Alternative Toxicological Methods

Bringing together the recent and relevant contributions of over 125 scientists from industry, government, and academia in North America and Western Europe, Alternative Toxicological Methods explores the development and validation of replacement, reduction, and refinement alternatives (the 3Rs) to animal testing. Internationally recognized scientists present what has been accomplished thus far in developing acceptable alternatives to traditional animal toxicological assessment and provide potentially new initiatives.

In over 40 chapters, the book addresses 7 themes, beginning with the validation and regulatory acceptance of alternatives in the US, the UK, and Western Europe. Then the book covers methods based on the mechanisms of eye irritation at the ocular surface, dermal toxicity testing, and assessing neurotoxicity. It also includes a case study in the use of alternatives to determine the mechanism of sulfur mustard action and discusses the role of transgenics and toxicokinetics in the development of alternative toxicity tests. Finally the book presents recent innovations in alternatives, including the use of archival data, and in silico techniques.

Focusing on the science and not the politics, Alternative Toxicological Methods concisely discusses the application of state-of-the-art methods and explores cutting-edge research related to developing and validating alternatives to animal testing. This book will benefit toxicologists, cosmetic chemists, pharmacologists, experimental biologists, dermatologists, ophthalmologists, and regulatory officers in their quest for applying the 3Rs to the use of animals in toxicological testing of drug candidates, chemicals, and cosmetics.

Table of Contents:
Part I - Progress in the Validation and Regulatory Acceptance of Alternatives
Overview, Neil Wilcox

Historical Developments in the Humane Care and Use of Research Animals: The First 4000 Years, Harry Salem and Sidney Katz

Historical Development from the Interagency Regulatory Alternatives Group to Interagency Coordinating Committee for the Validation of Alternative Methods, Sidney Green

The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM): Recent Progress in the Evaluation of Alternative Toxicity Testing Methods, William S. Stokes

Validation and Regulatory Acceptance of Alternative Test Methods: Current Situation in the European Union, Julia Fentem and Michael Balls

Integrating In Vitro Approaches for Assessing Systemic Toxicity, Anna Forsby and Bas Blaauboer

Summary of the OECD Guidance Document on the Recognition, Assessment and Use of Clinical Signs as Humane Endpoints for Experimental Animals Used in Safety Evaluation, Errol Zeiger

Pain and Distress Management in Animal Research and Testing: The HSUS Pain and Distress Initiative, Martin L. Stephens, F. Dolins, A. N. Rowan, L. Donley, and A. Gleason

Part II - Development and Predictive Methods Based on Mechanisms of Eye Irritation at the Ocular Surface
Overview, Sherry Ward and Wiley Chambers

Meeting Industry and Regulatory Needs for Alternative Tests to the Draize Rabbit Eye Irritation Test, Sherry L. Ward

The Ocular Surface: Barrier Function and Mechanisms of Injury and Repair, Martin Reim

Evaluation and Refinement of the Bovine Cornea Opacity and Permeability Assay, John Ubels, James Paauw, and Phillip Casterton

The Use of Corneal Organ Culture as an Ex Vivo Model for Ocular Toxicity Test of Commercial Hair Care Products, Fu-Shin Yu and Ke-Ping Xu

Human Corneal Equivalents for In Vitro Testing, May Griffith and Erik Suuronen

The EpiOcular Prediction Model: A Reproducible In Vitro Means of Assessing Ocular Irritancy, M. Klausner, P. Hayden, B. Breyfogle, K. Bellevance, M. Osborn, D. Cerven, G. DeGeorge, and J. Kubilus

Three-Dimensional Construct of the Human Corneal Epithelium for In Vitro Toxicology, Doan Nguyen, Roger Beuerman, Bart DeWever, and Martin Rosdy

Performance of the HCE-T TEP Human Corneal Epithelial Transepithelial Fluorescein Permeability Assay, Sherry L. Ward, Maximo Gacula Jr., and Henry F. Edelhauser

Part III - Dermal Testing Alternatives
Overview, Harry Salem and Sidney Katz

Alternative Methods for Dermal Toxicity Testing, Robert L. Bronaugh

Allergic Contact Hypersensitivity: Mechanisms and Methods, Denise Sailstad

Validating In Vitro Dermal Absorption Studies: An Introductory Case Study, Robert Zendzian and Michael Dellarco

A Molecular Diagnostic Approach to Irritant or Allergic Patch Testing Using DermPatch, Melissa Fitzgerald, Vera Morhenn, Stacy Humphrey, Nirmala Jayakumar, and Lawrence Rheins

In Vitro Skin Equivalent Models for Toxicity Testing, P. Hayden, S. Ayehunie, G.R. Jackson, S. Kupfer, T.J. Last, M. Klausner, and J. Kubilus

