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2013 Continuing Education Courses

SR01 A Refresher of Immunoglobulin and Fc-Receptor Biology and Advances Related to Therapeutic Antibody Development Basic
AM02 Basic Principles of Human Risk Assessment Basic
AM03 Recent Developments in Cardiovascular Physiology-Based Toxicology Basic
AM04 Approval of Biosimilar Monoclonal Antibodies: Scientific, Regulatory, and Legal Challenges Basic
AM05 The What, When, and How of Nonclinical Support for an IND Submission Basic
AM06 The Practice and Implementation of Neural Stem Cell-Based Approaches to Neurotoxicology, Jointly Sponsored by: UAMS College of Medicine and SOT Basic/CME
AM07 Toxic Effects of Metals Basic
PM08 Advances in Nanotoxicology—Challenges Advanced
PM09 Gonadal Development, Function, and Toxicology Basic
PM10 The REACH Regulation and Safety Assessment Approaches for Chemicals That Come in Contact with the Skin Basic
PM11 T4: Tools and Technologies in Translational Toxicology Advanced
PM12 Understanding Toxic Neuropathy in Drug Development: Both Clinical and Nonclinical Perspectives Advanced
PM13 Weighing in on Nutrition—Essential Concepts for Toxicologists Basic

A Refresher of Immunoglobulin and Fc-Receptor Biology and Advances Related to Therapeutic Antibody Development

SR01—CE Basic

Theme: Biomarkers for Exposure Assessment, Safety Evaluation, and Translational Medicine

Chairperson(s): Theodora W. Salcedo, Bristol-Myers Squibb Company, New Brunswick, NJ.

Sponsor: Biotechnology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section
Toxicologic and Exploratory Pathology Specialty Section

The presentation will review the immunobiology of antibodies and Fc receptors and explore the field of therapeutic antibody development and advances in “antibody engineering” leading to the development of improved therapeutics. A basic overview will be provided on the structure and function of antibodies, as well as the various types and formats of antibody therapeutics and technological methods of production. In addition, the immunobiology of human leukocyte Fc receptors will be discussed. These receptors serve to link humoral immune responses to cellular activities within the immune system, and generally function as either antibody-binding receptors that trigger immune cell effector functions, or as transport receptors (FcRn). Highlights will include how immunoglobulin Fc sequences are now being tailored to trigger specific Fc receptors to improve therapeutic outcomes by introducing amino acid mutations, glycoengineering, or other approaches leading to next generation formats. Known species differences in immunoglobulins and Fc receptors that may be important for pharmacologic and toxicologic evaluations will be explored, as well as other challenges in assessing the nonclinical toxicities of new antibody formats. Building upon these basic themes, the presentation will explore the current landscape of approved therapeutics and forecasts for future developments in the field. The course will provide something for those seeking basic knowledge in the field of immunology and therapeutic antibody development, as well as those seeking to refresh and enhance their knowledge of recent advances.

A Refresher of Immunoglobulin and Fc-Receptor Biology and Advances Related to Therapeutic Antibody Development. Theodora W. Salcedo, Bristol-Myers Squibb Company, New Brunswick, NJ.

Basic Principles of Human Risk Assessment

AM02—CE Basic

Theme: Regulatory Science: Advancing New Approaches for Hazard Identification and Risk Assessment

Chairperson(s): Qiyu (Jay) Zhao, US EPA, Cincinnati, OH, and M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Sponsor: Risk Assessment Specialty Section

An overview of the fundamental guiding principles and general methods used in chemical risk assessment will be provided. These principles and methods are addressed in presentations and discussions organized by the four components identified by the National Research Council in the Risk Assessment Paradigm: Hazard Identification and Characterization; Dose- Response Assessment; Exposure Assessment; and Risk Characterization. Guiding principles and key concepts in risk assessment will be illustrated by examples from the literature and sample calculations for dose-response assessment, exposure assessment, and risk characterization will presented.

Introduction to Chemical Risk Assessment. Qiyu (Jay) Zhao, US EPA, Cincinnati, OH.

Hazard Identification and Characterization. Jeffrey Lewis, ExxonMobil Biomedical Sciences, Inc., Annandale, NJ.

Dose-Response Assessment. John C. Lipscomb, US EPA, Cincinnati, OH.

Exposure Assessment. Robinan Gentry, ENVIRON International Corporation, Monroe, LA.

