, DVM, DACLAMDirector, Research ResourcesPrinceton UniversityOffice of the Dean of Research91 Prospect AvenuePrinceton, NJ 08540609.258.7857 [email protected]

Mary Ellen Cosenza, Ph.D., DABT Emerging Markets International Regulatory Affairs and Safety Regulatory AffairsAmgen Inc.One Amgen Center Drive 38-4-C Thousand Oaks, CA 91320805.447.6318 [email protected]

Kevin P. CrossVice President of Product EngineeringLeadscope, Inc.1393 Dublin RoadColumbus, OH [email protected]

Jon Daniels, Ph.D., DABT, ERTExecutive Vice President/ Senior ToxicologistIntrinsik Health Sciences, Inc.6605 Hurontario Street, Suite 500Mississauga, Ontario L5T [email protected]

John P. Devine, DABTGeneral Manager BASi10424 Middle Mount Vernon RoadMount Vernon, IN 47620812-985-3400 (X 102)[email protected]

Michael J. DiNovi, Ph.D. ChemistUS FDACFSANHFS-255Riverdale, MD 20770301.436.1320 [email protected]










mailto:[email protected]/[email protected]


John Dooley, Ph.D.Senior Research Fellow, Preclinical R&DCodman & Shurtleff, Inc.(Division of Johnson & Johnson)Welsh & McKean RoadsP. O. Box 776Spring House, PA 19477-0776215.628.5315 [email protected]

Robert T. Dorsam, Ph.D.PharmacologistUS FDADivsion of Drug Oncology Products10903 New Hampshire AvenueWO Bldg., Rm. 2366Silver Spring, MD [email protected]

Holly Dursema, MS, DABTSenior Principle ScientistBoehringer Ingelheim Pharma, Inc.900 Rodgebury RoadRidgefield, CT [email protected]

Kimberly D. Ehman, Ph.D., DABTSenior Toxicologist, Program ManagerToxicology Regulatory Services2365 Hunters WayCharlottesville, VA 22911434.977.5957 [email protected]

Amy Ellis, Ph.D.Pharm/Tox ReviewerUS FDA CDER, OND10903 New Hampshire AvenueSilver Springs, MD 20993301.796.1400 [email protected]

Nancy Everds, DVM, DACVPClinical PathologistAmgen Inc.1201 Amgen Court WestSeattle, WA 98119206.265.8334 [email protected]

Dr Andrew Feilden CSci CChem MRSCPrincipal ConsultantSmithers Rapra ShrewsburyShropshire, SY4 4NRUnited Kingdom +44 (0)1939 250383Direct Dial +44 (0)1939 252418 [email protected]

Susan P. Felter, Ph.D.Procter & Gamble CompanyMiami Valley Innovation CenterP. O. Box 538707Cincinnati, OH 45253-8707513.627.1958 513.386.1504f [email protected]

Nicolay Ferrari, Ph.D.Director PharmacologyTopigen Pharmaceuticals part of Pharmaxis Ltd Grp2901 Rachel Street East, Suite 13Montreal, QB, H1W 4A4Canada514.868.0077 x239 [email protected]

Oliver Flint, Ph.D.Research FellowBristol-Myers SquibbP. O. Box 5400Princeton, NJ [email protected]

James J. Freeman, Ph.D., DABTDistinguished Toxicology AssociateExxonMobil Biomedical Sciences, Inc. (EMBSI) 1545 Route 22 EastAnnandale NJ 08801908-730-1123 [email protected]

Shayne C. Gad, Ph.D., DABT, ATSPrincipalGad Consulting Services102 Woodtrail LaneCary, NC 27518919.233.2926 [email protected]













Alema Galijatovic-Idrizbegovic, Ph.D. Associate DirectorMerck & Co., Inc.Dept. of Safety Assessment770 Sumneytown Pike, WP45-201West Point, PA [email protected]

Prof. Dr. Paul-Georg Germann, DVM, MSC Toxicol, DECVP, Fellow IATPSr. Vice President, Discovery to Preclin DvlpmntNycomed GmbHByk-Gulden-Str.2Konstanz, 78467Germany0049.151.18056573 [email protected]

Hanan Ghantous, Ph.D., DABT Supervisory ToxicologistUS FDA, CDER, OND, OAP10903 New Hampshire AveCDER/OND/OAP/Div. of Antiviral ProductsSilver Spring, MD 20903301.796.1500 [email protected]

Gary A. Gintant, Ph.D.Research Fellow Chairman, Abbott QT Working Group Global Pharmaceutical R&DAbbott100 Abbott Park RdAbbott Park , IL [email protected]

Warren E. Glaab, Ph.D. Safety Assessment Merck and Co. 770 Sumneytown Pike-WP45-320West Point, PA 19486-0004215.652.8398 [email protected]

Thomas GraySenior Scientific AdvisorAmerican Petroleum Institute1220 L Street, N.W.Washington, DC202.682.8480 [email protected]

Nigel Greene Ph.D.Associate Research Fellow Pfizer Inc. Compound Safety Prediction GroupWorldwide Medicinal ChemistryMS 8118-B3Eastern Point RoadGroton, CT 06340860.715.4921 [email protected]

Markus Grompe, M.DDirector, Oregon Stem Cell CenterFounder and Chief Scientific OfficerYecuris CorporationOregon Health & Science University3181 SW Sam Jackson Park RoadPortland, OR 97239503.494.6888 [email protected]

Robert J. Guttendorf, RPh, Ph.D. Sr. Consultant, DMPK Aclairo Pharma Development Group, Inc. 1950 Old Gallows Rd., Suite 300Vienna, VA 22182703.506.6760, Ext 316 [email protected]

Robin Guy, MS, DABTRobin Guy Consulting, LLCP.O. Box 830Lake Forest, IL 60045847.295.9250 [email protected]

Steve Hachtman, MADirector of Applications DevelopmentDSI119 14th Street NWSt Paul, MN [email protected]

Robert Hall, DVM, Ph.D., DACVP Clinical PathologistCovance Laboratories Inc. 3301 Kinsman Blvd.Madison, WI 53704608.242.2712 ext. [email protected] m













Robert L. Hamlin, Ph.D., DVMProfessor Veterinary Med, Prof. Biomed Eng.Ohio State University480 VMAB1900 Coffey RoadColumbus, OH614.292.8122 [email protected]

Jeff A. Handler, Ph.D., MBA, DABTPresidentJAH Associates, LLC651 Crestwood RoadWayne, PA 19087610.716.1848 [email protected]

Jerry F. Hardisty, DVM, DACVP, Fellow IATPCEO/Veterinary PathologistEPL, Inc.P.O.Box 12766Research Triangle Park, NC 27709919.998.9407 [email protected]

Patricia P. Harlow, Ph.D. Pharmacologist US FDA 10903 New Hampshire AvenueSilver Spring, MD 20993-0002301.796.5318 [email protected]

Alison Harrill, Ph.D. Hamner Center for Drug Safety Sciences The Hamner Institutes for Health Sciences 6 Davis DriveP.O. Box 12137Research Triangle Park, North Carolina 27709919.558.1200 [email protected]

Wafa A. Harrouk, M.Sc., Ph.D.Senior Pharmacology/Toxicology ReviewerUS FDA, CDER, OND, ODEIV10903 New Hampshire AvenueSilver Spring, MD 20993301.796.0908 [email protected]

Melanie Hartsough, Ph.D. Senior ConsultantBiologics Consulting Group, Inc. 400 N. Washington Street, Suite 100Alexandria, VA 22314301.742.3665 [email protected]

Catrin HasselgrenPrinicipal ScientistAstraZeneca R&DGlobal Safety AssessmentPepparedsleden 1MoIndal, Sweden+46 (0) 31 7064283 +46 (0) [email protected]

Craig R. Hassler PhDManager of Safety PharmacologyBattelle Memorial Institute505 King Ave. Columbus OH [email protected]

Kenneth L. Hastings, DrPH, DABT, ATSAssociate VP, Regulatory Policysanofi-aventisCorporate Reg Affairs Office4520 East West Highway, #210Bethesda, MD 20814301. 771.4267 [email protected]

Shawn M. Heidel, DVM, PhDDirector, Toxicology Eli Lilly and Company Lilly Corporate Center, DC1940 Indianapolis, IN 46285 317.433.5876 [email protected]

Scott P. Henry, Ph.D.ISIS Pharmaceuticals2292 Faraday AvenueCarlsbad, CA 92008760.603.3813 [email protected]













David W. Hobson, Ph.D., DABTPresidentLoneStar Pharm Tox LLC613 Pleasant Valley DriveBoerne, TX 78006210.269.6169 [email protected]

Dr. Henry HolzgrefeScientific Advisor, Navigator ServicesCharles River Laboratories6995 Longley LaneReno, NV [email protected]

Kristin Horn, Ph.D. Research Investigator II Bristol-Myers Squibb 4601 Hwy 62 EastBuilding 101P.O. Box 1500Mt. Vernon, Indiana 47620812.307.2196 [email protected]

Kristina Howard, D.V.M., Ph.D. Commissioner’s FellowU.S. Food and Drug AdministrationN29B RM4G139000 Rockville PikeBethesda, MD [email protected]

Timothy HummerPharmacology/Toxicology ReviewerUS FDACDER10903 New Hampshire AvenueWhite Oak Bldg. 22, Rm. 3109Silver Spring, MD [email protected]

Laurie Iciek, PhDPrincipal ToxicologistMedImmuneBiologics Safety Assessment; Translational ScienceOne MedImmune WayGaithersburg, MD 20878301.398.4793 [email protected] Jeff JamisonOphthy-DS, Inc. and MPI Research

54943 N. Main Street Mattawan, MI 49071269.250.2177 [email protected]

G. Allan Johnson, Ph.D. Charles E. Putman Professor of Radiology, Physics, and Biomedical Engineering Duke University Medical Center Center for In Vivo Microscopy Room 139, Bryan Res Bldg. for NeurobiologyDurham, NC [email protected]

Mary Jeanne Kallman, Ph.D. Director, NeuroscienceCovance Laboratories, Inc.671 S. MeridianGreenfield, IN 46140-5006317.467.2428 [email protected]

Thomas T. Kawabata, Ph.D.Pfizer, Inc.MS 8274-1206Groton, CT [email protected]

Norman Kim, M.S., DABTDirector, PharmacotoxicologyBiogen Idec, Inc.14 Cambridge CenterCambridge, MA [email protected]

Fred Kirchner, Ph.D. Executive Director, Toxicology, Pathology, Safety PharmacologyCovance Labs. 3301 Kinsman BoulevardMadison, WI 53532608 [email protected]













Doug Kornbrust, Ph.D., DABTPresident Preclinsight7245 Lingfield DriveReno, NV 89502775.857.4113 [email protected]

Joseph Krueger, Ph.D.Director of BiologyFlagship Biosciences5 Ivy LaneAndover, MA [email protected]

Periannan Kupasami, Ph.D. ProfessorThe Ohio State University College of Medicine420 W 12th Ave. Columbus OH [email protected]

Pierre LaineePrinciple Scientist R & DAstra Zeneca, UKMacclesfield England, United [email protected]

Richard W. Lane, Ph.D., DABT Scientific & Regulatory Affairs PepsiCo350 Columbus AvenueValhalla, NY 10595914.742.4538 [email protected]

Donna Lee, PhD, DABTAssociate Scientist, Safety AssessmentGenentech1 DNA WaySouth San Francisco, CA 94080650-467-4587l [email protected]

Kathy Lee, Ph.D.Lead Interdisciplinary Scientist US FDA-CDER900 Rockville PikeN29A, Rm. 2D16Bethesda, MD [email protected]

Patrice LeeSenior Director of Pharma and ToxicologyArray BioPharma, Inc.3200 Walnut StreetBoulder, CO 80301303.386.1482 [email protected]

Serguei Liachenko Director, Bio-Imaging US FDA, NCTR NCTR/OCS/NCTR/DDR/DNT Mail stop HFT-1323900 NCTR RoadJefferson AR 72079870.543.7203 [email protected]

Gordon R. Loewen, Ph.D. Sr. Dir., Drug Metabolism & Pharmacokinetics Infinity Pharmaceuticals 780 Memorial Dr.Cambridge, MA 02139617.453.1341 [email protected]

Russette M. Lyons, PhDHead, Education OfficeNovartis Institutes for BioMedical Research250 Massachusetts Avenue607/931FCambridge, MA 02139617. [email protected]

Peter C. Mann, DVM, DACVPManager, EPL NorthWestEPL, Inc.2544 13th Avenue, WSeattle, WA 98119206.284.1900 [email protected]













Kevin S. McDorman, DVM, PhD, DACVP General ManagerCharles River Pathology Associates15 Worman's Mill CourtFrederick, MD 21701301.624.2918 [email protected]

Timothy J. McGovern, Ph.D. Nonclincal/Regulatory ConsultantSciLucent LLC 585 Grove StreetSuite 300Herndon, VA 20170703.435.0333 x242 [email protected]

Kathy McGown Director, Knowledge Resources FoxKiser 750 17th St NW, Suite 1100Washington, DC [email protected]

Richard H. McKeeDistinguished Toxicology Associate ExxonMobil Biomedical Sciences, Inc. 1545 Route 22 EastAnnandale, NJ 08801-3059908.730.1037 [email protected]

Susan McPherson, MSc Executive Director ToxicologyWuxiAppTec1318 Wuzhong AvenueWuzhong DistrictSuzhou, China86 512 6650 9570 86 512 6883 [email protected]

Barbara J. Mounho, PhD, DABTDirector, Global Regulatory Affairs Biosimilar Policy and StrategyAmgen Inc.One Amgen Center Drive17-1-CThousand Oaks, CA 91320-1799805.447.5619 [email protected]

Vincent A. Murphy, Ph.D., DABTPrincipal Research InvestigatorArray BioPharma, Inc.3200 Walnut StreetBoulder, CO 80301303.386.1343 [email protected]

James MurrayStaff Scientist, ToxicologyGenzyme5 Mountain RoadFramingham MA [email protected]

L. Peyton Myers, Ph.D. Pharmacology/Toxicology ReviewerUS FDA, CDER/OND/OAPDiv. of Antiviral Products10903 New Hampshire AveSilver Spring, MD 20903301.796.2217 [email protected]

Mark Nicolich, Ph.D.StatisticianCogimet 24 Lakeview RoadLambertville, NJ [email protected]

Mark NiehoffStudy Director ToxicologyCovance LaboratoriesKesselfeld 29Munster, DE [email protected]

Todd Palmby, Ph.D.Pharmacology/Toxicology ReviewerUS FDACDER10903 New Hampshire AvenueW022-5205Silver Spring, MD [email protected]












Richard S. Paules, Ph.D.Acting Chief, Lab of Toxicology & PharmaHead, Environmental Stress and Cancer Group Director, NIEHS Microarray Core Facility NIEHS, NIH111 Alexander Drive, Room D266BP.O. Box 12233, Mail Drop D2-03Research Triangle Park, NC 27709-2233919.541.3710 [email protected]

Syril Pettit, MEM HESI Associate DirectorHESI1156 15th St NWWashington DC 20005202.659.3306 202.659.3617spettit@ilsi . org

Mark W. Powley, Ph.D.PharmacologistU.S. Food and Drug AdministrationDivision of Antiviral ProductsW022 RM 637310903 New Hampshire AvenueSilver Spring, MD [email protected]

Lynnda Reid, Ph.D.Supervisory PharmacologistUS FDA, CDERDivision of Reproductive & Urologic Products10903 New Hampshire AvenueWhite Oak Bldg. 22, Rm. 5388Silver Spring, MD 20993301.796.0984 [email protected]

Melissa ReinertSenior Quality Assurance AuditorBiotechnical Services, Inc.4610 West Commercial DriveNorth Little Rock, AR 72116501.758.6290 x116 [email protected]

William T. ReinholtManager, Quality Assurance MPI Research, Inc. 54943 North Main StreetMattawan, MI 49071-9399269.668.3336 [email protected]

James Render, DVM, PhD, DACVPVeterinary PathologistNAMSA6750 Wales RoadNorthwood, OH 43619419.662.4451 [email protected]

M. Stacey Ricci, Sc.D.Senior ToxicologistUS FDA10903 New Hampshire AvenueHFD-107Silver Spring, MD, [email protected]

Richard E. Ridgewell, Ph.D.,Associate Director, Drug Metabolism Covance Laboratories Inc. 3301 Kinsman Boulevard-02Madison, MI 53704608.310.8225 [email protected]

Maria I. RiveraPharmacologist/ToxicologistUS FDACDER10903 New Hampshire AvenueBldg. 22Silver Spring, MD20993301.796.0796 [email protected]

Beatriz Rocha DirectorMerck & Co., Inc.126 E. Lincoln AveRahway, NJ 07065-0900732.594.3804 [email protected]












Brian M. Roche, PhDAssociate Manager Safety PharmacologyBattelle Memorial Institute505 King Ave. Columbus OH [email protected]

Paul L. Roney, Ph.D., DABT Senior Consultant, Toxicology INC Research7361 Calhoun Place, Suite 500Rockville, MD 20855301. 296.1363 [email protected]

Tom Rosol Ohio State University1925 Coffey RoadColumbus, Ohio 43210614.292.5661 [email protected]

Philip Sager, M.D., FACC, FAHAChair, Scientific Program Committee, Cardiac Safety Research Consortium & Pharmaceutical/Device Consultant719 Carolina St. San Francisco CA [email protected]

Nico Scheer, Ph.D.Head of ADMET R&DTaconicArtemis GmbHNeurater Ring 1Cologne, 51063Germany+49.221.9645343 [email protected]

Capt. Mark Seaton, USPHS Regulatory Review OfficerUS FDA 10903 New Hampshire AvenueSilver Spring, MD 20993-0002301.796.3408 [email protected]

Hilary Sheevers, Ph.D. President, CEO Aclairo PDG, Inc.1950 Old Gallows Rd., Suite 300Vienna, VA 22182703.506.6760 X307 [email protected]

Michael SheltonTechnical DirectorExova Inc.9240 Santa Fe Springs RoadSanta Fe Springs, CA 90670-2618562.948.2225 [email protected]

Paul W. Snyder, DVM, Ph.D.Professor of Pathology Purdue University725 Harrison StreetWest Lafayette, IN 47907765.494.9676 [email protected]

Steve M. Snyder, MSPresidentOutsourcing Support Services, Inc. 1148 Leesburg DriveLeland, NC 28451317. 408.0286 317. [email protected]

Marta Sokolowska , Ph.D.Director, Cntr of Excellence for Abuse Liability Grünenthal USA, Inc. One Pluckemin WayBedminster, NJ 07921908.306.0024 [email protected]

Richard C. J. Somerville, Ph.D.Distinguished Professor Emeritus & Research ProfessorScripps Institution of OceanographyUniversity of California San Diego9500 Gilman Drive, Dept. 0224La Jolla, CA 92093-0224858.534.4644 [email protected]













Christopher J. SompsPfizerEastern Point RoadGroton, CT860.715.2841 [email protected]

Ron Steigerwalt, Ph.D., DABTPreclinical DirectorAmgen Inc.One Amgen Center DriveMS: 29-2AThousand Oaks, CA 91320805.313.5210rsteiger @amgen.com

Jacqueline Tarrant, BVSc, PhD, DACVPScientist - Pathologist Genentech 1 DNA waySouth San Francisco, CA [email protected]

Marque Todd, DVM MS DABTRegulatory Strategy LeadPfizer, Inc.10646 Science Center DriveSan Diego, CA [email protected]

Molly (Shea) TopperPharmacology/Toxicology SupervisorUS FDA, CDERDivision of Pulmonary, Allergy, and Rheumatology ProductsCDER-White Oak, Bld.22, Rm 324210903 New Hampshire AvenueSilver Spring, MD 20993301.796.1291 [email protected]

Vince Torti, Ph.D., DABTPfizer1077 Science DriveLa Jolla, CA [email protected]

Dr. O. Joseph Trask, Jr.Head, Cellular Imaging CoreThe Hamner Institutes for Health Sciences6 Davis DriveResearch Triangle Park, NC [email protected]

Mingyi Trimble, ScD, DABTStudy Director Covance Laboratories Inc. 2701 E. Ryan Rd.Chandler AZ 85286480.384.3637 [email protected]

Niraj Tripathi, BVSc, MVSc, PhD, DACVPClinical PathologistCovance Laboratories Inc. 3301 Kinsman Blvd.Madison, WI 53704608.242.2712 ext. [email protected]

Patricia V. Turner, BSc, MSc, DVM, DVSc, DACLAM, DABTAssoc. Prof. Dept. PathobiologyProgram LeaderGraduate Studies in Laboratory Animal ScienceUniversity of GuelphGuelph, ON N1G 2W1Canada519.824.4120 [email protected]

CT Viswanathan, Ph.D.CT Viswanathan & Associates [email protected]

Jennie L. Walgren, Ph.D. Senior Research Scientist Eli Lilly and CompanyLilly Corporate CenterIndianapolis, IN 46285317.433.0834 [email protected]












Mark D. Walker, DVMToxicologistFrontier BioSciences, Inc.20251 Century Blvd., Suite 325Germantown, MD [email protected]

Rob WallisExec. Director, Head of Centres of EmphasisPfizer Drug Safety Research & DevelopmentEastern Point RoadGroton, CT [email protected]

Klaus Weber, Ph.D., DVM, MSToxicologic PathologistHarlan Laboratories, Inc.Zelgliweg 1Itingen, 4452Switzerland+41.61.975.1268 [email protected]

Clynn Wilker, Ph.D., DABTArdea Biosciences 4939 Directory PlaceSan Diego, CA [email protected]

Dr. Jackie WilliamsPresident-Elect, Radiation Research SocietyResearch Professor, Dept. Radiation Oncology James P. Wilmot Cancer CenterUniv Rochester School of Medicine & Dentistry601 Elmwood AvenueBox 647Rochester, NY 14642585.275.1687 [email protected]

G. David Young, DVM, DACVP, DABTPresident and Chief PathologistFlagship Biosciences, LLC4683 Lee Hill DriveBoulder, CO 80302303.817.7886 [email protected]







ABSTRACTSPlenary Lectures

Monday GLP MODERNIZATION: WHAT DOES THIS MEAN TO YOU CT Viswanathan, Ph.D., CT Viswanathan & Associates Inc. Nonclinical data generated in the early stages of drug development are significant and form the basis of understanding for possible safety concerns of the drug candidate. This information is often critical in allowing the clinical trials in humans to proceed. Current GLP regulations provide a framework to conduct nonclinical studies in a satisfactory manner. Optimization of these regulations will provide further opportunities to effectively collect robust and quality data. This presentation will discuss the need for modernization, the issues that need to be resolved, the outdated practices that need to be eliminated and ways for possibly reducing the regulatory burden. The ways in which your future work can be affected and the ongoing review of the comments for ANPRM (advanced notice for proposed rule making) will be discussed. The desirable future direction can be enabled by collaborative efforts from Industry and the Regulatory Agency.

Tuesday CLIMATE CHANGE AND SPEAKING TRUTH TO POWER: HOW SOUND SCIENCE CAN INFORM WISE POLICY Richard C. J. Somerville, Ph.D., Distinguished Professor Emeritus & Research Professor, Scripps Institution of Oceanography, University of California San Diego. Man-made climate change is already occurring. The science is compelling. Recent research findings include measurements showing the Greenland and Antarctic ice-sheets are losing mass and contributing to accelerate sea level rise. Global sea level increases may well exceed 1 meter (about 3 feet) by 2100, with a rise of up to 2 meters (6 feet) considered possible. In addition, Arctic sea ice has recently melted far beyond the predictions of climate models. Patterns of precipitation and weather extremes such as floods and droughts are also changing. Yet, mankind continues to emit gases that amplify the greenhouse effect. Recent annual carbon dioxide emissions from fossil fuels were about 40% higher than those in 1990. At today’s emissions rates, after only 20 more years, the world will no longer have a reasonable chance of limiting global warming to less than levels widely considered to be dangerous. To avoid severe climate disruption, global emissions must peak and then start to decline

rapidly within the next five to ten years, reaching near-zero well within this century. Conveying the scientific rationale for urgent action is a critical communications challenge, and the nature of the climate that we leave to our children and grandchildren depends on it.

Wednesday FALLOUT FROM FALLOUT: RISKS VERSUS HYPE Jacqueline P. Williams, Ph.D., Research Professor, University of Rochester School of Medicine & Dentistry, Department of Radiation Oncology, Rochester, New York. This talk will provide a brief overview of the acute effects of radiation, but will focus more on the delayed outcomes from short-term and long-term exposure to irradiation, drawing on our understanding from such events as the Japanese A-bombs and Chernobyl, and applying such findings to the recent incident at the reactor site in Fukushima. Although relatively large databases are available from these accidents and incidents as well as the therapeutic field, our true understanding of the biological mechanisms and pathways that underlie the development of radiation-induced late effects still remains somewhat hypothetical. Some of the main theories currently being considered will be discussed, together with suggestions for the likely strategies that may be used to mitigate such outcomes.

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PLENARY ABSTRACTS

SYMPOSIA ABSTRACTS

IaBASIC TESTING REQUIREMENTS: ISO AND FDA Joseph W. Carraway, DVM, MS, Director of Toxicology, NAMSA, Northwood, OH Medical device manufacturers want to get their devices onto the market as soon as possible. However, they are often confused about the preclinical testing requirements necessary for submission to the US FDA as well as countries outside the US. This session will provide an overview of the testing preclinical tests requirements for medical devices based on the ISO 10993 - Biological evaluation of medical devices. Part 1 of ISO 10993 will be reviewed and how a device’s testing requirements are based on the devices tissue contact and contact duration. In addition, some of the unique requirements for the US and other countries will be discussed.

IbANALYTICAL APPROACHES FOR DEGRADATION PRODUCTS, EXTRACTABLES AND LEACHABLES FROM MEDICAL DEVICES Michael Shelton, Technical Director, Exova, Inc., Santa Fe Springs, CA This presentation will provide an overview of the types of analytical testing which can be used to characterize extractable and leachable compounds from medical devices. These compounds may include artifacts from the raw materials (e.g., plasticizers, anti-oxidants, residual monomers), residues from manufacturing (residual solvents from adhesives, mold release agents, sterilant residues) or post-manufacturing (oxidation or other degradation products). It will include approaches for initial identification of potential leachables, development of appropriate leachate conditions, depending on the intended use of the device, and analytical methods for the measurement of leachables in finished products. We will consider USP, EP, ISO and FDA methods and guidances, and how they are applied to different types of devices.

IcNANOTECHNOLOGY ENABLED DEVICE DESIGN AND SAFETY ASSESSMENT. David W. Hobson, Ph.D., DABT., LoneStar PharmTox LLC, Boerne, Texas. The technologic ability to manipulate matter at the atomic and nanometer scale reliably enough to produce useful medical devices has been applied for nearly two decades. Beginning with various applications of simple nanoparticles, medical devices that utilize nanotechnology now include a wide array of device types and applications. Nanoparticles have

been widely used as antimicrobial agents in bandages and surface coatings, they are increasingly being used to enable in vitro diagnostic devices and various types of nanoparticulate coatings are used to enhance biocompatibility of implanted devices. Because nanoparticulate dimensions create tremendous surface area for both chemical and physical biologic interactions and exist within the dimension between enzymes and cellular structures, there is little wonder that the use of nanotechnology in medical devices results in concern for safety assessment. Because nanotechnology is rapidly advancing and continuously creating new and more elaborate and complex forms, case by case assessment of safety has become the most rational approach because safety assessment procedures that were developed primarily to evaluate the effects of chemicals often cannot be used without at least some modification to evaluate nanotechnologies. Characterization and expression of dose and exposure for nanomaterials can be challenging. Current approaches and procedures for safety assessment of medical devices that incorporate nanotechnology will be presented along with an examination of the nature of the driving forces that are increasingly demanding completion of such assessments prior to their medical use

IdBiocompatability Assessment of Antimicrobial Devices Shayne C Gad, Principal, Gad Consulting Services The assessment of biologic safety of a medical device treated to avoid or minimize the risks of infection requires assessment of two potential sources of risk (device and antimicrobial actives) yet such assessment needs to be performed in a manner which avoids duplication effort or unnecessary testing, yet assures safety and regulatory compliance. The case of forms of indwelling catheter for long term dialysis will be used as an example to illustrate considerations, challenges and their solutions.

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IeBIOCOMPATIBILITY TESTING OF INJECTABLE MEDICAL DEVICES. Jeffrey A. Handler, JAH Associates LLC, Wayne, PA. Injectable medical devices are used for a wide variety of indications, including dermal filling in lipoatrophy patients and for cosmetic reasons, vocal fold bulking and to control stress urinary incontinence. Constituents of injectable devices vary, but often include long-chain polymers such as poly-l-lactic acid and/or poly-l-glycolic acid as well as excipients such as carboxymethylcellulose and mannitol. Particle size varies depending upon the desired effect, and is an important consideration in the approach to safety assessment. Resorption time of the injectable device can vary, but often it can take up to 2 years for full resorption of all injected materials. Biocompatibility testing for injectable medical devices follows standard ISO 10993 and G95-1 memo approaches, including tests for genotoxicity, cytotoxicity, irritation and sensitization, and systemic toxicity. Injection of poly-l-lactic acid and/or poly-l-glycolic acid typically results in a localized inflammatory response and encapsulation of the device. Accordingly, chronic toxicity tests of 6 months in rats are typically required to demonstrate safety, with particular attention to potential migration of materials to lymph glands and possible granuloma formation. More recent device approvals have also included preclinical demonstration of resorption of the device over time; this can vary significantly depending upon the size of the particles in the device and location of implantation. Many excipients such as mannitol and carboxymethylcellulose have been used extensively in many products and a literature search of toxicity, such as reports of sensitivity to carboxymethylcellulose, typically suffices to demonstrate safety and what precautions are necessary based on inclusion of these excipients in the product.

IIaONCOLOGY PHARMACOLOGY MODELS: VALUABLE PREDICTIVE TOOLS? Patrice Lee, Array BioPharma Inc, Boulder, CO. The value of non-clinical cancer pharmacology models has been a raging debate for decades. Cancers have been cured in mice and rats many times but these non-clinical successes have not fully translated to the heterogeneous clinical oncology disease setting. The best correlations have been seen with cytotoxic agents while targeted therapies have seen less validation in the clinic. Yet, efficacy data in non-clinical studies can give oncologists the confidence to move forward with an unproven experimental agent in clinical trials. This

presentation will focus on the pros and cons of various non-clinical model systems with emphasis on how closely these models replicate the human disease. Detailed discussion will include: models to choose (xenograft, syngeneic, orthotopic, GEM); endpoints to measure and importance of pharmacodynamic evaluations which can be used to inform one as to which clinical patient populations could best benefit from a therapy. The importance of the identification and use of biomarkers of activity and/or safety early in discovery pharmacology and toxicology studies will also be reviewed.

IIbINTRODUCTION TO THE TOXICOLOGY SIDE OF ONCOLOGY DRUG DEVELOPMENT Hilary Sheevers and Vincent Murphy, Aclairo and Array BioPharma. This presentation is designed to give the toxicologist new to oncology an overview of what studies are needed to develop an oncology drug for a serious indication as noted in the ICH S9 guidance . It will serve as a refresher or update for those who only occasionally work in this area. An example will be presented to demonstrate how nonclinical safety studies can be modified or excluded per ICH S9 compared to the development of pharmaceuticals for non-life-threatening chronic indications per ICH M3. The downsides and upsides to following the guidance will also be discussed. This section will also serve as an introduction to the final talk of what to do when your oncology drug shifts to non-life threatening chronic indications.

IIcOPTIMIZING LARGE AND SMALL MOLECULE ONCOLOGY DRUG DEVELOPMENT Ian Pyrah, Amgen Inc., Thousand Oaks, CA The presentation will describe the differences and similarities of small and large molecule drugs in the context oncology therapeutic development. A detailed analysis of the differential burden placed on drug development between the ICHS9 guideline versus ICHS6/ICHM3 will be presented, and strategies for switching between the two development paths will be discussed with examples from both the large and small molecule classes. Of particular concern for transition from an oncology indication to a non-oncology indication is the requirement for carcinogenicity studies which are costly and time consuming. Potential strategies for managing carcinogenicity risk will be discussed.

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SYMPOSIA

ABSTRACTS

IIdWHEN TO CHOOSE ICH M3(R2) FOR THE DEVELOPMENT OF ONCOLOGY PRODUCTS Todd Palmby, US FDA, CDER, Silver Spring, MD The recently finalized ICH S9 guidance provides stakeholders and regulators a recommended pathway for nonclinical development of drugs and biopharmaceuticals for use in oncology indications for advanced cancer. Development programs for investigational drugs and biologics can impinge on multiple indications including advanced cancer as well as less serious conditions for which the life expectancy is long enough to warrant more substantial nonclinical testing. In addition, development of new therapies for certain oncology indications may improve the clinical outcome in the patient population(s) being studied, thereby changing the life expectancy for those indications. The goal of this discussion is to provide a framework for understanding when ICH M3(R2) may be more suitable for a given development program versus the more abbreviated program described in ICH S9.

IIIaMOUSE MODELS IN TOXICOLOGY STUDIES . Peter C. Mann, Experimental Pathology Laboratories, Inc., Seattle, WA. Many toxicologists use outbred mice in their toxicity and carcinogenicity studies. The many years of using outbred mice, such as the CD-1, has permitted development of large databases of background lesions that can be useful in interpreting study outcomes. Because outbred mice are genetically undefined, their use in toxicology screening studies represents an uncontrolled variable when the experimental goal is to test a single variable: the test agent. Consequently, it can be argued that one cannot tell if an observed response is due to genetic or non-genetic causes. Proponents for toxicity testing in an outbred stock consider that the genetic heterogeneity in their random-bred mice reflects genetic heterogeneity in human populations and that at least a few mice will respond to the test agent with a relevant signal if that agent has human health consequences. Geneticists have argued for several years that the genetically undefined outbred mouse is the wrong animal model for routine toxicity studies and a better strategy would be to use a small selection of inbred strains without having to increase the number of test animals. Since inbred mice of a given sex are isogenic (i.e., genetically identical) the toxicologist has control of an important test variable. It is further argued that the genetic spectrum provided by multiple inbred strains is a realistic representation of the type of genetic diversity seen in human populations, with sensitive as well as

resistant individuals being represented. The NTP has used the F1 hybrid B6C3F1 mouse for toxicity and carcinogenicity testing for over 40 years. Much like inbred mice, the B6C3F1 mouse is isogenic. However, the B6C3F1 mouse represents only a single genetic set, and while useful because of its genetic uniformity, it has proven to be a liability in toxicity testing because of a genetically related exaggerated liver tumor background incidence and response to test agents. Over the last decade, the use of genetically-modified mice in toxicology studies has dramatically increased. These mice, which have genetic modifications specific for cancer, provide another model in which the effect should be due to the effect of compound on the genetic modification, rather than the background strain of mouse. The most commonly used genetically modified mice (rasH2 transgenic, p53 heterzygous knockout and Tg.AC mice) will be discussed and their relative strengths and weaknesses compared.

IIIbRAT MODELS IN TOXICOLOGY STUDIES Paul-Georg Germann 1 and Dr. Klaus Weber 2 1Senior Vice President, Discovery to Preclinical Development, Nycomed GmbH, Byk-Gulden-Sr. 2, 78467 Konstanz, Germany; 2Head of Pathology, Harlan Laboratories, Zelgiweg 1, 4452 Ittingen, Switzerland Due to many factors the selection of the appropriate rat model for toxicology studies has sometimes been a difficult decision. There are numerous advantages and disadvantages for each of the available strains and stocks that may be considered. The most commonly used rat models include the Fischer 344, Sprague Dawley, Wistar, Brown Norway, and Long Evans strains. Unlike mouse models, transgenic rat models have not been commonly used. This presentation will discuss the advantages and disadvantages of these various rat models and the most appropriate rat model for different types of toxicology as well for pharmacology studies.

