Laboratory and Basic Science Research Commons^™

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

Jarrod Bailey, PhD

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 …

Animal Carcinogenicity Studies: 3. Alternatives To The Bioassay, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, PhD

Conventional animal carcinogenicity tests take around three years to design, conduct and interpret. Consequently, only a tiny fraction of the thousands of industrial chemicals currently in use have been tested for carcinogenicity. Despite the costs of hundreds of millions of dollars and millions of skilled personnel hours, as well as millions of animal lives, several investigations have revealed that animal carcinogenicity data lack human specificity (i.e. the ability to identify human non-carcinogens), which severely limits the human predictivity of the bioassay. This is due to the scientific inadequacies of many carcinogenicity bioassays, and numerous serious biological obstacles, which render profoundly …

Animal Carcinogenicity Studies: 2. Obstacles To Extrapolation Of Data To Humans, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, PhD

Due to limited human exposure data, risk classification and the consequent regulation of exposure to potential carcinogens has conventionally relied mainly upon animal tests. However, several investigations have revealed animal carcinogenicity data to be lacking in human predictivity. To investigate the reasons for this, we surveyed 160 chemicals possessing animal but not human exposure data within the US Environmental Protection Agency chemicals database, but which had received human carcinogenicity assessments by 1 January 2004. We discovered the use of a wide variety of species, with rodents predominating, and of a wide variety of routes of administration, and that there were …

Rethinking The Ethics Of Research Involving Nonhuman Animals: Introduction, Tom L. Beauchamp, Hope Ferdowsian, John P. Gluck

John P. Gluck, PhD

No abstract provided.

Lessons From Toxicology: Developing A 21st‑Century Paradigm For Medical Research, Gill Langley, Christopher P. Austin, Anil K. Balapure, Linda S. Birnbaum, John R. Bucher, Julia Fentem, Suzanne C. Fitzpatrick, John R. Fowle Iii, Robert J. Kavlock, Hiroaki Kitano, Brett A. Lidbury, Alysson R. Muotri, Shuang-Qing Peng, Dmitry Sakharov, Troy Seidle, Thales Trez, Alexander Tonevitsky, Anja Van De Stolpe, Maurice Whelan, Catherine Willett

Gill Langley, PhD

Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual …

Alzheimer Disease Research In The 21st Century: Past And Current Failures, New Perspectives And Funding Priorities, Francesca Pistollato, Elan L. Ohayon, Ann Lam, Gillian R. Langley, Thomas J. Novak, David Pamies, George Perry, Eugenia Trushina, Robin S.B. Williams, Alex E. Roher, Thomas Hartung, Stevan Harnad, Neal D. Barnard, Martha Clare Morris, Mei-Chun Lai, Ryan Merkley, P. Charukeshi Chandrasekera

Gill Langley, PhD

Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human-based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and …

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

Martin Stephens, PhD

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 …

Pursuing Medawar’S Challenge For Full Replacement, Martin Stephens

Martin Stephens, PhD

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 …

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

Martin Stephens, PhD

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, …

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

Martin Stephens, PhD

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 …

Addressing Distress And Pain In Animal Research: The Veterinary, Research, Societal, Regulatory And Ethical Contexts For Moving Forward, Kathleen Conlee, Martin Stephens, Andrew N. Rowan

Martin Stephens, PhD

While most people recognize that biomedical scientists are searching for knowledge that will improve the health of humans and animals, the image of someone deliberately causing harm to an animal in order to produce data that may lead to some future benefit has always prompted an uncomfortable reaction outside the laboratory. However, proponents of animal research have usually justified the practice by reference to greater benefits (new knowledge and medical treatments) over lesser costs (in animal suffering and death). Given that one of the costs of animal research is the suffering experienced by the animals, the goal of eliminating distress …

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

Martin Stephens, PhD

No abstract provided.

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

Martin Stephens, PhD

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 …

Consensus Report On The Future Of Animal-Free Systemic Toxicity Testing, Marcel Leist, Nina Hasiwa, Costanza Rovida, Mardas Daneshian, David Basketter, Ian Kimber, Harvey Clewell, Tilman Gocht, Alan Goldberg, Francois Busquet, Anna-Maria Rossi, Michael Schwarz, Martin Stephens, Rob Taalman, Thomas B. Knudsen, James Mckim, Georgina Harris, David Pamies, Thomas Hartung

Martin Stephens, PhD

Since March 2013, animal use for cosmetics testing for the European market has been banned. This requires a renewed view on risk assessment in this field. However, in other fields as well, traditional animal experimentation does not always satisfy requirements in safety testing, as the need for human-relevant information is ever increasing. A general strategy for animal-free test approaches was outlined by the US National Research Council’s vision document for Toxicity Testing in the 21st Century in 2007. It is now possible to provide a more defined roadmap on how to implement this vision for the four principal areas of …

Resolving Animal Distress And Pain: Principles And Examples Of Good Practice In Various Fields Of Research, Alicia Karas, Matthew C. Leach, Karl A. Andrutis, Kathleen Conlee, John P. Gluck, Andrew N. Rowan, Martin L. Stephens

Martin Stephens, PhD

Pain and distress are central topics in legislation, regulations, and standards regarding the use of animals in research. However, in practice, pain has received greatly increased attention in recent years, while attention to distress has lagged far behind, especially for distress that is not induced by pain. A contributing factor is that there is less information readily available on distress, including practical information on its recognition, assessment and alleviation.