Risk Characterization. M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Recent Developments in Cardiovascular Physiology-Based Toxicology

AM03—CE Basic

Chairperson(s): Travis L. Knuckles, West Virginia University, Morgantown, WV, and W. David McGuinn, US FDA-CDER, Columbia, MD.

Sponsor: Cardiovascular Toxicology Specialty Section

Endorsed by:
Comparative and Veterinary Specialty Section
Mechanisms Specialty Section
Toxicologic and Exploratory Pathology Specialty Section

Contemporary drug development and toxicity assessments are focused on exploiting specific molecular targets that can improve disease outcomes with minimal untoward effects. Unfortunately, modern training in toxicology and pharmacology is directed primarily at specific ligand-receptor interactions at the expense of systems physiology. An overview of cardiovascular physiology, with a thematic focus on toxicology, will be provided. The presentations will include: overall physiological changes that manifest at the whole-animal level following toxicant exposure; in vivo, in vitro, and ex vivo cardiac testing protocols in the regulatory environment, and how current testing strategies may potentially miss cardiac effects that manifest chronically; vascular and microvascular effects that result from toxicity initiated in other tissues; and microvascular physiology and toxicology in the context of model development, application, and underlying pathology. The course will be of interest to a broad scope of scientists that are increasingly being requested to consider the impact of novel compounds and toxicants on the physiology of the entire cardiovascular system.

Introduction to Cardiovascular Physiology. Travis L. Knuckles, West Virginia University, Morgantown, WV.

Role of Physiological Responses in Toxicant-Induced Cardiovascular Injury. Medhi Hazari, US EPA, Research Triangle Park, NC.

The Mechanisms and Manifestations of Cardiac Toxicity Associated with Chronic Drug Administration, with Examples from Experience with Oncology Drugs. W. David McGuinn, US FDA-CDER, Columbia, MD.

Principles of Microvascular Assessments in Toxicology. Timothy Nurkiewicz, West Virginia University, Morgantown, WV.

Microvascular Perfusion: Where Do the Red Cells Go Following Toxicant or Oxidative Damage? Mary (Molly) D. Frame, Stony Brook University, Stony Brook, NY.

Cardiovascular Responses to Particulate Matter and Nanoparticles. Vincent Castranova, CDC-NIOSH, Morgantown, WV.

Approval of Biosimilar Monoclonal Antibodies: Scientific, Regulatory, and Legal Challenges

AM04—CE Basic

Theme: Regulatory Science: Advancing New Approaches for Hazard Identification and Risk Assessment

Chairperson(s): Lynne LeSauteur, Charles River Laboratories, Senneville, QC, Canada, and Jonathan D. Urban, ToxStrategies, Inc., Austin, TX.

Sponsor: Immunotoxicology Specialty Section

Endorsed by:
Biotechnology Specialty Section

Technological advances have resulted in the development of a wide range of innovative monoclonal antibodies (mAb). As the patents for these monoclonal antibodies expire, there has been a growing interest in the market of “generic” follow-on products, or biosimilars. These biosimilar drugs, however, are not generic in the same sense as small molecule drugs since they do not have identical active component(s) as the innovative drug product due to the differences in production. While established standard analytical methodologies enable manufacturers of generic small molecule drugs to demonstrate pharmaceutical equivalence, the complex and sensitive nature of even the most similar biological manufacturing systems (e.g., commercial cell lines) makes producing identical copies of the innovative monoclonal antibody products impossible. Therefore, the scientific and regulatory paradigm for demonstrating that the products are highly similar and that there are no clinically meaningful differences between a biosimilar product and an innovative therapeutic in order to obtain drug approval is necessarily much more complex. Adding to this complexity is the regulatory environment that impacts on the biosimilar approval process. Case studies will compare and contrast the scientific and regulatory approaches used for mAb biosimilar drug development. These examples will cover the GMP to clinical strategies in broad scope but focus on the preclinical breadth of studies conducted based on the extent of GMP and clinical similarity data available. Within these presentations the scientific rational for similarity with the innovator drug will be highlighted. The basic concepts of the legal challenges and recent Biologics Price Competition and Innovation Act (BPCIA), which creates an abbreviated approval framework for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with a US FDA-licensed biological product, along with the role the patent and data exclusivity provisions will play in biosimilar drug development, will also be discussed.