IIIcDOG MODELS IN TOXICOLOGY STUDIES. Dr. Klaus Weber Harlan Laboratories Ltd., Itingen, Switzerland Beagle dogs of different breeders were used over 25 years at Harlan Laboratories Ltd. Switzerland. There is little literature on background data available. Therefore, in-life data, hematology, clinical biochemistry and urinalysis data, gross lesions, organ weights and histopathology data were collected for the Hsd: DOBE beagle dog and compared with data from animals used in toxicology studies from 9 different breeders. The data were analysed according to study lengths

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including 2-, 4-, 13-, 26-, 39- and 52-Week studies. Furthermore, the data were compared for similar ages in steps of 2 months (e.g. age: 5-7 months, 8-9 months etc). Major differences to other strains consisted of a different onset of maturation in males, i.e. in 4 week studies there were only 9.56% of the DOBE beagles immature compared to 19.75% of dogs from other sources. In 13-Week studies, 1.72% of the DOBE males were still immature vs. 7.46% from other strains. Interestingly, tubular hypoplasia in testes is a not often encountered in some strains whereas in others, this is the case. For females, the differences were not as significant. It is noteworthy, that beagle arteritis is only an exceptional finding in the DOBE strain. Over the years, it was recorded in only a few cases.

IIIdNONHUMAN PRIMATE MODELS IN TOXICOLOGY STUDIES Kevin S. McDorman, Charles River Laboratories Studies using nonhuman primate models of toxicity are becoming more common. This is partially due to the types of test articles being examined as well as the need for comparison to the human which is often the end-user of the test article being evaluated. More recent applications of nonhuman primate models in toxicology include developmental and reproductive toxicology, imunotoxicology, inhalation/respiratory toxicology, neurotoxicology and neurobehavioral toxicology. Although the cynomolgus macaque has become the most commonly used nonhuman primate model, several other models are available. These include the rhesus macaque, squirrel monkey, and marmosets. Background pathology findings are commonly observed in nonhuman primate toxicology models, and are defined as spontaneous lesions, normal physiologic variations, and concurrent natural diseases or pathologic changes that may or may not be influenced by test article administration. In addition, background findings can be influenced by age, supplier and/or geographical source, genetics, and husbandry practices. Distinguishing normal clinical and anatomic/morphologic variability from test article-induced changes is critical, and it is the responsibility of the pathologist to determine which clinical pathology, gross and histopathology observations should be designated as background findings in each study or series of studies. Balanced and accurate interpretations require experience with the nonhuman primate model, knowledge of the test article and its pharmacology, and integration of all available data, including historical control data. All information

should be taken into consideration when selecting the best nonhuman primate model for your studies.

IVaCDER/CDRH REGULATORY PERSPECTIVE ON COMBINATION PRODUCT DEVELOPMENT Kathy Lee, Ph.D., US FDA-CDER, Bethesda, MD For “traditional” medical products, a single set of regulations governs the review and regulation of the product. In the case of combination products; however, the regulations associated with each Center are available for use and are applied as necessary to insure the most appropriate control of the potential risk to the treated population and/or user. The applicable regulations range from those associated with non-clinical studies (Good Laboratory Practices) to conduct of clinical trials (informed consent, clinical trial design and reporting, institutional review boards and investigator selection) to manufacturing (cGMPs and QSR), and are dependent on the lead Center.The work necessary to bring a combination product to market incorporates a complicated regulatory process involving interactions with at least two Centers within FDA. Because of differences in legal/regulatory requirements between the various Centers, the non-clinical and clinical evaluation of a combination product can be a more difficult, but not insurmountable task. This presentation will attempt to outline some of the similarities and differences between traditional and combination products, as well some of the similarities and differences between the Centers and how these impact the evaluation and regulation of combination products.

IVbPRECLINICAL TESTING REQUIREMENTS FOR STENTS: A CHANGED REGULATORY LANDSCAPE John Dooley, Ph.D., Codman & Shurtleff, Inc. (Division of Johnson & Johnson), Spring House, PA The CYPHER® Sirolimus-eluting Stent was the first drug-eluting stent (DES) to receive regulatory approval in Europe (CE Mark 2002) and the US (PMA Approval 2003). During development and approval of CYPHER, no Guidance Documents were in place, and preclinical testing requirements for IDE and PMA approval were negotiated with the FDA. The interactions with the FDA and the preclinical testing conducted on CYPHER Stents will be presented and compared to the recommendations in the recent FDA Guidance Document on DES, as well as our ongoing interactions with the FDA and preclinical testing being conducted on our NEVO™ Sirolimus-eluting “Reservoir” Stents.IVcREGULATION AND NONCLINICAL ASSESSMENT STRATEGIES FOR DRUG-DRUG COMBINATIONS

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INTENDED FOR COADMINISTRATION Timothy Hummer, PhD, DABT, US FDA, CDER, Silver Spring, MD This Presentation will focus on the nonclinical studies recommended to support clinical investigation and approval of drug-drug and drug-biologic combinations, including fixed-dose combination products, copackaged products, as well as some adjunctive therapies. The extent of nonclinical requirements is dependent on the amount of available nonclinical and clinical information for each individual drug and the combination. Accordingly, varying amounts of additional nonclinical information will be required to support the coadministration of two or more marketed drugs; a marketed drug with an unmarketed investigational drug; and two unmarketed investigational drugs. Recommendations for the codevelopment of two or more unmarketed investigational drugs will also be highlighted.

VaUSE OF TRANSGENIC MOUSE MODELS FOR PK AND SAFETY PROFILING OF COMPOUNDS Nico Scheer, Ph.D., Taconic-Artemis GmbH, Cologne, Germany Transgenic mouse models humanized for key proteins involved in drug metabolism and disposition can help to improve the selection of the most promising drug candidates in preclinical development by reducing the impact of species differences. Thereby such models can make a positive contribution to reducing clinical stage attrition rates by removing problematic compounds earlier in development. This presentation will summarize the state-of-the-art in this field, describe different applications of this approach and provide some selected examples on the use of these models.

VbMOUSE MODELS WITH HIGHLY HUMANIZED LIVERS: CURRENT APPLICATIONS AND FUTURE DIRECTIONS Markus Grompe, M.D., Oregon Health & Science University, Yecuris Corporation, Portland OR Chimeric mouse models with highly humanized livers hold considerable promise for more predictive preclinical studies in small animals. Several transgenic mouse strains capable of being repopulated by human hepatocytes will be presented, in particular albumin-uPA transgenics and Fah knockouts. Validated applications will be described, as well as ongoing further development in the areas of drug metabolism/pharmacokinetics, toxicology, and infectious diseases. VcA HUMAN IMMUNE SYSTEM IN THE MOUSE: CURRENT STATE OF THE MODEL AND RESEARCH

POTENTIAL Kristina Howard, D.V.M., Ph.D., US FDA, Bethesda, MD This talk will focus on a mouse model with a human immune system. The background and derivation of various humanized mouse models will be introduced. Discussion will focus on potential uses in drug development including better predicting the biologic effects of therapeutic proteins, monoclonal antibodies, and other pharmaceuticals in humans.

VdHUMANIZED DRUG METABOLIZING ENZYME MOUSE MODELS – POTENTIAL APPLICATION IN SAFETY ASSESSMENT Alema Galijatovic-Idrizbegovic, Ph.D., Merck & Co., Inc., West Point, PA Nonclinical development of drug candidates may be confounded by species differences in drug metabolism. Metabolites formed in humans may be unique as compared to nonclinical test species. Metabolism in nonclinical species may also result in unique or disproportionate metabolites leading to toxicities of questionable human relevance. Genetically engineered mouse models that express human P450 enzymes could provide one potential approach to minimize the impact of metabolite related challenges in drug development. These models may have the ability to generate major human metabolites and eliminate or reduce the formation of rodent specific metabolites. Prior to utilization of such models, it is important to qualify by characterizing protein expression, establishing whether the model generates an in vivo metabolite profile more closely related to that of humans than the wild-type mouse, verifying genetic stability, and evaluating animal health. Since the current strategy for handling metabolite challenges through direct administration of metabolites is expensive and can significantly extend development of drug candidates, identifying an appropriate human P450 expressing model could provide a number of benefits. An in vitro and in vivo approach has been utilized for an evaluation of humanized CYP3A4 drug metabolizing mouse model and its potential utility in toxicology studies to address exposure issues with a highly abundant human metabolite for Merck Compound A for which adequate coverage could not be obtained in routine toxicology species.

VeFDA PERSPECTIVE ON HUMANIZED ADME MODELS Mark W. Powley, Pharmacologist, Division of Anti-Viral Products, US FDA This brief presentation will provide regulatory perspective on use of humanized ADME models. The primary focus will be potential regulatory applications in non-clinical drug development. Key questions for

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regulatory decision making will be discussed as will the need to understand potential liabilities resulting from genetic modification.

VIaOCULAR TOXICITY IN AN ONCOLOGY THERAPEUTIC: OBSTACLES AND IMPACT TO DEVELOPMENT Vince Torti, Pfizer, Inc., LaJolla, CA Covered in this talk will be a case which significant ocular toxicity was found associated with an oncology therapeutic. Ocular toxicity was first observed in a 1-month IND-enabling study and occurred in the dog retina only despite both dog and rat studies being performed. First indications of adverse effects were observed clinically after 10-20 days of daily (QD) exposure and were validated via microscopic pathology and electroretinogram (ERG) assessment. Topics covered for this case will be: a complete review of the preclinical toxicology data and various considerations from the preclinical, clinical, and regulatory perspectives impacting development. Specifically, considerations of target pharmacology-based effects, non-clinical assays useful for earlier detection of ocular toxicology, potential clinical monitoring assays, and an overall assessment of risk for pursuing oncology clinical studies will be discussed.

VIbDETECTION OF MICROSCOPIC FINDINGS OF OCULAR TOXICITY James A. Render, NAMSA, Northwood, OH This presentation will review factors that are involved in detecting microscopic ocular findings caused by toxicity. An accurate interpretation of microscopic ocular findings requires an understanding of comparative ocular anatomy, spontaneous ocular findings, iatrogenic ocular findings, microscopic ocular artifacts and possible toxicological changes for a given compound, chemical or medical device. Unlike other organs, except for the skin, findings involving the eye are often identified clinically and it is up to the pathologist and the histotechnologist to capture the clinical finding in a histologic section. Therefore, in order to have a microscopic correlation, it is important for the study pathologist to be aware of clinical ocular findings at the time of necropsy, tissue trimming and microscopic examination. Detection of microscopic changes is not possible without the preparation of good quality histologic sections. These sections require proper ocular orientation and minimal tissue artifacts. Terms used to denote clinical and microscopic ocular findings should be descriptive to allow for interpretation. All of these factors should be considered at the time of protocol review, especially if the in-life portion of a study and the microscopic

portion of the study are going to be conducted at different locations.

VIcFIRST DO NO HARM: NONINVASIVE MEASURES OF STRUCTURE AND FUNCTION IN OCULAR TOXICOLOGY AND DRUG DISCOVERY Jeff Jamison, Ophthy-DS, Inc. and MPI Research, Mattawan, MI This presentation will review methods of noninvasive in vivo techniques used to evaluate the health of the retina and extra-ocular tissues relevant to models of ocular disease and toxicology. Methods and examples of imaging of ocular tissues using slit lamp, fundus photography, retinal angiography and OCT (optical coherence tomography) will be presented. Techniques for assessing retinal function such as electrophysiology of the retina (ERG), the Optokenetic response and operant conditioning using visual discrimination tasks will be reviewed. This talk will concentrate on the usefulness of various techniques to capture specific endpoints with various instruments. Where possible, case examples of induced ocular pathology or pathology due to drug toxicity will be reviewed or relevant examples from the literature will be cited. In addition, species differences will be highlighted as well, with most examples coming from rodents, rabbits, canine and non-human primates.

VIdCLINICAL AND NONCLINICAL CORRELATES OF OCULAR TOXICITY: EVALUATION AND REGULATORY CONSIDERATIONS Maria I. Rivera, UD FDA CDER, Silver Spring, MD This talk will explore the relationship between ocular findings from nonclinical studies and the occurrence or lack of occurrence of such findings in the clinical setting. In addition, the presentation will describe the evaluation of both nonclinical and clinical findings from a regulatory perspective and how these findings could potentially impede further clinical development. The talk will present some examples of findings observed in the nonclinical setting, the factors taken into consideration to decide if development should or should not continue, and the required clinical monitoring program when the trials were allowed to proceed.

VIIaAN INDUSTRIAL PERSPECTIVE ON MUTAGENICITY MODELING Catrin Hasselgren, Principal Scientist, AstraZeneca R&D, MoIndal, Sweden

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The application of computational methods for risk assessment of compounds is common practice for Pharmaceutical companies today and ranges from early discovery (library design) to post marketing (e.g., qualification of degradants). Different phases in the drug development require different levels of information and an extensive toolbox of methods, each suitable for the stage at which it is used, is desirable. This talk will briefly cover the commercial tools available for genotoxicity prediction. It will also in more detail describe how these and internally developed tools are used within AstraZeneca throughout the Drug development process.

VIIbAPPLICATION OF COMPUTATIONAL MODELS FOR TOXICOLOGY IN PHARMACEUTICAL DEVELOPMENT Nigel Greene Ph.D., Pfizer, Inc., Groton, CT For many years the pharmaceutical industry has been developing and using computational models for genotoxicity and these are now routinely used in the identification and control of genotoxic impurities. More recently the application of these models has been gaining increasing regulatory interest and acceptance. However, there is also a desire to expand computational models to other areas of toxicology such as hepatotoxicity. This presentation will touch on some of the recent advances in in silico models for toxicity and highlight some industry perspectives on their successful application in drug discovery and development.

VIIcCOMPUTATIONAL METHODS BASED ON CHEMICAL STRUCTURE– HOW USEFUL ARE THEY? Oliver Flint, Ph.D., Bristol-Myers Squibb, Princeton, NJ Since Hansch’s first studies in the mid 60’s showing a relationship between the lipophilicity (LogP) and biological effect of toxic agents, it has been the goal of computational chemistry (chemometrics) to predict the safety of chemicals using molecular descriptors. In the past 50 years software programs for determining toxic risk have evolved to the point that several important products are currently being used by Pharma and by the regulators who review our drug submissions. We have learned that there appears to be a practical limit on our capacity to predict toxicity, and this limit is not determined by the capacity of our CPUs to process data or by our ability to describe molecular properties. In this presentation we will provide examples from our own studies of teratogens and mutagens that illustrate the two main issues that most influence the ability of computational algorithms to determine risk: the biological data used to develop the

QSAR relationships, and the generality of the questions being asked of these algorithms.Topics covered1. Prediction of mutagenicity - issues with the standard

structure-based approaches2. Prediction of arylamine mutagenicity using a novel

reaction-based approach3. Prediction of teratogenicity - issues with standard

structure-based approaches4. Prediction of triazole antifungal mutagenicity using a

novel approach based on a comprehensive analysis of molecular descriptors and recursive partitioning.

5. A summary of what these studies tell us about the capabilities and limitations of computational methods for predicting toxicity.

VIIdREGULATORY UTILITY OF IN SILICO PREDICTIONS: PERSPECTIVES FROM AN FDA REVIEWER Mark W. Powley, Ph.D., US FDA, Silver Spring, MD The presentation will focus on the regulatory utility of in silico predictions for evaluating potentially genotoxic impurities. Primary areas of discussion will be current (Q)SAR approaches, the FDA internal process for evaluating impurities, and the role of in silico predictions in regulatory decision making. Limitations of the various approaches, areas of regulatory concern, opportunities for improvement, and suggestions for regulatory submissions will also be covered.

VIIeTHE EXPERIENCE OF THE US FDA/CDER (Q)SAR GROUP: CRITERIA FOR USING COMPUTATIONAL TOXICOLOGY FOR CDER REGULATORY DECISIONS R. Daniel Benz, Ph.D., US FDA, CDER, Silver Spring, MD This presentation will recommend minimum requirements for predictions from (Q)SAR computational toxicology software models to provide results acceptable for regulatory consideration, e.g., how diverse training sets should be, how good coverage is necessary, and what level of sensitivity (confidence for negative predictions) is acceptable. Also to be presented is why it is useful to use multiple computational platforms to reach an overall conclusion, how many software programs are enough, and how conflicting predictions can be interpreted. Other information that needs to be considered when evaluating the validity of computational results are how similar the training chemicals that are the basis of the prediction need to be to the chemical of interest and the benefit of comparing the results of related (Q)SAR models. Finally, the need for industry submitters and government reviewers to use the same

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software versions, models and interpretation will be emphasized.

VIIIaUSE OF IMAGING BIOMARKERS IN DRUG DISCOVERY AND IN RESEARCH AND DEVELOPMENT PROGRAMS Dr. Norman Barlow and Dr. Xiaoyou Ying, Sanofi, Bridgewater, NJ Imaging biomarkers have become valuable tools in drug discovery and research and development programs within pharmaceutical companies. They are useful to help monitor the efficacy and the toxicity of test substances in nonclinical studies. These types of biomarkers are being requested more and more by regulatory agencies. However, before imaging biomarkers can be used as surrogate endpoints in clinical trials, they must be confirmed in nonclinical animal models. Types of imaging biomarkers that are currently available and are in use in research programs today will be reviewed in this presentation. Developments that may be promising to help monitor the effects of test substances in nonclinical models and patients will also be discussed.

VIIIbUSE OF IMAGING BIOMARKERS IN BASIC RESEARCH AND APPLICATION TO THE DEVELOPMENT OF PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODELING FOR RISK ASSESSMENT Dr. O. Joseph Trask, Jr., The Hamner Institutes for Health Sciences, Research Triangle Park, NC The advancements in modern-day cellular imaging, along with genomic information, has allowed scientists to probe deeper into the underlying mechanisms of cellular functions, effects of protein transcription, cell pathway signaling, and ultimate fate of the cell's life cycle all in an effort to better understand the developmental processes and finding treatment or even cure of human diseases. It has been a little more than a decade since automated fluorescent microscopy image analysis or better known as High Content Screening (HCS) was introduced to the scientific community, but the approach has been occurring for almost 20 years, the knowledge and lessons learned over this time has provided an insight of where the technology is today and what to expect in the coming years. Today, almost every pharmaceutical company has implemented some version of HCS into the drug discovery process, as well as many biotechnical firms with the promise of identifying new drug target indications, validating targets, and use in small compound drug discovery, toxicity assessment, biomarker identification, and pre-clinical studies. The technology is used in basic science programs to extract large amounts of cellular data information to better understand cell functions and mechanisms of actions in

developmental biology and target-based identification in diseased tissue. This presentation will discuss the use of image analysis techniques and the application of the data in predictive toxicology models.

VIIIcUSE OF DIGITAL PATHOLOGY TO PROVIDE AGGREGATE MEASUREMENTS OF EFFICACY AND TOXICITY IN NONCLINICAL AND CLINICAL STUDIES Dr. David Young, Flagship Biosciences, LLC, Boulder, CO The decision to advance an early-stage compound into formal preclinical testing depends on confidence in mechanism, efficacy and toxicity profiles. A substantial percentage of this confidence comes from histopathology interpretation, as the local tissue environment contains strong signals of both efficacy and toxicity. Accessing this tissue information is made difficult by biological variability across organs and tissues, an insufficient pool of pathology experts working in discovery, and the high subjectivity and individual isolation of microscope-based observations. This presentation will discuss how whole-slide imaging and quantitative analysis by trained pathologists are improving early-stage decision-making and its application to resulting clinical studies.

VIIIdANALYZING DISCRETE BIOLOGICAL ENDPOINTS IN SOLID TUMORS UTILIZING NOVEL DIGITAL PATHOLOGY APPROACHES Joseph Krueger, Ph.D., Director of Biology, Flagship Biosciences Although experimental molecular targeted therapies (MTTs) for oncology are based on a strong biological rationale for the target, they often fail in clinical trials due to lack of efficacy. A significant cause for a disconnect between biological rationale and clinical efficacy is the inability to use preclinical drug discovery models in a manner which represents the true nature of clinical disease. To translate the appropriate disease hypothesis from early discovery into clinical trials, preclinical models must emphasize a systems biology approach, which anticipates biological processes which can lead to adaptation and resistance to a therapy. Many drug resistance mechanisms are dependent on tumor microenvironment directed processes, and thus are discrete, context dependent events. These biological processes are often focused on a particular tumor compartment, such as tumor-associated stroma, blood vessels, areas on inflammation, necrotic regions, and groups of tumor cells with regional phenotypic behavior which can best be observed using pathology based approaches. Classical IHC quantification approaches, which take an average expression across a slide, do not convey sufficient information about these discrete events and

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do not account for the inherent variability in the tumor. Digital pathology approaches can be used to efficiently detect these discrete biological endpoints, identify biomarkers which represent these processes, and quantify these biomarkers. These approaches can be directly translated into a clinical companion diagnostic, which can facilitate better prediction of a patient’s potential for response to a therapy, and provide rationale for patient selection that will enable clinical success.

IXaINTRODUCTION AND BACKGROUND TO ELSIE AND THE ELSIE DATABASE Laurie Iciek, Ph.D., Principal Toxicologist, MedImmune, Gaithersburg, MD. Introduction and background to the ELSIE consortium, impetus and development of the database concept, objectives of the database effort, on-going work and future plans.

IXbSAFETY ASSESSMENT OF EXTRACTABLES AND LEACHABLES: CHALLENGES AND APPROACHES William P. Beierschmitt, Pfizer Worldwide Research & Development, Groton, CT An essential, critical component of the registration package for a parenteral product that is addressed by the toxicologist is the risk assessment of leachables and extractables. From a toxicology perspective, while extractable data can provide valuable information (i.e., what chemicals might migrate into the drug during storage), formal risk assessments are typically only performed on leachables (i.e. what chemicals did migrate into the drug during storage). The basic premise of this procedure is to assess the potential risk to humans resulting from unintentional exposure to the chemicals that migrate into drug product from packaging. Early involvement of the toxicologist in leachable and extractable studies from the earliest experimental planning stage through the data collection greatly facilitates arriving at a timely and successful assessment of these chemical impurities. Continued improvement in communication and information exchange with manufacturers regarding constituents/chemical make up of packaging components would also facilitate the risk assessment process. This presentation will provide an overview of the current realities and challenges in the risk assessment process and highlight the pragmatic ways in which the ELSIE database could improve the process.

IXcTHE MATERIAL SELECTION PROCESS FOR DRUG PRODUCT PACKAGING/DEVICES AND THE ELSIE

MATERIALS INITIATIVE Andrew Feilden, AstraZeneca, Loughborough, Leicester, UK Leachables, chemicals that migrate from the materials into the drug product, can cause safety toxicity concerns and/or stability issues from unwanted reactions with the drug product. Testing is required to demonstrate the quality and safety of the drug product at end-of-shelf-life. To meet global supply requirements, a shelf-life period of 2 or more years is normally desired. A mis-step in the selection of packaging or device materials can lead to costly material change issues and delayed launch schedules if detection of unwanted leachables occur during late stage testing. A QbD approach to the selection of materials used to package drug products or to construct medical devices that deliver drug products is proposed to de-risk the material selection process. The presentation will provide concrete examples and will discuss industry initiatives currently under development (ELSIE materials database) to help in the material selection, testing, and evaluation of extractables and leachables.

IXdDEMONSTRATION OF THE ELSIE DATABASE Steve Beck, GlaxoSmithKline Research & Development, Ware, Hertfordshire, UK Real time demonstration of ELSIE database.ELSIE has designed a database which contains current, searchable, safety information for a wide range of extractables and leachables. It is ELSIE's intention to create a database that will support companies’ safety assessments produced as part of regulatory submissions and be viewed as a credible and valuable resource by industry (and regulators) worldwide. This presentation will include a practical demonstration of the prototype database, illustrating its function with the use of specific examples.

XaINTRODUCTION TO OLIGONUCLEOTIDE THERAPEUTICS: STRUCTURE, FUNCTION, AND APPLICATIONS Scott Henry, Ph.D., DABT, Isis Pharmaceuticals Oligonucleotide therapeutics endeavor to become a broadly applicable platform for novel drug discovery. The opportunity is that this technology can potentially take advantage of the known human gene sequence and the ever-increasing knowledge of the genetic basis of disease to help patients in ever more selective ways. Many diseases that are difficult to target with standard small molecule- or protein/antibody-based therapies lend themselves to oligonucleotide-based therapeutics. In the past 5 to 10 years, there has been tremendous advancement in understanding the

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complex function that RNA plays in the cell. This has led to structural modifications that optimize potency, tolerability, and PK properties of antisense inhibitors and to the understanding of how to exploit multiple cellular mechanisms to affect RNA biology. Cellular mechanisms that lead to reduction in targeted RNA can be achieved through either DNA:RNA (RNase H) or RNA:RNA (RISC complex) interactions. Oligonucleotide therapeutic can be used to alter splicing of RNA, either skipping exons or including exons. The more recent discovery of non-coding RNA in cells, such as microRNAs, and the role they play in regulating the transcription of larger families of RNA have further expanded the opportunity. These microRNAs can be used to supplement or compete for endogenous microRNAs to either increase or decrease expression. The potential therapeutic applications of oligonucleotides are very broad, and limited primarily by oligonucleotide uptake by target cell types. Still, pharmacology has been demonstrated in liver, fat, tumors, kidney, and muscle following systemic administration. Indications range from cancer to metabolic disease, cardiovascular disease and other rare genetic diseases. There is also the potential for local application for CNS, ocular, and pulmonary diseases.

XbOLIGOS: AKIN TO SMALL MOLECULES OR BIOLOGICS? Cindy L. Berman, Ph.D., Independent Consultant At the FDA, oligonucleotide therapeutics are currently regulated under CDER-like guidelines based on the fact that the molecules are chemically synthesized. On the other hand, ICH S6 indicates that the guidance for biotechnology-derived pharmaceuticals may be applicable to oligos. In reality, oligonucleotides have many properties that are distinct from either small molecules or biotechnology-derived products. A ‘polymeric’ structure that utilizes basic endogenous building blocks distinguishes oligos and biologics from small molecule drugs. This structure and the inherent size of the molecules impact chemical purity, distribution, metabolism, and the toxicity of the metabolites. Pharmacodynamic properties on most oligos are dependent on the tissues concentrations and pharmacokinetic tissue half-lives are often long, thus activity may not correlate directly with plasma concentration. In addition, like biologics, many oligos are rationally designed to modulate specific human targets. This can confer not only specificity to the target, which decreases off-target toxicity, but also specificity to primates, which impacts the nonclinical development program. This presentation will explore these and other similarities and differences between oligonucleotides, small-molecule drugs, and biologics and will examine the applicability of regulatory guidances to the nonclinical development of ON therapeutics.

XcCLASS EFFECTS AND OTHER SPECIAL CONSIDERATIONS IN THE SAFETY TESTING OF OLIGONUCLEOTIDE THERAPEUTICS Doug Kornbrust, Ph.D., Preclinsight The first generation of oligonucleotide (ON) therapeutics was largely based on structures containing a phosphorothioate (PS) backbone, which conferred a spectrum of toxicities that were generally independent of the nucleotide sequence and, hence, are referred to as “class effects”. These toxicities and the current understanding of their mechanisms will be profiled. In more recent times, the ON therapeutic world has expanded substantially through optimization of medicinal chemistry and with the emergence of various other subclasses and mechanisms of action, including aptamers, Toll-like receptor agonists/antagonists, and siRNAs, with even more applications on the horizon. These newer types of ONs may share some of the PS class effects, depending on the chemistry employed, but also exhibit unique toxicologic properties. As the potency of ONs is increasingly improved, the need to characterize

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adverse effects stemming from exaggerated pharmacology has expanded and evolved. In addition, for an increasing percentage of ON programs, specialized delivery formulations have been employed. This growing diversity has created new challenges for addressing the safety of these products. This presentation will summarize the evolution of oligonucleotide safety evaluation from a historical perspective and provide general insights into appropriate strategies for various subclasses.

XdPRECLINICAL SAFETY ASSESSMENT OF INHALED OLIGONUCLEOTIDES Nicolay Ferrari, Ph.D., Pharmaxis Ltd Oligonucleotide (ON) drug candidates are currently being assessed in clinical trials as new therapeutic agents for many indications. Currently, the vast majority of strategies for the development of ON have focused on systemic administration, in particular in the field of oncology or metabolic and cardiovascular diseases. The toxicology and pharmacokinetics of ON following systemic administration (e.g., intravenous and subcutaneous routes of administration) has been well described. Some pharmaceutical companies and investigators have explored alternative dosing routes such as the pulmonary route of administration. However, there is a relatively little information on the efficacy, deposition, and tolerability following local delivery to the lungs via inhalation. Furthermore, the Pulmonary Division of the FDA indicated having reviewed only six ON through Investigational New Drug (IND) or pre-IND application meetings (ref. DIA 2010). The direct consequence of such limited experience in the development of inhalation ON is therefore a poor understanding of 1) the lung response to inhalation of ON in different species from pre-clinical animal models to human; 2) the response induced by different ON types and chemistries/formulations; and 3) the appropriate methods and readouts needed to adequately assess and monitor potential toxicity in human. This has rendered the interpretation of potential adverse effects caused by inhalation of ON and their relevance for human safety challenging both for the industry and the regulatory agencies. This presentation will summarize the preclinical safety of inhaled ON and will discuss the challenges and issues of the development of such drug candidates.

XeOLIGONUCLEOTIDE THERAPEUTICS: A PHARM/TOX REVIEWER’S PERSPECTIVE Robert T. Dorsam, Food and Drug Administration, CDER Oligonucleotide therapeutics are currently being developed for a wide variety of disease states. This class acts by various mechanisms of action and comprises different backbone chemistries that contribute to their diverse pharmacologic and toxicologic activities. In addition, they may be delivered by many routes of administration and in complex formulations. All of these factors may confer pharmacokinetic or pharmacodynamic advantages but may also present specific toxicity profiles or safety considerations, which can be addressed by careful design of the non-clinical studies. Like most therapeutic classes, a case-by-case approach to the non-clinical development plan is warranted for oligonucleotide therapeutics. With a primary goal of patient safety, pharm/tox reviewers must consider several elements in their safety assessment. This presentation will include a reviewer’s perspective on how a safety assessment is made, along with how elements of non-clinical studies may be tailored to address safety considerations with oligonucleotides. In addition, an overview will be given of internal and external initiatives in which pharm/tox reviewers participate in order to maintain an informed and consistant approach to the review of an evolving class of drugs with the goal of assisting their safe entry into clinical trials.

XIaTHE CHALLENGES AND CONSIDERATIONS OF HOMOLOGOUS MOLECULES USED IN BIOPHARMACEUTICAL DEVELOPMENT Donna Lee, Ph.D., DABT, Genentech, South San Francisco, CA Alternative approaches for evaluating the safety of a biotherapeutic with limited species specificity include the use of transgenic animals, animal models of disease, and homologous molecules. A homologous antibody can be a useful tool for characterizing preclinical safety if the clinical candidate is active only in humans or chimpanzees. However careful consideration should be given to rigorous and appropriate characterization of homologs. Both in vitro and in vivo assessments should demonstrate similarities between the clinical candidate and homolog. These may include structural and sequence properties of the antigen, antibody affinity, and biologic activities (e.g. signaling comparability, in vivo PK/PD parameters).Standard and alternative approaches in the utility of homologous molecules in various development programs will be presented; with focus on a case study

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of an anti-B-cell antigen antibody drug conjugate (ADC) being developed for B-cell malignancies. A homologous ADC was generated due to the limited/no cross-reactivity of the clinical candidate to the human receptor. This enabled the use of cynomolgus monkeys in determining antigen-specific toxicity and PK/PD in an IND-enabling repeat-dose toxicity study. Results from this study confirmed the pharmacodynamic effect of the homologous ADC and established the relevance of using a homologous molecule for safety assessment of the clinical candidate.

XIbANIMAL MODELS OF DISEASE: UNIQUE OPPORTUNITIES AND CHALLENGES Marque Todd, DVM MS DABT, Pfizer, Inc., San Diego, CA Animal models of disease have traditionally been used in discovery to assess the efficacy of new potential drug candidates. Drug candidates today are more complex both in modality (Fc enhanced, antibody-drug conjugates, fusion proteins, bi-modal molecules) and in their targets and associated biology (pathogens, genetic diseases, targets only up-regulated in the disease state). It becomes difficult in some cases to justify the use of traditional toxicology studies to assess these complex drug/target combinations and this has led to an increased interest in animal models of disease. The generation of disease models has also advanced with the ability to genetically engineer animals to manifest a variety of disease states. Thus, new questions are being raised: how well do these models mimic human disease; how can they best be validated and utilized to assess human safety; and what are the primary issues and challenges if this approach is undertaken over the use of more traditional approaches. A general overview of various animal models of disease and associated case studies highlighting the advantages and potential issues will be given.

XIcA TRANSGENIC ANIMAL MODEL AS A USEFUL AND RELEVANT TOOL FOR SAFETY STUDIES: A CASE PRESENTATION James Murray, Genzyme, Framingham, MA Traditional animal models are the most often used species for the toxicological evaluation of biotherapeutics. Investigation into the utility of alternative animal models has only recently become an experimental option. With species specificity of monoclonal antibodies or disease models showing enhanced and relevant pharmacology, consideration needs to be given to the most appropriate animal model for toxicological investigations. A brief review

of the alternatives to traditional toxicology studies will be discussed. In addition a case study of the utility and data generated using a transgenic animal for the toxicological assessment of a biotherapeutic will be described.

XIdA REGULATORY PERSPECTIVE M. Stacey Ricci, Sc.D., US FDA, Silver Spring, MD The FDA will provide a regulatory perspective on the challenges and considerations associated with transgenics, animal models and surrogate molecules for the development of biological candidates for therapy.

XIIaBIOMARKERS AND TRANSLATION: WHERE ARE PHYSIOLOGICAL BIOMARKERS EFFECTIVE IN TOXICOLOGY AND SAFETY ASSESSMENT? Rob Wallis, Pfizer, Inc., Groton, CT This discussion addresses the science around biomarkers as a translational tool. How well does our current science support the use of biomarkers as outcome predictors in clinical trials? Present scientific methods will be related to animal model selection and where our science is limited.

XIIbCARDIAC PHYSIOLOGY AND CARDIOVASCULAR TOXICITY… DO WE HAVE MODELS AND MARKERS THAT MAKE SENSE AND WORK Robert Hamlin, DVM, Ph.D., Ohio State University, Columbus, OH What can we say about what we are doing that grounds us in good conclusions for predicting human trial results? What does toxicity look like in our current cardiovascular data? Our science and our models will be discussed as a factor determining how well we can translate toxicology and safety data to clinical outcome expectations.

XIIcIMPROVING CARDIOVASCULAR ASSESSMENT IN CANINE TOXICOLOGY STUDIES Pierre Lainee, Astra Zeneca, UK, Macclesfield, UK A review of 100 preclinical studies resulted in refinement of methodology for canine ECG recording. Sensitivity comparisons of several methods resulted in conclusions for including ECG in toxicology safety studies. The value and benefit of external telemetry for ECG recordings in toxicology studies will be discussed in detail and related to recent case examples in dogs and primates.XIId

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BLOOD PRESSURE ASSESSMENT AS A MARKER IN REGULAR TOXICOLOGY STUDIES Marc Niehoff, Covance Laboratories, Munste,r Germany Regular toxicology studies are a challenge when hyper and hypo tensive compound effects need sensitive assessment. Current blood pressure measurement techniques like HDO still require animal restraint causing stress related increases in cardiovascular endpoints. This validation study explores the feasibility of a minimally invasive approach to continuously measure blood pressure in conscious, freely moving animals. Furthermore, it indicates that no adverse histopathological side effects or changes in clinical pathology are accompanied by the surgical implantation of the miniature blood pressure implant.