This chapter attempts to help fill that void by reversing the usual pattern and giving greater attention to distress than to pain. In addition, we also bypass the pain versus distress …

Scientific Autonomy And The 3rs, Bernard E. Rollin

Bernard Rollin, PhD

No abstract provided.

The Moral Status Of Invasive Animal Research, Bernard E. Rollin

Bernard Rollin, PhD

No abstract provided.

Alzheimer Disease Research In The 21st Century: Past And Current Failures, New Perspectives And Funding Priorities, Francesca Pistollato, Elan L. Ohayon, Ann Lam, Gillian R. Langley, Thomas J. Novak, David Pamies, George Perry, Eugenia Trushina, Robin S.B. Williams, Alex E. Roher, Thomas Hartung, Stevan Harnad, Neal D. Barnard, Martha Clare Morris, Mei-Chun Lai, Ryan Merkley, P. Charukeshi Chandrasekera

Experimentation Collection

Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human-based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and …

Reviewing Existing Knowledge Prior To Conducting Animal Studies, Andrew Knight

Andrew Knight, Ph.D.

Highly polarised viewpoints about animal experimentation have often prevented agreement. However, important common ground between advocates and opponents was demonstrated within a discussion forum hosted at www.research-methodology.org.uk in July–August 2008, by the independent charity, SABRE Research UK. Agreement existed that many animal studies have methodological flaws — such as inappropriate sample sizes, lack of randomised treatments, and unblinded outcome assessments — that may introduce bias and limit statistical validity. There was also agreement that systematic reviews of the human utility of animal models yield the highest quality of evidence, as their reliance on methodical and impartial methods to select significant …

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

Andrew Knight, PhD

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

Andrew Knight, PhD

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 …

Animal Carcinogenicity Studies: 3. Alternatives To The Bioassay, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Andrew Knight, Ph.D.

Conventional animal carcinogenicity tests take around three years to design, conduct and interpret. Consequently, only a tiny fraction of the thousands of industrial chemicals currently in use have been tested for carcinogenicity. Despite the costs of hundreds of millions of dollars and millions of skilled personnel hours, as well as millions of animal lives, several investigations have revealed that animal carcinogenicity data lack human specificity (i.e. the ability to identify human non-carcinogens), which severely limits the human predictivity of the bioassay. This is due to the scientific inadequacies of many carcinogenicity bioassays, and numerous serious biological obstacles, which render profoundly …

Animal Carcinogenicity Studies: 3. Alternatives To The Bioassay, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jonathan Balcombe, PhD

Conventional animal carcinogenicity tests take around three years to design, conduct and interpret. Consequently, only a tiny fraction of the thousands of industrial chemicals currently in use have been tested for carcinogenicity. Despite the costs of hundreds of millions of dollars and millions of skilled personnel hours, as well as millions of animal lives, several investigations have revealed that animal carcinogenicity data lack human specificity (i.e. the ability to identify human non-carcinogens), which severely limits the human predictivity of the bioassay. This is due to the scientific inadequacies of many carcinogenicity bioassays, and numerous serious biological obstacles, which render profoundly …

Animal Carcinogenicity Studies: 2. Obstacles To Extrapolation Of Data To Humans, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jonathan Balcombe, PhD

Due to limited human exposure data, risk classification and the consequent regulation of exposure to potential carcinogens has conventionally relied mainly upon animal tests. However, several investigations have revealed animal carcinogenicity data to be lacking in human predictivity. To investigate the reasons for this, we surveyed 160 chemicals possessing animal but not human exposure data within the US Environmental Protection Agency chemicals database, but which had received human carcinogenicity assessments by 1 January 2004. We discovered the use of a wide variety of species, with rodents predominating, and of a wide variety of routes of administration, and that there were …

A New Invasiveness Scale: Its Role In Reducing Animal Distress, Kenneth J. Shapiro, Peter B. Field

Kenneth J. Shapiro, PhD

No abstract provided.

Privatization Of Biomedical Research: A Short Term Answer With Long Term Consequences, Frederick Azalekor

Nebraska College Preparatory Academy: Senior Capstone Projects

Biomedical research owned by the government is now available to be owned by private institutions. This results in stagnant innovations because researchers have trouble with all the restrictions that are placed by private institutions. Privatization of biomedical research has short term positive effects but its negative effects are overarching and disastrous. One way to combat this, is for licenses to be deployed slowly with future consequences in mind.

• Privatization has short term benefits but long term disadvantages are disastrous. • To reduce damaging effect, privatization must be deployed slowly and carefully. • Patents or proprietary ownership must be given …