Regulatory Standards for the Approval of Biosimilar Products: A Global Review. Barbara Mounho-Zamora, ToxStrategies, Inc., Bend, OR.

Preclinical Strategies to Support Clinical Development of Biosimilar Monoclonal Antibodies. Christine Grimaldi, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT.

Toxicology Evaluation of Biosimilars: A Case Study. Danuta J. Herzyk, Merck & Co., Inc., West Point, PA.

Nonclinical Development of Biosimilars: Adjusting the Strategy to Fit the Program. Michael W. Leach, Pfizer, Inc., Andover, MA.

The Intersection of Current Patent and Data Exclusivity Provisions and the Biologics Price Competition and Innovation Act (BPCIA) on the Biosimilar Drug Development Process. Kimberly Greco, Amgen, Washington, DC.

Regulatory Considerations for Biosimilar Monoclonal Antibodies. Marjorie Shapiro, US FDA, Washington, DC.

The What, When, and How of Nonclinical Support for an IND Submission

AM05—CE Basic

Theme: Regulatory Science: Advancing New Approaches for Hazard Identification and Risk Assessment

Chairperson(s): Paul Nugent, Pfizer Worldwide Research and Development, Groton, CT, and Dorothy Colagiovanni, N30 Pharmaceuticals, LLC, Boulder, CO.

Sponsor: Regulatory and Safety Evaluation Specialty Section

Endorsed by:
Cardiovascular Toxicology Specialty Section
Drug Discovery Specialty Section
Toxicologic and Exploratory Pathology Specialty Section

The initiation of dosing of human subjects in a Phase 1 clinical trial represents the culmination of years of drug development, and immediately preceding the start of dosing, months of work to prepare and submit the Investigational New Drug (IND) application (or Clinical Trial Application (CTA)). A critical part of the submission dossier is the sections that describe the nonclinical data and interpretation that underwrite the clinical plan; specifically, the results of studies in pharmacology, pharmacokinetics, and toxicology, and their integration into a coherent argument that justifies the clinical starting dose, escalation of dose, and “stopping criteria” to be used in the clinical trial. The objective of the course is to elucidate the path to a successful IND/CTA submission by outlining what needs to be done (concentrating principally on the toxicology and safety pharmacology studies), the timeline and order of activities, and the presentation of the data and its integration into a coherent risk assessment to support introduction of the investigational compound into the clinic. The focus will be the content of the Nonclinical Overview (NCO), which represents an integrated detailed summary of the nonclinical studies conducted to support the clinical plan for first-in-human (FIH) dosing. The course will address the expectations of the two main “customers” for the NCO: the US FDA pharmacology/toxicology reviewer evaluating the data to determine if it supports the safety considerations of the clinical plan, and the clinician designing the clinical protocol and conducting the FIH trial.

Introduction. Paul Nugent, Pfizer Worldwide Research and Development, Groton, CT.

Overview of the Nonclinical Toxicology Support for Clinical Trials. Paul Nugent, Pfizer Worldwide Research and Development, Groton, CT.

The IND Review Process from the Perspective of the Nonclinical Reviewer. Ronald Wange, US FDA, Silver Spring, MD.

Toxicology Studies in Drug Development and Their Contribution to the NCO. Dorothy Colagiovanni, N30 Pharmaceuticals, LLC, Boulder, CO.

The Content of the Nonclinical Overview (NCO). J. Neil Duncan, Pfizer Worldwide Research and Development, Groton, CT.

Clinical Perspective on the NCO. Drew Rasco, South Texas Accelerated Research Therapeutics (START), San Antonio, TX.

The Practice and Implementation of Neural Stem Cell-Based Approaches to Neurotoxicology

AM06—CE Basic/CME

CME AM06 Course Flyer

Jointly Sponsored by: University of Arkansas for Medical Sciences College of Medicine and SOT

CME Task Force: John G. Benitez, MD, MPH (Chair), Dori R. Germolec, PhD (Council Contact), Martin A. Philbert, PhD, Kenneth S. Ramos, MD, PhD, Dr. Richard Y. Wang, MD

Chairperson(s): Timothy J. Shafer, US EPA, Research Triangle Park, NC, and Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.

