Laboratory and Basic Science Research Commons^™

Food For Thought … Mechanistic Validation, Thomas Hartung, Sebastian Hoffman, Martin Stephens

Experimentation Collection

Validation of new approaches in regulatory toxicology is commonly defined as the independent assessment of the reproducibility and relevance (the scientific basis and predictive capacity) of a test for a particular purpose. In large ring trials, the emphasis to date has been mainly on reproducibility and predictive capacity (comparison to the traditional test) with less attention given to the scientific or mechanistic basis. Assessing predictive capacity is difficult for novel approaches (which are based on mechanism), such as pathways of toxicity or the complex networks within the organism (systems toxicology). This is highly relevant for implementing Toxicology for the 21st …

A Vision Becoming Reality, Gill Langley

Laboratory Experiments Collection

Non-animal science in toxicology and health research has been progressing for decades, but only now is it being seen widely as advanced science. The emergence of novel human biology-based tools and models, combined with legislative and regulatory change, a 21st century concept for toxicology, continuing failures in the drug pipeline, and systematic critiques of animal models, have created a pivotal moment of change. The leading edge is starting to become the norm. Humans and other animals are likely to benefit as a result.

History Of The 3rs In Toxicity Testing: From Russell And Burch To 21st Century Toxicology, Martin L. Stephens, Nina S. Mak

Humane Science Movement Collection

Toxicity testing is a key part of the process of assessing the hazards, safety, or risk that chemicals and other substances pose to humans, animals, or the environment. Standardized methods for such testing, typically involving animals, began to emerge during the first half of the 20th century. In 1959, British scientists William Russell and Rex Burch proposed a framework for reducing, refining, or replacing animal use in toxicology and other forms of biomedical experimentation. This “3Rs” or “alternatives” approach emerged at a time of growing sensitivity to the use of animals in experimentation, and progress in its implementation has been …

Humane Society International’S Global Campaign To End Animal Testing, Troy Seidle

Experimentation Collection

The Research & Toxicology Department of Humane Society International (HSI) operates a multifaceted and science-driven global programme aimed at ending the use of animals in toxicity testing and research. The key strategic objectives include: a) ending cosmetics animal testing worldwide, via the multinational Be Cruelty-Free campaign; b) achieving near-term reductions in animal testing requirements through revision of product sector regulations; and c) advancing humane science by exposing failing animal models of human disease and shifting science funding toward human biology-based research and testing tools fit for the 21st century. HSI was instrumental in ensuring the implementation of the March 2013 …

The Use Of Biomarkers Of Toxicity For Integrating In Vitro Hazard Estimates Into Risk Assessment For Humans, Bas Blaauboer, Kim Boekelheide, Harvey Clewell, Mardas Daneshian, Milou M.L. Dingemans, Alan M. Goldberg, Marjoke Heneweer, Joanna Jaworska, Nynke I. Kramer, Marcel Leist, Hasso Seibert, Emanuela Testai, Rob J. Vandebriel, James D. Yager, Joanne Zurlo

in Vitro Research Models Collection

The role that in vitro systems can play in toxicological risk assessment is determined by the appropriateness of the chosen methods, with respect to the way in which in vitro data can be extrapolated to the in vivo situation. This report presents the results of a workshop aimed at better defining the use of in vitro-derived biomarkers of toxicity (BoT) and determining the place these data can have in human risk assessment. As a result, a conceptual framework is presented for the incorporation of in vitro-derived toxicity data into the risk assessment process. The selection of BoT takes into account …

Alternative Approaches For Medical Countermeasures To Biological And Chemical Terrorism And Warfare, Thomas Hartung, Joanne Zurlo

Biomedical Research and Alternative Methods Collection

The desire to develop and evaluate drugs as potential countermeasures for biological and chemical threats requires test systems that can also substitute for the clinical trials normally crucial for drug development. Animal models have limited predictivity for drug efficacy, as is well known from many disappointments in clinical trials. Traditional in vitro and in silico approaches are not really game changers here, but the substantial investment into novel tools now underway might bring about a second generation of alternative approaches. The avenue pursued focuses primarily on the development of a Human on a Chip, i.e., the combination of different three-dimensional …