Part IV - A Case Study in the Use of Alternatives to Determine the Mechanism of Sulfur Mustard Action
Overview: Integration of Sulfur Mustard Data Derived from Alternative Toxicology Methods to Define Mechanisms of Action, William Smith

Cellular Resistance of Tetrahymena to Sulfur Mustard, Peter Platteborze and William Smith

Biochemical Changes Induced in Human Cells by the Vesicating Agent Sulfur Mustard, William Smith, Offie Clark, Fred Cowan, Maura Dejoseph, Charisse Davenport, and Clark Gross

Human Keratinocyte Inflammatory Transcript Gene Activity Following Sulfur Mustard, John Schlager, Kashif Ali, Hilma Benjamin, Claire Levine, Douglas Avery, and James Clark

Evaluation of Cytotoxicity Assay of Human Epidermal Keratinocytes Exposed In Vitro to Sulfur Mustard, Susan Kelly, Juanita Guzman, Clark Gross, and William Smith

Comparison of Spectrophotometric and Fluorometric Assays of Proteolysis in Cultured Human Cells Exposed to Sulfur Mustard, Susan Kelly, Charlene Corun, Marian Nelson, Clark Gross, and William Smith

Effects of Low Dose Sulfur Mustard on Growth and DNA Damage in Human Cells in Culture, William Smith, Bethany Toliver, Offie Clark, Janet Moser, Eric Nealley, Juanita Guzman, and Clark Gross

Imaging Sulfur Mustard Lesions in Basal Cells and Human Epidermal Tissues by Confocal and Multi-Photon Laser Scanning Microscopy, Robert Werrlein and Janna Madren-Whalley

Suppression of Sulfur Mustard-Increased IL-8 in Human Keratinocyte Cultures by Serine Protease Inhibitors: Implications for Toxicity and Medical Countermeasures, Fred Cowan, Clarence Broomfield, and William Smith

Development of Medical Countermeasures to Sulfur Mustard Vesication, William Smith, Michael Babin, Robyn Kiser, and Robert Casillas

Part V - Molecular Biomarkers, and Transgenics for Assessing Neurotoxicity
Overview, William Slikker and Thomas Sobotka

Molecular Neurotoxicology of 6-Hydroxydopamine and Methamphetamine: Lessons Perused from Transgenic Models, Jean Lud Cadet

A Microassay Method Using a Neuroblastoma Cell Line to Examine Neurotoxicity of Organophosphate Mixtures, Laurie Roszell, B. C. Kramer, and Glen Leach

Development of a Model of Integrin Expression as a Molecular Biomarker for Early Sensitive Detection of Neurotoxicity, Joyce Royland

Two-photon Fluorescence Microscopy: A Review of Recent Advances in Deep-Tissue Imaging, Chen-Yuan Dong, Lily Hsu, Ki-Hean Kim, Christof Buehle, Peter D. Kaplan, Thomas D. Hancewicz, and Peter T. C. So

Part VI - Role of Transgenics and Toxicogenomics in the Development of Alternative Toxicity Tests
Overview, Jerry Heindel

The Application of Genomics and Proteomics to Toxicological Sciences, Stephen Chevalier, William Pennie, and Ian Kimber

Use of Transgenics in Carcinogenicity Testing, Frank Sistare

Changes in Gene Expression after Exposure to Organophosphorus (OP) Agents, Jennifer Sekowski, K. P. O'Connell, A. S. Khan, J. J. Valdes, M. Vahey, M. Nau, M. Khalil, M.S. Eldefrawi, and Walter Reed

Part VII - Recent Innovations in Alternatives
Overview, Harry Salem and Sidney Katz

Archival Data in Toxicology: Minimizing Need for Animal Experiments, Millard Mershon

Archival Data and Information Management at the Library of Congress: An Overview with Special Reference to Biomedicine and Toxicology, Roman Worobec

World Wide Web Biomedical, Chemical and Toxicological Information Resources from the National Library of Medicine, George Fonger, James Knoben, Stephanie Publicker, Philip Wexler, and Georgette Whiting

In Silico Approaches for Developing Physiologically-based Pharmacokinetic (PBPK) Models, Martin Beliveau and Kannan Krishnan

In Silico Application of Quantum Chemical Methods for Relating Toxicity to Chemical Reactivity, William White

In Silico Cardiac Toxicity: Increasing the Discovery of Therapeutics through High Performance Computing, C. K. Zoltani and S. I. Baskin

Submillimeter Wave Frequency Studies of the Vibrational Modes of Deoxyribonucleic Acid: A Metric for Mutagenicity, T. R. Globus, B. L. Gelmont, M. Bykhovskaia, J. Hesler, D. L. Woodard, A. C. Samuels, J. O. Jensen, H. Salem, and W. R. Loerop

Trophoblast Toxicity Assay (TTA): A Gestational Toxicity Test Utilizing Human Placenta Tropoblasts, Harvey Kliman