Sponsor: Neurotoxicology Specialty Section

Endorsed by:
Mechanisms Specialty Section
Metals Specialty Section
Reproductive and Developmental Toxicology Specialty Section
Stem Cells Specialty Section

The availability and use of human pluripotent stem cells (hPSC) and human neural stem cells (hNSC) for toxicology has dramatically increased in the past decade. hNSC are powerful tools for toxicologists and can provide tissue that would otherwise be unobtainable. This includes a renewable source of neural tissue from the same genetic stock that is not transformed or derived from a tumor, a source of normal human nervous system tissue, and sources of nervous system tissue from patients with clinical disease. However, culture and differentiation of hNSC are unique from culture of primary or transformed neural tissue. The course will bring together experts in the culture of various types of neural stem cells, including embryonic human derived neural stem cells, neurospheres, and neural cells derived from hPSC. Each expert will discuss the basic approaches to culturing different types of hNSC, including propagation of the cells in a progenitor status, as well as protocols for differentiation of the cells into different types of neurons. Pitfalls that are both common to the different models as well as unique ones will be described. The goal of the course is to provide the student with knowledge regarding different types of neural stem cell cultures, the techniques to successfully culture and differentiate these models, and application of these model systems to neurotoxicology. The course will conclude with an examination of appropriate outcome measures and discuss the possibility of personalized neurotoxicological assessment.

Accreditation and AMA Designation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The University of Arkansas for Medical Sciences (UAMS) College of Medicine and the Society of Toxicology (SOT). The UAMS College of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The UAMS College of Medicine designates this live activity for a maximum of 3.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Target Audience

Medical Doctors, health professionals and researchers with an interest in stem cell research and neural stem cell based approaches to neurotoxicology, neurology and regenerative medicine.

Statement of Need, Overall Purpose, and Learner Objectives

The novel technology of applying human stem cell models to research in environmental health and medicine means that the challenges and possibilities of this research was not covered in didactic training of most practitioners; this course will provide

  • an overview of the field;
  • applications of the technology to human disease;
  • an understanding of the pros and cons of this research to enhance the ability of physicians to respond to questions regarding this topic from patients.

Basic background information on the use of appropriate controls and methodologies will be provided to facilitate and improve understanding of the reasonable or practical applications of this technology in answering questions about human disease.

At the conclusion of this activity, participants will acquire an understanding of the application of neural stem cell based approaches to neurotoxicology.

Specifically, participants will be able to

  • understand the use of neurospheres as 3D cultures for developmental neurotoxicity testing;
  • identify neurotoxicity tests and mechanistic-based toxicology approaches using human neural stem cells.

This will ultimately help physicians explain stem cell research and treatments based on stem cell research to their patients.

Disclosure Statement

It is the policy of the University of Arkansas for Medical Sciences (UAMS) College of Medicine to ensure balance, independence, objectivity, and scientific rigor in all sponsored or jointly sponsored educational activities. All individuals who are in a position to control the content of the educational activity (course/activity directors, planning committee members, staff, teachers, or authors of CME) must disclose all relevant financial relationships they have with any commercial interest(s) as well as the nature of the relationship. Financial relationships of the individual’s spouse or partner must also be disclosed, if the nature of the relationship could influence the objectivity of the individual in a position to control the content of the CME. The ACCME describes relevant financial relationships as those in any amount occurring within the past 12 months that create a conflict of interest. Individuals who refuse to disclose will be disqualified from participation in the development, management, presentation, or evaluation of the CME activity.

Special Needs: We are committed to making this CME activity accessible to all individuals. If you need auxiliary aid(s) or service(s) as identified in the Americans with Disabilities Act, or have a dietary restriction, please describe your needs on the registration form. Most requests can be accommodated if notification is received by March 1, 2013.

8:15 AM–8:30 AM Introduction. Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.
8:30 AM–9:15 AM Cultural and Neural Differentiation of Human ESC-Derived Neural Cells. Steven L. Stice, University of Georgia and ArunA Biomedical, Inc., Athens, GA.
9:15 AM–10:00 AM Neurospheres As 3D Cultures for Developmental Neurotoxicity Testing. Ellen Fritsche, Leibniz Research Institute of Environmental Medicine, Düsseldorf, Germany.
10:00 AM–10:30 AM Break
10:30 AM–11:15 AM Culture and Differentiation of hPSC-Derived Neurons and the Promise of Personalized Toxicology. Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.
11:15 AM–12:00 Noon Neurotoxicity Test Development and Mechanistic-Based Toxicology Using hNSC. Timothy J. Shafer, US EPA, Research Triangle Park, NC.