XIIeFUNCTIONAL BIOMARKERS IN THE INTEGRATED STUDY DESIGN: WHAT MAKES SENSE AND WHEN Ted Baird, Ph.D., MPI Research, Mattawan, MI The recent use of integrated study designs has provided the ability to include functional biomarkers for safety assessment in early toxicology studies. This new design approach offers the ability to advance programs more rapidly. The issues around using this approach will be addressed using data from recent validation studies with discussion of how and where this added effort has value.

XIIIaOVERVIEW OF PETROLEUM SUBSTANCES James J. Freeman, ExxonMobil Biomedical Sciences, Inc., Annandale, NJ Petroleum substances are derived from crude oil by physical separation (i.e., distillation), which may be followed by chemical modification (e.g., hydrogenation, cracking, etc.) to achieve desired performance characteristics and/or emission reduction goals. There are many different types of crude oil and each consists of many thousands of constituents, predominantly hydrocarbons. The composition of the petroleum substances will be dependent on the source crude oil itself, hydrocarbon partitioning into distillate fractions and the subsequent refining steps. It follows that petroleum substances are of variable chemical composition (UVCBs). Crude oil contains certain hazardous constituents (e.g., benzene, polycyclic aromatic hydrocarbons) which may partition into different product groups (e.g., fuels, lubricants, asphalt, etc) due to distillation/refining considerations. However, despite possible occurrence of such hazardous constituents, tests may show that the full petroleum substance may not in itself be hazardous. This is usually because the hazardous constituents are

often reduced to low levels during refining. For purposes of toxicological evaluation, petroleum substances can be arranged into groups or categories of “similar” substances. The rationale for such groupings is that the petroleum substances within a group are derived from similar starting materials, have similar physico-chemical properties and have generally similar compositions and hazard profiles. Grouping was used to meet REACH registration and HPV (High Production Volume) program objectives. The remaining talks in this symposium will focus on specific substances / substance groups (categories) and discuss the approach and interpretation for safety evaluations.

XIIIbASSIGNING AN ADI TO WHITE MINERAL OIL: USE OF PHARMACOKINETIC DATA Peter J. Boogaard, Shell International bv, The Hague, The Netherlands Mineral hydrocarbons (MHC) have important uses in various food applications, as outlined by United States Pharmacopoeia (USP) and Code of Federal Regulations (CFR). MHC residue can be identified in human autopsy samples, and inflammatory responses in mesenteric lymph nodes and liver have been identified in F-344 rats but not in other rat strains or species. Long-term animal studies have established a SAR and low hazard potential for MHC. Comparative pharmacokinetic studies in F-344 and SD rats and in human volunteers were used to establish an appropriate Acceptable Daily Limit (ADI) which has been provided to the World Health Organization (WHO) Joint Expert Committee on Food Additives (JECFA).

XIIIcRECENT STUDIES ON THE POTENTIAL CARCINOGENICITY OF ASPHALT FUMES Charles R. Clark, ConocoPhillips Company, Bartlesville, OK NIOSH-sponsored studies in the 1980s identified fume condensate from a built-up roofing asphalt as carcinogenic to mouse skin. However those fumes, which were generated under laboratory conditions, were found to be compositionally different from fumes to which workers are exposed. Advances in fume generation and collection technology now allow for collection of sufficient quantities of “field-matched” fume condensate to conduct lifetime animal bioassays. The results of bioassays of field-matched fume from both roofing and paving asphalts will be discussed as well as studies investigating the role of temperature on the composition and biological activity of fumes. The outcome of the International Agency for Research on Cancer (IARC) reevaluation of bitumen (asphalt) carcinogenicity, scheduled for October 2011, will also be summarized and discussed.

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XIIIdHAZARD CHARACTERIZATION OF COMPLEX PETROLEUM SUBSTANCES Richard H. McKee, ExxonMobil Biomedical Sciences, Inc., Annandale, NJ Most petroleum substances have complex and variable compositions. As it is not practical to separately characterize the hazard properties of each of the constituents, the approach taken by the industry is to test “representative” substances and use these data for other “similar” substances. Within the High Production Volume (HPV) challenge program, it was necessary to provide information to characterize the human health hazards of approximately 400 petroleum substances identified by CAS number. A review of the existing information, and new analytical and toxicological data generated as part of the HPV process afforded the opportunity to consider the extent to which substances were representative, how these relate to other substances, and to determine whether new hazards could be identified. It was known that certain high boiling substances contained polycyclic aromatic constituents (PACs), and that petroleum substances containing these constituents at sufficiently high levels were dermal carcinogens. A predictive model was developed which permitted hazard predictions for PAC-containing substances to be extended to include repeat-dose toxicity and developmental toxicity. Because reproductive hazards could not be predicted from the compositional data, a number of subchronic toxicity/reproductive toxicity screening tests were conducted. The presentation will summarize the previously available data and new information. A toxicological evaluation of raw and refined lubricant base oils will be presented as an example of the use of both predictive modeling and read-across as a means of characterizing the hazard properties of petroleum-derived substances.

XIIIePREDICTION OF TOXICITY BASED ON A STATISTICAL ANALYSIS OF AROMATIC COMPOUNDS PRESENT IN A PETROLEUM STREAM Mark Nicolich, Ph.D., Cogimet, Lambertville, NJ As part of the US HPV (high production volume) challenge program, the American Petroleum Institute summarized data for a variety of toxicity endpoints on complex petroleum substances and the weight percent of their aromatic ring class (ARC) using a chromatographic test referred to as PAC2. We have developed a series of predictive models based on the ARC ring profile and basic biological measures such as body weight to describe and predict repeat-dose and developmental toxicity endpoints for a number of petroleum substances. There are 7 models that predict selected Screening Information Data Set (SIDS) subchronic and reproductive endpoints and are based on 39 unique petroleum substances; the correlation between observed and predicted values are greater than 0.89 for these models. There is also a mutagenicity model that predicts the modified Ames score as less than 1 or not, this model is based on 242 unique substances and correctly scored over 94% of the substances tested. The presentation will describe the development and form of the models, model efficacy, demonstrate their predictive ability, and discuss the sensitivity analyses and validation of the models. We also discuss the domain of applicability of these models, which is important because of the relative complexity of the models.

XIVaINDUSTRY VIEW POINT OF NONCLINICAL ISSUES IN DRUG DEVELOPMENT AND NDA Clynn Wilker, Ph.D., DABT, Ardea Biosciences, San Diego, CA An overview of industry’s perspective of nonclinical aspects of drug development and NDA will be presented. Challenges of drug development under the current corporate and regulatory environment will be provided. The presentation will include duration and cost of drug development, challenges of working with CROs, and differences in small vs large pharmaceutical companies on how drug discovery and development is handled. Examples will be given.

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XIVbIND AND NDA REVIEW PROCESS – PERSPECTIVES FROM A PRIMARY REVIEWER Amy Ellis, Ph.D., US FDA, CDER, OND, Silver Spring, MD The presentation will focus on IND packages, format and content of NDA per electronic Common Technical Document (eCTD), NDA review process, and accelerated review process. The speaker will discuss key aspects of the primary review process and highlight challenges encountered in developing a safety recommendation from scientific and adminsitrative perspectives.

XIVcNDA PROCEDURES – SECONDARY REVIEW PERSPECTIVES Lynnda Reid, Ph.D., US FDA, CDER, OND, Silver Spring, MD The presentation will discuss the PDUFA, Pre-NDA meeting, NDA submission process, Refusal to File, review cycles, advisory committees, final action of approval and complete action, labeling process, and post-approval commitments.

XIVdNONCLINICAL REGULATORY & SAFETY OVERVIEW FOR NONPRESCRIPTION (OVER THE COUNTER) PRODUCTS AT THE FDA Wafa A. Harrouk, Ph.D., US FDA, CDER, OND, ODEIV, Silver Spring, MD The presentation will focus on the special aspects of OTC approval processes which include IND/NDA packages, OTC monograph regulations, and Rx-to-OTC switches. The speaker will discuss key aspects of the similarities and differences between Rx and OTC review process, and highlight challenges encountered in developing a safety recommendation from the regulatory and scientific perspectives.

XVaSTRUCTURE-BASED THRESHOLD OF TOXICOLOGICAL CONCERN IN RISK ASSESSMENT Susan P. Felter, Procter & Gamble In the absence of chemical-specific data, TTC provides a method to determine a conservative estimate of a chronic oral exposure below which there is a very low probability of risk. The utility of TTC as a pragmatic risk assessment tool has been well-established and accepted by regulatory bodies in a number of areas (e.g., indirect food additives, flavor chemicals, genotoxic impurities in pharmaceuticals). Another area for which TTC has received extensive consideration is in the area of cosmetics and personal and household care products. In extending the applicability of TTC to these areas, a number of factors have been considered including the chemical domain of the databases supporting the TTC exposure limits, how relative bioavailability can be addressed for

dermal exposures, and how less-than-lifetime exposures might be considered. In addition, recent work has focused on how TTC might be used to support complex mixtures such as botanical extracts, and how the principles of TTC might be extended to address local effects such as allergic contact dermatitis and effects in the respiratory tract following inhalation. This talk will provide an overview of how these issues have been addressed and what opportunities remain for further expansion of TTC as a first-tier risk assessment tool to evaluate and substantiate human safety of low-level exposures and appropriately focus societal resources to avoid unnecessary animal testing.

XVbREDEFINING THE CRAMER DECISION TREE FOR THE SAFETY EVALUATION OF NEW FOOD ADDITIVES . Timothy B. Adams, The Flavor and Extract Manufacturers Association, Washington, DC The 1978 Cramer et. al. Decision Tree (DT) was the first rigorous attempt to relate chemical structure to toxic potential. Based upon toxicity and metabolism data available at the time, it proposed three classes of toxic potential: Class I, structures suggesting a low order of oral toxicity; Class II, structures less innocuous than those in Class I, but having insufficient data to support placing them in Class I or III; Class III, structures that permit no presumption of safety or whose structural features may even suggest increased toxic potential. More than twenty years later, a toxicity database was developed to identify intake thresholds for each DT class (Munro et al., 1996). These thresholds became part of the larger thinking about Thresholds of Toxicological Concern (TTC). Based on the chemical structure, the TTC values provided a conservative estimate of a chronic oral exposure below which the substance would not present a significant toxic potential. Although the use of TTC has expanded into a number of areas (e.g., indirect food additives, flavor chemicals, genotoxic impurities in pharmaceuticals), no attempt has yet been made to update the data upon which the DT was developed. This presentation will focus on the revision of the DT and its impact on the TTC concept. The DT revision is, in fact, an expansion of the original DT, based primarily on the use of current knowledge of metabolism, structure activity relationships, and toxicity. The expanded DT will provide the basis for further subdivision within the DT and, as a consequence, the development of additional structural classes. The application of new steps in the expanded DT will be discussed in the context of the updating of TTC.

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APPLICATION OF THE MARGIN-OF-EXPOSURE (MOE) APPROACH TO FOOD ADDITIVES Michael J. DiNovi, US FDA, Riverdale, MD Global regulatory agencies have long relied on a safety assessment approach to evaluating new additives or new uses for additives currently in the food supply. This approach involves a simple comparison between an estimate of daily intake (EDI) and an acceptable daily intake (ADI), which is typically derived from animal studies. While this approach is effective for a yes/no system, it does not allow comparisons between additives. A margin of exposure approach has been developed for the risk assessment of contaminants in food (Benford 2010) that can be broadened for use with food additives. In this approach, a toxicological point of departure (the benchmark dose) is determined from observed effect levels in animal tests. A statistical evaluation of the dose-response curve allows for the determination of upper and lower bounds for each dose point. Commonly, a 5th or 10th percentile of the effect is evaluated (i.e., the dose where the effect is noted in 5 or 10 percent of the animals tested), with the lower confidence limit supplying the point of departure. This point is called the BMDL5 (or 10). The ratio of the BMDL to the EDI is the margin of exposure, with larger values indicative of “safer” additives. Examples from the cited paper and for some commonly used additives will be shown.1) Benford, D., Bolger, P.M., Carthew, P., Coulet,

M., DiNovi, M., Leblanc, J.-C., Renwick, A.G., Setzer, R.W., Schlatter, J., Smith, B., Slob, W., Williams, G., and Wildemann, T. (2010) Application of the Margin of Exposure (MoE) Approach to Substances in Food that are Genotoxic and Carcinogenic. Food and Chemical Toxicology, 48(1):S2-S24.

XVdCHEMOINFORMATIC APPROACHES FOR TOXICOLOGY PREDICTIONS Kevin P. Cross1, Edwin Matthews2, Luis G. Valerio, Jr3., 1Leadscope, Inc. 1393 Dublin Rd, Columbus, OH 43215, 2Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food & Drug Administration, College Park, MD 20740, 3Science and Research Staff, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993 Chemoinformatic (computational) approaches are comprised of a variety of tools, many of which are enabled with predictive power to screen and analyze substances found in a wide range of regulated products (food additives, dietary supplements, proposed drugs). In this presentation, the use of various scenarios and chemoinformatic systems for in

silico analysis of compound safety liabilities will be discussed. An overview of these approaches, including their strengths and limitations will be presented. Validation studies on the predictive accuracy of these systems for various toxicology endpoints will be explained as well as how clinical trial data are used to develop hypothesis-based models. Examples where chemoinformatic tools have been employed in applied regulatory research at FDA in order to screen naturally occurring chemicals found in botanical preparations for signals of hepatic toxicity will also be presented. Given that many botanicals and chemical substances within dietary supplements can in fact be data poor, with respect to toxicology animal study data, the use of chemoinformatics may be considered as an alternative method to animal testing. One of the goals in our collaboration is to help support safety assessments via additional predictive evidence to help prioritize substances for animal testing.

XVeREGULATORY USE OF COMPUTATIONAL TOXICOLOGY TOOLS AND DATABASES AT THE FDA, OFFICE OF FOOD ADDITIVE SAFETY Kirk Arvidson, Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, MD Over ten years ago, the U.S. Food and Drug Administration’s Office of Food Additive Safety (OFAS) implemented the formal use of structure activity relationship (SAR) analysis and quantitative structure activity relationship (QSAR) analysis in the premarket review of food-contact substances. Currently, OFAS uses multiple (Q)SAR models in its (Q)SAR evaluations of food-contact substances and is investigating the use of metabolism data and metabolism predictive models. More recently, OFAS has been developing a sustainable data management and storage system (Chemical Evaluation and Risk Estimation System (CERES)), that will provide decision support tools for both pre-market and post-market safety assessments of food additives and food-contact substances and food contamination issues. The development of CERES will provide a single unified data repository and analysis system that compiles available information on a substance, including: chemical structures and properties, regulatory records, toxicity studies, biological screening assays, (Q)SAR models and application programming interfaces (APIs) to commercial (Q)SAR tools. In cases where no information is available for a particular substance, CERES provides tools to identify potential safety concerns by applying mode-of-action-driven (Q)SAR prediction models and for identification and analysis of

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data on structural and biological analogs (read-across). The presentation will describe the (Q)SAR tools available at OFAS, the application of (Q)SAR tools to a real-world example and the future directions of (Q)SAR within OFAS through the CERES system.

XVIaSUMMARY OF ISSUES COVERED IN THE FDA-INDUSTRY 2010 DIALOGUE SESSION ON THE DRAFT GUIDANCE ON ASSESSMENT OF ABUSE POTENTIAL OF DRUGS Jennie L. Walgren, Ph.D., Eli Lilly and Company, Indianapolis, IN Over the past several years there has been an active effort in both industry and the FDA to openly discuss and debate approaches to abuse liability assessments of pharmaceuticals in development. The first FDA-Industry dialogue held in 2008 involved a question and answer session with FDA’s Controlled Substances Staff addressing case studies provided by industry colleagues. Following the release of the draft FDA guidance on Assessment of Abuse Potential of Drugs in January 2010 and extensive comments submitted to the FDA from industry, additional dialogue was proposed. A second dialogue session between industry representatives and FDA staff occurred in November 2010 where industry colleagues in a cross-company group posed specific questions and proposals on topics covered in the draft guidance. These topics included general/cross-functional issues such as definitions of terms in the guidance and guidelines for determining when abuse liability assessments are required; regulatory/procedural issues in determining abuse potential; strategy of approach and design of nonclinical abuse liability studies; evaluation of clinical trial data, and the design and interpretation of human abuse potential studies; and risk assessment and risk management. The presentations in this symposium will be focused on providing an overview of the topics highlighted by the industry group and the feedback that was received in several of these areas, including nonclinical and clinical abuse liability study designs, regulatory expectations, and a proposed flow scheme for nonclinical abuse liability assessments.

XVIbSTUDY DESIGN OF ANIMAL BEHAVIOR STUDIES Kristin Horn, Ph.D., Bristol-Myers Squibb, Mt. Vernon, IN Data from abuse liability evaluations are needed to support New Drug Applications and inform final scheduling under the Controlled Substances Act. Preclinical assessments of abuse liability are performed to provide an early indication of a drug’s abuse potential and can contribute to key strategic decisions surrounding the development of drug products. The

behavioral assessment of drugs in animals is an evolving field and a variety of approaches should be considered when designing studies to assess the abuse potential of a drug product. Recent dialogue between representatives of the pharmaceutical industry and the FDA’s Controlled Substance Staff has provided guidance regarding best practices when designing preclinical abuse liability studies. The purpose of this presentation is to describe the rationale and procedures for conducting preclinical abuse liability studies, with a focus on best practices, as discussed during the 2010 FDA-Industry Dialogue. To this end, the audience will be introduced to general concepts and considerations when developing a preclinical strategy. Following this introduction, the discussion will focus on the intricacies of key preclinical behavioral studies including self-administration, drug discrimination, and withdrawal/dependence studies.

XVIcCLINICAL STUDY DESIGN CONSIDERATIONS Marta Sokolowska , Ph.D., Grünenthal USA, Inc., Bedminster, NJ Abuse potential of drugs is evaluated based on data collected throughout the drug development program. The clinical assessments incorporate analyses of the human abuse potential study in addition to examination of adverse events of special interest and aberrant behaviors observed in Phases I - III. Even though the FDA Draft Guidance for Industry: Assessment of Abuse Potential of Drugs (Jan 2010) clarified some aspects of these assessments, further gaps have been identified. This presentation will focus on interactions between the Cross Company Abuse Liability Consortium and FDA discussing issues associated with the human abuse potential study design, impact of various factors on data analysis including the differentiation between statistically significant versus clinically important differences. Additionally, methodology to evaluate adverse events and aberrant behaviors will be discussed.

XVIdREGULATORY EXPECTATIONS Beatriz Rocha, MD., Ph.D. Worldwide Regulatory Affairs, Merck & Co., Inc., Rahway, NJ On January 2010 FDA published the Draft Guidance on Assessment of Abuse Potential of Drugs. Key comments to the Draft Guidance that were proposed by the Cross Company Abuse Liability Consortium (CCALC) were incorporated into many of the individual company's and PhRMA's submissions to the FDA docket. During the commenting period the Controlled Substance Staff of the FDA (CSS), in an attempt to better understand stakeholder comments on the draft

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guidance, approached the CCALC to explore the possibility of a dialogue session focused on the guidance. The CCALC/CSS Dialogue Session occurred on November 2010, and gave origin to an extremely collaborative discussion towards addressing critical public health needs and bridging scientific gaps of the assessment of abuse potential. This presentation will focus on CCALC's comments of the regulatory topics included in the FDA Draft Guidance. Procedural details regarding CSS review process of the Abuse Potential package included in the filing of the New Drug Application (NDA), timelines of the CSS review during the review of the NDA, and communication with the sponsor are highlighted, mostly in the context of the frequent gap that occurs between NDA approval by the FDA and scheduling recommendation by the DEA, which is in the critical path for commercialization. The CSS/CCALC Dialogue Session opened the door for productive interaction towards the advance of the science of abuse potential assessment and significantly contributed towards a solid collaborative relationship between industry and the FDA.

XVIeFLOW CHART HIGHLIGHTING KEY DECISION POINTS IN PRECLINICAL PROGRESSION Mary Jeanne Kallman, Ph.D., Covance Laboratories, Inc., Greenfield, IN This presentation will provide an update on the requirements and expectancies for preclinical testing of new compounds for FDA registration. New insights gained from the 2010 interaction with the FDA Controlled Substance Staff will be the primary focus of the discussion. The evolving dialogue with the Controlled Substance Staff has focused on the future expectancies of the agency.

XVIIaWHAT’S NEW IN ANIMAL WELFARE AND IN THE NEW GUIDE? WHERE DID WE COME FROM, WHY ARE WE HERE, AND WHERE ARE WE GOING? Patricia V. Turner, BSc, MSc, DVM, DVSc, DACLAM, DABT, University of Guelph, Guelph, Canada A quick review of the philosophy, ethics, and cultural thinking behind today’s regulations and their context within our science will set the groundwork for understanding current developments in the regulatory environments and the cultural settings that have created them. The current changes and updates to the new guide will be emphasized and their relevance to in vivo toxicology and safety assessment laboratory settings will be discussed. Emphasis will be on practical adjustment to the guideline and how common sense and the new regulations can be integrated together into a reasonable achievable successful outcome.

XVIIbSCIENCE, 3R’S AND EXPERIMENTAL DESIGN…. SHIFTING THE BALANCE WITH NEW TECHNOLOGY AND BETTER EXPERIMENTAL DESIGNS TO SUPPORT IMPROVED ANIMAL WELFARE Henry Holzgrefe, Scientific Advisor, Navigator Services, Charles River Laboratories This talk will present an understanding of the approaches that can be made with technology while meeting with 3R’s philosophical directions. The emphasis on improved experimental constructs using better designs, better technology, and improved measures to enhance statistical power, reduce animals, and improve outcomes will be emphasized. Practical suggestions from experience with statistical perspectives for selecting better designs with increased study power and improved outcome planning to yield fewer animals used will be shared with participants.

XVIIcDIRECTIVE 2010/63/EU: THE RENEWED EUROPEAN FOCUS ON PROTECTION OF ANIMALS USED FOR SCIENTIFIC PURPOSES AND ITS INFLUENCE ON OUR RESEARCH Karen Blumer, Ph.D., Novartis International AG, Basel, Switzerland This talk will cover the prior EU regulatory landscape and will take the attendees forward into understanding the new directive changes that are now legislated and moving into EU research laboratories. The role of the 3R’s, the EU cultural context, and details of the directive will be reviewed in this comparison of the old and new legislation. Current legal and ethical implications that affect our future scientific in vivo research environments will be shared.

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XVIIdDEPARTMENTAL COOPERATION FOR BETTER SCIENCE AND BETTER WELFARE: A CASE STUDY Russell Bialecki, Ph.D., Astra Zeneca, Wilmington, DE This case study presents an example and validation for using a new approach to integrated study designs that improves scientific outcomes while satisfying animal welfare goals. Combining the efforts of three separate corporate research departments (PK/PD, Metabolism, and Pharmacology), combining several studies into a single design, and sharing data sets accomplished several improved outcomes: reduction of animals, fewer studies, and advancing the compound over several research hurdles.

XVIIIaCURRENT STATUS OF BIOSIMILAR LEGISLATION Barbara J. Mounho, PhD, DABT, Amgen Inc., Thousand Oaks, CA Biosimilars are biological products derived from recombinant DNA technology, which are claimed to be highly similar to an innovative biological product (reference product) in terms of quality, efficacy, and safety. While biosimilars are a relatively new category of biological therapeutics, interest in the development and marketing of biosimilars continues to increase in the pharmaceutical industry as innovator products reach the end of their patent protection period. The first formal regulatory pathway for the approval of biosimilar products was established in 2003/2004 in the European Union (EU). Subsequent to the regulatory guidelines established by the EU, guidelines for the approval of biosimilar products have been issued by the World Health Organization (WHO) as well as in numerous regions around the world, such as Japan and Canada. This presentation will provide a high level review of the approaches of the WHO and regulatory authorities in various key regions in the world, as well as review some of the issues relating to the approval of biosimilars.

XVIIIdUPDATE ON ICH M7 GUIDANCE WITH EMPHASIS ON QSAR AND GENOTOXIC IMPURITIES Kenneth Hastings, MPH, DrPH, DABT, Sanofi-Aventis While commercially available and proprietary Quantitative Structure-Activity Relationship (QSAR) programs have long been used by PhRMA companies, the application to genotoxic impurities (GTI) is the first instance where these tools are being used in a regulatory context. The EMA and FDA have published guidance on identification and control of GTIs in human drugs and currently an ICH guideline (M7) is under development. While there is a consensus that QSAR programs should be used to identify potential GTIs, the types and number of programs which should be employed has not been clarified. This presentation will be given by the acting chair of the PhRMA (Q)SAR subcommittee who will provide a status update of ICH M7 and associated discussions around (Q)SAR and genotoxic impurities.

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POSTER ABSTRACTS

100 series – Methodology P100ENHANCEMENT OF URINE SAMPLES FROM MICE Anthony Rohr, BS, LATG, Nichole James, BS, LATG, Erin Warren, AAS, MLT (ASCP), Ty Schoenborn, BS, LAT, Lacey Ciaravino, Thomas Dailey, BS, ALAT, Jan VanSteenhouse, DVM, PhD, DACVP Historically, all animals had been fasted prior to blood and urine collections for toxicology studies. Because of the mouse’s propensity to not drink if not fed, this often resulted in varying degrees of dehydration and low blood and urine volumes. Thus, fasting was abandoned for mice with resultant dramatic improvements in obtainable blood volumes with no detrimental interpretive effect on other hematology or clinical chemistry parameters. However, the usable volume and quality of urine samples remained a quality issue. Urine samples in the past and until recently were collected via dripping into an open container positioned below the cage allowing for considerable evaporation. In spite of mesh filters over the outflow collection tube, urine samples tended to be flocculent with varying amounts of diet debris contamination. We have developed a method by which a gelatinous form of food is offered to mice during urine collection to eliminate the contamination issues and the physical collection device has been modified to mitigate the potential for evaporation. Two internal studies were conducted using the newly created protocol for urine collection in mice. These studies demonstrated clear advantages of this procedure over the previous protocol for collecting urine from mice. The number of samples that met the minimum volume requirements for analysis using the Clinitek Atlas® Automated Urine Chemistry Analyzer were increased by 56%. In addition, the quality of the urine was also enhanced as evidenced by the analysis of the data produced by the Clinitek Atlas® and the drastic reduction of foreign sediments in the microscopic evaluation. There were no physiological or toxicologically meaningful differences relative to the different diets that would affect interpretation of hematology or clinical chemistry results. MPI Research has adopted this as our standard protocol for urine collection in mice.

P101PHARMACOKINETIC EVALUATION OF DILTIAZEM COMPARING MANUALLY-SPOTTED DRIED BLOOD SPOTS (DBS) WITH AUTOMATED DRIED BLOOD SPOTS, AND PLASMA SAMPLES, COLLECTED BY THE CULEX ® AUTOMATED SAMPLING SYSTEM Bradley Gien, Peter White, Robin Lane, Tyler DeGraw, Bhavna Mistry, Amanda Plumb, John Maltas, and David Hopper, BAS Inc. 2701 Kent Avenue, West Lafayette, IN 47906 Dried blood spot (DBS) sample collection has many advantages compared with traditional sampling techniques. Here we describe pharmacokinetic evaluation of a single dose of diltiazem (DTZ) comparing use of a novel automated DBS technique to manually spotted DBS, and traditional plasma samples, all collected using the Culex® Automated Blood Sampling system (ABS). One group of 8 male rats was prepared with intra-arterial catheters in both femoral and carotid arteries externalized for connection to the ABS. The rats were administered DTZ by oral gavage, at a dose of 20 mg/kg. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 3, 4, 6, and 8 hours post dose. The ABS was successfully used to robotically collect whole blood samples in the DBS format in support of a rat pharmacokinetic study. Exposure profiles were similar when measured in plasma, ABS-spotted DBS, or manually pipetted DBS. Differences in the mean AUC0-8 and CMAX between manually and Culex collected DBS were <14.0%. Lowest AUC0-8 and CMAX

variability was observed with automated DBS (39.0 / 40.0% CV respectively). Blood collected before and after the sampling schedule indicated some decrease in red cell mass from the intensive bleeding schedule, but post-study results remained within the laboratory reference range (RBC) or slightly lower (Hgb and HCT). Manually-spotted DBS were more variable in size, shape and appearance than automated DBS. Labor required for manual spotting, and for traditional plasma processing, was greater than for automated DBS. Sample shipment was easier and less costly for DBS cards vs. frozen plasma.

POSTER ABSTRACTS

P102THE EYES HAVE IT: CALF VERSUS ADULT EYES IN THE BOVINE CORNEAL OPACITY AND PERMEABILITY (BCOP) ASSAY. Donahue, DA1, Hall, D2, Cerven D2, DeGeorge, G2, and Avalos, J1. 1-Kao Brands Company, Cincinnati, OH. 2-MB Research Laboratories, Spinnerstown, PA. The Bovine Corneal Opacity and Permeability (BCOP) assay uses excised bovine corneas obtained from cattle slaughtered for food use. Consequently, the age of the cattle is generally not provided with the corneas. This introduces a variable at the start of the assay, which can be reduced by using eyes from cattle at a defined age. The OECD guidelines for the testing of Chemicals No. 437 recommends the use of eyes from cattle 6 to 12 months of age but encourages investigators to report the estimated age and/or weight of the animals providing the corneas. In a commercial operation, capable of killing large numbers of cattle to provide suitable numbers of eyes, it may not be possible to determine age and weight since animals are received from a number of suppliers. Additionally, random-source animals typically have not been raised in constant environment and are subject to numerous environmental variables. This study looked at the effect of the cattle’s age on the BCOP assay. The calf eyes used in this study were obtained from a well-managed barn-raised herd, which had weekly veterinary monitoring and controlled feed and medication.In this study we compared the In Vitro Scores (IVS) from random source cattle corneas with those of corneas from a well-managed calf herd of 4 to 5 months of age. Thirty over the counter cleaners, hair dyes, hair sprays, deodorants and moisturizers, which had IVS scores obtained from random-age animals were used in the evaluation. The IVS scores from the random aged animals ranged from -0.62 to 111.58. The IVS scores from age-defined calf eye corneas ranged from -1.11 to 22.86.

P103GENE EXPRESSION PROFILING OF AN IN VITRO HUMAN SKIN MODEL AFTER PSORALEN PLUS ULTRAVIOLET LIGHT-INDUCED PHOTOTOXICITY. Pratt, Lisa F.1; DeGeorge, George L.1; Cunningham, Mary Jane2. 1. MB Research Laboratories, Spinnerstown, PA. 2. Nanomics Biosciences, Inc., Cary, NC. TO REDUCE THE NUMBER OF ANIMALS FOR SAFETY SCREENING OF POTENTIAL IRRITATING CHEMICALS AND PHOTOTOXINS, EFFORTS HAVE BEEN MADE TO DEVELOP MORE PREDICTIVE IN VITRO ASSAYS. ONE MODEL IN MORE COMMON USE IS RECONSTITUTED HUMAN EPIDERMIS (MATTEK EPIDERM) RESEMBLING IN VIVO HUMAN SKIN. IN THIS INVESTIGATION, THESE HUMAN SKIN MODELS

WERE EXPOSED TO A KNOWN SKIN IRRITANT, 8-METHOXYPSORALEN (8MOP), AT A DOSE COMPARABLE TO THE EC10. THE SAMPLES WERE ALSO EITHER KEPT IN THE DARK OR EXPOSED TO SOLAR SIMULATED LIGHT (SSL). GENE ACTIVITY WAS ANALYZED WITH MRNA MICROARRAYS AT 1, 6, AND 20 HR TO DETERMINE POTENTIAL CELLULAR AND MOLECULAR MECHANISMS OF ACTION. TWO LEVELS OF BIOLOGICAL CONTROL SAMPLES WERE USED: A) SAMPLES NOT TREATED WITH 8MOP AND KEPT IN THE DARK OR EXPOSED TO UV LIGHT AND B) SAMPLES TREATED WITH SODIUM DODECYL SULFATE (SDS) [POSITIVE CONTROL]. PURIFIED, LABELED, AND FRACTIONATED CRNA ISOLATED FROM EACH OF THE BIOLOGICAL SAMPLES WERE HYBRIDIZED ONTO WHOLE HUMAN GENOME MRNA EXPRESSION MICROARRAYS, EACH CONTAINING 41,000 UNIQUE PROBES. DATA ANALYSIS WAS DONE BY A TIERED APPROACH. COEFFICIENTS OF VARIATION (CV) FROM ALL THE PROBES PASSING QUALITY MEASURES OR A TOTAL OF 11,335 PROBES FOR EACH BIOLOGICAL SAMPLE WITHIN THE TREATMENT GROUPS RANGED FROM 18.5-33.1%. THE LEAST VARIABILITY WAS OBSERVED WITH THE PRINCIPAL COMPONENTS ANALYSIS (PCA) FOR THE NEGATIVE CONTROL SAMPLES (THOSE NOT EXPOSED TO 8MOP) AND THE SAMPLES EXPOSED TO 8MOP UNDER DARK CONDITIONS. THE MOST ACTIVITY WAS SEEN WITH 8MOP AND SSL EXPOSURES AT 6 AND 20 HR AS WELL AS EXPOSURES TO SDS, THE POSITIVE CONTROL. SEVERAL GENES IN COMMON BETWEEN TREATMENTS WITH SDS AND 8MOP WERE CXCL14, FIBRILLIN2, TROPOMYOSIN ALPHA 1, CYP26B1, HSP70B AND VEGF-A. FUNDING WAS PROVIDED BY NIEHS GRANT NO. 5-R44-ES-11927-02.

P104VEHICLE-DEPENDENT EFFECTS ON HEXYLCINNAMAL-DEHYDE RESPONSES IN THE LLNA. G. L. DeGeorge, M. Carathers, J. Tao, D. R. Cerven. MB Research Laboratories, Spinnerstown, PA. Hexylcinnamaldehyde (HCA) is the default, preferred positive control substance in the Local Lymph Node Assay (LLNA), due to its moderately potent dermal sensitizing properties. We have tested the effects of use of varying vehicle solvents for HCA on the endpoints of Stimulation Index (SI), lymphotype subsets (immunophenotyping; IP), and irritation as measured by ear swelling. Herein, we show that the choice of vehicle does biologically and statistically significantly (P>0.05) impact the HCA endpoint values, most importantly, the SI. HCA at 25% was evaluated in all vehicles (AOO, DMSO, Acetone, Ethanol and DAE433, petrolatum, PG, etc.), and compared to naïve or untreated controls, as appropriate. Most importantly, some vehicles (besides the default AOO) that are commonly used were more prone to causing or enhancing irritation induced by vehicle-alone treatment, or either

decreased or increased SI values and variability when compared to AOO. Generally, DAE433 was a ‘better’ vehicle than DMSO alone, resulting in lower background proliferation and less irritation (ear swelling Day 1 through Day 6). Petrolatum gave good results as a vehicle for 25% HCA with an SI=10.3, comparable to AOO SI=9.8 and DMF SI=9.9. Acetone and PEG had significantly higher SI values and B:T cell ratios than DMSO and AOO. DMSO and DMA had the lowest SI values for 25% HCA, at 7.8 and 5.8, respectively. In addition, DMSO was significantly irritating to the ears of mice as a vehicle, and caused very pronounced ear swelling when used as a vehicle for HCA (>15% increase). In conclusion, the vehicle chosen for the LLNA can significantly affect multiple endpoints of interest in the assay, especially the Stimulation Index, and that this variability should be taken into account when testing similar or borderline test substances in vehicles other than AOO.