Accelerating The Development Of 21st-Century Toxicology: Outcome Of A Human Toxicology Project Consortium Workshop, Martin L. Stephens, Craig Barrow, Melvin E. Andersen, Kim Boekelheide, Paul L. Carmichael, Michael P. Holsapple, Mark Lafranconi

in Vitro Research Models Collection

The U.S. National Research Council (NRC) report on “Toxicity Testing in the 21st century” calls for a fundamental shift in the way that chemicals are tested for human health effects and evaluated in risk assessments. The new approach would move toward in vitro methods, typically using human cells in a high-throughput context. The in vitro methods would be designed to detect significant perturbations to “toxicity pathways,” i.e., key biological pathways that, when sufficiently perturbed, lead to adverse health outcomes. To explore progress on the report’s implementation, the Human Toxicology Project Consortium hosted a workshop on 9–10 November 2010 in Washington, …

A Roadmap For The Development Of Alternative (Non-Animal) Methods For Systemic Toxicity Testing, David Basketter, Harvey Clewell, Ian Kimber, Annamaria Rossi, Bas Blaauboer, Robert Burrier, Mardas Daneshian, Chantra Eskes, Alan Goldberg, Nina Hasiwa, Sebastian Hoffmann, Joanna Jaworska, Thomas B. Knudsen, Robert Landsiedel, Marcel Leist, Paul Locke, Gavin Maxwell, James Mckim, Emily Mcvey, Gladys Ouédraogo, Grace Patlewicz, Olavi Pelkonen, Erwin Roggen, Costanza Rovida, Irmela Ruhdel, Michael Schwarz, Andreas Schepky, Greet Schoeters, Nigel Skinner, Kerstin Trentz, Marian Turner, Philippe Vanparys, James Yager, Joanne Zurlo, Thomas Hartung

Biomedical Research and Alternative Methods Collection

Systemic toxicity testing forms the cornerstone for the safety evaluation of substances. Pressures to move from traditional animal models to novel technologies arise from various concerns, including: the need to evaluate large numbers of previously untested chemicals and new products (such as nanoparticles or cell therapies), the limited predictivity of traditional tests for human health effects, duration and costs of current approaches, and animal welfare considerations. The latter holds especially true in the context of the scheduled 2013 marketing ban on cosmetic ingredients tested for systemic toxicity. Based on a major analysis of the status of alternative methods (Adler et …

Pursuing Medawar’S Challenge For Full Replacement, Martin Stephens

Experimentation Collection

In 1969, Nobel Prize-winning scientist Peter Medawar predicted that scientific innovation would someday fully replace the use of animals in biomedical research. Medawar correctly forecast the leveling off and subsequent decline in animal use in the last quarter of the 20th century – a period of remarkable innovation in the life sciences. A 2007 report by the U.S. National Academy of Sciences, Toxicity Testing in the 21st Century, proposed a strategy that is likely to replace all routine animal use in toxicology with innovative methods within one to two decades. Replacing animal use throughout biomedical research is more challenging given …

Harnessing Opportunities In Non-Animal Asthma Research For A 21st-Century Science, Gemma L. Buckland

Experimentation Collection

The incidence of asthma is on the increase and calls for research are growing, yet asthma is a disease that scientists are still trying to come to grips with. Asthma research has relied heavily on animal use; however, in light of increasingly robust in vitro and computational models and the need to more fully incorporate the ‘Three Rs’ principles of Replacement, Reduction and Refinement, is it time to reassess the asthma research paradigm? Progress in non-animal research techniques is reaching a level where commitment and integration are necessary. Many scientists believe that progress in this field rests on linking disciplines …

Calling On Science: Making “Alternatives” The New Gold Standard, Melvin E. Andersen

in Vitro Research Models Collection

All of life’s great journeys start with a goal in mind! The 2007 NAS report, Toxicity Testing in the 21st Century – A Vision and A Strategy, has proposed a clear goal. This report envisions a not-so-distant future where all routine toxicity testing for environmental agents will be conducted in human cells in vitro evaluating perturbations of cellular responses in a suite of toxicity pathway assays. Dose response modeling would utilize computational systems biology models of the circuitry underlying each toxicity pathway; in vitro to in vivo extrapolations would use pharmacokinetic models, ideally physiologically based pharmacokinetic models, to predict human …