Toxic Effects of Metals

AM07—CE Basic

Theme: Regulatory Science: Advancing New Approaches for Hazard Identification and Risk Assessment

Chairperson(s): Michael P. Waalkes, NIEHS, Research Triangle Park, NC, and Michael F. Hughes, US EPA, Research Triangle Park, NC.

Sponsor: Metals Specialty Section

Endorsed by:
Risk Assessment Specialty Section
Mechanisms Specialty Section
Neurotoxicology Specialty Section
Stem Cells Specialty Section

Human exposures to metals are a daily occurrence because of their natural presence in the environment—their uses in production of many commercial products—are byproducts of energy production and are found in many hazardous waste sites. The objective of the course is to highlight the fundamentals of metals toxicology. Metals have unique chemical and physical properties that distinguish them from organic-based chemicals. Even though some metals are essential to life, overexposure to these and other metals may result in a toxic effect in one or more organ systems. Upon exposure, metals may be absorbed, distributed throughout the systemic circulation, metabolized, and eliminated. The response of an organism following exposure to metals may be protective (e.g., induction of the metal-binding protein metallothionein), or toxicological by several mechanisms including oxidative stress. Key organ systems such as the central nervous system, the vascular system, as well as the skeleton system are affected by metals including manganese, lead, aluminum, and others. Accumulation of metals in bone has recently gained renewed interest as an eventual source of internal exposure. Noninvasive methods such as neutron activation are now being used to quantitate bone metal levels. Metals can influence gene expression, signal transduction, and epigenetics. Various toxic and carcinogenic metals such as arsenic and chromium alter the epigenetic program in cells; these effects on DNA methylation, histone tail modifications, and microRNA may be involved in metal-induced toxicity. Metals are known to cause cancer by several proposed mechanisms, including oxidative stress and the cancer stem cell hypothesis. Recent evidence suggests that developmental exposure to metals may affect stem cell population dynamics, which could result in adult onset of cancer. Overall, this is intended to be a basic course on metals toxicology, and is ideal to those who desire knowledge on the health effects of metals and useful tools used in metals toxicology research.

Introduction. Michael P. Waalkes, NIEHS, Research Triangle Park, NC.

Essentials of Metals Toxicology. Michael F. Hughes, US EPA, Research Triangle Park, NC.

Metal-Induced Organ Systems Toxicities. Wei Zheng, Purdue University, West Lafayette, IN.

Mode of Metals Toxicities: Example of Epigenetics. Max Costa, New York University School of Medicine, Tuxedo Park, NY.

Metals in Carcinogenesis and Developmental Origins of Adult Disorders. Erik J. Tokar, NIEHS, Research Triangle Park, NC.

Advances in Nanotoxicology—Challenges

PM08—CE Advanced

Theme: Effects of Nanomaterials on Biological Systems

Chairperson(s): Saber M. Hussain, US Air Force, Wright-Patterson AFB, Dayton, OH, and Syed F. Ali, US FDA-NCTR, Jefferson, AR.

Sponsor: Nanotoxicology Specialty Section

Recent developments in nanotechnology have generated a degree of apprehension concerning the potential risk to human health and the environment from manufactured nanomaterials (NM). The unique chemical and physical properties of NM, coupled with their high surface area per unit mass, require an extensive suite of characterization tools to effectively assess the toxicity of NM. Not only must the size and surface area of the NM be characterized prior to cellular exposure, but also a number of other specific features must be additionally evaluated, such as the size distribution, chemical composition, crystallinity, surface structure, shape, and solubility. The ionic strength of biological fluids may produce NM instability, resulting in environmental-specific aggregation tendencies that may impact toxicological results. Since aggregation of NM can modify uptake rates, transport properties, and clearance by the cell model or organ system, it is critical to interpret the data from NM toxicity experiments with a detailed knowledge of the physicochemical properties of the NM at all experimental time points. Due to the lack of standardized methods to determine the physicochemical behavior of NM in biological systems, the mechanisms and nature of acute or chronic toxicity of engineered NM cannot be fully understood at this time. An understanding of a proper manner by which NM should be introduced to a biological environment has yet to be established, and consistency between cellular assay techniques has not been verified—both situations presenting clear challenges that must be addressed. This course raises issues to consider for the toxicity assessment of NM, and addresses recent advances and technical obstructions associated with conducting or interpreting in vitro or in vivo toxicity studies. The goal is to provide a comprehensive understanding of NM characterization, as well as facilitate valuable discussions of key challenges and advancements in the newly emerging field of nanotoxicology.