P105IRRITATION IN THE LLNA: 2000 MICE EAR THICKNESS MEASUREMENTS DEPENDENCE ON VEHICLE AND HCA TREATMENT. DeGeorge, George L., Carathers, Micheal R.; Cerven, Daniel R.. MB Research Laboratories, Spinnerstown, PA. THE LOCAL LYMPH NODE ASSAY (LLNA) IS KNOWN TO BE SUSCEPTIBLE TO FALSE-POSITIVES CAUSED BY IRRITATING TEST SUBSTANCES. WE HAVE INCORPORATED EAR THICKNESS MEASUREMENTS ON DAYS 1, 3 AND 6 OF THE LLNA IN ORDER TO MEASURE DERMAL IRRITATION-INDUCED EAR SWELLING. KNOWN LLNA FALSE-POSITIVE IRRITANTS SLS AND BAC CAUSED INCREASES IN EAR SWELLING ON DAY 6 (WHEN COMPARED TO DAY 1) OF 25% OR GREATER (>1.25-FOLD). IN ADDITION, THE DEFAULT POSITIVE CONTROL HEXYLCINNAMALDEHYDE (HCA) HAS IRRITATION POTENTIAL, WHICH WAS CONFIRMED AT CONCENTRATIONS ABOVE 10% HCA. INTERESTINGLY, ALL COMMON LLNA VEHICLES (ACETONE:OLIVE OIL 4:1(AOO), ACETONE, ETHANOL, DIMETHYLACETAMIDE:ACETONE:ETHANOL 4:3:3 (DAE433), ETC.) DID NOT AFFECT EAR SWELLING THROUGH DAY 6, WITH THE NOTABLE EXCEPTION OF DIMETHYLSULFOXIDE (DMSO). DMSO-TREATED MOUSE EAR SWELLING WAS INCREASED OVER 15% DURING THE SIX-DAY EXPERIMENTAL TERM. THIS IMPLICATES DMSO AS MODERATELY IRRITATING AND POSSIBLY A PROBLEMATIC VEHICLE FOR THE LLNA.

P106DEVELOPMENT OF THE REPLACEMENT OCULAR BATTERY-ROBATT - TIERED TESTING STRATEGY OF ALTERNATIVE TOXICOLOGY TESTS TO REPLACE THE NEED FOR RABBIT EYE TESTS. Cerven, D., Piehl, M., DeGeorge, G. MB Research Laboratories, Spinnerstown, PA 18968

Using a series of non-animals assays in a tiered approach, the Replacement Ocular Battery (ROBatt) accurately predicts the categories of acute ocular irritation corresponding to OECD, EPA and GHS guidelines. At present, no single alternative assay has been accepted by regulatory agencies to completely replace the use of live animals. The BCOP (Bovine Cornea Opacity/Permeability) test has been accepted by OECD as a screen for severe and corrosive materials. The Cytosensor Microphysiometer has been accepted for sub-severe testing but it applicable for aqueous-based materials. The ROBatt approach uses a series of two to three non-animal assays to categorize both aqueous and non-aqueous materials. An NIH/FDA Grant has been awarded to develop the ROBatt decision tree criteria. Initially screening will use the Chorioallantoic Membrane Vascular Assay (CAMVA) to discriminate slight or non-irritants from moderate to severe irritants. Slight or non-irritating materials will be categorized using the Porcine Cornea Confocal Assay (PorFocal). The Bovine Cornea Opacity/Permeability test (BCOP) will be used for discriminating between moderate and severe to corrosive materials and the Porcine Cornea Opacity Reversibility Assay (PorCORA) will be used to categorize severe irritants and corrosives.Fifty validation chemicals from the ECETOC database of ocular irritation will be initially used. Having performed over 6,700 CAMVA, 5,700 BCOPs, and nearly 100 PorCORA assays, the researchers are confident of the ability to complete categorize any material to international standards.

P107COMPARATIVE STUDY OF PLASMA MICROSAMPLING IN MALE RATS AFTER A SINGLE-DOSE OF ACETAMINOPHEN Alan Stokes 1 , Tammy Moose 1 , Carie Kimbrough 2 , Mark Mullin 3 , Jim Kenney 4 , Joe Siple 4 , Neil Spooner 5 1 Safety Assessment, GlaxoSmithKline, Research Triangle Park, NC, USA, 2 Statistical Sciences, GlaxoSmithKline, Research Triangle Park, NC, USA, 3 Bioanalytical Sciences and Toxicokinetics, GlaxoSmithKline, Research Triangle Park, NC, USA, 4 Drummond Scientific Company, Broomall, PA, USA, 5

Bioanalytical Sciences and Toxicokinetics, GlaxoSmithKline, Ware, UK Total blood volumes in animals, especially rodents, present a practical limitation when sampling blood over a 24 hour period to obtain toxicokinetic data. This limitation can increase the numbers of rats or mice used on a study and/or limit the number of samples collected per animal. Microsampling strategies (e.g., dried bloodspots) are one way to overcome this limitation and have

become more common in recent years due to the increased pressure on the pharmaceutical industry to reduce animal use and costs. Reducing the volume of blood collected at each time point can have a positive impact by decreasing the number of animals used on a study and allowing for more robust serial sampling in an individual animal. Plasma microsampling (~75 L of blood per time point) significantly decreases the amount of blood (~70%) collected per time point for toxicokinetic analysis. Using EDTA coated capillary tubes with a thixotropic agent, it is possible to decrease the volume of blood collected for plasma exposure analysis. The current study compared data collected in male rats (n = 8) after a single 600 mg/kg dose of acetaminophen using a plasma microsampling method and a standardized plasma collection method (250 L of blood per time point). Drug exposure at 4 separate time points (1, 2, 5, and 8 hours) were compared and found to be within 8% overall and within 5% for the majority of samples (23 of 32). Mean AUC and Cmax values were within 1% of each other using the 2 different collection methods with individual AUC or Cmax values within 5% or 6% of each other, respectively.

P108EVALUATION OF SEX SENSITIVITY IN LOCAL LYMPH NODE ASSAY TIWARI V.K ., DALAL V ., VERMA R . DUBEY V., MANISH R. , PANDEY S ., PATEL R , BRAHMANKAR M . BOVERHOF, D . * AND WOOLHISER M .* (JAI RESEARCH FOUNDATION, VALVADA 396 108, GUJARAT, INDIA) *TERC, THE DOW CHEMICAL COMPANY, MIDLAND, MI, USA The current OECD Test Guideline for the conduct of the Local Lymph Node Assay (LLNA) recommends the use of only female mice for the assessment of skin sensitization potential for a given chemical. The NIH publication no. 99-4494 recommends that only female CBA mice be used, as they reportedly develop a stronger contact dermatitis response when compared to males. Males were also reported to display a larger variation in response due to a greater tendency to fight and to be involved in ‘social ranking’ behavior when group housed. However, there are several advantages to consider with the inclusion of male mice in LLNA testing including a more refined and responsible use of animals from supplier breeding programmes. The NIH publication highlights that if males are to be considered, systematic studies evaluating potential sex differences should be conducted. Therefore, to begin to systematically assess the appropriateness of using male mice in the LLNA a comparative guideline study was conducted with individually housed mice using the well known sensitizer, α-Hexylcinnamaldehyde (HCA). The study compared 5

male and 5 female CBA/J mice/group, at three test material concentrations (3%, 10% and 30% (w/v) HCA), with 1 % aqueous (v/v) pluronic L92 surfactant as the vehicle. Stimulation indices (SI) for the three HCA treatment groups were 3.75, 5.59 and 12.50 for male and 2.19, 4.05 and 7.37 for females, respectively. The results revealed no significant difference between samples means or variability between the sexes and the SI values observed for both male and female mice were within the range of historical control data for female mice. EC3 value for male could not be calculated; however EC3 value for female (6.05%) was in range of reported value (4.9 to 15%) in guideline. These data provide initial support for the use of male mice in the LLNA and will be followed by further experimentation with a variety of chemicals to systematically evaluate potential for sex differences in an effort to support the use of male mice in the LLNA as a further assay refinement.

P109PRECLINICAL EVALUATION OF A DOCETAXEL FORMULATION . Lorraine Webster, John Risvanis, and Darryl Whittaker. Hospira Australia Pty Ltd, Melbourne, Australia. Background: Hospira has developed a stable one-vial presentation of docetaxel, a cytotoxic anti-mitotic drug. Docetaxel has very low water solubility, and its delivery in the infusion solution is achieved by micelle formation in polysorbate 80 (PS80). Hospira Docetaxel contains the same amount of PS80 as the innovator, with additional excipients to permit a stable, ready-to-dilute product. Aim: A preclinical program was designed to confirm that the changes in the excipients would not alter the in vivo pharmacology of docetaxel. Methods and Results: All studies compared Hospira Docetaxel with a then marketed product and all methods were validated. Some studies were GLP. The drug released from micelles in the infusion solution was similar. At clinically relevant plasma concentrations (0.2 to 2.0 mcg/mL), protein binding by equilibrium dialysis was similar in dog and human plasma. The immunogenic potential was also equivalent, as measured by complement terminal complex (SC5b-9) formation in 10 human serum samples. A cross-over pharmacokinetic study was performed in 10 male Beagle dogs at 1 mg/kg. Where neutropenia was noted, all animals had recovered prior to the second dose. Docetaxel was quantitated by a validated LC/MS/MS method, and plasma protein binding was determined using equilibrium dialysis. Pharmacokinetics of total and unbound docetaxel were equivalent between the two products. Conclusion: These preclinical studies formed the basis of assuring that the in vivo pharmacology of a non-aqueous formulation of docetaxel was

comparable to a then marketed product. Hospira Docetaxel has been granted marketing approval in many countries.

P110NEEDLE-FREE INJECTIONS VIA THE SUBCUTANEOUS ROUTE IN RATS USING THE BIOJECT DEVICE (AN ALTERNATIVE TO DOSING PRE-CLINICAL SPECIES) S. Hadd 1 , G. Ruppert 1 ,R. Stout 2 , D. Hargreaves 1 , C. Coffey 1 , S. Frantz1 1MPI Research, Mattawan, Michigan, 2Bioject, Tualatin, Oregon The industry standard for subcutaneous and other parenteral routes of drug administration has historically involved the use of a needle and syringe system. However, there are many drawbacks to needle usage in pre-clinical and clinical settings such as: passage of infectious diseases, potential fear of needles, and accidental needle sticks. Alternatively, needle-free injection systems (NFIS) provide an empowering technology that work by forcing liquid medications at high speed through a tiny orifice held against the skin. This creates a fine stream of high-pressure fluid penetrating the skin and depositing medication in the tissue beneath in a fraction of a second. The novel technology of NFIS has been used recently in pre-clinical and clinical research but has not been previously used in rodents via all routes of injection: intradermal, intramuscular, and subcutaneous. In a recent two-phase study conducted to evaluate and characterize the acute toxicity and estimate the maximum tolerated dose following a single subcutaneous dose, and evaluate the toxicity and toxicokinetics of the test article following 7 days of repeat subcutaneous dosing in CD® [Crl:CD®(SD)] rats, NFIS was used as an alternative to the traditional needle and syringe system. The Bioject® device had not been previously used for subcutaneous injection in rats and this poster will describe the different trials used to determine the best technique for administration. Several techniques were employed to determine the ideal method to deliver the test article formulation in the subcutaneous space consistently and accurately that would result in predictable and repeatable results. The technique used on study involved “tenting” the skin with the injection taking place perpendicular to the animal.

P111TAPE STRIPPING REPETITIONS REDUCE THE STRATUM CORNEUM INVERSELY IN YUCATAN MINIATURE SWINE Horlen KP, Brown L, Hanks C, Liu J, Bouchard GF, Sinclair Research Center, LLC Miniature swine are a recognized predictive model for human drug candidate dermato-pharmacology studies. Tape stripping is a simple and

effective method for removing the stratum corneum (SC) and is commonly employed during in vivo studies investigating the percutaneous penetration and disposition of topically applied candidate drugs. The objective of this study was to assess the remaining thickness of the SC following 0, 10, 20, 30, 40, and 50 repetitions of tape stripping of skin. Animals were young adult, male Yucatan miniature swine weighing 33-36kg (N=3). Animals were maintained under general anesthesia for the entire duration of the procedures. Following clipping of the pelage over the dorsal lumbar and thoracic areas, 6 sites, approximately 5cm by 5cm, were demarcated and skin was stripped using U-Line 1.8mm clear acrylic adhesive tape applied with uniform, firm pressure. Following tape applications, the center of the each test area was punch biopsied (8mm) and samples fixed in 10% neutral buffered formalin. Samples were processed, stained by H&E, and read under light microscopy. The results showed an inverse pattern to the number of tape stripping repetitions. Fifty passes were required to remove nearly all SC. These data demonstrate that skin can be stripped of SC in a linear fashion based upon repetition of the technique.

P112GUIDANCE ON THE DERIVATION OF ACCEPTABLE DAILY EXPOSURE (ADE) VALUES FOR PHARMACEUTICALS – AN INDUSTRY PROPOSAL T. Pfister, and A. Flueckiger. Safety, Security, Health & Environmental Protection. F. Hoffmann-La Roche, Basel, Switzerland The Acceptable Daily Exposure (ADE) concept follows a well-established paradigm that has long been successfully used in nutritional toxicology to set acceptable levels of chemical food contamination (oral intake) and in occupational toxicology to derive acceptable levels of workplace exposure (via inhalation). ADEs are now being introduced as a measure of safe residual contamination of “multi-product” manufacturing equipment. Therefore, they will become the object of new regulatory scrutiny. ADE is defined as a substance-specific dose that is unlikely to cause an adverse health event or undesirable physiological effect if an individual is exposed daily at or below this dose during lifetime. The ADE is typically based on nonclinical and clinical data. Here we propose a standard procedure for ADE setting from nonclinical safety data: The reference effect level (e.g. NOAEL) established in the most sensitive species is multiplied with a human body weight of 60 kg. The resulting dose has to be divided by adjustment factors to compensate for uncertainties in the model applied. These include interindividual variability (F1), interspecies differences (F2), duration of the toxicity study (F3), severity of toxicity (F4), and the quality of the reference effect level (F5). While default values for F1 - F5 are provided, we recommend replacing them by substance-specific values wherever possible. Modifications of this standard procedure are proposed for CMR substances. Limitations of the proposed procedure, different routes of exposure, and differential sensitivity in human subpopulations are discussed. In conclusion, we are presenting a standard approach implemented at F. Hoffmann-La Roche for the derivation of ADEs which may provide some guidance for also other toxicologists in charge of ADE setting.

P113IDENTIFYING APPROPRIATE READ-ACROSS SURROGATES IN THE REACH REGISTRATION OF 2,6 XYLENOL Sanders, M; ARCADIS-US, Waites, R; SABIC As part of an integrated testing strategy under the Registration, Evaluation, and Authorisation of Chemicals (REACH) regulation, the European Chemicals Agency (ECHA) has specified that vertebrate animal testing shall be avoided and/or minimized through the development of read-across strategies and the identification of acceptable

surrogates. The relevance of the approach must be substantiated however through a robust evaluation of the physicochemical properties and available toxicological parameters. This case study, the application of read-across to fulfill physicochemical and toxicological parameters in the REACH registration of 2,6-xylenol (2,6-dimethylphenol), presents the rationale for the use of the structural analogues chosen. Various options including read-across to mixed xylenol isomers or to specific isomers sharing similar functional groups were critically evaluated. Consideration was given to the presence of the phenolic hydroxyl group and the position of methyl groups as well as data availability. The predicted metabolic pathways for the substances chosen were broadly similar based on similar reactions considering probable and plausible transformations. A matrix of available REACH Annex VII and VIII human health toxicity data including the oral and dermal acute toxicity, skin and eye irritation, mutagenicity, and repeat dose data were evaluated to determine the appropriateness of the approach for extrapolation to higher-tiered study requirements. The overall strategy required a well-documented, well-defined methodical approach for submission under the regulatory framework. A substance registration was developed using the read across approach that defines the impact and importance of the substance categories, while including other options such as data waivers. An overview of the strategy, matrix, hazard analysis and overall risk assessment will be presented.

P114THE IN VITRO 3T3 NEUTRAL RED UPTAKE PHOTOTOXICITY TEST: HISTORICAL CONTROL DATA DEMONSTRATE REPRODUCIBILITY WITH MULTIPLE TEST SUBSTANCES AND DIFFERENT IRRADIATION CONDITIONS. M. Schwartz 1 ,D. Learn 1 , M. Arocena 1 , A. Brower 1 , M. Brennan 1 , A. Hoberman 1

1Preclinical Services, Charles River Laboratories, Horsham PA The 3T3 NRU Phototoxicity Test historical control data demonstrates a robust and reproducible assay in this laboratory. Chlorpromazine (CPZ) as the positive control for 60 plus sponsored assays displays reproducibility and assay validation as per the OECD 432 guideline. The overall IC50 (irradiated) and IC50

(non-irradiated) was 1.037±0.403 mg/L and 29.198 ±12.053 mg/L, respectively, agreeing with the OECD guideline requirements. We have also run assays using different light sources, UVA/UVB irradiance ratios and the number of dosed wells per concentration. In all cases the data are reproducible and within guidance limits. Evaluation of test articles with the 96 well plate lids removed, increases the

UVB portion of the irradiance from approximately 19 mJ/cm2 to approximately 32 mJ/cm2 concomitant with the recommended 5 J/cm2 of UVA irradiance. The resulting IC50, PIF, and MPE data show no adverse effect on the assay from the increased UVB fluence and acceptable CPZ results, allowing evaluation of test articles absorbing primarily in the UVB. Cell sensitivity to UVR and cell viability met the recommended levels, regardless of the UVR exposure conditions. The dosing of a single well per test article concentration, as opposed to the typical dosing of six wells per test article concentration, generates usable and valid data and increases the throughput of the assay in a ‘screening mode’. The 3T3 NRU Phototoxicity assay has proven to be a useful, robust and valid hazard assessment tool in the preclinical process of drug discovery, either under standard or other conditions of use.

P115QUANTITATIVE CHARACTERIZATION OF HEMATOLOGY EFFECTS FOLLOWING SPARSE BLOOD SAMPLING IN RATS: CONSIDERATIONS FOR NONCLINICAL STUDY DESIGN . C.R. Mattis, P.Katavolos, D.J. Desmond, J.C. Kinney, R.L. Yeager, L.A. Gallenberg. Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064. Assessment of toxicokinetics (TK) using “sparse” blood sampling in main study rats instead of a separate satellite cohort provides an opportunity to reduce the number of rats required to conduct nonclinical safety studies. In this approach, the volume and/or number of TK blood samples collected from each rat are typically reduced in an attempt to minimize potential blood withdrawal effects on clinical pathology data, particularly hematological parameters. The objective of the present study was to evaluate how a sparse TK blood collection approach prior to a multiday necropsy interval affects hematology parameters. Seventy-five female Crl:CD (SD) rats, 11 weeks old and weighing 192-230g each, were assigned to 3 groups (Groups 1-3; 25 rats/group). Blood samples (0.375 ml each) were collected via the lateral tail vein on Day 1 (Group 3 rats) and Day 2 (Group 2 and Group 3 rats) to mimic 6 and 24 hour TK blood sampling, respectively. Terminal samples were then collected from Groups 1 (control), 2, and 3 on Days 2 (approximately 2 hours following the mock 24-hour TK collection in Groups 2 and 3), and then in the mornings of Day 3, 4, 5 and 8 (5 rats/group). In Group 2 rats, there were no noteworthy hematology changes. In Group 3 rats, there were statistically (P <0.05) and physiologically significant decreases in red blood cell-associated parameters (red blood cell counts, hemoglobin concentrations

and/or hematocrit values) compared to pretest and control values beginning on Day 2 with a compensatory increase in reticulocyte counts (notably “high” RNA reticulocytes) observable by Day 4. Red blood cell parameters were subsequently increased towards control/pretest range by Day 5 following the TK blood sampling. The results from this study demonstrate a temporal effect of sparse TK blood sampling on hematology parameters over a 4-day necropsy interval that is influenced by the number of TK blood samples collected relative to necropsy. These effects, which could confound interpretability of test item-related hematology changes, should be considered when designing nonclinical safety studies in rats.

P116NEW MODEL OF NONCLINICAL CARDIAC RISK ASSESSMENT . Kramer JK 1 , Myatt, GJ. 2 ; Obejero-Paz, C.1, Breuning-Wright, A. 1 Brown AM. 1ChanTest Corp., Cleveland, OH, USA. 2Leadscope Inc., Columbus, OH, USA Drug-induced inhibition of the cardiac hERG potassium channel is assumed to predict delayed cardiac repolarization (DR). The consequent QTc prolongation is a surrogate marker of torsade de pointes (TdP), a rare but potentially lethal iatrogenic outcome. Drugs with effective therapeutic plasma concentrations (ETPC) within 30-fold of their hERG IC50s are thought to be dangerous despite the fact that multiple ion channel effects (MICE) can mitigate DR. Here we demonstrate that a logistic regression model, which integrates MICE, predicts TdP with much greater certainty than the hERG safety ratio (hERG IC50/ETPC) alone. Safety ratios were calculated for 40 drugs (19 +TdP and 21 -TdP) from multiple classes by dividing their hERG, Nav1.5 and Cav1.2 IC50

values by each drug’s ETPC. Two logistic regression models were constructed; one using the hERG IC50/ETPC ratio alone (Model 1), the other integrating hERG IC50/ETPC + Nav1.5 IC50/ETPC + Cav1.2 IC50/ETPC data (Model 2). The predictive power of each model was evaluated by performing leave-one-out cross validations. Each model’s accuracy for discriminating +TdP and -TdP drugs was determined by comparing their receiver–operator characteristics (ROC, true vs. false positive rates). Model 1 had a 52% False Positive Rate associated with a 90% True Positive Rate and a ROC area under the curve (AUC) of 0.72. Model 2 significantly improved accuracy showing a 15% False Positive Rate associated with a 90% True Positive Rate and a ROC AUC of 0.86. We propose that models that incorporate quantitative drug effects on multiple cardiac ion channels will be robust nonclinical predictors of cardiac risk.

P117

IN VITRO MULTIPARAMETER HEPATOTOXICITY ASSAY DEVELOPMENT IN HUMAN PRIMARY HEPATOCYTES AND HEPG2 CELLS WITH S9 LIVER FRACTIONS 1Marcoe, KF; Garside, HJ 2 ; Chesnut-Speelman, J 1 ; Foster, AF 2 ; Ovechkina, Y 1 ; Warrior, U; 1

Kenna, JG 2 ; Bowes, J 2 ; O’Day, C 1 1Ricerca Biosciences, Bothell, USA and 2AstraZeneca Safety Assessment UK, Innovative Medicines, Alderley Park, UK Drug-induced liver injury (DILI) remains a major cause of failed drug development and withdrawal of drugs post marketing. Therefore predictive toxicology screening assays are required which enable early identification and deselection of compounds that have the potential to cause DILI in man. In this study, multiplexed high content screening (HCS) with automated fluorescence microscopy and image analysis based technology was used to develop cellular assays that detect key mechanisms considered relevant to DILI. The following parameters were evaluated: cell proliferation (nuclear dyes): apoptosis (antibodies to activated caspase 3); cell cycle (antibodies to pHistone H3); stress (antibodies to HSP70/72); reactive oxygen species (ROS) generation (H2DFFDA staining), and mitochondrial damage (TMRE staining). Experiments were undertaken in human primary hepatocytes and in HepG2 cells at 4, 24 and 48 hrs. In addition, in some studies S9 liver fractions from Arochlor induced rats were added extracellularly to overcome the inherent metabolic limitations of HepG2 cells. In HepG2 cells dosed with cyclophosphamide (CP), an effect on cellular proliferation and induction of apoptosis was observed in the presence of S9, but not in the absence of S9, which is consistent with the metabolism of CP to toxic metabolites. No effect was observed in the absence of S9 or NADPH. In addition, a concentration dependent decrease in expression of pHistone H3 was observed with CP in the presence of S9 after 24 hours of exposure but not at 48 hours, which suggests a potential metabolite dependent cell cycle block that recovers after reactive species dissipate. Another interesting observation was HSP70/72 induction in HepG2 cells dosed with low concentrations of Geldanamycin, which is known to cause cellular stress in vivo and induce HSP proteins. This raises the possibility that evaluation of drug induced elevation of HSP70/72 in human liver cells could serve as an earlier indicator of cellular changes that may be relevant could be toxicity. These results indicate that multiplexing of markers directly linked to cellular mechanisms of toxicity is useful for evaluation of the ability of test compounds to cause toxicity to isolated liver-derived cells in vitro. To determine the value of this approach for prediction of DILI in vivo, it will be

important to undertake a follow up evaluation of a broad range of marketed drugs which cause DILI or do not cause DILI in man.

P118ENHANCED DELIVERY OF INTRANASALLY-ADMINISTERED NUCLEOSIDE DRUGS TO THE CENTRAL NERVOUS SYSTEM Mansi Krishan 1 , Gary Gudelsky 2 , Pankaj Desai 2 and Mary Beth Genter 1 1 Environmental Health and 2 College of Pharmacy, University of Cincinnati Delivery of therapeutics to the brain to treat neurological diseases and other central nervous system (CNS) disorders is a challenge due to the impenetrable nature of the blood brain barrier (BBB). Intranasal (IN) drug administration is a non-invasive approach for rapid direct delivery from the nasal cavity to the CNS, thereby minimizing systemic exposure. The pathways along olfactory and trigeminal nerves innervating the nasal passages are involved in the nasal uptake of drugs by transcellular or transneuronal transport. Other agents are believed to access the CNS from the nasal cavity by moving between the epithelial cells, a process called paracellular transport. On the basis of previous reports, the current study focuses on the use of the IN route for direct delivery of the nucleoside drug gemcitabine (GEM) to treat brain tumors. GEM is structurally similar to zidovudine (AZT), the latter of which can be delivered to the brain by the IN route. In order to enhance drug delivery to the CNS, we propose to use papaverine (PV), which has been demonstrated to transiently increase the permeability of the brain-tumor barrier (BTB) and BBB after systemic administration. We hypothesize that by transiently increasing the permeability of nasal epithelial tight junctions, we will increase the concentration of GEM in the brain extracellular fluid (BECF) following intranasal drug administration, with the goal of delivering therapeutic concentrations of nucleoside drugs to treat HIV dementia and brain tumors. Experimental methods include in vivo brain microdialysis for collection of BECF to analyze drug levels, in vitro recovery of GEM, and HPLC analysis to measure the concentration of GEM in BECF. A non-toxic dose of PV, which enhanced delivery of GEM to BECF, was determined. BECF pharmacokinetics of GEM shows AUC=6.95±1.17 μg.h/ml for PV (1.4%) + GEM- (50mg/kg) treated animals (n=3) and it is comparable to the AUC values when GEM and another BBB permeabilizer (RMP-7) were administered intravenously. Thus, it appears that transient permeabilization of nasal epithelial tight junctions can enhance delivery of nucleoside drugs to the CNS.

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METHODS FOR EXTERNAL VALIDATION AND INTERPRETATION OF (Q)SAR MODELS FOR PREDICTING GENOTOXIC IMPURITIES Joseph F. Contrera, Ph. D., Computational Toxicology Services LLC, P.O. Box 1565 Olney, MD. Kevin P. Cross, Ph.D., Leadscope, Inc., 1393 Dublin Road, Columbus, OH The proposed ICH M7 draft guidance on submission of new drug approvals to regulatory agencies includes the opportunity to submit in silico predictions of genotoxicity instead of Ames tests for low-level impurities. This issue raises questions concerning the qualification of robust (Q)SAR models that are appropriate for predicting genotoxic impurities. This approach investigates how external validation sets (such as the public Hansen data set) should be appropriately used for validation of (Q)SAR models. Fingerprints representing the toxicophores of the external validation sets are compared with model training sets to determine the how the domains of a (Q)SAR model and validation set overlap. Performance characteristics specific to individual toxicophores in the overlapping set are proposed. Interpretation of individual (Q)SAR predictions using results contributed from underlying structural features present as model descriptors is also investigated. The goal is to help establish a method of qualifying (Q)SAR models for predicting genotoxic impurities based on model robustness and interpretability.

200 series – Test Systems P200UNIFORM ULTRASTRUCTURAL CHANGES IN PC12 NEURONAL CELLS EXPOSED TO THREE DIFFERENT PROTEASOME INHIBITOR CHEMOTYPES Vilmos Csizmadia, Lee Silverman, Matthew Gallacher, Kym Cardoza, Eric R. Fedyk, Carl L. Alden, Bernard Jortner and Vivek J. Kadambi, Millennium: The Takeda Oncology Company, Cambridge, MA, USA Proteasome inhibitors (PIs) have the potential to cause peripheral neuropathy. This peripheral neuropathy has been linked to development of multifocal ubiquitin-positive protein aggregates (UPAs) in vivo and in vitro. In a mouse model of PI-induced peripheral neuropathy, UPAs appeared in the dorsal root ganglion cells; nerve injury subsequently developed. In differentiated PC12 neuronal cells exposed to PIs from 3 chemical scaffolds (peptide boronate, peptide epoxyketone and a lactacystin analog), correlative UPA formation was observed. To further dissect these effects in neurons, differentiated PC12 neuronal cell cultures were exposed to these 3 PI chemotypes at the concentrations resulting in 90%±5% inhibition of 20S proteasome activity (IC90) and at the concentrations resulting in 50% cell death (LD50). Cellular effects were assessed by electron microscope (EM) imaging. All treatments elicited similar microscopic changes: in the dying cells prominent juxtanuclear inclusions with varying size, loss of surface microvilli, diminished organelles in the peripheral regions and swollen nuclei and other cytoplasmic organelles. The inclusions were structurally consistent with aggresomes. In addition, ultra-structural observations indicated that necrotic cell death had occurred. In conclusion, consistent with the earlier findings on mechanism-based UPA formation in PC12 neuronal cells, EM images show that PIs induce qualitative ultra-structural changes regardless of the chemical scaffold of the PI. Thus, these effects in vitro are mechanism-based, not chemistry-based.

P201ARSENIC EXPOSURE INFLUENCES HEPATOCYTE MATURATION Arnab Bhattacharya 1 , Pushpa Dhar 2 , Raj D. Mehra 3 1Senior Resident, Deptt. of Anatomy, Lady Hardinge Medical College, New Delhi, India. 2Additional Professor; 3Professor; Dept. of Anatomy, All India Institute of Medical Sciences, New Delhi, India. The effects of sodium arsenite exposure on parameters of hepatocyte maturation during the cellular and functional reorganization period (PND 9 - 28) of developing rat liver were studied. Wistar rat pups belonging to the experimental group received sodium arsenite (1.5 mg/kg body weight) and the

control group received distilled water by intraperitoneal (i.p.) route from PND 9 until the day of sacrifice (PND 29). Perfusion fixed liver tissue was processed for paraffin embedding and H&E staining. Fresh liver tissue was processed for Sudan Black B (SBB) staining and for biochemical estimation of reduced glutathione (Ellman’s method). Microscopic observations revealed mature hepatic lobular pattern along with comparable distribution of uninucleate and binucleate hepatocytes in the control and experimental groups. Using an Image Analysis system (NIS-Elements AR 3.1) increase in mean nuclear area (34.42 ± 3.28 µm²) and nuclear diameter (6.65 ± 0.31 µm) of hepatocytes was observed in experimental group. The experimental group also showed decreased levels of reduced glutathione (11.23 ± 0.98 µg/g of wet liver tissue). Lipid droplet distribution pattern (SBB stained) revealed higher centrilobular staining (mature) in both the groups and semiquantitative estimation showed lower cumulative grey values in zone 3 against zone 2 and 1 (suggestive of setting in of the adult pattern). The developing hepatocytes (PND 9 - 28) exposed to low dose arsenic showed increased vulnerability.

P202THE ANESTHETIZED GUINEA PIG: A VALUABLE CARDIOVASCULAR LEAD OPTIMIZATION SCREEN Pierre Morissette, Masahiro Nishida, Jeff Travis, Desiree Steve, Gloria Zingaro, Pam Gerenser, Tara Grady-Styring, Richard Woltmann, Alysia Chaves, Ying-Ying Zhou, Greg Friedrichs, Kimberly Hoagland and Joseph Salata. Merck & Co., Safety Assessment, West Point, PA. A resource-sparing in vivo cardiovascular screen is valuable for the selection of lead drug candidates early in development prior to the start of longer, more resource intensive safety pharmacology and toxicology studies. Our goal was to develop a sensitive and predictive anesthetized small animal model to assess effects on ECG that are predictive of the non-rodent safety pharmacology telemetry models. We compared the ECG effects of 26 compounds in this anesthetized guinea pig model with those in non-rodent telemetry models. Results: ECG effects in guinea pigs were 92%, 100% and 92% concordant with effects in non-rodent telemetry for PR, QRS and QTc intervals changes, respectively. The rates of false positives and false negatives for QTc and PR interval changes in guinea pigs were 0% and 8% when compared to telemetry. For QRS interval, rates of false positives and false negatives were 0% compared to telemetry. Further, this model has shown to be sensitive for detection of AV block and QTc prolongation mediated by hERG, IKs

and IK1 inhibitors and for evaluating the effects of mixed ion channel blockers on the QTc interval.Conclusion: The anesthetized guinea pig is a sensitive model for assessing QTc interval prolongation and predictive of ECG effects relative to non-rodent telemetry models. Thus, ECG parameters can be reliably evaluated using this resource-sparing small animal model that reduces test article requirements, reduces the number and cost of animals, and improves overall data throughput. Importantly, the design and implementation of this model is consistent with the "3Rs" for animal research.

P203YUCATAN MINIATURE SWINE SURGICAL GLAUCOMA MODEL DEVELOPMENT AND RESPONSE TO THERAPY Renna S, Moore C, Liu J, Burks Z, Blair E, Hanks BC, Horlen K, White D, Brown LD, Bouchard GF. Sinclair Research Center, LLC The purpose of this project was to develop a model of glaucoma via surgical induction of increased intraocular pressure (IOP) in Yucatan miniature swine. Three pigs (two female, one male) had bilateral IOP measurements performed prior to surgical intervention to establish a baseline IOP for each animal from which future changes in IOP could be identified. IOP measurements (mm Hg) were taken with a Tonopen Vet Tonometer. In order to reduce venous drainage from the eyes, episcleral veins were scarified by cauterization in each eye. IOPs were periodically measured for several weeks post-cauterization surgery. Pharmacologic intervention was then instituted with a commercially available synthetic prostamide analog with ocular hypotensive activity. Drops were applied once daily, and IOPs continued to be measured. After 7 weeks of daily treatment, eye drops were discontinued, and IOP measurements continued to be obtained. All animals presented with significant increases in IOP measurements post surgical intervention and significant decreases in IOP with pharmacological therapy. Statistical tests included sample mean comparison by 2-tail T-test P-value (T≤t). Data by phase as follows-Mean±SD (N readings), P-value: Baseline:19±4 (65); Post-Surgery: 24±5 (124), ≤0.005 (Baseline vs. Post-Surg); Treatment: 18±4 (75), ≤0.0006 (Post-Surg vs Treatment) Recovery: 20±4 (80), ≤0.006 (Treatment vs Recovery). Therefore, the Yucatan miniature swine should be considered a viable model for surgically induced glaucoma. The miniature swine eye is also responsive to pharmacological therapy to reduce IOP and as such could be a potential model for future pharmacological research.