Cross-Sector Review Of Drivers And Available 3rs Approaches For Acute Systemic Toxicity Testing, Troy Seidle, Sally Robinson, Tom Holmes, Stuart Creton, Pilar Prieto, Julia Scheel, Magda Chlebus

Experimentation Collection

Acute systemic toxicity studies are carried out in many sectors in which synthetic chemicals are manufactured or used and are among the most criticized of all toxicology tests on both scientific and ethical grounds. A review of the drivers for acute toxicity testing within the pharmaceutical industry led to a paradigm shift whereby in vivo acute toxicity data are no longer routinely required in advance of human clinical trials. Based on this experience, the following review was undertaken to identify (1) regulatory and scientific drivers for acute toxicity testing in other industrial sectors, (2) activities aimed at replacing, reducing, or …

Toxicity Testing In The 21st Century: A Vision And A Strategy, Daniel Krewski, Daniel Acosta Jr, Melvin Anderson, Henry Anderson, John C. Bailar Iii, Kim Boekelheide, Robert Brent, Gail Charnley, Vivian G. Cheung, Sidney Green Jr, Karl T. Kelsey, Nancy I. Kerkvliet, Abby A. Li, Lawrence Mccray, Otto Meyer, Reid D. Patterson, William Pennie, Robert A. Scala, Gina M. Solomon, Martin Stephens, James Yager, Lauren Zeise

Experimentation Collection

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems …

The Current Scientific And Legal Status Of Alternative Methods To The Ld50 Test For Botulinum Neurotoxin Potency Testing, Sarah Adler, Gerd Bicker, Hans Bigalke, Christopher Bishop, Jörg Blümel, Dirk Dressler, Joan Fitzgerald, Frank Gessler, Heide Heuschen, Birgit Kegel, Andreas Luch, Catherine Milne, Andrew Pickett, Heidemarie Ratsch, Irmela Ruhdel, Dorothea Sesardic, Martin Stephens, Gerhard Stiens, Peter D. Thornton, René Thürmer, Martin Vey, Horst Spielmann, Barbara Grune, Manfred Liebsch

Experimentation Collection

No abstract provided.

Bringing Toxicology Into The 21st Century: A Global Call To Action, Troy Seidle, Martin Stephens

Experimentation Collection

Conventional toxicological testing methods are often decades old, costly and low-throughput, with questionable relevance to the human condition. Several of these factors have contributed to a backlog of chemicals that have been inadequately assessed for toxicity. Some authorities have responded to this challenge by implementing large-scale testing programmes. Others have concluded that a paradigm shift in toxicology is warranted. One such call came in 2007 from the United States National Research Council (NRC), which articulated a vision of ‘‘21st century toxicology” based predominantly on non-animal techniques. Potential advantages of such an approach include the capacity to examine a far greater …

Scientific Autonomy And The 3rs, Bernard E. Rollin

Experimentation Collection

No abstract provided.

Personal Reflections On Russell And Burch, Frame, And The Hsus, Martin Stephens

Animal Welfare Collection

The coincidence of anniversaries associated with the publication of William Russell and Rex Burch’s The Principles of Humane Experimental Technique, the founding of the Fund for the Replacement of Animals in Medical Experiments (FRAME), and the establishment of the collaboration between FRAME and the University of Nottingham, provides an opportunity to reflect on Russell and Burch’s legacy and how it was carried forward by FRAME. The Principles, published in 1959, was the pioneering work in what later became the alternatives or Three Rs field of replacement, reduction, and refinement of animal use. Such was the book’s initial and undeserved obscurity, …

Volunteer Studies In Pain Research — Opportunities And Challenges To Replace Animal Experiments: The Report And Recommendations Of A Focus On Alternatives Workshop, C. K. Langley, Q. Aziz, C. Bountra, N. Gordon, P. Hawkins, A. Jones, G. Langley, T. Nurmikko, I. Tracey

Experimentation Collection

Despite considerable research, effective and safe treatments for human pain disorders remain elusive. Understanding the biology of different human pain conditions and researching effective treatments continue to be dominated by animal models, some of which are of limited value. British and European legislation demands that non-animal approaches should be considered before embarking on research using experimental animals. Recent scientific and technical developments, particularly in human neuroimaging, offer the potential to replace some animal procedures in the study of human pain. A group of pain research experts from academia and industry met with the aim of exploring creatively the tools, strategies …