Characterizing Techniques for Conducting Nanotoxicity: Complexity and Challenges. Saber M. Hussain, US Air Force, Wright-Patterson AFB, Dayton, OH.

Robust Characterization of Nanomaterials Is Necessary before Toxicity Studies/Assessment Can Be Undertaken. David B. Warheit, DuPont Haskell Laboratories, Newark, DE.

Surface Modification and Characterization of Nanomaterials for Toxicity Studies: Material Science Aspects. Kimberly Hamad-Schifferli, Massachusetts Institute of Technology, Cambridge, MA.

Aggregation Behavior of Nanomaterials under Biological Exposure Conditions. Navid Saleh, University of South Carolina, Columbia, SC.

In Vitro and In Vivo Toxicology Using Silicon-Based NP As an Example. Dominique Lison, Catholic University of Louvain, Brussels, Belgium.

Gonadal Development, Function, and Toxicology

PM09—CE Basic

Chairperson(s): Barry S. McIntyre, NIEHS, Research Triangle Park, NC, and Jodi A. Flaws, University of Illinois Urbana-Champaign, Urbana, IL.

Sponsor: Reproductive and Developmental Toxicology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

The course objectives are to provide the basic tools for toxicologists who desire a better understanding of how to assess the effects of toxicants on the male and female gonads from development through adulthood. A focus on reproductive biology, study design considerations, reproductive endpoints, data interpretation, and use of data in risk assessment will be highlighted. Reproductive toxicity studies are among the most complex and challenging studies in the field of toxicology. The studies assess multiple interrelated endpoints of male and female reproductive development and function. To properly design, conduct, and interpret these studies, a fundamental knowledge of male and female gonadal development, anatomy, physiology, and endocrinology are required. Individual lectures will discuss the anatomy and physiology of the male and female gonads, as well as endocrine regulation of these systems. Evaluation of toxicity endpoints to assess male and female reproductive function will also be discussed, including folliculogenesis, spermatogenesis, hormone analysis, cyclicity, fertility, histopathology, and proper use of statistical analysis. The regulatory expectations related to reproductive toxicity testing, interpretation of results, and how these results are ultimately used to assess potential risks to human reproduction, will be presented. The course will conclude with methodologies for in vitro reproductive toxicity assessments for screening and investigation of mode of action. In summary, key information required for the design of reproductive toxicity studies and interpretation of reproductive toxicity data, and provide guidance for use of the data for risk assessment of reproduction, will be presented.

Male Reproductive System: Development and Function of the Gonads. Katie Turner, RTI International, Research Triangle Park, NC.

Female Reproductive System: Development and Function of the Gonads. Ulrike Luderer, University of California Irvine, Irvine, CA.

Reproductive Toxicity Testing in Product Safety Assessment. Reza Rasoulpour, The Dow Chemical Company, Midland, MI.

Strengths and Limitations of In Vitro Test Methods for Reproductive Toxicology. Warren Foster, McMaster University, Hamilton, ON, Canada.

The REACH Regulation and Safety Assessment Approaches for Chemicals That Come in Contact with the Skin

PM10—CE Basic

Theme: Regulatory Science: Advancing New Approaches for Hazard Identification and Risk Assessment

Chairperson(s): Jens Thing Mortensen, CiToxLAB Scantox, Lille Skensved, Denmark, and Jon Heylings, Dermal Technology Laboratory Ltd., Keele University Science Park, United Kingdom.