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HOMOZYGOUS AND HETEROZYGOUS P53 KNOCK OUT RATS DEVELOP METASTASIZING SARCOMAS WITH HIGH FREQUENCY Ruben Van Boxtel 1 , Raoul V. Kuiper 1 , Pim W. Toonen 1 , Sebastian van Heesch 1 , Roel Hermsen 1 , Alain deBruin 1 , Pamela Riley 2 , Jack Crawford 3and Edwin Cuppen 1 . 1Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht, The Netherlands.2Charles River Laboratories, Wilmington, MA 01887 3Transposagen, Lexington, KY 40507 The TP53 gene is one of the most extensively studied tumor suppressor genes and has been found to be mutated in almost all cases of human cancer. In designing animal models to mimic the involvement of TP53 several lines of transgenic mice have been developed and have shown, when homozygotes are used, a relatively uniform tumor spectrum with thymic lymphomas as the dominant tumor type, and a fast onset of disease. However, the tumor spectrum when heterozygotes are used is more diverse and is similar to humans with a slower onset of tumorgenesis, indicating that a loss of heterozygosity has to precede tumor development. Here we present the first in-depth characterization of a TP53 deficiency in the rat, generated using a target-selected mutagenesis approach. Homozygous rats, completely lacking TP53 protein, display a decrease in survival due to tumorgenesis, developing sarcomas with a high incidence of pulmonary metastases, at 4 months of age. In contrast, heterozygous rats exhibit a slower onset to tumorigenesis with sarcomas developing by 8 months of age. Molecular analysis of these tumors shows a loss of heterozygosity of the wild type P53 allele. These unique features complement existing rodent p53 knock out models and provide a versatile tool for investigating tumorigenesis

P205THE SLOW ONSET ATRIOVENTRICULAR BLOCK IN A CONSCIOUS TELEMETERED GUINEA PIG MODEL Ying-Ying Zhou, Yu-Jing Gao, Richard Tedesco, Kathryn Pula and Gregory Friedrichs. Merck & Co., Safety Assessment, Summit, PA.Introduction: The most common evaluation of ECG from both toxicology and safety pharmacology standard studies is focused on acute and regular events such as ECG interval changes or arrhythmias. However, some of these changes are irregular or develop as a slow onset phenomenon. This case study highlighted the value of chronic monitoring of ECG when using a telemetered guinea pig model in detecting irregular and slow onset atrioventricular block (AV block). Methods: Guinea pigs instrumented with radiotelemetry transmitters for continuous collection of ECG signals were utilized to investigate potential chronic cardiac conduction issues with Merck compound X. A single oral dose study with vehicle, 10, 30 and 100 mg/kg compound X using a dose escalating design was conducted initially for dose range finding. In the repeat dose study which followed, five guinea pigs were dosed orally with 100 mg/kg compound X and three with vehicle as a control for 5 days. Results: The baseline incidence of AV block was low in naive guinea pigs. Sporadic and slow onset second degree AV block was noted in 2 out of 3 guinea pigs following 100 mpk single dose of compound X. The AV block was preceded by progressive PR prolongation and followed by PR shortening as a typical Mobitz type 1 or Wenckebach AV block. The occurrence of AV block appeared to be dose-dependent. The incidence of AV block also increased with multiple daily doses of compound X with more than 300 instances of AV block on average at day 4. Heart rate was significantly decreased after multiple dosing too. There were no test article related changes in other measured ECG intervals (PR, QRS and QT/QTc). Discussion and Conclusion: The data suggest that conscious telemetered guinea pig is a sensitive model to detect irregular and slow onset AV block. The results are consistent with the findings from dog and human, although different from preliminary data from rat and monkey. The potential mechanisms behind these findings will be discussed.

P206OPTIMAL DURATION OF JACKET HABITUATION BASED ON CARDIOVASCULAR ENDPOINTS IN BEAGLE DOGS AND CYNOMOLGUS MONKEYS J ulie Sentz, BS, RLATg, SRA , Danielle Higgins, BS, RLATg, Jen Sheehan, BS, RLATg, SRS, Mutsumi Miyamoto, DVM, MS, PhD The invasive telemetry system and snapshot recording of ECG are commonly used to monitor cardiovascular (CV) endpoints in safety pharmacology and toxicity studies. Due to the recent development of non-invasive jacket telemetry systems, CV endpoints can be monitored for longer periods on toxicity studies in unrestrained dogs and monkeys. It is essential to habituate animals to the jacket prior to the data collection period to obtain good quality data. The purpose of this study was to determine the optimal habituation period based on heart rate response. Heart rate (HR) was collected from 4 jacketed non-human primates (NHPs) following 3 consecutive occasions of jacket habituation. Heart rate was also collected from jacketed dogs following 3 and 7 consecutive occasions of jacket habituation. Heart rate data collected following 3 and 7 day jacket habituation was compared with the Testing Facility’s historical control data collected from non-jacketed, invasive telemetry models in both species. Heart rate collected from jacketed monkeys (following 3 day habituation) and dogs (following 3 and 7 day habituation) are comparable to data from non-jacketed animals. Therefore, we concluded that a three day habituation is optimal to prevent undesirable effects in the CV data that may result from insufficient jacket habituation. Index Terms: 1. Jacket Habituation 2. Telemetry 3. Safety Pharmacology

P207HIGH CONTENT ZEBRAFISH HISTOLOGY: NEW DIRECTIONS IN EARLY DRUG SCREENING H Diekmann, A Dodd, A Cracknell, O Murphy, M Jones and A Hill. Evotec (UK) Ltd, Abingdon, United Kingdom In recent years, zebrafish larvae have emerged as an exciting and predictive in vivo platform for assessing toxic liabilities of compounds early in the drug development process. These assays often rely on relatively simple morphological or behavioural readouts to allow a medium to high throughput for screening. Although these readouts are predictive for identifying toxic compounds, in order to realise the full value of this platform, high content technologies can be applied to help understand the underlying pathology induced after toxic insult. Evotec has developed a medium throughput semi-automated histology platform capable of

simultaneously capturing full-body histological sections from up to 50 zebrafish larvae. This approach offers the opportunity to integrate diverse histological endpoints into the established zebrafish screening assays. In this study, 12 compounds with known hepatotoxic liabilities were assessed using a combined phenotypic and histological screening approach. Zebrafish larvae were treated for 48hr with up to four concentrations of compound alongside a vehicle control, scored for liver abnormalities and sectioned using the histology array. Liver tissue in sequential sections was assessed for morphological alterations (H&E stain), glycogen levels (periodic acid-Schiff stain) and fibrosis (trichrome stain). The outcome of how these histological data support the morphological analysis will be reported.

P208DIFFERENTIATION BETWEEN DEVELOPMENTAL AND ACUTE TOXICITY OF DRUG LIKE COMPOUNDS USING ZEBRAFISH Hill, A, Michael Richardson, Jones, M, Diekmann H. Evotec (UK) Ltd, Abingdon, United Kingdom Zebrafish have gained increasing popularity for toxicity testing over the past decade due to numerous advantages over other vertebrates, including the use of an in vitro-like assay format in multi-well plates, requiring only single milligrams of test compound for a full dose response and the transparency of the zebrafish larva, which decreases the need for invasive procedures and dissection. Evotec previously evaluated its zebrafish developmental toxicity assay by testing 90 blinded compounds. In comparison to results from mammalian embryo-foetal developmental toxicity studies, the zebrafish assay was ~90% predictive for identifying toxic compounds. One key challenge highlighted in the study was the need to distinguish distinct embryotoxic effects from acute toxicity (effects that would commonly be detected as maternal toxicity in mammalian assays). In the current study, 20 compounds with known teratogenic liabilities were assessed using a combined embryonic and larval screening approach. Zebrafish were treated for 96hr with five concentrations of compound alongside a vehicle control and scored for morphological abnormalities and lethality throughout the assay. Since compound uptake by zebrafish larvae could vary during development, the actual body burden (ng/larva) was determined at the respective NOECs and LOECs for both embryos and larvae via LC-MS. A comparison of toxicity exhibited in embryonic versus larval zebrafish together with how this outcome supports a

classification for teratogenic and/or embryotoxic compounds will be reported.

P209NONHUMAN PRIMATE MODELS IN PRECLINICAL REPRODUCTIVE TOXICOLOGY: OPPORTUNITIES AND IMPLEMENTATION OF THE ICH S6(R1) GUIDELINE N. Makori1, N. Lalayeva1, R. Watson1, S. Oneda1, P. Franklin1, T. Beck1, R. Nagata2

1SNBL USA, Ltd., Everett, WA, USA; 2Shin Nippon Biomedical Laboratories, Ltd., Kagoshima, Japan. The ICH S6(R1) guideline was issued in June 2011. Part of the guideline specifically addresses study design elements and study initiation timing in nonhuman primates (NHPs). Embryo-fetal (EFD) and enhanced pre/postnatal (ePPND) studies may be conducted prior to or concurrently with Phase III clinical trials. Initiating studies concurrent with Phase III will require extremely stringent timelines. In collaboration with pharmaceutical companies, contract research laboratories that offer these resource- and time-consuming EFD/ePPND studies in NHPs may need to shorten study timelines. One of the approaches to consider is expedited enrollment of pregnant animals to study. For example, instead of 16 weeks to fill a 60-animal study, the duration would be 10 weeks. This may require adjustments both to resource management and the approach to breeding practices. One key factor to take into account is the historical rates of pregnancy loss in NHPs unique to each laboratory setting. The question then is, will the pregnancy loss rates compromise the timing by requiring replacement animals on study? As an example, of 398 pregnant monkeys in our facility between 2007 and 2011, there was 17.8% embryo/fetal loss on or before gestation day 130 (GD130), 2.5% infant loss due to premature birth (viable or dead infant) between GD131 and GD145, and 15.3% loss due to non-viable births (delivery of dead infant on or after GD146). Even though these loss rates are within normal historical values and published data, three of the 24 studies (13%) required additional animal replacements resulting in an extension of the study timelines. To cater for potential animal replacements and other unforeseen events that may result in extensions of study timelines despite potential decrease in enrollment duration, it is always encouraged to plan EFD/ePPND studies as far in advance as possible

P210COMPARISON OF BASIC COAGULATION PARAMETERS FOR CYNOMOLGUS MACAQUES (Macaca fascicularis) FROM DIFFERENT SOURCES . Donald Waller 1 , Elizabeth McGeehan 2 , Jean Dubach 3 , Debra A. Hoppensteadt 2 , Jawed Fareed 2 , Il , 1Prelabs

LLC, Oak Park, IL, 2Loyola University, Maywood, Il, 3PrimGen LLC, Oak Park, IL Non-human primates are used extensively for anticoagulant therapy development. Availability, cost and size has led to an increased use of M. fascicularis (cynomolgus) for testing. Differences for coagulation responses between M. mulatta and M. fascicularis were previously demonstrated and, in addition, genetic diversity among macaques from different sources has also been observed. The present study examines potential disparities of coagulation responses for animals attributed to sources in Vietnam, Philippines, Indonesia, China and Mauritius. The coagulation cascade is evaluated by determination of clotting tests such as prothrombin time (PT), activated partial thromboplastin time (aPTT), common pathway (Heptest®), and thrombin time (TT). Blood was drawn and immediately transferred to sodium citrate tubes (3.2% at 9 parts blood to 1 part sodium citrate), centrifuged to obtain plasma and stored at -80oC. Clotting tests performed included PT, aPTT, Heptest®, and TT assays using the ACL 300+ and BBL Fibro System manual fibrometers. PT values, regardless of source, were within a range of + 2 seconds. Similar results were also observed for the aPTT data. However, Heptest® values appeared to vary with animal source. The lowest values (mean 16.4) were observed for the Vietnamese and the highest values (mean 24.5) for Mauritius sourced animals. Thrombin Time had the largest variance in values, but no differences between sources were observed. The data show differences for some coagulation parameters depending upon the source of the animals. It is essential to identify the source of animals and determine baseline values for studies in which coagulation parameters play a major role. A clear understanding of these differences is essential when interpreting past data and assessing new anticoagulants for efficacy, safety and pharmacokinetics.

P211COMPARISON OF CYNOMOLGUS ( MACACA FASCICULARIS ) AND HUMAN MICROSOMAL METABOLISM OF A CYP 450 PHENOTYPING COCKTAIL Joseph McGraw 1 , Steven Scholzen 1 , Donald Waller 2 , 1Concordia University, Mequon, WI, 2Prelabs LLC, Oak Park, IL Cynomolgus monkeys are often used as a surrogate model for human CYP 450 mediated metabolism. Cynomolgous monkeys share similar CYPs as humans with a high percentage of amino acid sequence homology. Major human CYPs and homolgous Cynomolgous monkey CYPs (Cyno CYP, % amino acid sequence homology) are as follows: 1A2 (1A2, 93), 2C9 (2C43, 93), 2D6 (2D17, 93), 2E1 (2E1, 94), and 3A4 (3A8, 93). A UHPLC/MS/MS CYP 450 phenotyping assay was used to compare the major human CYP 450s to the cynomolgus monkey using in-vitro microsomal incubations. Microsomes were prepared from cynomolgous monkeys and compared to pooled human microsomes. UHPLC separation was carried out on a Waters Acquity HSS T3 1.8mcm (2.1x100mm) column with an Acquity HSS T3 1.8mcM Vanguard Pre-Column. Compounds were eluted with a gradient of Acetonitrile/ THF/ Formic Acid (20/ 4/ 0.1) in methanol. Mass spectrometry detection was carried out with a AB Sciex 4000 Qtrap triple quadrupole mass spectrometer equipped with a Turbo V IonSpray as an LC/MS interface. Positive ion mode ESI mass spectra were acquired from microsomal extracts for the following probes (corresponding CYP 450 in parenthesis): caffeine (1A2), dextromethorphan (2D6 and 3A4), and testosterone (3A4) along with their metabolites paraxanthine, dextrorphan, hydroxymorphinan, and 6-beta hydroxytestosterone. Negative ion mode was used to identify probes (CYP 450): chlorzoxazone (2E1) and diclofenac (2C9) along with their metabolites 6-hydroxychlorzoxazone and 4-hydroxydiclofenac. Incubations show large differences in dextromethorphan metabolism, which was a probe for 2D6 (dextrorphan) mediated metabolism and 3A4 (hydroxymorphinan) metabolism.eywords: cynomolgous, CYP 450, phenotype, metabolism, probe

P212HUMANIZING THE NOD.CG-PRKDCSCID IL2RGTM1WJL/ SZJ FOR USE IN DRUG SAFETY AND DEVELOPMENT Amen Phagura1, Ryan Rodriguez 1 , Jared Bagley 1 , Elizabeth Ontano 1 , Leon Hall 1 1The Jackson Laboratory, 4910 Raley Blvd, Sacramento CA 95838 There is a need for better models to assess the safety of biologics and for testing human specific therapies. The NSG mouse presents a unique

opportunity to establish the human immune system in vivo. The objective of this project was to establish the efficacy of utilizing the humanized mouse in drug development and safety. We standardized 3 protocols for humanizing the NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice engrafting human CD34+ stem cells (HSC) at P0 to P2 by intracardiac injection or in juveniles via tail vein injection. In juveniles donor matched liver and/or thymus can be co-transplanted. Humanized NSG mice express B and T cells, T helper cells, cytotoxic T cells, dendritic cells and monocytes and other. The cells types are expressed in ratios similar to what is seen in humans. The mice have shown immune system functionality in delayed type hypersensitivity models and in the dextran sodium sulfate model of inflammatory bowel disease. Preliminary data also indicates that the model is suitable for safety studies to assess the immunogenicity of biologics. The humanized mouse is an invaluable tool for modeling infectious diseases restricted to the human host providing an option to the use of non-human primates; however the applications for this model extend much further. Complications of the use of biologics include the induction of acute inflammatory responses and the humanized mouse makes an ideal tool for early assessment of the immunogenicity of biologics. Additionally, the humanized mouse is an ideal tool for assessing human specific therapies targeting the immune system.

P213INTEGRATION OF PIG-A, MICRONUCLEUS AND COMET ASSAY ENDPOINTS IN 28-DAY RODENT TOXICITY STUDIES WITH 7,12-DIMETHYLBENZ(a)ANTHRACENE (DMBA) AND DIETHYLNITROSAMINE (DEN) LF Stankowski, Jr1, B Krsmanovic1, S Bruce1, T Kelley1, M Paranjpel1, K Szabol1, S Springer1, J Sly1, M Klug-LaForce1, M Arevalo1, S Atta-Safoh1, F Debelie1, P Sareen1, S Dertinger2 and J Shi1 1BioReliance Corporation, Rockville, MD, United States, 2Litron Laboratories, Rochester, NY, United States As part of a multi-lab validation, we examined induction of Pig-a mutant red blood cells (RBCs) and reticulocytes (RETs) by flow cytometry (FCM) during 28-day subchronic studies in male Sprague-Dawley rats treated with 2.5, 5 and 10 mg/kg/day DMBA, or 5, 10, 20 and 35 mg/kg/day DEN. The same animals were analyzed for micronucleated RETs (mnRETs) in peripheral blood by FCM, and DNA damage in liver via Comet assay. Also analyzed were Comet response in peripheral blood (DEN-treated animals), or micronucleated polychromatic erythrocytes (mnPCEs) in bone marrow (DMBA-treated animals,

by manual scoring). DMBA induced dose-related increases in Pig-a mutant RBCs and RETs (Days 15 and 29), mnRETs (Days 4 and 29), and mnPCEs (Day 29), but no increase in Comet response was observed in liver at doses up to 10 mg/kg/day, which appeared to be below the MTD (upon re-testing up to 200 mg/kg/day for 3 days in a follow-up acute study, DMBA induced a positive Comet response in liver, but was negative in peripheral blood). In contrast, DEN was negative for induction of Pig-a mutant RBCs and RETs (Days 15 and 29) and mnRETs (Days 4 and 29), but induced dose-dependent increases in Comet response in liver and blood (Day 29), at doses up to 10 mg/kg/day (higher dose groups were terminated early due to excessive toxicity/mortality). These results emphasize the extreme care that must be taken in dose and endpoint selection when incorporating genotoxicity endpoints into routine toxicity studies.

P214INTEGRATION OF PIG-A, MICRONUCLEUS, CHROMOSOME ABERRATION AND COMET ASSAY ENDPOINTS IN RODENT TOXICITY STUDIES WITH 4-NITROQUINOLINE-1-OXIDE (4NQO): EFFECT OF DOSE FRACTIONATION ON GENOTOXIC RESPONSES

LF Stankowski, Jr1, DJ Roberts2, H Chen3, T Lawlor3, M McKeon3, H Murli3, A Thakur3 and Y Xu3 1BioReliance Corporation, Rockville, MD, United States, 2Bristol-Myers Squibb, New Brunswick, NJ, United States, 3Covance Laboratories, Inc., Vienna, VA, United States As part of a multi-lab validation, we examined induction of Pig-a mutant red blood cells (RBCs) and reticulocytes (RETs) by flow cytometry (FCM) during a 28-day subchronic study in male Sprague-Dawley rats using 4NQO. Animals also were analyzed for: micronucleated RETs (mnRETs) by FCM; DNA damage in blood, liver, and stomach by the Comet assay; and chromosome aberrations (CAbs) in peripheral blood lymphocytes (PBLs). Dose-and time-related increases were observed in Pig-a mutant RBCs and RETs (Days 15 and 29), as well as mnRETs (Day 29, but not Day 4). No increases were observed in PBL CAbs (Days 4 and 29), or DNA damage in liver (Days 15 and 29), stomach (Day 29), or PBLs (Days 1, 15 and 29). A follow-up study was performed at the same cumulative doses given in 1 or 3 daily doses (the latter as in a typical Comet/micronucleus combo assay). Dose-related increases were observed for Pig-a mutant RBCs and RETs (15 and 29 days after last dose), mnRETs (3 days after last dose), and Comet responses in PBLs, liver and stomach (3 hours after last dose). Except for Pig-a mutant RETs and RBCs, all responses decreased at the later timepoints. Dose-dependent increases in

micronucleated bone marrow polychromatic erythrocytes also were observed 3 hours after the last of 3 doses, but no increase in CAb was observed in PBLs, possibly due to technical issues. These results emphasize the extreme care that must be taken in dose and endpoint selection when incorporating genotoxicity endpoints into routine toxicity studies as recommended in ICH S2(R1).

P215AN EXPLORATORY EFFICACY STUDY OF PULMONARY ARTERIAL PRESSURE IN SPRAGUE-DAWLEY RATS, D. Poulin 1 , K. McInally 1 , J. Gizzi 2 , H. Bogie 2 . 1ITR Canada, Montreal, Quebec 2 Data Sciences International, St-Paul, MN The objective of the study was to evaluate the pulmonary artery pressure (PAP) of Sprague-Dawley rats, equipped with a telemetry implant, when administered U-44069, a PGH2 analog, similar to endogenously formed thromboxane A2 which can be titrated to induce the desired degree of pulmonary vasoconstriction, 3 times a day. Prior to the study, rats had a subcutaneous telemetry device implanted and the catheter was placed in the right ventricle and advanced into the pulmonary artery. Rats received intravenous infusions of U-44069 at a formulation concentration of 0.5 mg/mL, administered for 15 minutes at a dose rate of 10 mL/kg/hr, 3 times per day, separated by approximately 1 hour. Additional control rats were kept in the restrainer and followed the same regimen (ie. 3 times per day). The PAP increases were similar after each administration, although slightly less significant increases were observed after the second and third administrations. However, there were still significant increases in PAP of at least 51%, and therefore, it is considered that multiple daily administrations are appropriate for this model. In addition, there were no significant changes in PAP in control animals, therefore the restraint procedure is not considered to have an impact on the evaluation and interpretation of the data with this model.

P216TESTICULAR AND EPIDIDYMAL HISTOLOGIC CHANGES AROUND THE PERIOD OF SEXUAL MATURATION IN YUCATAN BOARS T. Evans, University of Missouri, Columbia, MO, J. Trickey, L. Brown, G. Bouchard, Sinclair Bio-Resources LLC, Auxvasse, MO Preclinical guidelines often specify the use of prepubertal, pubertal, or sexually mature animals. However, “puberty” and “sexual maturity” can be defined in a number of different ways which reflect androgen production, including the onset of mounting behavior, penile erection and/or ejaculation ± sperm capabilities, or, histologically, by a “threshold” portion of seminiferous tubules engaged in spermatogenesis ± epididymal sperm. Furthermore, “sexual maturity” can also be interpreted slightly differently, depending on the type of toxicology study programs (e.g., DART versus repeat dosing studies). Since Yucatan boars have been reported to reach “puberty” as early as 12 weeks or as late as 16 to 20 weeks of age, it is critical, regardless of how the stages of sexual development are defined, to know what is happening histologically in the testes at these various ages. Modified Davidson’s-fixed and PAS-stained testicular and epididymal sections were evaluated from 12-, 14-, 16-, 18-, 20-, 22-, and 24-week-old Yucatan boars (n=minimum of 4/age group). Approximately 200 seminiferous tubules were evaluated per testis for the presence of round spermatids only (immature tubules), as well as for species-specific cellular associations (stages) involving round and/or elongate spermatids (“mature” tubules). The proportion of the total number of seminiferous tubules represented by “mature tubules” was calculated. The presence of sperm in the caudae epididymides was also noted. Round spermatids began to appear at 12 weeks of age, and a majority of 14-week-old boars had seminiferous tubules containing both round and elongate spermatids. While sparse numbers of sperm appeared in the epididymides of one boar at 14 weeks of age, at least half of the 16- and 18-week-old boars exhibited some spermiation with sperm in the excurrent duct system. By 20 weeks of age almost all seminiferous tubules were “mature”, with sperm present in the epididymides. These novel data can be taken into consideration, along with other indices of sexual development, when designing toxicology experiments of varying durations which require Yucatan boars at a given stage of sexual maturity.

300 series – General Toxicology P300DETECTION OF IBUPROFEN IN POSTMORTEM RAT TISSUES Prof. Dr. M.H. El Karadawey*, M.fa Elden**, Mohamed H. Kreet***, Head of Medico Legal of Great Cairo Area, Ministry of Justice, Cairo, Egvypt. ** Department of Toxic and Narcotic DrugForensic Medcine, Ministry of Justice, Egypt. *** Department of Toxic and Narcotic Drug Forensic Medicine, Ministry of Justice, Egypt Iboprofen is an Analgesics which mainly used for the relief of mild or moderate pain and some of which have antipyretic actions. Many analgesics have marked anti-inflammatory actions and are used in the treatment of arthritis, rheumatism and other inflammatory conditions. This study was done to detect quantity of Ibuprofen in different organs after death in albino rat organs. The quantitative estimation of ibuprofen residue in postmortem albino rat organs was done by high performance liquid chromotogrpahy (HPLC) using methanol:water (80:20) as solvent and eluent at λ= 274 nm with flow rate 2ml/min . and C18 column. The concentration of ibuprofen residue in different tissues and blood was obtained where brain and kidney were found to be the organs which have the highest concentration. Ammonium sulphate method was used for extraction and purification for blood and tissue specimens. The present study would be of great importance for investigation of any overdoes toxicological mystery death of ibuprofen and we can conclude that the best organ of postmortem sampling as it has the highest concentration ibuprofen and it can help us in extracting ibuprofen to be identified and detected.

P301HOMIDIUM CHLORIDE AND DIMINAZENE ACETURATE MODULATED BIOCHEMICAL AND MORPHOLOGICAL CHANGES IN TRYPANOSOMA BRUCEI BRUCEI- INFECTED RATS *1Adeyemi, O.S. and 1 Sulaiman, F.A. *1 Redeemer’s University, College of Natural Sciences, Department of Chemical Sciences, PMB 3005, Mowe-121001, Nigeria, 1University of Ilorin, Department of Biochemistry, PMB 1515, Ilorin, Nigeria, Correspondence to [email protected] Study presented effects of two trypanocides (Novidium® - homidium chloride and Berenil® - diminazene aceturate) on the pathology of tissues and selected parameters in an experimental infection by Trypanosoma brucei brucei. Data revealed significant (p<0.05) increases in the activities of alkaline phosphatase (ALP), alanine transaminase (ALT) and aspartate transaminase (AST) of infected rats compared to the uninfected

animals. ALP and AST activities in the infected animals treated with novidium® showed a significantly (p<0.05) lower values relative to the infected positive control animals. In contrast ALT activity was higher (p<0.05) in novidium® treated rats. There was no significant (p>0.05) difference between the activity of ALP in infected group and the animals treated with berenil®. Activities of ALT and AST in the berenil® treated animals were however significantly (p<0.05) increased relative to the other groups. Histopathological examination of tissues from T. b. brucei infected animals revealed loss of tissue architecture with pronounced presence of inflamed cells and haemorrhage. Treatment of infected animals with the trypanocides however did little to restore the integrity of damaged tissues when compared to the uninfected control group. Results underscores further the need for new and improved trypanocides moreso that chemotherapy is one of the major ways for controlling trypanosomal infections.

P302AFUCOSYLATED ANTI-IL-5 RECEPTOR ALPHA ANTIBODY (BENRALIZUMAB): NINE MONTH CHRONIC TOXICOLOGY STUDY IN SEXUALLY MATURE CYNOMOLGUS MONKEYS . Manetz, TS, Leininger, JR, Wang, B, Ryan, PR, Kolbeck, R, and Dixit, R. MedImmune, LLC, Gaithersburg, MD USA. Benralizumab (MEDI-563) is a humanized, monoclonal antibody that specifically binds to the human interleukin-5 receptor alpha subunit expressed predominantly on eosinophils, a cell believed to play a functional role in bronchial asthma. Similar to the mechanism of other anti-IL-5 antibodies, benralizumab blocks the binding of IL-5 to its receptor, but benralizumab was also engineered to be afucosylated, which is anticipated to result in enhanced ADCC-mediated destruction of eosinophils and basophils, offers a novel approach to asthma treatment. To support benralizumab clinical development for the treatment of asthma, a chronic intravenous infusion (10 or 25 mg/kg) or subcutaneous (30 mg/kg) dose study was performed in cynomolgus monkeys (6/sex/group) with benralizumab administration every other week for 39 weeks (20 total doses). Necropsies were performed 3 days and 12 weeks after the final benralizumab dose administration. Following repeated benralizumab administration, the expected pharmacologically-mediated depletion of blood and bone marrow eosinophils was observed. An instance of transient petechiae and ecchymosis, decreased platelet count, and indicators of circulating erythrocyte mass occurred in one female in the 25 mg/kg IV dose group after the fourth dose

(Day 43). After a dosing holiday on Day 57, this animal remained on study with continued benralizumab dosing (Platelet values and red blood cell mass in this animal fluctuated after dosing was resumed but were near baseline levels by the end of the dosing period and lacked any correlating macroscopic or microscopic findings at scheduled necropsy). There were no benralizumab -related effects observed including no effects on male and female fertility parameters. Under the conditions of this study, the benralizumab NOAEL was 25 mg/kg/dose (IV) and 30 mg/kg/dose (SC), the highest doses evaluated for each route of administration.

P303A NOVEL APPROACH FOR CONTINUOUS OR INTERMITTENT SUBCUTANEOUS INFUSION USING SINGLE OR MULTIPLE SITES IN MINI-PIGS, Prefontaine A., Trudel Y., Caron S., Copeman C., Charles River Laboratories The mini-pig is considered a suitable model for local tolerance and safety assessments of formulations administered subcutaneously because skin and subcutaneous space closely resembles that of humans. Consequently, the feasibility of continuous subcutaneous infusion (24 hrs) utilizing a daily rotation of sites, in the Göttingen Mini-pig was evaluated over 10 days. Using two mini-pigs (12.8 and 19.0 kg, respectively), a subcutaneous tissue infusion set was inserted through the skin and secured in place using adhesive dressing. The mini-pig was fitted with a jacket connected to a tether system and the cannula to a swivel and external infusion pump. Saline was continuously infused (2.5 mL/h) subcutaneously, through a 0.22 µM filter, at sites between the scapular and lumbar thoracic regions for 10 days alternating through different site each day. Parameters evaluated were daily detailed examinations, weekly body weights, daily food evaluation, clinical pathology evaluations (Days 1, 3, 5, 7, and 10), macroscopic and microscopic examinations. Continuous subcutaneous infusion was successfully conducted for 10 days. As expected, no adverse effects in parameters of systemic toxicity were seen and no unexpected events were encountered during blood collections. Local responses of slight, well-defined areas of erythema and dark areas and/or swelling at the infusion sites were noted macroscopically. Microscopically, some procedure-related findings of minimal or slight inflammation, hemorrhage and/or necrosis were noted, however the adjacent skeletal muscle was unaffected. The low incidence and severity of the local responses at the infusion sites were considered unlikely to hinder study interpretation. In conclusion, 24 hour subcutaneous

infusion in the Gottingen Mini-pig was well tolerated systemically and presented minimal experimental background changes. Indications of recovery at the infusion sites suggest that repeat administration at a given site may be acceptable with an appropriate recovery period between administrations.

P304TWENTY-EIGHT DAY TOXICITY STUDY WITH THE NON-TRADITIONAL VEHICLES PEG 400 WITH EITHER SOLUTOL™ HS15 OR CREMOPHOR ™ RH 40 IN BEAGLE DOGS Daniel Kemp 1 , Brenda Faiola 1,2 , James Hailey 1 , Holly Jordan 1 , Christine Merrill 1 , Randy Brown 1 , David Bailey 1 1 Safety Assessment, GlaxoSmithKline, Research Triangle Park, NC, USA 2

Currently at RTI International, Research Triangle Park, NC, USA This study determined the tolerability and toxicity of various formulations of Solutol/PEG 400 on female dogs and Cremophor/PEG in male dogs, in two 28-day, oral, repeat-dose studies. Five groups of 3 female dogs were given either water vehicle, 10% Solutol/90% PEG (2 mL/kg/day (mkd)), 30% Solutol/70% PEG (2 mkd), 10% Solutol/90% PEG (5 mL/kg/day), or 30% Solutol/70% PEG (5 mkd). All dogs tolerated the administration of 10% Solutol/90% PEG or 30% Solutol/70% PEG ( 2 mkd). Three groups of male dogs were given either water vehicle or 10% Cremophor /90% PEG at a dose volume of 2 or 5 mkd. Loose/watery feces and minimal mucus-cell hyperplasia of the ileum were present in all Solutol groups. Total bilirubin was minimally ↑ at all doses of Solutol. ↑ red blood cell mass and ↓ urine volume in animals given 30% Solutol/70% PEG (5 mkd) were likely due to subclinical dehydration and hemoconcetration associated with the loose/watery feces. Emesis was present in all animals given Cremophor with a dose volume-dependent ↑ incidence of emesis and minimal subepithelial gastric hemorrhage. Minimally ↑ serum urea nitrogen was seen in dogs given 5 mkd Cremophor/PEG. Neither 10% Solutol/90% PEG , 30% Solutol/70% PEG nor 10% Cremophor/90% PEG at either dose volume produced overt toxicity, however using the lower dose volume of 2 mkd minimized the incidence of loose/watery feces and emesis.

P305AN 85-DAY REPEAT DOSE TRANSCUTANEOUS TOXICITY STUDY OF AN ENTEROTOXIGENIC E. COLI VACCINE IN NEW ZEALAND WHITE RABBITS . Godin, C.S. 1 ; Wenzel, H. 2 ; O’Dowd, A. 3 ; Maciel, M. 3 ; Poole, S. 3 ; Bourgeois, A.L. 4 ; Savarino, S. 3 1AVANZA Laboratories, LLC, Gaithersburg, MD; 2ABL, Inc., Rockville, MD; 3Naval Medical Research Center, Silver Spring, MD; 4PATH, Washington, DC

A vaccine against enterotoxigenic E. coli (ETEC) is being developed for travelers and young children at high risk of ETEC diarrhea. The purpose of this study was to determine the potential toxicity and immunogenic potential of the vaccine when administered alone or with an enterotoxin adjuvant to New Zealand White (NZW) rabbits by the transcutaneous route. This study was also designed to determine the persistence, late onset, or reversibility of any toxic effects over a 20-day no-treatment recovery period. NZW rabbits (14/sex/group) were assigned to the study and were treated via wet skin patch with either PBS; vaccine (250 µg/dose); adjuvant (50 µg/dose); or both vaccine (250 µg) and adjuvant (50 µg) on Study Days (SD) 1, 22, 43, and 64. Two animals/sex/group were sacrificed on SD 3 (interim), six animals/sex/group were sacrificed on SD 66 (terminal), and the remaining animals were sacrificed following the recovery period on SD 85 (recovery). Parameters evaluated included mortality, physical examinations, cageside observations, dermal Draize observations, measurement of dosing sites, body weight and changes, body temperatures, humoral responses to the vaccine and adjuvant, clinical pathology (serum chemistry, hematology, coagulation, and C-reactive protein), gross pathology, organ weight data, and microscopic pathology. When administered alone or together, treatment with the adjuvant or vaccine did not produce systemic toxicity. Treatment with the adjuvant alone or in combination with the vaccine was associated with dose site reactions, including erythema, edema, and inflammation; however, these findings were transient and non-adverse. Treatment with the vaccine alone was not associated with dose site reactogenicity. Both the vaccine and adjuvant were highly immunogenic.

P306AN 85-DAY REPEAT DOSE INTRADERMAL TOXICITY STUDY OF AN ENTEROTOXIGENIC E. COLI VACCINE IN GUINEA PIGS . Godin, C.S. 1 ; O’Dowd, A. 2 , Maciel, M. 2 ; Savarino, S. 2 1AVANZA Laboratories, LLC, Gaithersburg, MD; 2Naval Medical Research Center, Silver Spring, MD A vaccine against enterotoxigenic E. coli (ETEC) is being developed to protect travelers and young children that are at risk from this disease. The purpose of this study was to determine the immunogenicity, local skin reactogenicity, and potential toxicity of the ETEC vaccine candidate, when administered alone or in combination with an adjuvant derived from E. coli, to Dunkin Hartley guinea pigs by the intradermal route on Study Days 1, 22, 43, and 64. Guinea pigs were treated with 100 µL of the vaccine given alone or the adjuvant mixed with either PBS or the vaccine. Parameters evaluated included mortality, cageside observations, physical examinations, body weights, body temperatures, dermal Draize scores, dose site induration measurements, gross pathology, organ weights, and histopathology. Treatment with vaccine with or without adjuvant had no effect on mortality, cageside observations, physical examinations, body weights, body temperature, gross pathology, or organ weights. Administration of the vaccine alone resulted in a few observations of mild erythema but no induration. Administration of the adjuvant resulted in a dose-related increase in severity of erythema and edema but the severity appeared to decrease with repeated dosing. In addition, the incidence of positive Draize scores appeared to be lower in those animals that received vaccine in combination with adjuvant. Administration of adjuvant alone or in combination with vaccine resulted in areas of induration following the first dose that increased with dose level. However, only animals receiving the adjuvant without vaccine developed areas of induration at subsequent intervals. The tested vaccine components all produced variable inflammation at the inoculation site that was evident two days post-inoculation but which had resolved completely by three weeks post-inoculation.