Non-Animal Methodologies Within Biomedical Research And Toxicity Testing, Andrew Knight

Experimentation Collection

Laboratory animal models are limited by scientific constraints on human applicability, and increasing regulatory restrictions, driven by social concerns. Reliance on laboratory animals also incurs marked – and in some cases, prohibitive – logistical challenges, within high-throughput chemical testing programmes, such as those currently underway within Europe and the US. However, a range of non-animal methodologies is available within biomedical research and toxicity testing. These include: mechanisms to enhance the sharing and assessment of existing data prior to conducting further studies, and physicochemical evaluation and computerised modelling, including the use of structure-activity relationships and expert systems. Minimally-sentient animals from lower …

The Development Of New Concepts For Assessing Reproductive Toxicity Applicable To Large Scale Toxicological Programmes, S. Bremer, C. Pellizzer, S. Hoffmann, T. Seidle, T. Hartung

Experimentation Collection

Large scale toxicological testing programmes which are currently ongoing such as the new European chemical legislation REACH require the development of new integrated testing strategies rather than applying traditional testing schemes to thousands of chemicals. The current practice of requiring in vivo testing for every possible adverse effect endanger the success of these programmes due (i) to limited testing facilities and sufficient capacity of scientific/technical knowledge for reproductive toxicity; (ii) an unacceptable number of laboratory animals involved (iii) an intolerable number of chemicals classified as false positive.

A key aspect of the implementation of new testing strategies is the determination …

Acute Toxicity Testing Without Animals: More Scientific And Less Of A Gamble, Gillian R. Langley

Application of Alternative Methods Collection

In this report, we argue specifically that acute toxicity data should not be sought from animal tests. The underlying principle of such tests on rats and mice is that the results can be effectively extrapolated to humans. In fact, after nearly 80 years of use of these tests, the predictivity of rodent data for human acute toxic effects has been disputed but never proven.

The Future Of Teratology Research Is In Vitro, Jarrod Bailey, Andrew Knight, Jonathan Balcombe

Experimentation Collection

Birth defects induced by maternal exposure to exogenous agents during pregnancy are preventable, if the agents themselves can be identified and avoided. Billions of dollars and manhours have been dedicated to animal-based discovery and characterisation methods over decades. We show here, via a comprehensive systematic review and analysis of this data, that these methods constitute questionable science and pose a hazard to humans. Mean positive and negative predictivities barely exceed 50%; discordance among the species used is substantial; reliable extrapolation from animal data to humans is impossible, and virtually all known human teratogens have so far been identified in spite …

Ld50 Testing Of Botulinum Toxin For Use As A Cosmetic, Martin L. Stephens, Michael Balls

Experimentation Collection

In 2003, the Fund for the Replacement of Animals in Medical Experiments (FRAME) revealed that the potency of botulinum toxin for use as a popular wrinkle treatment is assessed by using the LD50 Test. The endpoint in this mouse-based testing is death through suffocation. In 2004, The Humane Society of the United States (HSUS) sought to work with Allergan, the US-based manufacturer of Botox® Cosmetic, and the U.S. Food and Drug Administration (FDA), on ways to refine, reduce, and replace this LD50 testing. This article summarises The HSUS’s campaign in the United States and provides an update on FRAME’s continuing …

Ideology Masquerading As Science: The Case Of Endocrine Disrupter Screening Programmes, Troy Seidle

Experimentation Collection

The global move to develop novel testing methods and strategies to identify suspected endocrine disrupting chemicals offers a unique opportunity to move away from traditional animal testing paradigms in this new area of regulatory concern. Regrettably, the programmes under development, both in the USA and internationally through the OECD, have thus far failed to consider in vitro and other nonanimal test methods as more than “pre-screening” or “priority-setting” tools in a larger, animal-based testing strategy. Validation efforts to date have focused almost exclusively on the modification of existing animal tests to detect “endocrine effects”, with no demonstrable effort to promote …

Animals And Alternatives: Societal Expectations And Scientific Need, Alan M. Goldberg

Experimentation Collection

As Russell and Burch suggested more than 40 years ago, the most humane science is the best science. The path ahead is clear: pain and distress must be eliminated in animal experiments or reduced to an absolute minimum, and, as scientists, we must use the most humane approaches in our research. To accomplish the best science, we must train those who come after us in the principles and practice of humane science.