Sponsor: Dermal Toxicology Specialty Section

Endorsed by:
In Vitro and Alternative Methods Specialty Section

REACH (Registration, Evaluation, Authorization, and Restriction of Chemical substances) is the European Union regulation on chemicals and their safe use, which came into force on June 1, 2007. The aim of REACH is to improve the protection of human health and the environment through better and earlier identification of the intrinsic properties of chemical substances. REACH places greater responsibility on the industry to manage the risks from chemicals, and to provide safety information on their substances. The regulation will come gradually into force in the period up to 2018. Under REACH, 30–40,000 new and existing chemicals will have to be (re)classified and registered. The regulation requires companies to conduct risk assessment and safety classification, with a minimal use of experimental animals, and to share information via databases managed by the European Chemicals Agency (ECHA). The skin (together with the respiratory system) is important as a route of chemical exposure, and as a target organ for toxicity induced by chemicals. Since under REACH so many chemicals need to be evaluated, it is important to use and develop testing methods that reliably predict human exposure and safety, while minimizing the use of experimental animals. An overview of the REACH regulation, and its practical implications for toxicological safety evaluation of chemicals marketed in Europe, will be given. Efforts to develop new methods and validation status of alternative methods that will limit the number of experimental animals to be used will be highlighted. Specifically, state-of-the art investigational methods within dermal toxicology will be discussed since the skin is very important, both as a barrier to exposure and as a target organ. Practical examples of the use of the collected dermal safety data in the risk assessment of chemicals under REACH will be presented.

Introduction. Jens Thing Mortensen, CiToxLAB Scantox, Lille Skensved, Denmark.

The REACH Process and Dermal Safety Testing. Laura Rossi, European Chemicals Agency (ECHA), Helsinki, Finland.

Dermal Corrosivity and Irritation Testing under REACH: Application of Valid Nonanimal Test Methods. Hans Raabe, Institute for In Vitro Sciences, Gaithersburg, MD.

Skin Sensitization Testing under REACH. David J. Esdaile, CiToxLAB Hungary, Veszprem, Hungary.

Skin Penetration Testing under REACH: Methods and Use in Risk Assessment. Jon Heylings, Dermal Technology Laboratory Ltd., Keele University Science Park, United Kingdom.

T4: Tools and Technologies in Translational Toxicology

PM11—CE Advanced

Theme: Application of Systems Biology to Toxicology

Chairperson(s): Vishal S. Vaidya, Harvard Medical School, Boston, MA, and Donna L. Mendrick, US FDA-NCTR, Jefferson, AR.

Sponsor: Drug Discovery Toxicology Specialty Section

Endorsed by:
Association of Scientists of Indian Origin Special Interest Group
Biotechnology Specialty Section
Disease Prevention Task Force

The last decade has seen revolutionary advances in the tools and technologies available for biomedical scientists such that researchers can now conduct transformative experiments to solve unmet medical needs moving from a single cell to whole organism, and vice versa. Novel tools and innovative technologies have facilitated the development of sophisticated molecular diagnostics, enabled the use of new approaches in safety evaluation and risk assessment, and led to the development of targeted therapeutics. The development and utilization of novel technologies and tools requires interaction between scientists of differing backgrounds and talents (e.g., biologists, chemists and programmers). Only with this shared effort can medicine transform itself to meet the needs of the 21st century. The panel of experts will decode and demystify the potential of these translational and transformative technologies over a wide variety of applications, including safety/efficacy screening of compounds, imaging, ‘omics, and in silico modeling. The key goals are to enable you to understand how recent advances in “T4”: 1) help in solving important problems that have been critical barriers to progress in the field and, 2) transform the field by generating foundational resources that will be widely used throughout biomedical science for safety evaluation and risk assessment.

Introduction. Vishal S. Vaidya, Harvard Medical School, Boston, MA.

Engineered Approaches to Assess Liver Toxicity. Salman Khetani, Colorado State University, Fort Collins, CO.

Nuts and Bolts of High-Throughput Compound Toxicity Testing. Menghang Xia, NIH, Bethesda, MD.

Imaging Technologies in Translational Toxicology. Serguei Liachenko, US FDA-NCTR, Benton, AR.

Systems Biology: In Silico Modeling to ‘Omic Biomarkers. Donna L. Mendrick, US FDA-NCTR, Jefferson, AR.

Understanding Toxic Neuropathy in Drug Development: Both Clinical and Nonclinical Perspectives

PM12—CE Advanced

Theme: Biomarkers for Exposure Assessment, Safety Evaluation, and Translational Medicine

Chairperson(s): Mary Jeanne Kallman, Covance Research Laboratories, Greenfield, IN, and John Benitez, Vanderbilt University, Nashville, TN.