P307EFFECTS OF α-CHLOROHYDRIN WHEN ADMINISTERED TO MALE Crl:CD(SD) RATS FOR 2-WEEKS ORALLY OR BY SUBCUTANEOUS INJECTION WITH A 1-WEEK RECOVERY James Ford, Jr.1, James Kosco1, David Schuette1, John-Michael Sauer1, Jay Albretsen1, Duane Belote1, Lynn Zuwannin2 and Cathy Moore 1 1 Covance Laboratories, Chandler, AZ 2

Covance Laboratories, Chantilly, VA

α-Chlorohydrin (αCH) is reported to produce spermatotoxicity, however little is known of the lasting effects of αCH. The purpose of this study was to evaluate the effects of αCH given orally (p.o.) or subcutaneously (SQ) on male reproductive parameters and body weight (BW) and food consumption (FC) in rats with a 1-week recovery. Sixty rats > 9 weeks old were randomly divided into 5 groups of 12 and given control (water) or 5, 20 or 40 mg/kg/day αCH p.o. or 40 mg/kg/day αCH SC. Following treatment (TRT), half the animals were euthanized. The remaining animals were euthanized following a 1-week recovery (REC). The right vas deferens was collected for sperm motility and right epididymis was collected for sperm count and morphology. Mean sperm counts decreased in animals given 40 mg/kg/day αCH p.o. or SQ (TRT~320 million/g; REC~300 million/g) compared with controls (TRT=1416 million/g; REC=1630 million/g). Percent abnormal sperm increased in animals given 40 mg/kg/day αCH p.o. or SQ (TRT>50%; REC~90%) compared with controls (TRT=0.4%; REC=0.9%). The percent of sperm with missing tails increased in animals given 40 mg/kg/day αCH p.o. or SQ (TRT>50%; REC>90%) compared with controls (TRT and REC~5%). Body weight was decreased in males given 40 mg/kg/day αCH p.o. or SQ (TRT~9%, p<0.05; REC~10%) compared with controls. This was reflected in decreased BW gain and FC (~50% and ~80% of controls, respectively) during TRT. REC FC was similar while REC BW and BW gain were different between rats given αCH or control. In conclusion, route of administration of αCH had similar effects on measured parameters. Rats given 40 mg/kg/day αCH p.o. or SQ with a 1-week recovery had a higher percentage of abnormal sperm and sperm with missing tails than rats at the completion of treatment.

P308SAFETY OF HIGH MOLECULAR WEIGHT POLYETHYLENE GLYCOL (PEG) IN BIOTHERAPEUTICS -- CASE OF PEGYLATED FVIII TA McDonald, IA Ivens, Bayer HealthCare, San Francisco, California Polyethylene glycol (PEG) molecules have been linked to protein drugs to alter the kinetics or reduce the immunogenicity of the protein. Of the PEGylated proteins on the market, 4 contain PEG ≥30 kDa -- the largest PEG is a branched 40 kDa PEG. Several other PEGylated proteins are in clinical development. No PEG-related systemic toxicity has been reported for these drugs. BAY 94-9027, a PEGylated, recombinant FVIII (rFVIII) developed for hemophilia A, contains a single, 60 kDa PEG to prolong half-life and therefore efficacy. A clinical intravenous dose of 50 IU/kg for BAY 94-9027

corresponds to a very low PEG intake of approximately 3 microgram PEG/kg per dose. Before clinical trials, potential safety of PEG-FVIII was evaluated, including any special concerns over the use of a large PEG molecule. In intravenous toxicology studies of 60 kDa PEG, no adverse effects and no histopathological changes were observed up to and including the highest doses tested: 210 mg/kg after single dose or 11 mg/kg dosed every other day for 4 weeks. The dose of 11 mg/kg is more than the cumulative clinical lifetime dose of 60 kDa PEG received from BAY 94-9027. A literature evaluation of the safety and elimination of PEGylated proteins (PEG ≥30 kDa) is provided, and this information is consistent with the lack of toxicity seen for 60 kDa PEG here. The data indicate that long-term treatment with BAY 94-9027 will not result in PEG-related systemic toxicity.

400 series – Special Studies P400TOXICITY ON BONE MARROW PROGENITORS FROM DIFFERENT SPECIES: AN IN VITRO TEST TO PREDICT MYELOSUPPRESSION AND NEUTOPENIA Elaine Lau1, Mary Huber1, Diane Monteith1, Annie Tam1, Chista Farzim1, Allen Eaves1,2 and Jackie Damen1. 1STEMCELL Technologies Inc. Vancouver, BC, Canada, 2Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada The use of hematopoietic stem and progenitor cells in colony-forming cell (CFC) assays to test the effects of environmental toxins, chemotherapeutics, and other drug classes has been well documented. These assays have been used to screen compounds for toxicity before the initiation of costly clinical trials and as a tool to help determine maximum tolerated doses (MTDs). While several assays exist for studying different progenitor types, a great deal of research has focused on use of the colony forming unit-granulocyte/macrophage (CFU-GM) assay as a measure of the progenitors of the granulocytic/monocytic lineage. In fact, this assay has been optimized and validated for use as an in vitro predictor of acute-onset neutropenia by potential hematotoxicants. Choice of species is an important consideration when testing a new drug. Mouse CFC assays can be an important tool for determining toxic doses before committing to an in vivo study. Previous studies by Pessina et al. (Tox Sci. 2003. 75:355-367) indicate that for many drugs, human maximum tolerated doses (MTDs) can be predicted by adjusting mouse-derived MTDs. However, some studies indicate that significant differences exist among human, canine, rat and mouse hematosensitivities to certain

pharmaceuticals/toxins, with human cells showing higher sensitivity to the toxic effects of the compounds studied. Consequently, information from comparative CFC assays may be of great importance before entering clinical trials. Recent studies were conducted using chemotherapeutics and an environmental toxin to evaluate their effects on myeloid (CFU-GM) progenitors acquired from human, canine, rat and mouse bone marrow. The resulting data show that while all tested compounds displayed a dose-dependent toxic effect on colony growth, each compound demonstrated species specificity. While conditions in the human body cannot be completely reproduced in vitro, CFC assays can be used to help bridge the gap between high throughput screening technologies and in vivo studies.

P401CHARACTERIZATION OF BASELINE CARDIOVASCULAR FUNCTION IN THE CONSCIOUS, FREELY-MOVING, JUVENILE NON-HUMAN PRIMATE Ali S. Faqi, John C. Resendez and Theodore J. Baird, MPI Research, Mattawan, MI 49071 Most nonclinical/clinical drug safety assessments are conducted in developmentally mature subjects, which may not represent the most appropriate test sample for evaluating compounds with pediatric-specific indications. When children are the primary population, age-appropriate studies in juvenile animals are important for assessing direct toxic or developmental risks. With emerging trends in biologics, the necessity of conducting juvenile toxicology studies in non-human primates (NHP) will likely increase. The purpose of this study was to characterize the postnatal developmental progression of key cardiovascular safety endpoints in approximately 7-14 month old juvenile NHPs. To assure a comprehensive evaluation, utilizing continuous data sampling procedures without complications associated with chemical or physical restraint; eight recently weaned cynomolgus macaques were surgically instrumented with radiotelemetry transmitters to measure systemic arterial pressures and body temperature, and to record a standard electrocardiogram (ECG). A pressure-sensitive catheter was introduced femorally and positioned within the descending aorta, and bipolar electrode implanted to record a Lead II ECG. To facilitate long-term vascular access, a femoral venous catheter was implanted and connected to a subcutaneous vascular access port. Heart rate, blood pressure, body temperature and the ECG were collected according to a bi-weekly schedule using PoNeMah (Ver 4.1) software. Telemetry data, including standard ECG reference intervals (RR, PR, QRS, QT, QTc), heart rate, blood pressure, body

temperature will be presented and compared to a reference historical control dataset previously collected from a large sample of adult NHP subjects (Gauvin et al., 2006, J Pharmacol Toxicol Methods 53:140-51). The nature and putative bases for observed differences in baseline values for these physiological variables between adult and developing juvenile animals will be discussed.

P402LONGITUDINAL PROFILES OF BIOMARKERS ASSOCIATED WITH NEPHROTOXICITY IN RATS TREATED WITH DOXORUBICIN OR CISPLATIN J. Smith, S. Nodop Mazurek, K. Lincoln, F. Pack, A. Mineo, A. Muthukumarana, A. Hudak, P. Harrison, R. Fryer, J. Phillips, Boehringer-Ingelheim Pharmaceuticals, Inc. Ridgefield CT Several renal injury biomarkers can outperform or add value to conventional serum BUN and creatinine (sCr) in rat toxicology studies. Here we report daily measurement of exploratory urinary biomarkers of renal function, tissue injury and leakage during 15 day studies in rats treated with doxorubicin (DOX), or cisplatin (CDDP). Biomarker results are compared to terminal histopathology and serum chemistries (pretest, d7 and terminal). Renal histopathology showed dose-dependent glomerular, proximal convoluted tubule (PCT) and collecting duct damage in DOX-treated animals and PCT necrosis in CDDP-treated animals. Serum BUN and sCr were unchanged compared to vehicle controls in all treatment groups. In contrast to BUN and sCr, albuminuria increased in DOX-treated animals compared to vehicle (high dose at d4 and low dose at d7). Albumin increases were followed by changes in other functional biomarkers (d6-7 high dose, d9-10 low dose) such as 2 microglobulin and cystatin C which were then followed by inducible injury marker responses (d8-10 high dose, d13-15 low dose) such as KIM-1, lipocalin-2 and clusterin. Biomarker responses matched well with type and incidence of histopathology findings. Biomarker profile in CDDP-treated animals differed from that seen in DOX-treated animals, consistent with a mechanistic link between biomarker and type of injury.These results suggest differences in biomarker profiles are indicative of direct and indirect PCT damage. The dose-related onset and severity of injury also matched well with temporal biomarker responses in both models.

P403MINI)PIGS IN DEVELOPMENTAL AND REPRODUCTIVE TOXICITY ( ( DART) STUDIES Ganderup, NC (1) & Navratil, N (2) 1: Ellegaard Göttingen Minipigs, Denmark, [email protected]. 2:

Marshall BioResources, USA, [email protected]. Reproductive studies in the context of safety assessment of new medicines are performed routinely in a rodent and the rabbit. However, in cases where the rabbit may not be suitable as the non-rodent model, the minipig may be a suitable alternative, and should be considered before utilising non-human primates (NHPs). This poster has three components:1) Male and female reproductive characteristics,

including embryonic development, and a comparison with other commonly used species.

2) Data about the nature and frequency of congenital malformations and abnormalities observed in the Göttingen Minipig production herd. Although such data cannot be a substitute for data obtained from control groups, this information can be valuable when interpreting DART studies.

3) A literature review on the use of pigs and minipigs in teratology studies provide additional knowledge about the species in this context.

Pros and cons of minipigs in the context of DART studies will also be presented. Minipigs have been used for regulatory segment II studies and should be considered as a relevant alternative to the rabbit (if unsuitable). The minipig should be considered before using NHPs.

P404ACUTE CARDIOVASCULAR EFFECTS IN DOGS TREATED INTRAVENOUSLY WITH CAPTISOL®

Vincent L. Reynolds1, Derek J. Leishman1, Bradley W. Main2, Christine Clawson2, and Courtney R. Burch2

1Eli Lilly and Company, Indianapolis, IN; 2Covance Laboratories, Greenfield, IN Captisol® (β-cyclodextrin sulfobutyl ether sodium salt) is an excipient used in toxicology studies to solubilize and stabilize test materials. To evaluate the potential for vehicle effects on cardiovascular (CV) parameters with Captisol®, beagle dogs (n = 2 females/group; instrumented with left ventricular and aortic pressure sensors) received i.v. doses (6 mL/kg as 1- to 2-minute bolus doses via catheters placed in the cephalic vein) of saline (0.9%) or Captisol® (12% in purified water, pH 6). CV parameters (systolic, diastolic, mean arterial, and pulse pressure, dP/dtmax, and heart rate) and body temperatures were measured 30 min pre-dose through 3.5 hrs post-dose. The dogs were placed in slings for the duration of CV data collection. Noteworthy clinical signs occurred only with Captisol® and included tremor, loss of consciousness, loss of muscle control, and/or aggression. A transient increase in heart rate occurred with both saline and Captisol® that persisted only during the 1- to 2-

minute dosing interval. With saline, there were no appreciable effects on blood pressure or inotropy. Captisol® caused a biphasic blood pressure response, with an initial increase followed by a severe (>50%) transient decrease that necessitated the i.v. administration fluids to 1 dog as rescue therapy. A decrease in left ventricular inotropic state was noted in the dogs treated with Captisol®. Because of the concomitant decrease in blood pressure, it was not possible to determine if the decreased inotropy was a direct effect or secondary to a decrease in afterload.

P405DEVELOPMENTAL TOXICITY OF ACETYLSALICYLIC ACID IN RATS . E. Mylchreest, K.S. Gilbert, C.B Cagle, Southern Research, Birmingham, AL. A positive control study was conducted with acetylsalicylic acid (ASA) to support training on identification of fetal anomalies. Rats (10-12/group) were administered a single dose of ASA orally by gavage at 0 or 500 mg/kg (5 mL/kg in 0.2% methylcellulose) on gestation day (GD) 9, 10, 11, or 12. A laparohysterectomy was performed on GD 21 and fetuses were weighed and examined for external, visceral, and skeletal anomalies. Postimplantation loss was increased in the GD 9 and 10 groups (mean of 54.2% and 13.3% vs. 3.5% in controls). In the GD 9 group, this was due to increased dead fetuses (mean of 1.0 vs. 0 in controls), early resorptions (6.3 vs. 0.6 in controls), and late resorptions (0.6 vs. 0 in controls); but was due to increased early resorptions in the GD 10 group (2.0 vs. 0.6 in controls). There was a resultant decrease in the number of live fetuses in the GD 9 and 10 groups (7.0 and 12.8 vs. 15.4 in controls). Neural tube, abdominal wall, and tail anomalies were observed in the GD 9 group, and cleft lip/palate in the GD 9, 10, and 11 groups. Cardiovascular, reproductive, liver, renal, adrenal, spleen, and diaphragm anomalies were observed with the overall group incidence in the order GD 9>10>11>12. The most common anomalies were great vessel transposition, absent aortic arch, ectopic testes/ovaries, abnormal liver lobation, absent diaphragm; and supernumerary kidney (GD 11>9). Axial skeletal development was markedly affected in the GD 9 group with numerous skull, rib, sternebral, and vertebral anomalies, most notably absent and fused structures. In conclusion, ASA administration to rats during major organogenesis resulted in embryolethality and/or malformations, which is consistent with the published literature. A single oral dose on GD 9 produced the most severe effects, followed by GD 10, and to a lesser extent GD 11 and 12.

P406A 13-WEEK NONCLINICAL PHOTOSAFETY STUDY IN HAIRLESS MICE TO CHARACTERIZE THE BIOMARKER RESPONSES OF HIGH DOSES OF ULTRAVIOLET RADIATION (UVR) AND 8- METHOXYPSORALEN (8-MOP ) T Coston1, D Learn1, C Sambuco, D Forbes2, S Johanssen3, C Guenther 3 1

Preclinical Services, Charles River Laboratories, Horsham PA2 Toxarus Inc., Malvern PA, 3 Preclinical Development, Intendis GmbH, Berlin Germany The purpose of the presented study was to characterize the response of biomarkers for photocarcinogenicity of high doses of simulated sunlight (UVR) and the combination of 8-Methoxypsoralen (8-MOP) and UVR. Both exposure to UVR alone and 8-MOP+UVR are known to enhance photocarcinogensis in mice and humans, and were chosen to evaluate biomarker response as a surrogate for skin tumor development in hairless mice. The employed biomarkers included apoptosis as determined by sunburn cell production, cell proliferation as determined by incorporation of bromo-deoxyuridine during DNA synthesis, epidermal cellularity and thickness, and dermal inflammatory infiltration. Clinical observations, skin reaction observations, body weights and skin thickness measurements were recorded. Six groups of albino hairless mice were treated over 13 weeks as follows: untreated control, UVR low dose (600 Robertson-Berger Units/week (RBU/wk)), UVR mid dose (1200 RBU/wk), UVR high dose (2400 RBU/wk), 8-MOP low dose + UVR low dose, 8-MOP high dose + UVR low dose. Low dose 8-MOP formulation concentration was 0.01 mg/mL (100µL/25 cm²) in Weeks 1-8 and 0.1 mg/mL in Weeks 9-13. High dose 8-MOP formulation concentration was 0.1 mg/mL in Weeks 1-8 and 1 mg/mL in Weeks 9-13. UVR caused a dose-related increase in all biomarkers. The combination of 8-MOP and UVR had only minimal effects on biomarkers at the low dose of 8-MOP, whereas the effects of high dose of 8-MOP with UVR were generally greater than UVR alone. Skin reaction observations and skin thickness measurements generally correlated well with the biomarker results. The findings indicate that the evaluated biomarkers were clearly affected by two stimuli known to enhance photocarcinogenesis: simulated sunlight exposure alone; and a phototoxic regimen (8-MOP + UVR).

P407CONTEXTUAL FEAR CONDITIONING ASSESSMENT WITH SCOPOLAMINE IN THE ADULT MALE RAT Jonathan D. Toot, Lynette M. Vana, Matt R. Bennett, Melissa J. Beck, Donald G. Stump and Mark D. Nemec. WIL Research Laboratories, LLC. 1407 George Road, Ashland, OH, 44805-8946

The objective of this study was to assess the modified contextual fear conditioning (CFC) testing paradigm utilized at WIL Research Laboratories, LLC, using scopolamine hydrochloride as the positive control agent . The animals used for this study consisted of adult Long Evans males (n=10/group), approximately 12 weeks of age at initiation of testing. The CFC assessments took place over 2 days, with the initial training on Day 1, followed by cue and contextual testing on Day 2. Animals were given an intraperitoneal injection of either scopolamine (20 mg/kg) or vehicle (saline) approximately 15 minutes following the completion of training. Training on Day 1 consisted of a single 3 minute session in which a 2 second 0.5 mA foot shock (aversive stimulus) was paired with an 85 dB auditory tone (neutral stimulus). Context Testing on Day 2 consisted of a single 5 minute session without the aversive and neutral stimuli. Cue testing on Day 2 consisted of single 6 minute session with a modified floor overlay and presentation of the neutral stimulus. The parameters included freeze count, percent time freezing, time spent freezing, and average motion index were recorded and analyzed quantitatively. As expected, there were no differences between either treatment groups during training on Day 1. However, both context and cue testing on Day 2 indicated impaired performance in the scopolamine versus vehicle treated group with an increased number of freeze counts, decreased time spent freezing, decreased percent time spent freezing and increased motion index over each test session. Therefore, these results validate that the methodologies and testing procedures described at WIL Research.

P408DRUG DISCRIMINATION ASSESSMENTS WITH MORPHINE, TRAMADOL, AND OXYCODONE IN THE ADULT MALE RAT Jonathan D. Toot, Melissa J. Beck, Donald G. Stump, Michelle L. Hackman and Mark D. Nemec. WIL Research Laboratories, LLC. 1407 George Road, Ashland, OH, 44805-8946 The objective of this study was to assess the drug discrimination (DD) testing paradigm utilized at WIL Research Laboratories, LLC, using morphine as the reference compound with test drug substitutions including tramadol hydrochloride, oxycodone hydrochloride and morphine sulfate in the rat within the scope of the European Medicines Agency guidelines. The animals used for this study consisted of adult Sprague Dawley males (n=12-16), approximately 8 weeks of age at initiation of training and testing. Rats were first trained by food pellet reinforcement under a fixed ratio (FR) 20 schedule to discriminate between the compound associated levers when administered the reference compound

(RC), morphine (5.6 mg/kg), or the vehicle control (saline) via intraperitoneal injection approximately 30 minutes prior to the drug discrimination session. Discrimination testing was conducted following compound substitution of the following test drugs: tramadol at 1.0, 10, 20 and 30 mg/kg; oxycodone at 1.0, 5.0, 10 and 20.0 mg/kg; and morphine at 0.3, 3.0, and 9.0 mg/kg. Using this paradigm, the first 20 lever presses were reported as the relative percent of RC lever selection. The results of this study showed RC lever selection (>80%) for substitution with oxycodone (5.0 mg/kg) and morphine (5.6 and 9.0 mg/kg). Tramadol resulted in intermediate levels of substitution over the dose levels administered, with RC lever selection between 10 and 60%. Also, the remaining dosage levels for each compound did not fully substitute (RC level selection below 25%) or substitution assessment criteria was not achieved (failure to complete the first FR) over the high dose levels administered. The DD testing paradigm was able to characterize the selected compounds for their known discriminative potential. Therefore, these results validate that the methodologies described at WIL Research are in accordance with the EMEA guidelines.

P409NEUROBEHAVIORAL ASSESSMENTS OF STARTLE RESPONSE, MOTOR ACTIVITY, AND LEARNING/MEMORY IN ADULT RATS Jonathan D. Toot, Michelle L. Pershing, Melissa J. Beck, Donald G. Stump, Mark D. Nemec WIL Research Laboratories, LLC. 1407 George Road, Ashland, OH, 44805-8946 The purpose of this study was to evaluate the ability of Kinder Scientific Startle Response Chamber, Kinder Scientific Motor Activity Chamber and Complex water T-maze to detect decreases and increases (as appropriate) in each endpoint following treatment with various CNS acting compounds in adult male and female Sprague-Dawley Crl:CD rats. For each neurobehavioral assessment and compound, separate subsets of 20 rats/sex were assigned to each control and treatment group. To assess decreased auditory startle response, chlorpromazine was administered (SQ) at dosage levels of 0, 2 and 10 mg/kg on PND 60. For increased auditory startle response, amphetamine was administered (IP) at dosage levels of 0, 1.0 and 5.0 mg/kg on PND 60. To assess decreased motor activity, haloperidol was administered (IP) at dosage levels of 0, 0.05, 0.1, and 0.5 mg/kg prior to behavioral testing on PND 61. For assessments of increased motor activity, amphetamine was administered (IP) at dosage levels of 0, 1.0 and 5.0 mg/kg on PND 61. For impaired learning/memory performance, scopolamine was administered (IP) twice daily at dosage levels of 0, 0.5, 1.5 mg/kg from PND 62-68. The results of this neurobehavioral study in adult rats found that treatment on PND 60 with chlorpromazine resulted in a dose dependent decrease in the maximum force across all blocks of trials, with an increase in the time to reach the maximum force. Amphetamine-treated males and females exhibited an increase in the mean maximum response force on PND 60. Treatment with haloperidol caused a dose-dependent decrease in locomotor activity (total activity counts and ambulatory counts) for both male and female rats at PND 61. Amphetamine treatment resulted in an increase in locomotor activity (mean total and ambulatory activity) in male and female rats on PND 61. Scopolamine administration from PND 62-68 resulted in a generalized and dose dependent impairment, with an increased time to escape the maze and increased error number. Therefore, these results validate that the methodologies and testing procedures described at WIL Research.

P410NONCLINICAL SAFETY EVALUATION OF XOMA 3AB, A NOVEL TRIPLE MONOCLONAL ANTIBODY DRUG PRODUCT TARGETING BOTULINUM TOXIN TYPE A, IN SPRAGUE-DAWLEY RATS K Meyer1, H Ng2, T Parman2, A D’Andrea2, T Harrison2, C Green2, J Ma1, L Cao1, B Shimizu1, K Der1, J Mirsalis2. XOMA (US) LLC1, Berkeley, CA; SRI International2, Menlo Park, CA. XOMA 3AB is being evaluated for the treatment and prevention of botulinum toxin type A (BoNT/A) poisoning. XOMA 3AB is composed of an equimolar mixture of three human or humanized IgG1

monoclonal antibodies (mAb), referred to as NX01, NX02 and NX11, that target unique non-overlapping regions on BoNT/A. These antitoxin mAbs bind to BoNT/A resulting in rapid clearance of the toxin from the systemic circulation. Nonclinical safety evaluation pharmacokinetics (PK) and toxicology studies were conducted in Sprague-Dawley rats to support the clinical development of XOMA 3AB. The PK of XOMA 3AB was evaluated in rats for 71 days following a single intravenous injection at dose levels 0.1, 1 and 10 mg/kg. XOMA 3AB was administered weekly for five weeks by intravenous injection at doses up to 50 mg/kg and by intramuscular injection at a dose level of 3 mg/kg for toxicology assessment. Parameters evaluated included clinical observations, food consumption, body weights, clinical pathology, ophthalmology, urinalysis, macroscopic and microscopic evaluation. Bioanalytical assays were developed using an electrochemiluminescence (ECL) format to measure the individual mAbs in rat serum. An ECL assay was also developed to measure total anti-drug antibodies to XOMA 3AB. The results show that NX01, NX02 and NX11 have similar PK profiles and demonstrate a dose proportional bi-exponential decline in initial and terminal half-lives, clearance and volume of distribution. The half-lives of NX01, NX02 and NX11 ranged from 12.4 to 17.2 days. Animals with anti-drug antibodies showed increased clearance of XOMA 3AB from the serum. There were no toxicologically significant findings related to administration of XOMA 3AB to rats. The no-observable-adverse-effect level (NOAEL) following intravenous administration was ≥ 50 mg/kg, the highest dose tested. In summary, the three mAb components of XOMA 3AB show similar PK profiles following IV and IM injection, and there were no drug-related adverse toxicological findings in rats. This project has been funded in whole or in part with federal funds from the NIAID, NIH, DHHS contract numbers HHSN266200600008C and HHSN266200600011C.P411ABSENCE OF GENOTOXICITY BY THE ANTISENSE OLIGONUCLEOTIDE PRO044. Yolanda Ponstein-

Simarro Doorten and Sjef J. de Kimpe, Prosensa Therapeutics BV, 2333 CH Leiden, The Netherlands PRO044 is a 2’-O-methyl phosphorothioate RNA antisense oligonucleotide (AON) product that is currently being developed for the treatment of Duchenne Muscular Dystrophy (DMD), a lethal orphan disease for which currently no therapy exists. The fundamental cause of this disease is mutations in the DMD gene leading to out of frame transcripts for the muscle protein dystrophin. AON-induced exon skipping of exon 44 in the human dystrophin pre-mRNA results in the restoration of the reading frame and might result in a (partially) functional dystrophin protein. The mutagenic and clastogenic potential of PRO044 was assessed using in vitro tests in bacteria and mammalian cells and an in vivo rodent assay. The bacterial reverse mutation assay (i.e. Ames test using Salmonella typhimurium TA98, TA100, TA102, TA1535 and TA1537) showed that PRO044 has no mutagenic activity at concentrations up to 10.000 µg per plate, in the presence or absence of an in vitro metabolic activation system (S9-mix). The Chinese hamster ovary (CHO) chromosomal aberration assay showed that PRO044 did not induce structural aberrations in the presence or absence of S9-mix, up to the maximum tested concentration of 5.000 µg/mL. In addition, PRO044 didn’t induce any polyploidy nor gave indications of mutagenic properties in the presence or absence of S9-mix at 5.000 µg/mL. In the in vivo micronucleus assay, no genotoxic effect was observed in the bone marrow of mice following repeated subcutaneous administrations at three PRO044 dose levels (i.e. 80, 200 and 500 mg/kg on days 1, 3, 5 and 8) resulting in a weekly exposure of 320, 800 or 2.000 mg/kg. In conclusion, results from the above mentioned tests demonstrate that PRO044 is not mutagenic nor clastogenic which confirms the uniform consensus that 2’O-methyl AONs do not exert mutagenic nor clastogenic effects.

P412COMPLEMENT ACTIVATION AFTER TREATMENT WITH ANTISENSE OLIGONUCLEOTIDES IN VIVO AND IN VITRO . Yolanda Ponstein-Simarro Doorten, Ingrid G.M. Kolfschoten, Suzanne Bijl and Sjef J. de Kimpe, Prosensa Therapeutics BV, 2333 CH Leiden, The Netherlands. One of the class toxicities of phosphorothioate antisense oligonucleotides (AONs) is the activation of the complement pathway shown in non-human primates. Rapid infusion of high levels of AONs can result in clinical, hematologic, and hemodynamic disturbances. This condition has been linked to the activation of the alternative complement pathway, since complement split products C3a and Bb were shown to increase in plasma, which may activate neutrophils and macrophages. In order to assess the predictive value of in vitro analysis of the levels of the complement split factors C3a and Bb, monkey plasma was incubated with AONs PRO044 and PRO046 (containing a full 2’O-methylated backbone) and compared to in vivo data obtained with cynomolgus monkeys treated with these AONs. The mentioned AONs are currently developed by Prosensa for the treatment of Duchenne Muscular Dystrophy (DMD), by means of exon skipping. As a positive control, monkey plasma was also incubated with cobra venom factor (CVF). In vitro, levels of C3a and Bb increased upon exposure to the AONs and CVF. In vivo, a similar activation pattern of the alternative pathway was found for the tested AONs. These results indicate that an in vitro screening of the activation of complement pathway by AONs can be used to predict in vivo complement activation in monkeys. Activation of the alternative pathway by AONs was also tested in human plasma. PRO044 did not activate the alternative complement pathway, while PRO046 and CVF showed an increase in the levels of complement split factors C3a and Bb. In contrast to PRO044, PRO046 has been shown to form multimers, which seems to be a stimulating factor for complement activation. These results substantiate that the activation of the alternative pathway by 2’O-methyl AONs is sequence and species specific and that monkeys are more sensitive than humans.

P413SAFETY PHARMACOLOGY ASSSESSMENT OF THE ANTISENSE OLIGONUCLEOTIDE PRO044 . Yolanda Ponstein-Simarro Doorten and Sjef J. de Kimpe, Prosensa Therapeutics BV, 2333 CH Leiden, The Netherlands PRO044 is a 2’-O-methyl phosphorothioate RNA antisense oligonucleotide (AON) product that is currently being developed for the treatment of Duchenne Muscular Dystrophy (DMD). The aim of PRO044 is to restore the human dystrophin pre-mRNA reading frame by means of exon skipping, resulting in a (partially) functional dystrophin protein. In order to identify potential signals that could subsequently be monitored in human clinical trials, PRO044 was tested in several safety pharmacology studies. The overt central and peripheral nervous system effects were assessed in mice, by means of the so-called IRWIN test. Actions on respiratory and cardiovascular systems were tested in the in vitro electro-conductivity (so-called hERG) assay and an in vivo study using non-human primates. In the IRWIN test, repeated subcutaneous administrations of PRO044 at dose levels of 50, 100 and 200 mg/kg on test days 1, 3, 5 and 8, did not result in any effect on neurobehavioral functional assessments reflecting normal central and peripheral nervous system activity. In the hERG assay, Chinese Hamster Ovary (CHO) cells stably expressing the potassium channel hERG were exposed to PRO044 and the channel tail current was measured by means of the patch-clamp technique. No effects on the channel tail current were observed after exposure to PRO044 concentrations of 15, 75 and 150 μM, corresponding to 0.11, 0.55 and 1.09 mg/ml, respectively. Cardiovascular and respiratory effects potentially induced by PRO044 were investigated in a sub-chronic repeated dose study in monkeys. No changes in ECG parameters, including QT intervals up to 13 weeks at a maximum dose of 54 mg PRO044/kg/week were observed. In conclusion, no PRO044-induced effects were observed in the tested battery of safety pharmacology studies.

P414DOES ORAL D- -TOCOPHERYL POLYETHYLENE GLYCOL 1000 SUCCINATE AFFECT DRUG TOXICITY?

RW Lange, TW Salcedo, M Donegan, RK Perrone, RT Bunch, TP Sanderson, and MH Davies Bristol-Myers Squibb Drug Safety Evaluation, Bioanalytical Research, and Drug Product Science and Technology; Mt.Vernon, IN, New Brunswick and Lawrenceville, NJ, and Wallingford, CT D--tocopheryl polyethylene glycol 1000 succinate (TPGS) is a valuable excipient for hydrophilic and lipophilic drug vehicles because it is

an emulsifier, solubilizer, and absorption enhancer. However, TPGS has been said to affect (mask) drug effects because of potential anti-cancer/anti-oxidant effects. Tocopherol succinate (TS), the vitamin E (VitE) form in TPGS, has anti-cancer/anti-oxidant effects in vitro and when injected into tumors or given intraperitoneally (IP) in animal cancer models. When TPGS is administered orally (PO), TS is hydrolyzed in the gastrointestinal tract to tocopherol (TOC), the less active VitE. The goal of this study was to evaluate TS exposure after PO TPGS, 2 groups of rats (N= 10/group) were given different TPGS-containing vehicles for 7 days: 60% polyethylene glycol 400 (PEG-400)/40% TPGS (550 mg/kg/d TS) or aqueous 75% 0.1M phosphate buffer/15% PEG-400/5% polyvinyl pyrrolidone/5% TPGS (70 mg/kg/d TS). Two control groups received daily PO PEG-400 (no VitE supplement) or IP TS (100 mg/kg, days 1, 3, 5, 7). On Day 8, plasma, liver, kidney, brain, and adrenal TS and TOC concentrations were measured by LC-MS. Plasma and tissue TS and TOC were not significantly increased after PO TPGS vehicles and TS was poorly absorbed when given PO. These data support the conclusion that VitE concentrations are not significantly increased in rats following PO TPGS, even at a TS dose of 550 mg/kg/d. Thus, TPGS-containing drug vehicles are unlikely to mask drug effects in PO toxicity studies.

500 series – Environmental Toxicology P500TOXICITY OF MANEB AND MANCOZEB PESTICIDES CONTRIBUTING TO RAT PHEOCHROMOCYTOMA CELLULAR DEATH AND THE POTENTIAL NEUROPROTECTIVE EFFECTS OF POLYPHENOLS AGAINST THESE INSULTS Marcela Velasco, Graduate Student, John Jay College of Criminal Justice Parkinson’s Disease is the second most common neurodegenerative disorder in the United States. Its pathology is characterized by a selective loss of pigmented neurons in the substantia nigra resulting in dopamine depletion. Pesticides causing chemical alterations that lead to neuronal apoptosis will also hinder the production of this neurotransmitter, possibly resulting in Parkinsonism or other diseases such as Alzheimer’s and Attention Deficit Hyperactivity Disorder. The present study investigated the effects of Maneb and Mancozeb pesticides in PC12 cells, which resemble the chemistry and physiology of dopaminergic neurons. Cells were treated with a 20 M Maneb and 20 M Mancozeb for 1 hour. Using MTT toxicology assay Maneb and Mancozeb treated cells showed a

decrease in mitochondrial function of 24.64% and 21.56% respectively. These PC12 groups were then treated with Polyphenols (10 M), known to be potent ROS scavengers, in order to study potential neuroprotective effects. No PC12 cell survival was observed in affected cells treated with Polyphenols suggesting that Maneb and Mancozeb do not act as oxidative stressors or that neuron death results from multiple mechanisms in which oxidative stress is not the driving event. DNA fragmentation was also examined using comet-assay. DNA breakage was evident in Maneb and Mancozeb exposed groups, demonstrating that these neurotoxins are capable of causing considerable genetic damage. Findings indicate that both pesticides do in fact disrupt PC12 mitochondrial function and cause DNA damage. This study confirmed the neurotoxicity of Maneb and Mancozeb adding to their relevance in the pathogenesis of neurodegenerative diseases.