Medical Training Using Simulation: Toward Fewer Animals And Safer Patients, Jonathan Balcombe

Experimentation Collection

This paper presents the current status of computer-based simulation in medicine. Recent technological advances have enabled this field to emerge from esoteric explorations in academic laboratories to commercially available simulators designed to train users to perform medical procedures from start to finish. Today, more than a dozen companies are producing virtual reality simulators and interactive manikins for training in endoscopy, laparoscopy, anaesthesia, trauma management, angiography, and needle insertion. For many of these procedures, thousands of animals are still being used in training. Yet simulation has many advantages that can transcend scientific, ethical, economic and logistical problems that arise when using …

Levels Of Citation Of Nonhuman Animal Studies Conducted At A Canadian Research Hospital, Anne Innis Dagg, Troy K. Seidle

Experimentation Collection

The publication of scientific articles that receive few or no citations raises questions of the appropriate use of resources as well as ethics. In the case of animal research, the ethics issue extends beyond human patients to nonhuman animals, as the research subjects them to pain and, typically, to death. This study is a citation analysis of animal research conducted at Toronto's Hospital for Sick Children (HSC). Of the 594 publications (1990 to 1995) on animal research by affiliates of HSC, 29% received Iower than 10 citations in a 10-year period. We compare the research history of 13 "best" and …

Possibilities For Refinement And Reduction: Future Improvements Within Regulatory Testing, Martin L. Stephens, Kathleen Conlee, Gina Alvino, Andrew N. Rowan

Experimentation Collection

Approaches and challenges to refining and reducing animal use in regulatory testing are reviewed. Regulatory testing accounts for the majority of animals reported in the most painful and/or distressful categories in the United States and Canada. Refinements in testing, including the use of humane endpoints, are of increasing concern. Traditional approaches to reduction (e.g., improving experimental design) are being supplemented with complementary approaches, such as the use of tier testing to eliminate some chemicals prior to in vivo testing. Technological advances in telemetry and noninvasive techniques will help decrease either the demand for animals in testing or animal suffering. Further …

Anatomy And Three-Dimensional Reconstructions Of The Brain Of A Bottlenose Dolphin (Tursiops Truncatus) From Magnetic Resonance Images, Lori Marino, Keith D. Sudheimer, Timothy L. Murphy, Kristina K. Davis, D. Ann Pabst, William A. Mclellan, James K. Rilling, John I. Johnson

Veterinary Science and Medicine Collection

Cetacean (dolphin, whale, and porpoise) brains are among the least studied mammalian brains because of the formidability of collecting and histologically preparing such relatively rare and large specimens. Magnetic resonance imaging offers a means of observing the internal structure of the brain when traditional histological procedures are not practical. Furthermore, internal structures can be analyzed in their precise anatomic positions, which is difficult to accomplish after the spatial distortions often accompanying histological processing. In this study, images of the brain of an adult bottlenose dolphin, Tursiops truncatus, were scanned in the coronal plane at 148 antero-posterior levels. From these scans …

Magnetic Resonance Imaging And Three-Dimensional Reconstructions Of The Brain Of A Fetal Common Dolphin, Delphinus Delphis, Lori Marino, Timothy L. Murphy, Lyad Gozal, John I. Johnson

Veterinary Science and Medicine Collection

To demonstrate the kinds of data that can be obtained non-destructively and non-invasively from preserved museum specimens using modern imaging technology the head region of a whole body fetal specimen of the common dolphin, Delphinus delphis, aged 8–9 months post-conception, was scanned using Magnetic Resonance Imaging (MRI). Series of scans were obtained in coronal, sagittal and horizontal planes. A digital three-dimensional reconstruction of the whole brain was prepared from the coronal series of scans. Sectional areas and three-dimensional volumes were obtained of the cerebral hemispheres and of the brainstemplus-cerebellum. Neuroanatomical features identified in the scans include the major sulci of …