Sponsor: Scientific Liaison Coalition

Endorsed by:
Clinical and Translational Toxicology Specialty Section
Neurotoxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

The topic of risk assessment of peripheral neuropathies is timely due to the increased clinical incidence of challenges related to multiple antecedents for the clinical presentation of neuropathies. The integration of both nonclinical and clinical dialogue on peripheral neuropathies will provide greater possibilities for successful drug development and improved patient outcomes. Peripheral nervous system toxicity is a common complication of exposure to industrial chemicals and drugs such as chemotherapeutics. Neuropathy can be caused by either limited or long-term exposure to drugs or chemicals, and toxic neuropathies can be classified by their presentation (e.g., motor vs. sensory), their electrodiagnostic features or their neuroanatomical location within the peripheral nerve. Identification of toxic neuropathology prior to human exposure in the drug development process requires a multidisciplinary approach. Presentations will include information on the preclinical and clinical syndromes that have been characterized and the specific techniques for assessment. The preclinical presenters will focus on the application of preclinical data to provide risk assessment and to direct clinical assessment possibilities. The clinical presenters will emphasize the clinical situation and current treatment approaches. The course will conclude with open discussion between the presenters and the audience about opportunities for future risk assessment and the application to clinical management.

Overview. Mary Jeanne Kallman, Covance Research Laboratories, Greenfield, IN.

Anatomy of the Peripheral Nervous System and Recognition of Common Neuropathies. Mark Cartwright, Merck & Co. Inc., Sparta, NJ.

Clinical Overview of Toxic Neuropathy. Amy Chappell, Eli Lilly and Company, Indianapolis, IN.

Assessment of Peripheral Nerve Function: Risk Assessments for Neuropathy and Potential Translation to the Clinic. Joseph Arezzo, Albert Einstein College of Medicine, Bronx, NY.

Examples of Clinical Neuropathies Associated with Oncolytic Drugs. John Benitez, Vanderbilt University, Nashville, TN.

Weighing in on Nutrition—Essential Concepts for Toxicologists

PM13—CE Basic

Theme: Molecular Basis of Genetic Variability and Susceptibility to Toxicants

Chairperson(s): Daniel M. Wilson, The Dow Chemical Company, Midland, MI, and Angela L. Slitt, University of Rhode Island, Kingston, RI.

Sponsor: Food Safety Specialty Section

Endorsed by:
Cardiovascular Toxicology Specialty Section
Ethical, Legal, and Social Issues Specialty Section
Mechanisms Specialty Section
Women in Toxicology Special Interest Group

There has been an exponential increase in the attention focused on the potential role of nutrition in reducing the risk for numerous health complications, ranging from birth defects to age-associated vascular disease. Underscoring the above is the increasing number of presentations and publications related to this subject, and hallmarks such as the recently revamped Food Pyramid into a Plate Icon. Chronic nutritional diseases are accepted to be a current crisis in our society; three nutrition-related diseases alone, obesity, Metabolic Syndrome, and Type 2 Diabetes, afflict over one-third of the American population. To better understand the components and etiology of nutritional diseases, it’s essential for toxicologists to be well versed in the science of nutrition. A comprehensive understanding of nutrition has broad applications in toxicology, especially considering that many of us have roles in investigating the safety of nutrients, food additives or food ingredients, studying nutritional disease, or designing and interpreting preclinical or clinical studies wherein the need to consider and understand nutritional homeostasis is essential. The potential for intersection of normal nutritional metabolic pathways with adverse outcome pathways is becoming even more important to delineate. This course on general nutrition, the biochemistry of nutritional pathways, the essential role of vitamins, the channeling of nutrients such as carbohydrates, proteins and fats, cellular and molecular details of nutrition, and nutritional aspects of development and reproduction, will heighten awareness of their importance in human and animal health at multiple levels. The focus will be on relevant information, starting with an introduction to nutrition, followed by a review of biochemical and metabolic reactions in nutrition, with an emphasis on their relation to toxicology. How the nutritional status of a woman can modulate the developmental toxicity of a number of diverse toxicants, including alcohol, will be presented, along with a seminar describing the tools and applications of molecular and genetic models of nutritional disease.

Nutrition 101. Jo Ann S. Carson, University of Texas Southwestern, Dallas, TX.

The Biochemistry of Nutrition. Daniel M. Wilson, The Dow Chemical Company, Midland, MI.

Studying Nutritional Disease in Rodent and Cell-Based Models: Proper Selection of Molecular and Systemic Endpoints. Angela L. Slitt, University of Rhode Island, Kingston, RI.

Nutrition and Pregnancy. Carl L. Keen, University of California Davis, Davis, CA.