P501EFFECTS OF GARLIC ON BLOOD LEAD CONCENTRATIONS AND HEMATOLOGICAL AND BIOCHEMICAL INDICES IN CAR BATTERY WORKERS Sina Kianoush a , Mahdi Balali-Mood a , Seyed Reza Mousavi a , Valiollah Moradi a , Mahmoud Sadeghi a , Bita Dadpour a a. Medical Toxicology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Introduction: Previous studies on animals have revealed that garlic (Allium sativum) is effective in reducing blood and tissue lead concentration. In this study, we investigated the effects of garlic on lead poisoning as well as hematological and biochemical parameters. Methods: After coordination and obtaining informed consent, clinical data, blood lead concentrations (BLC), hematological and biochemical indices of 59 workers at a car battery industry were recorded. All patients were treated by Garlet tablets (garlic powder tablets; 400 mg; 3 times daily) for 4 weeks. Clinical and laboratory tests were performed again on 14th day post-treatment. Results: Finally, 38 patients completed treatment. Irritability (P= 0.031), headache (P=0.028) and decreased DTRs (P=0.019) improved significantly following treatment with garlic. BLCs reduced significantly (P=0.002) from 426.32 ± 185.12 to 347.34 ± 121.05 µg/dL. Hemoglobin, Hematocrit, MCV, RBC count, MCH and MCHC of patients decreased (p<0.001) and fasting blood glucose increased (P=0.027) significantly. There was no correlation between BLCs and hemato-biochemical indices. Conclusion: Garlic tablets showed therapeutic effects in patients with chronic occupational lead poisoning.

P502

MORPHOLOGIC AND PROTEIN ALTERATIONS IN FISHER RAT TRACHEA EXPOSED TO MAINSTREAM CIGARETTE SMOKE *Charleata A. Carter, *Manoj Misra and #Robert R. Maronpot. *A.W. Spears Research Center, Lorillard Tobacco Company, Greensboro, NC 27405 and #EPL, Inc, Research Triangle Park, NC 27709 USA A short-term 5-day nose-only smoke exposure study was conducted in Fisher 344 rats to identify smoke-induced tracheal protein changes. Groups of 10 male and female 5 wk old rats were assigned to 1 of 4 exposure groups. Animals received filtered air, or 75, 200 or 400 mg total particulate matter (TPM)/m3 of diluted 3R4F Kentucky reference cigarette mainstream smoke. Exposures were conducted for 3 hrs/day, for 5 consecutive days. Half of the tracheal tissue was processed for pathology, and the other half frozen immediately for proteomics. We hypothesized that smoke activated tracheal inflammatory and stress-induced pathways. Mucosal epithelial toxicity from the inhaled material was evidenced by cilia loss in smoke-treated animals. Tracheal changes in females were more severe than in males. Mucosal atrophy occurred in females in the 200 mg TPM/m3 group. In the 400 mg TPM/m3

group mucosal epithelial hyperplasia was evident, but was more severe in females. Tracheal lysates from control vs. treated animals were screened for 800 proteins using antibody-based microarray technology and subsequently the 18 most changed proteins evaluated by Western blot. Tracheal proteins expressed at high levels that were markedly increased or decreased by smoke treatment depended on dose and gender and included: caspase 5, ERK 1/2, p38, protein phosphatase 2C (PP2C/), protein phosphatase 6 catalytic subunit (PP6C) and pyruvate kinase, muscle (PKM2). Thus, smoke affected protein pathways include stress, inflammation, tumor suppression, cell cycle control, cell proliferation and survival, apoptosis, and transformation. Inflammatory protein changes occurred with proteomics and pathology. Changes in identified proteins affected by smoke exposure may induce functional tracheal changes and could serve as early indicators of tracheal damage and associated disease.

P503DEVELOPMENT OF AN IN VITRO WHOLE SMOKE CO- CULTURE MODEL OF HUMAN SMOKING CONDITIONS Manoj Misra and William Polk. A.W. Spears Research Center, Lorillard Tobacco Company, 420 N. English Street, Greensboro, NC 27405, USA. The initiation of cigarette smoking related lung damage in both acute and chronic exposure conditions is associated with inflammation in smokers’ lung concomitant with the recruitment of

inflammatory cells to sites of airway injury. We developed a novel in vitro cell system to model conditions related to smoke-exposed human lung by exposing normal human lung epithelial cells (BEAS-2B) co-cultured with human macrophage inflammatory cells (U937) to mainstream cigarette smoke. The co-culture was exposed in a chamber attached to a smoking machine which delivered various amount of mainstream smoke from one, two or three 3R4F Kentucky reference cigarettes (ISO smoking conditions). The system was incubated for 24 hours in a cell culture incubator prior to cytotoxicity and inflammatory cytokines analysis. Exposure to 1, 2, 3 cigarettes smoke resulted in about 15%, 50%, 80% cell death, respectively. The co-culture supernatant was analyzed for a 42-plex human cytokine panel. Cytokine release was independent of U937 number in the absence of smoke, but 8 of 42 cytokines were unique to U937 in smoke exposed co-culture indicating the role of U937 cells in smoke response. The levels of most cytokines were inhibited at 2 or 3 cigarette smoke exposure due to cytotoxicity. Our in vitro co-culture study indicates that the presence of macrophage-like inflammatory cells, U937, is essential to induce various inflammatory responses typically seen in animal and human smoking conditions. This co-culture system provides an improved, relevant platform for toxicological inflammatory testing for cigarette ingredients and prototypes.

P504DIMETHOATE-INDUCED OXIDATIVE DAMAGE IN MALE RAT: ATTENUATION BY VITAMIN C Fatma El-Demerdash, University of Alexandria, Institute of Graduate Studies and Research, Department of Environmental Studies, Alexandria, Egypt. Email: [email protected] The present study is carried out to investigate the role of vitamin C in protection against oxidative damage induced by dimethoate insecticide in male rat. The exposure of rats to dimethoate for 30 days promoted oxidative stress with an increase in thiobarbituric acid reactive substances (TBARS) and a decrease in glutathione (GSH) level as compared to control. Moreover, the activities of liver antioxidant enzymes like GPx, GST, GR, SOD and CAT were also diminished by oxidant damage. Treatment with vitamin C significantly improves the liver damage from the oxidative stress caused by dimethoate and shifts the trend towards the normal status. In conclusion, vitamin C can be very effective in reducing liver injury and in overcoming oxidant damage caused by environmental stressors as pesticides.

P505

PROTECTIVE EFFECT OF SELENIUM AGAINST CARBOFURAN INDUCED OXIDATIVE STRESS IN RAT LIVER Hoda M. Nasr*, Fatma El-Demerdash** *Department of Pest Control and Environmental Protection, Faculty of Agriculture, Damanhour University, Damanhour, Egypt. Email: [email protected], ** Department of Environmental Studies, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt. Email: [email protected] Carbofuran (Furadan) is a broad spectrum carbamate insecticide mainly used to control household pests. Because of the widespread use of pesticides for domestic and industrial applications, evaluation of their toxic effects is of major concern to public health. Therefore, the present study was carried out to investigate oxidative stress, lipid peroxidation and antioxidant enzymes activities induced by carbofuran in rat liver, and the role of selenium in alleviating its negative effects. The administration of carbofuran significantly caused elevation in LPO level and perturbations in the activities of antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD) and glutathione S-transferase (GST). A significant decrease in glutathione (GSH) content was observed. Selenium treatment to carbofuran intoxicated rat decreased LPO level and normalized CAT, SOD and GST activities, while GSH content was increased. In conclusion, Se has beneficial effects and could be able to antagonize carbofuran toxicity.

600 series – Data Sets P600(MINI)PIGS IN DEVELOPMENTAL AND REPRODUCTIVE TOXICITY (DART) STUDIES Ganderup, NC (1) & Navratil, N (2) 1: Ellegaard Göttingen Minipigs, Denmark, [email protected]. 2: Marshall BioResources, USA, [email protected]. Reproductive studies in the context of safety assessment of new medicines are performed routinely in a rodent and the rabbit. However, in cases where the rabbit may not be suitable as the non-rodent model, the minipig may be a suitable alternative, and should be considered before utilising non-human primates (NHPs). This poster has three components:4) Male and female reproductive characteristics,

including embryonic development, and a comparison with other commonly used species.

5) Data about the nature and frequency of congenital malformations and abnormalities observed in the Göttingen Minipig production herd. Although such data cannot be a substitute for data obtained from control groups, this information can be valuable when interpreting DART studies.

6) A literature review on the use of pigs and minipigs in teratology studies provide additional knowledge about the species in this context.

Pros and cons of minipigs in the context of DART studies will also be presented. Minipigs have been used for regulatory segment II studies and should be considered as a relevant alternative to the rabbit (if unsuitable). The minipig should be considered before using NHPs.

P601VEHICLES & EXCIPIENTS UTILISED IN MINIPIGS – REVIEW OF USE IN MARKETED DRUG PRODUCTS Ganderup, NC, Ellegaard Göttingen Minipigs, DK. Selection of suitable vehicles and/or excipients is critical in both non-clinical and clinical studies as formulation impacts the intrinsic characteristics of the final drug product, e.g., (extended) release, absorption, distribution and (local) tolerance, to mention some. Inappropriate selection of vehicles and/or excipients can have negative impact on drug evaluation (which may be unwarranted) and consequently delay or stop development. This type of information is available for mice, rats, rabbits, dogs and non-human primates (NHP), but information specific to minipigs is scarce. More than forty marketed drug products (FDA/EMA dossiers) have been reviewed and vehicles and excipients used are presented in this poster. Data includes information on route of

administration, dosage, study duration, and (where possible) notable reactions. Published literature on this topic is also included. This provides the non-clinical experimenter with a valuable tool in his or her work.

P602BACKGROUND DATA IN THE INSTRUMENTED AND NON-INSTRUMENTED GÖTTINGEN MINIPIG Bernier, L., Mansell, P., Copeman, C., Preclinical Services Charles River Montréal With recent publications from the European RETHINK Project on the evaluation of the minipig as an alternative non-rodent species in toxicity testing, and following recommendations to systematically take minipigs into account during selection of an appropriate species, it is important to evaluate the background historical data and assess the suitability of the animal model for various routes of administration. Minipigs have been used by Charles River Laboratories as a non-rodent species for toxicity testing over more than 20 years. Pharmacokinetic, safety pharmacology, and toxicity studies using various dose routes including oral (gavage and pilling), intravenous and subcutaneous injections or infusion as well as studies utilizing target tissue dosing; dermal and ocular (instillation, intravitreal and subretinal injections) administrations have been conducted in minipigs. Dosing regimens varied from a single dose to 26-week daily administration (oral or IV infusion). Data types collected included clinical observations, body weights, food consumption, electrocardiograms, electroretinograms, ophthalmology, ocular pressure, blood pressure, clinical pathology (hematology, clinical biochemistry) and anatomic pathology (organ weights, macroscopic and microscopic findings).Comparisons of basic parameters obtained from control minipigs surgically instrumented or surgically manipulated, with that of minipigs given control substances orally, revealed that data sets were generally comparable, with predictable variability observed in parameters affected by differences in study design inherent to each route of administration. In conclusion, models utilizing the minipig are considered to be predictable and a suitable alternative as a non-rodent species for use in toxicology studies.

P603SAFETY ASSESSMENT OF SUBSTANCES IN ACCORDANCE WITH THE NEW GUIDANCE FOR NEW DIETARY INGREDIENTS Gavin P. Thompson and Gregory J. Sower, ENVIRON International Corporation, 1702 E. Highland Avenue, Suite 412, Phoenix, AZ 85016 USA. In the US, the Dietary Supplement Health and Education Act of 1994 (DSHEA) established that the manufacturer or distributor is responsible for ensuring that its dietary supplements are safe before they are marketed. Unlike drugs, FDA does not approve dietary supplements for safety or effectiveness before they are marketed. However, a manufacturer or distributor of a new dietary ingredient (NDI) submits a notification to FDA containing safety data to support the proposed use of the NDI. Although FDA does not opine on the safety of the NDI, it may issue an adverse status statement declaring the notification contains an “inadequate basis for reasonable expectation of safety.” To prevent this, an adequate and appropriate NDI safety dossier is needed. The authors investigate how various manufacturing process changes and various product use scenarios proposed for the NDI alter the needs of the safety data set. Strategies for assembling adequate safety data to support the use of the NDI are discussed. The authors analyzed the potential impacts of various processing methods for select ingredients on the safety of the NDI and its components. While minor changes in volatile components or concentration in aqueous solution or a solid in suspension may have no significant impact on composition and hence safety, other changes such as hydrolysis or esterification, removal of some components by chromatography, distillation or filtration may change the chemical composition of the NDI. Processing with a solvent other than water or aqueous ethanol to make an extract of the NDI may also change the chemical composition of the ingredient. The impacts of several alternative processing methods on the requirements for the safety dossier are considered and alternative approaches to obtaining adequate and sufficient data are discussed. The authors describe a variety of assessment tools including bridging data from studies of components of the NDI; and conclude that sufficient data may be available for an NDI even when the NDI is produced using new methods or in new formulated products.

P604SEND: ELECTRONIC SUBMISSION OF NONCLINICAL DATA Lou Ann Kramer 1 , Fred Wood 2 , Timothy Kropp 3 , Paul Cornwell 1 , Lorrene A Buckley 1 , Mary Jo Brucker 4 , Christopher Eley 5 , William Houser 6 1 Eli Lilly & Co., 2 Octagon Research; 3 USFDA; 4 Merck; 5

Pfizer; 6 Bristol Meyer Squibb Through the collaborative work of contract research organizations (CROs), industry and FDA, the production release of the SEND (Standard for Exchange of Nonclinical Data) Implementation Guide v 3.0 has been completed (www.cdisc.org/send). A rapid adoption of this standard is planned, and regular submissions are expected in 2012. SEND benefits include increased reviewer efficiency and enhanced communications between CROs, sponsors, and FDA’s Center for Drug Evaluation and Research (CDER). SEND supports automated creation of tables and graphs and allows data subsetting and mining, thus facilitating collaborative inter-industry efforts to interrogate information across boundaries. SEND will also enable FDA’s objective to develop a reposit-ory for all study data, clinical and nonclinical. SEND datasets are intended to replace data tabulations currently submitted as paper or PDFs; the study report will continue to provide methods and interpretive information. The purpose of SEND is to promote improvements in submission efficiency and quality through the establishment of a single international data standard for nonclinical data. Development of this standard began more than a decade ago and has gained momentum through piloting programs and the active participation of more than 50 volunteers across a wide array of pharmaceutical companies, CROs, vendors and the FDA. The current release defines standards for general toxicology, and carcinogenicity studies. Work is continuing to finalize standards for safety pharmacology and reproductive toxicology studies. CDER has already established processes and technology infrastructure to support the receipt, processing, review, and archiving of SEND formatted datasets. This abstract reflects the views of the author and should not be construed to represent FDA’s views or policies

P605ANTICANER DRUG-INDUCED CARDIOTOXICITY:: A RETROSPECTIVE ANALYSIS OF THE ACCURACY OF NONCLINICAL SAFETY STUDIES TO PREDICT FOR ADVERSE CARDIOVASCULAR EVENTS IN THE CLINIC Craig D. Fisher, Peter F. Smith and Vivek J. Kadambi Drug-induced cardiovascular toxicity can manifest as changes in blood pressure, arrhythmias (especially torsades de pointes induced by QT prolonging drugs), myocardial ischemia, thrombosis or impairment in myocardial contraction and/or relaxation. In the clinic, these toxicities can range from subclinical abnormalities to life-threatening and in some cases fatal events. Anticancer drugs have long been known to cause adverse cardiovascular events in the clinic. However, because these drugs are highly effective in settings where treatment options are limited, cardiovascular risk is rarely a development limiting barrier. The prevalence of literature highlighting anticancer drug-induced cardiovascular toxicity prompted us to conduct a meta-analysis to determine whether nonclinical safety data submitted for approval of these drugs accurately predicted for adverse cardiovascular events observed in the clinic. Inclusion criteria consisted of anticancer drugs with (1) cardiovascular toxicity listed as a “boxed warning” or “adverse event” on the drug label, and (2) accessible FDA or EMA drug approval package documents. Our results revealed that of the 33 anticancer drugs analyzed, approved between 1993 and 2011, only 17 had definitive findings of cardiovascular toxicity identified in nonclinical safety studies. Moreover, 2 drugs with boxed warnings for cardiovascular toxicity (trastuzumab and arsenic trioxide) had no indication of cardiac abnormalities in their nonclinical safety studies. Although results of this analysis suggest that traditional nonclinical safety studies may not accurately predict for anticancer drug-induced cardiotoxicity in the clinic, it should be noted that cancer patients represent a population with comorbidities and/or a history of prior treatment that may predispose them to adverse cardiotoxic events upon further drug administration. Taking this into account, the authors conclude that the addition of specialized nonclinical studies, including the use of stem cell derived cardiomyocytes as well as animal models with pre-existing disease or pre-exposure to relevant drugs (e.g. anthracyclines), may be useful when assessing the risk of anticancer drugs for cardiotoxicity in this complicated patient population.

P606AN INTEGRATED PREDICTION SYSTEM TO SUPPORT TOXICOLOGY ASSESSMENTS OF CHEMICALS. Bower D 1 , Cross KP 1 , Crump M 1 , Miller S 1 , Myatt GJ 1 , Saiahkov R 3 , Tice RR 2 , Wright M 4 1) Leadscope, Inc., Columbus, OH USA. 2) National Institute for Environmental Health Sciences, RTP, NC USA. 3) MultiCASE, Inc., Beachwood, OH USA. 4) Lhasa Limited, Leeds, UK Accessing toxicology data is challenging today because the data is located in many different places, with each database requiring the use of separate applications or web sites to search the information. Supplementing known information with results from multiple types of predictive models is often desirable; however, it can be difficult to use different software applications. This poster describes a prototype of an integrated prediction system that brings together toxicity data and predictions within a single graphical user interface running in a web browser. This user interface provides access to toxicology endpoints and studies from multiple databases, including public and proprietary data. The user is able to assess the toxicity of an existing or new compound using QSAR models or structural alerts from multiple suppliers including Leadscope, Inc., Lhasa Limited, and MultiCASE, Inc. The system was designed for use by scientists with different backgrounds; hence, it had to be easy to use and transparent to all stake holders. This poster will illustrate how the platform can be used to profile a set of compounds based on known toxicity information, browse prediction model results and explanations from multiple vendors and understand associations between different toxicity tests.

P607IN VIVO COMPARABILITY STUDIES FOR MONOCLONAL ANTIBODY PRODUCTS: A REGULATORY INTELLIGENCE REVIEW. Elena Whitley 1 and John An 2 . 1Preclinical Development and 2Global Regulatory Intelligence, Global Regulatory Affairs, PPD, Inc. Regulatory guidances state that comparability assessment of biotechnology-derived products is required to assess the potential impact of manufacturing changes on quality, safety and efficacy. Nonclinical comparability programs are generally designed in a step-wise fashion. Physicochemical and biochemical analytical data and results of in vitro pharmacology assays inform decisions on whether or not in vivo nonclinical studies are warranted, and if so, how they should be designed. Regulatory guidances on monoclonal antibody development and comparability testing are largely silent on specific nonclinical study design features.

A regulatory intelligence review of publicly available information was performed for 26 monoclonal antibody products approved from 1994 to 2011, with a focus on nonclinical in vitro and in vivo comparability programs as described in regulatory authority approval packages. When nonclinical studies were presented, comparative in vitro pharmacology studies and single-dose pharmacokinetic/pharmacodynamic (PK/PD) studies were more common than repeat-dose toxicity studies, consistent with an incremental approach to comparability assessment. The implications of the results of the regulatory intelligence review for nonclinical development of innovator and biosimilar monoclonal antibody products are discussed.

P608INCIDENCE OF NONNEOPLASTIC AND NEOPLASTIC LESIONS IN HISTORICAL CONTROL HARLAN RCC:HAN WISTAR RATS AFTER 28, 90, AND 180 DAYS OF ORAL GAVAGE DOSING Hollie Skaggs, PhD1, Rachel Avery, BS1, and Brad Blankenship, DVM, Diplomate, ACVP1 Covance Laboratories, Inc., Madison, WI Historical control data are important for the evaluation of certain histologic lesions identified during subchronic rodent toxicity studies. For uncommon lesions or lesions of uncertain relationship to the test article, historical control data can provide information about the incidence of spontaneously occurring background lesions in the species and strain of animal used on test. By providing this information, historical control data help support the significance (or lack thereof) of common and uncommon histopathology findings. In this work, an initial study was performed to investigate and develop a preliminary historical control database for the Harlan Rcc:Han Wistar rat strain at Covance Laboratories, Madison. Sixty male and sixty female Harlan RccHan:Wistar rats were sacrificed after 28, 90, or 180 days (360 animals total) of daily oral gavage dosing with reverse osmosis water. At initiation, animals were 4 to 8 weeks of age. Clinical signs, body weight, and food consumption were recorded; and hematology, clinical chemistry, coagulation, and urinalysis samples were analyzed. Animals were necropsied; macroscopic observations recorded; organs weighed; and tissues processed for microscopic evaluation. Electron microscopy was performed on selected tissues from a limited number of animals. Among the data analyzed, the incidence of spontaneously occurring nonneoplastic and neoplastic histologic lesions was determined and are presented in this work. Lesions included spontaneous degenerative and inflammatory changes, as well as a limited number of neoplasms.

Additionally, histopathologic findings considered part of normal morphologic changes due to age progression are also discussed. Overall, the purpose of this data is to facilitate the selection of the most appropriate animal model for subchronic toxicity studies and to facilitate the interpretation of results using the Harlan RccHan:Wistar rat strain.

P609A BATTERY OF ASSAYS FOR SELECTION OF DERMAL DRUG CANDIDATES - AND THE REGULATORY NON-CLINICAL SAFETY PROGRAM FOR DERMAL DRUGS Jens Thing Mortensen, CiToxLAB Scantox, Denmark and David J Esdaile, CiToxLAB Hungary Screening of molecules as candidates in a new dermal drug program is mostly based on the desired pharmacological properties and potency of the molecules (e.g. anti-inflammatory, anti-proliferative, anti-microbial, etc.) and their “drugability” (chemical structure, solubility, etc. that lead to desirable ADME properties). However, once the screening procedure has reduced the number of dermal candidate molecules to a relatively small number, it is important to assess these molecules for potential adverse effects. For dermal drug candidates, which will reach a high concentration in the skin, local skin irritation, contact sensitization and phototoxicity, are important hazards that should be assessed before making the final selection. The skin penetration properties of these molecules, or the influence of various formulation ingredients on the penetration of the molecule into the skin are important. We propose a tiered battery of in silico, in vitro and in vivo assays focused on providing a range of data to assist the development program in candidate selection for active ingredients and formulations. Once the final, optimised dermal drug candidate has been selected, a regulatory non-clinical safety program must be conducted to support clinical trial and marketing of the drug. The program will comply with regulatory guidance and be built in a step-wise manner to support each consecutive phase of the specific dermal clinical trial program. Important program and study design decisions to be made include: 1) choice of rodent and non-rodent species for the program, 2) choice of a suitable dermal vehicle for the non-clinical dermal studies, and 3) potential inclusion of systemic route of administration in the tox program.

700 series – Preclinical Safety Assessment P700THE PRECLINICAL SAFETY ASSESSMENT OF LY2196044, A PAN OPIOID ANTAGONIST FOR THE TREATMENT OF ALCOHOL USE DISORDERS WJ

Breslin, PJ Cocke. Lilly Research Laboratories, Indianapolis, IN 46285. LY2196044, a pan (kappa, mu and delta) opioid receptor antagonist under development for the treatment of alcohol use disorders was evaluated in a series of nonclinical acute, repeat-dose, reproductive and genetic toxicology and safety pharmacology studies. A single oral dose of 2000 mg/kg given to rats resulted in no important effects. Repeated oral doses of 1500 mg/kg to rats and dogs produced dose-limiting toxicity indicative of excitatory central nervous system (CNS) toxicity, including convulsions and increased mortality/euthanasia. In a rat 6-month study, males given 1500 mg/kg/day also exhibited atrophy/degeneration of the testes and histiocytosis in the ileum and mesenteric lymph node. These changes occurred at exposure levels ≥28x the exposure at the maximum proposed clinical dose of 250 mg and were completely (testes) or partially (ileum and lymph node) reversible following a 1-month recovery period. No clear adverse effects were observed in a 9-month dog study at doses up to 1000 mg/kg. LY2196044 was negative in a standard battery of genotoxicity tests and no adverse reproductive or developmental effects were observed at doses up to 1000 mg/kg in rats or 500 mg/kg in rabbits. In a mouse CNS safety pharmacology study, transient hypoactivity and enhanced effects of barbiturates were observed at 300 mg/kg. No substantive changes in cardiovascular function or QTc interval were observed in dogs at doses up to 800 mg/kg and no changes in respiratory function in rats or gastrointestinal motility in mice were observed at doses up to 300 mg/kg. In conclusion, the results of nonclinical toxicology and safety pharmacology studies demonstrate an acceptable safety profile for the clinical study of LY2196044. The lowest margins of safety (MOS) for LY2196044 based on systemic exposure from chronic rat and dog studies and the highest proposed clinical dose of 250 mg were 5-fold for Cmax (rats) and 6-fold for AUC (dog).

P701NONCLINICAL TOXICITY STUDIES FOR A NOVEL ANTICANCER AGENT, LOR-253 Yoon Lee1, Mario Huesca 1 , Geoff Goodfellow2, Jon Daniels2, Aiping Young1 1 Lorus Therapeutics Inc.; 2 Intrinsik Health Sciences Inc. LOR-253 is a first-in-class inhibitor of the Metal Transcription Factor-1 (MTF-1) with a novel mode of action. This consists of the induction of the tumor suppressor factor Krüppel like factor 4 (KLF4) leading to the down regulation of cyclin D1, an important regulator of cell cycle progression and cell proliferation, and decreased expression of genes involved in tumor hypoxia and angiogenesis. The toxicity profile of LOR-253 HCl has been investigated in intravenous (IV) infusion toxicology studies in Sprague-Dawley rats and Beagle dogs. In the single-dose toxicity studies, LOR-253 HCl was administered by IV infusion (over 4 hours) to rats at doses up to 384 mg/m2 and to dogs at doses up to 840 mg/m2. In rats, LOR-253 HCl was well tolerated at all dose levels tested and was not associated with any adverse effects or histopathological findings. In dogs, LOR-253 HCl was well tolerated up to 350 mg/m2, with the maximum tolerated dose (MTD) determined to be 840 mg/m2, based on changes in body weight, clinical chemistry parameters and kidney microscopic findings. In the pivotal GLP, 4-cycle toxicity studies in rats (0/125/200/350 mg/m2) and dogs (0/175/250/350 mg/m2), a single cycle was equivalent to 5 consecutive days of dosing per week. Based on the results of these studies, the kidney, liver/biliary gland, and blood were identified as primary target organs of toxicity for LOR-253 HCl. Toxicokinetic results showed significant dose-related exposure. The results of the pivotal LOR-253 HCl toxicity studies in rats (STD10 >200 mg/m2) and dogs (HNSTD= 250 mg/m2) supported the initiation of a Phase 1 clinical trial in cancer patients at a starting dose of 20 mg/m2 (1/10 of the STD10). In the Phase 1 trial, the dose frequency was reduced to a 2-day dosing period over 14 days based on supporting data from mouse xenograft studies.

P702NONCLINICAL SAFETY EVALUATION OF AN ANTIBODY-DRUG CONJUGATE (STEAP1 ADC) FOR THE POTENTIAL TREATMENT OF PROSTATE

CANCER. Willy A. Solis, Bonnee Rubinfeld, Kedan Lin, Douglas Leipold, Michael Mamounas, Khiem Tran, Fiona Zhong, Joseph Beyer, Kelly M. Flagella, Reina N. Fuji, Genentech, South San Francisco, California. Antibody-drug conjugates (ADCs) constitute an expanding class of therapeutic molecules in preclinical and clinical development for oncology indications. These biologic-based drugs are designed to increase delivery of cytotoxic payloads to tumor targets in order to improve efficacy and minimize toxicity. Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) is a multi-transmembrane, cell-surface antigen that is over expressed in the majority of human epithelial prostate cancers. STEAP1 ADC is comprised of anti-STEAP1 monoclonal antibody and monomethyl auristatin E (MMAE). MMAE is a potent anti-mitotic agent that is conjugated to the antibody through an enzyme-cleavable linker. STEAP1 ADC has anti-tumor activity in STEAP1-positive explant and xenograft prostate cancer models. The safety profile of STEAP1 ADC was evaluated in antigen-dependent and antigen-independent animal models. The main clinical and anatomic pathology findings showed toxicities to the bone marrow, liver, and testis. These findings were considered antigen-independent, clinically manageable, and consistent with the anti-proliferative effects of MMAE. In summary, STEAP1 ADC shows favorable efficacy and safety profiles in nonclinical models and is currently being evaluated as a new therapy for prostate cancer patients.

800 series – Molecular Mechanisms P800TOXICOLOGICAL ASSESSMENT OF A SPLEEN TYROSINE KINASE INHIBITOR, CC-118, IN SPRAGUE-DAWLEY RATS. Dinah L. Misner, Mike A. Breider, Kamran Ghoreishi, Brandon Jeffy, Dale Baker, and Rosana Magpantay. Exploratory Toxicology, Celgene Corporation, San Diego, CA. Inhibition of the spleen tyrosine kinase (Syk) enzyme has been advocated as therapy for autoimmune disease, due to the important role of Syk in signaling downstream from immunoglobulin receptors on cells integral to the inflammatory process. CC-118 is a small molecule selective kinase inhibitor with high potency against the Syk target (enzyme IC50 of 7 nM) and slightly less potency for the Janus kinase-2 (Jak2; enzyme IC50 of 30 nM) and colony stimulating factor-1 receptor (CSF1-R; enzyme IC50 of 28 nM) targets. The objective of this study was to determine the effects of CC-118 in Sprague-Dawley rats when dosed once daily via oral gavage for 7 days. In female rats dosed with 0, 50, 200, 400,

and 1000 mg/kg/day, doses of 400 and 1000 mg/kg/day were not tolerated with deaths and/or early sacrifice required by Days 3 – 6. Doses of 0, 25, 50, and 200 mg/kg/day were well-tolerated in male rats. Accumulation of CC-118 was observed at doses greater than 200 mg/kg/day, resulting in both higher Cmax and AUC levels upon repeated dosing. Exposures were generally similar across doses between males and females. In both sexes, decreased body weight was observed at ≥200 mg/kg/day and relative spleen and thymus weights were decreased at ≥200 mg/kg/day. Hematological changes included increased neutrophil counts at ≥200 mg/kg/day and decreased white blood cell, lymphocyte, and eosinophil counts at 400 mg/kg/day. Increased serum blood urea nitrogen was observed at ≥200 mg/kg/day and serum alanine transaminase and aspartate transaminase were observed at ≥200 mg/kg/day. At necropsy, the thymus and spleen were small and the mesenteric lymph nodes were mottled red. Microscopic changes consisted of myelosuppression (bone marrow hypocellularity) and lymph node erythrocytosis at ≥50 mg/kg/day and lymphoid depletion (thymus and spleen) and femur physeal dysplasia in females only at ≥200 mg/kg/day. These changes were generally attributed to inhibition of targeted kinases including Syk (lymphoid depletion), Jak2 (myelosuppression), and CSF1-R (physeal dysplasia, splenic red pulp atrophy, and elevated liver enzymes).

P801TOXICOLOGY PROFILE OF SMALL MOLECULE IAP ANTAGONIST GDC-0152 IS ASSOCIATED WITH TNF-ALPHA PHARMACOLOGY Rebecca Erickson 12 , Jacqueline Tarrant 12 , Gary Cain 12 , Noel Dybdal 12 , Sock-Cheng Lewin-Koh 13 , Harvey Wong 14 , Elizabeth Blackwood 15 , Kristina West 15 , Davi Almeida 12 , Kenjie Amemiya 12 , Donna Dambach 12 , Wayne Fairbrother 16 , Dolo Diaz 12 1 Genentech, South San Francisco, CA, 2

Dept. of Safety Assessment. 3 Dept. of Nonclinical Biostatistics, 4 Dept. of Drug Metabolism and Pharmacokinetics, 5 Dept. of Translational Oncology, 6 Dept. of Early Stage Discovery Biochemistry. Inhibitor of apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. GDC-0152 is a small molecule that triggers tumor cell apoptosis by selectively antagonizing IAPs. Several cytokines and chemokines are expressed in tumor cells as a result of GDC-0152-induced NFκB transcriptional activity, with tumor necrosis factor alpha (TNFα) being the most important for single-agent tumor activity. However, a variety of normal cells also produce TNFα upon IAP antagonism, which may contribute to both efficacy and toxicity. Here, we characterized the toxicology

profile of GDC-0152 in rats and dogs following intravenous dose administration once every two weeks. Findings in both species consisted of a dose-related, acute inflammatory response and hepatic injury. Specifically, in-life observations included cytokine/chemokine production, an inflammatory leukogram, and elevated transaminases in addition to histopathological findings of inflammatory infiltrates and apoptosis/necrosis in multiple tissues. All findings were biologically linked, by direct or indirect mechanisms, to TNFα and are

therefore expected to track with efficacy. The relationships between plasma cytokine/chemokine levels, specific pathology findings, and GDC-0152 plasma exposures were explored. Elevations in blood neutrophil count, serum MCP-1 and other markers of inflammation corresponded to GDC-0152 exposure and toxicity and show promise for further safety biomarker qualification.

ABSTRACT AUTHORS

Adams, T.B. – XVAdeyemi, O.S. – P105Albretsen, J. – P307Alden, C.L. – P200Almeida, D. - P801Amemiya, K. – P801An, J. – P607Arevalo, M. – P213Arocena, M. – P114Arvidson, K.B. – XVAtta-Safoh, S. – P213Avalos, J. – P102Avery, R. – P608

Bagley, J. – P212Bailey, D. – P304Baird, T. – XII, P401Baker, D. – P800Balali-Mood, M. – P501Barlow, N. – VIIIBeck, M.J. – P407, P408, P409Beck, S. – IXBeck, T. – P209Beierschmitt, W.P. – IXBelote, D. – P307Bennett, M.R. – P407Benz, R.D. – VIIBerman, C.L. – XBernier, L. – P602Beyer, J. – P702Bhattacharya, A. – P201Bialecki, R. – XVIIBijl, S. – P412Blackwood, E. – P801Blair, E. – P203Blankenship, B. 0 P608Blumer, K. – XVIIBogie, H. – P215Boogaard, P.J. – XIIIBouchard, G. F. – P111, P203, P216Bourgeois, A.L. – P305Boverhof, D. – P108

Bower, D. – P606Bowes, J. – P117

Brahmankar, M. – P108Breider, M.A. – P800Brennan, M. – P114Breslin, W.J. – P700Breuning-Wright, A. – P116Brown, A.M. – P114, P116Brown, L. – P111, P203, P216Brown, R. – P304Bruce, S. – P213Brucker, M.J. – P604Buckley, L.A. – P604Bunch, R.T. – P414Burch, C.R. – P404Burks, Z. – P203

Cagle, C.B. – P405Cain, G. – P801Cao, L. – P410Carathers, M.R. – P104, P105Cardoza, K. – P200Caron, S. – P303Carraway, J.W. – ICarter, C.A. – P502Cerven, D.R. – P102, P104, P105, P106Chaves, A. – P202Chen, H. – P214Chesnut-Speelman, J. – P117Ciaravino, L. – P100Clark, C.R. – XIIIClawson, C. – P404Cocke, P.J. – P700Coffey, C. – P110Contrera, J.F. – P119Copeman, C. – P303, P602Cornwell, P. – P604Coston, T. – P406Cracknell, A. – P207Crawford, J. – P204Cross, K.P. – XV, P119, P606Crump, M. – P606

Csizmadia, V. – P200Cunningham, M.J. – P103Cuppen, E. – P204

D’Andrea, A. – P410Dadpour, B. – P501Dailey, T. – P100Dalal, V. – P108Dambach, D. – P801Damen, J. – P400Daniels, J. – P701Davies, M.H. – P414de Kimpe, S.J. – P411, P412, P413Debelie, F. – P213deBruin, A. – P204DeGeorge, G.L. – P102, P103, P104, P105, P106DeGraw, T. – P101Der, K. – P410Dertinger, S. – P213Desai, P. – P118Desmond, D.J. – P115Dhar, P. – P201Diaz, D. – P801Diekmann, H. – P207, P208DiNovi, M.J. – XVDixit, R. – P302Dodd, A. – P207Donahue, D.A. – P102Donegan, M. – P414Dooley, J. – IVDorsam, R.T. –XDubach, J. – P210Dubey, V. – P108Dybdal, N. – P801

Eaves, A. – P400El Karadawey, M.H. – P300El-Demerdash, F. – P504, P505Elden, M.fa – P300Eley, C. – P604Ellis, A. – XIVErickson, R. – P801Esdaile, D.J. – P609Evans, T. – P216

Faiola, B. – P304Fairbrother, W. – P801Faqi, A.S. – P401

Fareed, J. – P210Farzim, C. – P400Fedyk, E.R. – P200Feilden, A. – IXFelter, S.P. – XVFerrari, N. – XFisher, C.D. – P605Flagella, K.M. – P702Flint, O. – VIIFlueckiger, A. – P113Forbes, D. – P406Ford, Jr., J. – P307Foster, A.F. – P117Franklin, P. – P209Frantz, S. – P110Freeman, J.J. – XIIIFriedrichs, G. – P202, P205Fryer, R. – P402Fuji, R.N. – P702

Gad, S.C. – IGalijatovic-Idrizbegovic, A. – VGallacher, M. - P200Gallenberg, L.A. – P115Ganderup, N.C. – P403, P600Gao, Y-J. – P205Garside, H.J. – P117Genter, M.B. – P118Gerenser, P. – P202Germann, P-G. – IIIGhoreishi, K. – P800Gien, B. – P101Gilbert, K.S. – P405Gizzi, J. – P215Godin, C.S. – P305, P306Goodfellow, G. – P701Grady-Styring, T. – P202Green, C. – P410Greene, N. – VIIGrompe, M. – VGudelsky, G. – P118Guenther, C. – P406

Hackman, M.L. – P408Hadd, S. – P110Hailey, J. – P304Hall, D. – P102Hall, L. – P212Hamlin, R. – XII

Handler, J.A. – IHanks, B.C. – P203Hanks, C. – P111Hargreaves, D. – P110Harrison, P. – P402Harrison, T. – P410Harrouk, W.A. – XIVHasselgren, C. – VIIHastings, K.L. - XVIIIHeidel, S.M. – XVIIIHenry, S. – XHermsen, R. – P204Higgins, D. – P206Hill, A. – P207, P208Hoagland, K. – P202Hoberman, A. – P114Hobson, D.W. – IHolzgrefe, H. – XVIIHoppensteadt, D.A. – P210Hopper, D. – P101Horlen, K.P. – P111, P203Horn, K. – XVIHouser, W. – P604Howard, K. – VHuber, M. – P400Hudak, A. – P402Huesca, M. – P701Hummer, T. – IV

Iciek, L. – IXIvens, I.A. – P308

James, N. – P100Jamison, J. – VIJeffy, B. – P800Johanssen, S. - P406Jones, M. – P207, P208Jordan, H. – P304Jortner, B. – P200

Kadambi, V.J. – P200, P605Kallman, M.J. – XVIKatavolos, P. – P115Kelley, T. – P213Kemp, D. – P304Kenna, J.G. – P117Kenney, J. – P107Kianoush, S. – P501Kimbrough, C. – P107Kinney, J.C. – P115

Klug-LaForce, M. – P213Kolbeck, R. – P302Kolfschoten, I.G.M. – P412Kornbrust, D. – XKosco, J. – P307Kramer, J.K. – P116Kramer, L.A. – P604Kreet, M.H. – P300Krishnan, M. – P118Kropp, T. – P604Krsmanovic, B. – P213Krueger, J. – VIIIKuiper, R.V. – P204

Lainee, P. – XIILalayeva, N. – P209Lane, R. – P101Lange, R.W. – P414Lau, E. – P400Lawlor, T. – P214Learn, D. – P114, P406Lee, D. – XILee, K. – IVLee, P. – IILee, Y. – P701Leininger, J.R. – P302Leipold, D. – P702Leishman, D.J. – P404Lewin-Koh, S-C. – P801Lin, K. – P702Lincoln, K. – P402Liu, J. – P111, P203

Ma, J. – P410Maciel, M. – P305, P306Magpantay, R. – P800Main, B.W. – P404Makori, N. – P209Maltas, J. – P101Mamounas, M. – P702Manetz, T.S. – P302Manish, R. – P108Mann, P.C. – IIIMansell, P. – P602Marcoe, K.F. – P117Maronpot, R.R. – P502Matthews, E. – XVMattis, C.R. – P115McDonald, T.A. – P308McDorman, K.S. – III

McGeehan, E. – P210McGraw, J. – P211McInally, K. – P215McKee, R.H. – XIIIMcKeon, M. – P214Mehra, R.D. – P201Merrill, C. – P304Meyer, K. – P410Miller, S. – P606Mineo, A. – P402Mirsalis, J. – P410Misner, D.L. – P800Misra, M – P502, P503Mistry, B. – P101Miyamoto, M. – P206Monteith, D. – P400Moore, C. – P203, P307Moose, T. – P107Moradi, V. – P501Morissette, P. – P202Mortensen, J.T. – P609Mounho, B.J. – XVIIIMousavi, S.R. – P501Mullin, M. – P107Murli, H. – P214Murphy, O. – P207Murphy, V.A. – IIMurray, J. – XIMuthukumarana, A. – P402Myatt, G.J. – P116, P606Mylchreest, E. – P405

Nagata, R. – P209Nasr, H.M. – P505Navratil, N. – P403Nemec, M.D. – P407, P408, P409Ng, H. – P410Nicolich. M. – XIIINiehoff, M. – XIINishida, M. – P202Nodop Mazurek, S. – P402

O’Day, C. – P117O’Dowd, A. – P305, P306Obejero-Paz, C. – P116Oneda, S. – P209Ontano, E. – P212Ovechkina, Y. – P117

Pack, F. – P402Palmby, T. – IIPandey, S. – P108Paranjpel, M. – P213Parman, T. – P410Patel, R. – P108Perrone, R.K. – P414Pershing, M.L. – P409Pfister, T. – P112Phagura, A. – P212Phillipa, J. – P402Piehl, M. – P106Plumb, A. – P101Polk, W. – P503Ponstein-Simarro Doorten, Y. – P411, P412, P413Poole, S. – P305Poulin, D. – P215Powley, M.W. – V, VIIPratt, L.F. – P103Prefontaine, A. – P303Pula, K. – P205Pyrah, I. – II

Reid, L. – XIVRender, J.A. – VIRenna, S. – P203Resendez, J.C. – P401Reynolds, V.L. – P404Ricci, M.S. – XIRichardson, M. – P208Riley, P. – P204Risvanis, J. – P109Rivera, M.I. – VIRoberts, D.J. – P214Rocha, B. – XVIRodriguez, R. – P212Rohr, A. – P100Rubinfeld, B. – P702Ruppert, G. – P110Ryan, P.R. – P302

Sadeghi, M. – P501Saiahkov, R. – P606Salata, J. – P202Salcedo, T.W. – P414Sambuco, C. – P406Sanders, M. – P113Sanderson, T.P. – P414Sareen, P. – P213

Sauer, J-M. – P307Savarino, S. – P305, P306Scheer, N. – VSchoenborn, T. – P100Scholzen, S. – P211Schuette, D. – P307Schwartz, M. – P114Sentz, J. – P206Sheehan, J. – P206Sheevers, H.V. – IIShelton, M. – IShi, J. – P213Shimizu, B. – P410Silverman, L. – P200Siple, J. – P107Skaggs, H. – P608Sly, J. – P213Smith, J. – P402Smith, P.F. – P605Sokolowska, M. – XVISolis, W.A. – P702Sower, G.J. – P603Spooner, N. – P107Springer, S. – P213Stankowski, Jr., L.F. – P213, P214Steve, D. – P202Stokes, A. – P107Stout, R. – P110Stump, D.G. – P407, P408, P409Sulaiman, F.A. – P105Szabol, K. – P213

Tam, A. – P400Tao, J. – P104Tarrant, J. – P801Tedesco, R. – P205Thakur, A. – P214Thompson, G.P. – P603Tice, R.R. – P606Tiwari, V.K. – P108Todd, M. – XIToonen, P.W. – P204Toot, J.D. – P407, P408, P409Topper, M. – XVIIITorti, V. – VITran, K. – P702

Trask, Jr., O.J. – VIIITravis, J. – P202Trickey, J. – P216Trudel, Y. – P303Turner, P.V. – XVII

Valerio, L.G. – XVVan Boxtel, R. – P204Van Heesch, S. – P204Van Steenhouse, J. – P100Vana, L.M. – P407Velasco, M. – P500Verma, R. – P108

Waites, R. – P113Walgren, J.L. – XVIWaller, D. – P210, P211Wallis, R. – XIIWang, B. – P302Warren, E. – P100Warrior, U. – P117Watson, R. – P209Weber, K. – IIIWebster, L. – P109

Wenzel, H. – P305West, K. – P801White, D. – P203White, P. – P101Whitley, E. – P607Whittaker, D. – P109Wilker, C. – XIVWoltmann, R. – P202Wong, H. – P801Wood, F. – P604Woolhiser, M. – P108Wright, M. – P606

Xu, Y. – P214

Yeager, R.L. – P115Young, A. – P701Young, G.D. – VIII

Zhong, F. – P702Zhou, Y-Y. – P202, P205Zingaro, G. – P202Zuwannin, L. – P307

THANK YOU TO OUR EXHIBITORS

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IIT Research Institute (IITRI)Chicago, IL www.iitri.org

ITR Laboratories Canada Inc.Baie d’Urfe, Canadawww.itrlab.com

Leadscope, Inc.Columbus, OH www.leadscope.com

Lovelace Respiratory Research InstituteAlbuquerque, NMwww.lrri.org

Marshall BioResourcesNorth Rose, NYwww.marshallbio.com

MetaSystemsWaltham, MA www.metasystems.org

Millar Instruments, Inc.Houston TXwww.millar.com

MPI ResearchMattawan, MI www.mpiresearch.com

Pacific BioLabsHercules, CA www.pacificbiolabs.com

PDS Preclinical Data Systems, Inc.

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Pharmaron Inc.Louisville, KY www.pharmaron.com

Pre-clinical Research Services, Inc.Fort Collins, COwww.preclinicalresearch.com

PreLabsOak Park, IL www.prelabs.com

Primate Products, Inc.Immokalee, FLwww.primateproducts.com

Product Safety LabsDayton, NJwww.productsafetylabs.com

QPSNewark, DEwww.qps.com

Ricerca BiosciencesConcord, OHwww.ricerca.com

SAGEThousand Oaks, CA www.sagepub.com

SAI Infusion Technologies (Strategic Applications, Inc.)Libertyville, IL www.sai-infusion.com

Seventh Wave Laboratories LLCChesterfield, MO www.7thwavelabs.com

Sinclair Bio ResourcesColumbia, MO www.sinclairbioresources. com

Sinclair Research CenterAuxvasse, MO www.sinclairreserch.com

SNBL USA, Ltd.Everett, WA www.snblusa.com

Southern Research Birmingham, AL www.southernresearch.org

SRI InternationalMenlo Park, CAwww.sri.com/biosciences STEMCELL Technologies Inc.Vancouver, Canadawww.stemcell.com

Transposagen BiopharmaceuticalsLexington, KYwww.transposagenbio.com

Vet Path Services, Inc.Mason, OH www.vetpathservicesinc.com

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WuXi AppTec, Inc.Shanghai, Chinawww.wuxiapptec.com

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AMERICAN COLLEGE OF TOXICOLOGY 2011 COUNCIL

President President-Elect Vice PresidentRussette Lyons David Serota Robin Guy

Treasurer Secretary Past-PresidentNorman Kim Tracey Spriggs Carol Auletta

Councilor – 2011 Councilor – 2011 Councilor - 2011Drew Badger Suzanne Wolford Grace Furman

Councilor - 2012 Councilor – 2012 Councilor – 2012Lorrene Buckley Angelique Braen James Freeman

Councilor – 2013 Councilor – 2013 Councilor - 2013David Compton Hanan Ghantous Deborah Novicki

Editor-in-ChiefMary Beth Genter

AMERICAN COLLEGE OF TOXICOLOGY – 2011

PRESIDENT PRESIDENT ELECT VICE PRESIDENTRussette M. Lyons, Ph.D. David G. Serota, Ph.D., DABT Robin C. Guy, DABT, MS, RQAP-GLPHead, Education Office Sr.VP, Drug Safety Development Toxicology and GLP ConsultantNovartis Institutes for Biomedical Research Sr. Principal Study Director Robin Guy Consulting, LLC250 Massachusetts Avenue MPI Research Preclinical Toxicology & GLP Training607/913F 54943 N. Main Street P. O. Box 830Cambridge, MA 02139 Mattawan, MI 49071 Lake Forest, IL 60045-0830T: 617-871-3112 T: 269-668-3336 F: 269-668-4151 T: 847-295-9250 F: 847-295-9251Email: [email protected] Email: Email: [email protected]

SECRETARY TREASURER PAST PRESIDENTTracey L. Spriggs, Ph.D., DABT Norman N. Kim, M.S., DABT Carol S. Auletta, MBA, DABTDirector, Toxicology, Worldwide R&D Director, Pharmacotoxicology Director, Program ManagementGlaxoSmithKline Biogen Idec, Inc. Huntingdon Life Sciences1500 Littleton Road 10 Cambridge Center P. O. Box 2360Parsippany, NJ 07054-3884 Cambridge, MA 02142 Mettlers RoadT: 973-889-2503 F: 973-889-2469 T: 617-679-4995 East Millstone, NJ 08875-2360Email: Email: [email protected] T: 732-873-2550 F: 732-873-3992

Email: [email protected]

COUNCILORS – 2011 (only)

Drew A. Badger, Ph.D. DABT Grace M. Furman, Ph.D., DABT Suzanne R. Wolford, Ph.D., DABTDirector - Regulatory Affairs President/CEO Study DirectorAmgen Inc. Paracelsus, Inc. Covance Inc.One Amgen Center Drive 128 Daphne Street 3301 Kinsman BlvdThousand Oaks, CA 91320 Leucadia, CA 92024 Madison, WI 53704T: 805-447-5875 T: 760-271-2858 T: 608-242-2721 F: 608-242-2736Email: [email protected] Email: [email protected] Email: [email protected]

COUNCILORS - 2010- 2012

Lorrene Alice Buckley, Ph.D., DABT Angélique Braen, Ph.D., DABT James J. Freeman, Ph.D., DABTResearch Fellow Toxicologist Distinguished Toxicology AssociateEli Lilly and Company Hoffmann-La Roche, Inc. ExxonMobil Biomedical Sciences, Inc.Lilly Corporate Center 340 Kingsland Street P. O. Box 971Delaware St - MD 1940 Nutley, NJ 07110 1545 Route 22 EastIndianapolis, IN 46285 T: 973- 235-3860 F: 973- 235-4710 Annandale, NJ 08801T: 317- 277-7324 F: 317- 433-0533 Email: [email protected] T: 908- 730-1123 F: 908- 730-1199Email: [email protected] Email: [email protected]

COUNCILORS - 2010- 2013

David R. Compton, PhD, DABT Hanan N. Ghantous, PhD, DABT Deborah L. Novicki, PhD, DABT Principal Res Investigator-Toxicology Pharma/Toxicologist Supervisor Global Head, Toxicology sanofi-aventis U.S. Inc. US FDA Novartis Vaccines 1041 Route 202-206 - MC: JR2-103A CDER/OAP/DAVP 350 Massachusetts Avenue P O Box 6800 10903 New Hampshire Avenue Cambridge, MA 02139 Bridgewater, NJ 08807-0800 Silver Spring, MD 20993 T: 617-871-8206 T: 908-541-5328 F: 908-231-2629 T: 301-796-0717 F: 301-796-9883 Email: Email: [email protected] Email: [email protected] [email protected]

EDITOR-IN-CHIEFMary Beth Genter, Ph.D., DABTAssociate ProfessorUniversity of Cincinnati3223 Eden Ave., ML 670056144 Kettering LabCincinnati, OH 45267-0056T: 513-558-6266 F: 513-558-4397Email: [email protected]

ACT COMMITTEES – 2011AWARDS COMMITTEE

Robin C. Guy, DABT, RQAP-GLP, MS, Chair

2009-2011 2010-2012 2011-2013

Timothy Jon Raczniak, PhD, DABT Tracey Zoetis, M.S. Leigh Ann Burns Naas, PhD, DABTDirector, Safety Assessment Managing Consultant Senior DirectorStiefel, a GSK Company SciLucent, LLC Pfizer Global R&DResearch & Preclinical Development 585 Grove Street Drug Safety Res & Development20 T. W. Alexander Drive Suite 300 10646 Science Center Dr.Research Triangle Park, NC 27709 Herndon VA 20170 San Diego, CA 92121T:919-624-7203 F: 919-990-6982 T: 703-435-0033 F: 703-435-0440 T: 858-526-4908 F:858-678-8290Email: [email protected] Email: [email protected] Email:

[email protected]

EDUCATION COMMITTEESuzanne Wolford, Ph.D., Chair, Lorrene A. Buckley, Ph.D., DABT & Hanan N. Ghantous, Ph.D., DABT, Co-Chairs

2010 -2011 2011 - 2012

Lisa D. Beilke, Ph.D. Anthony Ndifor, PhDResearch Scientist II DirectorGilead Sciences, Inc. J&J PRDDrug Safety Evaluation 3210 Merryfield Row333 Lakeside Drive, Bldg. 324 San Diego, CA 92121Foster City, CA 94404 T: 858-784-3260 F: 858-450-2026T: 650-522-6361 F: 650-522-5266 Email: [email protected] Email: [email protected]

Timothy Joseph McGovern, Ph.D. Melissa Rhodes, PhD, DABTConsultant Sr. Manager, Sfty Assess.Proj.DvlpmntScilucent LLC GlaxoSmithKline585 Grove Street, Suite 300 5 Moore DriveHerndon, VA 20170 Res Triangle Park, NC 27709T: 703-435-0033 F: 703-435-0440 T: 919-483-6908 F: 919-483-0131Email: [email protected] Email: [email protected]

FINANCE COMMITTEE

Norman N. Kim, DABT, MS, Chair

2009-2011 2010 – 2012 2011-2013

Steven M. Snyder, M.S. Merrill R. Osheroff, Ph.D.,DABT Ronald J. Christopher, PhD, DABTPresident President Assoc. Vice PresidentOutsourcing Support Services, Inc. Osheroff Consulting Services LLC Ambit Biosciences, Inc.6569 Braemar Avenue 8418 Parkstone Terrace Toxicology & Preclinical DvlpmntNoblesville, IN 46062 Mattawan. MI 49071 4215 Sorrento Valley Blvd.T: 317-408-0286 F: 317-770-7750 T: 269-375-6656 F:269- 375-6656 San Diego, CA 92121Email: [email protected] Email: [email protected] T: 858-334-2137


MEMBERSHIP COMMITTEEAngélique Braen, Ph.D., DABT, Chair, James J. Freeman, Ph.D., DABT & Deborah L. Novicki, Ph.D., DABT, Co-Chair

2009-2011 2010 – 2012 2011 - 2013Ted Alan Birkebak, Ph.D., DVM Sandra L. Morseth, Ph.D. Suzanne C. Fitzpatrick, PhD, DABTsanofi-aventis Owner Senior Science AdvisorDrug Safety Evaluation Morseth Consulting, LLC US FDA(JR2-103A) 4804 Old Middletown Rd office of the Chief Scientist1041 Route 202-206 Jefferson, MD 21755 Office of the CommissionerBridgewater, NJ 08870 T: 301-473-4730 10903 New Hampshire Ave WO32 T: 908-231-3408 F: 908-231-3408 Email: [email protected] Room 4202Email: [email protected] Silver Spring, MD 20993

T: 301-796-8527 F: 301-847-8617 Email:

[email protected]

NOMINATING COMMITTEECarol S. Auletta, MBA, DABT, Chair

2011 2011John E. Atkinson, PhD, DABT Mary Ellen Cosenza, PhD, DABT, RACDirector, Toxicology Executive Director, Emerging MarketsAgensys Inc. Amgen Inc.2225 Colorado Ave International Regulatory AffairsSanta Monica, CA 90404 1 Amgen Center DriveT: 310-820-8029 x222 Mail Stop 17-2-A Email: [email protected] Thousand Oaks, CA 91320-1789

T: 805-447-6318 F: 805-499-9228


OUTREACH COMMITTEECarol S. Auletta, MBA, DABT, Chair

2009 – 2011 2010-2012Alan H. Stokes, Ph.D., DABT Alan P. Brown, Ph.D., DABTSr. Scientific Investigator – Toxicology Senior ToxicologistGlaxoSmithKline NAMSARD9-2136 6750 Wales RoadFive Moore Drive Northwood OH 43619Res Triangle Pk, NC 27709-3398 T: 419-662-4408 F: 419-666-2954T: 919-315-2598 F: 919-483-6858 Email: [email protected]: [email protected]

PUBLICATIONS COMMITTEEMary Beth Genter, Ph.D., Chair

Shayne C. Gad, Ph.D., DABT, ATS David W. Hobson, Ph.D., DABTGad Consulting Services LoneStar PharmTox LLC

102 Woodtrail Lane 613 Pleasant Valley DriveCary, NC 275118 Boerne, TX 78006Thousand Oaks CA 91320-1789 T: 919-233-2926 F: 919-233-2927 T: 210-269-6169 F: 830-229-5782T: 805-447-6318 F: 805-499-9228 Email: [email protected] Email: [email protected]: [email protected]

Robert Snyder, Ph.D., ATS Norman N. Kim, DABT, MS Tracey Zoetis, MSAssociate Dean, Research Director, Pharmacotoxicology Managing ConsultantRutgers State Univ of NJ Biogen Idec, Inc. SciLucent, LLCErnest Mario School of Pharmacy 10 Cambridge Center 585 Grove Street, Suite 300160 Frelinghuysen Road, Rm. 104 Cambridge, MA 02142 Herndon, VA 20170Piscataway, NJ 08854-8020 T: 617-679-4995 T:703-435-0033 F: 703-435-0440T: 732-445-2675 x615 F: 732-445-5767 Email: [email protected] Email: [email protected]: [email protected]

Kenneth L. Hastings, DrPH, DABT, ATS Tracey L. Spriggs, Ph.D., DABTAssociate VP, Regulatory Policy Director, Toxicology, Worldwide R&Dsanofi-aventis GlaxoSmithKlineCorporate Reg Affairs Office 1500 Littleton Road4520 East West Highway, #210 Parsippany, NJ 07054-3884Bethesda, MD 20814 T: 973-889-2503 F: 973-889-2469T: 301-771-4267 F: 301-771-4287 Email: [email protected]: [email protected]

PROGRAM COMMITTEEDavid G. Serota, Ph.D., DABT, Chair

2009 - 2011Scott Coleman, Ph.D. Shana Azri-Meehan, Ph.D., DABTDirector Investigative/Mechanistic Tox Senior Principal ScientistCubist Pharmaceuticals, Inc. Forest Research65 Hayden Ave Harborside Financial Center – Plaza VLexington, MA 02421 Jersey City, NJ 07311T: 781-860-8643 T: 201-427-8451 F: 201-427-8100Email: [email protected] Email: [email protected]

Drew A. Badger, PhD, DABTSenior Director, Tox & Reg AffairsAmira Pharmaceuticals9535 Waples Street, Ste. 100San Diego, CA 92121T: 858-228-4688Email: [email protected]

Alan P. Brown, Ph.D., DABTSenior Toxicology ConsultantIntegrated Nonclinical Development Solutions Inc3005 Miller AvenueAnn Arbor, MI 48103T: 734- 929-5392 F: 734- 929-5393Email: [email protected]

Anne Harman Chappelle, PhD, DABTChappelle Toxicology Services3850 Rotherfield LaneChadds Ford, PA 19317T: 484- 844-7662 F: 610- 358-0542Email: [email protected]

Robin C. Guy, MS, DABT, RQAP-GLPToxicology and GLP ConsultantRobin Guy Consulting, LLCToxicology and GLP TrainingP. O. Box 830Preclinical Toxicology & GLP TrainingLake Forest, IL 60045-0830T: 847- 295-9250 F: 847- 295-9251Email: [email protected]

Steven Hachtman, MADirector of Education

Data Sciences International119 14th Street NWSaint Paul, MN 55112T: 651) 481-7400 F: 651) 481-7417Email: [email protected]

Jerry F. Hardisty, DVMCEOEPL, Inc.P. O. Box 12766Res Triangle Pk, NC 27709T: 919-998-9407 (ext 600)Email: [email protected]

Nancy Holmes, PhD, DABTSr. Program ManagerBattelleHealth & Life Sciences Global Business505 King AvenueColumbus, OH 43235T: 614- 424-3776 F: 614- 458-3776Email: [email protected]

Steven C. Kunder, PhD, DABTUS FDACBER1401 Rockville PikeRockville, MD 20852T: 301-827-6000Email: [email protected]

Kate E Lane, PhD, DABTDirector, ToxicologySunovion Pharmaceuticals Inc.84 Waterford DriveMarlborough, MA 01752T: 508-357 7541 F: 508-357 7493Email: [email protected]

Russette M. Lyons, PhDHead, Education OfficeNovartis Institutes for BioMedical Res.250 Massachusetts Avenue607/931FCambridge, MA 02139T: 617-871-3112Email: [email protected]

Lynnda Reid, PhDPharmacology/Toxicology SupervisorUS FDACDER- White Oak Bldg. 2210903 New Hampshire Ave.Silver Spring, MD 20993T: 301-796-0984 F: 301-796-9897Email: [email protected]

Melissa Rhodes, PhD, DABTSr. Manager, Sfty Assess.Proj.DvlpmntGlaxoSmithKline5 Moore DriveRes Triangle Pk, NC 27709T: 919-483-6908 F: 919-483-0131Email: [email protected]

Hilary V. Sheevers, PhDPresident, CEOAclairo PDG., Inc.1950 Old Gallows Road,Suite 300Vienna, VA 22182T: 703-506-6760 (x307) F: 703-506-0142Email: [email protected]

Tracey Zoetis, MSManaging ConsultantSciLucent, LLC585 Grove StreetSuite 300Herndon, VA 20170T: 703-435-0033 F: 703-435-0440Email: [email protected]

ACT PAST PRESIDENTS

1979-1980 M. Selikoff (Deceased)

1980-1981 Myron Mehlman, Ph.D.

1981-1982 Yula Bingham, Ph.D.

1982-1983 Arthur Furst, Ph.D., Sc.D. (Deceased)

1983-1984 Gary Flamm, Ph.D.

1984-1985 Ronald W. Hart, Ph.D.

1985-1986 Marshall Steinberg, Ph.D. (Deceased)

1986-1987 Gordon W. Newell, Ph.D.

1987-1988 Robert M. Diener, D.V.M.

1988-1989 Richard M. Hoar, Ph.D.

1989-1990 Carol M. Henry, Ph.D., DABT

1990-1991 Shayne C. Gad, Ph.D., DABT

1991-1992 Mildred S. Christian, Ph.D., ATS (Deceased)

1992-1993 Karen M. MacKenzie, Ph.D., DABT

1993-1994 Richard D. Thomas, Ph.D., DABT

1994-1995 Sharon J. Northup, Ph.D.

1995-1996 Sidney Green, Ph.D.

1996-1997 John A. Thomas, Ph.D.

1997-1998 Christopher P. Chengelis, Ph.D.

1998-1999 David W. Hobson, Ph.D., DABT

1999-2000 Merrill R. Osheroff, Ph.D., DABT

2000-2001 Suzanne C. Fitzpatrick, Ph.D., DABT

2001-2002 Robert E. Osterberg, Ph.D.

2002-2003 John E. Atkinson, Ph.D., DABT

2003-2004 Robert Snyder, Ph.D., ATS

2004-2005 Patricia Frank, Ph.D.

2005-2006 Leigh Ann Burns Naas, Ph.D., DABT

2006-2007 Stephen B. Harris, Ph.D., FATS

2007-2008 A.Wallace Hayes, Ph.D., DABT, FATS

2008-2009 Kenneth L. Hastings, Dr.P.H.

2009-2010 Carol S. Auletta, MBA, DABT

This activity is supported by educational donations provided by

32ND ANNUAL MEETING SPONSORS – 2011

Aclairo Pharma Dvlpmnt Grp IncVienna, VAwww.aclairo.com

Altria Client Services, Inc.Richmond, VAwww. altria.com

American Petroleum InstituteWashington, DCwww.api.org

Asphalt InstituteLexington, KYwww.asphaltinstitute . org

BASiWest Lafayette, INwww.bastox.com

BattelleColumbus, OHwww.battelle.org/hhs/toxicology

BioReliance CorporationRockville, MDwww.bioreliance.com

Boehringer Ingelheim Ridgefield, CTwww.boehringer-ingelheim.com

Bristol-Myers Squibb CompanyPrinceton, NJwww.bms.com

Calvert LaboratoriesOlyphant, PAwww.calvertlabs.com

Charles RiverWilmington, MAwww.criver.com

Cubist Pharmaceuticals Inc.Lexington, MAwww.cubist.com

Data Sciences InternationalSt. Paul, MNwww.datasci . com

Eisai Inc.Andover, MAwww.eisai . com

Eli LillyIndianapolis, INwww.lilly.com

EPL, Inc.Sterling, VAwww.epl-inc.com

ExxonMobil Biomedical Sciences, Inc.Annandale, NJwww.exxonmobil.com

ExperimurChicago, ILwww.experimur.com

Flagship BiosciencesFlagstaff, AZwww.flagshipbio . com

Forest Research Institute, Inc.Jersey City, NJwww.frx.com

GlaxoSmithKlineResearch Triangle Park, NCwww.gsk.com

Harlan Laboratories, Inc.Indianapolis, INwww.harlan.com

Huntingdon Life SciencesEast Millstone, NJwww.huntingdon.com

ISIS Pharmaceuticals, Inc.Carlsbad, CA

http://www.huntingdon.com/

http://www.harlan.com/

http://www.gsk.com/

http://www.frx.com/

http://www.flagshipbio.com/

http://www.experimur.com/

http://www.exxonmobil.com/

http://www.epl-inc.com/

http://www.lilly.com/

http://www.eisai.com/

http://www.datasci.com/

http://www.cubist.com/

http://www.criver.com/

http://www.calvertlabs.com/

http://www.bms.com/

http://www.boehringer-ingelheim.com/

http://www.bioreliance.com/

http://www.battelle.org/hhs/toxicology

http://www.bastox.com/

http://www.asphaltinstitute.org/

http://www.api.org/

http://www.altria.com/

http://www.aclairo.com/

www.isispharm.com

MPI ResearchMattawan, MIwww.mpiresearch.com

PepsiCo Inc.Valhalla, NYwww.pepsico.com

Pfizer Inc.Groton, CTwww.pfizer.com

Ricerca BiosciencesConcord, OHwww.ricerca.com

SageThousand Oaks, CAwww.sagepub.com

sanofi-aventis USBridgewater, NJwww.sanofi-aventis.com

SciLucent, LLCHerndon, VAwww.scilucent.com

Southern Research InstituteBirmingham, ALwww.southernresearch.org

WIL Research CompanyAshland, OHwww.wilresearch.com

http://www.wilresearch.com/

http://www.southernresearch.org/

http://www.scilucent.com/

http://www.sanofi-aventis.com/

http://www.sagepub.com/

http://www.ricerca.com/

http://www.pfizer.com/

http://www.pepsico.com/

http://www.mpiresearch.com/

http://www.isispharm.com/

32nd ANNUAL MEETING CONSULTANT SPONSORSHIP

William J. Brock, Ph.D., DABT, ATSBrock Scientific Consulting, LLC

[email protected]

John A. Budny, Ph.D.PharmaCal, Ltd.

[email protected]

Nancy J. Chew, MS, RACRegulatory Affairs, North America, Inc.

[email protected]

Chris R. Coggins, Ph.D.Carson Watts Consulting, LLC

[email protected]

Shayne C. Gad, Ph.D., DABTGad Consulting Services

Elliot B. Gordon, Ph.D., DABT, MSElliot Gordon Consulting, LLC

[email protected]

Robin C. Guy, M.S., DABTRobin Guy Consulting, [email protected]

William C. Hall, VMD, Ph.D., DACVPHall Consulting, Inc.

Stephen B. Harris, Ph.D.Stephen B. Harris Group

Alan C. Katz, M.S., DABTtoXcel LLC

Dennis J. Naas, B.S., PMP®ProDev Consulting Services, Ltd

[email protected]

Sharon Northup, Ph.D.Northup RTS

[email protected]

Vincent J. Piccirillo, Ph.D., DABTVJP Consulting [email protected]

Steven M. Snyder, M.S.Outsourcing Support Services, Inc.

Robert J. Staab, Ph.D.Regulatory & Technical Associates Inc.

[email protected]

Robert L. Susick, Ph.D., DABTSusick Consulting, LLC

[email protected]

ACT CORPORATE MEMBERSHIP - 2011

Abbott Laboratories, Abbott Park, ILAllergan, Irvine, CA

Altria Client Services, Inc., Richmond, VAAmgen Inc., Thousand Oaks, CA

BASi, West Lafayette, INBattelle, Columbus, OH

Baxter Healthcare Corporation, Round Lake, ILBayer Healthcare Pharmaceuticals, Pine Brook, NJ

Biogen Idec MA, Inc., Cambridge, MABioReliance, Rockville, MD

Boehringer Ingelheim, Ridgefield, CTBristol-Myers Squibb, PRI, Princeton, NJ

Cantox Health Sciences International, Mississauga, CanadaCharles River, Wilmington, MA

Covance Laboratories Inc., Madison, WIData Sciences International, Saint Paul, MN

Eli Lilly and Company, Indianapolis, INEPL, Inc., Sterling, VA

Experimur, Chicago, ILExxonMobil Biomedical Sciences, Inc., Annandale, NJ

Forest Research Institute, Inc., Jersey City, NJGenentech, Inc., South San Francisco, CA

GlaxoSmithKline, Research Triangle Park, NC

Hoffmann-La Roche, Inc., Nutley, NJHuntingdon Life Sciences, PRC, East Millstone, NJ

J&J Pharma Co (Centocor/J&J PRD/Tibotec), Radnor, PAMPI Research, Mattawan, MI

Novartis Pharmaceutical Corporation, East Hanover, NJPfizer Inc., Groton, CT

Purdue Pharma, LP, Cranbury, NJR. J. Reynolds Tobacco Co., Winston-Salem, NC

sanofi-aventis US, Bridgewater, NJSequani Limited, Ledbury, United Kingdom

Takeda Global R&D, Lake Forest, ILWIL Research Company, Ashland, OH

UPCOMING MEETINGS

ACT 33rd ANNUAL MEETING

NOVEMBER 4 – 7, 2012

OMNI ORLANDO

CHAMPIONSGATE (Orlando), FL

**************************************

ACT 34th ANNUAL MEETING

NOVEMBER 3 – 6, 2013

JW MARRIOTT HILL COUNTRY

SAN ANTONIO, TX

**************************************

ACT 35th ANNUAL MEETING

November 9 - 12, 2014

HYATT GRAND CYPRESS

ORLANDO, FL

**************************************

American College of Toxicology 31st Annual Meeting · Web viewAmerican College of Toxicology 32nd...

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